Engineering Human Cardiac Muscle Patch Constructs for Prevention of Post-infarction LV Remodeling

Abstract

Tissue engineering combines principles of engineering and biology to generate living tissue equivalents for drug testing, disease modeling, and regenerative medicine. As techniques for reprogramming human somatic cells into induced pluripotent stem cells (iPSCs) and subsequently differentiating them into cardiomyocytes and other cardiac cells have become increasingly efficient, progress toward the development of engineered human cardiac muscle patch (hCMP) and heart tissue analogs has accelerated. A few pilot clinical studies in patients with post-infarction LV remodeling have been already approved. Conventional methods for hCMP fabrication include suspending cells within scaffolds, consisting of biocompatible materials, or growing two-dimensional sheets that can be stacked to form multilayered constructs. More recently, advanced technologies, such as micropatterning and three-dimensional bioprinting, have enabled fabrication of hCMP architectures at unprecedented spatiotemporal resolution. However, the studies working on various hCMP-based strategies for in vivo tissue repair face several major obstacles, including the inadequate scalability for clinical applications, poor integration and engraftment rate, and the lack of functional vasculature. Here, we review many of the recent advancements and key concerns in cardiac tissue engineering, focusing primarily on the production of hCMPs at clinical/industrial scales that are suitable for administration to patients with myocardial disease. The wide variety of cardiac cell types and sources that are applicable to hCMP biomanufacturing are elaborated. Finally, some of the key challenges remaining in the field and potential future directions to address these obstacles are discussed.

A three-dimensional culture system for generating cardiac spheroids composed of cardiomyocytes, endothelial cells, smooth-muscle cells, and cardiac fibroblasts derived from human induced-pluripotent stem cells

“…The suspension culture system used in this report is broadly compatible with existing research equipment, and quality control checkpoints can be incorporated to maximize reproducibility; thus, our protocol can be readily adapted for a wide range of applications ( Mattapally et al, 2018 ; LaBarge et al, 2019a ; LaBarge et al, 2019b ; Kim et al, 2020 ; Daly et al, 2021 ; Polonchuk et al, 2021 ) and production facilities ( Abbasalizadeh et al, 2017 ; Adil and Schaffer, 2017 ; Li et al, 2017 ; Tomov et al, 2019 ). Furthermore, techniques for promoting spheroid fusion ( Kim et al, 2018 ; Mattapally et al, 2018 ) and for the use of spheroids in 3D bioprinting ( Duan, 2016 ; Maiullari et al, 2018 ; Aguilar et al, 2019 ; Alonzo et al, 2019 ; LaBarge et al, 2019b ; Qasim et al, 2019 ; Lu Wang et al, 2021 ) have already been established, so the spheroids generated via this protocol could serve as building blocks for even larger and more sophisticated cardiac-tissue constructs, and because ECM production occurred spontaneously in C4 spheroids, exogenously administered ECM components may be unnecessary. However, only ∼50 spheroids per batch were produced in this study, and several of the steps were performed manually, so additional automation will be necessary to maximize productivity on an industrial scale.…”

New Perspectives to Improve Mesenchymal Stem Cell Therapies for Drug-Induced Liver Injury

“…However, this is one of the most promising areas for the development of new therapeutic alternatives for liver diseases. In that sense, the potential benefits of engineered human cardiac muscle patch for the treatment of myocardial injury are readily observable in clinical studies [ 112 , 113 ].…”

Bidirectional Relationship Between Cardiac Extracellular Matrix and Cardiac Cells in Ischemic Heart Disease

“…Cardiac patches are being made to recapitulate the native ECM, enabling higher rates of engraftment and wound healing when implanted at the targeted tissue. 69 These constructs allow membrane modification to activate signaling pathways that support the injured myocardium to restore its contractile function. Researchers have investigated the potential of both biological and synthetic biomaterials to increase stem cell retention, maturation, and ability to modify the local microenvironment.…”