Kimmel, Jeremy D.
(2011)
Characterizing Cytokine Transport in Hemoadsorption Beads Used to Treat Sepsis.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Extracorporeal blood purification is a promising therapeutic modality for sepsis, a potentially fatal, dysfunctional immune disorder caused by infection. During sepsis, dysregulation of the innate immune system leads to excessive release of inflammatory mediators known as cytokines into the bloodstream. Removal of cytokines from the circulating blood may attenuate hyper-inflammatory signaling and promote immunologic homeostasis. We are developing an extracorporeal blood purification device to remove cytokines from the blood using biocompatible, porous, polymeric beads. Hemoadsorption therapy using our device has demonstrated improved survival in a murine sepsis model, and may serve as a novel adjuvant therapy to improve patient outcomes in the setting of severe sepsis and septic shock.We developed a mathematical model to characterize cytokine adsorption dynamics within the device, and used confocal laser scanning microscopy (CLSM) to quantify cytokine transport within single sorbent beads. Finite element modeling was utilized to estimate model parameters based on best fits to CLSM data, and the fitted model was used to simulate cytokine adsorption behavior under clinically relevant conditions. We investigated intraparticle cytokine transport under competitive and non-competitive adsorption conditions, and demonstrated that effects due to coadsorption of serum solutes are likely negligible under physiologic cytokine concentrations. CLSM results indicate that less than 20% of available sorbent surface area is utilized for cytokine adsorption. Tumor necrosis factor (TNF) is a pleiotropic, pro-inflammatory cytokine, and serves as a primary initiator of systemic inflammation during sepsis. Removal of TNF within the device is slow, putatively due to hindered diffusion of the large TNF molecule (51kD) within the sorbent pores. We induced deoligomerization of trimeric TNF into its monomeric subunits, and demonstrated significantly accelerated capture of monomerized TNF within the device, compared to native TNF. We investigated small molecules capable of facilitating TNF deoligomerization, and proposed techniques to immobilize such molecules on the sorbent surface. Functionalized sorbent beads capable of locally dissociating TNF at the bead surface may significantly accelerate capture of TNF from the circulating blood. This concept could be expanded to enhance capture of oligomeric biomolecules using size exclusion filtration materials for a variety of disease states.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
19 September 2011 |
| Date Type: |
Completion |
| Defense Date: |
11 May 2011 |
| Approval Date: |
19 September 2011 |
| Submission Date: |
5 July 2011 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| 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: |
confocal microscopy; cytokine; hemoadsorption; sepsis |
| Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-07052011-152234/, etd-07052011-152234 |
| Date Deposited: |
10 Nov 2011 19:50 |
| Last Modified: |
19 Dec 2016 14:36 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/8274 |
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