Neurosurg Rev DOI 10.1007/s10143-014-0559-1

REVIEW

Nerve repair: toward a sutureless approach Matthew J. Barton & John W. Morley & Marcus A. Stoodley & Antonio. Lauto & David A. Mahns

Received: 9 August 2013 / Revised: 4 February 2014 / Accepted: 13 April 2014 # Springer-Verlag Berlin Heidelberg 2014

Abstract Peripheral nerve repair for complete section injuries employ reconstructive techniques that invariably require sutures in their application. Sutures are unable to seal the nerve, thus incapable of preventing leakage of important intraneural fluids from the regenerating nerve. Furthermore, sutures are technically demanding to apply for direct repairs and often induce detrimental scarring that impedes healing and functional recovery. To overcome these limitations, biocompatible and biodegradable glues have been used to seal and repair peripheral nerves. Although creating a sufficient seal, they can lack flexibility and present infection risks or cytotoxicity. Other adhesive biomaterials have recently emerged into practice that are usually based on proteins such as albumin and collagen or polysaccharides like chitosan. These adhesives form their union to nerve tissue by either photothermal (tissue welding) or photochemical (tissue bonding) activation with laser light. These biomaterial adhesives offer significant advantages over sutures, such as their capacity to unite and seal the epineurium, ease of application, reduced invasiveness and add the potential for drug delivery in situ to facilitate regeneration. This paper reviews a number of different peripheral nerve repair (or reconstructive) techniques currently used clinically and in experimental procedures for nerve injuries with or without tissue deficit. M. J. Barton (*) Griffith Health Institute, Griffith University, Gold Coast Campus, Queensland 4222, Australia e-mail: [email protected] J. W. Morley : A. Lauto : D. A. Mahns School of Medicine, University of Western Sydney, Locked Bag 1797, Penrith, NSW 2751, Australia J. W. Morley : A. Lauto : D. A. Mahns The Bioelectronics and Neuroscience (BENS) Research Group, The MARCS Institute, University of Western Sydney, Locked Bag 1797, Penrith, NSW 2751, Australia M. A. Stoodley The Australian School of Advanced Medicine, Macquarie University, 2 Technology Place, Sydney, Australia

Keywords Photochemical tissue bonding . Peripheral nerve repair . Nerve conduits . Biomaterials . Lasers . Sutures

Introduction Currently, the outcome of peripheral nerve repair remains dependent and influenced by the severity of nerve injury, timing of surgery, surgical technique, surgeons experience, compliance to postsurgical/injury rehabilitation, patient age and their underlying comorbidities [30]. While the choice of nerve repair technique is dependent on the size of the gap between the severed nerve ends, if the two nerve ends can be coapted without eliciting tension on the nerve, direct end-to-end suture repair, possibly in conjunction with fibrin glue is the surgical standard approach [6, 15]. However, in cases of substantial nerve tissue loss, with a consequent gap (>2 cm), nerve grafting or nerve conduits are the standard technique for nerve repair [83]. All these methods generally employ sutures in their application, a technology that possesses several unavoidable disadvantages, including foreign body reactions, additional trauma on the nerve and incomplete tissue sealing, a known augmenter for neuroma formation. Therefore, a limitation of sutures in nerve repair appears to be the presence of sutures themselves, signifying that the full potential of this nerve repair technique has been achieved, and highlighting the need for an alternative approach. This review will evaluate existing nerve coaptation techniques (direct repairs, grafting, conduits and transfers) together with more recent sutureless coaptation techniques (glues, laser tissue welding and photochemical tissue bonding), excluding regeneration enhancing substances. Understanding these techniques, harnessing their beneficial characteristics and restricting their limitations will advance nerve reconstructive technology resulting in improved efficiency and overall efficacy of peripheral nerve surgery.

