Organ Model: Digestive System

Abstract

Inflammatory bowel disease (IBD) is a complex inflammatory disease, for which few effective therapies exist. The goal of our current work was to show that:

1. Such a complex, immune cell-driven pathogenesis could be captured on Emulate’s human Colon Intestine-Chips
2. This could be used as a novel human-centric system to support IBD drug development including anti-TNF-α antibodies. We previously developed an advanced primary human vascularized Colon Intestine-Chip model and showed that it can recapitulate physiologic cell composition, morphology and barrier integrity.

The model described in this poster is advantageous in recapitulating in vivo inflammatory effector functions in that it supports immune cell trafficking under fluid flow conditions, uses primary cell co-culture, and provides a physiologically relevant peristaltic-like stretch.

Organ Model: Intestine (Necrotizing Enterocolitis)

Application: Immunology & Inflammation, Microbiome

Abstract

Necrotizing enterocolitis (NEC) is a severe and potentially fatal intestinal disease that has been difficult to study due to its complex pathogenesis, which remains incompletely understood. The pathophysiology of NEC includes disruption of intestinal tight junctions, increased gut barrier permeability, epithelial cell death, microbial dysbiosis, and dysregulated inflammation. Traditional tools to study NEC include animal models, cell lines, and human or mouse intestinal organoids. While studies using those model systems have improved the field’s understanding of disease pathophysiology, their ability to recapitulate the complexity of human NEC is limited. An improved in vitro model of NEC using microfluidic technology, named NEC-on-a-chip, has now been developed. The NEC-on-a-chip model consists of a microfluidic device seeded with intestinal enteroids derived from a preterm neonate, co-cultured with human endothelial cells and the microbiome from an infant with severe NEC. This model is a valuable tool for mechanistic studies into the pathophysiology of NEC and a new resource for drug discovery testing for neonatal intestinal diseases. In this manuscript, a detailed description of the NEC-on-a-chip model will be provided.

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Webinar Abstract

Inflammatory bowel disease (IBD) represents an enormous area of unmet medical need. Despite ~10 million people suffering from IBD globally, ~50% of patients fail to respond to on-market therapy, and ~90% fail to experience long-term remission.

The limited efficacy of IBD therapeutics is due in part to the limited human relevance of conventional preclinical models, which restrict researchers to studying just one aspect of IBD at a time. These models fail to accurately predict drug effects within the complex intestinal microenvironment, leading to high clinical trial failure rates.

It’s time for a human-centric approach to IBD drug discovery and development.

In this webinar, Marianne Kanellias discussed how researchers can use Emulate Organ-on-a-Chip technology to create a more representative and complex model of IBD pathogenesis. With the Emulate human Colon Intestine-Chip, researchers can recapitulate the inflammatory response of IBD—from immune cell vascular attachment, to migration, to downstream effector function and barrier damage—and evaluate the efficacy of anti-inflammatory therapeutics in a more human-relevant model of IBD.

Key highlights from this IBD webinar:

• Common challenges in modeling inflammatory disease
• Recreating gut- and inflammation-specific immune cell recruitment with the Colon Intestine-Chip
• Evaluating clinically relevant IBD therapeutics across a range of mechanisms of action
• A panel discussion and live Q&A with Marianne Kanellias and Chris Carman, PhD who led the development of the immune cell recruitment application for the Colon Intestine-Chip

For additional data, see the data in the inflammatory immune cell recruitment application note.

Webinar Abstract

Over the past 15 years, organoids have revolutionized the study of human organ and tumor behavior. In the coming years, Organ-on-a-Chip technology promises to rapidly increase the complexity of human organotypic models, enabling the discovery of more physiologically relevant insights into human health and disease. 

In this on-demand webinar, Jens Puschhof, PhD, of the German Cancer Research Center (DKFZ) discusses how lessons learned from organoid biology can be applied to Organ-on-a-Chip research and examine areas where these two technologies are being combined with great potential for synergy. In particular, he shares aspects of his team’s work studying the impact of cancer-associated bacteria in colorectal cancer metastasis using Emulate Organ-Chip models. 

Key discussion points / learnings: 

• The synergies that exist between organoids and Organ-on-a-Chip technology 
• How insights from organoid research can be translated to Organ-Chips  
• How Organ-Chips can be used to study the cancer-microbiome

