Acellular dermal matrix scaffolds coated with connective tissue growth factor accelerate diabetic wound healing by increasing fibronectin through PKC signalling pathway

Abstract

The regional injection of connective tissue growth factor (CTGF) for diabetic wound healing requires multiple components and results in a substantial loss of its biological activity. Acellular dermal matrix (ADM) scaffolds are optimal candidates for delivering these factors to local ischaemic environments. In this study, we explored whether CTGF loaded on ADM scaffolds can enhance fibronectin (FN) expression to accelerate diabetic wound healing via the protein kinase C (PKC) signalling pathway. The performance of CTGF and CTGF + PKC inhibitor, which were loaded on ADM scaffolds to treat dorsal skin wounds in streptozotocin-induced diabetic mice, was evaluated with naked ADM as a control. Wound closure showed that ADM scaffolds loaded with CTGF induced greater diabetic wound healing in the early stage of the wound in diabetic mice. Moreover, ADM scaffolds loaded with CTGF obviously increased the expression of FN both at the mRNA and protein levels, whereas the expression of FN was significantly reduced in the inhibitor group. Furthermore, the ADM + CTGF group, which produce FN, obviously promoted alpha-smooth muscle actin and transforming growth factor-beta expression and enhanced neovasculature and collagen synthesis at the wound sites. ADM scaffolds loaded with CTGF + PKC inhibitor delayed diabetic wound healing, indicating that FN expression was mediated by the PKC signalling pathway. Our findings offer new perspectives for the treatment of diabetic wound healing and suggest a rationale for the clinical evaluation of CTGF use in diabetic wound healing.

Supercritical Carbon Dioxide-decellularized Porcine Acellular Dermal Matrix combined with Autologous Adipose-derived Stem Cells: Its Role in Accelerated Diabetic Wound Healing

“…To overcome these limitations, tissue engineering studies have suggested the use of ADM as a scaffold for the delivery of ASCs into the wound healing microenvironment [21]. The 3D structure of ECM in ADM scaffolds provides tensile attachment niches for specific cells, cell surface receptors, or signaling factors that modulate the wound healing process [7,24]. ADM scaffolds were found to be biocompatible, as assessed by NIH3T3 cells stained with DAPI [54].…”

“…Diabetic wounds are chronic wounds [4]; the normal wound healing process controlled by appropriate inflammation, cell proliferation and migration, and epidermal regeneration is impaired in DM patients [5]. Diabetic wound healing is mainly delayed by prolonged inflammation [6], and the most severe consequence of delayed healing is amputation due to local infection and acral necrosis [7]. The annual incidence of diabetic foot ulcers and amputation is estimated at 1%-4.1% and 0.21%-1.37%, respectively [8,9].…”

“…ADM is mainly composed of extracellular matrix (ECM), which comprises a wide range of biological factors that induce cell growth and regulate tissue responses, and the 3D microstructure of ECM in ADM serves as scaffolds for tissue engineering [21][22][23]. The 3D structure offers tensile attachment positions for specific cells, cell surface receptors, or signaling factors that modulate the wound healing process [7,24].…”

Decellularized Extracellular Matrix Materials for Cardiac Repair and Regeneration

“…GF addition to biomaterials can significantly improve regenerative outcomes in vivo . Functional improvement from GF loading is seen with dECM therapies for other tissues, such as for diabetic wound healing . GFs induce tissue remodeling, reduce inflammation, enhance angiogenesis in vivo, and modulate stem cell response based on different GF levels .…”

Dynamic multiphoton imaging of acellular dermal matrix scaffolds seeded with mesenchymal stem cells in diabetic wound healing

“…The strength of mouse ADM scaffolds was significantly lower than that of mouse normal skin . Therefore, wounds transplanted with ADM scaffolds were covered with continuous ECM, and the amino acids degraded from the ADM scaffolds were raw materials for new collagen synthesis, which contributed to diabetic wound healing with reduction in wound contraction . The ADM scaffolds are composed of collagen fibers with appropriate pore diameters (Figure C).…”