It’s been about 15 years since the advent of desktop 3D printing gave people the power to make real the whimsy of their digital designs. Or that was the pitch. The marvel didn’t necessarily endure for those of us who invested in budget models only to spend three hours smelling molten plastic as it accrued into a wonky bar coaster. So much for printing new cutlery. “We have to say it: The reality of 3D printing does not always meet expectations,” the New York Times wrote in a review of home printers in 2023. “No one could deny that it would be quicker and cheaper to go to Target.”
It didn’t exactly seem like a technology you’d bet your health on. But 3D printing has always been about more than low-end plastic extruders—a variety that Stanford professor Joseph DeSimone likens to glorified glue guns. Back in the ’80s, the first 3D printer to receive a patent used ultraviolet light to harden liquid resin, an approach that DeSimone refined decades later into printers capable of executing intricate, tunable designs at manufacturing speed, like a three-millimeter Eiffel Tower with details one-fifth the diameter of a red blood cell. Other printers use lasers that fuse plastic powders or needle-like nozzles that extrude living cells to create living tissue. Some use concrete extruders to print structures, like houses.
Just because you can 3D print something doesn’t mean you should, DeSimone says. You can print a house, but he’s not sure there’s a compelling reason to do so. Traditional methods work well enough. But 3D printing is finding a sweet spot in medicine, where its three-dimensional creative powers have the rare ability to match our three-dimensional bodies. “As we get closer and closer to how nature actually does it, it’ll become more and more successful and widely used,” says David Mohler, ’79, a clinical professor of orthopedic surgery who uses 3D-printed bone to replace pieces he must remove during cancer surgeries. What follows are four tales of how Stanford professors are changing human health, layer by layer.
No More Tears
The dawn of the microneedle.
Joseph DeSimone
Long before anyone connected his name with tiny needles, Joseph DeSimone was known for his knack at converting complex chemistry into real-world applications. As a chemist at the University of North Carolina, DeSimone had led the creation of an environmentally friendly process for making Teflon, a nontoxic approach to dry cleaning, and a bioabsorbable coronary stent, among other inventions.
At the Vancouver TED Conference in March 2015, and in an article in Science published the next day, he would reveal something more playful, though perhaps just as powerful: a 3D printer that pulled creations out of a pool of liquid resin, like some sort of Hollywood special effect. 3D printers had been around for decades, but they were exacting machines that took hours to build creations layer by layer. “3D printing is actually a misnomer; it’s actually 2D printing over and over again,” DeSimone told the crowd. “There are mushrooms that grow faster than 3D printed parts.” That might suffice for making prototypes—their niche in industry—where designers often let printers run overnight. But long execution times made it hard to iterate quickly and put absolute limits on using the devices to make goods at scale.
DeSimone and his co-inventors had created something quicker. Their printers used an interplay of UV light (a venerable printing technique to solidify resin) and oxygen (which keeps resin liquid) to enable a novel process that was, they said, up to 1,000 times faster than its predecessor. The printers, extruding items in minutes rather than building them layer by layer, in distinct strata, over hours, created cohesive parts free from the weakness inherent in layering (think sedimentary rock). The resulting combination of speed and strength wasn’t simply a faster way to prototype; it was a potential path to a new kind of manufacturing. In the future that DeSimone saw coming, you might not need rigid injection molds in faraway factories, or warehouses full of inventory. You could print complex parts on-site using specs that could be finely tuned with a keyboard.
A decade later, Carbon—the company DeSimone co-founded based on the technology—has helped bring his vision to reality. Today you can buy Adidas running shoes with intricate lattice midsoles made on Carbon printers that rebound force forward to improve your run. Or Specialized bike seats designed to cushion force, easing your ride. Ford makes car parts on Carbon printers, as has Lamborghini. Professional football and hockey players trust their brains to helmets with bespoke liners printed by Carbon to match the contour of their heads and hair.
But DeSimone still has a point to make about the power of printing. Now a professor of chemical engineering and of radiology at Stanford, he has continued to push the bounds of fast, manufacturing-quality 3D printing into the microscopic scale. The implications may one day find their way into your body, if only skin deep.
EASY PRICKINGS: With microneedles, vaccines could be delivered more effectively, in smaller doses, with less pain.
