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The Interplay Between Stiffness and Hyperglycemia on Diabetic Foot Ulcer Wound Closure
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Thesis/Dissertation
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2025-05
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Bioengineering
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https://doi.org/10.34944/rv0y-rs83
Abstract
Diabetes impairs fibroblast migration, hindering wound closure and contributing to diabetic foot ulcers. Although diabetic plantar skin exhibits greater stiffness, which should enhance fibroblast mechanotransduction, fibroblasts still fail to migrate effectively. This suggests that impaired wound closure is driven by another factor; hyperglycemia (≥ 11.1 mM glucose), which alters fibroblast mechanotransduction. Mechanotransduction regulates migration parameters such as velocity, directionality, and actin alignment, all of which influence wound healing. A potential mechanism is Rac1 activation at the leading edge of migrating cells, regulating lamellipodia formation and migration direction. We aim to simulate diabetic foot ulcers by developing a 2D circular in vitro wound closure model system to investigate the role of diabetic plantar stiffness and hyperglycemia on fibroblast mechanotransduction. To mimic skin stiffness, polydimethylsiloxane will be used as the cell culture substrate and fabricated at 57±5 kPa for normal plantar skin and 90±6 kPa for diabetic plantar skin. Cell culture media will have altered glycemic concentrations, 5.5 mM glucose represents normal blood glucose, while 11.1 mM represents hyperglycemia. In the model system, I hypothesize that the combination of stiffness and glucose concentration will reveal a new behavioral pattern by fibroblasts in wound healing, specific to DFU. Time-lapse microscopy results reveal a new restrictive effect of higher stiffness on migrating cells under normal glucose, in addition to a biphasic response to hyperglycemia. Cells on normal stiffness have a decreased velocity as predicted, whereas on higher stiffness, high glucose increased cell velocity, overcoming the stiffness's restrictive effect. The relationship between velocity and directionality was reversed at higher stiffness, yet wounds under normal glucose still closed faster than those under diabetic glucose. These findings suggest Rac1 as a key candidate for future investigation, as it directly contributes to migration directionality. Inhibiting Rac1 in the context of higher stiffness could enhance the directed migration of faster-moving fibroblasts in diabetic conditions, aligning their wound closure efficiency with that of normal glucose conditions on the same stiffness. This research establishes a wound closure model that demonstrates significantly slower healing in diabetic plantar skin stiffness and hyperglycemic glucose compared to normal conditions. It also reveals how migration dynamics vary significantly in response to stiffness, emphasizing the importance of considering substrate stiffness in mechanotransduction studies. The fibroblast migration behavior observed in this model suggests that hyperglycemia impairs wound closure in diabetic foot ulcers by disrupting directionality. These findings could inform therapeutic strategies to improve diabetic wound healing, with Rac1 as a promising target.
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