Point-of Care System for Determination of Bilirubin Capacity in Neonates

描述(申请人提供)：长期以来，新生儿高胆红素血症(黄疸)无法控制会导致神经功能障碍，包括不可逆的手足徐动性脑性瘫痪，伴有言语、眼睛和听力障碍，甚至死亡。现代治疗的基础是监测血清总胆红素(TBS)，考虑出生体重和胎龄等其他临床参数，并根据需要实施有效的治疗(光疗和/或罕见的换血)。不幸的是，看似健康的新生儿在出生后不久就出院的趋势使该人群中随后的黄疸的管理变得更加困难。长期以来，人们一直建议(但没有使用)一个更好的预测新生儿因胆红素升高而出现神经后遗症的风险的指标，即通过与血清白蛋白结合来衡量胆红素在血液中隔离的能力。游离胆红素是胆红素从血管系统逃逸的驱动力，它的浓度可以从总胆红素和结合容量中计算出来。目前，现有的测定结合容量和未结合胆红素的方法并不简便。然而，通过利用胆红素与白蛋白结合的天然荧光，可以在非常少量的全血中简单地直接测量所有这些参数，使用多年前首次描述的特殊用途荧光计-血液荧光计。这项技术适用于就近使用。 该项目的目标是将第一阶段开发的现代化和微型化血液荧光仪改造成适合在各种护理地点环境下运行的产品，包括重症监护和健康婴儿托儿所、新生儿住院诊所和儿科医生办公室。第一个目标是优化基本的光学和电子设计：重新设计电子设备，以支持医院信息管理要求，如条形码阅读器、打印机，并直接或通过本地互联网与计算机接口。这个 第二个目标是开发一种使用方便、价格低廉的试剂盒。第一阶段的工作表明，需要做更多的工作来设计满足这些要求的工具包，然后将此设计扩展到可以批量生产的产品。第三个目标是在临床环境中用新生儿血液样本测试该仪器，以证明它很适合满足需求。考虑到这一目标，斯坦福大学医学院和儿童医院已同意作为分包商参与评估这项新技术。有了这些拟议的改进，该仪器将为下一阶段做好准备：将其投放市场，立即用于研发和临床研究，并最终获得FDA的批准，用于一般用途。 与公共卫生相关：长期以来，人们一直建议(但没有使用)一个更好的预测新生儿因胆红素升高而出现神经后遗症的风险的指标，这是一种衡量胆红素与血清白蛋白结合在血液中隔离胆红素能力的指标。游离胆红素是胆红素从血管系统逃逸的驱动力，它的浓度可以从总胆红素和结合容量中计算出来。目前，现有的测定结合容量和未结合胆红素的方法并不简便。 然而，通过利用胆红素与白蛋白结合的天然荧光，可以在非常少量的全血中简单地直接测量所有这些参数，使用多年前首次描述的特殊用途荧光计-血液荧光计。该项目的目标是将第一阶段开发的现代化和微型化血液荧光仪转变为适合在各种护理点环境下使用的产品，完成易于使用的样本处理一次性设备的开发，并验证该系统对特定新生儿群体样本的性能。

DESCRIPTION (provided by applicant): Uncontrolled hyperbilirubinemia (jaundice) in neonates has long been known to lead to neurological dysfunction including irreversible athetoid cerebral palsy with speech, ocular and hearing impairments, and even death. Contemporary management is based upon monitoring the total serum bilirubin (TBS), taking into account other clinical parameters such as birth weight and gestational age, and administering effective treatment (phototherapy and/or the rare exchange transfusion), if dictated. Unfortunately, the trend towards discharge of apparently healthy neonates from the hospital very soon after birth has made the management of subsequent jaundice more difficult in that population. A long suggested, but not used, better predictor of the neonate's risk for neurological sequelae due to elevated bilirubin is a measure of the capacity to sequester bilirubin in the blood compartment by its binding to serum albumin. The concentration of unbound bilirubin, the driver for bilirubin escaping from the vasculature, can be calculated from the TBS and binding capacitl. Presently existing methods for assaying binding capacity and unbound bilirubin are not facile. However, all these parameters can be directly measured simply in a very small volume of whole blood with a special purpose fluorometer, the hematofluorometer, first described years ago, by making use of the natural fluorescence of bilirubin bound to albumin. This technology is amenable to point-of-care use. The aims of this project are to transform the modernized and miniaturized hematofluorometer developed in Phase I into a product suitable for operation in various point-of-care environments, including the intensive care and healthy baby nurseries, the neonatal inpatient clinic, and the pediatrician's office. The first aim is to optimize the basic optical and electronic design: redesin the electronics to support the hospital information management requirements, such as a bar code reader, printer, and interface with a computer, either directly or via the local internet. The second aim is to develop a reagent kit that is easy to use and inexpensive. Phase I work demonstrated that significantly more work is needed to design a kit meeting these requirements, and then scaling this design up into a product that can be mass produced. The third aim is to test the instrument with neonate blood samples in a clinical environment to demonstrate that it well suited to meet the needs. With this goal in mind, Stanford University's Medical School and Children's Hospital has agreed to participate as a subcontractor to evaluate the new technology. With these proposed improvements, the instrument will be ready for the next stages: releasing it to the market for immediate R&D uses and clinical studies, and eventual approval by the FDA for general use. PUBLIC HEALTH RELEVANCE: A long suggested, but not used, better predictor of the neonate's risk for neurological sequelae due to elevated bilirubin is a measure of the capacity to sequester bilirubin in the blood compartment by its binding to serum albumin. The concentration of unbound bilirubin, the driver for bilirubin escaping from the vasculature, can be calculated from the TBS and binding capacitl. Presently existing methods for assaying binding capacity and unbound bilirubin are not facile. However, all these parameters can be directly measured simply in a very small volume of whole blood with a special purpose fluorometer, the hematofluorometer, first described years ago, by making use of the natural fluorescence of bilirubin bound to albumin. This technology is amenable to point-of-care use.The aims of this project are to transform the modernized and miniaturized hematofluorometer developed in Phase I into a product suitable for operation in various point-of-care environments, to complete development of easy-to-use sample handling disposables, and to verify the performance of the system for samples from a specified population of neonates.