All right, good afternoon. Thank you to the society and to John Kelly for the invitation to speak here today. I'm going to talk about the basic science of rotator cuff disease, focusing on tendon, muscle, and bone, and that's a bit of a stiff task to do in 11 minutes, so it'll be a relatively cursory, 10 minutes, relatively cursory talk covering many of these aspects just briefly. So I'll try to talk about the normal enthesis and what makes that environment unique, and then we'll talk about mechanisms of rotator cuff pathology, mostly focusing on the tendon, and then we'll get into risk factors for repair failure, and in this last little bit, focus on bone and muscle changes, disclosures there that aren't relevant. So the enthesis is a very unique environment where we have a significant mismatch in modulus between a very soft tendon and a very stiff bone, and this mismatch plays a role in healing and failure rates, and what we see is in order for this enthesis to work properly, there have to be different zones. We have the tendon mid-substance, which then transitions into unmineralized fibrocartilage, mineralized fibrocartilage, and then eventually bone, and with this zonal attachment, you can have significant force transmission from the soft tendon to the hard bone, but as Dr. Rodeo showed, the problem with rotator cuff repair is we don't reestablish this zonal enthesis, we have indirect attachment, we have slow healing, and we have reactive scar tissue formation that never reestablishes or recapitulates the normal enthesis, and that leads to our high failure rates. So in terms of mechanisms of rotator cuff tendinopathy, we have intrinsic and extrinsic factors, and this slide here shows there are a lot of factors that go into this, and again, in 10 minutes, we won't cover most of these, but intrinsic factors are really within the tendon related to vascularity, related to the collagen structure, the extracellular matrix, and this is where blood supply and genetics and other comorbidities play a role, and then with extrinsic factors, we have subacromial or external impingement, as well as internal impingement, and this gets into anatomical factors, muscle imbalance, and then there's the interplay between extrinsic and intrinsic factors, which may be in part due to overuse, but other factors as well. So again, not only is aging a risk factor for re-tear, it's a risk factor for developing rotator cuff tears, numerous cadaver and imaging studies showing the increasing prevalence of tears, both partial thickness and full thickness with increasing age. We looked in a mouse model at supraspinatus changes in young mice, 90 day old, 300 day old, and then 570 day old mice, and what we found was that tendon properties changed with increasing age, we saw decreased percent relaxation, as well as increased disorganization within the tendon itself with age. This can be due to a number of different things, advanced glycation in products have been proposed, and this is not only a factor in aging, but also other comorbidities such as diabetes. With aging, advanced glycation in products increase as a result of cell senescence and then accumulate within the collagen due to low collagen turnover rates, and in this recent study that came out that was a cell culture study, the authors looked at human supraspinatus tissue and then cultured it in control media as well as media that had low and high concentrations of ages, and what they found was that cell viability decreased with increasing concentration or with higher concentrations of advanced glycation in products. They also found that growth factors such as VEGF and HIF-1-alpha were increased with these ages present, and both VEGF and HIF-1-alpha have been associated with tendon degeneration and the development of muscle fatty atrophy, and they also found decreased tensile strength in the tendon cells, and so what we see is that the tendons with age become stiffer and more disorganized, and again, that's likely multifactorial. In terms of comorbidities, there are a number of different comorbidities that have been proposed. One of the ones that has been more popular recently looking at is the effect of hypercholesterolemia and hyperlipidemia. Joe Abood was the first to report on his patients that had increased serum lipids in the presence of rotator cuff tears, and this has been borne out in several other more recent studies. This study looked at insurance databases and found that patients that had higher total cholesterol and higher LDL levels were more likely to have revision rotator cuff surgery, but interestingly, the use of statins mitigated this risk, and then in a similar study looking at a retrospective review of a cohort of patients with ultrasound, they found increased re-tear rates in patients who had hyperlipidemia. When Joe Abood had first looked at this, we had access to a number of different animal tendons at Penn due to cardiovascular research going on there. These animals all had high cholesterol, and what we found in the supraspinatus tendons of multiple animal species, the stiffness and elasticity in the supraspinatus increased in the presence of hypercholesterolemia. And then when we looked at our rat rotator cuff repair model, we found decreased normalized stiffness in the healing tendon compared to the non-hypercholesterolemic animals. So again, similar to aging, we see changes in stiffness, we see changes in internal structure, both with normal aging and in the healing response. So now to shift mechanisms and move to extrinsic mechanisms, again, overuse plays a role here. I won't get