- Welcome to "The Minor Consult" where I speak with leaders shaping our world in diverse ways. I'm your host, Dr. Lloyd Minor, Dean of the Stanford School of Medicine and Vice President for Medical Affairs at Stanford University. Today in our "Big Idea" series, we're exploring how advances in material science and manufacturing are opening new frontiers in medicine. My guest is Joseph DeSimone. He's a professor of translational medicine and of chemical engineering here at Stanford. And he's a prolific inventor and entrepreneur who has founded multiple companies to translate his discoveries into real-world impact. Over the course of his career, Joe has asked a fundamental question, how can we make materials and devices better, faster and more precisely and with greater impact? That question has led to breakthroughs in chemical engineering, 3D printing, and drug discovery that are reshaping how we design and produce technologies, enabling new approaches to treating disease. Joe, welcome to "The Minor Consult."

- Yeah, great to be here, Lloyd, thank you.

- Joe, you've spent your entire career in polymer science, and you've taken it in a variety of different directions and many, many innovations coming from the work that you've done. What's been the thread that's linked the work that you've done in field spanning, you know, from biomedicine to sustainability to energy technology, what's been the common thread throughout all of your work?

- Well, I love polymers, it's sort of crazy. I got exposed to this as an undergraduate at a small liberal arts college outside Philly called Ursinus College. And it was rare for a small school to have a class in polymers. I fell in love with it. So, this is a mid '80s and it was also there's parallel thing with Moore's Law and microelectronics. And I got exposed to how polymers is useful in making electronic devices, all the patterns. And so where maybe, you know, you know, from a biology point of view, people think a lot about sequence, protein sequencing.

- Yep.

- And I thought about that, you know, chemical structures matter a lot. But as you think about proteins and you got, you know, secondary and tertiary structure and then you go up to cells and others, polymers has a similar approach. And the fact that you can have structure and performance that has multiple length scales and I found that really fascinating.

- Yeah. Now, your work recently past several years has also focused a lot on biomedicine. Can you talk some about that and how you have come to focus on some really, really important problems and challenges in biomedicine and how your previous background in polymers and other fields of manufacturing has enabled you to have particular impact in biomedicine?

- Yeah, so as a polymer guy at Carolina, I was at the University of North Carolina, I got approached by a professor in School of Medicine for delivering back then silencing RNA. And at the time in polymers, you know, the thing where people were using colloids almost analogous to LNPs, lipid nanoparticles used in vaccines. So, could we marry this amazingly precise molecule in medicine, nucleic acids? And the solution at the time for me and others was a cousin to PRINT technology. And they, and to me that was such a pedestrian answer to these beautiful molecules in medicine that I though, well, why don't we bring some of the deterministic to precision of microelectronics manufacturing methods associated with polymers and marry that with the drug delivery space, and related kinds of structures. So, our first foray, I was approached by, to deliver siRNA as a particle. And I was also approached by a professor at Duke, an interventional cardiologist that had a vision for a biodegradable stent. So, we married these capabilities and we started a company that developed a degradable, a drug-eluting degradable stent. And the thesis was that at the time, you know, angioplasty was obviously a big deal, some of those blood vessels would collapse, and so people were leaving stents in there. But people believed that you didn't need a stent permanently-

- Sure.

- You just need the vessel to remodel. So, the thesis was, why have a permanent prosthetic to a temporary healing problem? So, we designed polymers that were degradable over months, that were balloon expandable and deployable, and we launched a company that was acquired by Guidant, became part of Abbott. We've had over 150,000 people with the degradable stents. And just a month ago, Abbott announced they're doing it below the knee for peripheral artery disease to complement coronary artery disease. So, I fell in love with the utilitarian aspects of problem solving in medicine.

- Yep.

- That example of drug-eluting stents, or in this case, a drug being siRNA, but going beyond these colloidal particles and getting into microelectronics fabrication techniques. And so we invented processes to make precision particles. We call it the PRINT technology.

- Yes.