For decades, scientists have known that patches of tiny needles that barely puncture the skin offer advantages over single jabs that plunge vaccines into our muscles. Not only do they hurt less—by one account, more like the raspy lick of a cat’s tongue than the bite of a hypodermic—but they deliver their payload where it packs a bigger punch. As befits the barrier between our bodies and a world full of bacteria and other pathogens, the middle of our skin is heavily patrolled by the immune system. “We humans have 100 to 1,000 times more immune cells in the dermis of our skin than we do in our muscle,” DeSimone says. If you could effectively target this middle layer of skin, he says the benefits would range from requiring a fraction of the typical dose—crucial in epidemics, like the recent mpox outbreak, so there’s enough to go around—to enticing needlephobes to get vaccinated. “The largest manufacturer of vaccines has told me the biggest inhibitor for getting a seasonal vaccine trifecta of influenzas, COVID, and RSV is that people hate needles,” DeSimone says.
But manufacturing microneedles is challenging. Early production methods using silicon required multiple steps and were expensive, says Netra Rajesh, a bioengineering doctoral student in DeSimone’s lab and the lead author on two recent papers on the topic. Later approaches using molds struggled to maintain sharpness. By instead using new, high-resolution printing techniques, DeSimone’s lab has not only surmounted those issues but also found ways to create complex shapes that can be tweaked for, say, a child’s thinner skin or to avoid the “bed-of-nails effect,” where arrays with similarly sized needles don’t puncture the skin well. They can also create needles with lattice-like bodies with holes for storing liquid doses—the most common form of vaccines—and anchors for holding doses in solidified form, which have longer shelf lives. Designs can even be altered to control the rate at which dosages are released.
Ultimately, the technology may allow self-administered patches that require less vaccine per treatment, inspire less fear, can be delivered anywhere in the world, and work better than the familiar stab into our muscles. “We had a paper published in 2021 that showed if you deliver the same vaccine and the same amount into the dermis versus the muscle, you can get a 50-fold increase in antibody response,” DeSimone says.
They also have a reverse application. Like more familiar needles, microneedles can collect liquid from the body, notably interstitial fluid—the watery substance surrounding the body’s cells and tissues, including skin cells—which can act like a painless proxy for blood. “Interstitial fluid is exciting because its biochemicals are very similar in composition and concentration to blood’s,” says Stanford chemical engineering professor Zhenan Bao, the faculty director of the Stanford Wearable Electronics Initiative. But she says effectively accessing the fluid is difficult. DeSimone’s needles are an exciting way to tap this resource, she says. DeSimone imagines a world in which customers at the supermarket stick on a bandage-like device while they walk the aisles, then turn in the device a few minutes later. The result, he says, will be like a “liquid biopsy,” requiring no blood, that painlessly provides people a broad picture of the molecular happenings in their body whenever they want. He is co-founder of the start-up PinPrint, which aims to make microneedle patches that dispense vaccines and collect interstitial fluids. If that sounds a bit like one of Silicon Valley’s recent scandals, DeSimone is aware. “Maybe Theranos got it right,” he says. “Except for the fraud. And they went after the wrong circulation system.”
Photos: Mary Anne Kochenderfer; Gaurav A. Kamat/Netra Unni Rajesh/DeSimone Lab Stanford University
Clearing the Way
A new solution for blood clots.
Renee Zhao
It takes Stanford surgeon Jeremy Heit as little as four minutes to guide a catheter from an entry point in the leg past the neck to remove the blockage in the brain of a stroke patient. He uses a combination of suction and dragging to remove the blood clot that’s cutting off oxygen. It’s a powerful intervention—developed only in the past decade—that helps some 200,000 patients in the United States a year.
But mechanical thrombectomy, as it’s called, is not a perfect solution, especially with large fibrous clots, which can be a challenge to remove. The technique also carries the risk of fragmentation, potentially causing blockages downstream. So, when a fellow faculty member recommended Heit, MD ’04, PhD ’07, look at Renee Zhao’s work on a new approach to remove clots, he paid a visit to her lab. “About 10 seconds after seeing what she was doing, I said, ‘We have to do this in stroke,’ ” says Heit, an associate professor of radiology.
SMALL FEAT: Zhao calls her clot-busting devices millispinner robots.