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Anatomy, injury and repair Anatomy A peripheral nerve consists of a bundle of nerve fibres forming a fascicle, each fascicle surrounded by the perineurium, which is a dense mechanically robust sheath [21]. The perineurium is the major contributor to the tensile strength of the nerve [42], while being the smallest structure capable of receiving sutures for repair [49]. Within a fascicle the predominant cell (approximately 85 %) is a glial cell known as a Schwann cell, with the remaining cellular content (approximately 15 %) being fibroblasts and macrophages [10]. Each peripheral nerve whether uni- or multifascicular is also supported by the epineurium, a thick, loose outer sheath that protects the fascicles from external compression and torsional forces [14]. The smallest functional unit of a peripheral nerve is the nerve fibre, which contains the axon, the axolemma (axonal membrane) and the outermost nucleated cytoplasmic layer of the Schwann cell surrounded by connective tissue known as the endoneurium [90]. The endoneurium is a collagenous tube, protecting and nourishing axons passing through [11]. Axons can be either myelinated or unmyelinated with the diameter of myelinated nerve fibres ranging from 2–25 μm, while unmyelinated nerve fibres are 0.15–2.0 μm in diameter [49]. Myelin is possibly the most important molecule for the nerve fibre, which is formed by Schwann cells through a process that occurs during their development, thus forming the layers of myelin around individual axons [64]. There are discontinuities in the myelin, termed ‘nodes of Ranvier’, at regular intervals along the length of the axon, which allow saltatory conduction (nerve impulses) of the action potential along the axon. The functional and structural integrity of the axon is maintained by the cell body, with further trophic support by Schwann cells along with an intact blood vessel network [25]. This vascular network is composed of two major longitudinal systems anastomosing with one minor longitudinal system, the minor longitudinal system is within the perineurium and together with endothelial cells in the endoneurium functions as the blood–nerve barrier, functionally similar to the blood–brain barrier in the CNS [77]. This barrier can be compromised through ischemia, torsion injury, mechanical and chemical traumas [42]. Injury The aetiology of peripheral nerve injuries range from highenergy trauma such as crush, laceration and penetrating accidents to ischemic and stretch-related events [75]. In peripheral nerve lesions where there is separation of nerve fibres, a coordinated array of events occur to remove damaged tissue, to make way for the regenerative process, thus a disruption of nerve conductance will result [99]. This in turn will cause

axonal degeneration, a process known as Wallerian degeneration (WDG) taking place initially (1–2 days following the trauma) at the distal end of the lesion [49]. WDG is compounded by the isolation from the structurally and functionally supportive cell body [23]. The permeability of the blood–nerve barrier increases during WDG and as a consequence, macrophages from the neighbouring blood vessels network will recruit and accumulate at the site of injury [59]. At the proximal end of the lesion, the central nerve end undergoes retrograde degeneration back to the last intact node of Ranvier, with its myelin, like that in WDG, phagocytosed by macrophages and Schwann cells [46]. At the distal end of the lesion, the axons initially swell and break into numerous spheres along their entire length, causing Schwann cells to undergo a morphological change caused by the lack of contact with the axon. They rapidly multiply within the endoneurial tubes, filling areas previously occupied by axons to provide a directional longitudinal path (bands of Büngner) for regenerating axons, thus facilitating regeneration and repair [7]. Although the primary response to nerve injury is inflammation and degeneration, the damaged axons are able to produce sprouting neurite projections within 24 to 48 h of nerve damage [1]. Both myelinated and unmyelinated nerves sprout from the proximal end of the injury, creating a regenerating growth cone (filopodia) that follows a milieu of neurotrophic factors at a rate of at least 1 mm per day along the bands of Büngner [22]. Spontaneous reinnervation in most cases will occur naturally, driven by axonal directional growth (neurotropism), axon maturity (neurotrophy), axon guidance (contact guidance) and precise axon reinnervation (specificity) [14]. However, in a large gap (>2 cm) between the proximal and distal ends, these axonal inherent properties will be affected [23], along with tension, infection, foreign bodies or scar tissue formation (neuroma), thus warranting surgical intervention [71]. Repair The success of regenerating axons is dependent on several factors, most notably the severity of injury (Table 1). Peripheral nerve injuries have traditionally been classified into clinicopathological groupings for convenience (Table 1). Seddon in 1942 outlined three classifications [79], Roaf added an extra classification in 1943 [73], while Sunderland in 1951 refined the classification into 5° groups [90], based on axonal continuity and conductivity. Although these classification systems appear simplistic, many nerve injuries, due to their varied nature, cannot be classified into a single group and for the following reason the review will focus on complete nerve section (neurotomesis) injuries. The principal indications for nerve repair are injury or nerve continuity impairment that cannot regain normal function without surgery, and/or

