title: A bioengineered living cell construct activates an acute wound healing response in venous leg ulcers.
abstract: Chronic nonhealing venous leg ulcers (VLUs) are widespread and debilitating, with high morbidity and associated costs; about $15 billion is spent annually on the care of VLUs in the United States. Despite this, there is a paucity of treatments for VLUs because of the lack of pathophysiologic insight into ulcer development as well as the lack of knowledge regarding biologic actions of existing VLU-targeted therapies. The bioengineered bilayered living cellular construct (BLCC) skin substitute is a U.S. Food and Drug Administration-approved biologic treatment for healing VLUs. To elucidate the mechanisms through which the BLCC promotes healing of chronic VLUs, we conducted a clinical trial (NCT01327937) in which patients with nonhealing VLUs were treated with either standard of care (compression therapy) or the BLCC together with standard of care. Tissue was collected from the VLU edge before and 1 week after treatment, and the samples underwent comprehensive microarray mRNA and protein analyses. Ulcers treated with the BLCC skin substitute displayed three distinct transcriptomic patterns, suggesting that BLCC induced a shift from a nonhealing to a healing tissue response, involving modulation of inflammatory and growth factor signaling, keratinocyte activation, and attenuation of Wnt/β-catenin signaling. In these ways, BLCC application orchestrated a shift from the chronic nonhealing ulcer microenvironment to a distinctive healing milieu resembling that of an acute, healing wound. Our findings provide in vivo evidence in VLU patients of pathways that can be targeted in the design of new therapies to promote healing of chronic VLUs.
authors.affiliation: Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA.|Research Residency Program, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Rivka C
authors.initials: RC
authors.lastname: Stone
authors.affiliation: Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Olivera
authors.initials: O
authors.lastname: Stojadinovic
authors.affiliation: Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Rosa
authors.affiliation: Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA.|Human Genetics and Genomics Graduate Program in Biomedical Sciences, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Horacio A
authors.initials: HA
authors.lastname: Ramirez
authors.affiliation: Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA.|Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Evangelos
authors.initials: E
authors.lastname: Badiavas
authors.affiliation: Ronald O. Perelman Department of Dermatology, New York University Langone Medical Center, New York, NY 10012, USA.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Blumenberg
authors.affiliation: Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA. mtcanic@med.miami.edu.|Human Genetics and Genomics Graduate Program in Biomedical Sciences, University of Miami Miller School of Medicine, Miami, FL 33136, USA.|John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors.forename: Marjana
authors.initials: M
authors.lastname: Tomic-Canic
mesh_terms: D000328:Adult; D000368:Aged; D001672:Biocompatible Materials; D001698:Biomedical Engineering / Q000379:methods*; D001706:Biopsy; D003094:Collagen / Q000627:therapeutic use; D018592:Cross-Over Studies; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007871:Leg Ulcer / Q000628:therapy*; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D012867:Skin / Q000378:metabolism; D017768:Skin, Artificial; D016896:Treatment Outcome; D014647:Varicose Ulcer / Q000628:therapy*; D014945:Wound Healing; D055815:Young Adult; D051176:beta Catenin / Q000378:metabolism
chemical_list: C117898:Apligraf; D001672:Biocompatible Materials; D051176:beta Catenin; D003094:Collagen