Session: 06-03-02 Biologically Enabled Microfluidics and Biomicrofluidics

Paper Number: 65892

Start Time: August 11th, 10:50 AM

65892 - A Comprehensive Review of Three-Dimensional Neuro-Organoids and Engineering Brain-on-a-Chip Microfluidic Devices 

Three-dimensional (3D) organoid engineering has gained increasing traction in recent years. Organoids may be viewed as self-organized organ-like cell aggregates that originate from multipotent stem cells. The long-term goal of organoid systems has been to physiologically mimic human tissue and organ systems at the cellular level, serving as tissue and organ proxies that recapitulate biological parameters (e.g., spatial organization of heterogenous tissue-specific cells, etc.) with the added advantage of proving amenable to extended cultivation, manipulation and reconstruction in a controlled manner. However, as organoid systems allow the autonomous self-organizing properties of stem cells to dictate the diversity and architecture of the multi-cellular tissue proxy they create, it is often difficult to control the cell type and 3D organization within such systems; this may be why most organoid models represent only a single or partial component of a tissue. Accordingly, proposed bioengineering strategies may be used to steer cell composition and their 3D organization within organoids in order to provide enhanced model systems that may serve of great use in endeavors such as regenerative therapy, drug discovery, and studies of physiological and pathological processes.

3D human tissue and organ models may be furthered through organ-on-a-chip systems, or miniaturized 3D microfluidic devices that may provide a platform for studying biochemical and metabolic processes under conditions resembling those of in vivo. Microfluidic chips address the issue of interior tissue accessibility seen in conventional 3D organoid systems as they grow over time. A significant obstacle in growing mature organoid systems, the average diameter of which is up to 3 mm, is the restricted vascular access and resultant dearth of nutrients, gas exchange and waste removal at the interior of organoids. As 3D organoid models increase in size and volume, the interior becomes isolated (or distant) from the surface in contact with fresh medium. As a result: simple diffusion processes cannot provide sufficient oxygen and nutrients to the growing cells at the core of the system, and they consequently do not survive. Microfluidic platforms can enable adequate mass transport that may address issues of access that are often encountered in 3D cell cultures, ultimately preventing cell death at the core of the organoids.

We focus herein on the brain-on-a-chip model, a micro-engineered chip platform that mimics the physiological microenvironment and tissue of the brain. Because cellular bio-architecture varies significantly in different regions of the brain, the brain-on-a-chip design process envisions compartmentalized microenvironments that can represent such varied structures and circuitries. Current attempts of brain organoid development do not mature beyond the prenatal brain equivalent, the major obstacle being the aforementioned lack of vascularization that limits the growth and maturation of the organoids and ultimately hinders the study of disorders and diseases that develop after the fetal development stage. Thus, attention is turned toward generation of a brain-on-a-chip model that can serve as a relevant model of the human brain and overcome limitations in vascularization through microfluidic perfusion networks.

In addition, microfluidic-based organ-on-a-chip systems allow control and monitoring of features such as cell position, fluid flow, and mechanical cues, helping to dissect their contribution to tissue and organ function. While conventional analytical methods of microfluidic chips require manual sample collection and frequent system disturbance of the microfluidic system, recent studies have demonstrated tracking of cell activity through noninvasive multisensory systems for monitoring of microenvironment biophysical, biochemical and optical parameters. Finally, microfluidic chips allow for integration of multiple organoid models in a single fluid circuit and provide capability for analysis of multiorgan interactions.

The focus of this review is to describe advances in 3D organoid and microfluidic device platforms in the literature with a focus on neuro-organoid engineering. Furthermore, the paper will assess current limitations in microfluidic design as related to the brain-on-a-chip model.

 

Keywords: organoid, engineering, microfluidics, organ-on-a-chip, brain-on-a-chip, mini-brain

Presenting Author: Lamees I. El Nihum Texas A&M University; Houston Methodist Hospital;

Authors:

Lamees I. El Nihum Texas A&M University; Houston Methodist Hospital;
Nandan Shettigar Texas A&M University
Debjyoti Banerjee Texas A&M University
Robert Krencik Houston Methodist Research Institute