Collagen-based Nerve Research Articles

Bioresorbable and Mechanically Optimized Nerve Guidance Conduit Based on a Naturally Derived Medium Chain Length Polyhydroxyalkanoate and Poly(ε-Caprolactone) Blend.

Severe peripheral nerve injuries represent a large clinical problem with relevant challenges such as the development of successful synthetic scaffolds as substitutes to autologous nerve grafting. Numerous studies have reported the use of polyesters and type I collagen-based nerve guidance conduits (NGCs) to promote nerve regeneration through critical nerve defects while providing protection from external factors. However, none of the commercially available hollow bioresorbable NGCs have demonstrated superior clinical outcomes to an autologous nerve graft. Hence, new materials and NGC geometries have been explored in the literature to mimic the native nerve properties and architecture. Here, we report a novel blend of a natural medium chain length polyhydroxyalkanoate (MCL-PHA) with a synthetic aliphatic polyester, poly(ε-caprolactone) (PCL), suitable for extrusion-based high-throughput manufacturing. The blend was designed to combine the excellent ability of PHAs to support the growth and proliferation of mammalian cells with the good processability of PCL. The material exhibited excellent neuroregenerative properties and a good bioresorption rate, while the extruded porous tubes exhibited similar mechanical properties to the rat sciatic nerve. The NGCs were implanted to treat a 10 mm long sciatic nerve defect in rats, where significant differences were found between thin and thick wall thickness implants, and both electrophysiological and histological data, as well as the number of recovered animals, provided superior outcomes than the well-referenced synthetic Neurolac NGC.

Assessment of physico-chemical and biological properties of sericin-collagen substrates for PNS regeneration

Peripheral nerve injuries may lead to a significant function loss, which deeply affect patient’s quality of life. In this context, tissue engineered collagen-based nerve guides are a promising alternative to autografts. To enhance the regeneration of the injured nerve tract, several bioactive molecules can be adopted as further components of the collagen-based conduits. Herein, sericin (Ser), a waste product of textile industry, was combined with type I collagen (Col), for the development of a bioactive substrate potentially able to support and enhance the regeneration of the peripheral nervous system. In particular, in order to identify an optimal substrate composition in terms of physicochemical and biological properties, thin Ser-Col films with different Ser:Col ratios were produced by air-drying and subsequently crosslinked through two different crosslinking methods. Then, Ser:Col films were characterized from a physicochemical point of view by examining secondary protein structure modifications via FTIR spectroscopy, swelling ratios, degradation rates and Ser release kinetics. Moreover, Ser:Col films ability to promote adhesion and proliferation of Schwann cells was evaluated in vitro. The results obtained in this study, although preliminary, suggest that Ser:Col blends could represent a promising strategy to enhance the repair of damaged peripheral nerves, by providing a sustained release of Ser from collagen-based nerve substrates.

Decellularized sciatic nerve matrix as a biodegradable conduit for peripheral nerve regeneration.

The use of autologous nerve grafts remains the gold standard for treating nerve defects, but current nerve repair techniques are limited by donor tissue availability and morbidity associated with tissue loss. Recently, the use of conduits in nerve injury repair, made possible by tissue engineering, has shown therapeutic potential. We manufactured a biodegradable, collagen-based nerve conduit containing decellularized sciatic nerve matrix and compared this with a silicone conduit for peripheral nerve regeneration using a rat model. The collagen-based conduit contains nerve growth factor, brain-derived neurotrophic factor, and laminin, as demonstrated by enzyme-linked immunosorbent assay. Scanning electron microscopy images showed that the collagen-based conduit had an outer wall to prevent scar tissue infiltration and a porous inner structure to allow axonal growth. Rats that were implanted with the collagen-based conduit to bridge a sciatic nerve defect experienced significantly improved motor and sensory nerve functions and greatly enhanced nerve regeneration compared with rats in the sham control group and the silicone conduit group. Our results suggest that the biodegradable collagen-based nerve conduit is more effective for peripheral nerve regeneration than the silicone conduit.

