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Peripheral nerve repair in humans using muscle autografts. A new technique
Abstract
Coaxial autografts of skeletal muscle which had been frozen then thawed were used to repair injured digital nerves in eight patients. Assessment from three to 11 months after operation showed recovery to MRC sensory category S3+ in all but one patient, an excellent level of recovery. We conclude that bespoke muscle grafts treated and used in this way may offer significant advantages over conventional nerve grafts or cable grafts especially where large peripheral nerves are involved.
... Alternatively, veins and muscle grafts were used both experimentally and in clinical practice as bridging material for short defect gaps (Norris et al., 1988;Gattuso et al., 1989;Walton et al., 1989;Glasby et al., 1990). Due to their structure, they favor the longitudinal orientation of the sprouting axons. ...
... Compared with autografts, in sheep, Glasby (Glasby et al., 1990) counted a significantly higher number of myelinated fibers distally in 5 centimeter long autologous muscle grafts. The clinical results with autologous veins (Walton et al., 1989), autologous muscle grafts (Norris et al., 1988) and regeneration chambers of polyglycolic acid (Mackinnon and Dellon, 1990a) for the reconstruction of short, digital neural defects in human patients are at the very least comparable with the classic nerve graft. ...
Autologous nerve grafts are steadily regarded as the method of choice for bridging the nerve gaps resulting after peripheral nerve lesions with substance defects. Microsurgical techniques and the perineurial suture of corresponding fascicles have improved the functional results following peripheral nerve graft.
However, regeneration success is often disappointing, despite the most thorough technique and expertise. The loss of spinal motoneurons associated with a nerve lesion and the growth of axon sprouts in inadequate endoneurial sheaths were held responsible as the reason for the lowered muscular strength, limited movement coordination and fine motor skills, poor differentiation and localization of sensory stimuli and for the lack of tactile gnosis.
In this experimental study, it is assumed that the central effects at the level of the spinal motoneuron nuclei show an image of the peripheral misinnervation in topographical-morphological terms, and can supply an explanatory model for the functional motor deficits after peripheral nerve graft.
On the other hand, the plastic changes of a motor cell column in the reinnervation process influence the structural-functional relationships of the motor units in a variety of clinically relevant ways.
... Sanes et al. demonstrated that the histological resemblance of muscle and nerve basement membrane further promotes hope for advanced functional regeneration [18]. Also, muscle alone can be interposed into a nerve defect to allow regeneration [19]. The muscle graft provides a clinically acceptable graft material, which is abundantly available [19]. ...
... Also, muscle alone can be interposed into a nerve defect to allow regeneration [19]. The muscle graft provides a clinically acceptable graft material, which is abundantly available [19]. Nevertheless, dispersion of regenerating axons out of the muscle is a known problem [20,21]. ...
Good clinical outcome after digital nerve repair is highly relevant for proper hand function and has a significant socioeconomic impact. However, level of evidence for competing surgical techniques is low. The aim is to summarize and compare the outcomes of digital nerve repair with different methods (end-to-end and end-to-side coaptations, nerve grafts, artificial conduit-, vein-, muscle, and muscle-in-vein reconstructions, and replantations) to provide an aid for choosing an individual technique of nerve reconstruction and to create reference values of standard repair for nonrandomized clinical studies. 87 publications including 2,997 nerve repairs were suitable for a precise evaluation. For digital nerve repairs there was practically no particular technique superior to another. Only end-to-side coaptation had an inferior two-point discrimination in comparison to end-to-end coaptation or nerve grafting. Furthermore, this meta-analysis showed that youth was associated with an improved sensory recovery outcome in patients who underwent digital replantation. For end-to-end coaptations, recent publications had significantly better sensory recovery outcomes than older ones. Given minor differences in outcome, the main criteria in choosing an adequate surgical technique should be gap length and donor site morbidity caused by graft material harvesting. Our clinical experience was used to provide a decision tree for digital nerve repair.
... The use of longitudinally orientated muscle fibres has garnered the most popularity in this role whereby axonal progression is along the fibres' basal laminae (rich in laminin and fibronectin). These studies were done by Glasby et al. (1986) and Norris et al. (1988) who demonstrated the importance of muscle basal lamina to guide the regenerating axons and efficacy in repairing digital nerves. Moreover, fresh muscle may promote the maturation of axons, through colonization and proliferation of SCs (Geuna et al., 2004). ...
From the first surgical repair of a nerve in the 6th century, progress in the field of peripheral nerve surgery has marched on; at first slowly but today at great pace. Whether performing primary neurorrhaphy or managing multiple large nerve defects, the modern nerve surgeon has an extensive range of tools, techniques and choices available to them. Continuous innovation in surgical equipment and technique has enabled the maturation of autografting as a gold standard for reconstruction and welcomed the era of nerve transfer techniques all while bioengineers have continued to add to our armamentarium with implantable devices, such as conduits and acellular allografts. We provide the reader a concise and up-to-date summary of the techniques available to them, and the evidence base for their use when managing nerve transection including current use and applicability of nerve transfer procedures.
... Only a few clinical studies have been published reporting the use of muscle fiber grafts to repair nerve defects in patients. In a series of clinical papers published in the first half of the nineties, satisfactory functional recovery was reported in most patients after reconstruction of nerve defects up to 6 cm (61,62). Most studies recommend an upper limit of 5 cm for the largest animal models (sheep femoral nerve) and 2 cm for the rat sciatic nerve (58). ...
... Traditionally, methods for the treatment of damage in muscle tissues include the autografting of patient cells or allografting of donor cells [56,57]. Recently, to overcome limitations derived from the conventional therapeutic approaches, such as stable cell supply problems, multipotential stem-cell-based methods have been studied [10,12]. ...
Direct reprogramming of somatic cells to myoblasts and myotubes holds great potential for muscle development, disease modeling and regenerative medicine. According to recent studies, direct conversion of fibroblasts to myoblasts was performed by using a transcription factor, myoblast determination protein (MyoD), which belongs to a family of myogenic regulatory factors. Therefore, MyoD is considered to be a key driver in the generation of induced myoblasts. In this study, we compared the direct phenotypic conversion of bovine dermal fibroblasts (BDFs) into myoblasts and myotubes by supplementing a transcription factor, bovine MyoD (bMyoD), in the form of recombinant protein or the bMyoD gene, through retroviral vectors. As a result, the delivery of the bMyoD gene to BDFs was more efficient for inducing reprogramming, resulting in direct conversion to myoblasts and myotubes, when compared with protein delivery. BDFs cultured with retrovirus encoding bMyoD increased myogenic gene expression, such as MyoG, MYH3 and MYMK. In addition, the cells expressed myoblast or myotube-specific marker proteins, MyoG and Desmin, respectively. Our findings provide an informative tool for the myogenesis of domestic-animal-derived somatic cells via transgenic technology. By using this method, a new era of regenerative medicine and cultured meat is expected.
... Moreover, Norris et al. showed that the basal membrane tubes derived from skeletal muscles had sufficient diameter to match the largest nerve fibers (Norris, Glasby, Gattuso, & Bowden, 1988). Basal membranes of muscle fibers were in the form of long cylinders lying parallel to each other and provide a suitable substrate for the growing axons (Houštava, Dubový, Haninec, & Grim, 1999). ...
Introduction: Peripheral nerve injury is one of the mos common damages that lead to physical
disability. Considering the similarity between the coatings of skeletal muscles and nerve fbers,
we conducted this research to determine the effect of muscle graft with Nerve Growth Factor
(NGF) and Laminin (L) on nerve repair.
