Injections of Blood and Fatty Products for Select Indications - Clinical Medical Policy Bulletins (2023)

Number: 0784

Index

Policy
Anwendbare CPT / HCPCS / ICD-10-Codes
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references

Policy

Aetna is considering experimental and experimental autologous blood injection for all indications, including the following (non-exhaustive list), as efficacy has not been demonstrated:

• radiculopatía cervical
• chronic hives
• Epicondylitis laterally
• lumbar radiculopathy
• muscle injury
• plantar fasciopathy
• Dislocation of the temporomandibular joint (TMJ)
• Tendinopathies (eg, elbow, heel, knee, patella, and shoulder).

Injection of platelet-poor plasma or platelet-rich plasma is considered experimental and experimental by Aetna for all indications, including the following (non-exhaustive list):because its effectiveness has not been proven:

• Achilles tendon tears / Achilles tendonitis
• Alopecia areata (androgenetic alopecia)
• ankle sprain
• Anterior Cruciate Ligament Surgery
• As additional material for bone transplantation
• Avascular necrosis of the hip and shoulder.
• Cerebral palsy
• chronic wounds
• Perianal fistula associated with Crohn's disease
• discogenic back pain
• Gastrocnemius (calf) tear
• Greater trochanteric pain syndrome
• tendon injury
• hip fractures
• lumbar facet gel syndrome
• Osteoarthritis (eg, hip, knee, and temporomandibular joint (TMJ))
• osteonecrosis of the jaw
• plantar fasciitis
• Rotator cuff injuries
• Tendinopathies (eg, elbow, heel, knee, and shoulder)
• urethral stricture
• Vitiligo.

Aetna is considering experimental and experimental autologous platelet gel for the following, as efficacy has not been demonstrated:

• Use after total knee arthroplasty
• Diabetic foot ulcer.

Platelet-rich plasma in combination with stem cells (eg, Regenexx) is considered experimental and experimental for all indications by Aetna as its effectiveness has not been proven. To seeCPB 0411 - Substitutes and adjuvants for bone and tendon grafts.

Experimental and experimental bone marrow plasma injections are being considered by Aetna for the treatment of tendinopathies (eg, elbow, heel, knee, and shoulder) and all other indications as their effectiveness has not been proven.

Bone marrow-derived and experimental mesenchymal stromal cells are being considered by Aetna for injections into the facet joints and for the treatment of avascular necrosis of the shoulder, Crohn's disease, and osteoarthritis, as their efficacy has not been demonstrated.

Aetna is considering injecting adipose-derived stem cells (habeo cell therapy) for the treatment of chondromalacia patellar, osteoarthritis of the knee, and scleroderma (systemic sclerosis) and for all other experimental and investigational indications, as they are not efficacy has been demonstrated for these indications.

Aetna considers autologous cell-based therapy for critical lower extremity ischemia experimental and experimental as its efficacy has not been demonstrated.

Autologous interleukin-1 receptor antagonist blood products for osteoarthritis of the knee are considered experimental and investigational by Aetna because their efficacy has not been established.

Aetna considers autologous whole blood or autologous serum injection therapy at acupuncture points for chronic urticaria to be experimental and experimental, as efficacy has not been demonstrated.

Aetna is considering platelet-rich fibrin for intrabony defects in chronic periodontitis and experimental and experimental rotator cuff tears because its efficacy has not been demonstrated.

Aetna considers autologous adipose-derived regenerative cell (ADRC) therapy experimental and experimental for the treatment of partial rotator cuff tears, as efficacy has not been demonstrated.

Related Policies

• CPB 0207 - Prolotherapy and Sclerotherapy
• CPB 0235 - Plantar Fasciitis Treatments
• CPB 0649 - Extracorporeal Shock Wave Therapy for Musculoskeletal Indications and Soft Tissue Injuries
• CPB 0934 – Puffer epidural

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autologous blood injection

Tendinopathy (tendinopathy), also known as tendinitis and tendinosis, refers to painful conditions that occur in and around the tendons in response to overuse. The tendons most commonly affected are those of the elbow (lateral epicondyle), heel (Achilles tendon), knee (patella), and shoulder (rotator cuff). Conservative therapies for patients with tendinopathies include rest, eccentric exercise, physical therapy, analgesic therapy (eg, nonsteroidal anti-inflammatory drugs), use of orthopedic devices, and local steroid injections. Autologous blood injection is used when conservative therapies fail. Blood drawn from the patient through a standard vein is injected into the area around the damaged tendon. This approach is believed to promote healing by activating stem cell recruitment, angiogenesis, and fibroblast stimulation. Local anesthesia is usually used, and ultrasound can provide clues. Dry needling can be performed prior to injection. Following the procedure, patients are advised to avoid strenuous or excessive use of the tendon for several weeks.

Suresh et al. (2006) evaluated whether ultrasound-guided autologous blood injection is an effective treatment for refractory medial epicondylitis. A total of 20 patients (13 men and 7 women) with a duration of symptoms of 12 months were examined ultrasonographically. The tendinosis was confirmed according to 3 ultrasound criteria:

1. echo texture,
2. interstitial tears and
3. Neovascularization.

The tendon was then dried with needles and autologous blood was injected. The patients were reviewed at 4 weeks and 10 months. Visual analogue scores (VAS) and modified Nirschl scores were assessed before and after the procedure. There was a significant reduction in the VAS between the pre-procedure and 10 months after the procedure when the mean interquartile range (IQR) was 1.00 (1 to 1.75), range 0 to 7. The mean IQR-Nirschl score before of the procedure was 6.00 (5 to 7), range from 4 to 7, decreased to 4.00 (2.25 to 5) at 4 weeks, range from 2 to 7, and at 10 months to 1.00 (1 to 1.75), range from 0 to 7, giving a significant decrease (z = 3.763, p < 0.001). Hypoechoic flexor tendon change decreased significantly between the preoperative period, when the mean (SD) was 6.45 (1.47), and at 10 months, when it was 3.85 (2.37) (p<0.001). . Doppler ultrasound showed that neovascularization varied from 4 to 9 between the pre-procedure, when the mean (SD) was 6.10 (1.62), and at 10 months, when it was 3.60 (2.56). with a range from 0 to 9, it decreased (p<0.001). The authors concluded that the combined effect of dry needling and autologous blood injection under ultrasound guidance appears to be an effective treatment for refractory medial epicondylitis, as evidenced by a significant decrease in VAS and a decrease in modified Nirschl scores.

Connell et al. (2006) evaluated the efficacy of autologous blood injection under ultrasound guidance for the treatment of refractory lateral epicondylitis. A total of 35 patients (23 men and 12 women, mean age 40.9 years, mean duration of symptoms 13.8 months) were examined ultrasonographically before dry puncture of the tendon and autologous blood injection. Patients were reviewed and Nirschl and VAS measurements were taken before and after the procedure at 4 weeks and 6 months. Significant reductions in Nirschl scores were reported after autologous blood injections, from a mean IQR score before surgery of 6 (6 to 7) to 4 (2 to 5) at 4 weeks (p<0.001 ) and 0 (0 to 1) at 6 months (p<0.001). Similarly, significant reductions in VAS scores were reported from a median IQR score at baseline of 9 (8 to 10) to 6 (3 to 8) at 4 weeks (p<0.001) and to 0 (0 to 1 ) 6 months (p <0.001). Ultrasonography showed a reduction in the total number of interstitial tear formations and anechoic foci; A significant decrease in tendon thickness was observed from a mean (SD) of 5.15 mm (0.79) at baseline to 4.82 mm (0.62) 6 months after the procedure (p<0.001). Hypoechoic change was significantly reduced from a median IQR of 7 (6 to 7) at baseline to 2 (1 to 3) 6 months after the procedure (p<0.001). Neovascularization also decreased significantly from a median (IQR) of 6 (4 to 7) at baseline to 1 (0 to 3) 6 months after the procedure (p<0.001), although the ultrasonographic abnormality persisted in many asymptomatic patients. The authors concluded that autologous blood injection is a primary technique for treating lateral epicondylitis. Ultrasound can be used to guide injections and monitor changes in the common extensor origin.

In a prospective cohort study, James et al. (2007) The efficacy of ultrasound-guided dry needling and autologous blood injection for the treatment of refractory patellar tendonitis. A total of 47 knees from 44 patients (40 men and 7 women, mean age 34.5 years, range 17 to 54 years) presented with a clinical diagnosis of patellar tendon syndrome (mean duration of symptoms 12.9 months). ) after derivation. Ultrasound-guided dry needling and autologous blood injection at the patellar tendinitis site were performed twice, 4 weeks apart. Pre- and post-procedure assessments from the Victorian Institute of Sport Assessment (VISA) were collected to assess the patient's response to treatment. Follow-up ultrasound was performed in 21 patients (22 knees). Therapeutic intervention resulted in a significant improvement in VISA score: mean pre-procedure score 39.8 (range 8-72) vs. mean post-procedure score 74.3 (range 29-100), p<0.001; mean follow-up of 14.8 months (range 6 to 22 months). The patients were able to return to their sporting interests. Subsequent ultrasound examination showed a reduction in the overall thickness of the tendon and in the size of the tendon area. A reduction in interstitial tears in the tendon tissue was observed. Neovascularization did not significantly decrease or even increase. The authors concluded that dry needling and autologous blood injection under ultrasound guidance hold promise as treatment for patients with patellar tendon syndrome.

In a randomized, single-blind clinical trial, Kazemi et al. (2010) compared local corticosteroids with autologous injections for the short-term treatment of lateral elbow tendinopathy. A total of 60 patients between the ages of 27 and 64 years with a new episode of tennis elbow were recruited: 30 patients were randomly assigned to methylprednisolone and 30 to autologous blood grouping for 1 year. pain intensity in the last 24 hours; member role; pain and power at maximum grip; Deficiencies in the results of the Quick Arm, Shoulder, and Hand (Quick DASH) questionnaire; modified Nirschl scores; and threshold sensitivity were assessed before injection and 4 and 8 weeks after injection. Data were analyzed using the chi and t test. Within-group analyzes showed better results for autologous blood (all p values ​​< 0.001, except grip strength, p = 0.005). In the corticosteroid group, differences in pain intensity (p = 0.008) and grip strength (p = 0.001) were significant. At 4 weeks, between-group analyzes showed superiority of autologous blood in pain intensity (p=0.001), pain on holding (p=0.002), sensitivity threshold (p=0.031), and Quick-Score. DASH (p=0.004). There were no significant differences in modified Nirschl score, grip strength, and limb function. After 8 weeks, autologous blood was more effective across all endpoints (allp values ​​< 0.001). The authors concluded that autologous blood was more effective than short-term corticosteroid injections. The results of this small single-blind study need to be validated by further investigation with larger numbers of subjects and longer follow-up.

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

The American College of Occupational and Environmental Medicine (2007) did not recommend autologous blood injection to treat patients with elbow disease. The NICE guideline on autologous blood injection for tendinopathy (2009) states that the current evidence on the safety and efficacy of autologous blood injection for tendinopathy is both quantitatively and qualitatively insufficient. Furthermore, the NICE committee notes that although some of the published studies involved the use of dry needling prior to injecting autologous blood, it was not possible to distinguish between the effects of these two components of the procedure. The Committee also notes that future research should be placed in the context of randomized controlled trials that define the chronicity of tendinopathy and describe any prior or concomitant therapy (eg, physiotherapy and dry needling) and tendons treated. These studies should address the role of ultrasound guidance and include results on function and quality of life with a minimum follow-up of 1 year. It is also interesting that the Work Loss Data Institute guideline for the management of acute and chronic diseases of the shoulder (2007) does not mention autologous blood injection as a form of therapy.

Autologous blood injection for the treatment of cervical radiculopathy

In a pilot study, Goni et al. (2015) Efficacy of autologous conditioned saline (ACS) perineural epidural injection compared with methylprednisone (MPS) in patients with unilateral cervical radiculopathy. A total of 40 patients were divided equally into the ACS and MPS groups and received image-guided injections of 2.5 to 3 mL of ACS or MPS, respectively, into the perineural area of ​​the affected nerve root. They were followed for 6 months using VAS for pain, Neck Pain Disability Scale in Hindi, Neck Disability Index, and Health Survey Brief Form-12 (SF-12). Patients who received ACS and MPS injections showed improvements in assessment tool scores. Improvement in ACS patients was gradual and sustained throughout the study period, while there was some deterioration over time in the MPS group. No major complications were observed between the two groups; Minor complications were observed in both groups. The authors concluded that SCA can be considered an equally good or better modality of non-surgical treatment in patients with unilateral cervical radiculopathy as MPS. They stated that this approach could be offered to affected patients prior to offering surgery. The results of this pilot study need to be validated by well-designed studies.

Autologous blood injection for the treatment of chronic urticaria

In a parallel group, randomized, double-blind controlled trial (RCT), Debbarman and colleagues (2014) evaluated the efficacy of autologous serum therapy (AST) in chronic urticaria (UC) and also determined its utility in autoreactive urticaria. . (AU). . In both arms, a total of 54 patients received AST and 57 patients received normal saline injections (placebo) along with cetirizine as needed. Autologous serum/placebo therapy was administered weekly for 9 weeks and followed for a total of 24 weeks. Autoreactive urticaria was diagnosed by skin tests with autologous serum. The primary efficacy endpoints used were total urticaria severity score (TSS), urticaria activity score (UAS), and dermatologic life quality index (DLQI). The safety parameters evaluated were spontaneously reported adverse events and laboratory parameters. The overall severity of urticaria showed a significant improvement from baseline at week 7(a) and week 8(a) in the AST and placebo groups, respectively. The group comparison showed a significant improvement after the fourth week. The urticaria activity score showed similar results; DLQI showed a significant improvement in the AST group compared to placebo at the end of the study. Both AU and non-AU patients showed comparable improvement in TSS. The authors concluded that AST holds promise in the treatment of urticaria, regardless of its autoreactive nature. These preliminary results need to be validated by well-designed studies.

Autologous blood injection to treat muscle injuries

Calandruccio and Steiner (2017) found that lateral epicondylitis is a common cause of elbow pain; Most patients (80% to 90%) are successfully managed with standard nonsurgical methods (rest, nonsteroidal anti-inflammatory drugs [NSAIDs], braces, and physical therapy). Autologous blood injections and PRP injections are the 2 most widely used orthobiological techniques in the treatment of lateral epicondylitis. Studies on the effectiveness of autologous blood injections and PRP have reported mixed results, with some citing significant clinical relief and others reporting no beneficial effects. The authors concluded that more research is needed to determine the best way to use orthobiologic techniques in the treatment of lateral epicondylitis.

