Advertisement

Nonoperative and Operative Soft-Tissue and Cartilage Regeneration and Orthopaedic Biologics of the Foot and Ankle: An Orthoregeneration Network Foundation Review

Open AccessPublished:May 22, 2022DOI:https://doi.org/10.1016/j.arthro.2022.04.018

      Abstract

      Orthoregeneration is defined as a solution for orthopaedic conditions that harnesses the benefits of biology to improve healing, reduce pain, improve function, and optimally, provide an environment for tissue regeneration. Options include drugs, surgical intervention, scaffolds, biologics as a product of cells, and physical and electromagnetic stimuli. The goal of regenerative medicine is to enhance the healing of tissue after musculoskeletal injuries as both isolated treatment and adjunct to surgical management, using novel therapies to improve recovery and outcomes. Various orthopaedic biologics (orthobiologics) have been investigated for the treatment of pathology involving the foot and ankle (including acute traumatic injuries and fractures, tumor, infection, osteochondral lesions, arthritis, and tendinopathy) and procedures, including osteotomy or fusion. Promising and established treatment modalities include 1) bone-based therapies (such as cancellous or cortical autograft from the iliac crest, proximal tibia, and/or calcaneus, fresh-frozen or freeze-dried cortical or cancellous allograft, including demineralized bone matrix putty or powder combined with growth factors, and synthetic bone graft substitutes, such as calcium sulfate, calcium phosphate, tricalcium phosphate, bioactive glasses (often in combination with bone marrow aspirate), and polymers; proteins such as bone morphogenic proteins; and platelet-derived growth factors; 2) cartilage-based therapies such as debridement, bone marrow stimulation (such as microfracture or drilling), scaffold-based techniques (such as autologous chondrocyte implantation [ACI] and matrix-induced ACI, autologous matrix-induced chondrogenesis, matrix-associated stem cell transplantation, particulated juvenile cartilage allograft transplantation, and minced local cartilage cells mixed with fibrin and platelet rich plasma [PRP]); and 3) blood, cell-based, and injectable therapies such as PRP, platelet-poor plasma biomatrix loaded with mesenchymal stromal cells, concentrated bone marrow aspirate, hyaluronic acid, and stem or stromal cell therapy, including mesenchymal stem cell allografts, and adipose tissue-derived stem cells, and micronized adipose tissue injections.

      Level of Evidence

      Level V, expert opinion.

      Introduction

      Orthobiologics is a broad term used to define substances and materials used to aid in the healing of musculoskeletal injuries in the operative and nonoperative setting. Although the field of orthobiologics is not new, the bulk of advances have occurred within the past 20 years, and innovation continues to progress at a rapid pace, particularly within the foot and ankle subspecialty where several clinical pathologies present unique opportunities for biological augmentation. The aim of this article is to outline the current state of orthoregenerative approaches for foot and ankle pathology via three broad categories of bone-based, cartilage-based, as well as blood/stem cell and injectable modalities. Despite physical and mechanistic differences between the categories, there is significant interplay and combinations of each that can be used to treat a spectrum of pathology.

      Bone-Based Therapies

      Autograft

      Bone-based biologic therapies for foot and ankle conditions are comprised primarily of various grafting options. The gold standard bone grafting material is cancellous or cortical autograft, depending on the procedural need. In foot and ankle procedures, autograft is commonly harvested from the iliac crest, proximal tibia, and/or calcaneus, with the amount of available graft decreasing in that order.
      • Burk T.
      • Del Valle J.
      • Finn R.A.
      • Phillips C.
      Maximum Quantity of bone available for harvest from the anterior iliac crest, posterior iliac crest, and proximal tibia using a standardized surgical approach: A cadaveric study.
      Despite multiple inherent benefits, autograft is not without its drawbacks in the form of limited supply. A significant complication rate of up to 8.6% is reported in the literature.
      • Younger E.M.
      • Chapman M.W.
      Morbidity at bone graft donor sites.
      One recent review has advocated for use of lower extremity autograft harvests as opposed to the iliac crest due to potentially lower complication rates.

      Attia AK, Mahmoud K, ElSweify K, Bariteau J, Labib SA. Donor site morbidity of calcaneal, distal tibial, and proximal tibial cancellous bone autografts in foot and ankle surgery. A systematic review and meta-analysis of 2296 bone grafts. Foot Ankle Surg In press. doi:10.1016/j.fas.2021.09.005

      For cases in which autograft is either not an option or is insufficient, allograft and various synthetic bone graft substitutes can be employed.

      Allograft

      There is no shortage of allograft bone grafting options available, which exist in various forms. Cortical bone graft is harvested from cadavers and is generally used to provide structural support, often needed after acute traumatic injuries or to supplement osteotomy or fusion procedures about the ankle.
      • Baldwin P.
      • Li D.J.
      • Auston D.A.
      • Mir H.S.
      • Yoon R.S.
      • Koval K.J.
      Autograft, allograft, and bone graft substitutes: Clinical evidence and indications for use in the setting of orthopaedic trauma surgery.
      Depending on the preservation technique used, the graft can vary in mechanical integrity and osteogenic/osteoinductive potential.
      • Roberts T.T.
      • Rosenbaum A.J.
      Bone grafts, bone substitutes and orthobiologics: The bridge between basic science and clinical advancements in fracture healing.
      Fresh-frozen grafts retain the most structural integrity due to less formation of free radicals. Freeze-dried grafts are a more cost-effective option that also have the advantage of storage at room temperature, a disadvantage is the reduced mechanical strength.
      • Delloye C.
      • Cornu O.
      • Druez V.
      • Barbier O.
      Bone allografts: What they can offer and what they cannot.
      Prior studies have shown effective incorporation and host remodeling of these structural allografts.
      • Butscheidt S.
      • Moritz M.
      • Gehrke T.
      • et al.
      Incorporation and remodeling of structural allografts in acetabular reconstruction: Multiscale, micro-morphological analysis of 13 pelvic explants.
      • John S.
      • Child B.J.
      • Hix J.
      • et al.
      A retrospective analysis of anterior calcaneal osteotomy with allogenic bone graft.
      • Philbin T.M.
      • Pokabla C.
      • Berlet G.C.
      Lateral column lengthening using allograft interposition and cervical plate fixation.
      Cancellous allografts come in various shapes and sizes (typically in the form of "chips") and are primarily used to fill bony voids and assist with fusion, but in areas where structural integrity is not necessary. These grafts are primarily osteoconductive. The high-level literature comparing autologous and allogenic bone grafting in foot and ankle procedures is sparce; despite this, a single level II systematic review by Müller et al. included 928 hindfoot arthrodeses and osteotomies with equivalent fusion rates between structural allografts and autografts. However, the authors caution on the quality of the individual studies included.
      • Müller M.A.
      • Frank A.
      • Briel M.
      • et al.
      Substitutes of structural and non-structural autologous bone grafts in hindfoot arthrodeses and osteotomies: A systematic review.
      The final, most widely used grafting option in the allograft family is demineralized bone matrix (DBM), which is a highly processed allograft combined with various growth factors. Similar to other allograft options, the osteogenic and osteoinductive capacity of the specific DBM is based on the specific preparation technique.
      • Shehadi J.A.
      • Elzein S.M.
      Review of commercially available demineralized bone matrix products for spinal fusions: A selection paradigm.
      As a result of the highly processed nature of DBM, manufacturers have the ability to provide it in various forms, including powder or putty, thereby fitting a wide spectrum of clinical needs.

