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Introduction: What is PRECISION Medicine? 

“Precision medicine” (also called personalized medicine) has become a guiding aspiration in healthcare: treating each person not as a generic patient but based on their unique biology, disease subtype, and treatment responsiveness. In its ideal form, clinicians would know in advance which therapy will work — and which ones won’t — for a given patient, thereby improving outcomes and reducing unnecessary treatments and potential toxicity. 

Yet in practice, personalized medicine still faces major hurdles: 

• Many therapies are selected on the basis of genomics or biomarkers only, but these approaches don’t always capture how the patient’s cells will actually behave when exposed to treatment. 

• Current in vitro models used for personalized medicine (2D cell culture, simple organoids) often lack the complexity of the human tissue environment — including perfusion, stromal interactions, biomechanical forces, and multi-cellular cross-talk. 

• Accessing meaningful patient-derived samples (especially for internal organs or complex microenvironments) is difficult, and replicating their physiology ex vivo is challenging. 

This is where Organ-on-a-Chip technology is emerging as a powerful agent of change. By creating microfluidic devices lined with human cells and recreating organ-specific tissue architecture, fluid flow, and cell-cell interactions, Organ-Chips offer the most realistic “home away from home” for patient samples. These systems can more faithfully reproduce how a patient’s cells behave in situ, making them a promising bridge from patient-derived sample to clinical decision. 

In this blog, we explore how Organ-Chips are being used in personalized medicine, and then dive into three compelling case studies that illustrate how they are making a real-world difference. 

How Organ-on-a-Chip Technology Elevates Patient-Derived Models 

Organ-on-a-Chip technology recreates the functional unit of an organ using living human cells and an organ-specific microenvironment, giving researchers a real-time view of human biology. These small devices consist of two parallel channels, which can be seeded with multiple human-relevant cell types—including primary cells, iPSCs, organoids, and immune cells—and are separated by a thin, porous membrane that allows cell-cell communication across a tissue-vascular interface. 

A defining advantage of Organ-Chips is the precise control users have over biomechanical forces. When subjected to media flow and cyclic strain, cells experience the same stresses they would in the body, including intestinal peristalsis, breathing, and vascular flow.  Collectively, this organ-specific microenvironment drives more in vivo-relevant gene expression, morphology, and function than standard culture methods, enabling deeper insights into human biology. 

In a personalized medicine context, the advantages of Organ-Chips are that they can: 

• Use patient-derived samples (stem-cells, primary tumor cells, fibroblasts, endothelial/stromal cells) to create a model specific to that person’s biology. 

• Incorporate microenvironmental features (stromal cells, ECM, vascular endothelium, fluid flow, nutrient and gas gradients) that standard culture lacks. 

• Deliver drugs under physiologically relevant flow and dosing regimes, better simulating exposure in a patient. 

• Allow read-outs of cellular response, toxicities, or disease mechanism with higher fidelity. 

• Support functional assays (how the cells behave, not just what mutation they carry), which is increasingly recognized as central to precision medicine. 

In short: when you want to make the most of a patient-derived sample (tumor, stem cell, primary tissue), a tumor-in-a-dish or patient-derived organoid may be a start — but an Organ-Chip can be a far better “home away from home” to drive physiologically accurate results. 

Below are three case studies illustrating how this plays out across the body, including bone-marrow toxicity, neurodegeneration, and oncology. 

Case Study 1

Bone Marrow-on-a-Chip for Drug Toxicity & Patient‐Specific Pathophysiology 

Human bone marrow is notoriously difficult to access and study outside the body. Traditional 2D or static 3D culture systems fail to capture the marrow’s complex cellular diversity, mechanical cues, and dynamic exchange between blood and stroma. As a result, predicting myelosuppression from drug exposure or studying patient-specific marrow dysfunction (e.g., in bone marrow failure syndromes) has remained a major challenge. 

Organ-on-a-Chip technology provides a physiologically relevant microenvironment that enables direct observation and manipulation of human bone marrow function. Researchers from the Wyss Institute at Harvard University leveraged these advantages to develop a Bone Marrow-Chip as a patient-specific alternative to animal testing for the study of bone marrow pathophysiology:

The Bone Marrow-Chip overcomes long-standing limitations by: 

• Recreating bone marrow architecture in vitro: The chip houses hematopoietic progenitor and stromal cells within a 3D extracellular matrix adjacent to a perfused vascular channel lined with endothelial cells. This arrangement mimics the spatial organization of bone marrow sinusoids and the interface between vascular and hematopoietic niches. 

• Simulating continuous perfusion: Microfluidic flow delivers nutrients and removes waste—mirroring circulation within the bone marrow. This supports long-term maintenance and differentiation of multiple blood cell lineages, unlike static cultures that quickly lose viability or differentiation potential. 

• Providing an in vivo-relevant yet accessible platform: The system combines the physiological complexity of living tissue with the experimental control of an in vitro assay, enabling fine-tuned manipulation of dosing, timing, and microenvironmental factors. 

• Supporting the use of patient-derived cells: Researchers could populate the chip with CD34⁺ hematopoietic stem and progenitor cells from both healthy donors and patients with bone marrow failure syndromes—making it a powerful platform for studying patient-specific hematopoietic pathophysiology. 

Together, these capabilities create a functional “bone marrow surrogate” that can be experimentally accessed, imaged, and perturbed—something not possible in the human body and rarely achieved in static culture systems. 

Major findings & impact: 

The Bone Marrow-Chip accurately recapitulated clinical hematologic toxicities, such as lineage-specific depletion after chemotherapy and radiation. Chips seeded with patient-derived cells reproduced hallmark features of Shwachman-Diamond syndrome, including impaired neutrophil maturation. 

These results show that the Bone Marrow-Chip can serve as an accessible, human-relevant platform for predicting marrow toxicity, studying disease mechanisms, and testing patient-specific treatment regimens—bridging the gap between in vitro models and human clinical outcomes. 

Case Study 2

A Spinal-Cord Organ-Chip Model of Sporadic ALS Using iPSC-Derived Motor Neurons and Blood-Brain-Like Barrier 

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by progressive loss of motor neurons. The majority of cases are sporadic, meaning they have no known genetic cause, thus making it difficult to study early disease mechanisms or test personalized treatments. Traditional in vitro models, such as 2D neuron cultures or brain organoids, fall short because they lack the multicellular complexity, vascular interactions, and physiological cues present in the human central nervous system. Moreover, the blood-brain barrier (BBB)—a critical component influencing disease progression and drug delivery—is nearly impossible to replicate in static culture. 

Organ-on-a-Chip technology provides a dynamic, multicellular, and perfused platform that bridges this gap between simplified in vitro models and the human nervous system. In this 2025 study published in Cell Stem Cell, researchers from Cedars-Sinai leveraged a microfluidic spinal cord–on–a–chip (SC-Chip) to model sporadic ALS using patient-derived induced pluripotent stem cells (iPSCs).

Experimental setup: 

Using Organ-on-a-Chip technology in this study enabled them to overcome conventional limitations by: 

• Recreating the neurovascular unit: The chip featured two adjacent microchannels—one seeded with iPSC-derived spinal motor neurons and the other with brain microvascular endothelial-like cells—separated by a porous membrane. This setup mimics the structural and functional interface between the spinal cord and blood-brain barrier. 

• Introducing controlled fluid flow: Continuous microfluidic perfusion supplied nutrients, removed waste, and applied gentle shear stress, promoting maturation of both neuronal and endothelial compartments. This dynamic environment better reproduces physiological conditions than static culture. 

• Accommodating patient-derived iPSCs: Using motor neurons reprogrammed from ALS patients’ cells made it possible to model disease-specific phenotypes and compare them directly with healthy control lines. 

• Capturing functional cross-talk: The co-culture of spinal cord tissue with a vascular-like channel introduced metabolic and molecular interactions that influence neuronal health—factors missing from most traditional ALS models. 

Together, these features created a living, human-relevant “spinal cord microenvironment” that could be accessed and analyzed in unprecedented detail—offering new insight into how ALS develops at the cellular level. 

Major findings & impact: 

• The perfused SC-Chip supported enhanced maturation and survival of human motor neurons compared to static cultures. 

• In chips derived from ALS patient cells, researchers observed early, disease-specific alterations—including disrupted glutamatergic signaling, metabolic dysregulation, and neurofilament accumulation—that were not detectable in traditional culture systems. 

• The integrated blood-brain-like barrier exhibited functional permeability properties, enabling exploration of how vascular dysfunction contributes to ALS pathology and how it might affect drug penetration. 

By combining patient-derived neurons with a physiologically active barrier under flow, the SC-Chip revealed patient-specific disease mechanisms and potential therapeutic targets previously masked in simpler systems. 

This study demonstrates that Organ-on-a-Chip technology can serve as a window into complex, patient-specific neurodegenerative processes—offering an accessible yet physiologically authentic platform for mechanistic discovery and, ultimately, personalized drug testing in ALS. 

