Biology-inspired dynamic microphysiological system approaches to revolutionize basic research, healthcare and animal welfare.

The regular workshops held by the Center for Alternatives to Animal Testing (CAAT) on biology-inspired microphysiological systems (MPS) taking place every four years, have become a reliable measure to assess fundamental scientific, industrial and regulatory trends for translational science in the MPS-field from a bird's eye view. The 2023 workshop participants at that time concluded that the technology as used within academia has matured significantly, underlined by the broad use of MPS and the steadily increasing number of high quality research publications - yet, broad industry adoption of MPS has been slow, despite strong interest. Academic research using MPS primarily aims to accurately recapitulate human biology in MPS-based organ models in areas where traditional models have been lacking key elements of human physiology, thereby enabling breakthrough discoveries for life sciences.

Extracellular RNA communication: A decade of NIH common fund support illuminates exRNA biology.

The discovery that extracellular RNAs (exRNA) can act as endocrine signalling molecules established a novel paradigm in intercellular communication. ExRNAs can be transported, both locally and systemically in virtually all body fluids. In association with an array of carrier vehicles of varying complexity, exRNA can alter target cell phenotype.

Leveraging biomarkers and translational medicine for preclinical safety - Lessons for advancing the validation of alternatives to animal testing.

This article explores the potential of principles established in translational medicine for the use of bio-markers to advance the validation of alternatives to animal testing in preclinical safety assessment. It examines especially how such principles can enhance the predictive power, mechanistic under-standing, and human relevance of new approach methodologies (NAMs). Key concepts from translational medicine, such as fit-for-purpose validation, evidence-based approaches, and inte-grated testing strategies, are already being applied to the development and validation of NAMs.

Engineering multicellular living systems-a Keystone Symposia report.

The ability to engineer complex multicellular systems has enormous potential to inform our understanding of biological processes and disease and alter the drug development process. Engineering living systems to emulate natural processes or to incorporate new functions relies on a detailed understanding of the biochemical, mechanical, and other cues between cells and between cells and their environment that result in the coordinated action of multicellular systems. On April 3-6, 2022, experts in the field met at the Keystone symposium "Engineering Multicellular Living Systems" to discuss recent advances in understanding how cells cooperate within a multicellular system, as well as recent efforts to engineer systems like organ-on-a-chip models, biological robots, and organoids.

Pivoting Novel Exosome-Based Technologies for the Detection of SARS-CoV-2.

The National Institutes of Health (NIH) launched the Rapid Acceleration of Diagnostics (RADx) initiative to meet the needs for COVID-19 diagnostic and surveillance testing, and to speed its innovation in the development, commercialization, and implementation of new technologies and approaches. The RADx Radical (RADx-Rad) initiative is one component of the NIH RADx program which focuses on the development of new or non-traditional applications of existing approaches, to enhance their usability, accessibility, and/or accuracy for the detection of SARS-CoV-2. Exosomes are a subpopulation of extracellular vesicles (EVs) 30-140 nm in size, that are critical in cell-to-cell communication.

Microphysiological Systems: Stakeholder Challenges to Adoption in Drug Development.

Microphysiological systems (MPS) or tissue chips/organs-on-chips are novel in vitro models that emulate human physiology at the most basic functional level. In this review, we discuss various hurdles to widespread adoption of MPS technology focusing on issues from multiple stakeholder sectors, e.g.

Microphysiological systems: What it takes for community adoption.

Microphysiological systems (MPS) are promising tools which could substantially improve the drug development process, particularly for underserved patient populations such as those with rare diseases, neural disorders, and diseases impacting pediatric populations. Currently, one of the major goals of the National Institutes of Health MPS program, led by the National Center for Advancing Translational Sciences (NCATS), is to demonstrate the utility of this emerging technology and help support the path to community adoption. However, community adoption of MPS technology has been hindered by a variety of factors including biological and technological challenges in device creation, issues with validation and standardization of MPS technology, and potential complications related to commercialization.

Exploring Novel Biologically-Relevant Chemical Space Through Artificial Intelligence: The NCATS ASPIRE Program.

