Abstract
Statement of Purpose: Long-term chemotherapy in cancer treatment may lead to serious myocardiopathy that then prompts heart failure (HF) or even death. Additionally, patients over 65 years of age are likely to have complications in other organs, making the treatment an insurmountable obstacle. In previous studies, regenerative therapy has been reported as a robust method to improve HF. Despite the successful proof of concept, one big challenge for clinical translational is to deliver the therapeutics in a minimally invasive way. To that end, we sought to develop a minimal-invasively injectable synthetic cardiac stromal cells (synCSC) adhesive (MISA) that could be delivered with small incisions on the chest wall, without an open-chest surgery. The MISA should be gelatinized easily right after transplantation to increase the retention of synCSCs in the pericardium cavity. To mimic aging patients with cardiomyopathy caused by HF, we have established an aging rat model with HF induced by doxorubicin. The overarching hypothesis is that minimal-invasively delivery of MISA improves synCSC therapeutic efficacy in the aging rat model of HF. Methods: We created an injectable MISA by embedding optimized synCSCs into a myoECM-fibrinogen gel in an adjusted concentration. MISA retains my ECM proteins and peptide fragments while gelatinizing fast after injection. After MISA fabrication, we characterized its 3D morphological features to determine synCSC embedding efficiency. To determine the safety, efficacy, and mechanism of MISA treatment, we employed multiple doxorubicin intraperitoneal injections as an oxidant generator and topoisomerase II inhibitors to create an aging rat model of HF. Results: MISA improved therapeutic efficacy in HF treatment after being injected minimal-invasively. Also, MISA polymerized fast after administration and formation of a thin layer of regenerative gel that released regenerative factors to the myocardium in a sustained release manner while degradation. MISA as therapeutic biologics has the potential to revolutionize cardiovascular regenerative medicine.
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