Case Study 3

Patient-Derived Esophageal Adenocarcinoma Organ-Chips for Functional Precision Oncology 

Esophageal adenocarcinoma (EAC) is one of the most aggressive cancers of the digestive tract, with limited treatment options and highly variable responses to chemotherapy. In clinical practice, many patients undergo neoadjuvant chemotherapy (NACT) before surgery, but up to half fail to respond—exposing them to unnecessary toxicity and delays in curative treatment. 

Traditional ex vivo models, such as patient-derived organoids (PDOs), provide valuable insights into tumor biology but often lack the dynamic tumor microenvironment (TME) features that govern therapeutic response—such as stromal interactions, nutrient gradients, and fluid flow. Without these elements, static models cannot reliably predict how a patient’s tumor will behave in the body. 

Organ-on-a-Chip technology offers a living, perfused model of the tumor microenvironment that maintains patient-specific biology while introducing physiologically relevant mechanical and chemical cues. In a 2025 study published in the Journal of Translational Medicine, researchers at McGill University and the Wyss Institute created an Esophageal Adenocarcinoma (EAC) Organ-Chip (EAC-Chip):

Experimental setup: 

The EAC-Chip overcame key challenges of functional precision oncology by: 

• Recreating the tumor–stroma interface: The chip contained two adjacent microchannels—one seeded with tumor organoids derived from patient biopsies and the other with matched cancer-associated fibroblasts—separated by a porous membrane that allowed bidirectional signaling. This setup recreates the communication between cancer and stromal compartments that strongly influences therapy response. 

• Supporting use of patient-derived samples: Each chip was seeded with tumor and fibroblast cells obtained directly from individual patients, preserving genetic heterogeneity and enabling patient-specific response prediction. 

• Simulating clinically relevant drug exposure: The microfluidic perfusion system allowed researchers to deliver chemotherapy drugs under time-dependent flow conditions that mirror intravenous (IV) administration in patients. This means that the concentration and exposure pattern of the drugs in the chip followed the same pharmacokinetic profile a patient would experience during neoadjuvant chemotherapy. As a result, cells within the chip received clinically relevant dosing regimens—something static organoid cultures cannot replicate. 

• Providing a clinically relevant yet accessible system: Because the assay and associated analysis can be completed in 2-3 months from the time of the diagnostic biopsy, results can align with patient treatment timelines—bridging the gap between laboratory modeling and actionable clinical decisions. 

Together, these design features make the EAC-Chip a functional and accessible “tumor-on-a-chip” that mirrors both the structure and drug-response behavior of human cancers. 

Major findings & impact: 

• The EAC-Chip faithfully preserved tumor architecture and genetic fidelity, maintaining hallmark features of each patient’s cancer. 

• Remarkably, the chip predicted individual patient responses to chemotherapy with 100% concordance: tumors that responded in the clinic also showed significant cell death in the chip, while resistant tumors remained viable. 

• The perfused chip system captured tumor–stroma interactions and microenvironmental effects that static organoid cultures failed to replicate, making it more predictive of clinical outcomes. 

• The ability to model response and gain actionable insights in 2-3 months demonstrates that Organ-Chip assays could realistically fit into the therapeutic workflow—allowing oncologists to refine or replace treatment plans before committing patients to ineffective regimens. 

• Beyond EAC, this approach establishes a template for functional precision oncology, where each patient’s tumor can be tested in a physiologically relevant environment to guide individualized therapy. 

In essence, the Esophageal Adenocarcinoma Organ-Chip transforms patient-derived samples into a living diagnostic tool—one that combines the fidelity of patient-specific tumor cells with the physiological realism of microfluidic perfusion. It’s a clear demonstration of how Organ-on-a-Chip technology can make the most of limited patient samples to deliver actionable insights that genomics alone cannot provide. 

What These Examples Teach Us About Personalized Medicine 

Together, the above case studies highlight several key themes for personalized medicine enabled by Organ-on-a-Chip technology: 

• Patient-derived samples matter: Whether CD34⁺ marrow progenitors, iPSC motor neurons, or tumor organoids and fibroblasts — using cells from the actual patient brings the model closer to reality. 

• Microenvironment and flow matter: Each study shows that recreating stromal/endothelial compartments, fluid perfusion, and physiological architecture makes a difference in predictive fidelity and mechanistic insight. 

• Functional assays (not just genomics) matter: These platforms go beyond just reading genetic mutations — they assess how the cells behave in a physiological context, a critical step for precision medicine. 

• Clinical-timescale results: The Bone Marrow-Chip matured cells over 4 weeks; the ALS SC-Chip achieved matured phenotypes earlier than static culture; the EAC-Chip delivered actionable insights in ~2 months from the time of diagnostic biopsy — all moves toward actionable timelines in a clinical or translational context. 

• Broad disease applicability: The three examples span hematology/toxicology, neurodegeneration and oncology — showing how Organ-Chips are broadly useful for personalized medicine, not just cancer. 

Future Outlook 

The convergence of personalized medicine and Organ-on-a-Chip technology offers a powerful pathway forward. As Organ-Chips platforms become more standardized, automated, and integrated with patient-derived samples and clinical workflows, we may eventually see them function as routine companion diagnostic tools, preclinical drug testing platforms, or even clinical decision support systems. 

For practitioners, researchers and clinicians interested in precision medicine, Organ-on-a-Chip technology offers an exciting opportunity: to make the most of patient-derived samples, to ask functional questions in physiologically-relevant systems, and to bring actionable model-based predictions closer to the bedside. 

Conclusion 

Personalized medicine demands models that reflect patient biology — not just genomics, but how those cells live, interact and respond under real-world conditions. Organ-Chip platforms provide that model: an in vivo-relevant milieu for patient-derived samples that preserves complexity, recreates organ-specific microenvironments, and allows functional read-outs. From modeling bone marrow toxicities, to uncovering neurodegenerative mechanisms in ALS, to predicting chemotherapy response in esophageal cancer — the promise of Organ-Chips in personalized medicine is already being realized. As the technology continues to mature and become integrated into translational workflows, we come closer to a future where every patient’s sample can be placed on a chip — and the best therapy chosen, before treatment begins. 

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Interested in learning more? Register for our upcoming webinar to hear directly from the senior authors of the EAC-Chip study on how they used Organ-Chips to improve functional precision oncology.

Women’s reproductive health has historically been underserved in biomedical research. Conditions such as bacterial vaginosis, cervical infections, and heavy menstrual bleeding affect millions worldwide, yet remain poorly understood and under-treated. One major reason is that conventional preclinical models—animal studies and static cell culture—cannot capture the complex, hormone-responsive biology of the human female reproductive tract. As Dr. Donald Ingber once famously quipped, “mice don’t menstruate.” Thus, without a good model, advancements in the understanding and treatment of women’s reproductive health have continued to lag. 

Organ-Chip models, also called microphysiological systems (MPS), are helping to close this critical gap. By recreating human tissue microenvironments in a dynamic, microengineered platform, Organ-Chips enable scientists to investigate reproductive health with unprecedented physiological relevance. Below, we highlight three case studies—the Vagina-Chip, Cervix-Chip, and a new project focused on Uterus-Chips for heavy menstrual bleeding—that demonstrate how this technology is transforming women’s health research. 

Modeling the Vaginal Microbiome: The Vagina-on-a-Chip  

The vaginal microbiome plays a vital role in reproductive health, influencing susceptibility to infections, pregnancy outcomes, and sexually transmitted diseases. Yet, until recently, researchers lacked a human-relevant model to study how microbial communities interact with vaginal tissue. 

In 2022, researchers published the first Vagina-on-a-Chip in Microbiome. This Organ-Chip was lined with primary human vaginal epithelial cells and perfused with culture media under controlled flow conditions, mimicking the dynamic vaginal environment. The platform allowed direct co-culture of live microbial consortia with human tissue—something impossible with animal models. 

Key findings included: 

• Stable colonization by Lactobacillus crispatus, a beneficial species linked to vaginal health, which maintained a protective acidic environment. 

• Dysbiosis-induced inflammation, where introducing a pathogenic community triggered epithelial damage and immune activation, closely mirroring bacterial vaginosis in patients. 

As lead author Gautham Mahajan, PhD, explained: 

“Our Vagina-Chip model provides an unprecedented opportunity to study host–microbiome interactions in a controlled human-relevant context. This platform can help us untangle how microbial imbalances drive disease and guide the development of targeted probiotics or other therapies.” 

By directly modeling the vaginal microbiome, the Vagina-Chip creates a new preclinical platform to evaluate probiotic interventions, antimicrobial therapies, and microbiome-targeted strategies that could improve outcomes in women’s reproductive health. 

Understanding Cervical Health: The Cervix-Chip 

The cervix regulates fertility, pregnancy maintenance, and protection against infection, but has historically been neglected in preclinical research. Two recent Cervix-Chip studies demonstrate how Organ-Chip models can reveal hormone-dependent and immune-regulated mechanisms of cervical function. 

