A first in human clinical study of TT101, a synthetic immunomodulatory material to build new functional tissue over exposed bone as a one time treatment for diabetic limb preservation patients

摘要/摘要 根据美国疾病控制中心的数据，有3400万美国人患有糖尿病。其中一个 糖尿病最常见的并发症是糖尿病足溃疡(DFU)。约25%的糖尿病患者将 在他们的一生中发展成一种无法愈合的足部溃疡。DFU对感染和组织坏死高度敏感 这需要极端的手术干预来移除大量的死亡组织并保留肢体。不幸的是， 组织损伤通常是如此广泛，以至于这些外科手术留下了复杂的伤口 裸露的骨、肌腱和/或筋膜--出了名的难以愈合，目前采用的是生物工程技术。 护肤品没有好处。事实上，足部溃疡是最常见的一种下肢前驱症状。 糖尿病患者中的截肢，是大约85%的下肢的先兆 仅在美国，每年就有超过10万人被截肢。此外，报告的死亡率 5年后，DFU患者的发病率从55%到74%不等，高于前列腺癌、乳腺癌、 和冒号。 目前复杂伤口的治疗选择很少。生物工程皮肤床单无法建造 新的组织覆盖在这些暴露的骨表面，基本的伤口护理也没有什么效果。负压 创伤治疗(NPWT)显示了愈合的改善，但这种管理工具需要密集的门诊患者 关心，而且很麻烦。显然，需要一种能够在垂直方向上产生效果的再生疗法。 创面愈合阶段，建立新的组织体积对成功至关重要。这个意义重大的临床 需求创造了相当大的市场机会。 为了响应这一市场需求，天宝治疗公司开发了MAP WINT MATRIX-一种可流动的合成 基于我们专有的微孔退火颗粒(MAP)技术的组织支架。贴图创伤矩阵 是可流动的(易于使用)，可以填充任何形状和大小的伤口，然后转化为超渗透 白光照射后伤口部位有海绵状网状结构。超孔隙几何结构快速升级 肉芽组织和早期血管形成，与领先的脱细胞组织基质相比， 在包括糖尿病猪在内的多种动物模型中，炎症反应最小。与大多数不同 矩阵，MAP不需要多个应用。天宝已经完成了必要的研究，以 向FDA提供安全和性能数据支持临床试验申请，并已完成初步扩大 产品制造。 在拟议的直接到第二阶段的工作中，我们将继续开发MAP Wound Matrix，并进行 评价其治疗糖尿病复杂创面疗效和安全性的多中心随机先导临床研究 病人。这项研究的成功完成将为MAP创伤基质的性能带来临床证据 以及关键信息，以设置下一个更大的临床研究，以推动伤口护理行业的采用。

SUMMARY / ABSTRACT According to the United States Centers for Disease Control, 34 million Americans have diabetes. One of the most prevalent complications of diabetes is the diabetic foot ulcer (DFU). Approximately 25% of diabetics will develop a non-healing foot ulcer in their lifetime. DFUs are highly susceptible to infection and tissue necrosis that require extreme surgical interventions to remove extensive dead tissue and preserve the limb. Unfortunately, tissue damage is often so extensive that these surgical procedures leave behind complex wounds with exposed bone, tendon, and or fascia – which are notoriously difficult to heal and where current bioengineered skin products do not have benefit. Indeed, foot ulceration is the most common single precursor of lower extremity amputations among persons with diabetes and is a precursor to approximately 85% of the lower extremity amputations within this population – exceeding 100K every year in the US alone. Furthermore, reported mortality rates for DFU patients range from 55 to 74% after 5 years, which are above cancers such as prostate, breast, and colon. The current treatment options for complex wounds are scarce. Bioengineered skin sheets are unable to build new tissue over these exposed bone surfaces, and basic wound care has little effect as well. Negative Pressure Wound Therapy (NPWT) has shown improved healing, but this management tool requires intensive outpatient care and is cumbersome. There is a clear need for a regenerative therapy that can have effect in the ‘vertical’ phase of wound healing, where building new tissue volume is paramount to success. This significant clinical need creates a considerable market opportunity. To answer this market need, Tempo Therapeutics has developed the MAP Wound Matrix – a flowable synthetic tissue scaffold based on our proprietary Microporous Annealed Particle (MAP) technology. MAP Wound Matrix is flowable (ease of application) and fills wounds of any shapes and sizes, and then converts to a hyper-porous sponge-like network in the wound site after exposure to white light. The hyper-porosity geometry promotes fast granulation tissue, and early vascularization, when compared to leading decellularized tissue-based matrices, with minimal inflammatory response in multiple animal models including diabetic pigs. Unlike most of these matrices, MAP does not require multiple applications. Tempo has already completed the necessary studies to support clinical trial application to FDA with safety and performance data and has completed initial scale-up of product manufacturing. In the proposed Direct-to-Phase II work, we will pursue the development of MAP Wound Matrix and conduct a multicenter, randomized pilot clinical study to evaluate its efficacy and safety to treat complex wounds in diabetic patients. Successful completion of this study will bring clinical evidence of the performance of MAP Wound Matrix as well as crucial information to set the next larger clinical study in order to drive adoption in wound care industry.