scholarly journals The development of a functional human small intestinal epithelium model for drug absorption

2021 ◽  
Vol 7 (23) ◽  
pp. eabh1586
Author(s):  
Ohman Kwon ◽  
Kwang Bo Jung ◽  
Kyeong-Ryoon Lee ◽  
Ye Seul Son ◽  
Hana Lee ◽  
...  
Keyword(s):  
Drug Absorption ◽  
Three Dimensional ◽  
Patient Specific ◽  
Oral Drug ◽  
Intestinal Epithelial ◽  
Molecular Features ◽  
Culture Models ◽  
Epithelial Physiology ◽  
Intestinal Transporters ◽  
And Function

Advanced technologies are required for generating human intestinal epithelial cells (hIECs) harboring cellular diversity and functionalities to predict oral drug absorption in humans and study normal intestinal epithelial physiology. We developed a reproducible two-step protocol to induce human pluripotent stem cells to differentiate into highly expandable hIEC progenitors and a functional hIEC monolayer exhibiting intestinal molecular features, cell type diversity, and high activities of intestinal transporters and metabolic enzymes such as cytochrome P450 3A4 (CYP3A4). Functional hIECs are more suitable for predicting compounds metabolized by CYP3A4 and absorbed in the intestine than Caco-2 cells. This system is a step toward the transition from three-dimensional (3D) intestinal organoids to 2D hIEC monolayers without compromising cellular diversity and function. A physiologically relevant hIEC model offers a novel platform for creating patient-specific assays and support translational applications, thereby bridging the gap between 3D and 2D culture models of the intestine.

Expression, regulation and function of intestinal drug transporters: an update

2017 ◽  
Vol 398 (2) ◽  
pp. 175-192 ◽  
Author(s):  
Janett Müller ◽  
Markus Keiser ◽  
Marek Drozdzik ◽  
Stefan Oswald
Keyword(s):  
Drug Absorption ◽  
Drug Transport ◽  
Drug Exposure ◽  
Oral Absorption ◽  
Basolateral Membrane ◽  
Oral Drug ◽  
Human Intestine ◽  
Intestinal Drug Absorption ◽  
Intestinal Transporters ◽  
And Function

Abstract Although oral drug administration is currently the favorable route of administration, intestinal drug absorption is challenged by several highly variable and poorly predictable processes such as gastrointestinal motility, intestinal drug solubility and intestinal metabolism. One further determinant identified and characterized during the last two decades is the intestinal drug transport that is mediated by several transmembrane proteins such as P-gp, BCRP, PEPT1 and OATP2B1. It is well-established that intestinal transporters can affect oral absorption of many drugs in a significant manner either by facilitating their cellular uptake or by pumping them back to gut lumen, which limits their oral bioavailability. Their functional relevance becomes even more apparent in cases of unwanted drug-drug interactions when concomitantly given drugs that cause transporter induction or inhibition, which in turn leads to increased or decreased drug exposure. The longitudinal expression of several intestinal transporters is not homogeneous along the human intestine, which may have functional implications on the preferable site of intestinal drug absorption. Besides the knowledge about the expression of pharmacologically relevant transporters in human intestinal tissue, their exact localization on the apical or basolateral membrane of enterocytes is also of interest but in several cases debatable. Finally, there is obviously a coordinative interplay of intestinal transporters (apical–basolateral), intestinal enzymes and transporters as well as intestinal and hepatic transporters. This review aims to give an updated overview about the expression, localization, regulation and function of clinically relevant transporter proteins in the human intestine.

Application of human IPSC-derived intestinal epithelial cells for evaluating oral drug absorption

2017 ◽  
Vol 32 (1) ◽  
pp. S70-S71
Author(s):  
Takanori Akazawa ◽  
Shinpei Yoshida ◽  
Koji Takahashi ◽  
Naoki Kusu ◽  
Yoshitaka Yamaguchi ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Drug Absorption ◽  
Intestinal Epithelial Cells ◽  
Oral Drug ◽  
Intestinal Epithelial ◽  
Oral Drug Absorption ◽  
Human Ipsc

scholarly journals Designing Hydrogel-Based Bone-On-Chips for Personalized Medicine

2021 ◽  
Vol 11 (10) ◽  
pp. 4495
Author(s):  
Gabriele Nasello ◽  
Mar Cóndor ◽  
Ted Vaughan ◽  
Jessica Schiavi
Keyword(s):  
Three Dimensional ◽  
In Vitro Models ◽  
Patient Specific ◽  
Specific Situation ◽  
Culture Chamber ◽  
Definition Of ◽  
And Function ◽  
Tissue Matrix ◽  
Hematopoietic Niche

