Bench Press

A few weeks ago I wrote a post about the development of the Standoff Patient Triage Tool, an impressive use of lasers in order to make health critical readings of patients from a distance. Well one of the best things about science is that many people can utilize the same tools to come up with unique methods and solutions for any given problem. In this case, researchers have used lasers to develop a technology that could someday revolutionize imaging procedures in medicine.

Photoacoustic imaging of melanoma in vivo.

Photoacoustic tomography is the basis behind a new imaging technology being developed in hopes of providing more flexible and cost effective devices for physicians. The technique takes advantage of ultrasonic emissions produced when a non-ionizing laser pulse is directed towards a tissue. The emissions, resulting from transient thermoelastic expansion of the target tissue due to absorption of the laser energy, are detected and analyzed with various algorithms to construct an image (2D or 3D) of the targeted area. This differs from the reliance on the doppler shift produced by the reflected laser beam in the SPTT.

Images of vasculature like the one seen on the right can be produced by using photoacoustic tomography without the injection of contrast as differences between the molecular composition of the target can be used instead. In the example to the right, the difference between oxygenated and deoxygenated blood is an effective natural contrast. Photoacoustic tomography also presents other benefits over traditional imaging techniques as explained by The Economist:

CT scans also involve potentially harmful ionising radiation. And MRI and CT scans are very expensive, using machines that cost millions of dollars and require dedicated staff to operate them. Photoacoustic tomography, by contrast, could eventually be performed using portable hand-held devices, similar to those used for ultrasound scanning. This would allow doctors to diagnose and monitor patients in clinics, and reduce the need to refer them to consultants.

The adaptability of this nascent technology is also impressive as researchers are already looking at using it to detect specific ailments such as brain lesions and cancer. In the case of cancer, the ability to accurately image vasculature could allow doctors to monitor patients for the development of new blood vessels (angiogenesis) a hallmark of cancer development.

While there are some issues to work out with this new technique, such as the lack of imaging depth (ultrasound signal emitted is reduced the deeper the tissue lies) and ultrasound distortion from varying tissue types within the human body (e.g. bone vs muscle), photoacoustic imaging is a very promising new technology.

(Source)

Today modern medicine provides patients with numerous drugs for an enormous number of health issues. For example, getting relief from a headache can be as simple as popping open a bottle of aspirin and swallowing a couple pills. While to the patient the delivery of the drug begins and ends with swallowing those two pills with a glass of water, to the scientists working on the drug that’s simply the beginning of numerous steps that hopefully result in a drug surviving the trip through the body to it’s intended target and doing it’s job.

Drugs are therefore designed not just to solve a problem but to survive the human body’s natural mechanisms. The gauntlet of obstacles that a drug faces upon entry into the body is a major reason why many researchers continue to look into innovative techniques for delivering pharmaceuticals.

That’s where research being conducted by Drs. Stefan Franzen and Steve Lommel comes in. Working with the red clover necrotic mosaic virus (RCNMV), Drs. Franzen and Lommel have developed a potential revolutionary drug delivery platform.

Figure 1. Production of Drug Vector

Drs. Franzen and Lommel take advantage of a 17 nanometer space within the 38 nanometer icosahedral capsid of RCNMV in order to store therapeutics. The RCNMV infused with the drugs could then be used to deliver the drugs in a cell specific manner with the addition of targeting peptides.

The preparation of the drug carrying virus is elegant in it’s simplicity and produces a robust delivery mechanism (See Fig 1). First RCNMV is treated with EDTA to open pores in the capsid. Next therapeutics are infused through these open pores. The pores are then sealed with Ca²⁺ which is key in releasing the drug later upon viral entry to the cell. The prepared virus can then be purified via dialysis followed by adding target specific peptides.

The elegance of using Ca²⁺ to seal the pores lies in the fact that the human bloodstream is abundant in calcium. Inside cells, calcium levels are much lower, allowing the pores to open up thereby delivering the infused therapeutics only when the target cell has been entered.

In vitro work with Doxorubicin, a cancer drug, infused RCNMV shows promising results (see Fig 2.) promoting apoptosis only when provided with targeting peptides allowing the drug to be delivered to the interior of cells.

