1 Introduction

Nonunion is a serious potential complication of hindfoot and/or ankle arthrodesis. Nonunion can lead to chronic pain and disability, poor patient satisfaction, and increased healthcare cost burdens. The overall incidence of nonunion following primary arthrodesis of the foot or ankle is typically between 10% and 12%,^1–5 but may be as great as 41% in patients with risk factors such as smoking, diabetes, Charcot neuroarthropathy, or obesity.^6,7

Although autograft has long been used in foot and ankle arthrodesis as the “gold-standard”, in recent years there has been an increase in the use of cellular bone allografts^8,9 or orthobiologics (i.e., synthetic bone graft material or from cadavers). These products have proved to be as viable alternatives to promote arthrodesis, without the additional surgical site and related donor-site pain caused in harvesting native bone with autograft.¹⁰ Recombinant human platelet-derived growth factor BB-homodimer, with beta-tricalcium phosphate (rhPDGF-BB/β-TCP; Augment® Bone Graft, Biomimetics Therapeutics – a subsidiary of Stryker, Franklin, TN, USA), has been shown in a prospective, randomized controlled trial to have comparable efficacy to autograft.¹⁰ The combined osteoinductive properties of rhPDGF-BB and the osteoconductive properties of β-TCP¹¹ results in a bone graft substitute that facilitates fusion and may lead to improved angiogenesis in the healing cascade.

This retrospective review assessed the outcomes of hindfoot and ankle arthrodesis procedures with the use of rhPDGF-BB/β-TCP, focusing on patients with high-risk factors, to further assess the impact. To avoid selection bias, we gathered all patients that underwent hindfoot and ankle arthrodesis procedures with rhPDGF-BB/β-TCP and identified patients at high-risk of nonunion as a subset of the overall patient population reviewed. The primary objective was to evaluate the clinical outcomes of rhPDGF-BB/β-TCP among these high-risk patients. We hypothesized that rhPDGF-BB/β-TCP use would result in union in most cases without significant complications.

2 Methods

3 Results

3.6

3.6 Operative procedures: case reports

(see Figs. 1 and 2).

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Fig. 1 Tibial-calcaneal Arthrodesis in a 67-year-old Male with Charcot-Marie-Tooth Disease and Peripheral Neuropathy. Following the two attempts, the patient developed a nonunion at the right ankle joint, varus deformity upon stance, and a long-standing ulceration under the 5th metatarsal head that was left unhealed after several months of local wound care. The initial hardware was removed, and the varus deformity was corrected, followed by the placement of intramedullary nail and screw fixation for a Tibiotalocalcaneal (TTC) fusion, along with rhPDGF-BB/β-TCP to promote healing at the fusion site. CT images at 16-weeks postop demonstrated complete fusion at the ankle and subtalar joints were achieved, and the ulceration had healed. The patient walked in a rocker-bottom shoe and was able to perform multiple activities. (A), (B), (C) Initial radiographs showing nonunion of the ankle arthrodesis fixated in varus deformity, (D), (E), (F) (G), (H), (I), (J) intraoperative image showing the removal of previous hardware, tibial and talar osteotomies to correct varus deformity, and Tibiotalocalcaneal arthrodesis with intramedullary nail and screw fixation along with recombinant human platelet derived growth factor BB homodimer with beta-tricalcium phosphate (rhPDGF-BB/β-TCP). (K), (L) 12-months postop, shows complete ankle and subtalar fusion were achieved.

