A novel organoid brain-chip platform for accelerating drug discovery

The National Institute on Alcohol Abuse and Alcoholism awarded Leaflabs, LLC $499,971 on September 1, 2026, under the Alcohol Research Programs (CFDA 93.273) to develop a novel organoid brain-chip platform for accelerating central nervous system drug discovery.

The recipient will design and build a fully automated, purpose-built organoid brain-on-a-chip platform to overcome barriers limiting adoption of brain organoid technology in drug development. The platform will internally perfuse mini-brain organoids via microfluidics under robotic control and integrate high-channel-count electrophysiology tools to enable continuous, long-term recordings of neuronal activity. The work aims to improve organoid health and maturation through internal perfusion to enhance oxygen delivery, addressing current limitations in growing mature and healthy brain organoids and enabling longitudinal functional studies unsuitable in traditional two-dimensional culture systems.

Performance of work occurs in Cambridge, Massachusetts, with a period of performance through August 31, 2028. This is an SBIR Phase II award, as indicated by the grant designation R44.

Abstract

Neurological conditions affect 1 in 3 people (3 billion worldwide), and the prevalence of age-related diseases like alzheimer's, parkinson's, and stroke is on the rise. Yet the industry's approach to CNS drug development is becoming less efficient (eroom's law); IT faces a 97% failure rate, lengthy development cycles (10-15 years), and escalating costs ($6 billion, doubling every 9 years). Traditional drug discovery relies on early-stage testing in animal models and reductive human models like 2D cell cultures. However, species differences and a lack of complexity in models reduce translatability, leading to high attrition rates moving from lab to clinic. Without innovation, the growing burden on an aging society will soon become unmanageable. Lab-grown miniature human organs, or organoids, are emerging as a potential alternative, combining the pharmaceutical industries' need for human/patient relevance, system complexity, and scalability. However, the adoption of this nascent technology is hindered by its high technical variability, difficulties in growing mature and healthy brain organoids, and the absence of tools for longitudinal functional studies. As a result, brain organoids remain unsuitable for modeling disorders associated with the mature brain or with the dysregulation of neuronal networks. A significant problem is the continued reliance on technology optimized for 2D cultures. This project will address barriers to adoption by developing a purpose-built, fully automated organoid brain-on-a-chip platform to accelerate CNS drug discovery. Mini-brain organoids will be internally perfused via microfluidics under robotic control and implanted with high-channel-count electrophysiology tools to enable continuous, long-term recordings of neuronal activity. Specifically, this proposal aims to improve organoid health and maturation by using internal perfusion to improve oxygen delivery and reduce technical variability by eliminating sources of variation introduced by humans and the periodic removal of cultures from the incubator to exchange media. Leaflabs' high-channel-count electrophysiology probes are particularly well-suited to capturing mesoscale network activity across the organoids' entire 3D structure, enabling studies not possible with existing solutions. The proposed work will support CNS drug discovery by building a modular, scalable system designed to meet the throughput demands of the industry, using a modified version of leaflabs' neurosensing IC chip to enable parallel organoid experiments using shared data acquisition hardware. IT will characterize brain-on-a-chip organoids' variability, health, and functional maturation to support the commercialization goal and help the industry reevaluate model readiness. Finally, IT will demonstrate mini-brain organoids' potential for drug screening and mechanistic studies using a patient-derived syngap-1 model, as supported by the FDA modernization act 2.0.