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Sophia Chen (2019), Synchronized Swimming Under The Microscope, The International Society for Optics and Photonics
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What different methods have scientists used so far to manipulate the motion of microbots and bacteria? What do you think are the positives and negatives of these methods?
One of the main methods used so far is using light to steer the microbots. Optical methods are advantageous because light has different properties that you can adjust to allow for more control over the microswimmer, for example, frequency and polarisation. Additionally, optical materials are generally softer and more similar to biological tissues so they are able to can mimic the natural environment and are easier to make biocompatible. Optical microswimmers can also have self‐regulatory autonomous behaviour depending on the environmental stimuli. However, the motion range using this technique is limited to the size of the light focus. Light also has a very short penetration depth - limiting its use in the human body. Another possible method is using magnetic fields to manipulate the microbots. Magnetic methods of actuation are generally able to produce faster motion and greater force outputs than optical methods. Furthermore, magnetic fields are able to penetrate deep into the medium you are using the microbots in, making this method very promising for medical applications. However, magnetic materials are very dense making it difficult to create neutrally buoyant microswimmers. Magnetic microrobots are also unable to be self‐autonomous because they always need an external magnetic field control. Microbots can also be driven acoustically, using sound driven pressure points. Researchers at the Max Planck Institute for Intelligent systems used this method of microbot actuation and managed to create a propulsion force two to three orders of magnitude stronger than the propulsion force of natural microorganisms such as bacteria or algae. As with magnetic fields, this method has promising medical applications because it can safely penetrate deep into the medium. However, this method is typically ineffective for addressing individual structures, as the acoustic fields do not have selectivity to the manipulated objects.
How could synthetic microbots and hijacked biological cells be used? Are there differences between them?
Synthetic microbots and hijacked biological cells could be used to deliver drugs directly to a specific site in the body, such as a malignant tumour. Additionally, they could be used to make intricate incisions in a tiny surgical operation. Since these microswimmers are on a microscopic scale - around the size of specks of dust - if controlled accurately, this could result in very precise medical treatment. Microswimmers can also be used to push blocks on a platform; thus, they could be used to create autonomous light-sensitive microsystems such as valves, pumps, mixers, cooling devices, and liquid lenses.
A difference between the two types is that researchers are able to bypass some synthetic technical challenges by hijacking natural cells that have undergone millions of years of evolution. Over time, these cells have developed efficient, precise machinery that can carry out their functions much better than artificial alternatives. But this can also result in more unknowns for scientists: for example, researchers don't fully comprehend some organisms' biology, as sometimes they move towards light, and other times away. This means that the response process is not yet understood fully. With synthetic microrobots, it is easier for scientists to understand what each component is and what function it has.
What issues can you foresee within the field of microswimmers?
One issue is that of the human immune response to these especially as they have not yet been tested in environments similar to the human body in most cases, and possibly the difficulty in controlling their movements in the human body using light, for example- one reason given for the choice of electric and magnetic fields previously was due to how easily they could penetrate human tissue. Another issue would also be their safety, both for synthetic and biological microswimmers, if released on a large scale into the ocean for example, and their effect on aquatic life.
Although microswimmers could be used to greatly advance the field of medicine, they still haven’t gone under in vivo trials and there is a possibility that the technology could be used maliciously, so we shouldn’t be overly optimistic. When it comes to testing the technology in vivo, we should consider that the bloodstream is a very complex area, and is full of salts, proteins, and other particles that would interact with the robots. Given that as of right now trials of microswimmers have been with simple mediums such as a mixture of water and lutidine, the next step would be to try to test the technology in more complex mediums. Once the in vivo trials are underway, and we can successfully manoeuvre microswimmers in the bloodstream, we should consider whether some patients may reject these specimens in their bodies, as well as how the microswimmers will be disposed of in the body. If they are injected in large numbers, it is still probable that small numbers will separate from the main group and move to other parts of the body. The question also arises whether this technology could be used maliciously. If this becomes mainstream medicine, surely it would be easy to use the microswimmers as a toxic drug delivery system, where they could easily access the body through mediums such as the water supply?
Below are some of the summaries provided of the linked articles in Sophia's piece on microswimmers.
