Autologous circulating angiogenic cells treated with osteopontin and delivered via a collagen scaffold enhance wound healing in the alloxan-induced diabetic rabbit ear ulcer model

Abstract

IntroductionDiabetic foot ulceration is the leading cause of amputation in people with diabetes mellitus. Peripheral vascular disease is present in the majority of patients with diabetic foot ulcers. Despite standard treatments there exists a high amputation rate. Circulating angiogenic cells previously known as early endothelial progenitor cells are derived from peripheral blood and support angiogenesis and vasculogenesis, providing a potential topical treatment for non-healing diabetic foot ulcers.MethodsA scaffold fabricated from Type 1 collagen facilitates topical cell delivery to a diabetic wound. Osteopontin is a matricellular protein involved in wound healing and increases the angiogenic potential of circulating angiogenic cells. A collagen scaffold seeded with circulating angiogenic cells was developed. Subsequently the effect of autologous circulating angiogenic cells that were seeded in a collagen scaffold and topically delivered to a hyperglycemic cutaneous wound was assessed. The alloxan-induced diabetic rabbit ear ulcer model was used to determine healing in response to the following treatments: collagen seeded with autologous circulating angiogenic cells exposed to osteopontin, collagen seeded with autologous circulating angiogenic cells, collagen alone and untreated wound. Stereology was used to assess angiogenesis in wounds.ResultsThe cells exposed to osteopontin and seeded on collagen increased percentage wound closure as compared to other groups. Increased angiogenesis was observed with the treatment of collagen and collagen seeded with circulating angiogenic cells.ConclusionsThese results demonstrate that topical treatment of full thickness cutaneous ulcers with autologous circulating angiogenic cells increases wound healing. Cells exposed to the matricellular protein osteopontin result in superior wound healing. The wound healing benefit is associated with a more efficient vascular network. This topical therapy provides a potential novel therapy for the treatment of non-healing diabetic foot ulcers in humans.

Circulating angiogenic cell function is inhibited by cortisol in vitro and associated with psychological stress and cortisol in vivo

“…Among healthy individuals without cardiovascular disease or diabetes, reduced CAC migration prospectively predicts greater carotid artery intima-media thickness (Keymel et al, 2008) and correlates with metabolic risk factors (Aschbacher et al, 2012a) and better endothelial function (Van Craenenbroeck et al, 2010). In animals, delivering CACs or CAC-conditioned media to sites of ischemic vascular injury can regenerate damaged tissue (Kalka et al, 2000; Di Santo et al, 2009; Ma et al, 2009; Toyama et al, 2012; O’Loughlin et al, 2013). Hence, CAC function is more than a “biomarker,” it is a mechanism of vascular repair.…”

Biomaterials for Promoting Wound Healing in Diabetes

“…O'Loughlin et al seeded autologous early endothelial progenitor cells onto collagen scaffolds. They observed that cells exposed to osteopontin accelerated the speed of wound closure along with increased angiogenesis [27]. It was noted that the wound Hydrogel-based biomaterials…”

“…Fibrin [19] Collagen-GAG [20] Gelatin microcryogels [23] GAG [28] BLCC [29] Freeze-drying sponges pGIcNAc [18] Collagen sponge [27] Electrospun patches Collagen/PLGA [21] Silk fibroin [24] Biomaterials with controlledrelease of signaling molecules Nanoparticles loaded with GF/chemokines VEGF, bFGF nanoparticles in PEtU-PDMS/ fibrin [33] Curcumin loaded chitosan nanoparticles into collagen-alginate [36] With vectors encoding functional molecules AdeNOS in fibrin scaffold [37] Hyaluronic acid-MMP hydrogels with VEGF plasmids [34] GF/Chemokines preloadedd within Hydrogels Glucophage-loaded collagen/PLGA [21] Gelatin-PGA-based scaffold payload MCP-1 [35] healing benefit was associated with a more efficient vascular network. Breitbart et al seeded mouse dermal fibroblasts onto polyglycolic acid scaffold matrices, on which the cells were retrovirally transduced with the human platelet-derived growth factor B (PDGF-B) gene [28].…”

Topical Application of Culture-Expanded CD34+ Umbilical Cord Blood Cells from Frozen Units Accelerates Healing of Diabetic Skin Wounds in Mice

“…Studies using a variety of different cells have demonstrated that the addition of exogenous healthy cells can override the diabetes phenotype and enhance the regeneration of skin wounds . For example, using rodent models of diabetic skin ulcers, it has been demonstrated that the therapeutic ability of blood cells, in part, is due to the CD34+ cell population .…”