Platelet rich plasma Injection grafts for musculoskeletal injuries：a review（5）.
Literature review
There is extensive documentation of both animal and human studies, with widespread applications, demonstrating the safety and efficacy of PRP for 20 years. However, most studies are pilot studies with small sample sizes. Recently, there is emerging literature on the beneficial effects of PRP for chronic non-healing tendon injuries including lateral epicondylitis and plantar fasciitis [1, 2]. Other orthopedic applications include diabetic wound management, treatment of non-unions, and use in acute tendon injuries. There is also a range of publications in other fields including ENT, cardiology, and plastic surgery. The following is a review of some of the more recent studies on PRP.
Elbow
In a recent study in the American Journal of Sports Medicine, Mishra et al. evaluated 140 patients with chronic epicondylar elbow pain. Of those patients, 20 met the study criteria and were surgical candidates who had failed conservative treatments. In total, 15 were treated with one PRP injection and five were controls with local anesthetic. The treatment group noted 60% improvement at 8 weeks, 81% at 6 months, and 93% at final follow-up at 12–38 months. Of note, there were no adverse effects or complications. Additionally, there was a 94% return to sporting activities and a 99% return to daily activities [1]. The major limitation of this study was the 60% attrition rate in the control group as 3/5 of the patients withdrew from the study or sought outside treatment at 8 weeks. This small retrospective series is considered a pilot study and a randomized clinical trial is needed to substantiate these findings.
In 2003 Edwards and Calandruccio, demonstrated that 22 of 28 patients (79%) with refractory chronic epicondylitis were completely pain free following autologous blood injection therapy [15]. There was no reported worsening or recurrence of pain and no other adverse events. Pain after autologous blood administration was variable, but most patients reported it to be similar to prior steroid injections they received before the study. One patient failed to improve satisfactorily and eventually underwent surgery [15]. This study is limited by its small sample size and lack of control group.
Foot and ankle
Barett et al. enrolled nine patients in a pilot study to evaluate PRP injections with plantar fasciitis. Patients met the criteria if they were willing to avoid conservative treatments including bracing, NSAIDS, and avoidance of a cortisone injection for 90 days prior. All patients demonstrated hypoechoic and thickened plantar fascia on ultrasound. While anesthetizing each patient with a block of the Posterior tibial and Sural nerve, 3 cc of autologous PRP was injected under ultrasound guidance (Fig. 7). Post-injection thickness and increased signal intensity of the fascial bands were seen on ultrasound. Six of nine patients achieved complete symptomatic relief after 2 months. One of the three unsuccessful patients eventually found complete relief following an additional PRP injection. At one year 77.9% patients had complete resolution of symptoms [2]. Again, this was a non-controlled pilot study with a small sample size.
Fig. 7
Ultrasound guided suprapatella bursa injection/graft
Knee
After injecting rat patellar tendons with PRP, Kajikawa et al. showed increased quantity of circulation-derived cells in the early phase of tendon repair after injury versus controls. Unfortunately, these helpful cells normally disappear with time; therefore prolonging their presence is beneficial. Furthermore, they showed increased type I & III collagen and macrophages [27].
Taylor, et al. demonstrated safety and efficacy while injecting autologous blood into New Zealand white rabbits at the patellar tendon. After reviewing the histology at 6 and 12 weeks, there was no adverse change in histology or tendon stiffness. However, the tendons injected with blood were significantly stronger [28].
Berghoff et al. retrospectively reviewed a large series of patients in an effort to access autologous blood product effects in patients undergoing total knee arthroplasty (TKA). The study included 66 control patients and 71 patients treated with autologous blood products at the wound site. The intervention group demonstrated higher hemoglobin levels and fewer transfusions as well as shorter hospitalization and greater knee range of motion at 6 weeks. Additionally, no infections occurred and significantly fewer narcotics were required [29]. Although limited by the retrospective nature of the study, the results are compelling.
Gardner et al. performed a similar retrospective study in a series of patients undergoing TKA. The patients were treated with an intra-operative Platelet gel; resulting in lower blood loss, improved early range of motion, and fewer narcotic requirements [30].
In a controlled study by Everts et al., of 160 patients undergoing Total Knee Replacements (TKA), 85 received Platelet gel and Fibrin sealants; which resulted in decreased blood transfusion requirements, lower post-surgical wound disturbances, shorter hospital stay, and fewer infections [31].
