From life-saving vaccines to innovative stem cell therapies, there is a clear rationale behind projections of the global biopharmaceutical market reaching USD 1.6 trillion by 2028 (1). Scientific discovery and technological innovation continue to drive this growth, supported by 3 major categories of cell cultivation systems: microcarriers, microfluidic devices, and bioreactors. While each has evolved substantially since its early prototypes, their foundational operational principles remain largely unchanged.
Sustainable and responsible cell expansion is no longer just about the vessel, instead, system design is a convergence point for unresolved trade-offs. © Green Elephant Biotech.
Cell cultivation is a century-old discipline, with the first documented in vitro growth of cells attributed to Ross Harrison (2). By demonstrating that neuroblasts could be maintained outside of an animal body, this work introduced the concept of defined growth conditions — an idea that underpins modern cultivation systems.
Contemporary cell culture platforms therefore focus on a system’s ability to reproduce physiological parameters, including temperature (e.g., 37 °C), pH (e.g., 7.2), oxygen-carbon dioxide balance (typically 20% O₂ and 5% CO₂), and controlled shear stress. A wide range of stem cells and mammalian cell lines, such as Vero, human embryonic kidney (HEK) 293, and Chinese hamster ovary (CHO-K1) cells, have been cultivated using the systems discussed in this article. The intended scale and application of production ultimately determine whether microcarriers, microfluidic devices, or bioreactors are selected.
Despite rapid advances from proof-of-concept to standardized workflows among biopharmaceutical leaders, the full potential of cell cultivation technologies has yet to be realized. This limitation is most evident in the persistent difficulty of scaling out production without proportionally increasing operational complexity or costs (3). In the wake of CRISPR-Cas9 advancements and the manufacturing demands during the COVID-19 pandemic, the need for efficient and regulated cell production has never been clearer.
Not fit for industrial scale today, microcarriers have contributed to poliomyelitis vaccine development
In cell cultivation, microcarriers represent a relatively small-scale technology designed to support the attachment of adherent cells to the surface of artificial beads. At their introduction in the late 1960s, microcarriers were highly innovative, enabling a surface-to-volume ratio approximately 10-fold higher than that achieved with T-flasks or multi-tray systems (2).
Typically measuring 100-300 µm in diameter, microcarriers provide efficient nutrient diffusion and cell-cell interactions, resulting in increased cell yields. Their physical properties are critical design parameters, as matrix stiffness has been shown to influence cell behavior. For example, softer matrices better support neurons found in brain tissue, whereas stiffer substrates are more suitable for cells derived from mechanically rigid tissues such as bone (2).
While microcarriers effectively mimic aspects of the native cellular environment and often promote differentiation, their industrial application remains limited. A key constraint is the challenge of harvesting cells without inducing mechanical damage during bead separation, which restricts scalability and introduces variability between batches (3).
In regenerative medicine, however, microcarriers remain highly relevant. Biodegradable microcarriers have been explored in tissue restoration, where preservation of tissue structure and function is critical. For instance, embedding human adipose-derived stem cells within biodegradable microcarriers and administering them subcutaneously was shown to promote vascularized adipose tissue formation, offering therapeutic potential for chronic wound healing and soft tissue reconstruction (3).
Microfluidic devices and their operational features inspired organs-on-a-chip
Microfluidic devices — often referred to as miniature bioreactors (MBRs) — can be considered scaled-down analogues of conventional bioreactors. Their application is not limited to suspension cultures, as surface coatings and perfusion systems enable adherent cell attachment and maintenance under precisely controlled conditions. Advances in real-time monitoring and high-throughput automation have further increased their adoption in research and development settings (5).
One of the defining advantages of microfluidic systems is their capacity to generate physiologically relevant mechanical stimuli. Shear stress is precisely regulated through microvalves, enabling simulation of blood or lymphatic flow. Such mechanical cues play a critical role in determining cell morphology and function in vivo, particularly for endothelial and immune cells (5).
Compared to large-scale bioreactors, MBRs require significantly smaller reagent volumes and offer improved cost efficiency at the experimental scale. In one study, human pluripotent stem cells (hPSCs) achieved a 277-fold expansion within less than one week, largely attributed to the precise regulation of chemical gradients guiding differentiation (6).
However, the complex fluid dynamics that make microfluidic systems attractive at small scale are difficult to translate to industrial volumes such as 2,000 L. Mechanical wear of microvalves and localized system complexity further limit their scalability, presenting regulatory and operational barriers for large-scale manufacturing (5).
