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INTRODUCTION: Cardiovascular diseases (CVDs) remain the leading cause of death worldwide, contributing a huge burden on healthcare providers. Myocardial infarction (MI) is one of the most fatal results of CVDs as it can lead to ultimate heart failure. Available treatments are used to mitigate many of the symptoms of MI, however they are not designed to repair the damaged tissue. A proposed solution to this lack of a regenerative treatment is a tissue engineered myocardial patch which would deliver healthy cells to repopulate the infarct area. In this research, natural and biocompatible materials, a polyhydroxyalkanoate (PHA)1-3 and alginate3, are used with the aim of producing a cellular multimaterial myocardial patch for this purpose. The patch would incorporate human induced pluripotent cardiomyocytes (hiPSC-CMs) and endothelial cells (hiPSC-ECs)
METHODS: Bacterial fermentation of Pseudomonas species was carried out to produce the PHA poly(3-hydroxyocatnoate-co-3-hydroxydecanoate), P(3HO-co-3HD), and this was purified and extracted from the bacteria using Soxhlet extraction. Resazurin assays with a C2C12 myoblast cell line were used to test the biocompatibility of P(3HO-co-3HD) and alginate hydrogel, the polymers were 3D printed (fused deposition modelling) to produce a multimaterial patch, with C2C12 cells encapsulated in the alginate and 3D-bioprinted. hiPSC-CMs and hiPSC-ECs were produced from (hiPSCs), seeded onto P(3HO-co-3HD) films, live/dead stained, and functionally analysed. Multimaterial patches were also tested in vivo in a rat model with an induced infarct.
RESULTS: P(3HO-co-3HD) has been successfully produced and characterised to confirm its chemical structure and 3HO:3HD molar ratio; mechanical properties which show that it is highly elastomeric, making it a suitable polymer for myocardial applications; and thermal properties, including a melting point of around 54oC making it easy to 3D print. P(3HO-co-3HD) and alginate were shown to both be non-cytotoxic via the resazurin assay. 3D printing was carried out with these materials, with C2C12 cells encapsulated in the alginate, and successfully produced cellular multimaterial patches at a high resolution, while maintaining cell viability. To improve the cell types included in the patch, hiPSC-CMs and hiPSC-ECs were produced, with initial results showing that they adhere to P(3HO-co-3HD) with good viability, and retain functionality through beating and calcium handling, as seen with Fluo-4 imaging.
CONCLUSIONS: Multimaterial patch production and successful encapsulation and printing of cells shows promise for the development of a functional cellular multimaterial patch. Future aims in this project are to include hiPSC-ECs and hiPSC-CMs in the multimaterial patch before carrying out in vitro and in vivo experiments in a rodent MI model.
REFERENCES:
Majid QA, et al. Natural biomaterials for cardiac tissue engineering: a highly biocompatible solution. Frontiers in Cardiovascular Medicine 7, 192, 2020
Bagdadi AV, et al. Poly(3-hydroxyoctanoate), a promising new material for cardiac tissue engineering. Journal of Tissue Engineering and Regenerative Medicine 12, 495, 2018
Rai R, et al. Medium chain length polyhydroxyalkanoates, promising new biomedical materials for the future. Materials Science and Engineering: R: Reports 72, 29, 2011
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