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Fig. 2 Ankle and Subtalar Arthrodesis in a Female (age = 69 years) with Diabetic Neuropathy Following Severe Ankle Fracture. A 69-year-old white female with diabetic neuropathy tripped and fell, injuring her left ankle 3 weeks prior to presentation at the clinic. The patient had been walking in shoes since that time but complained that the ankle had become swollen and painful. Her blood sugar levels were under control and her last HGA1C was 7.0. Initial radiographs showed an unstable left displaced fibular fracture with widening of the medial clear space. The ankle fracture was reduced, and primary ankle and subtalar joint arthrodesis was performed with IM nail fixation, along with the use of rhPDGF-BB/β-TCP. An external fixator was added for further fixation. After 14 weeks, the joints had fused, and she was walking in shoes at the 1-year follow-up visit. (A), (B) Pre-operative radiographs showing unstable and displaced left ankle fracture with widened medial clear space. (C), (D) Reduction of the ankle fracture with provisional fixation for IM nail for ankle fusion. Ankle and subtalar arthrodesis with IM nail fixation and placement of augment bone graft (recombinant human platelet-derived growth factor BB homodimer with beta-tricalcium phosphate; rhPDGF-BB/β-TCP). External fixator added for further fixation. Patient had achieved fusion at 14 weeks and had the external fixator removed. (E),(F) X-rays at 12 months postoperative with bone fusion at both the ankle and subtalar joints.

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4 Discussion

Nonunion, one of the most disconcerting outcomes following foot and ankle arthrodesis, occurs more frequently in high-risk patient populations. One hundred international foot and ankle surgeons cited the highest risk factors for nonunion as smoking, lack of fusion stability at the surgical site, and compromised local vascularity.⁵ The goal of reconstruction is to minimize the impact of these risk factors for nonunion. Surgical reconstruction is aided by the use of bone grafts to promote the repair and building of bone. While the gold standard is autologous bone graft,¹³ there are increased risks of infection, bleeding, sensation loss, donor site morbidity, persistent pain, and increased surgical time due to harvest site issues or the potential lack of histocompatibility from donor tissue.^13–15 Allografts may address these concerns. However, allografts have their own shortcomings: the potential for graft rejection, slower healing, disease transmission, and increased risk for failure or nonunion.^13,16

Orthobiologics are increasingly being used in foot and ankle arthrodesis, providing both surgeons and patients an alternative to more traditional treatment options. This study utilized the rhPDGF-BB/β-TCP as the bone graft substitute. rhPDGF-BB/β-TCP has 2 primary components: beta-tricalcium phosphate granules that acts as the osteoconductive scaffold and rhPDGF-BB solution that stimulates the proliferation of osteoblast and promotes revascularization.¹⁷ Two multi-centers, prospective, randomized clinical trials^10,11 have shown that rhPDGF-BB/β-TCP is a safe and effective alternative to autograft in foot and ankle arthrodesis procedures.

In the first prospective, randomized, controlled clinical trial by DiGiovanni et al.¹⁰ that studied the use of rhPDGF-BB/β-TCP in hindfoot and/or ankle arthrodesis in 434 patients, patients were randomized in a 2:1 fashion into autograft or rhPDGF-BB/β-TCP treatment groups. Fusion was defined as > 50% osseous bridging by CT scan. Fusion rates were similar: 62% of patients treated with rhPDGF-BB/β-TCP augment grafting material compared to 61.2% of patients treated with autografts. As well, at 52 weeks, clinical healing rates were similar: 86.2% of rhPDGF-BB/β-TCP patients compared with 87.6% of autograft patients. In addition, the rhPDGF-BB/β-TCP group experienced less pain and had fewer side effects than the autograft group.

In the second prospective, randomized, controlled clinical trial by Daniels et al. ,¹¹ rhPDGF-BB/β-TCP was also assessed in patients undergoing hindfoot and ankle fusion. As with DiGiovanni et al., joint fusion was defined as >50% osseous bridging on CT. Seventy-five patients with a randomization of 5:1 to treatment with rhPDGF-BB/β-TCP (63 patients) or autograft (12 patients). In a combined analysis with an additional 142 autograft patients (from a separate clinical trial with the same study protocol),⁸ the primary outcome of complete fusion at 24 weeks was statistically significantly greater, p < 0.001, in patients receiving rhPDGF-BB/β-TCP (84%; n = 53 of 63 patients) than autograft (65%; n = 100 of 154 patients). As well, the mean time to fusion was statistically significantly superior in the rhPDGF-BB/β-TCP group compared to autograft (rhPDGF-BB/β-TCP: 14.3 ± 8.9 weeks; autograft: 19.7 ± 11.5 weeks; p < 0.01).