- It's a molding technique. It's akin to like a ice cube tray on the nanoscale or the microscale, depending on what we wanted to make, precision-shaped particles that were molded in a roll-to-roll web-based process so we could scale it. And we were combining it with siRNA instead of colloidal particles and were really good at delivering molecules to cells that we wanted them to. And a company came out of that work called Liquidia. It's a $3 billion market cap now. The products are going into the lungs for COPD and pulmonary hypertension and the drug will do $400 million this year and 1 billion next year, all precision-molded particles.

- Right.

- But we ran into a problem with one type of disease and that was pancreatic cancer. The NCI wanted us to deliver drugs into, you know, we were delivering drugs in the lungs or you do intravenous, but there was a need for delivering drugs into the pancreas. And as you know, that's a terrible disease.

- Yes.

- Those tumors I learned compared to other tumors, have a poor blood supply.

- Yeah.

- And the blood system's a highway to get drugs in.

- Sure.

- So, there's no highway to get the drug in, and so part of my NIH Director's Pioneer Award, we had a new approach, a new engineering approach that uses a mild electric current, electric field that's really good at moving molecules that have a dipole moment. And so we invented a device that can sit on the pancreatic tumor-

- Yeah.

- And it's a reservoir that comes out to a PICC line. You turn on the electric field, you deliver, and it was a gemcitabine.

- Right, right.

- And we launched a company in that space. And we got IND approval in 2025, it took a long time.

- Yes.

- We're actually going to start treating patients in about two weeks at Michigan, Vanderbilt and West Virginia University using this approach. So, my point is I think there are engineering principles.

- Yes.

- That can be applied with molecular understanding with a little bit of guidance from medicine and biology. And it's that synergy of all those fields coming together, which was a lot of fun for us.

- Maybe if we go back to PRINT and PRINT technology for just a moment, as you mentioned it, as you mentioned, you developed it while you were at UNC, I think around 2005.

- That's right.

- Yeah. And walk us through the process, the discovery, the innovation process. Were there aha moments? Was this, as is often the case, a product of a lot of convergence in ideas and approaches, but how long did you have to work on it before you got the first sort of prototype device? And did it come from a single idea, an aha moment, or was it you bringing together many different ideas, many different approaches going on in your lab at the time?

- Yeah, that's a good question. It's, it was, now you sort of ask it that way, sort of reminiscing about the aha moment.

- Right.

- So, back to this ice cube tray. So, if you think about that, we were basically molding an ice cube tray and then taking the mold off. So, it was like the old-fashioned ice cube trays. And we were trying to make a real, if you can imagine an ice cube tray where you'd have mounds of things on top of another surface that reflect the ice cubes. And you know, sometimes when you overfill that ice cube tray, all the ice cubes are connected.

- Yes.

- With a thin layer of ice. That's what we were expecting to happen. My student came in with an electron micrograph and they're hard to see they're small, right? So, we're doing high resolution microscopy. And instead of all these mounds being in register like they were connected in ice cubed, they were all tumbled, they weren't connected, they were particles. And no one had molded particles at, these were like 80 nanometers, right? So, our red blood cells, 8,000 nanometers, or eight microns. So, these are really small.

- Yes.

- And we thought it was going to be a patterned surface, but they were isolated particles. We were molding, and they were all the same size and shape.

- Yeah.

- And they were of the size of a liquid and a lipid nanoparticle.

- Yeah.

- So, we've made the connection between precision particles and, you know, the FDA hates heterogeneity, Biology hates heterogeneity, here is the digital, so it's really fusing the tools of the microelectronics industry. This is what's called imprint lithography. The tools of the microelectronics industry to make precision particles for medicine. And it came out of just trying to make something, you know, a pattern surface and they turned out to be particles, and we drew the connections that we could apply those in drug delivery.

- Right, right. Well, it's brilliant. And obviously it's led to, as you just described, a lot of different advances are having impact in people's lives today.

- And that's rewarding.

- Absolutely.

- I remember watching when people, somebody got our first stent and watching that and the role that the regulatory challenges, the manufacturing challenges, how to scale that up to GMP. And so much about manufacturing is tied to these things, right? Because you can have all the experiments in a lab, which is, you know, a big part of the innovation process, but the invention process, but to turn an invention into an innovation, takes all these other dimensions of scalability, Good Manufacturing Practice, regulatory approvals, you learn a lot in that process as well.

