1. Institute of Microsurgery on Extremities, Shanghai Jiao Tong University Affiliated Shanghai Sixth People's Hospital, Shanghai 200233, China.
2. College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310027, China.
3. School of Materials Science and Engineering, Tianjin Key Laboratory of Composite and Functional Materials, Tianjin University, Tianjin 300350, China.
4. ZJU-Hangzhou Global Scientific and Technological Innovation Center, Hangzhou 311215, China.
5. Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Shanghai Sixth People's Hospital, Shanghai 200233, China.
6. Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510100, China.
7. Department of Cardiovascular Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510100, China.
# These authors contributed equally to this paper.
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.
Keywords: injectable hydrogel, myocardial infarction, matrix metalloproteinase, conductivity, hypoxia-inducible factor-1α