neurological dysfunctions such as anaesthesia, paraesthesia, dysesthesia or paralysis [97]. In cases of neurotomesis (transection) injuries, the principal objective is precise realignment of nerve ends, devoid of tension and enveloped in well vascularised tissue, thereby maximising the possibility for regenerating fibres to make appropriate connections with their distal targets. It is obvious therefore that the ideal reconstructive device should not disturb wound healing, minimise inflammation and scar tissue formation while facilitating the proximal sprouts to reinnervate their correct targets.

Immediate repair necessary

Delay repair, assess neural deficit. After delay, surgical exploration and reconstruction where necessary.

Delay surgery, observe for 3 mm cross-section) with collagen conduits, as the conduit filled with cellular debris and scar tissue, impeding axonal regrowth [87]. More recently, animal and human work has been conducted using degradable chitosan and caprolactone

conduits in gap models [16, 82, 100], and results suggest both conduits are more convenient and efficient when compared to grafting. Caprolactone conduits displayed functional outcomes superior to collagen and PGA conduits and comparable to autografts [16, 82], while chitosan conduits reported good functional recovery in human models with small gaps (2 mm) when compared to the direct suture method [100]. Nerve conduits, although significantly advantageous over autografts, are hamstrung by the requirement for anchoring sutures and are thus restricted by the inherent limitations pertaining to suturing. Nevertheless, current nerve conduit research is focused toward developing a strong biocompatible/ biodegradable material (potentially with nanoscaled viscoelastic properties) to generate a matrix to mimic the intraneural environment for supporting sprouting axons, limit scar infiltration, minimise immune reaction and avoid suture use to fulfil the requirements for the ‘ideal’ conduit described by Brunelli et al. The future appears optimistic for this method of peripheral nerve repair. Nerve transfer For proximal nerve or preganglionic (avulsion) injuries, which demand a large amount of nerve tissue to reinnervate their distal nerve element (brachial plexus injury), nerve transfers offer a practical surgical solution and have reported good outcomes in the last decade [99]. Nerve transfers can maximise regenerating axonal input into a degenerated distal nerve (recipient) by sacrificing a less important proximal nerve (donor), thereby providing a return of function to nerves with longstanding injuries [69]. Nevertheless, nerve transfers are considered palliative and incapable of re-establishing native anatomy to the nerve [99], moreover nerve transfers are limited by nerve-type mismatch, dissection difficulties and availability of expendable donor nerves [83]. All the aforementioned techniques (direct repairs, grafts, conduits and nerve transfers) could be employed with or without the use of sutures. Although the use of sutures in nerve repair is generally reliable, there are a number of limitations (i.e. scar formation and foreign body reactions) that affect functional outcomes. A major focus of nerve reconstructive research has been the development of techniques that avoid the use of sutures (Table 2), therefore, the later portion of this review will focus on these contemporary sutureless techniques.

Sutureless techniques Glues Glues such as fibrin have been employed as an alternative to the conventional direct end-to-end suture approach to seal

Minimal long term studies completed, application needs refinement.

Immediate

Immediate

∼21

∼37

Similar advantages to albumin soldering without harmful thermal effects and stronger tensile strength.

Lack flexibility and becomes brittle, thermal damage, viral infection risk.

Low tensile strengths days after surgery and induces thermal damage, requires dry surface to obtain welds. Immediate ∼8

Reduces local trauma, neuroma formation, scar formation, foreign body reactions, aberrant axon sprouting and fast application. Stronger bond and reduced thermal damage compared with LTW.

Toxicity, compresses nerve, becomes brittle and inflexible when glue sets. ∼300–600

Photochemical tissue bonding (PTB)

Albumin solder laser welding

Laser tissue welding (LTW)

Cyanoacrylate polymerises and hardens when in contact with water or cell membranes Laser energy converted into heat, denatures structural proteins, forming an adhesion between adjacent nerve edges. Laser energy heats water molecules in albumin, sterically linking with the collagen fibres in epineurium PTB utilises light absorbing dye (i.e. rose bengal). Reaction between the dye and epineural proteins. Cyanoacrylate

∼82

Easy application with strong tensile strength.

