Sexually Dimorphic Pattern of Pain Mitigation Following Prophylactic Regenerative Peripheral Nerve Interface (RPNI) in a Rat Neuroma Model.

BACKGROUND: Treating neuroma pain is a clinical challenge. Identification of sex-specific nociceptive pathways allows a more individualized pain management. The Regenerative Peripheral Nerve Interface (RPNI) consists of a neurotized autologous free muscle using a severed peripheral nerve to provide physiological targets for the regenerating axons. OBJECTIVE: To evaluate prophylactic RPNI to prevent neuroma pain in male and female rats. METHODS: F344 rats of each sex were assigned to neuroma, prophylactic RPNI, or sham groups. Neuromas and RPNIs were created in both male and female rats. Weekly pain assessments including neuroma site pain and mechanical, cold, and thermal allodynia were performed for 8 weeks. Immunohistochemistry was used to evaluate macrophage infiltration and microglial expansion in the corresponding dorsal root ganglia and spinal cord segments. RESULTS: Prophylactic RPNI prevented neuroma pain in both sexes; however, female rats displayed delayed pain attenuation when compared with males. Cold allodynia and thermal allodynia were attenuated exclusively in males. Macrophage infiltration was mitigated in males, whereas females showed a reduced number of spinal cord microglia. CONCLUSION: Prophylactic RPNI can prevent neuroma site pain in both sexes. However, attenuation of both cold allodynia and thermal allodynia occurred in males exclusively, potentially because of their sexually dimorphic effect on pathological changes of the central nervous system.

Gender Affirming Mastectomy Improves Quality of Life in Transmasculine Patients: A Single-center Prospective Study.

OBJECTIVE: To determine the impact of gender-affirming mastectomy on depression, anxiety, and body image. BACKGROUND: There are many cross-sectional and ad-hoc studies demonstrating the benefits of gender-affirming surgery. There are few prospective investigations of patient-reported outcomes in gender-affirming surgery using validated instruments. METHODS: In this prospective study, patients presenting to the University of Michigan for gender-affirming Mastectomy were surveyed preoperatively and 6-months postoperatively. Primary outcomes were patient-reported measurements of anxiety measured by General Anxiety Disorder-7, depression measured by Patient Health Questionnaire-9, body image measured by BODY-Q and Body Image Quality of Life Index, psychosocial and sexual functioning measured by BREAST-Q, and satisfaction with decision measured by BREAST-Q. Linear regression analysis was used to control for presence of complication and existing history of mental health conditions. RESULTS: A total of 70 patients completed the study. The average age of participants was 26.7. The mean Patient Health Questionnaire-9 score pre-operatively was 7.8 and postoperatively was 5.4 ( P =0.001). The mean preoperative and postoperative General Anxiety Disorder-7 scores were 7.6 and 4.6, respectively ( P <0.001). There were significant improvements in both psychosocial (35 to 79.2, P <0.001) and sexual (33.9 to 67.2, P< 0.001) functioning related to chest appearance as measured by the BREAST-Q and global psychosocial functioning (-15.6 to +32, P <0.001) as measured by the Body Image Quality of Life Index. Satisfaction with chest contour (14.3 to 93.8, P <0.001) and nipple appearance (29.3 to 85.9, P <0.001) measured by the BODY-Q significantly improved. Patients had a mean satisfaction with outcome score of 93.1. CONCLUSIONS: Patients undergoing gender-affirming mastectomy in this single-center prospective study reported significant improvements in anxiety, depression, body image, psychosocial, and sexual functioning after this procedure. Patients were extremely satisfied with the decision to undergo this operation.

Pathophysiological and Neuroplastic Changes in Postamputation and Neuropathic Pain: Review of the Literature.

