From Organoids to Organoid-on-a-Chip, Drug Discovery Requires New Approaches
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From organoids to organoid-on-a-chip, they are making a splash in the field of biological sciences.
As we all know, a new drug is a difficult process with high risk, long cycle and high cost. There is a traditional "Double Ten" in the world - it takes 10 years and 1 billion US dollars to successfully develop a new drug. Even so, only about 10% of new drugs can be approved into the clinical phase, and the efficacy and safety of drugs need to be verified in animal models before entering clinical research.
However, animal models have not been able to accurately simulate the real human pathophysiological system. According to FDA data, about 92 percent of drugs that prove safe and effective in animal tests fail in clinical trials. Therefore, with a higher degree of humanization, organoid chips based on human cells are expected to provide new ideas for improving the clinical transformation rate in new drug development.
At present, the pace of organoid chip technology is accelerating. Whether it is new drug development or precision treatment, we can see the participation of organoid chips.
Drug Development Requires New Approaches
Although the rapid development of modern medicine has saved more and more lives, it is an undeniable fact that the drugs that have been developed by modern medicine are still a drop in the bucket compared to the number of existing diseases. There are many diseases for which there is no cure, and new viruses are emerging one after another.
The pharmaceutical industry is a dangerous and fascinating business, expensive and long. The launch of a new drug needs to go through multiple stages such as drug discovery, preclinical research, clinical research, and approval for marketing, which often takes decades or even decades and costs billions of dollars. The US Food and Drug Administration (FDA) survey data shows that the average research and development cycle of each new drug is about 10 years, and the cost is about 1 billion US dollars, which is the origin of the "Double Ten" in the pharmaceutical industry.
Even so, after being confirmed to be safe and effective in animal experiments, up to 90% of the drugs are still declared to fail in clinical human trials, and the reason for "death" is nothing more than lack of efficacy or toxicity. Therefore, previously "burned" money can only be turned into irrecoverable sunk costs. Under such a screening ratio, it is no wonder that people in the pharmaceutical industry describe a new drug "from the laboratory to the clinical trial stage" as a "valley of death".
As a result, pharmaceutical companies need to bear the difficult pharmaceutical process and high pharmaceutical costs. A Deloitte report released in 2017 pointed out that the cost of successfully launching a new drug has increased from $1.188 billion in 2010 to $2 billion. In 2017, the return on investment of the global TOP12 pharmaceutical giants in research and development was as low as 3.2%, the lowest level in 8 years.
From the perspective of long-term development, if it is not possible to ensure that pharmaceutical companies can obtain sufficient income to cover the previous huge investment, it is very likely that the overall R&D chain will eventually break, and pharmaceutical companies will withdraw from the market. And in the end, it is the patients who will pay for all this - they will have to face a situation where there is no cure, and even if there is a cure, it will be expensive.
Therefore, in order to truly realize the cost reduction and efficiency increase of pharmaceutical companies and reduce "high-priced drugs", the key is to find a new drug development method, so as to reduce the research and development cost at the source link and improve the whole process of research and development, especially in the preclinical stage. The success rate greatly reduces the proportion of sunk costs.
Based on this goal orientation, after years of exploration, a new type of drug modeling and testing platform that can directly predict human responses has gradually become a research hotspot in the academic community, and has gradually entered the public eye, which is Organ-on-a-Chip (OoCs).
Around 2010, organoid and organ-on-a-chip technology began and embarked on the fast track of development. From early organ-on-chip prototypes, single-organ chips such as lung, intestine, and liver, to multi-organ chips that connect multiple organs in series, researchers have gradually developed models with more complete and complex functions and higher simulation.
In 2011, the U.S. government took the lead in launching the national strategy for human microphysiological systems (organ-on-a-chip), formulating support plans for organ-on-chips from a strategic level. Subsequently, European countries have successively increased their investment in organ-on-chips and organoids. In 2021, China will also begin to systematically promote the development and application of organoid and organ-on-a-chip technology from the level of basic research and regulation.
At present, organ chips are making waves in the life sciences. It can be said that the development of organ chips has changed human beings no less than new fuel cells and driverless cars have changed society.
From Organoids to Organoid-on-a-Chip
Organoids, as the name suggests, are similar to tissue organs. Organoids are three-dimensional cell complexes that are similar to the target organ or tissue in structure and function, and are formed by inducing the differentiation of stem cells or organ progenitor cells by 3D culture technology in vitro. Long-term culture in vitro.
Organoids can simulate the genetic and epigenetic characteristics of target tissues or organs to a large extent , and have broad application prospects in the fields of organ development, precision medicine, regenerative medicine, drug screening, gene editing, and disease modeling. As early as 2013, organoids were named the top ten technologies of the year by Science magazine; in addition, organoids were also named the 2017 Method of the Year by Nature Methods.
Organ-on-a-chip and organoids are independently developed technical routes. If organoids are more biologically inclined, using cytokines to induce the self-assembly of adult stem cells to form human micro-organs, then organ-on-a-chip wine is more inclined to biomedical engineering, that is, the use of micro-organisms. Fluidics technology controls fluid flow, combining cell-cell interactions, matrix properties, and biochemical and biomechanical properties to construct three-dimensional human organ physiological microsystems on a chip.
