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Principal Investigator: Mark H Schoenfisch
Organization: UNIV OF NORTH CAROLINA CHAPEL HILL
Fiscal Year: 2024
Award: $366,170
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
SUMMARY
The delayed healing observed in chronic wounds is exacerbated by persistent microbial infections and non-
resolving inflammation. Furthermore, the emergence of antibiotic-resistant bacteria has limited the use of these
agents for treating infected wounds. Adding to the complexity of chronic wound treatment, infection is usually
not the sole cause of wound chronicity. Underlying diseases such as diabetes leave individuals prone to infection
by affecting the host immune responses, including inflammatory cell migration, cell signaling, and effector
function. An ideal wound healing therapeutic must thus address the impairment of the host immune response while also
possessing antibacterial activity. Due to the high prevalence of chronic wound-related amputations and mortality, the need
for such a multi-action therapeutic is urgent. Nitric oxide (NO) is an endogenous signaling molecule that represents
an attractive, alternative therapeutic for treating chronic wounds due to its innate antibacterial and
immunomodulatory function in human physiology. We have pioneered the development of macromolecular
NO donor systems that store and spontaneously release NO in dissolved form (i.e., not as a gas) at
therapeutically relevant levels. We now aim to develop NO-releasing glycosaminoglycan biopolymers (GAGs)
as wound healing therapeutics. GAGs are naturally occurring biopolymers that are immunomodulatory and
known to be involved in wound healing physiology. We hypothesize that combining the multi-faceted roles of
GAGs and NO will allow for a therapeutic that effectively: 1) eradicates wound pathogens; 2) modulates
inflammation; and, 3) promotes re-epithelialization to facilitate timely wound closure.
The objective of this project is to define the roles of GAG molecular weight, sulfation patterns and NO-release
properties as they related to antibacterial and pro-wound healing activities. In developing a new class of wound-
healing therapeutics, we will characterize cell proliferation, adhesion, and migration as a function of NO
payloads and GAG structure using cell culture assays and a three-dimensional human skin tissue model. We
will evaluate the effect of NO-releasing GAGs on innate immune cell plasticity using primary human cell
systems. We will then determine the therapeutic efficacy of the most promising NO-releasing GAG derivatives
on antibacterial action, inflammation, and wound closure as a function of infection and diabetes. An iterative
approach will be taken to determine the optimal dose, time, and frequency of therapeutic intervention. A
systems biology approach will be used to elucidate mechanisms of efficacy and failure, which will inform clinical
translation of these therapeutic approaches. This new research program will allow us to build upon our previous
successes in developing NO-releasing macromolecular scaffolds, but now with a focus on wound healing. Our
goal is to develop a therapeutic that treats infection and promotes wound healing in populations afflicted by chronic wounds.
Terms: <2-dimensional><3-D><3-Dimensional><3D><Address><Adhesions><Adult-Onset Diabetes Mellitus><Affect><Amputation><Anti-Bacterial Agents><Antibiotic Agents><Antibiotic Drugs><Antibiotic Resistance><Antibiotics><Assay><Bacterial Antibiotic Resistance><Bioassay><Biological Assay><Biopolymers><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><Blood monocyte><Body Tissues><Cell Body><Cell Communication and Signaling><Cell Culture Techniques><Cell Growth in Number><Cell Locomotion><Cell Migration><Cell Movement><Cell Multiplication><Cell Proliferation><Cell Signaling><Cells><Cellular Immune Function><Cellular Migration><Cellular Motility><Cellular Proliferation><Complex><Dermal><Development><Diabetes Mellitus><Diabetic mouse><Diabetic wound><Disease><Disorder><Dose><Endogenous Nitrate Vasodilator><Endothelium-Derived Nitric Oxide><Failure><Frequencies><Future><Gases><Glycosaminoglycans><Goals><Hand><Healing abnormal><Healing delayed><High Prevalence><Human><Immune><Immune response><Immunes><Immunological response><Immunomodulation><Impaired healing><Impairment><In Vitro><Individual><Infection><Inflammation><Inflammatory><Intracellular Communication and Signaling><Ketosis-Resistant Diabetes Mellitus><Knowledge><Macrophage><Marrow Neutrophil><Marrow monocyte><Maturity-Onset Diabetes Mellitus><Mice><Mice Mammals><Miscellaneous Antibiotic><Modern Man><Molecular Weight><Monitor><Mononitrogen Monoxide><Morbidity><Morbidity - disease rate><Mucopolysaccharides><Murine><Mus><Mφ><NIDDM><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Nitric Oxide><Nitric Oxide Donors><Nitrogen Monoxide><Nitrogen Protoxide><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Patients><Pattern><Phenotype><Physiology><Play><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Population><Process><Production><Property><Punch Biopsy><Research><Resistance><Resistance to antibiotics><Resistant to antibiotics><Role><Series><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Molecule><Skin Tissue><Slow-Onset Diabetes Mellitus><Stable Diabetes Mellitus><Structure><Sulfate><System><Systems Biology><T2 DM><T2D><T2DM><Therapeutic><Therapeutic Intervention><Time><Tissue Model><Tissues><Toxic effect><Toxicities><Treatment Efficacy><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><Wound Infection><Wound Repair><Wound healing therapy><adult onset diabetes><anti-bacterial><antibiotic drug resistance><antibiotic resistant><antibiotic resistant bacteria><bacterial antibiotic resistant><bacterial resistance to antibiotic><biological signal transduction><cell culture><cell cultures><cell motility><chronic skin wound><chronic wound><clinical translation><clinically translatable><cutaneous tissue><determine efficacy><developmental><diabetes><diabetes mouse model><diabetes ulcer><diabetic skin wound><diabetic ulcer><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><endothelial cell derived relaxing factor><evaluate efficacy><examine efficacy><hands><host response><immune function><immune modulation><immune regulation><immune system response><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><in vivo><infected wound><injury response><intervention efficacy><intervention therapy><ketosis resistant diabetes><maturity onset diabetes><microbial><migration><monocyte><mortality><mouse model><murine model><neutrophil><pathogen><programs><re-epithelialization><resistance strain><resistant><resistant strain><response to injury><response to therapy><response to treatment><scaffold><scaffolding><social role><success><therapeutic efficacy><therapeutic response><therapeutically effective><therapy efficacy><therapy response><three dimensional><tissue reconstruction><tissue repair><tissue wound><translational therapeutics><translational therapy><treat wound><treatment response><treatment responsiveness><two-dimensional><type 2 DM><type II DM><type two diabetes><wound><wound closure><wound healing><wound healing therapeutics><wound management><wound recovery><wound resolution><wound therapeutics><wound therapy><wound treatment><wounding><wounds>