Methods: We cut a 10-mm length of the sciatic nerve from 42 female Wisar rats (Weight:
200±250 g) and equally divided the rats into three groups. In the muscle graft+NGF+laminin
group, the degenerated skeletal muscle was sutured with proximal and disal ends of the
transected sciatic nerve. Then, NGF (100 ng) and laminin (1.28 mg/mL) were injected into the
muscle graft. In the muscle graft group, normal saline was injected into the muscle graft. In
the control group, 10 mm of the sciatic nerve was removed without any treatment. Functional
recovery was assessed based on Sciatic Functional Index (SFI). Also, tracing motor neurons
and hisological sudies were performed to evaluate nerve repair. The obtained data were
analyzed by ANOVA tes.
Results: The Mean±SD SFI value signifcantly increased in the muscle graft+NGF+laminin
(-76.6±2.9) and muscle graft (-82.1±3.5) groups 60 days after the injury compared to the
control group. The Mean±SD number of labeled motor neurons signifcantly increased in the
muscle graft+NGF+laminin (78.6±3.1) and muscle graft (61.3±6.1) groups compared to the
control group (P<0.001). The mean number of myelinated axons in the disal segments of the
muscle graft+NGF+laminin increased signifcantly compared to the muscle graft group.
Conclusion: These fndings sugges that muscle graft followed by NGF and laminin
adminisration have therapeutic effects on nerve repair
... It has been shown that axonal regeneration could grow from the skeletal muscle grafts and reach the target muscle, and re ۱۱ Glasby, S. Gschmeissner, C.-H. Huang, et al., 1986). Moreover, Norris et al. showed that the basal membrane tubes derived from skeletal muscles was sufficient diameter to match the largest nerve fibers (Norris, Glasby, Gattuso, & Bowden, 1988). Basal membranes of muscle fibers were in the form of long cylinders lying parallel to each other and providing a suitable substrate for the growing axons (Houštava, Dubový, Haninec, & Grim, 1999). ...
Introduction:
Peripheral nerve injury is one of the most common damages that lead to physical disability. Considering the similarity between the coatings of skeletal muscles and nerve fibers, we conducted this research to determine the effect of muscle graft with Nerve Growth Factor (NGF) and Laminin (L) on nerve repair.
Methods:
We cut a 10-mm length of the sciatic nerve from 42 female Wistar rats (Weight: 200±250 g) and equally divided the rats into three groups. In the muscle graft+NGF+laminin group, the degenerated skeletal muscle was sutured with proximal and distal ends of the transected sciatic nerve. Then, NGF (100 ng) and laminin (1.28 mg/mL) were injected into the muscle graft. In the muscle graft group, normal saline was injected into the muscle graft. In the control group, 10 mm of the sciatic nerve was removed without any treatment. Functional recovery was assessed based on Sciatic Functional Index (SFI). Also, tracing motor neurons and histological studies were performed to evaluate nerve repair. The obtained data were analyzed by ANOVA test.
Results:
The Mean±SD SFI value significantly increased in the muscle graft+NGF+laminin (-76.6±2.9) and muscle graft (-82.1±3.5) groups 60 days after the injury compared to the control group. The Mean±SD number of labeled motor neurons significantly increased in the muscle graft+NGF+laminin (78.6±3.1) and muscle graft (61.3±6.1) groups compared to the control group (P<0.001). The mean number of myelinated axons in the distal segments of the muscle graft+NGF+laminin increased significantly compared to the muscle graft group.
Conclusion:
These findings suggest that muscle graft followed by NGF and laminin administration have therapeutic effects on nerve repair.
... Furthermore, research on animals and humans show that nerves can be satisfactorily repaired by using fresh and denatured muscle conduits and withal may yield better results than end-to-end suturing (Norris, Glasby, Gattuso, Gattuso, & Bowden, 1988). Brunelli, Battiston, Vigasio, Brunelli, and Marocolo (1993), suggested using a combined conduit when vein grafts were filled with muscle. ...
Peripheral nerve physiology and regeneration has been observed and investigated in literature but surgical applications to reconstruct and restore motor or sensory functions are still in a developmental phase. The peripheral nerve progresses slowly and incompletely compared with other tissues, it may provoke separations of the nerve stumps and the axonal proliferation of the conduits is restricted to 30 mm. Recent surgical attempts to treat proximal nerve injures include direct nerve restoration, transfer, and autografting measures with favorable results. Moreover, studies are suggesting that engineering tissue tubes maybe as effective as nerve grafting to restore separations of more than 4 cm toward optimal nerve repair. Peripheral nerve physiology and regeneration has been observed and investigated but surgical applications are still in a developmental phase. Recent surgical attempts to treat proximal nerve injures include direct nerve restoration, transfer, and autografting. The clinical application of human amniotic membrane (HAM) retains the structure and anatomical essence of tissues besides enhancing the healing process by reducing scarring and dysfunctions in postoperative aftermaths.
... Several types of both biological and artificial conduits have been reported in experimental models. Autologous tissues, such as arteries, veins, 7,35 and muscle, 1,28 have been used. Artificial tubulization methods include silicone, 11,19,20 collagen, 2,16 polyglactin, 27 poly-L-lactic acid (PLLA), 10 and polyglycolic acid (PGA), 22 as well as combinations of these materials. ...
Abstract
Background: The repair of a segmental peripheral nerve injury is a clinical challenge. Several studies have been performed to determine superior methods for overcoming nerve gaps. The purpose of this study was to investigate if the inside-out slided epineurium of the distal segment of an injured nerve can serve as a conduit to bridge a short nerve defect (10 mm). Methods: Nineteen sciatic nerves in Sprague–Dawley rats were transected, and a 10-mm gap was left between the ends. A section of distal epineurium was pulled inside out to bridge the gap. Walking track analysis was performed, and the sciatic function index (SFI) was calculated. Wet muscle mass and withdrawal reflex were measured. The density of axon fibers at different levels of repaired nerves was determined, and histological analysis was performed at 16 weeks. Results: The mean SFI improved from −81.0 at 4 weeks to 36.3 at 16 weeks. The axon densities showed regeneration through the epineural tube, and 5 of the rats demonstrated a withdrawal reflex. The weight of the tibialis anterior muscle of the injured limb at 16 weeks was 59% that of the uninjured side. Conclusions: The distal epineural sheath tube provided a size-matched conduit between the nerve stumps, with no histological donor-site morbidity. Histologically, regeneration occurred through the epineural tube without neuroma formation, and functional recovery was comparable to that of previous studies of nerve repair techniques. Technique may be an addition to the armamentarium of tools used to treat segmental nerve defects.
Keywords: defect, epineural, graft, nerve injury, nerve repair
... In treating peripheral nerve injuries, the objective is to achieve primary repair without tension on the suture. Situations in which there is no possibility of suturing, or in cases of loss of nerve segments, such as late injuries, or in complex cases, the treatment consists of reconstruction of the nerve. 1 Over recent decades, a variety of experimental studies have been developed to determine the best methods for filling the gap between the stumps of injured nerves. 2 Although research using autogenous tubes (from muscles or vessels) 3,4 and synthetic (non-autogenous) tubes 5 has been developed, grafts from autogenous nerves are still the material most indicated and used. 1,2 In choosing the nerve graft, the matters that need to be taken into consideration include whether it is sufficiently long to ensure tension-free anastomosis; whether the number of fasciculi is coincident with those of the receptor nerve; and whether the sequelae in the donor area are minimal. ...
