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

University Of California, San Francisco, San Francisco CA

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Abstract

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 ?m 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.