ORGAN-ON-CHIP

Organ-on-chip (OOC) or organ-on-a-chip (OOAC) refers to a microfluidic chip which enables the culture of cells mimicking some of the key functions of a living organ.  Microfluidic chips can contain microporous membranes to facilitate multi-cellular cultures and connecting microchannels which may be lined with a particular cell type and facilitate the delivery of nutrients, drugs or even model blood flow.  

 

One of the main applications of organ-on-chip is as a predictive tool for drug discovery.  Traditional cell-based toxicity assays (i.e. "tissue culture") are problematic in predicting drug toxicity because, very often, cultivated cells do not retain their original organ functions and morphologies when taken out of the context of intra-organ connection and interactions.  

For many years, the drug discovery industry has relied on animal testing which is not representative of the true in vivo situation.  If organ-on-chip systems are capable of providing models that truly mimic a human organ and are commercially available at a reasonable cost, then there is a possibility that they could also eliminate animal testing.

In the last 10 years, the development of different organ-on-chip models has exploded with numerous examples of lung-on-a-chip, heart-on-a-chip, kidney-on-a-chip and so on.  Cellix provides researchers with microfluidic solutions to get their organ-on-chip model up and running or organ-on-chip kits with microfluidic chips to get you started.

HOW DOES IT WORK?

Microfluidic chips are used to culture cells.  These chips are connected to microfluidic pumps via cell culture bottles (or other sample reservoirs) and flow sensors to ensure the precise delivery and flow control of culture media and other reagents to the cells in the microfluidic chip.

Organ-on-chip set-up:  using 1 channel

  • 1 x 4U Microfluidic pump (connected to vacuum and PC for SmartFlo control)

  • 2 x Culture bottles (1 for culture media and 1 for waste)

  • 1 x Flow Sensor

  • Microfluidic chip suitable for organ-on-chip studies (VenaT4 or Vena8 Endothelial+)  

  • Tubing & connectors.

The culture bottle from which the culture media is drawn (pulled by vacuum) has one inlet open to CO2 environment in the incubator.

Organ-on-chip Experimental Set-up.jpg

Organ-on-chip set-up:  using 4 channels

  • 1 x 4U Microfluidic pump (connected to vacuum and PC for SmartFlo control)

  • 8 x Culture bottles (4 for culture media and 4 for waste)

  • 4 x Flow Sensors

  • 1 x Microfluidic chip suitable for organ-on-chip studies (VenaT4 or Vena8 Endothelial+) or 4 x organ-on-chips.

  • Tubing & connectors.

Each of the 4 culture bottles from which the culture media is drawn (pulled by vacuum) has one inlet open to CO2 environment in the incubator.

Organ-on-chip Experimental Set-up.jpg
 
 

EXAMPLE EXPERIMENTAL SET-UPS:

WHAT DO I NEED TO GET STARTED?

We can provide you with a complete set-up (Organ-on-Chip Kit) or just the components you need.  Click here to see some example experimental set-ups.

In general, as a minimum, you will need the following to execute Organ-on-Chip experiments:

  • Microfluidic Chip or "Organ-Chip": These "organ-chips" are designed to mimic the physiological conditions and mechanical forces that cells experience in vivo.  Microchannels of chips can be lined with cells, such as endothelial cells in our Vena8 Endothelial+ biochip.  Or cells from different organs can be grown in separate chambers, such as the transwell chamber in our VenaT4 biochip, where connecting channels enable delivery of media, blood, or cell suspensions facilitating cell adhesion, transmigration and invasion assays under shear flow conditions.  Some researchers make their own chips with different geometries:  chambers with interconnecting channels that facilitate the delivery of both liquids and air, e.g. for lung-on-a-chip models.  

  • Microfluidic pumps: these provide the delivery of culture media to grow your cells in your chip; that is, culture your organs-on-chip.  Microfluidic pressure pumps are a good choice for organ-on-chip experimental set-ups as they can deliver both liquid and air samples, ensuring flexibility if you wish to study or develop lung-on-chip models. We recommend our 4U Pressure Pump which enables independent control of 4 different channels, controlling both pressure and flow.

  • Flow sensors:  required for active feedback of the flow control.  If you need to precisely control the flow (not just the pressure), then you need flow sensors.  They  protect against false readings due to pressure build-up (e.g. from bubbles in your channels).  Flow sensors will keep your experiments on-track ensuring the precise delivery of correct sample volume the your organ-on-chip.

  • Sample Reservoir:  this holds the culture media to feed your cells. Once your cells are cultured, reservoirs can be used to deliver drugs (concentration curve experiments), or to flow a cell suspension through your organ-on-chip.  Sample Reservoirs include:

    • Cell Culture bottle.

    • 15mL Falcon or Sarstedt tubes.

    • Eppendorf tubes.

  • Tubing & connectors.

Organ-on-chip Experimental Set-up:

Connect 4U pump to sample reservoir & flow sensor.

 

APPLICATIONS OF ORGAN-ON-CHIP

  • More predictive drug discovery:  disease target identification, drug efficacy and toxicity.

  • Alternatives to animal testing:  organs-on-chips support the 3Rs - "Reduce, Refine, Replace" with respect to animal testing.

  • Development of novel treatment modalities.

  • Personalised medicine: organs-on-chips tailored to an individual patient.

  • Disease models:  cancer, cardiovascular diseases, immunological diseases, skin diseases, neurological, and complex genetic diseases can all be studied with a variety of organ-on-chip models.