specifically into trauma, but to talk about impingement, there's external impingement and internal impingement, and the question always comes up, which came first? Is it a rotator cuff tear or rotator cuff pathology that results in scapular malposition and scapular mechanical changes, or is it the malposition and dyskinesis that results in these underlying changes? So we looked at a rat model of scapular dyskinesis, we transected the spinal accessory and long thoracic nerves to induce winging, and then looked at the changes in the supraspinatus and shoulder properties, and we found that normal healthy rats that then had an induced dyskinesis or winging had increased glenohumeral stiffness and decreased range of motion in their shoulder. They had altered tendon mechanics that were time-dependent. The cellularity in the tendon changed, there were more cells that were more rounded, less spindle-like, and then there were alterations in the collagen as well as in the extracellular matrix as well. We found that if you added overuse, this was further detrimental. Both overuse and nerve transection alone affected the properties of the tendon, but together they were even more detrimental. And then when we looked at rotator cuff repair in these animals, the tendons were more disorganized, had decreased mechanics, and had altered histology following rotator cuff repair in the setting of scapular dyskinesis. So this goes to show that extrinsic mechanisms can induce changes in the tendon and certainly can affect healing in the tendon at the time of repair. So now to talk a little bit more about bone and muscle in the final few minutes here. We heard before about the risk factors for re-tear, we've talked about age, we've talked about some comorbidities, I won't get into smoking specifically, but we'll talk about bone here. And then when it gets to tear factors, tear size, tendon retraction, and fatty infiltration will relate this to muscle changes. So we know that the proximal humerus is subject to osteopenia and osteoporosis just like the other bones in the body, but there may be more prone to disuse osteopenia due to the non-weight-bearing nature, and we see most severe changes in the aging female population. Not only is it more of a global process in the proximal humerus, but there are specific changes in the greater tuberosity as well that result from rotator cuff pathology. Eric Waldorf and colleagues demonstrated that there was focal osteopenia in the greater tuberosity in the setting of both partial and complete rotator cuff tears. Meyer and colleagues showed that there was a greater than 50% reduction in cancellous bone density in the setting of full thickness tears. And then Lisa Galitz in a delayed rat rotator cuff model showed that bone mineral density decreased with time from transection. So a rotator cuff repair results in changes in the tuberosity, but then similarly those changes in the tuberosity affect healing rates or re-tear potential. And this is probably a combination of biologic factors as well as mechanical factors. There have been numerous studies to show that decreased anchor pull-out strength was associated with decreased bone mineral density, and that more severe changes happened closer to the articular margin. It's something that we need to think about in the elderly patient population with medial row fixation, as well as how we prepare the tuberosity as the cortical bone and the superficial trabecular bone has the greatest strength, whereas the deeper bone loses more strength in this condition. So finally to touch on muscle, we know that tear size location and chronicity impact the extent of muscle atrophy and fatty infiltration, and the more severe the muscle changes are, the more inferior the outcomes and repair results are. And we can see that the changes are pretty substantial. This study by Meyer and colleagues showed that with only 9% of tendon retraction, the muscle penation angle increased by more than two-fold, resulting in more than a 50% decrease in muscle fiber length and significant increases in interstitial fat and fibrotic tissue. So again, very small changes are what we'd consider minimal retraction, resulting in significant changes in muscle. And Dr. Gerber in his sheet model, and this has been borne out in human literature as well, showing that the muscle does not recover following repair. This is probably, again, multifactorial, but there have been some growth factors and pathways that have been implicated in this. Here PPAR gamma regulates adipocytes, and in a sheet model, PPAR gamma was upregulated following rotator cuff transection. Another growth factor, AKTM TOR, alterations were noted in this pathway and in upregulation in the setting of a tear, but also with denervation. Not surprisingly, these two pathways are linked, and if you block this with rapamycin, which is an inhibitor of AKTM TOR, it may be able to decrease fatty infiltration. Last year's Basic Science Near Award winner was also looking at this, looking at a different growth factor receptor, platelet-derived growth factor receptor, and its blockade and how that may be a potential therapeutic as well. So as you can see, the NTHESIS is a very unique biomechanical environment, which we have not been able to reestablish in our treatments, and that rotator cuff pathology involves tendon, bone, and muscle, and we need to figure out the key pathways and genes to understand and target our future treatments. Thank you.

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rotator cuff tendinopathy

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