Guiding the Way: The Use of a Bioengineered Conduit to Improve Nerve Coaptation Outcomes in Targeted Muscle Reinnervation
Erica B Lee, MS1, Alison L Wong, MD, MSE, FRCSC1, Sai Pinni, BS1, Nicholas von Guionneau, MD2, Thomas G.W. Harris, MBChB2, Ruchita Kothari, BS1, Michael Lan, BME3, Bruce Enzmann, BS4, Chenhu Qiu, MS3, Anson Zhou, BS3, Jaimie T Shores, M.D.5, Alban Latremoliere, PhD1, Lintao Qu, PhD1, Ahmet Hoke, MD PhD1, Hai-Quan Mao, PhD3 and Sami Tuffaha, MD6, (1)Johns Hopkins University School of Medicine, Baltimore, MD, (2)Johns Hopkins School of Medicine, Baltimore, MD, (3)Johns Hopkins University, Baltimore, MD, (4)Johns Hopkins Univeristy, Baltimore, MD, (5)Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, (6)Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
Background: Targeted muscle reinnervation (TMR) has emerged as a promising approach for the treatment of neuromas. However, the significant size-mismatch that tends to occur with TMR results in substantial axonal escape from the coaptation site that may compromise outcomes. To address this concern, we developed a funnel-shaped conduit to mechanically guide the regenerating axons across the size-mismatched coaptation and thereby prevent axonal escape. Given the limited capacity of the distal nerve stump to accept axons regenerating from the larger proximal nerve, we incorporated chondroitin sulfate proteoglycans (CSPGs) within the lumen of the conduits to inhibit a portion of the regenerating axons. We applied the funnel conduit with and without CSPGs in a TMR rodent model to assess the impact on functional recovery and neuroma formation.
Methods: A conduit device composed of nonwoven poly-?-caprolactone (PCL), was developed by electrospinning. 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 axonal growth, muscle reinnervation, and neuroma formation.
Results: The significant size mismatch at the coaptation site between the sciatic nerve and tibial branch to the lateral gastrocnemius muscle resulted in neuroma formation in the TMR group, 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. Neuroma and TMR groups demonstrated more co-labelling of Substance P (pain marker) and SCG10 (regeneration marker) than conduit groups. No significant differences were observed between the Sham and CSPG-Conduit groups in gastrocnemius muscle mass, myofibril cross-sectional area, and neuromuscular junction reinnervation. However, the Sham 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. Autotomy scores of CSPG incorporated conduit scores were similar to Sham scores, suggesting successful prevention of neuroma formation.
Conclusions: We introduce a novel bioengineered device in which mechanical guidance of axons is combined with inhibition of axonal regeneration to prevent neuroma formation. This conduit presents a biologically compatible, non-invasive means by which we could optimize postoperative outcomes in targeted muscle reinnervation. Behavioral assays and changes in dorsal root ganglion electrophysiology and protein expression are being evaluated in ongoing studies.
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