Grants We Funded

Abstract

Project Summary: Major limb amputation affects 185,000 Americans each year and many more suffer nerve injuries contributing to neuropathic pain. Chronic pain is debilitating, severely compromises quality of life, can prevent the use of prostheses in amputees, and is associated with chronic opioid use. Management of amputations and neuromas has changed dramatically in the last decade with increasing use of targeted muscle reinnervation (TMR) and regenerative peripheral nerve interfaces (RPNIs). These surgical techniques re-route the injured nerves to small motor branches or denervated free muscle grafts. The clear connection to muscle activity accounts for how these techniques contribute to motorizing a prosthesis, but their connection to pain management is much less clear. This proposal will examine how these interventions change with increasing time from nerve injury and how the two interventions affect sensory neuron regeneration. In the first specific aim we will examine how time following injury affects the efficacy of TMR and RPNI. Clinical work has shown that the presence of ‘chronic' pain reduces the efficacy of TMR in amputees and our preliminary work in a rat model of neuropathic pain shows that a delay of 12 weeks from nerve injury to TMR prevents pain relief. In the second specific aim we will characterize the types of regenerating neurons to determine how the two interventions differentially affect sensory neuron populations. Finally, we will determine the effect of changing the input nerve from mixed motor-sensory nerve to a pure sensory nerve to determine if the lack of regenerating motor fibers results in a change in the quantity and quality of regenerating sensory neurons and the concomitant effect on pain behaviors. These analyses will increase our understanding of the mechanisms behind neuropathic pain and findings may be directly translated clinically as these techniques are currently used in patients.

Impact Statement: Nerve transfer surgery (both targeted muscle reinnervation and regenerative peripheral nerve interfaces) is becoming increasingly utilized for amputees and neuroma patients to prevent pain or reduce current pain. These procedures are being used interchangeably in these patients but they have not been compared directly. We will use an animal model to compare these interventions under different conditions, most critically, time from injury to intervention, in order to understand when one or the other might be a more effective option for a patient. Furthermore, these investigations will increase mechanistic understanding of how these different procedures affect pain pathways.

Biography
My research career began with cartilage but through my post graduate training I developed a growing affection for nerves. Compounding this, I found nerve surgery incredibly satisfying and I spent two years doing nerve research in Dr. Susan Mackinnon’s laboratory. I then pursued a fellowship in hand surgery and now as a plastic surgeon my practice is a mix of 100% hand and nerve surgery and 100% peripheral nerve research. The percentages do not add, but that is the beauty of an academic practice, there really are no boundaries between clinical work and research- I learn from both my human and rodent patients. Since 2018 I have been building my laboratory group and my original focus was nerve regeneration. However, the growing use of nerve transfers to treat pain combined with the incredible pain research community at Medical College of Wisconsin has allowed me to grow the laboratory in the direction of the interplay of nerve regeneration and pain. Nerve transfers for pain provide an unusual and surgically accessible insight to pain pathways while at the same time shedding new light on what we know about how nerve coaptations affect regeneration. It is my goal that these efforts expand the tools available to mitigate pain related to any nerve injury from amputation to diabetic neuropathy.