Objective:
To evaluate the clinical results from treating chronic peripheral nerve injuries using the superficial peroneal nerve as a graft donor source.
Methods:
This was a study on eleven patients with peripheral nerve injuries in the upper limbs that were treated with grafts from the sensitive branch of the superficial peroneal nerve. The mean time interval between the dates of the injury and surgery was 93 days. The ulnar nerve was injured in eight cases and the median nerve in six. There were three cases of injury to both nerves. In the surgery, a longitudinal incision was made on the anterolateral face of the ankle, thus viewing the superficial peroneal nerve, which was located anteriorly to the extensor digitorum longus muscle. Proximally, the deep fascia between the extensor digitorum longus and the peroneal longus muscles was dissected. Next, the motor branch of the short peroneal muscle (one of the branches of the superficial peroneal nerve) was identified. The proximal limit of the sensitive branch was found at this point.
Results:
The average space between the nerve stumps was 3.8 cm. The average length of the grafts was 16.44 cm. The number of segments used was two to four cables. In evaluating the recovery of sensitivity, 27.2% evolved to S2+, 54.5% to S3 and 18.1% to S3+. Regarding motor recovery, 72.7% presented grade 4 and 27.2% grade 3. There was no motor deficit in the donor area. A sensitive deficit in the lateral dorsal region of the ankle and the dorsal region of the foot was observed. None of the patients presented complaints in relation to walking.
Conclusions:
Use of the superficial peroneal nerve as a graft source for treating peripheral nerve injuries is safe and provides good clinical results similar to those from other nerve graft sources.
... Also the use of skeletal muscle autografts alone has been explored [43][44] and several authors have also proposed to perform predegeneration of the muscle fiber in order to avoid the presence of impeding material [45] . Although the published clinical studies showed that this technique can work well in patients [46][47][48] , it did not spread among nerve microsurgeons and it appears that nowadays it is almost abandoned. In more recent years, cell transplantation has attracted much attention also in peripheral nerve reconstruction. ...
It is today widely acknowledged that nerve repair is now more than a matter of perfect microsurgical reconstruction only and that, to further improve clinical outcome, the involvement of different scientific disciplines is required. This evolving reconstructive/regenerative approach is based on the interdisciplinary and integrated pillars of tissue engineering such as reconstructive microsurgery, transplantation and biomaterials. In this paper, some of the most promising innovations for the tissue engineering of nerves, emerging from basic science investigation, are critically overviewed with special focus on those approaches that appear today to be more suitable for clinical translation.
... The repair of peripheral nerves using sutures, no matter epineurial or perineurial, is the gold standard of care. Many researchers have recognized the shortcomings of conventional sutures (Norris et al., 1988;Maragh et al., 1990;Myles et al., 1992;Sierra, 1993). Several sutureless methods have been developed that, no matter what method they use, must fulfill certain criteria, including having enough tensile strength, cause less neural trauma than sutures, and be minimally toxic to tissues. ...
When repairing nerves with adhesives, most researchers place glue directly on the nerve stumps, but this method does not fix the nerve ends well and allows glue to easily invade the nerve ends. In this study, we established a rat model of completely transected sciatic nerve injury and repaired it using a modified 1 cm-length conduit with inner diameter of 1.5 mm. Each end of the cylindrical conduit contains a short linear channel, while the enclosed central tube protects the nerve ends well. Nerves were repaired with 2-octyl-cyanoacrylate and suture, which complement the function of the modified conduit. The results demonstrated that for the same conduit, the average operation time using the adhesive method was much shorter than with the suture method. No significant differences were found between the two groups in sciatic function index, motor evoked potential latency, motor evoked potential amplitude, muscular recovery rate, number of medullated nerve fibers, axon diameter, or medullary sheath thickness. Thus, the adhesive method for repairing nerves using a modified conduit is feasible and effective, and reduces the operation time while providing an equivalent repair effect.
... Up to now, only few clinical studies have been published reporting the used of muscle fiber grafts for repairing nerve defects in patients. In a series of interesting clinical papers published in the first half of the Nineties, satisfactory functional recovery was reported in most patients after reconstruction of nerve defects up to 6 cm [52][53][54][55][56][57]. In spite of these positive clinical results, the use of nerve guides made of skeletal muscle alone did not spread among surgeons so far. ...
Many surgical techniques are available for bridging peripheral nerve defects. Autologous nerve grafts are the current gold standard for most clinical conditions. In selected cases, alternative types of conduits can be used. Although most efforts are today directed towards the development of artificial synthetic nerve guides, the use of non-nervous autologous tissue-based conduits (biological tubulization) can still be considered a valuable alternative to nerve autografts. In this paper we will overview the advancements in biological tubulization of nerve defects, with either mono-component or multiple-component autotransplants, with a special focus on the use of a vein segment filled with skeletal muscle fibers, a technique that has been widely investigated in our laboratory and that has already been successfully introduced in the clinical practice.
... This technique, which was first reported in 1940 (Kraus and Reisner, 1940), finds its rationale in the similarities between the muscle basal lamina and the endoneurial tubes of degenerating nerves that guide Schwann cell (SC) migration and axonal regrowth (Fawcett & Keynes, 1986). Various experimental studies showed that both fresh and denatured muscle conduits have the potential for bridging peripheral nerve defects (Meek & Coert, 2002; Mligiliche, Tabata, Endoh, & Ide, 2001), and clinical studies showed that muscle grafts are effective in obtaining some degree of functional recovery in most patients (Fawcett & Keynes, 1986; Norris, Glasby, Gattuso, & Bowden, 1988; Pereira, Bowden, Gattuso, & Norris, 1991; Pereira, Bowden, Narayanakumar, & Gschmeissner, 1996; Pereira, Palande, et al., 1991; Rath, 2002). Since the effectiveness of both vein and muscle grafts is limited to short nerve gap repair, because long vein segments tend to collapse while regenerated axons tend to grow outside long muscle grafts without reaching the distal nerve stump (Battiston, Tos, Cushway, & Geuna, 2000; Battiston, Tos, Geuna, Giacobini-Robecchi, & Guglielmone, 2000), the possibility of combining the two approaches, that is, filling up vein tubes with muscle fibers, has been explored (Brunelli & Brunelli, 1993 ). ...
Nerve repair is no more regarded as merely a matter of microsurgical reconstruction. To define this evolving reconstructive/regenerative approach, the term tissue engineering is being increasingly used since it reflects the search for interdisciplinary and integrated treatment strategies. However, the drawback of this new approach is its intrinsic complexity, which is the result of the variety of scientific disciplines involved. This chapter presents a synthetic overview of the state of the art in peripheral nerve tissue engineering with a look forward at the most promising innovations emerging from basic science investigation. This review is intended to set the stage for the collection of papers in the thematic issue of the International Review of Neurobiology that is focused on the various interdisciplinary approaches in peripheral nerve tissue engineering.
... [19][20][21][22] Skeletal muscle grafts also have been used as nerve conduits. [23][24][25][26][27][28] Particular emphasis has focused on the use of bioabsorbable synthetic nerve conduits composed of polyglycolic acid and polyglactic acid 29-33 and on collagen tubes. 34,35 Previous and current interest continues in the application of expanded-polytetrafluoroethylene (e-PTFE or Gore-Tex [W.L. Gore and Associates, Inc, Flagstaff, AZ]) 36-38 with or without the use of laminin-containing neurotropic and neurotrophic factors to the nerve gap defect. ...
