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Multiple approaches to the treatment of sepsis using an extracorporeal device

Fedorchak, Morgan Virginia (2011) Multiple approaches to the treatment of sepsis using an extracorporeal device. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Sepsis is a systemic inflammatory response in the presence of infection that results in anuncontrolled release of inflammatory mediators called cytokines. High levels of cytokines,especially in immune-compromised patients, can contribute to detrimental outcomes. Previousattempts that targeted single mediators were unsuccessful. The usefulness of therapies likehemodialysis for treating sepsis has been attributed to adsorption on the hemofiltrationmembrane rather than convective removal of cytokines. Thus, the main focus of this work wasto develop a device that uses the principles of adsorption to nonspecifically remove cytokinesfrom blood. The device we have developed contains highly porous, biocompatible polymer beads made up of a polystyrene-divinylbenzene copolymer. In vitro testing of this device has demonstrated that it can remove over 90% of small cytokines such as interleukin-6 (IL-6) and interleukin-10 (IL-10) and up to 70% of the trimeric cytokine tumor necrosis factor (TNF) due to the large surface area for adsorption provided by the porous network. We have also developed amathematical model that provides a straightforward relationship between the operational parameters of the device and the removal rate of individual cytokines over time. Anexperimental validation of this model shows that the rate of removal for a given cytokinepolymercombination can be predicted with a high level of accuracy over a wide range of parameters. We have used this model to test several variations on the original device, including the addition of immobilized antibodies on the surface of the beads to improve the specific affinity for TNF. Lastly, we have used the techniques of covalent immobilization of proteins to attach interleukin-8 (IL-8), a chemoattractant cytokine, on the inner lumen of polymer fibers. By bringing leukocytes into contact with the IL-8 on the fibers within a device, we hope to be able to modulate the activation level of the cells and provide for improved outcomes in septic patients. We demonstrate here that, under the correct conditions, the immobilized IL-8 devicecan in fact result in significant changes in leukocyte activity. We feel that both of these devices are promising new treatment methods for sepsis and could have potential applications to other disease states.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Fedorchak, Morgan Virginiamod8@pitt.eduMOD8
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairFederspiel, William Jfederspielwj@upmc.eduWFEDERSP
Committee MemberKellum, John Akellumja@ccm.upmc.eduKELLUM
Committee MemberSingbartl,
Committee MemberLittle, Steven Rsrlittle@pitt.eduSRLITTLE
Committee MemberWagner, William Rwagnerwr@upmc.eduWAGNER
Date: 27 June 2011
Date Type: Completion
Defense Date: 14 January 2011
Approval Date: 27 June 2011
Submission Date: 29 March 2011
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
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: cytokine; extracorporeal blood purification; hemoadsorption; sepsis
Other ID:, etd-03292011-153634
Date Deposited: 10 Nov 2011 19:33
Last Modified: 19 Dec 2016 14:35


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