In recent years, artificial intelligence (AI)/machine learning (ML; a subset of AI) have become increasingly important to the biomedical research community. These technologies, coupled to big data and cheminformatics, have tremendous potential to improve the design of novel therapeutics and to provide safe and effective drugs to patients. A National Center for Advancing Translational Sciences (NCATS) program called A Specialized Platform for Innovative Research Exploration (ASPIRE) leverages advances in AI/ML, automated synthetic chemistry, and high-throughput biology, and seeks to enable translation and drug development by catalyzing exploration of biologically active chemical space.

Extracellular RNAs as potential biomarkers for cancer.

The discovery that all cells secrete extracellular vesicles (EVs) to shuttle proteins and nucleic acids to recipient cells suggested they play an important role in intercellular communication. EVs are widely distributed in many body fluids, including blood, cerebrospinal fluid, urine and saliva. Exosomes are nano-sized EVs of endosomal origin that regulate many pathophysiological processes including immune responses, inflammation, tumour growth, and infection.

Organs-on-chips: into the next decade.

Organs-on-chips (OoCs), also known as microphysiological systems or 'tissue chips' (the terms are synonymous), have attracted substantial interest in recent years owing to their potential to be informative at multiple stages of the drug discovery and development process. These innovative devices could provide insights into normal human organ function and disease pathophysiology, as well as more accurately predict the safety and efficacy of investigational drugs in humans. Therefore, they are likely to become useful additions to traditional preclinical cell culture methods and in vivo animal studies in the near term, and in some cases replacements for them in the longer term.

Organs-on-a-Chip.

Organs-on-chips, also known as "tissue chips" or microphysiological systems (MPS), are bioengineered microsystems capable of recreating aspects of human organ physiology and function and are in vitro tools with multiple applications in drug discovery and development. The ability to recapitulate human and animal tissues in physiologically relevant three-dimensional, multi-cellular environments allows applications in the drug development field, including; (1) use in assessing the safety and toxicity testing of potential therapeutics during early-stage preclinical drug development; (2) confirmation of drug/therapeutic efficacy in vitro; and (3) disease modeling of human tissues to recapitulate pathophysiology within specific subpopulations and even individuals, thereby advancing precision medicine efforts. This chapter will discuss the development and evolution of three-dimensional organ models over the past decade, and some of the opportunities offered by MPS technology that are not available through current standard two-dimensional cell cultures, or three-dimensional organoid systems.

Biology-inspired microphysiological systems to advance patient benefit and animal welfare in drug development.

The first microfluidic microphysiological systems (MPS) entered the academic scene more than 15 years ago and were considered an enabling technology to human (patho)biology in vitro and, therefore, provide alternative approaches to laboratory animals in pharmaceutical drug development and academic research. Nowadays, the field generates more than a thousand scientific publications per year. Despite the MPS hype in academia and by platform providers, which says this technology is about to reshape the entire in vitro culture landscape in basic and applied research, MPS approaches have neither been widely adopted by the pharmaceutical industry yet nor reached regulated drug authorization processes at all.

The NIH microphysiological systems program: developing in vitro tools for safety and efficacy in drug development.

Approximately 30% of drugs have failed in human clinical trials due to adverse reactions despite promising pre-clinical studies, and another 60% fail due to lack of efficacy. One of the major causes in the high attrition rate is the poor predictive value of current preclinical models used in drug development despite promising pre-clinical studies in 2-D cell culture and animal models. Microphysiological Systems or Tissue Chips are bioengineered microfluidic cell culture systems seeded with primary or stem cells that mimic the histoarchitecture, mechanics and physiological response of functional units of organs and organ systems.

Improved Ocular Tissue Models and Eye-On-A-Chip Technologies Will Facilitate Ophthalmic Drug Development.

In this study, we describe efforts by the National Eye Institute (NEI) and National Center for Advancing Translational Science (NCATS) to catalyze advances in 3-dimensional (3-D) ocular organoid and microphysiological systems (MPS). We reviewed the recent literature regarding ocular organoids and tissue chips. Animal models, 2-dimensional cell culture models, and postmortem human tissue samples provide the vision research community with insights critical to understanding pathophysiology and therapeutic development.

Mapping biologically active chemical space to accelerate drug discovery.

A specialized platform for innovative research exploration — ASPIRE — in preclinical drug discovery could help study unexplored biologically active chemical space through integrating automated synthetic chemistry, high-throughput biology and artificial intelligence technologies.

Microphysiological Systems (Tissue Chips) and their Utility for Rare Disease Research.