Autologous blood injection for the treatment of patellar tendon syndrome

In a pilot study, Resteghini et al (2015) evaluated the efficacy of autologous versus saline blood injections in patients with chronic recalcitrant patellar tendinopathy. Using 2 physicians, patients were randomized to receive autologous blood injections or saline injections. All patients completed the short-form McGill Pain Questionnaire (MPQ), VAS, and a Victoria Institute of Sport Patellar Tendinopathy Rating Scale over a 12-month period. A total of 22 patients completed the final 12-month review and enrolled in the study. Subjects ranged from 22 to 61 years of age and were randomized to receive 11 injections each in the autologous blood and saline groups. The autologous blood injection group had a mean duration of symptoms of 16.7 months, while the saline group was 19.2 months. The mean VAS score of the saline group decreased from 7.9 to 4.5 at one month (p=0.003) and 3.3 (p=0.005) at one year. With autologous blood injections, the score dropped from 7.5 to 4.5 (p = 0.005) at month and 3.1 (p = 0.003) at year. Victoria Institute of Sport assessment scores for patellar tendinopathy, MPQ, and VAS improved significantly in both groups. The authors concluded that the results of this study showed that both the autologous blood injection and saline groups experienced a significant improvement in symptoms. However, when comparing the results, there was no statistical difference between the two groups.

Autologous blood injection to treat temporomandibular joint dislocation

Varedi and Bohluli (2015) reviewed the English literature on the safety and efficacy of autologous blood injection in the treatment of patients with chronic recurrent TMJ dislocation. These investigators highlighted the major studies and current guidelines on this modality and discussed the mechanism, advantages, and disadvantages of this approach. A literature search of the PubMed, Medline, and Ovid Medline databases was performed to identify articles reporting autologous blood injection for the treatment of chronic recurrent TMJ dislocations. Other references cited in the reports found and the 'related articles' tool in PubMed Medline were also reviewed to improve the search and included in the study where appropriate. The search was limited to articles in English. A total of 7 studies that met the inclusion criteria were reviewed. The selected articles included 4 prospective clinical studies and 3 case report articles. The authors concluded that there are few articles on the clinical use of autologous blood to treat patients with chronic recurrent TMJ dislocation. Literature review has shown that there are successful results in this modality, but there are still some concerns about the effect of injected blood on articular cartilage and the formation of fibrous or bony ankylosis. Well-designed studies are needed to verify the efficacy of autologous injection in the treatment of temporomandibular dislocation.

Autologous blood products for the treatment of lateral epicondylitis and plantar fasciopathy

In a systematic review and meta-analysis, Tsikopoulos and colleagues (2016) compared the efficacy of autologous whole blood versus corticosteroid injections (ICS) for epicondylopathy and plantar fasciopathy. We searched PubMed, Web of Science, CENTRAL, and Scopus databases up to 6 May 2015. Randomized trials comparing the effects of autologous whole blood and ICS on epicondylopathy or plantar fasciopathy were included. Studies on the efficacy of platelet-rich plasma (PRP) were excluded. The primary outcome was pain relief. Secondary endpoints included assessment of composite endpoints. All results were assessed after 2 to 6 weeks (short term), 8 to 13 (medium term) weeks, and 24 to 26 (medium term) weeks. Quality assessment was performed using the Cochrane risk of bias tool. A total of 9 studies were included. For pain relief, there was a statistically significant difference in favor of short-acting corticosteroids (standardized mean difference (SMD) 0.52, 95% confidence interval (CI) 0.18 to 0.86; I2 = 53%, p<0.01). In the medium-term evaluation of pain relief in epicondylopathy, there was a statistically significant difference in favor of autologous whole blood. The authors concluded that corticosteroids were marginally superior to autologous whole blood in relieving pain in plantar fasciopathy at 2 to 6 weeks. They stated that autologous whole blood provided significant clinical relief of epicondylopathy within 8 to 24 weeks. Furthermore, they stated that the conclusions were limited by risk of bias.

In a meta-analysis, Qian and colleagues (2016) compared the safety and efficacy of autologous blood products (ATP) and ICS in the treatment of lateral epicondylitis. These investigators systematically searched Embase, PubMed, the Cochrane Library, and Web of Science to identify RCTs comparing ABP with ICS for the treatment of lateral epicondylitis without language limitation and published up to April 2015. Two investigators independently included quality and assessed the adequacy of each study according to the method recommended by the Cochrane Collaboration. Available data on key endpoints were extracted from each study and heterogeneity was assessed using the Q statistic and inconsistency index (I2). They also assessed publication bias and performed a subgroup analysis. Review Manager 5.2 software was used for data synthesis and analysis, and standardized mean difference (SMD) or mean difference (MD) was estimated using random-effects models with 95% CI. To assess efficacy at different study durations, follow-up periods were divided into short-term (2-4 weeks), intermediate (6-24 weeks), and long-term (greater than or equal to 24 weeks). A total of 10 RCTs (n = 509) were included in this meta-analysis. Pooled analysis showed that ICS were more effective than PBA for pain relief in the short term (SMD = 0.88, 95% CI 0.31 to 1.46%, P = 0.003). However, in the medium term, PAS showed 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), arm, shoulder and hand abnormalities (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). Long-term ABP CSIs were in 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 a) greater than -0.42%; p=0.001). Furthermore, no significant differences were found between the two therapies for the recovery of grip strength (p > 0.05). The authors concluded that limited evidence supports the conclusion that ICS are superior to PBAs for short-term pain relief; However, this result was reversed in the medium and long term. They indicated that ABPs appear to be more effective in restoring function in the medium term; However, due to the small sample size and the limited number of high-quality RCTs, more high-quality RCTs with larger samples are needed to validate this result.

In a randomized study, Varshney and colleagues (2017) compared autologous PRP versus corticosteroid in the treatment of epicondylitis of the elbow. The study population (n=83) included 2 groups: Group A (n=50) treated with local injection of steroids and Group B (n=33) treated with autologous PRP. Patients were randomized using a computer generated table of random numbers. Baseline assessment was performed using VAS and the Modified Mayo Elbow Performance Index (MAYO). Reassessment was performed after 1, 2, and 6 months of the procedure. Statistical analysis was performed using the independent t-test. Six months after PRP treatment, patients with epicondylitis of the elbow had a significant improvement in their VAS (p<0.05) and MAYO (p<0.05) in contrast to the steroid, while no statistical difference was observed between the two groups. at 1 was and 2 months after the procedure. The authors concluded that treatment of patients with epicondylitis of the elbow with PRP reduced pain and significantly increased function, outweighing the effects of corticosteroid injection.

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

These investigators stated that further studies are needed with larger numbers of patients in each group, with even longer follow-up periods.

In a randomized, controlled, blinded comparative study, Branson et al. (2017) compared 3 different ultrasound-guided (US) injections for chronic tennis elbow. A total of 44 patients with clinically diagnosed tennis elbow confirmed by US Doppler received a single corticosteroid injection (n=14) or 2 injections (4 weeks apart) of autologous blood (n=14) or polidocanol (n=16). under us. orientation). Clinical examination and ultrasonography were performed at baseline, at 4, 12, and 26 weeks. Complete recovery or marked improvement at 4 weeks was greater with corticosteroid injection than with autologous blood and polidocanol (p<0.001, number required for treatment of 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)). Recurrences after corticosteroid injection were significantly higher than after autologous blood or polidocanol (p = 0.007, number needed to injure 2 (1 to 4)). Corticosteroid injection resulted in greater reductions in tendon thickness and vascularity than autologous blood in just 4 weeks. Compared with autologous blood, polidocanol reduced tendon thickness at 4 and 12 weeks and reduced echogenicity and hyperemia at 12 and 26 weeks, respectively. The authors concluded that corticosteroid injections cannot be recommended over polidocanol or autologous blood because, despite the short-term benefit, the long-term effect is inferior. Furthermore, they noted that it is not known whether polidocanol or autologous blood injections are effective, especially since their overall efficacy profiles do not differ from previously reported wait-and-see.

In a meta-analysis, Sirico et al (2017) summarized the evidence on the effectiveness of corticosteroids and autologous blood injections for pain management in lateral epicondylitis. Studies were considered eligible based on the following inclusion criteria: adult human, diagnosis of lateral epicondylitis, RCTs comparing corticosteroids with autologous blood injection, pain assessment. Exclusion criteria were previous surgery for lateral epicondylitis or other elbow disorders, concomitant treatment with medication or physiotherapy, diagnosis of systemic musculoskeletal disorder. A systematic bibliographic search was carried out according to the PRISMA statement. The effect size of each included study was calculated and analyzed in a random effects model. A total of 4 studies with a total of 218 patients (139 women and 79 men) were included in the quantitative analysis. At 2 weeks, there was a trend toward a reduction in VAS score in the corticosteroid group (weighted mean difference [WMD] = 2.12 [95% CI 4.38 to 0.14], p = 0 .07). Intermediate (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: ]) no significant differences were observed. -2.40 to 3.66], p=0.68) follow-up. The authors concluded that few high-quality studies compared the effectiveness of corticosteroids and autologous injections in managing pain associated with lateral epicondylitis. The available data indicate that corticosteroids tend to decrease the VAS score at short-term follow-up, although these data were not statistically significant. No differences were found in the medium and long term. Contrary to popular belief among medical professionals, and despite pathophysiological evidence, currently available data do not support the efficacy of autologous blood injections in medium- and long-term follow-up. These researchers stated that more studies are needed to determine which treatment has the greatest impact on pain in lateral epicondylitis. These data could be used as the basis for practice guidelines and new treatment protocols.

platelet poor plasma injection

Floryan and Berghoff (2004) noted that as the use of autologous PRP and PPP for the intraoperative care of a variety of patients increases, it is important that perioperative nurses recognize their benefits. Autologous PRP can decrease postoperative drainage, reduce the need for narcotics, and facilitate a prompt return to mobility. After the operation, patients should have fewer complications, recover faster, and have a shorter hospital stay. The authors defined autologous PRP and PPP, described the processing and application of PRP and PPP, and reported the clinical results of the use of platelet concentrate for a group of patients undergoing TKA.

Muir and colleagues (2019) stated that PPP is currently a discarded residue of PRP and may contain valuable proteins. In a descriptive laboratory study, these investigators evaluated plasma concentration as a potential adjuvant biotherapy for the treatment of OA. They hypothesized that a new polyacrylamide concentrator would efficiently concentrate IGF-1 from PPP and add it to PRP or autologous protein solution (APS). A study was conducted with human and equine whole blood from healthy volunteers/donors. Fresh blood and plasma samples 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 receptor antagonist. IL-1 as representatives of the anabolic and inflammatory mediators of cartilage. The human and equine PPP polyacrylamide concentrator significantly concentrated a potent anabolic cartilage protein, IGF-1. The polyacrylamide device also significantly increased plasma proteins compared to whole blood, key proteins relevant to OA treatment, including TGF-B (29 times higher than in blood) and IL-1 receptor antagonist. (70 times more than plasma). The authors concluded that concentrated PPP is a unique source of biologically relevant levels of IGF-1; PRP and APS could produce higher levels of other anabolic and anti-inflammatory proteins not found in plasma.

Platelet Rich Plasma and Platelet Gel Injection

In addition to autologous blood injection, other blood product injection therapies used to treat patients with tendinopathy include platelet-rich plasma (PRP) and bone marrow plasma.

Growth factors are groups of proteins that can stimulate cell growth, proliferation, and differentiation. They are found in a variety of tissues and are important in the regulation of a variety of cellular processes. Platelets are small fragments of regularly shaped clear cells that circulate in the blood and play a key role in hemostasis (blood clotting). ; a natural source of growth factors. Platelet-derived growth factor (PDGF) is a protein secreted by platelets that attracts fibroblasts and macrophages and plays a role in the proliferative phase of wound healing by contributing to the repair of connective tissue, glial cells, and smooth muscle. .

Platelet-derived growth factors aid in the formation of blood vessels (angiogenesis) and can be obtained using recombinant DNA technology or by centrifuging your own blood. Autologous growth factors, including autologous platelet-derived growth factors (PDGFs), autologous platelet concentrate (APC), and autologous platelet gel (APG), also known as platelet-rich plasma (PRP) or "layer leukocyte", are obtained from the patient's own blood (autologous). APC and APG are applied topically to wounds or administered systemically to purportedly speed healing and reduce complications of chronic non-healing wounds unresponsive to conventional wound care methods, or used as an adjunct (add-on) of surgery to promote hemostasis, promote and reduce complications. wound.

In a pilot study, Mishra and Pavelko (2006) reported their results on the treatment of chronic elbow tendinosis with PRP. A total of 140 patients were evaluated in this study. Subjects initially received a standardized physiotherapy protocol and various non-surgical treatments. Twenty of these patients had significant persistent pain (mean 82/100; VAS range 60 to 100/100) for a median of 15 months despite these interventions. All patients considered surgery. This patient cohort then received a single percutaneous injection of PRP (n=15) or bupivacaine (n=5). Eight weeks after treatment, PRP-injected patients saw a 60% improvement in their VAS versus a 16% improvement in bupivacaine-treated patients (p=0.001). Treatments after the 8 week period, which precludes further direct analysis. Therefore, only PRP-treated patients were available for further analysis. After 6 months, PRP-treated subjects saw an 81% improvement in their VAS (p=0.0001). At the end of follow-up (mean 25.6 months; range 12 to 38 months), patients treated with PRP reported a 93% reduction in pain compared to before treatment (p<0.0001). The authors concluded that treatment of patients with chronic elbow tendinosis with PRP significantly reduced pain. In addition, they stated that further evaluation of this new treatment is needed.

In an RCT, Peerbooms et al (2010) evaluated the efficacy of PRP versus corticosteroid injections in patients with chronic lateral epicondylitis. A total of 100 patients with chronic lateral epicondylitis were randomized to the PRP group (n = 51) or corticosteroid group (n = 49). A central computer system performed randomization and assignment to the experimental group. Patients were randomized to receive corticosteroid injection or autologous platelet concentrate injection using a pepper technique. The primary analysis included VAS scores and the DASH (Arm, Shoulder, and Hand Impairments) outcome measure. Treatment success was defined as a reduction in VAS or DASH scores of more than 25% without reoperation at 1 year. The results showed that according to the VAS, 24 of 49 patients (49%) in the corticosteroid group and 37 of 51 patients (73%) in the PRP group were successful, which was significantly different (p<0.001). Furthermore, based on DASH scores, 25 of 49 patients (51%) in the corticosteroid group and 37 of 51 patients (73%) in the PRP group were successful, which was also significantly different (p = 0.005). The corticosteroid group did better initially and then tapered off, while the PRP group progressively improved. The authors concluded that treatment of patients with chronic lateral epicondylitis with PRP reduces pain and significantly increases function, outweighing the effects of corticosteroid injection. They stated that future decisions to use PRP in lateral epicondylitis should be confirmed by further follow-up of this study and should consider potential costs and harms, as well as benefits.

