Guiding The Way: The Use Of A Bioengineered Conduit Reduces Neuroma Formation And Associated Pain Behaviors
Erica Lee, MS, Bruce Enzmann, BS, Thomas Harris, MD, Alison Wong, MD, Sai Pinni, BS, Nicholas von Guionneau, MD, Ruchita Kothari, BS, Michael Lan, BME, Chenhu Qiu, BME, Anson Zhou, BME, Jaimie Shores, MD, Alban Latremoliere, MD, Lintao Qu, MD PhD, Ahmet Hoke, MD PhD, Hai-Quan Mao, PhD, Sami Tuffaha, MD.
Johns Hopkins University School of Medicine, Baltimore, MD, USA.
PURPOSE: Targeted muscle reinnervation (TMR) outcomes may be limited by axonal escape and consequential neuroma formation at the often size-mismatched coaptation. To overcome this concern, we developed a funnel-shaped conduit to mechanically guide regenerating axons across the coaptation and thereby prevent axonal escape. Given the limited capacity of the distal nerve stump to accept the axons regenerating from the larger proximal nerve, we incorporated chondroitin sulfate proteoglycans (CSPGs) within the lumen of the conduits to inhibit a proportion of the regenerating axons. We applied the funnel conduit with and without CSPGs in a TMR model to assess the impact on neuroma formation at the repair site.
METHODS: A conduit device composed of nonwoven poly-ε-caprolactone (PCL), was developed by electrospinning. The conduit walls prevent intraneural macrophage infiltration and inflammation, which limits scarring and fibrosis at the coaptation site. Within the conduit, CSPGs incorporated into a nanofiber hydrogel form an interpenetrating network. Using a TMR rodent hindlimb model, we tested the effects of this device on neuroma formation, axonal growth, muscle reinnervation, and pain behaviors. Our groups included: sham surgery (Positive Control), sciatic nerve transection without repair (Neuroma), and three TMR groups in which the sciatic nerve was coapted to the lateral gastrocnemius nerve - either with no conduit (TMR), an Empty Conduit without CSPGs, or a CSPG-Conduit. Pain behaviors were observed on a weekly basis until sacrifice.
RESULTS: By week 23, behavioral responses to mechanical stimulation of the coaptation site were significantly lower in the CSPG-Conduit animals as compared to Empty Conduit (p<0.01), TMR (p<0.001), and Neuroma groups (p<0.0001), demonstrating successful prevention of neuroma formation at the coaptation site. This decline in pain responses in the CSPG-Conduit group is particularly seen after Week 12 when the majority of nerves have fully regenerated and the pain inherent to regeneration has diminished. At Week 23, Empty Conduit group pain scores were significantly lower than Neuroma scores (p<0.01), indicating benefit in using the conduit alone. Upon sacrifice, qualitative assessment of the coaptation site showed that the significant size mismatch between the sciatic nerve and the lateral gastrocnemius nerve resulted in neuroma formation in the TMR and Neuroma groups, while the use of the conduit resulted in tapered reinnervation of the sciatic nerve, demonstrating the effectiveness of this device in mechanically guiding axonal growth. No significant differences were observed between the Positive Control and CSPG-Conduit groups in gastrocnemius muscle mass, myofibril cross-sectional area, and neuromuscular junction reinnervation. However, the Positive Control group exhibited significantly greater gastrocnemius mass than the TMR and the Neuroma groups, suggesting better axonal guidance and muscle reinnervation was enabled by the conduit.
CONCLUSIONS: We introduce a novel engineered device in which mechanical guidance of axons is combined with inhibition of axonal regeneration to prevent neuroma formation. This conduit presents a biologically compatible means by which we could optimize postoperative care of extremity amputee patients.
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