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Modification of the inflammatory microenvironment in Acellular Nerve Allografts (ANAs) using immunosuppressant FK506
Jesús A Acevedo-Cintron, BS1; Daniel A Hunter, RA2; Evan B Marsh, BS3; Mackinnon Susan, MD, FRCS(C), FACS4; Matthew D Wood, PhD5
1Washington University School of Medicine, St. Louis, MO; 2Department of Surgery, Division of Plastic and Reconstructive Surgery, Washington University School of Medicine, Saint Louis, MO; 3Washington University in Saint louis, Saint Louis, MO; 4Biomedical Engineering, Washington University in Saint Louis, Saint Louis, MO; 5Washington University School of Medicine, St Louis, MO

Introduction Due to disadvantages in nerve autografting, alternatives such as Acellular Nerve Allografts (ANAs), are desired. However, the regenerative potential of these alternatives is restricted by their length, with long ANAs (?4 cm) supporting limited axonal regeneration. Recently, we demonstrated changes in the morphology of blood vessels and increase in the expression of pro-inflammatory cytokines within long (4-cm) vs short (2-cm) ANAs. These findings suggested the development of an unresolved inflammatory environment within long ANAs by 4 weeks. We hypothesize reduction of this inflammatory environment will enable regeneration across long ANAs. Hence, the goal of this study was to observe the effect of immunosuppressant FK506 (tacrolimus) on inflammation and nerve regeneration across long ANAs.
Materials and Methods A rat sciatic nerve gap model was repaired using 4-cm ANAs, derived from cadaveric rats. Rats transplanted with ANAs were randomized to receive daily subcutaneous injections of either FK506 (2mg/kg) starting 3 days pre-surgery (pre-load group), FK506 starting at 4 weeks post-surgery (delayed group), or saline (control group). At 8 post-surgery, the ANAs were harvested and processed for morphometric histology to measure the cross-sectional areas of ANAs, the extent of axonal regeneration, and the density and morphology of blood vessels.
Results At 8-weeks post-surgery, the mid-distal region (~2-3 cm distal from the proximal suture line), of the ANAs from the FK506 pre-load group had a greater number of myelinated axons (7569) when compared to the mid-distal region of ANAs in the FK506 delayed group (1114) and the control group (729). The mid-distal graft regions for either FK506 group demonstrated greater cross-sectional area (4.30 mm2 and 2.81 mm2) when compared to ANAs in the control group (1.30 mm2). While there were no differences in the density of blood vessels, vessel morphology in the ANAs for FK506 groups resembled healthy nerve, while the vessels in the control group differed and suggested an inflammatory pathology.
Conclusions The observed changes in the number of myelinated axons, nerve area and blood vessel morphology suggest FK506 is modulating the microenvironment of long ANAs. Specifically, FK506 prevented the decrease in cross-sectional area and changes in blood vessel morphology observed in long ANAs. Moreover, early dosing of FK506 also increased the number of myelinated axons in long ANAs. Further experiments will focus on studying if FK506 affects the expression of inflammatory cytokines and promotes recovery


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