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Peripheral nerve repair with collagen conduit
Abstract
This paper describes the repair of peripheral nerves with a tubular conduit fabricated from collagen. The tubular collagen matrix was made semipermeable to permit nutrient exchange and accessibility of neurotrophic factors to the axonal growth zone during regeneration. In-vitro studies showed that the semipermeable collagen conduit allowed rapid diffusion of molecules the size of bovine serum albumin and was adequately cross-linked for controlled resorption in vivo. Studies on primates suggest that collagen conduits worked as effectively as nerve autografts in terms of physiological recovery of motor and sensory responses. The results of in-vitro and in-vivo studies of the collagen conduit represent a significant step towards our specific aim of developing suitable off-the-shelf prostheses for clinical repair of damaged peripheral nerves.
... The fibrillar structure of the collagen is maintained throughout the manufacturing process, permitting the construction of a biocompatible tubular matrix that has sufficient mechanical strength, defined permeability and a controlled rate of resorption. [63][64][65] However, this material is not expected to fully resorb for a period of up to 4 years post implantation. 26 The manufacturers advise prehydration of the tube for pliability and resilience in order to permit ease of handling provided in the manufacturers instructions for use (IFU). ...
... In these studies, there was no reported scar tissue or inflammatory response with complete absorption minimizing the possibility of nerve entrapment. 63,65 Tyner et al. 67 used NeuraGen 1 in a rat sciatic nerve model in an effort to stimulate linear neuronal outgrowth and reduce random axon sprouting. 13% (1 of 8) of animals receiving the conduit developed autotomy in comparison to 88% (7 of 8) to the control (neurectomy) group, which was significantly less (P < 0.01). ...
... 72 It has the same technological characteristics as NeuroMatrix TM ; its selective permeability allows nutrient diffusion, whilst blocking fibroblast cell migration. 65 It has also been shown to be well received by soft tissue and provokes limited inflammatory response, whilst exhibiting full levels of resorbability. 72 45 In addition it also appears as the degeneration interval is increased, the regenerative supporting ability of the stored nerve is compromised; hence, nerve storage for repair should not be excessively delayed. ...
... Many nerve protective materials including silicone sheets, collagen tubes, gels, and fluids have been developed in recent years to overcome these drawbacks. 2,3,6,9,13,15,[19][20][21][23][24][25][26]29,31,[39][40][41]45,46,60,64 We previously developed a novel biodegradable nerve conduit composed of poly(L-lactide) (PLA) and poly(ecaprolactone) (PCL) to treat peripheral nerve injury and confirmed that axonal regeneration was induced within the conduit. 22,30,40,56,57 This nerve conduit comprises 2 layers: an outer layer composed of PLA multifilament fiber mesh and an inner layer composed of a PLA-and PCL-containing porous sponge with pores of 10 to 50 mm. ...
... 12,14,16,34,38,45,47,50,58,62 Various nonbiodegradable or biodegradable materials such as silicone sheets, collagen, porcine extracellular matrix, biodegradable glass fiber wrap, PLA film, gel, and fluid have recently been used to cover neurolysis-treated nerves. 2,3,6,9,13,15,[19][20][21][23][24][25][26]29,31,[39][40][41]45,46,60,64 Neura Gen (Integra LifeSciences Corporation), which is a nerve conduit for peripheral nerve injuries, is used as a biodegradable wrapping material for peripheral nerves and effectively induces axonal growth and protects peripheral nerves. 2,9,31 The PLA-PCL material used in the present study has also been used for nerve conduits and has suitable flexibility and gentleness for nerves. ...
... 2,3,6,9,13,15,[19][20][21][23][24][25][26]29,31,[39][40][41]45,46,60,64 Neura Gen (Integra LifeSciences Corporation), which is a nerve conduit for peripheral nerve injuries, is used as a biodegradable wrapping material for peripheral nerves and effectively induces axonal growth and protects peripheral nerves. 2,9,31 The PLA-PCL material used in the present study has also been used for nerve conduits and has suitable flexibility and gentleness for nerves. 22,30,[55][56][57] As mentioned above, it is important to protect peripheral nerves from scar formation during the initial healing stage, which continues for several weeks after neurolysis. ...
OBJECTIVE
Peripheral nerve adhesion caused by extraneural and intraneural scar formation after neurolysis leads to nerve dysfunction. The authors previously developed a novel very flexible biodegradable nerve conduit composed of poly(L-lactide) and poly(ε-caprolactone) for use in peripheral nerve regeneration. In the present study, they investigated the effect of protective nerve wrapping on preventing adhesion in a rat sciatic nerve adhesion model.
METHODS
Rat sciatic nerves were randomly assigned to one of the following four groups: a no-adhesion group, which involved neurolysis alone without an adhesion procedure; an adhesion group, in which the adhesion procedure was performed after neurolysis, but no treatment was subsequently administered; a nerve wrap group, in which the adhesion procedure was performed after neurolysis and protective nerve wrapping was then performed with the nerve conduit; and a hyaluronic acid (HA) group, in which the adhesion procedure was performed after neurolysis and nerve wrapping was then performed with a 1% sodium HA viscous solution. Six weeks postoperatively, the authors evaluated the extent of scar formation using adhesion scores and biomechanical and histological examinations and assessed nerve function with electrophysiological examination and gastrocnemius muscle weight measurement.
RESULTS
In the adhesion group, prominent scar tissue surrounded the nerve and strongly adhered to the nerve biomechanically and histologically. The motor nerve conduction velocity and gastrocnemius muscle weight were the lowest in this group. Conversely, the adhesion scores were significantly lower, motor nerve conduction velocity was significantly higher, and gastrocnemius muscle weight was significantly higher in the nerve wrap group than in the adhesion group. Additionally, the biomechanical breaking strength was significantly lower in the nerve wrap group than in the adhesion group and HA group. The morphological properties of axons in the nerve wrap group were preserved. Intraneural macrophage invasion, as assessed by the number of CD68- and CCR7-positive cells, was less severe in the nerve wrap group than in the adhesion group.
CONCLUSIONS
The nerve conduit prevented post-neurolysis peripheral nerves from developing adhesion and allowed them to maintain their nerve function because it effectively blocked scarring and prevented adhesion-related damage in the peripheral nerves.
... In conclusion, a number of studies suggest that using porous materials to manufacture NRCs or NRC sheaths could have benefits for peripheral nerve regeneration [169,170,187,218,394]. In particular, the delivery of ...
... They found that impermeable constructs with a neurite promoting filler matrix yielded better functional recovery than both the porous construct with the same filler, and impermeable and porous constructs with a standard collagen filler. These papers provide a contrasting perspective to the work of Jenq et al. and Kim et al. among others[69,218,394] which conclude that porosity is beneficial for nerve repair.Asymetrically porous NRCs have also been manufactured and tested in vivo. For example, Oh et al. created hydrophilic porous tubes with nanopores (around 50 nm in size) on the inner surface, and micropores (around 50 µm) on the outer surface, so that approximately half way through the cross-sectional sheath the pore size changed[283,284]. ...
Currently, the design of tissue engineered constructs for peripheral nerve repair is informed predominantly by experiments. However, translation to the clinical setting is slow, and engineered tissues have not surpassed the outcomes achieved by nerve grafts. Therapeutic cell survival and vascularisation are important for the assimilation of engineered tissue, and vascularisation provides vital directional cues for regenerating nerves. In this thesis, mathematical modelling informed by experimental data is used to investigate the impact of different therapeutic cell seeding strategies on cell survival and vascularisation in engineered tissue nerve repair constructs. A mathematical model of interactions between cells, oxygen and vascular endothelial growth factor (VEGF), consisting of three partial differential equations, is developed and parameterised against in vitro data. Key cell type-specific parameter values are derived, and the model is then used to simulate cell-solute interactions in a nerve repair construct over the first five days post-implantation in vivo. Simulations using uniform seeding cell densities of 88 and 13 × 10⁶ cells/ml result in the highest mean viable cell densities across the construct after 1 and 5 days respectively. However, simulations using seeding densities in the range of 200 – 300 ×10⁶ cells/ml result in steeper VEGF gradients and higher total VEGF concentrations across the construct, which could be beneficial for vascularisation. Simulations incorporating a porous construct sheath result in higher viable cell density predictions, but also lower total VEGF concentrations, than those run using an impermeable sheath. Subsequently, the cell-solute model is combined with a discrete model of angiogenesis that simulates vascular growth in response to gradients of VEGF. Simulation results suggest that different cell seeding strategies could influence the density, rate and morphology of vascularisation. The predictions generated in this work demonstrate how mathematical modelling as part of a wider multidisciplinary approach can provide direction for future experimental work.
... Such characteristic was revealed in our experiment, as the collagen membrane slowly biodegraded and remained present when the nerve tissue was harvested after 2 and 4 weeks. Further, the semipermeable property of collagen conduits enables diffusion of neurotrophic factors from the external environment into the repair site [59]. ...
Background
Peripheral nerve injury is one of the most common injuries that might occur in oral and maxillofacial surgery. The purpose of this study was to determine the effect of FK506 loaded with collagen membrane and fibrin glue on the promotion of nerve regeneration after traction nerve injury in a rat model.
Methods
Thirty male Sprague-Dawley rats were divided into three groups: group A ( n = 10), a sham group whose sciatic nerve was exposed without any injury; and groups B ( n = 10) and C ( n = 10), which underwent traction nerve injury using 200 g of traction force for 1 min. The injured nerve in group C was covered with a collagen membrane soaked with FK506 (0.5 mg/0.1 mL) and fibrin glue. Functional analysis and microscopic evaluation were performed at 2 and 4 weeks after injury.
