Restoration of Muscular Function Following Direct Muscle Neurotization

Summary/Abstract More than 500,000 surgical procedures are performed annually in the US to address peripheral nerve injury (PNI), at a cost of more than $1.1B. PNI and their sequelae affect more than 20 million Americans, with total economic impacts in excess of $150B annually. Despite advances in microsurgical techniques and the inherent ability of the peripheral nervous system to regenerate, fewer than 50% of patients experience satisfactory functional recovery. Successful reanimation following significant neuromuscular tissue loss can pose a clinical challenge due to the absence of the distal nerve-muscle pedicle. In these cases, approaches such as free- functioning muscle transfer may be required to restore function. These procedures are complex and time consuming, cause loss of function at the donor site, and can pose substantial risks. Another approach to reinnervation is direct muscle neurotization (DMN), in which a nerve is transferred directly to a targeted muscle without relying on previously existing neuro-muscular bridges. The success of DMN relies on the ability of the nerve to establish new connections to existing or newly formed neuromuscular junctions (NMJ) within the denervated muscle. This process is significantly hindered by the loss of guiding nerve structures and regenerative cues and is further affected by the time of denervation before repair. To address this need, Renerva seeks to further the development of Peripheral Nerve Matrix (PNM) for clinical DNM use, and determine the ability of a terminally sterilized, clinical grade PNM product to facilitate functional recovery over time in both immediate and delayed DMN models. PNM contains naturally occurring structural and functional proteins that provide an ideal environment for nerve repair and regeneration. In prior work, PNM has been shown to promote improvements in outcomes associated with nerve crush, nerve transection and nerve gap injuries. In this Phase I project, Renerva seeks to further the development of PNM for clinical DNM use, and determine the ability of a terminally sterilized, clinical grade PNM product to facilitate functional recovery over time in both immediate and delayed DMN models. Specific Aims of this project are as follows: 1) Optimize the formulation of clinical grade PNM to provide ideal support for DMN in vitro; and 2) Determine the ability of PNM to accelerate and enhance functional recovery in a rodent DMN model. The proposed work will accelerate the development of a product for DMN applications. Such a product has the potential to provide new options for challenging clinical applications including severe sciatic injury at the hip, proximal nerve injuries, and extensive muscle tissue loss, which are often associated with delayed repair and poor outcomes. It would also provide support for emerging procedures such as targeted muscle reinnervation and regenerative peripheral nerve interfaces. The achievement of the aims of this proposal will support additional investigations in clinically relevant large animal models in Phase II.