Predicting the immunogenicity of candidate vaccines in humans remains a challenge. To address this issue, we developed a lymphoid organ-chip (LO chip) model based on a microfluidic chip seeded with human PBMC at high density within a 3D collagen matrix. Perfusion of the SARS-CoV-2 spike protein mimicked a vaccine boost by inducing a massive amplification of spike-specific memory B cells, plasmablast differentiation, and spike-specific antibody secretion.
View Article and Find Full Text PDFExpert Opin Drug Metab Toxicol
July 2024
Introduction: Drug induced Liver-Injury (DILI) is a leading cause of drug attrition and complex models (CIVMs), including three dimensional (3D) spheroids, 3D bio printed tissues and flow-based systems, could improve preclinical prediction. Although CIVMs have demonstrated good sensitivity and specificity in DILI detection their adoption remains limited.
Areas Covered: This article describes DILI, the challenges with its prediction and the current strategies and models that are being used.
Limitations with cell cultures and experimental animal-based studies have had the scientific and industrial communities searching for new approaches that can provide reliable human models for applications such as drug development, toxicological assessment, and pre-clinical evaluation. This has resulted in the development of microfluidic-based cultures that may better represent organs and organ systems than conventional monolayer cell cultures. Although there is considerable interest from industry and regulatory bodies in this technology, several challenges need to be addressed for it to reach its full potential.
View Article and Find Full Text PDFWith a recent amendment, India joined other countries that have removed the legislative barrier toward the use of human-relevant methods in drug development. Here, global stakeholders weigh in on the urgent need to globally harmonize the guidelines toward the standardization of microphysiological systems. We discuss a possible framework for establishing scientific confidence and regulatory approval of these methods.
View Article and Find Full Text PDFThe function of the glomerulus depends on the complex cell-cell/matrix interactions and replication of this in vitro would aid biological understanding in both health and disease. Previous models do not fully reflect all cell types and interactions present as they overlook mesangial cells within their 3D matrix. Herein, the development of a microphysiological system that contains all resident renal cell types in an anatomically relevant manner is presented.
View Article and Find Full Text PDFExpert Opin Drug Discov
November 2023
Introduction: Drug-induced liver injury (DILI) is a potentially lethal condition that heavily impacts the pharmaceutical industry, causing approximately 21% of drug withdrawals and 13% of clinical trial failures. Recent evidence suggests that the use of Liver-Chip technology in preclinical safety testing may significantly reduce DILI-related clinical trial failures and withdrawals. However, drug developers and regulators would benefit from guidance on the integration of Liver-Chip data into decision-making processes to facilitate the technology's adoption.
View Article and Find Full Text PDFMicrophysiological systems (MPS; organ-on-a-chip) aim to recapitulate the 3D organ microenvironment and improve clinical predictivity relative to previous approaches. Though MPS studies provide great promise to explore treatment options in a multifactorial manner, they are often very complex. It is therefore important to assess and manage technical confounding factors, to maximise power, efficiency and scalability.
View Article and Find Full Text PDFTraditional 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.
View Article and Find Full Text PDFBackground: Conventional preclinical models often miss drug toxicities, meaning the harm these drugs pose to humans is only realized in clinical trials or when they make it to market. This has caused the pharmaceutical industry to waste considerable time and resources developing drugs destined to fail. Organ-on-a-Chip technology has the potential improve success in drug development pipelines, as it can recapitulate organ-level pathophysiology and clinical responses; however, systematic and quantitative evaluations of Organ-Chips' predictive value have not yet been reported.
View Article and Find Full Text PDFSpecies differences in brain and blood-brain barrier (BBB) biology hamper the translation of findings from animal models to humans, impeding the development of therapeutics for brain diseases. Here, we present a human organotypic microphysiological system (MPS) that includes endothelial-like cells, pericytes, glia, and cortical neurons and maintains BBB permeability at relevant levels. This human Brain-Chip engineered to recapitulate critical aspects of the complex interactions that mediate neuroinflammation and demonstrates significant improvements in clinical mimicry compared to previously reported similar MPS.
