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Invest in Adherent Tide Motion Technology
for the Right Adherent Cell Culture Solution

Cell culture involves growing adherent cells in an artificially controlled environment for various biotechnological applications. Adherent and suspension cell cultures require optimized conditions for both nutritional (substrate or medium) and physicochemical requirements to achieve high product or cell yield. Adherent cell culture involves surface support for cell proliferation while suspension cell culture does not, as suspension cells grow free-floating in the culture medium.

Cell Nutrition

Cell Seeding

Cell Cultivation

Cell Attachment

Cell Harvesting

Cell Monitoring

Producing Stem Cells and Virus in Manufacturing Scale for Vaccines and Cell Therapy

Expansion processes for both stem cells and virus on 2-dimensional systems limit its potential to reach high product yield. These systems are enough for research and development scale which only caters to a small number of patients. As these applications evolve, bigger systems are required to achieve high amounts of virus and cells due to how these products are rather different but best when cultured in adherent.

Esco Healthcare’s TideXcell® Tide Motion bioreactor is designed to produce higher viral titers through its proprietary 100% media exchange and more than 90% stem cell harvest with the TideXcell® Harvesting System (TXLHS). This flexible technology provides cells with 3-dimensional in vivo environment, with extremely low shear stress and high productivity. With scalability of up to 100 L packed-bed volume, one can simply replace 100,000 pieces of flasks to save labor, time, and space requirements. TideXcell™ is available in both single-use or multiple-use technology with advanced, automated controls, equipped with pH, dissolved oxygen (DO) sensors, and sampling ports for cell monitoring and observation. This system is currently used worldwide for vaccine and cell therapy production, helping them bridge the gap of cell culture from discovery to delivery.

White papers for vaccine and viral production on Tide Motion bioreactors tackle the linearly-scalable capability of the technology for culturing adherent cells grown from bench-scale to TideXcell pilot scale bioreactor. This robust cGMP compliant platform allowed the production of higher viral titers and cells to break the barriers in cell manufacturing and cater to many patients.

The Tide Motion Technology

The term ‘Tide Motion’ is derived from the cyclical high rise and low rise of the bodies of water on earth. In bioreactors, this is the gentle upward and downward motion of the culture media for adherent cell aeration and nutrition exchange. This submerge and emerge principle allows cultured adherent cells to produce quality products that are of high yield.

The Principle
The Packed Bed
  1. Aeration Phase

    The cells atteched to the carriers are exposed to air

  2. Top Holding Time

    Determines how long the carriers will be exposed to nutrition

  3. Nutrition Phase

    The cells attached to the carriers are exposed to nutrition

  4. Bottom Holding Time

    Determines how long the carriers will be exposed to aeration

The Tide Motion Technology priniciple
The Principle
large surface
• Large Surface Area

5.5g of carrier is already equivalent up to 15,600 cm2 of surface area

(surface area varies depending on cell line morphology)
highest productivity
• Highest Productivity

5.5g of carrier can culture up to 2-3x109 VERO cells and 200 million mesenchymal stem cells (MSCs)

lowest downstream processing cost
• Lowest Downstream Processing Cost

Cells are fixed within proprietary BioNOC II® macrocarriers and are separated from the media. This makes cell harvesting or media harvesting much easier

the pack bed bionoc II
The Packed Bed

The Tide Motion Advantage:

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No Oxygen Limitation

Dual oxygenation action provides cells with ample oxygen regardless of the bioreactor scale.

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No Bubbling, No Foaming

Tide Motion bioreactors use separate vessels for culturing and stirring this isolating the cells being cultured from any form of bubbling or foaming.

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Immortal cell lines

Freezing cells in Go and G1 phase by nutrient starvation by deprivation of glucose to boost productivity of protein expression.

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Shortest bioprocess scale up development time

parameters developed in academic / industrial R&D can be easily translated into clinical trials and commercial production as parameters are identical and hence linearly scalable without complex scale up bioprocess calculations (as those found in Stirred tanks).

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Extremely Low Shear Stress

Gentle upward and download tide motion (2mm/s) provides nutrients and oxygen to cells without applying shear stress, perfect for shear sensitive cells. Minimizes impurities with host cell protein and DNA/RNA.

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Controlled cell growth (Batch mode)

Controlled cell growth during cell culture to promote productivity in batch mode via extending exposure time during tide motion without requiring additional feed control

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100% Continuous Processing > 3 months

Ideal for biosomilars/biobetters, monoclonal antibodies (MABs), and recombinant proteins. As cells are immobilized, cell retention devices which are typical for perfusion-based suspension cells such as Chinese Hamster Ovary (CHO) are not required to separate cells from media. This means no fouling, foaming, and scalability issues resulting from flow rate limitations of cell retention devices.

