With nearly 15 million units of red blood cells (RBCs) transfused to about 5 million patients in the U.S. every year, RBC transfusion is one of the most commonly prescribed therapies for hospital inpatients. In recent years, ample clinical evidence has accumulated that a significant proportion of morbidity and mortality in critically ill patientsis due to the toxic effects of RBC transfusions. Most transfusions involve RBCs that had been stored in an anticoagulant-preservative solution at 1-6 C for up to 6 weeks. The biochemical, mechanical and functional properties of RBCs deteriorate progressively - by the end of allowable storage up to 1% of stored RBCs undergo lysis, and as many as 25% of the remaining RBCs are irreparably damaged, non-viable cells. Moreover, the RBC storage medium accumulates known mediators of toxicity as byproducts of RBC metabolism and degradation. Infusion of these toxic mediators and the irreparably damaged cells into the recipient during transfusion reduces the therapeutic efficacy of transfusion and contributes to multiple adverse outcomes in 1-2% of U.S. citizens. The goal of this project is to devise a high-throughput technology for in-line removal of irreparably damaged cells and toxic mediators in the storage medium from units of stored RBCs in real-time, during the transfusion process. This project will initially focus on the design and performance optimization of the proposed technology on milliliter-size samples of stored RBCs. To support the design iterations, we will develop an auxiliary hematology-on-a-chip device for measuring all relevant geometric, mechanical and biochemical properties for thousands of individual RBCs at high throughput. At the second stage of the project, we will scale up the optimized design for processing clinical-size RBC units. We will perform a broad panel of in vitro tests to characterize the quality of processed RBCs. To perform an integrative test of the primary RBC function, we will develop another auxiliary device for measuring the ability of stored RBCs to load / offload oxygen in artificial capillary networks directly. The anticipated outcome of this project is a full-scale prototype of the proposed device that can be used to further test the processed well- preserved stored RBCs for pro-inflammatory and pro-thrombotic activity, and post-transfusion viability and intravascular survival in human subjects in vivo. Conventional paradigm postulates that all stored RBCs in a bag are homogeneous with respect to the storage-induced deterioration of their properties, and consequently attempts to 'rejuvenate' stored RBCs through manipulation of the overall storage conditions and re-formulation of additive solutions. Our approach challenges this conventional paradigm by leveraging the heterogeneity of stored RBCs to enable transfusion of only well-preserved cells, free from irreparably damaged cells and toxins in the storage medium. This is an entirely novel approach with a potentially game-changing, transformative impact on the safety and efficacy of transfusions administered throughout the practice of medicine.

Public Health Relevance

Red blood cell (RBC) transfusion is a life-saving therapy frequently administered to hospitalized patients throughout the practice of medicine. Massive transfusions of stored RBCs and transfusions of RBC units stored longer than 2 weeks has been associated with increased complications; including lung failure; inflammation; blood clots; infection and heart attack. This highly-innovative project plans to develop an inexpensive; disposable; high-throughput technology for removal of known mediators of these complications from RBC units during transfusion.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL117329-03
Application #
8773644
Study Section
Special Emphasis Panel (ZRG1-BCMB-A (51))
Program Officer
Mitchell, Phyllis
Project Start
2012-09-30
Project End
2017-12-31
Budget Start
2013-01-01
Budget End
2014-12-31
Support Year
Fiscal Year
2013
Total Cost
$364,963
Indirect Cost
$122,463
Name
University of Houston
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
036837920
City
Houston
State
TX
Country
United States
Zip Code
77204
Reinhart, Walter H; Piety, Nathaniel Z; Shevkoplyas, Sergey S (2016) Influence of red blood cell aggregation on perfusion of an artificial microvascular network. Microcirculation :
Piety, Nathaniel Z; Reinhart, Walter H; Pourreau, Patrick H et al. (2016) Shape matters: the effect of red blood cell shape on perfusion of an artificial microvascular network. Transfusion 56:844-51
Burns, Jennie M; Yoshida, Tatsuro; Dumont, Larry J et al. (2016) Deterioration of red blood cell mechanical properties is reduced in anaerobic storage. Blood Transfus 14:80-8
Piety, Nathaniel Z; Yang, Xiaoxi; Kanter, Julie et al. (2016) Validation of a Low-Cost Paper-Based Screening Test for Sickle Cell Anemia. PLoS One 11:e0144901
Xia, Hui; Strachan, Briony C; Gifford, Sean C et al. (2016) A high-throughput microfluidic approach for 1000-fold leukocyte reduction of platelet-rich plasma. Sci Rep 6:35943
Piety, Nathaniel Z; Yang, Xiaoxi; Lezzar, Dalia et al. (2015) A rapid paper-based test for quantifying sickle hemoglobin in blood samples from patients with sickle cell disease. Am J Hematol 90:478-82
Reinhart, Walter H; Piety, Nathaniel Z; Deuel, Jeremy W et al. (2015) Washing stored red blood cells in an albumin solution improves their morphologic and hemorheologic properties. Transfusion 55:1872-81
Piety, N Z; Gifford, S C; Yang, X et al. (2015) Quantifying morphological heterogeneity: a study of more than 1 000 000 individual stored red blood cells. Vox Sang 109:221-30
Reinhart, Walter H; Piety, Nathaniel Z; Goede, Jeroen S et al. (2015) Effect of osmolality on erythrocyte rheology and perfusion of an artificial microvascular network. Microvasc Res 98:102-7
Kumar, Ashok A; Patton, Matthew R; Hennek, Jonathan W et al. (2014) Density-based separation in multiphase systems provides a simple method to identify sickle cell disease. Proc Natl Acad Sci U S A 111:14864-9

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