Developing<i>in vitro</i>assays to transform gastrointestinal safety assessment: potential for microphysiological systems

Peters, Matthew F.; Choy, Allison L.; Pin, Carmen; Leishman, Derek J.; Moisan, Annie; Ewart, Lorna; Guzzie‐Peck, Peggy; Sura, Radhakrishna; Keller, Douglas A.; Scott, Clay W.; Kolaja, Kyle

doi:10.1039/c9lc01107b

Cited by 55 publications

(37 citation statements)

References 90 publications

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“…Finally, incorporation of mechanical factors mimicking peristalsis might further improve in vivo predictivity of intestinal MPS. Important considerations for MPS model specifi cations are discussed in detail by Peters and co-authors in their recent manuscript ( Peters et al, 2020 ).…”

Section: Intestinementioning

confidence: 99%

Microphysiological systems in early stage drug development: Perspectives on current applications and future impact

et al. 2021

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Microphysiological systems (MPS) are making advances to provide more standardized and predictive physiologically relevant responses to test articles in living tissues and organ systems. The excitement surrounding the potential of MPS to better predict human responses to medicines and improving clinical translation is overshadowed by their relatively slow adoption by the pharmaceutical industry and regulators. Collaboration between multiorganizational consortia and regulators is necessary to build an understanding of the strengths and limitations of MPS models and closing the current gaps. Here, we review some of the advances in MPS research, focusing on liver, intestine, vascular system, kidney and lung and present examples highlighting the context of use for these systems. For MPS to gain a foothold in drug development, they must have added value over existing approaches. Ideally, the application of MPS will augment in vivo studies and reduce the use of animals via tiered screening with less reliance on exploratory toxicology studies to screen compounds. Because MPS support multiple cell types (e.g. primary or stem-cell derived cells) and organ systems, identifying when MPS are more appropriate than simple 2D in vitro models for understanding physiological responses to test articles is necessary. Once identified, MPS models require qualification for that specific context of use and must be reproducible to allow future validation. Ultimately, the challenges of balancing complexity with reproducibility will inform the promise of advancing the MPS field and are critical for realization of the goal to reduce, refine and replace (3Rs) the use of animals in nonclinical research.

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Section: Intestinementioning

confidence: 99%

Microphysiological systems in early stage drug development: Perspectives on current applications and future impact

et al. 2021

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“…Peters et al highlighted the importance of in vitro testing to assess gastrointestinal safety [54]. In another approach, De Haan et al monitored enzymatic digestion of milk using a microfluidic chip and demonstrated the importance of adjusting and correlating digestion times at physiological conditions on OoC [69].…”

Section: Gut-on-a-chipmentioning

confidence: 99%

Organ-on-a-Chip systems for new drugs development

2021

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Research on alternatives to the use of animal models and cell cultures has led to the creation of organ-on-a-chip systems, in which organs and their physiological reactions to the presence of external stimuli are simulated. These systems could even replace the use of human beings as subjects for the study of drugs in clinical phases and have an impact on personalized therapies. Organ-on-a-chip technology present higher potential than traditional cell cultures for an appropriate prediction of functional impairments, appearance of adverse effects, the pharmacokinetic and toxicological profile and the efficacy of a drug. This potential is given by the possibility of placing different cell lines in a three-dimensional-arranged polymer piece and simulating and controlling specific conditions. Thus, the normal functioning of an organ, tissue, barrier, or physiological phenomenon can be simulated, as well as the interrelation between different systems. Furthermore, this alternative allows the study of physiological and pathophysiological processes. Its design combines different disciplines such as materials engineering, cell cultures, microfluidics and physiology, among others. This work presents the main considerations of OoC systems, the materials, methods and cell lines used for their design, and the conditions required for their proper functioning. Examples of applications and main challenges for the development of more robust systems are shown. This non-systematic review is intended to be a reference framework that facilitates research focused on the development of new OoC systems, as well as their use as alternatives in pharmacological, pharmacokinetic and toxicological studies.

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“…Drug Toxicity Studies Drug-induced gastrointestinal toxicity (DIGT) is among the most frequently occurring adverse effects in clinical studies (Peters et al 2020). To date, no specific mechanistic diagnostic/prognostic biomarkers or translatable preclinical models of DIGT exist (Carr et al 2017).…”

Section: Structure and Cellular Phenotypes Of Small Intestinal Epithementioning

confidence: 99%

Human small intestinal organotypic culture model for drug permeation, inflammation, and toxicity assays

Markus¹,

Landry

Stevens

et al. 2020

In Vitro Cell.Dev.Biol.-Animal

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The gastrointestinal tract (GIT), in particular, the small intestine, plays a significant role in food digestion, fluid and electrolyte transport, drug absorption and metabolism, and nutrient uptake. As the longest portion of the GIT, the small intestine also plays a vital role in protecting the host against pathogenic or opportunistic microbial invasion. However, establishing polarized intestinal tissue models in vitro that reflect the architecture and physiology of the gut has been a challenge for decades and the lack of translational models that predict human responses has impeded research in the drug absorption, metabolism, and drug-induced gastrointestinal toxicity space. Often, animals fail to recapitulate human physiology and do not predict human outcomes. Also, certain human pathogens are species specific and do not infect other hosts. Concerns such as variability of results, a low throughput format, and ethical considerations further complicate the use of animals for predicting the safety and efficacy xenobiotics in humans. These limitations necessitate the development of in vitro 3D human intestinal tissue models that recapitulate in vivo-like microenvironment and provide more physiologically relevant cellular responses so that they can better predict the safety and efficacy of pharmaceuticals and toxicants. Over the past decade, much progress has been made in the development of in vitro intestinal models (organoids and 3D-organotypic tissues) using either inducible pluripotent or adult stem cells. Among the models, the MatTek's intestinal tissue model (EpiIntestinal™ Ashland, MA) has been used extensively by the pharmaceutical industry to study drug permeation, metabolism, drug-induced GI toxicity, pathogen infections, inflammation, wound healing, and as a predictive model for a clinical adverse outcome (diarrhea) to pharmaceutical drugs. In this paper, our review will focus on the potential of in vitro small intestinal tissues as preclinical research tool and as alternative to the use of animals.

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Developingin vitroassays to transform gastrointestinal safety assessment: potential for microphysiological systems

Abstract: Drug-induced gastrointestinal toxicities (DI-GITs) are among the most common adverse events in clinical trials.

Cited by 55 publications

References 90 publications

Microphysiological systems in early stage drug development: Perspectives on current applications and future impact

Microphysiological systems in early stage drug development: Perspectives on current applications and future impact

Organ-on-a-Chip systems for new drugs development

Human small intestinal organotypic culture model for drug permeation, inflammation, and toxicity assays

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