Neurodegenerative diseases are serious brain disorders characterized by progressive loss of brain cells which leads to worsening of health over time like loss of memory in Alzheimer’s Disease and loss of motor control in Parkinson’s Disease. Today, over 1 billion people in the world suffer from such severe disorders. These diseases are a huge threat to global health as they are on a constant rise. It is predicted they can surpass diseases like cancer to become the leading cause of death worldwide.

What makes it worse is there are currently no specific treatments available for such debilitating disorders. This large-scale suffering of people has led to global research to identify therapeutic targets and develop new drugs, which could potentially lead to better treatment outcomes. A major barrier to developing a specific and effective treatment is the high failure rates of drug candidates in clinical trials. Statistics show that out of 10 drugs that are tested, 9 fail on humans. 

A major contributor to this failure rate is the employment of current preclinical models that are used to test drugs before warranting human testing. These models are animals, mainly mice. Throughout the history of medicine, animal models have aided the process of drug development. But they are not sufficient if we ought to find therapies for complex diseases like neurodegenerative diseases and cancer. Not only are they economically unfeasible, but they also do not accurately represent human physiological and pathological states. Moreover, they are not sustainable for drug screening, for instance, it would take a lot of time to screen thousands of potential drug candidates in animals. It will cost more and also delay the process. This delay contributes to worsening global health. 

Thus, current research is transitioning towards modern tools like in vitro 3D models that are accurate and can be used to understand disease mechanisms and also screen drugs effectively. 

There are various 3D cultured structures developed for this purpose like spheroids, organoids, 3D bio-printed tissues, and 3D microfluidic devices. Of these, microfluidic physiological systems, also known as organ-on-a-chip (OOC) are the most advanced with tremendous potential. It is an amalgamation of engineering and biology with the ability to recapitulate the functionality of an organ by mimicking the mechanical forces experienced by cells and interaction with other cells and their environment. In OOCs, there is a constant exchange of gases and nutrients and also a possibility of developing gradients of chemical cues for cells. To know more about OOCs, read here.

Researchers across the globe have developed different OOCs like lung-on-a-chip, and kidney-on-a-chip. Recently, lung-on-a-chip was used as a breathable lung model to study the efficacy of vaccines against the covid-19 virus. 

Realizing its potential, researchers are also employing OOCs to study the physiology of the brain and also to understand what goes wrong in brain disorders. Currently, several OOCs have been developed to understand the mechanisms of neurodegenerative diseases like Alzheimer’s and Parkinson’s. One of the main features of OOCs is that it allows us to study the interaction between different types of cells. In the case of neurodegenerative disorders, it is evident that dysfunction of the immune cells (microglial cells) of the brain has a significant role to play in the disease onset and progression. Brain-on-a-chip can be thus used to study the interaction between the microglial cells and neurons and also study the significance of neuroinflammation. This will lead to the identification of therapeutic interventions which will be crucial for the development of drugs. These models are also being used to assess effects of different drugs. For instance, in a particular study, a drug for multiple sclerosis was repurposed for the treatment of Alzheimer’s disease on an OOC which showed positive results. Moreover, the compact size of an OOC & low working volumes makes it an economic tool suitable for high throughput screening (HTS) of potential drugs. 

Although the use of organ-on-a-chip to understand brain disorders is limited, technical leaps and advances in the near future will ensure its application in research concerning deciphering the links between inflammation and degeneration, identification of molecular targets, HTS screening, and development of personalized medicines.

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Written by – Parth Choudhari, Science Communicator, Nanomedicine Research Group.