Viral and prion infection risk, sensitivities with bovine derivatives, poor results with tension repairs, requires dry surface for application. Quick and simple application, while reducing inflammation and scar tissue invasion. ∼60–300 ∼9.9 Sealant that mimics the coagulation cascade, thrombin+fibrinogen forms fibrin clot/adhesive glue. Fibrin

Activation time (s) Tensile strength (kPa) Mechanism Device

Table 2 Sutureless nerve repair techniques

Advantages

Side effects

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sectioned nerves. Fibrin glues mimic the end stages of the clotting cascade, in effect resembling a physiological blood clot, which can act as an envelope to hold the two nerve ends together [78]. Many rodent studies have indicated enhanced functional outcomes [61, 74] and superior histological results [19, 62], with fibrin glue compared to the direct end-to-end suturing approach. It is hypothesised that the favourable outcomes of fibrin are attributed to the way it can form a cocoon like cylinder externally, and an orientating matrix when applied internally to realign the regenerating fibres [48], while providing a barrier to the encroachment of scar tissue [78]. Furthermore, compared to direct end-to-end suturing, fibrin was quicker in application, devoid from generating secondary damage, while requiring less surgical experience to apply [94]. Nevertheless, one significant disadvantage of fibrin as a reconstructive device is the low tensile strength of the repair [91], invariably requiring coaptation maintenance with stay sutures [57]. A further complication in the clinical use of fibrin is the potential for viral and prion infection with further patient sensitivities using fibrin from bovine derivatives [62]. Cyanoacrylate glues have been used in nerve repair, most notably to overcome the infection risks of fibrin along with its questionable tensile strength [31]. A number of rat studies compared cyanoacrylate against the direct suture method on sciatic nerves and found no difference with regard to regeneration or functional outcome; however, the cyanoacrylate was simpler, although more time consuming (glue setting) [12, 31, 32]. A concern that has been frequently reported is the compression of regenerating nerve fibres when cyanoacrylate sets [32], along with its limited flexibility. However, this can be avoided, by overlapping the adjacent epineural sheaths and using minimal amounts of glue (Fig. 1f) [12, 72]. Choi et al. reported that applying the cyanoacrylate glue in micro-drops to the outer epineurium on rat sciatic nerves reduced the compression effects, while providing adequate tensile strength to the nerve ends [12]. Roth et al.reinforced the Choi et al. technique, concluding that cyanoacrylate glue repairs were superior functionally and histologically, although more prone to local tissue adhesion compared to direct suturing [98]. Moreover, cyanoacrylate has been unsuccessful in its biocompatibility, as it causes foreign body toxicity and fibrosis [29, 96]. Polyethylene glycol (PEG) can be cross-linked to create a biocompatible, nontoxic hydrogel [68], which can easily be moulded into a tube necessary for nerve repair [70]. Furthermore, PEG has the potential to act as a blank slate, to which cell-specific bioactive ligands can be covalently incorporated to enhance regeneration, while the tubular shaped glue once around the nerve ends can be photopolymerised with visible light, making it a simple and fast procedure [17]. When PEG glue was compared to fibrin glue, it was noted to have reduced scar tissuing around application and comparable tensile strength [38].

