Nerve Regeneration and Functional Recovery Following Delayed Application of Regenerative Peripheral Nerve Interface (RPNI) in a Rat Model
Ipek Berberoglu, BS1, Katherine L Burke, MD1, Matthew D Wood, PhD2, Paul S Cederna, M.D.3 and Stephen WP Kemp, Ph.D.1, 1University of Michigan, Ann Arbor, MI, 2Washington University School of Medicine, St. Louis, MO, 3Plastic Surgery, University of Michigan, Ann Arbor, MI
Introduction: There are an estimated 2 million people in the U.S. living with limb loss, many suffering from physical impairments and activity limitations. The Regenerative Peripheral Nerve Interface (RPNI) is a surgical technique that offers real-time control of myoelectric prosthetic devices to restore extremity function in these individuals. Although the clinical outcomes of RPNI are promising, considerably less is known about the differences in underlying pathophysiology and subsequent limitations when RPNI surgery is delayed for months to years following amputation. The denervated muscle of an RPNI directly impacts axonal sprouting, elongation, and muscle reinnervation. Delays in the performance of an RPNI after the initial amputation and nerve division may yield a different microenvironment which could impact these processes and consequently impact signal amplification necessary for intuitive control of a prosthetic device. The purpose of this study was to determine whether the timing of RPNI performance, following nerve injury, alters the microenvironment for nerve regeneration and impacts signal amplification.
Methods: Eighteen Lewis rats were randomly assigned to one of three groups (n=6/group): (1) Prophylactic RPNI, (2) neuroma surgery with delayed RPNI at 3 months, or (3) neuroma surgery with delayed RPNI at 6 months. The neuroma bulb was harvested en bloc for bulk RNA-sequencing before the delayed RPNI implantation. After a three-month maturation period, in vivo electrophysiologic analyses were conducted to record compound muscle action potentials (CMAPs). RPNI and proximal common peroneal (CP) nerve were then harvested for immunohistochemistry and histomorphometry to evaluate muscle reinnervation, the extent of axonal regeneration, and cell populations in the graft microenvironment. RNA was extracted from the RPNI for gene analysis.
Results: Following the maturation period, all RPNIs were viable and well-vascularized. RPNIs generated amplified CMAPs in all groups. Immunohistochemistry revealed reinnervated neuromuscular junctions and muscle spindles. Furthermore, percentage of Schwann cells, macrophages, and activated stromal cells within the RPNIs demonstrated a pro-regenerative environment.
Conclusion: The RPNI is a biologic neural interface which facilitates advanced control of prosthetic devices by amplifying neuronal signals in the setting of peripheral nerve injury. Delayed applications of RPNI can still offer promising results to help individuals to restore extremity motor function.
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