Skin grafts from genetically modified α-1,3-galactosyltransferase knockout miniature swine: A functional equivalent to allografts

Abstract

Burn is associated with a considerable burden of morbidity worldwide. Early excision of burned tissue and skin grafting of the resultant wound has been established as a mainstay of modern burn therapy. However, in large burns, donor sites for autologous skin may be limited. Numerous alternatives, from cadaver skin to synthetic substitutes have been described, each with varying benefits and limitations. We previously proposed the use of genetically modified (alpha-1,3-galactosyl transferase knockout, GalT-KO) porcine skin as a viable skin alternative. In contrast to wild type porcine skin, which has been used as a biologic dressing following glutaraldehyde fixation, GalT-KO porcine skin is a viable graft, which is not susceptible to loss by hyperacute rejection, and undergoes graft take and healing, prior to eventual rejection, comparable to cadaver allogeneic skin. In the current study we aimed to perform a detailed functional analysis of GalT-KO skin grafts in comparison to allogeneic grafts for temporary closure of full thickness wounds using our baboon dorsum wound model. Grafts were assessed by measurement of fluid loss, wound infection rate, and take, and healed appearance, of secondary autologous grafts following xenograft rejection. Comparison was also made between fresh and cryopreserved grafts. No statistically significant difference was identified between GalT-KO and allogeneic skin grafts in any of the assessed parameters, and graft take and function was not adversely effected by the freeze–thaw process. These data demonstrate that GalT-KO porcine grafts are functionally comparable to allogeneic skin grafts for temporary closure of full thickness wounds, and support their consideration as an alternative to cadaver allogeneic skin in the emergency management of large burns.

Skin xenotransplantation: Historical review and clinical potential

“…Albritton et al and Leto Barone et al confirmed these results by demonstrating comparable survival of MHC-mismatched allogeneic (baboon-to-baboon) skin grafts and xenogeneic (pig-to-baboon) skin grafts [9, 10]. Leonard et al have recently reported that cryopreserved GTKO pig skin grafts survive as long as fresh GTKO grafts (mean 11.8 vs 11.8 days) [84].…”

“…To the best of our knowledge, there are seven studies of genetically-modified pig skin xenotransplantation in NHPs reported in the literature. Five of these studies related to viable pig skin-to-NHPs xenotransplantation models relevant to the treatment of burns [45] [9] [44] [10] [84] (Table 4). Two of the seven studies related to induction of immunological tolerance, and were not relevant for the treatment of patients with burns [85, 86].…”

“…The demonstration that serial grafting of GTKO and allogeneic skin is possible (in either order) could potentially double the temporary skin graft coverage time in severely-burned patients, providing an extended period for healing of autologous graft donor sites or the in vitro culture of suitable autologous skin for permanent coverage [9, 10]. Moreover, definitive closure of a burn wound with an autologous graft is not adversely affected by rejection of a preceding GTKO pig xenograft or an allograft [84].…”

Advancements in Regenerative Strategies Through the Continuum of Burn Care

“…The next generation skin graft may currently be in development in the form of genetically modified porcine skin [α-1, 3-galactosyltransferase knockout (GalT-KO)] which could significantly ease the availability of clinically acceptable xenografts (Leto Barone et al, 2015 ). The GalT-KO xenografts are tolerated similarly to the fresh or cryopreserved allografts (Leonard et al, 2017 ). If proven safe to be applied clinically, the cost may be considerably reduced and immediate availability of off-the-shelf xenograft for burn victims can be expected.…”

Xenotransplantation: Progress Along Paths Uncertain from Models to Application

“…7,8 These experiences, however, did not deter use of xenogeneic skin as temporary covering for wounds in the past and proposals for such use today. 9,10 The experience in transplanting organs within and between species was quite different. Development of techniques to allow the surgical joining of the cut ends of blood vessels (the vascular anastomosis) sparked attempts to transplant intact organs.…”