I guess that follows, and thank you. This follows nicely on that discussion, then, so a little bit of information here on patches and we'll move ahead here. Disclosures here, some research support, nothing strictly relevant, frankly, to what we're going to discuss here today. So as you know, there are a number of different matrices marketed as these patches to reinforce soft tissue repair. They can be synthetic, biological, a lot of different materials we'll talk about briefly here. The FDA approval is listed here for reinforcement of the soft tissues which are repaired by suture or suture anchors during cuff repair surgery, and again, a number of materials have been used over the years, allograft materials, synthetics, xenogenic materials, some pictures here of the different formulations and sizes and compositions of these materials. So do these have a role in biologic augmentation? You've heard some nice talks that kind of sets the stage here. I think I'll start by saying these materials can have both mechanical and biologic functions in the shoulder. They can certainly augment the strength of repair, so as far as their biomechanical function, they also have a biologic role, providing a matrix structure and the composition of this material that may stimulate or support tissue formation. Some of these contain various bioactive factors as well that may play some role. We'll talk a little bit about that here. They can certainly act as a scaffold for cell attachment, proliferation, and ultimately matrix synthesis and so-called guided tissue generation. So that's sort of one of the underlying concepts for these patches when these developed and started to be used, gosh, 20 years ago. There is tremendous variability, though, in the materials, the resulting biologic response, and thus the ultimate clinical outcome in these materials. There are a number of different methods of processing, how these are decellulized, how they undergo manufacturing and processing and packaging, the degree of collagen cross-linking is variable amongst these materials, and these factors all contribute to the heterogeneity in both the local biologic response to the material as well as the degradation and remodeling process that occurs, and ultimately the structural properties of this material. There are varying rates of tissue resorption, incorporation into the native tendon, and then the remodeling and maturation of their material properties. So really a lot of heterogeneity amongst these different materials, and this is just a simple chart by no means exhaustive that lists some of the different devices out there, and just for me to focus on the kind of left side, the species, you'll see there's tissues derived from human tissues, porcine, bovine, there are synthetic materials. All the way on the right side, the different methods of sterilization, chemical, gamma radiation, some proprietary methods, so it just gives you a sense of the heterogeneity in these materials. Clearly, tissue processing and sterilization will have a very important role in the biologic incorporation of these materials. In general, a connective tissue matrix that is minimally processed will support some tissue regeneration, as you've seen in the nice talks that you heard on these porous collagen, this bioinductive implant. In contrast, tissues that are materials that have some degree of damage to the matrix, which can come from the processing, that can lead to more of a fibrotic response, which is less favorable. And lastly, some of these highly processed, in particular cross-linked materials, they're kind of encapsulated and walled off, kind of a foreign body response, which we don't want. So, these implants, in summary, have widely varying biologic and material properties. A list here, four different ways that these patches may be used to kind of set the stage to kind of, as we move along here. First is interposition, to bridge a gap when the tendon cannot be mobilized to bone, kind of you can't, you've got to do a full repair, so this is an interposition. Allison Toth has published some nice work in this area. Number two, it can be a load-sharing implant, where it's rigidly fixed to the tendon and bone to stress-protect your repair, to augment the biomechanics. This is used when the native tendon can be repaired to the footprint. You might put this patch on top to load-share. Third, it can be used in augment, and that's the talk she just heard, using this bioinductive implant, where it serves as a scaffold to support tissue formation in or on or around the tendon. And this application of the patch essentially serves as a scaffold to support cell migration, cell proliferation, ultimately matrix synthesis, where it does not provide any real mechanical role. And lastly, there's a new one developed now, it's placed at the interface, the tendon-bone interface, to support tissue healing at that tendon-bone interface, and I'll list some of these here. I have no relationship with any of these companies, but this gives you a sense of how these different patches may be used. So the question was, do you put them on the top or the bottom? Our recommendation is to place the patch on the superior aspect of the tendon, on top of the repair. I'll give you four reasons to support this recommendation. Number one, healing of a tendon of bone proceeds from bone