Cutting Through the Hype: Organoids vs. Organ-on-a-Chip – The Need for Clarity and Standardization in a Rapidly Evolving Field

In the past three months, VCBeat has conducted a series of interviews with companies related to organoids, organ-on-a-chip, or other upstream sectors, broadly categorizing them under the "organoid" field. At the end of last month, after we published our industry review article on organoids, some senior industry insiders provided feedback: although the industry is developing rapidly, it is not accurate to classify all related companies into the organoid sector.There are also ambiguous areas in the definition and understanding of organoids and organ chips in China.

An investor who has been following this field also expressed the same view, directly pointing out: "Compared with peers in Europe and the US...，In terms of industry understanding, we still have some gaps, across the entire industrial chain and even including regulatory agencies.The understanding of concepts is in the process of continuous upgrading and iteration.。”

In the early stages of industry development, it is normal to have ambiguities or disagreements. However, as VCBeat's recent interviews with New Medicine have deepened, we are increasingly realizing that,"How important is the clarification and gradual standardization of the concepts of 'organoids' and 'organ-on-a-chip' for the orderly competition and development of the industry later on."Only in this way can related industries in China catch up with or even surpass those in Europe and the United States.

"In China, the definitions of organoids and organ chips will be repeatedly discussed in the future and will definitely become increasingly clear," said a senior industry insider. "Of course, we also need regulatory agencies, such as the CDE, to push this forward."

This overused sentence structure, however, is highly applicable to the current "organoid" industry.

First, we see that the focus of discussion at home and abroad is somewhat different.At present, relevant policies in China still emphasize the concept of "organoids" quite a bit.As stated in the notice issued by the Ministry of Science and Technology in 2021, "malignant tumor disease models based on organoids" were listed as one of the first key special tasks in the "14th Five-Year Plan" National Key Research and Development Program. The Center for Drug Evaluation (CDE) also included organoids in the guidelines for gene therapy and gene-modified cell therapy products: "When suitable animal models are unavailable to meet experimental needs, alternative models such as organoids can be used for testing."

If you observe the operations and products of European and American companies, as well as relevant documents from the U.S. government, you can find thatMore mentions are "organ-on-a-chip" and "microphysiological systems" concepts.

As the U.S. House of Representatives passed the Food and Drug Amendments Act of 2022 in June this year, which included organ-on-a-chip and microphysiological systems as independent non-clinical drug evaluation systems into the legislation. This year's milestone event also includes the FDA’s approval of a new drug (NCT04658472) based on "organ-on-a-chip" research for preclinical data to enter clinical trials.

As early as 2011, the U.S. NIH, FDA, and Department of Defense launched the "Microphysiological Systems" program (MPS program), elevating the development and application of organ-on-a-chip technology to a national strategic level. After more than a decade of development, the U.S. government has collaborated with universities, research institutions, pharmaceutical companies, biotech firms, and even tech giants to continuously conduct tests and improve the standards for organ chips, promoting their development and use as a new technology for drug research.

After more than 10 years of exploration,The FDA's definition and requirements for microphysiological systems and organ-on-a-chip are continuously evolving.In the definition provided by the FDA, organ chips are a subset of microphysiological systems (MPS). Microphysiological systems are designed to provide and support physical (temperature, pH, and oxygen), biochemical, electrical, mechanical (flow or stretching), structural, and morphological conditions, enabling organ or tissue functionality.

In an interview with VCBeat's New Medicine,Industry professionals tend to classify organoids and organ-on-a-chip as two different approaches.Organoids refer to tissue analogs with a certain spatial structure formed by in vitro three-dimensional culture using adult stem cells or pluripotent stem cells. They can become a source of humanized cells through primary cell culture or iPSC culture and belong to the concept of developmental biology. Hans Clevers, often mentioned as the pioneer of organoids, has a background in developmental biology.

Organ-on-a-chip is a highly interdisciplinary frontier technology, covering multiple disciplines such as physics, chemistry, biology, materials science, engineering, and micro-electromechanical systems. The organ chip itself is a precision instrument, capable of providing an environment for the culture of two or more types of cells. Through perfusion protocols, it enables long-term cell culture under dynamic stress conditions. Most importantly, it provides the necessary support for realizing organ functions.

For example, Emulate's chips are equipped with vacuum devices that can simulate the contraction of alveoli, the peristalsis of intestines, and other functions through squeezing and stretching.

A simple comparison between the two is that organoids cannot be systematized and have limited ability to simulate the human environment.That is, organoids simulate tiny tissues of the human body, and drug metabolism, interactions between organs, etc., must rely on organ-on-a-chip platforms. If they are to gradually replace animal models and add value in drug development, organ-on-a-chip will ultimately be required to complete the task.