The benefits of rhPDGF-BB/β-TCP can be best characterized comparing nonunion rates between this patient population and historical autograft controls. In an earlier retrospective study,¹⁸ the charts of 12 patients who had undergone revisional arthrodesis, which included the talonavicular, calcaneocuboid, subtalar, and ankle joints, had received rhPDGF-BB/β-TCP bone grafting supplement with at least a 12-month follow-up. These 12 patients were at high-risk and had comorbidities that included Charcot neuroarthropathy (42%), neuropathy (33%), diabetes mellitus (33%), and hypertension (33%). Eleven (91.7%) patients achieved a union with a mean time to fusion of 12.9 ± 1.9 weeks and mean time return to activity of 16.6 ± 2.8 weeks. Two patients had infected hematomas, but both went on to achieve fusion. There were no complications related to the use of rhPDGF-BB/β-TCP. In addition, a previous study examining only patients with the risk factor of Charcot neuroarthropathy found a nonunion rate of 2.69% when rhPDGF-BB/β-TCP bone graft material was used. Collectively, these findings indicate that the use of rhPDGF-BB/β-TCP is effective overall among patients, including those with high-risk factors.¹⁹

In this current study of 133 patients with 209 joint fusions, the 7.18% nonunion rate observed among consecutive patients treated with rhPDGF-BB/β-TCP was below the 10% nonunion rate reported in the literature and well below the reported 41% rate for high-risk patients. When looking specifically at the high-risk sub-group of neuropathy patients, whether related to diabetes or not, the nonunion rate of 7.52% (10 of 209 joints) not only falls below the high-risk rate from the literature but also the general 10% rate for all patients. Collectively, these findings suggests that the use of rhPDGF-BB/β-TCP is effective overall among patients, including those with certain high-risk factors.

In addition to the size of the population that included a large percentage of high-risk patients, this study had a long length of follow-up: almost a mean of 2 years following surgery with several patients being followed up through 5 years. This demonstrates the persistence of effect experienced by patients treated with rhPDGF-BB/β-TCP. Furthermore, 15 patients had 1 nonunion each, 2 patients had infected hematomas, and 1 had wound dehiscence. However, no AE or complication in was attributed to the use of rhPDGF-BB/β-TCP.

Overall, the data from this study suggests that rhPDGF-BB/β-TCP may be effective in achieving high rates of fusion in neuropathic patients who are at high-risk for developing nonunions. This study used the second largest population reported in the literature as well as having substantial follow-up data. However, limitations of this study including the lack of comparison group outside of historical controls, and therefore limited statistical analyses; and its retrospective design, where only standard of care outcomes could be collected and therefore not all patients had CT scans.

This study of rhPDGF-BB/β-TCP in hindfoot and ankle arthrodesis procedures demonstrated both the efficacy and the safety of this orthobiologic. With its high fusion rate, relatively short times to fusion and return to function, and absence of complications considered due to the graft material itself, rhPDGF-BB/β-TCP demonstrated as a safe and effective alternative to autograft, regardless of high-risk status of patients. High rates of fusion translate directly to reduced pain and increased satisfaction for patients, lower likelihood of chronic disability, and potentially reduced healthcare costs. Future randomized, controlled clinical trials comparing rhPDGF-BB/β-TCP with autograft in high-risk patients are warranted which may demonstrate these multiple clinical benefits.

Statement and declarations

Dr. Loveland is a paid consultant for Stryker Corporation and Vilex, LLC.

Ethical statement

The Western Institutional Review Board (IRB; Columbia, MD) determined that this research was exempt from IRB oversight. IRB EXEMPTION — HIPAA FULL WAIVER OF AUTHORIZATION AND REGULATORY OPINION, 22 APR 2021 D4-Exemption-Loveland (04-22-2021) WCG IRB Work Order #1-1425820-1.

Funding

None.