Organ-on-a-chip: paving the way for commercialisation

What is organ-on-a-chip technology?

Organ-on-chip devices are microfluidic platforms that aim to mimic the structure and function of human organs in vitro. These devices consist of multiple interconnected microfluidic channels integrated with three-dimensional cell/tissue cultures, forming a circuit which can replicate the physiological functions, mechanics and responses of an entire organ or organ system.

The development of these devices is a particularly ‘hot’ academic research area, with an astonishing 430% increase in scientific publications between 2015 and 2021. This growth in research has been fuelled primarily by the potential of micro-scale biomimetic platforms to revolutionise the way we develop drugs.

What are the benefits of organ-on-a-chip devices?

Improving drug development

By building a highly controlled and in vivo accurate/representative disease model, on-chip devices offer a new approach to drug development. A prime example of this is the Vascularised Tumour Spheroid-on-a-Chip Model. Here, tumour and blood vessel cells or explants are isolated from a patient, before being transferred on a specially designed microfluidic chip and appropriately cultured, to form a vascularised tumour spheroid with perfusable channels. This is effectively a 3D model that replicates the structure and function of a tumour in vitro, consisting of a tumour spheroid which is a small, ball-shaped mass of cancer cells and a network of channels that are designed to mimic blood vessels. These can then in turn be used to introduce cancer therapies and evaluate their clinical efficacy by studying the spheroid response, offering a new approach to personalised medicine and drug screening .

An alternative to animal testing

Drugs that have been found safe and effective preclinically in animal studies have a 90% attrition rate in human clinical trials, which is by far the most expensive drug development phase. This is due to the inherent limitation of the pre-clinical research tools (two-dimensional cell cultures) in replicating the in vivo cell and tissue interactions and functions which are critical in demonstrating accurate drug response.

Organ-on-a-chip technology is capable of real-time imaging and in vitro monitoring of the biochemical, genetic, and metabolic activities of functional three-dimensional cultures. This allows for the early detection of drug toxicity, as well as the evaluation of efficacy and high-throughput screening. Combined with the small footprint, material and reagent requirements of these devices, this is a technology which is faster, far more cost-effective and more ethical than animal testing.

The challenges of commercialising
organ-on-a-chip technology

The challenges of commercialising organ-on-chip technologies are centred around the high cost of manufacturing and regulatory approval barriers that can be linked to the lack of standardisation in the field, due to its relative infancy and complexity. Organ-on-chip research prototypes are inherently ad hoc, “single-issue” solutions arising from isolated research efforts on a targeted organ or system. As a result, they come in many different designs, sizes, materials and connection interfaces, each serving the specific needs of the integrated biological component. Consequently, researchers and manufacturers are unable to agree on a standard to facilitate upscaling manufacturing, with limited regulatory guidelines for approval.

Advancements in standardising organ-on-chip devices

To help pave the way for commercialisation of organ-on-a-chip technology, the global standards and scientific communities have taken steps in defining standardisation needs. This has included mapping the standardisation opportunities over the last decade. For instance, the European Committee for Standardisation organised the ‘Organs on chip: building a roadmap towards standardization’ workshop in 2021, which identified primary needs for standardisation in the field and established the “basis for an active dialogue and cooperation between the communities of researchers and standardisers”.

The outcome of this workshop was the creation of the “Focus Group on Organ on chip”. Its purpose is to facilitate interaction between all relevant European stakeholders interested in standardisation of the field. It is also responsible for monitoring standardisation workstreams and ensuring that standards support the deployment of this technology in industry and regulatory acceptance. There have also been several scientific publications presenting gap analysis results, suggesting priorities and recommending approaches for organ-on-a-chip standardisation in line with existing relevant standards. From a diagnostic medical device development perspective, the consensus is that these standards should be developed based on four pillars:

1. Classification
2. Compatibility
3. Materials and production processes
4. Functionality and performance evaluation

Classification

Classification is of primary importance in standardisation as it will facilitate the defining of technical performance and compatibility requirements of organ-on-chip devices. This will ultimately decide which materials, production processes, and sterilisation processes to adopt to achieve these requirements. Classification of organ-on-a-chip technology has been particularly elusive though due to the ad hoc, “single-issue” nature of research prototypes. However, by taking a closer look we can identify common technical characteristics and features which can guide standardisation.

