Blood and Adipose Product Injections for Selected Indications

Number: 0784

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

Policy

Scope of Policy

This Clinical Policy Bulletin addresses blood and adipose product injections for selected indications.

Experimental and Investigational

The following procedures are considered experimental and investigational because the effectiveness of these approaches has not been established:
1. Autologous blood injection for all indications including the following (not an all-inclusive list):
  1. Cervical radiculopathy
  2. Chronic urticaria
  3. Lateral epicondylitis
  4. Lumbar radiculopathy
  5. Muscular injury
  6. Plantar fasciopathy
  7. Temporomandibular joint (TMJ) dislocation
  8. Tendinopathies (e.g., elbow, heel, knee, patella, and shoulder);
2. Platelet-poor plasma or platelet-rich plasma injection for all indications including the following (not an all-inclusive list):
  1. Achilles tendon ruptures / Achilles tendinopathy
  2. Alopecia areata (androgenetic alopecia)
  3. Ankle sprain
  4. Anterior cruciate ligament surgery
  5. As adjunctive material to bone graft
  6. Avascular necrosis of the hip, and the shoulder
  7. Carpometacarpal arthritis of the thumb
  8. Cerebral palsy
  9. Chronic wounds
  10. Crohn's disease-related perianal fistula
  11. Discogenic low back pain
  12. Facial rejuvenation
  13. Gastrocnemius (calf) tear
  14. Greater trochanteric pain syndrome
  15. Hamstring injury
  16. Hip fractures
  17. Lumbar facet joint syndrome
  18. Osteoarthritis (e.g., hip, knee, and temporomandibular joint (TMJ))
  19. Osteonecrosis of the jaw
  20. Plantar fasciitis
  21. Rotator cuff injuries
  22. Tendinopathies (e.g., elbow, heel, knee, and shoulder)
  23. Urethral stricture
  24. Vitiligo;
3. Autologous platelet gel for the following:
  1. Application following total knee arthroplasty
  2. Diabetic foot ulcer;
4. Adipose-tissue-derived stem cells injection (Habeo cell therapy) for the treatment of chondromalacia patellae, knee osteoarthritis, and scleroderma (systemic sclerosis) and all other indications;
5. Autologous adipose-derived regenerative cell (ADRC) therapy for the treatment of partial thickness rotator cuff tear;
6. Autologous cell-based therapy for critical lower limb ischemia;
7. Autologous fat for the treatment of carpometacarpal arthritis of the thumb;
8. Autologous interleukin-1 receptor antagonist blood products for knee osteoarthritis;
9. Autologous whole-blood or autologous serum acupoint injection therapy for chronic urticaria;
10. Bone marrow derived mesenchymal stromal cells administration for facet joint injections, and for the treatment of avascular necrosis of the shoulder, Crohn's disease and osteoarthritis;
11. Bone marrow plasma injection for the treatment of tendonopathies (e.g., elbow, heel, knee, and shoulder) and all other indications;
12. Platelet-rich fibrin for intra-bony defects in chronic periodontitis and rotator cuff tears;
13. Platelet-rich plasma combined with stem cells (e.g., Regenexx) for all indications (see CPB 0411 - Bone and Tendon Graft Substitutes and Adjuncts);
14. Stem cell therapy for the treatment of perianal fistulae;
15. Stromal vascular fraction with platelet-rich plasma injection for treatment-refractory perianal fistulizing Crohn's disease.
Related Policies

Table:
CPT Codes / HCPCS Codes / ICD-10 Codes
Code	Code Description
CPT codes not covered for indications listed in the CPB:
Autologous cell-based therapy, Autologous interleukin-1 receptor antagonist blood products, Autologous whole-blood or autologous serum acupoint injection therapy, Platelet-rich fibrin, platelet poor plasma - no specific code:
0232T	Injection(s), platelet rich plasma, any site, including image guidance, harvesting and preparation when performed.
0481T	Injection(s), autologous white blood cell concentrate (autologous protein solution), any site, including image guidance, harvesting and preparation, when performed
0489T	Autologous adipose-derived regenerative cell therapy for scleroderma in the hands; adipose tissue harvesting, isolation and preparation of harvested cells including incubation with cell dissociation enzymes, removal of non-viable cells and debris, determination of concentration and dilution of regenerative cells
0490T	multiple injections in one or both hands
0565T	Autologous cellular implant derived from adipose tissue for the treatment of osteoarthritis of the knees; tissue harvesting and cellular implant creation
0566T	Autologous cellular implant derived from adipose tissue for the treatment of osteoarthritis of the knees; injection of cellular implant into knee joint including ultrasound guidance, unilateral
0717T	Autologous adipose-derived regenerative cell (ADRC) therapy for partial thickness rotator cuff tear; adipose tissue harvesting, isolation and preparation of harvested cells, including incubation with cell dissociation enzymes, filtration, washing and concentration of ADRCs
0718T	Autologous adipose-derived regenerative cell (ADRC) therapy for partial thickness rotator cuff tear; adipose tissue harvesting, isolation and preparation of harvested cells, including incubation with cell dissociation enzymes, filtration, washing and concentration of ADRCs; injection into supraspinatus tendon including ultrasound guidance, unilateral
0748T	Injections of stem cell product into perianal perifistular soft tissue, including fistula preparation (eg, removal of setons, fistula curettage, closure of internal openings)
15771	Grafting of autologous fat harvested by liposuction technique to trunk, breasts, scalp, arms, and/or legs; 50 cc or less injectate
15772	each additional 50 cc injectate, or part thereof (List separately in addition to code for primary procedure)
15773	Grafting of autologous fat harvested by liposuction technique to face, eyelids, mouth, neck, ears, orbits, genitalia, hands, and/or feet; 25 cc or less injectate
15774	each additional 25 cc injectate, or part thereof (List separately in addition to code for primary procedure)
38232	Bone marrow harvesting for transplantation; autologous
38241	Hematopoietic progenitor cell (HPC); autologous transplantation
Other CPT codes related to the CPB:
0213T	Injection(s), diagnostic or therapeutic agent, paravertebral facet (zygapophyseal) joint (or nerves innervating that joint) with ultrasound guidance, cervical or thoracic; single level
0214T	second level (List separately in addition to code for primary procedure)
0215T	third and any additional level(s)
0216T	Injection(s), diagnostic or therapeutic agent, paravertebral facet (zygapophyseal) joint (or nerves innervating that joint) with ultrasound guidance, lumbar or sacral; single level
0217T	second level (List separately in addition to code for primary procedure)
0218T	third and any additional level(s)
20560	Needle insertion(s) without injection(s); 1 or 2 muscle(s)
20561	3 or more muscles
38205	Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection; allogeneic
38206	Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection; autologous
64490	Injection(s), diagnostic or therapeutic agent, paravertebral facet (zygapophyseal) joint (or nerves innervating that joint) with image guidance (fluoroscopy or CT), cervical or thoracic; single level
64491	second level (List separately in addition to code for primary procedure)
64492	third and any additional level(s)
64493	Injection(s), diagnostic or therapeutic agent, paravertebral facet (zygapophyseal) joint (or nerves innervating that joint) with image guidance (fluoroscopy or CT), lumbar or sacral; single level
64494	second level (List separately in addition to code for primary procedure)
64495	third and any additional level(s)
HCPCS codes not covered for indications listed in the CPB:
G0460	Autologous platelet rich plasma for chronic wounds/ulcers, including phlebotomy, centrifugation, and all other preparatory procedures, administration and dressings, per treatment
P9020	Platelet rich plasma, each unit
S9055	Procuren or other growth factor preparation to promote wound healing
ICD-10 codes not covered for indications listed in the CPB:
E08.621	Diabetes mellitus due to underlying condition with foot ulcer
E09.621	Drug or chemical induced diabetes mellitus with foot ulcer
E10.621	Type 1 diabetes mellitus with foot ulcer
E11.621	Type 2 diabetes mellitus with foot ulcer
E13.621	Other specified diabetes mellitus with foot ulcer
G80.0 - G80.9	Cerebral palsy
K05.30 - K05.329	Chronic periodontitis
K50.00 - K50.919	Crohn's disease [regional enteritis]
K60.3	Anal fistula
K60.4	Rectal fistula
K60.5	Anorectal fistula
L50.8	Other urticaria [chronic]
L63.0 - L63.9	Alopecia areata
L80	Vitiligo
M12.88	Other specific arthropathies, not elsewhere classified, other specified site [lumbar facet joint syndrome]
M12.9	Arthropathy, unspecified [lumbar facet joint syndrome]
M15.0 - M19.93	Osteoarthritis
M17.0 - M17.9	Osteoarthritis of knee
M18.0 - M18.9	Osteoarthritis of first carpometacarpal joint
M22.40 - M22.42	Chondromalacia patellae
M26.621 - M26.629	Arthralgia of temporomandibular joint
M26.69	Other specified disorders of temporomandibular joint [dislocation or osteoarthritis ]
M34.0 - M34.9	Systemic sclerosis (scleroderma)
M46.86	Other specified inflammatory spondylopathies, lumbar region [lumbar facet joint syndrome]
M46.96	Unspecified inflammatory spondylopathy, lumbar region [lumbar facet joint syndrome]
M53.86	Other specified dorsopathies, lumbar region [lumbar facet joint syndrome]
M54.12	Radiculopathy, cervical region
M54.16	Radiculopathy, lumbar region
M54.50 - M54.59	Low back pain [discogenic]
M62.251 - M62.279	Nontraumatic ischemic infarction of muscle, lower extremity [critical lower limb ischemia]
M70.031 - M79.9	Other soft tissue disorders
M76.50 - M76.52	Patellar tendinitis
M77.10 - M77.12	Lateral epicondylitis [musculoskeletal injury]
M84.459, M84.559, M84.659	Pathological fracture, hip
M84.750+ - M84.759+	Atypical femoral fracture
M87.011 - M87.029	Idiopathic aseptic necrosis of shoulder
M87.051 - M87.059	Idiopathic aseptic necrosis of femur [hip]
M87.08, M87.180	Aseptic necrosis of bone, jaw
M89.70 - M89.79	Major osseous defect
N35.010 - N35.92	Urethral stricture
S31.000+ - S31.839+	Open wound of abdomen, lower back, pelvis, and external genitals
S43.421+ - S43.429+	Sprain of rotator cuff capsule
S46.021A - S46.029S	Laceration of muscle(s) and tendon(s) of the rotator cuff of shoulder [partial thickness tear]
S72.001 - S72.046	Fracture of neck of femur [hip]
S76.301+ - S76.319+	Strain of muscle, fascia and tendon of the posterior muscle group at thigh level [hamstring injury]
S83.401+ - S83.409+, S83.8X1+ - S83.8X9+, S86.111+ - S86.119+, S86.211+ - S86.219+, S86.311+ - S86.319+, S86.811+ - S86.819+	Sprains and strains of other specified sites of knee and leg [Gastrocnemius tear]
S93.401+ - S93.499+	Sprain of ankle

Background

Autologous Blood Injection

Tendonopathy (tendinopathy), also known as tendonitis and tendonosis, refers to painful conditions occurring in and around tendons in response to overuse. Commonly involved tendons are those in the elbow (lateral epicondyle), heel (Achilles), knee (patella), and shoulder (rotator cuff). Conservative therapies for patients with tendinopathies include rest, eccentric exercise, physiotherapy, analgesic therapy (e.g. non-steroidal anti-inflammatory drugs), use of orthotic devices, as well as local injection of steroids. Autologous blood injection has been employed when conservative therapies have failed. Blood taken from the patient by standard venesection is injected into the area around the damaged tendon. This approach is thought to promote healing by triggering stem cell recruitment, angiogenesis and fibroblast stimulation. A local anesthetic is usually used and ultrasound may provide guidance. Before injection, dry needling may be carried out. After the procedure, patients are instructed to avoid strenuous or excessive use of the tendon for several weeks (NICE, 2009).

Suresh and colleagues (2006) assessed if ultrasound guided autologous blood injection is an effective treatment for refractory medial epicondylitis. A total of 20 patients (13 men and 7 women) with symptom duration of 12 months underwent sonographic evaluation. Tendonosis was confirmed according to 3 sonographic criteria:

echo texture,
interstitial tears and
neovascularity.

The tendon was then dry needled and autologous blood was injected. Patients were reviewed at 4 weeks and at 10 months. Visual analog scores (VAS) and modified Nirschl scores were assessed pre-procedure and post-procedure. There was significant reduction in VAS between pre-procedure and 10 months post-procedure when it had a median inter-quartile range (IQR) of 1.00 (1 to 1.75), range of 0 to 7. The median IQR Nirschl score, which at pre-procedure was 6.00 (5 to 7), range of 4 to 7, had decreased at 4 weeks to 4.00 (2.25 to 5), range of 2 to 7, and at 10 months to 1.00 (1 to 1.75), range of 0 to 7, revealing a significant decrease (z = 3.763, p < 0.001). The hypo-echoic change in the flexor tendon significantly decreased between pre-procedure, when there was a mean (SD) of 6.45 (1.47), and at 10 months, when it was 3.85 (2.37) (p < 0.001). Doppler ultrasound showed that neovascularity decreased between pre-procedure, when there was a mean (SD) of 6.10 (1.62), range of 4 to 9, and at 10 months, when it was 3.60 (2.56), range of 0 to 9 (p < 0.001). The authors concluded that the combined action of dry needling and autologous blood injection under ultrasound guidance appears to be an effective treatment for refractory medial epicondylitis as demonstrated by a significant decrease in VAS and a fall in the modified Nirschl scores.

Connell et al (2006) evaluated the effectiveness of autologous blood injection under sonographic guidance for the treatment of refractory lateral epicondylitis. A total of 35 patients (23 men and 12 women, mean age of 40.9 years, mean symptom duration of 13.8 months) underwent sonographic evaluation prior to dry needling the tendon and injection with autologous blood. Patients were reviewed, and measures of Nirschl and VAS were taken pre-procedure and post-procedure, at 4 weeks and 6 months. Following autologous blood injections, significant reductions were reported for Nirschl scores, which decreased from a median IQR pre-procedure score of 6 (6 to 7), to 4 (2 to 5) at 4 weeks (p < 0.001), and to 0 (0 to 1) at 6 months (p < 0.001). Similarly, significant reductions were reported for VAS scores from a median IQR pre-procedure score of 9 (8 to 10), to 6 (3 to 8) at 4 weeks (p < 0.001), and to 0 (0 to 1) at 6 months (p < 0.001). Sonography demonstrated a reduction in the total number of interstitial cleft formations and anechoic foci; a significant reduction in tendon thickness from a mean (SD) of 5.15 mm (0.79) at baseline to 4.82 mm (0.62) at 6 months post-procedure (p < 0.001) was observed. Hypoechoic change significantly reduced from a median IQR of 7 (6 to 7) at baseline to 2 (1 to 3) at 6 months post-procedure (p < 0.001). Neovascularity also significantly decreased from a median (IQR) of 6 (4 to 7) at baseline to 1 (0 to 3) at 6 months post-procedure (p < 0.001), although sonographic abnormality remained in many asymptomatic patients. The authors concluded that autologous blood injection is a primary technique for the treatment of lateral epicondylitis. Sonography can be used to guide injections and monitor changes to the common extensor origin.

In a prospective, cohort study, James et al (2007) evaluated the effectiveness of ultrasound-guided dry needling and autologous blood injection for the treatment of refractory patellar tendonosis. A total of 47 knees in 44 patients (40 men and 7 women, mean age of 34.5 years, age range of 17 to 54 years) underwent sonographic examination of the patellar tendon following referral with a clinical diagnosis of patellar tendonosis (mean symptom duration of 12.9 months). Ultrasound guided dry needling and injection of autologous blood into the site of patellar tendonosis was performed on two occasions 4 weeks apart. Pre-procedure and post-procedure Victorian Institute of Sport Assessment (VISA) scores were collected to assess patient response to treatment. Follow-up ultrasound examination was done in 21 patients (22 knees). Therapeutic intervention led to a significant improvement in VISA score: mean pre-procedure score of 39.8 (range of 8 to 72) versus mean post-procedure score of 74.3 (range of 29 to 100), p < 0.001; mean follow-up of 14.8 months (range of 6 to 22 months). Patients were able to return to their sporting interests. Follow-up sonographic assessment showed a reduction in overall tendon thickness and in the size of the area of tendonosis. A reduction was identified in interstitial tears within the tendon substance. Neovascularity did not reduce significantly or even increased. The authors concluded that dry needling and autologous blood injection under ultrasound guidance shows promise as a treatment for patients with patellar tendonosis.

In a single-blind, randomized, clinical study, Kazemi and colleagues (2010) compared local corticosteroid with autologous blood injections for the short-term treatment of lateral elbow tendinopathy. A total of 60 patients aged 27 to 64 years with a new episode of tennis elbow were recruited -- 30 patients were randomized to methylprednisolone and 30 to autologous blood group over 1 year. Severity of pain within last 24 hours; limb function; pain and strength in maximum grip; disabilities of the arm, shoulder, and hand quick questionnaire (Quick DASH) scores; modified Nirschl scores; and pressure pain threshold were evaluated before injection and at 4 and 8 weeks after injection. Data wer analyzed with the chi and t test. Within-group analyses showed better results for autologous blood (all p values < 0.001 except for grip strength, p = 0.005). In the corticosteroid group, differences in severity of pain (p = 0.008) and grip strength (p = 0.001) were significant. At 4 weeks, between-group analyses showed superiority of autologous blood for severity of pain (p = 0.001), pain in grip (p = 0.002), pressure pain threshold (p = 0.031), and Quick DASH questionnaire score (p = 0.004). There were no significant differences in modified Nirschl score, grip strength, and limb function. At 8 weeks, autologous blood was more effective in all the outcomes (all p values < 0.001). The authors concluded that autologous blood was more effective in short-term than the corticosteroid injection. The findings of this small, sinlge-blind study need to be validated by further investigation with larger number of subjects and longer follow-up.

The available evidence regarding the effectiveness of autologous blood injection for the treatment of tendinopathies is largely based on non-randomized studies. Their findings need to be validated by well-designed studies. Furthermore, available guidelines from the American College of Occupational and Environmental Medicine, National Institute for Health and Clinical Excellence (NICE), and Work Loss Data Institute do not support the use of autologous blood injection for tendinopathies.

The American College of Occupational and Environmental Medicine (2007) did not recommend autologous blood injection for managing patients with elbow disorders. The NICE's guideline on autologous blood injection for tendinopathy (2009) states that current evidence on the safety and effectiveness of autologous blood injection for tendinopathy is inadequate in quantity and quality. In addition, the NICE Committee notes that some of the published studies involved the use of dry needling prior to the injection of autologous blood, but it was not possible to differentiate between effects of these two components of the procedure. The Committee also states that future research should be in the context of randomized controlled studies that define chronicity of tendinopathy and describe any previous or adjunctive therapies (e.g., physiotherapy and dry needling) as well as the tendons treated. These studies should address the role of ultrasound guidance and include functional and quality of life outcomes with a minimum follow-up of 1 year. It is also interesting to note that the Work Loss Data Institute's guideline on the management of acute and chronic shoulder disorders (2007) did not mention the use of autologous blood injection as a means of therapy.

The Work Loss Data Institute's guideline on elbow (acute and chronic) (2011) stated that autologous blood injection is currently under study and is not specifically recommended.

Autologous Blood Injection for the Treatment of Achilles Tendinopathy

Sinnott and colleagues (2017) noted that Achilles tendinopathy is a painful condition commonly affecting the general and athletic population. It presents with localized pain, stiffness, and swelling in the mid-portion of the Achilles tendon. The physical stress placed on the tendon results in micro-trauma, which leads to subsequent inflammation and degeneration. While it is not surprising that this condition affects the physically active, nearly 1/3 of Achilles tendinopathy cases occur in sedentary individuals. Etiology for this condition stems from a change in loading patterns and/or over-use of the tendon, resulting in microscopic tearing and degenerative changes. There are numerous causes contributing to the mal-adaptive response in these patients, such as mechanical, age-related, genetic, and vascular factors. The treatment for these patients is typically load management and eccentric strengthening of the gastrocnemius-soleus complex. Unfortunately, conservative treatment can lead to surgical intervention in up to 45 % of cases. A relatively new phenomenon in the treatment of this condition is the use of autologous blood injections (ABI) and PRP injections (PRPI). This need for a less invasive treatment fostered more investigation into ABI and PRPI to treat these non-responsive patients. However, the evidence concerning the effectiveness of these treatments in patients with Achilles tendinopathy has not been synthesized.

Autologous Blood Injection for the Treatment of Cervical Radiculopathy

In a pilot study, Goni et al (2015) examined the effectiveness of epidural perineural injection of autologous conditioned serum (ACS) versus methylprednisone (MPS) in unilateral cervical radiculopathy patients. A total of 40 patients were equally allocated into ACS and MPS groups and were injected with 2.5 to 3 ml of ACS or MPS, respectively, under image guidance into the perineural area of the affected nerve root. They were followed-up for 6 months with VAS for pain, neck pain disability scale in Hindi language, neck disability index, and Short Form of Health Survey-12 (SF-12). Patients who had received injections of ACS and MPS both had improvements in the scores of the evaluation tools. The improvement in the ACS patients was gradual and sustained during the entire study period whereas that in the MPS group had some deterioration over time. No major complications were noted among the 2 groups; minor complications were noted in both the groups. The authors concluded that ACS can be considered an equally good or better modality of non-operative management in patients of unilateral cervical radiculopathy as MPS. They stated that this approach may be offered to affected patients before offering them surgery. The findings of this pilot study need to be validated by well-designed studies.

Autologous Blood Injection for the Treatment of Chronic Urticaria

In a double-blind, parallel group randomized controlled trial (RCT), Debbarman and colleagues (2014) evaluated the effectiveness of autologous serum therapy (AST) in chronic urticaria (CU) and also determined its usefulness in autoreactive urticaria (AU). A total of 54 patients were given AST and 57 patients were given injection normal saline (placebo), along with cetirizine in an on-demand basis in both groups. Autologous serum therapy/placebo was given weekly for 9 weeks and followed-up for a total period of 24 weeks. Autoreactive urticaria was diagnosed by autologous serum skin test. Urticaria total severity score (TSS), urticaria activity score (UAS), dermatologic life quality index (DLQI) was used as primary effectiveness variables. Safety parameters assessed were the spontaneously reported adverse events and laboratory parameters. Urticaria total severity score showed significant improvement from baseline, 7(th) week and 8(th) week onwards in AST group and placebo group, respectively. Group comparison showed significant improvement 4(th) week onwards. Urticaria activity score showed similar results; DLQI showed significant improvement in AST group compared to placebo at the end of study. Both AU and non-AU patients showed comparable improvement of TSS. The authors concluded that AST shows promise in treatment of urticaria regardless of the autoreactive nature. These preliminary findings need to be validated by well-designed studies.