In a double-blind, placebo-controlled, randomized block stratified study, de Vos and colleagues (2010) investigated whether PRP injection would improve outcome in chronic tendinopathy of the middle Achilles tendon. 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 exercise (usual care) with PRP injection (PRP group) or saline injection (placebo group); Randomization was stratified by activity level. The Victorian Institute of Sports Assessment-Achilles validated questionnaire (VISA-A), which assessed pain score and activity level, was completed at baseline and at 6, 12, and 24 weeks. VISA A scores ranged from 0 to 100, with higher scores corresponding to less pain and more activity. Treatment group effects were assessed using general linear models based on intention to treat. After randomization to the PRP group (n=27) or placebo group (n=27), all patients were followed up completely. 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 13.0 to 30.5). 95%: 11.6 to 29.4). The increase was not significantly different between the two groups (adjusted difference between groups from baseline to week 24, -0.9, 95% CI -12.4 to 10.6). This CI did not include the predefined relevant difference of 12 points in favor of PRP treatment. The authors concluded that in patients with chronic Achilles tendonitis treated with eccentric exercise, PRP injection did not produce greater improvement in pain and activity compared with saline injection. They do not recommend this treatment for chronic mid-range Achilles tendinopathy.

In a pilot study, Sampson et al. (2010) The clinical effects of intra-articular injections of PRP in a small group of patients with primary and secondary osteoarthritis (OA). A total of 14 patients with primary and secondary OA of the knee who met the study criteria received 3 PRP injections into the affected knee at intervals of approximately 4 weeks. Outcome measures included the Brittberg-Peterson Visual Pain (VAS) score, activities and expectations, and knee injury and osteoarthritis outcome scores at the pre-injection visit at 2, 5, 11, 18, and 52 weeks. of follow up. visits in. Musculoskeletal ultrasound was used to measure cartilage thickness. No adverse event was reported. The study showed significant near-linear improvements in knee injury and osteoarthritis outcomes, including pain and symptom relief. Brittberg-Peterson VAS has shown many improvements, including reduced pain after knee movement and at rest. The evaluation of cartilage was limited due to the small sample size. Most of the patients expressed a favorable result 12 months after treatment. The authors concluded that the demonstrated positive trends and safety profile could potentially be used to stimulate a larger, blinded, randomized clinical trial to determine whether PRP is safe and effective for the treatment of OA of the knee.

Filardo et al. (2011) studied the effects of intra-articular injections of PRP 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 study (24 patients had bilateral lesions, out of a total of 114 treated knees). All patients had a chronic degenerative condition of the knee and were treated with 3 intra-articular injections of PRP. For the clinical evaluation, the results of the International Knee Documentation Committee (IKDC) and the EQ-VAS were used. Complications, side effects, and patient satisfaction were also recorded. All parameters assessed worsened at the 24-month follow-up: these parameters were at significantly lower levels than at the 12-month evaluation (objective IKDC score dropped from 67 to 59% of normal and near-normal knees; subjective IKDC score The score fell from 60 to 51) even though they remained above the baseline. A subsequent analysis showed better results in younger patients (p=0.0001) and lower degrees of cartilage degeneration (p<0.0005). The median duration of clinical improvement was 9 months. The authors concluded that these results suggest that treatment with PRP injections can reduce pain and improve knee function and quality of life effectively in the short term. They state that more studies are needed to confirm these results and understand the mechanism of action, in addition to finding other application modalities with different concentrations of platelets and autologous blood growth factors and injection times that give better and longer lasting results.

Schepull et al. (2011) noted that animal studies showed that local application of PRP stimulates tendon repair. Preliminary results from a retrospective case series showed a more rapid return to exercise. In a randomized controlled trial, these investigators hypothesized that autologous PRP stimulates healing of acute Achilles tendon tears. A total of 30 patients were consecutively recruited. During surgery, tantalum beads were implanted in the Achilles tendon proximal and distal to the rupture. Before suturing the skin, randomization was performed and 16 patients received 10 ml of PRP (platelet concentration ten times that of peripheral blood), while 14 did not. Using three-dimensional radiographs (X-ray stereophotogrammetric analysis; RSA), the distance between the granules was measured at 7, 19, and 52 weeks while the patient endured various moments of dorsiflexion on the ankle, thus estimating tendon stress from loading. . An estimate of the elastic modulus was calculated using the callus dimensions from the computed tomography. At one year, functional outcome was assessed, including heel lift index and total Achilles tendon rupture score. The main effect variables were the modulus of elasticity after 7 weeks and the heel lift index after 1 year. The mechanical variables showed a large variation between patients that cannot be explained by a measurement error. No significant group differences can be shown in the modulus of elasticity. There were no significant differences in heel lift index. The total Achilles tendon rupture score was lower in the PRP group, suggesting an adverse effect. There was a correlation between Young's modulus at 7 and 19 weeks and heel lift index at 52 weeks. The authors concluded that these results suggest that PRP is not useful for the treatment of Achilles tendon tears. Variation in elastic modulus provides biologically relevant information, although it is not clear how early biomechanics relates to later clinical outcomes.

In a prospective, randomized, blinded, observer-controlled pilot study, Horstmann et al. (2011) The effect of autologous platelet gel (APG), prepared from the buffy coat of a unit of autologous blood, after total knee arthroplasty (TEP). Blood loss, wound healing, pain, range of motion, and hospitalization. A total of 40 patients with knee osteoarthritis alone were scheduled for TKA and were randomized into 2 groups. All patients in the treatment group were treated with the use of APG after implantation of the prosthesis. Control group patients were treated with the same protocol but APG was not used. Preoperative and postoperative hemoglobin levels did not show significant differences and allogeneic blood transfusions were not administered in either group. Bruising was significantly greater 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 day 3 (p=0.04). Wound healing disorders were observed in 4 patients in the control group and in no patients in the APG group (n.s.). Knee range of motion was similar postoperatively. Hospital stay was 6.2 days in the APG and 7.5 days in the control group (n.s.). The authors noted that differences were found in favor of the use of APG, but these were subjective assessments with marginal effect or failed to reach statistical significance. The use of drains may have reduced the concentration of platelets released and reduced the effect. However, no statistically significant or clinically significant effect in favor of the use of APG was found in this study. They concluded that further studies with larger numbers of patients and without the use of drains are needed to investigate the potential 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 hip AVN were treated with central decompression performed by drilling under fluoroscopic guidance. Liquid PRP was applied 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 placed by impaction through the decompression pathway of the nucleus. Fibrin membranes were applied to improve healing of the head and neck window and arthroscopic portals. Platelet-rich plasma was infiltrated into the central compartment. This arthroscopic approach aided diagnosis of the labrum and articular cartilage and allowed intraoperative treatment decisions. Visual control allowed precise localization and treatment of the necrotic area, preserving the integrity of the cartilage. The authors concluded that arthroscopic AVN femoral head repair is feasible and has significant advantages. They stated that clinical trials should justify the additional theoretical benefit of this approach. An UpToDate review of “Osteonecrosis (avascular bone necrosis)” (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) PRP injections in patients with hip osteoarthritis. A total of 40 patients with severe monolateral hip osteoarthritis were included in the study. Each joint received 3 AI injections of PRP administered once a week. The primary endpoint was significant pain relief, described as a reduction in pain intensity of at least 30% from baseline, as measured by the WOMAC subscale 6 months after treatment. The VAS subscale and the Harris hip pain scale were used to verify the results. Secondary endpoints included changes in disability score of at least 30% and the percentage of positive responders, specifically the number of patients achieving 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 in pain (45%, range 30-71%) as measured by the WOMAC subscale. Sixteen (40%) of these patients were classified as excellent responders, showing an early reduction in pain at 6 or 7 weeks that persisted at 6 months and a parallel reduction in disability. Side effects were negligible and limited to a feeling of heaviness at the injection site. with OA of the hip. These results need to be validated by prospective RCTs.

Bocanegra-Perez et al. (2012) described the results of the use of PRP in the treatment of jaw necrosis associated with bisphosphonates. A total of 8 patients diagnosed with bisphosphonate-associated necrosis of the jaw underwent surgery to remove debridement and necrotic bone, followed by application of autologous platelet concentrate supplemented with growth factors and primary suture. The patients were periodically examined clinically and radiologically. All patients showed clinical improvement and oral lesions disappeared 2 to 4 weeks after treatment. After a mean follow-up of 14 months, the patients remained asymptomatic. The authors concluded that, although not conclusive, the combination of necrotic bone curettage and PRP for the treatment of refractory osteonecrosis of the jaw produced promising results.

Gross et al. (2013) performed a systematic review of clinical outcomes after injectable therapy for Achilles tendon without attachment, identified patient-specific factors that predict treatment outcomes, provided treatment recommendations based on the best available literature, and identified knowledge necessary for further investigation. . These investigators searched Medline (1948 to Week 1 March 2012) and Embase (1980 to Week 9 2012) for clinical trials evaluating the efficacy of injectable therapies in non-insertion related Achilles tendonitis. In particular, they included RCTs and cohort studies with a comparative control group. Data extraction was performed by 2 independent reviewers. Oxford level of evidence guidelines and GRADE recommendations were used to assess the quality of the evidence and make treatment recommendations. Nine studies met the inclusion criteria for this review and included 312 Achilles tendons at end of follow up. Interventions of interest included PRP (n=54), autologous injection (n=40), sclerosants (n=72), protease inhibitors (n=26), hemodialysis (n=60), corticosteroids (n=52) and prolotherapy. (n=20). Only 1 study met the criteria for a high-quality RCT. All studies were classified as studies with low-quality evidence. While some studies have shown statistically significant effects of treatment modalities, studies have often found that certain injectables were no better than a placebo. The authors concluded that the literature on injectable treatments for non-insertional Achilles tendonitis has mixed results with conflicting methods and inconclusive evidence on the indications for treatment and the mechanism of its effects in chronically degenerated tendons. They stated that prospective randomized trials are needed to make treatment recommendations for Achilles tendonitis with injectable therapies.

In an RCT, Kesikburun et al (2013) examined the effect of PRP injections on shoulder pain and function in patients with chronic rotator cuff tendinopathy. A total of 40 patients between 18 and 70 years

1. History of shoulder pain for more than 3 months during throwing activities,
2. Magnetic resonance imaging (MRI) findings of rotator cuff tendinopathy or partial tears of the tendon and
3. This double-blind, placebo-controlled RCT included at least a 50% reduction in shoulder pain due to subacromial injections of an anesthetic.

Patients were randomly assigned to a PRP group (n=20) or a placebo group (n=20). Patients received an ultrasound-guided injection into the subacromial space containing 5 mL of PRP from autologous venous blood or 5 mL of saline. All patients underwent a 6-week standard exercise program. Outcome measures (Western Ontario Rotator Cuff Index [WORC], Shoulder Pain and Disability Index [SPADI], 100mm VAS of shoulder pain with Neer's test, and shoulder range of motion) were assessed at baseline and at 3, 6, 12, and 12 years 24 weeks and 1 year after injection. The comparison of patients did not reveal significant differences between the groups in the WORC, SPADI and VAS scores at one year of follow-up (p=0.174, p=0.314 and p=0.904, respectively). Similar results were found at other test points. Within each group, WORC, SPADI, and VAS scores showed significant improvements from baseline at all time points (p<0.001). There were no significant interactions between group and time for range of motion measures. The authors concluded that after 1 year of follow-up, PRP injection was no more effective than placebo in improving quality of life, pain, disability, and range of motion of the shoulder in patients with chronic tendinopathy of the arm cuffs. rotators treated with an exercise program.

In a randomized, double-blind, parallel-group, placebo-controlled, active, half-head study, Trink et al. (2013) the safety and efficacy of PRP for the treatment of alopecia areata (AA). A total of 45 AA patients were randomized to receive intralesional injections of PRP, triamcinolone acetonide (TA), or placebo in 50% of the scalp. The other 50% received no treatment. Each patient received a total of 3 treatments 1 month apart. Endpoints were hair growth, capillary dystrophy as measured by dermoscopy, burning/itching, and cell proliferation as measured by Ki-67 assessment. The patients were followed up for 1 year. Platelet-rich plasma was found to significantly increase hair growth and reduce capillary dystrophy and burning/itching compared to TA or placebo, and Ki-67 levels, which serve as a marker for cell proliferation, they were significantly higher. No side effects were observed during treatment. The authors concluded that this pilot study, which is the first to examine the effects of PRP in AA, suggests that PRP may serve as a safe and effective treatment option in AA and that larger controlled studies of this method are needed. .

Grifo et al. (2013) evaluated the efficacy of PRP therapy in the treatment of patients with typical osteoporotic hip fracture in a blinded, single-center, parallel-group RCT. This study enrolled 200 of 315 eligible patients 65 years of age or older with any type of intracapsular fracture of the proximal femur. Patients were excluded if their fracture prevented internal fixation. Participants underwent internal fixation of the fracture with cannulated screws and were randomized to receive or not receive a PRP injection at the fracture site. The primary outcome was fixation failure at 12 months, defined as any revision surgery. Primary outcome data were available for 82 of 101 and 78 of 99 participants allocated to the test and control groups, respectively; the remainder died before final follow-up. There was an absolute risk reduction of 5.6% (95% CI -10.6% to 21.8%) in favor of PRP treatment (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 secondary endpoints, with the exception of length of stay in favor of PRP therapy treatment (mean difference 8 days, Mann-Whitney U test; p = 0.03). The number and distribution of adverse events were similar. The estimated cumulative incidence functions for the competitive events of death and revision showed 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 who received no treatment. However, the authors cannot definitively rule out a clinically significant difference.

Kumar et al. (2013) evaluated the effectiveness of PRP in chronic cases of plantar fasciitis. Plantar fasciitis patients who failed standard conservative treatment for at least one year received PRP therapy. The injections were performed in the theater as a day event. Roles-Maudsley (RM), VAS, AOFAS, and "would have reinjected" scores were compared preoperatively, 3, and 6 months after surgery. Prospective data from 50 jumps (44 patients) were collected. At the 6-month review, MR score improved from 4 to 2 (p<0.001), VAS from 7.7 to 4.2 (p<0.001), and AOFAS from 60.6 to 81.9 (p<0.001 ). A total of 28 patients (64%) were very satisfied and would receive the injection again. No complications were reported. The authors concluded that PRP achieved an efficacy rate of almost 2 out of 3 in these chronic cases. The procedure was safe and no complications were reported. The authors felt that PRP may have some role in treatment and warrants further study with a prospective randomized trial.

Osterman et al. (2015) found that PRP has anti-inflammatory effects with potential applications in the treatment of OA. In a controlled laboratory study, these investigators used an in vitro coculture model of OA in human cartilage and synovium to study the anti-inflammatory effects of 2 different PRP preparations. A conjoint culture system was established using osteoarthritic cartilage and synovial membrane from 9 patients undergoing total knee arthroplasty. Interleukin-1β (IL-1β) was added to each coculture to induce inflammation. Two PRP preparations were obtained: one that produces low concentrations of white blood cells and platelets (PRPLP) and another that produces high concentrations of platelets and white blood cells (PRPHP). PRPLP, PRPHP, or medium was added to the coculture wells. Control wells contained OA cartilage and synovial membrane, but no IL-1β or PRP. Normal cartilage, not OA, was obtained to determine baseline levels of gene expression. Quantitative polymerase chain reaction was used to measure changes in inflammatory markers in tissues (a disintegrin and a thrombospondin-motif metalloproteinase-5 [ADAMTS-5], tissue inhibitor of metalloproteinase-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 TIMP-1 and ADAMTS-5 expression in cartilage, increased aggrecan expression in cartilage, and decreased ADAMTS-5, VEGF, and TIMP-1 expression in synovium compared with control cocultures (p < 0.05). There was significantly less nitric oxide production in the PRPLP and PRPHP groups compared to controls (p<0.05). There were significant differences in gene expression in normal cartilage compared to the 4 OA cartilage groups at all 4 time points. Treatment with PRPLP or PRPHP restored some gene expression to the same level in normal cartilage, but not for all inflammatory markers. The authors concluded that this coculture model evaluated two 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 anti-inflammatory activity between the two preparations. These investigators determined that OA is an important cause of chronic disability and that less invasive treatments are needed; These results suggested that PRP injections could be an effective alternative anti-inflammatory agent in the treatment of OA.

