Injectable Myoblast Scaffold to Regenerate Chronically Denervated Muscle
Abstract
Background: Peripheral nerve injuries cause lifelong disability, chronic pain, and reduced quality of life. They occur in 1%-3% of extremity traumas in the general United States population and are even more common among military Service Members, comprising 8% of all combat casualties. Long-term functional recovery is typically poor, and most injured Soldiers do not return to full military duty. These functional impairments are often due to a condition termed chronic denervation-induced muscle atrophy, which is a process of progressive muscle degeneration that takes place while a muscle is disconnected from its nerve supply. There are currently no treatments to restore muscle function in this common situation. Objective: Our goal is to develop the first targeted therapy for chronic denervation-induced muscle atrophy. In this proposed treatment, muscle progenitor cells from a patient s own unaffected muscle (i.e., autologous myoblasts) will be injected into atrophic muscle along with the bioactive factors, insulin-like growth factor 1 (IGF-1) and agrin. The objective of this proposal is to evaluate the effectiveness of our therapy in restoring muscle strength in a translational small-animal model. We will achieve this objective through accomplishing two independent specific aims: (1) optimize survival and reinnervation of autologous myoblasts within injured muscle and (2) evaluate post-treatment functional recovery in muscle that has been chronically weakened by a period of denervation. Rationale: Our novel therapy involves the targeted delivery of four components directly into affected muscle via a single injection: cultured autologous myoblasts, IGF-1 nanoparticles, agrin nanoparticles, and a biodegradable nanofiber hydrogel composite (NHC) carrier. We hypothesize that the introduced myoblasts will develop into mature muscle cells that will serve to increase muscle strength. We further hypothesize (1) that the NHC will improve survival of introduced myoblasts, (2) that IGF-1 will stimulate myoblast proliferation and nerve fiber ingrowth, and (3) that agrin will facilitate the connection of these myoblasts to the native nerve supply. Our translational small-animal model will allow us to examine myoblast proliferation and maturation within atrophic muscle and to link how these cellular changes correspond to muscle strength. Applications: This proposal addresses the following FY22 PRORP Applied Research Award Focus Area: composite tissue regeneration (muscle and nerve). Despite advances that have been made in nerve reconstruction, some degree of denervation-induced muscle atrophy is often unavoidable. Our proposed approach is logical and could be readily applied to clinical practice. We envision that this injectable therapy would be administered in clinic under ultrasound guidance to patients who have reached a stable but reduced functional plateau years after nerve injury. Timeline: These studies will achieve a clinically relevant outcome upon their conclusion in 3 years. Isolation and proliferation of autologous myoblasts, sustained local release of IGF-1 and agrin using biodegradable nanoparticles, and the mechanistic effects of IGF-1 and agrin on muscle development have already been established. Therefore, in our proposed translational research, we will study the unique application of these technologies toward improving long-term functional recovery after traumatic orthopaedic injuries. Autologous myoblast transplantation has been studied in several pediatric and adult clinical trials over the past 20 years. The NHC is also currently being investigated in a clinical trial, and biodegradable nanoparticles are well-developed technologies that have been used in U.S. Food and Drug Administration-approved formulations. Following successful completion of the studies in this proposal, we aim to evaluate the long-term safety of our novel therapy in a large-animal model before beginning clinical t
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310476
Entities
People
- Sami Tuffaha
Organizations
- Johns Hopkins University
- United States Army