Self-cross-linkable hydrogels composed of partially oxidized alginate and gelatin for myocardial infarction repair

Abstract

Calcium cross-linked alginate hydrogel has shown positive results for the treatment of myocardial infarction in both acute and chronic rat models. However, cross-linked alginate hydrogels possess poor mechanical properties, uncontrollable degradation, and poor cell adhesion and infiltration. In this study, covalent cross-linking of partially oxidized alginate and gelatin hydrogel was developed for myocardial infarction treatment, as compared to cross-linked alginate hydrogel and saline. Specifically, the gelation process, mechanical properties, and biodegradation of both crosslinked alginate hydrogel and oxidized alginate and gelatin hydrogel were examined in vitro and in vivo; and a rat myocardial infarction model was developed by injecting hydrogel into hearts, and postinjection, echocardiography was performed at 2, 4, and 6 weeks, respectively. Matrix metalloprotease-2/9 activity was also examined by in situ zymography on frozen slices of the treated hearts. Based on the results, that both hydrogels enhanced scar thickness and attenuated heart remodeling compared with the saline control group and that, compared to cross-linked Downloaded from Bai et al. 127alginate hydrogel, oxidized alginate and gelatin hydrogel exhibited the increased mechanical strength, enhanced angiogenesis, and stronger cell-recruiting capacity. It has also been illustrated that oxidized alginate and gelatin hydrogel-treated hearts have much weaker cardiac remodeling, enhanced extracellular matrix accumulation, and reduced matrix metalloprotease activity than cross-linked alginate hydrogel-treated ones. All results suggest oxidized alginate and gelatin hydrogel may be more suitable for the myocardial infarction treatment.

Sustained co-delivery of BIO and IGF-1 by a novel hybrid hydrogel system to stimulate endogenous cardiac repair in myocardial infarcted rat hearts

“…Our previous study showed that the covalent cross-linking of gelatin with alginate forms a hydrogel with both enhanced mechanical properties and bioactive motifs for cell attachment, biodegradability, and functional recovery. 26 In the current study, we developed a novel hybrid hydrogel system with chemically encapsulated gelatin NPs, which are pH sensitive, for the sustained co-delivery of BIO + IGF-1 in MI treatment. The oxidation of sodium alginate produced aldehyde groups, which can form unstable amines found within the free amino group in the gelatin NPs; thus, they covalently linked the NPs to the alginate polymer chain.…”

“…Both the labeled gelatin NPs alone, as well as the labeled gelatin NPs that conjugated to the hydrogels, were injected into the area affected by MI in 20 rats (ten rats in each group), as described in a previous study. 26 The fluorescence of both groups was examined and recorded by an in vivo imaging system (DXS 4000 PRO; Eastman Kodak Co, Rochester, NY, USA) every 5 days.…”

“…Scar thickness was measured under a microscope, and on this basis, the relative scar thickness (defined by the average scar thickness divided by the average wall thickness) and the heart expansion index (defined by the LV cavity area/whole LV area/relative scar thickness) were evaluated, as in our previous study. 26 The detection of various tissue antigens was conducted using the primary antibody, CD31, for endothelial cells (Abcam plc). Double staining with anti-cardiac troponin-T (green, cardiomyocyte marker; Abcam plc) and anti-PCNA (red, proliferation marker; Abcam plc) was performed.…”

“…The gelation process and the mechanical properties of oxidized alginate and gelatin hydrogel were evaluated by examining the time of gelation onset and the evolution of elasticity at 37°C in the constant strain mode by means of a Bohlin Gemini II rheometer (Malvern Instruments) featuring a parallel plate geometry (40 mm in diameter), as in our previous study. 26 …”

“…26 Briefly, oxidized alginate was obtained by mixing sodium peroxide and sodium alginate (in distilled water) with mass ratios of 1:2. The reaction was conducted at 4°C overnight, and the degree of oxidation was evaluated by measuring the concentration of sodium peroxide, which was left unconsumed after 24 hours.…”