Biology subjects

Barrile, R.

Publications and source records attributed to Barrile, R..

5 recordsLinked to original sources

bioRxiv2025

Engineering Large-Scale and Innervated Functional Human Gut for Transplantation

A confined culture system (CCS) establishes methods to generate complex functional human gastrointestinal tissues. This approach yields large-scale innervated small intestinal, colonic and gastric organoids with an elongated tubular shape for both in vitro and in vivo studies. Transcriptomic and electrophysiological data demonstrate the co-development of a functional de novo enteric nervous system, which is absent from conventional organoids. When compared to traditional methods, CCS derived small intestinal, colonic and gastric organoids reached maturation supporting transplantation in half of the time, resulting in enhanced engraftment rates and sizes. Murine luminal content exposure within CCS organoids in vivo further augmented function, supporting the potential translational benefits required to model complex intestinal diseases. In summary, the CCS methodology simplifies current protocols while adding complexity and expediting the generation of clinically relevant functional gut tissues.

bioengineering↗

bioRxiv2021

Human immunocompetent Organs-on-Chips platforms allow safety profiling of tumor-targeted T-cell bispecific antibodies

AbstractTraditional drug safety assessment often fails to predict complications in humans, especially when the drug targets the immune system. Here, we show the unprecedented capability of two Organs-on-Chips to evaluate the safety profile of T-cell bispecific antibodies (TCBs) targeting tumor antigens. Although promising for cancer immunotherapy, TCBs are associated with an on-target, off-tumor risk due to low levels of expression of tumor antigens in healthy tissues. We leveraged in vivo target expression and toxicity data of TCBs targeting folate receptor 1 (FOLR1) or carcinoembryonic antigen (CEA) to design and validate human immunocompetent Organs-on-Chips safety platforms. We discovered that the Lung-Chip and Intestine-Chip could reproduce and predict target-dependent TCB safety liabilities, based on sensitivity to key determinants thereof, such as target expression and antibody affinity. These novel tools broaden the research options available for mechanistic understandings of engineered therapeutic antibodies and assessing safety in tissues susceptible to adverse events.

cancer biology↗

bioRxiv2020

A novel Organ-Chip system emulates three-dimensional architecture of the human epithelia and allows fine control of mechanical forces acting on it.

Successful translation of in vivo experimental data to human patients is an unmet need and a bottleneck in the development of effective therapeutics. micro technology aims to address this need with significant advancements reported recently that enable modeling of organ level function. These microengineered chips enable researcher to recreate critical elements such as in vivo relevant tissue-tissue interface, air-liquid interface, and mechanical forces, such as mechanical stretch and fluidic shear stress, are crucial in emulating tissue level functions. Here, we present the development of a new, comprehensive 3D cell-culture system, where we combined our proprietary Organ-Chip technology with recent advantages in three-dimensional organotypic culture. Leveraging microfabrication techniques, we engineered a flexible chip that consists of a channel containing an organotypic epithelium surrounded by two vacuum channels that can be actuated to stretch the hydrogel throughout its thickness. Furthermore, the ceiling of this channel is a removable lid with a built-in microchannel that can be perfused with liquid or air and removed as needed for direct access to the tissue. The floor of this channel is a porous flexible membrane in contact with a microfluidic channel that provides diffusive mass transport to and from the channel. This additional microfluidic channel can be coated with endothelial cells to emulate a blood vessel and capture endothelial interactions. Our results show that the Open-Top Chip design successfully addresses common challenges associated with the Organs-on-Chips technology, including the capability to incorporate a tissue-specific extracellular matrix gel seeded with primary stromal cells, to reproduce the architectural complexity of tissues by micropatterning the gel, that can be extracted for H&E staining. We provide proof-of-concept data on the feasibility of the system using skin and alveolar epithelial primary cells and by simulating alveolar inflammation.

bioengineering↗

bioRxiv2020

A lung-on-chip infection model reveals protective and permissive roles of alveolar epithelial cells in tuberculosis

Mycobacterium tuberculosis (Mtb) makes first contact with a host in the alveolar space, an interaction largely inaccessible to experimental observation. We establish a lung-on-chip model for early tuberculosis and use time-lapse imaging to reveal the dynamics of host-Mtb interactions at an air-liquid interface with a spatiotemporal resolution unattainable in animal models. By reconstituting host physiology in a modular manner, we probe the role of pulmonary surfactant secreted by alveolar epithelial cells (AECs) in early infection. This is difficult to study directly in animal models, as surfactant-deficient animals are either non-viable or develop acute lung pathologies. We demonstrate that surfactant deficiency results in rapid and uncontrolled Mtb growth in both macrophages and AECs. In contrast, under normal surfactant levels, a significant fraction of intracellular bacteria are non-growing. The surfactant-deficient phenotype is rescued by exogenous addition of surfactant replacement formulations, which have no effect on bacterial viability in the absence of host cells. Surfactant partially removes virulence-associated lipids and proteins 1,2 from the bacterial cell surface and consistent with this mechanism of action, we show that attenuation of bacteria lacking the virulence-associated ESX-1 secretion system is independent of surfactant levels. These findings may partly explain why individuals with compromised surfactant function, such as smokers and elderly persons, are at increased risk of developing active tuberculosis.

microbiology↗

bioRxiv2019

Liver-Chip: Reproducing Human and Cross-Species Toxicities

Nonclinical rodent and non-rodent toxicity models used to support clinical trials of candidate drugs may produce discordant results or fail to predict complications in humans contributing to drug failures in the clinic. Here we applied microengineered Organ-on-Chip (Organ-Chip) technology to design rat, dog, and human Liver-Chips containing species-specific primary hepatocytes interfaced with liver sinusoidal endothelial cells, with or without Kupffer cells and hepatic stellate cells, cultured under physiological fluid flow. The Liver-Chips detected diverse phenotypes of liver toxicity including hepatocellular injury, steatosis, cholestasis, and fibrosis as well as species-specific toxicities when treated with tool compounds. Multi-species Liver-Chips may provide a useful platform for prediction of liver toxicity and inform human relevance of liver toxicities detected in animal studies to better determine safety and human risk.\n\nOne Sentence SummaryMicroengineered Organ-Chip technology has been used to design rat, dog and human Liver-Chips that recapitulate species-specific liver toxicities.

pharmacology and toxicology↗