Organ Model: Esophagus

Application: Cancer

Abstract: The pathogenesis of subsquamous intestinal metaplasia (SSIM), in which glands of Barrett’s esophagus (BE) are buried under esophageal squamous epithelium, is unknown. In a rat model of reflux esophagitis, we found that columnar-lined esophagus developed via a wound-healing process involving epithelial-mesenchymal plasticity (EMP) that buried glands under ulcerated squamous epithelium. To explore a role for reflux-induced EMP in BE, we established and characterized human Barrett’s organoids and sought evidence of EMP after treatment with acidic bile salts (AB). We optimized media to grow human BE organoids from immortalized human Barrett’s cells and from BE biopsies from seven patients, and we characterized histological, morphological, and molecular features of organoid development. Features and markers of EMP were explored following organoid exposure to AB, with and without a collagen I (COL1) matrix to simulate a wound-healing environment. All media successfully initiated organoid growth, but advanced DMEM/F12 (aDMEM) was best at sustaining organoid viability. Using aDMEM, organoids comprising nongoblet and goblet columnar cells that expressed gastric and intestinal cell markers were generated from BE biopsies of all seven patients. After AB treatment, early-stage Barrett’s organoids exhibited EMP with loss of membranous E-cadherin and increased protrusive cell migration, events significantly enhanced by COL1. Using human BE biopsies, we have established Barrett’s organoids that recapitulate key histological and molecular features of BE to serve as high-fidelity BE models. Our findings suggest that reflux can induce EMP in human BE, potentially enabling Barrett’s cells to migrate under adjacent squamous epithelium to form SSIM.NEW & NOTEWORTHY Using Barrett’s esophagus (BE) biopsies, we established organoids recapitulating key BE features. During early stages of organoid development, a GERD-like wound environment-induced features of epithelial-mesenchymal plasticity (EMP) in Barrett’s progenitor cells, suggesting that reflux-induced EMP can enable Barrett’s cells to migrate underneath squamous epithelium to form subsquamous intestinal metaplasia, a condition that may underlie Barrett’s cancers that escape detection by endoscopic surveillance, and recurrences of Barrett’s metaplasia following endoscopic eradication therapy.

To learn more about these findings, view our webinar “Organ-Chips 201: The Importance of Flow, Stretch, and Stroma for in vitro Modeling.”

Inflammatory bowel disease (IBD) is characterized by dysregulated immune response, ultimately leading to barrier damage. Unfortunately, conventional research models are not capable of capturing this complexity, resulting in an incomplete understanding of disease biology and high clinical trial attrition.

In this video, see how Emulate Organ-Chips offer an unparalleled window into IBD human immune response. By incorporating critical features of the human tissue microenvironment, Organ-Chips enable researchers to model the complexity of immune cell recruitment in a tissue-, disease-, and species-specific manner, and evaluate the efficacy of clinically relevant drug candidates.

OVERVIEW

The Duodenum Intestine-Chip S1 BioKit includes the essential components needed to create the Duodenum Intestine-Chip, including pre-qualified cells.

OVERVIEW

The Colon Intestine-Chip S1 BioKit includes the essential components needed to create the Colon Intestine-Chip S1. Download the data sheet to learn more about its characterization and how it can be used to study cytokine-mediated inflammation, inflammatory immune cell recruitment, and more.

Organ Model: Lung (Alveolus) & Intestine (Colon)

Application: Immunology

Abstract: Traditional drug safety assessments often fail to predict complications in humans, especially when the drug targets the immune system. Rodent-based preclinical animal models are often ill-suited for predicting immunotherapy-mediated adverse events in humans, in part because of the fundamental differences in immunological responses between species and the human relevant expression profile of the target antigen, if it is expected to be present in normal, healthy tissue. While human-relevant cell-based models of tissues and organs promise to bridge this gap, conventional in vitro two-dimensional models fail to provide the complexity required to model the biological mechanisms of immunotherapeutic effects. Also, like animal models, they fail to recapitulate physiologically relevant levels and patterns of organ-specific proteins, crucial for capturing pharmacology and safety liabilities. Organ-on-Chip models aim to overcome these limitations by combining micro-engineering with cultured primary human cells to recreate the complex multifactorial microenvironment and functions of native tissues and organs. In this protocol, we show the unprecedented capability of two human Organs-on-Chip models to evaluate the safety profile of T cell-bispecific antibodies (TCBs) targeting tumor antigens. These novel tools broaden the research options available for a mechanistic understanding of engineered therapeutic antibodies and for assessing safety in tissues susceptible to adverse events. Graphical abstract Figure 1. Graphical representation of the major steps in target-dependent T cell-bispecific antibodies engagement and immunomodulation, as performed in the Colon Intestine-Chip.

Article Type: Review

Organ Models: Small Intestine, Large Intestine, Lung (Airway), Cervix, Vagina

Abstract: The surfaces of human internal organs are lined by a mucus layer that ensures symbiotic relationships with commensal microbiome while protecting against potentially injurious environmental chemicals, toxins, and pathogens, and disruption of this layer can contribute to disease development. Studying mucus biology has been challenging due to the lack of physiologically relevant human in vitro models. Here we review recent progress that has been made in the development of human organ-on-a-chip microfluidic culture models that reconstitute epithelial tissue barriers and physiologically relevant mucus layers with a focus on lung, colon, small intestine, cervix and vagina. These organ-on-a-chip models that incorporate dynamic fluid flow, air–liquid interfaces, and physiologically relevant mechanical cues can be used to study mucus composition, mechanics, and structure, as well as investigate its contributions to human health and disease with a level of biomimicry not possible in the past.