Stem Cell-Containing Hyaluronic Acid-Based Spongy Hydrogels for Integrated Diabetic Wound Healing

Abstract

The detailed pathophysiology of diabetic foot ulcers is yet to be established and improved treatments are still required. We propose a strategy that directs inflammation, neovascularization, and neoinnervation of diabetic wounds. Aiming to potentiate a relevant secretome for nerve regeneration, stem cells were precultured in hyaluronic acid-based spongy hydrogels under neurogenic/standard media before transplantation into diabetic mice full-thickness wounds. Acellular spongy hydrogels and empty wounds were used as controls. Re-epithelialization was attained 4 weeks after transplantation independently of the test groups, whereas a thicker and more differentiated epidermis was observed for the cellular spongy hydrogels. A switch from the inflammatory to the proliferative phase of wound healing was revealed for all the experimental groups 2 weeks after injury, but a significantly higher M2(CD163)/M1(CD86) subtype ratio was observed in the neurogenic preconditioned group that also failed to promote neoinnervation. A higher number of intraepidermal nerve fibers were observed for the unconditioned group probably due to a more controlled transition from the inflammatory to the proliferative phase. Overall, stem cell-containing spongy hydrogels represent a promising approach to enhance diabetic wound healing by positively impacting re-epithelialization and by modulating the inflammatory response to promote a successful neoinnervation.

Prevascularization of dermal substitutes with adipose tissue-derived microvascular fragments enhances early skin grafting

“…In the last decade, skin tissue engineering has evolved dramatically with promising approaches to manage difficult wounds 16 . In fact, preconditioned hydrogels 17 – 19 , microporous gels 20 or engineered cell sheets 21 , 22 exhibit a tremendous wound healing potential in the preclinical setting. However, the majority of these techniques involves complex in vitro steps and, thus, is not suitable for intraoperative one-step procedures.…”

Combining Stem Cells and Biomaterial Scaffolds for Constructing Tissues and Cell Delivery

“…Other approaches have combined hyaluronan scaffolds with stem cells derived from keratinocytes and adipose for engineering skin and bone respectively [162,163]. Such engineered tissues can be used as novel ways to promote wound healing as well as for repairing damaged nerve tissues [164][165][166]. Encapsulating stem cells into hyaluronic acid microcarriers is another popular tissue engineering strategy due to its ability to provide a supportive environment for stem cell survival [167,168].…”

Stem cell therapy for diabetic foot ulcers: a review of preclinical and clinical research

“…Of the 89 selected articles, there were 54 preclinical studies (60.7%) [ 15 – 68 ] and 36 clinical studies (40.4%) [ 38 , 69 – 103 ]; one article reported data for both preclinical and clinical studies [ 38 ].…”

“…Topical administration was also frequently performed; topical delivery was used in 23 preclinical studies (43%) and five clinical studies (14%). Collagen hydrogels and scaffolds were the most commonly used vehicles to deliver cells [ 15 , 17 , 22 , 29 , 34 , 58 , 64 ]. Various other delivery methods were also used, including a silicon membrane with atelocollagen matrix to deliver murine ADSC [ 52 ], and artificial dermis containing human BM-MSC to treat two DFU patients [ 103 ].…”