A Bile Duct‐on‐a‐Chip With Organ‐Level Functions

Du, Yu; Khandekar, Gauri; Llewellyn, Jessica; Polacheck, William J.; Chen, Christopher; Wells, Rebecca G.

doi:10.1002/hep.30918

Cited by 58 publications

(60 citation statements)

References 44 publications

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“…Cholangiocytes form a monolayer within these devices, form a cylindrical tube, express CK19, tight (ZO1) and cell junction (E-cadherin 1) proteins, show polarity and respond to luminal shear flow. The device format offers significant advantage over traditional cholangiocyte spheroids and overcomes the difficulties of sampling lumen contents, accessing apical surface and the inability to control positional spheroid growth in the gel ( 113 ). Such a system can prove highly beneficial and indispensable to study cellular biology of human cholangiocytes regionally derived from either livers, GB, or duct remnants from patients with BA.…”

Section: Disease Modeling In Bamentioning

confidence: 99%

Recent developments in etiology and disease modeling of biliary atresia: a narrative review

et al. 2020

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Biliary atresia (BA) is a rare but severe fibroinflammatory disease of the extrahepatic and the intrahepatic bile ducts. Without prompt interventions, BA has fatal outcomes and is the most common indicator for pediatric liver transplantation (LTx). While the mainstay of treatment involves surgically correcting the extrahepatic biliary obstruction via Kasai hepato-portoenterostomy (KHPE), activation of a multitude of biological pathways and yet-to-be-determined etiology in BA continue to foster liver inflammation, cirrhosis and need for LTx. However, important caveats still exist in our understandings of the biliary pathophysiology, the rapidity of liver fibrosis and progression to liver failure, largely due to limited knowledge of the triggers of biliary injury and the inability to accurately model human BA. Although inconclusive, a large body of existing literature points to a potential viral infection in the early peri- or postnatal period as triggers of epithelial injury that perpetuates the downstream biliary disease. Further confounding this issue, are the lack of in-vivo and in-vitro models to efficiently recapitulate the cardinal features of BA, primarily liver fibrosis. To overcome these barriers in BA research, new directions in recent years have enabled (I) identification of additional triggers of biliary injury linked mostly to environmental toxins, (II) development of models to investigate liver fibrogenesis, and (III) translational research using patient-derived organoids. Here, we discuss recent advances that undoubtedly will stimulate future efforts investigating these new and exciting avenues towards mechanistic and drug discovery efforts and disease-preventive measures. The implications of these emerging scientific investigations and disease modeling in severe fibrosing cholangiopathies like BA are enormous and contribute substantially in our understandings of this rare but deadly disease. These findings are also expected to facilitate expeditious identification of translationally targetable pathways and bring us one step closer in treating an infant with BA, a population highly vulnerable to life-long liver related complications.

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Section: Disease Modeling In Bamentioning

confidence: 99%

Recent developments in etiology and disease modeling of biliary atresia: a narrative review

et al. 2020

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“…Unfortunately, this is a major effort and is the topic of our current studies. Furthermore, pharmacological studies to evaluate the biliary content and permeability of the bile ducts (Du et al, 2020) would provide further evidence for the functionality of the bile ducts formed in between the spheroids. To our knowledge, this study presents the first example of an in vitro microliver tissue platform composed of three different cell types, hepatocytes, cholangiocytes, and fibroblasts, demonstrating a functional biliary network interconnected with the BC structure in spheroid clusters.…”

Section: Discussionmentioning

confidence: 99%

Development of liver microtissues with functional biliary ductular network

Hafiz

Bulutoglu

Mansy

et al. 2020

Biotech & Bioengineering

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Liver tissue engineering aims to create transplantable liver grafts that can serve as substitutes for donor's livers. One major challenge in creating a fully functional liver tissue has been to recreate the biliary drainage in an engineered liver construct through integration of bile canaliculi (BC) with the biliary ductular network that would enable the clearance of bile from the hepatocytes to the host duodenum. In this study, we show the formation of such a hepatic microtissue by coculturing rat primary hepatocytes with cholangiocytes and stromal cells. Our results indicate that within the spheroids, hepatocytes maintained viability and function for up to 7 days. Viable hepatocytes became polarized by forming BC with the presence of tight junctions. Morphologically, hepatocytes formed the core of the spheroids, while cholangiocytes resided at the periphery forming a monolayer microcysts and tubular structures extending outward. The spheroids were subsequently cultured in clusters to create a higher order ductular network resembling hepatic lobule. The cholangiocytes formed functional biliary ductular channels in between hepatic spheroids that were able to collect, transport, and secrete bile. Our results constitute the first step to recreate hepatic building blocks with biliary drainage for repopulating the whole liver scaffolds to be used as transplantable liver grafts.

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“…In 2016, the US National Center for Advancing Translational Sciences spearheaded funding for the development of Tissue Chip Testing Centers to further develop and validate tissue chip technology for drug development in regulatory, academic, and industry settings [ 232 ]. In recent years, researchers have used the tissue assembly approach in microfluidic devices to create a variety of tissue constructs relevant for drug development, such as bile ducts [ 233 ] required for liver metabolism and adipose chips for ADME studies [ 234 ]. Table 1 summarizes recent representative advances in tissue chips relevant for drug development, as well as other chips for modeling human tissue physiology that are applicable to disease areas discussed in this review.…”

Section: Engineering Advances: Assembling Advanced In Vitromentioning

confidence: 99%

Engineered tissues and strategies to overcome challenges in drug development

Khalil

Jaenisch

Mooney

2020

Advanced Drug Delivery Reviews

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Current preclinical studies in drug development utilize high-throughput in vitro screens to identify lead drug candidates, followed by both in vitro and in vivo models to predict lead candidates' pharmacokinetic and pharmacodynamic properties. The goal of these studies is to reduce the number of lead drug candidates down to the most likely to succeed in later human clinical trials. However, only 1 in 10 drug candidates that emerge from preclinical studies will succeed and become an approved therapeutic. Lack of efficacy or undetected toxicity represents roughly 75% of the causes for these failures, despite these parameters being the primary exclusion criteria in preclinical studies. Recently, advances in both biology and engineering have created new tools for constructing new preclinical models. These models can complement those used in current preclinical studies by helping to create more realistic representations of human tissues in vitro and in vivo . In this review, we describe current preclinical models to identify their value and limitations and then discuss select areas of research where improvements in preclinical models are particularly needed to advance drug development. Following this, we discuss design considerations for constructing preclinical models and then highlight recent advances in these efforts. Taken together, we aim to review the advances as of 2020 surrounding the prospect of biological and engineering tools for adding enhanced biological relevance to preclinical studies to aid in the challenges of failed drug candidates and the burden this poses on the drug development enterprise and thus healthcare.

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A Bile Duct‐on‐a‐Chip With Organ‐Level Functions

Cited by 58 publications

References 44 publications

Recent developments in etiology and disease modeling of biliary atresia: a narrative review

Recent developments in etiology and disease modeling of biliary atresia: a narrative review

Development of liver microtissues with functional biliary ductular network

Engineered tissues and strategies to overcome challenges in drug development

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