SBIR Phase I: Vasoreactive Perfused in Vitro Vascular Network

这个SBIR一期项目建议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。每一种给人的药物都要通过血管网络输送到目标组织或作为切除的一部分。血管网络的一个基本特征是由平滑肌包围的小血管组成的广泛网络，这些血管可以收缩和扩张以控制血液流动，从而控制药物输送。尽管心血管毒性是临床试验失败的主要原因，但目前还没有可以模拟这种生物功能的体外人体平台。因此，评估血管毒性的临床前工具将对药物开发过程产生重大影响。开发一种成功的药物平均需要10-12年，耗资近26亿美元。尽管总开发成本的60%左右用于人体临床试验，但进入临床试验的药物中只有不到十分之一会成功。提高临床前药物筛选的准确性是一个重要的机会，这反过来将大大节省成本并缩短上市时间。该公司提出的血管活性人体血管网络代表了模拟人类对新药物和现有药物反应技术的飞跃。此外，该平台技术具有广泛的应用前景，包括结合组织特异性功能（如人类肿瘤细胞）和患者特异性，这将进一步推动药物开发和精准医疗。目前还没有能够模拟血管收缩或血管松弛的体外平台，这些过程需要血管反应性平滑肌细胞。竞争技术将预制管或膜与内皮细胞连接起来，以模拟血管系统，而这些技术永远无法模拟血管活性。由于该公司的平台由动态微型容器组成，因此该公司具有独特的定位，可以创建具有此功能的平台。主要目标是开发具有平滑肌的3D灌注人体血管网络，提供表征血管活性物质的能力。该公司将通过完成两个特定目标来实现主要目标：1)将人类平滑肌细胞纳入体外3D血管网络；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现象的首次演示，并将满足制药行业的重要商业需求。该奖项反映了美国国家科学基金会的法定使命，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.