SBIR Phase I: Vasoreactive Perfused in Vitro Vascular Network

SBIR第一阶段项目旨在商业化开发一个体外（细胞培养）平台，以提高药物发现的效率。每一种输送到人体的药物都会与血管网络结合，以输送到靶组织或作为清除的一部分。血管网络的基本特征是由平滑肌包围的小血管的广泛网络，平滑肌可以收缩和扩张以控制血流，从而控制药物递送。尽管心血管毒性是临床试验失败的主要原因，但没有体外人体平台可以模拟这种生物学功能。因此，评估血管毒性的临床前工具将显著影响药物开发过程。开发一种成功的药物平均需要10-12年，花费近26亿美元。尽管总开发成本的约60%用于人体临床试验，但只有不到十分之一的临床试验能够成功。有一个重要的机会来提高临床前药物筛选的准确性，这反过来又将产生显着的成本节约和缩短上市时间。该公司提出的血管活性人体血管网络代表了技术的飞跃，以模拟人类对新的和现有的药物的反应。此外，该平台技术具有广泛的未来应用，包括组织特异性功能（例如，人类肿瘤细胞）和患者特异性的结合，这将进一步推进药物开发和精确医学。目前还没有体外平台可以模拟血管收缩或血管舒张，这需要血管反应性平滑肌细胞的过程。竞争性技术将内皮细胞排列在预制管或膜上，以模拟血管系统，但这永远无法模拟血管活性。由于该公司的平台由活的动态微血管组成，因此该公司在创建具有此功能的平台方面具有独特的优势。主要目的是开发具有平滑肌的3D灌注人体血管网络，以提供表征血管活性物质的能力。该公司将通过完成两个具体目标来实现主要目标：1）将人类平滑肌细胞整合到3D体外血管网络中; 2）量化3D灌注血管网络对一组血管活性药物的剂量反应。在体外血管网络中实现血管活性功能将是这一关键生物学现象的首次展示，并将满足制药行业的重要商业需求。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

This SBIR Phase I project proposes to commercially develop an in vitro (cell culture) platform to enhance the efficiency of drug discovery. Every drug delivered to a human engages the network of blood vessels for delivery to the target tissue or as part of the removal. An essential feature of the blood vessel network is an extensive network of small vessels surrounded by smooth muscle which can contract and dilate to control blood flow, and thus drug delivery. There are no in vitro human platforms that can mimic this biological function, despite the fact that cardiovascular toxicity is the leading cause of failure in clinical trials. As such, a pre-clinical tool to assess vascular toxicity would significantly impact the drug development process. Developing a successful drug averages 10-12 years and nearly $2.6 billion. Despite the fact that ~60% of the total development costs are spent on human clinical trials, fewer than 1 in 10 entering clinical trials will succeed. There is a significant opportunity to improve the accuracy of preclinical drug screening which, in turn, will generate dramatic cost savings and shorten time-to-market. The company's proposed vasoactive human vascular network represents a leap forward in technology to simulate the human response to new and existing drugs. Furthermore, the platform technology has broad future applications including the incorporation of tissue specific function (e.g, human tumor cells) and patient specificity which will further advance drug development and precision medicine.There are currently no in vitro platforms that can mimic vasoconstriction or vasorelaxation, processes which require vasoresponsive smooth muscle cells. Competing technologies line prefabricated tubes or membranes with endothelial cells to mimic the vasculature which will never be able to simulate vasoactivity. Since the company's platform is comprised of living dynamic microvessels, the company is uniquely positioned to create a platform with this functionality. The primary objective is to develop a 3D perfused human vascular network with smooth muscle providing the capacity to characterize vasoactive substances. The company will achieve the primary objective by completing two specific aims: 1) Incorporate human smooth muscle cells into a 3D in vitro vascular network; and 2) Quantify the dose-response of the 3D perfused vessel network to a panel of vasoactive drugs. Achieving vasoactive functionality in an in vitro vascular network will be the first demonstration of this critical biological phenomenon, and will meet an important commercial need in the pharmaceutical industry.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.