The Role of Tissue Engineering and Three-Dimensional–Filled Conduits in Bridging Nerve Gaps: A Review of Recent Advancements

Abstract

Tissue-engineered nerve guidance conduits (NGCs) are an area of research interest and investment. Currently, two separate three-dimensional, filled NGCs have Food and Drug Administration approval in the management of nerve gaps up to 3 cm in length, with more on the horizon. Future NGC options will leverage increasingly intricate designs to mimic the natural biology and architecture of native nerve tissue. To enhance the development of next-generation NGCs, experimental protocols and models should be standardized. For the NGCs currently on the market, more clinical data and randomized comparative studies are needed. Tissue-engineered nerve guidance conduits (NGCs) are an area of research interest and investment. Currently, two separate three-dimensional, filled NGCs have Food and Drug Administration approval in the management of nerve gaps up to 3 cm in length, with more on the horizon. Future NGC options will leverage increasingly intricate designs to mimic the natural biology and architecture of native nerve tissue. To enhance the development of next-generation NGCs, experimental protocols and models should be standardized. For the NGCs currently on the market, more clinical data and randomized comparative studies are needed. Peripheral nerve injuries (PNIs) are commonly encountered and challenging to manage. Peripheral nerve injuries have been estimated to impact 2.3% of patients presenting to the emergency department after trauma.1Padovano W.M. Dengler J. Patterson M.M. et al.Incidence of nerve injury after extremity trauma in the United States.Hand (N Y). 2022; 17: 615-623Crossref PubMed Scopus (35) Google Scholar Typically associated with crush injuries, joint dislocations, and motor vehicle accidents, PNIs carry with them significant comorbidity and subsequent societal cost.2Taylor C.A. Braza D. Rice J.B. Dillingham T. The incidence of peripheral nerve injury in extremity trauma.Am J Phys Med Rehabil. 2008; 87: 381-385Crossref PubMed Scopus (379) Google Scholar When possible, tension-free primary repair of nerve lacerations remains the ideal treatment of PNIs. In situations where direct repair is precluded by the presence of a nerve gap, nerve autograft is the gold standard treatment. Autograft carries with it significant limitations, including added surgical time, additional risk, and donor site morbidity. Because of this, other approaches have been advocated, including venous and arterial autograft conduits, nerve allografts, and interpositional nerve guidance conduits (NGCs). Early NGCs comprised various hollow tubes made of silicone or polyglycolic acid (PGA), placed between lacerated nerve ends.3Deal D.N. Griffin J.W. Hogan M.V. Nerve conduits for nerve repair or reconstruction.J Am Acad Orthop Surg. 2012; 20: 63-68Crossref PubMed Scopus (0) Google Scholar In the years since, multiple hollow NGCs have received Food and Drug Administration (FDA) approval for the repair of nerve gaps.4Kehoe S. Zhang X.F. Boyd D. FDA approved guidance conduits and wraps for peripheral nerve injury: a review of materials and efficacy.Injury. 2012; 43: 553-572Abstract Full Text Full Text PDF PubMed Scopus (553) Google Scholar One drawback to hollow NGCs is a limited efficacy in gaps greater than 1–1.5 cm.5Weber M.B. Isaacs J.E. Digital nerve injury: assessment and treatment.J Am Acad Orthop Surg. 2023; 31: 802-812Crossref Scopus (1) Google Scholar As knowledge of the pathophysiology of nerve degeneration and repair has improved, advancements in tissue engineering have enabled more sophisticated NGCs to be imagined along with the promise of bridging longer gaps. These developments leverage three-dimensional (3D) architectural and biochemical signals in an attempt to replicate native nerve regeneration and optimize the regenerative potential of contemporary NGCs. Given the promise of modern tissue engineering techniques along with the considerable research effort being poured into nerve gap repair, the purpose of this review was to report on recent advancements in the management of PNIs with a specific focus on newer, 3D-filled nerve conduits. Nerve injuries comprise a spectrum of trauma increasing in severity from neurapraxia to axonotmesis and neurotmesis described by Seddon and Sunderland.6Seddon H.J. Peripheral nerve injuries.Glasgow Med J. 1943; 139: 61-75PubMed Google Scholar,7Sunderland S. A classification of peripheral nerve injuries producing loss of function.Brain. 