Great, thank you. I always wanted to be on Shark Tank, but I guess this will do. So I'm really excited to be here. This is a unique session, as you've all heard. This is a partnership, our proposal, between the University of Pennsylvania and a spinout company called McKenna Therapeutics. In the setting of cartilage repair, the development of novel cartilage restoration procedures has led to an advancement in the field and ultimately a shift in how these patients are more successfully treated. However, cartilage integration following defect repair remains a clinical challenge. So our proposal is focused on improving cartilage to cartilage integration, as you can see in the blue CTA image there, and filling in this cartilage gap. Now we know that therapeutics have great potential to enhance cartilage regeneration, but current regenerative strategies have significant limitations, including uncontrolled passive release, rapid joint clearance, and lack of tissue targeting. Introducing mechanoactivated drug delivery. Leveraging the mechanical force of the joint, we created a unique delivery system to overcome the aforementioned limitations, known as mechanoactivated microcapsules, or MAMCs. The novelty here is the use of mechanical-loaded environments to cause rupture of the microcapsule shell and release the therapeutic payload, allowing for controlled and targeted delivery for stimulating cartilage regeneration. We've previously shown that we can modify the shell thickness to diameter ratios of these microcapsules, which results in different rupture profiles at different loads. The advantages of MAMCs include, as I just mentioned, mechanoactivated drug release, tissue adhesiveness, and controlled delivery or the ability of controlled delivery of therapeutics, all of which allow for improved tissue regeneration and functional outcomes. In addition to this unique delivery system, for our study, we chose FGF18 as a therapeutic. FGF18 is a fibroblast growth factor, and it really has an amazing profile, with strong in vitro evidence and clinical trial data all showing increased chondrogenic properties, making it an ideal therapeutic for us to include in our drug delivery system. Therefore, the aims of our project are, one, to fabricate MAMCs with an active biological therapeutic. In our cases, I've just introduced FGF18. Aim two is to evaluate the efficacy of MAMC-released FGF18 on improving cartilage regeneration and integrative strength. We hypothesize that treatment with MAMC-encapsulated growth factors will increase matrix synthesis and improve integration strength. Now, we're using an experimental, ex vivo experimental model over the course of four weeks. We will use six-millimeter bovine cartilage disks with a three-millimeter chondral defect. Outcome measures will include mechanical testing for repair strength, biochemical and histological analysis. We will establish the allograft model with one of two groups, fiber and glue versus no fiber and glue, and then compare across four treatments. No treatment, MAMC-encapsulated TGF-beta as a positive control, soluble FGF18, or MAMC-encapsulated FGF18. Then we will perform an allograft transplant and activate MAMCs with a mallet mimicking a true clinical scenario. Now, this technology was originally developed by our partner, Daeyoon Lee. The microcapsules are formed using a glass capillary microfluidic device using a double emulsion process in which the inner fluid, you can see in green, contains an aqueous solution where you can put any drug or model therapeutic of choice. So why propose this study? Well, we have exciting preliminary data that shows ultimately we can encapsulate and release active biological therapeutics from MAMCs. In this particular study, in this data, we encapsulated TGF-beta and released them from ruptured MAMCs that stimulated mesenchymal stem cell chondrogenesis. In addition, we've shown success with the delivery of anakinra, which is an interleukin-1 receptor antagonist, and showed that we could successfully inhibit the degradative effects of IL-1 comparable to soluble IL-1RA. Additionally, we have preliminary data using our allograft model that I just presented and in calculating integrative strength, which is peak force at time of failure divided by interfacial area. And in this chart, you can see that FGF18 can significantly enhance cartilage integration strength after four weeks of treatment. Now, this is all made possible thanks to our great team, Dr. George Dodge and myself, along with partners, Drs. Kelly, Malk, Lee, and Mohanraj. Collectively, you can see that we have expertise in cartilage biology, orthopedic surgery, sports medicine, mechanobiology, chemical and mechanical engineering. So, in summary, we propose an ex vivo experimental model using FGF18 to enhance cartilage integration and regeneration through novel MAMC delivery. If successful, this has the potential to revolutionize cartilage regeneration for cartilage repair procedures. By combining this novel platform technology with incredibly strong preliminary data and a right-click and a novel expert multidisciplinary team and a clinically relevant problem puts us in an ideal position not only to succeed, but rather in a position where we cannot fail, ultimately permitting bench-to-bedside translation with the unified goal of improving patient outcomes. Thank you very much. All right, great. Thank you. So, we've got a strict 10 minutes for Q&A. I'd like to start with our panelists who are here in the room. And just to avoid any communication issues, we'll then move to the remote panelists at about five to six minutes. Yeah, Nick, a great presentation, I guess. Overall, what is the proposal, which I think is very well outlined and excellent work, what do you see as the biggest limitations to the success of the proposal in terms of obstacles to overcome? Of the proposal itself or the technology? Both. Of the proposal itself, I think the biggest limitations are after we put the MAMCs in the defect and use a mallet to rupture them is getting them to stay in the defect. How can we quantify that? Obviously, besides just using a visual. And then for the technology, it's really about can we successfully activate them in a clinical