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"INTRODUCTION: Diabetic foot ulcer is a common chronic inflammatory condition associated with individuals with type II diabetes. It is characterized by delayed or absence of wound healing eventually leading to gangrene formation necessitating limb amputation. Despite current management and treatment strategies, one in three wounds fails to heal. Hence, there is a pressing need to develop novel therapeutic strategies to accelerate healing of foot ulcers. As chronic inflammation is a hallmark of diabetic wounds, we hypothesized that immunomodulation of the wound microenvironment can accelerate healing.
METHODOLOGY: We developed a hydrogel-based drug delivery system to deliver an immunomodulator to the wounds in the form of a patch. Drug release kinetics of the developed system was tested in vitro for tuning material properties of the system to achieve a sustained release over a period of 72 hours. Efficacy of the developed system was tested in leptin receptor knockout mouse model which is an obese diabetic mouse model closely mimicking conditions of type 2 diabetes observed in humans. Wound healing was studied using a splinted surgically induced wound model and change in wound area was monitored for a period of 20 days. Simultaneously, this mouse model was also characterized for systemic changes in myeloid cell frequency and phenotype via immunophenotyping and quantified using flowcytometry. Immunophenotyping was performed post ex-vivo activation of circulating immune cells using antibodies against various activation markers. Littermate wildtypes served as controls.
RESULTS: The developed system showed a sustained release of drug over a period of 72 hours in vitro releasing 60% of the loaded drug. We next tested this system in a mouse model for diabetes, the leptin receptor knockout mouse. As circulating myeloid cells play a vital role in wound healing, we first characterized this mouse for systemic changes in frequency and phenotype of myeloid cells that can affect healing upon reaching wound site. We observed that frequency of myeloid cells, specifically neutrophils and monocytes, were higher in diabetic obese mouse compared to WT counterparts indicating presence of chronic systemic inflammation. We also observed that the neutrophils of the diabetic mouse showed deficits in upregulation of certain markers upon activation, indicating compromised function. Hence, we tested if immunomodulation via local delivery of an immunomodulator would accelerate healing of surgically induced wounds on diabetic mouse. Interestingly, a low dose of immunomodulator accelerated healing compared to high dose or no drug.
CONCLUSION: Together, these data suggest that diabetic show systemic changes in myeloid cell frequency and phenotype which can have compromised function upon reaching wound site. Thus, local immunomodulation using the developed bandage can serve as a promising strategy to accelerate diabetic wound healing. Upon further understanding of mechanism of drug action, which is currently under investigation, we believe that this system has a strong potential for clinical translation."
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