Animal testing has shaped modern drug development for decades, but its limitations become especially visible when scientists evaluate cancer immunotherapies. These treatments are designed to stimulate the immune system to recognize and destroy malignant cells, yet the same powerful immune activation can trigger life-threatening complications in patients. Researchers at the University of Rochester are developing a human-cell-based alternative: miniature tissue models known as organs-on-a-chip that could help predict these toxicities before experimental medicines reach clinical trials.

The work is being led through the university’s Translational Center for Barrier Microphysiological Systems, or TraCe-bMPS. The center is building drug-development tools around modular µSiM tissue chips, devices that contain ultrathin membranes populated with human cells. Unlike conventional laboratory cultures, these systems are engineered to reproduce key features of biological barriers, including the physical separation between tissues, controlled exposure to drugs, and measurable inflammatory responses. Their modular construction also allows the devices to be manufactured in large quantities with consistent dimensions and materials.

The platform is based primarily on acrylic components and incorporates membranes designed to mimic interfaces found in the human body. Such barriers regulate the movement of molecules and immune cells between compartments, making them central to drug absorption, toxicity, and inflammation. By assembling reproducible chips with human cells, researchers can study how a therapy affects a tissue under conditions that more closely approximate human biology than many animal models. The design also makes it possible to modify individual components for different organs or disease settings.

A major feature of the Rochester system is the integration of sensors directly into the chips. Developed in part through the work of biomedical engineering professor Benjamin Miller, these sensors can track barrier function and inflammatory signaling in real time. Instead of waiting until the end of an experiment to examine damaged cells, researchers can observe how a tissue responds as a drug is introduced. Changes in electrical or molecular signals may reveal that a barrier is becoming more permeable or that inflammatory pathways are being activated, providing an early warning of toxicity.

The immediate focus is on two severe complications associated with some cancer immunotherapies. Cytokine release syndrome, commonly called CRS, occurs when activated immune cells release large quantities of signaling proteins known as cytokines. The resulting systemic inflammation can cause fever, low blood pressure, breathing difficulties, and, in the most serious cases, organ failure. Immune effector cell-associated neurotoxicity syndrome, or ICANS, can affect the nervous system, producing confusion, seizures, impaired speech, or other neurological symptoms. Both conditions are difficult to predict reliably with animal testing because species differ in immune signaling networks and cell-surface receptors.

“The goal is to predict these toxicities from human cells on a chip, before a drug ever reaches a patient, and to do it without relying on animal models that have repeatedly failed to predict CRS in people,” says James McGrath, director of TraCe-bMPS and the William R. Kenan Jr. Professor of Biomedical Engineering. The approach does not simply attempt to reproduce a whole human body in miniature. Instead, it focuses on specific biological barriers and immune interactions that are directly relevant to the safety question being studied.

The project has now reached an important regulatory stage. The team was accepted into the US Food and Drug Administration’s Innovative Science and Technology Approaches for New Drugs, or ISTAND, pilot program. ISTAND is intended to help evaluate emerging methods that could improve drug development and eventually support regulatory decisions. Acceptance does not mean that the tissue-chip platform has already been approved for routine use, but it creates a formal pathway for the researchers to work with the FDA on defining the evidence needed for qualification.

The Rochester group is preparing a detailed qualification plan that will describe clinical considerations, timelines, data-sharing procedures, and statistical methods for evaluating the technology. If the platform ultimately receives FDA qualification, pharmaceutical companies could use its results as part of the evidence submitted in support of new drug applications. Such recognition would represent a significant step for organs-on-a-chip research, which has expanded rapidly but has only rarely progressed into formal regulatory programs.

The effort comes as US regulators seek alternatives to animal testing in preclinical safety studies. The FDA Modernization Act 2.0, enacted in 2022, opened the door for non-animal methods, while the agency’s 2025 roadmap outlined further efforts to reduce reliance on animal models. Researchers say pharmaceutical companies are showing strong interest because many immunotherapies are already in clinical development and carry risks of CRS or ICANS. The Rochester team collaborated with Graham Marsh of the Critical Path Institute and consulted with scientists at Pfizer about how the tool could fit into real-world drug development. If successful, the technology could give researchers a more human-relevant way to identify dangerous immune reactions early, helping developers eliminate unsafe candidates and refine promising treatments before patients are exposed.

Subject of Research: Human-cell tissue chips for predicting cancer immunotherapy toxicities.

Web References: University of Rochester; Translational Center for Barrier Microphysiological Systems; University of Rochester Biomedical Engineering; FDA ISTAND pilot program; FDA Modernization Act 2.0.

Image Credits: URochester photo / J. Adam Fenster.

Keywords: Drug discovery, tissue chips, organs-on-a-chip, cancer immunotherapy, cytokine release syndrome, CRS, ICANS, neurotoxicity, animal testing alternatives, biomedical engineering, microphysiological systems, human-cell models.