... The paper on freeze-thawed muscle grafts in repair of the lateral cord of the marmoset demonstrates a scrupulous attention to detail which is characteristic of the work of Glasby and his colleagues. It is one step further in establishing the value of muscle grafts in the repair of human trunk nerves, for the technique is already proven in the repair of the human sensory nerve (Norris, Glasby, Gattuso and Bowden, 1988) and it is showing promise in the treatment of the difficult problem of the painful neuroma from a divided nerve (Stirratt et al., 1991). A great deal of work was done in Britain in and after the First World War on nerve grafting and on tubulization. ...
... Des supports de repousse nerveuse ont également été utilisés. Cette technique consiste à positionner entre les deux extrémités nerveuses du tissu conjonctif de remplacement (Lewin-Kowalik et al., 2003), des bandelettes de peau, des fibres musculaires (Norris et al., 1988 ;Fields et al., 1989 ;Calder et Norris, 1993 ;Lundborg, 2000a). Afin d'améliorer la régénération axonale, certains auteurs utilisèrent même la technique d'enrobage de la suture nerveuse (« wrapping »). ...
Introduction
Nerve injury compromises sensory and motor functions. Techniques of peripheral nerve repair are based on our knowledge regarding regeneration. Microsurgical techniques introduced in the late 1950s and widely developed for the past 20 years have improved repairs. However, functional recovery following a peripheral mixed nerve injury is still incomplete.
State of art
Good motor and sensory function after nerve injury depends on the reinnervation of the motor end plates and sensory receptors. Nerve regeneration does not begin if the cell body has not survived the initial injury or if it is unable to initiate regeneration. The regenerated axons must reach and reinnervate the appropriate target end-organs in a timely fashion. Recovery of motor function requires a critical number of motor axons reinnervating the muscle fibers. Sensory recovery is possible if the delay in reinnervation is short. Many additional factors influence the success of nerve repair or reconstruction. The timing of the repair, the level of injury, the extent of the zone of injury, the technical skill of the surgeon, and the method of repair and reconstruction contribute to the functional outcome after nerve injury.
Conclusion
This review presents the recent advances in understanding of neural regeneration and their application to the management of primary repairs and nerve gaps.
... 81 Studies in animals and humans have demonstrated that both fresh and denatured muscle conduits can lead to successful regeneration and even lead to superior results when compared with end-to-end sutures. [82][83][84][85] Most studies suggest an upper limit of 5 cm for the largest animal models (sheep femoral nerve) and 2 cm in rat sciatic nerve. However, in longer nerve defects, the effectiveness of skeletal muscle autografts may be progressively reduced. ...
Peripheral nerve injury may result in injury without gaps or injury with gaps between nerve stumps. In the presence of a nerve defect, the placement of an autologous nerve graft is the current gold standard for nerve restoration. The clinical employment of tubes as an alternative to autogenous nerve grafts is mainly justified by the limited availability of donor tissue for nerve autografts and their related morbidity. The purpose of this review is to present an overview of the literature on the applications of nerve conduits in peripheral nerve repair. Moreover, the different steps that are involved in the design of an ideal nerve conduit for peripheral nerve repair, including the choice of biomaterial, fabrication technique, and the various potential modifications to the common hollow nerve tube, are also discussed.
... 2,3 Muscle grafts may also be an effective option for digital nerve repair. 46,47 After digital nerve surgery, it does not seem to be necessary to splint the digit, 18 while stimulating tactile stimulation may be encouraged to improve the results of surgery. 19 Prognostic factors influencing the results are mentioned in all studies: patients and lesions age, type and severity of the injury and associated injuries diminish the sensory recovery. ...
Background
An intact digital nerve is obligatory for hand function. When transected, the hand surgeon has several options. However, there is no hard evidence which technique to choose.
Objective
The aim of this study was to provide an evidence-based overview of the effectiveness of interventions used in reconstruction and post-surgical management of digital nerve injuries.
Methods
The Cochrane Library, PubMed, EMBASE, CINAHL and PEDro databases were searched. Two reviewers independently applied the inclusion criteria to select potential relevant randomised controlled trials (RCTs) and controlled clinical trials (CCTs), extracted data and performed a methodological quality assessment of the included studies. The Grades of Recommendation, Assessment, Development and Evaluation (GRADE) method was used to summarise the results.
Results
Eight RCTs were included, five on surgical and three on post-surgical interventions. Low-quality evidence was found for effectiveness in favour of a polyglycolic acid conduit compared to primary neurrorhaphy or autologous graft, in digital nerve gaps of ≤4 mm and ≥8 mm at long-term follow-up. Very low quality of evidence was found for effectiveness in favour of EMLA crème, compared to placebo, in enhancing sensory relearning for the short-term, but not for the long-term outcomes. Low quality of evidence was found for effectiveness in favour of sensory re-education compared with control at long-term follow-up. For other interventions, no evidence for effectiveness was found.
Conclusions
Indications for effectiveness of some treatment strategies in digital nerve repair were found, but due to a minimal number of RCTs in this field no firm conclusions could be drawn for the different techniques. More high-quality RCTs are needed for a more confident estimate of effect.
Level of evidence
Therapeutic II.
... Since then, conduits from many different biological tissues have been used with varying success. These include the use of arteries [10,11], veins [12][13][14], muscle [15][16][17][18], and other materials which are extensively reviewed by Doolabh et al. [19]. Other nerve tube conduits have been made from modified biological tissues such as laminin [19] and collagen [20,21] and have proved successful in specific situations. ...
Peripheral nerve injuries (PNI) can lead to lifetime loss of function and disfigurement. Different methods such as conventional allograft procedures and using of biological tubes have problems for damaged peripheral nerves reconstruction. Designed scaffolds with natural and synthetic materials are now widely used in the reconstruction of damaged tissues. Utilization of absorbable and non-absorbable synthetic and natural polymers with unique characteristics can be an appropriate solution to repair damaged nerve tissues. Polymeric nanofibrous scaffolds with properties similar to neural structure can be more effective in the reconstruction process. Better cell adhesion and migration, more guiding of axons and structural features such as porosity provide clearer role of nanofibers for the restoration of neural tissues. In this paper, basic concepts of peripheral nerve injury, types of artificial and natural guides and the methods to improve the performance of tubes like orientation, nanotechnology applications for nerve reconstruction, fiber and nanofibers, electrospinning methods and their application in the peripheral nerve reconstruction have been reviewed.
Description
Written by an international group of industry experts, regulators, and academics, this new ASTM publication provides the latest data on tissue engineering and the standards available for manufacturing TEMPs.
Twenty-three peer-reviewed papers cover
This new publication serves as a valuable resource for regulators, manufacturers, suppliers, developers, academics, patent examiners, and lawyers.
Background
Surgical treatment of finger nerve injury is common for hand trauma. However, there are various surgical options with different functional outcomes. The aims of this study are to compare the outcomes of various finger nerve surgeries and to identify factors associated with the postsurgical outcomes via a systematic review and meta-analysis.
Methods
The literature related to digital nerve repairs were retrieved comprehensively by searching the online databases of PubMed from January 1, 1965, to August 31, 2021. Data extraction, assessment of bias risk and the quality evaluation were then performed. Meta-analysis was performed using the postoperative static 2-point discrimination (S2PD) value, moving 2-point discrimination (M2PD) value, and Semmes–Weinstein monofilament testing (SWMF) good rate, modified Highet classification of nerve recovery good rate. Statistical analysis was performed using the R (V.3.6.3) software. The random effects model was used for the analysis. A systematic review was also performed on the other influencing factors especially the type of injury and postoperative complications of digital nerve repair.