Molly's summary of: Phototactic Algae-Driven Unidirectional Transport of Submillimeter-Sized Cargo in a Microchannel. Micromachines, 10(2), p.130.
This study used a species of green microalgae, known as Volvox carteri, as microswimmers to move and manipulate objects less than a millimetre across. The algae V. carteri was selected because it demonstrated positive phototaxis, so could be controlled by light, and exhibited a swimming force of approximately 1nN. The researchers demonstrated that colonies of V. carteri could be controlled using a green LED (λ=525nm) as approximately 50% of total colonies migrated towards the lit LED. They also demonstrated the one-way transport of a block using the same mechanism. The authors envision that with technologies such as these light-controlled micro motors, we could see the development of fluidic valves, pumps, mixers, drug-delivery devices and more.
Angelika's summary of: Dynamic density shaping of photokinetic E. coli. eLife, [online] 7.
In 2018 scientists realised that they could steer groups of genetically modified bacteria using a light projector and by changing the projected pattern, they directed millions of bacteria to arrange themselves into microscopic portraits. This relies on the connection between density and local speed of bacteria. Proteorhodopsin, a protein extracted from free-swimming micro-organisms in the ocean, is an energy source that helps this bacterium move. The protein is located close to the surface of the cell, where it acts like a solar panel and converts light into energy for motion, the intensity of incident light determining the swimming speed (brighter light causes faster movement). Similarly to cars in the city, bacteria in motion tends to accumulate in areas where their speed decreases – where they are hit with lower intensity light. Therefore, Proteorhodopsin can be used to manipulate the local density of bacteria by projecting different light patterns, accumulating bacteria into images of the Mona Lisa, Albert Einstein, and Charles Darwin. Frangipane and his team of researchers also investigated an alternative strategy to produce static patterns of bacteria: biofilm lithography. In this method, an optical template of blue light is used to attract membrane proteins that promote cell-cell and cell-substrate attachment, which can also create images; however, unlike the density shaping technique, this one is static and forms over several hours. It is rather interesting that the two techniques can be used in conjunction for even faster and more complex three-dimensional images. Other than creating amazing images, a potential useful application of dynamic density shaping of photokinetic bacteria is to build new strategies for transport and manipulation of small cargoes inside microdevices.
Yen Li's summary of: Orthogonal navigation of multiple visible-light driven artificial microswimmers, Nature Communications, 1438 (8).
In this paper, the authors first briefly discuss existing methods used to control microrobots, including a magnetic or electric field. The disadvantages of these methods were that the field affects all microswimmers, making it very difficult to control individual robots independently of others in the group. However, the authors then go on to show an alternative method of controlling the microswimmers: using different-coloured dyes to code each robot separately. The robots were Janus nanotrees with titanium dioxide nanowire branches and a silicon trunk. To stain the robots, they were placed in a solution of dye for five hours in order to complete the absorption process, and three different samples of nanotree were created (sensitive to either blue, red or green light). With the branches acting as an anode and the trunk as a cathode, the unbalanced distribution of ions propelled each microswimmer. The microswimmers travelled at peak speed, indicating peak efficiency, at the specific wavelength corresponding to the colour of the dye they were coded for. Thus, the authors proved that the robots’ response to light was determined by the absorption spectrum of the dye on the nanotrees.
James's summary of: Self -propelled particles that transport cargo through flowing blood and halt haemorrhage.
Addressing the problem of uncontrolled bleeding, scientists have formulated self propelling microparticles that can be injected into wounds carrying clotting agents to the source of blood flow stemming blood loss. The propulsion and delivery mechanism is relatively simple, using calcium carbonate microparticles mixed with an organic acid a vigorous neutralization reaction is triggered generating lots of carbon dioxide bubbles which carry microparticles with them upstream. Biological agents can be readily attached to these microparticles such as active thrombin which trigger the clotting process. Scientists first tested this out by cutting off mice tails then applying the calcium carbonate attached with thrombin with organic acid solution to the site of the wound then repeated this process by rupturing pigs major arteries to see if the system still worked for more traumatic works. This yielded positive results as 7/9 mice stopped bleeding after 10 minutes and all 5 pigs treated survived the procedure whereas the control group weren’t so lucky.