Autologous Blood Injection for the Treatment of Muscular Injury

Calandruccio and Steiner (2017) stated that lateral epicondylitis is a frequent cause of elbow pain; most patients (80% to 90%) are successfully treated with standard non-operative methods (rest, non-steroidal anti-inflammatory drugs [NSAIDs], bracing, and physical therapy). Autologous blood injections and PRP injections are the 2 most frequently used ortho-biologic techniques in the treatment of lateral epicondylitis. Studies of the effectiveness of autologous blood injections and PRP had reported varying outcomes, some citing significant clinical relief and others reporting no beneficial effect. The authors concluded that more research is needed to determine how to best use ortho-biologic techniques in the treatment of lateral epicondylitis.

Autologous Blood Injection for the Treatment of Patella Tendinopathy

In a pilot study, Resteghini and associates (2015) evaluated the effectiveness of autologous blood injections against saline in patients with chronic recalcitrant patella tendinopathy. Using 2 practitioners, patients were randomized to either receive autologous blood injections or saline injections. All patients completed the Short-Form McGill Pain Questionnaire (MPQ), VAS, and a Victoria Institute of Sport Assessment for Patella Tendinopathy scale over a 12-month period. A total of 22 patients completed the final review at 12 months and were included in the study. Subjects ranged in age from 22 and 61 years and were randomized to 11 in each autologous blood injection and saline groups. Autologous blood injection group had a mean duration of symptoms of 16.7 months, whereas that of the saline group was 19.2 months. The saline group mean VAS score was reduced from 7.9 to 4.5 at 1 month (p = 0.003) and 3.3 (p = 0.005) at 1 year. With autologous blood injections, the score was reduced from 7.5 to 4.5 (p = 0.005) at 1 month and 3.1 (p = 0.003) at 1 year. Victoria Institute of Sport Assessment for Patella Tendinopathy, MPQ, and VAS scores improved significantly in both groups. The authors concluded that the findings of this study demonstrated that both the autologous blood injection and saline groups experienced a significant improvement in symptoms. However, when the results were compared, there was no statistical difference between the 2 groups.

Autologous Blood Injection for the Treatment of Temporomandibular Joint Dislocation

Varedi and Bohluli (2015) reviewed the English literature about the safety and effectiveness of autologous blood injection in the treatment of patients suffering from chronic recurrent temporo-mandibular joint (TMJ) dislocation. These investigators highlighted the key trials and recent directions about this modality and discussed about the mechanism, advantages, and disadvantages of this approach. A literature search was performed using PubMed, Medline, and Ovid Medline databases to identify articles reporting on the injection of autologous blood for treatment of chronic recurrent dislocation of TMJ. Other references cited in the retrieved reports, as well as the "related articles" tool in PubMed Medline, were also checked to improve the search and, if relevant, were included in the study. The search was restricted to articles published in the English language. A total of 7 studies meeting the inclusion criteria were reviewed. The selected articles included 4 prospective clinical trials and 3 case report articles. The authors concluded that there are a few articles about the clinical use of autologous blood for treating patients with chronic recurrent TMJ dislocation. Reviewing of the literature showed that there are successful results about this modality, but there are still some concerns about it in terms of the effect of the injected blood on the articular cartilage and formation of fibrous or bony ankylosis. Well-designed studies are needed to ascertain the effectiveness of autologous blood injection in the treatment of TMJ dislocation.

Autologous Blood Products in the Treatment of Lateral Epicondylitis and Plantar Fasciopathy

In a systematic review and meta-analysis, Tsikopoulos and associates (2016) compared the effectiveness of autologous whole blood with that of corticosteroid injections (CSIs) on epicondylopathy and plantar fasciopathy. The databases of PubMed, Web of Science, CENTRAL, and Scopus were searched up to May 6, 2015. Randomized trials comparing the effects of autologous whole blood and CSIs on epicondylopathy or plantar fasciopathy were included. Trials exploring the effectiveness of platelet-rich plasma (PRP) were excluded. The primary outcome was pain relief. The secondary outcome included the assessment of composite outcomes. All outcomes were assessed at 2 to 6 (short-term) weeks, 8 to 13 (intermediate-term) weeks and 24 to 26 (medium-term) weeks. Quality assessment was performed with the Cochrane risk of bias tool. A total of 9 trials were included. For pain relief, there was a statistically significant difference in favor of corticosteroids in the short-term (standardized mean difference [SMD] 0.52; 95 % confidence interval (CI): 0.18 to 0.86; I2 = 53 %; p < 0.01). A statistically significant difference in favor of autologous whole blood was indicated in the medium-term assessment of pain relief on epicondylopathy. The authors concluded that corticosteroids were marginally superior to autologous whole blood in relieving pain on plantar fasciopathy at 2 to 6 weeks. They stated that autologous whole blood provided significant clinical relief on epicondylopathy at 8 to 24 weeks. Moreover, they stated that conclusions were limited by the risk of bias.

In a meta-analysis, Qian and colleagues (2016) compared the safety and effectiveness of autologous blood products (ABPs) and CSIs in the treatment of lateral epicondylitis. These investigators systematically searched Embase, PubMed, the Cochrane Library, and Web of Science to identify RCTs that compared ABPs with CSIs for the treatment of lateral epicondylitis without language and publication date restriction through April 2015. Two investigators independently included and assessed the quality of each eligible study according to the method recommended by the Cochrane Collaboration. Available data about the main outcomes were extracted from each study and heterogeneity was assessed using the Q statistic and the inconsistency index (I2). They also evaluated the publication bias and conducted a subgroup analysis. Review Manager 5.2 software was used for data syntheses and analyses, and the standardized mean difference (SMD) or mean difference (MD) was estimated by using random effects models with a 95 % CI. To investigate the effectiveness among different trial durations, the follow-up times were divided into short periods (2 to 4 weeks), intermediate periods (6 to 24 weeks) and long-term periods (greater than or equal to 24 weeks). A total of 10 RCTs (n = 509) were included in this meta-analysis. The pooled analysis showed that CSIs were more effective than ABPs for pain relief in the short-term (SMD = 0.88; 95 % CI: 0.31 to 1.46 %; p = 0.003). However, in the intermediate-term, ABPs exhibited a better therapeutic effect for pain relief (SMD = -0.38; 95 % CI: -0.70 to -0.07 %; p = 0.02), function (SMD = -0.60; 95 % CI: -1.13 to -0.08 %; p = 0.03), disabilities of the arm, shoulder, and hand (MD = -11.04; 95 % CI: -21.72 to -0.36 %; p = 0.04), and Nirschl stage (MD = -0.81; 95 % CI: -1.11 to -0.51 %; p < 0.0001). In the long-term, ABPs were superior to CSIs for pain relief (SMD = -0.94; 95 % CI: -1.32 to -0.57 %; p < 0.0001) and Nirschl stage (MD = -1.04; 95 % CI: -1.66 to -0.42 %; p = 0.001). Moreover, for grip strength recovery, no significant difference was found between the 2 therapies (p > 0.05). The authors concluded that limited evidence supported the conclusion that CSIs are superior to ABPs for pain relief in the short-term; however, this result was reversed in the intermediate- and long-term. They stated that ABPs appeared to be more effective at restoring function in the intermediate-term; however, because of the small sample size and the limited number of high-quality RCTs, more high-quality RCTs with large sample sizes are needed to validate this result.

In a randomized study, Varshney and colleagues (2017) compared autologous PRP versus corticosteroid in the management of elbow epicondylitis. The study population (n = 83) comprised 2 groups: Group A (n = 50) treated with local steroid injection, and Group B (n = 33) treated with autologous PRP. Patients were allocated randomly using computer-generated random number table. The base-line evaluation was done using VAS and modified Mayo performance index for elbow (MAYO). Re-evaluation was after 1, 2, and 6 months of the procedure. Statistical analysis was done using independent t-test. Six months after treatment with PRP, patient's with elbow epicondylitis had a significant improvement in their VAS (p < 0.05) and MAYO (p < 0.05) in contrast to steroid, whereas no statistical difference was found between the 2 groups at 1 and 2 months after intervention. The authors concluded that treatment of patients with elbow epicondylitis with PRP reduced pain and significantly increased function, exceeding the effect of corticosteroid injection The drawbacks of this study were:

a comparatively small study group (n = 33 for PRP), and
short-term follow-up (6 months).

These researchers stated that further studies are needed with a greater number of patients in each group with even longer periods of follow-up.

In an assessor-blinded, randomized controlled comparative study, Branson and associates (2017) compared 3 different ultrasound (US)-guided injections for chronic tennis elbow. A total of 44 patients with clinically diagnosed tennis elbow, confirmed by Doppler US, received under US guidance, a single corticosteroid injection (n = 14), or 2 injections (separated by 4 weeks) of either autologous blood (n = 14) or polidocanol (n = 16). Clinical and US examination was performed at baseline, 4, 12 and 26 weeks. Complete recovery or much improvement was greater for corticosteroid injection than autologous blood and polidocanol at 4 weeks (p < 0.001, number needed to treat 1 (95 % CI: 1 to 2)). In contrast, at 26 weeks corticosteroid was significantly worse than polidocanol (p = 0.004, number needed to harm 2 (1 to 6)). Recurrence after corticosteroid injection was significantly higher than autologous blood or polidocanol (p = 0.007, number needed to harm 2 (1 to 4)). Corticosteroid injection produced greater reduction in tendon thickness and vascularity than autologous blood at 4 weeks only. Compared to autologous blood, polidocanol reduced tendon thickness at 4 and 12 weeks and reduced echogenicity and hyperemia after 12 or 26 weeks respectively. The authors concluded that injections of corticosteroid cannot be recommended over polidocanol or autologous blood, because despite beneficial short-term effect there were inferior long-term effects. Moreover, they noted that whether polidocanol or autologous blood injections are effective is unknown, especially as their global effect profiles are not unlike previously reported for wait-and-see.

In a meta-analysis, Sirico and co-workers (2017) summarized the evidence regarding the effectiveness of corticosteroids and autologous blood injections for treatment of pain in lateral epicondylitis. Studies were considered eligible based on the following inclusion criteria: adult human, diagnosis of lateral epicondylitis, RCTs comparing corticosteroids versus autologous blood injections, pain assessment. Exclusion criteria were previous surgery for lateral epicondylitis or for other elbow disorders, concurrent treatment with drugs or physiotherapy, diagnosis of musculoskeletal systemic disorder. A systematic search of literature was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Effect size of each included study was calculated and analyzed in a random-effects model. A total of 4 studies, enrolling total of 218 patients (139 women and 79 men), were included in quantitative analysis. At 2 weeks, there was a trend towards a reduction of VAS score in the corticosteroid group (weighted mean difference [WMD] = 2.12 [95 % CI: 4.38 to 0.14], p = 0.07). No significant differences were seen in the medium-term (4 to 12 weeks; WMD = 0.85 [95 % CI: -0.44 to 2.15], p = 0.19) and long-term (24 weeks; WMD = 0.63 [95 % CI: -2.40 to 3.66], p = 0.68) follow-up. The authors concluded that few high-quality trials compared the effectiveness of corticosteroid and autologous blood injections in the control of pain related to lateral epicondylitis. Available data indicated that corticosteroids tend to reduce VAS score in short-term follow-up, although these data were not statistically significant. No differences were recorded in the medium- and long-term. Contrary to popular opinion among medical professionals, and despite pathophysiological cues, the currently available data offer no support for the effectiveness of autologous blood injections in medium- and long-term follow-up. These investigators stated that further studies are needed to determine which treatment has more impact on pain in lateral epicondylitis. These data could be then used as a basis for practical guidelines and new protocols of treatment.

Platelet Poor Plasma Injection

Floryan and Berghoff (2004) stated that as use of autologous PRP and PPP increases for intra-operative care of a variety of patients, it is important for peri-operative nurses to recognize their benefits. Autologous PRP may decrease post-operative drainage, reduce narcotic requirements, and facilitate an early return to mobility. Post-operatively, patients should experience fewer complications, recover more rapidly, and have a reduced hospital stay. The authors defined autologous PRP and PPP, described processing and application of PRP and PPP, and reported clinical outcomes of the use of platelet concentrate for a group of patients who underwent TKA.

Muir and colleagues (2019) stated that PPP is currently a discarded waste product of PRP and may contain valuable proteins. In a descriptive laboratory study, these researchers examined the concentration of plasma as a potential additive biotherapy for the treatment of OA. They hypothesized that a novel polyacrylamide concentration device would efficiently concentrate IGF-1 from PPP and be additive to PRP or autologous protein solution (APS). A study was carried out with human and equine whole blood from healthy volunteers/donors. Fresh samples of blood and plasma were processed and characterized for platelet, white blood cell, and growth factor/cytokine content and then quantified by ELISA specific for IGF-1, TGF-B, IL-1β, and IL-1 receptor antagonist as representatives of cartilage anabolic and inflammatory mediators. A potent cartilage anabolic protein, IGF-1, was significantly concentrated by the polyacrylamide concentration device in both human and equine PPP. The polyacrylamide device also substantially increased plasma proteins over whole blood, most dramatically key proteins relevant to the treatment of OA, including TGF-B (29-fold over blood) and IL-1 receptor antagonist (70-fold over plasma). The authors concluded that concentrated PPP was an unique source for biologically relevant concentrations of IGF-1; PRP and APS could produce greater concentrations of other anabolic and anti-inflammatory proteins not found in plasma.

Platelet-Rich Plasma Injection and Platelet Gel

Besides autologous blood injection, other blood product injection therapies for the treatment of patients with tendinopathies include platelet-rich plasma (PRP) and bone marrow plasma.

Growth factors are groups of proteins capable of stimulating cellular growth, proliferation and cellular differentiation. They occur in a wide range of tissues and are important for regulating a variety of cellular processes Platelets are small, regularly-shaped clear cell fragment that circulates in the blood and plays a fundamental role in hemostasis (cessation of bleeding); a natural source of growth factors. Platelet-Derived Growth Factor (PDGF) is a protein that is secreted by platelets which attracts fibroblasts and macrophages and plays a role in the proliferation phase of wound healing by contributing to the repair of connective tissue, glial and smooth muscle cells.

Growth factors that are derived from platelets assist in the process of blood vessel formation (angiogenesis) and can be obtained either by using recombinant DNA technology or through centrifuged autologous blood. Autologous growth factors, including autologous platelet-derived growth factors (PDGF), autologous platelet concentrate (APC) and autologous platelet gel (APG), also known as platelet-rich plasma (PRP) or "buffy coat," are harvested from a patient’s own (autologous) blood. APC and APG are topically applied to wounds or systemically administered to purportedly accelerate healing and reduce complications of chronic nonhealing wounds that fail to respond to conventional methods of wound treatment or used as an adjunct (addition) to surgery to promote hemostasis and reduce wound complications.

In a pilot study, Mishra and Pavelko (2006) reported their findings on the treatment of chronic elbow tendonosis with PRP. A total of 140 patients were evaluated in this study. Subjects were initially given a standardized physical therapy protocol and various non-operative treatments. Twenty of these patients had significant persistent pain (mean of 82 of 100; range of 60 to 100 of 100 on VAS) for a mean of 15 months despite these interventions. All patients were considering surgery. This cohort of patients was then given either a single percutaneous injection of PRP (n = 15) or bupivacaine (n = 5). Eight weeks after the treatment, the PRP-injected patients noted a 60 % improvement in their VAS versus 16 % improvement in bupivacaine-treated patients (p = 0.001). Three of 5 of the control subjects (bupivacaine-treated) withdrew or sought other treatments after the 8-week period, preventing further direct analysis. Thus, only PRP-treated patients were available for continued evaluation. At 6 months, PRP-treated subjects noted a 81 % improvement in their VAS (p = 0.0001). At final follow-up (mean of 25.6 months; range of 12 to 38 months), the PRP-treated patients reported a 93 % reduction in pain compared with before the treatment (p < 0.0001). The authors concluded that treatment of patients with chronic elbow tendinosis with PRP reduced pain significantly. Moreover, they stated that further evaluation of this novel treatment is warranted.

In a RCT, Peerbooms and associates (2010) examined the effectiveness of PRP compared with corticosteroid injections in patients with chronic lateral epicondylitis. A total of 100 patients with chronic lateral epicondylitis were randomly assigned in the PRP group (n = 51) or the corticosteroid group (n = 49). A central computer system carried out randomization and allocation to the trial group. Patients were randomized to receive either a corticosteroid injection or an autologous platelet concentrate injection through a peppering technique. The primary analysis included VAS and DASH Outcome Measure scores (DASH: Disabilities of the Arm, Shoulder, and Hand). Successful treatment was defined as more than a 25 % reduction in VAS or DASH score without a re-intervention after 1 year. The results showed that, according to the VAS, 24 of the 49 patients (49 %) in the corticosteroid group and 37 of the 51 patients (73 %) in the PRP group were successful, which was significantly different (p < 0.001). Furthermore, according to the DASH scores, 25 of the 49 patients (51 %) in the corticosteroid group and 37 of the 51 patients (73 %) in the PRP group were successful, which was also significantly different (p = 0.005). The corticosteroid group was better initially and then declined, whereas the PRP group progressively improved. The authors concluded that treatment of patients with chronic lateral epicondylitis with PRP reduces pain and significantly increases function, exceeding the effect of corticosteroid injection. They stated that future decisions for application of the PRP for lateral epicondylitis should be confirmed by further follow-up from this trial and should take into account possible costs and harms as well as benefits.

In a stratified, block-randomized, double-blind, placebo-controlled trial, de Vos and colleagues (2010) examined if a PRP injection would improve outcome in chronic mid-portion Achilles tendinopathy. A total of 54 randomized patients aged 18 to 70 years with chronic tendinopathy 2 to 7 cm above the Achilles tendon insertion were included in the study. Subjects received eccentric exercises (usual care) with either a PRP injection (PRP group) or saline injection (placebo group); randomization was stratified by activity level. The validated Victorian Institute of Sports Assessment-Achilles (VISA-A) questionnaire, which evaluated pain score and activity level, was completed at baseline and 6, 12, and 24 weeks. The VISA-A score ranged from 0 to 100, with higher scores corresponding with less pain and increased activity. Treatment group effects were evaluated using general linear models on the basis of intention-to-treat. After randomization into the PRP group (n = 27) or placebo group (n = 27), there was complete follow-up of all patients. The mean VISA-A score improved significantly after 24 weeks in the PRP group by 21.7 points (95 % CI: 13.0 to 30.5) and in the placebo group by 20.5 points (95 % CI: 11.6 to 29.4). The increase was not significantly different between both groups (adjusted between-group difference from baseline to 24 weeks, -0.9; 95 % CI: -12.4 to 10.6). This CI did not include the pre-defined relevant difference of 12 points in favor of PRP treatment. The authors concluded that among patients with chronic Achilles tendinopathy who were treated with eccentric exercises, a PRP injection compared with a saline injection did not result in greater improvement in pain and activity. They do not recommend this treatment for chronic mid-portion Achilles tendinopathy.

In a pilot study, Sampson et al (2010) evaluated the clinical effects of intra-articular PRP injections in a small group of patients with primary and secondary osteoarthritis (OA). A total of 14 patients with primary and secondary knee OA who met the study criteria received 3 PRP injections in the affected knee at approximately 4-week intervals. Outcome measures included the Brittberg-Peterson Visual Pain (VAS), Activities, and Expectations score and the Knee Injury and Osteoarthritis Outcome Scores at pre-injection visit at 2-, 5-, 11-, 18-, and 52-week follow-up visits. Musculoskeletal ultrasound was used to measure cartilage thickness. There were no adverse events reported. The study demonstrated significant and almost linear improvements in Knee Injury and Osteoarthritis Outcome Scores, including pain and symptom relief. Brittberg-Peterson VAS showed many improvements including reduced pain after knee movement and at rest. Cartilage assessment was limited because of the small sample size. The majority of the patients expressed a favorable outcome at 12 months after treatment. The authors concluded that the positive trends and safety profile demonstrated could potentially be used to inspire a larger, blinded, and randomized clinical trial to determine whether PRP is safe and effective for the treatment of knee OA.

Filardo et al (2011) examined the effects of intra-articular PRP injections for the treatment of degenerative cartilage lesions and osteoarthritis of the knee. Of the 91 patients evaluated in the previous 12-month follow-up study, 90 were available for the 2-year follow-up (24 patients presented a bilateral lesion, in a total of 114 knees treated). All of the patients presented a chronic knee degenerative condition and were treated with 3 intra-articular PRP injections. International Knee Documentation Committee (IKDC) and EQ-VAS scores were used for clinical evaluation. Complications, adverse events and patient satisfaction were also recorded. All of the evaluated parameters worsened at the 24-month follow-up: these parameters were at significantly lower levels with respect to the 12-month evaluation (the IKDC objective evaluation fell from 67 to 59 % of normal and nearly normal knees; the IKDC subjective score fell from 60 to 51), even if they remained higher than the basal level. Further analysis showed better results in younger patients (p = 0.0001) and lower degrees of cartilage degeneration (p < 0.0005). The median duration of the clinical improvement was 9 months. The authors concluded that these findings indicated that treatment with PRP injections can reduce pain and improve knee function and quality of life with short-term efficacy. They stated that further studies are needed to confirm these results and understand the mechanism of action, and to find other application modalities, with different platelet and autologous blood growth factors concentrations and injection timing, which provide better and more durable results.

Schepull et al (2011) noted that animal studies have shown that local application of PRP stimulates tendon repair. Preliminary results from a retrospective case series have shown faster return to sports. In a randomized controlled trial, these researchers hypothesized that autologous PRP stimulates healing of acute Achilles tendon ruptures. A total of 30 patients were recruited consecutively. During surgery, tantalum beads were implanted in the Achilles tendon proximal and distal to the rupture. Before skin suture, randomization was performed, and 16 patients were injected with 10 ml PRP (10 times higher platelet concentration than peripheral blood) whereas 14 were not. With 3-dimensional radiographs (roentgen stereophotogrammetric analysis; RSA), the distance between the beads was measured at 7, 19, and 52 weeks while the patient resisted different dorsal flexion moments over the ankle joint, thereby estimating tendon strain per load. An estimate of elasticity modulus was calculated using callus dimensions from computed tomography. At 1 year, functional outcome was evaluated, including the heel raise index and Achilles Tendon Total Rupture Score. The primary effect variables were elasticity modulus at 7 weeks and heel raise index at 1 year. The mechanical variables showed a large degree of variation between patients that could not be explained by measuring error. No significant group differences in elasticity modulus could be shown. There was no significant difference in heel raise index. The Achilles Tendon Total Rupture Score was lower in the PRP group, suggesting a detrimental effect. There was a correlation between the elasticity modulus at 7 and 19 weeks and the heel raise index at 52 weeks. The authors concluded that these findings suggested that PRP is not useful for treatment of Achilles tendon ruptures. The variation in elasticity modulus provides biologically relevant information, although it is unclear how early biomechanics is connected to late clinical results.