Results
Sixty-six studies with 2446 cases were included in this study. The polyglycolic acid conduit group has the best S2PD value (6.71 mm), while the neurorrhaphy group has the best M2PD value (4.91 mm). End-to-side coaptation has the highest modified Highet’s scoring (98%), and autologous nerve graft has the highest SWMF (91%). Age, the size of the gap, and the type of injury were factors that may affect recovery. The type of injury has an impact on the postoperative outcome of neurorrhaphy. Complications reported in the studies were mainly neuroma, cold sensitivity, paresthesia, postoperative infection, and pain.
Conclusion
Our study demonstrated that the results of surgical treatment of digital nerve injury are generally satisfactory; however, no nerve repair method has absolute advantages. When choosing a surgical approach to repair finger nerve injury, we must comprehensively consider various factors, especially the gap size of the nerve defect, and postoperative complications.
Type of study/level of evidence Therapeutic IV.
Background and objective:
In complex hand traumas nerves and vessels are often destructed without the possibility for primary repair. For bridging defects of nerves, veins and arteries grafts are necessary. Commonly nerve and vein grafts from adjacent donor sites as the wrist, forearm or cubital region are harvested.
Methods:
This study is a retrospective cohort study. Between 2017 and 2019, 10 patients with complex hand injuries were treated. There were 8 males and 2 females, with an average age of 39 years (range 8-63 years). In all cases grafts were used of the dorsum of the foot for reconstructing of the severed digital nerves and arteries. All donor sites could be closed primarily.
Results:
In 100%of cases nerves and veins of the dorsum of the foot showed a good size match as well as adequate length for a sufficient repair. The overall Hand Injury Severity Score (HISS) was determined with a median of 86 (range 57 to 286). In the area of the donor site no relevant complications were seen.
Conclusions:
In complex hand injuries the dorsum of the foot is a favorable donor site for nerve and vein graft harvest.
This is a comprehensive overview of the epidemiology of each type of soft tissue defects and the current successful applications of regenerative medicine and methods of advancing the regeneration of these tissues. The authors discuss the epidemiology of soft tissue defects, successful application of regenerative treatments, challenges associated with regeneration, surgical techniques, scaffold-based treatments, drug-based therapy, cell-based therapy, and other treatments. There are unsolved questions discussed, such as vascularization in the process of regeneration, functional tissue regeneration, immune system problems, and problems with biomaterials, regulations and ethics. An outlook is given on necessary future developments for successful translation of advanced concepts of regenerative medicine to day-to-day routine in plastic surgery.
Artificial and non-artificial nerve grafts are the gold standard in peripheral nerve reconstruction in cases with extensive loss of nerve tissue, particularly where a direct end-to-end suture or an autologous nerve graft is inauspicious. Different materials are marketed and approved by the US Food and Drug Administration (FDA) for peripheral nerve graft reconstruction. The most frequently used materials are collagen and poly(DL-lactide-ε-caprolactone). Only one human nerve allograft is listed for peripheral nerve reconstruction by the FDA. All marketed nerve grafts are able to demonstrate sufficient nerve regeneration over small distances not exceeding 3.0 cm. A key question in the field is whether nerve reconstruction on large defect lengths extending 4.0 cm or more is possible. This review gives a summary of current clinical and experimental approaches in peripheral nerve surgery using artificial and non-artificial nerve grafts in short and long distance nerve defects. Strategies to extend nerve graft lengths for long nerve defects, such as enhancing axonal regeneration, include the additional application of Schwann cells, mesenchymal stem cells or supporting co-factors like growth factors on defect sizes between 4.0 and 8.0 cm.
Treatment of peripheral nerve injuries remains a challenge to modern medicine due to the complexity of the neurobiological nerve regenerating process. Unlike other tissues in the body, peripheral nerve regeneration is slow and usually incomplete. Although clinical outcomes of peripheral nerve injuries are often suboptimal, an adherence to well-established basic principles of evaluation and repair can optimize results of even the most complex injuries.
Nerve tubes, guides, or conduits are a promising alternative for autologous nerve graft repair. If in the case of injuries of neural structures a stress-free microsurgical coaptation of nerve endings is not possible, the gold standard for the reconstruction is autologous nerve transplantation. A disadvantage is, in addition to donor-site morbidity, the limited amount of available resources. Next to this situation, the duration of operation time will be prolonged for removal of the graft. An alternative method is the tubulization with veins (with or without the insertion of muscle strips) or by means of established procedures with artificial tubes or muscle-in-vein conduits. The different tubulization possibilities, including their limitations, shall be presented. New materials such as chitosan tubes provide characteristics for the bridging of neural defects. Recently, decellularized allogeneic nerve grafts have also become available in Europe. This new option will be discussed on the basis of the international literature already available.
Unter den umschriebenen Nervenschäden ist die vollständige Durchtrennung eines Nervs einschließlich seiner Hüllen die schwerwiegendste. Es scheint zwar vorzukommen, daß proximaler und distaler Stumpf eines durchtrennten Nerven auch beim Menschen durch einen Gewebsstrang überbrückt werden können [30]. Eine solche Gewebsbrücke ist aber funktionell bedeutungslos. Die Kontinuität eines durchtrennten Nerven muß deshalb, ist eine Funktionsrückkehr das Ziel, chirurgisch wiederhergestellt werden. Ist der Defekt klein, dann kann man ihn durch eine direkte Wiedervereinigung der Nervenstümpfe schließen. Unter allen rekonstruktiven Eingriffen an peripheren Nerven hat eine solche End-zuEnd-Naht die besten Ergebnisse, wenn sie möglichst atraumatisch und spannungsfrei durchgeführt wird. Ist der Defekt jedoch nicht oder nur unter größerer Spannung auf die Nervenenden zu schließen, dann verbietet sich diese Operationstechnik, denn eine Naht unter größerer Spannung hat eine schlechte Regeneration des Nervs und eine gegenüber einer spannungsfreien oder unter nur geringer Spannung ausgeführten Naht deutlich schlechtere Funktionsrückkehr zur Folge. In solchen Fällen muß der Nervendefekt durch ein Transplantat überbrückt werden. Zwar wurden schon im vergangenen Jahrhundert erste Nerventransplantationen durchgeführt [29]. Es ist aber der Pionierarbeit Millesis zu verdanken, mit der Technik der interfaszikulären Nervennaht und Transplantation neue Dimensionen für die Nervenchirurgie und deshalb für die erzielbaren funktionellen Ergebnisse eröffnet zu haben [21–24]. Eine unverzichtbare Voraussetzung dafür war und ist das Operationsmikroskop.
Avaliar resultados clínicos do tratamento das lesões crônicas de nervos periféricos com o nervo fibular superficial como fonte doadora de enxerto.
Despite an intrinsic regenerative capacity of the peripheral nervous system, in most cases of peripheral nerve injury, especially those involving substantial nerve gaps, therapeutic interventions are always required to support peripheral nerve regeneration and functional recovery. With the advancement of tissue engineering and translational medicine, extensive research has focused on the development of tissue-engineered nerve grafts, as a promising alternative to autologous nerve grafts, for bridging nerve gaps in peripheral nerve repair. The typical design of tissue-engineered nerve grafts is composed of a nerve scaffold combined with cellular and/or molecular components. This chapter separately describes a diverse array of physical and biochemical components of tissue-engineered nerve grafts with regard to their features, functions, structure or composition, and fabrication or procurement, and further discusses many representative examples of tissue-engineered nerve grafts and their pros and cons. We also highlight the current clinical applications of tissue-engineered nerve grafts and outline the future prospects for tissue engineering in peripheral nerve regeneration.
