Towards a Human Body on a Chip - Part III

Creating a human body on a chip is the dream of some researchers. In the first part of this series, I talked about the lung on a chip device and how we can improve the current drug development model by building those organ on a chip devices. Combining the chips to create an ultimate human body on a chip platform will speed up the drug development progress, end drug testing on animals and make drug testing more reliable. The second part described some of the ongoing problems with these device and how they can be solved. In the last part of this series, I will focus on the current status of this research. What has been done so far? How far are we into commercializing these products? What's left to do?

Which organ on a chip devices are out there?

The most-advanced organ on a chip device is currently the lung, developed by scientists at the Wyss Institute. Another device created by the same scientists is the gut on a chip (shown below). This chip is made of PDMS (a flexible polymer commonly used in microfluidics) and features microfluidic channels. In the image below you see two different colored fluids running inside the channel and exiting on the bottom. The structure of this chip is very similar to the lung on a chip developed by the same group. It has two channels (red and blue), one is running on top of the other one. In between there is a horizontally aligned porous membrane lined with real human intestinal epithelial cells. On the side of the colored channels are two chambers which can be pressurized in a cyclical motion to mimic the digestion happening in our body. These two are the most advanced organ on a chip devices out there. Scientists are also working on creating artificial muscles to mimic the movement in the heart, as well as on organs like the kidney, liver and bones.

Gut on a chip device
Image courtesy: Wyss Institute

Who is investing in the human on a chip?

In July 2013, DARPA (Defense Advanced Research Projects Agency, USA) announced a $37 million grant for the Wyss Institute at Harward for the development of an array of organ on a chip devices. The Wyss Institute has already developed a lung, as well as the gut on a chip device above. Further projects will include the heart, liver and kidney. Furthermore, they are developing chips that will mimic the human skin and muscles. The NIH (National Institute of Health, USA) also funded several researchers all over the country to develop organ on a chip devices. Their total funding amount was $13 million. The European Union is also funding a Switzerland based company, called InSphero AG with €1.4million for 3 years (starting June 2012). InSphero is focusing to solve the 3D structure implementation of the cell cultures, one of the main problems of current devices (see part II).

What is left to do?

To create a human body on a chip, several organs have to be fabricated, including the lung, heart, bones, kidney, liver, gut (see below). Other devices of interest are the skin, arteries and muscles. Ultimately, all of these single device will be connected via tubes to each other to form the human body on a chip. 

Concept for the human body on a chip.
Image from: D.E.Ingber, Trends in Cell Biology (2011) 21, 12, p. 745-754

Challenging and complex organs like the heart have not been fabricated in full detail yet. It will still take some years to form a complete human body on a chip, but more and more parts are ready to be commercially available and already help transforming the drug testing method. It will be incredible and exciting to follow this development.  

Towards a Human Body on a chip - Part II

Is the revolution among us?

This is part II of the series about how we can accelerate the current drug development strategy by building a human body on a chip. The current drug development model is mainly based on animal testing and intensive clinical studies afterwards. Testing new drugs on animals is not only an ethical issue, but also faces crucial problems, as animals are similar to humans but do not react quite the same on new drugs than we do. Therefore, many scientists focus on designing a human body on a chip which can simulate parts of the body without the need of animal testing. By combining microfluidic chips (see my intro to microfluidics) that features the function for parts of our body, like the lung, the gastrointestinal tract or the heart, new drugs can be tested on human like models. In my last entry, the lung on a chip was described, check out the post. 

How far along are we with organ on a chip device?

Some of you might think that it is still a long way to go until these chips are being used for real applications. You're wrong! This revolution is already among us. In January, researchers from the Institute of Bioengineering and Nanotechnology (IBN) in Singapore have announced that they are partnering with Johnson and Hoffman La-Roche, two big pharmaceutical companies to produce and test the first commercially available liver on a chip. The liver is an important organ for the dug development, as this is the stage where all drugs are being detoxified. Harmfull substances will be reduced, however if a drug is toxic to the body and can't be detoxified by the liver, the human is in danger. Therefore, it is crucial to test new drugs on the liver to see the effect of it's toxicity.

What are the main problems?

One of the main problem in designing organ on a chip devices, is to replicate the important functions of the organ in very great detail. Especially the cells are of importance, as these interact with the drug and determine if the drug is good or bad for your body. The problem with cell cultures in a lab is that they are usually grown in a petri dish, this is a round plastic dish with a gel (called agra) which includes all the nutrients necessary for the cells to survice and grow happily. However, these cells are grown on a flat substrate, that means they can not grow as a cell network (3D) in all directions possible and therefore might not behave like they would in an organ. The researchers from IBN solve this issue by using a foam like structure, called hydroxylpropyl cellulose, which is a FDA approved materials and the building block of cotton and paper. Liver cells can naturally grow within the 3D structure of the material and therefore act more like they would in a real liver.