Clinical and biometrical 12-month follow-up in patients after reconstruction of the sural nerve biopsy defect by the collagen-based nerve guide Neuromaix

Many new strategies for the reconstruction of peripheral nerve injuries have been explored for their effectiveness in supporting nerve regeneration. However only a few of these materials were actually clinically evaluated and approved for human use. This open, mono-center, non-randomized clinical study summarizes the 12-month follow-up of patients receiving reconstruction of the sural nerve biopsy defect by the collagen-based nerve guide Neuromaix. Neuromaix was implanted as a micro-structured, two-component scaffold bridging 20–40 mm nerve defects after sural nerve biopsy in twenty patients (eighteen evaluated, two lost in follow-up). Safety of the material was evaluated by clinical examination of wound healing. Performance was assessed by sensory testing of modalities, pain assessment, and palpation for the Hoffmann–Tinel’s sign as well as demarcating the asensitive area at each follow-up visit. Every patient demonstrated uneventful wound healing during the complete 12-month time course of the study. Two patients reported complete return of sensation, whereas eleven out of eighteen patients reported a positive Hoffmann–Tinel’s sign at the lower leg with simultaneous reduction of the asensitive area by 12 months. Our data show that Neuromaix can be implanted safely in humans to bridge sural nerve gaps. No procedure-related, adverse events, or severe adverse events were reported. These first clinical data on Neuromaix provide promising perspectives for the bridging of larger nerve gaps in combined nerves, which should be investigated more through extensive, multi-center clinical trials in the near future.

Neural stem/progenitor cells on collagen with anchored basic fibroblast growth factor as potential natural nerve conduits for facial nerve regeneration.

Neural stem/progenitor cells (NS/PCs) were beneficial for the treatment of nervous system diseases. However, after transplantation, the beneficial was limited because the number of living NS/PCs decreased rapidly due to insufficient signaling molecules, such as growth factors, in the microenvironments surrounding transplanted cells. In the present study, we constructed collagen-based nerve conduit with anchored bFGF to achieve higher numbers of NS/PCs for repairing facial nerve injury. Compared with other methods involving neutral salt treatment or dialysis, the fabrication method of collagen scaffolds was simple, low-cost and safe, requiring a relatively short time to prepare. At 12weeks after transplantation, the functional and histological results of natural nerve conduits treated group showed significant similarities to the gold standard method of nerve autografting.

Peripheral nerve regeneration inside collagen-based artificial nerve guides in humans.

Nerve gap injuries may be associated with lesions in other structures, like tendons or bones; in these cases, it is common to plan a second surgery to improve functional recovery. Since macroscopic observations of nerve regeneration in humans are rare, we exploited these second surgeries for the purpose of studying nerve regeneration in humans. We assessed the clinical outcomes of 50 implants of collagen-based nerve guides in the upper limb. We performed a second look at 20, assessing macroscopically both nerve regeneration and collagen degradation. Pain was never recorded in these patients. An adequate sensory recovery took place whenever nerve regeneration was found inside the guide. Motor recovery seemed to occur only when the gap lesion was shorter than 10 mm. The degree of degradation appeared to be variable and was not directly correlated with time; we hypothesize that it could be associated with the site of implantation. Such a large number of second looks in humans has never been previously reported in the literature.

Crosslinking of micropatterned collagen-based nerve guides to modulate the expected half-life

The microstructural, mechanical, compositional, and degradative properties of a nerve conduit are known to strongly affect the regenerative process of the injured peripheral nerve. Starting from the fabrication of micropatterned collagen-based nerve guides, according to a spin-casting process reported in the literature, this study further investigates the possibility to modulate the degradation rate of the scaffolds over a wide time frame, in an attempt to match different rates of nerve regeneration that might be encountered in vivo. To this aim, three different crosslinking methods, that is, dehydrothermal (DHT), carbodiimide-based (EDAC), and glutaraldehyde-based (GTA) crosslinking, were selected. The elastically effective degree of crosslinking, attained by each method and evaluated according to the classical rubber elasticity theory, was found to significantly tune the in vitro half-life (t1/2 ) of the matrices, with an exponential dependence of the latter on the crosslink density. The high crosslinking efficacy of EDAC and GTA treatments, respectively threefold and fourfold when compared to the one attained by DHT, led to a sharp increase of the corresponding in vitro half-lives (ca., 10, 172, and 690 h, for DHT, EDAC, and GTA treated matrices, respectively). As shown by cell viability assays, the cytocompatibility of both DHT and EDAC treatments, as opposed to the toxicity of GTA, suggests that such methods are suitable to crosslink collagen-based scaffolds conceived for clinical use. In particular, nerve guides with expected high residence times in vivo might be produced by finely controlling the biocompatible reaction(s) adopted for crosslinking.