      Synthetic Bone Graft Substitutes

      In cases where autograft or allograft is unavailable, bone graft substitutes can be applied to provide an osteoconductive environment. Favored for their widespread availability, reasonable cost, flexibility in preparation and form, and minimal risk profile, bone graft substitutes are commonly used.
      • Roberts T.T.
      • Rosenbaum A.J.
      Bone grafts, bone substitutes and orthobiologics: The bridge between basic science and clinical advancements in fracture healing.
      The primary benefits of bone graft substitutes are the elimination of risks associated with autograft harvester and the theoretical concerns of disease transmission or culture beliefs associated with allograft. The mechanism of bone graft substitutes relies primarily on providing a scaffold into which native osteoprogenitor cells can migrate and begin to form new bony growth while also being resorbed over time as the patient’s bone fills the space previously occupied by the graft.
      • Nakahara H.
      • Goldberg V.M.
      • Caplan A.I.
      Culture-expanded periosteal-derived cells exhibit osteochondrogenic potential in porous calcium phosphate ceramics in vivo.
      The three primary synthetic bone graft substitute options that are widely available are calcium sulfate (CS), calcium phosphate (CP), and tricalcium phosphate (TCP). Other less frequently used materials, such as bioactive glasses and polymers, are also available.
      Calcium phosphate primarily comes in cement form and has been used since the mid-1990s.
      • Campana V.
      • Milano G.
      • Pagano E.
      • et al.
      Bone substitutes in orthopaedic surgery: From basic science to clinical practice.
      With the ability to conform to almost any shape, a slow integration profile of up to 2 years postimplantation, and mechanical properties superior to cancellous bone, CP provides a flexibility in application that is not available in autograft or allograft options.
      • Russell T.A.
      • Leighton R.K.
      Comparison of autogenous bone graft and endothermic calcium phosphate cement for defect augmentation in tibial plateau fractures. A multicenter, prospective, randomized study.
      ,
      • Knaack D.
      • Goad M.E.
      • Aiolova M.
      • et al.
      Resorbable calcium phosphate bone substitute.
      Conversely, the brittle nature of CP cement has been shown in a meta-analysis on skull reconstruction to have a high complication rate of up to 13% with its use, with 9% considered a major complication.
      • Afifi A.M.
      • Gordon C.R.
      • Pryor L.S.
      • Sweeney W.
      • Papay F.A.
      • Zins J.E.
      Calcium phosphate cements in skull reconstruction: a meta-analysis.
      Calcium sulfate was next to gain U.S. Food and Drug Administration (FDA) approval in the mid-1990s. CS has similar advantages to CP in that it is plentiful, does not elicit a strong host response, and is versatile in application.
      • Chai F.
      • Raoul G.
      • Wiss A.
      • Ferri J.
      • Hildebrand H.F.
      [Bone substitutes: Classification and concerns].
      Unlike CP, CS is resorbed much quicker (up to one month postimplantation) and cannot be used in cases where early weight-bearing and mobilization through the graft is necessary.
      • Roberts T.T.
      • Rosenbaum A.J.
      Bone grafts, bone substitutes and orthobiologics: The bridge between basic science and clinical advancements in fracture healing.
      ,
      • Chai F.
      • Raoul G.
      • Wiss A.
      • Ferri J.
      • Hildebrand H.F.
      [Bone substitutes: Classification and concerns].
      Moreover, too rapid resorption may lead to nonunion if the host has not produced enough bone extracellular matrix.
      TCP is a grafting substitute similar in physical properties to cancellous bone and is, thus, used commonly in cases where structural support is required.
      • Frankenburg E.P.
      • Goldstein S.A.
      • Bauer T.W.
      • Harris S.A.
      • Poser R.D.
      Biomechanical and histological evaluation of a calcium phosphate cement.
      Studies have shown TCP to be safe, with minimal host reaction, and is generally incorporated anywhere between 6 and 8 months after implantation.
      • Moore W.R.
      • Graves S.E.
      • Bain G.I.
      Synthetic bone graft substitutes.
      ,
      • Wiltfang J.
      • Merten H.A.
      • Schlegel K.A.
      • et al.
      Degradation characteristics of alpha and beta tri-calcium-phosphate (TCP) in minipigs.
      Noninferiority studies focusing on the use of TCP in reconstructive efforts reveal a similar fusion rate when compared to autograft.
      • Hernigou P.
      • Dubory A.
      • Pariat J.
      • et al.
      Beta-tricalcium phosphate for orthopedic reconstructions as an alternative to autogenous bone graft.
      In the foot and ankle specifically, TCP use was studied retrospectively as part of calcaneal fracture ORIF in 74 patients by Jiang et al., who found that the mean Böhler angle reduced by only 4° at one-year post-operatively, with similar changes in the angle of Gissane, combined with over 90% of patients reporting good or excellent results on the Maryland foot score.
      • Jiang S.D.
      • Jiang L.S.
      • Dai L.Y.
      Surgical treatment of calcaneal fractures with use of beta-tricalcium phosphate ceramic grafting.
      Similar positive results have been reported in smaller case series focusing on TCP use in foot and ankle trauma, arthrodesis, and oncology cases.
      • Galois L.
      • Mainard D.
      • Pfeffer F.
      • Traversari R.
      • Delagoutte J.P.
      Use of β-tricalcium phosphate in foot and ankle surgery: A report of 20 cases.
      Bioactive glasses offer an additional option outside of the more widely used calcium-based substitutes. Bioactive glass is an osteoconductive material that, when combined with body fluids, forms a gel-like calcium phosphate layer that, within a few hours, will further reconstitute into a hydroxycarbonate apatite layer that closely resembles native bone and promotes attachment of local tissues.
      • Greenspan D.C.
      Bioactive glass: Mechanisms of bone bonding.
      ,
      • Hench L.L.
      • West J.K.
      Biological applications of bioactive glasses.
      The resorptive time frame of the bioactive glass depends on composition, but can be as soon as 6 months postimplantation for silica-based options.
      • Moimas L.
      • Biasotto M.
      • Di Lenarda R.
      • Olivo A.
      • Schmid C.
      Rabbit pilot study on the resorbability of three-dimensional bioactive glass fibre scaffolds.
      The primary drawback of bioactive glasses is their mechanical properties, as they tend to be brittle and exhibit inferior biomechanical strength properties in comparison to calcium-based substitutes.
      • Chai F.
      • Raoul G.
      • Wiss A.
      • Ferri J.
      • Hildebrand H.F.
      [Bone substitutes: Classification and concerns].
      The outcomes after use of bioactive glasses have been studied in foot and ankle arthrodesis in combination with other additives, including bone marrow aspirate (BMA). Shi et al. studied hindfoot arthrodesis using bioactive glass and BMA in 48 joints about the hindfoot in 29 patients, resulting in a union rate comparable to autograft and other graft substitute options.
      • Shi E.
      • Carter R.
      • Weinraub G.M.
      Outcomes of hindfoot arthrodesis supplemented with bioactive glass and bone marrow aspirate: A retrospective radiographic study.
      Additional studies in the foot and ankle tumor and infection literature cite similar positive outcomes with the use of bioglass and present the material as a safe and effective option in the appropriate clinical setting.
      • De Giglio R.
      • Di Vieste G.
      • Mondello T.
      • et al.
      Efficacy and safety of bioactive glass S53P4 as a treatment for diabetic foot osteomyelitis.
      ,
      • Ma H.
      • Shi Y.
      • Zhang W.
      • Liu F.
      • Han Y.
      • Yang M.
      Open curettage with bone augmentation for symptomatic tumors and tumor-like lesions of calcaneus: A comparison of bioactive glass versus allogeneic bone.

      Proteins

      BMP

      Bone morphogenic proteins, or BMPs, are growth factors within a subclass of the transforming growth factor family known to have osteogenic potential.
      • Bibbo C.
      • Nelson J.
      • Ehrlich D.
      • Rougeux B.
      Bone morphogenetic proteins: Indications and uses.
      There are currently only two forms of BMPs available on the market, those being recombinant human (rh) forms: rhBMP-2 and rh-BMP-7, with rhBMP-2 being the more widely used.
      • Bibbo C.
      • Nelson J.
      • Ehrlich D.
      • Rougeux B.
      Bone morphogenetic proteins: Indications and uses.
      Despite the narrow FDA indications for use, including lumbar spine fusions and open tibial fractures, rhBMP-2 has been studied in the foot and ankle as well, with promising results.
      • Lin S.S.
      • Montemurro N.J.
      • Krell E.S.
      Orthobiologics in foot and ankle surgery.
      The highest-level study was performed by Fourman et al., who performed a retrospective case-control study on the off-label use of rhBMP-2 in ankle arthrodesis using Ilizarov technique within a subset of 82 medically complex patients with comorbidities that predispose to difficulty healing. They found a significantly higher union rate of 93% in the rhBMP-2 group vs. only 53% in the control group, less time in the frame (124 vs 161 days), and more bridging on CT scans (48% vs 32%).
      • Fourman M.S.
      • Borst E.W.
      • Bogner E.
      • Rozbruch S.R.
      • Fragomen A.T.
      Recombinant human BMP-2 increases the incidence and rate of healing in complex ankle arthrodesis.
      Similarly high fusion and uniBion rates were reported by Bibbo et al., with rhBMP-2 adjunct use in hindfoot arthrodesis at 96%, and by Rearick et al. in an assortment of foot and ankle procedures at 92%.
      • Bibbo C.
      • Patel D.V.
      • Haskell M.D.
      Recombinant bone morphogenetic protein-2 (rhBMP-2) in high-risk ankle and hindfoot fusions.
      ,
      • Rearick T.
      • Charlton T.P.
      • Thordarson D.
      Effectiveness and complications associated with recombinant human bone morphogenetic protein-2 augmentation of foot and ankle fusions and fracture nonunions.

