title: A novel model of chronic wounds: importance of redox imbalance and biofilm-forming bacteria for establishment of chronicity.
abstract: Chronic wounds have a large impact on health, affecting ∼6.5 M people and costing ∼$25B/year in the US alone. We previously discovered that a genetically modified mouse model displays impaired healing similar to problematic wounds in humans and that sometimes the wounds become chronic. Here we show how and why these impaired wounds become chronic, describe a way whereby we can drive impaired wounds to chronicity at will and propose that the same processes are involved in chronic wound development in humans. We hypothesize that exacerbated levels of oxidative stress are critical for initiation of chronicity. We show that, very early after injury, wounds with impaired healing contain elevated levels of reactive oxygen and nitrogen species and, much like in humans, these levels increase with age. Moreover, the activity of anti-oxidant enzymes is not elevated, leading to buildup of oxidative stress in the wound environment. To induce chronicity, we exacerbated the redox imbalance by further inhibiting the antioxidant enzymes and by infecting the wounds with biofilm-forming bacteria isolated from the chronic wounds that developed naturally in these mice. These wounds do not re-epithelialize, the granulation tissue lacks vascularization and interstitial collagen fibers, they contain an antibiotic-resistant mixed bioflora with biofilm-forming capacity, and they stay open for several weeks. These findings are highly significant because they show for the first time that chronic wounds can be generated in an animal model effectively and consistently. The availability of such a model will significantly propel the field forward because it can be used to develop strategies to regain redox balance that may result in inhibition of biofilm formation and result in restoration of healthy wound tissue. Furthermore, the model can lead to the understanding of other fundamental mechanisms of chronic wound development that can potentially lead to novel therapies.
authors.affiliation: Departments of Cell Biology and Neuroscience, University of California Riverside, Riverside, California, United States of America; Bioengineering Interdepartmental Graduate Program, University of California Riverside, Riverside, California, United States of America.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Dhall
authors.affiliation: Division of Biomedical Sciences, University of California Riverside, Riverside, California, United States of America.
authors.forename: Danh
authors.initials: D
authors.lastname: Do
authors.affiliation: Departments of Cell Biology and Neuroscience, University of California Riverside, Riverside, California, United States of America.
authors.forename: Monika
authors.initials: M
authors.lastname: Garcia
authors.affiliation: Hunter Holmes McGuire Veterans Administration Medical Center, Richmond, Virginia, United States of America; Department of Biochemistry & Molecular Biology, Virginia Commonwealth University, Richmond, Virginia, United States of America; Virginia Commonwealth University Reanimation Engineering Science Center, Richmond, Virginia, United States of America; The Massey Cancer Center, Richmond, Virginia, United States of America.
authors.forename: Dayanjan Shanaka
authors.initials: DS
authors.lastname: Wijesinghe
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Angela
authors.initials: A
authors.lastname: Brandon
authors.affiliation: Department of Botany and Plant Sciences, University of California Riverside, Riverside, California, United States of America.
authors.forename: Jane
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Product Technology, UVP, LLC, an Analytik Jena Company, Upland, California, United States of America.
authors.forename: Antonio
authors.initials: A
authors.lastname: Sanchez
authors.affiliation: Department of Bioengineering, University of California Riverside, Riverside, California, United States of America.
authors.forename: Julia
authors.initials: J
authors.lastname: Lyubovitsky
authors.affiliation: Department of Product Technology, UVP, LLC, an Analytik Jena Company, Upland, California, United States of America.
authors.forename: Sean
authors.initials: S
authors.lastname: Gallagher
authors.affiliation: Department of Botany and Plant Sciences, University of California Riverside, Riverside, California, United States of America.
authors.forename: Eugene A
authors.initials: EA
authors.lastname: Nothnagel
authors.affiliation: Hunter Holmes McGuire Veterans Administration Medical Center, Richmond, Virginia, United States of America; Department of Biochemistry & Molecular Biology, Virginia Commonwealth University, Richmond, Virginia, United States of America; Virginia Commonwealth University Reanimation Engineering Science Center, Richmond, Virginia, United States of America; The Massey Cancer Center, Richmond, Virginia, United States of America.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Chalfant
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Rakesh P
authors.initials: RP
authors.lastname: Patel
authors.affiliation: Division of Biomedical Sciences, University of California Riverside, Riverside, California, United States of America.
authors.forename: Neal
authors.initials: N
authors.lastname: Schiller
authors.affiliation: Departments of Cell Biology and Neuroscience, University of California Riverside, Riverside, California, United States of America; Bioengineering Interdepartmental Graduate Program, University of California Riverside, Riverside, California, United States of America.
authors.forename: Manuela
authors.initials: M
authors.lastname: Martins-Green
mesh_terms: D000818:Animals; D018441:Biofilms; D002908:Chronic Disease; D004195:Disease Models, Animal; D024881:Drug Resistance, Bacterial; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D013203:Staphylococcal Infections / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D013207:Staphylococcal Skin Infections / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D013290:Streptococcal Infections / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14 / Q000235:genetics; D014945:Wound Healing
chemical_list: D017382:Reactive Oxygen Species; C505915:Tnfsf14 protein, mouse; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14