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Oby: From the campus of Harvard Medical School, this is Think Research, a podcast devoted to the stories behind clinical research. I'm OBY.

Brendan: And I'm Brendan. And we are your hosts. Think Research is brought to you by Harvard Catalyst, Harvard University's Clinical and Translational Science Center.

Oby: And by NCATS, the National Center for Advancing Translational Sciences.

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Everyday, we walk by and interact with nature that can offer solutions to complex problems. On today's episode, join us as we talk to Dr. Ben Freedman about his research, which focuses on the design and synthesis of adhesive bio materials for applications in orthopedic, cardiovascular, and neuro surgeries.

Dr. Ben Freedman is a research associate with Dr. David Mooney's lab at the Wyss Institute at Harvard University.

Hi, Dr. Freedman. Welcome to the show.

Ben Freedman: Thanks so much for having me.

Oby: Thanks for being here. I want to start by asking what led you to research. And then we can talk about the work you're doing now and where you hope this will lead in the future. So can you talk to us about how you got your start in research, a bit about your background and interest that led you up to your work today?

Ben Freedman: Yeah, definitely. So, kind of growing up I was always interested in kind of the sciences. I like to build things. I remember building this kind of toy robot that was turned into a life sized robot. And I didn't really like the design of the rest of the robot. I didn't think it allowed enough degrees of freedom and motion like a normal human wrist. So I added some motors so it could move in multiple dimensions. And I think that might have been an early sign that I was destined to be a biomedical engineer.

In high school, I was definitely interested in the sciences, not really sure if I wanted to go to medical school or what. And when I was looking at undergrad programs, the field of biomedical training was really expanding quite a bit. There were a number of new BME programs that were being formed. And it seemed like the really perfect blend of engineering and medicine. And that's what really led me to pursue an undergrad degree in biomedical engineering.

Got involved with research relatively early on in undergrad years, ranging from a bunch of different areas, not necessarily bio materials or adhesives at that point in time, but things ranging from trying to model different stresses in the knee joint using different finite element modeling techniques to looking at new imaging modalities to study motion of joints in the human body to even some more biological aspects involving mechanisms of joint replacement failure. And for all these areas, kind of cover the full spectrum of multi-skill properties within the body. And it really motivated me to want to pursue a PhD in biomedical engineering and bioengineering.

So I transitioned from University of Rochester. I spent a couple of summers at the NIH to the University of Pennsylvania to basically do my PhD in bioengineering. And there I had a special focus in understanding tendon and ligament healing. And we basically conducted a number of different types of studies during that period of time, trying to basically understand why tendons become injured. And if there might be some simple strategies that we can do to further improve the healing process by tuning different surgical procedures or post-op rehab strategies.

And that work was what really provided an awesome foundation for me, but I want to take a step deeper to try to understand if we could think about developing new therapies to improve the healing process. And it led me to Harvard and the Wyss Institute to work with David Mooney to really try to develop new biomaterial strategies to try to improve healing in really diverse tissue surfaces, still had a specific focus in tendon.

But it was really during this time that we realized that an adhesive material that could attach directly to tendon surfaces, given their motion and dynamic nature, would really be something important to try to improve tissue healing. So that's kind of what inspired a lot of our ongoing work and efforts, thinking about novel hydrogel based adhesives for tendon and other tissues throughout the body.

Oby: Wow. That is pretty impressive, even from childhood. I love the story about the robot and creating more movement in the wrist. That's fantastic. So we were reading about your collaborative research with Harvard School of Engineering and Applied Sciences. And can you tell us about your research and get a little more into that?

Ben Freedman: Yeah so I think I came into my post-doc very focused in orthopedics and quickly realized that there was a lot of opportunities in this work beyond orthopedics. Actually one of the biggest things that got me really interested in joining Professor Mooney's lab initially was all the exciting projects that were taking place within orthopedics, in other areas involving virtually every disease state, I think, in the body. So I think it really broadened my understanding for different indications that these materials could be used for.

And then we've also really been fortunate to have a number of exciting collaborators and interest from a number of different researchers and other groups within the Boston area and really the whole country for trying to apply these materials in different ways.

So within the Harvard ecosystem, we have a number of collaborators within the School of Engineering. We collaborate with many different surgical specialties in all the major hospitals in Boston. You know, ranging from the cardiovascular space, the orthopedic space, neurosurgery, dermatology, and beyond.

Oby: Can you take us a little bit more into and talk a bit more about replicating elements of nature into scientific innovations?

