3D Tissue-Engineered Vascular Drug Screening Platforms: Promise and Considerations

Abstract

Despite the efforts devoted to drug discovery and development, the number of new drug approvals have been decreasing. Specifically, cardiovascular developments have been showing amongst the lowest levels of approvals. In addition, concerns over the adverse effects of drugs to the cardiovascular system have been increasing and resulting in failure at the preclinical level as well as withdrawal of drugs post-marketing. Besides factors such as the increased cost of clinical trials and increases in the requirements and the complexity of the regulatory processes, there is also a gap between the currently existing pre-clinical screening methods and the clinical studies in humans. This gap is mainly caused by the lack of complexity in the currently used 2D cell culture-based screening systems, which do not accurately reflect human physiological conditions. Cell-based drug screening is widely accepted and extensively used and can provide an initial indication of the drugs' therapeutic efficacy and potential cytotoxicity. However, in vitro cell-based evaluation could in many instances provide contradictory findings to the in vivo testing in animal models and clinical trials. This drawback is related to the failure of these 2D cell culture systems to recapitulate the human physiological microenvironment in which the cells reside. In the body, cells reside within a complex physiological setting, where they interact with and respond to neighboring cells, extracellular matrix, mechanical stress, blood shear stress, and many other factors. These factors in sum affect the cellular response and the specific pathways that regulate variable vital functions such as proliferation, apoptosis, and differentiation. Although pre-clinical in vivo animal models provide this level of complexity, cross species differences can also cause contradictory results from that seen when the drug enters clinical trials. Thus, there is a need to better mimic human physiological conditions in pre-clinical studies to improve the efficiency of drug screening. A novel approach is to develop 3D tissue engineered miniaturized constructs in vitro that are based on human cells. In this review, we discuss the factors that should be considered to produce a successful vascular construct that is derived from human cells and is both reliable and reproducible.

Steering Stem Cell Fate within 3D Living Composite Tissues Using Stimuli‐Responsive Cell‐Adhesive Micromaterials

“…3D cell cultures have the potential to closely emulate the architecture and function of our native tissues. [ 1 ] Material‐free microtissues in the form of cellular spheroids or organoids are considered the most biomimetic 3D culture models with myriad applications including disease modeling, [ 2 ] drug screening, [ 3 ] and modular tissue engineering. [ 4 ] 3D microtissues are typically formed via self‐assembly through cell–cell interactions within a non‐cell‐adhesive environment, such as a hanging drop, nonadhesive microwell, or spinner flask.…”

3D Human iPSC Blood Vessel Organoids as a Source of Flow‐Adaptive Vascular Cells for Creating a Human‐Relevant 3D‐Scaffold Based Macrovessel Model

“…[40,41] Still, only a limited number of these used iPSC-derived vascular cells to create a bilayered TEVG. [38,39,42] Nakayama et al successfully produced bilayered aligned nanofibrillar collagen graft, using iPSC-derived vascular cells as a cell source and demonstrated in their experiments that EC-seeded aligned scaffolds significantly reduced inflammatory response, based on monocytes adhesion and thus provided an atheroprotective function, even without application of flow on these constructs . [38] In 2019, the group of Generali et al also demonstrated a PGA-based bilayered vascular graft based on both iPSC-derived endothelial cells and vascular smooth muscle cells under flow.…”

3D Models as a Tool to Assess the Anti-Tumor Efficacy of Therapeutic Antibodies: Advantages and Limitations

“…Particularly demanding is the development of 3D tissue engineered blood vessels, due to their multi-layered cellular composition (endothelial cells, smooth muscle cells, and pericytes), which varies depending on vessel location, lumen size and function; exposure to flow and shear conditions, and expression of vascular tissue functions, including vasoactivity, permeability and secretory functions [ 91 ]. Several vascular 3D models are in development, as recently reviewed in [ 91 ], ranging from simpler scaffold-free and scaffold-based 3D models [ 92 ], to bioprinting techniques, dynamic culture in bioreactors and microfluidic systems. An additional challenge to these approaches is posed by tumor-associated vessels, which, as discussed above, are abnormal, making even more difficult to model a reliable TME suitable to assess the impact of anti-angiogenic therapies.…”