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Novel Rheology-Based Therapies for the Potential Treatment of Sickle Cell Disease

Crompton, Daniel (2021) Novel Rheology-Based Therapies for the Potential Treatment of Sickle Cell Disease. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Sickle Cell Disease (SCD) is a group of inherited hemoglobinopathies affecting over 100,000 individuals in the United States and millions more worldwide. Sickle cell anemia, the most common and severe type of SCD, is the result of a point mutation which allows intraerythrocytic hemoglobin to polymerize with itself under oxygen-poor conditions, forming long crystalline or polymeric chains within red blood cells (RBCs) and causing these cells to become sickle-shaped and prone to hemolysis. Due to their decreased deformability and higher affinity to adhere to the endothelium and other blood cells, sickled RBCs occlude the microvasculature, resulting in flow obstruction, tissue hypoxia and ischemia, and an inflammatory response. These effects lead to sudden, severe pain due to systemic vaso-occlusive episodes (VOE) which requires acute care and extended hospitalization.
Although multiple pharmacologic therapies are currently approved by the FDA for the treatment of SCD, there exists a lack of adequate treatment options for the prevention of vaso-occlusion and related SCD comorbidities. The overarching purpose of this work is to develop and test two novel rheological-based approaches as potential options for the treatment of SCD. First, the use of blood soluble additives known as drag-reducing polymers (DRPs) were examined for their potential to improve blood flow within microvessels and reduce vaso-occlusion. Our in vitro findings suggest that DRPs may improve the circulation of less-deformable RBCs such as sickle RBCs by reducing their near wall margination and altering their traffic patterns through microchannel bifurcations. Transgenic SCD mice administered DRPs were also found to have significantly reduced hepatic vaso-occlusion during intravital imaging following an inflammatory stimulus. The second rheological-based approach for the treatment of SCD explored a method of intracellular hemoglobin replacement, where we show proof-of-concept feasibility of a technique to remove sickle hemoglobin from sickle RBCs and subsequently replace their intracellular contents with healthy donor hemoglobin. ‘Refilled’ SCD RBCs showed an inability to sickle and improved rheological characteristics, demonstrating this process as a potential novel transfusion therapy in order to eliminate the risk of alloimmunization in SCD patients.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Crompton, Danieldac160@pitt.edudac160
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairKameneva, Marinakamenevamv@upmc.edu
Committee MemberSundd, PrithuPRS51@pitt.eduPRS51
Committee MemberVande Geest, Jonathanjpv20@pitt.edujpv20
Committee MemberWaters, Jonathanwatejh@upmc.edu
Date: 26 January 2021
Date Type: Publication
Defense Date: 14 October 2020
Approval Date: 26 January 2021
Submission Date: 10 November 2020
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 158
Institution: University of Pittsburgh
Schools and Programs: Swanson School of Engineering > Bioengineering
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Blood, hemorheology, rheology, Sickle Cell Disease, Drag Reducing Polymers
Date Deposited: 26 Jan 2021 19:08
Last Modified: 26 Jan 2021 19:08
URI: http://d-scholarship.pitt.edu/id/eprint/39872

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