Results
The sciatic function index was − 5.78 ± 3.07 for group A, − 20.69 ± 5.22 for group B, and − 12.01 ± 4.20 for group C at 2 weeks after injury. However, at 4 weeks, the sciatic function index was − 5.58 ± 2.45 for group A, − 19.69 ± 4.81 for group B, and − 11.95 ± 1.94 for group C. In both periods, statistically significant differences were found among the groups ( p <0.017). Histomorphometric evaluation revealed improved nerve regeneration in group C compared to that in group B. However, no statistical differences in axonal density were found among the three groups ( p < 0.017).
Conclusion
Localized FK506 with collagen membrane and fibrin glue could promote axonal regeneration in a rat model of traction nerve injury.
... In 1982, it was reported that the non-degradable silicone tube was used to wrap the severed sciatic nerve of the rats to repair the 6 mm gap in vivo system (37). The semipermeable collagen catheter could also repair the PNI in vitro (48). However, these scaffolds are unstable and inactive in vivo, so they are gradually eliminated. ...
A peripheral nerve injury (PNI) has severe and profound effects on the life of a patient. The therapeutic approach remains one of the most challenging clinical problems. In recent years, many constructive nerve regeneration schemes are proposed at home and abroad. Nerve tissue engineering plays an important role. It develops an ideal nerve substitute called artificial nerve. Given the complexity of nerve regeneration, this review summarizes the pathophysiology and tissue-engineered repairing strategies of the PNI. Moreover, we discussed the scaffolds and seed cells for neural tissue engineering. Furthermore, we have emphasized the role of 3D printing in tissue engineering.
... Collagen tubes/sheets (Neuragen/NeuraWrap, Neuromed/Neuromatrix/Neurofl ex -collagen type I FDA approved) have been proved to permit nutrient exchange and accessibility of neurotrophic factors at the axonal growth zone during regeneration 44 . Kim et al. demonstrated decreased inner epineural connective tissue formation with use of a collagen nerve wrap (NeuraWrap) during primary repair of peripheral nerve transection in a rat sciatic nerve model 45 . ...
Peripheral nerve injuries have a high incidence in limb trauma and have a devastating impact on the quality of life of the patients. Microsurgical repair of nerves remains the gold standard in severed nerves, but outcomes remain unsatisfactory although this technique has been refi ned in the last fi ve to six decades. Current medical practice dictates the need for the development and application of novel adjuvant techniques to address the fi eld. Nerve protecting materials, nerve guide conduits (NGCs), autologous nerve conduits, pharmacological agents, growth factor therapies, stem cell therapies, low current nerve stimulation, tissue glue, photochemical tissue bonding are all valuable directions of research with encouraging results. In this review, we are trying to summarize the benefi ts of each technique and to point out the necessity of a multimodal approach to peripheral nerve regeneration and the opportunity for clinical translation of all the abundant research in current literature. Rezumat Incidenţa leziunilor nervilor periferici în traumatismele membrelor este crescută și are un impact devastator asupra calităţii vieţii pacienţilor. Repararea microchirurgicală a nervilor periferici rămâne standardul de aur în cazul nervilor sectionaţi, dar rezultatele acestor proceduri rămân nesatisfăcătoare în pofi da faptului că aceste tehnici au fost con-tinuu rafi nate pe parcursul ultimelor șase decenii. Practica medicală actuală dictează necesitatea dezvoltării și apli-cării unor tehnici noi și complementare în acest domeniu. Materiale care protejează nervul, tuburi pentru ghidarea regenerării nervilor, tuburi din ţesuturi autoloage, medicamente, terapii cu factori de creștere, terapii cu celule stem, stimulare folosind curent de joasă frecvenţă, adezivi tisulari, adezivi tisulari activaţi fotochimic reprezintă direcţii importante de cercetare cu rezultate încurajatoare. În această lucrare de revizuire a literaturii, autorul încearcă să sumarizeze benefi ciile fi ecărei tehnici în parte și să sublinieze necesitatea unei abordări multimodale a domeniului regenerării nervilor periferici, dar și necesitatea translaţiei acestor tehnici, larg tratate în literatură, în practica clinică. Cuvinte cheie: regenerarea nervilor periferici, repararea nervilor, microchirurgie, tuburi pentru ghidarea regenerării nervilor, factori de creștere, celule stem REVIEWS Victor Ioan Popa et al.
... Next-generation nerve conduits made use of biologically derived materials (e.g., collagen) as conduits and hydrogel substrates [53,54]. Conduits containing collagen hydrogels were found to perform better than hollow or salinefilled conduits, and performed the same as autografts when used to bridge short nerve gaps [55]. More recently, Bozkurt et al. [56] showed that microstructured collagen conduits seeded with Schwann cells that possessed aligned topography resembling the endoneurial tubes induced significant Schwann cell migration, formation of bands of Büngner, and axonal regeneration. ...
Tissue engineering is the use of engineering methods to replace, replicate, or improve biological tissues. Neural tissue engineering involves the integrated use of biomaterials, cellular engineering, and drug delivery technologies with the purpose of protecting, repairing, or regenerating cells and tissues of the nervous system. Through the introduction of biochemical, topographic, immunomodulatory, and other types of cues, tissues can be therapeutically controlled to direct growth and tissue function in order to overcome biological constraints on tissue repair and regeneration. These strategies can be applied when injury or disease occurs in the brain, spinal cord, for damaged peripheral nerves, or to improve chronic functionality of implantable neural interfaces. In this chapter, we present an overview of neural tissue engineering using examples of therapeutic systems including nerve conduits, implantable hydrogels, delivery of neurotrophic factors and stem cells, genetic approaches to tissue engineering, immunomodulation, and electrical stimulation.
... In this biomaterial, the fibrillar structure of collagen is preserved throughout the whole process, giving rise to a biocompatible matrix with mechanical strength similar to the native collagen, defined permeability and controlled rate of resorption. 111,112 As described by Stang and co-workers, 113 and more recently by Pandit and coworkers, 105,114 the wall structure, the thickness of the scaffold, its porosity and alignment, as well as its inner structure and diameter of the fibers are important parameters to consider. The regeneration is enhanced with porous small-diameter grafts and well-aligned fibers. ...
This work describes the design of tunable biomaterials for tissue engineering. The composite approach provides numerous advantages to enhance cell adhesion and control bioactivity by complying both with structural and functional requirements. The host matrix, made from a natural macromolecule (collagen), or from synthetic supramolecular polymers (peptide amphiphiles), provides a suitable structural environment to the cells and can also display intrinsic biochemical cues to influence cell behavior. Functionalized silica nanoparticles can be added to be used as platforms either to further tune the architecture of the scaffold or display additional bioactive ligands. The combination of peptide amphiphiles with such nanoparticles led to composite biomaterials with high modularity allowing to compare different displays of one bioactive epitope and the simultaneous grafting of two epitopes known to work in a distance-dependent manner. The next step was to achieve the control of the spatial organization of several functions on the surface of a single nanoparticle. We have developed an original and challenging strategy based on the synthesis of self-assembling alkoxysilane precursors that could form pre-organized domains to be transferred at the silica nanoparticle surface to create patches. A large library of mono- and bifunctional particles were prepared that were incorporated in collagen-based threads evaluated in a model of peripheral nerve regeneration. Finally, we have elaborated thin porous scaffolds by electrospinning collagen in non-denaturing conditions that should allow to improve the cells access to the functional nanoparticles.
... The predominantly preferred treatment is still an autograft [1]. A tissue engineered NGC is a viable clinical alternative for clinicians to treat peripheral nerve injury [2][3][4][5]. This construct has the potential to replace the use of autografts, thus eliminating some of the limitations, such as limited supply, diminished Schwann cell viability after harvest, size mismatch, and donor site morbidity [6]. ...
Artificial nerve guidance conduits (NGCs) are being investigated as an alternative to autografts, since autografts are limited in supply. A polycaprolactone (PCL)-based spiral NGC with crosslinked laminin on aligned nanofibers was evaluated in vivo post a successful in vitro assessment. PC-12 cell assays confirmed that the aligned nanofibers functionalized with laminin were able to guide and enhance neurite outgrowth. In the rodent model, the data demonstrated that axons were able to regenerate across the critical nerve gap, when laminin was present. Without laminin, the spiral NGC with aligned nanofibers group resulted in a random cluster of extracellular matrix tissue following injuries. The reversed autograft group performed best, showing the most substantial improvement based on nerve histological assessment and gastrocnemius muscle measurement. Nevertheless, the recovery time was too short to obtain meaningful data for the motor functional assessments. A full motor recovery may take up to years. An interesting observation was noted in the crosslinked laminin group. Numerous new blood capillary-like structures were found around the regenerated nerve. Owing to recent studies, we hypothesized that new blood vessel formation could be one of the key factors to increase the successful rate of nerve regeneration in the current study. Overall, these findings indicated that the incorporation of laminin into polymeric nerve conduits is a promising strategy for enhancing peripheral nerve regeneration. However, the best combination of contact-guidance cues, haptotactic cues, and chemotactic cues have yet to be realized. The natural sequence of nerve regeneration should be studied more in-depth before modulating any strategies.
... Conduits provide a protective semipermeable (absorbable) hollow environment to isolate the nerve from the surrounding tissue, allowing for the collection of fibrin to serve as a scaffold for axonal regeneration toward the distal stump. 7 Processed nerve allografts consist of decellularized human nerves, maintaining the internal microstructure and extracellular matrix of native nerve tissue. 8 Both techniques have been extensively studied for purely sensory nerve repairs; several studies have reported high rates of recovery and few complications or adverse events. ...