- Absolutely. Now, another technology that you've developed and applied through companies is 3D printing. Can you talk about how you became interest? Of course, also a polymer process, but how did you first transition into large-scale 3D printing? And also maybe in the context of describing that, you brought some examples of things that you're making in one of your companies with 3D printing. And can you walk us through that process?

- Yeah. So, I got exposed to 3D printing about 25 years ago. And I fell in love with it. It was really fascinating, the concepts of digital CAD file and creating something. But as soon as you got into the field, I started hating it at the same time. And I hated it because it was really, really slow. The parts you saw were not great. They had lines and the like, and the materials were often left mostly brittle plastics and nobody wants a lot of brittle plastics for anything. And, you know, and it was so slow. You know, there are mushrooms that grow faster than many 3D printed parts, and so that was noodling on me. And then, you know, I had a former postdoc come who was part of Liquidia, the molding company, and he approached me about, you know, let's get into 3D printing. And I asked him, I said, "What's the idea?" He said, "Well, I think we can build 3D printers faster than anybody else, cheaper than everybody else." I said, "Well, Alex, that's more of a activity than an idea. What's the idea?" I said, "Well, that was it." I said, "Well, go look up these five keywords and patents." And I love patents. Patents are insightful about how people do things.

- Yeah.

- And he came back all the press. There was like 400 patents in this area. And I said, "No, I love patents, let's look at these." And we started looking carefully and what you realize, everything was layer by layer. 3D printing's a misnomer. It's kind of 2D printing over and over and over again, that's why it's slow.

- Right.

- So, let's try to do this continuously. And which would, you know, if we could pull that off. And so we toyed around with how could we do that? And we had an insight that uses light and oxygen to cure parts. And I don't want to get into too many technical details, but it allowed the printer to go 100 to 1,000 times faster.

- Wow.

- And so all of a sudden, you know, this is, now, some people didn't care about that, that were in the industry. They said, "Look, we'll load the printer on an afternoon and next morning we'll come and the parts will be there."

- Yeah.

- But that doesn't mean you can manufacture which you need speed. So, we invented this process. It worked like a champ immediately. We saw how this could work, but we also need great materials. And here's another big roadblock because most were brittle plastics. And being a polymer guy, it's like, you know, we want elastomers, we want degradable materials, we want tough, durable materials.

- Right.

- Combined with drugs, all sorts of things. And light is not a great way to make a polymer. It's very limiting. And so we thought, we actually did a play, something similar to what Carolyn Bertozzi does with orthogonal... She does orthogonal chemistry in a cell. Does a certain kind of chemistry, it doesn't interfere with the biochemistry of a cell.

- Right.

- We invented orthogonal chemistry for inside a printer.

- Okay.

- So, basically we have a resin that 10% of the resin is light sensitive and the other 90% is normal polymers. And no one had ever combined the two in an orthogonal way. And that opened the door to great elastomers that were energy returning or dissipative. And so we can now combine all this beautiful things about light-based printing with a wide range of materials. And we launched a really great company and I think of it as the intersection of hardware, software and chemistry all coming together to make amazing parts like we have here.

- Great, why don't you show us a few examples?

- Yeah, so well, one wear sort of a signature part, a big partnership with Adidas, the shoe company, Adidas.

- Right.

- And you just think about something like this with that kind of structure. This is classically an unmakeable design. It's, you can't mold something with this intricacy, you couldn't get it out of a mold. And with this kind of design and an amazing material, this is really lightweight. And it's actually designed when you put your foot down, it actually will throw you forward 13 degrees. It's almost like cheating in running. So, that's one example.

- That's great.

- Another one here, this is a bicycle saddle from Specialized. And this actually is designed with blood flow in mind, airflow, and it actually has 20% less maximum force on the sit bones than you can get from foam material. So, it's high performance, breathability, ergonomically satisfying, and it's massively scaled. Another big one would be football helmets.

- Yeah, yeah.

- Every NFL player-

- Sure.

- Is using a, has a helmet whose liner is all printed with our technology. Their head gets scanned. So, it's like in dentistry, like this denture, we have over three million people now wearing dentures.

- Yeah.

