Therapeutic glucose responsive dual gene delivery system for diabetic wound healing

Diabetic wound is a severe and multifactorial pathology that results from hyperglycemia. Despite intensive treatment regimes, there has been limited success in promoting diabetic wound healing. Gene therapy demonstrates significant potential in treating a range of life-threatening diseases and conditions. Employing a glucose responsive gene delivery system as a method of treating diabetic wounds represents an innovative approach. The primary aim of this thesis was to design and fabricate a glucose responsive dual gene delivery system and subsequently evaluate its therapeutic potential in promoting diabetic wound healing in a genetically diabetic mice animal model. The fabricated system comprised two scaffolds: fibrin hollow microcapsules and glucose responsive fibrin hydrogel. The fibrin microcapsules were constructed through layer-by-layer assembly on a CaCO3 template, while the glucose responsive fibrin hydrogel was synthesised by adding glucose oxidase enzyme. Both scaffolds were loaded with two separate reporter genes and topically applied to the wounds of the genetically diabetic db/db mice. The group of animals receiving the glucose responsive treatment displayed increased expression of the reporter genes. Most importantly, the fabricated glucose responsive delivery system exhibited significant therapeutic potential, significantly improving diabetic wound healing after seven days post-surgery. Angiogenesis was enhanced, and inflammation was reduced in the glucose responsive treatment group. A total of 23 proteins were altered in the glucose responsive treatment group compared to the non-treated group. Actinin 2, desmin, and MYBPC1 were the most significantly up-regulated proteins in the glucose responsive treatment group. The increased expression of these proteins in the glucose responsive treatment group was validated through immunohistochemistry analysis. The dual gene delivery system that is responsive to glucose, integrated with fibrin, presents itself as a highly promising therapeutic approach for the purpose of normalising diabetic wound healing. The system's cargo may be complemented in order to achieve the desired outcome.

Publisher

University of Galway

Rights

Attribution-NonCommercial-NoDerivatives 4.0 International

cbn

Collections

University of Galway Theses (PhD Theses)