      PDGF

      PDGF is an autologous product contained within the alpha granules of platelets and acts via chemotaxis to attract various inflammatory and regenerative cells to the site of injection, thereby, theoretically promoting healing. Multiple randomized controlled studies have been conducted to study the use of PDGF in foot and ankle fusion in comparison to the gold standard of autograft, with each study showing noninferiority and a reduction in the side effects associated with autograft use.
      • DiGiovanni C.W.
      • Lin S.S.
      • Baumhauer J.F.
      • et al.
      Recombinant human platelet-derived growth factor-BB and beta-tricalcium phosphate (rhPDGF-BB/β-TCP): An alternative to autogenous bone graft.
      • Daniels T.R.
      • Younger A.S.
      • Penner M.J.
      • et al.
      Prospective randomized controlled trial of hindfoot and ankle fusions treated with rhPDGF-BB in combination with a β-TCP-collagen matrix.
      • Daniels T.R.
      • Anderson J.
      • Swords M.P.
      • et al.
      Recombinant human platelet-derived growth factor BB in combination with a beta-tricalcium phosphate (rhPDGF-BB/β-TCP)-collagen matrix as an alternative to autograft.

      Cartilage Based Therapies

      Cartilage is a particular area of interest in the setting of orthobiologics owing to the lack of natural regenerative capacity. A number of orthoregenerative approaches to cartilage restoration in the ankle over the years, with variable levels of documented success. The first line of surgical treatment for a symptomatic osteochondral lesion of the ankle is a form of debridement with or without a bone marrow stimulation procedure (e.g., microfracture, drilling). While bone marrow stimulation has historically shown success as a minimally invasive, effective treatment option, more recent literature has demonstrated inferior outcomes over longer-term follow up, particularly with larger lesions and lesions located at the talar shoulder.
      • Chuckpaiwong B.
      • Berkson E.M.
      • Theodore G.H.
      Microfracture for osteochondral lesions of the ankle: Outcome analysis and outcome predictors of 105 cases.
      • Choi W.J.
      • Choi G.W.
      • Kim J.S.
      • Lee J.W.
      Prognostic significance of the containment and location of osteochondral lesions of the talus: Independent adverse outcomes associated with uncontained lesions of the talar shoulder.
      • Hannon C.P.
      • Bayer S.
      • Murawski C.D.
      • et al.
      Debridement, curettage, and bone marrow stimulation: Proceedings of the International Consensus Meeting on Cartilage Repair of the Ankle.
      • Ramponi L.
      • Yasui Y.
      • Murawski C.D.
      • et al.
      Lesion size is a predictor of clinical outcomes after bone marrow stimulation for osteochondral lesions of the talus: A systematic review.
      Several revision or salvage options exist for use in the setting of failed primary or revision procedures for osteochondral lesions of the ankle, including numerous different scaffold-based techniques. Autologous chondrocyte implantation (ACI) is one such option that has been used since the 1980s and involves a biopsy with subsequent lab growth of patient-specific cartilage cells that are later implanted back into the defect.
      • Mistry H.
      • Connock M.
      • Pink J.
      • et al.
      Autologous chondrocyte implantation in the knee: Systematic review and economic evaluation.
      In the first generation of ACI, the cells were placed in liquid form and covered with a periosteal cap, which was notable for postoperative pain at the donor site and an incidence of periosteal hypertrophy that was substantial.
      • Brittberg M.
      • Lindahl A.
      • Nilsson A.
      • Ohlsson C.
      • Isaksson O.
      • Peterson L.
      Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation.
      ,
      • Nam E.K.
      • Ferkel R.D.
      • Applegate G.R.
      Autologous chondrocyte implantation of the ankle: a 2- to 5-year follow-up.
      Second-generation ACI techniques addressed these concerns by using a collagen cap instead of a periosteal graft. Giannini et al. reported on their experience in eight patients with the first-generation technique on the talus and found reparative cartilage tissue in all patients on second-look arthroscopy, with resolution of pain.
      • Giannini S.
      • Buda R.
      • Grigolo B.
      • Vannini F.
      Autologous chondrocyte transplantation in osteochondral lesions of the ankle joint.
      In a sample of 10 year follow-up patients, 70% reported excellent results, 20% good, and 10% fair, with no complications, which are similar to results found by Whittaker et al. with 4 years follow up, that reported 90% of patients as pleased or extremely pleased with their outcome.
      • Giannini S.
      • Battaglia M.
      • Buda R.
      • Cavallo M.
      • Ruffilli A.
      • Vannini F.
      Surgical treatment of osteochondral lesions of the talus by open-field autologous chondrocyte implantation: a 10-year follow-up clinical and magnetic resonance imaging T2-mapping evaluation.
      ,
      • Whittaker J.P.
      • Smith G.
      • Makwana N.
      • et al.
      Early results of autologous chondrocyte implantation in the talus.
      Subsequently, third-generation ACI techniques were developed with a biodegradable porcine matrix loaded with harvested chondrocytes. This became known as matrix-induced autologous chondrocyte implantation (MACI) and has been approved for use in the knee in the United States, but not in the ankle and still requires a second procedure after the index harvest. Despite the innovation, the issue of overgrowth still remains in the latest generation of ACI.
      • Aurich M.
      • Bedi H.S.
      • Smith P.J.
      • et al.
      Arthroscopic treatment of osteochondral lesions of the ankle with matrix-associated chondrocyte implantation: early clinical and magnetic resonance imaging results.
      Combining microfracture and autologous chondrocyte implantation procedures, autologous matrix-induced chondrogenesis (e.g., AMIC) involves a 1-step process of bone marrow stimulation or abrasionplasty and subsequent application of a porcine based type I/III collagen membrane.
      • Benthien J.P.
      • Behrens P.
      Autologous matrix-induced chondrogenesis (AMIC): Combining microfracturing and a collagen I/III matrix for articular cartilage resurfacing.
      These techniques have become known as "enhanced bone marrow stimulation" techniques. One recent consensus by Rothrauff et al. suggested that this procedure can be used for lesions >1 cm2 in both primary and revision scenarios and can be accompanied with bone grafting if needed.
      • Rothrauff B.B.
      • Murawski C.D.
      • Angthong C.
      • et al.
      Scaffold-based therapies: Proceedings of the International Consensus Meeting on Cartilage Repair of the Ankle.
      Matrix-augmented BMS provides the advantage of a 1-stage procedure, in which autologous cells are endogenously recruited into the defect site. Although several scaffolds are available, the scientific evidence is highest for the use of a collagen I/III membrane.
      • Walther M.
      • Valderrabano V.
      • Wiewiorski M.
      • et al.
      Is there clinical evidence to support autologous matrix-induced chondrogenesis (AMIC) for chondral defects in the talus? A systematic review and meta-analysis.
      Usuelli studied 20 patients who underwent the AMIC procedure for types III and IV talar lesions and found improvements in PROs (American Orthopedic Foot and Ankle Society, visual analog scale [VAS], 12-Item Short Form Health Survey) and magnetic resonance observation of cartilage repair tissue (MOCART) at up to 24 months post-op.
      • Usuelli F.G.
      • D'Ambrosi R.
      • Maccario C.
      • Boga M.
      • de Girolamo L.
      All-arthroscopic AMIC(®) (AT-AMIC(®)) technique with autologous bone graft for talar osteochondral defects: clinical and radiological results.
      Similarly, Weigelt followed a cohort of 33 patient who underwent AMIC for talar lesions at an average of 4.7 years post-op (range: 2.3-8 years) and found sustained improvements in PROs despite MOCART scores not correlating with the clinical success, suggesting a difficulty in proper interpretation in postoperative imaging over time.
      • Weigelt L.
      • Hartmann R.
      • Pfirrmann C.
      • Espinosa N.
      • Wirth S.H.
      Autologous matrix-induced chondrogenesis for osteochondral lesions of the talus: A clinical and radiological 2- to 8-year follow-up study.
      Matrix-associated stem cell transplantation (MAST) is a modification of the technique that attempts to use a higher concentration of stem cells into the microfracture defect. As part of this technique, aspirate is taken from the iliac crest, centrifuged, and impregnated into a similar Type I/III collagen matrix as in traditional matrix-augmented BMS.
      • Richter M.
      • Zech S.
      Matrix-associated stem cell transplantation (MAST) in chondral defects of foot and ankle is effective.
      The remaining steps are similar with bone marrow stimulation of the lesion and subsequent covering with the matrix. Results after a 2-year follow up by Richter et al. on 26 chondral lesions treated with MAST found a significant improvement in VAS foot and ankle to 94.5 and 89% of patients returning to sports.
      • Richter M.
      • Zech S.
      Matrix-associated stem cell transplantation (MAST) in chondral defects of foot and ankle is effective.
      Richter later reported on 130 patients with 2-year follow-up and 100 patients with 5-year follow-up and found similar positive results, with the 2-year cohort VAS-FA improving significantly to 87.5 on average and the 5-year cohort improving to 84.4 on average.
      • Richter M.
      • Zech S.
      • Andreas Meissner S.
      Matrix-associated stem cell transplantation (MAST) in chondral defects of the ankle is safe and effective—2-year-followup in 130 patients.
      ,
      • Richter M.
      • Zech S.
      Matrix-associated stem cell transplantation (MAST) in chondral lesions at the ankle as part of a complex surgical approach- 5-year-follow-up in 100 patients.
      Particulated juvenile cartilage allograft transplantation (PJCAT) is one additional technique in the realm of orthoregenerative procedures, in which fresh juvenile cartilage allograft tissue is embedded within the native extracellular matrix and is fixed with fibrin adhesive inside the lesion.
      • Adams Jr., S.B.
      • Demetracopoulos C.A.
      • Parekh S.G.
      • Easley M.E.
      • Robbins J.
      Arthroscopic particulated juvenile cartilage allograft transplantation for the treatment of osteochondral lesions of the talus.
      The cartilage allograft is obtained from donors from newborn to 13 years old, but primarily from donors less than 2 years of age.
      • Adams Jr., S.B.
      • Demetracopoulos C.A.
      • Parekh S.G.
      • Easley M.E.
      • Robbins J.
      Arthroscopic particulated juvenile cartilage allograft transplantation for the treatment of osteochondral lesions of the talus.
      ,
      • Adams Jr., S.B.
      • Yao J.Q.
      • Schon L.C.
      Particulated juvenile articular cartilage allograft transplantation for osteochondral lesions of the talus.
      This procedure has gained popularity due to its relative simplicity in execution, being single-stage with no donor site morbidity, and a minimal chance of immunological reaction, as cartilage tissue is considered immune privileged compared to other allogenic materials. Conversely, downsides of PJCAT include the relative scarcity of juvenile donor cartilage and potential for disease transmission.
      • Adams Jr., S.B.
      • Yao J.Q.
      • Schon L.C.
      Particulated juvenile articular cartilage allograft transplantation for osteochondral lesions of the talus.
      Several clinical studies have been reported in the talus, with mixed results.
      • Dekker T.J.
      • Steele J.R.
      • Federer A.E.
      • Easley M.E.
      • Hamid K.S.
      • Adams S.B.
      Efficacy of particulated juvenile cartilage allograft transplantation for osteochondral lesions of the talus.
      ,
      • Coetzee J.C.
      • Giza E.
      • Schon L.C.
      • et al.
      Treatment of osteochondral lesions of the talus with particulated juvenile cartilage.
      Figure 1 shows the use of PJCAT in the treatment of a large talar cartilage lesion.
      Figure thumbnail gr1
      Fig 1(A) Arthroscopic view of talar cartilage lesion. (B) Fullthickness cartilage lesion after debridement. (C) Microfracture of lesion. (D) Application of particulated juvenile cartilage to lesion.
      Lately, the use of local cartilage cells from the defect has been discussed in the treatment of cartilage defects to overcome the scarcity of juvenile cartilage.
      • Christensen B.B.
      • Olesen M.L.
      • Hede K.T.C.
      • Bergholt N.L.
      • Foldager C.B.
      • Lind M.
      Particulated cartilage for chondral and osteochondral repair: A review.
      Cartilage from the defect site contains still viable cells.
      • Levinson C.
      • Cavalli E.
      • Sindi D.M.
      • et al.
      Chondrocytes from device-minced articular cartilage show potent outgrowth into fibrin and collagen hydrogels.
      The cells are minced and mixed with fibrin and PRP.
      • Levinson C.
      • Cavalli E.
      • Sindi D.M.
      • et al.
      Chondrocytes from device-minced articular cartilage show potent outgrowth into fibrin and collagen hydrogels.
      For stabilization, the minced cartilage is covered with a scaffold (e.g., AMIC membrane).
      • Massen F.K.
      • Inauen C.R.
      • Harder L.P.
      • Runer A.
      • Preiss S.
      • Salzmann G.M.
      One-step autologous minced cartilage procedure for the treatment of knee joint chondral and osteochondral lesions: A series of 27 patients with 2-year follow-up.
      First studies on the knee reported a safe application.
      • Salzmann G.M.
      • Ossendorff R.
      • Gilat R.
      • Cole B.J.
      Autologous minced cartilage implantation for treatment of chondral and osteochondral lesions in the knee joint: An overview.
      However, the cellular outgrowth from adult cartilage tissue was largely absent in an in vitro model.
      • Zingler C.
      • Carl H.D.
      • Swoboda B.
      • Krinner S.
      • Hennig F.
      • Gelse K.
      Limited evidence of chondrocyte outgrowth from adult human articular cartilage.
      Regarding the ankle, so far, there are no clinical studies available to assess the value of this technique finally.

