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. 2022 Jun 27;8(11):4643–4647. doi: 10.1021/acsbiomaterials.1c01536

Developer’s Guide to an Organ-on-Chip Model

Julia Rogal ‡, Katharina Schlünder ‡,§, Peter Loskill ‡,§,⊥,*
PMCID: PMC9667877  PMID: 35760397

Abstract

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Over the past decade, organ-on-chip research has been one of the most prolific areas of the entire field of tissue engineering. The development of organ-on-chip models requires an integrated interdisciplinary approach merging technologies and concepts from several different disciplines, including microfabrication, microfluidics, biomaterials, stem cell science, pharma-/toxicology, and medicine. In this perspective, we follow the journey of an organ-on-chip through its many different stages, from (i) the initial idea/specific scientific question to (ii) the design/concept phase, (iii) the engineering (fabrication and materials, sensor/actuator integration) and (iv) biology considerations (cell sources, biomaterials/scaffold), (v) the cell injection and tissue assembly process, (vi) the assay development, and (vii) the functional validation, all the way to (viii) the final applications. By summarizing some of the key learnings and findings from a developer’s perspective and identifying suitable introductory reviews, this perspective strives to provide a conceptual, stepwise guide for the holistic development of an organ-on-chip model.

Keywords: organ-on-chip, microphysiological systems, tissue chips, microfluidics, tissue engineering, in vitro models

Over the past decade, organ-on-chip (OoC) research has been one of the most prolific areas of the entire field of tissue engineering. Diverse efforts worldwide have resulted in a variety of exciting approaches and models, some of which have successfully been transferred into commercial products.1−5 At the same time, these efforts have created a huge space of opportunities for the OoC technology.6−12 In this perspective, we strive to provide a conceptual, stepwise guide (Figure 1) for the holistic development of an organ-on-chip model, summarizing some of the key learnings and findings from a developer’s perspective and suggesting suitable introductory reviews elaborating on the respective individual steps.

Figure 1.

Figure 1

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Schematic depiction of the journey of an organ-on-chip model from the initial idea to its application.

1. Idea/Specific Scientific Question

The starting point for any effort in developing an OoC model is the targeted scientific question, viz. the definition of the specific, intended application purpose of the model. Combined with the general underlying idea of an OoC—the recapitulation of the minimal functional unit of an organ in a microfluidic device by using the human body as a structural blueprint and cell source4,13—this provides the foundation for the entire subsequent process.

2. Design/Concept

The first step toward realizing the idea is the establishment of the overall concept and design of the model. Here, the key challenge is to design a platform and procedure that is as simple as possible but as close as feasible to the respective in vivo situation. Both a thorough knowledge on target organ physiological function and a proper understanding of existing modeling approaches and platforms are crucial for lowering the complexity of this step. Designing the model is usually executed using computer-aided design (CAD) software. The design defines arrangements and geometries of microchannels and chambers anticipated to lead to targeted compartmentalization, fluidic mechanics, and transport process, as well as emulation of tissue interfaces.

  • Exemplification: When designing an OoC system intended for the generation of a 3D tissue, design aspects worth considering beforehand include, among others, (i) tissue-specific chamber dimensions/volumes to integrate sufficient cell numbers, (ii) channel architectures to enable gentle but reproducible cell injection, (iii) media perfusion structures to provide sufficient nutrition throughout the tissues, (iv) chip dimensions enabling easy access for common 3D imaging techniques, and (v) a straightforward chip-to-world connection interface with easily accessible connection ports.

The following steps focusing on the implementation of the concept can be categorized in principle into engineering and biology branches. Crucial, however, is the appreciation that these two branches are in no way independent from each other but closely interconnected and that the entire path encompassing aspects 2–5 is not a linear but an iterative process (cf. Figure 1).

3. Engineering Branch

3.1. Fabrication and Materials

With a design in mind, the first step of implementation is the selection of chip materials. Most commonly, polymers are the material of choice, with polydimethylsiloxane (PDMS) as the most widely used one, which can be easily structured via lithography and replica molding. Although PDMS certainly has its advantages (and limitations),14,15 several alternatives are available, including thermoplastics, which can be microfabricated via laser structuring, injection molding, hot embossing, or 3D printing.16

Considerations in material selection should depend on the intended purpose of the model and are based on material characteristics such as biocompatibility, absorption properties and oxygen permeability. Additionally, with a future technology transfer and large-scale application in mind, aspects such as material availability and cost as well as scalability of the fabrication process should be considered early on.

