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Nerve Gap Repair with Human Epineural Sheath Conduit Supported with Human Mesenchymal Stem Cells – Preliminary Report
Grzegorz Kwiecien, MD1, Halil Safak Uygur, MD1, Adam Bobkiewicz, MD1, Maria Madajka, PhD1, Arnold Caplan, PhD2 and Maria Siemionow, MD, PhD, DSc1
1Department of Plastic Surgery, Cleveland Clinic, Cleveland, OH, 2Skeletal Research Center, Department of Biology, Case Western Reserve University, Cleveland, OH
Introduction: Peripheral nerve repair is often challenging and results in unsatisfactory outcomes. Based on our experience, rat epineural sheath conduit supported with rat bone marrow stromal cells demonstrates excellent neuroregenerative potential. Human mesenchymal stem cells (hMSC) modulate migration and replication of progenitor cells of the non-mesenchymal lineages including neurons, oligodendrocytes, and Schwann cells, with the capacity to improve neuronal regeneration. Thus, to bring this approach closer to clinical applications we have developed human epineural sheath (hES) conduit supported with hMSC as a new cellular therapy supporting nerve regeneration. Purpose: The aim of this study was to assess the outcome of peripheral nerve repair using hES conduit supported with hMSC in the nude rat model. Material and Methods: 20mm long sciatic nerve defect was created in 24 nude male rats. Animals were divided into four experimental groups (n=6 each): Group 1 - no repair; Group 2 - nerve autograft; Group 3 - hES filled with 0.1cc of normal saline; and Group 4 - hES supported with 3-4 x 10^6 hMSC suspended in 0.1cc of normal saline. hES conduit was created by fascicles removal using pull out technique. Bone marrow derived hMSC were cultured for 14 days and immunostained for cell surface antigens to ensure homogenicity prior to injection into the empty hES conduit. Outcome assessment included: sensory pinprick (PP) and motor toe-spread (TS) tests at 1, 3, 6, 12 weeks. Somatosensory evoked potentials (SSEP), gastrocnemius muscle index (GMI), histomorphometry, immunostaining for GFAP, NGF, S-100, HLA I / II, vWF and laminin B2 were performed 12 weeks after surgery. Results: Cultured hMSC expressed CD105, CD73 and CD90, and lacked expression of CD45, CD34, CD14, CD11b, CD79a, CD19 and HLA-DR surface molecules. No leakage of cells was observed at the time of injection during conduit implantation. hES conduit maintained its shape and integrity at 12 weeks following repair. No local inflammation or scarring was observed at the end of the follow up. Clinical evaluation and SSEP analysis confirmed sciatic nerve recovery in groups 3 and 4 with outcomes comparable to nerve autograft repair. Immunostaining showed presence of the hMSC in the conduit at 12 weeks post-transplantation. Quantitative nerve and muscle histological analysis is currently in progress. Conclusion: This study confirms feasibility of application of hES conduit in restoration of nerve defects yielding comparable functional outcome to the autograft technique. The role of local hMSC application in nerve regeneration is currently under investigation.
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