... The commercial collagen matrices are in the form of conduit or wrap. They serve as a guide for axon regeneration across the nerve gap and help to align the regenerating axons [86,170]. Also, they function as a barrier to prevent scar formation, while allowing nutrient exchange and neurotrophic factors across the matrix. ...
Collagen type I is the most abundant matrix protein in the human body and is highly demanded in tissue engineering, regenerative medicine, and pharmaceutical applications. To meet the uprising demand in biomedical applications, collagen type I has been isolated from mammalians (bovine, porcine, goat and rat) and non-mammalians (fish, amphibian, and sea plant) source using various extraction techniques. Recent advancement enables fabrication of collagen scaffolds in multiple forms such as film, sponge, and hydrogel, with or without other biomaterials. The scaffolds are extensively used to develop tissue substitutes in regenerating or repairing diseased or damaged tissues. The 3D scaffolds are also used to develop in vitro model and as a vehicle for delivering drugs or active compounds.
... It can be used as both conduit material as well as luminal filler. One of the earlier successful studies using collagenbased nerve guide conduits showed that it was as effective as nerve autograft for repairing short sub-critical nerve gap (4 mm) in rat (Archibald et al., 1991;Li et al., 1992). More recent endeavors have been focused on treating critical nerve defect by using collagen-based scaffold as cell delivery platform to improve nerve regeneration. ...
Nerve injuries can be life-long debilitating traumas that severely impact patients' quality of life. While many acellular neural scaffolds have been developed to aid the process of nerve regeneration, complete functional recovery is still very difficult to achieve, especially for long-gap peripheral nerve injury and most cases of spinal cord injury. Cell-based therapies have shown many promising results for improving nerve regeneration. With recent advances in neural tissue engineering, the integration of biomaterial scaffolds and cell transplantation are emerging as a more promising approach to enhance nerve regeneration. This review provides an overview of important considerations for designing cell-carrier biomaterial scaffolds. It also discusses current biomaterials used for scaffolds that provide permissive and instructive microenvironments for improved cell transplantation.
... Conduits provide a protective semipermeable (absorbable) hollow environment to isolate the nerve from the surrounding tissue, allowing for the collection of fibrin to serve as a scaffold for axonal regeneration toward the distal stump. 7 Processed nerve allografts consist of decellularized human nerves, maintaining the internal microstructure and extracellular matrix of native nerve tissue. 8 Both techniques have been extensively studied for purely sensory nerve repairs; several studies have reported high rates of recovery and few complications or adverse events. ...
... [366] In a rabbit model, the dura was replaced with cyanamide crosslinked collagen films, which displayed very low inflammatory response and increased synthesis of new collagen by connective tissue cells that infil trated the film by day 56 postimplantation. [156] Collagen films wrapped in form of tube have been extensively used in clinic as nerve guidance conduits (e.g., NeuraWrap, NeuroMend, NeuroMatrix, and NeuraGen), [367] demonstrating limited myofibroblast infiltration, guided Schwann cell migra tion and axonal regrowth toward their distal targets. [368] Nonetheless, such materials are limited to nerve gaps smaller than 4 cm in length. ...
Collagen is the oldest and most abundant extracellular matrix protein that has found many applications in food, cosmetic, pharmaceutical, and biomedical industries. First, an overview of the family of collagens and their respective structures, conformation, and biosynthesis is provided. The advances and shortfalls of various collagen preparations (e.g., mammalian/marine extracted collagen, cell-produced collagens, recombinant collagens, and collagen-like peptides) and crosslinking technologies (e.g., chemical, physical, and biological) are then critically discussed. Subsequently, an array of structural, thermal, mechanical, biochemical, and biological assays is examined, which are developed to analyze and characterize collagenous structures. Lastly, a comprehensive review is provided on how advances in engineering, chemistry, and biology have enabled the development of bioactive, 3D structures (e.g., tissue grafts, biomaterials, cell-assembled tissue equivalents) that closely imitate native supramolecular assemblies and have the capacity to deliver in a localized and sustained manner viable cell populations and/or bioactive/therapeutic molecules. Clearly, collagens have a long history in both evolution and biotechnology and continue to offer both challenges and exciting opportunities in regenerative medicine as nature's biomaterial of choice.
... The biomaterials collagen and fibrin have both been used for decades in attempts to improve peripheral nerve injuries as luminal fillers and substrates for Schwann cells. 12,13 Previously we developed engineered neural tissue (EngNT), in which selfalignment of Schwann cells within a collagen type I hydrogel, followed by stabilization of the aligned structure by removal of some interstitial fluid, results in a tissue-like material suitable for nerve tissue engineering. 14 Fibrin, its formation and degradation, is one of the major components in wound healing; not only in hemostasis but also as a provisional growth matrix for a variety of tissue specific cells. ...
Tissue engineering approaches in nerve regeneration often aim to improve results by bridging nerve defects with conduits that mimic key features of the nerve autograft. One such approach uses Schwann cell self-alignment and stabilization within collagen gels to generate engineered neural tissue (EngNT). In this study, we investigated whether a novel blend of fibrin and collagen could be used to form EngNT, as before EngNT design a beneficial effect of fibrin on Schwann cell proliferation was observed. A range of blend formulations was tested in terms of mechanical behavior (gel formation, stabilization, swelling, tensile strength, and stiffness), and lead formulations were assessed in vitro. A 90% collagen 10% fibrin blend was found to promote SCL4.1/F7 Schwann cell viability and supported the formation of aligned EngNT, which enhanced neurite outgrowth in vitro (NG108 cells) compared to formulations with higher and lower fibrin content. Initial in vivo tests in an 8 mm rat sciatic nerve model using rolled collagen-fibrin EngNT rods revealed a significantly enhanced axonal count in the midsection of the repair, as well as in the distal part of the nerve after 4 weeks. This optimized collagen-fibrin blend therefore provides a novel way to improve the capacity of EngNT to promote regeneration following peripheral nerve injury.
... The remaining eight of the 20 mm and five of the 50 mm nerve repairs were performed with collagen nerve guides as described above. The construction and physical properties of the type I collagen nerve guides used in this study have been described previously (Li et al., 1992;Archibald et al., 1995;. ...
Functional recovery after nerve lesions in the peripheral nervous system requires the accurate regeneration of axons to their original target end organs. This paper examines axonal regeneration of the primate median nerve lesioned at the wrist over nerve gap distances of up to 50 mm. Nerve gaps were bridged by either a sural nerve graft or a biodegradable collagen nerve guide tube, and recovery was followed for up to 1100 d. Nondestructive physiological methods were used to serially examine the number of regenerated motor units, and binomial statistics were used to compare the observed number of regenerated motor units with that expected if axonal regeneration of motor neurons were random. We found up to twice the number of motor units expected by random regeneration in direct suture and sural cable graft groups but not in nerve guide repairs of 20 or 50 mm. In all repaired nerves, aberrant motor axon collaterals were detected in digital sensory nerve territory. The results support the contention that the aberrant fibers represent collaterals of an α-motor axon, which also innervates muscle. Although the aberrant motor axon collaterals remained in digital sensory nerve territory for long periods, they remained relatively immature compared with their sibling collateral projecting to muscle, or sensory axons within the digital nerve. The number of such aberrant motor axon collaterals decreased over time in some repair groups, suggesting a selective pruning of the inappropriate collateral under certain conditions.
... The biomaterials collagen and fibrin have both been used for decades in attempts to improve peripheral nerve injuries as luminal fillers and substrates for Schwann cells. 12,13 Previously we developed engineered neural tissue (EngNT), in which selfalignment of Schwann cells within a collagen type I hydrogel, followed by stabilization of the aligned structure by removal of some interstitial fluid, results in a tissue-like material suitable for nerve tissue engineering. 14 Fibrin, its formation and degradation, is one of the major components in wound healing; not only in hemostasis but also as a provisional growth matrix for a variety of tissue specific cells. ...
Tissue engineering approaches in nerve regeneration often aim to improve results by bridging nerve defects with conduits that mimic key features of the nerve autograft. One such approach uses Schwann cell self-alignment and stabilisation within collagen gels to generate engineered neural tissue (EngNT). Here we investigated whether a novel blend of fibrin and collagen could be used to form EngNT, as prior to EngNT design a beneficial effect of fibrin on Schwann cell proliferation was observed. A range of blend formulations was tested in terms of mechanical behavior (gel formation, stabilisation, swelling, tensile strength and stiffness) and lead formulations were assessed in vitro. A 90% collagen 10% fibrin blend was found to promote SCL4.1/F7 Schwann cell viability and supported the formation of aligned EngNT which enhanced neurite outgrowth in vitro (NG108 cells) compared to formulations with higher and lower fibrin content. Initial in vivo tests in an 8 mm rat sciatic nerve model using rolled collagen-fibrin EngNT rods revealed a significantly enhanced axonal count in the mid-section of the repair as well as in the distal part of the nerve after 4 weeks. This optimized collagen-fibrin blend therefore provides a novel way to improve the capacity of EngNT to promote regeneration following peripheral nerve injury
... The layer in contact with the subchondral bone is a dense collagen which prevents fibroblast ingrowth from below while allowing the influx of endogenous tissue factors that promote cell growth. 23 The second layer is a porous matrix optimised to support chondrocyte growth and metabolism. 21 We performed studies in vitro to determine whether the cells in the porous component of the implant retained the chondrocyte phenotype, 24,25 and to evaluate the ability of the dense component of the implant to prevent fibrous ingrowth. ...
