 So listen, those of you who were at that event last night in the part of the pre-training for Lensex, we had a lot of residents there, Nick and I just, it was hard to bite our tongues but do know that there was a certain salesmanship going on there in regards to the technology and the rest. I mean, we've got it. They don't need to sell us on it. We're going to use it, but to make claims of refractive superiority or that the perfect capsule definitely results in different refractive outcomes is controversial at the very least. One study has shown that there have been multiple studies, in fact, essentially every other study has not been able to show that. So I just wanted the residents to know that it's very hard for me not to speak up when I'm hearing a sales pitch that's not supported by the literature, but rather than raise a meeting that was already going too long, going longer, I just wanted to announce that. Nick, anything you want to add to that as well? I mean, we hope with this technology to find out some of those facts and the rest. I think we're excited that we actually have the technology here to do some studies to see if we can substantiate some of the needs. Yeah, please. Thanks, Dr. Olson. So welcome to Grand Rounds. Today we're lucky, we're hearing from the Ophthalmic Pathology and Research Fellows, starting off we have Greg Kramer from New York. He's talking to us about prevention of PCO, so thanks Greg. Thanks, Brian. I'm Greg Kramer. I'm one of the Acura Pathology and Research Fellows this year in the Mamelis Werner lab at the Moran. And this morning I'm going to be presenting on IOLs and endocapsular devices that prevent post-operative capsular opacification through maintaining the capsular bag in an open or expanded confirmation. And I'll discuss more about what those terms mean in a little while. So I'm going to start by giving a brief overview of the relevant lens pathology. So incision of the anterior capsule, whether this occurs during the capsular rexis during cataract surgery or in the event of a trauma incites a wound healing response in the lens epithelium. And you could divide the lens epithelial cells into two groups based on their location and their functional behavior. The E-cells are equatorial cells located at the lens equator. When they're disturbed, they tend to migrate posteriorly and give rise to somarine during proliferation and the pearl form of PCO. In contrast, the anterior cells are A-cells. When they're disturbed, they tend to remain stationary, undergoing pseudofibrous metaplasia and giving rise to fibrosis. In addition, the natural aqueous humor is full of cytokines and growth factors that also have an effect on lens epithelial cell proliferation. TGF-beta is an example of an inhibitory factor, whereas interleukin-1 enhances LEC proliferation. Ultimately, however, devices in IOLs that enhance the circulation of aqueous humor throughout the capsular bag lead to a decrease in LEC proliferation. And Nishi impostulated in a letter to the editor at JSCRS that by increasing the flow of aqueous humor throughout the bag, you dilute the stimulatory factors and prevent them from reaching threshold levels required to have a stimulatory response. Now, while PCO has traditionally been the subject that's been given the most attention, the development and advent of specialized IOLs, in particular, dual-optic accommodative lenses, which require, rely on, relative movement of the anterior capsule relative to, anterior optic, sorry, relative to the posterior optic, these devices have spurred an increased interest in ACO. And this is because ACO is a fibrotic entity, and being fibrotic, it can interfere with this kind of movement and the proper functioning of these devices. And in this study by Dr. Warner and colleagues, she looked into many different PCIOL configurations and found that plate haptic silicone IOLs were associated with the greatest amount of ACO. And here you could see, at your left, a plate haptic silicone IOL. And in areas where the optic, the anterior surface of the optic contacts the posterior surface of the anterior capsule, it's practically completely opacified, whereas surrounding areas are relatively transparent. So the pathogenic mechanism in IOL-related ACO formation is this contact between the capsule and the optic. And this is confirmed histopathologically at right with that ribbon of fibrotic material. Now, PCO, there are six traditional mechanisms postulated in its prevention, three related to the surgery and three related to the IOL itself. And for the purposes of this presentation, I'm going to focus on the IOL-related factors. So first, biocompatibility. You want a lens that minimizes the inflammatory response when introduced into the eye. The second one is really important because this is what people traditionally associate with IOL-related PCO prevention. And this is the shrink-wrap effect, the idea of having tight contact between the optic and the posterior capsule. And in Apple et al's 1991 review paper on PCO, this is often referred to as the no-space, no-cells effect. And finally, having sharp edges, a square rectangular optic edge is also important in PCO prevention. However, through review of the literature and including several devices studied in this lab at the Moran, Drs. Mamelis and Werner noticed a pattern. They noticed that devices that expanded the capsular bag or maintained the anterior capsule far away from the posterior capsule and opened the bag were associated with capsular transparency. And there were 10 such devices that this has been observed in and has manifested in both PCO and ACO prevention. So why does this occur? And there are many mechanisms that have been postulated. And before I start, I want to say that it's likely the complex interactions of combinations of these mechanisms with