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However, it degrades very slowly and can persist for up to 20 months following implantation [33]. Laser tissue welding Effective use of lasers in soft tissue sealing (i.e. blood vessels or intestines) resulted in laser tissue welding (LTW) also being assessed for a possible role in peripheral nerve repair. Nerve LTW repair uses laser energy to produce focal points that are converted into heat, coagulating and denaturing structural proteins in the epineurium (Fig. 1g), thus welding the distal and proximal nerve edges in direct repairs [40], and sealing the axons into the endoneural tubes [80]. Nerve LTW has been applied using lasers that are absorbed well in tissue, such as CO2 [86]. Considering most nervous tissue is composed of water, CO2 laser energy is primarily absorbed at the epineurium and has low penetration and spread, thus suitable for endto-end nerve repair [52]. CO2 welding has been shown to be advantageous compared with direct suturing in animals, as it reduces local trauma, neuroma formation, scar formation, foreign body reactions and aberrant axonal sprouting, while being faster and less invasive [5, 40]. Menovsky and colleagues studied the effects of CO2 laser on rat sciatic nerves and found pathological changes were dependent on energy delivered: at higher power, there was significant neural destruction with only minimal healthy fibres remaining, while at lower powers, a small degree of WDG was present with oedema, yet, the centre of the nerve was unaffected [53]. However, what has proved particularly beneficial is the speed of anastomosis, especially in restricted surgical fields, such as cranial nerve surgery [56]. On the other hand, three significant disadvantages have been identified using LTW: (1) low tensile strength immediately and up to a few days postsurgery, and as a result, many surgeons still employing support sutures; (2) localised thermal damage; and (3) inconsistent, thus unreliable results [4, 13, 67]. Laser-activated solders To overcome the limitations with LTW, protein-derived solders were added to the weld (Fig. 1h), and significantly Fig. 2 Photochemical tissue bonding: a photograph of rose bengal (RB) chitosan adhesive (Ad) irradiated by green laser (L) on epineurium (Ep); b SEM image of RB-chitosan adhesive attached to collagen fibres (Cf) within epineurium of median nerve (×2,000, scale bar 10 μm)

improved the tensile strength compared to LTW alone [59]. Moreover, the solder can protect the underlying tissue from thermal damage, while being able to bridge small gaps that would be impossible to weld or direct suture without eliciting nerve tension [51]. Laser-activated solders for nerve repair are conventionally supported by protein derivatives, most commonly: albumin, fibrinogen and collagen [41]. Albumin solders are the most researched and successfully applied, relying on laser energy heating water molecules and subsequently denaturing its proteinaceous structure [34], intertwining and linking sterically with the collagen fibres in the epineurium [38]. Albumin solders have shown more reliable results than LTW alone, with improved weld strengths, while decreasing thermal damage locally [35]. However, albumin soldering has been shown to cause inflammatory reactions to the epineurium of rat sciatic nerves [50]. Furthermore, albumin being a blood protein possesses risks of viral infections for the recipient, and becomes brittle and inflexible immediately after laser irradiation [51]. More recent albumin applications use the support of cross-linking agents, such as genipin, with positive results noted regarding its flexibility and reduced brittleness while increasing adhesion strengths [37]. However, the thermal damage that can be inflicted through its activation continues to present immediate problems [8]; therefore, surgeons remain reluctant to use this method of nerve repair [39]. Laser-activated dyes Heating the epineurium may affect the nerve’s functional recovery and cause dehiscence. Research addressing this concern has used the addition of light-absorbing (photothermal) dyes, such as indocyanine green (Fig. 1i) [36, 81], into the laser repair. Results demonstrated good tensile strength with an immediate seal to direct repairs [65]; however, temperatures in localised tissue increased to >56 °C during irradiation and consequently caused demyelination [36]. The thermal damage induced by repairs using photothermal dyes, solders and LTW presents immediate problems in terms of functional outcomes, thus highlighting the need for an alternate approach to the photothermal mechanism. One such approach is photochemical tissue bonding