Despite advancements in surgical and rehabilitation strategies, extremity amputations are frequently associated with disability, phantom limb sensations, and chronic pain. Investigation into potential treatment modalities has focused on the pathophysiological changes in both the peripheral and central nervous systems to better understand the underlying mechanism in the development of chronic pain in persons with amputations. Methods: Presented in this article is a discussion outlining the physiological changes that occur in the peripheral and central nervous systems following amputation. In this review, the authors examine the molecular and neuroplastic changes occurring in the nervous system, as well as the state-of-the-art treatment to help reduce the development of postamputation pain. Results: This review summarizes the current literature regarding neurological changes following amputation. Development of both central sensitization and neuronal remodeling in the spinal cord and cerebral cortex allows for the development of neuropathic and phantom limb pain postamputation. Recently developed treatments targeting these pathophysiological changes have enabled a reduction in the severity of pain; however, complete resolution remains elusive. Conclusions: Changes in the peripheral and central nervous systems following amputation should not be viewed as separate pathologies, but rather two interdependent mechanisms that underlie the development of pathological pain. A better understanding of the physiological changes following amputation will allow for improvements in therapeutic treatments to minimize pathological pain caused by amputation.

The Muscle Cuff Regenerative Peripheral Nerve Interface for the Amplification of Intact Peripheral Nerve Signals.

Robotic exoskeletons have gained recent acclaim within the field of rehabilitative medicine as a promising modality for functional restoration for those individuals with extremity weakness. However, their use remains largely confined to research institutions, frequently operating as a means of static extremity support as motor detection methods remain unreliable. Peripheral nerve interfaces have arisen as a potential solution to this shortcoming; however, due to their inherently small amplitudes, these signals can be difficult to differentiate from background noise, lowering their overall motor detection accuracy. As current interfaces rely on abiotic materials, inherent material breakdown can occur alongside foreign body tissue reaction over time, further impacting their accuracy. The Muscle Cuff Regenerative Peripheral Nerve Interface (MC-RPNI) was designed to overcome these noted complications. Consisting of a segment of free muscle graft secured circumferentially to an intact peripheral nerve, the construct regenerates and becomes reinnervated by the contained nerve over time. In rats, this construct has demonstrated the ability to amplify a peripheral nerve's motor efferent action potentials up to 100 times the normal value through the generation of compound muscle action potentials (CMAPs). This signal amplification facilitates high accuracy detection of motor intent, potentially enabling reliable utilization of exoskeleton devices.

Physiologic signaling and viability of the muscle cuff regenerative peripheral nerve interface (MC-RPNI) for intact peripheral nerves.

Background. Robotic exoskeleton devices have become a promising modality for restoration of extremity function in individuals with limb loss or functional weakness. However, there exists no consistent or reliable way to record efferent motor action potentials from intact peripheral nerves to control device movement. Peripheral nerve motor action potentials are similar in amplitude to that of background noise, producing an unfavorable signal-to-noise ratio (SNR) that makes these signals difficult to detect and interpret. To address this issue, we have developed the muscle cuff regenerative peripheral nerve interface (MC-RPNI), a construct consisting of a free skeletal muscle graft wrapped circumferentially around an intact peripheral nerve. Over time, the muscle graft regenerates, and the intact nerve undergoes collateral axonal sprouting to reinnervate the muscle. The MC-RPNI amplifies efferent motor action potentials by several magnitudes, thereby increasing the SNR, allowing for higher fidelity signaling and detection of motor intention. The goal of this study was to characterize the signaling capabilities and viability of the MC-RPNI over time.Methods. Thirty-seven rats were randomly assigned to one of five experimental groups (Groups A-E). For MC-RPNI animals, their contralateral extensor digitorum longus (EDL) muscle was harvested and trimmed to either 8 mm (Group A) or 13 mm (Group B) in length, wrapped circumferentially around the intact ipsilateral common peroneal (CP) nerve, secured, and allowed to heal for 3 months. Additionally, one 8 mm (Group C) and one 13 mm (Group D) length group had an epineurial window created in the CP nerve immediately preceding MC-RPNI creation. Group E consisted of sham surgery animals. At 3 months, electrophysiologic analyses were conducted to determine the signaling capabilities of the MC-RPNI. Additionally, electromyography and isometric force analyses were performed on the CP-innervated EDL to determine the effects of the MC-RPNI on end organ function. Following evaluation, the CP nerve, MC-RPNI, and ipsilateral EDL muscle were harvested for histomorphometric analysis.Results. Study endpoint analysis was performed at 3 months post-surgery. All rats displayed visible muscle contractions in both the MC-RPNI and EDL following proximal CP nerve stimulation. Compound muscle action potentials were recorded from the MC-RPNI following proximal CP nerve stimulation and ranged from 3.67 ± 0.58 mV to 6.04 ± 1.01 mV, providing efferent motor action potential amplification of 10-20 times that of a normal physiologic nerve action potential. Maximum tetanic isometric force (Fo) testing of the distally-innervated EDL muscle in MC-RPNI groups producedFo(2341 ± 114 mN-2832 ± 102 mN) similar to controls (2497 ± 122 mN), thus demonstrating that creation of MC-RPNIs did not adversely impact the function of the distally-innervated EDL muscle. Overall, comparison between all MC-RPNI sub-groups did not reveal any statistically significant differences in signaling capabilities or negative effects on distal-innervated muscle function as compared to the control group.Conclusions. MC-RPNIs have the capability to provide efferent motor action potential amplification from intact nerves without adversely impacting distal muscle function. Neither the size of the muscle graft nor the presence of an epineurial window in the nerve had any significant impact on the ability of the MC-RPNI to amplify efferent motor action potentials from intact nerves. These results support the potential for the MC-RPNI to serve as a biologic nerve interface to control advanced exoskeleton devices.