Hormone Sensitivity and Immune Function

A 2024 Nature Communications publication used Cervix-Chips lined with epithelial and stromal cells to study the effects of cyclical hormones on cervical physiology. The chips replicated hormone-driven changes in: 

• Mucus secretion, essential for regulating fertility and pathogen defense. 

• Immune signaling, showing how estrogen and progesterone modulate innate immune pathways. 

These insights have direct implications for understanding cervical infections, infertility, and preterm birth. 

Crosstalk Between Cervix and Vagina

In 2025, researchers extended this work in npj Women’s Health by linking Cervix-Chips with Vagina-Chips. This integrated Organ-Chip system demonstrated how cervical mucus influences vaginal microbial balance. Disruption of mucus secretion allowed pathogenic bacteria to dominate, reproducing clinical patterns of dysbiosis and infection risk. 

Together, these findings highlight how human-relevant preclinical models can uncover organ–organ interactions critical to women’s reproductive health—insights that were inaccessible with traditional animal models. 

Tackling Heavy Menstrual Bleeding: A Uterus-on-a-Chip Approach 

Heavy menstrual bleeding (HMB) affects nearly one in three women of reproductive age and is more prevalent than asthma or diabetes. It contributes to anemia, fatigue, and lost productivity, yet remains poorly understood because no animal models accurately reproduce menstruation. 

Just this month, the Wyss Institute announced a Wellcome Leap–funded project to develop the first Uterus-on-a-Chip model of heavy menstrual bleeding. This project will build a microengineered system incorporating the endometrial lining, stromal cells, and vascular networks to replicate both normal menstruation and pathological bleeding. 

The initiative aims to integrate: 

• Multi-omics analyses, capturing transcriptomic, proteomic, and metabolomic signatures of abnormal bleeding. 

• AI-driven data pipelines, accelerating biomarker discovery and therapeutic target identification. 

Wyss Founding Director Dr. Donald Ingber emphasized the project’s potential: 

“By creating the first physiologically relevant human model of heavy menstrual bleeding, we hope to not only uncover its root causes but also unlock new, life-changing treatments that can be delivered to patients in months rather than years.” 

The ultimate goal is to reduce the average time to effective treatment for heavy menstrual bleeding patients from five years to just five months—accelerating progress in an area of women’s health that has been neglected for decades. 

Why Organ-Chip Models Are a Turning Point for Women’s Health

The Vagina, Cervix, and Uterus Chips illustrate the broader promise of Organ-Chip technology in women’s reproductive health research: 

• Human relevance: Organ-Chips use primary human cells under physiologically realistic flow and hormone conditions, avoiding species differences that limit animal studies. 

• Dynamic microenvironments: Media perfusion and biomechanical cues replicate the living tissue environment, capturing complexity that static 2D cultures miss. 

• System-level biology: Linking multiple Organ-Chips (e.g., cervix and vagina) enables the study of organ–organ interactions that shape reproductive health and disease. 

• Therapeutic discovery: Integration with omics technologies and computational models accelerates identification of novel biomarkers, drug targets, and treatment strategies. 

By addressing previously unanswerable questions—how microbial dysbiosis drives bacterial vaginosis, how cervical mucus supports fertility and infection defense, or how abnormal menstruation occurs—Organ-Chip models are redefining the landscape of women’s health research. 

Looking Ahead

Organ-on-a-Chip technology is advancing from proof-of-concept models to regulatory-relevant preclinical platforms. For women’s reproductive health, this progress could not be more timely. 

From microbiome research to cervical biology to menstrual disorders, Organ-Chips are generating actionable insights that could lead to: 

• New non-hormonal treatments for heavy menstrual bleeding. 

• Microbiome-based interventions to restore vaginal health. 

• Improved diagnostics and preventive therapies for cervical infections and preterm birth. 

These advances not only improve care for women but also strengthen overall public health. Better reproductive health research means healthier pregnancies, healthier families, and a more equitable healthcare system. 

For too long, women’s health conditions were marginalized as too complex or too difficult to model. With Organ-on-a-Chip technology, those barriers are falling—chip by chip, breakthrough by breakthrough. 

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Ready to LEARN MORE?

Continue your learning by watching the on-demand webinar, “Assessing Reproductive Health with a Human Vagina-on-a-Chip”

By Jim Corbett, CEO, Emulate 

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Drug discovery is at a crossroads. With nearly 90% of clinical trial candidates failing to reach FDA approval, the need for more predictive, human-relevant models has never been greater. That’s why Emulate recently launched the AVA™ Emulation System, the first self-contained Organ-on-a-Chip workstation designed to bring scale, reproducibility, and accessibility to this transformative technology. As the company’s CEO, Jim Corbett brings a unique perspective on how AVA will accelerate adoption across pharma, biotech, and academia—and why it represents a turning point for human-relevant drug discovery. In this blog post, Jim shares how AVA was built to overcome longstanding barriers in the field and what its introduction means for the future of drug development. 

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Rethinking Preclinical Models 

The pharmaceutical industry faces a staggering challenge: nearly 90% of candidate drugs that enter clinical trials fail to gain FDA approval. Traditional reliance on animal models has proven insufficient for predicting human responses, leaving researchers searching for more accurate and efficient solutions. 

Organ-on-a-Chip technology offers a transformative alternative by modeling human biology with unprecedented fidelity. Yet for years, adoption was constrained by scale and cost. That’s where AVA comes in. Designed as the first self-contained Organ-on-a-Chip workstation, AVA integrates high-throughput microfluidic culture, full environmental control, and real-time imaging—all within a compact benchtop unit. Supporting up to 96 Organ-Chip Emulations in a single run, AVA delivers insights at a scale that makes Organ-Chips viable as a standard tool in preclinical workflows. 

Building Confidence Through Scale and Reproducibility 

For Organ-on-a-Chip technology to impact drug development meaningfully, the data must be both accurate and reproducible. AVA enables exactly that. By allowing large-scale experiments, it empowers scientists to generate robust datasets that validate predictive models for efficacy and safety. The result: researchers can make more confident decisions about which drug candidates to advance, reducing costly late-stage failures. 

From Liver-Chip to AVA: A Foundation of Regulatory Trust 

A landmark 2022 study in Communications Medicine demonstrated the predictive power of Emulate’s Liver-Chip in identifying drug-induced liver injury. That study not only paved the way for the Liver-Chip’s inclusion in FDA’s ISTAND program but also set the benchmark for AVA. 

Building on that foundation, AVA incorporates equivalency studies designed to show performance on par with or better than previous generations of Organ-Chip technology. By combining this proven biological fidelity with higher throughput, AVA strengthens regulatory confidence while accelerating the path to qualification as a recognized tool for drug development. 

Empowering Pharma to Capitalize on Regulatory Shifts 

Regulators are now explicitly encouraging the inclusion of New Approach Methodologies (NAMs) like Organ-Chips in IND submissions. With AVA, pharmaceutical companies can generate human-relevant data at the throughput and scale required for regulatory acceptance. 

Importantly, AVA also complements other NAMs—such as computational modeling and omics-based approaches—by providing organ-level validation. This synergy creates a weight-of-evidence approach that strengthens submissions and supports the global movement toward reducing animal testing. 

Making Human-Relevant Research Accessible to Academia 

While industry adoption is critical, academic research plays a pivotal role in innovation. Historically, cost has limited Organ-Chip use in academic settings. AVA changes this dynamic by reducing the cost per sample by more than 75%, making it feasible for academic labs and core facilities to run Organ-Chip experiments regularly. The result is broader access to human-relevant models that can shape early-stage discoveries and future therapies. 

Overcoming Persistent Barriers: Scale, Cost, and Workflow Efficiency 

High-throughput and reproducibility have long been bottlenecks in Organ-on-a-Chip research. AVA was designed to overcome these barriers by automating workflows, integrating imaging directly into the system, and enabling seamless compatibility with robotic liquid handlers. This means researchers can scale experiments without sacrificing quality or disturbing biological conditions, producing harmonized datasets suitable for regulatory and industrial pipelines. 

Shaping the Future of Drug Discovery 

Looking ahead, AVA has the potential to transform how pharma and biotech approach drug discovery. From helping companies like Moderna pre-screen lipid nanoparticles for safety, to accelerating early-stage research in academic labs, AVA is enabling more efficient, cost-effective, and human-relevant workflows. 

The convergence of regulatory change and technological innovation makes this moment especially pivotal. With the FDA and NIH shifting expectations toward human-relevant data, Organ-on-a-Chip technology—uniquely capable of recapitulating organ physiology—stands at the forefront of this new era. By delivering high-fidelity datasets that fuel both regulatory decision-making and AI-driven predictive models, AVA is not just advancing science—it’s redefining the standard for drug discovery. 

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2024 was filled with groundbreaking discoveries that showcase the transformative potential of Organ-on-a-Chip technology. From uncovering new disease mechanisms to advancing drug safety and efficacy testing, these studies highlight the various way that Organ-Chips are contributing to cutting-edge research. Let’s take a closer look at ten of the most impactful Organ-Chip publications of 2024. 

