Tissue Engineering Strategies to Maintain Distal Target Efficacy and Promote Full Functional Recovery Following Major Peripheral Nerve Injury
Abstract
Peripheral nerves are the main conduits through which the brain and spinal cord are able to communicate with the rest of the body, including signals to muscles to move limbs and sensory input to relay temperature, pressure, and limb position. Modern Warfighter protection focuses on body core (i.e., armor vests) and head (i.e., helmets), leaving the extremities relatively unprotected. Therefore, it is not surprising that extremity trauma due to blast and/or penetrating injuries account for as much as 79% of trauma cases from theater. Such severe battlefield trauma can result in significant tissue loss, often losing entire segments of major nerves (as long as 5-20 cm). For Warfighters requiring surgical reconstruction following such major nerve injuries, only a fraction will achieve good to normal restoration of function, regardless of the repair strategy, and most will be left with debilitating and life-altering deficits. Tragically, there have been cases where a limb was salvaged only to later be amputated once it became obvious that nerve regeneration, and hence the ability to feel and control the limb, would not occur. In these cases, nerve regeneration does not fail because axons -- the individual fibers growing from neurons residing in or around the spinal cord -- lose their ability to grow; rather, regeneration fails because the support structure of the distal nerve segments wither away and end targets such as muscle lose their capacity for reinnervation. Therefore, nerve repair strategies must be equally concerned with (1) providing a suitable bridge to guide axons across missing nerve segments and (2) maintaining the capacity of distal nerve segments and end targets to support and receive regenerating axons. Our research team at the University of Pennsylvania, in conjunction with our commercial partner, Axonova Medical, is pioneering the first dual peripheral nerve strategy that provides living "bridges" across missing nerve segments while maintaining the full regenerative pathway and target receptiveness -- a phenomenon we refer to as "babysitting." We have developed proprietary technology that allows us to create lab-grown tissue engineered nerve grafts (TENGs) comprised of living neurons and axonal tracts grown to remarkable length of 5 cm within 2 weeks. Importantly, we have previously validated this strategy by demonstrating that custom TENGs serve as a "living scaffold" capable of both "bridging" nerve gaps and "babysitting" distal nerve pathways. The goal of the current project is to establish the composition and efficacy of our final product biomass with the additional feature of "babysitting" target muscle vitality and reinnervation capacity. Specifically, we will explore the use of TENGs consisting of motor neurons/axons and/or mixed motor-sensory neurons/axons to "babysit" muscle when transplanted within nerve segments distal afield from the primary surgical repair in our established preclinical models of major peripheral nerve injury. This project will also investigate the capability of clinically relevant stem cell based starting materials to generate TENGs. Importantly, we have previously shown that transplanted TENG neurons extend axons within the host distal nerve sheath to reach muscle and sensory end targets, which we predict will maintain their vitality and regenerative capacity while long-distance host axonal regeneration ensues -- in extreme cases taking on the order of many months. We predict that our tissue engineered "bridging" and "babysitting" strategies used together will be the first approach to enable functional recovery in nerve injury cases necessitating ultra-long distance axon regeneration. Eventual clinical deployment of our novel TENGs will represent a paradigm shift for nerve reconstruction in our Wounded Warfighters and may enable robust restoration of motor and sensory function in cases not otherwise possible. The technology to generate TENGs and their applicati
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610796
Entities
People
- Daniel Cullen
Organizations
- United States Army
- University of Pennsylvania