  • Exemplification: If the intended OoC application is pharmacokinetic/pharmacodynamic modeling of small hydrophobic compounds, for instance, using PDMS as the main chip material will be unfavorable. The choice of a thermoplastic polymer will minimize the risk of absorption into the bulk material; yet, because of the low gas permeability of thermoplastics, on-chip oxygen availability must be considered carefully to avoid hypoxia. For exploring cell therapies, antibodies, or large molecules, the PDMS’ absorbing properties might not directly be a cause of problems. Importantly, however, it is not only the absorption of administered substances but also that of cellular secretions, such as endocrine signaling molecules, for instance, that must be considered. For some applications, it might be favorable to employ hybrid material chips, made, for example, from thermoplastics and PDMS providing a compromise between absorption and oxygenation.

3.2. Sensor/Actuator Integration

The transparent nature of most microfluidic platforms and the continuous perfusion provide an excellent optical accessibility and the opportunity to do time-resolved sampling of the perfused media (effluent). Although a variety of data can be collected via microscopy and off-chip effluent analysis, these approaches entail limitations especially regarding real-time monitoring. Hence, numerous approaches for the integration of sensors into OoC systems are available and provide the opportunity to monitor cell culture conditions and biological function in situ and in real-time, as comprehensively reviewed by Fuchs et al.17 Similarly, different types of actuators can be incorporated into OoC platforms to provide, e.g., mechanical18 or electrical stimuli.19 In the end, the choice of sensor or actuator and integration approach is intricately linked to the targeted biological function and chosen chip fabrication approach as discussed in detail by Kavand et al.20

  • Exemplification: Generally, the less stable the analyte (or the analyte’s concentration) of interest is, the closer the sensor should be to the analyte’s production site. On-chip oxygen concentrations can be determined using optical, contactless oxygen sensors, thereby enabling a real-time monitoring of oxygen supply to and metabolic activity of on-chip tissues. Yet, when sensing oxygen, the chip’s material must be considered carefully: using PDMS for applications involving oxygen sensing might be unfavorable because of the PDMS’ gas permeability, which might distort measured oxygen levels.

4. Biology Branch

4.1. Cell Sources

When choosing adequate cell sources, first, the cell types forming the minimal unit responsible for the targeted function have to be identified. Second, aspects relevant for the targeted scientific question, such as the necessity of autologous or human leukocyte antigen (HLA) matching as well as the availability of primary material or of robust differentiation protocols, need to be considered. As for tissue engineering in general, OoCs can be based on immortalized cell lines, primary cells, and adult or pluripotent stem cells. Immortalized cell lines provide a cheap, robust, and standardized option; however, they commonly are animal- or tumor-derived and lack critical phenotypical or functional characteristics. Hence, they often are the choice for prototyping stages but typically later replaced by other cell sources. Primary cells from biopsies can provide a more mature phenotype and a better functional recapitulation as well as the option for patient-specific autologous models. The small size and physiological microenvironment of OoCs addresses some of the conventional challenges of primary cells such as limited cell numbers and loss of function in long-term culture. Yet, primary cells are not available for all organ types and hardly amenable for standardization.

Adult and pluripotent stem cells such as induced pluripotent stem cells (iPSCs) combine the advantages of cell lines and primary cells. Especially iPSCs have emerged as a uniquely promising cell source for OoCs (not only for personalized medicine applications), allowing the generation of fully autologous and standardizable tissues.21,22 In many cases, however, robust differentiation and maturation protocols to achieve fully functional adult cell types are still under development.

  • Exemplification: For precision/personalized medicine applications, solely primary or stem cells are a suitable source. Choosing between these two options, one needs to consider on the one hand whether biopsies and robust isolation protocols are available and on the other hand if robust differentiation protocols exist that provide cells mature enough to mimic the desired model functionality.

4.2. Biomaterials/Scaffold

Apart from the right choice of cell source, appropriate biomaterials to recreate a physiologically relevant 3D microenvironment are required. Physical and biochemical cues derived from the extracellular matrix (ECM) in vivo need to be emulated in vitro to guide assembly and functional maturation of the tissue. Just like cells, native ECM’s composition is organotypic and takes over organ-specific functions, among them (i) mechanical support and resistance to external forces, (ii) regulation of cell shape, and (iii) signal transduction.23 In an OoC, both scaffold-based and scaffold-free approaches are possible.24−26 In terms of scaffolds, hydrogels engineered from either natural or synthetic materials are most commonly employed. Both the integration of matrix producing cells as well as proper initial configuration have to be ensured to enable scaffold-free approaches.

Exemplification: Ideally, specific ECM components are produced and secreted by the cells directly on-chip, requiring, however, the integration of ECM-producing cell types. In this case, a biomaterial/scaffold only serves as a supporting structure, initially guiding the alignment and organization of the cells to form cell–cell and cell–matrix interactions and gradually being replaced by the native ECM. Critical for this approach, though, is that tissue formation timelines are in line with experimental time frames.