The majority of bioreactors resemble designs from 40 years ago, but change is on the horizon
Bioreactors were originally developed to provide stable growth environments and prolonged culture longevity, with early prototypes dating back to the 1940s. Since then, numerous configurations, including airlift, packed-bed, and photobioreactors, have emerged. Among these, the stirred tank bioreactor (STR), first tested with baby hamster kidney (BHK) cells in 1965, remains a cornerstone of industrial bioprocessing (7).
With working volumes reaching up to 25,000 L, STRs are widely adopted across biopharmaceutical and food industries. Although vessel composition varies by application, stainless steel remains the predominant construction material. While valued for corrosion resistance and mechanical strength, stainless steel is associated with low heat transfer efficiency and stringent quality control demands, both of which complicate cell cultivation processes (8).
Innovation in adherent cell bioreactors has progressed more slowly than in suspension systems. Established vessels readily support suspension cultures but lack inherent surfaces for cell attachment. Incorporating microcarriers introduces additional complexity, while single-use fixed-bed bioreactors provide attachment matrices at the cost of increased labor intensity (3).
Although bioreactors remain central to vaccine production and are increasingly used in cell and gene therapy manufacturing, current infrastructure is highly expected to evolve in response to growing demands for sustainability and accessibility. The integration of nano- and biodegradable materials represents one potential pathway toward meeting future compliance and environmental objectives (3, 8).
Across microcarriers, microfluidic devices, and bioreactors, a consistent theme emerges: each system encounters limitations when transitioning from experimental success to accessible production. While microcarriers excel at mimicking cellular environments, microfluidic devices enable system control at small scale. Bioreactors remain the pillar of the biopharmaceutical industry, but their fundamental designs have changed relatively little over the decades.
Looking ahead to 2026 and beyond, progress in cell cultivation will depend on redefining the adaptation of existing and novel platforms to enable meaningful automation and footprint optimization. Bridging the gap between physiological relevance, scalability, and operational efficiency therefore requires innovations in materials, system architecture, and workflow design.
Why wait for the old technologies to upgrade, when CellScrew® is available today?
Designed to accommodate anchorage-dependent cells, CellScrew® offers smaller footprint, easier handling, and homogeneous shear-force conditions additionally to the benefits of a conventional bioreactor. Instead of waiting for the incorporation of modern approaches, the CellScrew® system already uses them to streamline a range of workflows sustainably and responsibly.
Discover what Green Elephant Biotech has to offer today by exploring CellScrew® application notes and the bench-to-bedside showcase.
References:
- Biopharma will be worth $1.6tn in 2028, analysts predict. (2023). Diana Turner, DDW. Available https://www.ddw-online.com/biopharma-will-be-worth-1-6tn-in-2028-analysts-predict-25403-202308/#:~:text=Biopharma (Accessed 06 February 2026).
- Swan SY, Hairunnaja, A, Samsuddin, N, Mahmood, S, Aziz, MAA, Arifin, MA, A Review on the Development of Microcarriers for Cell Culture Application (2024), Pertanika JST 32, pp. 1939-62. doi: 10.47836/pjst.32.5.01.
- A Brief History of Adherent Cell Culture: Where We Come From and Where We Should Go. (2019). Alex Chatel, BioProcess International. Available https://www.bioprocessintl.com/bioreactors/a-brief-history-of-adherent-cell-culture-where-we-come-from-and-where-we-should-go (Accessed 06 February 2026).
- Li, B, Wang, X, Wang, Y, Gou, W, Yuan, X, Peng, J, Guo, Q, Lu, S, Past, present, and future of microcarrier-based tissue engineering (2015), J Orthop Translat 3, pp. 51-7. doi: 10.1016/j.jot.2015.02.003.
- Pasirayi, G, Auger, V, Scott, SM, Rahman, PKSM, Islam, M, O’Hare, L, Ali, Z, Microfluidic Bioreactors for Cell Culturing: A Review (2011), Micro Nanosyst 3, pp. 137-60. doi: 10.2174/1876402911103020137.
- Rajalekshmi, R, Agrawal, DK, Synergistic potential of stem cells and microfluidics in regenerative medicine (2025), Mol Cell Biochem 480, pp. 1481-93. doi: 10.1007/s11010-024-05108-8.
- Sharma, R, Harrison, STL, Tai, SL, Advances in Bioreactor Systems for the Production of Biologicals in Mammalian Cells (2022), ChemBioEng Rev 9, pp. 42-62. doi: 10.1002/cben.202100022.
- Stainless Steel Bioreactor Fermenter. (2025). Fermenter, BAILUN. Available https://fermentorchina.com/stainless-steel-bioreactor-fermenter/#:~:text=They (Accessed 05 February 2026).
