PRP and BMAC: Is There a Role?

PRP has received much more attention recently in its role to stimulate healing and even revascularization with in vitro studies with growing evidence in its use in the setting of foot and ankle pathology. PRP is defined as plasma with a twofold or more platelet concentration above baseline level. In vitro studies have shown PRP to release platelet-derived growth factors (PDGFs), multiple transforming growth factors including TGF-B1/B2, and growth factors used in healing and stimulating the inflammatory response. The platelets also contain cytokines and chemical mediators such as histamine, fibrinogen, fibronectin, and serotonin to help induce the inflammatory response. Biologic studies have also shown that PRP can enhance type I and type III collagen synthesis by tendons. The use of PRP has been investigated in mice with positive results. Kaux et al. examined the use of PRP injection in mice after Achilles tendon rupture and found that those with PRP injections had earlier tendon healing and stronger mechanical resistance at 30 days.

PRP has been used in humans as well for chronic Achilles tendinopathy with mixed results. de Jong et al. found that patients with chronic Achilles tendinopathy had no significant clinical or ultrasonographic tendon differences with PRP versus placebo at 1 year. PRP may have more of a role in assisting in the healing of partial or full-thickness tendon tears. Several mice studies have demonstrated increased neovascularization and accelerated healing with Achilles tendon tears. Filardo et al. presented a case report of a competitive athlete with partial Achilles tendon rupture who was treated nonoperatively with PRP injections. Their study found that with three injections within 3 weeks, the patient was able to go back to baseline sports performance within 75 days of the initial injury. Plasma rich in growth factors has also been examined and has demonstrated superior tendon healing compared to control. Despite the more promising results of PRP in animal studies, its effect on human studies have been mixed. The literature has shown that PRP may be more useful with healing of the acute tendon rupture rather than chronic tendinopathies.

Along with PRP, bone marrow aspirate has also been used for possible treatment of Achilles tendinopathy. Bone marrow aspirate differs from PRP in that it contains mesenchymal and hematopoietic stems cells along with PDGFs. The bone marrow concentrate is done via aspiration usually from the iliac crest and produced by centrifugation, isolating stem cells to be reinjected into the Achilles tendon. Stein et al. examined the use of bone marrow aspirate in a small cohort of patients who underwent open Achilles tendon repair with BMAC injections and found no rerupture, with 92% of patients returning to their sport at a mean of 5.9 months. The use of bone marrow cell injection has also been supported in animal studies. Okamoto et al. compared the use of bone marrow cell transplantation versus mesenchymal stem cells in mice after Achilles tendon rupture. They found significantly increased type III collage at 1 week and type I collagen at 1 month with bone marrow cell transplantation. Despite the early benefits seen in both the clinical and animal studies, long-term data in its use in Achilles tendon are not yet available. This will help assess the risk of these stems developing into tumor lineages which is a potential concern of BMAC.

Acellular Dermal Matrices for Strengthening Repairs

More recently, acellular dermal matrices (ADMs) have been examined for their use in Achilles tendon repair. ADM is derived from cadaveric skin with techniques that allow preservation of the extracellular matrix. The matrix is used to act as scaffold for reepithialization, neovascularization, and fibroblast proliferation without theoretically inducing an inflammatory response. The acellular matrix contains collagen, elastin, and proteoglycans along basement membrane connective tissues which allow for integration and support into the host tissue. ADMs allow for mechanical support while enhancing healing through host cell infiltration. Lee et al. examined the effectiveness of acellular dermal tissue matrix as an augment to Achilles tendon repair which was sutured circumferentially around the tendon. They saw no cases of rerupture or recurrent pain at 20 months, with an average time to baseline activity by 11 weeks.

Rerupture of an Achilles tendon repair after use of ADM augment has been reported. Bertasi removed part of the ADM after rerupture for histological examination, which showed excellent attachment of the ADM to the paratenon at 8 weeks postoperatively. They also identified vast vascularization in the graft paratenon interface. Their study showed excellent integration of the matrix with remodeling of the ADM into the tendon. The use of ADM augments in Achilles tendon ruptures is still in its infancy with limited available long-term data; however, the available studies have demonstrated good results with little complications with in vitro use.

