Next, we'd like to invite Scott Rodeo back to the podium for a discussion on scaffold cytokines and pharmacologic agents. Scott. All right, thank you. Well, Nicholas, it took you a nice talk there, kind of beyond PRP. I'd like to go even further beyond and talk about other options and provide kind of a broader perspective on this whole field of orthobiologics. So obviously, we've heard a lot about blood products and cell therapy formulations, right, pretty much the whole morning and most of this meeting. I would submit to you there are other ways to augment soft tissue biology. We can use cytokines. We'll talk briefly about patches and scaffold materials, various pharmacologic agents that can be used that off-label or for new indications, nutraceuticals even, and lastly, even physical modalities. All of these are routes that we can potentially leverage in our patients. At the end of the day, maybe it's a combination of the above that is going to be most effective. Let's kind of jump in and start with cytokines. There are currently two currently available cytokines, purified cytokines that have osteoinductive activity. One is the Augment product from Wright Medical. I have no relationship with any of these companies. This is a platelet-derived growth factor with Abadia tricalcium phosphate carrier vehicle. The label is for ankle and hindfoot arthrosis, and then, of course, BMP2 delivered on a type one collagen carrier, approval for spine fusion as well as tibial shaft fracture and some oral maxillofacial procedures. So two purified cytokines, both osteoinductive. I would submit to you that off-label use in sports medicine might be considered for augmentation of soft tissue to bone healing. Think about the common things we do, rotator cuff repair, ACL reconstruction with a tendon graft and a bone tunnel, or a meniscus root repair. In all these situations, we need osteoinduction, we need bone kind of growing into soft tissue. Our laboratory over the past, gosh, well over 20 years, we have published a number of preclinical studies evaluating PDGF and BMPs and other osteoinductive factors in soft tissue repair. Our challenge as clinicians now is how do we take that to clinical trials in our patients? Here's just one example of an off-label use where I'd use BMP2 in the shoulders in a cromulofracture and most of the young patient, standard fixation with screws and a tension band wire, but I used BMP2 on a collagen carrier and then actually applied a bone marrow aspirate with thrombin calcium chloride to clot it there. So this is off-label, so we have to tell your patient that, but this is we're using osteoinduction. But there are some emerging candidate cytokines beyond osteoinduction for soft tissue repair that would be relevant to sports medicine. Probably two of them more important are connective tissue growth factor and TGF-beta-3. Some nice work from Chong Li at Columbia, just one particular example here on a meniscus explant model, where they looked at TGF-beta-3 at a sustained release formulation as well as connective tissue growth factor. Essentially this was a meniscus explant model and culture, but what they showed is that the combined delivery of these two factors did seem to improve healing of a vascular meniscus tear. Just one example of preclinical work, and our job as clinicians and scientists is how we translate this to clinical application. One further example, work we did, gosh, 15 years ago, we published a different BMP, BMP-12, which may be able to augment soft tissue repair. This is in a sheep model, rotator cuff repair, BMP-12 delivered on a collagen sponge. We look at these animals, we find improvements in fibrocollage formation. We see improvements in tendon repair strength. So again, just another example of preclinical work, cytokines, purified cytokines that might eventually have a role in this whole area of orthobiologics. Scaffold materials are certainly available. These are generally, there's a number of these materials that are marketed as essentially patches. They're marketed to reinforce soft tissue repair, sort of the indication. They are both synthetic and biologic materials, and a number of different materials have been used, kind of listed here, from allograft to synthetic materials to xenogenetic materials and then human dermal matrix-derived materials. Essentially, these materials can have either a biomechanical and or a biologic function. Biomechanically, they may be used to augment strength of repair, to kind of load share with the repair. And biologically, they can act as the scaffold. The matrix structure can support, essentially serve as a scaffold to support cell attachment, cell proliferation, ultimate matrix synthesis. So we're not asking it to have any biomechanical function, but just serve as a scaffold to support tissue regeneration. A number of these patches do have various bioactive factors and gets this whole concept of guided tissue regeneration. Most of these have been used over the years for tendon repair, but here's an example of using it. Oh, I don't know. Well, I don't know how to make that video play. This is actually a video. I don't know if you guys can make it play. Kind of cool. This is a guy named Thomas Piontek in Poland gave me this video. He's using a collagen patch here to augment meniscus repair. Just another concept of using these patch materials. I've not done this. It's kind of complex. But he uses type one and three collagen patch material kind of to augment a complex meniscus repair. And then he actually injects a bone maraspirate concentrate with this. So just another example of scaffolds. Another scaffold approach I would submit is stem cell sheet. So essentially, if you culture cells to confluency in a culture dish, they'll make a sheet that you can actually kind of peel off of the bottom of the petri dish. And these cell sheets that are kind of produced while the cells proliferate in culture, these sheets maintain the intact surface proteins. They form a matrix that may be very cell friendly. This matrix can facilitate cell adhesion, ultimate tissue repair, and regenerations. In this particular study, they used this type of cell sheet in a meniscus defect model and demonstrated that these sheets could promote regeneration of meniscus. So another scaffold approach for us. I'm using scaffolds produced by cells. Another area is pharmacologic agents. An active area of research is repurposing already approved medications, you know, essentially identifying new uses for approved or investigational drugs that are outside of