Neuromodulatory nerve regeneration: Adipose tissue‐derived stem cells and neurotrophic mediation in peripheral nerve regeneration

Peripheral nerve injury requiring nerve gap reconstruction remains a major problem. In the quest to find an alternative to autogenous nerve graft procedures, attempts have been made to differentiate mesenchymal stem cells into neuronal lineages in vitro and utilize these cellular constructs for nerve regeneration. Unfortunately, this has produced mixed results, with no definitive procedure matching or surpassing traditional nerve grafting procedures. This review presents a different approach to nerve regeneration. The literature was reviewed to evaluate current methods of using adipose-derived stem cells (ADSCs) for peripheral nerve regeneration in in vivo models of animal peripheral nerve injury. The authors present cited evidence for directing nerve regeneration through paracrine effects of ADSCs rather than through in vitro nerve regeneration. The paracrine effects rely mainly, but not solely, on the elaboration of nerve growth factors and neurotrophic mediators that influence surrounding host cells to orchestrate in vivo nerve regeneration. Although this paradigm has been indirectly referred to in a host of publications, few major efforts for this type of neuromodulatory nerve regeneration have been forthcoming. The ADSCs are initially "primed" in vitro using specialized controlled medium (not for neuronal differentiation but for sustainability) and then incorporated into a hydrogel base matrix designed for this purpose. This core matrix is then introduced into a natural collagen-based nerve conduit. The prototype design concepts, evidence for paracrine influences, and regulatory hurdles that are avoided using this approach are discussed.

The role of microstructured and interconnected pore channels in a collagen-based nerve guide on axonal regeneration in peripheral nerves

The use of bioengineered nerve guides as alternatives for autologous nerve transplantation (ANT) is a promising strategy for the repair of peripheral nerve defects. In the present investigation, we present a collagen-based micro-structured nerve guide (Perimaix) for the repair of 2 cm rat sciatic nerve defects. Perimaix is an open-porous biodegradable nerve guide containing continuous, longitudinally orientated channels for orientated nerve growth. The effects of these nerve guides on axon regeneration by six weeks after implantation have been compared with those of ANT. Investigation of the regenerated sciatic nerve indicated that Perimaix strongly supported directed axon regeneration. When seeded with cultivated rat Schwann cells (SC), the Perimaix nerve guide was found to be almost as supportive of axon regeneration as ANT. The use of SC from transgenic green-fluorescent-protein (GFP) rats allowed us to detect the viability of donor SC at 1 week and 6 weeks after transplantation. The GFP-positive SC were aligned in a columnar fashion within the longitudinally orientated micro-channels. This cellular arrangement was not only observed prior to implantation, but also at one week and 6 weeks after implantation. It may be concluded that Perimaix nerve guides hold great promise for the repair of peripheral nerve defects.

Multichanneled Collagen Conduits for Peripheral Nerve Regeneration: Design, Fabrication, and Characterization

In the absence of donor tissues, conduits are needed for axons to regenerate across nerve defects, yet single-channel conduits may result in axonal dispersion, and multichannel synthetic polymer conduits have failed due to dimensional instability. The goal of this study was to create a robust collagen-based nerve conduit with multiple submillimeter-diameter channels to facilitate nerve guidance. Toward this goal, we have developed a novel multistep molding technique to create single-, four-, and seven-channel conduits from collagen and examined the effects of crosslinking with 0-60 mM (1-ethyl-3-(3-dimethylaminopropyl) carbodiimide [EDC] in N-hydroxysuccinimide) on geometric, enzymatic, and thermal stability, mechanical properties, and cellular behavior. Multichannel collagen conduits crosslinked with 30 mM EDC and 10 mM N-hydroxysuccinimide demonstrated low degradation rate (∼10% at 2 days), high shrinkage temperature (>75°C), and constant channel morphology out to 30 days in saline. Neurite outgrowth remained unaffected from cultured dorsal root ganglia explants seeded on collagen scaffolds with up to 30 mM EDC crosslinking. Compared with single-channel conduits, multichannel collagen conduits showed superior structural compressive, tensile, and bending stiffness. Taken together, these results suggest that the crosslinked multichannel collagen conduits possess favorable material and mechanical properties for nerve regeneration applications.