We have developed a novel, two-layered, collagen matrix seeded with chondrocytes for repair of articular cartilage. It consists of a dense collagen layer which is in contact with bone and a porous matrix to support the seeded chondrocytes. The matrices were implanted in rabbit femoral trochleas for up to 24 weeks. The control groups received either a matrix without cells or no implant.
The best histological repair was seen with cell-seeded implants. The permeability and glycosaminoglycan content of both implant groups were nearly normal, but were significantly less in tissue from empty defects. The type-II collagen content of the seeded implants was normal. For unseeded implants it was 74.3% of the normal and for empty defects only 20%. The current treatments for articular injury often result in a fibrous repair which deteriorates with time. This bilayer implant allowed sustained hyaline-like repair of articular defects during the entire six-month period of observation.
... Collagen films wrapped in form of tube have been extensively used in clinic as nerve guidance conduits (e.g. NeuraWrap™, NeuroMend™, NeuroMatrix™, NeuraGen™) [367] , demonstrating limited myofibroblast infiltration, guided Schwann cell migration and axonal regrowth towards 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 their distal targets [368] . Nonetheless, such materials are limited to nerve gaps smaller than 4 cm in length [369] . ...
Collagen is the oldest extracellular matrix component in the animal kingdom. Currently, 29 homo- and hetero-trimmers have been identified, all of which have in common the amino acid repeat [Gly-X-Y]n that distinguishes their primary structure from other proteins and enables the signature quaternary structure, the triple helix. Depending on the aggregate structure, collagens have been classified as fibrous, non-fibrous, filamentous and fibril associated collagens with interrupted triple-helices. Among them, collagen type I is the most abundant collagen in mammalian tissues (70–90% of the collagen found in the body). Collagen type I fibrils are the primary structural elements of all connective tissues, providing a structural scaffold for other components primarily due to native cross-linking pathway of lysyl oxidase. Collagen type I is also associated with cell interaction, migration, attachment, differentiation and organisation. For these reasons, collagen type I is extensively used for tissue engineering applications. Mammalian extracted collagen (acid or pepsin derived) is almost exclusively used for industrial applications in leather, food, biomaterial, cosmetic and pharmaceutical industry. Fear, however, of interspecies transmission of disease has encouraged the development of synthetic and recombinant collagen technologies, which may hold the future in biomaterials applications. Numerous fabrication, stabilisation and functionalisation strategies have been developed over the years in order to produce tissue facsimiles that will promote functional regeneration. A number of collagen-specific assays have also been developed to ensure reproducibility and full characterisation of collagen preparations and collagen-based devices.
... Collagen is the most abundant mammalian protein comprising the majority of connective tissue (Glowacki and Mizuno 2008 ;Miyata et al. 1992 ;Cen et al. 2008 ;Walker et al. 2009 ). The indigenous nature of collagen and potential ability to supply both structural and nutritive support make it an attractive material for nerve scaffold fabrication (Li et al. 1992 ;Archibald et al. 1991 ;1995 ;Mackinnon and Dellon 1990 ;Ceballos et al. 1999 ;Hodde 2002 ). Mollers et al. described the cytocompatibility of a micro-structured porcine collagen scaffold for nerve tissue repair lgzhang@gwu.edu ...
Nerve regeneration involves a series of complex physiological phenomena. Larger peripheral nerve injuries must be surgically treated, typically with autografts harvested from elsewhere in the body. Central nervous injuries and diseases are more complicated, as there are inhibitive factors resulting in less than ideal repair. Currently, many researches in peripheral nerve regeneration are focused on developing alternatives to the autograft, while efforts for treating central nervous injuries and diseases are devoted to creating a permissive microenvironment for neural regeneration and therapeutic delivery. In recent years, neural tissue engineering has emerged as one of the very promising strategies for treating various nervous system injuries and diseases. Particularly, advancement in both biomaterials and 3D biomimetic scaffolds fabrication techniques such as 3D printing has inspired this field into a new era. This book chapter will focus on the two key pillars and discuss their current progress for improving neural regeneration.
... [(a) and (c) p, 0.05 compared to untreated control and (b) and (d) p, 0.05 compared to agarose control]. The data represent mean AE SEM [51] containing conduits were found to perform better than hollow or saline filled conduits, and performed the same as autografts when used to bridge short nerve gaps [71]. More recently, Bozkurt et al. [72] showed that Schwann cell seeded collagen microstructured conduits with aligned topography resembling the endoneurial tubes induced significant Schwann cell migration, formation of Bands of Büngner, and axonal regeneration. ...
Injury to the nervous system leads to several debilitating long-term disabilities that can severely impair quality of life. Regenerative failure following injury is the primary cause of disability and is mainly attributed to the localized upregulation of nerve inhibitory molecules in the case of central nervous system (CNS) injuries, and the presence of inhibitory molecules along with the absence of structural support in the case of peripheral nervous system (PNS) injuries. While treatments using autografts and allografts do result in appreciable nerve regeneration in the case of peripheral nerve gaps, the same is not true of CNS injuries which are difficult to treat.
This chapter discusses innate differences and challenges in treating CNS and PNS injuries, and the current methodologies being employed to enhance the endogenous regenerative potential and plasticity. The state-of-the-art in facilitating repair and rehabilitation by means of biochemical and cellular therapies as well as by electrical stimulation of neuromuscular tissue are also discussed.
... Synthetic devices, such as Neuragen (Integra) and Axoguard (Stryker), are composed of an absorbable semipermeable collagen that is absorbed by the body over time through normal metabolic pathways (31). During this process, no scar tissue forms nor does an inflammatory reaction arise, as the device is composed of a semipermeable membrane which blocks fibroblasts and in this manner lessens perineural fibrosis (47,51). Synthetic nerve wraps used for revision carpal tunnel surgery have the advantages of decreased operative time and donor site morbidity. ...
Carpal tunnel syndrome (CTS) affects 1% of the general population and 5% of the working population. Consequently, carpal tunnel release (CTR) is one of the most common procedures performed on the hand. Median nerve entrapment symptoms at the carpal tunnel after CTR can be defined as either failed (persistent or new symptoms) or recurrent CTS. Recurrent CTS is characterized by a symptom-free interval after surgery. The cause of recurrent carpal tunnel is thought to be due to progressive constriction of the nerve via scar formation.
There are a number of methods to manage perineural fibrosis, a condition thought to be responsible for recurrent compression and restricted nerve gliding. These include procedures to isolate the nerve from scar and others that are intended to bring neovascularization to the median nerve. While many surgical procedures for recurrent CTS have been described in the literature, there is a paucity of comparative studies on the subject. Almost all published articles report on results of a single technique or a few techniques, without a comparison of efficacy. This chapter describes the surgical techniques for recurrent CTR and their reported outcomes.
... Many researchers have developed collagen-based nerve conduits to repair short nerve gaps [38]. Few examples of commercially available, FDA-approved collagen-based tubes that have been clinically used are NeuroGen, NeuroFlex, NeuroMatrix, NeuroWrap, and NeuroMend [39][40][41][42][43]. A nerve tube fabricated from highly purified type I + III collagen derived from porcine skin, Revolnev, has also been used to repair 1 cm rat peroneal nerve with satisfactory functional recovery [44]. ...
Regenerative medicine requires materials that are biodegradable, biocompatible, structurally and chemically stable, and that can mimic the properties of the native extracellular matrix (ECM). Hydrogels are hydrophilic three-dimensional networks that have long received attention in the field of regenerative medicine due to their unique properties. Hydrogels have a potential to be the future of regenerative medicine due to their desirable mechanical and chemical properties, ease of their synthesis, and their multiple applicability as drug delivery vehicles, scaffolds, and constructs for cell culture. In this chapter, we have described hydrogels in terms of their cross-linking and then discussed the most recent developments in the use of hydrogels for peripheral nerve regeneration, tooth regeneration, and 3D bioprinting.
... Many researchers have developed collagen-based nerve conduits to repair short nerve gaps [38]. Few examples of commercially available, FDA-approved collagen-based tubes that have been clinically used are NeuroGen, NeuroFlex, NeuroMatrix, NeuroWrap, and NeuroMend [39][40][41][42][43]. A nerve tube fabricated from highly purified type I + III collagen derived from porcine skin, Revolnev, has also been used to repair 1 cm rat peroneal nerve with satisfactory functional recovery [44]. ...
Regenerative medicine requires materials that are biodegradable, biocompatible, structurally and chemically stable, and that can mimic the properties of the native extracellular matrix (ECM). Hydrogels are hydrophilic three-dimensional networks that have long received attention in the field of regenerative medicine due to their unique properties. Hydrogels have a potential to be the future of regenerative medicine due to their desirable mechanical and chemical properties, ease of their synthesis, and their multiple applicability as drug delivery vehicles, scaffolds, and constructs for cell culture. In this chapter, we have described hydrogels in terms of their cross-linking and then discussed the most recent developments in the use of hydrogels for peripheral nerve regeneration, tooth regeneration, and 3D bioprinting.
... We compared the mechanical properties of braided E0000 conduits, non-porous dipcoated E0000 conduits with 183 ± 15 µm thick walls, and the clinically used NeuraGen ® conduits consisting of collagen I (Integra Lifesciences, South Plainfield, NJ). 40,41 Due to the inability to secure a sufficient quantity of the NeuraGen ® conduits, not all experiments could be replicated with these conduits and the previous findings of Yao et al. 42 using these conduits are cited to complete the comparison. ...
