Impaired Biomechanical Properties of Diabetic Skin

Abstract

Diabetic skin is known to have deficient wound healing properties, but little is known of its intrinsic biomechanical properties. We hypothesize that diabetic skin possesses inferior biomechanical properties at baseline, rendering it more prone to injury. Skin from diabetic and nondiabetic mice and humans underwent biomechanical testing. Real-time PCR was performed for genes integral to collagen synthesis and degradation. MMP-2 and MMP-9, and TIMP-1 protein levels were assessed by ELISA and zymography. Collagen I and III content was assessed using Western blot analysis. At baseline, both murine and human diabetic skin was biomechanically inferior compared to nondiabetic skin, with decreased maximum stress and decreased modulus (P < 0.001 and < 0.05, respectively). Surprisingly, the expression of genes involved in collagen synthesis were significantly up-regulated, and genes involved in collagen degradation were significantly down-regulated in murine diabetic skin (P < 0.01). In addition, MMP-2 and MMP-9/TIMP-1 protein ratios were significantly lower in murine diabetic skin (P < 0.05). Collagen I levels and I:III ratios were lower in diabetic skin (P < 0.05). These findings suggest that the predisposition of diabetics to wounds may be the result of impaired tissue integrity at baseline, and are due, in part, to a defect in the regulation of collagen protein synthesis at the post-transcriptional level. Diabetes is associated with increased morbidity and mortality, 1 as well as impaired wound healing. 2 Diabetesrelated admissions accounted for 22% of all hospital inpatient days in 2007, and diabetic foot ulcers account for 20% of all hospital admissions in diabetic patients, which are the leading cause of lower extremity amputations. 2 Improvements made in diabetic wound management and prevention clearly have the potential to affect a large number of patients and decrease diabetic-related health care expenditures.More than 100 factors have been identified that contribute to the impairment in diabetic wound healing. 3 Decreased angiogenesis, 4 impaired growth factor production, 5 an altered inflammatory and immune response, 5 a decreased rate of wound contraction, 6 and an imbalance between the accumulation of extracellular components and their remodeling by matrix metalloproteinases (MMPs) 7,8 have all been demonstrated in diabetic wounds. MMP-2 and MMP-9 have been shown to be present in greater concentration in wounded diabetic animals than their nondiabetic littermates, which is similar to findings from patients with nonhealing ulcers. 9 Diabetes is characterized by significantly increased cross linking and nonenzymatic glycation of collagen, as well as elevated levels of advanced glycation end products (AGEs). 10,11 Blockade of the receptor for advanced glycation end products (RAGEs) can restore the wound healing properties of diabetic (Db/Db) mice. 12 Hyperglycemic animals have been shown to have significantly higher concentrations of glycated collagen and higher levels of collagenase activity. 9,13 Furthermore...

Histomorphological and biochemical properties of plantar soft tissue in diabetes

“…Waldecker and Lehr [18] examined biopsied metatarsal fat pad tissue but found no difference in adipocyte size between diabetic and non-diabetic tissue. Others have found that skin (on the dorsum of the foot and elsewhere) is thicker in people with diabetes [19, 20] and the expression of genes related to the remodeling of the extracellular matrix is impaired resulting in decreased mechanical properties [21]. Our previous stereological studies have supported the observation that diabetic tissue has thicker elastic septae measured at the heel and the first metatarsal [22].…”

Topical Collagen-Based Biomaterials for Chronic Wounds: Rationale and Clinical Application

“…4 The degraded matrix components contribute to a prolonged inflammatory response. 5 Diabetic fibroblasts are dysfunctional in many aspects with decreased migration and proliferation, decreased collagen production, elevated MMP-9 production, and reduced vascular endothelial growth factor production. 6,7 Chronic wound fibroblasts from venous ulcers also exhibit phenotypic differences from normal, with altered MMP and TIMP activity resulting in destruction of the ECM.…”

Diabetes Alters Mechanical Properties and Collagen Fiber Re-Alignment in Multiple Mouse Tendons

“…19, 28 We have recently reported that the skin from the db/db mouse, a model of type II Diabetes, and the skin from human diabetics exhibit decreased maximum stress and modulus compared to non-diabetic skin. 4 However, the mechanical function of the tendons in this diabetic mouse model has not yet been studied. While studies have revealed the presence of advanced glycation end-products in tendons of diabetic animal models, 28, 29, 33 it is also still unclear if there are changes in other extracellular matrix proteins that could cause changes in mechanical properties, such as proteoglycans or glycosaminoglycans (GAGs).…”