Ben Freedman: Yeah, great question. So we do a lot of work, not only with the School of Engineering, but also with the Wyss Institute. It's the Wyss Institute for Biologically Inspired Engineering. So a lot of the work that we do is really founded on the concept that nature has figured out some of the most complicated engineering strategies. Nature is really the world's most powerful engineer that's been innovating since the beginning of time. And we try to use some concepts from nature to try to inspire the design of new materials.

So in our case, we turn to nature and look at some natural adhesives that have really incredible adhesive properties. We try to use some of those features of nature to not only better understand some of the limitations of existing commercial adhesives, but also begin to think about how we can use those same design principles in our materials.

And when we turn to nature here, we were inspired by the adhesive slime secreted by the dusky arion slug. And this slug, as you may know, when it becomes threatened, it secretes a highly sticky and thick mucus that prevents it from being taken away by a predator. And this elastic and tough slime is basically composed of a dual network of many proteins, ions, and sugars that give the slime really incredible matrix mechanical properties that basically help it stay in place and prevent it from being taken away by a predator in times of trouble.

Basically there's a whole host of slug researchers that have analyzed the composition of this mucus and have identified its composition, but also its mechanical properties. And the mechanical properties of slug slime are actually quite interesting. The materials are quite tough. You can pull slug slime 10 to 15 times its length before breaking. And it has this dual interplanetary network. So we kind of said, oh that's interesting.

At the time in the lab, there was already a material that had similar toughness properties. We called it a tough hydrogel. It was a system that was developed before my time in the lab in collaboration with Zhigang Suo's lab and Dave Mooney's lab. And basically this material has really unprecedented toughness and stretch-ability for hydrogel systems. Most hydrogels are relatively weak or brittle in tension. This material you could stretch it 20 times its initial length without breaking. It's actually stretchier than a rubber band and it's about 90% water.

And it's interesting because if you look at the composition of slick slime, it's also about 90% water. It has a dual network just like our material. So we said, oh that's interesting. You know, what if we could use the high toughness properties of this base material and try to couple it to tissues?

So through a series of studies and the papers now that have been accepted for the past few years, a postdoc in the lab had done a big screen of potential ways to couple this tough hydrogel to tissues, and identify that basically a layer of chitosan was the ideal candidate to do the job. And this bridging polymer would diffuse into the gel and tissue surface and then form strong adhesion through really a multi-component adhesion strategy involving electrostatic interactions, physical interpenetration, and covalent bonding.

And we basically have been expanding upon the system over the past few years during my postdoc in the lab to basically investigate new strategies to take the materials to the next level. So we've been exploring things like making the materials degrade over time. Thinking about ways that we can apply them to all sorts of other indications and disease states throughout the body. Making the materials serve as drug or cell delivery systems and beyond.

So there's a lot of interesting things that we're working on to create the next generation of these tough hydrogels and tough adhesive materials. And we're really excited for some of the data that we've been collecting so far and think it has some exciting opportunities for improving tissue healing inside and outside the body.

Oby: That is incredible. So I have kind of, it may even be a bit of a silly question. How do you even know what to study, right, to your point about nature's the best engineer? There are a lot of things that you can figure out from that. And then you're talking about the slug. How do you get to the point of thinking about, oh, a slug may be the solution.

Ben Freedman: That's a fantastic question. There are some other adhesives that are out there in nature. And what's different about the slug is that when you look at the existing commercial product, there's been a lot of focus on exclusively trying to understand properties of the adhesive features of these materials and making really strong adhesion. But usually the issue is that these existing technologies may have very strong adhesion, but the matrix that makes up that adhesive is actually relatively weak. So the materials fail cohesively.

And the difference with our strategy here is that we're trying to think about a material that's actually stretchable. That has high toughness to prevent that failure of the matrix. And really once you do that, you're able to then take kind of the level of overall inter-facial toughness and adhesion that you can generate the next level.

Oby: Great. So we were able to meet you because you participated in one of our hybrid courses, TRANSCEND, which is a course for medical device developers looking to bring a device to market. Can you briefly discuss your experience and how it benefited your work?

Ben Freedman: Yes, so probably about a year or so ago, we applied to the 2021 TRANSCEND Program as a medical device. We were excited to gain more expertise in thinking about how to translate technologies and Transcend seemed a really fantastic fit geared towards med device and establishing the community of other researchers and entrepreneurs in that space. So we really enjoyed going through the TRANSCEND Program.