Citing the views of industry insiders, organoids and organ-on-a-chip are "not in conflict," as organ-on-a-chip modeling requires organoids as a source—high-quality organoids—and "the two will eventually merge into one, moving towards the integration of medicine and engineering."

In addition to organoids and organ-on-a-chip, we also observe some other conceptual terms in China. For exampleTumor OrganoidsThe confusing part is that the tumor itself is not an organ. However, based on the business descriptions of related companies, "tumor organoids" likely correspond to the term "tumoroids" (sometimes translated as "tumor bodies" or "tumor-like structures"), which refers to the process of breaking down patient tumor tissues into uniform microspheres and conducting 3D culture in a microenvironment that mimics in vivo conditions.

Xilis, a foreign company, is dedicated to this field. Through Xilis' technical platform, tissue samples from cancer patients can maintain the same heterogeneous tumor microenvironment as found in the primary tissue samples, thereby representing the patient’s complete disease state.

Organoid ChipOne term that is also used by quite a few companies, but organ chips themselves cannot cultivate organoids because organ chips and organoids are two different forms. The former simulates the perfusion state of blood vessels, while the operation method of organoids involves using a highly viscous gel to differentiate cells.

However, according to the explanation of organoid-on-a-chip, it more often refers to the integration of organ chips with organoids, promoting a more biomimetic organoid structure and more mature functions. But if we start from this point, organoids themselves are a source of cells for organ chips. Well-differentiated organoids can be extracted and placed onto chips to simulate the human system.

It is a normal phenomenon for various terms and concepts to emerge in the early stages of industry development.But organoids and organ-on-a-chip technologies have moved beyond the laboratory, even reaching clinicians and patients, and the industry urgently needs to clear away the "clouds" of conceptual confusion.

At present, organoid and organ-on-a-chip companies can have various positions in the industrial chain.Such as focusing more on upstream materials, improving the economy, accuracy, and reproducibility of organoids through material innovation and enhancing the automation level of organoid culture; or mainly providing organ-on-a-chip products and supporting instruments, such as Emulate and Mimetas; or developing for clinical applications, providing personalized treatment for cancer patients through automated instruments; there are also companies that provide both products and CRO drug testing services, such as InSphero; some companies are more inclined to be biotech companies, hoping to combine organ-on-a-chip for disease modeling, and then use AI, dry-wet combination methods to discover new targets.

In commercial attempts, the company's business will not go in one direction. In the process of exploration, many companies advance on multiple fronts.

For example, in China, there are companies positioned as "serving the entire organoid and organ-on-a-chip industry." Although their strategic focus is on the organ-on-a-chip business and they are more optimistic about its future development prospects, considering the characteristics of the domestic market, they "are not willing to give up such a large market for organoids."

Some companies initially pursued the "biological line," focusing on materials and organoid models, and later incorporated microfluidic technology with the aim of expanding into organ-on-a-chip business. Meanwhile, some companies position themselves as biotech or pharma tech, utilizing organoids and organ-on-a-chip as technical means.

VCBeat has observed that the common path for China's organoid and organ-on-a-chip companies is as follows: In the first stage, they develop organoid models and chips, focusing on precision medicine drug sensitivity screening. In the second stage, based on the data accumulated from drug sensitivity screening, they gradually collaborate with pharmaceutical companies to expand into drug indications or venture into new drug development. Finally, some companies will proactively reserve resources for the field of regenerative medicine.

Chinese companies are increasingly adopting precision medicine as a starting business, which is related to the domestic market environment. As the potentially largest market in the biopharmaceutical field, China has the advantage of market scale. Particularly in clinical settings, there are millions of new cancer patients every year, making for a large patient population.

Such attempts are reasonable, and we also see many companies in China striving to address issues of ethical compliance: where do the raw materials for organoids come from, how to legally obtain samples, what kind of regulation should be applied, and whether they can ultimately be used for profit-making purposes.

But in Europe and the United States, organ chips have been closely linked to drug development from an early stage.

Phase I of organ-on-a-chip research in the United States can be traced back to 2012, focusing on the development of the most basic chips, organoids, and cells. Phase II began in 2015, integrating chips with cells and initiating drug testing collaborations with 40 pharmaceutical companies, including GlaxoSmithKline. Phase III, starting from 2017, involved the construction of various disease models and the screening of these models with drugs.

Currently, on a global scale, the United States is leading the definition and application of this technology. To make progress in this critical biotechnology, it is essential to align with the forefront of international advancements.

A technical leader of an organ chip company stated: "The ultimate goal of organ chips is to enable accurate drug evaluation in vitro. It should not be developed just for the sake of making chips, but rather, based on existing industrial conditions, a functional chip that meets standards needs to be designed."