Joshua's summary of: Phototaxis of synthetic microswimmers in optical landscapes
Synthetic microswimmers are able to be moved and propelled with a light gradient and the use of lasers. Many microorganisms such as bacteria and algae respond to external chemical or optical gradients and when reorientation of the microorganism occurs, they are propelled and move. Synthetic microswimmers were made from half-coating silica particles with carbon and they are placed into a binary critical mixture of water and lutidine where the spheres can propel themselves because when the laser illuminates the sphere, it is only absorbed by the carbon cap which results in a concentration gradient as the lutidine and water separate. In order to balance the gradient, the liquid moves along the sphere from its transparent side to the carbon-coated part and this resulting flow of liquid propels the sphere.
Jared's summary of: Diffusing Wave Paradox of Phototactic Particles in Travelling Light Pulses
One of the problems found with hijacking organisms for use as microswimmers is that they sometimes don’t react exactly as they want us to, because they have their own survival interests intrinsically programmed into them which can make them display complex behaviour patterns. This idea is addressed in this paper: the “diffusing wave paradox” is the display of a complex behaviour of an organism, where in the presence of traveling chemical waves, organisms such as amoebae migrate counter to the running wave. This suggests that the organism has a directional memory, so that it can locate possible food sources around it for energy. This paper addresses this particular behaviour and tries to recreate the behaviour with synthetic microswimmers in the laboratory, in the hope of improving the efficiency of migration of microswimmers so that one day it may be used in the bloodstream.
Instead of chemical waves, the researchers use slowly travelling laser beams for light pulses, and they deploy phototactic microswimmers which consist of a sphere which is half-coated in carbon. By using laser beams which have a maximum in intensity at the centre and then decrease in intensity at either side, it was possible to deploy a series of beams that were moved across the area with microswimmers, providing laser pulses. It was found that when the speed of the laser pulse is a lot less than the maximum speed of the microswimmer, all the microswimmers are displaced with the pulse, as it is a strong source of light and does not move faster than they can. When the speed of the laser pulse was around the same as the maximum speed of the microswimmers, they travelled in both directions, but mostly against the direction of travel of the laser pulses – evidence for the diffusing wave paradox. When the speed of the laser pulses was a lot greater than the maximum speed of the microswimmers, no significant changes in the position of the particles were observed.
The article then provides an explanation for the phenomena observed. The authors used a microswimmer which consisted of a sphere half coated in carbon, and when light is shone on it, it would move in the direction of the side without carbon. When the laser pulse passes the sphere, it starts to rotate to try and get back to the height of the beam, but the rotation requires a strong turning force to do that in the short period of time. The only way for the particle to stick to the maximum would be to slow the laser pulse down. It is also found that the torques are affected by the diameter of the particle, and with increasing pulse width, the displacement counter to the pulse motion becomes weaker and eventually vanishes, as the particle has more time to rotate. This new data will help with designing microswimmers that can use this behaviour pattern to navigate.
1. What is a microswimmer?
An object that is in the micrometer size range (1-10micrometers) that can propel itself or be steered externally. It’s an object that exists at the nanometer-micrometer level but is controlled, in some sense, by humans.
2. What are the advantages to using light to direct microswimmers over something like electric or magnetic fields?
Light is more tunable – you can alter its wavelength or its polarisation – and so you can transmit more ‘instructions’ via light. Equally, you can use the multiple channels of light to give different instructions to different microswimmers, whereas an applied electric/magmetic field would tend to affect all of the microswimmers similarly.
3. How does Jinyao Tang use light to steer microswimmers?
They first coat different microswimmers in different coloured dyes. Each different coloured microswimmer then has a different response to particular portions of the EM spectrum e.g. the red-coated swimmer responds more strongly to red light. Whilst all of the swimmers still have some response to all wavelengths of light, the strongest response is reserved for the swimmer of the corresponding colour.
4. How does Jinyao Tang use light to power microswimmers?
Light is used as the trigger to initiate chemical reactions between the components of the microswimmer and the surrounding liquid. Tang’s simple microswimmer somewhat resembles an arrow – a silicon shaft with titanium bristles at one end. The light stimulates the silicon and the surrounding liquid to produce negatively charged (hydroxide) ions, whilst the titanium bristles react with the liquid (on absorbing light) to produce positively charged (hydrogen) ions. The attraction between these oppositely charged ions brings them towards each other, and the effect of this within the surrounding fluid is to pull the swimmer forwards (due to the shape of the ‘arrow’).