In a prospective, randomized, observer-blind controlled pilot study, Horstmann et al (2011) examined the effects of autologous platelet gel (APG), prepared from the buffy coat of a unit of autologous blood, after total knee arthroplasty (TKA) on blood loss, wound healing, pain, range of motion, and hospital stay. A total of 40 patients with only osteoarthritis of the knee were scheduled to have a TKA, and they were randomized into 2 groups. Patients in the treatment group were all treated with the application of APG after the prosthesis was implanted. Patients in the control group were treated with the same protocol but no APG was used. Pre-operative and post-operative hemoglobin levels showed no significant difference and allogeneic blood transfusions were not given in either group. Hematomas were significantly larger in the control group than in the platelet gel group (p = 0.03). The pain score at rest was higher in the control group on the 3rd day (p = 0.04). Wound healing disturbances were seen in 4 patients in the control group and in no patients in the APG group (n.s.). Range of motion of the knee was similar post-operatively. Hospital stay was 6.2 days in the APG and 7.5 days in the control group (n.s.). The authors noted that differences in favor of the use of APG were found, but these were subjective evaluations, marginal in effect, or did not reach statistical significance. The use of drains might have decreased the concentration of delivered platelets and may have diminished the effect. However, in this study, a statistically significant clinically important effect in favor of APG application was not found. They concluded that further studies with larger numbers of patients, and without the use of drains, are needed to investigate the possible benefits of APG in total knee arthroplasty.

Guadilla et al (2012) described a non-invasive arthroscopic procedure as an alternative to open surgery for avascular necrosis (AVN) of the hip. Patients with grade I or IIA AVN of the hip were treated by core decompression performed by drilling under fluoroscopic guidance. Liquid PRP was delivered through a trocar, saturating the necrotic area. In more severe conditions, the necrotic bone is decompressed and debrided, through a cortical window at the head-neck junction. A composite graft made of autologous bone and PRP was delivered by impactation through the core decompression track. Fibrin membranes were applied to enhance healing of the head-neck window and arthroscopic portals. Platelet-rich plasma was infiltrated in the central compartment. This arthroscopic approach aided in making diagnosis of the labrum and articular cartilage and permitted intra-operative treatment decisions. Visual control allowed the precise localization and treatment for the necrotic area allowing cartilage integrity to be preserved. The authors concluded that arthroscopic management of AVN of the femoral head is viable and has significant advantages. They stated that clinical studies should justify the theoretical additional benefits of this approach. An UpToDate review on "Osteonecrosis (avascular necrosis of bone)" (Jones, 2012) does not mention the use of PRP as a therapeutic option.

Sanchez et al (2012) evaluated the safety and symptomatic changes of intra-articular (IA) injections of PRP in patients with OA of the hip. A total of 40 patients affected by monolateral severe hip OA were included in the study. Each joint received 3 IA injections of PRP, which were administered once-weekly. The primary end point was meaningful pain relief, which was described as a reduction in pain intensity of at least 30 % from baseline levels as evaluated by the WOMAC subscale at 6-months post-treatment. The VAS and Harris hip score subscale for pain were used to verify the results. Secondary end points included changes in the level of disability of at least 30 % and the percentage of positive responders, namwly., the number of patients that achieved a greater than 30 % reduction in pain and disability. Statistically significant reductions in VAS, WOMAC and Harris hip subscores for pain and function were reported at 7 weeks and 6 months (p < 0.05). Twenty-three (57.5 %) patients reported a clinically relevant reduction of pain (45 %, range of 30 to 71 %) as assessed by the WOMAC subscale. Sixteen (40 %) of these patients were classified as excellent responders who showed an early pain reduction at 6 to 7 weeks, which was sustained at 6 months, and a parallel reduction of disability. Side effects were negligible and were limited to a sensation of heaviness in the injection site. The authors concluded that this preliminary non-controlled prospective study supported the safety, tolerability and efficacy of PRP injections for pain relief and improved function in a limited number of patients with OA of the hip. These findings need to be validated by prospective RCTs.

Bocanegra-Perez et al (2012) described the results of using PRP in the management of bisphosphonate-associated necrosis of the jaw. A total of 8 patients with a diagnosis of bisphosphonate-associated necrosis of the jaw were surgically treated for debridement and removal of necrotic bone, followed by application of autologous platelet concentrate enriched with growth factors and primary suture of the wound. Patients underwent periodic clinical and radiological follow-up examinations. All patients showed clinical improvement and oral lesions resolved 2 to 4 weeks following treatment. After an average 14-month follow-up period, patients remained asymptomatic. The authors concluded that although not conclusive, the combination of necrotic-bone curettage and PRP to treat refractory osteonecrosis of the jaw yielded promising results.

Gross et al (2013) performed a systematic review of clinical outcomes following injectable therapy of non-insertional Achilles tendinosis, identified patient-specific factors that are prognostic of treatment outcomes, provided treatment recommendations based on the best available literature, and identified knowledge deficits that require further investigation. These investigators searched Medline (1948 to week 1 of March 2012) and Embase (1980 to week 9 of 2012) for clinical studies evaluating the efficacy of injectable therapies for non-insertional Achilles tendinosis. Specifically, they included RCTs and cohort studies with a comparative control group. Data abstraction was performed by 2 independent reviewers. The Oxford Level of Evidence Guidelines and GRADE recommendations were used to rate the quality of evidence and to make treatment recommendations. A total of 9 studies fit the inclusion criteria for this review, constituting 312 Achilles tendons at final follow-up. The interventions of interest included PRP (n = 54), autologous blood injection (n = 40), sclerosing agents (n = 72), protease inhibitors (n = 26), hemodialysate (n = 60), corticosteroids (n = 52), and prolotherapy (n = 20). Only 1 study met the criteria for a high-quality RCT. All of the studies were designated as having a low-quality of evidence. While some studies showed statistically significant effects of the treatment modalities, often studies revealed that certain injectables were no better than a placebo. The authors concluded that the literature surrounding injectable treatments for non-insertional Achilles tendinosis has variable results with conflicting methodologies and inconclusive evidence concerning indications for treatment and the mechanism of their effects on chronically degenerated tendons. They stated that prospective, randomized studies are needed to guide Achilles tendinosis treatment recommendations using injectable therapies.

In a RCT, Kesikburun and associates (2013) examined the effect of PRP injections on pain and shoulder functions in patients with chronic rotator cuff tendinopathy. A total of 40 patients, 18 to 70 years of age, with

a history of shoulder pain for greater than 3 months during overhead-throwing activities,
magnetic resonance imaging (MRI) findings of rotator cuff tendinopathy or partial tendon ruptures, and
a minimum 50 % reduction in shoulder pain with subacromial injections of an anesthetic were included in this placebo-controlled, double-blind RCT.

Patients were randomized into a PRP group (n = 20) or placebo group (n = 20). Patients received an ultrasound-guided injection into the subacromial space that contained either 5 ml of PRP prepared from autologous venous blood or 5 ml of saline solution. All patients underwent a 6-week standard exercise program. Outcome measures (Western Ontario Rotator Cuff Index [WORC], Shoulder Pain and Disability Index [SPADI], 100-mm VAS of shoulder pain with the Neer test, and shoulder range of motion) were assessed at baseline and at 3, 6, 12, and 24 weeks and 1 year after injection. Comparison of the patients revealed no significant difference between the groups in WORC, SPADI, and VAS scores at 1-year follow-up (p = 0.174, p = 0.314, and p = 0.904, respectively). Similar results were found at other assessment points. Within each group, the WORC, SPADI, and VAS scores showed significant improvements compared with baseline at all time-points (p < 0.001). In the range of motion measures, there were no significant group × time interactions. The authors concluded that at 1-year follow-up, a PRP injection was found to be no more effective in improving quality of life, pain, disability, and shoulder range of motion than placebo in patients with chronic rotator cuff tendinopathy who were treated with an exercise program.

In a randomized, double-blinded, placebo and active-controlled, half-head, parallel-group study, Trink et al (2013) evaluated the safety and effectiveness of PRP for the treatment of alopecia areata (AA). A total of 45 AA patients were randomized to receive intra-lesional injections of PRP, triamcinolone acetonide (TA) or placebo on 50 % of their scalp. The other 50 % was not treated. A total of 3 treatments were given for each patient, with an interval of 1 month from each other. The end-points were hair regrowth, hair dystrophy as measured by dermoscopy, burning/itching sensation and cell proliferation as measured by Ki-67 evaluation. Patients were followed for 1 year. Platelet-rich plasma was found to significantly increase hair regrowth and decrease hair dystrophy and burning/itching sensation when compared with TA or placebo, and Ki-67 levels, which served as markers for cell proliferation, were significantly higher. No side effects were noted during treatment. The authors concluded that in this pilot study, which is the first to investigate the effects of PRP on AA, suggested that PRP may serve as a safe and effective treatment option in AA, and calls for more extensive controlled studies with this method.

In a single-center, parallel-group, participant-blinded RCT, Griffin et al (2013) examined the effectiveness of PRP therapy in the management of patients with a typical osteoporotic fracture of the hip. In this study, 200 of 315 eligible patients aged 65 years and over with any type of intra-capsular fracture of the proximal femur were included. Patients were excluded if their fracture precluded internal fixation. Participants underwent internal fixation of the fracture with cannulated screws and were randomly allocated to receive an injection of PRP into the fracture site or not. Main outcome measure was failure of fixation within 12 months, defined as any revision surgery. Primary outcome data were available for 82 of 101 and 78 of 99 participants allocated to test and control groups, respectively; the remainder died prior to final follow-up. There was an absolute risk reduction of 5.6 % (95 % CI: -10.6 % to 21.8 %) favoring treatment with PRP therapy (χ(2) test, p = 0.569). An adjusted effect estimate from a logistic regression model was similar (odds ratio [OR] = 0.71, 95 % CI: 0.36 to 1.40, z test; p = 0.325). There were no significant differences in any of the secondary outcome measures excepting length of stay favoring treatment with PRP therapy (median difference 8 days, Mann-Whitney U test; p = 0.03). The number and distribution of adverse events were similar. Estimated cumulative incidence functions for the competing events of death and revision demonstrated no evidence of a significant treatment effect (hazard ratio [HR] 0.895, 95 % CI: 0.533 to 1.504; p = 0.680 in favor of PRP therapy). The authors concluded that there was no evidence of a difference in the risk of revision surgery within 1 year in participants treated with PRP therapy compared with those not treated. However, the authors cannot definitively exclude a clinically meaningful difference.

Kumar et al (2013) evaluated the effectiveness of PRP in chronic cases of plantar fasciitis. Patients with plantar fasciitis not responded to a minimum of 1 year standard conservative management were offered PRP therapy. Injections were performed in theatre as a day case. Roles-Maudsley (RM) scores, VAS, AOFAS scores and “would have injection again” were collated pre-operatively, 3 and 6 months post-operatively. Prospective data were collected of 50 heels (44 patients). At 6 month review, RM score improved from mean 4 to 2 (p < 0.001), VAS improved from 7.7 to 4.2 (p < 0.001) and AOFAS improved from 60.6 to 81.9 (p < 0.001). A total of 28 patients (64 %) were very satisfied and would have the injection again. No complications were reported. The authors concluded that in these chronic cases, PRP produced an efficacy rate, approaching 2 out of every 3. The procedure was safe with no reported complications. The authors felt that PRP may have some role in treatment, and merits further study with a prospective randomized trial.

Osterman et al (2015) noted that PRP has anti-inflammatory effects with potential applications in the treatment of OA. In a controlled laboratory study, these researchers used an in-vitro co-culture model of OA in human cartilage and synovium to investigate the anti-inflammatory effects of 2 different PRP preparations. A co-culture system was created using osteoarthritic cartilage and synovium from 9 patients undergoing total knee arthroplasty. Interleukin-1β (IL-1β) was added to each co-culture to induce inflammation. Two PRP preparations were obtained -- one yielding low white blood cell and platelet concentrations (PRPLP) and one yielding high platelet and white blood cell concentrations (PRPHP). Either PRPLP, PRPHP, or medium was added to the co-culture wells. Control wells contained OA cartilage and synovium but neither IL-1β nor PRP. Normal, non-OA cartilage was obtained to establish baseline gene expression levels. Quantitative polymerase chain reaction was used to measure changes in markers of inflammation in the tissues (a disintegrin and metalloproteinase with thrombospondin motifs-5 [ADAMTS-5], tissue inhibitor of metalloproteinases-1 [TIMP-1], vascular endothelial growth factor [VEGF], aggrecan, and type I collagen) at 0, 24, 48, and 72 hours. Treatment with PRPLP or PRPHP significantly decreased expression of TIMP-1 and ADAMTS-5 in cartilage, increased aggrecan expression in cartilage, and decreased ADAMTS-5, VEGF, and TIMP-1 expression in synovium compared with control co-cultures (p < 0.05). There was significantly less nitric oxide production in the PRPLP and PRPHP groups compared with controls (p < 0.05). There were significant differences in gene expression in the normal cartilage compared with all 4 groups of OA cartilage at all 4 time points. Treatment with either PRPLP or PRPHP returned some gene expression to the same levels in normal cartilage but not for all markers of inflammation. The authors concluded that this co-culture model assessed 2 different PRP preparations and their anti-inflammatory effects over time on human OA cartilage and synovium. Both had a significant anti-inflammatory effect on gene expression; however, there was no difference in the anti-inflammatory effect between the 2 preparations. These investigators stated that OA is a leading cause of chronic disability, and less invasive treatment methods are needed; these findings suggested that PRP injections may be an effective alternative anti-inflammatory agent in the treatment of OA.

On behalf of the Osteoarthritis Section of the French Society for Rheumatology, Ornetti et al (2016) stated that PRP has been generating considerable attention as an intra-articular treatment to alleviate the symptoms of OA. Activated platelets release a host of soluble mediators such as growth factors and cytokines, thereby inducing complex interactions that vary across tissues within the joint. In-vivo, PRP may promote chondrocyte proliferation and differentiation. The available data are somewhat conflicting regarding potential effects on synovial cells and angiogenesis modulation. Platelet-rich plasma probably exerts an early anti-inflammatory effect, which may be chiefly mediated by inhibition of the NF-κB pathway, a hypothesis that requires confirmation by proof-of-concept studies. The authors stated that it is far too early to draw conclusions about the effectiveness of PRP as a treatment for hip OA.

Nourissat et al (2015) stated that although tendinopathies constitute a heterogeneous group of conditions, they are often treated by similar combinations of local and systemic symptomatic interventions. The vast number of causes, pathophysiological mechanisms, and histological changes that characterizes tendinopathies may explain that the standard treatment fails in some patients. Platelet-rich plasma (PRP), which contains a host of soluble mediators including growth factors, has been suggested as a second-line treatment for refractory tendinopathy, with the goal of expediting tendon healing or remodeling. These investigators reported a systematic literature review of basic research data from humans and animals that support the clinical use of PRP in tendinopathies and of clinical studies in the most common tendinopathies (elbow, knee, shoulder, and Achilles tendon). The objective was to clarify the role for this new injectable treatment, which is garnering increasing attention. The level of evidence remains low, as few well-designed randomized controlled trials have been published. The available scientific evidence does not warrant the use of PRP for the first-line treatment of tendinopathy. PRP therapy may deserve consideration in specific tendinopathy subtypes, after failure of ultrasound-guided corticosteroid injections. Nevertheless, further studies are needed to define these potential indications and the optimal treatment protocols.

Balasubramaniam et al (2015) systematically reviewed the literature regarding PRP therapy in chronic tendinopathy. The databases used in the search include the Elton B. Stephens Co. (EBSCO) database, Medline, the Cochrane library, Ovid, and Embase (the Excerpta Medica database). A total of 389 articles were reviewed from Feb 2010 to April 2014, for possible inclusion. Of these articles, a total of 9 randomized controlled trials (RCTs) met the inclusion criteria. Only 1 RCT was excluded due to previous surgery in both the trial and control groups. Each article was reviewed independently by 2 authors. Each article was analyzed using the Cochrane Criteria checklist. Where any discrepancy occurred in results, a 3rd independent reviewer was consulted. The review found that PRP was most effective in patellar and lateral epicondylar tendinopathy, with both RCTs in the patellar section of the study supporting the use of PRP in pain reduction at 3 and 12 months, whereas 2 of 4 studies in the lateral epicondylar section showed improvements in pain and disability at 6 and 12 months. There was a lack of evidence to support the use of PRP in Achilles and rotator cuff tendinopathy. The authors concluded that although the results of this review showed promise for the use of PRP in chronic tendinopathy, the analysis highlighted the need for more controlled clinical trials comparing PRP with placebo.

Di Matteo et al (2015) PRP has been introduced in the clinical practice to treat a growing number of different musculoskeletal pathologies. It is currently applied in the treatment of Achilles and patellar tendinopathies, which are common sport-related injuries very challenging to manage. Aim of the present paper was to review systematically the available clinical evidence concerning the application of PRP in the treatment of patellar and Achilles tendinopathy. A systematic review of the literature was performed according to the following inclusion criteria for relevant articles:

clinical reports of any level of evidence,
written in the English language,
with no time limitation, and
on the use of PRP to treat conservatively Achilles and patellar tendinopathy.

A total of 22 studies were included and analyzed. Two studies on patellar tendinopathy were RCTs, whereas just 1 RCT was published on Achilles tendon. All the papers concerning patellar tendon reported positive outcome for PRP, which proved to be superior to other traditional approaches such as shock-wave therapy and dry needling. In the case of Achilles tendon, despite the encouraging findings reported by case series, the only RCT available showed no significant clinical difference between PRP and saline solution. The main finding of this study was the paucity of high-level literature regarding the application of PRP in the management of patellar and Achilles tendinopathy. However, the authors noted that clinical data currently available, although not univocal, suggest considering PRP as a therapeutic option for recalcitrant patellar and Achilles tendinopathies.

Gholami et al (2016) examined the effectiveness of PRP in improving sports injuries and subsequently threw some light on these controversies. These researchers performed a systematic review of the literature and meta-analysis of results. All related databases, such as PubMed, Cochrane Database of Systematic Reviews, DARE, and EMBASE, were searched on the use of PRP on athletes and in sports medicine. The search was conducted from June 2013 to February 2014. The search retrieved 905 studies, of which 13 RCTs met inclusion criteria for systematic review and meta-analysis. All articles were appraised by Critical Appraisal Skills Program (CASP) check-list for RCTs. The analysis of the results of pain scores and physical activity/functions did not show any superiority for PRP as opposed to the other options. The authors concluded that this meta-analysis showed no more effectiveness for PRP application in sports-related injuries in terms of physical function improvement and pain relief. Therefore, they stated that the extensive use of PRP for such injuries should be limited; well-designed RCTs are needed to support the findings.

An UpToDate review on “Overview of the management of overuse (chronic) tendinopathy” (Khan and Scott, 2016) lists “Dry needling and autologous blood/platelet rich plasma injection” as investigational treatments. It states that “small randomized trials of patients with mid-portion Achilles tendinopathy demonstrated no benefit from platelet rich plasma (PRP) or autologous blood injection when added to an eccentric training program. A similar study performed in patients with rotator cuff tendinopathy also reported no benefit from PRP when performed in patients treated with standard physical therapy”.

Kearney et al (2021) noted that PRP injections are used as a treatment for chronic mid-portion Achilles tendinopathy; however, the evidence for this treatment is limited. In a multi-center, participant-blinded, randomized clinical trial, these researchers examined the effects of a single PRP injection, compared with sham injection, on the outcome of the VISA-A score (a single composite measure of Achilles tendinopathy severity). This trial included 240 individuals from 24 sites assigned to either a PRP injection or a sham injection between April 2016 and February 2020. Final follow-up was July 2020. Subjects were older than 18 years with mid-portion Achilles tendon pain for more than 3 months as confirmed by US, MRI, or both. Interventions entailed a single intra-tendinous PRP injection (n = 121) or a single sham injection (insertion of a subcutaneous dry needle not entering the tendon) (n = 119). The primary outcome was the VISA-A score, measured 6 months after treatment allocation. The VISA-A score contains 8 questions that cover 3 domains of pain, function, and activity, analyzed as a composite score (range, 0 [worst symptoms] to 100 [no symptoms]; minimal clinically important difference in score, 12 points). The primary analysis was adjusted for laterality, age, sex, and baseline VISA-A score. Among 240 patients assigned to a PRP or sham injection (mean age of 52 years; 138 [58 %] women), 221 (92 %) completed the trial. At 6-month follow-up, mean VISA-A score values in the PRP group versus the sham injection group were 54.4 versus 53.4 (adjusted MD, -2.7 [95 % CI: -8.8 to 3.3]). The most common AEs compared between patients in the PRP group versus the sham group were injection site discomfort (97 versus 73 patients), swelling (56 versus 52 patients) and bruising (48 versus 49 patients). The authors concluded that among patients with chronic mid-portion Achilles tendinopathy, treatment with a single injection of intra-tendinous PRP, compared with insertion of a subcutaneous dry needle, did not reduce Achilles tendon dysfunction at 6 months. These findings do not support the use of this treatment for chronic mid-portion Achilles tendinopathy.

Bennell et al (2021) stated that most clinical guidelines do not recommend PRP for knee OA because of lack of high-quality evidence on its effectiveness for symptoms and joint structure; however, the guidelines emphasize the need for rigorous studies. Despite this, use of PRP in knee OA is increasing. In a randomized, 2-group, placebo-controlled, participant-, injector-, and assessor-blinded study, these researchers examined the effects of intra-articular PRP injections on symptoms and joint structure in patients with symptomatic mild-to-moderate radiographic medial knee OA. This trial enrolled community-based subjects (n = 288) aged 50 years or older with symptomatic medial knee OA (Kellgren and Lawrence grade 2 or 3) in Sydney and Melbourne, Australia, from August 24, 2017 to July 5, 2019. The 12-month follow-up was completed on July 22, 2020. Interventions entailed 3 intra-articular injections at weekly intervals of either leukocyte-poor PRP using a commercially available product (n = 144 subjects) or saline placebo (n = 144 subjects). The 2 primary outcomes were 12-month change in overall average knee pain scores (11-point scale; range of 0 to 10, with higher scores indicating worse pain; minimum clinically important difference of 1.8) and percentage change in medial tibial cartilage volume as assessed by MRI. A total of 31 secondary outcomes (25 symptom-related and 6 MRI-assessed; minimum clinically important difference not known) evaluated pain, function, QOL, global change, and joint structures at 2-month and/or 12-month follow-up. Among 288 patients who were randomized (mean age of 61.9 [SD, 6.5] years; 169 [59 %] women), 269 (93 %) completed the trial. In both groups, 140 subjects (97 %) received all 3 injections. After 12 months, treatment with PRP versus placebo injection resulted in a mean change in knee pain scores of −2.1 versus −1.8 points, respectively (difference, −0.4 [95 % CI: −0.9 to 0.2] points; p = 0.17). The mean change in medial tibial cartilage volume was −1.4 % versus −1.2 %, respectively (difference, −0.2 % [95 % CI: −1.9 % to 1.5 %]; p = 0.81). Of 31 pre-specified secondary outcomes, 29 showed no significant between-group differences. The authors concluded that among patients with symptomatic mild-to-moderate radiographic knee OA, intra-articular injection of PRP, compared with injection of saline placebo, did not result in a significant difference in symptoms or joint structure at 12 months. These findings do not support use of PRP for the management of knee OA.