A tiny microscope weighing just five grams could give neuroscientists an unprecedented view of how individual brain cells control behavior while animals move naturally. Researchers at the University of Colorado Anschutz Medical Campus and the University of Colorado Boulder have developed a head-mounted device that can both record neural activity and selectively activate individual neurons during movement. The technology could help scientists investigate how brain circuits generate behavior and how those circuits become disrupted in conditions such as Alzheimer’s disease, Parkinson’s disease and epilepsy.

The device, called Opto2P-FCM, combines two powerful techniques that have traditionally been difficult to use together in a freely moving animal. Two-photon microscopy provides detailed images of living brain tissue at cellular resolution, while optogenetics uses light-sensitive proteins to control selected neurons. By integrating both capabilities into a miniature instrument, the researchers can observe specific cells as they become active and then stimulate chosen neurons to test how they influence the surrounding network.

“These miniature microscopes have been increasingly used to study the neural basis of behavior in freely moving animals,” said Emily Gibson, PhD, associate professor of biomedical engineering at CU Anschutz and the study’s senior author. “This new microscope allows deeper penetration and higher resolution images in the brain. Importantly, it can also excite select neurons using optogenetics.”

For decades, conventional two-photon microscopes have been regarded as the gold standard for imaging neurons in living brains. These systems use infrared laser light to produce high-resolution images deep within tissue, allowing researchers to track calcium signals and other indicators of neural activity. However, conventional microscopes are generally large, stationary instruments. Animals must often remain immobilized beneath the objective, making it difficult to study brain activity during walking, exploration, social interaction or other natural behaviors.

Miniature microscopes have helped overcome that limitation by moving the imaging system onto the animal’s head. Yet reducing the size and weight of the equipment has often required compromises. Some compact systems provide lower-resolution images, while others can record neural activity but cannot stimulate precisely selected cells. The Colorado team designed Opto2P-FCM to address both problems through a dual-path optical architecture that separates imaging from stimulation.

In the imaging pathway, infrared light is directed through the brain to generate two-photon signals from fluorescent markers inside neurons. These markers can report changes in calcium concentration, which occur when neurons fire. The resulting signals are collected to create detailed images of neural activity at the level of individual cells. A separate optical pathway delivers patterned light for optogenetic stimulation, allowing researchers to activate specific neurons without disrupting the imaging beam or overwhelming the detectors.

This separation is technically important because imaging and stimulation place different demands on an optical system. High-resolution imaging requires precise focusing, efficient light collection and minimal optical distortion. Optogenetic activation, by contrast, requires intense, accurately positioned light capable of reaching the light-sensitive proteins expressed by selected neurons. Designing both functions into a device small enough to be carried by an animal required careful control of the alignment, geometry and weight of every optical component.

“This microscope is a game changer,” said Juliet Gopinath, PhD, professor of electrical, computer and energy engineering and physics at CU Boulder and a study co-author. “Being able to demonstrate a state-of-the-art instrument for both read-out and photo-stimulation of neurons is amazing.” The research team included engineers, physicists and neuroscientists who worked together to solve problems involving miniature lenses, mechanical tolerances, optical alignment and three-dimensional fabrication.

The device weighs approximately five grams, but its small size made construction unusually demanding. Mo Zohrabi, PhD, a senior research scientist at CU Boulder and co-first author, said the team initially thought such an instrument might be impossible to build because of the tight tolerances required by the optics and available 3D-printing technology. Gregory Futia, PhD, a senior research associate at CU Anschutz and co-first author, said that every component had to be designed and accounted for with extreme precision. Even slight misalignment could reduce image quality or prevent the stimulation beam from reaching the intended cells.

The researchers believe the platform could transform experiments designed to distinguish correlation from causation in the brain. Recording a neuron’s activity can show that it is associated with a behavior, but it does not prove that the cell helps produce that behavior. With optogenetic stimulation, scientists can activate a selected population and observe whether movement, decision-making or other actions change. At the same time, the microscope can record how neighboring neurons respond, providing a view of how local circuits coordinate activity.

The current Opto2P-FCM system is a prototype, and the researchers are working on future versions that could be smaller, lighter and faster. They also hope to expand the field of view so that more neurons can be monitored at once. Such improvements could make it possible to track larger networks over longer periods while animals engage in increasingly complex behaviors. By combining cellular-resolution observation with targeted manipulation in a freely moving subject, the technology may help reveal how healthy neural circuits operate and how neurological disease changes the communication between them.

Subject of Research: Miniature two-photon microscopy, optogenetics, neural circuits and brain activity during natural movement

Article Title: New Miniature Microscope Allows Scientists to Watch and Control Brain Cells During Natural Movement

News Publication Date: Aug. 11, 2026

Web References: University of Colorado Anschutz Medical Campus; University of Colorado Boulder; Optica study

References: Optica, “New Miniature Microscope Allows Scientists to Watch and Control Brain Cells During Natural Movement,” article publication date: Aug. 7, 2026

Keywords

Miniature microscope, two-photon microscopy, optogenetics, neuroscience, brain imaging, neural circuits, freely moving animals, biomedical engineering, applied physics, neurological disease, brain research

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