Zhao, an assistant professor of mechanical engineering, is known for taking inspiration from art and nature—from origami to octopus arms—to craft millimeter-scale polypropylene bots with the flexibility to navigate through the body for potential noninvasive medical interventions. In 2023, MIT Technology Review dubbed her one of its Innovators Under 35. The creativity for which she’s known rests on cutting-edge engineering, enabled by 3D printers that allow her to test prototypes by the hundreds to fine-tune complicated geometries. “Without 3D printing,” she says, “it’s impossible.”
Part of 3D printing’s importance to the work is its simplicity (as judged by a bunch of top-notch scientists and engineers). When her lab’s commercial printers failed to print with sufficient resolution to create the lab’s designs, its members created their own, capable of printing down to 10 microns, not much larger than the diameter of a red blood cell. “You can easily adapt the technology and then customize it so that it fits your needs more,” she says. “It’s not a secret.”
In a paper published in 2022, Zhao and her teammates showed how they had created an amphibious pea-sized robot, shaped like a hollow cylinder, that was able to both roll and swim in an environment like the stomach, potentially offering a tool for drug delivery. The spinning that propelled the bot showed promise in other applications, including reducing blood clots. In a collaboration with Heit that began later that year, Zhao shrunk the idea into a crumb-size tool that fits within the catheters used for clot removal.
Spinning rapidly, the device besieges a clot with a whirl of compression and shear forces. As trapped red blood cells are freed, the clot’s fibrin fiber network withers to a densified clump, like a cotton ball being rubbed back and forth between your palms. Reduced to as little as a tenth of its size, the clot is then sucked into the catheter. In animal models, the researchers were able to remove clots on the first attempt more than 90 percent of the time, more than doubling the efficacy of current technology, Heit says. They hope to start in-human testing within two years. “We’re very excited about this technology,” Zhao says.
Photos: Steve Fisch/Stanford Engineering; Stanford Zhao Lab
Bridging Gaps
Bones made to order.
Yunzhi Peter Yang
With acres of pasture to choose from, her young thoroughbred managed to get her halter snared on the one fence with a cracked board, Kentucky horse breeder Sharon Banford recalls. Annunaki’s hoofmarks testified to what followed: a frenzy to free herself and a fractured jaw. “I found her halter right next to that fence board,” she says. “It was pretty easy to determine what had most likely happened.”
Such injuries aren’t rare, but what came next was. A large cyst removed from the wound during surgery soon returned with a vengeance, continually enlarging and abscessing. The dental specialist reviewing the case was reluctant to perform a second operation to remove a chunk of bone and tissue from the left side of Annunaki’s jaw that was too large to replace with bone graft. “It was like six or seven inches of her mandible,” Banford says. “How’s she supposed to live without that?” But letting the cyst grow raised similarly bleak questions.
The dilemma forced a novel turn. The dental specialist’s son happened to be veterinarian Jeremiah Easley, director of the Preclinical Surgical Research Laboratory located at Colorado State University, who had been testing devices with Yunzhi Peter Yang, a Stanford professor of orthopedic surgery. Yang’s lab had developed a 3D-printed scaffold designed to mend breaks too large to heal on their own. The scaffold had showed promise in the lab, doubling bone volume compared with autografts, or bone grafted from other parts of the body, Yang says. But it had never been used outside the lab. “I called him up and said, ‘I think I have a case for you,’ ” Easley says.
Using a CT scan of Annunaki’s jaw, Yang’s lab set about printing a lattice-like scaffolding shaped to fill an irregular gap about the size of a toddler’s shoe, which would be created by the removal of the diseased jaw. The printed scaffold—a mix of bioabsorbable polymer with a calcium-based ceramic akin to bone mineral—was about “90 percent holes,” printed with a porosity mimicking that of inner bone to promote growth. The greater part of its healing power came from a freeze-dried coat of hydrogel containing bone-growth-inducing protein, which Yang likens to an SOS signal to bone-building stem cells. After the device was FedExed to Kentucky, a surgical team in Lexington performed a two-hour surgery on October 12, 2023, to nest the scaffold in the afflicted section of Annunaki’s jaw. “3D printing allows you to really control the geometry to personalize the devices,” Yang says.
JAW DROPPING: A 3D-printed scaffold stems large bone breaks and releases growth factors into the bloodstream steadily over weeks to aid healing.