Marrow Stimulation and Osteochondral Allografts in the Talar Dome

Following a trial of conservative therapy aimed at reducing symptoms rather than direct repair of the lesion, several treatment modalities exist. Microfracture involves penetrating subchondral bone in multiple areas causing stimulation of mesenchymal stem cells and a local inflammatory cascade that eventually produces fibrocartilagenous ingrowth into the defect. This new tissue is predominantly type-1 collagen that has different mechanical and physiologic properties from the type-2 dominant articular cartilage. In a prospective cohort study of 105 patients with osteochondral defects of varying size, 100% of patients with lesions <15 mm (n = 73) met the authors’ criteria for successful outcome after microfracture. In those remaining patients with lesions >15 mm, only one patient obtained a successful outcome. These results were corroborated by a later study of 120 patients showing that lesions 12.3 mm and greater had an 80% rate of failure. It should be noted that clinical improvement does not necessarily correlate with the quality of repair tissue or extent of consolidation within the chondral defect.

For larger lesions, osteochondral grafting may be used. This approach attempts to replenish a localized defect with articular cartilage and subchondral bone of similar structural properties. Autologous grafts, most commonly taken from the ipsilateral knee margin, have the benefit of a native immunologic profile that comes with the cost of donor site morbidity, whereas allografts taken from cadavers avoid this problem while increasing risks of systemic rejection and being constrained by limited availability. Furthermore, allograft procurement falls in a narrow window of less than 1 week for fresh samples to maximize active chondrocyte availability, although frozen specimens can offer up to 4 weeks of viable tissue. Results of these treatments are generally positive. At an average of 7 years follow-up, Imhoff et al. retrospectively reported excellent clinical results in 25 patients who underwent autograft implantation for symptomatic talar defects less than 3 cm ² . 80% of patients reported return to their preoperative exercise capacity. Relatively fewer studies exist evaluating allograft implantation outcomes; however, at an average of 37.7 months, El-Rashidy and colleagues reported good, very good, or excellent outcomes in 73% of their 38 patients treated with fresh allograft.

Lateral Column Lengthening

In 2007 Dolan et al. performed a randomized prospective study comparing tricortical iliac crest autograft to allograft for lateral column lengthening as part of surgical correction for posterior tibial tendon dysfunction (PTTD). They followed up 33 patients (18 allograft group, 15 autograft) to 1 year and demonstrated union in both the groups at 12 weeks. They concluded that allograft was a viable alternative to autograft while avoiding donor site morbidity.

Subtalar Bone Block Arthrodesis

In 1988 Carr et al. described incorporating a subtalar bone block into arthrodesis to restore calcaneal height and width lost in trauma. In this setting the use of a structural graft during fusion is required as unrestored calcaneal height can lead to fibular abutment, peroneal impingement, and tibiotalar impingement. Schepers, in a 2013 systematic review of level 4 retrospective case series reviewed 456 patients treated with subtalar distraction bone block arthrodesis for late complications of calcaneal fractures. In most cases, authors preferred the use of tricortical iliac crest bone (ICB), and they achieved good results: an average-modified american orthopedic foot and ankle society (AOFAS) score of 73 points (range 64–83) at final follow-up, with an average union rate of 96%. In three studies included in this review, allograft consisting of fresh frozen femoral head was used. One of these studies was performed by Trnka et al., in which a surprisingly high 80% nonunion rate was noted. This complication rate was inconsistent with that of the other studies in which allograft or iliac crest (IC) autograft was used.