engrowth and new tissue formation from the bone into the outer tendon. We want to avoid a barrier at this interface. We've done a number of studies over the years in our laboratory and different animals. This is a sheet model of cuff repair. You see this vigorous new bone formation at the healing attachment site, a route model where we used a dual-touch acyclic label to look at mineral opposition. Again, you see it's mineralization, it's bone that grows into the outer tendon. Rabbit model here, again, demonstrating new bone formation, so healing comes from the bone side. I would submit to you we want to avoid a barrier right between the two there. Number two, healing occurs by formation of a fibrovascular interface tissue at the attachment site, and so that scar zone forms. We would like a narrower interface tissue, because that correlates with superior attachment strength. Again, some work from our lab is actually a rat model and an ACL reconstruction model, but the biologic events are very similar and are instructive here. In this particular data I show here, we used a substance, a bisphosphonate, to deplete macrophages. When we did that, by doing that, you diminished that scar tissue interface. Essentially, what we find is if you have a narrower interface, as you see on the bottom histology there, that is associated with improved attachment strength, better material properties or structural properties. So the macrophage depleted group, we had this narrow interface. That correlates with superior attachment strength. Number three, I think that, frankly, the most reasonable rationale for these patches appears to be the ability of a patch to support new tissue formation, thus thickening the native tendon. That's what you just heard in the bioinductive implant talks there. Thickening the tendon decreases stress concentration in the pericellular matrix. This is based on nicely done finite element models. This is one from Itoi here, on the bottom there. If your tendon is thinner, you see there's higher strains, the brighter colors, in your tendon. We know the local strain at the injury site does contribute to impaired healing and may play a role in tear propagation for these partial tears, and that's kind of the rationale for using these materials in your partial tears, as you heard from Dr. Bushnell there. The goal being the induction of a new layer of tissue on the bursal side can reduce microstrains in the tendon and optimize your mechanical environment. You see anywhere from 40 to 50 percent reductions in strain if the tendon is thicker, and this is based on finite element models. So this new tissue formation would appear to be more likely to occur in the subacromial space versus the intrasynovial environment. I'm going to put that same point right here to start this next slide. Again, new tissue formation would appear to be more likely in the space versus in the joint. And here's some data here. Des Bakker published a small study, 13 patients, partial thickness cuff tears. You've heard a nice study now with certainly more patients, again, using the same highly porous collagen implant material, but they used MR here to look at tissue thickness, and they measured about a 2.2 millimeter increase in thickness. So these materials do support tissue formation. Now how that ultimately functions remains to be known, and further information is needed, but clearly these materials can't support tissue formation. Steve Arnoxy then went on and looked at biopsies in a small number of patients using the same highly porous collagen material. What they see is progressive infiltration with host cells. So this does support cell infiltration. Cells become aligned along the orientation of the collagen implant structure with loading. There's gradual collagen formation, maturation, and eventual organization of this tissue, which suggests that the tissue is being loaded. So it is playing some role. It's being loaded here. We see over time at six months, more regularly oriented connective tissue. There's no evidence of the implant at the six-month biopsy, and importantly, no real evidence of an inflammatory or foreign body reaction. Again, these are minimally processed tissues. Remember at the beginning I said if these are more highly processed tissues, you get a different response. So these seem to be quite inert and well tolerated. And my last reason to favor putting the patch on top is the intra-articular environment is harsh. It is not favorable to tissue formation, whether that's in the shoulder or in the knee after an ACL graft. Fibrin clot formation we know serves as a provisional scaffold in connective tissue healing. We know there are fibrinolysates, enzymes in the post-surgical joint that break down and prevent formation of a stable fibrin clot. Some work from our group, Katherine Robertson is a fellow, about nine years ago we looked at a group of 35 patients undergoing cuff repair. We biopsied tendon, synovium, and bursa. And we looked at tendon healing with ultrasound. And we found upregulation of two important MMPs, MMP1 and 9, these proteases. And presence of these MMPs was highly correlated with failed healing. So the presence of these excessive enzymes may break down your healing tissue, that early granulation tissue that you want to form there. So instead of on top or the bottom, how about in between? Again, this