Modelling tissues in 3D: the next future of pharmaco-toxicology and food research?

Abstract

The development and validation of reliable in vitro methods alternative to conventional in vivo studies in experimental animals is a well-recognised priority in the fields of pharmaco-toxicology and food research. Conventional studies based on two-dimensional (2-D) cell monolayers have demonstrated their significant limitations: the chemically and spatially defined three-dimensional (3-D) network of extracellular matrix components, cell-to-cell and cell-to-matrix interactions that governs differentiation, proliferation and function of cells in vivo is, in fact, lost under the simplified 2-D condition. Being able to reproduce specific tissue-like structures and to mimic functions and responses of real tissues in a way that is more physiologically relevant than what can be achieved through traditional 2-D cell monolayers, 3-D cell culture represents a potential bridge to cover the gap between animal models and human studies. This article addresses the significance and the potential of 3-D in vitro systems to improve the predictive value of cell-based assays for safety and risk assessment studies and for new drugs development and testing. The crucial role of tissue engineering and of the new microscale technologies for improving and optimising these models, as well as the necessity of developing new protocols and analytical methods for their full exploitation, will be also discussed.

Three-dimensional cell culture: the missing link in drug discovery

“…Lack of clinical efficacy and/or unacceptable toxicity are two of the main causes of drug failures during development [3,4]. Because of the high costs (typically 1 billion US dollars) in getting new drugs approved and the fact that many oncology drugs fail during clinical testing, especially during phase III -the most expensive phase of clinical development [5,6], it is imperative that compounds that are potentially ineffective or have an unacceptable toxicity profile are dismissed as early in the evaluation process as possible. This would preferably be before clinical trials and, ideally, even before animal testing has begun.…”

“…Failing early in the developmental stages enables the cost of failed molecules to remain relatively low, that is, the further into the development process a compound fails, understandably the more money a company has invested and so stands to lose [7]. It is, therefore, necessary to improve in vitro cell-based testing methods for a more informed prediction of drug candidate efficacy and safety, and thereby sieve out poorly functioning compounds while prioritising promising candidates [6].…”

“…It is probable, therefore, that 3D cellular assays would be more analogous to -and so predictive of -in vivo events compared to more simplified 2D cultures in which essential signalling pathways may have been lost or, at least, compromised [13]. The use of 3D in vitro systems in drug research and development has, therefore, been suggested as a potential link to bridge the gap between monolayer cultures and animal model studies [6,14].…”

Current standing and future prospects for the technologies proposed to transform toxicity testing in the 21st century

“…scaffolds), or in matrix-based conditions (e.g., agars and gels) . Several comparative studies between primary 3D and monolayer cultures have shown improvements in cell function and behavior, including improved cell-cell interactions, signal transduction, and gene expression (Mazzoleni et al, 2009;Pampaloni et al, 2009). Because 3D models reproduce and maintain organ-specific functions better, the interest in developing and applying these models for toxicity testing has increased during the last years (Stevens, 2009;Pampaloni et al, 2009).…”

Reconfigurable microfluidic hanging drop network for multi-tissue interaction and analysis

“…This loss of function in 2D motivates the strong current effort to develop three-dimensional tissue structures, as they have been proven to exhibit properties that more closely resemble those of a living organism 6,[8][9][10] . In analogy to the 2D case, microfluidic systems can be used to better control culturing conditions and to render those as similar as possible to the in vivo situation.…”