On behalf of the Osteoarthritis Section of the French Rheumatology Society, Ornetti et al. (2016) state that PRP has received considerable attention as an intra-articular treatment to alleviate the symptoms of osteoarthritis. Activated platelets release a variety of soluble mediators, such as growth factors and cytokines, inducing complex interactions that vary between tissues within the joint. In vivo, PRP can promote chondrocyte proliferation and differentiation. The available data are somewhat conflicting with respect to possible effects on synovial cells and modulation of angiogenesis. Platelet-rich plasma likely exerts an early anti-inflammatory effect that may be mediated primarily through inhibition of NF-κB signaling, a hypothesis that is not supported by proof-of-concept studies. The authors stated that it is too early to draw any conclusions about the efficacy of PRP for the treatment of OA of the hip.

Nourisat et al. (2015) noted that although tendinopathies represent a heterogeneous group of disorders, they are often treated by similar combinations of local and systemic symptomatic interventions. The myriad of causes, pathophysiological mechanisms, and histological changes that characterize tendinopathies may explain the failure of standard care in some patients. Platelet-rich plasma (PRP), which contains a variety of soluble mediators including growth factors, has been proposed as a second-line treatment for refractory tendinopathy, with the goal of accelerating tendon healing or remodeling. These investigators reported a systematic review of the literature of basic human and animal research data supporting the clinical use of PRP in tendinopathies and clinical trials in the most common tendinopathies (elbow, knee, shoulder, and Achilles tendon). The aim was to clarify the role of this new injectable treatment, which is attracting increasing attention. The level of evidence remains low, as few well-designed randomized controlled trials have been published. The available scientific evidence does not justify the use of PRP for the first line treatment of tendinopathies. PRP therapy may be considered for certain subtypes of tendinopathies after failed ultrasound-guided corticosteroid injections. However, further studies are needed to define these possible indications and ideal treatment protocols.

Balasubramaniam et al. (2015) systematically reviewed the literature on PRP therapy in chronic tendinopathy. Databases used in the research include Elton B. Stephens Co. (EBSCO), Medline, Cochrane Library, Ovid, and Embase (the Excerpta Medica database). A total of 389 articles were reviewed for possible inclusion between February 2010 and April 2014. Of these articles, a total of 9 randomized controlled trials ( RCTs ) met the inclusion criteria. In both the test and control groups, only 1 RCT was excluded due to previous surgery. Each article was reviewed independently by 2 authors. Each article was analyzed using the Cochrane Criteria Checklist. In case of discrepancies in the results, a third independent expert was consulted. The review found that PRP was most effective in patellar and lateral epicondylar tendinopathy, with both RCTs on the patellar section of the study supporting the use of PRP for pain relief at 3 and 12 months, while 2 of 4 studies on section of the lateral epicondyle showed improvements for pain and disability after 6 and 12 months. Evidence for the use of PRP in Achilles tendinopathy and rotator cuff tendinopathy was lacking. The authors concluded that although the results of this review are promising for the use of PRP in chronic tendinopathy, the analysis highlighted the need for more controlled clinical trials comparing PRP with placebo.

DiMatteo et al. (2015) PRP has been introduced into clinical practice to treat an increasing number of different musculoskeletal disorders. It is currently used in the treatment of Achilles tendon and patellar tendon disorders, which are common sports-related injuries and very difficult to treat. The aim of this study was to systematically review the available clinical evidence on the use of PRP in the treatment of patellar and Achilles tendinitis. A systematic bibliographic search was carried out according to the following inclusion criteria of relevant articles:

1. clinical reports of all levels of evidence,
2. written in English,
3. no time limit and
4. on the use of PRP in the conservative treatment of Achilles tendon syndrome and the tip of the patella.

A total of 22 studies were included and analysed. Two studies on patellar tendon syndrome were RCTs, while only 1 RCT on the Achilles tendon was published. All work on the patellar tendon reported a positive result for PRP, which proved to be superior to other traditional approaches such as shock wave therapy and dry needling. In the case of the Achilles tendon, the only RCT available showed no clinically significant difference between PRP and saline, despite the encouraging results reported by case series. The main finding of this study was the lack of high-level literature on the use of PRP in the treatment of patellar and Achilles tendinopathy. However, the authors noted that currently available clinical data, while inconclusive, 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 then shed light on these controversies. These investigators performed a systematic review of the literature and a meta-analysis of the results. All related databases, such as PubMed, Cochrane Database of Systematic Reviews, DARE, and EMBASE, were searched for the use of PRP in athletes and in sports medicine. The search was conducted from June 2013 to February 2014. The search returned 905 studies, of which 13 RCTs met the inclusion criteria for a systematic review and meta-analysis. All articles were assessed using the Critical Appraisal Skills Program (CASP) checklist for RCTs. Analysis of pain scores and physical activity/function scores did not show superiority of PRP over other options. The authors concluded that this meta-analysis did not show increased efficacy for the use of PRP in sports-related injuries in terms of improved physical function and pain relief. For this reason, they indicated that the extensive use of PRP in this type of injury should be limited; Well-designed RCTs are needed to corroborate the results.

An UpToDate review of “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. He notes that “small randomized trials in patients with median Achilles tendinopathy have not shown any benefit of platelet-rich plasma (PRP) or autologous injection when added to an eccentric exercise program. A similar study conducted 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 to treat chronic mid-range tendinopathy of the Achilles tendon; However, the evidence for this treatment is limited. In a multicenter randomized clinical trial with blinded participants, these investigators evaluated the effects of a single versus a sham injection of PRP on VISA A-scores (a single composite measure of Achilles tendonitis severity). This study enrolled 240 subjects from 24 sites designated for PRP injection or sham injection between April 2016 and February 2020. The last follow-up was in July 2020. Subjects were 18 years of age or older and had tendon pain. of medial Achilles for more than 3 months, as confirmed by ultrasound, MRI, or both. Procedures included a single intratendinous injection of PRP (n=121) or a single sham injection (insertion of a subcutaneous dry needle without penetrating the tendon) (n=119). The primary endpoint was the VISA A score measured 6 months after treatment assignment. The VISA A-Score contains 8 questions covering 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 hand, age, gender, and baseline VISA A score. Of 240 patients assigned to receive PRP or placebo injection (mean age 52 years; 138 [58%] women), 221 (92%) completed the study. At 6-month follow-up, the mean VISA A-score values ​​in the PRP group vs. the sham group were 54.4 vs 53.4 (adjusted MD, -2.7 [95% CI: -8, 8 to 3.3]). The most common AEs comparing patients in the PRP versus 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 in patients with chronic mid-range Achilles tendinopathy, treatment with a single intratendinous injection of PRP compared with subcutaneous dry needling did not reduce Achilles tendon dysfunction at 6 months. These results do not support the use of this treatment in chronic tendinopathy of the middle Achilles tendon.

Bennell et al. (2021) noted that most clinical guidelines do not recommend PRP for OA of the knee due to a lack of high-quality evidence on its efficacy on symptoms and joint structure; However, the guidelines emphasize the need for rigorous studies. However, the use of PRP in knee osteoarthritis is increasing. In a randomized, 2-arm, placebo-controlled, participant, injector, and rater-blind study, these investigators evaluated the effects of intra-articular injections of PRP on symptoms and joint structure in patients with mild to moderately symptomatic radiographic findings. Medial OA of the knee. For this study, subjects (n = 288) 50 years of age or older with symptomatic osteoarthritis of the medial knee (Kellgren and Lawrence grade 2 or 3) enrolled with a 12-month follow-up completed on July 22, 2020. Interventions included 3 intra-articular injections at weekly intervals of leukocyte-poor PRP using a commercial product (n=144 subjects) or a saline placebo (n=144 subjects). The 2 primary endpoints were the 12-month change in mean total knee pain scores (11-point scale; range 0 to 10, with higher scores indicating worse pain; minimal clinically significant difference of 1.8 ) and percent change in volume of medial tibial cartilage, as assessed by MRI. A total of 31 secondary endpoints (25 symptom-related and 6 assessed by MRI; clinically significant minimal difference unknown) assessed pain, function, quality of life, global changes, and joint structures at 2 months. and/or 12 months after treatment. tall. Of 288 randomized patients (mean age 61.9 [SD, 6.5] years; 169 [59%] female), 269 (93%) completed the study. In both groups, 140 subjects (97%) received all 3 injections. At 12 months, PRP treatment resulted in a mean change in knee pain scores of -2.1 and -1.8 points, respectively, compared with placebo injection (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% vs -1.2%, respectively (difference -0.2% [95% CI -1.9% to 1.5%]; p = 0.81). Of 31 predefined secondary endpoints, 29 did not show significant differences between groups. The authors concluded that in patients with mild to moderate symptomatic radiographic knee osteoarthritis, intra-articular injection of PRP compared with placebo saline injection did not produce significant differences in symptoms or joint structure at 12 months. These results do not support the use of PRP to treat osteoarthritis of the knee.

Autologous platelet gel in diabetic foot ulcer

Xu et al. (2019) stated that research on the efficacy of autologous platelet-rich gel (APRG) and continuous vacuum drainage (CVSD) in diabetic foot ulcer (DFU) is increasing. Despite the growing knowledge on the subject, the results remain contradictory. These investigators will provide information on the efficacy of APRG and CVSD for patients with UPD. They will search electronic databases of Medline, Embase, Cochrane Library, CINAHL, AMED, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure from inception to October 1, 2019. There were no language restrictions for these databases; 2 authors will independently perform study selection, data extraction and risk of bias assessment. Differences of opinion between 2 authors are resolved by discussion with a third author. The safety and efficacy of APRG and CVSD for patients with UPD will be assessed based on time to complete healing, proportion of ulcers healed during the study period, change in ulcer size, quality of life related to health, length of hospital stay (LOS). and ea. The authors concluded that the results of this study will provide useful evidence for APRG and CVSD for patients with UPD. This study will also provide guidelines for future clinical practice and research.

Platelet-rich plasma in Achilles tendinitis

Kearney et al. (2021) noted that PRP injections are used to treat chronic mid-range tendinopathy of the Achilles tendon; However, the evidence for this treatment is limited. In a multicenter randomized clinical trial with blinded participants, these investigators evaluated the effects of a single versus a sham injection of PRP on VISA A-scores (a single composite measure of Achilles tendonitis severity). This study enrolled 240 subjects from 24 sites designated for PRP injection or sham injection between April 2016 and February 2020. The last follow-up was in July 2020. Subjects were 18 years of age or older and had tendon pain. of medial Achilles for more than 3 months, as confirmed by ultrasound, MRI, or both. Procedures included a single intratendinous injection of PRP (n=121) or a single sham injection (insertion of a subcutaneous dry needle without penetrating the tendon) (n=119). The primary endpoint was the VISA A score measured 6 months after treatment assignment. The VISA A-Score contains 8 questions covering 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 hand, age, gender, and baseline VISA A score. Of 240 patients assigned to receive PRP or placebo injection (mean age 52 years; 138 [58%] women), 221 (92%) completed the study. At 6-month follow-up, the mean VISA A-score values ​​in the PRP group vs. the sham group were 54.4 vs 53.4 (adjusted MD, -2.7 [95% CI: -8, 8 to 3.3]). The most common AEs comparing patients in the PRP versus 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 in patients with chronic mid-range Achilles tendinopathy, treatment with a single intratendinous injection of PRP compared with subcutaneous dry needling did not reduce Achilles tendon dysfunction at 6 months. These results do not support the use of this treatment in chronic tendinopathy of the middle Achilles tendon.

Platelet Rich Plasma Injection to Treat Ankle Sprains

Platelet-rich plasma injection to treat cerebral palsy

Platelet-rich plasma injection for the treatment of perianal fistulas associated with Crohn's disease

In a prospective pilot study, Gottgens et al. (2015) to improve the cure rates of high perianal fistulas associated with Crohn's disease (CD) by combining the well-known mucosal advancement flap with PRP. Consecutive patients with CD-related primary or recurrent high perianal fistulae, defined as involving the middle and/or upper third of the anal sphincter complex, were included. First, a staged procedure was performed with blunt seton treatment for 3 months, followed by a mucosal advancement flap with PRP injection into the fistula tract. A total of 10 consecutive patients underwent surgery between 2009 and 2014; 50% of the patients had previously undergone fistula surgery. The mean follow-up time was 23.3 months (SD 13.0). Fistula healing was 70% (95% CI 33 to 89%) at 1 year. One (10%) patient recurred and 2 (20%) patients retained the fistula after treatment. An abscess occurred in 1 (10%) patient. The median postoperative Vaizey score was 8.0 (range 0-21), indicating moderate to severe incontinence. The authors concluded that the results of combining the mucosal advancement flap with PRP in patients with CD-associated high perianal fistulae are modest with a 70% cure rate. They stated that more research is needed to determine the benefits and risks of this technique in relation to continence status in this patient population.

Platelet Rich Plasma Injection to Treat Thigh Injuries

In a 3-arm, randomized (double-blind to injection arms), parallel-group study, Hamilton et al. (2015) The effectiveness of a single PRP injection in reducing the duration of return to exercise in athletes with an acute hamstring injury (HI). A total of 90 professional athletes with positive MRI for HI were randomly assigned to injection with PRP intervention, platelet-poor plasma (PPP control), or no injection. All received an intensive standardized rehabilitation program. The primary outcome was time to return to play, with secondary measures including relapse rate at 2 and 6.5 months. The adjusted HR for the PRP group compared to the PPP group was 2.29 (95% CI 1.30 to 4.04, p=0.004); for the PRP group compared to the no injection group 1.48 (95% CI 0.869 to 2.520; p=0.15) and for the PPP group compared to the no injection group 1.57 (95% CI 0.869 to 2.520; p=0.15) 95%: 0.88 to -2.80, p= 0.13). The adjusted difference in time back to sport between the PRP and PPP groups was -5.7½ days (95% CI -10.1 to -1.4; p=0.01); between PRP and no injection group -2.9 days (95% CI: -7.2 to 1.4; p=0.189) and between PPP and no injection group 2.8 days (95% CI: - 1, 6 to 7.2, p=0.210). There were no significant differences for the secondary endpoints. No side effects have been reported. The authors concluded that these results suggest that a single injection of PRP has no benefit over intensive rehabilitation in athletes who have experienced acute MRI-positive IH. Intensive rehabilitation physiotherapy remains the most important means of ensuring an optimal return to sport after muscle injury.

