Adipose-Derived Stromal/Stem Cell Therapy for Pressure Ulcers

描述（由申请人提供）：本I期SBIR响应NIA标题为“T1衰老转化研究”的RFA-AG-12-009，探索了治疗老年人压疮和全层皮肤伤口的新型细胞治疗方法。虽然众所周知，预防压疮需要劳动密集型护理，但辅助生活中心和疗养院的患者仍有发生压疮的高风险。事实上，超过70%的压力性溃疡发生在70岁以上的美国人中，他们每年的住院费用超过110亿美元。目前对压疮的治疗主要依赖于外科清创术、高压氧、生长因子和负压装置。这项“原理证明”研究将使用小鼠模型来测试LaCell的假设，即脂肪源性基质/干细胞（ASC）疗法将加速和改善老年人压疮的愈合。将使用瘦素受体缺陷（db/db）肥胖糖尿病小鼠（3 - 4个月）作为阳性对照，在年轻（3 -4个月）和老年（24个月）C57 B1/6雄性小鼠中进行研究。将在每只小鼠的背部产生双侧全层皮肤伤口。这些将由圆环形状的硅夹板保护，以防止伤口边缘自发回缩。这将允许准确测量伤口上皮形成和愈合速率。脂肪基质/干细胞（ASC）将从绿色荧光蛋白（GFP）转基因的C57 B1/6小鼠中分离。在每只动物中，将GFP+ ASC注射到一个全层缺损的伤口床中，而注射磷酸盐缓冲盐水的相应伤口将作为对照。将在术后1、3和10天收获动物组。定量实验结果将解决ASC对修复影响的潜在机制，包括上皮形成率、伤口闭合率、细胞因子和基质金属蛋白酶表达率以及免疫细胞浸润率。这些结果将确定基于ASC的治疗加速老年人压疮和全层皮肤伤口修复的可行性和有效性。I期将为II期研究中鼠和人ASC的未来药代动力学和毒理学测试奠定基础。此外，它们将为与食品和药物管理局进行详细的IND前讨论提供基础。LaCell LLC是一家生物技术公司，由领先的研究人员和发明家在脂肪基质/干细胞应用于再生医学。作为顾问，LaCell已经获得了整形外科和伤口愈合领域专家的帮助。 公共卫生相关性：老年人患压疮的风险很高，压疮是一种使人衰弱和危及生命的疾病，在美国仍然是一个主要的医疗负担。LaCell提出开发一种用于压疮的脂肪基质/干细胞疗法。这种方法有可能加速和改善伤口闭合和长期恢复的速度。这项集中的“原则证明”临床前研究的结果与美国和国外老年医学的一个独特重要的临床问题有关。凭借其在脂肪基质/干细胞生物技术方面的背景，LaCell及其顾问在解决这一未满足的医疗需求方面具有独特的优势。

DESCRIPTION (provided by applicant): 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.