Standardization Beyond Industry Defaults: The Path Forward for Organoids and Organ-on-a-Chip Technologies

Over the past year, domestic companies specializing in organoids and organ-on-a-chip technologies have attracted significant attention from the capital market, with continuous financing activities. Meanwhile, the industry has entered the “2.0 era” of technological development and application, pursuing high-throughput, standardization, automation, and integration with other technologies. Since the second half of 2022, VCBeat New Medicine has interviewed and reported on multiple organoid and organ-on-a-chip companies, witnessing alongside the industry a year of rapid advancement. Consequently, the “7th Future Healthcare Top 100 Conference” has established an Organoid and Organ-on-a-Chip Forum for the first time.

Despite the rapid development of the industry, quality control for organoid culture remains unstable due to the lack of relevant quality control standards. Furthermore, demand in the mid- and downstream sectors has not yet scaled up, and no trusted standards—whether adopted by end-users or implemented top-down by regulatory authorities—have emerged.As a leading supplier of organoids and 3D cell culture, Corning Life Sciences is advancing the standardization of organoid technology. During the roundtable session at this forum, Wang Xuebin, Applied Technology Manager for Corning Life Sciences China, served as the moderator and engaged with multiple industry experts in discussions on the development of organoid technology and the establishment of future standardization frameworks.

The following is the full transcript compiled by VCBeat New Medicine:

Moderator:Wang Xuebin, Application Technology Manager, Corning Life Sciences China

Guest:

Daxiang TechCEOZhou Yu

Founder of Suzhou Nuopu Regenerative Medicine Co., Ltd.,CEOYang Xi

Founder of Xirui Biotech andGeneral ManagerChen Zongzheng

Song Guangqi, Founder of Puheng Technology

Yi Sun, Senior Scientist, In Vitro Modeling, Crown Bioscience

Wang Xuebin (Corning Life Sciences): Technologies such as organoids and organ-on-a-chip, microfluidics, novel biomaterials, as well as AI-driven data analysis and automated production, are advancing rapidly, with progress being made almost daily. The integration of these technologies will lead to more mature assay solutions and more accurate experimental results. Importantly, technological advancements are embedded within the expansion of application scenarios, yielding innovative outcomes through integrated applications. As we stand in mid-2023, what technological advances or even breakthroughs have been achieved in organoid and organ-on-a-chip fields? And what innovative results can we expect to see in the next two years?

Zhou Yu (Daxiang Technology):First, organoids should represent a continuous maturation and stable breakthrough in highly biomimetic models featuring multicellular co-culture or multi-organ interactions. Whether developing organoids or organ-on-a-chip systems, our primary objective is to construct models that differ from traditional ones by more closely resembling human physiology and offering higher clinical translatability. By "closely resembling humans," we mean that these models mimic human organs more accurately in terms of morphology, function, and other aspects. Tumor organoids typically consist of various tumor subtype cells but lack key components of the tumor microenvironment, such as immune cells, fibroblasts, and the vascular system. We are now capable of reconstructing all these elements in vitro, thereby fully recapitulating the tumor microenvironment. In terms of applications, there is relatively less focus on small molecules; instead, emphasis is increasingly placed on studying drug mechanisms involving antibodies and cell therapies that modulate the overall immune environment, which further necessitates human-relevant in vitro models. Additionally, for non-neoplastic diseases derived from patients, such as neurodegenerative disorders, we build models using patient-derived materials, faithfully preserving the patients' omics, genetic information, and morphological characteristics.

Second, the application of automated, intelligent, and standardized tools has brought significant breakthroughs to both the production and subsequent application processes of organoids. This not only frees technicians from manual labor but also reduces uncertainties or variations arising from differences in individual operational techniques, thereby facilitating a standardized process.

Third, we should see an increasing number of application cases gaining regulatory recognition. This year, many pharmaceutical companies we have partnered with have submitted data from our joint research as part of their Investigational New Drug (IND) applications. A notable example is the CAR-T molecule for solid tumors recently announced by BeiGene. Therefore, we believe that as standardization continues to improve and application data accumulates, such positive developments will become increasingly common.

Yang Xi (Nuopu Regeneration):We believe that the breakthroughs in high-fidelity biomimicry achieved by organoids and organ-on-a-chip technologies over the past two years have gained widespread recognition. Furthermore, I believe that for a new technology to advance and achieve commercialization, the accessibility and effectiveness of its supply side are paramount. Innovations such as novel materials, automation, and 3D printing will undoubtedly significantly enhance efficacy within this field.