All organ-on-chip devices have multiple culture chambers to accommodate the biological model, which are often linked to a microfluidic channel network to support the culture. Three configurations are particularly common and can serve as an initial classification method:

1. Combinations of multiple organs: These consist of multiple chambers, each hosting a different cell type, connected via a microfluidic channel allowing the exchange of nutrients and signalling molecules.
2. Barrier function: Cells are cultured in opposite chambers separated by porous membranes.
3. Co-cultures in relevant microenvironment: Various cell types are cultured in and/or on a hydrogel scaffold with appropriate composition and properties mimicking the in vivo extracellular environment of those cells.

Compatibility

Each organ-on-a-chip model is always accompanied by common laboratory equipment to carry out assays, such as pumping and fluid control systems, sensor readout systems, incubators and imaging tools. Even though organ-on-chip devices comprise of the same functional elements (microfluidic channels, culture chambers, hydraulic valves, integrated sensors etc.), there’s an inherent lack of compatibility with peripheral laboratory equipment across devices produced by different developers. This is exacerbated by the fact that commercial devices are often made uniquely compatible with a family of other products and/or platforms produced and marketed by the same manufacturer. These platforms do offer the ability to manage multiple devices for high throughput assays, but they have different sizes and layouts and cannot be easily interfaced with one another. Inevitably, this forces researchers to purchase an entire family of products from the same supplier, which is often too expensive, and also limits research to cell-lines and barrier membranes uniquely compatible to that platform.

To overcome this challenge, the European Organ-on-Chip Society recommends the establishment of Open technology platforms where the devices themselves (size and footprint) and their interfaces with existing laboratory equipment and workflows are standardised. This could greatly boost the implementation of organ-on-a-chip devices by smaller groups, whilst retaining the unique functional elements of their devices which are critical to their particular purpose.

A major step in the right direction was the introduction of ISO 22916:2022, Microfluidic devices — Interoperability requirements for dimensions, connections and initial device classification. As outlined in the Scope of this document, it “specifies requirements for the seamless integration with other microfluidic components and systems to facilitate the process of designing new microfluidic devices (e.g. microfluidic chips, sensors, actuators, connectors)”. Specifically, it specifies chip reference points, topology, dimensions, top and side connections.

Following the same ethos, the University of Twente is developing the Translational Organ-on-chip Platform (TOP), which is designed to provide a common infrastructure for automated microfluidic chip control, which can be adapted to various devices provided that they follow simple design rules based on ISO 22916:2022. TOP implements a multi-layer approach where custom chips and flow control boards featuring valves and clamps are assembled as stackable modules via common design features.

With regards to integration of sensors, the same modular approach is utilised by Moore4Medical’s Smart Multi-Well Plate for interfacing sensors and electrodes for live measurements, where the transducers and electrodes are embedded as an additional layer. Other active components needed for assays such as heaters or electrowetting electrodes can be integrated in a similar multi-layer modularity fashion. Cable connectivity and controller/data-logger interfacing should also be standardised. The European Committee for Standardisation recommends simple USB connections but highlights the need to add these features with careful consideration of the fluidic control system, incubator conditions and other factors that could influence sensor performance.

Standard solutions for making organ-on-a-chip devices compatible with imaging platforms are necessary for the analysis phase of assays. A transparent bottom providing optical access is seen across almost all devices, but securely mounting the device on the imaging platform is also crucial when physically accessing the chip to streamline the assay processes. Therefore, standard dimensions and tolerances of common labware, such as multi-well plates and glass slides, should be inherited into dimensional standards for chips.

Materials and production processes

When it comes to materials for organ-on-chip and their microfluidic elements, biocompatibility and biochemical inertness are key. There is currently enough availability of materials with desirable and well-known properties, each with well-established manufacturing processes. Ultimately, the choice of material and fabrication process depends heavily on the technology readiness level.

Soft-photolithography and Polydimethylsiloxane casting are widely used in conceptualising and prototyping devices at the research level. There have also been advances in Projection Micro Stereolithography (additive manufacturing), where companies like Boston Micro Fabrication have introduced durable and biocompatible resins such as HTL and RG. These are generally cheap processes but are slow and practically unscalable. In more mature development stages, there has been a shift towards standardised injection moulding processes and amenable materials, such us polystyrene, polycarbonate, polymethylmethacrylate, and cyclic olefin copolymer (COC), bringing devices closer to industrialisation. However, committing to tooling for moulding is often an expensive venture, requiring several rounds of design polishing according to Design for Manufacturing (DfM) practices, which can often significantly conflict with prototype designs.