APPLICATION VIDEOS

 

CELLIX TOP TIPS - Resolve common challenges with Organ-on-Chip Set-ups

There has been huge progress in the field of organ-on-chip in the last number of years, however there are still some challenges to be overcome.  They are broadly divided into two areas:  Biological and Technical.  Biological challenges include sourcing induced pluripotent stem cells (iPSCs), appropriate organ scaling, vascularisation of tissues and inclusion of immune components. Here, we will focus on the technical challenges and what Cellix can do to help resolve some of the issues you may experience with organ-on-chip set-ups.

1. Plug & Play Tubing with Connectors for ease-of-use & to maintain sterility: Despite advances in microfluidics, joining the macro world to the micro-world is still not easy.  This is mainly because most organ-on-chip systems are connected to external pumps via tubing and connections with multiple connection points which can be cumbersome to connect and are often a source of contamination due to disconnecting and reconnecting.

Cellix's top tips:

  • Always wear gloves when assembling and connecting tubing and connectors.

  • Avoid multiple connection points - this will reduce potential contamination points.

  • Use autoclaveable tubing and connectors.

Cellix recommends Kima Tubing Kit autoclaveable 8-way connections or our single-inlet assembled tubing with connectors.

Cellix's Kima Tubing Kit is a reusable, autoclaveable 8-way connection from your microfulidic pump to your chip and from your chip to waste.  The spacing between the pins is 4.5mm (SBS standard distance between wells on a 384 well-plate) so it may be easily integrated with SBS standards including robotics.  The 8-way outlet tubing with connectors enables easy collection of culture media thereby reducing manual pipetting and handling - a source of potential contamination.

Cellix also has single inlet/outlet tubing assembled with connectors to facilitate direct connection to one inlet/outlet of an organ-on-chip system.  These tubings and connectors are also autoclaveable and plug-and-play for easy connection with no dead volume.  .

2. Avoiding bubbles: avoiding bubbles is still a problem.  If they are large and move (travelling through the tube into your organ-on-chip), they can potentially ruin an entire experiment.  They can push out cells that have seeded and are culturing in your chip, washing away your entire experiment.

Cellix's top tip:

Prime (or 'wet') the tubing and inlet pin/connection before connecting to your chip:  Bubbles are usually introduced into the chip at the start of the experiment and can potentially ruin an entire experiment.  To avoid bubbles, using your microfluidic pump, pump your liquid (e.g culture media) through the tubing from the sample reservoir (e.g. cell culture bottle) ensuring until you see a droplet on the outlet pin of your tubing.  This ensures that all the air is pushed out of your tubing and your fluidic path to your chip is "primed".  You should also visually check the tubing to ensure there are no bubbles collected inside.  

Priming tubing to avoid bubbles.jpg

Priming tubing before connection to organ-on-chip:

Ensure droplets have formed at the pins

3. Flow rate differences between platforms:  Flow control is a crucial element of organ-on-chip experimental set-ups and most organ-on-chips connect to external microfluidic pumps.  Pressure pumps, such as Cellix's 4U or UniGo pumps, are a popular choice for organ-on-chip systems as they can facilitate long-term cell culture in microfluidic chips via connection to a large cell culture bottle and they have the flexibility of pumping both liquid and air samples.  However, pressure pumps alone will only read the pressure within the organ-on-chip system.  So if a microchannel in your organ-on-chip becomes blocked, the resistance changes, and the flow rate will be reduced (or increased if a seal is broken and there is a leak).  This means the flow rate and sample volume will be incorrect!

Flow Sensor_2.jpg

Flow sensors ensure accurate delivery of the correct sample volume.

Cellix's top tip:

Use a flow sensor!  To ensure precise flow control, connect your pressure pump to a flow sensor and keep the distance between the flow sensor and your organ-on-chip as short as possible.  This ensures that the active feedback measured by the flow sensor is measuring exactly what's happening at the chip level - always delivering the correct flow rate and sample volume.  Flow sensors are calibrated by liquid type (e.g. aqueous flow sensor for culture media) and flow range.

4. Different flow rates required by different organ systems:  Like the organs they represent, different organ-on-chip systems have different flow rate requirements.  This becomes trickier for models that integrate different organ-on-chip systems, e.g. integration of a lung-on-a-chip system with a heart-on-a-chip system.  To model these systems, researchers require pumps that have independent channel control.

Cellix's top tip:

Use 4U (4-channel) pump with flow sensors:  Cellix's 4U pump can simultaneously and independently control 4-channels giving the user great flexibility. 

4U 4-channel Pressure pump.jpg

4U (4-channel) Pressure Pump

5. Drug adsorption and binding to PDMS microfluidic chips:  PDMS is still the material of choice for many researchers to explore their different models.  However, the surface of PDMS is highly hydrophobic, binding many of the drugs and compounds that are introduced into your organ-on-chip system. This can lead to incorrect results for example, for drug concentration curves for your organ-on-chip.

Cellix's top tips:

  • Coat with BSA:  this will block all non-specific binding sites.

  • Plasma-treat your chip:  usually only lasts a short time but should be long enough for your experiment.

  • Coat with inert polymer.

 

RECOMMENDED PRODUCTS

Microfluidic Pressure Pumps.jpg

4U Pressure Pump

Droplet Generation - Microfluidic Pressu

UniGo Pressure Pump

Pump Accessories.jpg

Flow Sensors

VenaT4_edited.jpg

VenaT4 Biochip

 
 

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