In a meta-analysis, Pas et al. (2015) updated and reanalyzed the efficacy of conservative IH treatments. We searched PubMed, EMBASE, Web of Science, Cochrane Library, CINAHL, and SPORTDiscus up to mid-February 2015. Randomized controlled trials on the effect of conservative interventions compared with a control group or other interventions in HF were included. The survey results were independently selected by 2 authors. Risk of bias assessment was performed using a modified Downs and Black scale with a maximum score of 28. Whenever possible, meta-analysis was performed. A total of 10 RCTs (526 participants) were identified, including 6 new RCTs. Two RCTs were of good/excellent quality, the rest fair or poor (average low and black scores 16 (IQR 9)). Meta-analysis of 2 studies on rehabilitation exercises (stretching) showed a significantly shorter time to return to play (HR 3.22 (95% CI 2.17 to 4.77), p<0.0001), but no difference in the risk of re-injury. Meta-analysis of 3 studies examining PRP showed no effect compared to control (HR 1.03 (95% CI 0.87 to 1.22), p=0.73). Limited evidence has been found that progressive core mobility and stability training can reduce relapse rates. The authors concluded that the meta-analysis showed superior efficacy for exercise rehabilitation; PRP injection had no effect on acute HI.

Platelet-rich plasma injection for the treatment of osteoarthritis of the temporomandibular joint

In an RCT, Comert et al. (2015) compared the long-term clinical and radiological outcomes of temporomandibular joint osteoarthritis (TMJ-OA) treated with arthrocentesis plus PRP with arthrocentesis alone. The sample consisted of 30 consecutive TMJ-OA patients randomly treated with arthrocentesis alone (control group) or initial arthrocentesis plus PRP injection and then 4 consecutive PRP injections (study group). The predictor variable was the treatment technique. Outcome variables were VAS scores (chewing efficiency, joint sounds, and pain discomfort), maximum interincisal opening, and cone beam computed tomography (CBCT) findings. Outcome variables were recorded before the operation and 12 months after surgery. Descriptive and bivariate statistics were calculated and significance was set at a "p" value less than 0.05. Paired t-test and Student's t-test were used for intragroup and intergroup comparisons, respectively. The sample consisted of 47 joints of 30 patients with osteoarthritis (control group: 15 joints of 12 patients; mean age 35.08 ± 14.84 years; study group: 32 joints of 18 patients; mean age 32.22 ± 14. 32 years) . Joint sounds and general pain symptoms decreased statistically in both groups, while masticatory efficiency, pain-free interincisal opening, and lateral movement increased statistically only in the study group. However, only chewing efficiency showed a statistically greater improvement in the study group compared to the control group. Cone beam CT evaluations showed that reparative remodeling of bone abnormalities occurred in 87.5% and 46.6% of the study and control groups, respectively. The authors concluded that these results suggest that arthrocentesis and PRP injections represent a safe and promising method of treating TMJ-OA that is superior to arthrocentesis alone. These preliminary results need to be validated by well-designed studies.

Platelet Rich Plasma Injection for Treatment of Lumbar Facet Joint Syndrome

Wu and colleagues (2016) stated that lumbar facet joint syndrome is currently suspected to be the primary cause of axial back pain and that a large proportion of axial back pain is caused by disorders of the lumbar facet joints. Intra-articular injection is one of the most common treatment methods in early clinical use. These investigators attempted to search for a new injectable material, autologous PRP, to treat lumbar facet syndrome and to assess its safety and efficacy. A total of 19 patients with lumbar facet joint syndrome (8 men, 11 women; mean age 52.53 ± 6.79 years, range 38 to 62 years) were enrolled to receive lumbar facet joint injection with autologous PRP. under fluoroscopic guidance. Patients were followed up immediately, 1 week, 1 month, 2 months, and 3 months after treatment, and items in this analysis included LBP VAS at rest and during flexion, RDQ, ODI, and modified MacNab criteria for pain relief. All 19 patients successfully completed intra-articular injections with autologous PRP. One week after treatment, low back pain decreased significantly compared to before treatment, both at rest and during flexion. The results were obtained immediately after treatment in 9 patients (47.37%), after a week in 14 patients (73.68%), after a month in 15 patients (78.95%) and in 15 patients (78.95%). %) rated as “good” or “excellent”. ” at 2 months and 15 patients (78.95%) at 3 months. Based on the RDQ, statistically significant differences were observed, and based on the ODI, a greater than 10% improvement in lumbar function was observed between pretreatment and posttreatment. In addition, no relevant serious complications occurred during the entire injection process and the follow-up period. The authors concluded that the new lumbar facet joint injection technique with autologous PRP was safe and effective for patients with lumbar facet joint syndrome in the short time of 3 months. The main disadvantages of this study were:

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

Platelet-rich plasma injection for the treatment of urethral strictures

Gul (2016) noted that urethral stricture is one of the most problematic urological conditions among urologists and has a significant impact on quality of life (QoL) and healthcare costs. Although easily cured with internal urethrotomy, postoperative stricture recurrence is challenging. Several adjuvant therapies have been used in conjunction with internal urethrotomy, but none are routinely used because the pathophysiology of the disease is still unclear. Fibrosis is the most commonly blamed hypothesis for the action. Platelet-rich plasma is an autologous blood product that contains a high concentration of platelets and is used for a variety of clinical curative applications. Contains a concentration of key protein growth factors that have been shown to be actively secreted by platelets to initiate precise wound healing. Although PRP may play a crucial role in wound healing and has been used successfully in fibrotic diseases, it contains some harmful cytokines, such as transforming growth factor β1 (TGF β1), which can also cause fibrosis. The authors concluded that the new hypothesis is that subcutaneous injection of PRP neutralized with TGFβ1 antibodies into 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, can take on the properties of neighboring cells. Cell-based surrogates include, but are not limited to, stem cells that have been combined with PRP (eg, Regenexx). Injection of stem cells or cell-based surrogates is suggested to promote wound and injury healing.

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

Moon et al. (2008) hypothesized that injection of plasma into the pelvic bone marrow after arthroscopic debridement of degenerative tissue will result in biologic healing. Therefore, it will not only relieve pain but also improve function in patients with resistant tendonitis of the elbow. A total of 24 patients (26 elbows) with significant persistent pain for a mean of 15 months despite the standard rehabilitation protocol and a variety of other non-surgical modalities were treated arthroscopically. Debridement Bone marrow plasma is prepared by centrifuging blood from the pelvic bone marrow at 1800 rpm for 20 to 30 minutes. Patients received full range of motion exercises after 2 to 3 days. Cytokine analyzes were performed for this injector material. Outcome was assessed by postoperative ultrasound, VAS, and Mayo Elbow Performance Scores (MEPS) at 8-week and 6-month follow-up. All patients in this study reported improvement in both VAS and MEPS; no complications were observed. Postoperative ultrasound showed healing of the tendon. The predominant cytokines in this study were interleukin-12, the inducible protein interferon gamma-10, and RANTES (regulated upon activation, normal T cells express and secrete). The authors concluded that injection of iliac bone marrow plasma after arthroscopic debridement of severe elbow tendinosis showed early recovery of daily activities and marked improvement.

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

Gupta et al. (2012) stated that OA is a degenerative connective tissue disease that progresses with age in older people or develops in young athletes after sports-related injuries. Articular cartilage is particularly susceptible to damage and has a low regenerative potential due to the lack of vessels in the tissue. The normal resilience and biomechanical properties of thinned cartilage are severely compromised as the disease progresses. Although surgical and pharmaceutical interventions are now available for the treatment of OA, restoration of normal cartilage function has been difficult to achieve. Because the tissue is composed primarily of chondrocytes dispersed in a bed of specialized extracellular matrix, bone marrow stromal cells (BMSCs), also known as bone marrow-derived "mesenchymal stem cells," emerge. or "mesenchymal stromal cells", with inherent chondrogenic differentiation potential. ideal for therapeutic use in cartilage regeneration. Bone marrow stromal cells can be readily isolated and massively expanded in culture in an undifferentiated state for therapeutic use. Due to their potential to modulate the local microenvironment through anti-inflammatory and immunosuppressive functions, BMSCs have additional advantage for allogeneic application. Furthermore, by secreting various bioactive soluble factors, BMSCs can protect cartilage from further tissue destruction and facilitate the regeneration of remaining progenitor cells in situ. The authors described the advances that have been made in BMSCs in recent years and their therapeutic potential for repairing cartilage damage in OA.

Makihara et al. (2017) reported the outcome of 5 shoulders in 4 patients affected by advanced osteonecrosis of the humeral head treated with concentrated autologous bone marrow transplantation. The bone marrow sample was aspirated from the iliac crests, concentrated using a centrifugation technique, and injected into the necrotic site. Shoulders were assessed radiologically with X-ray scoring and clinically with range of motion (ROM) measurement and pain scoring (visual analogue scale, VAS). The mean follow-up time was 49.4 (range 24 to 73) months. The nucleated cell concentration ratio was calculated and the number of transplanted mesenchymal stem cells (MSC) was estimated by colony formation assay. The 4 shoulders with stage 3 disease managed to save the joint. A shoulder with stage 4 disease required replacement surgery. Clinical evaluation of the preserved joints showed ROM improvement 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 MSCs was 1,125. The authors concluded that the results of autologous bone marrow transplantation for advanced osteonecrosis of the humeral head were mixed; More research is needed to determine the effectiveness and indications for this surgery.

Sanapati et al. (2018) noted that several cell-based therapies have been proposed to treat low back pain in recent years, including injection of medicinal signaling cells or MSCs and PRP; However, there is only new clinical evidence supporting its use at this time. In a systematic review and meta-analysis, these investigators examined the efficacy of MSC or PRP injections in the treatment of low back and lower extremity pain. Data sources included PubMed, Cochrane Library, US National Guideline Clearinghouse, previous systematic reviews, and reference lists. The literature search was performed from 1966 to June 2018. Randomized controlled trials, observational studies, and case reports of biologic injections into the disc, epidural space, facet joints, or sacroiliac joints were selected for analysis. Data extraction and methodological quality assessment were performed using the Cochrane Review Methodological Quality Assessment and Interventional Pain Management Techniques - Quality Assessment of Reliability and Assessment of Risk of Bias (IPM-QRB). ) and the Interventional Pain Management Techniques - Quality Assessment of Reliability and Risk of Bias Assessment for Non-Randomised Trials (IPM-QRBNR). Evidence was summarized on a scale of 1 to 5 using best evidence synthesis principles. A total of 21 injection studies met the inclusion criteria. There were 12 lumbar disc injections, 5 epidural injections, 3 lumbar facet joint studies, and 3 sacroiliac joint studies. Evidence synthesis based on a single-arm meta-analysis, RCTs and observational studies, PRP disc injections and MSC showed level 3 evidence (on a scale of level I to V). The evidence for epidural injections based on a single-arm meta-analysis, a single RCT, and other available studies showed evidence at level 4 (on a scale from level I to V). Similarly, without meta-analysis, the evidence for injections into the lumbar facet joints and sacroiliac joints was level 4 evidence (on a scale of levels I to V). The authors concluded that the results of this systematic review and single-arm meta-analysis showed that MSCs and PRP may be effective in treating discogenic low back pain, radicular pain, facet joint pain, and joint pain. sacroiliacs with varying degrees of evidence supporting these techniques The authors stated that the main shortcoming of this study was the lack of high-quality RCTs.

Navani et al. (2019) pointed out that regenerative medicine is a medical specialty that aims to recruit and enhance the body's own curative arsenal for the treatment of the patient's pathology. The intent of this therapy is to aid in the repair and potentially replace or restore damaged tissue through the use of autologous or allogeneic biologics. This field is rising like a phoenix from the ashes of underperforming conventional therapies amid the high hopes and expectations of patients and healthcare professionals. However, since it is a relatively new field of medicine and its results are yet to be proven, caution should be exercised both in its public presentation and promise, as well as in its use. These investigators provided guidelines for the responsible, safe, and effective use of biologic therapies in the lumbar spine. Present a model for building standardized therapies with biologics. Basing potential administrators of biologics on knowledge of current outcome statistics and encouraging those interested in offering biologic therapies to participate in quality research that will ultimately advance and advance this area of ​​medicine. The methodology used included the development of goals and key questions. A panel of experts from various medical specialties and specialties and from various regions have contributed to the creation of this policy and have provided the appropriate Conflict of Interest Disclosures (if any). Reliable standards were used in the creation of these guidelines. The literature on regenerative medicine, its efficacy and side effects has been carefully reviewed using the best synthesis of the available bibliographical references. The recommendation rating was provided as described by the Agency for Healthcare Research and Quality (AHRQ). Lumbar disc injections: based on the available evidence on the use of PRP, including 1 high-quality RCT, several moderate-quality observational studies, one single-arm meta-analysis, and evidence from one systematic review, we graded qualitative evidence as Level III (at a Level I to V) using a modified qualitative approach to classify the evidence based on the best evidence synthesis. Based on the available evidence on the use of MSC/medical signaling with one high-quality RCT, several moderate-quality observational studies, one single-arm meta-analysis, and 2 systematic reviews, the qualitative evidence was classified as Level III (on a scale from levels I to V) using a modified qualitative approach to rank the evidence based on the best synthesis of evidence. Lumbar epidural injections: based on 1 high-quality RCT, several relevant observational studies of moderate quality, and one single-arm meta-analysis, the qualitative evidence was graded as Level IV (on a scale from Level I to V) using a qualitative scale. modified. approach to ranking evidence based on the best synthesis of evidence. 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 was graded as Level IV (on a scale from Level I to V) using a modified qualitative evidence rating 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 was graded as Level IV (on a scale from Level I to V) using a grading of qualitative approach modified evidence based on best evidence synthesis. The authors concluded that, based on the summary of evidence summarized above, level III evidence exists for intradiscal injections of PRP and MSC, whereas the evidence for PRP injections in the lumbar facet joints, lumbar PDA, and sacroiliac joints is superior. We considered the evidence to be Level IV (on a scale of Levels I to V) using a modified qualitative approach to classify the evidence based on the best synthesis of evidence. Regenerative therapy should be offered to patients after diagnostic evidence of the need for biologic therapy, a thorough discussion of the patient's needs and expectations, appropriate patient education regarding the use and administration of biologics, and consideration of history. patient's doctor. Regenerative therapy can be provided independently or in conjunction with other treatment modalities, including a structured exercise program, physical therapy, behavioral therapy, and in conjunction with appropriate conventional medical therapy, as needed. Appropriate precautions should be considered and followed before undertaking any biologic therapy. These guidelines list various Food and Drug Administration (FDA) guidelines, possible restrictions on the use of biologic therapies, and the corresponding requirements for FDA compliance.

In addition, the UpToDate reviews of Subacute and Chronic Low Back Pain: Non-Surgical Interventional Management (Chou, 2021) and Treatment and Prognosis of Cervical Radiculopathy (Robinson and Kothari, 2021) do not mention injection of facet joint mesenchymal stem cells as a management/therapy option.