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(PTB) that utilises light-absorbing dyes (Fig. 1i), such as rose bengal (RB), to produce an immediate water-tight seal [60]. RB becomes photochemically active when exposed to green light (532 nm; Fig. 2a) and although the mechanism is still not fully understood, it is believed that photons of laser light absorbed by RB create an abundance of free radical species that result in covalent cross-link bonding within the collagen fibres of the epineurium (Fig. 2b) [26]. The major and decisive advantage of PTB is the absence of an increase in temperature inside the nerve, thus avoiding the thermal damage seen with other laser repairs. In vivo PTB nerve repair in rats has been achieved integrating RB into epineural sleeves [26], human amniotic membranes [60] and chitosan bandages (Fig. 2a) [2]. The immediate tensile strength of rat median nerves repaired using PTB is comparable to the strength of direct end-to-end epineural (10-0 nylon) sutures and significantly stronger than LTW and soldering [2]. However, nerve tissue repaired by PTB is devoid of thermal injury seen in photothermal bonding, where temperatures never exceed 38 °C [2]. Moreover, photo-activated RB has been revealed to be nontoxic to cells in vitro and in vivo [2, 3]. When RB was incorporated into a chitosan bandage for median nerve repair, the bandage immediately and effectively sealed the epineurium, minimised inflammation and scar tissue infiltration, thereby providing the necessary mechanical support to the nerve while the underlying fibroblasts were able to regenerate and close the epineurium [2]. Within a week, the RB bandage detached from the epineurium, preventing nerve compression as seen with conduits and glues, while being devoid of foreign body reactions seen with sutures. Likewise, O’Neill et al. demonstrated that a similar approach based on RBintegrated amnion wraps produced superior functional and histological outcomes when compared to the direct suture repairs [60]. Despite not fully understanding the mechanism of PTB, the absence of thermal damage and sutures, the high tensile strength, the speed and ease of application and the capacity to deliver functional outcomes that are as good or exceeding that of suturing, suggests that this technique may represent an exciting new approach to nerve reconstruction. Nevertheless, future work is required on how PTB can be most effectively applied to nerves, especially in nerve gap models, along with further long-term studies.

Conclusion and future perspectives Peripheral nerve injury is relatively frequent (2–3 % of all traumas) and can have a significant impact on the patient’s quality of life. Although advances and innovations have been made through peripheral nerve reconstructive techniques over the past 40 years, suture repair still remains the most commonly employed technique. Thus functional recovery following

peripheral nerve injury may well have reached a plateau using suture based techniques [63, 94]. Sutures employed for nerve repair may produce many complications including foreign body reactions, inflicting further trauma and neuroma formation, while the surgery is challenging, time-consuming and the outcome is very dependent on the skills of the surgeon. Therefore, research has been directed toward sutureless, biocompatible techniques which are simpler and quicker in application and can provide the required mechanical support. The technique should enhance the direction and progression of axons toward the distal end and degrade at a controllable rate to prevent compression, while not inducing unwarranted inflammatory reactions. The technique must also be sufficiently porous to allow for early revascularisation and milieu diffusion, while able to withstand excessive scarring and aberrant axonal sprouting. Finally, the technique should mimic the nerve’s extracellular matrix, to enhance cellular activity and release beneficial growth factors over sustained periods to facilitate regeneration thus optimising functional recovery.

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Comments Kirsten Haastert-Talini, Hannover, Germany Barton et al. provide a comprehensive review on peripheral nerve reconstruction approaches. The authors focus on such approaches that have already found their way into clinical application including direct repair by end-to-end neurorrhaphy, autologous nerve grafting, implantation of approved nerve guidance conduits and nerve transfer. The authors present evidences that the use of sutures in all these peripheral nerve reconstruction techniques may impair optimal axonal and functional nerve regeneration by inducing secondary trauma and foreign body reaction. Furthermore, nerve suturing is technically demanding and outcome of recovery is thereby highly correlated to the skills of the surgeon. A sutureless nerve reconstruction might therefore provide an alternative that could minimise the impact of suturing on peripheral nerve regeneration. The authors describe the current state of knowledge about the feasibility of sutureless nerve reconstruction, which is mainly based on experimental work in rat models. The work by Barton et al. raises interest for the field of sutureless nerve repair which is after additional refinement supposable for direct nerve repair or autologous nerve grafting. More experimental work has to be performed to demonstrate that sutures could also be replaced when it comes to implantation of nerve guidance conduits to bridge longer nerve defects. However, the results presented open a promising perspective toward a new approach to nerve reconstruction that could find its way into clinical application. Shimon Rochkind, Tel Aviv, Israel This important paper addresses different peripheral nerve reconstructive devices, currently used in clinical and experimental procedures. Even though suture repair remains the gold standard treatment for peripheral nerve defects, possible complications, such as foreign body reaction, neuroma formation etc., lead toward development of simpler and quicker application of sutureless, biocompatible devices and techniques. In this extensive review, the author analyzes both the advantages and the disadvantages of different devices for nerve reconstruction, such as direct suturing, grafting, conduits, laser tissue welding, sutureless devices, glues, laser-activated solders and laser-activated dyes. The benefits of such devices, in terms of their improved efficiency and overall efficacy of peripheral nerve surgery, allow the advancement of nerve reconstructive technology even further. Though it is difficult, at this stage, to pinpoint the optimal technique or device, it seems that in the near future, a number of different combined approaches, such as sutureless tube/graft reconstruction, will amount to the preferred treatment of choice. Kartik G. Krishnan, Giessen, Germany I thoroughly enjoyed reviewing this landmark article. Wound repair, arresting of bleeding vessels by cauterisation or clipping, etc., have existed since times unreported. However, coaptation of severed nerves in open wounds did not take place till the middle ages, due to a dogmatic misconception of those times that manipulation of nerve ends led to epileptic seizures. The most noticeable aftermaths of wars were amputations and peripheral nerve injuries that had led to existing, but flail extremities in the

