Dozens of star-shaped mini machines, freed from their pill’s casing as it dissolves in stomach acid, sweep into the patient’s small intestine. As these devices, each the size of a dust mote, pass deeper into the jejunum, body heat starts to melt the paraffin wax holding their six arms in place. Like a starfish gripping its prey, the arms snap shut, latching onto the intestinal wall with a viselike grip. A springlike mechanism in the machine, constructed of metal and flexible film, now engages, puncturing the tissue and painlessly injecting a drug dose directly into the patient’s bloodstream.

This revolutionary method of drug delivery would avoid the need to inject medication subcutaneously — a standard route for administering drugs that has come to encompass treatment for a wide variety of illnesses, including insulin shots for people with diabetes, immunomodulators for autoimmune conditions, chemotherapy drugs for cancer treatment and GLP-1 agonists for weight loss.

“We would have a way to deliver medications without pain,” says David Gracias, Johns Hopkins professor of chemical and biomolecular engineering. “Keeping up on your medications and trips to the doctor would become a lot less stressful.”

Gracias, who holds a joint appointment in the Department of Oncology, is a prolific inventor specializing in miniaturized systems, self-folding materials and physically intelligent machines that can adapt to dynamic environments, drawing immense inspiration from the living world. “I think nature is very intelligent. It’s the best engineer,” he says.

The idea of these so-called “theragrippers,” or therapeutic grippers, is but one of many to have sprung from the mind of Gracias and his collaborators at the Johns Hopkins University School of Medicine. Much of their work focuses on developing engineered living materials that could deliver tremendous advances in health care. Toward this goal, these researchers often rely on biofabrication, which weds abiological craftsmanship, such as microchip manufacturing, to biological media such as cells.

Numerous examples of wild-sounding, dynamic devices have been born of their collaboration. These include:

• hyper-miniaturized sensors, nicknamed “cell tattoos,” that could adhere to individual cells and report on their health as proxies for larger organ systems;
• miniaturized biomedical robots, actively powered by microsprings wrought of thin films and “hydrogels” that absorb liquid and swell;
• origami-like, self-folding hydrogels that could help form artificial, transplantable tissues.

One of Gracias’ closest collaborators at Johns Hopkins is Florin Selaru, a professor in medicine, oncology and biomedical engineering. Together, Gracias and Selaru are developing theragrippers to perform a variety of tasks.

“One of the big ideas in medicine — and this has been around in movies — is, ‘Can we enter the body with small things?’ ” says Gracias. “Clearly if we could, it’s a game changer.”

Theragrippers take a cue from the way hookworm parasites attach themselves to intestinal walls. The grippers can be outfitted with chemical sensors to autonomously shape-shift in the presence of certain sugars, amino acids, DNA sequences, enzymes, pH levels and more to specifically target certain areas of the body.

These theragrippers could also be used for sustained drug delivery. Even with the advent of extended-release drug formulations, pharmacologists still have been limited in how effective they can make oral medications because of the unavoidably propulsive nature of the gastrointestinal tract, where wavelike muscle contractions known as peristalsis constantly move contents along.

“The GI tract is akin to an assembly line; it keeps going on and on,” says Selaru, who is also director of the Meyerhoff Inflammatory Bowel Disease Center.

As a result, patients often do not get full doses of even extended-release drugs. “If you wanted to develop a truly sustained-release formulation,” says Selaru, “then you would have to essentially latch the ingredient on the inside of the GI tract.” A pill that turns loose a fleet of theragrippers with pharmacological payloads onboard could do just that.

Gracias and Selaru are conducting preclinical testing of theragrippers fashioned in their labs. In one animal model, mice that received a pain-killing drug via theragrippers had the drug in their bloodstreams for 12 hours, versus just two hours for mice given the drug via the normal oral route, as reported in the journal Science Advances. 

The little grippers could also be used to conduct canvassing-like biopsies, grabbing tissue samples  by the hundreds as they move through the body. In this way, theragrippers could enable robust statistical sampling in a large organ such as the colon, or in hard-to-reach conduits in the body such as bile ducts, to offer sensitive new disease screening.

