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Application of the Epineural Sheath as a Stromal Cell Epineural Conduit and Protective Epineural Sheath Patch in Peripheral Nerve Regeneration
Can Ozturk, MD, Jacek Szopinski, MD, PhD, Maria Madajka, PhD, Amanda Mendiola, MD, Maria Siemionow, MD, PhD, DSC
Cleveland Clinic, Department of Plastic Surgery, Cleveland, OH, USA

PURPOSE: Autologous nerve grafts and synthetic conduits present with inherent co-morbidities and complications and are restricted to repair of short (3-5 cm) nerve gaps. In addition nerve regeneration in unfavorable wound conditions creates another challenge. To address these challenges we investigated application of the epineural sheath filled with bone marrow stromal cells (BMSC) as a new engineered conduit (SCEC) (Model I) and as a protective patch (ESP) after acute sciatic nerve injury (Model II).

METHODS:
Model I: Allogenic [ACI (RT1a) to LEW (RT1a)] SCEC were created ex-vivo by filling an empty epineural sheath (ES) with 3x106 allogenic fluorescently labeled BMSC. In Group 1 (n=6), SCECs were implanted into 2 cm sciatic nerve gaps of LEW recipient rats. Autografts (n=6) served as controls (Group 2).

Model II: In 80 rats 2mm crush injury (17,4Nt/mm) was applied for 5 minutes to the sciatic nerve. In Group 1 - control after crush - sciatic nerve was left without coverage, in (Group 2) was wrapped with fat, in Group 3 with isogenic ES or allogenic ES (Group 4). Unfavorable wound conditions were created by removal of the ES before crush. The nerve was left without coverage in Group 5 Control - or was wrapped with fat (Group 6), isogenic ES (Group 7) or allogenic ES (Group 8). In both models functional assessments included: SSEP, pin-prick (PP), and toe spread (TS). Gastrocnemius muscle index (GMI) assessed muscle atrophy, and histomorphometrical and immunostaining analysis was performed.

RESULTS:
Model I: Both groups revealed full sensory recovery at 12 weeks. No difference in TS score was recorded. Higher GMI was recorded in the autograft group (0.61) compared to the allogenic SCEC (0.19). SSEP demonstrated similar P1 (125.85% vs. 116.84%) and N2 (108.57% vs. 112.30%) latencies. Histomorphometric analysis revealed larger fiber diameters (3.92µ vs 3.75µ) and myelin thickness (1.15µ vs. 0.96µ) in SCEC compared to autograft whereas autograft revealed higher axon density (298.22 vs 122.28 axons/10000µm2). Immunofluorescent staining showed presence of H-filaments in all groups, without overlap with fluorescently labeled BMSC. Expression of both VEGF and NGF revealed co-staining with BMSC.

Model II: Functional evaluation showed improved motor recovery in unfavorable wound conditions after isogenic ESP application. Sensory recovery was improved in both normal and unfavorable wound conditions after isogenic and allogenic ESP applications at 6 weeks. At 6 and 12 weeks, GMI was similar in all groups, SSEP after ESP application revealed shorter P1 latency at 6 weeks when compared with Groups I and II. Under unfavorable wound conditions ESP applications showed shorter P1 latencies at 6 and 12 weeks. Isogenic ESP in groups 3-7 revealed highest amplitudes and better GMI outcomes at 12 weeks. Immunofluorescence staining showed that application of the epineural sheath reduced number of macrophages and enhanced VEGF expression compared to adipose tissue group.

CONCLUSION:
Application of ES in the form of engineered SCEC supported sciatic nerve regeneration with comparable outcomes to the autograft. Conduit support with BMSC served as a source for nerve growth factor release (NGF, VEGF) enhancing nerve regeneration. Application of ES in the form of patch served as a protective barrier and created an optimal microenvironment for nerve regeneration, acting as a proangiogenic scaffold expressing VEGF.


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