title: Chitosan-based dressings loaded with neurotensin--an efficient strategy to improve early diabetic wound healing.
abstract: One important complication of diabetes mellitus is chronic, non-healing diabetic foot ulcers (DFUs). This study aims to develop and use dressings based on chitosan derivatives for the sustained delivery of neurotensin (NT), a neuropeptide that acts as an inflammatory modulator in wound healing. Three different derivatives, namely N-carboxymethyl chitosan, 5-methyl pyrrolidinone chitosan (MPC) and N-succinyl chitosan, are presented as potential biomaterials for wound healing applications. Our results show that MPC has the best fluid handling capacity and delivery profile, also being non-toxic to Raw 264.7 and HaCaT cells. NT-loaded and non-loaded MPC dressings were applied to control/diabetic wounds to evaluate their in vitro/in vivo performance. The results show that the former induced more rapid healing (50% wound area reduction) in the early phases of wound healing in diabetic mice. A NT-loaded MPC foam also reduced expression of the inflammatory cytokine TNF-α (P<0.001) and decreased the amount of inflammatory infiltrate on day 3. On day 10 MMP-9 was reduced in diabetic skin (P<0.001), significantly increasing fibroblast migration and collagen (COL1A1, COL1A2 and COL3A1) expression and deposition. These results suggest that MPC-based dressings may work as an effective support for sustained NT release to reduce DFUs.
authors.affiliation: Center of Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal; CIEPQPF, Chemical Engineering Department, FCTUC, University of Coimbra, Rua Sílvio Lima, Pólo II - Pinhal de Marrocos, 3030-790 Coimbra, Portugal.
authors.forename: Liane I F
authors.initials: LI
authors.lastname: Moura
authors.affiliation: CIEPQPF, Chemical Engineering Department, FCTUC, University of Coimbra, Rua Sílvio Lima, Pólo II - Pinhal de Marrocos, 3030-790 Coimbra, Portugal.
authors.forename: Ana M A
authors.initials: AM
authors.lastname: Dias
authors.affiliation: Center of Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal.
authors.forename: Ermelindo C
authors.initials: EC
authors.lastname: Leal
authors.affiliation: Institute of Pathology, Faculty of Medicine, University of Coimbra, 3004-517 Coimbra, Portugal.
authors.forename: Lina
authors.initials: L
authors.lastname: Carvalho
authors.affiliation: CIEPQPF, Chemical Engineering Department, FCTUC, University of Coimbra, Rua Sílvio Lima, Pólo II - Pinhal de Marrocos, 3030-790 Coimbra, Portugal. Electronic address: hsousa@eq.uc.pt.
authors.forename: Hermínio C
authors.initials: HC
authors.lastname: de Sousa
authors.affiliation: Center of Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal; APDP, The Portuguese Diabetes Association, Rua do Salitre, no. 118-120, 1250-203 Lisboa, Portugal. Electronic address: ecarvalh@cnc.uc.pt.
authors.forename: Eugénia
authors.initials: E
authors.lastname: Carvalho
mesh_terms: D000818:Animals; D001458:Bandages; D001672:Biocompatible Materials / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D048271:Chitosan / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry*; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D017719:Diabetic Foot / Q000473:pathology*; D020869:Gene Expression Profiling; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D006909:Hydroxyproline / Q000378:metabolism; D007249:Inflammation / Q000473:pathology; D007700:Kinetics; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D009496:Neurotensin / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000138:chemical synthesis / Q000737:chemistry; D012867:Skin / Q000187:drug effects / Q000473:pathology; D013227:Steam; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D001672:Biocompatible Materials; D016207:Cytokines; C118639:N-succinyl-chitosan; D011760:Pyrrolidinones; D013227:Steam; C514968:carboxymethyl-chitosan; C085060:methylpyrrolidinone chitosan; D009496:Neurotensin; D003094:Collagen; D048271:Chitosan; D020780:Matrix Metalloproteinase 9; D005978:Glutathione; D006909:Hydroxyproline
keywords: Chitosan derivatives; Diabetic foot ulcers; Neurotensin; Wound dressings; Wound healing