5. Why is swimming at the microscale different to the macroscale?
At the macroscale, when humans swim through water, we interact with billions of particles at once, simply pushing against them to swim forwards – it’s a very classical picture. At the microscale, a swimmer isn’t interacting with a liquid as one continuous body, instead it’s small enough to have more complicated interactions with the molecules. Even if we consider the microswimmers as classical objects, as their size is much more comparable to the size of a water molecule, it is difficult to ‘flow’ through them. It would be like humans trying to swim through a ball pool. And then, on top of this, there are the complex interactions that may occur between the swimmer and the molecules that we can ignore at the macro scale.
6. What are the advantages of using ‘chassis from nature’ and starting with biological cells?
These cells have already developed the ability to swim effectively at the micro-scale.
7. “Some algae, for example, can move more than ten times their body length per second, which is more than a speeding car can do on the highway.” Find values and perform calculations to prove/disprove this statement.
A typical car has a length of 4m. To travel 10times its length in a second means travelling at 40m/s. To compare this to the speed of a car on a ‘highway’ (motorway), we need to convert it into km/hour (or miles per hour).
40m/s = 0.04km/s = 0.04x60x60 km/hour = 144km/hour (=90miles per hour). This is definitely speeding.
8. What is phototaxis? Give examples.
When an organism moves in response to light. Positive phototaxis occurs when an organism moves towards light, negative phototaxis occurs when an organism moves away from light. Moths show positive phototaxis, flying towards sources of light. Jellyfish can show positive or negative phototaxis – a lack of light may incite them to move away (due a predator causing a shadow) and they may move towards a light source to find part of their food source (photosynthesising single celled organisms).
9. How do Chlamydomonas manage to respond to light?
They have an eyespot which acts like a camera. On light hitting the eyespot, chemical reactions lead to the release of ions. Any movement of charge (ions have positive charge) is a current, and this electrical signal (just like those flowing through our own neurons) can trigger the flagella of the Chlamydomonas to move either towards or away from light.
10. What unanswered questions are there surrounding microswimmers and their eventual use within the human body?
We don’t yet understand what makes certain materials stick to bacteria – this affects what we could transport with bacteria and where we can send them. We also don’t understand why certain organisms move towards or away from light. Light acts to both orient cells and provide a source of energy – we don’t know how organisms switch between these uses. We also need to understand how the microswimmers will behave amongst the many different molecules within our blood, for example, which contains a huge number of different cells and molecules – all of which are in motion.
11. Describe the process behind the movement of Celia Lozano’s spheres.
Lozano’s spheres are transparent silica half-coated in carbon. Light will naturally interact different with the transparent and opaque portions of the sphere. The darker side will absorb more light, creating a temperature gradient across the sphere. The increased temperature on one side leads to a greater amount of separation between individual molecules in the surrounding fluid. The resulting concentration gradient in the surrounding liquid leads to movement of the liquid particles past the sphere which act to propel the sphere.
12. “To make a microscopic particle respond to light, it just needs to be asymmetrical in some way.” Analyse the truth behind this statement using example microswimmers from the article.
Lozano’s spheres are asymmetric as one side is coated and the other isn’t. The different coloured dyes used on Tang’s swimmers give them a semblance of asymmetry as they then respond differently to different colours of light. Tang’s other artificial swimmer has an asymmetric shape with bristles at one end of the shaft – the chemical reactions that occur are also asymmetric in the charges they produce which leads to motion. Simmchen and colleagues attached small silicon dioxide spheres to one side of e-coli bacteria to create an asymmetry.
Remember, reading a paper isn't like reading a piece of fiction or a newspaper article. Don't get frustrated if it doesn't immediately make sense - you might need to do a little research of your own to understand some of the ideas. This article gives you an idea of how scientists read differently.
Each question refers to a specific part of the paper e.g. Page 2, Column 3 is written as (P2, C3).
Next week, we'll publish solutions to the questions and the best submitted summaries from students across the country.
We'd really like to hear about any topics/article you'd like to look at over the summer so please email in any suggestions you have for new aspects of physics that you'd like to look at!