Nerve fiber regeneration into sciatic nerve branches was investigated in rats after repairing a 1 cm gap with freeze‐thawed autogenous muscle grafts in two configurations. “Prejunctional” grafts were introduced in the main trunk proximal to branching, while Y‐shaped “junctional” grafts replaced and reconstructed the site of division of the sciatic nerve into its tibial and peroneal branches. In addition to assessing functional and electrophysiological recovery, myelinated fibers in whole nerve cross sections were counted (i) in the sciatic nerve proximal to the site of transection, (ii) within the grafts themselves proximal to branching, and (iii) in individual tibial, peroneal, and sural branches.
Fibers regenerated into all three branches but eventual relative and absolute fiber counts differed between the two graft types, and these in turn from values in these nerves in unoperated controls. Thus, any specific influences directing appropriate fibers into particular branches that might exist did not exert a marked effect on regeneration in vivo. Differences in fiber counts at successively more distal cross‐sectional levels were described in terms of elongation, branching, or regression of regenerating fibers. In either graft type, fiber branching coincided with close anatomical relationship with more than one distal stump, and was particularly marked 150–300 days after graft implantation with junctional grafts. However, subsequent penetration of such fibers into the three major branches was more effective if the anatomy of the original branch site was preserved, by using prejunctional grafts. The implications of these findings to clinical nerve repair involving large nerve territories is discussed.
Bridging of nerve defects with muscle tissue is usually done with deep frozen grafts. The method has the disadvantage of considerable shrinkage and stiffening of the graft, as well as devitalization of the structures accompanying muscle fibers. As an alternative method an experiment on rats was done to test the use of refrigerated grafts, which do not have those disadvantages. The morphological evidence was that refrigerated grafts give as least as good results as deep frozen grafts.
Although autogenous nerve grafting remains the gold standard for repair of peripheral nerve defects, the use of various conduits can be a substitute provided these conduits meet the above-mentioned prerequisites. For the moment, autogenous vein grafts or denatured muscle grafts can be used to bridge short defects, especially in distal sensory nerves. Incorporation of muscle into a vein graft expands its application to longer defects in bigger nerves. PGA conduits have also been clinically proven to be reliable in reconstruction of digital nerve defects. Although nonabsorbable conduits cause irritation and nerve compression that necessitates secondary surgery removal, silicone tubes or Goretex tubes can be used in selected cases until absorbable conduits large enough for major peripheral nerves are available. To date, 3 cm seems to be the barrier for conduits. Incorporation of trophic factors and Schwann cells into the conduits will make their way into the clinic if problems like controlled release of trophic factors, obtaining and sustenance of an appropriate number of viable Schwann cells, are solved.
In recent times, tissue engineering researchers have been attempting to provide the scientific and medical communities with improvements in the repair of peripheral nerve injuries using synthetic grafts. Although the nerve autograft still remains the clinical gold standard in bridging nerve injury gaps, many advances on several fronts have been made in developing a more effective nerve tubular construct to guide regenerating axons across the lesion. This review discusses several strategies that have been employed to enhance the regenerative effectiveness of artificial nerve guidance channels. These strategies include the use of scaffolds, the integration of contact-mediated cues within the tubular construct, and incorporation or delivery of exogenous growth factors into the conduit lumen uniformly or in a gradient form. Animal and clinical studies are reviewed to explain some of the ideas involved in developing a guidance channel of the future.
Leprosy is one of the most common and potentially treatable causes of peripheral neuropathy. Despite the effective antibiotics to cure the infection, the immune-mediated peripheral nerve damage can continue long after effective antimicrobial treatment has started, and patients continue to be stigmatized. The initial management of leprous neuritis is always medical, using bactericidal drugs and high doses of corticosteroids given systemically. If medical treatment fails, nerve decompression by external neurolysis or by transposition of the nerves is attempted with variable success. Indications for decompressive surgery for neuritis include pain, motor, and/or sensory deficits. Preventing nerve damage in leprosy remains a challenge, and it is better to overtreat leprosy than to undertreat it. We still need to define the role of surgery on nerves in leprosy. Recently, the role of portable devices in early detection of nerve damage has been recognized; however, who are the candidates for surgery, when to perform surgery, extent of surgery, and what kind of procedure will give the best results are yet to be defined.
Optimal surgical management of digital nerve lesions remains uncertain despite the publication of numerous studies. The purposes of this review were primarily to analyze whether there is a superior surgical technique for digital nerve repair and secondarily to statistically verify the variables to be predictors of sensory recovery.
A literature search was performed using PubMed including citation from MEDLINE. Studies were included if they involved patients with digital nerve lacerations in whom end-to-end neurorrhaphy, nerve grafts, conduits, or end-to-side neurorrhaphy were performed. Further, the sensory outcome had to be assessed according to the modified American Society for Surgery of the Hand guidelines to stratify for two-point discrimination in millimeters. The variables age, follow-up, delay in repair, type of trauma, and gap length were extracted. The association between each predictor and response was assessed using a linear mixed model and corrected for heterogeneity between studies. Significance was considered present at p ≤ 0.05.
Of the 34 articles found, 14 articles were included giving appropriate individual data for 191 nerves. There was no statistically significant difference in outcome between operation techniques. Age and follow-up were verified predictors of sensory recovery.
In this review, the type of operation for digital nerve repair does not influence sensory outcome. However, we verified outcome to be influenced by the patient's age and the follow-up period. To add more scientific evidence to our results, larger cohort prospective studies need to be done with better detailed description of data.
We evaluated neurotization after transplantation with lyophilized nerves, muscles, and arteries, and examined the possibility of practical application of long bridging grafts. Grafts of 10 mm and 25 mm of lyophilized nerves, muscles, and arteries harvested from Fisher rats were transplanted to the sciatic nerves of recipient Lewis rats. The histological changes undergone by short grafts were observed at weekly intervals. The sham-operated and isograft groups were used to compare the results of long grafts. In both the nerve and muscle-graft group, regenerated axons grew out through the residual basement membrane tube. But in the muscle graft group, phagocytosis of myofibril debris took longer than that of degenerated axons. No statistical differences were found between results of TSI, induced EMG, and quantitative analysis of myelinated axons in the nerve and muscle graft groups. No neurotization was noted in the long artery graft. In long grafts, laminin found on the basement membrane may not be sufficient to accelerate neurotization, and arteries should not be used for tubulization. © 1997 Wiley-Liss, Inc. MICROSURGERY 17:525–534 1996
This paper describes the morphological appearances of long-term nerve repair using freeze-thawed, coaxially aligned autogenous skeletal muscle grafts in rats. The presence of minifascicles (compartmentation) within the muscle grafts confirms earlier reports of compartmentation whenever nerve regeneration occurs in a nonnerural environment. However, in contrast to the reports in the literature, there was no evidence of a loss of compartmentation at long intervals after nerve repair. It was found that a number of minifascicles became enclosed by a further proliferation of perineural cell to form distinct minifascicular groups. The term “midfascicle” is used to describe these larger perineural defined groups of minifascicles. The role of the perineurium is discussed.