The recent development of bone-on-chips (BOCs) holds the main advantage of requiring a low quantity of cells and material, compared to traditional In Vitro models. By incorporating hydrogels within BOCs, the culture system moved to a three dimensional culture environment for cells which is more representative of bone tissue matrix and function. The fundamental components of hydrogel-based BOCs, namely the cellular sources, the hydrogel and the culture chamber, have been tuned to mimic the hematopoietic niche in the bone aspirate marrow, cancer bone metastasis and osteo/chondrogenic differentiation. In this review, we examine the entire process of developing hydrogel-based BOCs to model In Vitro a patient specific situation. First, we provide bone biological understanding for BOCs design and then how hydrogel structural and mechanical properties can be tuned to meet those requirements. This is followed by a review on hydrogel-based BOCs, developed in the last 10 years, in terms of culture chamber design, hydrogel and cell source used. Finally, we provide guidelines for the definition of personalized pathological and physiological bone microenvironments. This review covers the information on bone, hydrogel and BOC that are required to develop personalized therapies for bone disease, by recreating clinically relevant scenarii in miniaturized devices.

scholarly journals Computational quantification of patient-specific changes in ventricular dynamics associated with pulmonary hypertension

2019 ◽  
Vol 317 (6) ◽  
pp. H1363-H1375 ◽  
Author(s):  
Henrik Finsberg ◽  
Ce Xi ◽  
Xiaodan Zhao ◽  
Ju Le Tan ◽  
Martin Genet ◽  
...  
Keyword(s):  
Three Dimensional ◽  
Volume Ratio ◽  
Volume Index ◽  
Patient Specific ◽  
Passive Stiffness ◽  
Modeling Framework ◽  
Physical Description ◽  
End Diastolic Volume ◽  
The Right ◽  
And Function

Pulmonary arterial hypertension (PAH) causes an increase in the mechanical loading imposed on the right ventricle (RV) that results in progressive changes to its mechanics and function. Here, we quantify the mechanical changes associated with PAH by assimilating clinical data consisting of reconstructed three-dimensional geometry, pressure, and volume waveforms, as well as regional strains measured in patients with PAH ( n = 12) and controls ( n = 6) within a computational modeling framework of the ventricles. Modeling parameters reflecting regional passive stiffness and load-independent contractility as indexed by the tissue active tension were optimized so that simulation results matched the measurements. The optimized parameters were compared with clinical metrics to find usable indicators associated with the underlying mechanical changes. Peak contractility of the RV free wall (RVFW) γRVFW,max was found to be strongly correlated and had an inverse relationship with the RV and left ventricle (LV) end-diastolic volume ratio (i.e., RVEDV/LVEDV) (RVEDV/LVEDV)+ 0.44, R2 = 0.77). Correlation with RV ejection fraction ( R2 = 0.50) and end-diastolic volume index ( R2 = 0.40) were comparatively weaker. Patients with with RVEDV/LVEDV > 1.5 had 25% lower γRVFW,max ( P < 0.05) than that of the control. On average, RVFW passive stiffness progressively increased with the degree of remodeling as indexed by RVEDV/LVEDV. These results suggest a mechanical basis of using RVEDV/LVEDV as a clinical index for delineating disease severity and estimating RVFW contractility in patients with PAH. NEW & NOTEWORTHY This article presents patient-specific data assimilation of a patient cohort and physical description of clinical observations.

scholarly journals A bioengineering perspective on modelling the intestinal epithelial physiology in vitro

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Maria Antfolk ◽  
Kim B. Jensen
Keyword(s):  
Small Intestine ◽  
Cell Layer ◽  
Three Dimensional ◽  
Intestinal Epithelial ◽  
Organ Function ◽  
Differentiated Cells ◽  
Recent Developments ◽  
Epithelial Cell Layer ◽  
Epithelial Physiology

AbstractThe small intestine is a specialised organ, essential for nutrient digestion and absorption. It is lined with a complex epithelial cell layer. Intestinal epithelial cells can be cultured in three-dimensional (3D) scaffolds as self-organising entities with distinct domains containing stem cells and differentiated cells. Recent developments in bioengineering provide new possibilities for directing the organisation of cells in vitro. In this Perspective, focusing on the small intestine, we discuss how studies at the interface between bioengineering and intestinal biology provide new insights into organ function. Specifically, we focus on engineered biomaterials, complex 3D structures resembling the intestinal architecture, and micro-physiological systems.

Targeting Intestinal Transporters for Optimizing Oral Drug Absorption

2010 ◽  
Vol 11 (9) ◽  
pp. 730-742 ◽  
Author(s):  
Manthena V. Varma ◽  
Catherine M. Ambler ◽  
Mohammad Ullah ◽  
Charles J. Rotter ◽  
Hao Sun ◽  
...  
Keyword(s):  
Drug Absorption ◽  
Oral Drug ◽  
Oral Drug Absorption ◽  
Intestinal Transporters
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