The Interaction between Mircroenvironments and Hemocompatibility in End Stage Renal Disease Patients

描述（由申请人提供）：透析是全球超过200万终末期肾病（ESRD）患者的生命维持治疗(1)。尽管血液透析取得了成功，但与其他慢性疾病相比，它仍然具有不成比例的发病率和死亡率风险(1)。ESRD进一步提出了一系列独特的血液相容性挑战，包括内在血小板功能障碍和血液透析微环境（膜表面、剪切应力、滚柱泵压应力等）的外在影响。因此，任何新的肾脏替代治疗都需要考虑到这些挑战，并针对ESRD人群进行优化。为了实现这一目标，微机电系统（MEMS）技术已被用于开发可植入生物人工肾（iBAK）。这种新型装置结合了用于血液过滤的高选择性硅纳米孔膜（SNM）和细胞生物反应器，以模拟天然肾脏的功能。然而，这项有前途的技术尚未探索ESRD患者群体中血液，剪切应力和表面之间的相互作用。因此，本提案将研究与ESRD相关的基本血液相容性问题。ESRD患者由于活化血小板在异物表面的粘附而经历器械血栓形成。我假设器械血栓形成是由剪切应力引起的液相血小板活化和表面化学作用导致的血小板粘附在表面之间的相互作用。因此，通过调节剪切应力（设备设计）和表面相互作用（化学），我们将减少活化的血小板粘附在表面。我将采用设计导向的方法在可植入生物人工肾脏中验证我的假设。我提出以下具体目标：1)研究ESRD患者在不同剪切应力条件和暴露时间下血小板活化的反应。剪切应力已被证明在血小板功能中起关键作用。沟槽高度是决定剪切应力的关键因素。我们将根据iBAK的通道高度尺寸（50-500 μm）和设置流量为2ml/min，调整通道高度以产生各种剪切应力条件（3.2-320yn/cm2）。我们将研究在不同剪切应力和暴露时间下，血小板在流体阶段与在表面的活化。2)探讨修饰表面化学对ESRD患者血小板粘附的影响。表面修饰是血液接触表面的关键组成部分，以尽量减少散装材料的生物反应性。为了更好地了解血小板功能障碍对ESRD的流体相和表面血液相容性的影响，我们将研究几种修饰的表面（聚乙二醇（PEG）和聚磺基甜菜碱甲基丙烯酸酯（pSBMA））。结果将确定相对的影响，表面化学对血小板活化和粘附在流体相相对于在表面。

DESCRIPTION (provided by applicant): Dialysis is a life sustaining treatment for over two million people with end stage renal disease (ESRD) worldwide (1). Despite the success of hemodialysis it still confers a disproportionate risk of morbidity and mortality compared to other chronic illnesses (1). ESRD further poses a set of unique hemocompatibility challenges in terms intrinsic platelet dysfunction and extrinsic effects from the hemodialysis microenvironment (membrane surface, shear stress, roller pump compressive stress, etc). Therefore, any new renal replacement treatments need to account for these challenges and be optimized for an ESRD population. To this goal, microelectromechanical systems (MEMS) technology has been utilized to develop an implantable bioartificial kidney (iBAK). This novel device combines a highly selective silicon nanopore membrane (SNM) for hemofiltration with a cell bioreactor in order to mimic the functions of a native kidney. However, this promising technology has yet to explore the interaction between blood, shear stress and surface in an ESRD patient population. Therefore, this proposal will investigate fundamental hemocompatibility issues associated with ESRD. Patients with ESRD experience device thrombosis due to adhesion of activated platelets on a foreign surface. I hypothesize that device thrombosis is an interplay between platelet activation in the fluid phase caused by shear stress and platelet adhesion on the surface due to surface chemistry. Therefore, by modulating both shear stress (device design) and surface interactions (chemistry) we will reduce activated platelet adhesion on the surface. I will use a design directed approach to test my hypothesis in the implantable bioartificial kidney. I propose the following specific aims: 1) Investigate the response of platelet activation in ESRD patients when exposed to various shear stress conditions and exposure times. Shear stress has been shown to play a critical role in platelet function. Channel height is a key optimizable determinate of shear stress. We will tune the channel height to produce various shear stress conditions (3.2-320yn/cm2) based on channel height dimensions (50-500 μm and set flow rate of 2ml/min, which are based on the iBAK. We will investigate platelet activation in the fluid phase versus at the surface for various shear stress and exposure times. 2) Investigate the effect of modified surface chemistry on platelet adhesion in ESRD patients. Surface modifications are a key component of blood contacting surfaces to minimize the biological reactivity of the bulk material. To better understand the effect of platelet dysfunction on fluid phase and surface hemocompatibility in ESRD we will examine several modified surfaces (poly-ethylene glycol (PEG) and polysulfobetaine methyacrylate (pSBMA)). The results will determine the relative effect of surface chemistry on platelet activation and adhesion in the fluid phase versus at the surface.