Fusogen Nanomedicine for Peripheral Nerve Repair
Abstract
This proposal, “Fusogen Nanomedicine for Peripheral Nerve Repair,” addresses the Topic Area of Tissue Regeneration and specifically targets a critically important Area of Encouragement, “Development of novel therapies to repair neurosensory damage.” The project deliverable will be a new class of therapeutic products, fusogenic nanoparticles (FNPs), which offer a potentially revolutionary approach for the treatment of traumatic nerve injuries. Fusogens are biomaterials that enable the plasma membranes of separate cells to come into close contact, allowing their component phospholipids, cholesterol, proteins, and polysaccharides to interact and fuse into a single continuous membrane. In this project, the FNPs will be formulated from biodegradable tyrosine-derived block copolymer surfactants (TyPSs) and cholesterol, which can work together to synergistically modify the fluidity and mechanical properties of nerve axon membranes, enabling nearly instantaneous reconnection of severed nerve ends and restoring sensory and motor functions. Nerve injuries are the second leading cause of unfitting conditions (amputations are the leading cause), which force military personnel to retire from active duty. The majority of combat wounds in recent conflicts have been to the extremities, and between 30% and 50% of those extremity wounds involve peripheral nerve axon injuries. In the majority of cases, those combat nerve injuries result in permanently disabling conditions. In civilian trauma cases, patients also suffer disabling nerve injuries; there are about 100,000 such cases each year and resultant average long-term healthcare costs exceed $1 million per patient. Peripheral nerves carry instructions from the brain to control voluntary motor functions (e.g., walking, running) and they carry sensory signals (e.g., touch, taste) back to the brain for processing. When peripheral nerves are severed, the nerves often fail to fully recover and most patients face lifelong disability and chronic pain. The main reason for poor recovery after severe nerve injuries is that peripheral nerves regrow very slowly (about 1-2 mm/day). That is insufficient to heal a large gap between severed nerve ends because of the rapid onset (within 24-36 hours) of a spontaneous degenerative process, which destroys the affected nerve cells. Surgeons repair severed nerves by suturing them together if the gap between severed ends is less than about one centimeter. For larger gaps, surgeons can implant nerve grafts taken from other parts of the body or they can transfer a connection to a functioning nerve. These surgical procedures often have poor outcomes due to several factors, particularly the limited ability of severed nerve axon membranes to fuse back together and make a functional reconnection. There are currently no commercial, Food and Drug Administration (FDA)-approved fusogens available for clinicians to use for nerve repair. The central hypothesis to be tested in this project is that a systematic exploration of structure-function relationships among novel TyPSs can lead to significantly more effective fusogens. Additionally, FNPs combining two membrane bilayer surface energy modifiers, the TyPSs and cholesterol, can facilitate more effective fusion of damaged axonal membranes and thereby provide substantial functional recovery. Cholesterol is a natural component of cell membranes that controls membrane phospholipid chain interactions and membrane fluidity critical to membrane fusion. The most thoroughly studied polymeric fusogens to date are poly(ethylene glycol) (PEG) and Poloxamer™ 188, industrial chemicals that have never been systematically optimized for fusogenicity. They produce incomplete repair and limited recovery. The innovative aspects of this proposal are, first and foremost, that the FNPs will allow immediate reestablishment of axonal continuity and function, which means that the slow, inherent nerve growth rate and the spont
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010048
Entities
People
- Joachim Kohn
Organizations
- Rutgers University
- United States Army