We are primarily engaged in regenerative medicine and would like to share some recent breakthroughs. First, an article published in *Science* a couple of years ago reported that researchers used bioprinting technology to construct a small, beating heart-like structure with atrial and ventricular components in vitro. This model is being applied to the highly active field of medical device development. Top-tier medical device companies may spend tens of millions on animal trials and require substantial personnel resources, yet struggle to achieve data consistency and standardization. In contrast, bioprinting-based construction can significantly enhance efficiency. Second, recent advances in bioprinting have enabled breakthroughs in tissue-level assembly, facilitating the development of large-scale, complex biomimetic tissues. By addressing the challenge of vascularization, such tissues can be utilized in drug development and are expected to enter clinical use as tissue-based therapies in the future.

Chen Zongzheng (Xirui Bio):As a startup, our primary mission is to create value for customers and address their pain points. Currently, Xirui Biology is fully leveraging the potential of interdisciplinary medicine-engineering collaboration to develop a series of products targeting issues such as poor uniformity, cavitation (hollowing), and inadequate vascularization during organoid culture. For instance, our culture microarray products significantly improve the uniformity of cultured organoids/cell spheroids, ensuring that the cell count in each 3D spheroid does not vary substantially. This consistency is crucial for drug toxicity evaluation. Regarding the issue of cavitation, extending the culture duration from 30 days to 50 or even 60 days allows organoids to exhibit more mature characteristics. Overall, by integrating microfluidic organ-on-a-chip technology with materials science, artificial intelligence, and other advanced technologies, the in vitro models we create are becoming increasingly biomimetic, thereby facilitating more accurate prediction of real-world drug responses.

Furthermore, it is worth noting that Hesperos, a foreign organ-on-a-chip company, entered the pre-IPO stage as early as March 2022. Its business model is quite distinctive: Hesperos has partnered with Sanofi to develop a platform for rare diseases, aiming to model a large number of rare diseases using organ-on-a-chip technology. This business model aligns well with the regulations issued by China’s Center for Drug Evaluation (CDE). Currently, animal testing remains the gold standard; however, in cases where animal models cannot be established, there is a critical need to leverage organoids or organ-on-a-chip systems to create disease models, such as for non-alcoholic steatohepatitis (NASH). If similar cases can emerge in China within the next one to two years and successfully pass CDE review, it would significantly benefit the advancement of this industry.

Song Guangqi (Puheng Technology):Currently, organoids and organ-on-a-chip systems are increasingly integrated with in vivo models, such as conducting early-stage in vitro studies followed by animal validation. Our focus is on replacing traditional 2D cell cultures, which lack sufficient complexity to enable multi-endpoint assessments. If a model can achieve a certain level of complexity while remaining standardized and easy to establish, it can enhance the efficiency of drug development.

Advances in biomaterials in recent years have enabled us to achieve what was previously difficult. By developing nano-scale editable materials, we can assemble different cells—particularly those spanning multiple layers—at precisely targeted locations to mimic specific physiological structures. This approach helps overcome certain limitations and facilitates the establishment of more complex models, such as chronic non-alcoholic steatohepatitis (NASH). New materials offer substantial potential for in vitro models; beyond simple assembly and positioning, they allow for the introduction of site-specific pH levels and regulated inflammation factors across different regions. We can even envision nanorobots automatically assembling these models. Conversely, greater complexity at the microscopic level enables simplification at the instrumental level. For instance, high-throughput instrument manufacturing can become simpler, more miniaturized, and more cost-effective, thereby improving the accessibility of standardized model production.

Yi Sun (WuXi AppTec):Over the past two years, the most significant breakthroughs in organoid technology have centered on the development of organoids derived from various tissue sources. These organoids exhibit high biomimicry of human organs, thereby holding substantial application value for both basic research and the development of clinical therapies. Furthermore, organoid libraries can be directly constructed and cross-screened with human antibody libraries to rapidly identify drug candidate target molecules with practical utility, facilitating their direct translation into clinical applications. Additionally, it is encouraging to observe the application of organoids in personalized treatment for clinical patients, which raises high expectations for their utilization over the next two years.

Wang Xuebin (Corning Life Sciences): All the guests have mentioned that the most significant breakthroughs in organoids or organ-on-a-chip technology lie in achieving high biomimicry and establishing organoids derived from multiple tissue sources. So, what challenges do we face during the culture process of organoids? And what technologies can help overcome these current challenges?

Sun Yi (Crown Bioscience):Organoid technology is not yet fully mature and cannot guarantee complete success. I believe three key areas require attention. First, it is essential to select the highest-quality tissue sources; the tissues themselves must meet quality standards, and significant loss during transportation must be avoided. Second, various culture conditions need to be optimized, including the selection of different types of matrix gels and cytokines, as there are considerable variations among products from different manufacturers. WuXi AppTec generally selects validated, optimal options to ensure the quality of our models. Third, rigorous quality control (QC) must be implemented. We conduct comprehensive QC at every stage, including genetic analysis, protein expression profiling, and histopathological examination. These QC measures ensure the establishment of high-quality organoids. Furthermore, through these processes, organoids undergo multiple rounds of in vitro culture while maintaining genetic consistency, which is critical for drug screening and efficacy evaluation.

