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PublicationTunable Acellular Hyaluronic Acid Hydrogel Systems to Attenuate Left Ventricular Remodeling(2012-01-01) Tous, ElenaFollowing 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. PublicationInjectable Hydrogel Properties Influence Infarct Expansion and Extent of Postinfarction Left Ventricular Remodeling in an Ovine Model(2010-05-19) Ifkovits, Jamie L.; Tous, Elena; Koomalsingh, Kevin J.; Gorman, Joseph H.; Gorman, Robert C.; Burdick, Jason A.; Minakawa, Masahito; Robb, J. DanielA recent trend has emerged that involves myocardial injection of biomaterials, containing cells or acellular, following myocardial infarction (MI) to influence the remodeling response through both biological and mechanical effects. Despite the number of different materials injected in these approaches, there has been little investigation into the importance of material properties on therapeutic outcomes. This work focuses on the investigation of injectable hyaluronic acid (MeHA) hydrogels that have tunable mechanics and gelation behavior. Specifically, two MeHA formulations that exhibit similar degradation and tissue distribution upon injection but have differential moduli (∼8 versus ∼43 kPa) were injected into a clinically relevant ovine MI model to evaluate the associated salutary effect of intramyocardial hydrogel injection on the remodeling response based on hydrogel mechanics. Treatment with both hydrogels significantly increased the wall thickness in the apex and basilar infarct regions compared with the control infarct. However, only the higher-modulus (MeHA High) treatment group had a statistically smaller infarct area compared with the control infarct group. Moreover, reductions in normalized end-diastolic and end-systolic volumes were observed for the MeHA High group. This group also tended to have better functional outcomes (cardiac output and ejection fraction) than the low-modulus (MeHA Low) and control infarct groups. This study provides fundamental information that can be used in the rational design of therapeutic materials for treatment of MI.