      Blood-Based/Injectable Preparations

      Injectable preparations of orthobiologics are increasingly popular in orthopaedics and have been studied in a variety of applications in foot and ankle surgery ranging from osteoarthritis (OA) to numerous soft tissue applications. Many of these products are derived from the patient’s own blood or tissue and are, therefore, considered safe options for most patients. Evidence derived from animal models has been extensively used for regenerative purposes, with positive results and set the foundation for clinical testing of blood-based products. Importantly, the findings of these animal models served to propel various specialties to perform investigations that provided encouraging results. This discussion is not meant to be exhaustive; instead, it merely highlights the most prominent current products and their applications in foot and ankle pathology.

      PRP

      Platelet-rich-plasma, or PRP, was first noted among hematologists in the 1970s and used for transfusions, with subsequent expansion into other medical specialties in the following years.
      • Andia I.
      • Abate M.
      Platelet-rich plasma: underlying biology and clinical correlates.
      PRP has become a popular option in musculoskeletal care based on the mechanism of providing a localized injection of growth factors and regenerative signaling molecules to a site of injury, theoretically prompting a host healing response and has been used extensively to treat the spectrum of foot and ankle pathologies.
      • Alves R.
      • Grimalt R.
      A review of platelet-rich plasma: History, biology, mechanism of action, and classification.
      There has been discussion on various techniques of PRP that contain a higher or lower concentration of leukocytes, termed leukocyte-rich or poor PRP, and how this may affect healing. There is some evidence suggesting that leukocyte-rich preparations may elicit too robust of a host inflammatory response that could result in increased scar formation and pain.
      • Hanisch K.
      • Wedderkopp N.
      Platelet-rich plasma (PRP) treatment of noninsertional Achilles tendinopathy in a two case series: no significant difference in effect between leukocyte-rich and leukocyte-poor PRP.
      Regarding outcomes, PRP has been studied extensively in foot and ankle-based trials, of varying quality, with mixed results. Multiple level I studies have been performed on PRP for noninsertional Achilles’ tendinopathy, with inconsistent evidence supporting its use over placebo.
      • de Vos R.J.
      • Weir A.
      • van Schie H.T.
      • et al.
      Platelet-rich plasma injection for chronic Achilles tendinopathy: A randomized controlled trial.
      • de Jonge S.
      • de Vos R.J.
      • Weir A.
      • et al.
      One-year follow-up of platelet-rich plasma treatment in chronic Achilles tendinopathy: A double-blind randomized placebo-controlled trial.
      • Boesen A.P.
      • Hansen R.
      • Boesen M.I.
      • Malliaras P.
      • Langberg H.
      Effect of high-volume injection, platelet-rich plasma, and sham treatment in chronic midportion Achilles tendinopathy: A randomized double-blinded prospective study.
      • Usuelli F.G.
      • Grassi M.
      • Maccario C.
      • et al.
      Intratendinous adipose-derived stromal vascular fraction (SVF) injection provides a safe, efficacious treatment for Achilles tendinopathy: Results of a randomized controlled clinical trial at a 6-month follow-up.
      For treatment of OA, Repetto et al. reviewed 20 patients with symptomatic ankle OA, who received weekly PRP injections and reported a significant improvement in pain, function, and satisfaction at an average follow-up of 17.7 months.
      • Repetto I.
      • Biti B.
      • Cerruti P.
      • Trentini R.
      • Felli L.
      Conservative treatment of ankle osteoarthritis: Can platelet-rich plasma effectively postpone surgery?.
      Similarly, Fukawa et al. reported on 20 patients with ankle OA who received biweekly injections and found a significant improvement in pain and function up to 6 months postinjection with maximum benefit at 3 months.
      • Fukawa T.
      • Yamaguchi S.
      • Akatsu Y.
      • Yamamoto Y.
      • Akagi R.
      • Sasho T.
      Safety and efficacy of intra-articular injection of platelet-rich plasma in patients with ankle osteoarthritis.
      Bulding on the momentum of PRP, other blood-based preparations are in the process of clinical trial testing, including mixtures of preparations in the search of synergistic activity. One such investigation involved the use of a platelet-poor plasma (PPP) biomatrix loaded with MSC, which was studied in regenerative endodontic procedures with good clinical results at 12-month follow-up.
      • Brizuela C.
      • Meza G.
      • Urrejola D.
      • et al.
      Cell-based regenerative endodontics for treatment of periapical lesions: A randomized, controlled phase I/II clinical trial.
      Building on these data, a current clinical trial is under way to evaluate both the safety and efficacy of this preparation for use in osteochondral lesions of the talus (ClinicalTrials.gov Identifier: NCT03905824).