Tide Motion advantage icon
Large Surface Area

5.5 g of carrier (amount of macroporous carriers in 1 CelCradle bottle) is already equivalent to up to 15,000cm2 of surface area. These carriers mimic the cells in vivo state resulting in higher cell or product yield.

The Tide Motion platform is composed of two parts :

The Packed-bed

Anchorage-dependent cells require surface to adhere in order to grow. Culture vessels such as t-flask and roller bottles are typically used but the difficulty in scale up has led to the development of carriers. Carriers provide optimum environment for adherent cell culture. The advantages of carriers are ease of scale up, cost reduction from serum and culture media, minimum risk of contamination, and reduction of handling process. Carriers are used to grow virus-generating or protein-producing adherent cells in a large-scale commercial production of vaccines and biologics.

Carriers come in different shapes and sizes. Microcarrier beads are spherical in shape and suitable in stirred tank bioreactors. Another form can be in sheets or fibers which are used in packed-bed or tide motion bioreactors. A wide variety of carriers are available in the market with different physical and chemical properties. The choice of carriers depends greatly on the type of cells to be cultured as different cells have varying anchorage requirements.

The BioNOC II® is a macroporous carrier that supports the growth of anchorage-dependent cells including animal, mammalian, and insect cells in either serum-containing or serum-free culture media. It is made of 100% pure polyester nonwoven fabric manufactured according to cGMP guidelines. The special 3-dimensional design and surface treatment on the carrier enhance fluid mixing, immobilization efficiency, protection from shear forces, and nutrient transfer during cell culture. Adherent cells have larger surface area to grow without compromising equipment footprint (Figure 1).

A comparison dimension for bench-scale and manufacturing Tide Motion bioreactors for adherent cell culture.
Figure 1. A comparison dimension for bench-scale and manufacturing Tide Motion bioreactors for adherent cell culture.
The size of the unit remains but the number of carriers to be used can be changed (TideXcell®).

Media Reservoir

The media reservoir varies from one Tide Motion bioreactor to the other. The research and development scale, CelCradle® system both have the packed bed and the reservoir in the same vessel. For production or manufacturing scale, the TideXcell® separates the media reservoir from the packed bed (Figure 2). This solves scaling up issues regarding aeration exchange. Dual oxygenation is possible through exposing the carriers to air during aeration phase as well as the available dissolved oxygen in the well-mixed culture media (Figure 3). Aside from that, the separation allows dual temperature control, which is an important factor for some cell cultures to achieve high product yield.

tide motion principle

Figure 2. A diagram showing the difference in Tide Motion principle for bench-scale system versus manufacturing-scale system.

tide motion solution

Figure 3. The separation of the matrix vessel from the mixing vessel solved aeration issues when scaling-up to a larger system.

Tide Motion is a bioprocess method that solves the adherent scale-up problem and provides a single-use bioprocessing method with closed, automated cell harvesting from seed preparation (0.1 L packed bed volume) to production scale (5,000 L packed-bed volume - bioequivalence of 50,000 L in suspension) all in the same 3D Tide Motion (Figure 4).

JOIN THE TIDE

Tide Motion Linear Scalability

Why Join the Tide?