Figure 2. Delivery of Doxorubicin RCNMV to HeLa cells

A potential application of this research is in cancer treatment. Current chemotherapy treatments often result in dramatic side effects as the drugs do not distinguish between diseased and healthy cells. While these results are probably still years from resulting in a commercial therapy it provides hope that in the near future doctors will be able to prescribe chemotherapy treatments with dramatically reduced side effects thanks to target specific delivery of the drugs.

(Sources: NCSU – results. , NCSU News , Franzen Presentation – Plant Virus Nanotechnology)

Having read and watched a fair amount of science fiction during my formative years, I’ve always been enamored with the concept of nanobots being used within the human body to help maintain our health. While the reality of microscopic machines moving to normally inaccessible areas of the human body and performing life saving tasks is still decades away, researchers led by Professor James Friend at Australia’s Monash University have demonstrated a proof of concept piezoelectric ultrasonic motor that could be a crucial step in providing locomotion for the nanosurgical robots of tomorrow.

In the abstract of their paper they describe their concept as:

A motor for in vivo microbot propulsion is presented with a stator diameter of 250 µm, demonstrating the potential to directly drive a flagellum for swimming at up to 1295 rpm with a torque of 13 nN m. The motor uses coupled axial-torsional vibration at 652–682 kHz in a helically cut structure excited by a thickness-polarized piezoelectric element.

Piezoelectric ultrasonic motors like the one designed by the team are built to harness special materials that exhibit the piezoelectric effect. Materials like lead zirconate titanate, thanks to the piezoelectric effect, are capable of producing electricity when stress is applied as well as the converse, producing stress when an electrical field is applied. This effect is already used in a variety of everyday applications, such as electric guitar pickups as well as auto-focus in reflex cameras. The motor (seen below), called the Proteus, designed by Friend’s team is made up of three main components: the piezoelectric element, the stator, and the rotor.

The team began to design the Proteus by utilizing computer models (seen below) to produce a novel robust stator design. They determined a helically cut stator would serve best in transferring stress and turning the rotor. The group hopes to improve their model in future work by incorporating further criteria and motor components.

After utilizing computer models to design the stator a prototype was fabricated for physical tests. Various tests were run to ascertain the potential of the Proteus. The group’s tests are promising as they found the “output power [is] on the order of what is necessary to navigate small human arteries.” In addition to the promising power output, the stator design is currently “70% smaller than the smallest design produced so far”.

While the design of a small motor is still just a small first step towards in vivo swimming surgical nanobot I can’t help but think about the possibilities this innovation will lead to. Maybe Professor Friend can contact Dr. Gracias at John Hopkins about working on a swimming microgripper next.

All graphics and quotes from:

B Watson, J Friend and L Yeo 2009. Piezoelectric ultrasonic resonant motor with stator diameter less than 250 µm: the Proteus motor. Journal of Micromechanics and Microengineering.

One thing great about basic biology research is that so much cool and inventive technology is built around trying to peer into the depths of how organs, tissues, and cells work their mojo. A lot of times, the best stuff is built around microscopy and imaging, because seeing is pretty much believing. And beautiful pictures make scientists just as happy as it does everyone else.

There’s an imaging technique that’s been emerging over the last ten or so years called imaging mass spectrometry, which can tell you where a whole bunch of different molecules are in tissue all in one go! Basically, you take a slice of the tissue you want to image, apply a chemical resin to it (which is called a “matrix”), and then you shine a fairly strong laser at the tissue. This causes a physical reaction in which the resin absorbs the laser, ionizes, and causes molecules from the tissue to get ejected into the air. The mass spectrometer then sucks those ejected molecules into its cavernous depths and weighs them, breaks them apart, and then weighs their fragments to try to identify what the molecules are. For proteins, this identification process is actually quite easily done.

What you end up with is a really remarkable picture, a 2D map of where a range of different molecules are in the slice of tissue. You can look at the distribution of molecules of different specific weights across the entire slice. By stacking images of adjacent slices, you can then reconstruct an approximate 3D map of where molecules are in a tissue, like a brain or a tumor. Pretty neat!