Sony invests in organ on a chip development

One more thing on the side note to convince you further that these organ on a chip are a promising tool for future drug testing. Yesterday, Sony announced that they are partnering with the Wyss Institute at Harvard University to develop new organ on a chips. The lung on a chip, described in my last post, was developed by researchers from the Wyss Institute. 18 months ago, Sony started to invest in life-science companies, especially those working in microfluidics and life-science technology, e.g. Micronics. The development towards the human body on a chip is definitely a very fascinating and exciting route to follow. 

Towards a Human Body on a Chip - Part I

How can we accelerate the current drug development model?

Before a pharmaceutical company will test a new drug on humans, it is most commonly tested on small animals. However, these animals may not react on the drug the same way as humans do. It would be much more reliable to test theses drugs directly on humans, but this would be too dangerous as the not yet approved drug might harm the person.

To overcome these issues, researchers are developing human-like systems to mimik parts of our body, like the lung, human intestine or a kidney. These device are called body on a chip or organ on a chip. The major technique behind these chip is microfluidics (check out my post on microfluidics to get a nice intro). One can see these chips as building blocks for something bigger. The aim of this research area is to connect the devices together to create a human on a chip, a human-like working system which is able to mimik parts of our body for drug testing purposes. This way we might even eliminate the use of animals for drug testing to avoid ethical issues. In my next few posts, I will introduce body-on-a-chip platforms which have been developed already and will explain how they work. I would like to start with a very important organ, our lung.

How can you mimik a human lung?

The lung is the crucial respiratory organ in our body. It's main function is to bring fresh oxygen from the air you breath in to the blood and get rid of carbon dioxide or other waster gases that your body does not need when you breath out. In June 2010, researchers from the Wyss Institute at Harvard have developed the very first lung on a chip. The microfluidic device is made using a flexible see-through polymer. The device features one main channel in the center which is divided by a thin membrane into two parts (see picture below). The membrane has small holes inside to let oxygen and other particles flow between the two compartments. On the top side of the membrane, lung cells are attached to the membrane whereas on the bottom side, human capillary cells are attached. Air flows through the top part and human blood through the bottom part. The two channels labeled "vacuum" on the sides are pressurized periodically and will deform the center channel to mimik breathing. 

Principle of the lung on a chip device.
Image courtesy of the Wyss Institute. 

What can you test with a lung on a chip?

The testing spectrum of the lung on a chip device is wide. For instance, one can analyze the influence of environmental pollutions on the lung. One can also model diseases which occur in the lung to see how a drug is affecting the lung cells and how it is healing the system. One major advantage is the transparency of the device, as you can see in the image below. The lung function can be directly monitored under a microscope in real-time. Traditionally, a biopsy is needed in order to see the direct effect of a drug on the body.  

Actual microfluidic lung on a chip device.
Image courtesy of the Wyss Institute. 

With this lung on a chip, pharmaceutical companies can directly test their drugs on a human like lung without the need of testing it on animals. The current drug development model is in a crisis, as it costs millions of dollar and takes many years to pass a drug from the animal testing phase to the human trial phase. The animal model is poor and most of the drugs fail the human test. The lung on a chip device could prevent animal testing and would allow the pharmaceutical companies to directly test on a human model which would be less time-consuming, much cheaper and eliminate the use of animals for testing. 

Nano in your Daily Life

Nano became a major trending label in the beginning of the 21st century. Nowadays, you see socks, packages, food, cars, mp3 players, etc. labeled with nano. Nano sells! I want to show you what’s the science behind some of the major nano labels. For this, let me first describe to you very quickly what nanoparticles are and why they are so beneficial.

What are Nanoparticles?
Nanoparticles are small structures with a diameter of 1-100nm. At this length scale, some materials have different properties than in their bigger bulk material. Because these particles are so small, the surface area per volume is much higher. Most reactions usually happen at the surface of a material, therefore, a higher surface area means more reaction happening. Nanoparticles are actually not an invention of the modern world. These particles were around since a long time. However, nowadays these particles are trending and a good selling label.

What are Socks with Silver Nanoparticles?
There are many brands who offer socks enhanced with silver particles. But what exactly do these silver particles do? These silver nanoparticles can kill many different types of bacteria and therefore the smell from your socks. Silver nanoparticles are not only added to the fabric of socks or underwear, but also to food packaging, cosmetics, tooth brushes and even bandages.

Why add Titanium Dioxide to Sunscreen?
Most of the available sunscreens contain titanium dioxide nanoparticles (TiO2) or zinc oxide (ZnO). These specific nanoparticles are added to sunscreens as they block ultraviolet (UV) light very efficiently. Usually, the higher the blocking factor of your sunscreen, the whiter the sunscreen appears. However, if you shrink the size of titanium dioxide to the nano size, these particles are transparent and can therefore be added to light sunscreens without the thickening white effect.