Stem cell therapy from adipose tissue (habeo cells) for the treatment of scleroderma (systemic sclerosis)

Systemic sclerosis (SS) is a connective tissue disease with heterogeneous clinical manifestations and a frequently progressive course. The diffuse cutaneous form of SSc (dcSSc) is characterized by thickening of the skin (scleroderma) and marked involvement of multiple internal organs. Patients with limited cutaneous SSc (lcSSc) usually present with long-standing Raynaud's phenomenon before other manifestations of SSc appear. In the past 10 years, interest in cultured adipose-derived stromal cell (ASC) therapy has increased; ASCs have exceptional developmental plasticity, including the ability to undergo multilineage differentiation and self-renewal. Furthermore, ASCs can be easily collected from small volumes of liposuction aspirates, demonstrating a high rate of proliferation and viability in vitro. Compared to bone marrow-derived mesenchymal stem cells (MSCs), ASCs are considered ideal for use in regenerative medicine.

Scuderi and colleagues (2013) evaluated the clinical outcome of ASC therapy for the treatment of skin manifestations in patients with SSc. These researchers developed an effective method to transplant ASC into scleroderma patients using a hyaluronic acid (HA) solution, which allowed them to obtain precise structural modifications. In this study, ASCs were isolated from the subcutaneous adipose tissue of 6 scleroderma patients and cultured in a defined chemical medium prior to autologous transplantation to restore skin sequelae. They found that transplantation of a combination of ASCs in HA solution resulted in a significant improvement in skin tightening without complications (eg, anechoic areas, fat necrosis, or infection); suggesting that ASCs are a potential source of cells for skin therapy in rare diseases such as SS and skin diseases in general.

In a single-center, single-arm, open-label study with 6-month follow-up, Granel et al. (2015) evaluated the safety, tolerability, and potential efficacy of local injections of adipose-derived stromal vascular fraction. . (ADSVF) cells in patients with SS lack of patients' hand. A total of 12 patients with Cochin Hand Function Scale scores greater than 20/90 were included in this analysis. Autologous FVS was obtained from liposuction using an automated processing system and then injected into the subcutaneous tissue of each finger in contact with the neurovascular pedicles. The primary endpoint was the number and severity of AEs associated with SVF-based therapy. Secondary endpoints were changes in hand disability and fibrosis, vascular manifestations, pain, and quality of life from baseline to 2 and 6.5 months after cell therapy. All included patients underwent surgery and there were no study dropouts or patients lost to follow-up. No serious side effects occurred during the procedure and follow-up; 4 minor AEs were reported and spontaneously rectified. There was a significant improvement in hand disability and pain, Raynaud's phenomenon, finger edema, and quality of life. The authors concluded that this study described the safety of injecting autologous SVF cells into the hands of SSc patients; Preliminary evaluations at 6½ months indicated potential efficacy that needs to be confirmed in a randomized placebo-controlled study in a larger population.

Del Papa et al. (2015) found that digital ulcers (UDs) are a common complication of SS, often with a tendency to heal very slowly or not at all, despite commonly used systemic and local therapeutic approaches. Recently, stem cell therapy has emerged as a new approach to speed wound healing. These investigators treated long-standing SS-related DU unresponsive to conventional therapies by implanting autologous adipose-derived cell (ATDC) fractions. A total of 15 SSc patients with longstanding ED in only one fingertip, unresponsive to intensive local and systemic treatment, were included in the study. The transplant procedure consisted of the injection of 0.5 to 1 ml of autologous ATDC fractions separated by centrifugation from adipose tissue collected by liposuction of subcutaneous abdominal fat. Post-procedure healing time was the primary outcome of the study, while reduction in pain intensity and analgesic consumption was a secondary outcome. In addition, post-therapeutic variation in the number of capillaries observed during videocapillaroscopy (NVC) examination of the nail folds and resistance in the arteries of the fingers measured with high-resolution Echocolor Doppler were also taken into account. Rapid DU healing was achieved in all enrolled patients (median healing time 4.23 weeks; range 2-7 weeks). A significant reduction in pain intensity was observed after a few weeks (p<0.001), while the number of capillaries in the CNV assessment increased significantly at 3 and 6 months (p<0.0001 in both cases). . Finally, there was also a significant reduction in the resistance of the arteries of the fingers after treatment (p < 0.0001). The authors concluded that despite the limitations related to the small number of patients included (n=15) and the open-label study design, these observations suggest that local transplantation with ATDC is a promising therapeutic option for ES DU-related cases. that do not respond to conventional therapies.

In an open study, Guillaume-Jugnot et al. (2016) on the safety and efficacy of subcutaneous (s.c.) injection of autologous ADSVF in the fingers of patients with SSc. A total of 12 women (mean age 54.5 years; SD 10.3) were examined 1 year after ADSVF injection. Patients were eligible if they had a Cochin Hand Function Scale score greater than 20/90. ADSVF was obtained by liposuction using an automated processing system and then injected into the subcutaneous injection. Tissue from each finger in contact with neurovascular pedicles in a single procedure. Study endpoints were changes in hand disability and skin fibrosis, vascular manifestations, pain, and quality of life at 12-month follow-up. During the visit, the patients assessed the benefit of the procedure using a specific self-completed questionnaire. There was a significant decrease from baseline of 51.3% (p < 0.001) for the Cochin Hand Function Scale score, 63.2% (p < 0.001) for Raynaud's severity, and 46. 8% (p = 0.001) for quality of life (Scleroderma Health Assessment). Questionnaire). Significant improvement was also seen in finger swelling, skin sclerosis, hand movement and strength, and vascular suppression score. The reduction in pain in the hand approached statistical significance (p=0.052). The questionnaire revealed a benefit in daily activities, household chores, and social activities. The authors concluded that ADSVF injection is a promising therapy and appears to have benefits that last for at least 1 year.

In a phase I open-label clinical trial, Daumas et al. (2017) evaluated the safety of s.c. ADSVF injection; and data at 6 and 12 months were reported. Because the patients were followed up at the authors' medical center, these investigators reported their long-term results beyond the end of the study. A total of 12 women (mean age 54.5 ± 10.3 years) originally enrolled in the clinical study were examined during a scheduled medical visit that occurred between 22 and 30 months after treatment. Several patient-reported outcomes showed sustained improvement compared to assessment performed immediately before surgery: 62.5% on the Cochin Hand Function Scale, 51.1% on the Cochin Health Assessment Questionnaire scleroderma, 33.1% in hand pain and 88.3% in Raynaud's condition score. A decrease in the number of DUs was observed. Hand mobility, strength, and fibrosis also improved. None of the 8 patients who had already received an infusion of iloprost required a new infusion. The authors concluded that despite the limitations of an open study, the data support the long-term safety of ADSVF injection. In addition, they stated that two randomized, double-blind, placebo-controlled studies of this therapeutic are ongoing in the United States and France and will help define the site of this innovative therapy for patients with SSc.

Song et al. (2017) reported the case of a 62-year-old woman with scleroderma who developed progressive digital necrosis, ulceration, gangrene, and impaired wound healing despite conventional therapy with vasodilator drugs. South Carolina. Waterjet-assisted abdominal fat liposuction was performed under general anesthesia by an experienced surgeon; ADSVF was collected on a disposable Q-graft collector. Cells were spun down and cell pellets aspirated into a 20 mL syringe filled with 0.9% saline. A total of approximately 2.72 million cells were isolated. However, amputations of the middle phalanx of fingers 2, 3, and 4 of the left hand were performed without closing the skin of the amputation stumps. The SVF cell suspension was injected subcutaneously into the metacarpophalangeal joints of both hands, into the amputation stump of the left middle finger, and under a skin necrosis on the right hand. The therapy was well tolerated by the patient without side effects. Despite open amputation, no infection was noted; No further amputation was required 3 weeks after stem cell therapy. The patient continued under regular clinical observation to determine the long-term effects of the therapy. The authors concluded that the use of isolated ASCs appears to be a promising approach in the treatment of SS; however, further clinical and experimental studies are needed to better understand the precise mechanisms of action and to standardize therapy.

Injection of fat stem cells to treat osteoarthritis of the knee

Biazzo and colleagues (2020) reviewed the safety and efficacy of ADSC or SVF injections for the treatment of knee osteoarthritis and reviewed all RCTs that have addressed this topic. The following search terms were used in PubMed, Embase, Scopus, and the Cochrane Library database on November 14, 2019: “adipose-derived stem cells” OR “vascular portion of the stroma” OR “SVF” OR “ multipotent mesenchymal stromal cells' OR 'stem cells' OR 'derived stem cells' OR 'autologous' AND 'knee' OR 'osteoarthritis' OR 'chondral defect' OR 'randomised' OR 'controlled study'. No time limit given. by the launch date.These investigators included RCTs based on the following criteria: studies in English; Population of patients diagnosed with osteoarthritis of the knee and treated with ADSC or SVF injections; Comparison group treated with placebo, surgery, or adjuvant injections as PRP or HA.Intra-articular injection of adipose stem cells in the form of ADSC or SVF was a safe procedure for the treatment of knee OA with good clinical and radiological results in the first follow-up period. ment (12 to 24 months). In addition, the treatment with cells of fatty origin had a very low rate of complications (16.15%), all classified as minor. The authors concluded that ADSC and SVF appeared to show good to very promising results for the treatment of osteoarthritis of the knee; However, the duration and modalities of follow-up for different diseases varied greatly. However, it appears that the use of ADSC has been associated with clinical and radiographic improvements and minimal complication rates. Furthermore, these investigators stated that RCTs comparing ADSC or SVF and other treatments (eg, PRP or HA injections) should be conducted to avoid bias due to the use of biologic adjuvants or surgical procedures.

Autologous cell-based therapy for critical lower extremity ischemia

Abdul Wahid and colleagues (2018) stated that revascularization is the gold standard for patients with critical limb ischemia (CLI). In more than 30% of patients who are unfit or who have failed prior revascularization therapy (ILC patients with no option), limb amputation is eventually unavoidable. Preliminary studies have reported encouraging results using autologous cell-based therapy to treat CLI in these "no-choice" patients. However, studies comparing the angiogenic potency and clinical effects of autologous cells from different sources have provided limited data. Data on cell doses and routes of administration were also limited. In a Cochrane review, these investigators compared the safety and efficacy of autologous cells derived from different sources, prepared with different protocols, administered at different doses, and delivered by different routes in treating patients with ILC without choice. 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 of Nursing and Allied Health Literature (CINAHL), Medicine Related and Complementary Database (AMED) and Study Registries (May 16, 2018). The review authors searched PubMed up to February 2017. They included RCTs with 'no choice' CLI patients and compared a specific source or regimen of autologous cell-based therapy with another source or regimen of autologous cell-based therapy; 3 reviewers independently assessed studies for eligibility and methodological quality. They extracted data from the results of each study and pooled them for a meta-analysis. They calculated effect estimates using a 95% CI RR or 95% CI MD. These investigators included 7 RCTs with a total of 359 participants. These studies compared bone marrow mononuclear cells (BM-MNC) with mobilized peripheral blood stem cells (mPBSCs), BM-MNC with bone marrow mesenchymal stem cells (BM-MSCs), high cell dose versus low cell dose and intramuscular (IM). versus routes of intra-arterial (IA) cell implantation. They did not identify other comparisons in these studies; and judged most studies to be at low risk of bias by generating randomized sequences, incomplete outcome data, and selective reporting of outcomes; at high risk of bias by blinding patients and staff; and with a clear risk of bias in obfuscating attribution and blinding of outcome assessors. The quality of the evidence was mostly low to very low, with risk of bias, imprecision, and indirectness of the results being the main factors for downgrading the quality; 3 RCTs (100 participants) reported a total of 9 deaths during the follow-up period of the study. These studies did not report deaths by treatment group. The results did not show a clear difference in amputation rates between the IM and LA routes (RR 0.80, 95% CI 0.54 to 1.18; 3 RCTs, 95 participants; low-quality evidence). Data from only one study showed no clear difference in amputation rates between the BM-MNC and mPBSC-treated groups (RR 1.54, 95% CI 0.45 to 5.24; 150 participants; evidence from low quality) 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-MNC with BM-MSC did not report amputations. Data from a single study with low-quality evidence showed a similar number 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 in the BM-MSC group appeared to have ulcer healing than in the BM-MNC group (RR 2.00, 95% CI 1.02 to 3.92; 1 RCT, 22 participants ; Moderate-quality evidence). Investigators comparing high and low doses of cells did not report ulcer healing. Data from individual studies showed a similar number of participants with reduced pain at rest between BM-MNC and mPBSC (RR 0.99, 95% CI 0.93 to 1.06; 104 participants; quality evidence moderate) and between IM and AI 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). Studies comparing high and low doses of cells did not report pain at rest. Data from a single study showed no significant difference in the number of participants with elevated ankle-brachial index (ABI; greater than 0.1 increase from pretreatment) between BM-MNC and mPBSC (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 values ​​appeared to be higher in the BM-MSC versus BM-MNC groups (MD 0.05, 95% CI 0.01 to 0.09; 1 RCT, 37 participants; quality evidence short). When comparing high and low cell doses, no ABI was reported. A similar number of participants 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 ). Data from single studies with low-quality evidence showed higher TcO₂ in the BM-MSC versus BM-MNC groups (MD 8.00, 95% CI 3.46 to 12.54; 37 participants) and in mPBSC-treated groups versus BM-MNC (MD 1.70, 95% CI 0.41 to 2.99; 150 participants). TcO₂ was not reported when comparing high versus low cell doses. The study authors reported no significant short-term side effects attributable to autologous cell implantation. The authors concluded that most of the low and very low quality evidence suggested that there were no clear differences between different stem cell sources and different autologous cell implantation treatments for outcomes such as all-cause mortality, rate of amputation, ulcer healing, and rest. pain Pooled analyzes did not show a clear difference in clinical outcomes whether cells were administered IM or AI. High-quality evidence was lacking; Therefore, the long-term efficacy and safety of autologous cells derived from different sources, manufactured with different protocols, administered at different doses, and delivered by different routes to treat patients with ILC without option have yet to be confirmed. These investigators stated that future RCTs with larger numbers of subjects are needed to determine the efficacy of cell-based therapy for patients with CLI along with the optimal cell source, phenotype, dose, and route of implantation. Furthermore, they stated that longer follow-up is needed to confirm the durability of the angiogenic potential and the long-term safety of the cell-based therapy.