The microfluidic chip system can control the diameter of microtissue organs to the millimeter or even micrometer level, and enhance its nutrient exchange to prevent the death of core cells of microtissue organs. In other words, the organ chip does not need to be completely reconstructed according to the complete organ, but also has the physiological activity and structural and functional characteristics of the original human organ tissue, and can become a good substitute for predicting the human body's response to drugs and various external stimuli.
The advantage of organoids is high simulation, with histological features and functions that are highly similar to human organs, but there are limitations in higher bionics, controllability, and repeatability; while the controllability of modeling in organ chips It has advantages in terms of standardization and standardization, and the construction of more complex models can be achieved through co-culture technology.
However, whether it is an organoid or an organ-on-a-chip, a model constructed from a single type of cell is still not biologically bionic enough . For example, organoids or organ-on-a-chip are not yet precise enough to control the local environment. In addition, such methods cannot replicate well the complex and dynamic microenvironment during organ development, which is a favorable factor for organ formation.
In view of the limitations and shortcomings of traditional culture techniques, experts in the field of stem cells and developmental biology have joined forces with physical scientists and engineers to develop more advanced in vitro techniques for organoid research. The "organoid-on-a-chip" technology formed by the integration of organs.
In theory, the organoid chip integrates the advantages of these two technical routes and is a practice of cross-integration of cutting-edge technologies . In 2019, a review published in the journal Science first proposed the concept of organoids on a chip. Organoid-on-a-chip is also regarded as one of the most cutting-edge directions in the development of organ-on-a-chip. It can be said that the organoid chip is an "upgraded" version of the organ chip or an extension of the concept of the organ chip.
Obviously, very different from semiconductor chips in the information industry, organoid chips emphasize organ physiology microsystems built on chips . This tissue-organ model can not only reproduce the physiological and pathological activities of human organs in vitro, but also enable researchers to witness and study various biological behaviors of the body in an unprecedented way, and predict the human body's response to drugs or the outside world. responses to stimuli.
For example, recently, a research team from Columbia University's School of Engineering reported that they had developed a model of human physiology in the form of a multi-organ chip consisting of engineered human heart, bone, liver and skin that flow and circulate immune cells through blood vessels. connected to allow the reproduction of interdependent organ functions. The researchers essentially created a plug-and-play multi-organ chip the size of a microscope slide that can be customized to fit a patient. It is also the first multi-organ chip made of engineered human tissue fluidly connected by blood vessels to improve modeling of systemic diseases like cancer.
It can be said that organ-on-a-chip is useful in understanding the biological mechanism of new drug targets, providing new perspectives for disease research, predicting the efficacy and safety of new drugs, exploring species differences and unexpected clinical manifestations, reducing animal testing, and improving personalized medicine. It has a wide range of application value.
Organoid chips are still in their infancy
Undoubtedly, as a "disruptive technology that may change the future", organoid chip research is in the ascendant. In general, the basic research in the whole field of organoid chips has been developed for nearly 20 years, and there has been considerable research and technical accumulation in the simulation of models.
In 2011, the US NIH, FDA and the Department of Defense led the launch of the "Micro Physiological System" program (MPS program), which raised the development and application of organ-on-a-chip technology to the national strategic level. They believe that the "highly bionic humanized chip model" can significantly reduce the cost and cycle of new drug discovery, bringing a major revolution to the field of new drug development. At the same time, European developed countries are also optimistic about the development prospects of organoid chip technology in new drug research and development and precision medicine, and continue to invest in supporting the development of this field. In 2021, China will also begin to systematically promote the development of organoid chip technology from the scientific research and regulatory level.
At the same time, pharmaceutical companies are also starting to enter the market, becoming another driving force in the field . Pharmaceutical giant Johnson & Johnson plans to use Emulate's human thrombus simulation chip system for drug trials, and use the liver chip to test the liver toxicity of drugs. The FDA has also announced that it will work with Emulate to introduce the technology to study potential chemical and biological toxicity in food, cosmetic or dietary supplements.
Of course, the most direct manifestation is that more and more funds have been poured into the research and development of organoid chips worldwide. For example, the National Center for the Advancement of Translational Science (NCATS) has invested heavily in the development of 11 human organ-on-a-chip systems.
But overall, organoid chips are still in the basic research stage, and there are still relatively few applications in drug research and development . The reason is that organoid chips are divided into two aspects: chip technology and model construction, which involve multidisciplinary knowledge such as pharmacy, biomedical engineering, biology, medicine, materials science, and fluid mechanics. Cross-industry, the development process covers a complete set of processes from chip design, process development and production, to model building and functional evaluation, and finally to drug testing.
Because of this, at present, organ-on-a-chip research is mainly concentrated in university laboratories, and the research products of laboratories are often aimed at a very specific local problem and lack system-level versatility. There are still deficiencies in use. However, there is a disconnect between the research and development of universities and the market demand. Therefore, the commercialization of the technology needs more start-ups and large pharmaceutical companies to join in to promote it.
Of course, in general, organoid chips can truly reproduce the physiological and pathological activities of human organs in a brand-new way, allowing people to intuitively observe and study various biological behaviors of the body. Biological mechanisms, provide new perspectives for disease research, and provide new methods for predicting the efficacy and safety of new drugs, exploring species differences and unexpected clinical manifestations.
With the continuous and vigorous development of innovative drugs and the continuous emergence of new therapies such as cell therapy and mRNA, the traditional drug evaluation model will no longer be applicable. In the future, organoid chip technology will continue to make technological breakthroughs, develop more complex and bionic humanized models, and even replace some human experiments, allowing further medical exploration.