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

描述（由申请人提供）：长期以来，人们一直认为，新生儿不受控制的高胆红素血症（黄疸）可导致神经功能障碍，包括不可逆的动脉样脑瘫，伴语言、视力和听力障碍，甚至死亡。当前的管理是基于监测血清总胆红素（TBS），考虑其他临床参数，如出生体重和胎龄，并给予有效的治疗（光疗和/或罕见的交换输血），如果需要的话。不幸的是，表面健康的新生儿在出生后很快就出院的趋势，使得对这一人群后续黄疸的治疗更加困难。长期以来，人们建议，但没有使用，更好的预测新生儿胆红素升高引起的神经系统后遗症的风险是测量胆红素与血清白蛋白结合在血室中的隔离能力。未结合胆红素的浓度是胆红素从脉管系统逃逸的驱动因素，可以通过TBS和结合容量来计算。目前现有的测定结合能力和未结合胆红素的方法并不方便。然而，所有这些参数都可以用一种特殊用途的荧光仪直接测量，这种荧光仪是几年前首次描述的，利用与白蛋白结合的胆红素的天然荧光。这项技术适用于即时使用。

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.