- The VA is the largest provider of dentures in the country.

- Right.

- This is a product I'm most proud of because it's a big part of upward mobility in society to have your teeth.

- Absolutely.

- Speaking properly, eating properly, getting a job, all these things, and it's all been done by hand.

- Yeah.

- Which typically takes eight chairside visits to be incrementally derivatized and fabricated by hand.

- Yeah.

- This is now done with intraoral scanning. It's only two chairside visits. And so when people come to our VA, their average drive time now is like two and a half hours. And they come eight times. And then if they lose, if it gets damaged, dog gets it, thrown in a fireplace by mistake, they got to come back in where you, digitally, you just get a four pack.

- Sure.

- And I've had, you know, it's really heartwarming, Lloyd. I've had people who, whose parents have Parkinson's disease.

- Right.

- And have dentures. And how horrific it is to go back into that chair when they lose their dentures. And so this just transforms healthcare.

- Yeah.

- And it's personalized.

- Absolutely.

- And it's all, you know, all done at cost that's way cheaper than handcrafting each one of those times, so very exciting.

- Very exciting. Now, other applications of Continuous Liquid Interface Printing or CLIP technology that you just so eloquently described is in microneedles to deliver medications, vaccines. Can you talk about that technology and what you're excited about and how it's being deployed?

- Yeah. So, you know, when we started the company and at the University of North Carolina, I'd spun it out, already hired a CEO, and the investors, Jim Goetz at Sequoia, asked me to lead it, and I told him all the reasons why it's terrible, "I have faculty lead companies," and he said, "No, why don't you do it? You can do it." And I agreed to do it for a year, turned out to be six. Moved the company out here to the Bay Area from Chapel Hill. And then led it for six years. We developed all these products and I got my life back in November of 2019. Sam Gambhir called me, you called me, we started having a conversation in spring of 2020.

- Right.

- And I joined the lab or Stanford in the fall of 2020, and I had a chance to start a new lab. And what are you going to do that's different? And I realized that you know, 3D printing was so valuable for these macroscopic things, but there was a lot of interest in making microscopic things. Kind of like my roots back in microelectronics.

- Sure.

- But there was a fabrication gap between like one in 1,000 microns. So, again, a red blood cell's eight microns, you know, a millimeter is 1,000 microns. So, if you think about that scale, so we actually developed printers here at Stanford that had a resolution down to a single digit micron in all three Cartesian coordinates, X, Y, and Z.

- Yeah, yeah.

- And so I spent the first couple years with my students, we built amazing new printers here.

- Yes.

- And it was a, it's a platform for making things just like beautiful things like this, but now three dimensions at very high resolution, and we developed and people were interested in microneedles, but these are now microfluidic microneedles. So, all of a sudden we have functionality and channels, tunnels in these microfluidics that were unmakeable by anybody else. And this opened up a whole area of drug delivery, but now intradermal.

- Yeah.

- So, patches that can deliver vaccines, lidocaine, hair regeneration molecules, antibodies, all sorts of molecules for delivery, very precise. And I, you know, I love your precision, medicine precision health view. One of the big opportunities of vaccines, and we're, you know, supported by the Bill & Melinda Gates Foundation and Wellcome Leap to do this, it's delivering mRNA-based vaccines and protein-based vaccines. And the locus, as, as you know, for these vaccines are immune cells.

- Right.

- And humans have 100 times more immune cells in our skin than we do in our muscle.

- Right.

- So, precision delivery now with these devices, we published during the height of COVID a paper with these needles and showed that we got a 50-fold increase in antigen-specific antibody response delivering the same vaccine, same amount of vaccine, but into the right location to have enhanced performance. And that was very, very exciting.

- That is exciting. Talk about exciting things. What are you excited about right now? What's going on right now?

- Well, delivery into the skin's exciting and we're looking at all the different places. But, you know, it's also exciting is to think about that fluid in the skin, interstitial fluid. Is, you know, our bodies we have our blood supply and, but we have three times as much clear fluid in our bodies called interstitial fluid. It's actually bathing cells. Blood is often some highway, hundreds of microns away feeding oxygen, but this fluid is actually bathing cells.

- Right.

