Regenerating new tissue using cell transplantation has relied on successful cell engraftment in the host; however, cell engraftment into the diabetic skin wound is not as successful as in many other tissues. We used a biodegradable and biocompatible triblock co-polymer poly(ethylene glycol-b-[DL-lactic acid-co-glycolic acid]-b-ethylene glycol) (PEG-PLGA-PEG), which forms a thermosensitive hydrogel, as a wound dressing and scaffold. We found that the thermosensitive hydrogel increased the engraftment of muscle-derived stem cells (MDSCs) by 20- to 30-fold until day 20, when the wound was completely closed in a db/db genetically diabetic mouse model. At day 9, 30% of the transplanted MDSCs were found to remain, and 15% remained at day 20 after transplantation. The increased engraftment resulted in enhanced wound healing, as indicated by the wound closure rate, epithelium migration, and collagen deposition. Using MDSCs stably expressing beta-gal and immunofluorescence, we found that 25% of MDSCs differentiated into fibroblasts, 10% into myofibroblasts, and 10% into endothelial cells. We conclude that using the thermosensitive hydrogel as a scaffold increased the engraftment of MDSCs, which leads to improved diabetic wound healing, possibly by retaining the cells at the wound site for longer.
Electrical stimulation (ES) is a therapeutic treatment for wound healing. Electroporation, a type of ES, is a well-established method for gene delivery. We hypothesize that proper conditions can be found with which both electrical and gene therapies can be additively applied to treat diabetic wound healing. For the studies of transforming growth factor-beta1 (TGF-beta1) local expression and therapeutic effects, full thickness excisional wound model of db/db mice was used, we measured TGF-beta1 cytokine level at 24 h postwounding and examined wounds histologically. Furthermore, wound closure was evaluated by wound-area measurements at each day for 14 d. We found that syringe electrodes are more effective than the conventional caliper electrodes. Furthermore, diabetic skin was more sensitive to the electroporative damage than the normal skin. The optimal condition for diabetic skin was six pulses of 100 V per cm for 20 ms. Under such condition, the healing rate of electrically treated wound was significantly accelerated. Furthermore, when TGF-beta1 gene was delivered by electric pulses, the healing rate was further enhanced. Five to seven days postapplication of intradermal injection of plasmid TGF-beta1 followed by electroporation, the wound bed showed an increased reepithelialization rate, collagen synthesis, and angiogenesis. The data indicates that indeed the electric effect and gene effect work synergistic in the genetically diabetic model.
Thermosensitive hydrogel made of PEG-PLGA-PEG triblock copolymer provides excellent wound dressing activity and delivers plasmid TGF-beta1 to promote wound healing in a diabetic mouse model.
These results suggest hydrogel formed by PEG-PLGA-PEG could be a promising platform for delivery of pDNA, which represents a novel strategy that may serve as a non-viral vector for gene therapy in wound healing.
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