Recombinant Human PDGF

During the inflammatory response, PDGF is released from platelets and macrophages in response to tissue injury. PDGF and other growth factors act by recruiting inflammatory cells, increasing collagen deposition, and promoting angiogenesis. Recombinant human PDGF-BB (rhPDGF-BB) is an isoform of PDGF, which, when combined with beta-tricalcim phosphate (B-TCP) as an osteoconductive scaffold, has been shown to promote healing in foot and ankle arthrodesis. To date, several high-quality studies exist. In a 2013 prospective, randomized, noninferiority trial, DiGiovanni et al. demonstrated that patients undergoing ankle or hindfoot fusions using rhPDGF-BB/B-TCP (n = 285) had statistically similar fusion rates to those treated with autograft (n = 149), with less complications while avoiding donor site morbidity. These findings were further supported by Daniels et al. in 2015 in another RCT in which 75 patients were randomized at a 5:1 ratio for treatment with rhPDGF-BB/B-TCP versus autograft and compared to 142 historical autograft controls. The mean time to fusion was not statistically different. Complete fusion at 24 weeks was present on CT in 84% of the rhPDGF-BB/B-TCP group and 65% of the controls. Ninety-one percent of fusions in the experimental and 78% of fusions in the control group were deemed a success at 1 year with no difference in complications. Younger et al. note that these findings have virtually eliminated the need for autograft harvest in high-risk patients and drastically lowered this need in patients for whom larger amounts of graft material are required. Sun et al., in 2017, performed a systematic review and metaanalysis of these studies and found rhPDGF to be no different from autograft in terms of fusion potential or safety. Clinical outcomes were identical with the exception of the autograft groups having better long-term Short Form-12 physical component scores. Additional clinical trials have suggested that sufficient graft quantity, rather than the type of graft material, is the essential variable for a successful fusion. The support for rhPDGF-BB/b-tcp is strong and generated from high-level studies, making it the best evidence-based alternative to autograft to date. Further study is warranted to address its potential to replace autograft as the standard of care.

Bone Marrow Aspirate Concentrate

BMAC has the osteogenic properties of ICBG while having the benefit of being less invasive. It is typically harvested from the ipsilateral iliac crest under local anesthesia and concentrated via centrifuge. Lee et al. in a randomized trial of 20 patients (10 each arm) looked at the effect of using BMAC plus PRP injection at the osteotomy site versus no injection for patients undergoing distraction osteogenesis for bilateral tibial lengthening. They noted no difference in mean external fixator index between the groups with improved mean cortical healing indexes in the experimental group. Average time to full weight-bearing, determined by the presence of healing at two cortices, was lower in the experimental group (avg. of 0.99 mos vs. 1.38 mos, P < .001).

BMAC has also shown utility in the setting of nonunion and nonunion prevention. Braly et al. in an 11-patient case series injected BMA under fluoroscopic guidance around distal tibial metaphyseal nonunion sites that were previously plated and went onto nonunion at an average of 8 months postoperatively. Nine of the 11 patients had united by 6 months after the injection. Six of the nine with successful union were followed up for an average of 4.4 years and were noted to have significant improvements in validated pain and function metrics. Murawski et al. in a 26-patient case series used BMAC and a “Charlotte Carolina” screw to percutaneously fix zone II and III fifth metatarsal Jones fractures in athletes. The authors note improvement at final follow-up in several metrics from preoperative values including foot and ankle orthopedic (FAO) score and short form – 12 (SF-12) score; however, this does not prove that BMAC was the reason for this finding. A total of 24 of 26 patients returned to their previous level of sport, and one patient had a delayed union. The authors concluded that BMAC use yielded more predictable results and allowed return to sport; however, with no control group, this claim is unsubstantiated. Overall, the support for BMAC in the foot and ankle literature is relatively weak and requires further investigation.

Bone Morphogenetic Proteins

Bone morphogenetic proteins are a group of proteins that belong to the TGF-B superfamily and found to influence a wide range of growth factor functions. Recombinant human BMP-2 (rhBMP-2) is one type, approved by the FDA for use in lumbar fusions and open tibial shaft fractures, often used off-label with good success. In 2009 Bibbo et al. evaluated 69 high-risk patients (64% smokers, 19% diabetic, 68% with history of high energy trauma, 32% with talar avascular necrosis (AVN)) undergoing ankle and hindfoot fusions at a total of 112 fusion sites. All patients received rhBMP-2 in addition to no graft, autograft, or allograft with graft only used when necessary for defects or malalignment. They achieved a 96% union rate at 11 weeks and no significant difference in union or time to union between subgroups. They concluded that rhBMP-2 appears to be an effective and safe adjunct to bone healing in this setting.

In 2014 Rearick et al. retrospectively reviewed 51 cases of high-risk patients augmented with rhBMP-2 during foot and ankle fusions and revisions for fracture nonunions. A proportion of 92.2% cases united with a per-site union rate of 95%. They found no significant difference in time to union (mean 111 days) or complication rates among patients for whom allograft, autograft, or differently sized rhBMP-2 kits were used. They concluded that rhBMP-2 is a safe and effective adjunct to these procedures and warrants further investigation.