Therapeutic Electrical Stimulation Using Wireless, Resorbable Implants to Accelerate Diaphragm Muscle Reinnervation after Phrenic Neuropathy

Project Abstract: Phrenic Neuropathy, a condition that impairs diaphragm muscle function, often leads to serious respiratory problems and requires mechanical ventilation. Our research proposal aims to enhance recovery from this condition through a novel Therapeutic Electrical Stimulation protocol, in conjunction with a custom-made, wireless, bioresorbable implant. Informed by a rising incidence of Phrenic Neuropathy due to complications from severe COVID-19 and greater diagnostic capabilities and other factors, this proposal is the result of collaboration among a multidisciplinary team with substantial expertise in all aspects of this proposed work. In general, there is a common misconception that recovery from peripheral axon injury is usually good, due to the fact there is some spontaneous axon regeneration, but this does not match the reality that recovery is actually slow and incomplete for approximately 90% of patients. This is also true for patients with Phrenic Neuropathy. Our data and others show that 68-96% of these patients have incomplete or no functional recovery of the diaphragm muscle. Despite varying causes of Phrenic Neuropathy, its impact on respiratory function and individual quality of life is significant. At its worst, people with Phrenic Neuropathy may require mechanical ventilation, but more typically they are severely limited in their ability to engage in routine exertion required for activities of daily life. Currently, clinical and surgical approaches do not sufficiently address the issue of slow axon regrowth. Our project aims to rectify this by developing a Therapeutic Electrical Stimulation protocol that can restore diaphragm muscle innervation and function faster and more completely than ever before. Briefly, our approach is focused on three specific aims: 1) determining if repeated Therapeutic Electrical Stimulation sessions are more effective than a single session, 2) assessing if repeated sessions enhance brain-derived neurotrophic factor-TrkB signaling more than a single session or control, and 3) establishing how essential brain-derived neurotrophic factor-TrkB signaling is to the effects of Therapeutic Electrical Stimulation treatment. We aim to deliver a new therapeutic electrical stimulation paradigm to accelerate diaphragm muscle innervation and improve functional outcomes after Phrenic Neuropathy, providing new insights into the underlying mechanism of how brain-derived neurotrophic factor-TrkB signaling can enhance muscle reinnervation. The prior success of clinical translation from rat model to human clinical trials for Therapeutic Electrical Stimulation to treat other nerve injuries implies a great opportunity to move quickly towards clinical translation upon the successful completion of these aims.