      Concentrated Bone Marrow Aspirate

      Concentrated bone marrow aspirate (CBMA) is another autologous product 'obtained by aspiration of marrow, typically from the iliac crest, tibia, or calcaneus, with subsequent centrifugation via one of several commercially available systems into its final concentrated form. CBMA contains similar platelet counts when compared to PRP but different cellular and cytokine compositions, including significantly increased interleukin-1 receptor antagonist protein in CBMA by comparison to PRP.
      • Cassano J.M.
      • Kennedy J.G.
      • Ross K.A.
      • Fraser E.J.
      • Goodale M.B.
      • Fortier L.A.
      Bone marrow concentrate and platelet-rich plasma differ in cell distribution and interleukin 1 receptor antagonist protein concentration.
      CBMA may be a useful adjunct in both cartilage and bone procedures.
      • Harford J.S.
      • Dekker T.J.
      • Adams S.B.
      Bone marrow aspirate concentrate for bone healing in foot and ankle surgery.
      ,
      • Smyth N.A.
      • Murawski C.D.
      • Haleem A.M.
      • Hannon C.P.
      • Savage-Elliott I.
      • Kennedy J.G.
      Establishing proof of concept: Platelet-rich plasma and bone marrow aspirate concentrate may improve cartilage repair following surgical treatment for osteochondral lesions of the talus.
      Currently, the bulk of the literature on CBMA use in foot and ankle is limited to retrospective studies. CBMA has been used to augment percutaneous Jones fracture fixation in multiple studies with union rates between 92.5% and 100% in athletes.
      • Murawski C.D.
      • Kennedy J.G.
      Percutaneous internal fixation of proximal fifth metatarsal jones fractures (Zones II and III) with Charlotte Carolina screw and bone marrow aspirate concentrate: An outcome study in athletes.
      ,
      • O'Malley M.P.
      • Milewski M.D.
      • Solomito M.J.
      • Erwteman A.S.
      • Nissen C.W.
      The association of tibial slope and anterior cruciate ligament rupture in skeletally immature patients.
      It has also been investigated in the treatment of osteochondral lesions of the talus as an adjunct to microfracture in several studies, including a cohort followed by Vannini et al. at a mean of 10 years postop that showed sustained improvements in multiple PRO measures at this late time period.
      • Vannini F.
      • Filardo G.
      • Altamura S.A.
      • et al.
      Bone marrow aspirate concentrate and scaffold for osteochondral lesions of the talus in ankle osteoarthritis: satisfactory clinical outcome at 10 years.
      ,
      • Kim Y.S.
      • Park E.H.
      • Kim Y.C.
      • Koh Y.G.
      Clinical outcomes of mesenchymal stem cell injection with arthroscopic treatment in older patients with osteochondral lesions of the talus.
      Figure 2 shows one example use of CBMA as part of a peroneal brevis tendon repair.
      Figure thumbnail gr2
      Fig 2(A) Diseased peroneus brevis tendon. (B) Injection of concentrated bone marrow aspirate (CBMA) into tubularized brevis tendon. (C) Continuation of tubularizaion of tendon. (D) Completed tubularization of tendon with CBMA embedded.

      Hyaluronic Acid

      Hyaluronic acid injections have been popularized as an alternative to corticosteroid with the theorized benefit of prolonged treatment effect. However, despite the theoretical benefits of HA of providing an arthritic joint with the proteoglycans and glycosaminoglycans that are lacking, the literature in treating ankle arthritis has not supported its use.
      • Altman R.D.
      • Manjoo A.
      • Fierlinger A.
      • Niazi F.
      • Nicholls M.
      The mechanism of action for hyaluronic acid treatment in the osteoarthritic knee: a systematic review.
      DeGroot et al. performed a randomized, double-blinded, placebo-controlled study to study the efficacy of HA injection compared to normal saline and found no difference in outcomes at 12 weeks, which is in line with the literature as a whole.
      • DeGroot 3rd, H.
      • Uzunishvili S.
      • Weir R.
      • Al-omari A.
      • Gomes B.
      Intra-articular injection of hyaluronic acid is not superior to saline solution injection for ankle arthritis: A randomized, double-blind, placebo-controlled study.
      ,
      • Jantzen C.
      • Ebskov L.B.
      • Andersen K.H.
      • Benyahia M.
      • Rasmussen P.B.
      • Johansen J.K.
      The effect of a single hyaluronic acid injection in ankle arthritis: A prospective cohort study.

      Cell-Based Therapy

      The most controversial, and widely misunderstood, class of injectable biologics currently available are the stem cell-based therapies. The most commonly used "stem cell" (stromal cell) therapy in foot and ankle is mesenchymal stem cell allografts from donor tissue. Used for its osteogenic, osteoconductive, and osteoinductive potential, allogenic mesenchymal stem cell preparations have been popularized in fusion procedures to assist in the formation of new bone, particularly in the revision setting.
      • Rush S.M.
      • Hamilton G.A.
      • Ackerson L.M.
      Mesenchymal stem cell allograft in revision foot and ankle surgery: A clinical and radiographic analysis.
      Studies have shown positive results in achieving fusion with the cellular bone grafts, particularly in patients with comorbidities associated with difficulty healing.
      • Scott R.T.
      • Hyer C.F.
      Role of cellular allograft containing mesenchymal stem cells in high-risk foot and ankle reconstructions.
      • Dekker T.J.
      • White P.
      • Adams S.B.
      Efficacy of a cellular bone allograft for foot and ankle arthrodesis and revision nonunion procedures.
      • Dekker T.J.
      • White P.
      • Adams S.B.
      Efficacy of a cellular allogeneic bone graft in foot and ankle arthrodesis procedures.
      Along similar lines, the use of adipose tissue derivatives has been a source of recent investigation with adipose tissue-derived stem cells micronized adipose tissue injections being a few of the examples. There is currently a lack of level 1 evidence to support the use of these adipose tissue-derived preparations; however, some smaller case series have shown promise for further investigation for its use in osteoarthritis, tendinopathy, and osteochondral lesions.
      • Shimozono Y.
      • Dankert J.F.
      • Kennedy J.G.
      Arthroscopic debridement and autologous micronized adipose tissue injection in the treatment of advanced-stage posttraumatic osteoarthritis of the ankle.
      • Natali S.
      • Screpis D.
      • Farinelli L.
      • et al.
      The use of intra-articular injection of autologous micro-fragmented adipose tissue as pain treatment for ankle osteoarthritis: A prospective not randomized clinical study.
      • Usuelli F.G.
      • D'Ambrosi R.
      • Maccario C.
      • Indino C.
      • Manzi L.
      • Maffulli N.
      Adipose-derived stem cells in orthopaedic pathologies.
      The use of various stem cell preparations is a rapidly evolving field with new, well-designed studies being conducted across orthopedic subspecialties that will continue to refine the proper use of these adjuncts.

