title: 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.
authors.affiliation: 3B's Research Group-Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark-Parque da Ciência e Tecnologia, Barco, Taipas, Guimarães, Portugal; ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Lucília Pereira
authors.initials: LP
authors.lastname: da Silva
authors.affiliation: 3B's Research Group-Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark-Parque da Ciência e Tecnologia, Barco, Taipas, Guimarães, Portugal; ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Tírcia Carlos
authors.initials: TC
authors.lastname: Santos
authors.affiliation: 3B's Research Group-Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark-Parque da Ciência e Tecnologia, Barco, Taipas, Guimarães, Portugal; ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Daniel Barreira
authors.initials: DB
authors.lastname: Rodrigues
authors.affiliation: 3B's Research Group-Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark-Parque da Ciência e Tecnologia, Barco, Taipas, Guimarães, Portugal; ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Rogério Pedro
authors.initials: RP
authors.lastname: Pirraco
authors.affiliation: 3B's Research Group-Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark-Parque da Ciência e Tecnologia, Barco, Taipas, Guimarães, Portugal; ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Mariana Teixeira
authors.initials: MT
authors.lastname: Cerqueira
authors.affiliation: 3B's Research Group-Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark-Parque da Ciência e Tecnologia, Barco, Taipas, Guimarães, Portugal; ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Rui Luís
authors.initials: RL
authors.lastname: Reis
authors.affiliation: 3B's Research Group-Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark-Parque da Ciência e Tecnologia, Barco, Taipas, Guimarães, Portugal; ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Vitor Manuel
authors.initials: VM
authors.lastname: Correlo
authors.affiliation: 3B's Research Group-Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark-Parque da Ciência e Tecnologia, Barco, Taipas, Guimarães, Portugal; ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal. Electronic address: apmarques@dep.uminho.pt.
authors.forename: Alexandra Pinto
authors.initials: AP
authors.lastname: Marques
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental; D017719:Diabetic Foot / Q000473:pathology / Q000628:therapy*; D006801:Humans; D006820:Hyaluronic Acid / Q000494:pharmacology*; D020100:Hydrogels / Q000494:pharmacology*; D015603:Keratinocytes / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D013234:Stem Cells; D016896:Treatment Outcome; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D020100:Hydrogels; D006820:Hyaluronic Acid