In humans, autografts are the gold standard for repairing a critical bone defect—typically, a break larger than twice the diameter of the bone, Yang says. But that means more trauma. Bone from cadavers provides a less intrusive alternative but consists of dead cells that are not as effective at promoting growth and can cause disease transmission and autoimmune response. Attempts at synthetic scaffolds like his own have struggled to find a way to steadily release regenerative proteins. “Once these growth factors enter the bloodstream, they quickly lose their effectiveness, within minutes,” Yang says. His lab’s design secretes the protein over time, he says. “His is a controlled release that goes over weeks as opposed to minutes or hours with the current applications,” says Mohler, a musculoskeletal tumors surgeon who has collaborated with Yang. “You get a more robust, more predictable, and more controllable application of those growth factors.”
The details of the horse’s care were unique, but 3D printing’s ability to fit into our three-dimensional bodies is making it an increasingly common tool in human medicine, Mohler says. Currently, he uses the technology most frequently to print cutting guides—essentially stencils developed directly from images of patients’ bodies that enable exact placement for his saws in complex cuts to remove tumors. He also sometimes uses 3D-printed bone to replace what he removes. But the day is coming when surgeons will be able to replace soft tissue such as muscle, skin, fat, and even organs with printed parts, he says. “Our bodies 3D print themselves starting in utero,” he says. “I think in 30 or 40 years, we’ll be able to print just about anything that’s not a brain.”
The device worked on Annunaki. Easley was pleased with how the bone grew back. Banford was concerned about nerve damage. But a year later, the future racehorse takes a bit and shows no sensitivity even to being pulled left. And though Annunaki’s jaw was swollen for months, Banford says she hardly sees it now. “Unless I pointed it out to you, I’m not sure you would even notice it,” she says. “I was real skeptical of this, but as of now, I think she’s doing phenomenal.”
Photos: Shipeng Fu; Hossein Vahid Alizadeh/Yunzhi Peter Yang Lab
Body Building
The heart of the matter.
Mark Skylar-Scott
More than 100,000 Americans are currently waiting for an organ transplant, and every day an estimated one in 17 of them dies. The urgency of those numbers echoes as much in familiar pleas to register as a donor as it does in scientists’ ambitious attempts at modifying pig organs for human use.
But what if doctors didn’t need to harvest organs from anyone or anything? What if they could create an organ from a patient’s own cells? What if they could 3D print a ready-to-beat heart in the same amount of time drugstores print photographs?
That’s the ultimate vision inspiring Stanford assistant professor of bioengineering Mark Skylar-Scott, principal investigator of a $26 million federal grant to print a working heart and implant it into a living pig within five years—a precursor, he hopes, to future clinical applications. It’s a moonshot project he wouldn’t have dreamed of so early in his career but for the intervention of the grant. “It changed everything. We are entering a new world and a different place,” he says. “But there is a lot of work and a lot of scientific engineering uncertainty remaining.”
The origins of bioprinting go back to the early 2000s, when former Clemson bio-engineering professor Thomas Boland filled a Lexmark inkjet cartridge with collagen and printed his initials with it. He was soon printing with E. coli and mammalian cells with 90 percent of the cells surviving the process. From such beginnings, a new vision for fabricating organs came further into focus. “It is safe to predict that in the 21st century, cell and organ printers will be as broadly used as biomedical research tools as was the electron microscope in the 20th century,” Boland and four others wrote in a 2003 paper in Trends in Biotechnology.
But it’s one thing to flatly print millions of cells and another to arrange billions of them into a functioning three-dimensional vital organ. In 2019, Skylar-Scott—then a researcher in the lab of Harvard professor and bioprinting pioneer Jennifer Lewis—was lead author on a study that made science headlines by turning half a billion cardiomyocytic and cardio fibroblast cells into a vascularized chunk of synchronously beating heart tissue. It was all of one centimeter tall.
The challenges of scaling up from that to a full heart are vast, complex, and, in many cases, unresolved. It’s unclear, for example, whether a printed heart will need all the organ’s approximately 30 cellular subtypes, or whether scientists can print with 11 main cell types and allow specialization to occur as the heart matures, Skylar-Scott says. And once you can print the heart’s form, there lurk many questions about activating its function. But the first hurdle has simply been amassing the raw material to start.