In a systematic review and meta-analysis, Masiello et al (2023) examined the effectiveness of US-guided injections of PRP as conservative treatment of tendinopathies. These investigators searched Medline, Embase, SCOPUS, OVID, and the Cochrane Library to identify RCTs on the use of US-guided PRP for the treatment of tendinopathies. They found 33 RCT (2,025 subjects) that met the inclusion criteria: 8 in lateral epicondylitis, 5 in plantar fasciitis, 5 in Achilles tendinopathy, 7 in rotator cuff tendinopathy, 3 in patellar tendinopathy and 5 in carpal tunnel syndrome (CTS). PRP, given as a single injection (20 trials) or multiple injections (13 trials), was compared to US-guided injection of steroids, saline, autologous whole blood, local anesthetic, dry needling, prolotherapy, bone marrow mesenchymal stem cells, or with non-injective interventions. The outcomes more commonly reported included pain and functional measures, sub-grouped as in the short-term (less than 3 months from the intervention), medium-term (3 to 6 months) or long-term (12 months or longer). No clear between-group differences in these outcomes were observed in patients with lateral epicondylitis, plantar fasciitis, or Achilles, rotator cuff or patellar tendinopathy. In patients with CTS, VAS for pain at 3 and 6 months and Boston Carpal Tunnel Questionnaire severity scores at 1, 3 and 6 months were significantly lower in PRP recipients than in controls. The certainty of evidence of all these comparisons was graded as low or very low due to risk of bias, imprecision and/or inconsistency. Pain at the injection site was more common among PRP recipients than among controls receiving other US-guided injections. The authors concluded that in patients with tendinopathies, a trend towards pain reduction and functional improvement from baseline was observed after US-guided PRP injection; however, in the majority of the comparisons, the effect size was comparable to that observed in control groups. These researchers stated that further large, randomized, well-designed studies are needed to better define potential indications for, long-term benefits of, and optimal treatment protocols for PRP as a conservative treatment in orthopedics. These studies should also perform an adequate cost-benefit analysis of US-guided PRP therapy compared to other US-guided interventions.

The authors stated that the quantitative analysis carried out in this systematic review had several drawbacks that do not allow these researchers to draw definite conclusions on the effectiveness of PRP in this setting. First, the lack of standardization of PRP production among the different studies, which made the PRP products heterogeneous and qualitatively different from each other, which limited the validity of inter-study comparisons. Compared to the previously published systematic reviews, however, the current review included only trials in which the PRP was injected under US guidance; therefore, reducing inconsistency related to anatomically-guided injection techniques. Second, only 13 of the 33 trials included in this review reported the long-term (12 months or longer) effect of PRP; thus, the comparison at 12 months for each clinical condition was often limited to 1 or 2 trials. It was possible, as claimed by some investigators, that the best clinical benefit of PRP application in orthopedics may occur in the long-term period. Nevertheless, in the current analysis no clear benefits of PRP over control were observed in long-term follow-up, with the exception of a significantly higher increase of functional index in patients with plantar fasciitis treated with PRP compared to controls. At present, specific contributions supporting the use of PRP in tendinopathies lack the methodological features essential to define the clinical effectiveness of the treatment. Third, there is no defined consensus on the type and standards of the product, or on the mode of application. There is wide variability in PRP production methods depending on the various instruments and concentration techniques used. Not all PRP treatments are the same, with the most important differences being related to the initial volume of blood, the centrifugation system used, the concentration of platelets per volume of PRP, and the type of activation. It is important that the amount of PRP per injection is standardized. The same holds true for the depth of the injection and the distance between injected sites.

Autologous Platelet Gel for Diabetic Foot Ulcer

Xu et al (2019) stated that research focusing on the efficacy of autologous platelet-rich gel (APRG) and continuous vacuum sealing drainage (CVSD) for diabetic foot ulcer (DFU) is increasing. Despite increasing knowledge on this theme, its results remain inconsistent. These researchers will provide insight into the efficacy of APRG and CVSD for patients with DFU. They will search electronic data-bases of Medline, Embase, Cochrane Library, CINAHL, AMED, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure from inception to October 1, 2019. No language limitation was employed to these data-bases; 2 authors will independently carry out study selection, data extraction, and risk of bias assessment. Disagreements between 2 authors will be solved through discussion with a 3rd author. The safety and efficacy of APRG and CVSD for patients with DFU will be evaluated by the time to complete healing, proportion of ulcers healed within trial period, change of size of ulcer, health-related QOL, patient length of hospital stay (LOS), and AEs. The authors concluded that the findings of this study will provide helpful evidence of APRG and CVSD for patients with DFU. This study will also provide guidance for both clinical practice and further research.

Platelet-Rich Plasma for Achilles Tendinopathy

Platelet-Rich Plasma Injection for the Treatment of Ankle Sprain

Rowden et al (2015) noted that over 23,000 people per day require treatment for ankle sprains. Platelet-rich plasma is an autologous concentration of platelets that is thought to improve healing by promoting inflammation through growth factor and cytokine release. Studies to-date had shown mixed results, with few randomized trials. In a prospective, double-blind, randomized, placebo-controlled study, these researchers determined patient function among patients randomized to receive standard therapy plus PRP, compared to patients who receive standard therapy plus sham injection (placebo). Patients with severe ankle sprains were randomized. Severity was graded on degree of swelling, ecchymosis, and ability to bear weight; PRP with lidocaine and bupivacaine was injected at the point of maximum tenderness by a blinded physician under ultrasound guidance. The control group was injected in a similar fashion with sterile 0.9 % saline. Both groups had VAS pain scores and Lower Extremity Functional Scale (LEFS) on days 0, 3, and 8; LEFS and a numeric pain score were obtained via phone call on day 30. All participants were splinted, given crutches, and instructed to not bear weight for 3 days; at this time patients were re-evaluated. There were 1,156 patients screened and 37 were enrolled. Four withdrew before PRP injection was complete; 18 were randomized to PRP and 15 to placebo. There was no statistically significant difference in VAS and LEFS scores between groups. The authors concluded that in this small study, PRP did not provide benefit in either pain control or function over placebo.

Platelet-Rich Plasma Injection for the Treatment of Anterior Cruciate Ligament Surgery

In a systematic review, Figueroa et al (2015) evaluated the current literature for evidence that would substantiate the use of PRP in the treatment of anterior cruciate ligament (ACL) ruptures. These researchers performed a systematic search in PubMed and Embase of studies written in the English and Spanish languages that compared the use of PRP with a control group in patients with ACL injuries assessing graft-to-bone healing, graft maturation, and/or clinical outcomes and were RCTs or prospective cohort studies. A total of 11 studies fulfilled the inclusion criteria, comprising 516 patients (266 ACL reconstructions using PRP and 250 ACL reconstructions without PRP); 6 studies reported a statistically significant difference (4 studies) or tendency toward faster graft maturation in the platelet group (2 studies); 1 study found no differences. Regarding tunnel healing/widening, 1 study showed faster healing in the PRP group and 5 studies showed no differences between the 2 groups. Considering clinical outcomes, 1 study showed better clinical outcomes with PRP use and 5 studies showed no benefits with the use of PRP. The authors concluded that concerning ACL graft maturation, there is promising evidence that the addition of PRP could be a synergic factor in acquiring maturity more quickly than grafts with no PRP, with the clinical implication of this remaining unclear. Regarding tunnel healing, it appeared that there is not an improvement with the addition of PRP. They stated that there is no proof that clinical outcomes of ACL surgery are enhanced by the use of PRP.

Platelet-Rich Plasma Injection as Adjunctive Material to Bone Graft

In a systematic review and meta-analysis, Pocaterra et al (2016) evaluated the scientific evidence on the effectiveness of PRP as an adjunctive material in the sinus floor elevation technique. The following databases were searched for relevant published studies: Medline, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, CINAHL, Science Direct, ISI Web of Knowledge, and SCOPUS. Only RCTs comparing a group receiving PRP as an adjunctive material to a control group without PRP, involving adult human subjects (age greater than18 years) with no systemic disease, were included. Of the studies identified, only 1 reported a significant difference in bone augmentation in favor of the adjunctive use of PRP, while 4 studies did not find any significant difference. None of the studies included reported a significant difference in the implant survival rate. The authors concluded that further RCTs are needed to clarify the effectiveness of adjunctive PRP.

In a systematic review and meta-analysis, Lemos et al (2016) evaluated the effect on bone formation and implant survival of combining PRP with bone grafts in maxillary augmentation. A comprehensive review of articles listed in the PubMed/Medline, Embase, and Cochrane Library databases covering the period January 2000 to January 2015 was performed. The meta-analysis was based on bone formation for which the mean difference (MD, in millimeters) was calculated. Implant survival was assessed as a dichotomous outcome and evaluated using the risk ratio (RR) with 95 % CI. The search identified 3,303 references. After inclusion and exclusion criteria were applied, 17 studies were selected for qualitative analysis and 13 for quantitative analysis. A total of 369 patients (mean age of 51.67 years) and 621 maxillary sinus augmentations were evaluated. After the data analysis, additional analyses were performed of the implant stability quotient, marginal bone loss, and alveolar bone height measured by MD. The results showed no significant difference in implant stability (p = 0.32, MD 1.00, 95 % CI: -0.98 to 2.98), marginal bone loss (p = 0.31, MD 0.06, 95 % CI: -0.05 to 0.16), alveolar bone height (p = 0.10, MD -0.72, 95 % CI: -1.59 to 0.14), implant survival (p = 0.22, RR 1.95, 95 % CI: 0.67 to 5.69), or bone formation (p = 0.81, MD -0.63, 95 % CI: -5.91 to 4.65). The authors concluded that the results of this meta-analysis indicated no influence of PRP with bone graft on bone formation and implant survival in maxillary sinus augmentation.

Platelet-Rich Plasma Injection for the Treatment of Cerebral Palsy

Alcaraz et al (2015) reported the case of a cerebral palsy (CP) patient who received intravenous PRP. These investigators administered an intravenous injection of concentrated PRP (25 cc) in a 6-year old boy with perinatal CP, cognitive impairment, and marked and severe generalized spasticity. They performed follow-up at 3 and 6 months after the injection. All serum samples for determination were obtained by enzyme-linked immunosorbent assay (ELISA) technique. Cognitive scales (Bayley, Battelle, M.S.C.A, Kaufman ABC, and Stanford-Binet Intelligence scale) were used before and after treatment. The determination protocol that was applied before the analysis was performed manually and the auto-transfusion was considered suitable for treatment. These researchers determined the plasma levels of factor similar to insulin-like growth factor-1 (IGF-1), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and transforming growth factor B (TGF-B) before and during treatment monitoring. No adverse effects were observed in the patient except for a small hematoma in the area channeling venous access. These investigators observed a clear improvement in the cognitive sphere (memory, ability to perform more complex tasks, and acquisition of new skills) and in language, maintaining stable levels of growth factor in plasma 3 to 5 times higher than average for his age group at both 3- and 6-month follow-up. Positron emission tomography (PET) images showed an evident increased demarcation in the cerebral cortex. The authors proposed that this therapy is useful in these patients to harness the neurostimulative and neuroregenerative power of endogenous growth factors derived from platelets. The findings of this single case study needs to be validated by well-designed studies.

Platelet-Rich Plasma Injection for the Treatment of Chronic Wounds

In a meta-analysis, Martinez-Zapata et al (2016) examined if autologous PRP promotes the healing of chronic wounds. In June 2015, for this first update, these investigators searched the Cochrane Wounds Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library): Ovid Medline; Ovid Medline (In-Process & Other Non-Indexed Citations); Ovid Embase; and Ebsco CINAHL. They also searched for ongoing and unpublished clinical trials in the WHO International Clinical Trials Registry Platform (ICTRP) (searched January 2015). They did not impose any restrictions with respect to language, date of publication, or study setting. These researchers included RCTs that compared autologous PRP with placebo or alternative treatments for any type of chronic wound in adults. They did not apply any date or language restrictions. They used standard Cochrane methodology, including 2 reviewers independently selecting studies for inclusion, extracting data, and assessing risk of bias. The search identified 1 new RCT, making a total of 10 included RCTs (442 participants, 42 % women). The median number of participants per RCT was 29 (range of 10 to 117); 4 RCTs recruited people with a range of chronic wounds; 3 RCTs recruited people with venous leg ulcers, and 3 RCTs considered foot ulcers in people with diabetes. The median length of treatment was 12 weeks (range of 8 to 40 weeks). It is unclear whether autologous PRP improves the healing of chronic wounds generally compared with standard treatment (with or without placebo) (RR 1.19, 95 % CI: 0.95 to 1.50; I(2) = 27 %, low quality evidence, 8 RCTs, 391 participants). Autologous PRP may increase the healing of foot ulcers in people with diabetes compared with standard care (with or without placebo) (RR 1.22, 95 % CI: 1.01 to 1.49; I(2) = 0 %, low quality evidence, 2 RCTs, 189 participants). It is unclear if autologous PRP affects the healing of venous leg ulcers (RR 1.02, 95 % CI: 0.81 to 1.27; I(2) = 0 % ). It is unclear if there is a difference in the risk of adverse events in people treated with PRP or standard care (RR 1.05, 95 % CI: 0.29 to 3.88; I(2) = 0 %, low quality evidence from 3 trials, 102 participants). The authors concluded that PRP may improve the healing of foot ulcers associated with diabetes, but this conclusion is based on low quality evidence from 2 small RCTs. It is unclear whether PRP influences the healing of other chronic wounds. The overall quality of evidence of autologous PRP for treating chronic wounds is low. There are very few RCTs evaluating PRP, they are under-powered to detect treatment effects, if they exist, and are generally at high or unclear risk of bias. They stated that Well designed and adequately powered clinical trials are needed.

Platelet-Rich Plasma Injection for the Treatment of Discogenic Low Back Pain

In a prospective study, Levi and associates (2016) evaluated changes in pain and function in patients with discogenic low back pain (LBP) after an intradiscal injection of PRP. Patients were diagnosed with discogenic LBP by clinical means, imaging, and exclusion of other structures. Provocation discography was used in a minority of the patients. Patients underwent a single treatment of intradiscal injection of PRP at 1 or multiple levels. Patients were considered a categorical success if they achieved at least 50 % improvement in the VAS and 30 % decrease in the Oswestry Disability Index (ODI) at 1, 2, and 6 months post-treatment. A total of 22 patients underwent intradiscal PRP; 9 underwent a single level injection, 10 at 2 levels, 2 at 3 levels, and 1 at 5 levels. Categorical success rates were as follows: 1 month: 3/22 = 14 % (95 % CI: 0 % to 28 %), 2 months: 7/22 = 32 % (95 % CI: 12 % to 51 %), 6 months: 9/19 = 47 % (95 % CI: 25 % to 70 %). The authors concluded that the findings of this study demonstrated encouraging preliminary 6 month findings, using strict categorical success criteria, for intradiscal PRP as a treatment for presumed discogenic LBP. Moreover, they stated that randomized placebo-controlled trials are needed to further evaluate the effectiveness of this treatment.

Monfett and co-workers (2016) provided an overview of clinical and translational research on intradiscal PRP as a minimally invasive treatment for discogenic LBP. These researchers performed a literature review of in-vitro, in-vivo, and clinical studies. There is strong in-vitro evidence that supports the use of intradiscal PRP for discogenic LBP. There are also promising findings in select pre-clinical animal studies. A clinical study of 29 participants who underwent intradiscal PRP injections for discogenic LBP found statistically and clinically significant improvements in pain and function through 2 years of follow-up. The authors concluded that intradiscal PRP is a safe and a possibly effective treatment for discogenic LBP. They stated that future studies are needed to determine the best candidates for this treatment, what the optimal injectate is and what relationships exist between patient-reported outcomes and radiological findings.

Akeda and colleagues (2017) determine the safety and effectiveness of intradiscal injection of autologous PRP releasate in patients with discogenic LBP. Inclusion criteria were chronic LBP without leg pain for more than 3 months; 1 or more lumbar discs (L3/L4 to L5/S1) with evidence of degeneration, as indicated via MRI; and at least 1 symptomatic disc, confirmed using standardized provocative discography; PRP releasate, isolated from clotted PRP, was injected into the center of the nucleus pulposus. Outcome measures included the use of a VAS and the Roland-Morris Disability Questionnaire (RDQ), as well as X-ray and MRI (T2-quantification). Data were analyzed from 14 patients (8 men and 6 women; mean age of 33.8 years). The average follow-up period was 10 months. Following treatment, no patient experienced adverse events (AEs) or significant narrowing of disc height. The mean pain scores before treatment (VAS, 7.5 ± 1.3; RDQ, 12.6 ± 4.1) were significantly decreased at 1 month, and this was generally sustained throughout the observation period (6 months after treatment: VAS, 3.2 ± 2.4, RDQ; 3.6 ± 4.5 and 12 months: VAS, 2.9 ± 2.8; RDQ, 2.8 ± 3.9; p < 0.01, respectively). The mean T2 values did not significantly change after treatment. The authors demonstrated that intradiscal injection of autologous PRP releasate in patients with LBP was safe, with no AEs observed during follow-up. Moreover, they stated that future RCTs should be performed to systematically evaluate the effects of this therapy.

Platelet-Rich Plasma Injection for the Treatment of Crohn's Disease-Related Perianal Fistula

In a prospective, pilot study, Gottgens et al (2015) attempted to improve healing rates of Crohn's disease (CD)-related high perianal fistulas by combining the well-known mucosal advancement flap with PRP. Consecutive patients with primary or recurrent CD-related high perianal fistulas, defined as involving the middle and/or upper third parts of the anal sphincter complex, were included. A staged procedure was performed with non-cutting seton treatment for 3 months first, followed by a mucosal advancement flap with injection of PRP into the fistula tract. A total of 10 consecutive patients were operated on between 2009 and 2014; 50 % of the patients had undergone previous fistula surgery. Mean follow-up was 23.3 months (SD 13.0). Healing of the fistula was 70 % (95 % CI: 33 to 89 %) at 1 year. One (10 %) patient had a recurrence, and in 2 (20 %) patients, the fistula was persistent after treatment. An abscess occurred in 1 (10 %) patient. The median post-operative Vaizey score was 8.0 (range of 0 to 21), indicating a moderate to severe continence impairment. The authors concluded that the results of combining the mucosal advancement flap with PRP in patients with CD-related high perianal fistulas are moderate with a healing rate of 70 %. They stated that further investigation is needed to determine the benefits and risks on continence status for this technique in this patient population.

Platelet-Rich Plasma Injection for the Treatment of Hamstring Injury

In a randomized, 3-arm (double-blind for the injection arms), parallel-group trial, Hamilton et al (2015) evaluated the effectiveness of a single PRP injection in reducing the return to sport duration in male athletes, following an acute hamstring injury (HI). A total of 90 professional athletes with MRI positive HI were randomized to injection with PRP-intervention, platelet-poor plasma (PPP-control) or no injection. All received an intensive standardized rehabilitation program. The primary outcome measure was time to return to play, with secondary measures including re-injury rate after 2 and 6 months. The adjusted HR for the PRP group compared with the PPP group was 2.29 (95 % CI: 1.30 to 4.04; p = 0.004); for the PRP group compared with the no injection group 1.48 (95 % CI: 0.869 to 2.520; p = 0.15), and for the PPP group compared with the no injection group 1.57 (95 % CI: 0.88 to -2.80; p = 0.13). The adjusted difference for time to return to sports between the PRP and PPP groups was -5.7 days (95 % CI: -10.1 to -1.4; p = 0.01); between the PRP and no injection groups -2.9 days (95 % CI: -7.2 to 1.4; p = 0.189) and between the PPP and no injection groups 2.8 days (95 % CI: -1.6 to 7.2; p = 0.210). There was no significant difference for the secondary outcome measures. No adverse effects were reported. The authors concluded that these findings indicated that there is no benefit of a single PRP injection over intensive rehabilitation in athletes who have sustained acute, MRI positive HI. Intensive physiotherapy led rehabilitation remains the primary means of ensuring an optimal return to sport following muscle injury.

In a meta-analysis, Pas and colleagues (2015) updated and re-analyzed the effectiveness of conservative treatments HI. PubMed, EMBASE, Web of Science, Cochrane library, CINAHL and SPORTDiscus were searched till mid-February 2015. Randomized controlled trials on the effect of conservative interventions versus a control group or other intervention for HI were included. The search results were screened independently by 2 authors. Risk of bias assessment was performed using a modified Downs and Black scale with a maximum score of 28. Meta-analysis was performed, where possible. A total of 10 RCTs (526 participants), including 6 new RCTs, were identified. Two RCTs were of good/excellent quality, the rest were fair or poor (median Downs and Black score 16 (IQR 9)). Meta-analysis of 2 studies on rehabilitation (lengthening) exercises showed a significantly reduced time to return to play (HR 3.22 (95 % CI: 2.17 to 4.77), p < 0.0001) but no difference in risk of re-injury. Meta-analysis of 3 studies investigating PRP showed no effect when compared to control (HR 1.03 (95 % CI: 0.87 to 1.22), p = 0.73). Limited evidence was found that progressive agility and trunk stability training may reduce re-injury rates. The authors concluded that meta-analysis showed superior effectiveness for rehabilitation exercises; PRP injection had no effect on acute HI.

Brukner (2015) stated that not all HI are the same and that certain types of injuries require prolonged rehabilitation and return to play. The slow stretch type of injury and injuries involving the central tendon both require longer times to return to play. A number of factors have been proposed as being indicators of time taken to return to play, but the evidence for these is conflicting. Recurrence rates remain high and it is now thought that strength deficits may be an important factor. Strengthening exercise should be performed with the hamstrings in a lengthened position. The author stated that there is conflicting evidence regarding the effectiveness of PRP injection in the treatment of HI so at this stage their use is not advised.

Platelet-Rich Plasma Injection for the Treatment of Osteoarthritis

Knop et al (2016) conducted a comprehensive and systematic search of the literature on the use of PRP in the treatment of osteoarthritis, using the Medline, Lilacs, Cochrane and SciELO databases, from May 2012 to October 2013. A total of 23 studies were selected, with 9 being controlled trials and, of these, 7 randomized, which included 725 patients. In this series, the group receiving PRP showed improvement in pain and joint function compared to placebo and hyaluronic acid. The response lasted up to 2 years and was better in milder cases. However, it was found that there was no standardization in the PRP production method, neither in the number, timing, and volume of applications. Furthermore, the populations studied were not clearly described in many studies. Thus, the authors concluded that these results should be analyzed with caution, and further studies with more standardized methods are needed for a more consistent conclusion about the PRP role in osteoarthritis.

