3D bioengineered tissues: From advancements in in vitro safety to new horizons in disease modeling

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There has been a groundswell of interest in developing more advanced in vitro models for use in drug safety assessment, with a variety of factors contributing to dissatisfaction with the existing systems, including lack of preclinical species congruence with human clinical outcomes, varied predictability and reliability of traditional 2D in vitro systems, increasing regulatory requirements to reduce risk of clinical toxicity, the growing cost of R&D, and pressure to reduce animal use in research.1 The chemical and consumer products industries have faced similar difficulties, with even greater pressure to reduce the quantity of animals used in research while adhering to growing regulatory pressures to analyze a large cache of compounds. In response, researchers have recently initiated efforts to either augment or replace the traditional gold‐standard 2D cultures with organotypic models.
It has long been accepted that 2D static cultures of primary cells are limited in their predictive capabilities, and pose significant challenges in longevity, propagation capacity, and maintenance of cellular identity. The use of immortalized cell lines in research ameliorated the longevity issue of primary cells, yet exacerbated the problem of recapitulating native cellular function in vitro; cell lines of cancerous origin display intracellular signaling pathways and gene expression patterns that are often significantly disparate from primary cells. For example, HepG2 and Caco‐2 cells, often utilized as 2D liver and intestinal cultures, respectively, provide useful data when employed to answer basic questions, but are known to be significantly divergent from primary cells in drug‐metabolizing enzyme and transporter gene expression, thus limiting their overall utility. More complex 2D cocultures, such as hepatocyte and nonparenchymal cell coculture, can sometimes impart improvements in functionality and maintain the differentiated state of a given primary cell for a slightly longer timeframe; however, such static cocultures still demonstrate significant, rapid divergence from the in vivo condition and lack native 3D tissue structural complexity. To overcome these challenges and approach an understanding of whole organ and body responses to a compound, animal models have long been utilized. However, the animal model used must be carefully chosen due to known and still unknown differences in gene expression patterns, isoform expression, protein subcellular localization, and downstream signaling cascades. Together, in vitro assays including 2D static culture systems and in vivo animal model data have been used for decades to bring numerous successful drugs to market; however, several well‐known failures due to the manifestation of toxicities in clinical trials and postmarketing surveillance has led the industry as a whole to question not just the efficiency, but also the predictive reliability of the traditional pipeline experimental paradigm.1 The development of advanced in vitro models therefore has significant potential to usher better and safer compounds to market through both improved safety predictability and mitigation of risks.
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