- And our cells are secreting molecules often through these little buds called exosomes. And that fluid gets secreted, it eventually gets into a lymphatic vessel and gets eventually gets into the bloodstream, but it goes through a much different path than-

- Sure.

- In the bloodstream. And that fluid is loaded with molecules that have a reflection of your health.

- Yeah.

- Biomarkers. It's where a lot of biomarkers first go before they get diluted and degraded in the bloodstream. So, we just published a paper. We did a big study here at Stanford under IRB with these microneedles that could take out this clear fluid. It's pain-free because the needles are so short. We get 15 milligrams of this clear fluid in five minutes. We did a dozen patients on campus. We see over 3,000 proteins. We see 150 proteins associated with early cancer detection. We see cytokines. We see all the immunoglobulins, everything about your status. And now with Steve Quake, it looks like we see RNA at a concentration that's 100 times higher than in blood.

- Right, right.

- Because enzymes that degrade nucleic acids are really high concentration in blood, but they're not in this medium that cells are communicating.

- Right.

- So, we're now profiling all these RNAs. And so what I think about is that we have a, you know, molecular diagnostics is a big part of precision health.

- Absolutely.

- And now we have... And it's hard to draw blood. You know, wealthy people, we, you know, we can get a blood draw annually or... But you know, you should get... Everyone should have access to this.

- Sure, sure.

- And it should be done at a much higher frequency.

- Absolutely.

- So, we just, an IRB just approved a new study here. We're now doing 100 patients, and 47 of them are Alzheimer's patients. We're looking for p-tau217 for early Alzheimer's detection. We're doing an early cancer detection. And so my, you know, what excites me is imagine walking into a grocery store or a Walmart and putting a patch on, doing your shopping, and leave the patch at the counter-

- Right.

- To get high frequency molecular diagnostics-

- Right.

- In a way that can help understand your health and wellbeing, early onset of disease. And so now part of the Canary Center here at Stanford, which is all about early detection-

- Yes, yes.

- It's these diagnostics that can be useful to really help us understand, you know, what baseline looks like and what the future could be. So, these microneedles I'm excited about through delivery and liquid biopsies.

- Indeed. We fast-forward a decade from now. I mean, we're already living in incredibly exciting times with the convergence of biology and technology and data science, AI. I think we're still at the very early stages of seeing how AI is going to transform the way we do fundamental discovery work all the way up through how we deliver healthcare. But what's your... Give us some predictions, Joe, since you've been so impactful at driving the future. How do you think things are going to be different 10 years from now in early diagnostics, your projection about overall health and wellbeing? What do you think we have the opportunity to achieve in the next decade?

- Well, it's exciting times.

- Yeah.

- And you know, all these data streams, all these modalities, you know, we're getting a point where we could be swamped with data.

- Yeah.

- Swamped with insights. And you think about, again, back to precision health, understanding, you know, what baseline looks like in your earliest beginning deviation from baseline.

- Yep.

- And how does one synthesize all that data and have a picture that matters? And so this is where I think AI is could be really powerful. And it's, you know, it's, you know, Stanford's a bit synonymous with AI, and it's exciting to be here. And what's also clear is, you know, there's a tenet in entrepreneurship called commoditize your compliment. And I think the compliment for medicine is going to be AI.

- Yes, yes.

- And it's going to become very inexpensive.

- Yes.

- And so the idea of having an AI doctor to help interpret, everyone's going to have these. You know, Vinod Khosla talks about this, a lot of people talk about this.

- Yes.

- With information like molecular diagnostics, imaging of different types skin cancer, lesions, or skin, watching how you sleep, you combine all this information, with AI, it's a real exciting time to bring all that together in actionable ways. And it's really exciting, and there's a lot of stuff we have to overcome between here and there.

- Yes.

- Adoption friction of different types that'll be, because it's, you know, you want actionable understanding, but we'll get there.

- Yes.

- But I think it's a real powerful opportunity for medicine to have AI combined with information on you to help guide the, you know, a healthier life and maybe prevent disease from getting, taking hold because you can change the trajectory of it.