By catching cancers and precancerous cell changes early in disease development or progression, clinicians could therapeutically nip the problem in the bud. This strategy potentially could prove more effective at catching malignancies than today’s taking of a limited number of chunky tissue specimens, a comparatively crude approach that can readily miss a small and still easily treatable bad spot. Other diseases, ranging from infections to metabolic disorders, could likewise be detected during early asymptomatic stages.

“Florin and I have been working on [the] idea of deploying theragrippers and giving an organ a ‘score’ to get an overall assessment of its health,” says Gracias. “You could potentially find cancers or other diseases much earlier this way.”

A Biomimetric Artery

Another pioneering project, which Gracias is conducting with Lewis Romer, a professor of anesthesiology and critical care medicine at the Johns Hopkins Children’s Center, is the biomimetic artery — a complexly layered and cellularly tiled tube that functions remarkably like real-life vasculature.

Physiologically, blood vessels are wonders of natural engineering. Although presenting as mere tubes, they are actually composed of three concentric layers of cells, all precisely working in concert. Flat endothelial cells line the vessel’s interior, backed by smooth muscle cells that contract and relax to enable blood blow, all wrapped in fibrous connective tissue cells.

Astoundingly, our bodies contain about 100,000 kilometers (60,000 miles) of blood vessels — enough to encircle Earth nearly two-and-a-half times. This vast network begins as branches of main arteries and veins, narrowing down into arterioles and venules, then wending further down into copious capillaries. Of the 100 trillion-some cells in our bodies, most are no more than a tenth of a millimeter (four-thousandth of an inch) away from a capillary.

A host of major ailments directly or significantly involve blood vessels, including of course cardiovascular disease, but also hypertension (high blood pressure) and cancer. Romer and Gracias want to dramatically improve our state of knowledge about vasculature for new insights into disease etiology and treatment.

“We’re interested in blood vessels because blood vessels are everywhere,” says Romer, who is also a professor of cell biology, biomedical engineering, and pediatrics. “The ways in which the walls of those blood vessels are put together have certain themes and certain geometries, and we’ve been trying to recapitulate those with very high-level biomimicry.”

To this end, the two researchers’ labs have invented and patented their biomimetic artery and are continuing to hone its abilities. 

Scientists have long struggled to engineer such convoluted devices. Gracias brought former experience as a senior engineer at Intel to Johns Hopkins, where tools and techniques of the microchip trade, such as photolithography — patterning materials using light — rub elbows with 3D printing and advanced imaging technologies.

For the biomimetic artery, Gracias, Romer, colleagues and students have employed such methods to create self-rolling layers of cells and tubular sensors. The upshot is a circular tube with accurately layered and aligned cells.

The researchers are now putting these biomimetic vessels through their paces by flowing biochemical gels into them containing medicines such as nitrates, which widen blood vessels, and hormones, gauging how the cellular structures respond. “We can better understand dysfunction in the tube and how it occurs by studying these systems,” says Gracias.

This approach offers significant advantages, both practical and ethical, over research in animal models or traditional laboratory setups.

“We’re able to stay true to many of the genetic and biochemical and anatomic parameters that exist in a person that are very different than they are in an animal or in vitro modeling,” says Romer, adding: “This research is a great credit to David’s ingenuity and ability to translate abstract ideas into very basic kinds of design parameters for systems production and engineering.”

Going Mainstream

Gracias’ and Romer’s blood vessel mimics could eventually find their way into fully realized, artificially grown masses of cells that work together to function like a bona fide organ. These so-called organoids — another interest area for Gracias — could allow researchers to deeply investigate disease pathologies and drug pharmacokinetics. 

As with his various micromedical bots, the idea of living pseudo-organs might sound far-fetched, but Gracias points out that today’s realities were yesterday’s big dreams.

“Any great technology, if you saw it 20 years ago, it would’ve seemed like science fiction, right?” says Gracias. “If you use that same metric and think toward the future, then I think definitely in the next 20–30 years, we will go into the body with robots and tiny sensors and it will become very mainstream.”