Are Nanoparticles dangerous?

There is a strong debate whether particles are harmfull to your body or not. Many believe, that due to their small size they can enter into parts of your body, where you do not want to have any other materials. One can not say that nanoparticles in general are dangerous, as these properties differ very strongly among different types. There is a lot of research going on to measure the effect of nanosized particles to our bodies and environment. But don't worry, most countries have very strict regulations about putting nanoparticles into the market. 

Writing with Atoms

How can you see single atoms?
Atoms are the building blocks of every cell and every material. An atom is only about 0.3 nm in diameter. To “see” these atoms, you have to use special microscopes. The most famous one, is the AFM (Atomic Force Microscope), which I briefly described in my first post. This technique basically feels the atoms underneath it with a very very sharp tip, ideally so sharp that there is only one atom at the tip. The tip (called cantilever) is scanning slowly over the whole surface and creates a topographical image. Below you can see salt at atomic resolution. Each "dot" is one single atom, isn't that just amazing?

Salt (NaCl) atoms under an AFM.
The frame size is 5nm.
(Image taken from: Jessica Topple)

Who wrote with atoms first?
The first amazing demonstration and milestone of modern nanotechnology, was the fact that one can write and manipulate single atoms. This was first archived by Don Eigler from IBM in 1989. He successfully managed to arrange 35 Xenon atoms to write the famous letters "IBM" (see image below). This was realized with an STM (Scanning Tunneling Microscope) tip. An STM works very similar to an AFM, the main difference is, that the tunneling current between the tip and the sample is controlled and kept constant. With an AFM, the force between the atoms are measured therefore it works on non-conducting materials as well. 

IBM logo with 35 Xenon atoms. (Image taken from IBM) 

How do you write?

Don Eigler, who was the first to ever write with atoms, used an low-temperature ulta-high vacuum (UHV) system (check out my other post on Extreme Science). This system is required in order to have a super clean environment with no other disturbing atoms and to reduce the vibration of the atoms by lowering the temperature. The trick now to move an atom across the surface is to get very close to the atom with the STM tip. At some point, a positive van der Waals attraction between the atom on the tip of the STM and the atom to be moved is created, the atom is attached to the tip. Now by keeping this distance short, the atom can be moved to a different location. Once at the correct position, the STM tip just needs to be moved away from the atom and it stays put. In only 22 hours, the first IBM logo written with single atoms was created.

Why is it important?

First of all, it's fun and amazing! Second, it was the first ever approach for nanometer scale manipulation. Third, you can now move atoms to where you want them to be to create new structures.

Since then, many more universities, institutes and companies all over the world created atomic sized versions of their logo. Here are some cool examples:

Image by: NIST, USA

Image by: Technische Universität München, Germany

Image by: University of British Columbia, Canada

The Wonderful Adventure of a Small Little Tiny Drop

What is microfluidics?
As explained in my first post, nanotechnology is all about reducing size and discovering new phenomena. Scaling down the volume inside a channel filled with water is no exception to this rule. Microfluidics is all about fluidic structures with a volume of about 1 microliter (as a comparison: one drop of water has a volume of approximately 60 µl). One main characteristics of microfluidics is that inside the channels, there is a so called laminar flow. This means the flow is not turbulent like we usually see a water stream. If you turn on your faucet and water flows out, you’ll see a lot of turbulences, this doesn’t happen with microfluidics. It’s incredible hart to mix two fluids in a microfluidic channel, as can be seen in the image below. Although different colored food-dye runs from separate channels into one big channel, it does not mix, it rather flows side by side. Mixing only occurs after a while due to diffusion. This main phenomenon of microfluidics can be tricky to handle, but also super useful.

Turbulent (left) vs. laminar flow (right)
(Image by: J. Schulze and D.B. Weibel)

How do you design a microfluidics device?
The most common material used for microfluidics is a polymer called polydimethylsiloxane (short PDMS). It is a viscous solution and will harden upon placing into an oven. Lets discover how you can create a simple channel (0.05 mm wide, that's 50 µm) with an in- and outlet. First, prepare a master mold of your structure to pour the PDMS into. This is done by spin coating a thin layer of a photoresist (which is a lightactive solution which will harden upon illumination) onto a wafer. Next, a photolithographic mask of your desired channel structure is illuminated onto the photoresist. This will harden the desired structure. The rest is washed away and one is left with a negative of your channel. Finally, PDMS is poured onto the master, cured in the oven and simply peeled of your master. Punch two holes into, one for your in- and one for your outlet. Because the channel is open on one side, the PDMS is bond to e.g. a glass substrate and you're done It's that simple!