Song Guangqi (Puheng Technology):We believe that cells and organoids derived from induced pluripotent stem (iPS) cells are more ideal for drug screening, as they can serve as standardized models with well-defined backgrounds. However, this approach still faces many challenges, such as issues with reproducibility. Factors including the degree of cell differentiation, cell quantity, and organoid size are easily influenced by various factors, some of which are even uncontrollable. Another challenge is how to induce differentiation in vitro to generate mature cells that are completely identical to those in vivo. Greater investment should be made in iPS cell-related technologies.

Yang Xi (Nuopu Regeneration):Organoids are generally based on self-assembly processes, whereas the 3D bioprinting we employ is a non-self-assembly process. Following this non-self-assembly phase, there is an integration process involving the entire cellular microenvironment, including interactions between cells and between cells and extracellular molecules, which we have observed during tissue regeneration. Bioprinting technology is also evolving. Initially, it may have only allowed for the precise arrangement of a single cell aggregate or a single cell type. Currently, however, it enables the differential arrangement of multiple cell types within the same three-dimensional structure. For example, in the intestine, which consists of different structural layers each with its own capillary distribution, bioprinting can now attempt to arrange and construct cells at this level of complexity. The efficacy of this approach still requires further validation by scientists as they continue to apply and refine this tool.

Wang Xuebin (Corning Life Sciences): Corning is primarily engaged in the sales of Matrigel. Back in 2018, when I was working at Corning’s laboratory, we already anticipated that organoids would emerge as a significant field. From 2019 to 2022, we witnessed the establishment of numerous organoid-focused companies. As the industry began to take off, China also released several consensus statements and standards related to organoids and organ-on-a-chip technologies. How should we view the progress of organoid standardization in China? Are there relevant international standards that could offer us some insights?

Zhou Yu (DaXiang Technology):Last year, the publication of two expert consensus statements and several group standards objectively advanced the standardization process within this industry. The expert consensus primarily focused on clinical applications, specifically the use of individualized drug susceptibility testing and diagnostic criteria for ECA. Meanwhile, the group standards centered on conceptual aspects of organoids, including their preparation and identification. I believe this development is undoubtedly beneficial for the industry. The next key step is to further optimize these group standards and promote their adoption at higher regulatory levels.

Compared to China, the advancement of standardization abroad has been more effective, as it is a more systematic and organized endeavor. In the United States, for instance, standardization efforts are primarily led by top-down regulatory frameworks established by agencies such as the National Institutes of Health (NIH) and the Food and Drug Administration (FDA), covering regulations, rules, and model validation. Data generated from these technologies are continuously evaluated and assessed, which in turn drives technological progress. From an application perspective, more than 20 pharmaceutical companies within the IQ Consortium have long explored and applied these new technologies. Their drug development processes have generated substantial data, which they have jointly validated through collaborations with organ-on-a-chip companies. Furthermore, many Investigational New Drug (IND) applications have been submitted. This approach significantly facilitates the systematic and organized implementation of standardized application scenarios.

Chen Zongzheng (Xirui Biotech):New drug development is inherently conservative, and this tendency is even more pronounced in China than abroad. Nevertheless, emerging technologies continue to attract attention, with regulatory bodies such as the National Medical Products Administration (NMPA) also seeking to promote their adoption. Although the two drugs granted clinical trial approval by the U.S. FDA based on organoid and organ-on-a-chip technologies were repurposed existing drugs whose safety had already been validated, the FDA’s top-down approach to advancing these innovations remains pioneering. From an industry perspective, establishing industry standards within the industrial sector, among end-users, or for specific application scenarios may hold greater significance for companies than merely obtaining regulatory approvals based on novel technologies. While some standards have already been issued, they remain insufficient in number and predominantly focus on technical uniformity, staying largely at the “conceptual” level. Their effectiveness in final application scenarios still warrants further discussion. Clearly, broader participation from diverse individuals and groups is needed. In particular, involving more materials scientists, biomedical researchers, microfluidics experts, and especially professionals from non-biomedical fields in standard-setting would be more beneficial to the overall development of the industry.

Moderator: This actually leads us to our next question. As he just mentioned, who are the users of organoids or organ-on-a-chip technologies? If we are talking about companion diagnostics or drug sensitivity testing, the end-users are clinicians, while the largest user base in the future will likely be in the industrial sector, particularly large pharmaceutical companies. How can we gain their acceptance of organoid technologies and establish industry-wide default standards? Are these standards sufficient? We invite our panelists to share their perspectives on how to truly promote the recognition of organoids across various application scenarios and support standardization efforts among all stakeholders.

