Animal models of nerve compression, crush, and transection injuries of peripheral nerves have been subject to extensive study in order to understand the mechanisms of injury and axon regeneration and to investigate methods to promote axon regeneration and improve functional outcomes following nerve injury. Six outcome measures of regenerative success including axon and neuron counts, muscle and motor unit contractile forces, and behavior are reviewed in the context of nerve injury types, crush, transection and nerve repair by direct coaptation, or transection and repair via a nerve graft or conduit. The measures are evaluated for sciatic, tibial, common peroneal, femoral, single nerve branches such as the soleus nerve, and facial nerves. Their validity is discussed in the context of study objectives and the nerve branch. The case is made that outcome measures of axon counts and muscle contractile forces may be valid during the early phases of axon regeneration when regenerating sprouts emerge asynchronously from the proximal nerve stump and regenerate towards their denervated targets. However, care must be taken especially when experimental interventions differentially affect how many neurons regenerate axons and the number of axons per neuron that sprout from the proximal nerve stumps. Examples of erroneous conclusions are given to illustrate the need for researchers to ensure that the appropriate outcome measures are used in the evaluation of the success of peripheral nerve regeneration.

Outcome measures of peripheral nerve regeneration.

https://science.sciencemag.org/content/sci/152/3724/951.1.full.pdf

Encyclopedia of physics.

The ability of injured peripheral nerves to regenerate and reinnervate their original targets is a characteristic feature of the peripheral nervous system (PNS). On the other hand, neurons of the central nervous system (CNS), including retinal ganglion cell (RGC) axons, are incapable of spontaneous regeneration. In the adult PNS, axonal regeneration after injury depends on well-orchestrated cellular and molecular processes that comprise a highly reproducible series of degenerative reactions distal to the site of injury. During this fine-tuned process, named Wallerian degeneration, a remodeling of the distal nerve fragment prepares a permissive microenvironment that permits successful axonal regrowth originating from the proximal nerve fragment. Therefore, a multitude of adjusted intrinsic and extrinsic factors are important for surviving neurons, Schwann cells, macrophages and fibroblasts as well as endothelial cells in order to achieve successful regeneration. The aim of this review is to summarize relevant extrinsic cellular and molecular determinants of successful axonal regeneration in rodents that contribute to the regenerative microenvironment of the PNS.

Extrinsic cellular and molecular mediators of peripheral axonal regeneration.

The pathogenesis of intraneural ganglia has been an issue of curiosity, controversy, and contention for 200 years. Three major theories have been proposed to explain their existence, namely, 1) degenerative, 2) synovial (articular), and 3) tumoral theories, each of which only partially explains the observations made by a number of investigators. As a result, differing operative strategies have been described; these generally meet with incomplete neurological recoveries and high rates of recurrence. Recent advances in magnetic resonance imaging and critical analysis of the literature have clarified the mechanisms underlying the formation and propagation of these cysts, thereby confirming the unifying articular (synovial) theory. By identifying the shared features of the typical cases and explaining atypical examples or clinical outliers, several fundamental principles have been described. These include: 1) a joint origin; 2) dissection of fluid from that joint along an articular nerve branch, extension occurring via a path of least resistance; and 3) cyst size, extent, and directionality being influenced by pressures and pressure fluxes. We believe that understanding the pathogenesis of these cysts will be reflected in optimal surgical approaches, improved outcomes, and decreased frequency, if not elimination, of recurrences. This article describes the ongoing process of critically analyzing and challenging previous observations and evidence in an effort to prove a concept and a theory.

The unifying articular (synovial) origin of intraneural ganglia: evolution-revelation-revolution.