Poor recovery is seen after repair of long defects in peripheral nerves when denatured muscle grafts or regeneration chambers providing physical support alone are used. The presence of Schwann cells and neurotrophic factors is required for axons to migrate significant distances. In this study we have used immunohistochemical techniques and axon counts to quantify the regeneration seen when 5 cm defects in rabbit sciatic nerve were repaired with a composite graft consisting of 2–3 mm lengths of fresh autologous nerve sandwiched between 1 cm frozen-thawed muscle grafts. This technique led to a similar pattern of regeneration as that seen in autologous nerve grafts, used as controls, and a significantly (P<0.0001) greater axonal and Schwann cell regeneration compared with that seen in frozen-thawed muscle grafts of the same total length. In conclusion, we present a simple technique for incorporating a depot of Schwann cells and other essential components into a nerve conduit which has a marked effect on axonal regeneration across long defects. © 1995 Wiley-Liss, Inc.
Group fascicular vein grafts with interposition of nerve slices were designed for reconstruction of three ulnar nerves with defects of 2.5–4.5 cm. The veins were taken from superficial veins in the forearm and reversed to bridge the fascicles in both stumps. Normal nerve slices were sectioned from fascicles in the proximal stump and inserted inside the corresponding vein conduits. Postoperatively, the Tinel's sign was detected across the vein conduits, and electromyography showed reinnervation of intrinsic muscles of the hands. Follow-up for more than 2 years revealed motor recovery to M4 and sensory recovery to S3–S4 in these three cases. This technique may be a promising alternative to group fascicular nerve grafting for long defects in peripheral nerve trunks. © 1993 Wiley-Liss Inc.
The management of peripheral nerve injury remains a major clinical problem. Progress in this field will almost certainly depend upon manipulating the pathophysiological processes which are triggered by traumatic injuries. One of the most important determinants of functional outcome after the reconstruction of a transected peripheral nerve is the length of the gap between proximal and distal nerve stumps. Long defects (> 2 cm) must be bridged by a suitable conduit in order to support axonal regrowth. This review examines the cellular and acellular elements which facilitate axonal regrowth and the use of acellular muscle grafts in the repair of injuries in the peripheral nervous system.
Repairing nerve defects with large gaps remains one of the most operative challenges for surgeons. Incomplete recovery from peripheral nerve injuries can produce a diversity of negative outcomes, including numbness, impairment of sensory or motor function, possibility of developing chronic pain, and devastating permanent disability. In the last few years, numerous microsurgical techniques, such as coaptation, nerve autograft, and different biological or polymeric nerve conduits, have been developed to reconstruct a long segment of damaged peripheral nerve. A few of these techniques are promising and have become popular among surgeons. Advancements in the field of tissue engineering have led to development of synthetic nerve conduits as an alternative for the nerve autograft technique, which is the current practice to bridge nerve defects with gaps larger than 30 mm. However, to date, despite significant progress in this field, no material has been found to be an ideal alternative to the nerve autograft. This article briefly reviews major up-to-date published studies using different materials as an alternative to the nerve autograft to bridge peripheral nerve gaps in an attempt to assess their ability to support and enhance nerve regeneration and their prospective drawbacks, and also highlights the promising hope for nerve regeneration with the next generation of nerve conduits, which has been significantly enhanced with the tissue engineering approach, especially with the aid of nanotechnology in development of the three-dimensional scaffold. The goal is to determine potential alternatives for nerve regeneration and repair that are simply and directly applicable in clinical conditions.
Peripheral nerve defects are common. The surgeon faced with these problems must provide the best functional recovery for the patient with the tools provided. The ideal nerve reconstruction would create a tensionless repair with direct coaptation. However, this is not always possible and other techniques must be employed. The alternatives to direct coaptation include nerve autografts, nerve conduits, and tissue-engineered constructs. This article reviews commonly used autogenous nerve grafts and conduits. Autogenous nerve grafts have been utilized in various techniques which include the trunk graft, cable graft, interfascicular graft, and vascularized graft. The nerve conduits reviewed fall into the category of autogenous biological conduits, nonautogenous biological conduits, and nonbiological conduits. New technologies are being developed to enhance peripheral nerve regeneration with the concept that conduits can be enriched and manipulated in the laboratory to promote regeneration of the peripheral nerve. Further clinical studies hold the promise of successful alternatives for treating peripheral nerve injuries.
Axons regenerate to reinnervate denervated skeletal muscle fibers precisely at original synaptic sites, and they differentiate into nerve terminals where they contact muscle fibers. The aim of this study was to determine the location of factors that influence the growth and differentiation of the regenerating axons. We damaged and denervated frog muscles, causing myofibers and nerve terminals to degenerate, and then irradiated the animals to prevent regeneration of myofibers. The sheath of basal lamina (BL) that surrounds each myofiber survives these treatments, and original synaptic sites on BL can be recognized by several histological criteria after nerve terminals and muscle cells have been completely removed. Axons regenerate into the region of damage within 2 wk. They contact surviving BL almost exclusively at original synaptic sites; thus, factors that guide the axon's growth are present at synaptic sites and stably maintained outside of the myofiber. Portions of axons that contact the BL acquire active zones and accumulations of synaptic vesicles; thus by morphological criteria they differentiate into nerve terminals even though their postsynaptic targets, the myofibers, are absent. Within the terminals, the synaptic organelles line up opposite periodic specializations in the myofiber's BL, demonstrating that components associated with the BL play a role in organizing the differentiation of the nerve terminal.
Basal laminae were separated from Schwann cells of mouse sciatic nerves by sonification, and the distributions of lectin-binding sites were demonstrated by electron microscopy using ferritin-conjugated lectins. Only three out of the 11 lectins examined were bound to the basal laminae of Schwann cells: they were Ricinus communis agglutinin-I (RCA-I), Canavalia ensiformis agglutinin (ConA) and Triticum vulgaris agglutinin (wheat germ agglutinin, WGA). It was notable that WGA was bound more densely to the cellular side than to the interstitial side, whereas in the case of RCA-I and ConA there were no differences in the binding density on the two sides of the basal lamina. These results indicate that there are sugar residues such as beta-D-galactose, alpha-D-mannose, alpha-D-glucose and beta(1-4) linked N-acetyl-D-glucosamine in the Schwann cell basal laminae. The first three sugar residues are almost equally densely distributed on the cellular and interstitial sides of the basal laminae, whereas beta(1-4) linked N-acetyl-D-glucosamine is more densely distributed on the cellular than on the interstitial side. This result suggests that the basal lamina has a polarity in chemical composition between the cellular and interstitial sides. These findings are discussed in the context of the preferential attachment of regenerating axons to the cellular side of the Schwann cell basal laminae.
A small piece of muscle tissue, 6–7 mm long, was excised from the biceps femoris of the mouse and treated several times by repetitive freezing and thawing to kill the muscle cells. The tissue so treated was then placed, end to end, in contact with the proximal stump of the transected sciatic nerve of the same animal. The growth of the regenerating nerve fibers through the graft was examined 2, 3, 5, 7, 10, 17 and 25 days after grafting.