1. Unlocking the Role of the Lung Glycocalyx in Bacterial Pneumonia 

The lungs’ glycocalyx, a thin protective layer, plays a vital role in shielding against infections. Researchers at Universitätsmedizin Berlin leveraged the Alveolus Lung-Chip to investigate how glycocalyx breakdown contributes to bacterial pneumonia caused by Streptococcus pneumoniae. Their findings revealed that enzymatic degradation of glycocalyx components, such as hyaluronan and heparan sulfate, exacerbates bacterial load, inflammation, and tissue damage. 

The study also highlighted potential therapeutic targets to preserve glycocalyx integrity, which could mitigate lung injury and prevent systemic disease progression. Using the Lung-Chip, the team replicated the human alveolar-capillary interface in a way that traditional animal models and static cell cultures could not. These insights offer a new perspective on respiratory health, laying the groundwork for therapies that could revolutionize pneumonia treatment​​. 

Read the publication 

2. Mitigating Radiation Injury 

Radiation-induced liver injury (RILI) is a significant side effect of radiotherapy and radiation exposure, with few effective prevention strategies. Traditional models often fail to mimic the complexity of human liver physiology, limiting the ability to predict clinical outcomes. The Emulate Liver-Chip’s co-culture system, combined with continuous perfusion, provided a closer approximation of in vivo conditions. 

The NIH utilized the Liver-Chip to study the human-specific effects of radiation, focusing on the interaction between hepatocytes and sinusoidal endothelial cells. This dynamic model revealed key biomarkers associated with radiation injury, including inflammation and fibrosis pathways. This research holds promise for improving cancer treatment safety and preparing for radiation-related emergencies, offering a human-relevant tool for developing mitigation strategies​​. 

Read the publication 

3. A New Approach to Organ Preservation with Biostasis Drugs 

Imagine a world where organs for transplantation remain viable for extended periods. Researchers have made strides toward this vision with SNC80, a biostasis drug that slows metabolism without cooling tissues. Using Gut-Chips and Liver-Chips, the team demonstrated how SNC80 reduces oxygen consumption and maintains tissue health, even under stress conditions similar to those during transplantation. 

What sets SNC80 apart is its reversibility—once the drug is removed, tissues return to normal metabolic activity without adverse effects. This research could pave the way for preserving organs longer and enabling life-saving procedures in remote or resource-limited settings. It’s a powerful example of how Organ-on-a-Chip technology can facilitate breakthroughs in critical care​​. 

Read the publication 

4. New Insights on Cancer Therapeutic-Induced Cardiotoxicity Using a Multi-Lineage Human Heart-Chip 

Cancer drugs like sorafenib are life–saving but can have harmful side effects on the heart that are difficult to predict in preclinical models. To address this, Cedars-Sinai researchers used a Heart-Chip model that mimics the human cardiovascular environment by integrating cardiomyocytes and vascular endothelial cells. The study uncovered how sorafenib affects both cell types, leading to reduced contractility and vascular dysfunction. 

What makes this research remarkable is the chip’s ability to replicate human-specific responses, surpassing the limitations of animal models. The Heart-Chip provides a scalable, precise platform for evaluating cardiotoxicity in drug candidates, enabling safer cancer treatments without compromising efficacy. This innovation is a step toward more patient-centered care in oncology​. 

Read the publication 

5. Breaking New Ground in Intestinal Barrier Modeling with the hiPSC-Derived Intestine-Chip 

The small intestine is a marvel of complexity, and replicating its environment has long been a challenge. Researchers at the University of Groningen tackled this with a hiPSC-derived Intestine-Chip, which mimics the gut’s crypt-villus structure and multi-lineage cell composition. This Organ-Chip model offers an unprecedented look at gut health, including nutrient absorption and immune interactions. 

By integrating dynamic conditions such as flow and growth factor gradients, the Intestine-Chip enables drug testing and disease modeling with unparalleled accuracy. This platform is not just a tool for research but a gateway to developing personalized treatments for gastrointestinal disorders​​. 

Read the publication 

6. Exploring the Intersection of Cannabidiol and Liver Health Through a Liver-Chip S1 Quad-Culture Model 

With the rise of CBD-based products, understanding their safety profile is essential. Using the Liver-Chip S1 Quad-Culture, researchers examined how high doses of cannabidiol affect liver health. They found that while therapeutic doses were generally safe, higher concentrations disrupted antioxidant pathways and triggered mild liver injury. 

The study highlights the importance of using human-relevant models to evaluate drug safety. The Liver-Chip’s ability to replicate complex liver functions provides a predictive tool for assessing the risks of CBD and other cannabinoids, ensuring safer consumer products​​. 

Read the publication 

7. Comparing Gut-on-a-Chip and Transwell Models for Peptide Formulations 

Testing oral drug formulations has long relied on models like Transwell systems, but these often fail to replicate the complexities of human intestinal physiology. To address this gap, researchers from Merck developed a Gut-Chip, a dynamic platform that mimics the structure and function of the human intestine with features like continuous flow and 3D villus-like structures. Their study demonstrated that the Gut-Chip provides more accurate predictions of intestinal absorption and drug permeability compared to traditional methods. 

What sets this research apart is the Gut-Chip’s ability to simulate in vivo-like conditions, reducing the reliance on animal models while enhancing translational success. This enables a more reliable preclinical assessment of oral drugs, helping pharmaceutical companies develop safer and more effective treatments. 

Read the publication 

8. Advancing Vaccine Testing with Organ-on-a-Chip Technology  

Understanding human immune responses to vaccines has been a longstanding challenge, often relying on animal models that fail to capture human-specific dynamics. Researchers at Institut Pasteur tackled this issue by developing a Lymphoid Organ-Chip, which enabled them to study memory B-cell activation and antibody production in response to mRNA vaccines. The platform revealed critical insights into how immune imprinting impacts booster efficacy for evolving viral strains. 

The Lymphoid Organ-Chip’s ability to replicate human immune responses using a minimal number of cells sets it apart from conventional models. This innovative tool is transforming vaccine development, offering faster, more accurate testing methods to improve pandemic preparedness and public health outcomes. 

Read the publication 

9. Progressing Women’s Health with Cervix Organ-Chips 

Reproductive health research has often been limited by the lack of models that capture the unique physiology of the cervix. To overcome this, researchers at the Wyss Institute developed the Cervix-Chip, a platform designed to replicate the cervical environment, including mucus production and host-microbiome interactions. Their work explored how healthy and dysbiotic bacterial communities affect cervical barrier function and immune responses. 

The Cervix-Chip’s ability to model hormone sensitivity and microbial dynamics offers a new lens for studying conditions like bacterial vaginosis and improving reproductive health. This platform could enable researchers to develop more effective therapies in a critical but under-researched area of women’s health. 

Read the publication 

10.  Shaping the Future of Brain Disease Research 

Predicting which drugs will cross the blood-brain barrier (BBB) presents one of the biggest challenges in developing drugs for neurological diseases. Researchers at Regeneron used the Brain-Chip, a platform combining key brain cell types with advanced microfluidics, to explore how therapeutics interact with the BBB. Their findings demonstrated the chip’s ability to model functional neuronal circuits, neuroinflammation, and the transport of drugs across the barrier. 

This breakthrough lies in the Brain-Chip’s capacity to mimic human-specific BBB dynamics, surpassing the limitations of animal models. The platform is paving the way for innovative treatments for Alzheimer’s, Parkinson’s, and other neurological conditions, revolutionizing the future of brain health research. 

Read the publication 

These publications were featured on our LinkedIn page in December of 2024 to celebrate reaching 25,000 subscribers. To stay up to date with the latest Organ-Chip research, news, and advancements, be sure to follow us on LinkedIn and Twitter! 

Want to explore Organ-Chip publications further? View our publications database here. 

Drug-induced liver injury (DILI) remains a persistent challenge in drug development, endangering patient safety and delaying the availability of critical therapies. Just days ago, the FDA issued a warning about Ocaliva (obeticholic acid), a treatment for primary biliary cholangitis, after reports of severe liver injury in patients without pre-existing cirrhosis. Among 81 patients treated with Ocaliva, seven required liver transplants compared to just one in the placebo group, and four patients died versus one death in the placebo group.  

Unfortunately, Ocaliva is far from an isolated case. On December 6^th, BioAge Labs announced the discontinuation of its STRIDES Phase I trial for Azelaprag, a promising obesity drug candidate, due to unexpected liver safety concerns. While Azelaprag initially showed potential to improve patient outcomes, concerns arose after 11 individuals in the treatment groups experienced elevated liver enzyme levels. 

These recent incidents add to the growing list of drugs derailed or delayed due to liver toxicity concerns, underscoring the persistent shortcomings of traditional preclinical models—such as animal studies and 2D cell cultures—which often fail to predict human liver toxicity with the accuracy needed to ensure patient safety. 