A section of a mouse brain imaged for molecules of various weight (from Stoeckli et al. (2001) Nature Medicine 7, 493–496.)

Up until now, there have been two main ways to see macromolecules like proteins and RNA in biological tissue. First, you can look at where a specific macromolecule is by sticking a fluorescent dye to it and looking for that “tag.” It’s a great technique, but it’s also pretty laborious and limited in scope, because you can only examine at most three or four things at a time or the colors will start overlapping together a little too much to reliably distinguish what you’re looking at. In addition, you have to know what molecules you’re interested in first in order to tag them.

Second, you can look at cells as a whole using high energy techniques like transmission electron microscopy (TEM), which uses beams of electrons to “X-ray” cells. Since electrons have a very short wavelength, that means that they can be blocked and scattered even by very small structures, including groups of proteins, which means that a TEM image can look at a lot of things with an insanely high amount of detail. Unfortunately, electron microscopy won’t really tell you what you’re looking at, though there are a few techniques (like sticking gold beads to stuff you’re interested in) that try to get around that. Nonetheless, it doesn’t tell you much besides the overall “visual” picture.

Imaging mass spectrometry gets over a lot of these hurdles of traditional microscopy by directly associating molecular weights with specific coordinates in a tissue sample. And because the mass spectrum measures a wide range of weights, a computer algorithm can potentially tease out patterns that might not have occurred to a researcher or doctor looking for a few things at a time. The amount of information that can be obtained from a simple mass spectrum image is tremendous. With newer, cheaper super-accuracy mass spectrometers coming out, such as the orbitrap, this technology is growing in popularity outside of specialized physics labs, and it promises to revolutionize the way a lot of science and medicine is done. In the clinic, for example, a ton more information could come out of a biopsy all at once using this technology, from identifying cancer markers to positively identifying infectious agents and inflammation. I look forward to what’s coming in the future!

Part of why I became so interested in science as a kid (apart from watching Bill Nye) was seeing the application of science in medicine. Seeing the development of new medicinal techniques thanks to innovative research made a lasting impression on me. I guess that’s why a level of childhood excitement tends to pop up when I read about things like new imaging technology and future surgical innovations.

A schematic of Dr. King's cancer filtering concept. E-selectin attracts the cancer cells thereby exposing them to TRAIL as they "roll" along the device wall. This triggers the cancer cell's death. Image: Kuldeep Rana

Once again I felt that childhood excitement popping up as I read about a new device being developed by Dr. Michael King and his group at Cornell designed to someday remove cancerous cells from a patient’s bloodstream. King’s device takes advantage of a well studied mechanism of our immune system which is the recruitment of white blood cells to blood vessel walls with adhesion molecules known as selectins. Since selectins recruit cells based on specific carbohydrates Dr. King realized that this adhesive property could be utilized for slowing down cancer cells in order to target and destroy them.

After slowing down the cancer cells to a “roll” the cells can then be exposed to a protein called TRAIL (Tumor Necrosis Factor Related Apoptosis-Inducing Ligand) resulting in the release and then the apoptotic death of the cancer cells. This makes King’s device more than a simple sieve as he explains, “It’s a little more sophisticated than just filtering the blood, because we’re not just accumulating cancer cells on the surface”.

King’s device is impressive in it’s simplicity and tests of the device’s efficacy appear promising.

King’s research showed that the device can capture and kill about 30 percent of cancer cells flowing past it a single time, with the potential to kill more in the closed-loop system of the body. Used in combination with traditional cancer therapies, King said, the device could remove a significant proportion of metastatic cells, “and give the body a fighting chance to remove the rest of them.”

The team also showed that a system in which the cancer cells “roll” over the target molecules – presenting their entire surface to the molecules – is four times more effective than a static setup in which the cells and proteins make contact at a single point.

Of course as excited as I am to see this type of work being done, as Dr. King points out moving his concept to the clinic may take many years. I’m looking forward to reading the paper in Biotechnology and Bioengineering and seeing what others will come up with from Dr. King’s work.