Doctor of Philosophy, University of Akron, 2024, Polymer Science

Polymer-based coacervates can be prepared from a large variety of compositions. This provides versatility to coacervates as a material platform, but can also make them difficult to characterize, especially when other molecules or biologics are used in the same solution. The Joy lab has previously developed a platform to make thermoresponsive coacervating polyesters in a modular fashion. This allows us to make incremental changes to the coacervate structure and thus better observe how the structure affects the properties in various applications. In this work, we look at coacervates for hemostatic materials for non-compressible torso hemorrhage, and as sustained release drug delivery vehicles for colchicine release. Through a variety of experimental methods, our goal is to link structural changes in the coacervating polyester to the performance of the coacervate. The performance of our hemostatic coacervate was evaluated using clotting time tests, hemolysis tests, and rheology to determine how our materials interact with blood components. The trend in this data was further confirmed with in vivo mouse model studies which showed that the coacervates can perform well as hemostatic materials, and that the in vitro studies can effectively screen materials. We have also shown that amines in our coacervates are not effective and contrary to expectations and literature may increase bleeding times. To better predict coacervate properties on drug release, we employ NMR techniques such as STD and DOSY to better understand the strength of interactions between the coacervate and drug. The final drug release study confirms our NMR findings, and while the NMR techniques are not easily quantifiable, they do show an excellent relative predictability which can also be used to screen materials for an application. Ultimately, the tools employed for understanding coacervate performance enhance our understanding of their behavior in applications such as hemostasis and sustained (open full item for complete abstract)

Committee: Abraham Joy (Advisor); James Eagan (Committee Chair); Nita Sahai (Committee Member); Toshikazu Miyoshi (Committee Member); Ge Zhang (Committee Member) Subjects: Biomedical Engineering; Biomedical Research; Chemistry; Experiments; Materials Science; Molecular Chemistry; Molecules; Nanotechnology; Organic Chemistry; Pharmaceuticals

Doctor of Philosophy, Case Western Reserve University, 2019, Macromolecular Science and Engineering

Poly(acrylic acid) (PAA) is an anionic polyelectrolyte that sees a number of commercial uses, chiefly to exploit crosslinked PAA's superabsorbance. These materials tend to be soft and brittle with low elasticity. In contrast, we have found that PAA hydrogels synthesized with high concentrations of salt exhibit properties markedly different from both PAA hydrogels synthesized without salt and those incubated in the same amount of salt post-synthesis. Examples of these changes include reduced equilibrium swelling, substantially increased elongation, increased modulus, and near-complete recovery after strain. Investigated salts include chloride salts of lithium, sodium, cesium, calcium, and zinc. The greatest enhancement in viscoelastic behavior comes from multivalent salts such as zinc chloride, but is also evident in lithium chloride-loaded samples. The enhanced mechanical properties of these salt-loaded gels significantly diminish upon washing the materials with water to remove the salt, and cannot be restored upon incubation in solutions containing equivalent concentrations of salt. This indicates that the presence and organization of the salt during synthesis is critical to the property changes. Furthermore, the inability of the materials to regain these mechanical properties by soaking them in salt solutions preclude simple explanations for enhancement, such as the chelation of multivalent ions leading to ionic crosslink formation. This fundamental study led to a strong curiosity into poly(acrylic acid) product design. Initially, the primary end-use envisioned for these gels was as a mimic for biological materials such as nerve and muscle tissue, which are essentially complex cation exchange membranes. Understanding the role and organization of the metal in these high-salt PAA gels gave insight into structuring an investigation of said tissue mimics. This then sparked interest in using each layer of knowledge that had been gathered to develop a sui (open full item for complete abstract)

Committee: Gary Wnek (Committee Chair); Michael Hore (Committee Member); Horst von Recum (Committee Member); David Schiraldi (Committee Member) Subjects: Biomedical Engineering; Materials Science; Polymers

Doctor of Philosophy, Case Western Reserve University, 2013, Biomedical Engineering

Uncontrolled hemorrhage comprises 60-70% of trauma-associated mortality in the absence of other lethal conditions (e.g. damage to central nervous or cardiac system). Immediate intervention is critical to improving chances of survival. While there are several products to control bleeding for external wounds including pressure dressings, tourniquets or topical hemostatic agents there are few, if any, effective treatments that can be administered in the field to help staunch internal bleeding. Intravenous hemostatic nanoparticles that augment blood clotting when administered after trauma have been previously shown to half bleeding times in a femoral artery injury model in rats. The aims of the present study were to: 1) Determine their efficacy in a lethal hemorrhagic liver injury model, 2) determine the impact of targeting ligand concentration on hemostasis, and 3) test them in a clinically relevant porcine model of hemorrhage. Nanoparticle administration (GRGDS-NP1, 40 mg/kg) after lethal liver resection in the rat increased 1-hour survival to 80% compared to 40-47% in controls. Targeting ligand conjugation was then increased 100-fold (GRGDS-NP100), and a dosing study performed. GRGDS-NP100 hemostatic nanoparticles (2.5 mg/kg) were efficacious at doses 8-fold lower than GRGDS-NP1, and increased 1-hour survival to 92%. In vitro analysis using rotational thromboelastometry (ROTEM) confirmed the increased dose-sensitivity of GRGDS-NP100 and laid the foundation for methods to determine optimal ligand concentration parameters. Hemostatic nanoparticles were then tested in a clinically relevant porcine liver injury model, which elucidated an unexpected adverse reaction, comprised of a massive hemorrhagic response. A naive (uninjured) porcine model was then employed. These experiments revealed an adverse reaction consistent with complement activation related pseudoallergy (CARPA), which could be mediated by tuning nanoparticles' zeta potential. Neutralizing the nanopa (open full item for complete abstract)

Committee: Erin Lavik Sc.D. (Committee Chair); Jeffrey Ustin M.D. (Committee Member); Horst von Recum Ph.D. (Committee Member); Robert Miller Ph.D. (Committee Member) Subjects: Biomedical Engineering; Biomedical Research; Medicine