Abstract
Introduction: Chronic inflammation and impaired neovascularization play critical roles in delayed wound healing in diabetic patients. To overcome the limitations of current diabetic wound (DBW) management interventions, we investigated the effects of a catechol-functionalized hyaluronic acid (HA-CA) patch combined with adipose-derived mesenchymal stem cells (ADSCs) in DBW mouse models. Methods: Diabetes in mice (C57BL/6, male) was induced by streptozotocin (50 mg/kg, >250 mg/dL). Mice were divided into four groups: control (DBW) group, ADSCs group, HA-CA group, and HA-CA + ADSCs group (n = 10 per group). Fluorescently labeled ADSCs (5 × 105 cells/100 µL) were transplanted into healthy tissues at the wound boundary or deposited at the HA-CA patch at the wound site. The wound area was visually examined. Collagen content, granulation tissue thickness and vascularity, cell apoptosis, and re-epithelialization were assessed. Angiogenesis was evaluated by immunohistochemistry, quantitative real-time polymerase chain reaction, and Western blot. Results: DBW size was significantly smaller in the HA-CA + ADSCs group (8% ± 2%) compared with the control (16% ± 5%, p < 0.01) and ADSCs (24% ± 17%, p < 0.05) groups. In mice treated with HA-CA + ADSCs, the epidermis was regenerated, and skin thickness was restored. CD31 and von Willebrand factor-positive vessels were detected in mice treated with HA-CA + ADSCs. The mRNA and protein levels of VEGF, IGF-1, FGF-2, ANG-1, PIK, and AKT in the HA-CA + ADSCs group were the highest among all groups, although the Spred1 and ERK expression levels remained unchanged. Conclusions: The combination of HA-CA and ADSCs provided synergistic wound healing effects by maximizing paracrine signaling and angiogenesis via the PI3K/AKT pathway. Therefore, ADSC-loaded HA-CA might represent a novel strategy for the treatment of DBW.
Highlights
Chronic inflammation and impaired neovascularization play critical roles in delayed wound healing in diabetic patients
The wound closure rate on day 3 was significantly higher in the treatment groups
The therapeutic effects of stem cells in diabetic wound (DBW) have been reported previously [29], our findings suggest that adipose-derived mesenchymal stem cells (ADSCs) promote wound healing and neovascularization, and that their effects are augmented when combined with hyaluronic acid (HA-CA)
Summary
Chronic inflammation and impaired neovascularization play critical roles in delayed wound healing in diabetic patients. Diabetic wound (DBW) is a broad term describing various pathological conditions that manifest as wounds or ulcers associated with diabetes. Diabetic foot ulcers and other DBWs are common complications in diabetes, occurring in approximately 20% of diabetic patients [1]. DBWs have been associated with hyperglycemia, which often results in diabetic peripheral neuropathy and blockage of peripheral blood vessels, leading to diabetic foot ulcers [2]. In addition to diabetic peripheral neuropathy and peripheral vascular disease, several other risk factors of DBW have been identified, including limited joint mobility and foot deformities [2,3]. Inflammation plays a crucial role in wound healing; in DBW, inflammatory responses are delayed, and the wound does not heal. Numerous recent studies have indicated that modulating extracellular matrix (ECM) synthesis, growth factor release, and vascularization-targeting approaches might be useful in the treatment of DBW
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