Indwelling biosensor for real-time chemotherapeutic blood level monitoring

 描述(由申请人提供)：这项建议的具体目的是测试开发一种基于导管的留置式生物传感器的可行性，用于实时、连续地监测肺癌患者的化疗血液水平。一个持续实时监测血液药物水平的工具将使人们能够前所未有地了解单个患者独特的新陈代谢和药物清除情况。迫切需要这些信息有三个原因：1)减少与药物剂量相关的毒性，如心脏组织损伤；2)通过确保患者维持治疗性药物的血液水平来潜在地提高化疗药物的疗效；3)促进治疗范围窄和个体间变异性高的新药的开发和批准。拟议的工具将每5秒测量一次流动静脉全血中化疗药物阿霉素的血液水平，以实时确定血液水平并准确计算累积药物暴露。目前的方法需要多次、及时的抽血，这很容易出错，并且需要人工采集样本和进行实验室分析。目前还没有可用于检测阿霉素的护理点法。拟议的工作是基于现有的阿霉素微流控生物传感器，该传感器在全血中工作超过4小时(Ferguson等人，2013年；见Plaxco的支持信)。我们建议设计和制造一种生物传感器，它利用现有系统有利的流体动力学，但它足够小，可以安装在患者手臂上的静脉导管中。诊断生物芯片公司已经开发了一种专有的MEMS工艺，用于制造可植入的多电极阵列。我们将通过以下方式实现我们的具体目标：1)使用有限元分析来模拟静脉、流动和全血中的流体流动，以演示传感器界面处的层流边界缓冲层，以防止生物污垢；2)制造优化的导管设计并使生物传感器具有功能；以及3)开发用于护理点使用的电子器件。可行性测试将是在生理相关浓度(10 NM-10微米；Eksborg等人，1985年)下在流动的全血中至少8小时内成功检测到阿霉素，该装置具有临床可实施的设计(由与现有静脉导管的尺寸和几何形状相似以及所提供的静脉液体的可接受水平来定义)。在第二阶段，我们将在活体动物身上测试我们的传感器，并利用稳健设计的原则，将我们的原型转化为商业产品。

 DESCRIPTION (provided by applicant): The Specific Aim of this proposal is to test the feasibility of developing a catheter-based, indwelling biosensor for the real-time, continuous monitoring of chemotherapeutic blood levels of lung cancer patients. A tool that continuously monitors blood drug levels in real-time will enable an unprecedented understanding of an individual patient's distinctive metabolism and clearance of drugs. This information is critically needed for three reasons: 1) to reduce drug dosing related toxicities, such as heart tissue damage, 2) to potentially improve efficacy of chemotherapeutics by ensuring patients maintain therapeutic drug blood levels, and 3) to facilitate development and approval of new drugs with narrow therapeutic ranges and high interindividual variability. The proposed tool will measure blood levels of chemotherapeutic drug doxorubicin every 5 seconds in flowing venous whole blood for real-time determination of blood levels and accurate calculation of cumulative drug exposure. Current methods require multiple, timely blood draws that are error prone and require manual labor for both sample collection and laboratory analysis. No point-of-care method is available to detect doxorubicin. The proposed work is based upon an existing doxorubicin microfluidic biosensor that works in whole blood for over 4 hours (Ferguson et al., 2013; see Plaxco letter of support). We propose to design and fabricate a biosensor that utilizes the advantageous fluidic dynamics of the existing system, but that is small enough to fit in an I.V. catheter in a patient's arm. Diagnostic Biochips has already developed a proprietary MEMS process for fabricating implantable multi-electrode arrays. We will accomplish our Specific Aim by: 1) using finite element analysis to model fluid flow in venous, flowing, whole blood to demonstrate a laminar boundary buffer layer at the sensor interface to prevent biofouling, 2) fabricate the optimized catheter design and functionalize the biosensor, and 3) develop electronics for point-of-care use. The test of feasibility will be the successful detection of doxorubicin in flowing whole blood for at least 8 hours at physiologically relevant concentrations (10 nM - 10 uM; Eksborg et al., 1985) in a device that with clinically implementable design (defined by similarity in size and geometry to existing I.V. catheters and acceptable levels of I.V fluid delivered). In Phase II, we will test our sensors in live animals and, using principles of robust design, turn our prototype into a commercial product.