Posted on by Dr. Francis Collins
Nanoparticles hold great promise for delivering next-generation therapeutics, including those based on CRISPR gene editing tools. The challenge is how to guide these tiny particles through the bloodstream and into the right target tissues. Now, scientists are enlisting some surprising partners in this quest: magnetic bacteria!
First a bit of background. Discovered in the 1960s during studies of bog sediments, “magnetotactic” bacteria contain magnetic, iron-rich particles that enable them to orient themselves to the Earth’s magnetic fields. To explore the potential of these microbes for targeted delivery of nanoparticles, the NIH-funded researchers devised the ingenious system you see in this fluorescence microscopy video. This system features a model blood vessel filled with a liquid that contains both fluorescently-tagged nanoparticles (red) and large swarms of a type of magnetic bacteria called Magnetospirillum magneticum (not visible).
At the touch of a button that rotates external magnetic fields, researchers can wirelessly control the direction in which the bacteria move through the liquid—up, down, left, right, and even “freestyle.” And—get this—the flow created by the synchronized swimming of all these bacteria pushes along any nearby nanoparticles in the same direction, even without any physical contact between the two. In fact, the researchers have found that this bacteria-guided system delivers nanoparticles into target model tissues three times faster than a similar system lacking such bacteria.
How did anyone ever dream this up? Most previous attempts to get nanoparticle-based therapies into diseased tissues have relied on simple diffusion or molecular targeting methods. Because those approaches are not always ideal, NIH-funded researchers Sangeeta Bhatia, Massachusetts Institute of Technology, Cambridge, MA, and Simone Schürle, formerly of MIT and now ETH Zurich, asked themselves: Could magnetic forces be used to propel nanoparticles through the bloodstream?
As a graduate student at ETH Zurich, Schürle had worked to develop and study tiny magnetic robots, each about the size of a cell. Those microbots, called artificial bacterial flagella (ABF), were designed to replicate the movements of bacteria, relying on miniature flagellum-like propellers to move them along in corkscrew-like fashion.
In a study published recently in Science Advances, the researchers found that the miniature robots worked as hoped in tests within a model blood vessel . Using magnets to propel a single microbot, the researchers found that 200-nanometer-sized polystyrene balls penetrated twice as far into a model tissue as they did without the aid of the magnet-driven forces.
At the same time, others in the Bhatia lab were developing bacteria that could be used to deliver cancer-fighting drugs. Schürle and Bhatia wished they could direct those microbial swarms using magnets as they could with the microbots. That’s when they learned about the potential of M. magneticum and developed the experimental system demonstrated in the video above.
The researchers’ next step will be to test their magnetic approach to drug delivery in a mouse model. Ultimately, they think their innovative strategy holds promise for delivering nanoparticles carrying a wide range of therapeutic payloads right to a tumor, infection, or other diseased tissue. It’s yet another example of how basic research combined with outside-the-box thinking can lead to surprisingly creative solutions with real potential to improve human health.
 Synthetic and living micropropellers for convection-enhanced nanoparticle transport. Schürle S, Soleimany AP, Yeh T, Anand GM, Häberli M, Fleming HE, Mirkhani N, Qiu F, Hauert S, Wang X, Nelson BJ, Bhatia SN. Sci Adv. 2019 Apr 26;5(4):eaav4803.
What are genome editing and CRISPR-Cas9? (National Library of Medicine/NIH)
Sangeeta Bhatia (Massachusetts Institute of Technology, Cambridge, MA)
Simone Schürle-Finke (ETH Zurich, Switzerland)
NIH Support: National Cancer Institute; National Institute of General Medical Sciences
Posted on by Dr. Francis Collins
The object in the image above might look like an ordinary plastic tube. But this tube is neither plastic nor ordinary. It’s a bioengineered replacement human blood vessel that could one day benefit people who receive kidney dialysis or undergo coronary bypass surgery.
