Porous Hyaluronic Acid Hydrogels for Localized Nonviral DNA Delivery in a Diabetic Wound Healing Model

Abstract

The treatment of impaired wounds requires the use of biomaterials that can provide mechanical and biological queues to the surrounding environment to promote angiogenesis, granulation tissue formation, and wound closure. Porous hydrogels have previously been shown to promote angiogenesis even in the absence of pro-angiogenic factors. We hypothesized that the added delivery of non-viral DNA encoding for pro-angiogenic growth factors could further enhance this effect. Here, 100 and 60 μm porous and non-porous (n-pore) hyaluronic acid-MMP hydrogels with encapsulated reporter (pGFPluc) or pro-angiogenic (pVEGF) plasmids were used to investigate scaffold-mediated gene delivery for local gene therapy in a diabetic wound healing mouse model. Porous hydrogels allowed for significantly faster wound closure compared to n-pore hydrogels, which did not degrade and essentially provided a mechanical barrier to closure. Interestingly, the delivery of pDNA/PEI polyplexes positively promoted granulation tissue formation even when the DNA did not encode for an angiogenic protein. And although transfected cells were present throughout the granulation tissue surrounding all hydrogels at 2 weeks, pVEGF delivery did not further enhance the angiogenic response. Despite this, the presence of transfected cells shows promise for the use of polyplex-loaded porous hydrogels for local gene delivery in the treatment of diabetic wounds.

Biomaterials for Promoting Wound Healing in Diabetes

“…Fibrin [19] Collagen-GAG [20] Gelatin microcryogels [23] GAG [28] BLCC [29] Freeze-drying sponges pGIcNAc [18] Collagen sponge [27] Electrospun patches Collagen/PLGA [21] Silk fibroin [24] Biomaterials with controlledrelease of signaling molecules Nanoparticles loaded with GF/chemokines VEGF, bFGF nanoparticles in PEtU-PDMS/ fibrin [33] Curcumin loaded chitosan nanoparticles into collagen-alginate [36] With vectors encoding functional molecules AdeNOS in fibrin scaffold [37] Hyaluronic acid-MMP hydrogels with VEGF plasmids [34] GF/Chemokines preloadedd within Hydrogels Glucophage-loaded collagen/PLGA [21] Gelatin-PGA-based scaffold payload MCP-1 [35] healing benefit was associated with a more efficient vascular network. Breitbart et al seeded mouse dermal fibroblasts onto polyglycolic acid scaffold matrices, on which the cells were retrovirally transduced with the human platelet-derived growth factor B (PDGF-B) gene [28].…”

“…The release of the molecules was maintained by encapsulating nanoparticles, vectors (virus, plasmid, DNA, etc.) as well as preloading molecules within hydrogels during preparation [33][34][35].…”

“…The combined material enhanced eNOS expression, inflammatory response and lead to a faster rate of re-epithelialisation, resulting in augmented production of nitric oxide and thereby acceleration of wound healing. Tokatlian et al created porous hyaluronic acid-MMP hydrogels with VEGF plasmids for local gene therapy in a diabetic mouse wound [34]. Yin et al engineered a gelatin-polyglycolicacid (PGA)-based scaffold with a payload of monocyte chemoattractant protein-1 (MCP-1) by electrospinning technique.…”

The Effects to GM-CSF Expression and Fibroblast Proliferation of pGMCSF Containing Chitosan/PVP Hydrogels

“…Lei et al studied with the incorporation of active DNA/ PEI polyplexes into hydrogel scaffolds (14). Tokatlian et al encapsulated VEGF gene containing plasmid into porous hyaluronic acid hydrogels to investigate scaffold-mediated local gene delivery in diabetic wound model (15). …”

Biologically Triggered Delivery of EGF from Polymer Fiber Patches

“…15,16 More complex materials seek to control the delivery of therapeutic proteins based on the biological environment. Paramount among these materials are responsive hydrogels designed to specifically degrade in the presence of matrix metalloproteinases (MMPs), 17,18 proteases secreted by the cellular components during the wound healing cascade. 19,20 As the material degrades, the therapeutic proteins contained within the gel release at an accelerated rate to the environment.…”