joint? And that's the biggest limitation that I can save you a question, perhaps. We haven't shown this in humans. We have in vivo data and small and large animal models, but what are going to be the effects when we load it in a human knee? Great proposal and presentation. For the impaction or the use of the mallet, how will you control for the force that's being applied and ensure that that is uniform for every specimen? How much force is required to cause breaking of the beads? How do you know about this? That's a good question. So we do have preliminary data that shows that we can rupture all MAMCs at a maximum of five newtons, but we had a difficult time. We try to do this in lab. We had a difficult time standardizing force. So that as of right now is going to be a limitation inherently, but I think the external validity that it's a clinically relevant act may overcome the lack of me using a mallet and putting in a chondral defect versus you. And the goal here is that we don't care about the rupture profiles. We just want them to release instantly. So even though I talked about that being an advantage, we're not really using that in this study. We just need them to release automatically. So great study, great concept. The devil is in the detail, right? And one of the things when you're working with growth factors is dosing. So how do you know and how do you control the amount that you're releasing if you don't know how many of these vesicles are going to rupture? So that's a great question. How do we know about the dosing? And we have previous data that shows that we can deliver a dose at a corresponding specific load. So we're going to manufacture MAMCs and change the shell thickness based on manipulating the size of the shells, the thickness to diameter. And we already have proven that there's corresponding correlated forces that will release drugs successfully after we encapsulate them. So this is all published data. So we're going to use, to answer your first question, use our standard processes that have shown us we're able to encapsulate release active biologics. Secondly, I think for dosing, for this study, we're going to do a hit and run approach where we use 100 nanograms per milliliter of FGF-18 every 24 hours, once a week. And I mean, that's why we do this study. It's a basic science study. I guess there's no real way to know if it works until we do it. But hopefully, did that answer your question? Encapsulation and release? Can you tell us a bit about the relationship between the private organization and Penn in general and how you think that impacts potential bias or outcomes of the study? Sure. Well, a startup company, which is McKenna Therapeutics, is made up of all Penn faculty. So it's really just a way for us to do more scalable research and development that has limitations at an academic institution. So they have done great work for the past four years developing this technology at Penn at the University of Pennsylvania, and they have patented this technology. So now our goal, with the help of ON and other sponsors and financial institutions, is to do research and development towards a pathway of commercialization. So, I mean, it's biased, but ultimately, University of Pennsylvania cannot translate this from lab into the market where you as an orthopedic surgeon can use it. So you need a spin-out company, and we're really just licensing the technology back from ourselves. All right. For the international guys on the call, any questions that you have for Nicholas? So it's my turn now, am I right? Yes, please go ahead. Thank you for the interesting proposal. I did not get in detail the action of release, honestly. So what do you think, what delay of delivery of release is meaningful in vivo? And can you control or adapt the time of release so that you control three days, seven days, maybe four weeks, or even longer? It might depend on different diseases and different stages of disease. Yes. So the question is regarding how can we change the properties for mechanoactivation? And time is something that we already currently can use with microsphere technology, where we can degrade capsules over time and they can release in the joint. So with our technology, we can manufacture capsules that are thinner or thicker, and we know the exact load that they will rupture. And I guess the utility of this clinically is that we can combine eventually multiple growth factors and multiple anti-inflammatory therapeutics into MAMCs that can release at different time points throughout the postoperative healing process. So imagine if an anti-inflammatory drug released in the early postoperative process, and then a growth factor in the middle stages, and then maybe another advanced biofactor that allowed to prevent osteoarthritis. I'm just making an example. So the delayed action that allows for the mechanical force of the joint based on weight-bearing status allows us to create a paradigm where the joint releases the drugs. Sorry, that was like an open-ended question, but did that help answer your question? Thank you, Aaron. Probably not. May I ask something? First of all, congratulations on the idea. Correct me if I'm wrong. I understand that you have four groups. One is a control group, one without fibrin glue. It's only one with fibrin glue. Why do you use one group with fibrin glue and what is the rationale behind it? You use fibrin glue to keep the MAMCs in place? Correct. So we're using fibrin glue, like a Tisyl, to see if it improves the adhesiveness of the MAMCs, staying in the chondral defect. But to go back, there are two groups, fibrin glue versus no fibrin glue. So then there will be four groups in each, so eight groups total. Okay. Thanks. Maybe if I may ask a question. Pardon? No, I was going to say we have about a minute left, so I'll give you the last question. Okay, last question. I'm wondering, what is the registration status of FGF18? Is it possible to use it clinically? So Spirifurmin is a drug that is the recombinant version of FGF18, and it's entering phase three clinical trials. Thank you. All right. Thanks very much, Nicholas.

ex vivo experimental model

mechanoactivated microcapsules

cartilage integration

cartilage regeneration

MAMCs