Autologous fat grafting for nerve regeneration and neuropathic pain: current state from bench-to-bedside.

Despite recent advances in microsurgical techniques, functional recovery following peripheral nerve injury remains slow and inadequate. Poor peripheral nerve regeneration not only leaves patients with significant impairments, but also commonly leads to the development of debilitating neuropathic pain. Recent research has demonstrated the potential therapeutic benefits of adipose-derived stem cells, to enhance nerve regeneration. However, clinical translation remains limited due to the current regulatory burdens of the US FDA. A reliable and immediately translatable alternative is autologous fat grafting, where native adipose-derived stem cells present in the transferred tissue can potentially act upon regenerating axons. This review presents the scope of adipose tissue-based therapies to enhance outcomes following peripheral nerve injury, specifically focusing on their role in regeneration and ameliorating neuropathic pain.

Fabrication of the Composite Regenerative Peripheral Nerve Interface (C-RPNI) in the Adult Rat.

Recent advances in neuroprosthetics have enabled those living with extremity loss to reproduce many functions native to the absent extremity, and this is often accomplished through integration with the peripheral nervous system. Unfortunately, methods currently employed are often associated with significant tissue damage which prevents prolonged use. Additionally, these devices often lack any meaningful degree of sensory feedback as their complex construction dampens any vibrations or other sensations a user may have previously depended on when using more simple prosthetics. The composite regenerative peripheral nerve interface (C-RPNI) was developed as a stable, biologic construct with the ability to amplify efferent motor nerve signals while providing simultaneous afferent sensory feedback. The C-RPNI consists of a segment of free dermal and muscle graft secured around a target mixed sensorimotor nerve, with preferential motor nerve reinnervation of the muscle graft and sensory nerve reinnervation of the dermal graft. In rats, this construct has demonstrated the generation of compound muscle action potentials (CMAPs), amplifying the target nerve's signal from the micro- to milli-volt level, with signal to noise ratios averaging approximately 30-50. Stimulation of the dermal component of the construct generates compound sensory nerve action potentials (CSNAPs) at the proximal nerve. As such, this construct has promising future utility towards the realization of the ideal, intuitive prosthetic.

Design and manufacture of combinatorial calcium phosphate bone scaffolds.

It is well known that pore design is an important determinant of both the quantity and distribution of regenerated bone in artificial bone tissue scaffolds. A requisite feature is that scaffolds must contain pore interconnections on the order of 100-1000 µm (termed macroporosity). Within this range, there is not a definitive optimal interconnection size. Recent results suggest that pore interconnections permeating the scaffold build material on the order of 2-20 µm (termed microporosity) drive bone growth into the macropore space at a faster rate and also provide a new space for bone growth, proliferating throughout the interconnected microporous network. The effects of microstructural features on bone growth has yet to be fully understood. This work presents the manufacture and characterization of novel combinatorial test scaffolds, scaffolds that test multiple microporosity and macroporosity designs within a single scaffold. Scaffolds such as this can efficiently evaluate multiple mechanical designs, with the advantage of having the designs colocated within a single defect site and therefore less susceptible to experimental variation. This paper provides the manufacturing platform, manufacturing control method, and demonstrates the manufacturing capabilities with three representative scaffolds.