Here, we report on the design of braided peripheral nerve conduits with barrier coatings. Braiding of extruded polymer fibers generates nerve conduits with excellent mechanical properties, high flexibility, and significant kink-resistance. However, braiding also results in variable levels of porosity in the conduit wall, which can lead to the infiltration of fibrous tissue into the interior of the conduit. This problem can be controlled by the application of secondary barrier coatings. Using a critical size defect in a rat sciatic nerve model, the importance of controlling the porosity of the nerve conduit walls was explored. Braided conduits without barrier coatings allowed cellular infiltration that limited nerve recovery. Several types of secondary barrier coatings were tested in animal studies, including (1) electrospinning a layer of polymer fibers onto the surface of the conduit and (2) coating the conduit with a cross-linked hyaluronic acid-based hydrogel. Sixteen weeks after implantation, hyaluronic acid-coated conduits had higher axonal density, displayed higher muscle weight, and better electrophysiological signal recovery than uncoated conduits or conduits having an electrospun layer of polymer fibers. This study indicates that braiding is a promising method of fabrication to improve the mechanical properties of peripheral nerve conduits and demonstrates the need to control the porosity of the conduit wall to optimize functional nerve recovery.
... Collagen: structural protein Chemically cross-linked protein, enzymatically degradable, good cell interactions, NC approved by the Food and Drug Administration (FDA) Archibald et al. (1991;; Li et al. (1992); Krarup Hydrogel-forming polymer, nonbiodegradable, stiffness in the range of nerve tissue Dalton et al. (2002); Belkas et al. (2005) the NC lumen or NC wall directly to the target nerve; (2) seeding cells inside the NC lumen that produce the growth factors; and (3) use of gene therapy to transfect resident cells to express a certain protein (Fig. 1). In addition to reviewing these different approaches, we will also discuss some of the pros and cons of these systems and emphasize the importance of delivery kinetics on peripheral nerve regeneration. ...
There are more than 600 conditions that can lead to nerve tissue loss and there is hardly any treatment other than the good old autologous nerve graft transplant to surpass the negative outcomes that result. Thus, nerve guide scaffolds are being essentially developed to fruitfully put stem cell-based therapy to use for nerve tissue repair and neuroregeneration.
We performed a literature search for studies on variety of electroconductive and electroactive scaffolds and conduits from different materials such as polypyrrole, polyurethane, graphene, carbon nanotubes, polycaprolactone and silk have been developed to achieve the aim of neuroregeneration.
The essential role of electrical stimulation (ES) and signaling has been realised in helping differentiation, proliferation, myelination and migration of neuronal cells along with axonal and neurite outgrowth. ES has also shown improved neurotrophic secretion by Schwann cells thereby increasing the chances of an efficient and functional regenerated nerve.
Electroconductive and electroactive nerve guide scaffolds and conduits are being essentially developed to fruitfully put stem cell-based therapy to use for nerve tissue repair and neuroregeneration.
In the development of electroconductive and electroactive nerve guide scaffolds and conduits, it is important to recreate all the characteristics of functional nerve tissue in their natural and functional form with appropriate mechanical strength and biocompatibility.
Hence, natural or synthetic biomaterials incorporated with electroconductive and electroactive potential may lead to a new generation of nerve conduits.
The following review sufficiently provides a detailed insight into the current research and future implications.
While rapid advancements in regenerative medicine strategies for spinal cord injury (SCI) have been made, most research in this field has focused on the early stages of incomplete injury. However, the majority of patients experience chronic severe injury; therefore, treatments for these situations are fundamentally important. Here, we hypothesized that environmental modulation via a clinically relevant hepatocyte growth factor (HGF)-releasing scaffold and human iPS cell-derived neural stem/progenitor cells (hNS/PCs) transplantation contributes to functional recovery after chronic complete transection SCI. Effective release of HGF from a collagen scaffold induced progressive axonal elongation and increased grafted cell viability by activating microglia/macrophages and meningeal cells, inhibiting inflammation, reducing scar formation, and enhancing vascularization. Furthermore, hNS/PCs transplantation enhanced endogenous neuronal regrowth, the extension of graft axons, and the formation of circuits around the lesion and lumbar enlargement between host and graft neurons, resulting in the restoration of locomotor and urinary function. This study presents an effective therapeutic strategy for severe chronic SCI and provides evidence for the feasibility of regenerative medicine strategies using clinically relevant materials.
We use dry-jet wet spinning in a coaxial configuration by extruding an aqueous colloidal suspension of oxidized nanocellulose (hydrogel shell) combined with airflow in the core. The coagulation of the hydrogel in a water bath results in hollow filaments (HF) that are drawn continuously at relatively high rates. Small-angle and wide-angle X-ray scattering (SAXS/WAXS) reveals the orientation and order of the cellulose sheath, depending on the applied shear flow and drying method (free-drying and drying under tension). The obtained dry HF show Young's modulus and tensile strength of up to 9 GPa and 66 MPa, respectively. Two types of phase-change materials (PCM), polyethylene glycol (PEG) and paraffin (PA), are used as infills to enable filaments for energy regulation. An increased strain (9%) is observed in the PCM-filled filaments (HF-PEG and HF-PA). The filaments display similar thermal behavior (dynamic scanning calorimetry) compared to the neat infill, PEG, or paraffin, reaching a maximum latent heat capacity of 170 J·g-1 (48-55 °C) and 169 J·g-1 (52-54 °C), respectively. Overall, this study demonstrates the facile and scalable production of two-component core-shell filaments that combine structural integrity, heat storage, and thermoregulation properties.
Background:
Peripheral nerve injuries represent a clinical challenge, especially when they are accompanied by loss of neural tissue. In this study, the authors attempted to attain a better outcome after a peripheral nerve injury by both repairing the nerve lesion and treating the denervated muscle at the same time.
Methods:
Rat sciatic nerves were transected to create 10-mm gaps. Repair was performed in five groups (n = 5 rats for each), as follows: group 1, nerve repair using poly-3-hydroxybutyrate strips to connect the proximal and distal stumps, in combination with control growth medium injection in the gastrocnemius muscle; group 2, nerve repair with poly-3-hydroxybutyrate strip seeded with Schwann cell-like differentiated adipose stem cells (differentiated adipose stem cell strip) in combination with growth medium intramuscular injection; group 3, differentiated adipose stem cell strip in combination with intramuscular injection of differentiated adipose stem cells; group 4, repair using autograft (reverse sciatic nerve graft) in combination with intramuscular injection of growth medium; and group 5, autograft in combination with intramuscular injection of differentiated adipose stem cells. Six weeks after nerve injury, the effects of the stem cells on muscle atrophy were assessed.
Results:
Poly-3-hydroxybutyrate strips seeded with differentiated adipose stem cells showed a high number of βIII-tubulin-positive axons entering the distal stump and abundant endothelial cells. Group 1 animals exhibited more muscle atrophy than all the other groups, and group 5 animals had the greatest muscle weights and muscle fibers size.
Conclusion:
Bioengineering nerve repair in combination with intramuscular stem cell injection is a promising technique to treat nerve lesions and associated muscle atrophy.
Clinical relevance statement:
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Introduction Collagen and human amniotic membrane (hAM) are Food and Drug Administration (FDA)-approved biomaterials that can be used as nerve wraps or conduits for repair of peripheral nerve injuries. Both biomaterials have been shown to reduce scarring and fibrosis of injured peripheral nerves. However, comparative advantages and disadvantages have not been definitively shown in the literature. The purpose of this systematic review is to comprehensively evaluate the literature regarding the roles of hAM and collagen nerve wraps and conduits on peripheral nerve regeneration in preclinical models.
Methods The MEDLINE database was queried using the PubMed search engine on July 7, 2019, with the following search strategy: (“amniotic membrane” OR “amnion”) OR (“collagen conduit” OR “nerve wrap”)] AND “nerve.” All resulting articles were screened by two independent reviewers. Nerve type, lesion type/injury model, repair type, treatment, and outcomes were assessed.
Results Two hundred and fifty-eight articles were identified, and 44 studies remained after application of inclusion and exclusion criteria. Seventeen studies utilized hAM, whereas 27 studies utilized collagen wraps or conduits. Twenty-three (85%) of the collagen studies utilized conduits, and four (15%) utilized wraps. Six (35%) of the hAM studies utilized conduits and 11 (65%) utilized wraps. Two (9%) collagen studies involving a conduit and one (25%) involving a wrap demonstrated at least one significant improvement in outcomes compared with a control. While none of the hAM conduit studies showed significant improvements, eight (73%) of the studies investigating hAM wraps showed at least one significant improvement in outcomes.
Conclusion The majority of studies reported positive outcomes, indicating that collagen and hAM nerve wraps and conduits both have the potential to enhance peripheral nerve regeneration. However, relatively few studies reported significant findings, except for studies evaluating hAM wraps. Preclinical models may help guide clinical practice regarding applications of these biomaterials in peripheral nerve repair.
Metallic implants are widely used in the field of implantology, but there are still problems leading to implant failures due to weak osseointegration, low mechanical strength for the implant, inadequate antibacterial properties, and low patient satisfaction. Implant failure can be caused by bacterial infections and poor osteointegration. To improve the implant functionalization, many researchers focus on surface modifications to prepare the proper physical and chemical conditions able to increase biocompatibility and osteointegration between implant and bone. Improving the antibacterial performance is also a key factor to avoid the inflammation in the human body. This paper is a brief review for the types of coatings used to increase osseointegration and biocompatibility for the successful use of metal alloys in the field of implantology.
