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Improving the outcome of acute wound injuries : dermal skin scaffold and allografts immunomodulation

University of British Columbia

Burn injuries and chronic wounds comprise approximately 67% of the advanced wound care sector, which accounts for almost $20 Billion of expenditure worldwide. Currently, extensive wound injuries are managed by either 1) Autologous grafting, or 2) Skin allografts mainly from cadavers as temporary coverage. Despite the general effectiveness of autologous grafting, there are practical limits of the available donor sites, as well as the need for these sites to undergo healing. The high degree of immunogenicity of skin precludes allograft usage as a permanent solution. We hypothesize that: 1) The expression of an immuno-modulatory enzyme, Indolamine 2-3 dioxygenase (IDO) by allogenic skin, can be employed to protect allografts from rejection. 2) A reconstitutable liquid scaffold can be used to improve the outcome of acute wounds and potentially acts as an adjunct therapy for optimizing skin autografting in extensive wounds. As the first objective of this research, we generated a reproducible rodent model of skin transplantation. Next, IDO-expressing and control fibroblast were injected into the dermis and hypodermis of the allografts. Using this model, rejection time was measured and compared. Other factors such as immune cell infiltration, IDO metabolite concentrations, migration of the injected cells to surrounding lymph nodes, and dendritic cells phenotype response were also compared. To evaluate the second hypothesis, we studied the in-vivo application of a novel GAG-collagen hydrogel and compared it with different control conditions including some available hydrogels. The novel grafting protocol has demonstrated the highest success rate among all the evaluated protocols and permitted the accurate assessment of secondary interventions. The allotransplantation study demonstrated that grafts with IDO-fibroblasts stay viable for a significantly longer time compared to controls (p<0.01). Using the novel scaffold, we observed significant improvement in wound closure, decreased number of CD45+ inflammatory cells and earlier rise and peak of Procollagen+ cells in the wound bed. Overall, the data presented in this research suggests two different approaches for improving the outcome of acute wounds. Local immunosuppression shows the potential of utilizing immunomodulated allografts for extensive acute wounds while employing dermal scaffold increases the ability of native healing to address skin defects.

Text

2022-01-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/76969

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/