SBIR-STTR Award

This Phase I SBIR, responding to RFA-AG-12-009 entitled "T1 Translational Research on Aging" from the NIA, explores novel cell-based therapeutic approaches to the treatment of pressure ulcers and full thickness skin wounds in the elderly. Although it is well established that the prevention of pressure ulcers requires labor- intensive nursing care, patients in assisted living centers and nursing homes remain at high risk for developing pressure ulcers. In fact, over 70% of pressure ulcers occur in Americans over the age of 70 and their hospital costs exceed $11 billion annually. Current treatment of pressure ulcers relies primarily on surgical debridement, hyperbaric oxygen, growth factors, and negative pressure devices. This "proof of principle" study will use a murine model to test LaCell's hypothesis that adipose-derived stromal/stem cell (ASC) therapy will accelerate and improve pressure ulcer healing in the elderly. Studies will be conducted in young (3-4 month) and old (24 month) C57Bl/6 male mice using leptin receptor deficient (db/db) obese diabetic mice (3-4 month) as positive controls. Bilateral full thickness skin wounds will be created dorsally on each mouse. These will be protected by a silicon splint in the shape of a donut to prevent spontaneous retraction of the wound edges. This will allow for accurate measurements of the wound epithelialization and healing rates. Adipose stromal/stem cells (ASC) will be isolated from C57Bl/6 mice transgenic for the green fluorescent protein (GFP). In each animal, GFP+ ASC will be injected into the wound bed of one full thickness defect while the corresponding wound, injected with phosphate buffered saline, will serve as a control. Groups of animals will be harvested after 1, 3, and 10 days post-operatively. Quantitative experimental outcomes will address the mechanisms underlying the ASC impact on repair that will include rates of epithelialization, wound closure, cytokine and matrix metalloproteinase expression, and immune cell infiltration. These outcomes will determine the feasibility and efficacy of ASC based therapies to accelerate the repair of pressure ulcers and full thickness skin wounds in the elderly. Phase I will lay the foundation for future pharmacokinetic and toxicological testing of both murine and human ASC in Phase II studies. Additionally, they will provide the basis for detailed pre-IND discussions with the Food and Drug Administration. LaCell LLC is a biotechnology company founded by leading investigators and inventors in the application of adipose stromal/stem cells to regenerative medicine. As consultants, LaCell has enlisted the assistance of experts in the field of plastic surgery and wound healing.

Public Health Relevance:
The elderly are at high risk for the development of pressure ulcers, a debilitating and life threatening condition that remains a major health care burden in the U.S. LaCell proposes to develop an adipose stromal/stem cell therapy for pressure ulcers. This approach has the potential to accelerate and improve the rate of wound closure and long-term recovery. The outcomes of this focused "proof of principle" pre-clinical study have relevance to a clinical issue of unique importance to geriatric medicine in the U.S. and abroad. With its background in adipose stromal/stem cell biotechnology, LaCell and its consultants are uniquely positioned to address this unmet medical need.

Public Health Relevance Statement:
The elderly are at high risk for the development of pressure ulcers, a debilitating and life threatening condition that remains a major health care burden in the U.S. LaCell proposes to develop an adipose stromal/stem cell therapy for pressure ulcers. This approach has the potential to accelerate and improve the rate of wound closure and long-term recovery. The outcomes of this focused "proof of principle" pre-clinical study have relevance to a clinical issue of unique importance to geriatric medicine in the U.S. and abroad. With its background in adipose stromal/stem cell biotechnology, LaCell and its consultants are uniquely positioned to address this unmet medical need.

NIH Spending Category:
Aging; Biotechnology; Diabetes; Regenerative Medicine; Stem Cell Research; Stem Cell Research - Nonembryonic - Non-Human; Transplantation

Project Terms:
Accounting; Address; Adipose tissue; Age; age related; Age-Years; Aging; American; Animals; Assisted Living Facilities; base; Beds; bench to bedside; Bilateral; Biochemical; Biomedical Research; Biotechnology; Budgets; Bulla; care burden; Care given by nurses; Cell Therapy; Cells; Clinic; Clinical; cohort; Collagen; commercialization; cytokine; db/db mouse; Debridement; Decubitus ulcer; Defect; demographics; Dependency (Psychology); Developed Countries; Development; Devices; Diabetes Mellitus; diabetic; Diabetic mouse; Dose; Drug Kinetics; Economic Burden; efficacy trial; Elderly; Erythema; experience; Foundations; Future; Geriatrics; Green Fluorescent Proteins; Growth Factor; Harvest; Healed; healing; Healthcare; high risk; Home environment; Hospital Costs; Hospitals; Human; Hyperbaric Oxygen; Immobilization; Immune; improved; In Vitro; in vivo; Incidence; Infiltration; Inflammatory; Intellectual Property; Legal patent; leptin receptor; Life; Literature; male; Matrix Metalloproteinases; Measurement; Medical; Modeling; Mus; novel; Nursing Homes; Obesity; Operative Surgical Procedures; Outcome; Patients; Peripheral Vascular Diseases; Pharmacology and Toxicology; Phase; phase 2 study; Phosphate Buffer; Plastic Surgical Procedures; Positioning Attribute; Pre-Clinical Model; preclinical study; pressure; prevent; Prevention; Publications; Rattus; Recovery; regenerative; Regenerative Medicine; repaired; Research Personnel; Risk; Rodent; Safety; Saline; Severities; Shapes; Silicon; Skin; Small Business Innovation Research Grant; Solid; Splint Device; stem cell biology; stem cell technology; stem cell therapy; Stem cells; Testing; Therapeutic; Thick; Transgenic Mice; Transgenic Organisms; Translating; Translational Research; Translations; Treatment Protocols; Trichrome stain method; Ulcer; United States Food and Drug Administration; wound; Wound Healing