Wounds
Non-healing cutaneous wounds represent a challenging problem and are commonly related to peripheral vascular disease, infection, trauma, neurologic and immunologic conditions, as well as neoplastic and metabolic disorders. These chronic ulcerative wounds represent significant impact both psychologically and socioeconomically. An analysis of the surfaces of chronic pressure wounds (decubitus ulcers) revealed a decreased growth factor concentration compared with an acute wound [32]. In a study by Crovetti et al., 24 patients with chronic cutaneous ulcers were treated with a series of PRP Gel treatments. Only three patients received Autologous blood PRP due to medical issues, while the others received Donor blood product. Nine patients demonstrated complete wound healing. Of those nine, one wound reopened at 4 months. There were two reports of wound infection, both with positive Staph Aureus which were successfully treated with oral antibiotics. There were no adverse effects encountered and all patients noted decreased pain [32].
Another wound study by McAleer et al., involved 24 patients with 33 chronic non-healing lower extremity wounds. Patients failed conservative treatment for >6 months with a lack of reduction of surface area. Surgical wound debridement was initially performed to convert chronic ulcers to acute wounds, in an effort to promote wound metabolism and chemotaxis. The wounds were injected with PRP every 2 weeks. Successful wound closure and epitheliazation was obtained in 20 wounds. The mean time for closure was 11.15 weeks. Five wounds displayed no improvement [33]. These findings were particularly significant because all patients had failed previously available treatment methods.
Bone
Diabetes impairs fracture healing with Reduced early proliferation of cells, Delayed osteogenesis, and Diminished biomechanical properties of the fracture callus [34, 35]. In an animal study by Gandhi et al., male Wister rats received closed mid-diaphyseal fractures after 14 days of the onset of diabetes. PRP did not alter blood glucose levels or HbA1c. The study demonstrated that diabetic rats had decreased growth factors compared to non-diabetic group [34].
Not all studies on autologous growth factors have shown favorable results with promoting bone formation and healing. In a recent study by Ranly et al., PRP was shown to decrease osteoinductivity of demineralized bone matrix in immunocompromised mice. PRP from six healthy men was implanted as gelatin capsules in the calves of inbred nude mice. After 56 days the mice were killed and the studied calf muscles suggest that PDGF may actually Reduce osteoinductivity [24]. The main criticism of this study is related to the PRP treatment protocol. Conventional PRP processing kits yield a 6-fold increase in platelet concentration. However, in the Ranly study the PRP concentration was only Four times above baseline. Additionally, the timing of the assays looking at osteoinduction may have been too late to accurately access early bone formation.
Spine
Generally, maintaining arthrodesis in a posterolateral lumbar fusion can be challenging and may necessitate revision [36]. Subsequently multiple strategies have evolved to Decrease non-union rates including screw instrumentation, interbody fusion, bone morphogenic protein, and Limiting risk factors such as smoking, NSAID, and corticosteroid use [37]. There is mixed literature and controversy surrounding the efficacy of platelet gel to supplement autologous bone graft during instrumented posterolateral spinal fusion [37–39]. The potential efficacy of PRP to facilitate osteoinduction in spine fusion remains uncertain at present time.
A study by Carreon et al. investigated 76 patients with posterior lateral lumbar fusion with autologous iliac crest bone graft mixed with PRP compared to a control group. Using 500 ml of whole blood, 30 ml of platelet concentrate was obtained. Non-union was diagnosed by either a revision intra-operatively or via plain radiographs or CT scan. The study concluded that the PRP group had a 25% non-union rate versus 17% in the control group at a minimal 2-year follow-up [37]. Of note, platelet concentrations were not measured before or after preparation, as this is not routinely performed clinically.
A study of single-level intertransverse fusions by Weiner and Walker demonstrated a 62% fusion rate in iliac graft augmented with PRP versus 91% fusion rate in bone graft alone [40].
Lowery et al. retrospectively reviewed 19 spinal fusion patients with PRP after 13 months. There was no pseudoarthrosis seen on exploration or plain radiographs in 100% of cases [41].
Hee et al. examined 23 patients who underwent instrumented transforaminal lumbar interbody fusions with PRP versus control with a 2-year follow-up. Interestingly they found accelerated bony healing in the PRP group; however it did not result in increased fusion rates versus control [36]. Platelet concentrations were measured after preparation and were increased 489% from baseline [36].
Jenis et al. explored anterior interbody lumbar fusions in 22 patients with autograph using iliac crest bone graft versus 15 patients with allograft combined with PRP. CT scans at 6 months and plain radiographs at 12 and 24 months demonstrated an 85% fusion rate for autograft versus 89% with PRP and allograft [38]. This could potentially eradicate the morbidity from iliac crest harvesting, and provide a more cost effective alternative to costly bone induction techniques.
A study from Chen et al. demonstrated that PRP might potentially play a role in prevention of disc degeneration. They demonstrated that PRP can act as a Growth factor cocktail to induce proliferation and differentiation and promote tissue-engineered nucleus formation regeneration via the Smad pathway [42]. This offers a conservative management option to patients with degenerative disc disease, besides traditional management options including cortosteroid injection and ultimately surgery.
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