title: The regenerative potential of fibroblasts in a new diabetes-induced delayed humanised wound healing model.
abstract: Cutaneous diabetic wounds greatly affect the quality of life of patients, causing a substantial economic impact on the healthcare system. The limited clinical success of conventional treatments is mainly attributed to the lack of knowledge of the pathogenic mechanisms related to chronic ulceration. Therefore, management of diabetic ulcers remains a challenging clinical issue. Within this context, reliable animal models that recapitulate situations of impaired wound healing have become essential. In this study, we established a new in vivo humanised model of delayed wound healing in a diabetic context that reproduces the main features of the human disease. Diabetes was induced by multiple low doses of streptozotocin in bioengineered human-skin-engrafted immunodeficient mice. The significant delay in wound closure exhibited in diabetic wounds was mainly attributed to alterations in the granulation tissue formation and resolution, involving defects in wound bed maturation, vascularisation, inflammatory response and collagen deposition. In the new model, a cell-based wound therapy consisting of the application of plasma-derived fibrin dermal scaffolds containing fibroblasts consistently improved the healing response by triggering granulation tissue maturation and further providing a suitable matrix for migrating keratinocytes during wound re-epithelialisation. The present preclinical wound healing model was able to shed light on the biological processes responsible for the improvement achieved, and these findings can be extended for designing new therapeutic approaches with clinical relevance.
authors.affiliation: Department of Bioengineering, Carlos III University, Madrid, Spain.
authors.forename: Lucía
authors.initials: L
authors.lastname: Martínez-Santamaría
authors.forename: Claudio J
authors.initials: CJ
authors.lastname: Conti
authors.forename: Sara
authors.initials: S
authors.lastname: Llames
authors.forename: Eva
authors.initials: E
authors.lastname: García
authors.forename: Luisa
authors.initials: L
authors.lastname: Retamosa
authors.forename: Almudena
authors.initials: A
authors.lastname: Holguín
authors.forename: Nuria
authors.initials: N
authors.lastname: Illera
authors.forename: Blanca
authors.initials: B
authors.lastname: Duarte
authors.forename: Lino
authors.initials: L
authors.lastname: Camblor
authors.forename: José M
authors.initials: JM
authors.lastname: Llaneza
authors.forename: José L
authors.initials: JL
authors.lastname: Jorcano
authors.forename: Fernando
authors.initials: F
authors.lastname: Larcher
authors.forename: Álvaro
authors.initials: Á
authors.lastname: Meana
authors.forename: María J
authors.initials: MJ
authors.lastname: Escámez
authors.forename: Marcela
authors.initials: M
authors.lastname: Del Río
mesh_terms: D000818:Animals; D057005:Bioengineering / Q000379:methods; D064987:Cell- and Tissue-Based Therapy / Q000379:methods; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D012038:Regeneration / Q000502:physiology*; D012879:Skin Physiological Phenomena; D013311:Streptozocin / Q000009:adverse effects; D013997:Time Factors; D054457:Tissue Scaffolds; D014183:Transplantation, Heterologous; D014945:Wound Healing / Q000502:physiology*
chemical_list: D013311:Streptozocin