Genomics

Dataset Information

51

Treatment of Venous Leg Ulcers with a Bioengineered Living Cell Construct Reactivates the Acute Wound Healing Response


ABSTRACT: Chronic non-healing venous leg ulcers (VLUs) are a widespread debilitating disease with high morbidity and associated costs, as approximately $15 billion annually are spent on the care of VLUs. Despite their socioeconomic burden, there is a paucity of novel treatments targeted towards healing VLUs, which can be attributed to both lack of pathophysiologic insight into VLU development as well as lack of knowledge regarding biologic actions of VLU-targeted therapies. Currently, the bioengineered bilayered living cellular construct (BLCC) skin substitute is the only FDA-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 non-healing VLUs were treated with either standard care (compression therapy) or with BLCC together with standard care. Tissue was collected from the VLU edge before and 1 week after treatment, and samples underwent comprehensive microarray, mRNA and protein analyses. Ulcers treated with BLCC skin substitute displayed three distinct patterns suggesting the mechanisms by which BLCC shifted a non-healing into a healing tissue response: it modulated inflammatory and growth factor signaling; it activated keratinocytes; and it attenuated Wnt/β-catenin signaling. In these ways, BLCC application orchestrated a shift of the chronic non-healing ulcer microenvironment into a distinctive healing milieu resembling that of an acute, healing wound. Our findings also provide first patient-derived in vivo evidence of specific biologic processes that can be targeted in the design of therapies to promote healing of chronic VLUs. Overall design: Study participants (ClinicalTrial.gov No. NCT01327937 (9)) were recruited from patients presenting to the wound clinic at the University of Miami with VLUs. All subjects, from Screening (Day -28) through Day 0 visit, received the standard-of-care including a dressing regimen of a foam dressing and a 4 layered compression bandage system. Participants with non-infected target ulcers of >5cm2 that had not reduced in area by >40% during the 4-week screening period were randomized to either the control group receiving standard-of-care compression therapy (foam dressing plus four layered compression bandage system, changed weekly by the Investigator), or to the treatment group receiving weekly BLCC applications (Apligraf®, Organogenesis, Inc.) along with standard-of-care compression therapy. Prior to all applications, the BLCC was fenestrated in a standardized manner using a #11 blade with 6 fenestrations per 44 cm2. Skin biopsy specimens were obtained from the non-healing edges of VLU’s at the time of randomization (week 0) as well as one week later (week 1). Specimens were clinically designated by a physician as the most proximal skin edge to the ulcer bed. All patients were debrided and local lidocaine injection was used for anesthesia. After Week 5, all patients were monitored in the wound clinic for 12 weeks or until wound closure was achieved.

INSTRUMENT(S): [HG-U133_Plus_2] Affymetrix Human Genome U133 Plus 2.0 Array

SUBMITTER: Horacio Adrian Ramirez  

PROVIDER: GSE84571 | GEO | 2016-09-01

SECONDARY ACCESSION(S): PRJNA329653

REPOSITORIES: GEO

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Publications

A bioengineered living cell construct activates an acute wound healing response in venous leg ulcers.

Stone Rivka C RC   Stojadinovic Olivera O   Rosa Ashley M AM   Ramirez Horacio A HA   Badiavas Evangelos E   Blumenberg Miroslav M   Tomic-Canic Marjana M  

Science translational medicine 20170101 371


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  ...[more]

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