      Conclusions

      The use of biologics in orthopedics is a rapidly expanding and evolving landscape, particularly within the subspeciality of the foot and ankle. Although it is difficult to compartmentalize such a broad field into a tidy framework, organizing the biologics into cartilage, bone, and blood/injectable-based therapies is one way to make sense of the plethora of current information available. While biologics are widely considered safe, studies on the efficacy, indications for use, and proper formulation are forthcoming as the role of biologics continues to expand.

      Supplementary Data

      References

        • Burk T.
        • Del Valle J.
        • Finn R.A.
        • Phillips C.
        Maximum Quantity of bone available for harvest from the anterior iliac crest, posterior iliac crest, and proximal tibia using a standardized surgical approach: A cadaveric study.
        J Oral Maxillofac Surg. 2016; 74: 2532-2548
        • Younger E.M.
        • Chapman M.W.
        Morbidity at bone graft donor sites.
        J Orthop Trauma. 1989; 3: 192-195
      1. Attia AK, Mahmoud K, ElSweify K, Bariteau J, Labib SA. Donor site morbidity of calcaneal, distal tibial, and proximal tibial cancellous bone autografts in foot and ankle surgery. A systematic review and meta-analysis of 2296 bone grafts. Foot Ankle Surg In press. doi:10.1016/j.fas.2021.09.005

