Carol Lucas CBET Div Of Chem, Bioeng, Env, & Transp Sys
ENG Directorate For Engineering
March 15, 2014
February 28, 2019 (Estimated)
Awarded Amount to Date:
Keith Neeves firstname.lastname@example.org (Principal Investigator)
Colorado School of Mines
Program Reference Code(s):
004E, 017E, 1045, 9251
Program Element Code(s):
Blood clots constitute an exquisitely engineered system, in which a complex fluid transforms into a solid plug at the site of an injury. Stable hemostatic clots are designed to arrest bleeding without occluding the vessel, withstand the forces of flowing blood, and slowly dissolve in concert with the wound healing process. Instabilities in any of these events can cause excessive clotting, or thrombosis, which is a leading cause of death. Despite the extensive knowledge base on the biochemistry and cell biology of clot formation, the mechanistic differences between a hemostatic clot and a thrombotic one remain largely unknown. Recent findings from the laboratory of the PI and from other labs suggest that impeding the transport of solutes away from the core of a clot is one mechanism that may prevent thrombosis. Based on this evidence, the hypothesis of the proposed studies is that transport of coagulation factors and platelet agonists within the interstitial space between blood cells is a key regulator of clot growth. If this hypothesis proves correct, then targeting this biophysical mechanism in conjunction with the conventional biochemical mechanisms could lead to more effective treatment of thrombosis.
This proposal investigates an important physiological system through the development of quantitative relationships between clot composition and growth. The conventional models of clot formation focus primarily on the kinetic processes involved in coagulation reactions and platelet signaling. The proposed studies build upon previous models by incorporating interstitial solute transport as a key mechanism of clot growth. With more capable predictive methods available, better drugs and drug delivery strategies can be developed. This hypothesis will be addressed by the following specific aims: (i) identifying the transport barriers that regulate clot growth and arrest, (ii) mapping the pore structure of clots, and (iii) exploiting interstitial transport to modulate clot growth. The implemented approach relies on applying theories and methods from the field of porous media transport to characterizing transport in tissues. In vitro and in vivo models of vascular injury will be used to measure transport properties in clots and the structure of their interstitial pore space. Constitutive relationships describing solute transport as a function of clot structure and composition will be developed for a range of physiological conditions. Results will be used to assess how known risk factors for thrombosis lead to uncontrolled clot growth and how this process can be physically impeded.
The proposed studies will develop theoretical and experimental models to predict blood clot growth and test novel therapeutic strategies. This is a potentially transformative outcome since controlling thrombosis is one of the grand challenges in medicine. The research plan integrates with the education plan by creating K-12 outreach programs and undergraduate research opportunities focused on the interface between engineering and biology. Specific educational and outreach objectives include (i) improving middle school students' attitudes towards science with hands-on curriculum, (ii) developing and assessing inquiry-based learning program in bioengineering at a high school with predominantly Latino students, and (iii) establishing a summer undergraduate research program in cellular biomechanics in partnership with the Children's Hospital Colorado for students in the Multicultural Engineering Program at the Colorado School of Mines.
PUBLICATIONS PRODUCED AS A RESULT OF THIS RESEARCH
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K. Rana, B.J. Timmer, K.B. Neeves. "A combined microfluidic-microstencil method for patterning molecules and cells," Biomicrofluidics, v.8, 2014, p. 056502.
A.A. Onasoga-Jarvis, T.J. Puls, S.K. O?Brien, L Kuang, H.J. Liang, K.B. Neeves. "Thrombin generation and fibrin formation under flow on biomimetic tissue factor rich surfaces," Journal of Thrombosis and Haemostasis, v.12, 2014, p. 372.
J.L. Sylman, S.M. Lantvit, M.M. Reynolds, K.B. Neeves. "The relative role of soluble guanylyl cylase dependent and independent pathways in nitric oxide inhibition of platelet aggregation under flow," Cellular and Molecular Bioengineering, v.7, 2015, p. 421.
A.L. Fogelson, K.B. Neeves. "Fluid mechanics of blood clot formation," Annual Reviews of Fluid Mechanics, v.47, 2015, p. 377.
K. Rana, B.J. Timmer, K.B. Neeves. "A combined microfluidic-microstencil method for patterning molecules and cells.," Biomicrofluidics, v.8, 2015, p. 056502.
O. Tasci, P.S. Herson, K.B. Neeves, D.W.M Marr. "Surface-enabled propulsion and control of colloidal microwheels," Nature Communication, v.7, 2016, p. 10225.
J.L. Sylman, D.T. Artzer, K. Rana, K.B. Neeves. "A vascular injury model using focal heat-induced activation of endothelial cells," Integrative Biology, v.15, 2015, p. 801.
B.R. Branchford, C.J. Ng, K.B. Neeves, J.A. Di Paola. "Microfluidic technology as an emerging clinical tool to evaluate thrombosis and hemostasis," Thrombosis Research, v.136, 2015, p. 13.
A.R. Wufsus, K. Rana, A. Brown, J.R. Dorgan, M.W. Liberatore, K.B. Neeves. "Elastic behavior and platelet retraction in low and high density fibrin gels," Biophysical Journal, v.108, 2015, p. 173.
M. Lehmann, A.M. Wallbank, K.A. Dennis, A.R. Wufsus, K.M. Davis, K. Rana, K.B. Neeves. "On-chip recalcification of citrated whole blood using a microfluidic herringbone mixer," Biomicrofluidics, v.6, 2015, p. 064106.
J.L. Sylman, S.M. Lantvit, M.M. Reynolds, K.B. Neeves. "The relative role of soluble guanylyl cylase dependent and independent pathways in nitric oxide inhibition of platelet aggregation under flow," Cellular and Molecular Bioengineering, v.7, 2014, p. 421.