Platelet-Rich Plasma Injection for the Treatment of Rotator Cuff Injuries

In a meta-analysis, Fu and colleagues (2017) examined the effectiveness of PRP and platelet-rich fibrin (PRF) matrix for improving healing of rotator cuff injuries. A meta-analysis of eligible studies was performed after searching Medline, Cochrane, and EMBASE on December 14, 2015. Databases were searched using the keywords "PRP or platelet-rich plasma", "PRFM or platelet-rich fibrin matrix", "rotator cuff" and "platelet-rich" for studies comparing outcomes of patients with rotator cuff injuries that did and did not receive a platelet-rich product. The primary outcome was a functional score change from pre- to post-treatment (Scorepost-Scorepre). The secondary outcome was a VAS pain score change from pre- to post-treatment (VASpost-VASpre). A total of 11 studies were included in the meta-analysis. The total number of patients that received PRP or PRF matrix was 320 and the number of control patients was 318. The standard difference in means of the functional scores was similar between patients administered PRP/PRF matrix and patients in the control group (standard difference in means for functional scores = 0.029; 95 % CI: -0.132 to 0.190; p = 0.725). The standard difference in means was similar between patients administered PRP and the controls (standard difference in means = 0.142; 95 % CI: -0.080 to 0.364; p = 0.209). The authors concluded that the results of this meta-analysis did not support the use of PRP/PRF matrix in patients with rotator cuff injuries.

Platelet-Rich Plasma Injection for the Treatment of Temporomandibular Joint Osteoarthritis

In a RCT, Comert et al (2015) compared the long-term clinical and radiologic outcomes of temporo-mandibular joint OA (TMJ-OA) treated with arthrocentesis plus PRP versus arthrocentesis alone. The sample was composed of 30 consecutive patients with TMJ-OA treated randomly with arthrocentesis alone (control group) or initial arthrocentesis plus PRP injection and then 4 consecutive PRP injections (study group). The predictor variable was treatment technique. The outcome variables were VAS evaluations (masticatory efficiency, joint sounds, and pain complaints), maximal inter-incisal opening, and cone-beam computed tomographic (CBCT) findings. Outcome variables were recorded pre-operatively and 12 months post-operatively. Descriptive and bivariate statistics were computed, and significance was set at a “p” value less than 0.05. The paired-t and Student-t tests were used for intra-group and inter-group comparisons, respectively. The sample was composed of 47 joints of 30 patients with OA (control group: 15 joints of 12 patients; mean age of 35.08 ± 14.84 years; study group: 32 joints of 18 patients; mean age of 32.22 ± 14.32 years). Joint sounds and general pain complaints decreased statistically in the 2 groups, whereas masticatory efficiency, painless inter-incisal opening, and lateral motion increased statistically only in the study group. However, only masticatory efficiency showed statistically greater improvement in the study group compared with the control group. Cone-beam CT evaluations showed that reparative re-modeling of the osseous abnormalities occurred at rates of 87.5 and 46.6 % in the study and control groups, respectively. The authors concluded that these findings suggested that arthrocentesis and PRP injections provided a safe and promising method for the treatment of TMJ-OA that is superior to arthrocentesis alone. These preliminary findings need to be validated by well-designed studies.

Platelet-Rich Plasma Injection for the Treatment of Lumbar Facet Joint Syndrome

Wu and colleagues (2016) stated that lumbar facet joint syndrome is currently suggested to be a main source of axial LBP, and a large portion of axial LBP is caused by disorders in lumbar facet joints. Intra-articular injection is one of the most common treatment methods in the early clinical application. These researchers attempted to seek a new injectable material, autologous PRP, to treat lumbar facet syndrome, as well as to assess its safety and effectiveness. A total 19 patients with lumbar facet joint syndrome (8 men, 11 women; mean age of 52.53 ± 6.79 years, range of 38 to 62 years) were enrolled to receive lumbar facet joint injection with autologous PRP under x-ray fluoroscopic control. Patients were followed-up immediately, at 1 week, 1 month, 2 months, and 3 months following treatment, and the elements of this analysis included LBP VAS at rest and during flexion, RDQ, ODI, and modified MacNab criteria for the pain relief. All the 19 patients completed the intra-articular injections with autologous PRP successfully. At 1 week after treatment, LBP reduced significantly compared with prior to treatment both at rest and during flexion. The outcomes were assessed as "good" or "excellent" for 9 patients (47.37 %) immediately after treatment, 14 patients (73.68 %) at 1 week, 15 patients (78.95 %) at 1 month, 15 patients (78.95 %) at 2 months, and 15 patients (78.95 %) at 3 months. Statistically significant differences were observed based on RDQ and a more than 10 % improvement in lumbar functional capacity was observed based on ODI between pre-treatment and post-treatment. In addition, there were no severe relevant complications during the whole process of injection and follow-up period. The authors concluded that in the short-term period of 3 months, the new technique of lumbar facet joint injection with autologous PRP was safe and effective for patients with lumbar facet joint syndrome. The main drawbacks of this study were:

lack of a control group,
small sample size (n = 19), and
short-term follow-up (3 months).

Platelet-Rich Plasma Injection for the Treatment of Urethral Stricture

Gul (2016) noted that urethral stricture is one of the most bothersome urologic disease among urologists and has a substantial impact on quality of life (QOL) and healthcare costs. Although it can be cured with internal urethrotomy easily, post-surgery stricture recurrence is challenging. Several adjuvant therapies have been used in conjunction with internal urethrotomy, but none of them is used routinely since the pathophysiology of the disease is still obscure. Fibrosis is the most accused hypothesis for the action. Platelet-rich plasma is an autologous blood product containing a high concentration of platelets that is being used for a very wide range of clinical healing applications. It comprises a concentration of fundamental protein growth factors shown to be actively excreted by platelets to initiate accurate wound healing. Although PRP can play a critical role in wound healing and has been used in fibrotic diseases successfully, it has some deleterious cytokines such as transforming growth factor β1 (TGF β1) that can also cause fibrosis. The authors concluded that the new hypothesis is that the subcutaneous injection of neutralized PRP with TGFβ1 antibody at the planned urethrotomy site may prevent recurrence and provide superior healing and long-term results.

Platelet-Rich Plasma Combined with Stem Cells

Stem cells are unspecialized cells that when injected into a specific area of the body, may take on the characteristics of surrounding cells. Cell-based substitutes include, but may not be limited to, stem cells that have been combined with PRP (eg, Regenexx). The injection of stem cells or cell-based substitutes is suggested to promote the healing of wounds and injuries.

Bone Marrow Plasma Injection / Bone Marrow Derived Mesenchymal Stromal Cells Administration

Moon and colleagues (2008) hypothesized that iliac bone marrow plasma injection after arthroscopic debridement of degenerative tissue will bring along biological cure. Thus, it will not only reduce pain but also improve function in patients with resistant elbow tendonitis. A total of 24 patients (26 elbows) with significant persistent pain for a mean of 15 months, despite of standard rehabilitation protocol and a variety of other non-surgical modalities were treated arthroscopically. These researchers examined the effects of autologous iliac bone marrow plasma injection following arthroscopic debridement. Bone marrow plasma is produced by centrifugation of iliac bone marrow blood at 1,800 rpm for 20 to 30 minutes. Patients were allowed full range of motion exercise after 2 to 3 days. Cytokine analyses for this injective material were done. Outcome was rated by post-operative sonography, VAS and Mayo elbow performance scores (MEPS) at 8 weeks and 6 months follow-up. All patients in this study reported improvement both in their VAS and MEPS; no complication was observed. Evidence of tendon healing was observed in post-operative sonographic examination. Predominant cytokines of this study were interleukin-12, interferon-gamma-inducible protein-10 and RANTES (regulated upon activation, normal T-cell expressed and secreted). The authors concluded the injection of iliac bone marrow plasma after arthroscopic debridement in severe elbow tendinosis demonstrated early recovery of daily activities and clear improvement.

In a phase I clinical trial, Duijvestein et al (2010) examined the safety and feasibility of autologous bone marrow derived mesenchymal stromal cells (MSCs) therapy in patients with refractory Crohn's disease. A total of 10 adult patients with refractory Crohn's disease (2 males and 8 females) underwent bone marrow aspiration under local anesthesia. Bone marrow MSCs were isolated and expanded ex vivo. Mesenchymal stromal cells were tested for phenotype and functionality in vitro. Overall, 9 patients received 2 doses of 1-2×10(6) cells/kg body weight, intravenously, 7 days apart. During follow-up, possible side effects and changes in patients' Crohn's disease activity index (CDAI) scores were monitored. Colonoscopies were performed at weeks 0 and 6, and mucosal inflammation was assessed by using the Crohn's disease endoscopic index of severity. Mesenchymal stromal cells isolated from patients with Crohn's disease showed similar morphology, phenotype and growth potential compared to MSCs from healthy donors. Importantly, immunomodulatory capacity was intact, as Crohn's disease MSCs significantly reduced peripheral blood mononuclear cell proliferation in vitro. Infusion of MSCs was without side effects, besides a mild allergic reaction probably due to the cryopreservant DMSO in 1 patient. Baseline median CDAI was 326 (224 to 378); 3 patients showed clinical response (CDAI decrease greater than or equal to 70 from baseline) 6 weeks post-treatment; conversely 3 patients required surgery due to disease worsening. The authors concluded that administration of autologous bone marrow derived MSCs appears safe and feasible in the treatment of refractory Crohn's disease. No serious adverse events were detected during bone marrow harvesting and administration. These preliminary findings of a phase I study need to be validated by well-designed studies.

Gupta and colleagues (2012) noted that OA is a degenerative disease of the connective tissue and progresses with age in the older population or develops in young athletes following sports-related injury. The articular cartilage is especially vulnerable to damage and has poor potential for regeneration because of the absence of vasculature within the tissue. Normal load-bearing capacity and biomechanical properties of thinning cartilage are severely compromised during the course of disease progression. Although surgical and pharmaceutical interventions are currently available for treating OA, restoration of normal cartilage function has been difficult to achieve. Since the tissue is composed primarily of chondrocytes distributed in a specialized extra-cellular matrix bed, bone marrow stromal cells (BMSCs), also known as bone marrow-derived "mesenchymal stem cells"or "mesenchymal stromal cells", with inherent chondrogenic differentiation potential appear to be ideally suited for therapeutic use in cartilage regeneration. Bone marrow stromal cells can be easily isolated and massively expanded in culture in an undifferentiated state for therapeutic use. Owing to their potential to modulate local micro-environment via anti-inflammatory and immunosuppressive functions, BMSCs have an additional advantage for allogeneic application. Moreover, by secreting various bioactive soluble factors, BMSCs can protect the cartilage from further tissue destruction and facilitate regeneration of the remaining progenitor cells in situ. The authors described the advances made during the last several years in BMSCs and their therapeutic potential for repairing cartilage damage in OA.

Makihara et al (2017) reported the findings of 5 shoulders in 4 patients who were affected by advanced osteonecrosis of the humeral head were treated with autologous concentrated bone marrow grafting. Bone marrow sample was aspirated from the iliac crests, concentrated by a centrifugation technique, and injected into the necrotic site. The shoulders were evaluated radiologically with X-ray scoring and clinically with measurement of range of motion (ROM) and pain score (visual analog scale, VAS). The mean follow-up period was 49.4 (range of 24 to 73) months. The concentration ratio of nucleated cells was calculated and the number of transplanted mesenchymal stem cells (MSC) was estimated by a colony-forming assay. All 4 shoulders with stage 3 disease achieved joint-sparing. One shoulder with stage 4 disease required replacement surgery. Clinical evaluation of the spared joints showed improvement in ROM in 2 cases and deterioration in 2 cases. VAS scores were 0 after surgery in 3 cases. The mean concentration ratio was 2.73, and the mean number of transplanted MSC was 1125. The authors concluded that the outcomes of autologous concentrated bone marrow grafting for advanced osteonecrosis of the humeral head were varied; further research is needed to determine the effectiveness and the indications of the present surgery.

Sanapati et al (2018) noted that several cell-based therapies have been proposed in recent years the management of LBP, including the injection of medicinal signaling cells or MSCs and PRP; however, there is only emerging clinical evidence to support their use at this time. In a systematic review and meta-analysis, these researchers examined the effectiveness of MSCs or PRP injections in the treatment of LBP and lower extremity pain. Data sources included PubMed, Cochrane Library, US National Guideline Clearinghouse, prior systematic reviews, and reference lists. The literature search was carried out from 1966 through June 2018. Randomized trials, observational studies, and case reports of injections of biologics into the disc, epidural space, facet joints, or sacroiliac joints were selected for analysis. Data extraction and methodological quality assessment were performed utilizing Cochrane review methodologic quality assessment and Interventional Pain Management Techniques - Quality Appraisal of Reliability and Risk of Bias Assessment (IPM-QRB) and Interventional Pain Management Techniques - Quality Appraisal of Reliability and Risk of Bias Assessment for Nonrandomized Studies (IPM-QRBNR). The evidence was summarized utilizing principles of best evidence synthesis on a scale of 1 to 5. A total of 21 injection studies met inclusion criteria. There were 12 lumbar disc injections, 5 epidural, 3 lumbar facet joint, and 3 sacroiliac joint studies. Evidence synthesis based on a single-arm meta-analysis, RCTs, and observational studies, disc injections of PRP and MSCs showed Level 3 evidence (on a scale of Level I through V). Evidence for epidural injections based on single-arm meta-analysis, a single RCT and other available studies demonstrated Level 4 (on a scale of Level I through V) evidence. Similarly, evidence for lumbar facet joint injections and sacroiliac joint injections without meta-analysis demonstrated Level 4 evidence (on a scale of Level I through V). The authors concluded that the findings of this systematic review and single-arm meta-analysis showed that MSCs and PRP may be effective in managing discogenic LBP, radicular pain, facet joint pain, and sacroiliac joint pain, with variable levels of evidence in favor of these techniques. The authors stated that the principal imitation pf this trial was the lack of high quality RCTs.

Navani et al (2019) stated that regenerative medicine is a medical subspecialty that seeks to recruit and enhance the body's own inherent healing armamentarium in the treatment of patient pathology. This therapy's intention is to assist in the repair, and to potentially replace or restore damaged tissue via the use of autologous or allogenic biologics. This field is rising like a Phoenix from the ashes of under-performing conventional therapy midst the hopes and high expectations of patients and medical personnel alike. However, because this is a relatively new area of medicine that has yet to substantiate its outcomes, care must be taken in its public presentation and promises as well as in its use. These investigators provided guidance for the responsible, safe, and effective use of biologic therapy in the lumbar spine. To present a template on which to build standardized therapies using biologics. To ground potential administrators of biologics in the knowledge of the current outcome statistics and to stimulate those interested in providing biologic therapy to participate in high quality research that will ultimately promote and further advance this area of medicine. The methodology used has included the development of objectives and key questions. A panel of experts from various medical specialties and subspecialties as well as differing regions collaborated in the formation of these guidelines and submitted (if any) their appropriate disclosures of conflicts of interest. Trustworthy standards were employed in the creation of these guidelines. The literature pertaining to regenerative medicine, its effectiveness, and adverse consequences was thoroughly reviewed using a best evidence synthesis of the available literature. The grading for recommendation was provided as described by the Agency for Healthcare Research and Quality (AHRQ). Lumbar Disc Injections: Based on the available evidence regarding the use of PRP, including 1 high-quality RCT, multiple moderate-quality observational studies, a single-arm meta-analysis and evidence from a systematic review, the qualitative evidence has been assessed as Level III (on a scale of Level I through V) using a qualitative modified approach to the grading of evidence based on best-evidence synthesis. Based on the available evidence regarding the use of medicinal signaling/ MSCs with a high-quality RCT, multiple moderate-quality observational studies, a single-arm meta-analysis, and 2 systematic reviews, the qualitative evidence has been assessed as Level III (on a scale of Level I through V) using a qualitative modified approach to the grading of evidence based on best evidence synthesis. Lumbar Epidural Injections: Based on 1 high-quality RCT, multiple relevant moderate-quality observational studies and a single-arm meta-analysis, the qualitative evidence has been assessed as Level IV (on a scale of Level I through V) using a qualitative modified approach to the grading of evidence based on best evidence synthesis. Lumbar Facet Joint Injections: Based on 1 high-quality RCT and 2 moderate-quality observational studies, the qualitative evidence for facet joint injections with PRP has been assessed as Level IV (on a scale of Level I through V) using a qualitative modified approach to the grading of evidence based on best evidence synthesis. Sacroiliac Joint Injections: Based on 1 high-quality RCT, 1 moderate-quality observational study, and 1 low-quality case report, the qualitative evidence has been assessed as Level IV (on a scale of Level I through V) using a qualitative modified approach to the grading of evidence based on best evidence synthesis. The authors concluded that based on the evidence synthesis summarized above, there is Level III evidence for intra-discal injections of PRP and MSCs, whereas the evidence was considered Level IV for lumbar facet joint, lumbar epidural, and sacroiliac joint injections of PRP, (on a scale of Level I through V) using a qualitative modified approach to the grading of evidence based on best evidence synthesis. Regenerative therapy should be provided to patients following diagnostic evidence of a need for biologic therapy, following a thorough discussion of the patient's needs and expectations, after properly educating the patient on the use and administration of biologics and in full light of the patient's medical history. Regenerative therapy may be provided independently or in conjunction with other modalities of treatment including a structured exercise program, physical therapy, behavioral therapy, and along with the appropriate conventional medical therapy as necessary. Appropriate precautions should be taken into consideration and followed prior to performing biologic therapy. Multiple guidelines from the Food and Drug Administration (FDA), potential limitations in the use of biologic therapy and the appropriate requirements for compliance with the FDA have been detailed in these guidelines.

Furthermore, UpToDate reviews on “Subacute and chronic low back pain: Nonsurgical interventional treatment” (Chou, 2021), and “Treatment and prognosis of cervical radiculopathy” (Robinson and Kothari, 2021) do not mention mesenchymal stem cell facet joint injection as a management / therapeutic option.

Adipose-Derived Stem Cell (Habeo Cell) Therapy for the Treatment of Scleroderma (Systemic Sclerosis)

Systemic sclerosis (SSc) is a connective tissue disorder with heterogeneous clinical manifestations and often a progressive course. The diffuse cutaneous form of SSc (dcSSc) is characterized by thickening of the skin (scleroderma) and distinctive involvement of multiple internal organs. Patients with limited cutaneous SSc (lcSSc) generally have long-standing Raynaud's phenomenon before other manifestations of SSc appear. In the past 10 years, interests in cultured adipose derived stromal cells (ASCs) therapy have increased; ASCs have an extraordinary developmental plasticity, including the ability to undergo multi-lineage differentiation and self-renewal. Moreover, ASCs can be easily harvested from small volumes of lipo-suction aspirate, showing great in-vitro viability and proliferation rate. Compared to bone marrow-derived mesenchymal stem cells (MSCs), ASCs are considered to be ideal for application in regenerative medicine.

Scuderi and colleagues (2013) evaluated the clinical outcome of ASCs therapy for the treatment of cutaneous manifestations in patients affected by SSc. These researchers developed an effective method for ASCs transplantation into sclerodermic patients by means of a hyaluronic acid (HA) solution, which allowed them to achieve precise structural modifications. In this study, ASCs were isolated from subcutaneous adipose tissue of 6 sclerodermic patients and cultured in a chemical-defined medium before autologous transplantation to restore skin sequelae. They found that transplantation of a combination of ASCs in HA solution resulted in significant improvement in tightening of the skin without complications (e.g., anechoic areas, fat necrosis, or infections); suggesting that ASCs are a potentially source of cells for skin therapy in rare diseases such as SSc and generally in skin disorders.

In an open-label, single-arm, single-center study with 6-month follow-up, Granel and associates (2015) examined the safety, tolerability and potential efficacy of adipose-derived stromal vascular fraction (ADSVF) cells local injections in patients with SSc patients with hand disability. A total of 12 female patients with Cochin Hand Function Scale score greater than 20/90 were included in this analysis. Autologous SVF was obtained from lipo-aspirates, using an automated processing system, and subsequently injected into the subcutaneous tissue of each finger in contact with neurovascular pedicles. Primary end-point was the number and the severity of AEs related to SVF-based therapy. Secondary end-points were changes in hand disability and fibrosis, vascular manifestations, pain and QOL from baseline to 2 and 6 months after cell therapy. All enrolled patients had surgery, and there were no drop-outs or patients lost to follow-up. No severe AEs occurred during the procedure and follow-up; 4 minor AEs were reported and resolved spontaneously. A significant improvement in hand disability and pain, Raynaud's phenomenon, finger edema and QOL was observed. The authors concluded that this study outlined the safety of the autologous SVF cells injection in the hands of patients with SSc; preliminary assessments at 6 months suggested potential efficacy needing confirmation in a randomized placebo-controlled trial in a larger population.

Del Papa and co-workers (2015) stated that digital ulcers (DUs) are a frequent complication in SSc, often showing a very slow or null tendency to heal, in spite of the commonly used systemic and local therapeutic procedures. Recently, stem cell therapy has emerged as a new approach to accelerate wound healing. These researchers treated long-lasting and poorly responsive to traditional therapy SSc-related DUs by implantation of autologous adipose tissue-derived cell (ATDC) fractions. A total of 15 patients with SSc having a long-lasting DU in only 1 fingertip who were unresponsive to intensive systemic and local treatment were enrolled in the study. The grafting procedure consisted of the injection of 0.5 to 1 ml of autologous ATDC fractions, separated by centrifugation of adipose tissue collected through liposuction from subcutaneous abdominal fat. Time to heal after the procedure was the primary end-point of the study, while reduction of pain intensity and of analgesic consumption represented a secondary end-point. Furthermore, the post-therapy variation of the number of capillaries, observed in the nail-fold video capillaroscopy (NVC) examination and of the resistivity in the digit arteries, measured by high-resolution echocolor-Doppler, were also taken into account. A fast healing of the DUs was reached in all of the enrolled patients (mean time to healing 4.23 weeks; range of 2 to 7 weeks). A significant reduction of pain intensity was observed after a few weeks (p < 0.001), while the number of capillaries was significantly increased at 3- and 6-month NVC assessment (p < 0.0001 in both cases). Finally, a significant after-treatment reduction of digit artery resistivity was also recorded (p < 0.0001). The authors concluded that even with the limitations related to the small number of patients (n = 15) included and to the open-label design of the study, these observations suggested that local grafting with ATDCs could represent a promising therapeutic option for SSc-related DUs unresponsive to conventional therapies.