There's a lot of details online about the week-to-week syllabus, and things like that with the program. But at a high level, the program was great to further pressure test our concepts for how to translate and hopefully commercialize our technology. It gave us additional feedback on our pitch deck. The program also was really beneficial in putting together other documents, whether that be an executive summary or things like that that are also important in terms of summarizing the work concisely.

And then getting feedback on giving a successful pitch. Hearing other case reports of other entrepreneurs and academic entrepreneurs at Harvard and the other areas, sharing their experiences in translation, how they approach technologies in their own lab and begin exploring ways to get them out of the lab. And hopefully into the hands of people and patients that need the technologies.

So hearing similar stories, building that community, I think has been the most valuable part of going through the Transcend course.

Oby: Perfect. What future plans do you have for the work you are doing?

Ben Freedman: We're ultimately interested in being able to answer some really interesting basic science questions with our technologies. But also some really important translational questions and hopefully we'll be able to get the technology out there into the hands of patients at sometime in the future.

A couple of years ago, one component of the materials in the dental space was licensed to a company in Florida called Amend Surgical. So those materials in that specific area will be translated definitely in the dental space to improve different cases within oral surgery. So we're really excited about that.

In parallel, we are actively exploring opportunities for our materials to be used in other areas, inside and outside the body to try to improve the healing process. So through the experiences and TRANSCEND and other programs within the Harvard ecosystem and beyond, we're actively trying to translate these materials and take the necessary steps hopefully to get approval from major organizations like the FDA and beyond. And hopefully, at some point in the future, these materials may be available to surgeons to use for a lot of these different interesting and exciting unmet needs that they currently are faced with.

Oby: For aspiring researchers and medical device developers, what parting wisdom would you like to share from your experiences?

Ben Freedman: A lot of my training is on the academic side. During PhD-years you definitely learn a lot of new things involving the scientific method, conducting experiments, asking fundamental questions that can be tested with hypotheses.

What's interesting that in the same space you also use some of these same skill sets. We received a grant from the NSF I-Corps program, which was fantastic, focused on customer discovery. And just like we said, and we try to think about our hypotheses for doing scientific experiments, you do the same thing with customer discovery. You have a hypothesis who might, for example, buy the technology. And you try to test that hypothesis, or you have a hypothesis that you need to go to a certain stakeholder for a certain question. A lot of those things actually apply if you're in an academic research or if you're thinking about entrepreneurship.

Another important feature of all this is talking to people, making sure you're talking to diverse audiences and groups, folks that will be really excited about the technology, but also those that will challenge you for whether the technology will be adopted. I think that's a big part of the med device space that may be overlooked historically. But it's now really super important to really identify those that are really passionate about and excited about the technology, but also those that will challenge how easily it may be adopted. Because I think those are all really important questions to ask upfront.

I think there's also a number of things to consider if you're transitioning or thinking even about academic research in the context of translation for how to best design studies to optimize resource use and things like that. There's a number of guidelines and considerations from major organizations, whether that be the FDA or ISO or ASTM for how to best conduct studies. So you're designing studies that align with accepted standards. This is super important for optimizing resource use, as well as just really making the most of time and designing studies appropriately so that you can save time down the road.

I think those are really important considerations. Then also thinking about what are the necessary established pre-clinical models that it will take to get something translated. I think if you do the upfront work on the regulatory side, even if you're not necessarily immediately considering translation, I think it's still beneficial to have those discussions early, to see for minor tweaks that you can make sure you're doing studies in the best established models, model systems. And not over interpreting simpler model systems if you really have an eye towards translation of your work within the academic setting and beyond.

And I think the other important thing is that the time it takes to establish different relationships with groups, whether that be other stakeholders, clinicians, folks in major companies, these things all take time. So you always have to be thinking about building your network. I remember I was hearing other folks talk in the space, and they try to meet somebody every few weeks. I think now we try to meet multiple people new every week, if not every day. Because there's just so many folks that are involved.

So many important opinions and thoughts that are important in this process. So you just have to go out there and not be afraid to chat with people, have your ideas be challenged, and just keep pushing forward. Because there's thousands of people that will tell you something cannot be done. But you just have to keep pushing through and find the best way to make things come to life.

Oby: Thank you for that parting wisdom. And thank you for joining us for the podcast. It's really been a pleasure to have this conversation with you.

Ben Freedman: Yeah, thanks so much again for having me. Thanks again for this opportunity.

Brendan: Thank you for listening. If you've enjoyed this podcast, please rate us on iTunes and help us spread the word about the amazing research taking place across the Harvard community.

Oby: To learn more about the guests on this episode, visit our website catalyst.harvard.edu/thinkresearch.