Collagen Nerve Conduits Promote Enhanced Axonal Regeneration, Schwann Cell Association, and Neovascularization Compared to Silicone Conduits

Peripheral nerve regeneration within guidance conduits involves a critical association between regenerating axons, Schwann cells (SCs), and neovascularization. However, it is currently unknown if there is a greater association between these factors in nonpermeable versus semipermeable nerve guide conduits. We therefore examined this collaboration in both silicone- and collagen-based nerve conduits in both 5- and 10-mm-injury gaps in rat sciatic nerves. Results indicate that collagen conduits promoted enhanced axonal and SC regeneration and association when compared to silicone conduits in the shorter 5-mm-gap model. In addition, collagen tubes displayed enhanced neovascularization over silicone conduits, suggesting that these three factors are intimately related in successful peripheral nerve regeneration. At later time points (1- and 2-month analysis) in a 10-mm-gap model, collagen tubes displayed enhanced axonal regeneration, myelination, and vascularization when compared to silicone-based conduits. Results from these studies suggest that regenerating cables within collagen-based conduits are revascularized earlier and more completely, which in turn enhances peripheral nerve regeneration through these nerve guides as compared to silicone conduits.

Factors that influence peripheral nerve regeneration: an electrophysiological study of the monkey median nerve.

Regeneration in the peripheral nervous system is often incomplete though it is uncertain which factors, such as the type and extent of the injury or the method or timing of repair, determine the degree of functional recovery. Serial electrophysiological techniques were used to follow recovery from median nerve lesions (n = 46) in nonhuman primates over 3 to 4 years, a time span comparable with such lesions in humans. Nerve gap distances of 5, 20, or 50mm were repaired with nerve grafts or collagen-based nerve guide tubes, and three electrophysiological outcome measures were followed: (1) compound muscle action potentials in the abductor pollicis brevis muscle, (2) the number and size of motor units in reinnervated muscle, and (3) compound sensory action potentials from digital nerve. A statistical model was used to assess the influence of three variables (repair type, nerve gap distance, and time to earliest muscle reinnervation) on the final recovery of the outcome measures. Nerve gap distance and the repair type, individually and concertedly, strongly influenced the time to earliest muscle reinnervation, and only time to reinnervation was significant when all three variables were included as outcome predictors. Thus, nerve gap distance and repair type exert their influence through time to muscle reinnervation. These findings emphasize that factors that control early axonal outgrowth influence the final level of recovery attained years later. They also highlight that a time window exists within which axons must grow through the distal nerve stump in order for recovery after nerve lesions to be optimal. Future work should focus on interventions that may accelerate the growth of axons from the lesion site into the distal nerve stump.

Monkey median nerve repaired by nerve graft or collagen nerve guide tube

Nerve regeneration was followed in 15 median and 1 ulnar nerve of eight Macaca fascicularis monkeys by serial electrophysiological assessments over a period of three and a half years. Nerve gaps of 5 mm at the wrist were bridged by collagen-based nerve guides, nerve autografts, or direct suture repairs. Thenar muscle reinnervation occurred between 50 and 70 d for all groups, indicating axonal elongation rates of approximately 1 mm/d. The recovery rates of the compound muscle action potential (CMAP) and the compound sensory action potential (CSAP) amplitudes were significantly slower after direct suture repair compared to the other two procedures, although the final levels of recovery were all comparable. Similar results were achieved in one median and one ulnar nerve following nerve guide repair of a 15 mm nerve gap. The functional reinnervation of Pacinian corpuscles was detected in all cases following either nerve graft or nerve guide repair, with similar amplitudes and latencies of the tactile evoked CSAP for both types of repair. Histological analysis demonstrated a significant increase in the number of myelinated axons in the median nerve distal to the nerve lesions following both nerve graft and nerve guide repairs compared to proximal and normal controls, with significant reductions of fiber diameter and corresponding increases in g-ratio. The return of a bimodal frequency distribution of myelinated axon fiber diameter was confirmed by three-dimensional surface plots which illustrate the frequency distribution of the relationship between fiber diameter and g-ratio. These combined results demonstrate that nerve regeneration after repair of a 5 mm nerve gap with a collagen nerve guide in the nonhuman primate is similar to that after graft repair, and the final level of physiological recovery for both repair procedures is comparable to direct suture repair of the median nerve.