each of the devices. And also that not every device has every mechanism and is associated with different combinations of these mechanisms. So in PCO prevention, the maintenance of the circular postoperative contour is important. Expansion of the bag or separating the anterior and posterior capsules. Exerting pressure on the lens epithelial cells at the side walls or mechanical compression inhibition of the capsular bag. And like we said previously due to the growth factors enhancing the flow and circulation of aqueous humor. And as was mentioned in association with Dr. Werner's paper, ACO prevention is mainly accomplished by preventing contact between the anterior optic surface and the posterior surface to the anterior capsule. So I'm going to onto the devices and I'm going to start with the capsular tension ring type devices. And I say CTR type devices because the equator ring, the capsular bending ring and the capsular adhesion preventing ring all have some critical differences from traditional CTRs. Traditional CTRs were designed to maintain the postoperative contour of the capsular bag and they do that successfully. However, these devices in addition are much thicker. And this thickness serves to expand the bag maintaining the anterior and posterior capsules maximally separated. In addition, all three devices incorporate sharp square or rectangular shaped edges. And this edge shifts the capsular bend from the equator to from the optic, I'm sorry, to the capsular equator. And by shifting the bend to the equator you create this sharp angle and prevent the centralized migration of lens epithelial cells via contact inhibition. And finally, the capsular adhesion preventing ring incorporates these holes into the apparatus that enhance the circulation of aqueous humor. And in this diagram it does a good job of showing that here you have the ring and the square edges prevent via contact inhibition the migration of lens epithelial cells. In addition, you could see that the thickness of the ring maintains the anterior capsule far away from the posterior capsule. And this is, I'm using the E-ring as an example and all three devices are similar. So at left you could see the arrows denoting the equator ring. In the center is a Sinsky style optic of the IOL. And as you could see here, the capsular bend is shifted to the equator. There's not much proliferative cortical material. And that the capsule is very expanded. And this visualization is enhanced via capsular staining. At right, the Sinsky IOL alone, you could see there's diffuse PCO and ACO. The capsular bag is contracted and the bend is at the optic. So in summary for the CTR type devices, PCO and ACO prevention occur. All right, I'll put this, shall I put it on hold? Okay, all right, I'll continue. So in summary, these devices prevent PCO and ACO by maintaining the circular. The square edge shifts the capsular bend to the equator. Expansion of the bag as we talked about with maintaining the anterior and posterior capsules maximally separated. Increasing the flow of aqueous humor. And ACO is prevented by maintaining the anterior capsule away from the optic. Now on to the IOLs themselves. And I'm going to start with the disc shaped lenses. Concept 360 is a disc shaped hydrophilic acrylic IOL. And it features six haptic components, angulated 10 degrees posteriorly. And there are three goals in its design. Maintenance of separation between the optic and the anterior capsule. And as you can see here, high frequency ultrasound in the human eye shows that the anterior capsule is far away from the optic. In addition, the Miyake Apple view, this is a posterior view, does a good job of illustrating its CTR effect. You could see that the device practically fills the entire capsular bag. And in addition, by exerting circumferential distension forces throughout the equator, it minimizes formation of posterior capsular striate and posterior capsular wrinkles, which can represent an additional pathway for LAC migration. And finally, PCO prevention. Next lens is the Zephyr IOL. It's also a disc shaped hydrophilic acrylic. And at the top left, you could see in high frequency ultrasound in the rabbit that the optic is vaulted posteriorly. And this allows maximal separation between the optic and the anterior capsule. In addition, it incorporates perforations into the haptic apparatus, enhancing the flow of aqueous humor throughout the bag. And in the rabbit studies, you can compare the Zephyr to an aqueous off control lens. And you could see the relative capsular transparency in the rabbit model. Very interesting in this study, in the rabbit study, was that even when the IOL was accidentally inserted upside down, due to its CTR like effect, because of its disc shape, it maintained, this did not affect PCO, illustrating that tight contact between the optic and the posterior capsule is not necessary in PCO prevention. And that other factors must be at play here. So the perforations enhanced aqueous humor flow. The CTR effect was very important. It expands the bag and ACO prevention via the same mechanism I've been mentioning previously. Now onto the dual optic lenses. And I'll start with Harrah's spring loaded IOL. And this is a precursor to the synchrony lens, which I'll talk about next. So this lens features two six millimeter PMMA optics and four obliquely oriented polyvinylene fluoride rings. And these rings have a spring like effect, allowing through torsional compression the device to be incision in the eye. However, once inside the capsular bag, it opens up very quickly and applies pressure to the sidewalls at the optics. And Harrah had all postulated that by this pressure on the lens epithelial cells prevented LEC metaplasia. And they termed this mechanical compression inhibition. And this lens was successful in preventing PCO and ACO at