An MMP-degradable and conductive hydrogel to stabilize HIF-1α for recovering cardiac functions

Abstract

Rationale: Although a few injectable hydrogels have shown a reliable biosafety and a moderate promise in treating myocardial infarction (MI), the updated hydrogel systems with an on-demand biodegradation and multi-biofunctions to deliver therapeutic drug would achieve more prominent efficacy in the future applications. In this report, a conductive and injectable hydrogel crosslinked by matrix metalloproteinase-sensitive peptides (MMP-SP) was rationally constructed to stabilize hypoxia-inducible factor-1α (HIF-1α) to recover heart functions after MI. Methods: Firstly, tetraaniline (TA) was incorporated into partially oxidized alginate (ALG-CHO) to endow the hydrogels with conductivity. The 1,4-dihydrophenonthrolin-4-one-3-carboxylic acid (DPCA) nanodrug was manufactured with high drug loading capacity and decorated with polymerized dopamine (PDA) to achieve a stable release of the drug. Both ALG-CHO and DPCA@PDA can be cross-linked by thiolated hyaluronic acid (HA-SH) and thiolated MMP-SP to construct a MMP-degradable and conductive hydrogel. After administration in the infarcted heart of rats, echocardiographic assessments, histological evaluation, and RT-PCR were used to evaluate therapeutic effects of hydrogels. Results: The cell viability and the results of subcutaneous implantation verify a good cytocompatibility and biocompatibility of the resulting hydrogels. The hydrogel shows remarkable strength in decreasing the expression of inflammatory factors, maintaining a high level of HIF-1α to promote the vascularization, and promoting the expression of junctional protein connexin 43. Meanwhile, the multifunctional hydrogels greatly reduce the infarcted area (by 33.8%) and improve cardiac functions dramatically with ejection fraction (EF) and fractional shortening (FS) being increased by 31.3% and 19.0%, respectively. Conclusion: The as-prepared hydrogels in this report achieve a favorable therapeutic effect, offering a promising therapeutic strategy for treating heart injury.

Maturation of induced pluripotent stem cell-derived cardiomyocytes and its therapeutic effect on myocardial infarction in mouse

“…From the above data, we know that mature iPSC-CMs can generate more gap junctions than immature cells, and these results are also consistent with previous studies [ 57 ]. After MI, improving intercellular signaling and promoting the formation of new blood vessels are the two most important aspects of improving prognosis [ 58 ]. In the case of Gel loading, the generated gap junction results are better than the transplantation of pure mature iPSC-CMs.…”

Knowledge Domain and Hotspots Predict Concerning Electroactive Biomaterials Applied in Tissue Engineering: A Bibliometric and Visualized Analysis From 2011 to 2021

“…This success encouraged the development of a wide range of conductive hydrogel-based myocardial tissue engineering scaffolds. For example, Liu et al (2022) and Wei et al (2022) developed paintable and rapidly bondable conductive hydrogels as therapeutic cardiac patches, which can improve the reconstruction of cardiac function and revascularization of infarct myocardium ( Wei et al, 2022 ). Works by Qian et al (2018a) , Qian et al (2018b) , and Xu et al (2018) successfully demonstrated that nerve tissue engineering scaffold-coated graphene-loaded polycaprolactone based on a conductive hydrogel can transmit electrical signals, thus realising nerve tissue regeneration and functional reconstruction.…”

Insight into Heart-Tailored Architectures of Hydrogel to Restore Cardiac Functions after Myocardial Infarction

“…4 Cross-linked by MMP-sensitive peptides (MMP-SP), the multifunctional injectable hydrogel based on oxidized alginate (ALG-CHO) and HA was constructed to deliver 1,4dihydrophenonthrolin-4-on hydroxylase (PHD) and a stabilizer of HIF-1α for MI treatment. 125 3.11. Injectable Hydrogels for Minimally Invasive Delivery.…”

“… Similarly, an ELRs-based hydrogel could allow for cell colonization and support post-MI remodeling . Cross-linked by MMP-sensitive peptides (MMP-SP), the multifunctional injectable hydrogel based on oxidized alginate (ALG-CHO) and HA was constructed to deliver 1,4-dihydrophenonthrolin-4-on hydroxylase (PHD) and a stabilizer of HIF-1α for MI treatment …”