Perspectives on optimizing local delivery of drugs to peripheral nerves using mathematical models

Drug therapies for treating peripheral nerve injury repair have shown significant promise in preclinical studies. Despite this, drug treatments are not used routinely clinically to treat patients with peripheral nerve injuries. Drugs delivered systemically are often associated with adverse effects to other tissues and organs; it remains challenging to predict the effective concentration needed at an injured nerve and the appropriate delivery strategy. Local drug delivery approaches are being developed to mitigate this, for example via injections or biomaterial-mediated release. We propose the integration of mathematical modeling into the development of local drug delivery protocols for peripheral nerve injury repair. Mathematical models have the potential to inform understanding of the different transport mechanisms at play, as well as quantitative predictions around the efficacy of individual local delivery protocols. We discuss existing approaches in the literature, including drawing from other research fields, and present a process for taking forward an integrated mathematical-experimental approach to accelerate local drug delivery approaches for peripheral nerve injury repair. This article is categorized under: Neurological Diseases > Molecular and Cellular Physiology Neurological Diseases > Computational Models Neurological Diseases > Biomedical Engineering

The Immune Response and Implications for Nerve Repair

This chapter aims to provide an overview of the host response to allografts or tissue-engineered constructs containing allogeneic cells in peripheral nerve repair, and potential approaches for promoting the survival of nerve grafts. A large body of current research aims to improve surgical approaches for nerve repair beyond that of the autograft. Potential approaches include nerve allografts, or tissue-engineered nerve constructs which could provide an unlimited source of donor tissue for nerve injury repair. This field requires an interdisciplinary approach to the design of novel therapies, and consideration of the immune response to transplants should not be overlooked. There are many benefits of including living donor cells within transplanted nerve conduits which can improve axonal guidance, vascularization, and promote the release of growth factors to increase regeneration. It is most likely that donor cells or tissues will be of allogeneic origin, with associated implications for eliciting an immune response on transplantation. The following sections provide a summary of the immune response to nerve grafts for consideration in the development of approaches to nerve repair, including some approaches currently under investigation for preventing rejection of transplants

Induced pluripotent stem cells derived from the developing striatum as a potential donor source for cell replacement therapy for Huntington disease

Background: Cell replacement therapy (CRT) for Huntington disease (HD) requires a source of striatal (STR) progenitors capable of restoring the function lost due to STR degeneration. Authentic STR progenitors can be collected from the fetal putative striatum, or whole ganglionic eminence (WGE), but these tissues remain impractical for widespread clinical application, and alternative donor sources are required. Here we begin exploring the possibility that induced pluripotent stem cells (iPSC) derived from WGE may retain an epigenetic memory of their tissue of origin, which could enhance their ability to differentiate into STR cells. / Results: We generate four iPSC lines from human WGE (hWGE) and establish that they have a capacity similar to human embryonic stem cells with regard to their ability to differentiate toward an STR phenotype, as measured by expression and demethylation of key STR genes, while maintaining an overall different methylome. Finally, we demonstrate that these STR-differentiated hWGE iPSCs share characteristics with hWGE (i.e., authentic STR tissues) both in vitro and following transplantation into an HD model. Overall, iPSCs derived from human WGE show promise as a donor source for CRT for HD