areas of contact. Now the synchrony IOL is an interesting lens. It's a dual optic accommodative lens. And as we mentioned with Dr. Werner's study, silicone plate haptic IOLs were associated with the greatest amount of ACO. And especially since this lens relies on the anterior displacement of the anterior optic relative to the posterior optic to get this accommodative design. And as you could see on the lower right, these red arrows denote these expansions emanating from the anterior optic surface that serve to lift the capsular rex's edge up and prevent contact between the two structures. And here, histopathologically, you could see that the bag is very expanded, the anterior capsules far away from the posterior capsule. And with the synchrony, there's just limited somerns ring formation at the equator. Contrast this with the traditional plate haptic silicone IOLs in which there is diffuse ACO and PCO. So by lifting the rex's edge away and expanding the bag, the synchrony prevented postoperative capsular opacification. And now onto the silicone oil filled fluid vision IOL. And this lens is very different. It features these gigantic haptic components that practically fill the capsular bag and maintain the anterior capsule and the posterior capsule at a great distance from one another. Now, these haptics are deformable and filled with refractive index matched silicone oil. And in efforts of accommodation, deformation of the haptics drives the fluid from the haptic components into the hollow hydrophobic acrylic optic chamber and making it a rounder shape. And this really simulates the natural accommodation. Now, in the rabbit studies, and I want to point out that this is six months. And for those of you who've worked with rabbits as a model for PCO and ACO, you'll know that six months in the rabbit is equivalent to years in the human eye. And to have this little proliferation and this kind of transparency at six months is truly incredible. And contrast this with the control IOL, which is plainly visible right there. And now I'd like to discuss our current project, which is a protective membrane. It's made of silicone and the silicone membrane is introduced into the capsular bag and an IOL is introduced into it. In addition, the membrane features a pattern on its posterior surface and this pattern has an in vitro study has been shown to decrease cellular adhesion. And due to the bulky nature of the device, you could see here that the capsular bag is very expanded. So far we've had success in PCO prevention and with the protective membrane at left, you could see that it's relatively transparent. And this has been submitted for presentation at the ASCII meeting and we're submitting it to JSCRS. And it's an ongoing project. So the take home message I want you to leave here with is that there are 10 devices in IOLs that have successfully prevented both PCO and ACO through expanding the capsular bag and one last time maintaining the antrink wrap effect traditionally postulated is not the whole story with regard to IOL related. Thank you very much. This is from my first fly fishing lesson surrounded by musicians that got my heart pumping. Clayne is going to now present to us about multi-component lens technology. Good morning. By the feet you pulled off the flashing lights and the noises. Hopefully I won't have anything like that again. But my name is Kyle, I'm Clayne. I am also an Octopathology and Research Fellow this year in the Mammal Smarter Lab. Just for clarification, I have no financial interests, any of the materials that I've made this morning. I'm excited to talk about a project that we've been working on and that we're now in the process of submission for involving a multi-component IOL system. And so I just want to talk a little bit about this technology, which is a fairly new thing. And as an overview of kind of what I'm going to discuss, first we'll just kind of give a little brief introduction to what the need might be. Or why is this technology being developed for IOLs in general, not just multi-component, but we'll look at a variety of different ideas that are out there as far as making an IOL that can change. And then the focus though will be on multi-component IOLs or multi-component IOL systems. And there's two in particular that are now advancing more in the trials, one in Europe and one in the United States. And this last one here is the one that we've had a chance to work with in particular. And we'll talk about maybe what are the benefits or what does the future hold for this kind of technology. And so, you know, why would there be a demand or a need or an interest in an adjustable IOL is the question. And there's probably many reasons. These are just a few maybe ideas, the first being, though most surgery is very successful, and you can see there's a large percentage of Kedric surgeries that get a very good outcome as far as refraction or need for refraction. There still is a decent percentage of people that might not be satisfied. You can see that according to the surveys Dr. Manlis hasn't explained that IOLs, it's still a very common reason for an explanation in exchange. And that is an incorrect lens power. And so it depends on the material, but I just pulled an example here. For example, on a three-piece hydrophobic lens, it was the most common reason in the last published survey. And so it is an issue and it's something that certainly can lead to better patient outcomes. Another interesting area that is being recently discussed and I'm sure has some controversy is in pediatric surgery, and possible benefit in children who have cataracts and need cataract surgery. And then the last area that I'll just touch on very briefly is possibilities with multifocal orthorica IOLs. And so what are some of the ideas that are floating around? And these are not an