Syndesome Therapeutics for Enhancing Diabetic Wound Healing

Abstract

Chronic wounds represent a major healthcare and economic problem worldwide. Advanced wound dressings that incorporate bioactive compounds have great potential for improving outcomes in patients with chronic wounds but significant challenges in designing treatments that are effective in long-standing, non-healing wounds. Here, we developed an optimized wound healing gel that delivers syndecan-4 proteoliposomes (“syndesomes”) with FGF-2 to enhance diabetic wound healing. In vitro studies demonstrated that syndesomes markedly increased migration of keratinocytes and fibroblasts isolated from both non-diabetic and diabetic donors. In addition, syndesome treatment led to increased endocytic processing of FGF-2 that included enhanced recycling of FGF-2 to the cell surface after uptake. The optimized syndesome formulation was incorporated into an alginate wound dressing and tested in a splinted wound model in diabetic, ob/ob mice. We found that wounds treated with syndesomes and FGF-2 had markedly enhanced wound closure in comparison to wounds treated with only FGF-2. Moreover, we show that syndesomes have an immunomodulatory effect on wound macrophages, leading to a shift towards the M2 macrophage phenotype and alterations in the wound cytokine profile. Together, these studies showed that delivery of exogenous syndecan-4 is an effective method for enhancing wound healing in the long-term diabetic diseased state.

Biomaterials and Nanotherapeutics for Enhancing Skin Wound Healing

“…One method to overcome this resistance is to deliver co-receptors in a proteoliposome along with the growth factors. This was tested in a diabetic mouse model and showed improved diabetic wound healing (Das et al, 2016a,c) and enhanced ischemic revascularization (Jang et al, 2012; Das et al, 2014, 2016b; Monteforte et al, 2016)(Figure 5). There are various other lipid NPs, which have shown promise for treating peripheral vascular disease and critical limb ischemia, reviewed elsewhere (Tu et al, 2015).…”

“…(G) Immunofluorescent images of sections of the wound bed stained with alpha smooth muscle actin (green), PECAM (red), and DAPI (blue). (E–G) are reproduced with permission from Das et al (2016c). …”

Proteoglycans in Biomedicine: Resurgence of an Underexploited Class of ECM Molecules

“…Co-therapy of Syndecan with FGF-2 successfully en han ced the rape ut ic an gio gen esis a nd sustaine d revascularization in the ischemic hind limb of diabetic, obese mice in comparison to the use of FGF2 alone (Das et al, 2016b). They also went on to test the effects of these proteoliposomes on PDGF-BB activity (Das et al, 2016b). Wounds treated with both syndecan-4 proteoliposomes and PDGF-BB had increased reepithelization and angiogenesis in comparison to wounds treated with PDGF-BB alone.…”

“…Syndecan 4 encapsulated in proteoliposomes as a delivery system showed promise in the treatment of diabetic ischemia in mice (Das et al, 2016a). Co-therapy of Syndecan with FGF-2 successfully en han ced the rape ut ic an gio gen esis a nd sustaine d revascularization in the ischemic hind limb of diabetic, obese mice in comparison to the use of FGF2 alone (Das et al, 2016b). They also went on to test the effects of these proteoliposomes on PDGF-BB activity (Das et al, 2016b).…”

Scarring vs. functional healing: Matrix-based strategies to regulate tissue repair

“…Syndecans are transmembrane HS-proteoglycans that control cell migration and wound closure [40], and act as a regulator of heart fibrosis [41]. HA-binding proteoglycans bind growth factors and have been exploited as growth factor delivery vehicles for diabetic wound healing [42]. The HS-proteoglycan perlecan is part of the basement membrane and involved in epithelial cell plasticity and angiogenesis.…”