MAP: a Flowable, Precision-Engineered, and Tunable Tissue Scaffold Leveraging Hyper-Porous Geometry to Control Inflammation and Promote Regenerative Healing in Diabetic Wounds

总结/摘要 慢性糖尿病足溃疡（DFU）是一个重大的全球医疗保健负担，达到11美元的成本 2014年仅在美国就有10亿美元。目前的处理能力受到以下限制：（i）标准湿-水处理系统的能力不足， 用于治愈这些伤口的干式包扎技术和（ii）高级治疗的高成本， 基于活细胞的生物工程皮肤替代品。这些治疗的高成本限制了 直到伤口愈合后才能报销。在美国，每年约有150万新发和持续的DFU病例 都记录在案在他们的一生中，足部伤口的糖尿病患者有20%的机会下肢受伤， 在美国截肢。报告的DFU患者5年后的死亡率范围为55%至74%， 高于前列腺癌乳腺癌和结肠癌 这一重大的临床需求和缺乏成本效益的产品创造了重大的市场机会， 以伤口为代价，采用具有高级皮肤替代品功效的生物材料治疗来解决 调味品。低产品成本和易用性将推动早期（急性）阶段的报销和采用 糖尿病高危患者的伤口护理。控制炎症和促进组织向内生长的能力 可以缓解慢性伤口阶段，改善患者的预后并降低支付者的成本。直到 现在，还没有低成本的治疗方法，当应用时，可以整合到伤口床中并促进 没有细胞或生物制剂的再生。 为了满足这一市场需求，克里思治疗公司正在开发一套组织再生生物材料 基于我们专有的微孔退火颗粒（MAP）技术。MAP使我们能够 具有独特几何支架结构的合成化学制剂。我们的MAP材料可流动 (ease并填充多种形状和尺寸的伤口， 在暴露于LED白色光后，伤口部位中的网状物。超高孔隙率的几何结构有助于快速组织 与导致脱细胞化相比， 组织基质，炎症反应最小。 克里思已开发出我们的第一个产品，MAP伤口基质，用于治疗急性健康伤口，并已 最近通过直接De Novo向FDA提交了监管申请，并提供了安全性和性能数据。 克里思已完成产品生产的初始规模扩大，并正在准备上市后临床数据 努力从2019年开始。 在拟议的直接进入第二阶段的工作中，我们将开发基于MAP技术的第二种产品， 靶向糖尿病伤口的受损愈合。我们将采用受损伤口愈合的专门模型， 糖尿病猪，根据药物非临床研究质量管理规范（GLP）进行，以检测一套三种制剂变体 已经在初步的健康猪研究中得到证实。MAP的最佳配方， 缓慢愈合环境和刺激组织再生将被选择用于安全性分析， 将在提案结束时提交试验用器械豁免（IDE）。

SUMMARY / ABSTRACT Chronic diabetic foot ulcers (DFUs) are a significant worldwide healthcare burden, reaching a cost of $11 billion in the US alone during 2014. The current treatment capability is limited by (i) inability of standard wet-to- dry bandaging techniques to heal these wounds and (ii) the high costs of advanced treatments such as tissue- based or living-cell bioengineered skin substitutes. The high costs of these treatments have limited reimbursement until after a wound is chronic. Each year in the US, ~1.5 million new and continuing DFU cases are documented. Over their lifetime, a diabetic patient with a foot wound has a 20% chance of lower limb amputation in the US. Reported mortality rates for DFU patients range from 55 to 74% after 5 years, which are above cancers such as prostate, breast, and colon. This significant clinical need and lack of cost-effective products creates significant market opportunity that can be addressed with a biomaterial therapy with the efficacy of an advanced skin substitute at the cost of a wound dressing. Low product cost and ease-of-use will drive reimbursement and adoption in the early (acute) phase of wound care in these at-risk diabetic patients. The ability to control inflammation and promote tissue ingrowth could mitigate the chronic wound phase, improving outcomes for patients and reducing costs to payers. Until now, there have been no low-cost treatments that when applied can integrate into the wound bed and promote regeneration without cells or biologics. To answer this market need, Tempo Therapeutics is developing a suite of tissue regeneration biomaterials based on our proprietary Microporous Annealed Particle (MAP) technology. MAP allows us to empower synthetic chemical formulations with unique geometric scaffold structure. Our MAP materials are flowable (ease of application) and fill wounds of multiple shapes and sizes and convert to a hyper-porous sponge-like network in the wound site after exposure to LED white light. The hyper-porosity geometry promotes fast tissue ingrowth, early vascularization, and faster wound re-epithelialization when compared to leading decellularized tissue-based matrices, with minimal inflammatory response. Tempo has developed our first product, the MAP Wound Matrix, for treatment of acute healthy wounds and has recently submitted a regulatory application via direct De Novo to FDA with safety and performance data. Tempo has completed initial scale-up of product manufacturing and is preparing for post market clinical data efforts beginning in 2019. In the proposed direct-to-phase II work, we will develop our second product based on the MAP technology, targeting impaired healing in diabetic wounds. We will employ specialized models of impaired wound healing in diabetic pigs, performed under Good Laboratory Practices (GLP), to test a suite of three formulation variants already demonstrated in a preliminary healthy swine study. The optimal formulation of MAP that performs in slow healing environments and stimulates tissue regeneration will be selected for safety profiling and an Investigational Device Exemption (IDE) will be submitted at the end of the proposal.