View Article and Find Full Text PDFDrug-induced liver injury (DILI) is a significant public health issue, but standard animal tests and clinical trials sometimes fail to predict DILI due to species differences and the relatively low number of human subjects involved in preapproval studies of a new drug, respectively. In vitro models have long been used to aid DILI prediction, with primary human hepatocytes (PHHs) being generally considered the gold standard. However, despite many efforts and decades of work, traditional culture methods have been unsuccessful in either fully preserving essential liver functions after isolation of PHHs or in emulating interactions between PHHs and hepatic nonparenchymal cells (NPCs), both of which are essential for the development of DILI under in vivo conditions.
View Article and Find Full Text PDFThe intestinal mucosa is a complex physical and biochemical barrier that fulfills a myriad of important functions. It enables the transport, absorption, and metabolism of nutrients and xenobiotics while facilitating a symbiotic relationship with microbiota and restricting the invasion of microorganisms. Functional interaction between various cell types and their physical and biochemical environment is vital to establish and maintain intestinal tissue homeostasis.
View Article and Find Full Text PDFParkinson's disease and related synucleinopathies are characterized by the abnormal accumulation of alpha-synuclein aggregates, loss of dopaminergic neurons, and gliosis of the substantia nigra. Although clinical evidence and in vitro studies indicate disruption of the Blood-Brain Barrier in Parkinson's disease, the mechanisms mediating the endothelial dysfunction is not well understood. Here we leveraged the Organs-on-Chips technology to develop a human Brain-Chip representative of the substantia nigra area of the brain containing dopaminergic neurons, astrocytes, microglia, pericytes, and microvascular brain endothelial cells, cultured under fluid flow.
View Article and Find Full Text PDFBackground & Aims: The limited availability of organoid systems that mimic the molecular signatures and architecture of human intestinal epithelium has been an impediment to allowing them to be harnessed for the development of therapeutics as well as physiological insights. We developed a microphysiological Organ-on-Chip (Emulate, Inc, Boston, MA) platform designed to mimic properties of human intestinal epithelium leading to insights into barrier integrity.
Methods: We combined the human biopsy-derived leucine-rich repeat-containing G-protein-coupled receptor 5-positive organoids and Organ-on-Chip technologies to establish a micro-engineered human Colon Intestine-Chip (Emulate, Inc, Boston, MA).
The European Partnership for Alternative Approaches to Animal Testing (EPAA) convened a 'Blue Sky Workshop' on new ideas for non-animal approaches to predict repeated-dose systemic toxicity. The aim of the Workshop was to formulate strategic ideas to improve and increase the applicability, implementation and acceptance of modern non-animal methods to determine systemic toxicity. The Workshop concluded that good progress is being made to assess repeated dose toxicity without animals taking advantage of existing knowledge in toxicology, thresholds of toxicological concern, adverse outcome pathways and read-across workflows.
View Article and Find Full Text PDFIntegrating nonclinical in vitro, in silico, and in vivo datasets holistically can improve hazard characterization and risk assessment. In pharmaceutical development, cardiovascular liabilities are a leading cause of compound attrition. Prior to clinical studies, functional cardiovascular data are generated in single-dose safety pharmacology telemetry studies, with structural pathology data obtained from repeat-dose toxicology studies with limited concurrent functional endpoints, eg, electrocardiogram via jacketed telemetry.
View Article and Find Full Text PDFDrug-induced gastrointestinal toxicities (DI-GITs) are among the most common adverse events in clinical trials. High prevalence of DI-GIT has persisted among new drugs due in part to the lack of robust experimental tools to allow early detection or to guide optimization of safer molecules. Developing in vitro assays for the leading GI toxicities (nausea, vomiting, diarrhoea, constipation, and abdominal pain) will likely involve recapitulating complex physiological properties that require contributions from diverse cell/tissue types including epithelial, immune, microbiome, nerve, and muscle.
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