young and the very young survivors, thereby playing a major role in designing their later life-styles, professions and hobbies. Although macroscopic peripheral nerve sutures were applied historically earlier than vascular anastomoses, it was not until after World War II that surgeons dared to electively explore ‘healed wounds’ specifically to get at the nerve stumps and reconnect them, hoping to return some muscle reinnervation and motor function. Even then, severed nerves were sutured directly, pulling the proximal and distal ends to each-other, sometimes under enormous tension, thereby immobilising joints in unfathomably uncomfortable positions for long periods of time. Reinnervation and consequently functional results were quite poor and understandably underreported. The technological development of microminiature sutures, optical magnification using operating microscopes, and above all their combination had revolutionised surgical practice after World War II. These applications came indeed a little late for the nerve: the historically most significant large-scale surge of peripheral nerve injuries requiring such microsutures followed World War II. Although the results of nerve repair were still quite poor, these two technological advances constituted a serious initial step in preparation for future developments. The 1960s and 1970s saw yet another revolution in peripheral nerve surgery—namely, nerve grafts. Whenever a tissue deficit with a nerve gap was encountered, autologous nerve grafts of some ‘less important’ sensory nerve (viz., sural nerve or the antebrachial cutaneous nerve of the forearm) were used to bridge the gap, of course thereby employing the microsurgical suturing technique. It seemed important to provide a tension-free milieu (i.e. minimising scarring) for the regenerating axons. Later, we understood that regeneration not only depended on perfect microsurgical and tension-free coaptation of nerves, but on the mechanism of nerve injury itself. We learned to differentiate between types of nerve injuries. Especially we learned that axons regenerate much better after clean cut injuries, as opposed to when the nerve had been crushed or pulled or twisted. We learned to differentiate between axons of proximal nerve stumps that showed readiness to sprout from those that did not. Nerve transfer was the next step, when an intact motor nerve of the anatomical neighbourhood was surgically transected and its proximal end transferred to a nonfunctional recipient distal nerve end. In the laboratory, there was a constant search for new materials for grafting and bridging nerve gaps. When we graft nerves, we actually graft Schwann cells, not axons. Thus work proceeded toward finding potent Schwann cell substitutes and in vitro cultured and augmented Schwann cells. Parallelly, there was a search for better basal membranes, including denatured spider web. All the developments and research notwithstanding, contemporary evidences suggest that the dependence of functional results after nerve repair may be deducted to three factors only, viz., (1) type of nerve injury, (1) meticulous, tension-free [coaptation] technique and (3) latency between injury and repair. Yet to be found is the compound that is more potent than the autologous nerve graft in enhancing nerve regeneration. Whether an axon decides to sprout or not, depends not on the peripheral axonotactic stimulus alone, but especially on the happenings within the body of the neural cell. Thus regeneration enhancers of the future have to have an influence on the cell body, either through electrical or molecularchemical stimuli, not on the peripheral axonal level alone. Today, surgeons have gone as miniature as their skills and supporting technology would allow them. Scientists have gone as basic as to culture Schwann cells or their pluripotent precursors and try to enhance axonal regeneration. The more complex a method, the more contained it will be to specific centres. Barton’s paper provides us with a new perspective. It may become a reality—in not so unpredictable a time point in future—that we would have developed a potent device for nerve coaptation, which will be universally applicable, which might additionally be able to deliver drugs or growth factors to enhance axonal sprouting and nerve regeneration generally, and yet be quite simple.