- Joe, you mentioned adoption friction. And given the number of technologies you've brought to humanity over a course of many years in a variety of different fields, what's your impression on the trajectory of adoption friction? Are we seeing less now than we did before? How much variability is there among different fields? But particularly now that advances are occurring at a much more rapid pace than they have before and advances that actually get to patients are occurring much more rapidly. The topic of adoption friction, not to suggest that it isn't a valid concern because particularly when we're bringing new therapeutics or new procedures, anything that we're bringing to people, of course we want appropriate vetting and regulatory processes. But are you seeing adoption friction becoming more of an impediment or less or about the same?

- It's significant and its significance varies depending on where you're at.

- Okay.

- I think in resource-limited situations, people are going to adopt it quicker, right? Because they don't have an alternative, and it's so impactful for them. I'm watching my amazing colleagues in radiology and they have to look at a scan of different types and they've got to put their name on that report.

- Right, right.

- They're responsible for that patient's diagnosis.

- Yes.

- And if some of the tools they're using is riddled with mistakes or hallucinations, it actually might take them longer right now. And so there's going to be friction here. It will get better.

- Yep.

- And some places will jump to the end quicker, then maybe some places that are going to be more thoughtful and so, but the dynamic, I think it's going to net out where it's coming. How we manage through this, it's going to be complicated. But you know, the adoption friction is real. And in these transition periods, it's going to be, different places are going to go different rates. But I think at the end of the day, we're going to see the impact on people, on costs and we'll have to adopt. And, but just recognize the challenges with that and how we manage those and adjudicate them, it's going to be important.

- Indeed. Well, Joe, I'd like to finish with two questions that I ask all my guests. First, what do you think are the most important qualities for a leader today?

- Well, I think clarity of vision, clarity of purpose is important, and communicating that. You know, I think the ability to, especially with AI, you know, ideas used to be the premium. We're in a sea of ideas now. The human quality, the leadership quality now is, which ideas? The discernment of which ideas to move forward and then how to lead people to affect and implement those ideas. I think those combinations are going to be really important. And I think that's a, ultimately a human quality.

- Yes.

- And that's what's great about Stanford, right? We have all the disciplines, medicine, engineering, the humanities, the liberal arts communication-

- Right.

- All coming together. That's what's so great about this environment to, because we're training the next generation of leaders out of Stanford. And imbuing those qualities of discernment and galvanizing people and the values to, and the aesthetics and all those things coming together about what to work on and how to make them a reality are going to be the key things going forward.

- And then finally, what gives you hope for the future?

- It's certainly our students, unequivocally. I have a good fortune at teaching a general engineering class, which has now almost 100 kids in it. All PhD candidates for the most part, maybe about 10% undergrads. And it's entitled Career Impact. And so they've take their, and you know, we got Edwin Moses tomorrow, we've had Vinod Khosla, we need to get you on here. And it's different kinds of leaders, but it's to give them a chance to reflect on their, where they're going. And they're busy, you know, they're in the, they're at the lab bench, you know, they're doing their research, but at the same time, taking a moment to reflect on themselves.

- Sure.

- Invest in themselves to do something where, you know, where are they going to go? How are they going to make a difference? Especially in this world of AI. And what I find is they're really thoughtful. They got a lot of ideas. They have a lot of, you know, mission driven, value driven, and I think that's why we're all here at a university as the students and it's energizing to see what they're thinking about and what could be done better and more impactfully.

- Well, Joe, thank you very much for joining me in this conversation today. As always, it's fascinating, and congratulations on the amazing things you're doing, and look forward to staying in touch because I know they're only going to get more amazing in the future.

- I appreciate that, and thanks for all your leadership here.

- Yeah, thank you. And thank you for listening to "The Minor Consult" with me, Stanford School of Medicine Dean Lloyd Minor. I hope you've enjoyed today's discussion with Joseph DeSimone, Professor of Translational Medicine and of Chemical Engineering at Stanford University. Please send your questions by email to the minorconsult@theminorconsult.com and check out our website, theminorconsult.com for updates, episodes and more. To get the latest episodes of "The Minor Consult," subscribe on Apple Podcasts, Spotify, or wherever you listen. Thank you so much for joining me today, I look forward to our next episode. Until then, stay safe, stay well and be kind.