Together, these cases emphasize the urgent need for more predictive preclinical models. More human-relevant approaches, like Organ-on-a-Chip technology, can help bridge the gap, offering a more accurate, human-centered approach to mitigate the risks of DILI and support safer drug development. 

Unpredicted DILI: A Persistent Patient Safety Concern 

Unexpected cases of DILI continue to pose significant risks to patients and disrupt drug development. Since January 2022, at least eleven clinical trials or marketed drugs have reported DILI, with some resulting in patient deaths. 

Recent examples include: 

• TNG348 (2024): Development of this USP1 inhibitor for cancer was halted after a Phase I/II study revealed grade 3 and life-threatening grade 4 liver function abnormalities after eight weeks of treatment. 

• Evobrutinib (2023): This Bruton tyrosine kinase (BTK) inhibitor for multiple sclerosis had its Phase III trials partially paused due to two cases of liver injury markers indicative of DILI. 

• Tolebrutinib (2022): Another BTK inhibitor for multiple sclerosis faced a partial clinical hold following DILI reports, including a case where a patient required a liver transplant and later died from complications. 

• Lumakras (sotorasib) in combination therapy (2022): In Phase Ib trials, combining this KRAS G12C inhibitor with immune checkpoint inhibitors like Keytruda or Tecentriq led to severe liver toxicity in 50% of patients, halting further combination studies. 

These examples highlight the pressing need for predictive models that better replicate human liver biology, reducing the risk of such severe outcomes. 

Why conventional models fall short in predicting liver injury 

Traditional preclinical models fail to emulate the complexity of the human liver, limiting their ability to predict toxicity effectively, leaving patients vulnerable to unanticipated adverse events, and delaying the development of life-saving therapies. 

Conventional model limitations include: 

• Animal Models: Differences in metabolism, immune responses, and drug transport mechanisms between species result in poor translation to human biology. Key contributors to DILI, like cytochrome P450 variability and immune-mediated hepatotoxicity, are often misrepresented in animals. 

• 2D hepatocyte cultures: These static systems lack cell-cell interactions, media flow, and mechanical forces, leading to a rapid loss of liver-specific functions and poor sensitivity in predicting DILI. 

• 3D Organoids and Spheroids: While these technologies improve cellular organization, they lack essential features like vascularization and mechanical forces, making it challenging to model the biological complexity of the human liver sinusoid. 

A paradigm shift toward more human-relevant preclinical models is urgently needed to bridge these gaps and ensure better outcomes for patients. 

The Emulate Liver-Chip: A Human-Relevant Solution 

To address the persistent challenge of drug-induced liver injury (DILI) and the limitations of traditional preclinical models, the Emulate Liver-Chip provides a human-relevant platform for assessing hepatotoxicity. By incorporating primary human liver cells in a dynamic Organ-Chip microenvironment, the Liver-Chip enables researchers to generate predictive and mechanistic insights that can improve drug safety assessments, helping to mitigate risks like those recently observed with Ocaliva, Azelaprag, and other therapies. 

High Predictive Accuracy 

In a study published in Communications Medicine, the Liver-Chip S1 demonstrated exceptional predictive accuracy, achieving a sensitivity of 77% and specificity of 100% across 27 small molecule drugs tested on a single donor. It effectively distinguished all seven pairs of hepatotoxic drugs and their non-toxic structural analogs, such as trovafloxacin and levofloxacin. When an additional donor was tested on 18 small molecule drugs, combining both datasets improved sensitivity to 87% while maintaining 100% specificity. These results are nearly double the sensitivity of 3D hepatic spheroids (47%) for the same drugs, emphasizing the Liver-Chip’s superior predictivity. 

Mechanistic Insights 

The Liver-Chip goes beyond prediction, providing insights into the mechanisms of liver injury. Its design includes hepatocytes, Kupffer cells, stellate cells, and endothelial cells, enabling cell-cell interactions that reveal pathways of damage. Researchers can measure albumin production and ALT release to track functionality and injury, while imaging highlights morphological changes, apoptosis, mitochondrial dysfunction, and lipid accumulation. These mechanistic insights empower researchers to understand how drugs cause liver toxicity, enabling earlier and more targeted design updates to improve drug safety. 

Regulatory Alignment 

In September 2024, the Liver-Chip S1 became the first Organ-on-a-Chip technology accepted into the FDA ISTAND Pilot Program. While not yet fully qualified, this milestone underscores the potential of the Liver-Chip S1 as a future standard for liver toxicity assessment in regulatory submissions, providing a more reliable basis for evaluating drug safety. 

Why the Liver-Chip Matters 

The ongoing issues with drug-induced liver injury, exemplified by Ocaliva, Azelaprag, and other recent cases, highlight the critical need for innovative tools that prioritize patient safety. The Emulate Liver-Chip directly addresses these challenges, offering a human-relevant platform that bridges the gap between preclinical testing and clinical outcomes. By enhancing the prediction of hepatotoxicity, providing detailed mechanistic insights, and aligning with evolving regulatory frameworks, the Liver-Chip supports safer and more efficient drug development. 

With this technology, the pharmaceutical industry can move beyond the limitations of outdated models, helping to prevent future DILI-related incidents, reduce patient risks, and accelerate the availability of life-saving therapies. 

Learn More 

For more information on how the Liver-Chip can enhance preclinical workflows and improve drug safety, download the Liver Toxicology White Paper. This resource demonstrates how Emulate Organ-Chips can advance toxicity prediction to support the development of safer therapies and better protect patients. 

Introduction

In recent years, the pharmaceutical and biotechnology industries have increasingly turned to complex in vitro models (CIVMs) to improve the predictability of preclinical studies. These models offer a more physiologically relevant environment for cells compared to traditional 2D cell cultures and avoid the species-translation issues of animal models. Because of this, their potential use in Investigational New Drug (IND) submissions to the U.S. Food and Drug Administration (FDA) has become a topic of significant interest. 

What are Complex In Vitro Models?

In vitro models are laboratory-based systems that use isolated cells, tissues, or biological molecules to study biological processes and drug effects outside of a living organism. CIVMs take it one step further—they are advanced laboratory cell culture tools designed to simulate the structure and function of human tissues and organs. The IQ MPS—an affiliate of the International Consortium for Innovation and Quality in Drug Development—classifies CIVMs into three major categories:

1. Static Models – Traditional in vitro cell culture systems that lack dynamic environmental factors found in vivo, such as fluid flow or mechanical forces. They include 2D cell cultures, such as transwells and co-cultures, and 3D models, such as spheroids or organoids. 

2. Static MPS Models – A subset of microphysiological systems (MPS) that incorporate advanced engineering features such as electrical sensors but lack dynamic environmental features such as continuous fluid flow or mechanical forces. 

3. Dynamic MPS Models – Advanced platforms designed to replicate the functional and mechanical aspects of human tissues and organs by integrating dynamic environmental conditions such as fluid flow, mechanical forces, and tissue-tissue interactions. The most prominent example is Organ-Chips. 

Each model aims to close the gap between conventional 2D in vitro testing and human biology. By doing so, they can offer improved predictability over traditional preclinical methods. 

Challenges in Preclinical Drug Development

In the preclinical stages of drug development, researchers assess the pharmacokinetics (PK) and pharmacodynamics (PD) of a drug candidate to evaluate its safety and efficacy. They rely on two main types of models to do so: 

2D Cell Cultures: These static models are simple and cost effective, but they lack the biological complexity of humans, meaning they often fail predict human response. 

Animal Models: Animals have long been integral to preclinical drug testing, largely because their biological complexity is similar to that of humans. However, there are still significant differences between human and animal physiology, leading to inaccurate predictions of drug responses in humans. 

The limitations of these model types contribute to the high failure rate of drug candidates in clinical trials, with some estimates suggesting that up to 90% of drugs fail in clinical stages due to unforeseen toxicity or lack of efficacy¹. 

How Complex In Vitro Models Enhance Preclinical Studies

Since CIVMs are designed to recreate the microphysiological environments of human organs, they address many of the limitations of conventional 2D cell culture and animal models: 

1. Physiological Relevance 

CIVMs are designed to more accurately mimic human tissue structure and function. For example, a key feature of Organ-Chips is that researchers can easily control and finely tune the mechanical forces cells experience. When Organ-Chips are placed under media flow and cyclic mechanical strain, cells experience the mechanical forces they would in the body—such as peristalsis in the intestines, breathing in lungs, and blood flow through vessels. All of these features combined—multicellular complexity, cell-cell interactions, tissue-specific ECM, and mechanical forces—result in more in vivo-relevant gene expression, morphology, and functionality than is possible with conventional cell culture methods. 

2. Better Prediction of Human Responses 

Because CIVMs can replicate human organ systems with high fidelity, they can often offer better predictive value compared to animal models. In fact, a 2022 survey conducted by the Linus Group on behalf of Emulate found that researchers who have used Organ-Chips in their experiments overwhelmingly agree—70% of experienced users rated the technology as more predictive than animal models, and an additional 21% said the technology is similarly predictive. 