In an open-label, Guillaume-Jugnot et al (2016) reported the safety and efficacy of subcutaneous (s.c.) injection of autologous ADSVF into the fingers in SSc patients. A total of 12 women (mean age of 54.5 years; SD 10.3) were evaluated 1 year after ADSVF injection. Patients were eligible if they had a Cochin Hand Function Scale score of greater than 20/90. ADSVF was obtained from lipo-aspirate using an automated processing system and subsequently injected into the s.c. tissue of each finger in contact with neurovascular pedicles in a 1-time procedure. Study end-points were changes in hand disability and skin fibrosis, vascular manifestations, pain and QOL at the 12 month follow-up. During the visit, patients estimated the benefit of the procedure with a specific self-completed questionnaire. A significant decrease from baseline of 51.3 % (p < 0.001) for Cochin Hand Function Scale score, 63.2 % (p < 0.001) for Raynaud’s phenomenon severity, and 46.8 % (p = 0.001) for QOL (Scleroderma Health Assessment Questionnaire) was observed. A significant improvement of finger edema, skin sclerosis, motion and strength of the hands and of the vascular suppression score was also noted. The reduction in hand pain approached statistical significance (p = 0.052). The questionnaire revealed a benefit in daily activities, housework and social activities. The authors concluded that ADSVF injection is a promising therapy and appeared to have benefits that extend for at least 1 year.

In a phase-I, open-label clinical trial, Daumas and associates (2017) evaluated the safety of s.c. injection of ADSVF; and 6- and 12-month data have been reported. As patients were followed in the authors’ medical center, these investigators reported their longer-term outcome beyond the end of the trial. A total of 12 women (mean age of 54.5 ± 10.3 years) initially enrolled in the clinical trial were assessed during a scheduled medical care, which took place between 22 and 30 months after treatment. Multiple patient-reported outcomes showed sustained improvement, in comparison with the assessment performed just before surgery: 62.5 % in the Cochin Hand Function Scale, 51.1 % in the Scleroderma Health Assessment Questionnaire, 33.1 % in hand pain, and 88.3 % in the Raynaud Condition Score. A decrease in the number of DUs was noted. Mobility, strength and fibrosis of the hand also showed improvement. None of the 8 patients who had previously received iloprost infusion required new infusion. The authors concluded that despite the limitations of an open-label study, the data were in favor of the long-term safety of the ADSVF injection. Moreover, they stated that 2 randomized, double blind, placebo-controlled trials of this therapeutic agent are ongoing in the United States and in France and will help determine the place of this innovative therapy for SSc patients.

Song et al (2017) reported the case of a 62-years old woman with scleroderma who presented with progressive digital necrosis, ulceration, gangrene and impaired wound healing, despite of conventional therapy with vasodilating drugs. Water-jet-assisted liposuction of s.c. abdominal fat was carried out under general anesthesia by an experienced surgeon; ADSVF was harvested by in a single-use Q-graft collector. Cells were centrifuged and cell pellets were aspirated in a 20-ml syringe filled with 0.9 % saline. A total of approximately 2.72 million cells were isolated. Meanwhile middle phalangeal amputation of digit 2, 3 and 4 of the left hand were performed, without closing the skin of the amputation stumps. The SVF cell suspension was injected subcutaneous into the area of metacarpophalangeal joints in both hands, as well as into the amputation stump of the left middle finger, and under a skin necrosis in the right hand. The therapy was well-tolerated by the patient with no adverse reactions. No infection was observed despite open amputation; 3 weeks after the stem cell therapy, further amputation was not needed. The patient was still under regular clinical observation to determine the long-term effects of the therapy. The authors concluded that application of isolated ASCs appeared to be a promising procedure in the treatment of SSc; however, more clinical and experimental studies are needed to better understand the exact mechanisms of action and standardize the therapy.

Adipose Stem Cells Injection for the Treatment of Knee Osteoarthritis

Biazzo and colleagues (2020) examined the safety and effectiveness of ADSCs or SVF injections for the treatment of OA of the knee by analyzing all RCTs dealing with this topic. The following search terms were used in PubMed, Embase, Scopus, and the Cochrane Library Database on November 14, 2019: “adipose derived stem cell” OR “stromal vascular fraction'” OR “SVF” OR “multipotent mesenchymal stromal cells” OR “stem cell” OR “derived stem cell” OR “autologous” AND “knee” OR “osteoarthritis” OR “chondral defect” OR “randomized” OR “controlled trial”. No time limit was given to publication date. These researchers included RCTs based on the following criteria: English studies; patient population diagnosed with knee OA and treated with ADSCs or SVF injections; comparison group treated with placebo, surgery, or adjuvant injections, such as PRP or HA. Intra-articular injections of adipose stem cell therapy in the form of ADSC or SVF was a safe procedure for the treatment of knee OA, with good clinical and radiological outcomes in the early follow-up period (12 to 24 months). Furthermore, treatment with fat-derived cells showed a very low complication rate (16.15 %) of which all were considered to be minor. The authors concluded that ADSCs and SVF appeared to produce promising good-to-excellent results for the treatment of knee OA; however, the length and modalities of follow-up in the different conditions were extremely variable. Nevertheless, it appeared that the use of ADSCs was associated with clinical and radiological improvements and minimal complication rates. Moreover, these researchers stated that to avoid bias deriving from the use of biological adjuvants or surgical procedures, RCTs comparing ADSCs or SVF and other treatments (e.g.,, PRP or HA injections) should be carried out.

Autologous Cell-Based Therapy for Critical Lower Limb Ischemia

Abdul Wahid and colleagues (2018) noted that re-vascularization is the gold standard therapy for patients with critical limb ischemia (CLI). In over 30 % of patients who are not suitable for or have failed previous re-vascularization therapy (the “no-option” CLI patients), limb amputation is eventually unavoidable. Preliminary studies have reported encouraging outcomes with autologous cell-based therapy for the treatment of CLI in these “no-option” patients. However, studies comparing the angiogenic potency and clinical effects of autologous cells derived from different sources have yielded limited data. Data regarding cell doses and routes of administration were also limited. In a Cochrane review, these researchers compared the safety and efficacy of autologous cells derived from different sources, prepared using different protocols, administered at different doses, and delivered via different routes for the treatment of “no-option” CLI patients. The Cochrane Vascular Information Specialist (CIS) searched the Cochrane Vascular Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Medline Ovid, Embase Ovid, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), the Allied and Complementary Medicine Database (AMED), and trials registries (May 16, 2018). Review authors searched PubMed until February 2017. They included RCTs involving “no-option” CLI patients comparing a particular source or regimen of autologous cell-based therapy against another source or regimen of autologous cell-based therapy; 3 review authors independently assessed the eligibility and methodological quality of the trials. They extracted outcome data from each trial and pooled them for meta-analysis. They calculated effect estimates using a RR with 95 % CI, or a MD with 95 % CI. These researchers included 7 RCTs with a total of 359 participants. These studies compared bone marrow-mononuclear cells (BM-MNCs) versus mobilized peripheral blood stem cells (mPBSCs), BM-MNCs versus bone marrow-mesenchymal stem cells (BM-MSCs), high cell dose versus low cell dose, and intra-muscular (IM) versus intra-arterial (IA) routes of cell implantation. They identified no other comparisons in these studies; and considered most studies to be at low risk of bias in random sequence generation, incomplete outcome data, and selective outcome reporting; at high risk of bias in blinding of patients and personnel; and at unclear risk of bias in allocation concealment and blinding of outcome assessors. The quality of evidence was most often low-to-very low, with risk of bias, imprecision, and indirectness of outcomes the major down-grading factors; 3 RCTs (100 participants) reported a total of 9 deaths during the study follow-up period. These studies did not report deaths according to treatment group. Results showed no clear difference in amputation rates between IM and IA routes (RR 0.80, 95 % CI: 0.54 to 1.18; 3 RCTs, 95 participants; low-quality evidence). Single-study data showed no clear difference in amputation rates between BM-MNC- and mPBSC-treated groups (RR 1.54, 95 % CI: 0.45 to 5.24; 150 participants; low-quality evidence) and between high and low cell dose (RR 3.21, 95 % CI: 0.87 to 11.90; 16 participants; very low-quality evidence). The study comparing BM-MNCs versus BM-MSCs reported no amputations. Single-study data with low-quality evidence showed similar numbers of participants with healing ulcers between BM-MNCs and mPBSCs (RR 0.89, 95% CI 0.44 to 1.83; 49 participants) and between IM and IA routes (RR 1.13, 95% CI 0.73 to 1.76; 41 participants). In contrast, more participants appeared to have healing ulcers in the BM-MSC group than in the BM-MNC group (RR 2.00, 95 % CI: 1.02 to 3.92; 1 RCT, 22 participants; moderate-quality evidence). Researchers comparing high versus low cell doses did not report ulcer healing. Single-study data showed similar numbers of participants with reduction in rest pain between BM-MNCs and mPBSCs (RR 0.99, 95 % CI: 0.93 to 1.06; 104 participants; moderate-quality evidence) and between IM and IA routes (RR 1.22, 95 % CI: 0.91 to 1.64; 32 participants; low-quality evidence). One study reported no clear difference in rest pain scores between BM-MNC and BM-MSC (MD 0.00, 95 % CI: -0.61 to 0.61; 37 participants; moderate-quality evidence). Trials comparing high versus low cell doses did not report rest pain. Single-study data showed no clear difference in the number of participants with increased ankle-brachial index (ABI; increase of greater than 0.1 from pre-treatment), between BM-MNCs and mPBSCs (RR 1.00, 95 % CI: 0.71 to 1.40; 104 participants; moderate-quality evidence), and between IM and IA routes (RR 0.93, 95 % CI: 0.43 to 2.00; 35 participants; very low-quality evidence). In contrast, ABI scores appeared higher in BM-MSC versus BM-MNC groups (MD 0.05, 95 % CI: 0.01 to 0.09; 1 RCT, 37 participants; low-quality evidence). ABI was not reported in the high versus low cell dose comparison. Similar numbers of participants had improved transcutaneous oxygen tension (TcO₂) with IM versus IA routes (RR 1.22, 95 % CI: 0.86 to 1.72; 2 RCTs, 62 participants; very low-quality evidence). Single-study data with low-quality evidence showed a higher TcO₂ reading in BM-MSC versus BM-MNC groups (MD 8.00, 95 % CI: 3.46 to 12.54; 37 participants) and in mPBSC- versus BM-MNC-treated groups (MD 1.70, 95 % CI: 0.41 to 2.99; 150 participants). TcO₂ was not reported in the high versus low cell dose comparison. Study authors reported no significant short-term adverse effects attributed to autologous cell implantation. The authors concluded that mostly low- and very low-quality evidence suggested no clear differences between different stem cell sources and different treatment regimens of autologous cell implantation for outcomes such as all-cause mortality, amputation rate, ulcer healing, and rest pain for “no-option” CLI patients. Pooled analyses did not show a clear difference in clinical outcomes whether cells were administered via IM or IA routes. High-quality evidence was lacking; thus, the efficacy and long-term safety of autologous cells derived from different sources, prepared using different protocols, administered at different doses, and delivered via different routes for the treatment of “no-option” CLI patients, remain to be confirmed. These researchers stated that future RCTs with larger numbers of subjects are needed to determine the efficacy of cell-based therapy for CLI patients, along with the optimal cell source, phenotype, dose, and route of implantation. Moreover, they stated that longer follow-up is needed to confirm the durability of angiogenic potential and the long-term safety of cell-based therapy.

Autologous Interleukin 1 Receptor Antagonist Blood-Derived Products for Knee Osteoarthritis

In a systematic review, Ajrawat and colleagues (2019) examined the available clinical data regarding the use of autologous interleukin (IL)-1 receptor antagonist blood products (AILBPs) and their validity as an alternative IA therapy for symptomatic knee OA. PubMed, Medline, Embase, and Cochrane Library databases were searched from inception to June 2018. All RCTs and non-comparative studies that evaluated the efficacy of AILBPs (i.e., autologous protein solution and autologous conditioned serum) for knee OA were included. The primary outcome measure was the Western Ontario and McMaster Universities Osteoarthritis Index; the secondary outcomes measured were the Knee Injury and Osteoarthritis Outcome Score, VAS score, Short Form 36 (SF-36) score, radiographic scores, and AEs, which were qualitatively analyzed. These researchers included 8 studies, comprising 3 RCTs (Level II) and 5 non-comparative studies (Level IV), with a total of 592 patients (mean age of 56.4 years; 49.7 % men). The RCTs represented high methodologic quality, whereas the non-comparative studies represented moderate-to-good quality. With AILBPs, 2 of 4 studies (50 %) showed improvements in the Knee Injury and Osteoarthritis Outcome Score symptom and sport subscales, 5 of 7 studies (71 %) achieved improvements in the Western Ontario and McMaster Universities Osteoarthritis Index score, and 4 of 5 studies (80 %) attained improvements in the VAS pain score from baseline to final follow-up. Most AEs associated with AILBPs were mild-to-moderate in severity and were primarily localized to the injection site. The authors concluded that limited evidence substantiated that AILBPs are a safe and tolerable IA injection therapy that may improve pain parameters and functionality for mild-to-moderate knee OA patients and may be an effective adjunct for those unresponsive to traditional IA therapies. Level of Evidence = IV.

The authors stated that this study had several limitations. First, this review included studies using AILBPs with different compositions, as discussed earlier, which may have affected patient-reported outcome measures (PROMs). Second, 2 studies permitted the use of analgesics and NSAIDs for pain-related symptoms, which may have slightly contributed to the improvement in PROMs. Third, 1 study included patients who underwent previous arthroscopic interventions, which could not be controlled for. Fourth, because only 50 % of the studies reported positive outcomes, there was a possibility of publication bias. Fifth, the widespread variation in the Kellgren-Lawrence grading scale may have affected PROMs and radiographic outcomes. Finally, the inclusion of varying levels of clinical studies potentially introduced confounding and selection bias.

Autologous Whole-Blood or Autologous Serum Acupoint Injection Therapy for Chronic Urticaria

Chang and associates (2019) noted that chronic spontaneous urticaria (CSU) is chronic wheals without identifiable exogenous stimuli. Autologous whole blood (AWB) injection and autologous serum therapy (AST) are alternative therapies for CSU that induce tolerance to circulating histamine-releasing factors. In a systematic review and meta-analysis, these investigators examined available evidence for the safety and efficacy of AWB therapy and AST for CSU. They searched 4 databases for eligible studies to perform meta-analysis. The primary outcome was the efficacy of AST or AWB therapy, and the secondary outcome was improvement after intervention based on the autologous serum skin test (ASST) status of patients. A total of 8 clinical trials, including 4 RCTs and 529 CSU patients, were identified. AST was not more effective than the placebo treatment in alleviating CSU symptoms at the end of treatment (p = 0.161), and AWB injection was also not more effective in response rates than the placebo at the end of follow-up (p = 0.099). Furthermore, the efficacy of AST or AWB injection for CSU and the ASST status were not significantly related. No remarkable AEs were recorded during therapy. The authors concluded that the findings of this meta-analysis suggested that AWB therapy and AST were not significantly more effective in alleviating CSU symptoms than the placebo treatment.

Zhang and colleagues (2019) stated that chronic urticaria (CU) is a common and easily recurring skin disease in the world. Many trials have shown that AWB or AST acupoint injection therapy is effective in treating CU. There is currently no systematic review of this therapy. These investigators examined the safety and effectiveness of this therapy in patients with CU. Literature search will be conducted at Medline, PubMed, Excerpt Medica Database, Springer, Web of Science, Cochrane Library, China National Knowledge Infrastructure, Chinese Scientific Journal Database, and other databases. The search date are until May 2019. They will search for popular terms including CU and this therapy. They will import the literature electronically; duplicate documents will be deleted. The primary outcome is the urticaria activity score or other validated scales. Secondary outcomes included response rate, QOL scale, recurrence rate, and AEs. These researchers will carry out a systematic review and search for a RCT of this therapy for CU; and implement the Cochrane RevMan V5.3 bias assessment tool to assess bias assessment risk, data integration risk, meta-analysis risk, and subgroup analysis risk (if conditions are met). The mean difference, standard MD, and binary data will be used to represent continuous results. This study will provide a comprehensive review of the available evidence for the treatment of CU with this therapy. The authors concluded that this study will provide new evidence for evaluating the effectiveness and side effects of this therapy for CU.

Platelet-Rich Fibrin Injection for Intra-Bony Defects in Chronic Periodontitis

In a meta-analysis, Li and colleagues (2019) determined the additive effectiveness of autologous PRF in the treatment of intra-bony defects in chronic periodontitis patients. Pertinent studies were identified by a search in Medline, Embase, the Web of Science, and the Cochrane Library. The trials searched were evaluated for eligibility. Cochrane Collaboration's Review Manager software was used to perform the meta-analyses. A total of 12 eligible clinical trials were included. Pooled data found that adjunctive PRF exactly yielded a significantly superior probing depth reduction compared with open flap debridement alone (WMD, 1.01; 95 % CI: 0.95 to 1.08; p < 0.00001). The clinical attachment level (CAL) gain after treatment for 9 months was higher in patients treated with PRF plus open flap debridement group than in open flap debridement-treated patients (WMD, 1.29; 95 % CI: 0.96 to 1.61; p < 0.00001). Similarly, the meta-analysis demonstrated that PRF was superior to single open flap debridement with respect to gingival marginal level change (WMD, 0.45; 95 % CI: 0.31 to 0.58; p < 0.00001). Regarding the hard tissue radiographic parameters, including defect depth reduction and percentage of fill defects in bone, adjunctive PRF yielded significantly superior results compared with open flap debridement alone. The authors concluded that adjunctive use of PRF with open flap debridement significantly improved fill defects when compared to open flap debridement alone. However, these researchers stated that additional powered studies with much larger sample sizes are needed to obtain a more concrete conclusion.

Platelet-Rich Fibrin Injection for Rotator Cuff Tears

In a meta-analysis, Mao and Zhan (2018) examined the safety and efficacy of PRF in improving clinical outcomes in rotator cuff tears. These investigators searched the following databases: PubMed, Embase, and Cochrane library databases from inception to April 2018. Studies that compared PRF versus placebo for rotator cuff tears were included in this meta-analysis; RR with 95 % CI was pooled for discontinuous outcome, and WMD with 95 % CI was pooled for continuous outcome; Stata 12.0 was used for meta-analysis. A total of 8 studies with 219 patients were finally included in this meta-analysis. Compared with the control group, PRF has a negative role in reducing the re-tear rate (RR = 1.30, 95 % CI: 0.97 to 1.75; p = 0.082). Subgroup analysis of re-tear rate was consistent in all subgroup analyses (single row or double row, volume, and risk of bias). There was no significant difference between the American Shoulder and Elbow Surgeons scale, University of California at Los Angeles scale, Constant score, and side effect (p > 0.05). The authors concluded that the findings of this meta-analysis suggested that the PRF did not have better effect on improving the overall clinical outcomes and re-tear rate in the arthroscopic repair of rotator cuff tears.

Platelet-Rich Plasma Injection for Achilles Tendonitis / Tendinopathy

In a meta-analysis, Liu and colleagues (2019) examined the evidence on the efficacy of PRP as a treatment for chronic Achilles tendinopathy (AT). The PubMed, Embase, Web of Science, and the Cochrane Library databases were searched for articles on RCTs that compared the efficacy of PRP with that of with placebo injections plus eccentric training as treatment for AT. The articles were up-loaded over the establishment of the databases to May 1, 2018. The Cochrane risk of bias (ROB) tool was used to assess methodological quality. Outcome measurements included the Victorian Institute of Sports Assessment-Achilles (VISA-A), VAS and Achilles tendon thickness. Statistical analysis was performed with RevMan 5.3.5 software. A total of 5 RCTs (n = 189) were included in this meta-analysis. Significant differences in the VISA-A were not observed between the PRP and placebo groups after 12 weeks (SMD)= 0.2, 95 % CI: 0.36 to 0.76, I = 71 %), 24 weeks (SMD = 0.77, 95 % CI: -0.10 to 1.65, I = 85 %) and 1 year (SMD = 0.83, 95 % CI: -0.76 to 2.42, I = 72 %) of treatment. However, PRP exhibited better efficacy than the placebo treatment after 6 weeks (SMD = 0.46, 95 % CI: 0.15 to 0.77, I = 34 %); 2 studies included VAS scores and tendon thickness. VAS scores after 6 weeks (SMD = 1.35, 95 % CI: -0.1.04 to 3.74, I = 93 %) and 24 weeks (SMD = 1.48, 95 % CI: -0.1.59 to 4.55, I = 95 %) were not significantly different. However, VAS scores at the 12th week (SMD = 1.10, 95 % CI: 0.53 to 1.68, I = 83 %) and tendon thickness (SMD = 1.51, 95 % CI: 0.39 to 2.63, I = 53 %) were significantly different. The authors concluded that PRP injection around the Achilles tendon is an option for the treatment of chronic AT; limited evidence supported the conclusion that PRP is not superior to placebo treatment. These researchers stated that these findings need verification by a large number of well designed, heterogeneous RCT studies.

In a systematic review, Wang and associates (2019) examined the efficacy of PRP injections in the treatment of Achilles tendonitis. These researchers performed a literature search in the Cochrane Library Central Register of Controlled Trials (2017), PubMed (January 1976 to March 2017) and Embase (January 1976 to March 2017) databases to retrieve the available clinical evidence for PRP in the treatment of Achilles tendon lesions. The inclusion criteria were conservative PRP treatment of Achilles tendon inflammation in a RCT, level I clinical research evidence, and published in English. The exclusion criteria were unclear experimental methods and data, and PRP treatment of other diseases. A total of 4 articles involving 152 cases were included in the analysis. The mean age of subjects was 49 years. Data on the VISA-A score, color Doppler US index and recovery time to normal exercise were extracted. There were no significant differences between the treatment groups and control groups following the PRP injections. The authors concluded that the lack of differences between data from the control group and the patient groups included in the studies may be related to the difficulty of performing a RCT; a strong basis for using PRP to treat Achilles tendonitis was not found.

Platelet-Rich Plasma Injection for Greater Trochanteric Pain Syndrome

In a systematic review, Ali and colleagues (2019) examined if PRP has any role in improving clinical outcomes in patients with symptomatic greater trochanteric pain syndrome (GTPS). These investigators carried out a search of NICE healthcare database advanced search (HDAS) via Athens (PubMed, Medline, CINAHL, Embase and AMED databases) from their year of inception to April 2018 with the keywords: “greater trochanteric pain syndrome” or “GTPS” or “gluteus medius” or “trochanteric bursitis” and “platelet rich plasma” (PRP). A quality assessment was performed using the JADAD score for RCTs and MINORS for non-RCT studies. A total of 5 full-text articles were included for analysis consisting of 3 RCTs and 2 case series. These researchers also identified 4 additional studies from published conference abstracts (1 RCT and 3 case series). The mean age in 209 patients was 58.4 years (range of 48 to 76.2 years). The majority of patients were women and the minimum duration of symptoms was 3 months. Diagnosis was made using US or MRI. Included studies used a variety of outcome measures. Improvement was observed during the first 3 months after injection. Significant improvement was also noted when patients were followed-up till 12 months post-treatment; PRP appeared to be a viable alternative injectable option for GTPS refractory to conservative measures. The authors concluded that the current literature has revealed that PRP is relatively safe and can be effective. Moreover, these researchers stated that considering the limitations in these studies, more large-sample and high-quality randomized clinical trials are needed to provide further evidence of the efficacy for PRP as a treatment in GTPS.