A collagen‐based nerve guide conduit for peripheral nerve repair: An electrophysiological study of nerve regeneration in rodents and nonhuman primates

When a peripheral nerve is severed and left untreated, the most likely result is the formation of an endbulb neuroma; this tangled mass of disorganized nerve fibers blocks functional recovery following nerve injury. Although there are several different approaches for promoting nerve repair, which have been greatly refined over recent years, the clinical results of peripheral nerve repair remain very disappointing. In this paper we compare the results of a collagen nerve guide conduit to the more standard clinical procedure of nerve autografting to promote repair of transected peripheral nerves in rats and nonhuman primates. In rats, we tested recovery from sciatic nerve transection and repair by 1) direct microsurgical suture, 2) 4 mm autograft, or 3) entubulation repair with collagen-based nerve guide conduits. Evoked muscle action potentials (MAP) were recorded from the gastrocnemius muscle at 4 and 12 weeks following sciatic nerve transection. At 4 weeks the repair group of direct suture demonstrated a significantly greater MAP, compared to the other surgical repair groups. However, at 12 weeks all four surgical repair groups displayed similar levels of recovery of the motor response. In six adult male Macaca fascicularis monkeys the median nerve was transected 2 cm above the wrist and repaired by either a 4 mm nerve autograft or a collagen-based nerve guide conduit leaving a 4 mm gap between nerve ends. Serial studies of motor and sensory fibers were performed by recording the evoked MAP from the abductor pollicis brevis muscle (APB) and the sensory action potential (SAP) evoked by stimulation of digital nerves (digit II), respectively, up to 760 days following surgery. Evoked muscle responses returned to normal baseline levels in all cases. Statistical analysis of the motor responses, as judged by the slope of the recovery curves, indicated a significantly more rapid rate of recovery for the nerve guide repair group. The final level of recovery of the MAP amplitudes was not significantly different between the groups. In contrast, the SAP amplitude only recovered to the low normal range and there were no statistically significant differences between the two groups in terms of sensory recovery rates. The rodent and primate studies suggest that in terms of recovery of physiological responses from target muscle and sensory nerves, entubulation repair of peripheral nerves with a collagen-based nerve guide conduit over a short nerve gap (4 mm) is as effective as a standard nerve autograft.(ABSTRACT TRUNCATED AT 400 WORDS)

Peripheral Neve Regeneration in Vivo with Tubular Prostheses

AbstractWe have developed a quantitative model which allows assessment of the number of primary motor and sensory neurons which regenerate an axon through a tubular prosthesis bridging a 4–5 mm gap of peripheral nerve (1). Labeled somas of motor and sensory neurons are quantified following retrograde transport of horseradish peroxidase (HRP) applied to the distal stump beyond the bridged transection site. The number of myelinated axons at mid-guide level is also quantified. We have studied biodegradable and nin-biodegradable materials as well as the effects on nerve regeneration of basement membrane materials, and specific proteins added to the nerve guide., Adding a laminin-oontaining gel (Matrigel, Collaborative Research, MA) to the lumen of polyethylene tubes increases the rate of nerve regeneration as well as the maximum distance that can be successfully bridged. Similar effects are seen with collagen-based nerve guides when the laminin-cxitaining gel is incorporated into the tube wall. Addition of highly purified acidic fibroblast growth factor (aFGF) to the lumen of polyethylene tubes filled with collagen significantly increases the number of myelinated axons at mid-tube level and the number of primary sensory neurons labeled with HRP.We coxpared collagen-based nerve guides of different wall porosities. Tubes freely permeable to bovine serum albumin (BSA) contain significantly more myelinated axons (4 week survival) than identical collagen tubes permeable to glucose-size molecules. These and additional experiments demonstrate that manipulation of the extracellular microenvironment of regenerating PNS axons can significantly enhance the early regenerative response.

