Gal-T Knockout Porcine Nerve Xenografts Support Axonal Regeneration in a Rodent Sciatic Nerve Model
Jane M Tsui, MD1, Marek A Hansdorfer, MD1, Samuel D Zarfos, BA1, Yingfang Fan, MD, PhD1, Ann S Kogosov, BS1, Philipp Tratnig-Frankl, MD1, Marco Visaggio, MD1, Robert W. Redmond, Ph.D.2, Mark A. Randolph, M.A.S.3 and Jonathan M. Winograd, M.D.4, (1)Massachusetts General Hospital, Boston, MA, (2)Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, (3)Plastic & Reconstructive Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, (4)Plastic and Reconstructive Surgery, Plastic & Reconstructive Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA
INTRODUCTION:
The current gold standard for reconstruction of large peripheral nerve gaps is use of autologous grafts. When donor nerve is unavailable, acellular nerve allografts (ANAs) are used. However, ANAs are costly, have limited availability, and lack living Schwann cells and endothelial cells to aid in axonal regeneration. A xenogeneic nerve graft substitute could provide living Schwann cells and intact intraneural vasculature could, therefore, provide a significant advantage over ANA. Alpha-1,3-galactosyltransferase knockout (GalTKO) transgenic pigs have undergone the deletion of the gene responsible for hyperacute rejection of non-primate xenografts in a primate host. GalTKO graft material have similar antigenicity to other primate xenografts and allografts and have the potential to create a limitless supply of tissue.
In this study, we examine GalTKO nerve xenografts in the reconstruction of peripheral nerve gap defects in a rodent sciatic nerve model. We evaluate both 1-week and 4-week cold preserved xenografts to determine differences in graft outcomes. Lastly, our lab developed a nerve repair technique, photochemical tissue bonding (PTB), where a light-activated amniotic membrane wrap is placed around the nerve repair and the nerve graft is photosealed in place. Our objective is to use cold-preserved porcine GalTKO xenografts, combined with PTB, to serve as an economical and readily available nerve autograft alternative.
MATERIALS & METHODS:
Upper extremity nerves from GalTKO pigs were preserved in University of Wisconsin solution at 4 degrees Celcius. Fifty male Lewis Rats underwent a 1-cm left sciatic nerve defect. Nerve repair was performed using five techniques: autograft/suture, 1-week cold-preserved xenograft/suture, 1-week cold-preserved xenograft/PTB, 4-week cold-preserved xenograft/suture, 4-week cold-preserved xenograft/PTB. Xenograft repairs were given FK506 for four months post-operatively. Functional outcomes were measured using monthly sciatic function index (SFI) and Von Frey assays. At four and seven months post-operatively, animals were euthanized and the sciatic nerves were harvested for histomorphometry and gastrocnemius muscle mass retention.
RESULTS
All groups showed evidence of recovery. There is no significant difference in recovery (SFI) between any of the groups at 2 months (p=0.73), 3 months (p=0.87), and 4 months (p=0.66). Further results for this study are pending.
CONCLUSIONS:
Cold-preserved porcine nerve xenografts may serve as an economical, abundant alternative for peripheral nerve gap injuries in cases where autologous nerve is scarce. Cold-preservation allows for maintenance of Schwann and endothelial cells that are vital to nerve regeneration and revascularization. Use of PTB for nerve repair helps decrease suture-related complications and may improve regeneration in GalTKO grafts.
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