Synthesis, characterization and therapeutic efficacy of a biodegradable, thermoresponsive hydrogel designed for application in chronic infarcted myocardium

Abstract

IntroductionProgressive remodeling of the left ventricular (LV) architecture occurs after myocardial infarction (MI). While initially required for maintenance of cardiac output, this response ultimately leads to LV dysfunction and heart failure in the absence of a recurrent ischemic event [1,2]. Even with current optimal therapy, mortality in end-stage-heart-failure amounts to 20-50% per year [3]. Heart transplantation is applied as the last therapeutic option for patients with terminal heart-failure, but requests for organ transplantation far outstrip the number of donor organs. Therefore, new therapeutic strategies are urgently needed in order to ameliorate both patient prognosis and quality of life.Following MI, dilatation of the LV cavity has the effect of increasing LV wall tension, which triggers further dilatation of the LV cavity, and progression down a spiral of adverse cardiac remodeling towards the advanced stages of cardiac failure [4]. To restore wall tension, the endoventricular circular patch plasty technique (the Dor procedure) [5,6] and partial left ventriculectomy (the Batista procedure) [4] have been clinically implemented for severe cardiac dilation and dysfunction many years after an infarction. Employing a similar strategy to limit the remodeling pathway at an earlier stage, epicardial restraint therapies, such as the Acorn Cardiac Support Device [7], and the Paracor device [8] have been investigated. However, these both apply materials that are non-biodegradable and result in a permanent foreign body encapsulating the epicardium. Using biodegradable and elastic polyester urethane urea, we recently reported that cardiac patch implantation onto a chronic myocardial infarct prevented further cardiac dilatation and improved contraction, while altering LV wall thickness and compliance [9].Supported by a finite element model simulation [10], another concept in locally treating the failing cardiac wall was proposed where a bulking material is injected into the infarcted left ventricular wall to positively alter cardiac mechanics and result in a potentially beneficial NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript reduction of elevated stresses in the infarcted wall. In this numerical model the local systolic fiber stress distribution was determined in an infarcted LV wall injected with a mechanically passive material. The simulation showed that injection of a volume 4.5% that of the total LV wall volume and with a stiffness (elastic modulus) 20% of the natural LV tissue into the infarct border zone could decrease the fiber stress in the border zone of the infarct by 20% compared to a control simulation in which there was no injection. The mechanical simulation also showed that this attenuation effect on LV wall stress increased with the injection volume and the modulus of the injected material.Thermally responsive hydrogels are particularly attractive materials for injection therapy following MI since it is possible to inject the necessary fluid volumes from a syrin...

Injectable Acellular Hydrogels for Cardiac Repair

“…1) [22]. Like Dex-PCL-HEMA/PNIPAAm, poly(NIPAAm-co-AAc-co-HEMAPTMC) was engineered to undergo gelation at body temperature.…”

“…If anything, these results reveal the complexity in the material interaction with the myocardial tissue, including both the biological (e.g., material remodeling and inflammatory response) and mechanical (e.g., stress reduction) responses. Variable results from these studies indicate that material thickness [21,26,29,34], infarct size [22] [34], and/or increased angiogenesis [19,24,64] do not necessarily correlate directly with improved heart function. However, discrepancies in results could be due to inconsistencies in methodology (Table 1; e.g., animal models, infarct, amount of material injected, and timing of injection), and material properties and the importance of these parameters should be considered when investigating LV remodeling.…”

“…However, these approaches are limited by the invasive procedure in which they are applied, and clinical adoption has not occurred. In order to circumvent the invasive surgical placement of restraining devices early post-MI, our group and others have begun to explore the use of injectable materials, and specifically hydrogels, to limit infarct expansion and normalize the regional stress distribution [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35].…”

PLGA‐PNIPAM Microspheres Loaded with the Gastrointestinal Nutrient NaB Ameliorate Cardiac Dysfunction by Activating Sirt3 in Acute Myocardial Infarction

“…However, the limitations of PLGA‐based microspheres are its high burst release, poor drug loading, rapid degradation, and rapid drug release issues, as well as the small amount of time it remains in the body; these issues restrict its application, so that the hybrid PLGA delivery system is necessary. Poly ( N ‐isopropylacrylamide) (PNIPAM) is a temperature‐sensitive amphiphilic polymer that contains hydrophilic segments and hydrophobic segments 10, 11. When the temperature is lower than the critical solution temperature, the hydrogen‐bonding of hydrophilic segments controls the interaction between polymer chains and water, contributing to the polymer absorbing water and the subsequent dissolution of polymer chains and a swollen state formation; when the temperature is higher than the critical solution temperature, the hydrophobic interactions of the hydrophobic segments dominate the interaction between the polymer chains and water, and the polymer chains collapse, polymer precipitation occurs and a gel‐like state appears 10, 11, 12, 13.…”

“…Poly ( N ‐isopropylacrylamide) (PNIPAM) is a temperature‐sensitive amphiphilic polymer that contains hydrophilic segments and hydrophobic segments 10, 11. When the temperature is lower than the critical solution temperature, the hydrogen‐bonding of hydrophilic segments controls the interaction between polymer chains and water, contributing to the polymer absorbing water and the subsequent dissolution of polymer chains and a swollen state formation; when the temperature is higher than the critical solution temperature, the hydrophobic interactions of the hydrophobic segments dominate the interaction between the polymer chains and water, and the polymer chains collapse, polymer precipitation occurs and a gel‐like state appears 10, 11, 12, 13. Based on the characteristics of PNIPAM, if the PNIPAM is enwrapped on the surface of PLGA microspheres, which can increase the encapsulation efficiency of PLGA by accelerating the microsphere solidification rate with the changing temperature, it can then also extend the drug release of PLGA by slowing its degradation 14.…”