Vascularised Brain Organoids: Engineering Strategies and Neurobiological Applications

TL;DR

This paper reviews strategies to add blood vessels to brain organoids, improving their realism for studying brain diseases and drug testing.

Contribution

The paper provides a comprehensive overview of vascularization methods and their impact on brain organoid functionality.

Findings

Vascularized brain organoids improve oxygen diffusion and synaptic development.

These organoids enable modeling of complex conditions like stroke and BBB dysfunction.

Current methods include co-culture with endothelial cells and 3D bioprinting.

Abstract

Brain organoids have become an essential platform for studying human neural development and neurological disorders. Yet, one major limitation of conventional brain organoids is their lack of vascular structures. This deficiency restricts organoid size, contributes to necrotic core formation, and hampers their functional maturation. Introducing vascularization offers a compelling solution—it enhances nutrient delivery, supports neurogenesis, and fosters the development of interfaces that resemble the blood–brain barrier (BBB). In this review, we explore how vascularization enhances the structural and physiological relevance of brain organoids and its growing significance in disease modelling and therapeutic screening. We examine current methodologies for engineering vascularized brain organoids (vBOs), including co‐culturing with endothelial cells (ECs), transcriptional programming, tissue fusion techniques, microfluidic perfusion systems, and 3D bioprinting. These strategies vary in complexity, scalability, and the extent to which they achieve vascular integration. Functionally, vBOs demonstrate improved oxygen diffusion, enhanced synaptic development, and more robust barrier properties. Such advances enable modelling of complex neurovascular conditions like stroke, glioblastoma, and BBB dysfunction. Moreover, vBOs are emerging as valuable tools in developmental studies and personalised medicine, supporting patient‐derived modelling and large‐scale drug testing in BBB‐relevant contexts. Despite these advances, replicating the structural complexity, functionality, and long‐term stability of native vasculature remains challenging. We discuss current limitations and highlight innovative approaches, including the use of next‐generation biomaterials and dynamic perfusion technologies. Ultimately, vBOs mark a significant step towards creating physiologically accurate in vitro models of the human brain—offering new opportunities for neuroscience research, drug development, and regenerative medicine.

This review highlights emerging strategies to engineer vascularized brain organoids—including endothelial co‐culture, genetic induction, perfusion systems, and in vivo transplantation—and their applications in modelling neurovascular diseases, evaluating BBB drug delivery, and advancing regenerative medicine.

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