The scientific and technological development of microphysiological systems (MPS) modeling organs-on-chips, or "tissue chips" (TCs), has progressed rapidly over the past decade. Stem cell research and microfluidic concepts have combined to lead to the development of microphysiological platforms representing an ever-expanding list of different human organ systems. In the context of rare diseases, these bioengineered microfluidics platforms hold promise for modeling of disorders and could prove useful in the screening and efficacy testing of existing therapeutics.

Organs-on-chips: Progress, challenges, and future directions.

The National Institutes of Health Microphysiological Systems (MPS) program, led by the National Center for Advancing Translational Sciences, is part of a joint effort on MPS development with the Defense Advanced Research Projects Agency and with regulatory guidance from FDA, is now in its final year of funding. The program has produced many tangible outcomes in tissue chip development in terms of stem cell differentiation, microfluidic engineering, platform development, and single and multi-organ systems-and continues to help facilitate the acceptance and use of tissue chips by the wider community. As the first iteration of the program draws to a close, this Commentary will highlight some of the goals met, and lay out some of the challenges uncovered that will remain to be addressed as the field progresses.

Facilitating the commercialization and use of organ platforms generated by the microphysiological systems (Tissue Chip) program through public-private partnerships.

Microphysiological systems (organs-on-chips, tissue chips) are devices designed to recapitulate human physiology that could be used to better understand drug responses not easily addressed using other in vivo systems or in vitro animal models. Although still in development, initial results seem promising as tissue chips exhibit in vivo systems-like functional responses. The National Center for Advancing Translation Science (NCATS) identifies this technology as a potential tool that could improve the process of getting safer, more effective treatments to patients, and has led to the Tissue Chip Program, which aims to develop, integrate and validate major organ systems for testing.

Biology-inspired microphysiological system approaches to solve the prediction dilemma of substance testing.

The recent advent of microphysiological systems - microfluidic biomimetic devices that aspire to emulate the biology of human tissues, organs and circulation in vitro - is envisaged to enable a global paradigm shift in drug development. An extraordinary US governmental initiative and various dedicated research programs in Europe and Asia have led recently to the first cutting-edge achievements of human single-organ and multi-organ engineering based on microphysiological systems. The expectation is that test systems established on this basis would model various disease stages, and predict toxicity, immunogenicity, ADME profiles and treatment efficacy prior to clinical testing.

Tissue Chips to aid drug development and modeling for rare diseases.

Introduction: The technologies used to design, create and use microphysiological systems (MPS, "tissue chips" or "organs-on-chips") have progressed rapidly in the last 5 years, and validation studies of the functional relevance of these platforms to human physiology, and response to drugs for individual model organ systems, are well underway. These studies are paving the way for integrated multi-organ systems that can model diseases and predict drug efficacy and toxicology of multiple organs in real-time, improving the potential for diagnostics and development of novel treatments of rare diseases in the future.

Areas Covered: This review will briefly summarize the current state of tissue chip research and highlight model systems where these microfabricated (or bioengineered) devices are already being used to screen therapeutics, model disease states, and provide potential treatments in addition to helping elucidate the basic molecular and cellular phenotypes of rare diseases.

The NIH Extracellular RNA Communication Consortium.

The Extracellular RNA (exRNA) Communication Consortium, funded as an initiative of the NIH Common Fund, represents a consortium of investigators assembled to address the critical issues in the exRNA research arena. The overarching goal is to generate a multi-component community resource for sharing fundamental scientific discoveries, protocols, and innovative tools and technologies. The key initiatives include (a) generating a reference catalogue of exRNAs present in body fluids of normal healthy individuals that would facilitate disease diagnosis and therapies, (b) defining the fundamental principles of exRNA biogenesis, distribution, uptake, and function, as well as development of molecular tools, technologies, and imaging modalities to enable these studies,

Perspectives on best practices for gene therapy programs.

With recent successes in gene therapy trials for hemophilia and retinal diseases, the promise and prospects for gene therapy are once again garnering significant attention. To build on this momentum, the National Institute of Neurological Disorders and Stroke and the Muscular Dystrophy Association jointly hosted a workshop in April 2014 on "Best Practices for Gene Therapy Programs," with a focus on neuromuscular disorders. Workshop participants included researchers from academia and industry as well as representatives from the regulatory, legal, and patient advocacy sectors to cover the gamut from preclinical optimization to intellectual property concerns and regulatory approval.