A fist-sized human heart contains tens of billions of specialized cells. Thanks to recent revolutions in stem cell biology, researchers can take common cells from, say, the skin and convert them into embryonic-like stem cells, which can then be induced into the array of the heart’s cellular citizenry. But propagating the vast volumes of cells required to repeatedly build test hearts is a costly undertaking in itself. Skylar-Scott’s lab has 18 bioreactors full of stem and heart cells. The largest of them measure 10 liters, contain some 30 billion cells, and cost more than $5,000 a day to keep fed and supported with nutrients.
And then there’s the urgent matter of keeping cells alive once they’re printed. Printed cells, like those assembled by nature, die without oxygen. That’s no problem in a petri dish, where oxygen surrounds, but it’s quickly deadly in dense three-dimensional clusters. Indeed, it’s the problem that got Skylar-Scott interested in 3D printing as a PhD student at MIT, where he grew cells into three-dimensional shapes only to witness his creations suffocate from within. “That’s when I got inspired to use bioprinting to tackle the vascular challenge, which has been a very long-standing problem in tissue engineering,” he says.
FINE PRINT: The first synchronously beating 3D-printed heart tissue was one centimeter tall. Now Skylar-Scott is leading a team trying to construct the entire organ.
One of the researchers’ first orders of business—led by the lab of Alison Marsden, a Stanford professor of pediatric cardiology and of bioengineering—was creating an algorithm for the printers that’s capable of rapidly mapping out an optimized network of arteries, veins, and capillaries. Ultimately, the network must perfuse every nook of a new heart with sufficient oxygen, and it must do so at speed. Their goal is to print the entire organ, with vasculature, in about an hour. Much beyond that, the printed heart will begin to die even as it’s being born.
To beat this ticking clock, Skylar-Scott’s lab has been collaborating with other Stanford researchers. Skylar-Scott uses a method of 3D printing called embedded printing, in which cells are placed into a supportive, gel-like bath. Imagine a viscous goo that is liquid enough to let a penlike print nozzle glide through but solid enough to hold the cells it prints. Blood vessels are then written in with a sort of disappearing ink that flushes out when warmed to leave empty space for future blood vessels to develop. To hasten this process, the lab is working on a multidirectional printer with extrusion nozzles reaching in from all six sides of a cube-like enclosure. And still, they remain a long way off from meeting the one-hour target. “We’re probably going to need on the order of 15 or 20 of these printers at once, working together,” Skylar-Scott says.
Unlike other 3D printing, bioprinting results in a living organ that continues the work itself. The scientists, for example, may lay out the bulk of the vasculature, but the living heart should finish the job of completing the network down to the finest capillaries. Lewis, Skylar-Scott’s mentor at Harvard, offers one metaphor: Build the highways; let the driveways build themselves. Paul Sheehan, a project manager for the Advanced Research Projects Agency for Health (ARPA-H), which funds the grant, offers another. He likens the printing of an organ to creating an ecosystem—say, a forest—in one grand stroke. It could be that you need to have all the components—from the pollinators to the trees—present at the same time for the system to work, oxygen absolutely included. But perhaps you don’t have to manage the scenario down to the last detail. “You have to put the bird in the tree, but you don’t have to build the nest,” he says. Nature should find a way.
ARPA-H was created in 2022 to invest in high-impact, high-potential health research that’s not supported through traditional investment. Sheehan says he’s heard nothing to make him believe Skylar-Scott’s lab won’t be successful, which would be a triumph in itself. And yet he expects the lessons learned to have implications well beyond the heart. “It also opens this door, this gateway, to organ replacement in general,” he says. “Pick another organ that you might want to replace, and one day this could extend to that.”
Skylar-Scott is optimistic but also careful to tamp down hype. Even under the best-case scenario, it would likely be decades before 3D-printed hearts could be approved to go into patients, and it may be that five years is insufficient for doing so in animals. “I do think five years is ambitious, I won’t tell you otherwise,” says Lewis, whose lab is studying how to print kidneys, the most frequently transplanted organ, as well as hearts. But she says that Skylar-Scott, who she calls a polymath and a leader in his field, is just the type of person to assemble the researchers to do it.
“There are very few people that I’ve worked with that are as broad but yet so simultaneously deep as Mark,” she says. “There’s real reason to be optimistic and excited about what he’s accomplishing.”
Photos: Andrew Brodhead (2)
Sam Scott is a senior writer at Stanford. Email him at sscott3@stanford.edu.