Sun Yi (WuXi AppTec):Organoid technology has advanced rapidly in recent years, and our standards have clearly not kept pace. Standards for intestinal and colorectal cancer organoids were only released last year, yet organoid models for more than a dozen cancer types have already been established. Like other technologies, organoid technology has progressed through stages of initial awareness, deeper understanding, and practical application. At WuXi AppTec’s Crown Bioscience division, we are fortunate to engage with leading pharmaceutical clients who put forward specific requirements and expectations for new models. We summarize these inputs; when a requirement is common across multiple clients, we adopt it as an internal standard. This proactive approach ensures that our standards remain ahead of the curve, so that when formal industry standards are eventually established, our practices will already be compliant. The purpose of our standards is to ensure that preclinical organoid models accurately reflect clinical outcomes, thereby maximizing the translation rate of investigational drugs from preclinical development to market approval.

Song Guangqi (Puheng Technology):Recently, China has established numerous standards for organoids, but most of these focus on standardizing culture and handling procedures. We currently lack standards tailored to specific application scenarios. Specifically, while large pharmaceutical companies have the capability to determine their required disease models and define the necessary characteristics, many innovative pharmaceutical firms and biotech companies lack sufficient experience to make such judgments. Consequently, their primary concern is how to determine whether these novel in vitro models are suitable. Endorsement through relevant standards would undoubtedly bolster their confidence in adopting in vitro model technologies. At present, different technologies used to establish models for the same disease may follow entirely distinct technical routes. Therefore, we need to reach a scientific consensus on model characteristics. For instance, an in vitro screening model for NASH drugs must possess certain essential features and exclude others. I believe we should develop more such detailed standards. This will be a lengthy process requiring collaboration among pharmaceutical companies, regulatory authorities, and companies like ours that develop in vitro model technologies.

Chen Zongzheng (Xirui Biotech):When we engage with investors, we are invariably asked about our competitive advantages. I must honestly admit that there is no established standard that truly demonstrates the superiority of data derived from organoids and organ-on-a-chip technologies. The models currently available may represent a “breakthrough” with significant potential advantages over those presently used in the pharmaceutical industry. At present, Xirui Biotech is addressing common pain points reported by customers, starting with specific niche areas, to develop standardized products and services. Of course, numerous technical challenges remain to be overcome. We have always believed that positive feedback from users and market validation constitute the most meaningful standards of success.

Yang Xi (Nuopu Regeneration):I offer another perspective: customer demands remain diverse and fragmented. Therefore, the promotion of new technologies is likely to drive standardization in technical processes. Although group standards may not standardize application scenarios, standardizing technical processes can still facilitate acceptance at the end-user level. Through accumulation in specific niches, it is possible to establish standards or general requirements for broader scenarios. Take the field of tissue regeneration as an example, where various new technologies are being adopted. We previously organized the development of a group standard; for instance, when developing an artificial skin product, what fundamental requirements must be met overall? This is a question pertaining to application scenarios, while allowing ample flexibility in technical methodologies. At that time, we engaged the National Medical Products Administration (NMPA), bringing them into the process through a top-down approach.

Zhou Yu (Da Xiang Technology):Comprehensive points have already been made; I will provide a brief summary. First, regarding the standardization of organoids and organ-on-a-chip technologies, stakeholders extend beyond companies like ours that develop these platforms. It is crucial to involve regulators, end users, and application partners, such as pharmaceutical companies. We maintain close communication with domestic regulatory authorities in China. We have consistently advocated for greater attention to these technological advancements, encouraged widespread adoption of these new technologies, and welcomed the submission of data generated from their practical applications.

Second, companies like ours can submit our model-building methodologies along with the results of our internal validations regarding reliability, consistency, data reproducibility, and standardization. These submissions can then be evaluated by the broader community. We could even establish a testing center, similar to those in the United States, to conduct practical re-certification of these methodologies. This approach would significantly enhance confidence in and understanding of standardization. Pharmaceutical companies can collaborate with firms like ours to address challenges that traditional models fail to resolve, with the resulting solutions subsequently undergoing evaluation. Through such collaborative efforts, where all parties participate and reach consensus, we can ultimately establish and perpetuate actionable, standardized practices.

Third, in contrast to traditional models, the animal models we currently use also undergo a standardization process. Continuous testing and data accumulation are performed on these models, followed by ongoing evaluation and review, ultimately leading to the establishment of standards. In essence, the path we need to take mirrors the path previously taken by animal models.