Nerve guidance conduits (NGCs) composed of biocompatible polymers have been attracting attention as an alternative for autograft surgery in peripheral nerve regeneration. However, the nerve tissues repaired by NGCs often tend to be inadequate and lead to functional failure because of the lack of cellular supports. This paper presents a chitosan-collagen hydrogel conduit containing cells to induce peripheral nerve regeneration with cellular support. The conduit composed of two coaxial hydrogel layers of chitosan and collagen is simply made by molding and mechanical anchoring attachment with holes made on the hydrogel tube. A chitosan layer strengthens the conduit mechanically, and a collagen layer provides a scaffold for cells supporting the axonal extension. The conduits of different diameters (outer diameter approximately 2–4 mm) are fabricated. The conduit is bioabsorbable with lysozyme, and biocompatible even under bio absorption. In the neuron culture demonstration, the conduit containing Schwann cells induced the extension of the axon of neurons directed to the conduit. Our easily fabricated conduit could help the high-quality regeneration of peripheral nerves and contribute to the nerve repair surgery.
The design and development of tissue-engineered products have benefited from the clinical utilization of a wide range of biodegradable polymers. Newly developed biodegradable polymers and modifications of previously developed biodegradable polymers have enhanced the tools available for tissue-engineering applications. Insights gained from studies of cell–matrix interactions, cell–cell signaling, and organization of cellular components are placing increased demands on medical implants to interact with the patient’s tissues in a more biologically suitable fashion. Whereas, in the 20th century, biocompatibility was largely equated with eliciting no harmful response, the biomaterials of the 21st century will have to elicit tissue responses that support healing or regeneration of the patient’s own tissues.
This chapter surveys the universe of biodegradable polymers that may be useful in the development of medical implants and tissue-engineered products. Here, we distinguish between biologically derived and synthetic polymers. The materials are described in terms of their chemical composition, breakdown products, mechanism of breakdown, mechanical properties, and clinical limitations. Also discussed are the product design considerations for processing biomaterials into a final form (e.g., gel, membrane, and matrix) that will induce the desired tissue response.
Case:
Recurrent carpal tunnel syndrome is a challenging problem. Nerve wraps have been introduced as a barrier to prevent scar traction neuritis for use during revision carpal tunnel surgery. We present 3 cases of inflammatory responses to bovine collagen and porcine subintestinal mucosal nerve wraps in patients undergoing revision carpal tunnel surgery. No patient had evidence of infection, and pathology revealed acute and chronic inflammation. All 3 patients responded favorably following wrap removal.
Conclusions:
We recommend caution with the routine use of nerve wraps in the setting of revision carpal tunnel surgery.
Contemporary reconstructive modalities focus on breast anatomy and attempt to reconstruct breasts that are soft, of adequate shape, size, and symmetry. However, a functional component, i.e. sensation, has largely been ignored. Flap neurotization addresses this shortcoming. While we are still in search of the ideal surgical technique to achieve this goal, a novel approach that limits nerve harvest to the sensory branch only, thus, minimizing abdominal donor‐site morbidity, is presented.
Background
A bridging nerve autograft is the gold standard for the repair of segmental nerve injury that cannot be repaired directly. However, limited availability and donor site morbidity remain major disadvantages of autografts. Here, a nerve allograft decellularized with elastase was compared with an autograft regarding functional motor outcome in a rat sciatic segmental nerve defect model. Furthermore, the effect of storage on this allograft was studied.
Methods
Sixty‐six Lewis rats (250–300 g) underwent a 10‐mm sciatic nerve reconstruction using either a cold‐ (n = 22) or frozen‐stored (n = 22) decellularized nerve allograft or an autograft (n = 22). Sprague–Dawley rats (300–350 g) served as full major histocompatibility complex‐mismatched donors. Functional motor outcome was evaluated after 12 and 16 weeks. Ankle angle, compound muscle action potential (CMAP), isometric tetanic force, wet muscle weight, and histomorphometry were tested bilaterally.
Results
For CMAP and isometric tetanic force, no significant differences were observed between groups. In contrast, for ankle angle, histomorphometry and muscle weight, the cold‐stored allograft performed comparable to the autograft, while the frozen‐stored allograft performed significantly inferior to the autograft. At week 16, ankle angle was 88.0 ± 3.1% in the cold‐stored group, 77.4 ± 3.6% in the frozen‐stored group, and 74.1 ± 3.1% in the autograft group (P < .001); At week 16, the muscle weight showed a recovery up to 71.1 ± 4.8% in the autograft group, 67.0 ± 6.6% in the cold‐stored group, and 64.7 ± 3.7% in the frozen‐stored group (P < .05).
Conclusions
A nerve allograft decellularized with elastase, if stored under the right conditions, results in comparable functional motor outcomes as the gold standard, the autograft.
Over the past two decades, a number of fabrication methods, including 3D printing and bioprinting, have emerged as promising technologies to bioengineer nerve conduits that closely replicate features of the native peripheral nerve, with the aim of augmenting or supplanting autologous nerve grafts. 3D printing and bioprinting offer the added advantage of rapidly creating composite peripheral nerve matrices from micron-scaled units, using an assortment of synthetic, natural and biologic materials. In this review, we explore the evolution of automated 3D manufacturing technologies for the development of peripheral nerve conduits and discuss aspects of conduit design, based on microarchitecture, material selection, cell and protein inclusion, and mechanical properties, as they are adaptable to 3D printing. Additionally, we highlight advancements in the application of bio-imaging modalities toward the fabrication of patient-specific nerve conduits. Lastly, we outline regulatory as well as clinical challenges that must be surmounted for the translation of 3D printing and bioprinting technology to the clinic. As a whole, this review addresses topics that may situate 3D manufacturing at the forefront of fabrication technologies that are exploited for the generation of future revolutionary therapies like in situ printing of peripheral nerves.
Carpal tunnel syndrome is the most common peripheral nerve compression syndrome. Surgical carpal tunnel release usually offers excellent clinical outcomes. However, in 3–19% of patients, recurrent carpal tunnel symptoms occur. This challenging subset of patients often experiences poor results even after revision surgery, with 40% of patients reporting unfavorable results and 95% with persistent symptoms. In this chapter, we explore the common etiologies of recurrent carpal tunnel syndrome and offer clinical assessment strategies for management. Surgical options for revision carpal tunnel surgery including revision transverse carpal ligament release, neurolysis, and interposition grafting are reviewed.
Many surgical techniques are available for the repair of peripheral nerve defects. Autologous nerve grafts are the gold standard for most clinical conditions. In selected cases, alternative types of reconstructions are performed to fill the nerve gap. Non-nervous autologous tissue-based conduits or synthetic ones are alternatives to nerve autografts. Allografts represent another new field of interest. Decision making in the treatment of nerve defects is based on timing of referral, level of the injury, type of lesion, and size of any gap. This review focuses on current clinical practice, influenced by the numerous new experimental researches.
Die Rekonstruktion durchtrennter peripherer Nerven stellt immer dann eine besondere Herausforderung dar, wenn eine spannungsfreie Koaptation der Nervenstümpfe nicht möglich ist. Nervendefekte von wenigen Millimetern Länge können in der Regel in End-zu-End-Nahttechnik koaptiert werden. Bei Nervendefekten mit überkritischer Länge führt die direkte Nervenkoaptation aufgrund der Spannung bzw. Zugkraft zu einer reaktiven Fibrose, die das Aussprossen regenerierender Axone behindert (Deumens et al. 2010). Deshalb bleibt die Rekonstruktion langstreckiger peripherer Nervenverletzungen eine große chirurgische Herausforderung. Ziel dabei ist es, regenerierende Nervenfasern mittels Leitstrukturen zu ihren ursprünglichen Zielgeweben zu „dirigieren“.
Depuis son introduction dans les années 1880, la restauration de la fonction nerveuse après une lésion traumatique nerveuse périphérique a bénéficié de multiples progrès (1) : le développement du microscope optique, l’amélioration des techniques microchirurgicales, une meilleure compréhension l’anatomie nerveuse intraneuronale. De même, les études cliniques et fondamentales ont permis de mieux comprendre la physiopathologie de la régénération nerveuse et donc les différentes étapes de réparation. Il y a plusieurs facteurs qui influencent la qualité de la récupération nerveuse périphérique après un traumatisme nerveux : le délai entre le traumatisme et la chirurgie, l’âge du patient, le mécanisme (section nette ou écrasement), le niveau de la lésion (proximal ou distal) et les lésions associées (tissus mous, artères) (2–4). Tous ces facteurs doivent être pris en compte pour choisir la technique de réparation nerveuse la mieux adaptée à chaque patient et ainsi optimiser la qualité de la réparation nerveuse.
Background:
We describe a new dual neurorrhaphy method for a free abdominal-based flap and compare sensory recovery with this novel technique to that with conventional neurorrhaphy technique for breast reconstruction.
Methods:
70 breast cancer patients underwent muscle sparing innervated transversal rectus abdominis myocutaneous flap (neuro ms-TRAM) breast reconstruction with either a novel dual neurorrhaphy technique (N = 41) or single (N = 29) neurorrhaphy only. Dual neurorrhaphy was performed on both sides and single neurorrhaphy on one side of the flap, using the end-to-end or end-to-side technique. Two years postoperatively, quantitative sensory testing (QST) was performed for tactile, and thermal sensory modalities, and other tests included sharp-blunt, vibration, and two-point discrimination. Sensory modalities were scored either zero (abnormal) or one point (normal) at each test site against normal reference values (five sites for most tests). The total sensory scores (TSC) were calculated on the basis of the sums of the individual test scores, and all data are presented as the median (interquartile range, IQR).