1951; 74: 491-516Crossref PubMed Scopus (956) Google Scholar Following neurotmesis, severed axons degenerate in a staged process known as Wallerian degeneration within 24–48 hours.8Conforti L. Gilley J. Coleman M.P. Wallerian degeneration: an emerging axon death pathway linking injury and disease.Nat Rev Neurosci. 2014; 15: 394-409Crossref PubMed Scopus (418) Google Scholar The initial phase of this process involves Schwann cell- and macrophage-mediated phagocytosis of myelin debris to leave an empty endoneurial tube. This is followed by Schwann cell proliferation and formation of bands of Bunger, which provide a scaffold for subsequent regeneration via the axonal growth cone originating from the proximal stump. This process is mediated by phenotypic changes in the Schwann cells at the area of injury, which leads to upregulation of specific adhesion molecules, secretion of extracellular matrix proteins, and release of numerous neurotropic growth factors and cytokines.9Carvalho C.R. Reis R.L. Oliveira J.M. Fundamentals and current strategies for peripheral nerve repair and regeneration.Adv Exp Med Biol. 2020; 1249: 173-201Crossref Scopus (24) Google Scholar Improved understanding of the interplay between these cues and factors has provided more targets for modern tissue-engineered NGCs to replicate the optimal mechanical and biologic cues available in nerve autograft or primary repair. Although hollow NGCs avoid donor site morbidity and provide structural support and guidance capabilities, they fail to capture the complexity of a nerve autograft. The ideal NGC leverages tissue engineering techniques to replicate biochemical and architectural signals known to support regenerating axonal bodies and guide them to their intended target.10Dixon A.R. Jariwala S.H. Bilis Z. Loverde J.R. Pasquina P.F. Alvarez L.M. Bridging the gap in peripheral nerve repair with 3D printed and bioprinted conduits.Biomaterials. 2018; 186 ([review]): 44-63Crossref PubMed Scopus (73) Google Scholar Physical properties of optimal NGCs include biocompatibility, degradation, suturability, and adequate strength and elasticity to withstand physiologic motion. Biocompatibility protects against inflammatory response and subsequent scarring of regenerating nerves.11Stocco E. Barbon S. Emmi A. et al.Bridging gaps in peripheral nerves: from current strategies to future perspectives in conduit design.Int J Mol Sci. 2023; 24: 9170Crossref Scopus (7) Google Scholar Degradation of NGCs in the months to years after grafting avoids the risk of later external compression from the conduit itself and involves a delicate balance where the rate of degradation does not outstrip regenerative capacity. Practically, NGCs must be able to tolerate suture coaptation to nerve ends and subsequent physiologic levels of motion without sustaining damage or kinking. To nurture axonal regeneration, NGCs must also provide biological support. This includes being permeable to allow diffusion of nutrients and oxygen while not allowing fibroblast infiltration, which may lead to glial scar formation.12Menorca R.M. Fussell T.S. Elfar J.C. Nerve physiology: mechanisms of injury and recovery.Hand Clin. 2013; 29: 317-330Abstract Full Text Full Text PDF PubMed Google Scholar The 3D microarchitecture of NGCs must account for the fascicular organization of the proximal and distal nerve stumps and serve as a guidance conduit to the distal endoneurial target. Furthermore, interior conduit design must provide structural support to regenerating axons, which includes containing appropriate adhesion molecules and extracellular matrix protein components.13Patel N.P. Lyon K.A. Huang J.H. An update–tissue engineered nerve grafts for the repair of peripheral nerve injuries.Neural Regen Res. 2018; 13: 764-774Crossref Scopus (49) Google Scholar Finally, NGCs ideally would be designed to provide sustained neurotropic growth factor and Schwann cell support, potentially in gradients that provide directional cues.10Dixon A.R. Jariwala S.H. Bilis Z. Loverde J.R. Pasquina P.F. Alvarez L.M. Bridging the gap in peripheral nerve repair with 3D printed and bioprinted conduits.Biomaterials. 