For example, according to FDA standards, a liver chip must contain four types of cells and maintain CYP450 enzyme activity for 14 to 28 days to be considered qualified.

In an interview with VCBeat's New Medicine,Many investors have also realized that the value of organoids and organ chips will ultimately be released on the B-end.A senior investor admitted: "If you only use samples for testing, then the organoid model can basically solve the problem. But if you want to develop new drugs, in the end, it will definitely come down to organ chips, which is also the most 'right path' for this business."

The industry is already in the process of commercial exploration, so the "definition" of organoids and organ-on-a-chip technologies is particularly important.

Since the introduction of various favorable policy bills by the FDA in the second half of this year, it has attracted domestic market attention and concentrated exposure of companies, but there are also "muddlers": those who align their businesses with the organoid concept or overstate their own technology beyond facts, hoping to inflate valuations amid the hype.

Only with clear definitions, cutting through the fog, or "separating truth from falsehood," can truly valuable new technologies stand out, gain market recognition, unlock more commercial potential, and standardize the industry's development path.

If you keep confusing the audience,The lack of clear industry definitions and regulations may lead to chaos., repeating some of the earlier missteps in the field of cell therapy,A market explosion will not only fail to drive industry growth but also harm the organoid and organ-on-a-chip technologies themselves.

As the application prospects of cutting-edge technologies gradually emerge, people tend to compare new tracks with past ones to help assess the scale and growth potential of the track.

Some compare the organoid and organ-on-a-chip fields to NGS in 2014 or 2015. In areas such as non-invasive prenatal testing, undiagnosed rare diseases, and tumor companion diagnostics, NGS has already demonstrated corresponding utility and benefits. Hans Clevers defines organoids as NGD, or Next Generation Diagnosis. Compared to NGS, NGD is in a phase of rapid growth. Correspondingly, some anticipate that the organoid field will produce its own Illumina.

Some also classify organoids as life science tools, with a logic similar to the CRO industry, playing the role of a "water seller" with corresponding rationale, demonstrating risk resistance and self-revenue generation capabilities, and showing phased milestones.

When a new technology emerges, it is often imagined to have great potential and expected to solve many problems. However, during the actual implementation process, more specific difficulties are encountered, and the industry will gradually calm down. Then, the part that best demonstrates value will slowly gain recognition.

The main issue facing the scaled growth of the organoid and organ-on-a-chip fields is the continued lack of standardization, a common understanding within the industry and among investors.

Zhou Yu, CEO of Daxiang Technology, stated: "There are already standards regarding the functional indicators of organ chips required for application in pharmaceutical companies' R&D pipelines. These standards just haven't been officially endorsed or certified by regulatory authorities yet. However, when developing these models, we should use these standards as a reference."

"How can pharmaceutical companies be encouraged to use organ chips on a large scale for drug development? It depends on the policies of the regulatory authorities. If the regulatory authorities can accept the data from organ chip tests as part of preclinical research data—for instance, specifying that data obtained from a certain alveolar chip could replace animal experiments—then the direction will be very clear, and pharmaceutical companies will adopt them," said Zhou Zhibo, Managing Director of Fosun Pharma's Fosun Health Capital, directly. "Why hasn't it reached this stage yet? The reason is insufficient validation data."

Without standard guidance or very effective practical cases, it is difficult to gain full trust from regulatory agencies or downstream customers.

We see that organoid and organ-on-a-chip companies in China are gradually improving their ability to grasp the needs of downstream customers. For example, they are working to meet the strict data requirements of pharmaceutical companies: whether the clinical data for drug screening is complete, whether there is data on drug tolerance, the stability of disease models after they are established, and so on. Alternatively, they can quickly understand the experimental conditions required by pharmaceutical companies and improve the testing environment of organ chips according to the R&D needs of these companies.

China is also in the process of formulating various standards for organoid models and organ-on-a-chip. At the Stem Cell Innovation Platform Conference held in September this year, a series of related standards in the stem cell field were released, including the group standards for "Human Colorectal Cancer Organoids" and "Human Intestinal Organoids." The "General Technical Requirements for Skin-on-a-Chip," led by Professor Gu Zhongze's team from Southeast University, has also been publicly announced for project approval. Many companies have gained a foothold in international organ-on-a-chip or microphysiological system-related organizations, standing alongside peers worldwide to discuss and strive for China’s say in the technology.

Overall, in a strategically significant field like "organoids" and "organ-on-a-chip," forming a consensus requires not only top-level design and guidance but also the impetus from industry professionals.

As Dr. Guoqiang Hua, founder of Dangwang Medical, previously stated at the主题活动of VCBeat's new pharmaceuticals sector,"Organoid and organ-on-a-chip technologies are like the rising sun, but they also need our care to mature and become standardized gradually."