all-inclusive list, certainly, and I am not an expert on most of these or probably any of these, you could say. But just to kind of give you an idea, there's been published the idea of mechanically adjustable IOL. And so one where you can go in and physically rotate a knob or something that will help change the lens power ever so slightly. Similarly, there's one that's magnetically controlled. And again, these are very, very experimental. These are not things that are going through trials or going to be on the market anytime soon. This one I just thought was really interesting. The idea that you can make an IOL with liquid crystal inside and that wirelessly you can change the makeup of what's inside the IOL to change the lens power. I thought it was very outside the box and very interesting. But again, very, very, very experimental. This fourth one here is further along. This is actually a lens that is going through trials and one that we've seen in our lab this last year. And that is the light adjustable lens. There's one from Calhan Vision that I believe was presented just about a year ago by a fellow in his talk. But this is a lens that using special apparatus and light, you can adjust the power of the lens. And then our last one here is what I'll be discussing and what our project revolved around. That is a lens with multiple components that can be changed to change lens power, for example. And so the first one I'll talk about is the Prethesite IOL. Again, this is from Infinite Vision Optics, which is a company based out of France. And this is an IOL that currently is in trials in Europe and looking for approval in Europe. It's a simple concept, a two-piece concept. So here you see there's a base plate or the base part of the IOL with two or four haptics, however you look at it, it's holding the bag open. And then on top, they've placed this optic piece with two little wings. And so these wings slip under these bridges that they've built into the base. And what's interesting about their design is that that second piece or the optic sits on top of the anterior capsule. So that is not within the bag. It is a hydrophilic acrylic design, again a two-piece system. And again, it's a little unique in that you have one piece sitting completely in the bag and then that optic which sits outside. And those wings are sitting on top of the anterior capsule. And they've actually done this in humans in six patients, six eyes. They've implanted this lens. And they did a two-year follow which came out recently last year. And it's still early, you know, it's just a two-year follow up. But so far they were very encouraged with what they've seen. No PCO has observed any of the eyes. The base of the IOL seemed very stable. And there was no entanglement to your fibrosis or pacification. And the patients in general were very satisfied with the outcomes. And there actually wasn't any need to consider any exchange or what they call enhancement surgery of changing out the optic. And so so far it looks like according to them things have gone very well with this lens. And so now I'll come to the Harmony Modular IOL system. And again, this is by Clarivista. This is a lens being developed in the United States and that is looking for approval in the United States. And it's a little bit different in its material, hydrophobic acrylic versus the hydrophilic acrylic lens. Again, though it does have a similar two-piece design where you have a base that sits within the bag. But this time, the optic as well will sit inside the bag within the base. We'll take a look at that a little bit closer to give you an idea of how that works. So this is just a video of how the lens will be implanted. And so you can do this through a clear coronial incision. There's an injector. Just like a standard IOL, you'll inject it into the bag. It is foldable material. And in our experience, it unfolds pretty nicely. Maybe not quite as nicely as that video. And then again, a second injector with the optic piece is placed. And then with a little bit of manipulation, you can slide the first wing into that base piece. Then using this little manipulator hole, slide the second one in as well. And so ideally, with two small manipulations, two small maneuvers, you could have the optic securely in place. And again, that hole allows you then, if you want to come back, to just slip that end out, pull this other end forward, make the optic out while leaving the base. And we haven't done that. There was one report of the Presse site, the European version. They've done one exchange. And it was outside of that study. So it was a commentary that they sent in, but they said it went well. So I'll introduce our study. This is a rabbit study with six rabbits. And the design was to put the test lens, the IOL system, in the right eye. And then a control lens, which is just a commercially available single-piece hydrochloric acrylic in the left eye. And we followed these rabbits for six weeks, doing slant-lamp exams throughout that time, followed by a nucleation and further examination through Miyake Apple View and Histopathology. And we found lots of interesting results, so much so that this will be something that is in submission, something that we'll be able to present later on at AskRace. But to get to the results, this was at two weeks. And you can see in this short time frame, not a lot is different. This is our control here on your right. And it looks nice and clear. And on the left here is the test piece. You can see it's nicely in the bag. You have the nice, manipulative hole here that's kind of going to orient us to make sure that this is stable and keeping this place in the bag. By week four, and again, as Greg mentioned, the Rata model is a very accelerated model of PCO. And so by four weeks, and a control lens like this, you expect to