This Phase II SBIR extends a Phase I proof of principle study originally submitted in response to RFA-AG-12-009 entitled "T1 Translational Research on Aging" from the NIA. In Phase I, LaCell has documented pre-clinical safety and efficacy of a novel adipose derived cell therapy for the treatment of pressure ulcers in young and old mice. The injection of murine ASC significantly accelerated and enhanced pressure ulcer repair in female mice of both age groups in a dose dependent manner as evidenced by the rate of wound closure, re-epithelialization, skin tissue architecture, inflammatory cell infiltratin and expression of molecular biomarkers. LaCell's studies pave the way for clinical translation and regulatory approval of ASC therapies. While it is well established that the prevention of pressure ulcers requires labor-intensive nursing care, patients in assisted living centers and nursing homes remain at high risk for developing pressure ulcers. Over 70% of pressure ulcers occur in Americans over the age of 70 and their hospital costs exceed $11 billion annually. Current treatment of pressure ulcers relies primarily on surgical debridement, hyperbaric oxygen, and negative pressure devices. The adipose derived- cell based therapies have the potential to substantially reduce the length of hospitalization and associated health care costs for pressure ulcer patients. LaCell has partnered with a Tissue Genesis, Inc., to use their established ICellator device to obtain clinical grade human SVF cells. This strategic partnership will accelerate the clinical translation of LaCell's cell therapeutic to the marketplace. Specific Aims (SA) will address pharmacotoxicology regulatory concerns in murine models and serve as a definitive protocol to the Food and Drug Administration for an Investigational Device Exemption in the case of SVF cells (SA1) and a Biologics License Application in the case of ASC (SA2). Each SA will evaluate the concentration dependency of human SVF cells and ASC in the treatment of a murine pressure ulcer therapy in immunodeficient and immunocompetent mice of both sexes; both young and old immunocompetent mice will be evaluated. Injection of PBS alone or with human dermal fibroblasts will serve as negative controls while topical application of the FDA approved diabetic wound therapeutic, beclapermin (PDGF-BB) will serve as a positive control. Quantitative outcomes will include rate of wound closure, inflammatory cell infiltration, pro-inflammatory cytokine expression, and immunohistochemical detection of human cells in situ. Since pressure ulcer treatment accounts for 1- 4% of the total health care budget in developed nations, LaCell's developing technologies have considerable market potential.

Public Health Relevance Statement:


Public Health Relevance:
The elderly are at high risk for the development of pressure ulcers, a life threatening condition that remains a major health care burden in the U.S. With its background in adipose stromal/stem cell biotechnology, LaCell, its strategic partner, Tissue Genesis, Inc., and its academic collaborators are uniquely positioned to address this unmet medical need. LaCell has peer review published Preliminary Data supporting the efficacy and safety of an adipose stromal/stem cell therapy for pressure ulcers. LaCell's approach has the potential to accelerate and improve the rate of wound closure and long-term recovery. This Phase II proposal will extend on LaCell's initial findings and develop essential pre-clinical data to advance adipose-derived cell therapies and translate them into an FDA approved clinical trial. LaCell's stem cell products are relevant to geriatric medicine and will improve healthcare for the rapidly growing number of elderly Americans.

Project Terms:
Accounting; Address; Adipocytes; Adipose tissue; Age; age group; Age-Years; Aging; Allogenic; American; angiogenesis; Animal Model; Architecture; Assisted Living Facilities; base; bench to bedside; Biological Assay; Biotechnology; Blood Vessels; Brain; Budgets; C57BL/6 Mouse; care burden; Care given by nurses; Cell Fraction; Cell Separation; Cell Therapy; Cells; Clinical; Clinical Data; Clinical Trials; Collaborations; cost; cytokine; Data; Debridement; Decubitus ulcer; Dependency; Dermal; Detection; Developed Countries; Development; Devices; Diabetic wound; Distant; Dose; Elderly; Etiology; experience; FDA approved; Female; Fibroblasts; Flow Cytometry; Foundations; Funding; Geriatrics; Grant; Healed; healing; Health Care Costs; Healthcare; Heart; high risk; Histology; Hospital Costs; Hospitalization; Hour; Human; Hyperbaric Oxygen; Immunocompetent; improved; In Situ; In Vitro; Infiltration; Inflammatory; Injection of therapeutic agent; Injury; Investigation; Ischemia; Joints; Kidney; Laboratories; Length; Licensing; Life; Link; Liver; Lung; Lymphangiogenesis; male; Malnutrition; man; Manufacturer Name; Manuscripts; Marketing; Medical; medical attention; Medical Economics; meetings; Memorial Sloan-Kettering Cancer Center; migration; molecular marker; Molecular Profiling; Monitor; Morphology; mouse model; mRNA Expression; Mus; Natural regeneration; novel; Nursing Homes; Operative Surgical Procedures; Organ; Outcome; Patients; Peer Review; Phase; Pilot Projects; platelet-derived growth factor BB; point of care; Positioning Attribute; pre-clinical; preclinical study; pressure; pressure ulcer prevention; Procedures; Process; Protocols documentation; public health relevance; Publishing; Publishing Peer Reviews; Quadriplegia; Quality of life; Recovery; regenerative; repaired; Reperfusion Therapy; Reporting; Research Design; response; Risk; Safety; sex; Skin; skin regeneration; Skin Temperature; Skin Tissue; Small Business Innovation Research Grant; South Korea; Spinal cord injury patients; Staging; stem cell therapy; Stem cells; Surface; Surveys; System; Technology; Temperature; Testing; Therapeutic; Time; Tissues; Topical application; Translating; Translational Research; Translations; Ulcer; United States Food and Drug Administration; Universities; Validation; wound