Platelet-Rich Plasma Injection for Vitiligo

Hesseler and Shyam (2019) stated that the field of dermatology has seen numerous therapeutic innovations in the past 10 years with PRP, recently garnering significant interest in alopecia, acne scarring, and skin rejuvenation. In other conditions of dermatology, such as chronic wounds and vitiligo, PRP has been examined but has received less attention. In a systematic review, these researchers focused on conditions of medical dermatology and consolidated the available evidence on PRP for the practicing dermatologist. They evaluated the literature up to October 31, 2018, and a search was conducted in the PubMed database for "platelet-rich plasma", "platelet releasate", "platelet gel", "platelet-rich fibrin" or "PRP" and "dermatology", "skin", "cutaneous", "wound" or "ulcer". A total of 14 articles met the inclusion criteria for this review. In studies representing Levels of Evidence Ib to IV according to the Centre for Evidence-Based Medicine, Oxford, PRP significantly improved wound healing in chronic diabetic ulcers, venous ulcers, pressure ulcers, leprosy ulcers, acute traumatic wounds, and ulcers of multi-factorial etiologies; 2 studies also documented benefits of adjunctive PRP in stable vitiligo. The authors concluded that in vitiligo as well as chronic wounds of multiple etiologies, PRP warrants further investigation because it represents a potential therapeutic adjunct or alternative with a favorable side effect profile.

Autologous Adipose-Derived Regenerative Cell (ADRC) Therapy for the Treatment of Partial Thickness Rotator Cuff Tear

In a prospective, randomized, controlled first-in-human, open-label, pilot study, Hurd et al (2020) tested the hypothesis that treatment of symptomatic, partial-thickness rotator cuff tears (sPTRCT) with fresh, uncultured, unmodified, autologous adipose-derived regenerative cells (UA-ADRCs) isolated from lipo-aspirate at the point of care is safe and more effective than corticosteroid injection. Subjects aged between 30 and 75 years with sPTRCT who did not respond to physical therapy (PT) treatments for at least 6 weeks were randomly assigned to receive a single injection of an average 11.4 × 10(6) UA-ADRCs (in 5 ml liquid; mean cell viability: 88 %) (n = 11; modified intention-to-treat (mITT) population) or a single injection of 80 mg of methylprednisolone (40 mg/ml; 2 ml) plus 3 ml of 0.25 % bupivacaine (n = 5; mITT population), respectively. Safety and effectiveness were examined using the American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES), RAND Short Form-36 Health Survey, and pain VAS at baseline (BL) as well as 3 weeks (W3), W6, W9, W12, W24, W32, W40, and W52 post-treatment. Fat-saturated T2-weighted MRI of the shoulder was carried out at BL as well as at W24 and W52 post-treatment. No severe AEs related to the injection of UA-ADRCs were observed in the 12 months post-treatment. The risks connected with treatment of sPTRCT with UA-ADRCs were not greater than those connected with treatment of sPTRCT with corticosteroid injection. However, 1 subject in the corticosteroid group developed a full rotator cuff tear during the course of this pilot study. Despite the small number of subjects in this pilot study, those in the UA-ADRCs group showed statistically significantly higher mean ASES total scores at W24 and W52 post-treatment than those in the corticosteroid group (p < 0.05). The authors concluded that the findings of this pilot study suggested that the use of UA-ADRCs in subjects with sPTRCT was safe and resulted in improved shoulder function without adverse effects. Moreover, these researchers stated that to verify the findings of this initial safety and feasibility pilot study, a RCT with 246 patients suffering from sPTRCT is currently ongoing.

The authors stated that because this prospective, randomized, controlled pilot study on UA-ADRCs versus corticosteroid for treating sPTRCT was a first-in-human pilot study with safety as primary clinical outcome, it was designed as open-label study: therefore, it had 2 main drawbacks. First, only a small sample of subjects suffering from sPTRCT was investigated, only a limited number of clinical examination methods was applied, no power analysis was performed, and neither the subjects nor the physicians who performed treatment and the assessors who performed baseline and follow-up examinations were blinded (only the physicians who analyzed the MRI scans were blinded). Second, only 1 control treatment was evaluated. Alternatives could have been placebo injection or supra-scapular nerve block. The latter was recently shown to result in better clinical outcome than subacromial injection of the same amount of 9-ml of 1 % ropivacaine and 1-ml of betamethasone at W6 and W12 post-treatment (follow-up beyond W12 was not reported). However, it was not the ultimate objective of this pilot study to conclusively establish UA-ADRCs as treatment of sPTRCT. Rather, the objective of this study was to collect safety data that are sufficient to develop an appropriate pivotal study that finally will include 246 subjects with sPTRCT. This pivotal study, which is not affected by the limitations outlined above, is now recruiting.

Alt et al (2021) noted that current therapeutic options for sPTRCT offer only limited potential for true tissue healing and improvement of clinical results. In animal models, injections of adult stem cells isolated from adipose tissue into tendon injuries showed histological regeneration of tendon tissue. However, it is unclear if such beneficial effects could also be observed in a human tendon treated with UA-ADRCs. A specific challenge in this regard is that UA-ADRCs cannot be labeled; thus, it is not unequivocally identified in the host tissue. Therefore, histological regeneration of injured human tendons after injection of UA-ADRCs must be assessed using comprehensive, immunohistochemical and microscopic analysis of biopsies taken from the treated tendon a few weeks after injection of UA-ADRCs. These investigators reported the findings of a 66-year-old patient who suffered from sPTRCT affecting the right supraspinatus and infraspinatus tendon, caused by a bicycle accident. On day-18 post-injury [day 16 post MRI examination] approximately 100 g of abdominal adipose tissue was harvested by lipo-suction, from which approximately 75 × 10(6) UA-ADRCs were isolated within 2 hours. Then, UA-ADRCs were injected (controlled by biplanar X-ray imaging) adjacent to the injured supraspinatus tendon immediately after isolation. Despite fast clinical recovery, a follow-up MRI examination 2.5 months post-treatment indicated the need for open revision of the injured infraspinatus tendon, which had not been treated with UA-ADRCs. During this operation, a biopsy was taken from the supraspinatus tendon at the position of the injury. A comprehensive, immunohistochemical and microscopic analysis of the biopsy (comprising 13 antibodies) was indicative of newly formed tendon tissue. The authors concluded that injection of UA-ADRCs could result in regeneration of injured human tendons by formation of new tendon tissue.

The authors stated that conclusions of this study were presented on the basis of a single time-point analysis of molecular and cellular events. As such, limitations consisted in the fact that only a single patient was examined; no control biopsy was analyzed, and the scientists who analyzed the biopsy were not blinded. Furthermore, it was not the objective of this trial to establish a clinical treatment. To more conclusively evaluate clinical results with UA-ADRCs for incomplete tendon tears, a prospective, pivotal RCT is now recruiting, which is based on the encouraging clinical results of the pilot study by Hurd et al (2020).

General Reviews

Rompe and colleagues (2008) stated that the management of Achilles tendinopathy is primarily conservative. Although many non-operative options are available, few have been tested under controlled conditions. Surgical intervention can be successful in refractory cases. However, surgery does not usually completely eliminate symptoms and complications are not rare. The authors stated that further studies are needed to discern the optimal non-operative and surgical management of mid-portion Achilles tendinopathy.

In a systematic review, Rabago et al (2009) appraised existing evidence for prolotherapy, polidocanol, autologous whole blood, and PRP injection therapies for lateral epicondylosis (LE). Results of 5 prospective case series and 4 controlled trials (3 prolotherapy, 2 polidocanol, 3 autologous whole blood and 1 PRP) suggested each of the 4 therapies is effective for LE. In follow-up periods ranging from 9 to 108 weeks, studies reported sustained, statistically significant (p < 0.05) improvement on VAS and disease specific questionnaires; relative effect sizes ranged from 51 % to 94 %; Cohen's d ranged from 0.68 to 6.68. Secondary outcomes also improved, including biomechanical elbow function assessment (polidocanol and prolotherapy), presence of abnormalities and increased vascularity on ultrasound (autologous whole blood and polidocanol). Subjects reported satisfaction with therapies on single-item assessments. All studies were limited by small sample size. The authors concluded that there is strong pilot-level evidence supporting the use of prolotherapy, polidocanol, autologous whole blood, and PRP injections in the treatment of LE. However, rigorous studies of sufficient sample size, assessing these injection therapies using validated clinical, radiological and biomechanical measures, and tissue injury/healing-responsive biomarkers, are needed to determine long-term safety and effectiveness, and whether these techniques can play a definitive role in the management of LE and other tendinopathies.

van Ark et al (2011) reviewed the different injection treatments, their rationales and the effectiveness of treating patellar tendinopathy. A computerized search of the Medline, Embase, CINAHL and Web of Knowledge databases was conducted on May 1, 2010 to identify studies on injection treatments for patellar tendinopathy. A total of 11 articles on 7 different injection treatments (dry needling, autologous blood, high-volume, PRP, sclerosis, steroids and aprotinin injections) were found: 4 RCTs, 1 non-RCT, 4 prospective cohort studies and 2 retrospective cohort studies. All studies reported positive results. The Delphi scores of the 4 RCTs ranged from 5 to 8 out of 9. Different and sometimes contradictory rationales were used for the injection treatments. The authors concluded that all 7 different injection treatments seem promising for treating patellar tendinopathy. Unlike the other injection treatments, steroid treatment often shows a relapse of symptoms in the long-term. They stated that results should be interpreted with caution as the number of studies is low, few high-quality studies have been conducted and the studies are hard to compare due to different methodology. They stated that more high-quality studies using the same cross-cultural reliable and valid outcome measure are needed, as well as further research into the pathophysiology.

Pak et al (2013) stated that mesenchymal stem cells from several sources (bone marrow, synovial tissue, cord blood, and adipose tissue) can differentiate into variable parts (bones, cartilage, muscle, and adipose tissue), representing a promising new therapy in regenerative medicine. In animal models, mesenchymal stem cells have been used successfully to regenerate cartilage and bones. However, there have been no follow-up studies on humans treated with adipose-tissue-derived stem cells (ADSCs) for the chondromalacia patellae. To obtain ADSCs, lipo-aspirates were obtained from lower abdominal subcutaneous adipose tissue. The stromal vascular fraction was separated from the lipo-aspirates by centrifugation after treatment with collagenase. The stem-cell-containing stromal vascular fraction was mixed with calcium chloride-activated PRP and hyaluronic acid, and this ADSCs mixture was then injected under ultrasonic guidance into the retro-patellar joints of all 3 patients. Patients were subjected to pre- and post-treatment MRI scans. Pre- and post-treatment subjective pain scores and physical therapy assessments measured clinical changes. One month after the injection of autologous ADSCs, each patient's pain improved 50 to 70 %. Three months after the treatment, the patients' pain improved 80 to 90 %. The pain improvement persisted over 1 year, confirmed by telephone follow-ups. Also, all 3 patients did not report any serious side effects. The repeated MRI scans at 3 months showed improvement of the damaged tissues (softened cartilages) on the patellae-femoral joints. The authors concluded that in patients with chondromalacia patellae who have continuous anterior knee pain, percutaneous injection of autologous ADSCs may play an important role in the restoration of the damaged tissues (softened cartilages). They stated that ADSCs treatment presents a glimpse of a new promising, effective, safe, and non-surgical method of treatment for chondromalacia patellae. These preliminary findings need to be validated by well-designed studies.

In summary, there is currently insufficient evidence to support the use of various blood product injection therapies (e.g., autologous blood, PRP, bone marrow plasma) for the treatment of tendinopathies.

Leucopatch (3C Patch) for the Treatment of Diabetic Foot Ulcers

In a prospective, uncontrolled, pilot study, Jorgensen et al (2011) examined the safety and clinical performance of Leucopatch in the treatment of recalcitrant chronic wounds. A total of 15 patients, with 16 lower extremity (LE) chronic wounds of varying etiologies were treated weekly with Leucopatch, prepared at the point of care (POC) from a donation of the patients' blood, for 6 weeks, or until healing was complete. The wounds had been present for 2 to 108 months (median of 24 months) and ranged in size from 0.4 to 15.7 cm(2) (median of 2.3 cm(2)) and had not responded to previous treatments. Of the 13 wounds (12 patients) included in the per-protocol effectiveness analysis, 4 healed completely (31 %). Mean wound area decreased significantly by 65 % (95 % confidence interval [CI]: 45.6 % to 83.8 %) resulting in a median wound size of 0.9 cm(2) (range of 0 to 9.6cm(2)). There were no serious adverse events (AEs). Two AEs, 1 of non-compliance and 1 infection, were observed; neither was considered to be related to treatment. The authors concluded that these findings indicated that Leucopatch was easy to prepare and apply in the clinic, was safe, and may be a clinically effective treatment of recalcitrant chronic wounds. Moreover, these researchers stated that further investigation from an appropriately powered, longer-term, randomized, controlled trial (RCT) is needed to confirm the potential wound-healing benefits of Leucopatch suggested in this study.

The authors stated that the conclusions from this pilot study were limited by many factors, not least its non-comparative and open nature. The small numbers of wounds (n = 16) studied of mixed etiologies meant that these researchers could not examine if the rates of wound healing observed varied with different wound types. Although all wounds in this trial were considered recalcitrant to conventional treatments, these investigators did not know how many wounds would have improved as a result of the additional care and attention the patients would have received as part of the clinical trial. There were many patient-related factors that could influence healing of ulcers, which were not controlled for in this study. These researchers could not entirely rule out that changing the method of manufacture influenced the results of the study. However, subgroup analysis suggested that that the device-prepared Leucopatch (as intended to be marketed) was unlikely to be less effective than the patches prepared on the laboratory scale.

Londahl et al (2015) stated that Leucopatch is a leukocyte and platelet-rich fibrin patch that provides concentrated blood cells and signal substances to the surface of an ulcer. It is produced by centrifugation of the patient's own venous blood. In a cohort, multi-center, pilot study, these researchers examined the effects of the leucocyte patch in patients with hard-to-heal diabetic foot ulcers (DFUs). Non-ischemic Wagner grade-1 or grade-2 DFUs with a duration of more than 6 weeks and a maximal area of 10cm² were included. Patients with greater than 40 % ulcer area change during a 2-week run-in period were excluded. The treatment was applied once-weekly for up to 19 treatments or until the foot ulcer was completely epithelialized. The primary endpoint was healing within 20 weeks. Of the 60 patients who gave consent, 16 were excluded during run-in period, 44 patients initiated study treatment and 39 were included in the per-protocol analysis. Complete epithelization was achieved in 34 % (per-protocol analysis 36 %) at 12 weeks and 52 % (59 %) at 20 weeks. In patients with ulcer duration of less than 6 months, 73 % of ulcers healed within 20 weeks. Patients with healed ulcers had larger ulcer area reduction during the first 2 treatment weeks compared to non-healers; AEs were mild and rare. The authors concluded that the leucocyte patch was well-tolerated, easy to use and has potential in the armamentarium of the DFU treatment, provided this outcome is confirmed in an appropriately powered, multi-center RCT.

These researchers stated that as this was a non-controlled cohort trial, not a RCT, bias may occur, bias may occur. Interventions such as more frequent visits to diabetic foot clinics and increased attention may affect the outcome; thus, their ulcer healing rates must be interpreted with caution. However, treatment strategies including off-loading, antibiotics, off-loading vascular intervention were the same.

In a small case-series study (n = 22 patients; 26 wounds), Fagher et al (2015) examined the safety and ulcer healing with Leucopatch treatment in at least Wagner grade-3 diabetic foot ulcers (i.e., ulcers with positive probing to bone test. The authors concluded that these results indicated that Leucopatch was safe to apply to bone surface in DFUs and may have beneficial effects on wound healing, although further RCTs are needed to prove its effectiveness before its use in clinical routine can be recommended.

Game et al (2018) stated that the Leucopatch device uses bedside centrifugation without additional reagents to generate a disc comprising autologous leucocytes, platelets, and fibrin, which is applied to the surface of the wound. In an international, observer-masked, multi-center RCT, these researchers examined the effectiveness of Leucopatch on the healing of hard-to-heal foot ulcers in patients with diabetes. This trial enrolled patients with diabetes and a hard-to-heal foot ulcer in 32 specialist diabetic foot clinics in 3countries (Denmark, Sweden, and the United Kingdom). After a 4-week run-in period, those with a reduction in ulcer area of less than 50 % were randomly allocated (1:1) by computer-generated, web-based randomization (block sizes of 2, 4, and 6) to either pre-specified good standard of care (SOC) alone or care plus weekly application of Leucopatch. The primary outcome was the proportion of ulcers that healed within 20 weeks assessed in the intention-to-treat (ITT) population (all subjects with post-randomization data collected), defined as complete epithelialization (confirmed by an observer who was masked to randomization group), and remained healed for 4 weeks. Between August 30, 2013, and May 3, 2017, a total of 269 participants were randomly allocated to receive treatment (137 to receive SOC and 132 to receive Leucopatch). The mean age was 61.9 years (SD 11.6), 217 (82 %) were men, and 222 (83 %) had type 2 diabetes mellitus. In the Leucopatch group, 45 (34 %) of 132 ulcers healed within 20 weeks versus 29 (22 %) of 134 ulcers in the SOC group (odds ratio [OR] of1.58, 96 % CI: 1.04 to 2.40; p = 0.0235) by ITT analysis. Time-to-healing was shorter in the Leucopatch group (p = 0·0246) than in the SOC group. No difference in AEs was observed between the 2 groups. The most common serious AE (SAE) was diabetic foot infection (24 events in the Leucopatch group [24 % of all SAEs] and 20 in the standard care group [27 % of all SAEs]. There were no device-related AEs. The authors concluded that the use of Leucopatch was associated with significant enhancement of healing of hard-to-heal foot ulcers in patients with diabetes.

The authors stated that the main drawback of this study design and conduct was that it was not possible to mask either the subject or the clinical researcher to treatment allocation. The use of sham vene-puncture was rejected as being unethical, but assessment of the primary outcome was undertaken by an independent and masked observer and backed up with digital imaging. The inclusion and exclusion criteria ensured that the recruited population was representative of a hard-to-heal population; this assumption was reflected in the low overall incidence of healing in the non-intervention group. Nevertheless, an element of selection was evident in that the mean age was slightly less than anticipated (62 years as opposed to the expected 67 years), which might reflect the need for participants to attend each week for up to 5 months. These investigators recruited a high proportion of men (82 % instead of the expected 67 %), but this finding is now recognized as a typical feature of large trials in this field. The overall incidence of healing was lower than anticipated, and lower than that observed in the pilot studies, but probably reflected the more rigid selection of a defined hard-to-heal population. It was also possible that the low healing rate reflected poor SOC, which might have been different between the 2 groups. These researchers believed that this hypothesis is unlikely because the low healing rate in those already preselected as having hard-to-heal ulcers after the 4-week run-in period was similar to that reported by Coerper et al (2009). Furthermore the 2 groups were well-matched in terms of their baseline characteristics and off-loading strategies, and similar numbers were re-vascularized during the 26-week follow-up. Thus, it was unlikely that a differential SOC would explain the additional benefit observed on healing in the intervention group.

In a commentary on the study by Game et al (2018), Alvaro-Afonso et al (2018) stated that a cost-effectiveness analysis will be required. The optimal treatment duration also needs to be better ascertained. Of note, healing was faster in the intervention group during the first 12 weeks, but not thereafter, tempting the authors to ponder whether Leucopatch treatment might be terminated before complete wound closure (13). They stated that the results by Game et al (2018) were very promising. Accordingly, experience in other types of DFUs and cost-effectiveness analysis are highly welcome to increase the use of this product for clinical practice.

The International Working Group on the Diabetic Foot (IWGDF)’s guideline on “Interventions to enhance healing of foot ulcers in persons with diabetes” (Rayman et al, 2019) provided the following recommendation:

Consider the use of autologous combined leucocyte, platelet and fibrin as an adjunctive treatment, in addition to best standard of care, in non-infected diabetic foot ulcers that are difficult to heal (Strength of recommendation: Weak; Quality of evidence: Moderate)

The ECRI’s assessment on “Platelet-rich Plasma Therapy for Diabetic Foot Ulcers” (2021) identified 3 guidelines that address DFU treatment: 2 do not recommend PRP therapy, and 1 makes no statement about PRP therapy.

In the Australian guideline on “Wound healing interventions to enhance healing of foot ulcers”, Chen et al (2022) stated that DFU has a substantial burden on both individuals and healthcare systems both globally and in Australia. There is a pressing need for updated guidelines on wound healing interventions to improve outcomes for individuals living with DFU. A national expert panel was convened to develop new Australian evidence-based guidelines on wound healing interventions for individuals with DFU by adapting suitable international guidelines to the Australian context. The panel followed National Health and Medical Research Council (NHMRC) procedures to adapt suitable international guidelines by the IWGDF to the Australian context. The panel systematically screened, evaluated and judged all IWGDF wound healing recommendations using ADAPTE and GRADE frameworks for adapting guidelines to decide which recommendations should be adopted, adapted or excluded in the Australian context. Each recommendation had their wording, quality of evidence, and strength of recommendation re-evaluated, plus rationale, justifications and implementation considerations provided for the Australian context. This guideline underwent public consultation, further revision and approval by 10 national peak bodies. A total of 13 IWGDF wound healing recommendations were evaluated in this process. After screening, 9 recommendations were adopted and 4 were adapted after full assessment; 2 recommendations had their strength of recommendations downgraded, 1 intervention was not currently approved for use in Australia, 1 intervention specified the need to obtain informed consent to be acceptable in Australia, and another was reworded to clarify best SOC. Overall, 5 wound healing interventions have been recommended as having the evidence-based potential to improve wound healing in specific types of DFU when used in conjunction with other best standards of DFU care, including sucrose-octasulfate impregnated dressing, systemic hyperbaric oxygen therapy (HBOT), negative pressure wound therapy (NPWT), placental-derived products, and the autologous combined leucocyte, platelet and fibrin dressing. The 6 new guidelines and the full protocol can be found at: Australian guidelines for diabetes-related foot disease. The authors concluded that the IWGDF guideline for wound healing interventions has been adapted to suit the Australian context, and in particular for geographically remote and Aboriginal and Torres Strait Islander people. This new national wound healing guideline, endorsed by 10 national peak bodies, also highlighted important considerations for implementation, monitoring, and future research priorities in Australia. The Australian guideline adapted the IWGDF guideline on the Leucopatch:

Consider the use of autologous combined leucocyte, platelet and fibrin as an adjunctive treatment, in addition to best standard of care, in non-infected diabetic foot ulcers that are difficult to heal only IF this adjunctive treatment becomes approved for use in Australia (Strength of recommendation: Weak; Quality of evidence: Moderate).

