Peripheral nerve injuries (PNI) have a high prevalence and can be debilitating, resulting in life‐long loss or disturbance in end‐organ function, which compromises quality of life for patients. Current therapies use microsurgical approaches but there is the potential for enhancing recovery through other therapeutic modalities such as; cell‐based conduits, gene therapy and small molecules. A number of molecular targets and drugs which have the potential to improve nerve regeneration have been identified, however, there are challenges associated with moving therapies toward clinical translation. Due to the lack of detailed knowledge about the pro‐regenerative effect of potential drug treatments, there is a need for effective in vitro models to screen compounds to inform future pre‐clinical and clinical studies. The interaction between regenerating neurites and supporting Schwann cells is a key feature of the nerve environment, therefore, in vitro models that mimic this cellular association are useful tools. In this study, we have investigated various cell culture models, including simple monolayer systems and more complex 3D‐engineered co‐cultures, as models for use in PNI drug development. Anat Rec, 301:1628–1637, 2018. © 2018 The Authors. The Anatomical Record published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists.

Schwann cells provide essential support for nerve growth and survival following peripheral nerve damage by producing various growth factors and other signalling molecules. Modulating the proliferation, differentiation, migration, or myelination of Schwann cells could result in accelerated repair and regeneration of injured nerves, ultimately leading to improved motor and sensory function. Therefore, Schwann cells are commonly advocated as therapeutic targets for nerve damage, which could be mediated by pharmacological intervention. This review discusses how compounds such as growth factors, hormones, and small molecules can regulate intracellular signalling pathways involved in modulating Schwann cells.

Objective. Poor clinical outcomes following peripheral nerve injury (PNI) are partly attributable to the limited rate of neuronal regeneration. Despite numerous potential drug candidates demonstrating positive effects on nerve regeneration rate in preclinical models, no drugs are routinely used to improve restoration of function in clinical practice. A key challenge associated with clinical adoption of drug treatments in nerve injured patients is the requirement for sustained administration of doses associated with undesirable systemic sideeffects. Local controlled-release drug delivery systems could potentially address this challenge, particularly through the use of biomaterials that can be implanted at the repair site during the microsurgical repair procedure. Approach. In order to test this concept, this study used various biomaterials to deliver ibuprofen sodium or sulindac sulfide locally in a controlled manner in a rat sciatic nerve injury model. Following characterisation of release parameters in vitro, ethylene vinyl acetate tubes or polylactic-co-glycolic acid wraps, loaded with ibuprofen sodium or sulindac sulfide, were placed around directly-repaired nerve transection or nerve crush injuries in rats. Main results. Ibuprofen sodium, but not sulindac sulfide caused an increase in neurites in distal nerve segments and improvements in functional recovery in comparison to controls with no drug treatment. Significance. This study showed for the first time that local delivery of ibuprofen sodium using biomaterials improves neurite growth and functional recovery following PNI and provides the basis for future development of drug-loaded biomaterials suitable for clinical translation.

The slow rate of neuronal regeneration that follows peripheral nerve repair results in poor recovery, particularly where reinnervation of muscles is delayed, leading to atrophy and permanent loss of function. There is a clear clinical need to develop drug treatments that can accelerate nerve regeneration safely, restoring connections before the target tissues deteriorate irreversibly. The identification that the Rho/Rho-associated kinase (ROCK) pathway acts to limit neuronal growth rate is a promising advancement towards the development of drugs. Targeting Rho or ROCK directly can act to suppress the activity of this pathway; however, the pathway can also be modulated through the activation of upstream receptors; one of particular interest being peroxisome proliferator-activated receptor gamma (PPAR-γ). The connection between the PPAR-γ receptor and the Rho/ROCK pathway is the suppression of the conversion of inactive guanosine diphosphate (GDP)-Rho to active guanosine triphosphate GTP-Rho, resulting in the suppression of Rho/ROCK activity. PPAR-γ is known for its role in cellular metabolism that leads to cell growth and differentiation. However, more recently there has been a growing interest in targeting PPAR-γ in peripheral nerve injury (PNI). The localisation and expression of PPAR-γ in neural cells following a PNI has been reported and further in vitro and in vivo studies have shown that delivering PPAR-γ agonists following injury promotes nerve regeneration, leading to improvements in functional recovery. This review explores the potential of repurposing PPAR-γ agonists to treat PNI and their prospective translation to the clinic.