Autologous Interleukin-1 Receptor Antagonist Blood Products for Osteoarthritis of the Knee

In a systematic review, Ajrawat and colleagues (2019) reviewed the available clinical data on the use of autologous interleukin (IL)-1 receptor antagonist (AILBP) blood products and their validity as alternative AI therapy in symptomatic knee OA. We searched PubMed, Medline, Embase, and Cochrane Library databases from inception to June 2018. All RCTs and non-comparative studies evaluating the efficacy of AILBPs (i.e., autologous protein solution and autologous conditioning serum) in knee osteoarthritis. The primary endpoint was the Western Ontario and McMaster Universities Osteoarthritis Index; Secondary outcomes measured were knee injury and osteoarthritis outcome score, VAS score, short form 36 (SF-36) score, radiological scores, and AEs, which were analyzed qualitatively. These investigators included 8 studies, including 3 RCTs (Level II) and 5 non-comparative studies (Level IV), with a total of 592 patients (mean age 56.4 years; 49.7% male). RCTs represented high methodological quality, while non-comparative studies represented moderate to good quality. With AILBPs, 2 of 4 studies (50%) showed improvements in sports injury and knee injury subscales and osteoarthritis symptom subscales, 5 of 7 studies (71%) showed improvements in osteoarthritis index score from Western Ontario and McMaster Universities, and 4 of 5 studies (80%) achieved improvements in VAS pain score from baseline to last follow-up. Most AILBP-associated AEs were mild to moderate in severity and were located primarily at the injection site. The authors concluded that limited evidence supports AILBPs as a safe and tolerable AI injection therapy that may improve pain parameters and function for patients with mild to moderate knee osteoarthritis and may be an effective adjunct for those who they do not respond to conventional AI 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 mentioned above, which may have influenced patient-reported outcome measures (PROMs). Second, 2 trials allowed the use of analgesics and NSAIDs for pain-related symptoms, which could easily have helped improve PROM. Third, 1 study included patients who had previously undergone arthroscopic procedures that could not be controlled. Fourth, there was the possibility of publication bias, as only 50% of the studies reported positive results. Fifth, the wide variation in the Kellgren-Lawrence rating scale may have affected the PROM and radiographic results. Finally, the inclusion of multiple levels of clinical trials potentially introduced selection bias and confounding.

Serum or Autologous Whole Blood Acupoint Injection Therapy for Chronic Urticaria

Chang and colleagues (2019) found that chronic spontaneous urticaria (CSU) are chronic papules 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 the available evidence on the safety and efficacy of AWB and AST therapy for CLD. They searched 4 databases for studies suitable for meta-analysis. The primary endpoint was the efficacy of AST or AWB therapy, and the secondary endpoint was improvement after intervention, based on the patients' autologous serum skin test (ASST) status. A total of 8 clinical trials were identified, including 4 RCTs and 529 patients with CSU. AST was no more effective than placebo treatment in alleviating CSU symptoms at the end of treatment (p=0.161), and AWB injection was also no more effective than placebo in response rates at end of follow-up (p=0.161). =0.099). Furthermore, the efficacy of AST or AWB injection for CSU and ASST status was not significantly related. No noteworthy AEs were recorded during therapy. The authors concluded that the results of this meta-analysis indicate that AWB and AST therapy was not significantly more effective than placebo treatment in relieving CSU symptoms.

Zhang and colleagues (2019) found that chronic urticaria (UC) is a common and easily recurring skin disease worldwide. Many studies have shown that AWB or AST acupuncture point injection therapy is effective in the treatment of UC. There is currently no systematic review of this therapy. These investigators studied the safety and efficacy of this therapy in patients with ulcerative colitis. The literature search was performed in 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 is May 2019. You will be looking for common terms such as UC and this therapy. You import the literature electronically; Duplicate documents will be removed. The primary outcome is the urticaria activity score or other validated scales. Secondary endpoints included response rate, quality of life scale, recurrence rate, and adverse events. These investigators will perform a systematic review and RCT of this therapy for UC; and implement the Cochrane RevMan V5.3 bias assessment tool to assess risk of assessment bias, risk of data integration, risk of meta-analysis, and risk of subgroup analysis (if conditions are met). Mean difference, standard MD, and binary data are used to present continuous results. This study will provide a comprehensive review of the available evidence supporting the treatment of UC with this therapy. The authors concluded that this study will provide new evidence to assess the efficacy and side effects of this therapy for UC.

Platelet-rich fibrin injection for intrabony defects in chronic periodontitis

In a meta-analysis, Li et al (2019) determined the additional efficacy of autologous PRF in the treatment of intrabony defects in patients with chronic periodontitis. Relevant studies were identified by searching Medline, Embase, Web of Science, and the Cochrane Library. The studies searched for were checked for eligibility. Cochrane Collaboration Review Manager software was used to perform meta-analyses. A total of 12 eligible trials were included. Pooled data revealed that adjuvant PRF resulted in precisely a significantly greater reduction in probing depth compared with open flap debridement alone (WMD, 1.01, 95% CI 0.95 to 1.08; p <0.00001). The increase in clinical connection level (CAL) after 9 months of treatment was greater in patients treated with PRF plus open debridement than in patients treated with open debridement (WMD, 1.29; 95% CI: 0.96 to 1.61, p < 0.00001). The meta-analysis also showed that PRF was superior to single flap debridement in terms of marginal gingival level change (WMD, 0.45, 95% CI 0.31 to 0.58, p<0.00001). In terms of hard tissue radiographic parameters, including reduction of defect depth and percentage of bone-fill defects, adjuvant PRF yielded significantly better results compared with open flap debridement. The authors concluded that the addition of PRF to open valve debridement significantly improved filling defects compared to open valve debridement alone. However, these investigators stated that further studies with much larger sample sizes are needed to reach a more concrete conclusion.

Platelet Rich Fibrin Injection for Rotator Cuff Tears

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

Platelet Rich Plasma Injection for Achilles Tendonitis/Tendinopathy

In a meta-analysis, Liu and colleagues (2019) reviewed the evidence on the effectiveness of PRP for the treatment of chronic Achilles tendinopathy (TA). The PubMed, Embase, Web of Science, and Cochrane Library databases were searched for articles on RCTs comparing the effectiveness of PRP versus placebo injections plus eccentric training as a treatment for BP. Articles were loaded during database setup up to 1 May 2018. The Cochrane Risk of Bias (ROB) tool was used to assess methodological quality. Outcome measures included Victorian Institute of Sport Assessment-Achilles (VISA-A), VAS, and Achilles tendon thickness. Statistical analysis was performed using RevMan 5.3.5 software. A total of 5 RCTs (n = 189) were included in this meta-analysis. Under VISA-A, there was no significant difference 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) observed: -0.10 to 1.65, I=85%) and 1 year (SMD=0.83, 95% CI: -0.76 to 2.42, I =72%) of the treatment. However, PRP showed greater efficacy than 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, the VAS scores at week 12 were (SMD = 1.10, 95% CI 0.53 to 1.68, I = 83%) and tendon thickness (SMD = 1.51, 95% CI 95%: 0.39) to 2.63, I = 53%) 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 investigators stated that these results need to be verified by a large number of well-designed, heterogeneous RCT studies.

In a systematic review, Wang et al (2019) examined the effectiveness of PRP injections in the treatment of Achilles tendinitis. These researchers conducted a literature search of the Cochrane Library Central Register of Controlled Trials (2017), PubMed (January 1976 to March 2017), and Embase (January 1976 to March 2017) databases to obtain clinical evidence. available for PRP in the treatment of Achilles tendon. lesions Inclusion criteria were conservative PRP treatment for Achilles tendonitis in one RCT, level I clinical research evidence, and one publication in English. Exclusion criteria were unclear methods and experimental data, as well as PRP treatment of other diseases. A total of 4 articles with 152 cases were included in the analysis. The average age of the participants was 49 years. Data on VISA A-score, color Doppler index, and recovery time to normal exertion were extracted. There were no significant differences between the treatment groups and the control groups after the PRP injections. The authors concluded that the lack of differences between the data of the control group and the groups of patients included in the studies could be related to the difficulty of conducting an RCT; No strong basis has been found for using PRP to treat Achilles tendonitis.

Platelet Rich Plasma Injection for Greater Trochanteric Pain Syndrome

In a systematic review, Ali and colleagues (2019) examined whether PRP plays a role in improving clinical outcomes in patients with symptomatic greater trochanteric pain syndrome (GTPS). These investigators performed a search of the NICE Health Database Advanced Search (HDAS) in Athens (PubMed, Medline, CINAHL, Embase, and AMED databases) from the base year to April 2018 using the keywords: " greater trochanteric pain syndrome" or "GTPS". . or "gluteus medius" or "trochanteric bursitis" and "platelet-rich plasma" (PRP). Quality assessment was performed using the JADAD score for RCTs and MINORS for non-RCT studies. A total of 5 full-text articles, consisting of 3 RCTs and 2 case series, were included for review. These investigators also identified 4 additional studies from published conference proceedings (1 RCT and 3 case series). The mean age of the 209 patients was 58.4 years (range 48 to 76.2 years). Most of the patients were women and the minimum duration of symptoms was 3 months. Diagnosis was made by ultrasound or magnetic resonance imaging. The included studies used a variety of outcome measures. Improvement was observed during the first 3 months after the injection. Significant improvement was also seen when patients were followed up to 12 months after treatment; PRP appeared to be a viable alternative injectable option for GTPS unresponsive to conservative measures. The authors concluded that the current literature shows that PRP is relatively safe and may be effective. Furthermore, these investigators stated that given the limitations of these studies, more high-quality randomized clinical trials with large samples are needed to provide further evidence of the effectiveness of PRP as a treatment for GTPS.

Platelet Rich Plasma Injection For Vitiligo

Hesseler and Shyam (2019) stated that the field of dermatology has seen numerous therapeutic innovations using PRP in the last 10 years and has recently gained significant interest in alopecia, acne scars, and skin rejuvenation. PRP has been studied in other dermatological conditions, such as chronic wounds and vitiligo, but has received less attention. In a systematic review, these investigators focused on medical dermatology terms and consolidated the available evidence on PRP for the practicing dermatologist. They reviewed the literature up to October 31, 2018, and searched the PubMed database for "platelet-rich plasma," "platelet release," "platelet gel," "platelet-rich fibrin," or "PRP." Dermatology", "skin", "skin", "wound" or "ulcer". A total of 14 articles met the inclusion criteria for this review. In studies with levels of evidence Ib to IV according to the Center for Evidence-Based Medicine , Oxford, PRP significantly improved wound healing in chronic diabetic ulcers, venous ulcers, pressure ulcers, leprosy ulcers, acute traumatic wounds, and multifactorial ulcer etiologies;2 studies also documented the benefits of adjunctive PRP in stable vitiligo The authors concluded that PRP in vitiligo as well as in chronic wounds with multiple etiologies deserves further investigation since it represents a potential adjuvant or therapeutic alternative with a favorable profile of side effects.

Autologous adipose-derived regenerative cell (ADRC) therapy for the treatment of partial tears of the rotator cuff

In a prospective, randomized, controlled, human-first, open-label pilot study, Hurd et al. (2020) hypothesized that treating symptomatic rotator cuff tears (sPTRCT) with fresh, uncultured, unmodified, autologous adipose-derived regenerative cells (AU-ADRC) isolated from point-of-care liposuction is safe. and more effective than injecting corticosteroids. . Patients 30 to 75 years of age with sPTRCT who had not responded to physical therapy (PT) for at least 6 weeks were randomized to receive a single injection of a mean of 11.4 × 10(6) AU-ADRC (in 5 mL of liquid) ; mean cell viability: 88% (n=11; modified intention-to-treat (mITT) population) or a single injection of methylprednisolone 80 mg (40 mg/mL; 2 mL) plus 0.25% bupivacaine 3 mL ( n = 5; mITT population). Safety and efficacy were assessed using the American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES), the RAND Short Form-36 Health Survey, and VAS pain at baseline (BL) and at 3 weeks (S3). , S6, S9, S12 examined , S24, S32, S40 and S52 post-treatment. Saturated fat T2-weighted MRI of the shoulder was performed at BL and at W24 and W52 after treatment. No serious side effects associated with UA-ADRC injection were observed for 12 months after treatment. The risks associated with treatment of sPTRCT with UA-ADRC were no greater than those associated with treatment of sPTRCT with corticosteroid injection. However, 1 subject in the corticosteroid group developed a complete rotator cuff tear during the course of this pilot study. Despite the small number of subjects in this pilot study, those in the UA-ADRC group demonstrated statistically significantly higher mean total ASES scores at W24 and W52 after treatment than those in the corticosteroid group (p<0.05). The authors concluded that the results of this pilot study indicated that the use of UA-ADRC in patients with sPTRCT was safe and improved shoulder function without side effects. Furthermore, these investigators stated that an RCT involving 246 sPTRCT patients is currently underway to verify the results of this first safety and feasibility pilot study.

The authors stated that this prospective, randomized, controlled pilot study of UA-ADRC versus corticosteroids for the treatment of sPTRCT was the first human pilot study with safety as the primary clinical outcome and was therefore designed as an open-label study: it had 2 main disadvantages. First, only a small sample of sPTRCT subjects were studied, only a limited number of clinical research methods were used, no power analysis was performed, and neither the subjects nor the clinicians who administered the treatment and the evaluators who performed baseline and follow-up MRIs were blinded (MRIs were only analyzed by clinicians). Second, only 1 control treatment was evaluated. Alternatives could have been a placebo injection or a suprascapular nerve block. The latter has recently been shown to lead to a better clinical outcome than subacromial injection of the same volume of 9 mL 1% ropivacaine and 1 mL betamethasone at W6 and W12 after treatment (no follow-up reported beyond S12). . However, the ultimate goal of this pilot study was not to definitively establish UA-ADRC as a treatment for sPTRCT. Rather, the goal of this study was to collect enough safety data to design a proper pivotal study, which would ultimately include 246 sPTRCT patients. This pivotal study, which was not affected by the limitations described above, is now recruiting.

Alt et al. (2021) noted that current therapeutic options for sPTRCT offer limited potential for actual tissue healing and improved clinical outcomes. In animal models, injections of adult stem cells isolated from adipose tissue into tendon lesions showed histological regeneration of tendon tissue. However, it is not clear whether such beneficial effects can also be observed in a human tendon treated with UA-ADRC. A particular challenge here is that AU ADRCs cannot be tagged; therefore, it is not clearly identifiable in the host tissue. Therefore, the histological regeneration of injured human tendons after UA-ADRC injection should be assessed based on a comprehensive microscopic and immunohistochemical analysis of biopsies taken from the treated tendon a few weeks after UA-ADRC injection. These investigators reported the results of a 66-year-old patient who suffered a sPTRCT involving the right supraspinatus and infraspinatus tendons as a result of a bicycle accident. On day 18 post-injury [day 16 post-MRI], approximately 100 g of abdominal fat tissue was removed by liposuction, of which approximately 75 x 10(6) AU-ADRCs were isolated within 2 hours. Then, immediately after isolation, UA-ADRCs were injected adjacent to the injured supraspinatus tendon (monitored by biplane X-ray imaging). Despite rapid clinical recovery, a follow-up MRI 2.5 months after treatment indicated the need for open revision of the injured infraspinatus tendon that had not been treated with UA-ADRC. During this operation, a biopsy was taken from the supraspinatus tendon at the injury site. A complete, immunohistochemical, and microscopic analysis of the biopsy (consisting of 13 antibodies) showed newly formed tendon tissue. The authors concluded that UA-ADRC injection can regenerate injured human tendons by forming new tendon tissue.