Results:
The median of TSC in the breast reconstruction with the dual neurorrhaphy was higher (15.3, IQR 11.8-19.4), than that with the single neurorrhaphy (11.5, IQR 9.1-17.4) (P = 0.037). Regarding the different sensory modalities, the dual technique especially enhanced the tactile (P = 0.005) and cool detection (P = 0.021) recovery compared to the single neurorrhaphy.
Conclusions:
Dual neurorrhaphy improved the sensory recovery of the reconstructed breast, and may therefore be recommended for clinical practice. © 2016 Wiley Periodicals, Inc. Microsurgery, 2016.
This chapter investigates the main medical, dental, and pharmaceutical applications of biopolymers. The chapter consists of five parts. The first part presents the main characteristics of the organic and inorganic biopolymers used in the medical sector. The second part gives an extensive overview of a large number of medical applications including uses such as wound enclosures, body implants, and tissue engineering materials. The third part examines drug delivery matrices or vehicles made of biopolymers. The fourth part refers to the dental applications of biopolymers, and the fifth part to applications of biopolymers in diagnostic and therapeutic imaging.
In this chapter, we aim at providing an up-to-date review on nerve tissue engineering, focusing on both the peripheral and the central nervous systems (PNS and CNS, respectively). After introducing the pathophysiology of nerves and the social impact of nerve injuries, we overview the therapeutic approaches oriented toward inducing nerve regeneration, involving cellular, molecular, and scaffold-based strategies. A section is dedicated specifically to the PNS, with a critical focus on the actual therapeutic potential of experimental devices for the development of tissue-engineered medical products. A case study regarding the implementation of micropatterned collagen-based conduits in a clinical trial on PNS regeneration is also presented. Another section is dedicated to the ongoing research investigating the regenerative mechanisms of the CNS. In this context, spinal cord injury is assumed as a model lesion, for which complex tissue-engineered devices are being developed, at least in animal studies. With such a structure, this chapter is intended to provide a comprehensive, though not exhaustive, overview of nerve tissue engineering, which might be useful to students, researchers, clinicians, and biomedical entrepreneurs.
We have investigated the repair of peripheral nerves in animal models using tubular guiding conduits. The materials used to fabricate the nerve conduits and their physicochemical and mechanical characteristics can influence the extent, rate and morphology of regeneration. Permeability of the conduit membranes is one parameter which seems to play an important role in nerve regeneration. In the present study, two types of nerve conduits were developed from bovine tendon collagen with distinctly different permeabilities. The permeability of the conduit membranes was determined by diffusion of various sized molecules across these membranes. One type of conduit had pores which only allowed small molecules such as glucose to pass (small pore collagen conduits). The other type had pores which were readily permeable to macromolecules such as bovine serum albumin (large pore collagen conduits). The large pore collagen conduits supported nerve regeneration to a greater degree than the small pore collagen conduits when tested in mice to bridge 4 mm gaps of the sciatic nerve. Studies in rats and primates suggested that large pore collagen conduits worked as effectively as nerve autografts in terms of physiological recovery of motor and sensory responses. The results of in vitro and in vivo studies of these conduits represent a significant step towards our specific aim of developing suitable off-the-shelf prostheses for clinical repair of damaged peripheral nerves.
This is a report of a study in which cuffs of biodegradable copolymers were placed about ulnar and peroneal nerves in legs of ten adult mongrel dogs. The results were evaluated by clinical response, electromyographic observations, nerve conduction studies, and light microscopic examination.
When a peripheral nerve is severed and left untreated, the most likely result is the formation of an endbulb neuroma; this tangled mass of disorganized nerve fibers blocks functional recovery following nerve injury. Although there are several different approaches for promoting nerve repair, which have been greatly refined over recent years, the clinical results of peripheral nerve repair remain very disappointing. In this paper we compare the results of a collagen nerve guide conduit to the more standard clinical procedure of nerve autografting to promote repair of transected peripheral nerves in rats and nonhuman primates.
In rats, we tested recovery from sciatic nerve transection and repair by (1) direct microsurgical suture, (2) 4 mm autograft, or (3) entubulation repair with collagen‐based nerve guide conduits. Evoked muscle action potentials (MAP), were recorded from the gastrocnemius muscle at 4 and 12 weeks following sciatic nerve transection. At 4 weeks the repair group of direct suture demonstrated a significantly greater MAP, compared to the other surgical repair groups. However, at 12 weeks all four surgical repair groups displayed similar levels of recovery of the motor response.
In six adult male Macaca fascicularis monkeys the median nerve was transected 2 cm above the wrist and repaired by either a 4 mm nerve autograft or a collagen‐based nerve guide conduit leaving a 4 mm gap between nerve ends. Serial studies of motor and sensory fibers were performed by recording the evoked MAP from the abductor pollicis brevis muscle (APB) and the sensory action potential (SAP) evoked by stimulation of digital nerves (digit II), respectively, up to 760 days following surgery. Evoked muscle responses returned to normal baseline levels in all cases. Statistical analysis of the motor responses, as judged by the slope of the recovery curves, indicated a significantly more rapid rate of recovery for the nerve guide repair group. The final level of recovery of the MAP amplitudes was not significantly different between the groups. In contrast, the SAP amplitude only recovered to the low normal range and there were no statistically significant differences between the two groups in terms of sensory recovery rates.
The rodent and primate studies suggest that in terms of recovery of physiological responses from target muscle and sensory nerves, entubulation repair of peripheral nerves with a collagen‐based nerve guide conduit over a short nerve gap (4 mm) is as effective as a standard nerve autograft. Furthermore, preliminary results show that entubulation repair with this material can support axon regeneration and maturation over a nerve gap distance of at least 15 mm.
A large gap in peripheral nerve will not allow effective regeneration unless a grafting conduit is used to bridge the defect. Conventionally, nerve tissue has been used as such a conduit in nerve reconstruction; however, results from techniques using these grafts are often unsatisfactory. A number of recent investigations have indicated that nerve fibers will regenerate through a non-neural tube. The purpose of this review is: 1) to provide an overview of the various tubulation techniques previously reported for peripheral nerve gap repair; 2) to investigate new possibilities for enhancing the regenerative capacity of nerves following these tubulation techniques by drawing from technical innovations in microsurgery and recent progress in immunology and neurobiology. The interposed graft thus may perform a more positive role, not merely as a pathway for deregenerating axons, but as a source for neuronotrophic factors and neurite-promoting factors, which would nurture and guide the neurons and axons. Such modifications in graft materials may lead to clinical applications of tubulation of nerve defects that would result in an improvement in clinical results.
The presence of a distal nerve segment is considered to be essential for peripheral nerve regeneration through impermeable synthetic guidance channels. The use of a perm-selective material may provide a more appropriate regenerating environment by allowing solute exchange across the wall of the channel. We compared perm-selective acrylic copolymer (AC) channels with impermeable silicone elastomer (SE) channels in terms of regeneration in the absence of a distal nerve stump. Cohorts of 6 animals received AC and SE channels for either 4 or 8 weeks, with the distal end of the polymer tube left open in half of the animals, and plugged with the same polymer ('capped') in the other half. Capped and uncapped AC channels contained regenerated nerve cables which extended fully to the distal end of the channel, whereas capped SE channels contained only 1 mm long granulomatous tissue cables, and uncapped SE channels showed small cables with only a few myelinated axons. The nerve cables regenerated in uncapped AC channels were smaller and contained fewer myelinated axons than those observed in capped AC channels. Capped AC channels sleeved with a tight-fitting silicone tube to render them impermeable, showed no regenerated tissue within their lumen. The use of a perm-selective channel may have allowed the influx of nutrients and growth factors from the external environment while concentrating factors released by the proximal nerve stump.
The sciatic nerve of adult mice was transected and proximal and distal nerve stumps were sutured into a nontoxic bioresorbable nerve guide. Nerve guide lumens were either empty or filled with a gel containing 80% laminin and additional extracellular matrix components. Two weeks later cells in the L3 through L5 dorsal root ganglia and the ventral horn of the spinal cord were retrogradely filled with horseradish peroxidase. All animals with the laminin-containing gel but none with empty nerve guides displayed labeled cells. This suggests that the laminin-containing gel significantly hastened axonal regeneration in vivo.
In a primate model a histologic assessment of neuroma formation is reported. Three experimental groups were defined. Transected sensory nerves left adjacent to the incisional wound in an area of movement (wrist) were considered the control group. In the "proximally cut" group the same sensory nerves were positioned well proximal to the incisional wound. In the "muscle-implantation" group these nerves were placed in adjacent muscles. At 6 months a histologic assessment of the neuroma formation in the three experimental groups was carried out. Implantation of the sensory nerve into muscle significantly altered the regenerative potential of that nerve. The muscle completely surrounded the sensory nerve. The minimal neuroma that formed had significantly less scar tissue and contained nerve fibers that were of a smaller diameter and decreased density than either the control or the proximally cut group. There were no histologic differences between these latter two groups. However, regeneration into the overlying skin that was noted in the control neuromas was not seen in those nerves which had been proximally cut.
One approach to repair of transected nerves is to attempt extrinsic guidance of axons across the gaps. We inserted the proximal and distal stumps of severed mouse sciatic nerves into opposite ends of biodegradable polyester tubes. The nerves and ensheathing tubes were examined after postoperative survival times of as long as 2 years. Myelinated fiber number in each successfully regenerated nerve was measured and correlated with the tube's residual lumen size. In selected regenerated nerves axonal sizes and myelin sheath widths were sampled and compared with control values. Swelling and deformation of tube walls occurred in nearly all tubes. Successful regeneration was obtained through more than half of the implants, and was more probable in tubes with larger initial lumens. Myelinated fiber number in regenerated nerves ranged from 231 to 3561 (normally 3900 to 4200); larger values again were found in tubes with larger initial lumens. Mean axonal areas in regenerated nerves were roughly half of normal, though myelin sheaths became appropriately thick. We concluded that the more biodegradable a tube, the more likely it was to incur distortion and luminal narrowing. Tube composition per se seemed of importance mainly as it related to maintenance of adequate luminal size over the length of the degrading tubes; luminal adequacy, not tube composition, seemed paramount in determining the extent of nerve regeneration.
