Mechano‐Activated Cell Therapy for Accelerated Diabetic Wound Healing

Abstract

Chronic diabetic wounds are a significant global healthcare challenge. Current strategies, such as biomaterials, cell therapies, and medical devices, however, only target a few pathological features and have limited efficacy. We developed a powerful platform technology combining magneto‐responsive hydrogel, cells, and wireless magneto‐induced dynamic mechanical stimulation (MDMS) to accelerate diabetic wound healing. Our hydrogel encapsulates FDA‐approved fibroblasts and keratinocytes to achieve ∼3‐fold better wound closure in a diabetic mouse model. MDMS acts as a non‐genetic mechano‐rheostat to activate fibroblasts, resulting in ∼240% better proliferation, ∼220% more collagen deposition and improved keratinocyte paracrine profiles via the Ras/MEK/ERK pathway to boost angiogenesis. The magneto‐responsive property also enables on‐demand insulin release for spatiotemporal glucose regulation through increasing network deformation and interstitial flow. By mining scRNAseq data, we identified a mechanosensitive fibroblast subpopulation that can be mechanically tuned for enhanced proliferation and collagen production, maximizing therapeutic impact. Our “all‐in‐one” system addresses major pathological factors associated with diabetic wounds in a single platform, with potential applications for other challenging wound types.This article is protected by copyright. All rights reserved

Stimulus-Responsive Bioactive Hydrogels in Diabetic Wound Healing

“…At present, there are three main physical factors: temperature, and exogenous stimuli (light, electric, ultrasonic and magnetic field). 47 4.3.1. Temperature-responsive Systems.…”

A Multifunctional Hydrogel Fabricated by Direct Self-Assembly of Natural Herbal Small Molecule Mangiferin for Treating Diabetic Wounds

“…24,25 Up to now, the definite mechanisms of poor diabetic wound healing are not yet well understood, but the unbalanced inflammatory response, oxidative stress effect, high blood glucose level, lack of angiogenesis and extremely high risk of bacterial infection are recognized as the primary reason for the lasting wounds. 26,27 Thus, antibiotics, growth factors, cells, and other biologically active substances are usually introduced into a hydrogel to realize precise and extended regulation of the wound microenvironment, which is anticipated to accelerate the healing of wounds. Indeed, the constructed compound hydrogels could meet the requirements of wound healing and n u m e r o u s i n n o v a t i v e s t u d i e s h a v e b e e n r eported.…”

“…Indeed, the constructed compound hydrogels could meet the requirements of wound healing and n u m e r o u s i n n o v a t i v e s t u d i e s h a v e b e e n r eported. 1,10,15,16,18,21,22,26,28,29 However, clinical researchers continually referred to the involvement of drug carriers significantly influencing the biocompatibility, biodegradability, and loading efficacy and having some potential side effects. Additionally, these compound hydrogels usually require complex synthesis and are relatively expensive, which significantly impede effective clinical application.…”

Microenvironment with NIR-Controlled ROS and Mechanical Tensions for Manipulating Cell Activities in Wound Healing

“…The activation of fibroblasts to myofibroblasts is a critical step during the wound healing process. Compared with fibroblasts, myofibroblasts are characterized by the expression of high levels of α-SMA that form contractile bundles and generate large cellular tractions to support wound closure. , It has been reported that the myofibroblast transition is promoted by soluble factors such as TGF-β and by mechanical forces as well. , Taking the NIR light and thermal responsive properties of PIC/CM@NPs hydrogel composites into consideration, we characterized the temperature and stiffness changes after NIR irradiation. CM@NPs slightly exhibit a photothermal effect that partially converts light into heat, leading to an approximate 4 °C increases from 37 to 41 °C under NIR for 150 s (Figure S7).…”

“…36,37 It has been reported that the myofibroblast transition is promoted by soluble factors such as TGF-β and by mechanical forces as well. 36,38 Taking the NIR light and thermal responsive properties of PIC/CM@NPs hydrogel composites into consideration, we characterized the temperature and stiffness changes after NIR irradiation. CM@NPs slightly exhibit a photothermal effect that partially converts light into heat, leading to an approximate 4 °C increases from 37 to 41 °C under NIR for 150 s (Figure S7).…”