The authors stated that the conclusions of this study were presented on the basis of an analysis of molecular and cellular events at a single point in time. Limitations were that only one patient was examined; no control biopsy was analyzed and the investigators who analyzed the biopsy were not blinded. Furthermore, the aim of this study was not to establish a clinical treatment. To more conclusively assess the clinical results with UA-ADRC in incomplete tendon ruptures, a prospective pivotal RCT will be recruited, based on the encouraging clinical results of the pilot study by Hurd et al. (2020) based.

General reviews

Rompeand's colleagues (2008) stated that the treatment of Achilles tendinitis is mainly conservative. Although there are many non-surgical options available, few have been tested under controlled conditions. In refractory cases, surgical intervention may be successful. However, surgery does not usually completely eliminate the symptoms and complications are not uncommon. The authors stated that further studies are needed to determine the optimal surgical and non-surgical treatment of tendinopathy of the middle Achilles tendon.

In a systematic review, Rabago et al. (2009) Existing evidence for the therapies of prolotherapy, polidocanol, autologous whole blood, and PRP injection for lateral epicondylosis (PE). Results from 5 prospective case series and 4 controlled studies (3 prolotherapy, 2 polidocanol, 3 autologous whole blood, and 1 PRP) suggested that each of the 4 therapies is effective in PD. Over follow-up periods of 9 to 108 weeks, the studies reported a statistically significant (p<0.05) sustained improvement in the 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 assessment of biomechanical function of the elbow (polidocanol and prolotherapy), presence of abnormalities, and increased vascularity on ultrasound (autologous whole blood and polidocanol). Subjects indicated their satisfaction with the therapies in individual ratings. All studies were limited by the small sample size. The authors concluded that there is strong pilot-level evidence supporting the use of prolotherapy injections, polidocanol, autologous whole blood, and PRP injections in the treatment of PD. However, rigorous studies with a sufficient sample size are needed to evaluate these injection therapies using validated clinical, radiological, and biomechanical measurements and biomarkers that respond to tissue injury/scarring to determine long-term safety and efficacy and to determine whether these techniques can be used in the Treatment of LE and other tendinopathies.

vanArk et al. (2011) reviewed the different injection treatments, their rationale, and the efficacy of treating patellar tendon syndrome. A computer search of the Medline, Embase, CINAHL, and Web of Knowledge databases was performed on May 1, 2010 to identify studies on injection treatments for patellar tendon syndrome. 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 cohorts. . All studies reported positive results. Delphi scores for the 4 RCTs ranged from 5 to 8 out of 9. Different and sometimes conflicting justifications were used for the injection treatments. The authors concluded that the 7 different injection treatments show promise for the treatment of patellar tendon syndrome. Unlike other injection treatments, long-term steroid treatment often shows a relapse of symptoms. They stated that the results should be interpreted with caution because the number of studies is small, few high-quality studies were conducted, and the studies are difficult to compare due to different methodology. They stated that more high-quality studies with the same reliable and valid cross-cultural outcome measure are needed, as well as more research on pathophysiology.

Pak et al. (2013) found that mesenchymal stem cells from different sources (bone marrow, synovial tissue, umbilical cord blood, and adipose tissue) can differentiate into variable parts (bone, 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 bone. However, there have been no follow-up studies in humans treated with adipose-derived stem cells (ADSCs) for chondromalacia patellae. To obtain ADSC, lipoaspirates of subcutaneous hypogastric adipose tissue were obtained. The stromal vascular fraction was separated from the lipoaspirates by centrifugation after collagenase treatment. The vascular stromal fraction containing stem cells was mixed with PRP activated by calcium chloride and hyaluronic acid, and this ADSC mixture was then injected under ultrasound guidance into the retropatellar joints of all 3 patients. Patients underwent magnetic resonance imaging before and after treatment. Subjective pain scores before and after treatment and physiotherapy assessments measured clinical changes. One month after autologous ADSC injection, each patient's pain improved by 50-70%. Three months after treatment, patients' pain improved by 80-90%. Pain improvement lasted for more than 1 year, which was confirmed by telephone follow-up. Furthermore, all 3 patients did not report serious side effects. Repeat MRIs at 3 months showed improvement in damaged tissue (softened cartilage) in the patella and femur joints. The authors concluded that in patients with chondromalacia patellae presenting with persistent anterior knee pain, percutaneous injection of autologous ADSCs may play an important role in repairing damaged tissue (softened cartilage). They stated that ADSC treatment offers a glimpse of a promising, effective, safe and non-surgical new treatment modality for chondromalacia patellae. These preliminary results 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 (eg, autologous blood, PRP, bone marrow plasma) for the treatment of tendinopathies.

Leucopatch (3C patch) for the treatment of diabetic foot ulcers

In an uncontrolled prospective pilot study, Jorgensen et al. (2011) Safety and clinical performance of Leucopatch in the treatment of chronic refractory wounds. A total of 15 patients with 16 chronic lower extremity (LE) wounds of various etiologies were treated weekly for 6 weeks or until healed with Leucopatch prepared at the point of care (POC) from a patient's blood donation. . Completely. The wounds were between 2 and 108 months old (median 24 months) and their size ranged from 0.4 to 15.7 cm(2) (median 2.3 cm(2)) and had not responded to previous treatments. Of the 13 wounds (12 patients) included in the per-protocol efficacy analysis, 4 healed completely (31%). Mean wound area decreased significantly by 65% ​​(95% confidence interval [CI] 45.6% to 83.8%), resulting in a mean wound size of 0.9 cm (2) (range 0 to 9.6 cm(2)). No serious adverse events (AEs) occurred. Two AEs were observed, 1 of non-adherence and 1 of infection; none were considered related to treatment. The authors concluded that these results indicate that Leucopatch is easy to prepare and apply in the clinic, is safe, and may provide clinically effective treatment for chronic refractory wounds. In addition, these investigators stated that further investigation from a properly designed long-term randomized controlled trial (RCT) is needed to confirm the potential wound healing benefits of Leucopatch proposed in this study.

The authors stated that the conclusions of this pilot study were limited by many factors, especially its open-label and non-comparative nature. The small number of wounds studied (n=16) with different etiologies meant that these investigators were unable to examine whether the observed wound healing rates varied across different types of wounds. Although all of the wounds in this study were found to be inconsistent with conventional treatments, these researchers did not know how many wounds would have improved with the additional care and attention patients received as part of the clinical study. There were many patient-related factors that could affect ulcer healing that were not controlled for in this study. These researchers could not completely rule out that a change in the manufacturing process would affect the results of the study. However, a subgroup analysis indicated that Leucopatch manufactured in a device (as intended to be marketed) is probably no less effective than patches on a laboratory scale.

Londahl et al. (2015) stated that Leucopatch is a leukocyte- and platelet-rich fibrin glue that delivers concentrated blood cells and signaling substances to the surface of an ulcer. It is made by centrifuging the patient's own venous blood. In a multicenter pilot cohort study, these investigators examined the effects of the leukocyte patch in patients with difficult-to-heal diabetic foot ulcers (DFUs). Wagner grade 1 or 2 non-ischemic DFUs with a duration greater than 6 weeks and a maximum area of ​​10 cm² were included. Patients with a change in ulcer area greater than 40% during a baseline period of 2 weeks were excluded. Treatment was administered once a week for up to 19 treatments or until the foot ulcer was completely epithelialized. The primary endpoint was cure within 20 weeks. Of the 60 patients who consented, 16 were excluded during the reference period, 44 patients entered study treatment, and 39 were included in the per-protocol analysis. Complete epithelialization was achieved in 34% (per protocol analysis 36%) at 12 weeks and 52% (59%) at 20 weeks. In patients with ulcers lasting less than 6 months, 73% of the ulcers healed within 20 weeks. Patients with healed ulcers experienced a greater reduction in ulcer area during the first 2 weeks of treatment compared with non-healing patients; The AAs were mild and rare. The authors concluded that the leukocyte patch is well tolerated, easy to use, and has potential in the DFU treatment armamentarium, provided this finding is confirmed in a sufficiently powered multicentre RCT.

These investigators stated that because this was an uncontrolled cohort study and not an RCT, bias could occur. Interventions such as more frequent visits to diabetic foot clinics and increased alertness may affect outcome; therefore, their ulcer healing rates should be interpreted with caution. However, treatment strategies, including offloading, antibiotics, offloading, and vascular intervention, were the same.

In a small case series study (n = 22 patients; 26 wounds), Fagher et al. (2015) evaluated the safety and ulcer healing of Leucopatch treatment in diabetic foot ulcers at least Wagner grade 3 (i.e. positive ulcer probing for authors concluded that these results suggest Leucopatch is suitable for application to the bone surface in DFU is safe and may have positive effects on wound healing, although more RCTs are needed to demonstrate its efficacy before its use in routine clinical practice can be recommended.

Game et al. (2018) stated that the Leucopatch device uses bedside centrifugation without additional reagents to generate a disc of autologous leukocytes, platelets, and fibrin that is applied to the wound surface. In a blinded international multicentre RCT, these investigators evaluated the efficacy of Leucopatch in healing difficult-to-heal foot ulcers in patients with diabetes. In this study, patients with diabetes and poorly healing foot ulcers were enrolled in 32 specialist diabetic foot clinics in 3 countries (Denmark, Sweden and the UK). After a 4-week run-in period, those with less than 50% reduction in ulcer area were randomized (1:1) using computer-generated web-based randomization (block sizes 2, 4, and 4). 6). Pre-established good standard of care (SOC) alone or treatment plus weekly use of Leucopatch. The primary endpoint was the proportion of ulcers healed at 20 weeks, assessed in the intention-to-treat (ITT) population (all subjects with data collected post-randomization), defined as complete epithelialization (confirmed by an observer who was masked for randomization). group) and remained cured for 4 weeks. Between August 30, 2013, and May 3, 2017, a total of 269 participants were randomized to treatment (137 received SOC and 132 received 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. at 20 weeks vs. 29 (22%) of 134 ulcers in the SOC group (odds ratio [OR] 1.58, 96% CI 1.04 to 2.40, p=0.0235) by ITT analysis. Healing time was shorter in the Leucopatch group (p=0.0246) than in the SOC group. No differences in AEs were observed between the two groups. The most common serious adverse event (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 a significant improvement in the healing of poorly healing foot ulcers in patients with diabetes.

The authors stated that the main disadvantage of the design and conduct of this study was the inability to mask the subject or clinical investigator to treatment assignment. The use of sham venipuncture was rejected as unethical, but the primary outcome assessment was performed by a blinded independent observer and supported by digital imaging. The inclusion and exclusion criteria ensured that the recruited population was representative of a difficult-to-cure population; this assumption was reflected in the overall low incidence of scarring in the no intervention group. However, an element of selection was evident as the median age was slightly lower than predicted (62 years vs. 67 years predicted), possibly reflecting the need for participants to attend every week for a maximum of 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 studies in this area. The overall incidence of scarring was lower than expected and lower than observed in the pilot studies, but likely reflected more rigorous selection from a defined hard-to-cure population. It was also possible that the low cure rate reflected a poor SOC, possibly different between the two groups. These investigators believe this hypothesis is unlikely as the low cure rate in already preselected patients with poorly healing ulcers after the initial 4-week period is similar to that reported by Coerper et al. (2009) reported. Furthermore, the two groups were well matched in terms of their baseline characteristics and palliation strategies, with similar numbers undergoing revascularization during the 26-week follow-up. Therefore, a different SOC was unlikely to explain the additional healing benefit observed in the intervention group.

Commenting on the Game et al (2018) study, Alvaro-Afonso et al (2018) state that a cost-benefit analysis will be necessary. The optimal duration of treatment also needs to be further determined. Notably, healing was faster in the intervention group during the first 12 weeks, but not thereafter, leading the authors to consider whether Leucopatch treatment can be discontinued before complete wound closure (13). They indicated that the results of Game et al (2018) are very promising. Therefore, experiences with other types of DFU and cost-benefit analyzes are very welcome to increase the use of this product in clinical practice.

The International Working Group on the Diabetic Foot (IWGDF) guideline on “Interventions to improve foot ulcer healing in people with diabetes” (Rayman et al., 2019) made the following recommendation:

• Consider use of pooled autologous leukocytes, platelets, and fibrin as add-on to best standard of care for poorly healing uninfected diabetic foot ulcers (Strength of recommendation: Weak; Quality of evidence: Moderate)

ECRI's review of platelet-rich plasma therapy for diabetic foot ulcers (2021) identified 3 guidelines addressing the treatment of DFU: 2 do not recommend PRP therapy and 1 makes no statement on PRP therapy.

In the Australian guide Wound Healing Interventions to Improve Healing of Foot Ulcers, Chen et al. (2022) find that DFU imposes a significant burden on both individuals and health systems, both globally and in Australia. There is an urgent need for updated guidelines on wound healing interventions to improve outcomes for people with UPD. A national panel of experts was convened to develop new evidence-based Australian guidelines on wound healing interventions for people with UPD and to adapt the international guidelines for the Australian context. The panel followed the National Health and Medical Research Council (NHMRC) procedures for adapting the appropriate international IWGDF guidelines to the Australian context. The panel systematically reviewed, evaluated and evaluated all the IWGDF wound healing recommendations using the adaptation frameworks from the ADAPTE and GRADE guidelines to decide which recommendations should be adopted, modified or removed in the Australian context. For each recommendation, the wording, quality of the evidence, and strength of the recommendation were reassessed, and implementation considerations and justification for the Australian context were provided. This policy was publicly consulted, then reviewed and approved by 10 national authorities. A total of 13 IWGDF wound healing recommendations were evaluated. After screening, 9 recommendations were accepted and 4 were adjusted after full evaluation; The strength of recommendation of 2 recommendations was downgraded, 1 intervention was not currently approved for use in Australia, 1 intervention specified the need for informed consent to be acceptable in Australia, and another was reformulated to clarify the best SOC. A total of 5 wound healing interventions were recommended that have evidence-based potential to improve wound healing in certain types of DFUs when used in conjunction with other DFU enhanced standards of care, including octasulfate-impregnated dressings. sucrose, systemic hyperbaric oxygen therapy (HBOT), Negative Pressure - Wound Therapy (NPWT), placental products, and the combined dressing of autologous leukocytes, platelets, and fibrin. The 6 new guidelines and the full protocol can be found at:Australian guidelines for diabetic foot conditions🇧🇷 The authors concluded that the IWGDF guidance for wound healing interventions has been adapted to the Australian context, particularly geographically remote peoples and Aboriginal and Torres Strait Islander peoples. This new National Wound Healing Policy, endorsed by 10 national bodies of excellence, also highlighted important considerations for implementation, monitoring and future research priorities in Australia. The Australian guide adapted the IWGDF guide in Leucopatch:

• Consider the combined use of autologous leukocytes, platelets and fibrin as adjunctive therapy to the best standard of care for non-infected diabetic foot ulcers that are difficult to heal ONLY IF such adjunctive therapy is approved for use in Australia (Strength of recommendation: Weak; Quality of evidence: moderate ).

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