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Surface Coatings for Modifying Circulating Blood Cell Behavior

Malkin, AD (2018) Surface Coatings for Modifying Circulating Blood Cell Behavior. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Advances to biomaterial polymers and surface coatings have markedly improved the safety and efficacy of extracorporeal devices, but there is untapped potential to use these surfaces to modulate blood cell behavior. Sepsis, a severe inflammatory response to infection that affects nearly 1 million Americans per year, results in high levels of interleukin (IL-8) spilling into the circulatory system and diffusing into healthy tissue. Subsequently, circulating neutrophils become redirected into these healthy tissues, where they impair organ function. The focus of this work is the development of an extracorporeal device which can “reprogram” neutrophils using IL-8 immobilized within the device. Additionally, a zwitterionic thromboresistant coating was developed to reduce platelet deposition in extracorporeal devices.

A mechanistic computational model was developed to study the role of IL-8 induced CXCR-1/2 neutrophil surface receptor downregulation and its role in the progression of sepsis. The findings suggest that a device which modulates receptor expression could reduce morbidity and mortality in sepsis, but there is also potential for harm if implemented incorrectly. Scaled prototypes of an extracorporeal device, which used immobilized IL-8 to reduce neutrophil migratory response, were constructed and evaluated. While significant downregulation of CXCR-1 and CXCR-2 was achieved, this effect was insufficient to cause consistent migratory shutoff to IL-8 as measured by a Boyden chamber chemotaxis assay. Learnings from this testing were used to develop alternate device concepts which modulate leukocyte activity within an extracorporeal circuit.

A zwitterionic macromolecule surface coating was developed to reduce platelet deposition on polymethylpentene (PMP) hollow fiber membranes (HFMs). Two techniques of PMP HFM functionalization and subsequent conjugation of sulfobetaine block copolymers were evaluated within scaled PMP fiber minimodules. Both fiber configurations resulted in an 80-95% reduction in adherent platelets from whole ovine blood, stability under shear stress, and uninhibited gas exchange performance relative to unmodified HFMs. Initial testing indicates this coating is effective on polycarbonate and poly(vinyl chloride), two other materials commonly found in extracorporeal circuits, which may allow for tip to tip coating of extracorporeal circuits.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Malkin, ADalm270@pitt.eduALM270
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairFederspiel, WJwfedersp@pitt.eduWFEDERSP
Committee MemberKellum, JAkellum@pitt.eduKELLUM0000-0003-1995-2653
Committee MemberClermont, Gillescler@pitt.eduCLER
Committee MemberSingbartl,
Committee MemberWagner, WRwagner@pitt.eduWAGNER
Date: 24 January 2018
Date Type: Publication
Defense Date: 28 August 2017
Approval Date: 24 January 2018
Submission Date: 30 August 2017
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 209
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: neutrophil leukocyte sepsis biomaterials "surface coating" "surface functionalization" extracorporeal IL-8 zwitterionic "computational modeling" "respiratory assist" "artificial lung"
Date Deposited: 24 Jan 2018 21:02
Last Modified: 24 Jan 2018 21:02

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