Chronic superficial wounds are difficult to treat and often never completely heal. Diabetic foot complications account for the majority of lower limb amputations in the world, and 25% of all diabetic hospital admissions in the US. The standard of care for these wounds has been unchanged for decades, and remains reduced weight bearing, debridement, antibiotics, and dressings. Other therapies have been examined, including vacuum-assisted closure devices, biomaterial-based dressings, and growth factor therapies. Their impact has been marginal, with little clinical improvement over placebo controls, and often with increased risk of complications. Growth factor therapy, while promising, has not translated into dramatic clinical success with high doses of single exogenous factors. For example, Regranex topical gel (high dose recombinant platelet- derived growth factor), improves closure of diabetic ulcers but with an increased retrospective incidence of cancer. CytoSolv, Inc., has developed technology to simultaneously deliver multiple regenerative factors derived from cultured choroid plexus (CP) to accelerate wound healing at low therapeutic doses. These factors are present in the cerebrospinal fluid of normal adults, as the CP forms the blood- cerebrospinal fluid barrier and is involved in growth factor maintenance. Vascular endothelial growth factor, platelet derived growth factor, connective tissue growth factor, and transforming growth factor beta are among hundreds of potentially regenerative factors secreted by the CP. The synergy of the collective activities of CP factors allows CytoSolv's technology to potentially overcome the limitations and side effects of mono-factor therapy by delivering lower doses over reduced treatment duration. Pilot studies using lyophilized CP factors to treat wounds in normal rats revealed faster healing and vastly improved histological quality of healed tissue compared to topical antibiotic controls, including features such as hair follicles and other dermal appendages. These findings, coupled with the impressive portfolio of bioactive agents in the CP secretome, provide support for continued investigation. The potential clinical applications of an acellular CP product are numerous, but diabetic ulcers represent the greatest unmet need and our first target. The extent of ischemic disease in these individuals could be well served by the multiple biologic activities contained within the CP transcriptome. The proposal contained within this SBIR application seeks to (i) continue development of a topical product by incorporating factors secreted by the CP in culture supernatant into a non-occlusive dressing that provides at least 24 hours of continuous factor delivery, as determined in vitro;and (ii) assess the formulated product in open wounds created in the splinted db/db mouse model of Type I diabetes. These projects will provide fundamental data within a 6-month time frame that will allow the company to continue its goal developing a topical product to rebuild damage tissue in diabetic ulcers, and may also uncover additional information relevant to the pursuit of alternative disease indications.

Public Health Relevance

The naturally occurring cocktail of bioactive molecules secreted by the choroid plexus is being developed by CytoSolv, Inc., as a topical regenerative product for accelerating superficial wound healing. The factors, which include many that are currently used in high dose mono-therapies to treat various forms of problematic wounds, range in biological activity from inflammation, to angiogenesis, to tissue rebuilding, and have demonstrated the ability to accelerate and improve the quality of wound repair in pilot studies in normal animals. CytoSolv aims to further characterize, formulate, and assess this early stage product in db/db diabetic mice, representing a stringent wound model with inherent healing impairments that mimic the company's target indication, diabetic ulcers.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
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Special Emphasis Panel (ZRG1-SSMI-Q (10))
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Somers, Scott D
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Cytosolv, Inc.
United States
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