        • Baldwin P.
        • Li D.J.
        • Auston D.A.
        • Mir H.S.
        • Yoon R.S.
        • Koval K.J.
        Autograft, allograft, and bone graft substitutes: Clinical evidence and indications for use in the setting of orthopaedic trauma surgery.
        J Orthop Trauma. 2019; 33: 203-213
        • Roberts T.T.
        • Rosenbaum A.J.
        Bone grafts, bone substitutes and orthobiologics: The bridge between basic science and clinical advancements in fracture healing.
        Organogenesis. 2012; 8: 114-124
        • Delloye C.
        • Cornu O.
        • Druez V.
        • Barbier O.
        Bone allografts: What they can offer and what they cannot.
        J Bone Joint Surg Br. 2007; 89: 574-579
        • Butscheidt S.
        • Moritz M.
        • Gehrke T.
        • et al.
        Incorporation and remodeling of structural allografts in acetabular reconstruction: Multiscale, micro-morphological analysis of 13 pelvic explants.
        J Bone Joint Surg Am. 2018; 100: 1406-1415
        • John S.
        • Child B.J.
        • Hix J.
        • et al.
        A retrospective analysis of anterior calcaneal osteotomy with allogenic bone graft.
        J Foot Ankle Surg. 2010; 49: 375-379
        • Philbin T.M.
        • Pokabla C.
        • Berlet G.C.
        Lateral column lengthening using allograft interposition and cervical plate fixation.
        Foot Ankle Spec. 2008; 1: 288-296
        • Müller M.A.
        • Frank A.
        • Briel M.
        • et al.
        Substitutes of structural and non-structural autologous bone grafts in hindfoot arthrodeses and osteotomies: A systematic review.
        BMC Musculoskelet Disord. 2013; 14: 59
        • Shehadi J.A.
        • Elzein S.M.
        Review of commercially available demineralized bone matrix products for spinal fusions: A selection paradigm.
        Surg Neurol Int. 2017; 8 (203-203)
        • Nakahara H.
        • Goldberg V.M.
        • Caplan A.I.
        Culture-expanded periosteal-derived cells exhibit osteochondrogenic potential in porous calcium phosphate ceramics in vivo.
        Clin Orthop Relat Res. 1992; : 291-298
        • Campana V.
        • Milano G.
        • Pagano E.
        • et al.
        Bone substitutes in orthopaedic surgery: From basic science to clinical practice.
        J Mater Sci Mater Med. 2014; 25: 2445-2461
        • Russell T.A.
        • Leighton R.K.
        Comparison of autogenous bone graft and endothermic calcium phosphate cement for defect augmentation in tibial plateau fractures. A multicenter, prospective, randomized study.
        J Bone Joint Surg Am. 2008; 90: 2057-2061
        • Knaack D.
        • Goad M.E.
        • Aiolova M.
        • et al.
        Resorbable calcium phosphate bone substitute.
        J Biomed Mater Res. 1998; 43: 399-409
        • Afifi A.M.
        • Gordon C.R.
        • Pryor L.S.
        • Sweeney W.
        • Papay F.A.
        • Zins J.E.
        Calcium phosphate cements in skull reconstruction: a meta-analysis.
        Plast Reconstr Surg. 2010; 126: 1300-1309
        • Chai F.
        • Raoul G.
        • Wiss A.
        • Ferri J.
        • Hildebrand H.F.
        [Bone substitutes: Classification and concerns].
        Rev Stomatol Chir Maxillofac. 2011; 112: 212-221
        • Frankenburg E.P.
        • Goldstein S.A.
        • Bauer T.W.
        • Harris S.A.
        • Poser R.D.
        Biomechanical and histological evaluation of a calcium phosphate cement.
        J Bone Joint Surg Am. 1998; 80: 1112-1124
        • Moore W.R.
        • Graves S.E.
        • Bain G.I.
        Synthetic bone graft substitutes.
        ANZ J Surg. 2001; 71: 354-361
        • Wiltfang J.
        • Merten H.A.
        • Schlegel K.A.
        • et al.
        Degradation characteristics of alpha and beta tri-calcium-phosphate (TCP) in minipigs.
        J Biomed Mater Res. 2002; 63: 115-121
        • Hernigou P.
        • Dubory A.
        • Pariat J.
        • et al.
        Beta-tricalcium phosphate for orthopedic reconstructions as an alternative to autogenous bone graft.
        Morphologie. 2017; 101: 173-179
        • Jiang S.D.
        • Jiang L.S.
        • Dai L.Y.
        Surgical treatment of calcaneal fractures with use of beta-tricalcium phosphate ceramic grafting.
        Foot Ankle Int. 2008; 29: 1015-1019
        • Galois L.
        • Mainard D.
        • Pfeffer F.
        • Traversari R.
        • Delagoutte J.P.
        Use of β-tricalcium phosphate in foot and ankle surgery: A report of 20 cases.
        Foot Ankle Surg. 2001; 7: 217-227
        • Greenspan D.C.
        Bioactive glass: Mechanisms of bone bonding.
        Tandläkartidningen. 1999; 91: 5
        • Hench L.L.
        • West J.K.
        Biological applications of bioactive glasses.
        Life Chem Rep. 1996; 13: 187-241
        • Moimas L.
        • Biasotto M.
        • Di Lenarda R.
        • Olivo A.
        • Schmid C.
        Rabbit pilot study on the resorbability of three-dimensional bioactive glass fibre scaffolds.
        Acta Biomater. 2006; 2: 191-199
        • Shi E.
        • Carter R.
        • Weinraub G.M.
        Outcomes of hindfoot arthrodesis supplemented with bioactive glass and bone marrow aspirate: A retrospective radiographic study.
        J Foot Ankle Surg. 2019; 58: 2-5
        • De Giglio R.
        • Di Vieste G.
        • Mondello T.
        • et al.
        Efficacy and safety of bioactive glass S53P4 as a treatment for diabetic foot osteomyelitis.
        J Foot Ankle Surg. 2021; 60: 292-296
        • Ma H.
        • Shi Y.
        • Zhang W.
        • Liu F.
        • Han Y.
        • Yang M.
        Open curettage with bone augmentation for symptomatic tumors and tumor-like lesions of calcaneus: A comparison of bioactive glass versus allogeneic bone.
        J Foot Ankle Surg. 2021; 60: 881-886
        • Bibbo C.
        • Nelson J.
        • Ehrlich D.
        • Rougeux B.
        Bone morphogenetic proteins: Indications and uses.
        Clin Podiatr Med Surg. 2015; 32: 35-43
        • Lin S.S.
        • Montemurro N.J.
        • Krell E.S.
        Orthobiologics in foot and ankle surgery.
        J Am Acad Orthop Surg. 2016; 24: 113-122
        • Fourman M.S.
        • Borst E.W.
        • Bogner E.
        • Rozbruch S.R.
        • Fragomen A.T.
        Recombinant human BMP-2 increases the incidence and rate of healing in complex ankle arthrodesis.
        Clin Orthop Relat Res. 2014; 472: 732-739
        • Bibbo C.
        • Patel D.V.
        • Haskell M.D.
        Recombinant bone morphogenetic protein-2 (rhBMP-2) in high-risk ankle and hindfoot fusions.
        Foot Ankle Int. 2009; 30: 597-603
        • Rearick T.
        • Charlton T.P.
        • Thordarson D.
        Effectiveness and complications associated with recombinant human bone morphogenetic protein-2 augmentation of foot and ankle fusions and fracture nonunions.
        Foot Ankle Int. 2014; 35: 783-788
        • DiGiovanni C.W.
        • Lin S.S.
        • Baumhauer J.F.
        • et al.
        Recombinant human platelet-derived growth factor-BB and beta-tricalcium phosphate (rhPDGF-BB/β-TCP): An alternative to autogenous bone graft.
        J Bone Joint Surg Am. 2013; 95: 1184-1192
        • Daniels T.R.
        • Younger A.S.
        • Penner M.J.
        • et al.
        Prospective randomized controlled trial of hindfoot and ankle fusions treated with rhPDGF-BB in combination with a β-TCP-collagen matrix.
        Foot Ankle Int. 2015; 36: 739-748
        • Daniels T.R.
        • Anderson J.
        • Swords M.P.
        • et al.
        Recombinant human platelet-derived growth factor BB in combination with a beta-tricalcium phosphate (rhPDGF-BB/β-TCP)-collagen matrix as an alternative to autograft.
        Foot Ankle Int. 2019; 40: 1068-1078
        • Chuckpaiwong B.
        • Berkson E.M.
        • Theodore G.H.
        Microfracture for osteochondral lesions of the ankle: Outcome analysis and outcome predictors of 105 cases.
        Arthroscopy. 2008; 24: 106-112
        • Choi W.J.
        • Choi G.W.
        • Kim J.S.
        • Lee J.W.
        Prognostic significance of the containment and location of osteochondral lesions of the talus: Independent adverse outcomes associated with uncontained lesions of the talar shoulder.
        Am J Sports Med. 2013; 41: 126-133
        • Hannon C.P.
        • Bayer S.
        • Murawski C.D.
        • et al.
        Debridement, curettage, and bone marrow stimulation: Proceedings of the International Consensus Meeting on Cartilage Repair of the Ankle.
        Foot Ankle Int. 2018; 39: 16s-22s
        • Ramponi L.
        • Yasui Y.
        • Murawski C.D.
        • et al.
        Lesion size is a predictor of clinical outcomes after bone marrow stimulation for osteochondral lesions of the talus: A systematic review.
        Am J Sports Med. 2017; 45: 1698-1705
        • Mistry H.
        • Connock M.
        • Pink J.
        • et al.
        Autologous chondrocyte implantation in the knee: Systematic review and economic evaluation.
        Health Technol Assess. 2017; 21: 1-294
        • Brittberg M.
        • Lindahl A.
        • Nilsson A.
        • Ohlsson C.
        • Isaksson O.
        • Peterson L.
        Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation.
        N Engl J Med. 1994; 331: 889-895
        • Nam E.K.
        • Ferkel R.D.
        • Applegate G.R.
        Autologous chondrocyte implantation of the ankle: a 2- to 5-year follow-up.
        Am J Sports Med. 2009; 37: 274-284
        • Giannini S.
        • Buda R.
        • Grigolo B.
        • Vannini F.
        Autologous chondrocyte transplantation in osteochondral lesions of the ankle joint.
        Foot Ankle Int. 2001; 22: 513-517
        • Giannini S.
        • Battaglia M.
        • Buda R.
        • Cavallo M.
        • Ruffilli A.
        • Vannini F.
        Surgical treatment of osteochondral lesions of the talus by open-field autologous chondrocyte implantation: a 10-year follow-up clinical and magnetic resonance imaging T2-mapping evaluation.
        Am J Sports Med. 2009; 37: 112s-118s
        • Whittaker J.P.
        • Smith G.
        • Makwana N.
        • et al.
        Early results of autologous chondrocyte implantation in the talus.
        J Bone Joint Surg Br. 2005; 87: 179-183
        • Aurich M.
        • Bedi H.S.
        • Smith P.J.
        • et al.
        Arthroscopic treatment of osteochondral lesions of the ankle with matrix-associated chondrocyte implantation: early clinical and magnetic resonance imaging results.
        Am J Sports Med. 2011; 39: 311-319
        • Benthien J.P.
        • Behrens P.
        Autologous matrix-induced chondrogenesis (AMIC): Combining microfracturing and a collagen I/III matrix for articular cartilage resurfacing.
        Cartilage. 2010; 1: 65-68
        • Rothrauff B.B.
        • Murawski C.D.
        • Angthong C.
        • et al.
        Scaffold-based therapies: Proceedings of the International Consensus Meeting on Cartilage Repair of the Ankle.
        Foot Ankle Int. 2018; 39: 41s-47s
        • Walther M.
        • Valderrabano V.