  • Ease of Usage - CelCradle® was designed to be used with basic scientific knowledge, good aseptic technique, good laboratory practice, like in normal static 2D culture (T Flasks, roller bottle systems, petri dishes, stacked planar culture) that provides higher cell density. It comes with simple caps like T-flask and easy parameter controls. For example, pH is controlled manually through adjusting the CO2 concentration inside the CO2 incubator. A wide variety of CelCradle bottles allows production of various adherent cell lines, viruses, and proteins.
  • LIMS - A simplified laboratory information and management systems (LIMS) allows ease of recording of data for DOE and eventual scaling up into TideXcell®.
  • Fully Single-use Perfusion Option with Closed Cell Harvesting
  • Portable and Intuitive - CelCradle® can easily fit inside a 6ft3 CO2 incubator for batch culture and 8ft3 CO2 incubator for recirculation culture. It has only two (2) parameters which can easily be optimized. The magnetic controller of the CelCradle® can be magnetized to the outer wall of the CO2 incubator, allowing parameter change without opening the incubator.
  • Technology Transfer Made Easy - CelCradle® uses the same principle as roller bottles, easily adapting whatever protocol or parameters are already established. Transferring from static culture like T-flasks or hyperstacks to CelCradle® is also just as easy. 
  • Flexible - Capable of doing batch, fed-batch and recirculation mode by simply changing accessories.
  • High Yield in a Small Footprint - One (1) CelCradle® bottle containing only 5.5g of macroporous carriers has a yield equivalent to twenty (20) 850cm2 roller bottles or one-hundred (100) pieces of 150cm2 T-flasks
  • 3D in vivo like Culture Environment - allows cell-to-cell contact and a large surface area to footprint ratio for culturing cells.
  • True Linear Scalability - CelCradle® is a 0.1L packed bed bioreactor that can easily be used for seed preparation for TideXcell™ bioreactor that scale all the way up to 5,000L packed bed volume production scale. This eliminates lengthy developmental processes and parameter optimization that are common in scaling up in microcarriers and/or suspension culture. Unlike other packed bed or hollow fiber systems, seed cells are not prepared in 2D and expanded in 3D, this is 3D to 3D
  • Isolator Capability - CelCradle® can be easily integrated inside an Esco Pharma isolator in case the application requires BSL3/4 environment or for autologous / allogeneic cell & gene therapy. Controls can be fully integrated into 1 common HMI with Esco BioVap hydrogen peroxide or biodecontamination system for 6 log reduction in bioburden and /or Esco Autoclave mounted on the side, Esco Centrifuges, Co2 Incubators, Peltier Blocks.
  • International support - Esco CelCradle® is sold & serviced globally by Esco’s 25 direct sales/service offices, factories and trained sales & service partners.
  • 3D in vivo like Culture Environment - allows cell-to-cell contact and a large surface area to footprint ratio for culturing cells.
  • True Linear Scalability - Same parameters are used from 0.1L packed bed volume lab scale for seed preparation, all the way up to 5,000L packed bed volume production scale. This eliminates lengthy developmental processes and parameter optimization common in scaling up in microcarriers and/or suspension culture. Unlike other packed bed or hollow fiber systems, seed cells are not prepared in 2D and expanded in 3D, this is 3D to 3D.
  • Closed Cell Harvesting System - TideXcell™ Cell Harvesting System (TXCHS) is a powerful, closed, automated system for harvesting viable cells from 2L to 20L TideXcell™ bioreactors with more than 90% recovery.
  • 100% nutrient exchange for highest virus titer - Media used for cell growth can be 100% pumped out as waste and 100 % new media is used after virus seeding for virus growth. This has higher yields for VLPs compared to stirred tank which new media can only be perfused in.
  • Hybrid System - Can be configured for either single use or combination of single use & autoclavable vessels.
  • Difficult Viruses - Parameters such as temperature, pH, and oxygen levels are automatically monitored and adjusted to cater specific virus requirements. TideXcell™ also has extremely low shear stress for stress sensitive viruses and is capable of harvesting using a closed automated harvesting system for non-secreted viruses.
  • Uniform seeding - Unlike other packed bed systems, single-use TideXcell™ matrix cassettes are designed and configured to allow even seeding within the packed bed.
  • Isolator Capability - CelCradle/ TideXcell™ can be easily integrated inside an Esco Pharma isolator in case the application requires BSL3/4 environment or for autologous / allogeneic cell & gene therapy. Controls can be fully integrated into 1 common HMI with Esco BioVap™ hydrogen peroxide biodecontamination or ammonia system for 6 log reduction in bioburden and/or Esco Autoclave mounted on the side.
  • cGMP References - TideXcell™ is used in current good manufacturing practice (cGMP) Facilities for both commercial human and animal vaccines that are certified to FDA, eucGMP, Japanese Industrial Standard (JIS), Pharmaceutical Inspection Co-operation Scheme (PIC/s) standards.
  • PAT/IPQC - Process Analytical Techniques (PAT) and In Process Quality Control (IPQC) via patented single use sampling method of BioNOC™ II allows IPQC for cell counting during production unlike other packed bed bioreactors which need to be dis-assembled during process development.
  • In Situ Configurable - batch, fed-batch, perfusion, continuous processing and parameters for low temperature, anaerobic/hypoxic conditions, single use/autoclavable as well as mixing, feed & harvest tanks with auto switch pumps can be easily configured in situ via Wonderware. These are easily programmed with minimal training without coding background.
  • SCADA enabled with 21 CFR part 11 compliance and CSV - Esco Healthcare factories globally in Singapore/USA/UK provide Supervisory Control and Data Acquisition (SCADA) or Distributed Control System (DCS) Configuration and deployment with computer system validation (CSV). We are well versed in DeltaV, Pcs7 by default SCADA system deployed on VacciXcell adherent single use platform is using Wonderware running on Siemens programmable logic controller (PLC). Siemens human machine interface (HMI) can be provided for standalone non-SCADA or non-multi-functional dedicated bioprocessing applications.
  • International support - Esco TideXcell™ is sold & serviced globally by Esco’s 25 direct sales/service offices, factories and trained sales & service partners
Esco Lifesciences Group
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