Now or Later?: Investigating the Effect of Surgical Intervention Timing on Symptomatic Neuroma Formation
Erica B Lee, MS1, Randal A Serafini, PhD2, Emma Rowley, BS1, Visakha Suresh, MD1, William M Padovano, MD MPHS1, Rachana Suresh, MBBS MPH1, Aidan Weitzner, BS1, Venetia Zachariou, PhD2 and Sami H Tuffaha, MD3, 1Johns Hopkins University School of Medicine, Baltimore, MD, 2Icahn School of Medicine at Mount Sinai, New York, NY, 3Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
Purpose: Neuroma formation following peripheral nerve injury often results in persistent, debilitating neuropathic pain that can become chronic and difficult to treat medically. Surgical approaches such as regenerative peripheral nerve interfaces (RPNIs) and vascularized denervated muscle targets (VDMTs) attempt to prevent and treat symptomatic neuromas. This study evaluated how prophylactic versus delayed intervention after the onset of chronic pain changes behavioral manifestations of pain in a rodent model.
Methods: Using a rodent VDMT hindlimb model, the timing of intervention was varied to model prophylactic intervention (P-VDMT) and delayed intervention following neuroma formation (S-VDMT). S-VDMTs were created by leaving the transected peroneal nerve in discontinuity for ten weeks before neuroma excision and VDMT formation with denervated lateral gastrocnemius muscle. Additional groups included Bury in Muscle (BIM) in which the transected peroneal nerve was buried into the lateral gastrocnemius muscle, Neuroma (peroneal nerve transection without repair), and Sham. Localized neuroma primary hypersensitivity was assessed on a weekly basis and secondary allodynia behaviors were evaluated at Week 18. Upon sacrifice at Week 20, bulk RNA-sequencing was performed on the L3-L5 DRGs with a differentially expressed gene (DEG) threshold cutoff of log2(Fold Change)>/=|0.32| and p-nominal<0.05.
Results: Upon primary mechanical allodynia behavioral assessment, P-VDMT animals demonstrated reduced allodynia compared to all other interventions prior to S-VDMT intervention (p<0.0001). After S-VDMT intervention at Week 10, S-VDMT animals demonstrated reduced primary allodynia compared to BIM (p<0.01); however, both S-VDMT and BIM scored significantly lower than Neuroma animals (p<0.001). P-VDMT continued to demonstrate reduced allodynia compared to other interventions through Week 19 (p<0.01). S-VDMT animals demonstrated significantly more severe secondary hindpaw mechanical allodynia compared to Neuroma (p<0.05) and Sham animals (p<0.0001). All groups displayed similar levels of thermal sensitivity. Upon RNA-sequencing analyses, P-VDMT animals were found to have activated pro-regenerative transcriptional signatures, while BIM activated and S-VDMT inhibited pro-inflammatory pathways. Relative to P-VDMT tissues, neuroma tissues appeared to have reduced muscle-associated signaling, ion homeostasis, and integrin-associated signaling.
Conclusions: Our findings suggest that prophylactic intervention provides the greatest prevention against symptomatic neuroma formation. Additionally, regardless of timing, denervated muscle targets provide greater benefit than implantation into innervated muscle. These findings are consistent with the clinical observation that intervention at the time of injury provides greater benefit than intervention after chronic pain has developed.
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