Purified insoluble bovine corium (IC) and dentin (DC) collagens were degraded with CNBr. Neither collagen was totally soluble in the acidic digestion mixture, even after prolonged or repeated digestion. The soluble peptides were resolved by a combination of ion-exchange and gel filtration Chromatographic procedures and compared with the peptides previously obtained from the isolated α1 and α2 chains from acid-soluble (SC) bovine corium or with β12 from the same source. The majority of peptides from IC and DC could be matched with the SC CNBr peptides. However, three distinct new classes of peptides were detected in the IC and DC digests. Both contained an acid-stable intermolecular crosslink component, α1-CB6′[α1-CB6 + α1-CB(0,1)]. Both also contained two additional peptides attributed to the presence of an α1(III) chain, α1(III)-CB3, and α1(III)-CB(4,5). While the α1(1) peptides of IC and DC were quite similar except for degree of hydroxylation, the α1(III) peptides showed more pronounced tissue specific differences. Evidence was also obtained indicating the presence of a peptide, α2-CB4′, consisting of α2-CB4 and a noncollagenous polypeptide attachment. The α2-CB4′ was present in both IC and DC but was not detected in SC. Each of the CNBr peptides common to both soluble and insoluble collagens was analyzed for hexose. In IC, a1(I)-CB5, α2-CB4, and α2-CB5 contained disaccharide units and α1(I)-CB6 contained a monosaccharide. In DC, only α1(I)-CB5 contained disaccharide, while α1(I)-CB3 and α1(I)-CB6 contained monosaccharide units. The DC α2-CB4 and α2-CB5 contained mixtures of mono- and disaccharide attachments. In addition to the hexose, DC a1(I)-CB6, α2-CB4, and α2-CB5 all contained covalently bound phosphate groups. The acid-insoluble CBNr digestion residues contained portions of collagen with uncleaved methionyl residues in close association, particularly in DC, with a highly acidic polypeptide. In DC, this polypeptide was rich in phosphoserine groups. These data indicate that the insoluble collagens do differ in several ways from acid-soluble collagen and it is suggested that these differences relate to the tissue-specific fibril organization as well as to the presence of intermolecular cross-linkages.
Nontoxic, bioresorbable "nerve guide" tubes were used to bridge the transected optic nerves of adult rats. Nerve guides were fabricated as polymers of synthetic poly D,L-lactates with 2% triethyl citrate added as a plasticizer. The local environment was manipulated further by the addition of the proteins collagen, fibrinogen, and anti-Thy-1 antibody to the nerve guide lumens at the time of operation. Neovascular growth through the nerve guide lumens was quantified with the aid of a computer-controlled microscope. Neovascular growth was greater in the nerve guides to which proteins had been added, compared with initially empty nerve guides. These experiments demonstrated the effectiveness of these nerve guide tubes in supporting and directing neovascular growth in the mammalian central nervous system, and suggested that specific alterations of the local environment within the nerve guide lumen can affect the extent of neovascular growth.
This report describes the use of a porous polymeric sleeve (Gore-tex) to direct nerve fiber growth after axotomy. Select nerves of the triceps surae muscles in 5 adult cats were surgically isolated, sectioned, and crossed or self- reunited . A piece of Gore-tex, 15 mm in length, was compressed to 5 mm and sleeved over each distal nerve end. The appropriate proximal and distal ends were stitched together, and the Gore-tex stretched back to its original length over the suture junction. The effectiveness of the Gore-tex sleeve was assessed 4-15 months post-operatively. Electrophysiological measurements of muscle force and dorsal root volleys revealed a complete absence of unintended reinnervation and a regeneration that was more substantial for motor than sensory axons. Finally, serial histological cross-sections were prepared for each nerve above, below and at the cross union. There was no evidence of nerve tissue invading the Gore-tex wall.
Nerve grafting was performed in a series of patients, 81% of whom had associated severe soft tissue injuries in the area in which nerve grafting was done. Other factors that have been shown to have an adverse effect on nerve grafting results were analyzed and were not thought to be major factors influencing results. Results were worse than those of previous reports in which the initial injury was less severe. The initial soft tissue injury is very important in predicting how well a nerve graft will function. Nerve grafting is a valuable procedure even in the face of severe soft tissue injuries, since it alone can restore protective sensation.
Severe nerve injuries may require microsurgical grafting to span a defect. Introduction of graft material into a highly vascular recipient bed is documented to aid in early regeneration of neuronal blood supply.
A silicone rod (SR)-induced fibrovascular sheath was employed to evaluate the regeneration of rat tibial nerve through 2-mmdiameter collagen tubes (CT) or contralateral nerve autografts (AUTO). At first operation, 5 mm of right tibial nerve was resected from 30 retired male breeder Sprague-Dawley rats. Resected nerve was replaced with either a 5 x 2 mm SR or the nerve ends were sutured to the intermuscular fascia.
Four weeks later, animals were repaired by replacing the SR with either a CT or a contralateral AUTO from the left tibial nerve. Three months later, EMG testing was performed, and histologic sections were prepared.
The EMG latency and the size of the compound action potential for sheathed or non-sheathed CT or AUTO were statistically superior to controls at the 95% confidence level. All other intergroup comparisons of latency and action potential size were statistically insignificant. The proportion of nerve fibers traversing the surgical sites was not influenced by the method of repair or by the presence or absence of sheathing. Tubulized repairs most closely resembled unoperated nerves, and autografted repairs had a large diameter, but much fibrosis, whereas controls displayed immaturity and disorganization.
Our observations suggest that there was no difference between repairs performed with or without a vascular pseudosheath. However, CT supported regeneration better than did AUTO repair.
Using the transected sciatic nerve model in adult mice, regeneration of a large bundle of axons organized into the form of a nerve with myelinated and unmyelinated axons, Schwann cells, fibroblasts, collagen, blood vessels, and connective tissue sheaths has been achieved with bioresorbable microtubular guidance channels over gaps of 5 mm in nonimmobilized animals. After 4-6 wks postoperatively, the regenerated nerve cable contains on the order of 40% as many myelinated axons as were measured in the proximal nerve stumps. With the channels used so far in this model, regenerating axons pass into the distal stump in about 3-6 wks postoperatively. The guidance channels used consist of synthetic polyesters and/or polyester composites including glycolic and lactic acid polymers, and polyesters derived from Krebs Cycle dicarboxylic acids. Inflammatory response to these materials has been minimal. Biodegradation/resorption rates can be controlled so as to be compatible with axon growth rates.
We describe an experimental in vivo system for studying peripheral nerve regeneration, in which the proximal stump of a transected nerve regrows through a transparent silicone chamber toward the distal stump. Physical separation permits examination of the effects of the humoral and/or cellular influences from the distal stump on regenerating fibers before they invade the distal segment itself. A small segment of the rat sciatic nerve was resected, leaving a 6 mm gap which was then encased by a cylindrical silicone chamber. Within the first weeks, a nerve trunk regenerated along the central axis of the chamber bridged the gap between the proximal and distal stumps. When the distal nerve stump was omitted from the distal opening of the chamber, only a thin structure with a few small-caliber fibers extended across the gap. In each instance regenerating nerve appeared as a cord-like structure completely surrounded by clear fluid, a feature which permits easy collection of the extracellular fluid for analysis of its chemical properties and biological activity. This feature also allows in vivo manipulation of the humoral environment in which nerve regeneration occurs.
The range of growth-promoting influences from a distal nerve stump on a regenerating proximal stump was determined using an experimental system in which a gap between cross-anastomosed rat sciatic nerves was encased by a cylindrical silicone chamber. Two arrangements were examined after 1 month in situ: A proximal-distal (PD) system in which both proximal and distal stumps were introduced into the ends of the chamber, and a proximal-open (PO) system in which the distal stump was omitted. When the gap was 6 mm long, a regenerated nerve extended all the way through the chamber in both the PD and PO systems. When the gap was increased to 10 mm, a similar regrowth occurred in the PD chamber, whereas in the PO chamber proximal regrowth was partial or nonexistent. When the gap was increased to 15 mm, no regeneration occurred, even in the presence of the distal stump. These observations confirm that the distal stump influences proximal regeneration and indicate that this influence can act only over a limited distance or volume. Such an influence could consist of humoral agents which support nerve growth and/or outgrowth from the distal stump.
To evaluate the usefulness of nerve grafting we studied 38 patients having 11 median, 7 ulnar, and 33 digital nerve grafts. Group funicular (interfascicular) grafting using magnification was performed in all patients. We followed 12 patients with 8 median and 5 ulnar nerve grafts for at least one year and 18 patients with 27 digital nerve grafts for at least six months. Medical Research Council criteria were used for evaluation of nerve function. Results in our patients and in previously reported patients having nerve grafting or repair were compared. Sensory function following ulnar nerve grafting was significantly better than that following nerve repair. Sensory function following median and digital nerve grafting was as good as that following nerve repair. Motor function following ulnar nerve grafting was as good as that following nerve repair. Previously reported patients having median nerve repairs or grafts had significantly better motor function than our patients.
Results of nerve repair in the hand
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The results of nerve grafting in the wrist and hand
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