3. Reduced Animal Use 

In recent years, there has been growing pressure to reduce the use of animals in preclinical testing. CIVMs offer a viable alternative, allowing researchers to perform toxicity and efficacy testing without relying solely on animal models. This not only allows researchers to avoid lengthy and rigid animal experiments, but it also aligns with the FDA’s ongoing efforts to promote alternatives to animal testing, as outlined in their Advancing Alternative Methods (AAM) initiative². 

CIVMs in IND Submissions to the FDA

The FDA requires extensive safety and efficacy data before approving an Investigational New Drug (IND) application, which is the first step towards clinical trials. CIVMs offer several ways to enhance the quality of the data submitted, potentially reducing the risk of delays or rejections. 

1. Safety Assessment 

The primary focus of an IND submission is to determine the safety of a drug candidate; CIVMs can provide highly predictive toxicology data. For example, Liver-Chips are increasingly used to study drug metabolism and liver toxicity, helping to identify adverse effects that might not be evident in standard in vitro assays. 

In a landmark study published in Communications Medicine, Emulate researchers showed that the Liver-Chip S1 outperformed conventional animal and hepatic spheroid models in predicting drug-induced liver injury (DILI), correctly identifying 87% of a set of 18 drugs that caused DILI in humans, despite passing through animal testing.​ Applied across the pharmaceutical development pipeline, widespread adoption of Organ-Chips in preclinical testing could create productivity gains of up to $3 billion through its increased predictive power. Perhaps most importantly, however, is that the Liver-Chip could have prevented 242 deaths in the clinic due to its predictive power in safety assessments.​ 

2. Pharmacokinetics and Pharmacodynamics 

In addition to safety, PK and PD data are essential components of an IND submission. Scientists can create CIVMs that simulate multiple organ systems to assess how a drug is absorbed, distributed, metabolized, and excreted (ADME) in the human body. For instance, a Kidney-Chip model can be used to predict renal clearance and drug-drug interactions, while a gut-on-chip system can study drug absorption³. 

These models can offer more accurate data on drug behavior in humans compared to animal models, leading to more confident dosing strategies in early-phase clinical trials. 

3. Improved Disease Modeling 

CIVMs can also be used to model specific disease states more accurately than animal models. For instance, researchers can create disease-specific Organ-Chip models (e.g., Lung-Chips for studying cystic fibrosis or asthma) to test how drug candidates perform in a human-relevant disease environment. This can provide additional support for an IND submission, demonstrating that a drug is not only safe but also effective in a human-specific disease context. 

4. Regulatory Acceptance and FDA Guidelines 

The FDA has shown increasing interest in the use of CIVMs for IND submissions, particularly in the context of toxicology and disease modeling. While these models are not yet required in IND submissions, they are becoming an accepted method to supplement traditional data. In 2020, the FDA launched the Innovative Science and Technology Approaches for New Drugs (ISTAND) pilot program, which aims to qualify novel approaches like Organ-Chips for regulatory use. In September 2024, the Liver-Chip S1 became the first Organ-Chip model to be accepted into the program, marking a significant step forward in the regulatory acceptance of CIVMs. 

Drug developers must work closely with the FDA during the pre-IND phase to ensure that any data generated using CIVMs aligns with regulatory expectations. The agency’s guidance on the use of alternative methods is evolving, and incorporating CIVMs could improve the chances of a successful IND application. 

Real-World Examples of CIVMs in Drug Development

Several high-profile pharmaceutical companies are already leveraging CIVMs to improve their drug development pipelines. Take for example Moderna: 

Samantha Atkins, PhD, is a scientist in the Investigative Pathology division at Moderna. Her goal is to de-risk their lipid nanoparticle (LNP) candidates to make them safer before they progress into NHP studies. To increase the efficiency of her research program, Dr. Atkins has started using the Emulate human Liver-Chip to screen for LNP-mediated toxicity instead of relying solely on NHPs. 

In a simple cost analysis, Dr. Atkins found that she was able to screen 35 novel LNPs in the Liver-Chip during a course of experiments that took 18 months at a total cost of $325,000. If she were to screen the same number of LNPs using traditional NHP studies, it would have cost Moderna over $5,000,000 and taken over 60 months to complete. 

Simply by incorporating Liver-Chips into her workflow, she is able to down-select LNPs over 4x faster and at a fraction of the cost of NHP studies. 

Another pharmaceutical company using CIVMs to improve their R&D programs is GlaxoSmithKline. Dr. Josie McAuliffe, the Lab Head of Cell Biology & In Vitro Models, has started incorporating Lymph Node-Chips into her preclinical assessment of vaccines to bridge gaps between in vitro models, animal studies, and clinical outcomes. Dr. McAuliffe’s goals are to test the chip’s capacity with RNA vaccines of varying effectiveness to evaluate the dynamic range of the chip, as well as to better correlate in vitro model outcomes with clinical efficacy to improve the overall translation of vaccine candidates. 

These real-world applications demonstrate how CIVMs are making their way into the regulatory landscape, offering valuable data to support IND submissions. 

Conclusion

CIVMs represent a significant leap forward in drug development. By providing more physiologically relevant data, reducing reliance on animal models, and offering better predictions of human responses, CIVMs are poised to play an increasingly important role in IND submissions to the FDA. As the regulatory landscape continues to evolve, companies that adopt these models early may have a competitive advantage, reducing the risk of late-stage clinical failures and improving the overall efficiency of their drug development process. 

By integrating CIVMs into their preclinical programs, pharmaceutical and biotechnology companies can enhance the quality of their IND submissions, ultimately leading to safer, more effective drugs reaching the market faster.

Continue Learning: 

• eBook: An Introduction to Organ-on-a-Chip Technology

• Blog: Microphysiological Systems: The Future of Research and Drug Development 

• Blog: Are Non-Human Primates a Research Dead End? 

• Webinar: Organ-Chips 101: Bridging the Gap Between Traditional Models and Human Biology

Sources: 

1. Sun D, Gao W, Hu H, Zhou S. Why 90% of clinical drug development fails and how to improve it? Acta Pharm Sin B. 2022 Jul;12(7):3049-3062. doi: 10.1016/j.apsb.2022.02.002. Epub 2022 Feb 11. PMID: 35865092; PMCID: PMC9293739. 

2. Commissioner, Office of the. “Advancing Alternative Methods at FDA.” FDA, 5 Jan. 2022, www.fda.gov/science-research/about-science-research-fda/advancing-alternative-methods-fda. 

3. Center for Drug Evaluation and Research. “Drug Development and Drug Interactions.” U.S. Food and Drug Administration, 2019, www.fda.gov/drugs/drug-interactions-labeling/drug-interactions-relevant-regulatory-guidance-and-policy-documents. 

Recently, we announced that the Emulate Liver-Chip S1 was accepted into the FDA’s ISTAND pilot program. To learn more, we sat down with Dr. Lorna Ewart, Chief Scientific Officer at Emulate, for a conversation about what this acceptance means for the company, the drug development industry, and the future of drug safety assessment. 

Q: What exactly is the FDA ISTAND program, and why is it relevant to drug development? 

Lorna Ewart: The ISTAND program—which stands for Innovative Science and Technology Approaches for New Drugs—is a pilot initiative introduced by the FDA to qualify innovative tools and technologies for use in regulatory submissions. Essentially, it provides a pathway for new methodologies, like our Organ-Chips, to be recognized by the FDA as a reliable and robust drug development tool in drug development. 

When sponsors include data from a  qualified drug development tool in their regulatory submissions, FDA reviewers can have confidence in that data’s quality and reproducibility. This allows them to focus on the experiment outcome and how the data support the sponsor’s proposal, such as initiating a clinical trial, without focusing on how the data was generated.  

Q: How does this acceptance impact Emulate and the broader pharmaceutical industry? 

LE: For Emulate, being accepted into the ISTAND program is an important milestone that represents the Liver-Chip S1’s potential applicability in regulatory contexts. For the pharmaceutical industry, it indicates the increasing interest in using more human-relevant models earlier in the drug development process. Ultimately, full qualification could mean more accurate prediction of drug-induced liver injury (DILI) for drugs whose structural analogs have previously shown a DILI response in the clinic. This could improve patient safety by reducing the risk of adverse effects that traditional models may miss. 

Q: Can you walk us through the process of gaining acceptance into the ISTAND program? 

LE: Certainly. The ISTAND program involves a three-stage process, the first of which is the Letter of Intent (LOI). For this, we submitted a detailed proposal outlining the unmet need in drug development that our technology addresses. In this stage, establishing a narrow context of use is paramount, and we focused on demonstrating how the Liver-Chip S1 can better predict small-molecule DILI compared to traditional models—specifically in cases comparing structurally similar compounds, where one is known to cause clinical DILI. 