Two to 5 days after grafting, dead muscle cells had disintegrated and were phagocytized by macrophages, leaving behind the basal laminae in a tube form (basal lamina scaffold) of the original muscle fibers. Seven days after grafting, regenerating nerve fibers were first observed to have grown out through such basal lamina scaffolds in the region near the proximal end of the graft. Ten days after grafting, such regenerating nerve fibers and accompanying Schwann cells became numerous in the basal lamina scaffolds when observed at the middle level of the graft. Few regenerating nerve fibers were found outside the scaffolds, i.e. in the connective tissue compartment. Seventeen days after grafting, regenerating fibers were sorted out and some of the thick fibers were myelinated. Twenty-five days after grafting, the myelination was more advanced, and regenerating fiber bundles in the basal lamina scaffolds were, as a whole, surrounded by cells resembling perineural cells. These findings show that basal lamina scaffolds of muscle cells provide a proper microenvironment for the growth of regenerating nerve fibers. This is discussed from the point of view of the general significance of the basal laminae for nerve regeneration.
Between seven days and six weeks after division the internal architecture of rat sciatic nerves is altered, their original mono- or di-fascicular configuration being replaced by a collection of small fascicles each surrounded by perineurium. This change, called by us compartmentation, has a minimum retrograde extent of 3.5 mm and is brought about by changes in Schwann cells and endoneurial fibroblasts, which undergo circumferential elongation to surround groups of axons and so come to resemble perineurial cells. Ultrastructural changes occur in these cells during compartmentation. There is a marked rise in the number of endoneurial fibroblasts in the distal segments of the proximal stump. The stimulus to the development of compartmentation is considered to be disturbance of the endoneurial environment following rupture of the perineurium. Changes in the structure and appearance of endoneurial cells suggest that metaplasia occurs between Schwann cells, endoneurial fibroblasts and perineurial cells, and it is concluded that these cell types in the endoneurium have a common origin from embryonic ectoderm. This suggests that the surgical treatment of peripheral nerve injuries should be primarily directed to the reconstitution of the endoneurial environment.
THOUGH valuable information continues to accumulate regarding the reparative process following experimental nerve injuries in lower mammals, the available information relating to repair in human material remains incomplete and is still too meager to enable one to determine whether the experimental results are directly applicable to man.
In the present inquiry an attempt has been made to calculate the rate of regeneration after lesions of human peripheral nerves and to analyze the events that occur in the interval between the injury and the onset of clinical recovery. The importance of this information in regard to the treatment and prognosis of peripheral nerve injuries is self evident. The investigation was commenced at an Australian military hospital in 1940, when it was apparent that large numbers of patients with nerve injuries would again come under observation. All the patients here reported on remained under my care until either (a) recovery was complete
This study reports the degree of spontaneous regeneration that will occur in the sciatic nerve of a rat 5 months after complete resection of the nerve. In 30 animals, the sciatic nerve was excised. Histological assessment at 5 months revealed evidence of regeneration for a variable distance (mean 23.7 mm +/- 6.4 mm). Histological sections were studied at 1-cm intervals along the length of the nerve. Evidence of compartmentation with "minifascicle" formation was noted. The orientation of the nerve fibers was parallel to the long axis of the nerve. This study assessing spontaneous regeneration is meant to serve as a control for other studies evaluating the effect of factors that may influence nerve regeneration in the rat model.
The basement membrane matrix of skeletal muscle has a tubular configuration resembling that of peripheral nerves. Grafts made of autogenous skeletal muscle denatured by freezing and thawing were used to repair the ulnar nerve in marmosets. By six months, normal hand function had returned and the grafts were shown to transmit normal compound extracellular action potentials in both directions. Morphological examination of the grafts and distal nerves revealed normal axon numbers and axon maturity. Myelination in the graft was found to take place more slowly than in the distal nerve segment. It is suggested that such grafts might be of use in the repair of human peripheral nerves.
The suitability of muscle basal lamina as a graft material for the repair of peripheral nerves was investigated. Grafts were prepared by evacuating the myoplasm from muscles excised from rats and rabbits. This produced a material consisting mainly of basal lamina and connective tissue, with the basal lamina arranged as parallel tubes. Rat- and rabbit-derived graft material in 0.5-cm lengths was sutured into rat sciatic nerves, and 4-cm lengths of rabbit-derived graft material were interposed into rabbit sciatic nerves. For controls, 0.5-cm nerve autografts were grafted into rats and 4-cm autografts into rabbits. After 2 to 3 months, the success of the grafts was assessed functionally, electrophysiologically, and anatomically. By all these criteria the basal lamina grafts were as successful as nerve autografts; essentially the same number of axons of the same size grew through both graft types, animals recovered their limb function equally well, and the nerve conduction velocities and relative refractory periods were the same in both groups of animals. In rats, following both basal lamina and nerve autografts, the number of axons distal to the grafts was approximately the same as that proximal to them, but axon diameter and speed of conduction were significantly less than normal. The authors conclude that muscle basal lamina grafts are as effective as nerve autografts for repairing severed rat or rabbit peripheral nerves, and suggest that grafts prepared in this way may prove to be useful for nerve repair in humans.
The localization of laminin and fibronectin was examined on the basal laminae of Schwann cells. Basal laminae from sciatic nerves were isolated by sonication, and the localization of laminin and fibronectin on such isolated basal laminae was studied by immunoferritin histochemistry. Laminin was localized mainly on the cellular side (i.e. the side originally facing the Schwann cell plasma membrane) of the basal laminae. On the other hand, fibronectin was found to be present as aggregates only on the interstitial side (i.e., the side originally facing the endoneurial connective tissue) of the basal laminae. Thus, the locations of laminin and fibronectin were distinctly different. It is presumed that laminin might be involved in the attachment of axons and Schwann cells to the basal laminae, while fibronectin mediates the adhesion of the basal laminae to connective tissue elements, including the collagen fibrils. These findings are discussed from a standpoint of nerve regeneration through the basal laminae scaffolds of Schwann cells.
Nerve segments approximately 7 mm long were excised from the predegenerated sciatic nerves of mice, and treated 5 times by repetitive freezing and thawing to kill the Schwann cells. Such treated nerve segments were grafted into the original places so as to be in contact with the proximal stumps. The animals were sacrificed 1, 2, 3, 5, 7 and 10 days after the grafting. The grafts were examined by electron microscopy in the middle part of the graft, i.e. 3-4 mm distal to the proximal end and/or near the proximal and distal ends of the graft. In other instances, the predegenerated nerve segments were minced with a razor blade after repetitive freezing and thawing. Such minced nerves were placed in contact with the proximal stumps of the same nerves. The animals were sacrificed 10 days after the grafting. Within 1-2 days after grafting, the dead Schwann cells had disintegrated into fragments. They were then gradually phagocytosed by macrophages. The basal laminae of Schwann cells, which were not attacked by macrophages, remained as empty tubes (basal lamina scaffolds). In the grafts we examined, no Schwann cells survived the freezing and thawing process. The regenerating axons always grew out through such basal lamina scaffolds, being in contact with the inner surface of the basal lamina (i.e. the side originally facing the Schwann cell plasma membrane). No axons were found outside of the scaffolds. One to two days after grafting, the regenerating axons were not associated with Schwann cells, but after 5-7 days they were accompanied by Schwann cells which were presumed to be migrating along axons from the proximal stumps. Ten days after grafting, proliferating Schwann cells observed in the middle part of the grafts had begun to sort out axons. In the grafts of minced nerves, the fragmented basal laminae of the Schwann cells re-arranged themselves into thicker strands or small aggregations of basal laminae. The regenerating axons, without exception, attached to one side of such modified basal laminae. Collagen fibrils were in contact with the other side, indicating that these modified basal laminae had the same polarity in terms of cell attachment as seen in the ordinary basal laminae of the scaffolds.(ABSTRACT TRUNCATED AT 400 WORDS)