2018; 186 ([review]): 44-63Crossref PubMed Scopus (73) Google Scholar Kehoe et al4Kehoe S. Zhang X.F. Boyd D. FDA approved guidance conduits and wraps for peripheral nerve injury: a review of materials and efficacy.Injury. 2012; 43: 553-572Abstract Full Text Full Text PDF PubMed Scopus (553) Google Scholar identified seven FDA-approved NGCs as of 2010. Since then, six new conduits have received FDA approval (Table 1). Four of these are hollow conduit designs of varying materials. NeuraGen 3D and Nerbridge are the first approved implants to offer 3D structure beyond the hollow tubular structure of standard NGCs (Fig. 1). These novel 3D conduits may ultimately allow for bridging longer gaps beyond 1.5 cm, but clinical data are currently lacking.Table 1FDA-Approved Synthetic Nerve Guidance Conduits as of January 1, 2023ProductCompanyMaterialStructureDegradation (Wk)Approval DateReaxon PlusMedovent GmbHChitosanHollow74–774/2018RFCNCCollagen Matrix, IncType I CollagenHollow266/2017 and 4/2020NeuraGen 3DIntegraType I CollagenCollagen and GAGs91–1221/2017Axoguard Nerve ConnectorCook Biotech IncECMHollowN/A10/2016NerbridgeToyobo CoPGAPorous CollagenN/A6/2016Neurolac Nerve GuidePolyganics, IncPLDLHollow4110/2011SaluBridge/SaluTunnelSalumedicaPVAHollow∞8/2010Neuroflex/NeuromatrixCollagen Matrix, IncType I CollagenHollow10–209/2001NeuraGenIntegraType I CollagenHollow91–1226/2001NeruotubeSynovisPGAHollow83/1999RFCNC, Reinforced flexible collagen nerve cuff. Open table in a new tab RFCNC, Reinforced flexible collagen nerve cuff. NeuraGen 3D is a type 1 collagen tube filled with a longitudinally aligned inner matrix of collagen and chondroitin-6-sulfate, which is an extracellular matrix protein upregulated in nerve injury and demonstrated to mediate Schwann cell migration.14Liu J. Chau C.H. Liu H. et al.Upregulation of chondroitin 6-sulphotransferase-1 facilitates Schwann cell migration during axonal growth.J Cell Sci. 2006; 119: 933-942Crossref Scopus (27) Google Scholar Preclinical studies compared a prototype of the NeuraGen 3D NGC with reversed autograft, hollow conduit (NeuraGen), and conduit with collagen matrix alone in a 1 cm rat sciatic nerve gap model.15Lee J.Y. Giusti G. Friedrich P.F. et al.The effect of collagen nerve conduits filled with collagen-glycosaminoglycan matrix on peripheral motor nerve regeneration in a rat model.J Bone Joint Surg Am. 2012; 94: 2084-2091Crossref PubMed Scopus (0) Google Scholar They found that NeuraGen 3D performed comparably with reversed autograft and better than hollow or collagen-filled NGCs in terms of nerve fiber density and myelinated axon count at 12 weeks.15Lee J.Y. Giusti G. Friedrich P.F. et al.The effect of collagen nerve conduits filled with collagen-glycosaminoglycan matrix on peripheral motor nerve regeneration in a rat model.J Bone Joint Surg Am. 2012; 94: 2084-2091Crossref PubMed Scopus (0) Google Scholar In vivo studies have demonstrated robust Schwann cell ingrowth along the collagen-glycosaminoglycan matrix.16Shakhbazau A. Archibald S.J. Shcharbin D. Bryszewska M. Midha R. Aligned collagen-GAG matrix as a 3D substrate for Schwann cell migration and dendrimer-based gene delivery.J Mater Sci Mater Med. 2014; 25: 1979-1989Crossref PubMed Scopus (0) Google Scholar Follow-up clinical studies are needed. Nerbridge is a woven PGA tube filled with a porous collagen matrix and external collagen coating. Kusuhara et al17Kusuhara H. Hirase Y. Isogai N. Sueyoshi Y. A clinical multi-center registry study on digital nerve repair using a biodegradable nerve conduit of PGA with external and internal collagen scaffolding.Microsurgery. 2019; 39 ([article]): 395-399Crossref Scopus (18) Google Scholar reported on the use of Nerbridge to bridge 20 digital nerve gaps at multiple centers with a mean length of 17 mm in which 90% of patients had meaningful recovery of sensibility. Although these results are promising, a comparative study using a rat sciatic nerve model found that Nerbridge performed worse than autograft and hollow collagen conduit on the maintenance of compound muscle action potential, maximal tetanic force generated, and maintenance of weight of the tibialis anterior muscle at 3–4 months postinjury.18Saltzman E.B. Villa J.C. Doty S.B. Feinberg J.H. Lee S.K. Wolfe S.W. A comparison between two collagen nerve