Stem Cell Therapy for the Treatment of Perianal Fistulae

Lightner et al (2018) stated that there has been a surge in studies examining the safety and effectiveness of MSC in the treatment of perianal CD. In a systematic review and meta-analysis, these investigators examined the literature to determine safety and effectiveness of MSC for the treatment of refractory perianal CD. Data sources included PubMed, Cochrane Library Central Register of Controlled Trials, and Embase. Studies that reported safety and/or effectiveness of MSC for the treatment of perianal CD were included; 2 independent reviewers assessed eligible articles. The study intervention was delivery of MSC to treat perianal CD. Safety and effectiveness of MSC used to treat perianal Crohn's disease were measured. A total of 11 studies met the inclusion criteria and were included in the systematic review; 3 trials with a comparison arm were included in the meta-analysis. There were no significant increases in adverse events (OR = 1.07 (95 % CI : 0.61 to 1.89); p = 0.81) or serious AEs (OR = 0.53 (95 % CI, 0.28 to 0.98); p = 0.04) in patients treated with MSC Mesenchymal stem cells were associated with improved healing as compared with control subjects at primary endpoints of 6 to 24 weeks (OR = 3.06 (95 % CI, 1.05 to 8.90); p = 0.04) and 24 to 52 weeks (OR = 2.37 (95 % CI: 0.90 to 6.25); p = 0.08). The authors concluded although MSCs appeared to offer a safe and effective treatment approach for CD perianal fistulas, there remains a lack of robust controlled data, significant heterogeneity in existing studies, and a lack of standard definition for fistula healing. These researchers stated that future study, with consistent use of a standardized definition of fistula healing, will be important for determining optimal MSC origin, culture conditions, dosing, frequency, and mode of delivery to improve treatment outcomes. These investigators stated that study was limited by small number of studies (n = 3’ and with significant disparity in the cohort size among the 3 studies), its multiple centers and heterogeneity in the study inclusion criteria, MSC cell origin, dose and frequency of delivery, use of scaffolding, and definition and time point of fistula healing.

Choi et al (2019) noted that treatment of complex anal fistulas remains difficult; however, stem cell therapy (SCT) has had an encouraging success rate when applied to complex perianal fistulas. In a meta-analysis, these investigators examined the available evidence of SCT for the treatment of complex perianal fistulas (CPFs). They carried out an electronic literature search on PubMed, Embase, and the Cochrane Library and identified studies (published between January 1946 and August 2017) that used stem cells to treat patients with CPF. Each study was examined for treatment success rate, target patients, types of stem cells used, number of cells used, and criteria for complete healing. Potential publication bias was assessed via visual inspection of a funnel plot and Orwin's fail-safe N. Out of 171 papers, 16 were included in the meta-analysis. The overall healing rate of SCT for patients with CPFs was 62.8 % (95 % CI: 53.5 to 71.2, I2 = 54.05 %), whereas those for patients with Crohn's perianal fistulas alone and complex anal fistulas not associated with CD were 64.1 % and 61.5 % (p = 0.840), respectively. Healing rates for autologous and allogenic SCT were 69.4 % and 50.7 % (p = 0.020), respectively. Four comparative studies out of 16 studies were analyzed separately; SCT increased the healing rate compared to the control groups (OR 0.379, 95 % CI: 0.152 to 0.947). The authors concluded that SCT is a good therapeutic option for CPFs that could not be healed by conventional operative procedures. Moreover, these researchers stated that further investigation for additional supportive evidence, such as a large-scale RCT, is needed.

The authors stated that this study had several drawbacks. The main drawback was that the meta-analysis was carried out by considering the complete healing rate of perianal fistula in each study as a simple value. However, each study used different time-points for determining the complete healing rate of perianal fistula. Considering the high recurrence rate of CPFs, complete healing rate may be influenced significantly by the time-point used to determine the complete healing rate. However, the meta-analysis was performed by simply considering the percentage of completely healed patients among all patients as a single value, without statistically supplementing this issue. Because different criteria were used for various key points, issues may be raised on whether it is appropriate to examine the total effect by a meta-analysis. Accordingly, these researchers conducted a subgroup analysis. However, the study methods were so diverse that few studies could be grouped. For example, the overview of individual studies depicted studies based on whether autologous or allogenic stem cells were used. It was difficult to confirm if any bias was introduced in the results from differences between adipose-derived stem cells (ADSCs) and bone marrow-derived stem cells.

Schwandner (2021) stated that despite tremendous progress in medical therapy and optimization of surgical strategies, considerable failure rates following surgery for complex anal fistula in CD have been reported; thus, SCT for the treatment of CPFs can be an innovative option with potential long-term healing. In a retrospective, single-center study, these investigators examined the effects of local administration of allogenic, ADSCs (darvadstrocel) for the treatment of complex anal Crohn's fistula. All patients with complex anal fistulas associated with CD who were amenable for definite fistula closure within a defined observation period were potential candidates for stem cell injection (darvadstrocel) if at least 1 conventional or surgical attempt to close the fistula had failed. Darvadstrocel was only indicated in patients without active CD and without presence of anorectal abscess. Local injection of darvadstrocel was carried out as a standardized procedure under general anesthesia including single-shot antibiotic prophylaxis, removal of seton drainage, fistula curettage, closure of the internal openings and local stem cell injection. Data collection focusing on healing rates, occurrence of abscess and follow-up was carried out on a regular basis of quality control and patient care. Data were retrospectively analyzed. Between July 2018 and January 2021, a total of 12 patients (6 women, 6 men) with a mean age of 42.5 (range of 26 to 61) years underwent SCT. All patients had a minimum of 1 complex fistula, including patients with 2 complex fistulas in 58.3 % (7/12). Two of the 12 patients had horse-shoe fistula and 3 had one complex fistula. According to Parks classification, the majority of fistulas were trans-sphincteric (76 %) or supra-sphincteric (14 %). All patients underwent removal of seton, fistula curettage, trans-anal closure of internal opening by suture (11/12) or mucosal flap (1/12) and stem cell injection. At a mean follow-up of 14.3 (range of 3 to 30) months, a healing rate was documented in 66.7 % (8/12); mean duration to achieve healing was 12 (range of 6 to 30) weeks. Within follow-up, 4 patients required re-operation due to perianal abscess (33.3 %). Focusing on patients with a minimum follow-up of 12 months (6/12) or 24 months (4/12), long-term healing rates were 66.7 % (4/6) and 50.0 % (2/4), respectively. The authors concluded that findings of this single-center experience were promising but limited due to the small number of patients (n = 12) and the retrospective analysis. These researchers stated that further inter-disciplinary efforts including controlled studies are needed to determine the definite role of SCT for the treatment of complex anal fistula in CD.

Colombo et al (2022) noted that 30 % to 70 % of patients with CD may develop perianal fistulas during their lifetime. The medical and surgical management of this complication is challenging, and its treatment still gives unsatisfactory results. However, recent studies on ADSCs have proven their anti-inflammatory and immuno-modulatory potential, representing a new promising approach in the treatment of such stubborn disease. These investigators reported their initial experience with t3 patients who had recurrent perianal CD treated with local infiltration of stem cell darvadstrocel (Alofisel). All subjects had a long history of perianal disease refractory to multiple medical and surgical treatments. The pre-operative work-up included trans-perineal ultrasound (TP-US), pelvic MRI, and colonoscopy that ruled out active proctitis in all the patients. The post-treatment follow-up included clinical assessment at 1, 3, and 6 months with repeated MRI and TP-US at 6 months. At 6 months, 2 patients had a clinical response despite radiological persistence of fistula tracts, while 1 patient presented perianal fistula recurrence complicated by perianal abscess. Th authors concluded that although their experience was limited to 3 patients and a short follow-up, these findings confirmed that darvadstrocel injection was a safe procedure, with a good clinical response in most of the patients, but that it apparently had no effect on the anatomical modification of the fistula tracts. Moreover, these researchers stated that further studies with long-term results and rigorous assessment of anatomical lesions, are still needed to support these promising findings.

Garcia-Olmo et al (2022) noted that darvadstrocel is an expanded allogeneic ADSCs for the treatment of CPFs in patients with CD. Safety and effectiveness outcomes from the clinical trial known as "Adipose derived mesenchymal stem cells for induction of remission in perianal fistulizing Crohn's disease," or ADMIRE-CD (NCT01541579), from up to 52 weeks post-treatment were previously reported. These investigators reported the outcomes from an extended 104-week follow-up. This study extension was carried out in multiple hospitals across 7 European countries and Israel. A total of 40 patients entered the extended follow-up period: 25 patients in the darvadstrocel treatment group and 15 in the control group. Darvadstrocel or saline solution (control group) was administered once, locally, after fistula tract curettage and internal opening closure (with previous seton placement). All patients were permitted to continue ongoing medical treatments for fistulas. Treatment-emergent serious AEs were recorded through week 104. Clinical remission, defined as closure of all treated external openings that were draining at baseline despite gentle finger compression, was assessed at week 104. Of 40 patients, 37 completed the extended follow-up. Through week 104, 7 treatment-emergent serious AEs were reported, of which 4 occurred between weeks 52 and 104. At week 104, clinical remission was reported in 14/25 (56 %) patients in the darvadstrocel group and 6/15 (40 %) patients in the control group. The authors concluded that darvadstrocel was well-tolerated and clinical remission after treatment with darvadstrocel may be sustained for up to 104 weeks in patients with perianal fistulizing CD.

The authors stated that this study had several drawbacks. First, at the time of the ADMIRE-CD protocol amendment, many patients had already completed the 52-week follow-up and had left the study; hence, they could not participate in this extended follow-up period to 104 weeks, and the relatively small sample size (n = 40) was a drawback of this study. Second, there was an imbalance in the number of patients in this extension study who were treated with darvadstrocel versus those in the control group (n = 25 versus n = 15, respectively), which could lead to potential bias in the analyses. Third, the lack of MRI examination at the end of the 104-week follow-up, hence combined remission rates (which included both clinical remission and absence of collections of greater than 2 cm diameter, confirmed by MRI) could not be determined (as previously reported for modified ITT population at weeks 24 and 52). It was anticipated that some of these drawbacks will be addressed by the ongoing INSPIRE global registry, which was set up to capture real-world safety and effectiveness data on a large number of patients with CPFs in CD treated with darvadstrocel and followed-up for over 36 months.

Panes et al (2022) stated that the effectiveness of a single administration of darvadstrocel (expanded allogeneic ADSCs) for treating CPFs in patients with CD was demonstrated in a randomized, double-blind trial (ADMIRE-CD [Adipose Derived Mesenchymal Stem Cells for Induction of Remission in Perianal Fistulizing Crohn\'s Disease] trial). The current chart review study (INSPECT [A retrospective chart review study evaluatINg the longer-term effectiveneSs of darvadstrocel in PatiEnts who CompleTed ADMIRE-CD]) evaluated the longer-term safety and effectiveness of darvadstrocel. Eligible patients had completed at least 52 weeks in the ADMIRE-CD trial. Data on clinical remission and fistula relapse outcomes were collected retrospectively at 104 and 156 weeks after treatment. AEs of special interest (tumorigenicity and ectopic tissue formation) were collected up to 208 weeks after treatment. A total of 89 patients were included (43 darvadstrocel patients, 46 control subjects). At 52-, 104-, and 156-week post-treatment, clinical remission was observed in 29 (67.4 %) of 43, 23 (53.5 %) of 43, and 23 (53.5% ) of 43 darvadstrocel-treated patients, compared with 24 (52.2% ) of 46, 20 (43.5 %) of 46, and 21 (45.7 %) of 46 control subjects, respectively. In patients with clinical remission at week 52, this remission was sustained at 104 and 156 weeks after treatment in 19 (65.5 %) of 29 and 16 (55.2 %) of 29 darvadstrocel-treated patients and in 17 (70.8 %) of 24 and 13 (54.2 %) of 24 control subjects, respectively. Time to fistula relapse and incidence of fistula relapse or new fistula occurrence were not significantly different between groups. Tumorigenicity was reported for 1 (2.2 %) patient in the control group (malignant epidermoid carcinoma). No ectopic tissue formation was reported. The authors concluded that real-world follow-up of patients from the ADMIRE-CD trial indicated that clinical remission of CPFs could be sustained in the long-term irrespective of whether it was achieved via darvadstrocel administration or maintenance treatment regimens and confirmed a favorable long-term safety profile of darvadstrocel. These researchers stated that darvadstrocel may represent an effective minimally invasive option to achieve long-term remission of CPFs in patients with CD.

The authors stated that this study had several drawbacks, including small patient numbers. Potential bias may arise from the fact that the patient population in this chart review included only those who completed at least 52 weeks of follow-up in the ADMIRE-CD trial; however, the demographic profile and clinical characteristics of patients included in the INSPECT chart review were similar to that of the whole ITT population in the ADMIRE-CD trial. Furthermore, because some patients in this study completed only 52 weeks, whereas others completed up to 104 weeks in the ADMIRE-CD trial, the proportion of time spent enrolled in the phase-III ADMIRE-CD Trial versus the time enrolled in the INSPECT chart review varied. Consequently, certain outcomes may have been influenced by time spent in the ADMIRE-CD Trial. This drawback was partly mitigated by the fact that treatment in the ADMIRE-CD Trial was a single administration of darvadstrocel or placebo at the start of the study and that, after treatment, all patients continued with concomitant therapies and management of complex perianal fistulas (real-world management of complex perianal fistulas was maintained throughout the INSPECT study). A comparison of the sustained remission outcomes between groups at 156 weeks could also be biased because fewer patients in the control group achieved clinical remission than in the darvadstrocel group, hence unidentified confounders in these patient groups may influence the long-term remission outcomes. Analyses of subgroups to examine clinical outcomes by baseline patient and disease characteristics or concomitant medication could minimize the risk of bias; however, small sample sizes prohibited such comparisons. Finally, an inherent limitation of chart reviews was that datasets could be incomplete, preventing robust comparisons across all outcomes. In the INSPECT Trial, data were collected at the original ADMIRE-CD Trial sites, but some patients were followed-up at a different site to where they were enrolled, which could have contributed to the missing data.

Autologous Fat for the Treatment of Carpometacarpal Arthritis of the Thumb

Karagergou et al (2022) stated that adipose tissue and its regenerative products which are isolated with enzymatic or mechanical processing of the harvested fat have been studied in a wide range of degenerative diseases, including OA of the knee and hip. Intra-articular injection of these products could provide symptomatic relief of pain and postpone surgery; however, their use in the treatment of thumb carpometacarpal joint (CMCJ) OA is limited and just a few studies have been published on that topic. These investigators carried out a review of the literature via a search of 8 terms using the PubMed database. A total of 7 human studies met the selection criteria, including case-control studies, case-series and 1 case report. In all studies, intra-articular injection of autologous fat in osteoarthritic thumb CMCJ provided reduction in pain and improvement in hand function. Grip and pinch strength showed variable results, from no change to significant improvement. Fat-processing techniques were based on centrifugation and mechanical homogenization; but biological characterization of the injected cells was not conducted in any study. The authors concluded that although the results were encouraging, a uniformly standardized method of fat processing and the conduction of RCTs in the future could better examine the effectiveness of this procedure for thumb CMCJ OA. Moreover, these researchers stated that future studies should focus on identifying the optimal fat processing technique that will improve the biological properties and effectiveness of the injected cells. Furthermore, RCTs are needed to evaluate whether injection of adipose-derived products could play a noticeable role in the symptomatic treatment of thumb CMCJ arthritis and prevent or delay the necessity of a major reconstructive procedure.

Winter et al (2023) noted that for the treatment of carpometacarpal arthritis of the thumb, various therapies are used. Infiltration therapy with autologous substances such as PRP and autologous fat have recently gained increasing attention because of beneficial pain-reducing effects in arthritis and the associated regenerative potential. However, the extent of clinical evidence in this area and how well autologous substances work in terms of pain reduction and improvements in hand function remain unclear. In a systematic review and meta-analysis, these investigators examined the available evidence and provided more insight into pain reduction and improvement in hand function following infiltration of autologous substances. They identified 11 clinical trials, of which 8 were included in the meta-analysis. Autologous substances attained a good and long-lasting pain reduction, which may also be accompanied by corresponding improvement in hand function. Autologous substances appeared to be more effective than corticoid infiltrations. The infiltration of autologous fat appeared to be particularly promising in more advanced stages of carpometacarpal arthritis of the thumb. The meta-analysis showed a mean pain reduction of 2.4 to 3 in VAS score and a reduction of 18 to 19 points in the DASH questionnaire after infiltration with autologous substances. The authors concluded that both PRP and autologous fat infiltration offer an efficient and long-lasting, minimally invasive therapy option in the treatment of carpometacarpal arthritis of the thumb. Moreover, these researchers stated that to gain more insight into this highly relevant research topic, further prospective RCTs are needed, as there remains a lack of these in current available literature.

The authors stated that the study design was the major drawback of the existing studies; thus, the major limitation of the meta-analysis these investigators carried out. It has to be emphasized that there were only 2 studies for the analysis of the pain reduction and the DASH questionnaire score after the infiltration of PRP. This was a clear limitation of the meta-analysis, especially related to PRP, and reflected the current state of the literature. Furthermore, it is unclear if a combination of both substances (fat and PRP), as already reported in other joints, may be more effective. This could be a promising option, as the combination of fat and PRP has been reported to be successful in other applications.

Platelet-Rich Plasma for the Treatment of Androgenetic Alopecia

de Oliveira et al (2023) stated that androgenetic alopecia is the leading cause of hair loss in men and women and often impacts self-esteem and QOL. In a systematic review and meta-analysis, these investigators examined the effectiveness of PRP in female pattern alopecia (FPA). Data sources included Medline/PubMed, Cochrane Library, ClinicalTrials.gov, and EMBASE up to May 2021. These researchers identified all studies examining the effect of PRP in FPA. They carried out a narrative synthesis from data on the effectiveness of PRP treatment and AEs; quantitative results of PRP use compared to control treatment for female androgenetic alopecia (AGA) were synthesized. The outcomes analyzed were terminal density and hair thickness. A total of 7 studies were selected for this review. Meta-analysis showed that PRP-based interventions were able to increase terminal hair density compared to control (MD = 2.98, 95 % CI: 1.10 to 4.85), with no significant increase in hair thickness (SMD = 1.16, 95 % CI: -0.96 to 3.28). During and after treatment, no major side effects were reported by patients or researchers. The authors concluded that the use of autologous PRP injections in female AGA appeared to be promising, with more consistent results on terminal hair density. However, these researchers stated that caution is recommended in the interpretation of these findings until they can be repeated in larger and more representative samples. They stated that further studies are needed to determine optimal PRP preparation, concentration, number of sessions, and interval between sessions. Furthermore, these interventions need to be randomized, double-blind, placebo-controlled, multi-center, clinical trials with minimal sample size calculations and long-term follow-ups to determine the real and sustained effects of PRP treatment.

The authors stated that this systematic review with meta-analysis had several drawbacks. First, 3 of the studies included in this review were pilot studies with small sample sizes. Second, on the issue of sample size, none of the studies provided minimal sample size calculations; thus, it was not possible to detect a clinically relevant treatment effect. Third, each study presented a different treatment protocol, with different PRP preparations, variable number of treatment sessions, follow-up times, etc. Fourth, it appeared that there is no standard or methodological consensus to examine the results of androgenic alopecia treatment, this aspect made it difficult to make direct comparisons between studies.

Platelet-Rich Plasma for the Treatment of Facial Rejuvenation

Gentile and Garcovich (2023) noted that an increasing interest in maintaining a youthful appearance has led to the development of innovative and non-invasive aesthetic procedures for the treatment of facial aging, such as the recent use of autologous PRP. In a systematic review, these investigators examined the available evidence regarding the effectiveness of autologous activated PRP and/or non-activated PRP injection used for facial rejuvenation. They carried out a systematic review regarding the clinical use of autologous activated PRP and autologous non-activated PRP injection in facial rejuvenation against signs of aging using the PubMed, Medline, Embase, PreMEDLINE, Embase, CINAHL, PsycINFO, Clinicaltrials.gov, Scopus, and Cochrane databases. The protocol was developed following the PRISMA guidelines. The included studies had to match pre-determined criteria according to the patients, intervention, comparator, outcomes, and study design approach. A total of 11 of the 12 studies identified, including 3 randomized split-face trials, showed improved results despite differences in study design and outcome measures, many of which were subjective. The authors concluded that further RCTs, related systematic reviews, and evidence-based medicine studies of level I are needed to confirm the effectiveness of PRP injection in facial rejuvenation, to consolidate the promising findings of the studies identified in this systematic review.

Stromal Vascular Fraction with Platelet-Rich Plasma Injection During Surgery for Treatment-Refractory Perianal Fistulizing Crohn's Disease

Arkenbosch et al (2023) stated that an unmet need remains for improved management in perianal fistulizing Crohn's disease (pCD). Recently, local administration of adipose-derived cells has shown promising results. In a pilot study, these researchers examined the safety and feasibility of injection of stromal vascular fraction (SVF) with PRP in patients with pCD. Patients 18 years of age or older with pCD were included and underwent fistula curettage, SVF with PRP injection, and closure of the internal opening. The primary endpoint was safety at 12 months; and the secondary outcomes were complete radiological healing at 3 months (absence of fluid-containing tracts on MRI) and partial and complete clinical response at 3 and 12 months (closure of 1 or more, respectively, all treated external opening(s)). A total of 25 patients were included (age of 35 years [IQR 25 to 40; 14 [56 %] women); median CD duration 4 [IQR 2 to 8] years; 24 (95 %) patients had previously undergone fistula surgery. No AEs were encountered at lipo-harvesting sites; 2 (8 %) patients were re-admitted to hospital and 6 (24 %) underwent unplanned re-interventions. Post-operative MRI (n = 24) showed complete radiological healing in 9 (37.5 %) patients. Partial clinical response was present in 48 % (12/25) at 3 months and in 68 % (17/25) at 12 months, and complete clinical closure in 5 (20 %) patients at 3 months and in 10 (40 %) patients at 12 months. The authors concluded that injection with autologous SVF with PRP was feasible and safe in patients with treatment-refractory pCD. Early complete radiological healing was observed in more than 1/3 of patients, and clinical response in 2/3 of patients at 12 months. The main drawbacks of this pilot study were the small sample size (n = 25) and the lack of a control group. These preliminary findings need to be validated in well-designed randomized trials; and the appropriate ratio between, and optimal amount of, SVF and PRP in correlation with clinical outcome need to be ascertained.

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The above policy is based on the following references:

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Last Review 10/26/2023

Effective: 05/08/2009

Next Review: 08/22/2024
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