the scope of the original indication. This essentially builds upon previous research on those different drugs. And right now, the improved digital technology and computing power allows very efficient searches of these tremendously large databases to screen compounds. And we can identify agents that are approved already for uses in other areas. So we already have data available now. We've got data on pharmacology, on toxicity, and that can certainly ease the FDA approval approach. So go through some currently available pharmaceuticals. These are all approved drugs that actually may affect soft tissue biology, just to run through a couple examples to give you a sense here. So parathyroid hormone, Forteo, used for osteoporosis. Well, in this particular study, they looked at using PTH to augment rotator cuff healing in patients. They had patients receive daily sub-Q injections for three months, and they had a matched propensity match control group. And essentially, PTH improved the rate of tendon healing. So it's an example where we might use this off-label. Simvastatin, the commonly used cholesterol drug. Statin medications do affect fibrochondrocyte proliferation. This has been done in vertebral discs. So this particular study looked at this for meniscus. In a rabid study, they made small cylindrical defects in the meniscus, applied simvastatin in a hydrogel. They found that simvastatin, in fact, promoted tissue regeneration in the avascular zone of the meniscus. Actually, we know simvastatins do affect BMP signaling and, thus, collagen. So again, a different use here for a commonly used medication. Cosentyx, IL-17 inhibitor, used for psoriatic arthritis. Nice work from Neil Millar has demonstrated increased expression of IL-17 in early tendon opathy. And they went ahead and used that concept, that baseline, that human work in an animal model, found that IL-17 inhibition attenuates tendonopathy in a RAP model. In this study, they used MR to look at tendon changes in this RAP model and found that IL-17 inhibition did have a positive effect. And that has actually led to an ongoing clinical trial looking at cosentyx for tendonopathy. And this is ongoing now, supported by Novartis. Cenolytic agents. So a whole concept of cellular senescence to become recognized as an important pathologic process that affects soft tissue biology. It's pretty well established now the loss of tendon stem or progenitor cells does occur with aging and that may affect the biology of tendons. So the ability to target senescent tendon progenitor cells may be a neat pathway that we can exploit or leverage here. There's a particular drug, dasatinib, which is actually used for leukemia that has an anti-senescence effect. But even more realistically or practically, quercetin and feicetin. These are two plant flavonoids that essentially have very potent antioxidant and senolytic properties. So again, just some ideas, some food for thought where we might eventually have some trials. COSAR, used of course for blood pressure. It's an angiotensin receptor blocker. We know that class of molecules inhibits TGF-beta-1. Johnny Ward's done a lot of work, this is when he was back at Pittsburgh, mouse models of muscle injury. They put losartan in the drinking water. They find improvement in muscle regeneration in those animals treated with losartan. See increases in the number of regenerating myofibers. There's reduction in fibrous tissue formation in these animals. And this has been used clinically now in some circumstances for prevention of fibrosis after muscle injury. Glucophage, metformin, commonly used diabetic medication. We know that there's accumulating data now that demonstrate that metformin attenuates OA by targeting chondrocyte apoptosis. These symptoms affect MMP expression in chondrocytes. They used a mouse model in this particular study where they put metformin in the drinking water and found some real effects histologically. So metformin administration to these animals led to reduction in cartilage degradation. There was improvements in the thickening and hyperplasia of the synovial membrane, decreased osteophyte formation, seemed to work through a protein kinase mechanism. But there was some accumulating data now on metformin here for arthritis. And lastly, doxycycline, the commonly used antibiotic. We know it's a broad spectrum inhibitor of MMPs. Work from Dan Grandy and his lab several years ago, they took a rat Achilles tendon transection model. Again, they gave these animals doxycycline via oral gavage. And they found that MMP activity was, in fact, decreased in these animals that were treated with doxycycline. And those animals that received doxy had improved biomechanical properties in their healing Achilles tendon and better collagen and fibro organization. This list, frankly, could go on. Vitamin D, testosterone, certainly it's anabolic. Vitamin C has antioxidant effects. There's work on natural glycerin patches in tendinopathy, this vasodilator effect. You might have heard earlier this morning, Shashish Bedi mentioned cermin, an antiparasitic drug that inhibits myostatin that may have a role in muscle. All these are kind of interesting pathways to think about. Lastly, don't forget factors that may impair soft tissue biology. These are other pathways that may be manipulated for biologic augmentation. That's simply the common things we should think about, smoking, diabetes, renal disease, vitamin D deficiency, obesity, fluoroquinolone antibiotics we know can affect soft tissues, nonsteroidals may affect soft tissues. All these we should think about. So in summary, certainly a lot of options beyond just bone marrow and PRP. I think discovery of these novel techniques is going to be informed by better understanding of the underlying cellular and molecular mechanisms of soft tissue healing. We certainly need to identify the biologic target. What is it we're trying to treat? Because that will help us to choose the appropriate and optimal biologic agent, like Bert was telling you about. We need to identify the optimal solution for different tissues and different targets. I think once we understand the underlying tissue pathology and we understand the biologic target, only then can we choose the optimal orthobiologic. And this should allow ultimately for this personalized approach to treating our patients. And at the end of the day, perhaps the most productive approach will be a combination of these therapies. Thank you.

soft tissue biology

platelet-rich plasma

cytokines

scaffold materials

soft tissue healing