A novel primate model of delayed wound healing in diabetes: dysregulation of connective tissue growth factor

Abstract

Aims/hypothesis Chronic non-healing wounds are a common complication of diabetes. Prolonged inflammation and decreased matrix accumulation may contribute. Connective tissue growth factor (CTGF) is induced during normal wound healing, but its regulation in diabetic wounds is unknown. We developed a primate model for the study of in vivo wound healing in baboons with long diabetes duration. Methods Drum implants were placed subcutaneously into thighs of diabetic and non-diabetic control baboons. After 2 and 4 weeks the skin incision sites were removed for measurement of breaking strength and epithelial thickness.Drum implants were removed for analysis of granulation tissue and inflammatory cells, CTGF and tissue inhibitor of matrix metalloproteinase (TIMP-1). Degradation of added CTGF by wound fluid was also examined. Results Healed incision site skin was stiffer (less elastic) in diabetic baboons and epithelial remodelling was slower compared with controls. Granulation tissue from diabetic baboons was reduced at 2 and 4 weeks, with increased vessel lumen areas at 4 weeks. Macrophages were reduced while neutrophils persisted in diabetic tissue. In diabetic wound tissue at 4 weeks there was less CTGF induced, as shown by immunohistochemistry, compared with controls. In contrast, Electronic supplementary material The online version of this article

Foreign Body Response to Subcutaneous Implants in Diabetic Rats

“…This result is consistent with reduced amounts of collagen and impaired angiogenesis in cutaneous wound healing and soft-tissue around implanted devices in diabetes [10]–[11], [18]–[19]. However, Hb content and VEGF levels (angiogenic markers) in implants from diabetic rats were not altered in our experiments.…”

“…This apparent discrepancy between a decreased number of vessels in implants from diabetic animals and no change in hemoglobin content may be explained by the increased vasodilatation observed in the histological sections of implants from the same group. Vascular dysfunctions, such as increased permeability, vasodilatation, and structural changes, are well established abnormalities in the diabetic state in experimental animal and human microvasculature [10], [20]–[21]. Because we have shown an increased number of mast cells in implants from diabetic animals when compared with that from normoglycemic rats, it is possible that the histamine’s well-known vasodilator effect may have contributed to maintaining the Hb content in both implants, despite the smaller number of blood vessels in implants from diabetic rats.…”

“…This is despite the fact that complications associated with the diabetes often require implantable devices such as glucose sensors, orthopedic implants, catheter, vascular grafts, drug-eluting stents, artificial organs, biosensors, scaffolds for tissue engineering, heart valves, and others [9]. In one study involving diabetic baboons bearing polystyrene subcutaneous implants, the inflammatory cell response, granulation tissue, and connective tissue ingrowth were shown to be reduced [10]. Similarly, delayed in matrix maturation and angiogenesis and higher numbers of inflammatory cells in titanium fiber mesh were seen around percutaneous implants in diabetic rabbits [11].…”

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“…Similarly, CTGF induces myofibroblast differentiation [67][68][69]. It is also interesting to note that conditions promoting deficiency of CTGF, for example, diabetes mellitus, show a clear delay in wound closure [68].…”

Implant Healing in Experimental Animal Models of Diabetes

“…One study 31 investigated wound healing in a diabetic baboon model using a polystyrene implant. Drum devices were implanted subcutaneously in the thighs of long-term diabetic baboons.…”