Accelerating the transition from prototyping to industrialisation is achievable in several ways. DfM practices and standards should be employed early-on in the device development life cycle with a healthy balance that does not hinder innovation. Simultaneously, microfluidic performance has been extensively studied and there are well established microfluidic channel geometries and features for certain applications, those being hydrogel pattering, membrane/cell adhesion and flow shear stress control, among others.

Industrial and early-stage developers should combine their efforts to generate open-source libraries of standardised channel geometries and dimensions. Ultimately, microfluidic and organ-on-a-chip design, could evolve into something like Printed Circuit Board (PCB) design, where developers get to choose from standardised libraries of channels and components and follow layout and stack-up rules. This will greatly facilitate design transfer and bring organ-on-chip devices closer to industrialisation.

Functionality and performance evaluation

To enhance the qualification of organ-on-chip devices it is essential to demonstrate their proper functioning within a specific usage scenario. An in vitro intricate methods survey suggests that developers and users often claim to carry out some sort of internal performance evaluation on their devices. These, however, do not adhere to any international qualification or validation guidelines and have an ad hoc, subjective, nature. Consequently, this lack of standardisation makes it challenging to even compare similar devices while crucial aspects of performance that require characterisation might be overlooked altogether.

It is therefore imperative to establish performance standards for organ-on-chip devices along with relevant practices and processes guidelines and acceptance criteria. Following the conventions of standardisation, this undertaking should be consensus-based and executed by all stakeholders (i.e. developers, end-users and regulatory experts). The operating pressure and temperature ranges classification method in Section 9 of ISO 22916:2022 is a great starting point, as it can be directly implemented to establish safety tests such as leakage and burst pressure tests. Beyond this, there’s a vast variety of tests that can be standardised according to the classifications discussed above. These include and are not limited to: flow throughput tests; cell culture adherence; hydrogel patterning; barrier membrane permeability; gas permeability and molecular absorbance; and of course, biocompatibility.

The characteristics, requirements and calibration strategies of integrated sensing instruments should be standardised in an application-specific way. Common sensor specifications can be utilised here including sensitivity, footprint, hysteresis, stability and position. Similarly, the characteristics and performance requirements of integrated active components and actuators need to be established within the context of technical functionality and reliability.

The report produced by the “Organ-on-chip: building a roadmap towards standardisation” workshop suggests that an expansive realm for standardisation lies in performance characterisation of the OoC system as a whole (i.e. chip, pump, incubator, sensors and actuators), rather than its individual components. This is accomplishable, first by unlocking compatibility as discussed above and then establishing a universal template for reporting organ-on-chip experimental protocols and sharing and interpreting data. Such an approach would enable the comparison of results obtained from different systems and ultimately automate the entire process, along with statistical interpretation of results.

The future of organ-on-a-chip devices: improving accessibility

The full realisation of organ-on-a-chip technology by the healthcare industry is currently hindered by high manufacturing costs and regulatory approval challenges. Despite this, it is now widely accepted that standardisation is the way forward to overcome these obstacles and there are several collaboration efforts underway to achieve that.

Furthermore, there is major investment in advancing materials and manufacturing techniques, aiming to reduce the cost of these devices and make them more accessible to the healthcare industry. Research is also ongoing to develop new applications for microfluidic devices in general, such as environmental monitoring and food safety testing, which can also drive commercialisation. With the potential benefits of these devices and ongoing efforts to standardise them, the future looks bright for the commercialisation of organ-on-a-chip technology.

References

Mordor Intelligence, “ORGAN-ON-CHIP MARKET – GROWTH, TRENDS, COVID-19 IMPACT, AND FORECASTS (2023 – 2028),” 2022.

MARKET RESEARCH FUTURE, “Organ-on-a-chip Market Research Report: By Organ Type, By Application and By End-User”, 2023.

DATA BRIDGE MARKER RESEARCH, “Global Organ-On-Chip Market – Industry Trends and Forecast to 2029,” 2022.