conduits and nerve autograft: a rat model of motor nerve regeneration.J Hand Surg Am. 2019; 44 ([article]): 700.e1-700.e9Abstract Full Text Full Text PDF Scopus (0) Google Scholar Query of ClinicalTrials.gov identified three registered clinical trials involving other engineered NGCs not currently approved by the FDA. One (NCT02970864) is ongoing and seeks to the and efficacy of of a tube with a inner on digital nerve R. A. J. A. for a phase I of a novel nerve conduit in with digital nerve injury 2019; ([article]): Google Scholar involves the use of a NGC with two to digital nerve with results not The other a collagen conduit with inner collagen which was to be in to bridge nerve gaps of mm after nerve A. S. et and in patients after of the nerve by the nerve guide J Med Res. Scopus Google Scholar A of conduit materials has been described and to varying provide adequate and properties of nerve grafts as and A.R. Jariwala S.H. Bilis Z. Loverde J.R. Pasquina P.F. Alvarez L.M. Bridging the gap in peripheral nerve repair with 3D printed and bioprinted conduits.Biomaterials. 2018; 186 ([review]): 44-63Crossref PubMed Scopus (73) Google Scholar and conduits are described and have been approved for use by the FDA (Table 1). be by and conduits are in and implants are as are of commonly conduit materials are to is an structural protein found in and other conduits are are and and Schwann cell C.R. Reis R.L. 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G. et conduits for peripheral nerve regeneration.J Scopus Google Scholar reported of NGCs using an and a NGC is being in an FDA on digital nerve repair using enhance nerve repair by a more natural and E. Barbon S. Emmi A. et al.Bridging gaps in peripheral nerves: from current strategies to future perspectives in conduit design.Int J Mol Sci. 2023; 24: 9170Crossref Scopus (7) Google M.B. Zhang in nerve conduits for peripheral nerve Surg. 2006; Scopus Google Scholar include natural and and and PGA M.B. Zhang in nerve conduits for peripheral nerve Surg. 2006; Scopus Google Scholar is area of research promise in NGC Aligned or may enhance directional guidance of regenerating via and support in a that endoneurial J.Y. Giusti G. Friedrich P.F. et al.The effect of collagen nerve conduits filled with collagen-glycosaminoglycan matrix on peripheral motor nerve regeneration in a rat model.J Bone Joint Surg Am. 2012; 94: 2084-2091Crossref PubMed Scopus (0) Google A. A. J.E. nerve guidance conduits for peripheral nerve 2018; Scopus Google Scholar (Fig. on the and from NGC to endoneurial architecture to and Future NGCs will 3D structure and to better support and guide regenerating axons and Schwann This is in the recent FDA approval of NeuraGen 3D and and the three registered clinical trials on nerve gap repair, which 3D NGC Because of the associated with nerve and tissue-engineered nerve grafts are being to biologic factors including and that may of the N.P. Lyon K.A. Huang J.H. An update–tissue engineered nerve grafts for the repair of peripheral nerve injuries.Neural Regen Res. 2018; 13: 764-774Crossref Scopus (49) Google Scholar Nerve guidance conduits with biologic the risk of or associated with using Future on biologic may be able to gap length of current NGC with approaches described Given their in nerve regeneration, NGC with Schwann cells has demonstrated In nerve grafts with Schwann cells had recovery to with J. 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Emmi A. et al.Bridging gaps in peripheral nerves: from current strategies to future perspectives in conduit design.Int J Mol Sci. 2023; 24: 9170Crossref Scopus (7) Google Scholar Conduits or that have been to be at muscle action motor and nerve in peripheral with Schwann S. M. D. et vivo studies of gold conduits for peripheral nerve PubMed Scopus (0) Google L. L. et with for peripheral nerve Mater 13: Scopus Google Scholar in 3D have novel NGC designs to mimic the biocompatibility, and mechanical properties of Y. J. the of nerve conduits for the treatment of peripheral nerve 2022; Scopus Google Scholar in which NGCs are being printed include which conduits by using to a of which a of the of in a ultimately the 3D which of a and them in a allowing for the of 3D A.R. Jariwala S.H. Bilis Z. Loverde J.R. Pasquina P.F. Alvarez L.M. 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