PRESSURE BLOCK IN NERVES PROVIDED WITH ARTERIAL SLEEVES

ArticlesPRESSURE BLOCK IN NERVES PROVIDED WITH ARTERIAL SLEEVESPaul Weiss, and Hallowell DavisPaul Weiss, and Hallowell DavisPublished Online:01 Jul 1943https://doi.org/10.1152/jn.1943.6.4.269MoreSectionsPDF (3 MB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Previous Back to Top Next Download PDF FiguresReferencesRelatedInformationCited BySynthesis and biomedical applications of aerogels: Possibilities and challengesAdvances in Colloid and Interface Science, Vol. 236Investigation of crosslinked silica aerogels for implant applicationsAn in vivo evaluation of a biodegradable genipin-cross-linked gelatin peripheral nerve guide conduit materialBiomaterials, Vol. 26, No. 18Effect of low-power pulsed laser on peripheral nerve regeneration in ratsMicrosurgery, Vol. 25, No. 1Multilayered peptide incorporated collagen tubules for peripheral nerve repairBiomaterials, Vol. 25, No. 13Nerve Guide Material Made from Fibronectin: Assessment of in Vitro PropertiesTissue Engineering, Vol. 9, No. 2Locally Administered Nerve Growth Factor Suppresses Ginsenoside Rb1 -enhanced Peripheral Nerve Regeneration5 April 2012 | The American Journal of Chinese Medicine, Vol. 31, No. 05Effects of percutaneous electrical stimulation on peripheral nerve regeneration using silicone rubber chambers1 January 2001 | Journal of Biomedical Materials Research, Vol. 57, No. 4Peripheral nerve regeneration using silicone rubber chambers filled with collagen, laminin and fibronectinBiomaterials, Vol. 21, No. 15Pathophysiology of Nerve Compression SyndromesThe Journal of Bone & Joint Surgery, Vol. 81, No. 11Biodegradable Controlled Release Glass in the Repair of Peripheral Nerve Injuries29 August 2016 | Journal of Hand Surgery, Vol. 23, No. 5Peripheral nerve repair with collagen conduitsClinical Materials, Vol. 9, No. 3-4A collagen-based nerve guide conduit for peripheral nerve repair: An electrophysiological study of nerve regeneration in rodents and nonhuman primatesThe Journal of Comparative Neurology, Vol. 306, No. 4Clinical Symptoms, Electrophysiological and Morphological Findings in Traumatic Lesions of the Ischiadic Nerve in Domestic FowlNerve regeneration through artificial tubular implantsProgress in Neurobiology, Vol. 33, No. 2Effects of pressure on fast axoplasmic flow. 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(With a model of the control mechanism)The Journal of Comparative Neurology, Vol. 144, No. 2Sensory conduction from digit to palm and from palm to wrist in the carpal tunnel syndromeJournal of Neurology, Neurosurgery & Psychiatry, Vol. 34, No. 3NEURONAL DYNAMICS AND NEUROPLASMIC (“AXONAL”) FLOWBIDIRECTIONAL SHIFT OF MITOCHONDRIA IN AXONS AFTER INJURYSyntheseort und Ferntransport von Proteinen im FischhirnZeitschrift f�r Zellforschung und Mikroskopische Anatomie, Vol. 86, No. 2Mast Cells in the Nervous SystemStudies on vascular permeability in peripheral nervesActa Neuropathologica, Vol. 7, No. 1A banded structure in the connective tissue of nerveJournal of Ultrastructure Research, Vol. 11, No. 5-6The Use of a Resorbable Wrapper for Peripheral-Nerve RepairJournal of Neurosurgery, Vol. 21, No. 9Quantitativ-morphologische Befunde zur Hypothese des Mitochondrientransportes im NeuronZeitschrift f�r Zellforschung und Mikroskopische Anatomie, Vol. 62, No. 4Protein Metabolism of The Nervous SystemAn experimental method for compressing the sciatic nerveExperientia, Vol. 18, No. 11Elektronenmikroskopische Befunde zur Feinstruktur von Axonver�nderungen in regenerierenden Nervenfasern des Nervus ischiadicus der wei�en RatteActa Neuropathologica, Vol. 1, No. 5Experimental observations on the prevention of neuroma formationJournal of Surgical Research, Vol. 1, No. 3Further evidence of perpetual growth of nerve fibers: Recovery of fiber diameter after the release of prolonged constrictionsJournal of Experimental Zoology, Vol. 142, No. 1Studies on the phrenic nerves and the diaphragm of the dogThe American Journal of Surgery, Vol. 97, No. 6Cell migrations from the rhombic lip to the inferior olive, the nucleus raphe and the pons. 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