interposition. Again, Allison Toth and others have done nice work in this area over the years. This is one nice study, 60 patients from Allison's group repaired this. Now, these are massive cuff tears using a porcine acellular dermal matrix. This is where the tendon could not be repaired. This is an interposition. And there's good subjective data reported. There is some weakness that persists in these patients. These are tough cuff cases. Ultrasound demonstrates there's tissue incontinuity. But one concern with this technique is muscle works in a length-tension relationship. If we can't reestablish that muscle tendon length, that will affect your power. And to kind of drill down further on these materials, Kathy Derwin did nice work back 15 years ago. Look at the material properties of four of these different patches. What she found is that all four of these different extracellular matrix patches required 10% to 30% stress before they began to really carry any substantial load. And in fact, the elastic moduli of all of these materials rock an order of magnitude lower than normal tendon, circled in the red there. So these are much less stiff than normal tendon. And this disparity between the moduli of these matrices and normal tendon would suggest that if you want this to be a load-sharing augmentation device, these matrices would likely really carry only small loads. So be careful about hoping this is going to have a biomechanical effect. If you use the primary graft to connect tendon to bone, these matrices could stretch appreciably under the associated muscle and joint load. So some further limitations of our patch materials, and maybe it sets our research agenda moving forward. Clearly, we need to match the rate of degradation of the material properties of the patch with the corresponding new tissue formation. It's kind of a race. As the material absorbs, we're going to form new tissue. There needs to be gradual stress transfer to this newly forming tissues, as appropriate mechanical loading is clearly critical for development of optimal matrix organization and ultimate material properties in this developing tissue. Some earlier studies demonstrated residual DNA that can be detected in some of these materials, in particular the porcine small intestinal submucosa, now off the market, but there is residual DNA. That may happen with other materials, and it certainly has implications for the underlying inflammatory response and immune-mediated reaction. We need further understanding of the changing material properties of these patches, and that will help inform our post-op rehab strategies. We clearly need a much more sophisticated or nuanced approach to mechanical loading of these materials. What is the optimal type of load? Is it just the tensile loading? Do we want to think about other modes of mechanical loading? What's the timing of application of load? What's the optimal load magnitude? These are critically important questions that we need to get our hands around clinically. Clearly further study is required. Most of the research over the years has kind of focused on the biomechanical function of these materials in mechanical studies. I would submit to you that we clearly need better understanding of the biologic events that ensue in these materials. Hopefully we can identify an optimal exogenous cell source that could potentially be added to this patch. Use this material as a carrier vehicle for cells. If we do that, we need to identify what are the signals to stimulate appropriate differentiation of these cells? Whether we put stromal cells or marrow cells or some other cell population, how do we stimulate those cells? What is the mechanism of healing between either the patch and the native tendon or bone on the lateral side, up to your tuberosity, or on the medial side to the muscle? What is the role of immune cell subtypes in the healing process? We and others have demonstrated various macrophage subpopulations, T-regulatory cells, other immune cells probably play critical roles in initiation and regulation of tendon healing. These are all outstanding questions that really we need to understand when we use these materials. So in conclusion, these patches may certainly play a role as an augment. They can serve as a scaffold to support cell proliferation and new matrix synthesis. Again, this biologic role I think is well established. I think we need to develop materials with improved material properties and probably surgical techniques as well to allow a patch to truly play a mechanical role in stress protection of a tendon or as an interposition for an irreparable tendon. Clearly, the microstructure, the tissue composition, the chemistry, and the material properties, all of these will affect the biology of graft incorporation. In the future, novel tissue engineering approaches using nanofibers are being developed and are very promising in this area. And I have to always end with a plug for biology. Nothing happens without cells. None of these materials integrate, heal, proliferate, synthesize matrix without cells. We need to understand the underlying molecular mechanisms of cell migration, how those cells proliferate, how they can differentiate and synthesize new and effective matrix. Thank you.

matrices

patches

soft tissue repair

mechanical functions

biological functions