Biologically Inspired PRINT Particles: Design, Fabrication, in vitro and in vivo Evaluations of Extremely Soft Particles Public Deposited

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Last Modified
  • March 21, 2019
Creator
  • Merkel, Timothy James
    • Affiliation: College of Arts and Sciences, Department of Chemistry
Abstract
  • This work utilized PRINT (particle replication in non-wetting templates) technology to fabricate extremely soft, biologically inspired particles. Using soft biological systems like cancer cells and red blood cells as an inspiration, hydrogels were designed with cell-like deformability. Preliminary studies, which utilized porogens added to otherwise highly crosslinked hydrogels, resulted in deformable, but rapidly cleared particles due to insufficient particle flexibility. A loosely crosslinked hydrogel system was developed and evaluated in bulk samples to determine the elastic modulus, and to closely match it to that of RBCs. Microfluidic models of vascular constriction were designed and fabricated in order to test in vitro the ability of particles to deform. RBC-sized particles (RBCMs) were fabricated from hydrogels having a range of modulus similar to that of RBCs. An intravital imaging technique allowed for direct observation of particles in the peripheral vasculature. Pharmacokinetic analysis of particle elimination showed an 8-fold decrease in particle modulus resulted in an over 30-fold increase in the elimination phase half-life for these particles. More deformable particles bypassed filtration in the lungs and elsewhere, resulting in extended circulation times. Novel hydrogel monomers were synthesized and used to fabricate low modulus particles with varying sizes to further probe the role of modulus on in vivo behavior. These particles avoided physical filtration in the circulation as a result of their ability to deform. These results demonstrated the critical nature of modulus as a design parameter for microparticles. As an application for such porous and long-circulating microgels, low modulus cationic RBCMs were tested for their ability to bind to, and affect the triggered release of, small nucleic acids. These particles may be able to capture and protect transiently available microRNA (miRNA) biomarkers for cancer from the circulation, potentiating the identification of novel biomarkers and early detection of the disease.
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  • In Copyright
Advisor
  • DeSimone, Joseph M.
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill
Graduation year
  • 2011
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