Tunable Acellular Hyaluronic Acid Hydrogel Systems to Attenuate Left Ventricular Remodeling

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Doctor of Philosophy (PhD)
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left ventricular remodeling
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Following myocardial infarction (MI), left ventricular (LV) remodeling initiates a series of maladaptive events that may induce heart failure (HF). The use of injectable biomaterials is an attractive approach to attenuate negative remodeling; however, optimal properties for these systems have not been identified. The general hypothesis is that the properties of injectable hydrogels control the magnitude and duration of stabilization in the weakened myocardium and the ability to attenuate LV remodeling. To test this hypothesis, three specific aims were developed. Increased stress due to geometric alterations is thought to exacerbate LV remodeling, causing infarct expansion. Aim 1 utilized methacrylated hyaluronic acid (MeHA) hydrogels to demonstrate ex vivo that macromer modification and oxidation-reduction (redox) initiator concentrations influence the mechanical properties of hydrogel/myocardium composites and their distribution in tissue. Experimental data incorporation into a finite element model of the dilated LV validated previous in vivo geometric outcomes and generally demonstrated the largest stress reduction with higher mechanics and larger volumes. Aims 2 and 3 evaluated the influence of temporal mechanical support on LV remodeling in an in vivo MI model. Hydroxyethyl methacrylate groups were coupled to HA to produce hydrolytically degradable hydrogels (HeMA-HA) polymerized via redox reactions. In Aim 2, hydrogel gelation, mechanics, and degradation properties were varied by altering HeMA modification to yield low and high HeMA-HA with similar gelation and initial mechanics but accelerated degradation kinetics compared to previously studied low and high MeHA. High HeMA-HA was more effective than low HeMA-HA treatment in limiting remodeling; however, high HeMA-HA only limited LV dilation for 2 weeks, while its high MeHA counterpart sustained support up to 8 weeks. In Aim 3, a hydrogel/microsphere composite system was evaluated as an alternative approach to enhance temporal support via collagen bulking through controlled macrophage responses. The composite treatment increased myocardial thickness and decreased chamber volumes compared to hydrogel alone. This work demonstrates the significance of the magnitude and duration of mechanical support in attenuating LV remodeling and provides insight on optimal material properties for injectable biomaterials to develop better therapies to prevent HF.

Jason A. Burdick
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