It’s called a human acellular vessel (HAV), and an NIH-funded team, led by Heather Prichard, Humacyte Inc., Durham, NC, grows these acellular vessels. They can run up to about 16-inches long with a diameter of 0.2 inches, which is well within the range of a human blood vessel.
Prichard and team start with a lightweight and biodegradable polymer mesh. They then seed the mesh scaffold with cells taken from human donor tissue within a 3D bioreactor system in the lab. The system is specially designed to provide nutrients and mechanical pulsations similar to those present in an intact human circulatory system.
After incubating the growing vessels for eight weeks, the researchers remove all the living cells, leaving behind mostly human collagen, a fibrous protein and major structural component of a blood vessel wall. It forms a non-living, replacement vessel that retains the physical and mechanical integrity of a human blood vessel. But, because these HAVs don’t have cells, they potentially can be surgically implanted into any human patient without risk of an immune reaction.
As reported recently in Science Translational Medicine, the best part is what happens after an HAV is implanted into the body . The patient’s own cells infiltrate the HAVs. Over the course of many weeks, these cells produce multiple layers of living tissue to transform the acellular HAV into a functional, living blood vessel.
So far, HAVs have been tested in more than 240 people with end-stage kidney failure. The HAVs were implanted into the upper arms of participants and remained there from 16 to 200 weeks while these patients underwent dialysis three times per week to filter waste products from their blood. The early results indicate these bioengineered blood vessels were safe and fully functional. More research, though, will be needed to ensure that’s indeed the case.
For people who receive kidney dialysis, doctors now typically access the vasculature by linking an artery to a vein under the skin of the arm, making an “AV fistula.” But doctors can also use the HAV tube to make the needed connection.
What’s potentially game changing about HAVs is they offer the same “off-the-shelf” ease of a plastic tube but with the advantages of living tissue. Those advantages include the ability to fight infection and self-heal from the inevitable injury that comes with repeated needle pokes.
Though most of the work to date has focused on people undergoing kidney dialysis, an ongoing clinical trial is testing the potential of HAVs to improve blood flow when surgically implanted into the legs of patients with peripheral arterial disease . Prichard also sees potential for HAVs in heart surgery. For example, HAVs might be useful during coronary bypass surgery to repair a narrowed or blocked blood vessel. They could also be used to replace blood vessels damaged or missing due to congenital defects or traumatic injuries. Not bad for an object that looks like an ordinary plastic tube.
 Bioengineered human acellular vessels recellularize and evolve into living blood vessels after human implantation. Kirkton RD, Santiago-Maysonet M, Lawson JH, Tente WE, Dahl SLM, Niklason LE, Prichard HL. Sci Transl Med. 2019 Mar 27;11(485).
 Kidney Disease Statistics for the United States. National Institute of Diabetes and Digestive and Kidney Diseases/NIH
 Humacyte’s HAV for Femoro-Popliteal Bypass in Patients With PAD. Clinicaltrials.gov
Hemodialysis (National Institute of Diabetes and Digestive and Kidney Diseases/NIH)
Tissue Engineering and Regenerative Medicine (National Institute of Biomedical Imaging and Bioengineering/NIH)
Humacyte (Durham, NC)
NIH Support: National Heart, Lung, and Blood Institute
Posted on by Dr. Francis Collins
This might look a bit like a fish net, but what’s actually caught in this image is the structure of the endothelium—the thin layer of cells lining your blood vessels that controls the flow of molecules in and out of the bloodstream. The red lines are the actin filaments that give each endothelial cell its shape, while the purple are proteins called cadherins.
Most of the time, the actin “ropes” and cadherin “glue” act together to form a tight seal between endothelial cells, ensuring that nothing leaks out of blood vessels into surrounding tissue. However, when endothelial cells sense an infection or an injury, the cadherins open gaps that allow various disease-fighting or healing factors or cells present in the blood to breach the barrier and enter infected or injured tissue. After the infection subsides or wound heals, the gaps close and the blood vessel is once again impenetrable.