start to see some of the pacification of the capsule. And that's illustrated very nicely here. And traditionally, it will start at the optic haptic junction, as you see. Here's the haptic here coming down. And it's budding out and starting to fill into the center. And the same thing is kind of happening over here. It's a little bit shadowed. However, if you look over on your left, the test lens looks very good at this point, focused on the posterior capsule. And again, that manipulative hole is right down where we left it. And so it's holding a good position. It's very stable within the bag of this. And by week six, you can see we have quite a mess of a pacification in our control lens, covering the entire thing. Whereas in our test lens, it's pretty clear. A few giant cells here and there. Other than that, though, it's very clear. And again, the manipulator hole is in the same little spot where we left it. Showing some good stability. And so I want to flip 180 degrees now. And so after the rabbits are sacrificed and the globes are repaired, we've got a nice Miyake apple view. And if we again look at our control over here, standard IOL, you can see the entire posterior surface of that capsule is opacified in contrast to our control lens here. And luckily I'm coming, I'm presenting after Greg who presented kind of some of the theories and the reasons that that we might see the reduction in PCO. And what we feel is in play with this particular device is this nice long square haptic here. Covering this entire side and creating that contact inhibition with the capsule bag, preventing migration of the lens of the cells. So that's kind of what we feel is working here in this device. And so just to confirm that with some histopathol. Again, this is our test device. I'm going to outline the bag here for you. Very clean on both the anterior and posterior surfaces. No summaries ring. In general, it looks like a very good, very nice eye. In contrast to our control, which only after six weeks, again, not a particularly long study like the six-month study we saw before. But already you can see significant material forming on the posterior capsule and anterior capsule as well as two very nice large summaries rings. And so, you know, we were very, we thought the results were very, very interesting and had some interesting future implications, which I'll discuss just briefly. And one of those is for use in pediatric surgery, as I mentioned before. And I know this is, you know, this is a topic that will be debated, discussed. But there's actually a nice little commentary paper by Dr. Portaleo, who is working with the Presocyte lens, the European lens out of Greece. And she presents some interesting ideas. One is pretty understandable given the design of the lens. And that is that there might be an easier time adjusting or changing out the optic, particularly in a child whose refractive means will change with time as they grow and as the eye develops. Also, the children are big problems, PCOs and inevitability. And again, encouraging the rabbit model is that this lens seems to at least slow the progression of that from occurring. And then she presents some other ideas I thought I would just mention briefly, particularly in very young children where there's a lot of debate as far as whether in Iowa should even ever be considered whether a child should be left at faking and just to give in context. And then that opens a discussion about what is compliance and trying to use context in a child. And so she presents, maybe this will give surgeons more confidence in considering a lens like a multi-component lens that is adjustable, that might slow PCO and some of the other positives that we've seen. Another point that she brings up also is that if a laser treatment were to be used, and this is not just for a child or a posterior capsular axis is made, because that base piece stays in place, it might make future surgeries safer because you can just remove the optic, leaving a nice base in the bag, preventing vitro fluid leak, for example, and providing a more stable surgery in the future after such treatments. And so some interesting ideas certainly, an interesting concept to consider, a benefit this might provide in the pediatric population. And then, of course, in adults some of the same things are of great benefit. As we saw, it's not going to be 100% as far as reaching the ideal lens power, refractive outcome. And there are a number of ways you can approach how to treat a patient afterwards, whether it's coronal surgery or adjustment of the lens, but this might make lens adjustment easier, particularly on patients who maybe don't have other options. And then, of course, PCO is still an issue, particularly in patients on the younger side of the adult cataract. And then the last little point is multifocal IOLs. You probably can see along the same lines as what's mentioned for lens power. This might provide an opportunity for a patient to try to see if they will adapt well to the multifocal, or to use the multifocal, and then if they later were to develop something like a macular degeneration, it might provide an easier exchange to a different lens or a monofocal lens from the multifocal lens. And so, you know, it's an interesting project, and I think it's an interesting technology, and there's still a lot to discover. Again, we in our project haven't taken out lenses or been exchanging back and forth, and so that's certainly an area that will be further explored. And I think another interesting thing to think about is, you know, the base is made to stay in permanently. If it does have to come out, how will that work, how easy will that be, I think is another interesting question that we'll be exploring. I'd like to thank my mentors, my co-fellows, who also work very hard on this project and others.