        • Wiewiorski M.
        • et al.
        Is there clinical evidence to support autologous matrix-induced chondrogenesis (AMIC) for chondral defects in the talus? A systematic review and meta-analysis.
        Foot Ankle Surg. 2021; 27: 236-245
        • Usuelli F.G.
        • D'Ambrosi R.
        • Maccario C.
        • Boga M.
        • de Girolamo L.
        All-arthroscopic AMIC(®) (AT-AMIC(®)) technique with autologous bone graft for talar osteochondral defects: clinical and radiological results.
        Knee Surg Sports Traumatol Arthrosc. 2018; 26: 875-881
        • Weigelt L.
        • Hartmann R.
        • Pfirrmann C.
        • Espinosa N.
        • Wirth S.H.
        Autologous matrix-induced chondrogenesis for osteochondral lesions of the talus: A clinical and radiological 2- to 8-year follow-up study.
        Am J Sports Med. 2019; 47: 1679-1686
        • Richter M.
        • Zech S.
        Matrix-associated stem cell transplantation (MAST) in chondral defects of foot and ankle is effective.
        Foot Ankle Surg. 2013; 19: 84-90
        • Richter M.
        • Zech S.
        • Andreas Meissner S.
        Matrix-associated stem cell transplantation (MAST) in chondral defects of the ankle is safe and effective—2-year-followup in 130 patients.
        Foot Ankle Surg. 2017; 23: 236-242
        • Richter M.
        • Zech S.
        Matrix-associated stem cell transplantation (MAST) in chondral lesions at the ankle as part of a complex surgical approach- 5-year-follow-up in 100 patients.
        Foot Ankle Surg. 2019; 25: 264-271
        • Adams Jr., S.B.
        • Demetracopoulos C.A.
        • Parekh S.G.
        • Easley M.E.
        • Robbins J.
        Arthroscopic particulated juvenile cartilage allograft transplantation for the treatment of osteochondral lesions of the talus.
        Arthrosc Tech. 2014; 3: e533-e537
        • Adams Jr., S.B.
        • Yao J.Q.
        • Schon L.C.
        Particulated juvenile articular cartilage allograft transplantation for osteochondral lesions of the talus.
        Tech Foot Ankle Surg. 2011; 10
        • Dekker T.J.
        • Steele J.R.
        • Federer A.E.
        • Easley M.E.
        • Hamid K.S.
        • Adams S.B.
        Efficacy of particulated juvenile cartilage allograft transplantation for osteochondral lesions of the talus.
        Foot Ankle Int. 2018; 39: 278-283
        • Coetzee J.C.
        • Giza E.
        • Schon L.C.
        • et al.
        Treatment of osteochondral lesions of the talus with particulated juvenile cartilage.
        Foot Ankle Int. 2013; 34: 1205-1211
        • Christensen B.B.
        • Olesen M.L.
        • Hede K.T.C.
        • Bergholt N.L.
        • Foldager C.B.
        • Lind M.
        Particulated cartilage for chondral and osteochondral repair: A review.
        Cartilage. 2021; 13: 1047S-1057S
        • Levinson C.
        • Cavalli E.
        • Sindi D.M.
        • et al.
        Chondrocytes from device-minced articular cartilage show potent outgrowth into fibrin and collagen hydrogels.
        Orthop J Sports Med. 2019; 72325967119867618
        • Massen F.K.
        • Inauen C.R.
        • Harder L.P.
        • Runer A.
        • Preiss S.
        • Salzmann G.M.
        One-step autologous minced cartilage procedure for the treatment of knee joint chondral and osteochondral lesions: A series of 27 patients with 2-year follow-up.
        Orthop J Sports Med. 2019; 72325967119853773
        • Salzmann G.M.
        • Ossendorff R.
        • Gilat R.
        • Cole B.J.
        Autologous minced cartilage implantation for treatment of chondral and osteochondral lesions in the knee joint: An overview.
        Cartilage. 2021; 13: 1124S-1136S
        • Zingler C.
        • Carl H.D.
        • Swoboda B.
        • Krinner S.
        • Hennig F.
        • Gelse K.
        Limited evidence of chondrocyte outgrowth from adult human articular cartilage.
        Osteoarthritis Cartilage. 2016; 24: 124-128
        • Andia I.
        • Abate M.
        Platelet-rich plasma: underlying biology and clinical correlates.
        Regen Med. 2013; 8: 645-658
        • Alves R.
        • Grimalt R.
        A review of platelet-rich plasma: History, biology, mechanism of action, and classification.
        Skin Appendage Disord. 2018; 4: 18-24
        • Hanisch K.
        • Wedderkopp N.
        Platelet-rich plasma (PRP) treatment of noninsertional Achilles tendinopathy in a two case series: no significant difference in effect between leukocyte-rich and leukocyte-poor PRP.
        Orthop Res Rev. 2019; 11: 55-60
        • de Vos R.J.
        • Weir A.
        • van Schie H.T.
        • et al.
        Platelet-rich plasma injection for chronic Achilles tendinopathy: A randomized controlled trial.
        JAMA. 2010; 303: 144-149
        • de Jonge S.
        • de Vos R.J.
        • Weir A.
        • et al.
        One-year follow-up of platelet-rich plasma treatment in chronic Achilles tendinopathy: A double-blind randomized placebo-controlled trial.
        Am J Sports Med. 2011; 39: 1623-1629
        • Boesen A.P.
        • Hansen R.
        • Boesen M.I.
        • Malliaras P.
        • Langberg H.
        Effect of high-volume injection, platelet-rich plasma, and sham treatment in chronic midportion Achilles tendinopathy: A randomized double-blinded prospective study.
        Am J Sports Med. 2017; 45: 2034-2043
        • Usuelli F.G.
        • Grassi M.
        • Maccario C.
        • et al.
        Intratendinous adipose-derived stromal vascular fraction (SVF) injection provides a safe, efficacious treatment for Achilles tendinopathy: Results of a randomized controlled clinical trial at a 6-month follow-up.
        Knee Surg Sports Traumatol. 2018; 26: 2000-2010
        • Repetto I.
        • Biti B.
        • Cerruti P.
        • Trentini R.
        • Felli L.
        Conservative treatment of ankle osteoarthritis: Can platelet-rich plasma effectively postpone surgery?.
        J Foot Ankle Surg. 2017; 56: 362-365
        • Fukawa T.
        • Yamaguchi S.
        • Akatsu Y.
        • Yamamoto Y.
        • Akagi R.
        • Sasho T.
        Safety and efficacy of intra-articular injection of platelet-rich plasma in patients with ankle osteoarthritis.
        Foot Ankle Int. 2017; 38: 596-604
        • Brizuela C.
        • Meza G.
        • Urrejola D.
        • et al.
        Cell-based regenerative endodontics for treatment of periapical lesions: A randomized, controlled phase I/II clinical trial.
        J Dent Res. 2020; 99: 523-529
        • Cassano J.M.
        • Kennedy J.G.
        • Ross K.A.
        • Fraser E.J.
        • Goodale M.B.
        • Fortier L.A.
        Bone marrow concentrate and platelet-rich plasma differ in cell distribution and interleukin 1 receptor antagonist protein concentration.
        Knee Surg Sports Traumatol Arthrosc. 2018; 26: 333-342
        • Harford J.S.
        • Dekker T.J.
        • Adams S.B.
        Bone marrow aspirate concentrate for bone healing in foot and ankle surgery.
        Foot Ankle Clinics. 2016; 21: 839-845
        • Smyth N.A.
        • Murawski C.D.
        • Haleem A.M.
        • Hannon C.P.
        • Savage-Elliott I.
        • Kennedy J.G.
        Establishing proof of concept: Platelet-rich plasma and bone marrow aspirate concentrate may improve cartilage repair following surgical treatment for osteochondral lesions of the talus.
        World J Orthop. 2012; 3: 101-108
        • Murawski C.D.
        • Kennedy J.G.
        Percutaneous internal fixation of proximal fifth metatarsal jones fractures (Zones II and III) with Charlotte Carolina screw and bone marrow aspirate concentrate: An outcome study in athletes.
        Am J Sports Med. 2011; 39: 1295-1301
        • O'Malley M.P.
        • Milewski M.D.
        • Solomito M.J.
        • Erwteman A.S.
        • Nissen C.W.
        The association of tibial slope and anterior cruciate ligament rupture in skeletally immature patients.
        Arthroscopy. 2015; 31: 77-82
        • Vannini F.
        • Filardo G.
        • Altamura S.A.
        • et al.
        Bone marrow aspirate concentrate and scaffold for osteochondral lesions of the talus in ankle osteoarthritis: satisfactory clinical outcome at 10 years.
        Knee Surg Sports Traumatol Arthrosc. 2021; 29: 2504-2510
        • Kim Y.S.
        • Park E.H.
        • Kim Y.C.
        • Koh Y.G.
        Clinical outcomes of mesenchymal stem cell injection with arthroscopic treatment in older patients with osteochondral lesions of the talus.
        Am J Sports Med. 2013; 41: 1090-1099
        • Altman R.D.
        • Manjoo A.
        • Fierlinger A.
        • Niazi F.
        • Nicholls M.
        The mechanism of action for hyaluronic acid treatment in the osteoarthritic knee: a systematic review.
        BMC Musculoskel Disord. 2015; 16 (321-321)
        • DeGroot 3rd, H.
        • Uzunishvili S.
        • Weir R.
        • Al-omari A.
        • Gomes B.
        Intra-articular injection of hyaluronic acid is not superior to saline solution injection for ankle arthritis: A randomized, double-blind, placebo-controlled study.
        J Bone Joint Surg Am. 2012; 94: 2-8
        • Jantzen C.
        • Ebskov L.B.
        • Andersen K.H.
        • Benyahia M.
        • Rasmussen P.B.
        • Johansen J.K.
        The effect of a single hyaluronic acid injection in ankle arthritis: A prospective cohort study.
        J Foot Ankle Surg. 2020; 59: 961-963
        • Rush S.M.
        • Hamilton G.A.
        • Ackerson L.M.
        Mesenchymal stem cell allograft in revision foot and ankle surgery: A clinical and radiographic analysis.
        J Foot Ankle Surg. 2009; 48: 163-169
        • Scott R.T.
        • Hyer C.F.
        Role of cellular allograft containing mesenchymal stem cells in high-risk foot and ankle reconstructions.
        J Foot Ankle Surg. 2013; 52: 32-35
        • Dekker T.J.
        • White P.
        • Adams S.B.
        Efficacy of a cellular bone allograft for foot and ankle arthrodesis and revision nonunion procedures.
        Foot Ankle Int. 2017; 38: 277-282
        • Dekker T.J.
        • White P.
        • Adams S.B.
        Efficacy of a cellular allogeneic bone graft in foot and ankle arthrodesis procedures.
        Foot Ankle Clin. 2016; 21: 855-861
        • Shimozono Y.
        • Dankert J.F.
        • Kennedy J.G.
        Arthroscopic debridement and autologous micronized adipose tissue injection in the treatment of advanced-stage posttraumatic osteoarthritis of the ankle.
        Cartilage. 2021; 13: 1337S-1343S
        • Natali S.
        • Screpis D.
        • Farinelli L.
        • et al.
        The use of intra-articular injection of autologous micro-fragmented adipose tissue as pain treatment for ankle osteoarthritis: A prospective not randomized clinical study.
        Int Orthop. 2021; 45: 2239-2244
        • Usuelli F.G.
        • D'Ambrosi R.
        • Maccario C.
        • Indino C.
        • Manzi L.
        • Maffulli N.
        Adipose-derived stem cells in orthopaedic pathologies.
        Brit Med Bull. 2017; 124: 31-54