We used morphological, immunohistochemical and functional assessments to determine the impact of genetically-modified peripheral nerve (PN) grafts on axonal regeneration after injury. Grafts were assembled from acellular nerve sheaths repopulated ex vivo with Schwann cells (SCs) modified to express brain-derived neurotrophic factor (BDNF), a secretable form of ciliary neurotrophic factor (CNTF), or neurotrophin-3 (NT3). Grafts were used to repair unilateral 1 cm defects in rat peroneal nerves and 10 weeks later outcomes were compared to normal nerves and various controls: autografts, acellular grafts and grafts with unmodified SCs. The number of regenerated βIII-Tubulin positive axons was similar in all grafts with the exception of CNTF, which contained the fewest immunostained axons. There were significantly lower fiber counts in acellular, untransduced SC and NT3 groups using a PanNF antibody, suggesting a paucity of large caliber axons. In addition, NT3 grafts contained the greatest number of sensory fibres, identified with either IB4 or CGRP markers. Examination of semi- and ultra-thin sections revealed heterogeneous graft morphologies, particularly in BDNF and NT3 grafts in which the fascicular organization was pronounced. Unmyelinated axons were loosely organized in numerous Remak bundles in NT3 grafts, while the BDNF graft group displayed the lowest ratio of umyelinated to myelinated axons. Gait analysis revealed that stance width was increased in rats with CNTF and NT3 grafts, and step length involving the injured left hindlimb was significantly greater in NT3 grafted rats, suggesting enhanced sensory sensitivity in these animals. In summary, the selective expression of BDNF, CNTF or NT3 by genetically modified SCs had differential effects on PN graft morphology, the number and type of regenerating axons, myelination, and locomotor function.

/pdf/immunohistochemical-ultrastructural-and-functional-analysis-11wayfn3go.pdf

Immunohistochemical, ultrastructural and functional analysis of axonal regeneration through peripheral nerve grafts containing Schwann cells expressing BDNF, CNTF or NT3

Intraneural ganglion cysts have been considered a curiosity for 2 centuries. Based on a unifying articular (synovial) theory, recent evidence has provided a logical explanation for their formation and propagation. The fundamental principle is that of a joint origin and a capsular defect through which synovial fluid escapes following the articular branch, typically into the parent nerve. A stereotypical, reproducible appearance has been characterized that suggests a shared pathogenesis. In the present report the authors will provide a mechanistic explanation that can then be mathematically tested using a preliminary model created by finite element analysis.

/pdf/intraneural-ganglia-a-clinical-problem-deserving-a-57zauqo4am.pdf

Intraneural ganglia: a clinical problem deserving a mechanistic explanation and model.

http://research.me.mtu.edu/abstracts/Odegard-%20An%20Elastic%20Micropolar%20Mixture%20Theory%20for%20Predicting%20Elastic%20Properties%20of%20Cellular%20Materials.pdf

An elastic micropolar mixture theory for predicting elastic properties of cellular materials

An efficient modeling approach is established to predict the elastic response of cellular materials with distributions of cell geometries. The approach does not require complex and time-consuming computational techniques usually associated with modeling such materials. Unlike most current analytical techniques, the modeling approach directly accounts for the cellular material microstructure. The approach combines micropolar elasticity theory and elastic mixture theory to predict elastic response of cellular materials to a wide range of loading conditions. The modeling approach is applied to the two-dimensional balsa wood material. Predicted properties are in good agreement with experimentally determined properties, which emphasizes the model’s potential to predict the elastic response of other cellular solids, such as open cell and closed cell foams.

/pdf/an-elastic-micropolar-mixture-theory-for-predicting-elastic-1gloyyn7bv.pdf

An Elastic Micropolar Mixture Theory for Predicting Elastic Properties of Cellular Materials

Intraneural Ganglion Cysts [IGC] are a set of medical conditions that result in denervation of the muscles innervated by the cystic nerve leading to pain and loss of function. Current treatment approaches only temporarily alleviate pain and denervation which, however, does not prevent cyst recurrence. Hence, a mechanistic understanding of the pathogenesis of IGC can help clinicians understand them better and therefore device more effective treatment options. In this study, a preliminary analysis methodology is established to investigate the pathogenesis of IGC.Copyright © 2009 by ASME

Finite Element Modeling of Intraneural Ganglion Cysts of the Common Peroneal Nerve

A constitutive model has been developed to predict the elastic response of two dimensional balsa wood material with a distribution of cell geometries. Two planar triangular grids, each assumed to represent the structural network of an open cell foam material, are superimposed to model an overall cellular structure with a distribution of cell geometries. The elastic mixture theory is applied in conjunction with the micropolar elasticity theory to homogenize the cellular structure and to establish the overall constitutive relationship.Copyright © 2007 by ASME

Shreehari Elangovan

Papers

Intraneural ganglia: a clinical problem deserving a mechanistic explanation and model.

An elastic micropolar mixture theory for predicting elastic properties of cellular materials

An Elastic Micropolar Mixture Theory for Predicting Elastic Properties of Cellular Materials

Finite Element Modeling of Intraneural Ganglion Cysts of the Common Peroneal Nerve

An elastic micropolar mixture theory approach for predicting elastic properties of open cell foams