Taking it to the next level
Because it can be that simple to fabricate a microfluidics structure, several people are using microfluidics to handle small sample volumes, reduce costs and be able to fast fabricate these devices. Several applications do exist on the market or are promising candidates for market ready device. Most of them are in the field of biosensing. As explained before one can detect a disease in a smaller volume more easily and most importantly less costly. However, microfluidics devices do not only have one straight channel and that's it. Rather it can get really complex. You can integrate all sorts of features like pumps and mixers. Hundreds of in-/outlets, valves and channels can be integrated into one microfluidic chip.

Valve in action, closed position (left) and
open position (right)

What is paper microfluidics?
One really awesome application platform is the so-called paper microfluidics. These devices are simply made from paper, no PDMS, no glass etc. On a paper the outer lines of your channels are printed with a hydrophobic solution, i.e. liquids will avoid these areas and therefore stay within your desired channel configuration. One of the first of these structures is shown in the image below and used for glucose testing for people having diabetes. These devices are easy to use, disposable and very cheap. More and more applications are coming out of these paper based microfluidics, like body-on-a-chip, lab-on-a-chip and organ-on-a-chip devices (which I will cover in more detail in one of my next posts).

Paper microfluidics to test the glucose level in urine
(Image by: Whitesides, Harvard)

Microfluidics meets art!

Now sit back and enjoy these beautiful microfluidic art pieces. Doesn't they look just amazing? Science can be so great.

Images taken from (in order top to bottom): 

Albert Folch, Michael Roukes, Stephen Quake, Albert Folch, Ann-Lauriene Haag

Extreme Science

Why do we care about ultra, micro, high and fast?
Science is trying to push human knowledge a bit further every day. In science you can find people working with extreme conditions to push these limits and gain an even deeper knowledge about fundamental science. To be able to know what happens in fundamental processes, you have to push these limits. Here, I want to walk you through some of the main extreme sides of research in physics and try to explain why we care about them.

Nano 
As this blog focuses mostly on nanotechnology, let’s start with that extreme. Trying to work on smaller and smaller length scales opens up a whole new dimension and possible discoveries. Why? If you want to study or manipulate single atoms or molecules, you have to work in the nano scale, which is a hundred thousand times smaller than the width of a hair.

One of the four huge detectors at CERN. In the centre
is the actual beamline (image: CERN). 

High-energy
One of the most famous example of high-energy physics is the large hadron collider (LHC) established in 2008 at Cern in Geneva, Switzerland. This massive huge ring underneath the surface is accelerating protons, the positive charged particles in an atom, to energies up to 7 Teraelectronvolt. The energy is so high that two protons are accelerated in the ring to almost near the speed of light, to be precise it's 99.9999991% of the speed of light. The protons travel in opposite directions in this ring and at some point they collide. Detectors like the one in the left image are recording these collisions. Why? The purpose of the LHC is to discover new particles. Once the two protons collide, they will break into smaller particles  One specific particle, the Higgs-Boson is of special interest, as this is supposed to be the particle giving mass to all other particles.

Low-Temperature

Many experiments on single atoms are performed at low temperatures. Temperature is a measure of how fast atoms move. If the temperature of e.g. water is above 100°C it will boil, the movement of water molecules is so strong that it will become a gas. If the temperature is below 0°C, the atoms do not move that much anymore and ice is formed. The absolute zero for the temperature is -273.15°C (or 0 Kelvin, the temperature unit system used most commonly in science). At this temperature, atoms do not move any more. However, it is really difficult to reach this zero value. Most low-temperature experiments usually run at the milli Kelvin scale, which is 1000 times colder than 1 Kelvin (-272.15°C), so already pretty cold. Why? Because the atoms almost do not move anymore, you can measure them very precisely. It's like taking a picture of moving object, it's so much easier to take a sharp image of still objects. You can study quantum mechanical effects e.g. to better understand how to improve quantum computers. 

Typical UHV set-up

Ultra High Vacuum (UHV)

In my last blog, I talked about cleanrooms. An UHV system is like an even better cleanroom on smaller scale. However, you can not enter a UHV system, as there is almost no air in there, only the samples are inside. For a vacuum in the range of 10^-11 mBar, one atom has to travel for about 7000 km to collide with another particle. In practice, one atom is hitting the wall of the chamber much earlier than any other particle. It’s amazing how few atoms are in the whole system. It is also amazing to see how these UHV systems look like. Usually, you'll find a UHV system covered with a huge amount of aluminium foil and cables hanging everywhere. ;-) Why? In a UHV system, one can study atomic structures without ANY other unwanted particles. As explained before, it's like the ultimate cleanroom. 

If you want to know more about these individual techniques, subscribe to my blog. See you soon.