This week Visikol CEO Michael Johnson PhD was asked to speak as a keynote at the Millipore Sigma Scientific Symposium on the future of science and more specifically the field of 3D cell culture.
Five years ago, the field of 3D cell culture was primarily an academic pursuit with graduate students and post docs at poster sessions trying to convince anyone who would listen that 3D cell culture was the future.
Now only a few years later, most major pharmaceutical companies have adopted 3D cell culture models in a meaningful way as part of their drug discovery programs in an effort to accelerate their programs and also to prevent late stage failures. The field as a whole has dramatically changed in a short period of time with dozens of companies focused on commercializing 3D cell culture models and services.
Shifting Business Models
When 3D cell culture models were first commercialized by companies such as InSphero, there was a large focus on selling live and ready-to-use models that any researcher could purchase and use in their lab. At the time, generating 3D cell culture models was incredibly challenging due to the lack of easy-to-use 3D cell culturing techniques and the field being so new that processes had yet to be standardized. Therefore, in the beginning, this business model of selling living plates of cell culture models addressed a substantial customer pain point while allowing any researcher to quickly bring these models into their lab.
However, in a relatively short period of time, protocols and technologies such as Corning ULA plates have been introduced that have drastically reduced the barrier to adoption for labs in generating their own 3D cell models. Furthermore, with the introduction of these technologies and the development of the field, many researchers began to realize that 3D cell culturing was not all that complicated and in many cases was actually easier than traditional 2D cell culture. At about the same time, contract research services in this field began to blossom as researchers interested in 3D cell culture models, but not interested in running the assays themselves began to send compounds and antibodies to experts in the field on a fee-for-service basis.
Today, we see interest from pharmaceutical and biotech companies split evenly between DIY cell culture (i.e. internal assays) and CRO services with about one in ten researchers still interested in living plates of 3D cell culture models. From our experience, pharmaceutical companies are only interested in living 3D cell culture model plates when they do not have internal cell culture bandwidth/expertise or they are interested in a model that is too technically challenging to internalize such as a primary human islet model or a neuronal organoid model that could take 6+ months to differentiate.
Like all life science research fields, technology can be highly disruptive and that has certainly been the case in the 3D cell culture field where the barrier to adoption has dropped dramatically. Just a few years ago it was very challenging and expensive to generate models wherein with the introduction of technologies such as ULA plates now allow any research group currently using 2D cell culture to make the switch to 3D overnight without any special equipment or know-how.
We see it as our responsibility as a company in this space to actively shed light on the limitations of 3D cell culture as the field too often tries to paint the picture that 2D cell culture is dead and that animal models will no longer be required. This couldn’t be any farther from the truth and what we see is that the most rapid adoption of 3D cell culture has not been to replace 2D cell culture or animal models but instead to answer research questions that we cannot necessarily address today. 3D cell culture models fit into the drug discovery continuum between animal models and 2D cell culture models and will replace some applications from each of these tools but like all tools there are trade offs. Typically, 3D cell culture will be more expensive and lower throughput than 2D cell culture and when compared to animal models will tend to do a poorer job of mimicking in vivo functionality.
Imaging, Image Analysis and Data Processing
As a company focused on transforming tissues into large datasets and mining these datasets for actionable insights, we commonly encounter a major problem with 3D cell culture models which is their characterization. Being 100X thicker than a microscope slide and too small to effectively process with traditional histopathology means that their characterization can be highly challenging as it requires the combination of whole mount immunolabeling, 3D microscopy, tissue clearing, 3D image analysis and complex multi-dimensional data processing. Commercially available tools and protocols for many of these sub-disciplines do not yet exist and thus even the largest of pharmaceutical companies struggle with pulling these disciplines together. Because of these limitations, many companies leveraging 3D cell culture models will employ highly simplistic end-points such as total-ATP and will not make any use of the spatial data inherent within these models which intrinsically makes them more valuable than 2D models.
Trends in 3D Cell Culture
In working with dozens of pharmaceutical and biotech companies, we have seen a number of trends present across the space in regard to the adoption of these models.
- Pharmaceutical and biotech companies are very hesitant to work with proprietary 3rd party models: Many startup companies entering into this space have tried to commercialize proprietary models which have overall been met with a lot of pushback. The rationale for this is that if a company is acquired or goes bankrupt then the pharmaceutical company will have shifted their in vitro program over to a system that they can no longer use. In the liver, kidney and cardiac safety/tox spaces, researchers at pharma companies are actively pushing for open source industry standard models so that all pharma companies are using the same gold-standards. The exception to this feedback are models that convey a substantial value that cannot be replicated inhouse such as a neuronal organoid model that takes several years to develop. Otherwise, pharmaceutical companies are very fearful of business continuity problems and dependency on a startup.
- Most researchers have shifted to using Corning ULA plates for their 3D cell culture model generation: A few years ago, researchers were working with dozens of different types of cell culturing techniques but over the last few years have transitioned to mostly working with ULA plates due to their ease-of-use and cost. While there are other ultra-low attachment plates in the marketplace, Corning has control over the patent to black-walled ULA plates which substantially improve imaging quality compared to other ULA plates from other companies.
- There has been a slow adoption of 3D cell culture models by safety/toxicity (ADME) researchers: While safety and toxicity researchers were some of the first adopters of 3D cell culture, they have been slow to integrate these models in routine workflows and typically we see investigational toxicology groups much more readily adopting these technologies. The rationale for this is that safety/toxicity studies have been in place for decades and changing the paradigm requires extensive validation. Without a gold-standard model and years of validation data, these researchers are highly reticent to switch to a new model and especially a model that is proprietary and not open source.
- Organs on a chip and bioprinting have not been adopted by pharmaceutical and biotech companies in a meaningful way: While there are many pharma companies evaluating these technologies such as the Emulate platform, these technologies have not permeated into routine use as it is not clear yet what the ‘killer app” for these platforms is and where they provide more value than 3D cell culture or animal models. These technologies currently are higher cost than animal models, provide low throughput and do not better recapitulate in vivo functionality.
Opportunities and Where is the Field Going?
While we unfortunately cannot predict exactly where the field is going, there are a few gaps currently in the market which we see a lot of researchers working on currently.
- 3D Cell Culture Image Analysis Software: Currently there is a major gap in the field of 3D cell culture image analysis software and we see several companies filling in this gap in the next few years and making the characetrization process easier.
- Industry-Wide Safety/Tox Consensus: In the next few years we see consortiums of pharmaceutical companies building consensus around which models are acceptable for specific research questions in order to maximize in vivo relevancy and throughput while minimizing cost. Essentially, we see these 3D cell culture fields transitioning in the short-term to open source gold-standard assays and models with industry-wide validation criteria.
- Reduction in Cost of Models: One of the barriers to adoption for 3D cell culture models has been that on a per well basis they tend to cost more than traditional 2D cell culture assays. Like any new technology, we see this cost coming down over the next few years and further facilitating more wide-spread adoption.
- Improvements in Neuroscience Models: There is a great need for improved neuroscience 3D models and we see several companies commercializing disease models in this space that better mimic in vivo features/functionalities over the next few years.