With the LOI accepted, we’re moving into the second stage of the ISTAND program, the Qualification Plan. In this phase, we will work with the FDA to design a study plan aimed at demonstrating reproducibility and repeatability of our Liver-Chip S1 in predicting DILI in the approved context of use. More specifically, when carrying out these studies, we’ll be showing that our technology produces consistent results across different laboratories and with various hepatocyte donors. We’ll also be working closely with the FDA to ensure our Qualification Plan meets all regulatory expectations. This partnership is crucial for addressing any questions and aligning the data requirements. 

The third and final stage is Full Qualification. Here, we will present the data from our Qualification Plan to the FDA. If successful, our Liver-Chip S1 would be fully qualified for use in regulatory submissions within the stated context of use. 

Q: What were some key findings from your studies that supported your submission? 

LE: Our submission was underpinned by robust data from our study published in Communications Medicine, where we evaluated 27 small-molecule drugs using the Liver-Chip S1 on a single donor. The drugs were categorized into five levels of severity based on their Garside DILI rank and included seven pairs of toxic drugs and their non-toxic structural analogs for direct comparison. The Liver-Chip S1 achieved an impressive 77% sensitivity and 100% specificity for all 27 compounds tested. We then tested a subset of 18 drugs on an additional donor and combined the data from both donors, where we found that the sensitivity increased to 87%, while specificity was maintained at 100%.  Importantly, the Liver-Chip S1 also successfully distinguished between all seven pairs of the drugs and their structural analogs—a result that proved crucial to our submission. Altogether, these results mean that the Liver-Chip S1 was highly effective in correctly identifying both toxic and non-toxic compounds. 

The Liver-Chip S1 was able to detect liver toxicity that conventional models—including spheroids and animal models—failed to predict. This highlights the potential of our technology to improve drug safety assessments. In a follow-up study, we developed the Liver-Chip S1 DILI Score, which quantifies the severity of liver injury on a scale of 1 to 5. This score aligns with clinical outcomes and provides a nuanced understanding of a compound’s hepatotoxic potential. 

Q: How might the Liver-Chip S1 change the way companies assess drug safety, particularly regarding liver toxicity? 

LE: Once the Liver-Chip S1 has passed each of the qualification stages, it could help to significantly enhance how pharmaceutical companies evaluate liver toxicity within the context-of-use defined for the submission. By providing a more human-relevant model, companies can better predict the potential liver toxicity of drugs whose structural analogs have previously shown a toxic response, reducing the risk of late-stage failures. Data from the Liver-Chip S1 can inform go/no-go decisions and guide modifications to chemical structures to improve safety profiles. 

Q: Are there other applications for the Liver-Chip S1 beyond the scope of the ISTAND program? 

LE: Absolutely. While our ISTAND submission focuses on a very specific context of use, researchers around the world have leveraged the Liver-Chip for various applications. Beyond small molecule toxicity testing, Liver-Chips have been used to assess the safety of monoclonal antibodies, cannabinoids, and gene therapy delivery vehicles. One particularly impactful example is its use in early drug development: Scientists at Moderna leveraged the Liver-Chip to screen 35 novel lipid nanoparticles (LNPs), allowing them to identify the most promising candidates before advancing to costly and lengthy non-human primate studies. Additionally, the Liver-Chip can model liver diseases, providing unique insights into disease progression and potential therapeutic approaches. For example, in a 2021 Cell paper, researchers used a Liver-Chip to model alcohol-associated liver disease (ALD) using human-relevant blood alcohol levels and clinically meaningful endpoints. The Liver-Chip exhibited key markers of ALD, such as lipid accumulation, oxidative stress, and bile canalicular remodeling, after ethanol exposure. These findings indicate that the Liver-Chip could provide more human-relevant assessments of ALD and aid in the development of novel therapies. 

Q: Any final thoughts you’d like to share about this milestone? 

LE: We’re excited about this significant step forward. The Liver-Chip S1’s acceptance into the ISTAND program is not only a promising development for our technology but also marks progress towards widespread incorporation of more predictive and human-relevant models in drug development. We look forward to working with the FDA in the next phase and are enthusiastic about the potential our technology has in helping the broader scientific community enhance drug safety and efficacy.

From July 3^rd–5^th, 2024, Emulate joined the European Organ-on-Chip society (EUROoCS) annual conference hosted at the historical Leonardo Campus of Politecnico di Milano in the splendid city of Milan, Italy.

What is EUROoCS?

EUROoCS is an independent, not-for-profit organization established to encourage and develop research into Organ-Chips and provide opportunities to share knowledge and advance the field with the ultimate goal of creating a healthier future. EUROoCS holds an annual conference fostering worldwide delegates active in the field of Organ-on-a-Chip technology and microphysiological systems to showcase the latest scientific breakthroughs and engage in meaningful discussions on the field’s cutting-edge advancements. The conference brings together a broad audience of Organ-Chip experts and enthusiasts from government, academia, pharma, medicine, and other institutions.

Learn how you can join EUROoCS here.

EUROoCS in Review

This exciting event started with the plenary talk from Prof Andries D. van der Meer, EUROoCS Chair, highlighting the “Official publication of the international Roadmap for Organ-on-Chip Standardization.” This was followed by a keynote talk titled, “Building a roadmap towards Regulatory Acceptance of NAMs in the Development and Approval of Pharmaceuticals,” delivered by Sonja Beken, PhD, Coordinator of the Unit of non-clinical evaluators at the Belgian Federal Agency for Medicines and Health Products (FAMHP), which highlighted the vision of the 3Rs Working Party and Member of the Non-Clinical Working Party at the European Medicines Agency. There was also a consecutive regulatory industrial round table discussion on Organ-Chip-based test methods for the authorization of medicinal products. Another interesting keynote was delivered by Kimberly Homan, PhD, where she discussed how combining organoids with Organ-Chips opens new doors in drug research and development.

Another interesting keynote was delivered by Genentech’s Kimberly Homan, PhD, where she discussed how combining organoids with Organ-Chips allows researchers to unlock new possibilities in drug research and development.

At the conference, Emulate provided attendees an opportunity to gain hands-on experience in our Organ-Chip wet lab and explore cutting-edge innovations, including the Chip-A1 Accessible Chip and our new CAR T Organ-Chip application.

Our customers also showcased their latest scientific breakthroughs in presentations and poster sessions.

Talks:

• “Comparison of Spheroids and a Microfluidic Chip Model as Advanced in Vitro Liver Models” by Heidrun Ellinger-Ziegelbauer, PhD, Principal Scientist, Bayer AG Pharmaceuticals
• “Recapitulating memory B cell responses in a Lymphoid Organ-Chip to evaluate mRNA vaccine boosting strategies” by Lisa Chakrabarti, PhD, Control of Chronic Viral Infections Group, Virus and Immunity Unit, Institute Pasteur, Université de Paris
• “Development and validation of an organ-chip model of breast cancer bone metastasis” by Stefaan Verbruggen PhD, Centre for Predictive in vitro Models, Engineering and Materials Science, Queen Mary University of London, London, United Kingdom

Posters:

• “Impact of tissue microenvironment and mechanical forces of the human gut on pathogens invasion” by Samy Gobaa, PhD, Head of Organ-on-Chip Center, Institute Pasteur
• “Lung organoid-on-chip models to study respiratory infections” by Barbara Fonseca, PhD, Researcher, Institut Pasteur
• “Evaluation of Cell-Type Specific miRNA Secretion in a Liver-Chip Model” by Nicole Reisinger, DSM-Firmenich, ANH R&D Center, Tulln, Austria

EUROoCS2024 was an amazing opportunity to connect with fellow Organ-Chip enthusiasts and see how scientists are using Emulate Organ-on-a-Chip technology to advance research across a wide variety of areas. The field of Organ-Chips is in a better place than it’s ever been, and we’re excited to see what new achievements will be made over the next year. See you at EUROoCS2025!

__________________

Explore past and future Emulate events here.

Discover the exciting work of our user community by downloading our Publication Digest.

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In this Emulate guest blog, Vivek Thacker, PhD, Group Leader at University Hospital Heidelberg, explains how he and his team at his previous organization, École Polytechnique Fédérale de Lausanne, used the Emulate Lung-Chip to study how bacterial “cords” contribute to the pathogenesis of Mycobacterium tuberculosis.

What is tuberculosis, and what makes it so interesting to study?

Tuberculosis (TB), an infectious bacterial disease, is humankind’s oldest and deadliest foe, still responsible for roughly 1.5 million deaths per year globally. The causative bacterium, Mycobacterium tuberculosis (Mtb), has co-evolved with humans over thousands of years, making TB a chronic disease with a wide spectrum of manifestations. Today, the most common treatment is a multi-drug antibiotic regimen that needs to be administered for several months, leading to poor treatment compliance and an increasing profile of drug resistance.

Interestingly, many individuals in high-risk countries are frequently exposed to Mtb but do not go on to develop TB or adaptive immune responses to Mtb antigens. This suggests that it is important to understand how the human innate immune system effectively halts disease progression. As such, my team and I wanted to characterize Mtb’s earliest interactions with epithelial cells and macrophages in the lung, study how Mtb adapts to the lung microenvironment, and investigate what causes tissue resident immune cells to succeed or fail in their quest to contain infection.