5. Cell Injection and Tissue Assembly

Important aspects to assembling the targeted tissues inside the microfluidic platform are cellular composition, tissue stratification, and geometry, as well as physiological cell density and cell to ECM ratio. Hence, for each individual platform, customized injection processes might be necessary. In general, they can be classified into bottom-up approaches (injecting single cell suspensions), building block assembly [injecting preformed organoids and/or spheroids (in addition to single cells)] or explant integration (injecting microfragments from biopsies) (Figure 2). Cells need to be arranged in a spatially defined manner, e.g., via compartmentalization of the platform and/or sequential cell injection processes, to achieve adequate tissue geometry and stratification. Lastly, with respect to cell densities, it is important to keep in mind that tissues in vivo typically consist of 1 billion to 3 billion cells/mL and are not lonely cells hanging out in an ECM hydrogel.27 Because the final aim is a tissue in a homeostatic state, it is moreover crucial to provide proper confinements to prevent overgrowth, in the case of proliferating cell types, or to generate high cell densities during the initial cell injection step, in the case of postmitotic cells.

  • Exemplification: Aiming for maximum flexibility to study, for example, the specific contribution of individual cell types or malfunctions to tissue function or pathophysiology, the bottom-up approach is the most suitable. It allows to selectively include/exclude or modify specific cell types and combine them in a mix and match fashion to tissues. The challenge this approach entails, however, is robustly guiding the self-assembly of single cells to form tissues with a physiological structure and possibly stratification.

Figure 2.

Figure 2

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Overview of possible strategies for the assembly of tissues in microfluidic platforms.

6. Assay Development (Culture Protocols and Readouts)

Because there is literally no value in setting up a model system without being able to properly monitor its function, the establishment of tailored readouts and the development of assays is of utmost importance. Hence, before conducting any experiment, it is crucial to establish a toolbox of readouts that builds the foundation for the high-content characteristic of OoCs. This encompasses both generic readouts to investigate, for example, cellular viability and morphology, as well as organ- and application-specific functional readouts such as barrier integrity, endocrine activity, or contractile forces. Moreover, readouts of different levels can be combined: (i) online (also frequently labeled as “in-line” or “in situ”) monitoring, usually implying noninvasive real-time assessment through optical interrogation or integrated sensors; (ii) at-line measurements, i.e., effluent analyses; and (iii) off-line measurements, occurring at the end of the process and usually involving invasive methods.

In parallel to the establishment of readouts, protocols for long-term culture will need to be optimized. This includes both biochemical aspects such as cell culture media composition, especially relevant when integrating different cell types, but also biophysical aspects such as perfusion rates.

  • Exemplification: Established readout methods, including commercially available kits, for instance, broadly used in conventional cell and molecular biology can be modified to OoC readouts. However, this transfer of protocols entails a careful consideration of cell number and/or volume ratios. The cell count on the chip as well as volumes of cell culture media are usually much lower than using traditional cell culture methods.

7. Functional Validation

The final step of the OoC development process is the functional validation: Only through a comprehensive characterization of the model’s capability to recreate in vivo functions and mechanisms as well as of its limitations, it is possible to build confidence in its predictivity and the translatability of results.12,28,29 This functional validation can encompass different types of case studies depending on its specific intended use, for example, (i) the assessment of its response to sets of training and validation compounds, (ii) the recapitulation of known physiological mechanisms and responses to defined stimuli, or (iii) the recreation of defined pathogenesis processes and pathophysiological responses. In addition to the validation of the function, it is crucial to also define the window of functional stability, i.e., the time frame during which studies can be conducted.

8. Applications

Lastly, after this comprehensive and interdisciplinary journey, the OoC model is ready to be applied under a defined context of use, for example, to tackle the specific scientific question it was designed to target. Depending on the modularity and flexibility of the chosen approach as well as the amount of data generated with and about it, the model may also be potentially “recycled” for a different context of use, provided it fulfils functional validation requirements.

Conclusion

The OoC technology merges approaches and concepts from various disciplines.30 Although this provides a great opportunity for innovation and novel solutions, it entails the complexity of a huge parameter space and challenging choices to be made requiring very different expertise. Hence, to ensure that your developed model is not only a nice technological toy but can actually make an impact, it is of utmost importance to (i) involve experts with different backgrounds in the development and (ii) always start with a concrete context of use for the model and keep it in mind for all choices throughout the journey. The past decade has seen multiple successful commercialization examples of well-developed models,5 and there is plenty of room and need for further success stories. At the same time, partially driven by the academic community, a strong push for standardization has been initiated.31,32 Although both commercialization as well as standardization are crucial for the future of the OoC technology, it is imperative to maintain flexibility to tailor models to make them fit-for-purpose and to provide space for continuous innovation.

Author Present Address

$ Division of Nanobiotechnology, KTH Royal Institute of Technology & AIMES Center for the Advancement of Integrated Medical and Engineering Sciences, Karolinska Institute, 171 77 Stockholm, Sweden

Author Contributions

† J.R. and K.S. contributed equally.

The authors declare no competing financial interest.

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