What makes tuberculosis so challenging to study?

TB is spread by aerosols, meaning that the earliest host-pathogen interactions should be single-cell interactions in the vast alveolar spaces of the lung. However, early TB activity in these alveolar spaces is relatively understudied, as it is difficult to isolate a few hundred bacteria in the lungs of any animal model, and it is even more challenging to study the spatiotemporal dynamics of host-pathogen interactions, particularly in BSL-3 conditions.

How did Organ-Chips allow you to overcome these challenges?

These challenges are perfectly suited to Organ-Chips, which fit into the large space in the “middle”—that is, they recapitulate complex cellular interactions that do not occur in simple model systems, allowing us to study the mechanisms of early-stage bacterial exposure and response with high spatiotemporal resolution. As you can imagine, this opens many new research avenues.

Organ-Chips are invaluable for discovery research, allowing us to identify new phenomena or roles for certain cell types in specific host niches. On top of this, the modular nature of this technology allows us to perturb only specific cells in a co-culture for targeted studies. Many “traditional” assays can also be made more precise and quantitative—e.g., fast and accurate measurements of bacterial killing and regrowth after antibiotic treatment. Organ-Chips also enable new kinds of measurements, such as in situ electron microscopy.

Can you describe the model you developed and the insights it yielded?

The Lung-Chip recreates the physiological air-liquid interface seen in alveolar biology while being accessible to long-term live-cell imaging. Using this model, we found that pulmonary surfactant secreted by epithelial cells protected the host from Mtb infection, rendering many Mtb unable to grow in host cells. However, exposure to surfactant in turn stimulated the bacteria to produce lipids that survived this first interaction, leading to the formation of biofilm-like cords in host cells that help Mtb bacteria evade clearance by antibiotics.

The consistent growth of Mtb cords in the Lung-Chip led us to search for these structures in the early stages of infection. To do this, we designed an experimental strategy wherein we imaged thick tissue slices with confocal microscopy in order to search for these cords in situ. We were then able to identify cords in an animal model, not only providing crucial validation but also expanding the predictive reach of the Organ-Chips. This provides a roadmap for future iterative development of the Lung-Chip to explore more aspects of Mtb pathogenesis.

How have these findings changed your research, and what does the future look like for you?

Clearly demonstrating that cords play a role in Mtb pathogenesis opens several new research avenues. In future studies, we will seek to understand how the mechanical rigidity of these structures affects immune function as well as focus on dissecting this complex host-pathogen interaction, with the aim to develop better protective strategies. We will also focus on gaining a better understanding of antibiotic responses within specific tissue microenvironments. Using Organ-Chips, we can study how specific tissue niches and barriers change the “effective” antibiotic concentrations that bacteria may experience and how these antibiotics may be processed differently within these bacteria (e.g., restricted access due to tight packing in cords).

Learn more in the full article published in Cell.

The Origins of Modern Cell Culture

The tone of Robert Hooke’s writing in 1665 was one of unmistakable glee. Hooke, having recently constructed a rudimentary but powerful microscope, was now able to document in detail the underlying components that afforded plants, rocks, and animals their functional properties. To Hooke, this newfound world held the key to understanding the nature of life.  

“And could we so easily and certainly discover the [design] and texture even of these films and of several other bodies…we might as readily render the true reason of all their phenomena.”  

Driven by this potential, Hooke proceeded to catalogue the microscopic world around him. His work, documented in Micrographia, not only introduced the term ‘cell’, but also demonstrated the benefits of meticulously studying the cellular world, thus laying the groundwork for modern cell biology.  

Today, cell culture, which involves growing cells outside of their native organism, is a foundational tool in the molecular sciences. Cells that have been isolated from a patient or immortalized long ago allow researchers to study various aspects of the human body, using the cells as proxies for the larger organs they hail from. However, deriving valuable information about an organism from its cells is far from simple. Cells isolated from the human body (in vitro) are unlikely to behave naturally, and those within the body (in vivo) are often difficult to observe. There have been significant strides towards understanding the mechanics of life and disease at the cellular level, and recent advances in the technology used to study cells are opening up even newer possibilities.  

In vitro cell culture involves growing living cells in a highly controlled, non-living environment. In vitro is Latin for “in the glass,” and as the name suggests, this kind of cell culture is most often carried out by growing cells in a two-dimensional (2D) plane on glass or plastic petri dishes. These cells may be sourced directly from patients (known as patient-derived cells) or collected from a patient long ago and subsequently engineered to enable long-term propagation (so called immortalized cell lines).  

In Vitro Cell Culture Advantages and Disadvantages

Advantages 

• Growing and maintaining cells is relatively inexpensive. 

• Researchers gain a high degree of control over the cell’s environment, maintaining control over the nutrients, temperature, and other variables that cells are exposed to.  
• These cells are often far easier to observe through a microscope, enabling high-content studies of the cell’s behavior. 
• This approach is often amenable to high-throughput applications, such as drug or functional screening. 

Disadvantages 

• The in vitro environment is far removed from the cell’s natural environment in the human body, where cells experience three-dimensional contact with proteins and other cells, biomechanical forces, as well as dynamic nutrient and waste gradients. Each of these factors can influence how the cell behaves. By removing cells from a complex environment to a far more simplified one, the translational value of in vitro cell culture diminishes.  
• In vitro cell culture may result in artificial mutations that cause cells to behave abnormally. 

In Vivo Studies: Advantages and Disadvantages

In vivo, meaning “within the living,” involves studying cells within their native organism. This method provides the most accurate representation of how cells behave in their physiological context. In vivo studies have long been viewed as the gold standard for understanding complex interactions within tissues, organs, and systems, as well as for assessing the real-world effects of drugs and treatments. This is largely because of the aforementioned drawbacks of traditional in vitro cell culture systems.  

However, in vivo studies come with a significant cost. The in vivo environment is inherently more complex, making it difficult to isolate the effects of specific variables on cell and organismal behavior. Additionally, many in vivo studies are performed in model organisms, such as rats and dogs, to predict how the human body will respond to disease or therapeutics. The genetic and physiological differences between animals and humans can erode the accuracy of these models. This is particularly hazardous in preclinical drug safety testing, where inaccurate predictions can lead to dangerous compounds advancing into the clinic.  

Bridging the gap with more advanced in vitro systems  

Recent advances to in vitro cell culture are helping to alleviate the challenges researchers have faced historically, particularly by incorporating more complex, in vivo-relevant environments. The most powerful example of this comes from Organ-on-a-Chip technology, also known as “Organ-Chips.” 

Organ-Chips are advanced, three-dimensional in vitro culture systems that closely mimic the natural environment of a cell. Specifically, these systems expose cells to biomechanical forces, dynamic fluid flow, and heterogenous cell populations while providing three-dimensional contact with proteins or other cells. Collectively, these features encourage the cells to behave as they would in a living organism, thus greatly improving researchers’ ability to accurately study the behavior of cells in vitro. And, unlike many in vivo model systems, Organ-Chips can be constructed with human cells, thus circumventing the interspecies differences that plague many in vivo systems. As such, Organ-Chips are now being used in a variety of applications to help researchers study cell behavior with increasing accuracy. 

Cell biology has evolved considerably since Hooke’s discovery, progressing in ways that allow researchers to study the cellular world with ever greater accuracy. That progression has often been catalyzed by technological development, from Hooke’s microscope to the advent of Organ-on-a-Chip technology. 

Commonly Asked Questions About Modern Cell Culture 

What is Ex Vivo Cell Culture?

Ex vivo cell culture is a form of in vitro cell culture that uses cells or tissue freshly collected from a living organism. Ex vivo cell culture may be particularly valuable when studying patient-specific conditions or when working with mature, terminally differentiated cell types that are difficult to produce with stem cells.  

Are in vitro studies reliable? 

Yes, to an extent. In vitro studies can be extremely valuable tools for studying cell biology and human physiology. While the traditional in vitro cell culture environment is very different from an in vivo environment—and thus cells are less likely to behave as they would in vivo—many cellular phenotypes are quite robust. This means that some cell behaviors in vitro do accurately represent how cells in vivo would behave. However, the reliability of in vitro studies can be greatly improved by using more complex culture systems, such as Organ-Chips, that faithfully emulate the cells’ natural environment.  

What is a typical in vitro study design? 

In vitro studies can be vastly different in design and scale; therefore, there is no single template for an in vitro study. However, there are common elements within subdisciplines. For example, in vitro studies for pharmaceutical development often use human cell lines (for larger scale studies, immortalized cells are common early in the drug development process). These cells may be grown in 96-well plates that allow for automated handling. Candidate drugs may then be added, one to each well of cells, followed by a period of observation. The cell’s ability to survive, proliferate, or release various signaling factors may be measured (among many potential response mechanisms).