 I'm going to be soft-spoken, so I'll try my best to speak up today. I'm Ashley Brondrette. I'm one of the cornea fellows. And today I'm going to be talking about Dweck or DSO, which I'll explain later, and other new therapeutic possibilities for patients with corneal endothelial dysfunction. I have no financial disclosures. So kind of a basic review here. The corneal endothelium is the innermost layer of the cornea. Its job is to maintain transparency of the cornea by regulating the amount of water in the cornea, and basically by ionic pumps and also barrier function. It has a poor regenerative capability. So in general, when there's damage to the endothelium, the main mode of repair is compensatory migration of the residual cells into that damaged area, usually with enlargement of the cells. Normal endothelial cell density is around 2,000 to 2,500 cells per millimeter squared. Depends on age. And typically, when you reach a critical level of between 500 to 1,000, this can result in corneal decompensation, corneal edema, decreased vision, and even scarring. So the most common causes of endothelial dysfunction that we encounter, number one, fuchs endothelial dystrophy. So a dystrophy of the endothelium causing an eventual loss of endothelial cells in patients, usually presenting in the fourth or fifth decade of life. Iodrogenic, so typically after intraocular surgery, trauma, and then also just other corneal endothelial dystrophies congenital or otherwise. So just some pictures here on the bottom left is just that beaten bronze appearance of the corneal endothelium you can see at slit lamp. And then a specular microscopy photo showing normal endothelial cells on the left and on the right drop out of endothelial cells and loss of morphology. So typically what you'll see with endothelial cell dystrophy. So current therapeutic options include medical therapies. So we'll use hypertonic saline drops or ointments to draw water out of the cornea or detragesit. But a lot of patients have so much corneal edema and scarring and issues that they usually need some type of surgical intervention. In the past, full thickness PK or corneal transplant used to be the standard of care. But as more recently, partial thickness transplants, mostly just the interlayers of the corneas become great standard of care for these patients. So there's desec and DMEC, decimay stripping, automatic endothelial care deplasty, as well as decimay membrane endothelial care deplasty. So endothelial care deplasty, the basic procedure is to remove the central area of decimay's membrane endothelium that's diseased, called a desmetorexus. Typically remove 6.5 to 8 millimeters of the central cornea. And then we place a partial thickness graft. It's held in place with some type of gas bubble, usually air, and sometimes with DMEC SF6. So desec versus DMEC, they mainly differ in the thickness of the grafts or the components of them. So desec, there's donor desimay membrane endothelium and also some stroma. With DMEC, it's a much thinner graft, it's just the desimay's membrane and endothelium. And there are a lot of other differences between DMEC and desec, but I'm not really going into those today. But on the left here is desec. I can see the outline of the graft there. And on the right is DMEC. It's kind of hard to see, but you can maybe see a little bit of tinted blue of the graft, a much thinner graft. So advantage of EK, as compared to PK, better visual outcomes, less astigmatism, postoperatively, shorter recovery times, and lower rates of transplant rejection. So overall really great surgery and great options for these patients. Some obstacles though with these surgeries is difficult and daunting. You can have postoperative complications including pupillary block from the gas bubble, graft dislocation, requiring a re-bubble, very low, but you can have some graft rejection. Acute and chronic endothelial cell loss that can lead to graft failure. And you're still reliant on the availability of quality donor tissue. So the search is still on for maybe something more simple, straightforward and not as invasive as an option for these patients. So there are some new therapies being studied with potential. One is a Planned Desimateraxis without doing a transplant. So Dweck and DSO are some of the acronyms being thrown around, but basically Desimateraxis without endothelial caretoplasty or decimacy stripping only. Pharmaceutical therapy, rock inhibitors, and then tissue engineering, so the use of cultured endothelial cells. So Dweck or DSO, the basic origin is there was observed cases of patients that had spontaneous corneal clearing after one, if they had graft attachment after EK, or two, if you had inadvertent damage to the decimation membrane during intraocular surgery. And the proposed mechanism for the corneal clearing without any type of intervention, they thought was maybe migration or regeneration of the host endothelium. And specifically with endothelial caretoplasty, some thoughts were that there could be transfer from the donor endothelium free-floating graft of cells that repopulate. So most, in the literature right now, most are small case series or interventional case reports where they performed a planned Desimateraxis to see their standard size or smaller size without placement of a partial thickness transplant. The results so far vary pretty widely. They do have patients that respond clinically, but it's, I guess, not predictable and they're unknown determinants of clinical success. Kind of a summary of some of the studies I looked at. One study found that a lot of patients ended up with stromal opacities or regular stigmatism. One study felt that if a patient ended up requiring a DMIC, if this failed, it was less likely to attach or for it to succeed. And in general, there are different clinical response times for all these studies, but typically it was between four to six months that people had corneal clearing and increased endothelial cell density, which is a lot longer than doing DMIC or DSEC. You get visual recovery with those much sooner. So most of these studies at this time don't really recommend doing just Desimateraxis at this time until more studies are done and get a little more idea of what works and what doesn't. So some of the proposed factors that they felt promoted success or failure of this included young age, earlier mostly central disease, a smaller Desimateraxis at the time, so about three to four millimeters. One is to avoid scraping the posterior stroma. I felt that when you roughen the posterior stroma, it was less likely for endothelial cells to migrate to that area. And then for failure, usually thicker preoperative corneas tended to do worse. So one study I was gonna focus on, one of the larger studies, it was a retrospective case series where they did Desimateraxis without transplant and patients with Fuchs. It was 13 eyes, patients with Fuchs dystrophy and a cataract. And they confirmed that, that there was uncomfocal microscopy, that they had uncountable endothelial cells centrally, but intact peripheral endothelium. And they also had to have a cataract. They did a planned cataract surgery with a four millimeter Decimae stripping without graft placement and looked at visual acuity, central corneal thickness and endothelial cell density for up to six months post-operatively. And actually about 10 of the 13 eyes responded clinically. And they found that there were different times of response for certain patients. Four eyes were fast responders where they resolved by one month. Four eyes resolved by three months. Two eyes were slow responders for the resolution wasn't until six months. And there are actually three eyes in that study that failed and required endothelial care to plastic. In general, the non-responders had the thickest corneas pre-operatively, greater than 625 micrometers. So their conclusion, 10 out of 13 eyes had improved corneal thickness, endothelial cell density, but they couldn't really tell what differentiated patients into who would respond and who would respond faster. Other modalities that are looked at are rock inhibitors. So these are drugs that are directed at the roe, roe kinase pathway, involved in regulation of the cytoskeleton, cell migration, cell proliferation apoptosis. This has been looked at with glaucoma, ripazodil is a roe kinase inhibitor that's actually approved for use in Japan for glaucoma and ocular hypertension. But they've been looking specifically at a selective rock inhibitor, Y27632, shown to promote cell adhesion proliferation, inhibit apoptosis of corneal endothelial cells. So it's being studied for its effect on the corneal endothelium, especially for cell proliferation. And it's been looked at alone or with DUI in DSO, or also with injection or transplantation of cultured endothelial cells. It has been demonstrated in animal models to promote corneal endothelial wound healing. They did both rabbit and primate animal models, and they also did this alone or with combined use of cultured corneal endothelial cells. There were a few small pilot studies for its use in humans. Once again, they're not controlled or randomized in small studies, specifically for endothelial dysfunction. For eight patients that had endothelial dysfunction that were scheduled for DSEC, four of those that had fuchs with mainly just central corneal edema, four had diffuse corneal edema that was more secondary or iatrogenic, all underwent central trans-corneal freezing process that's to damage the endothelial cells. And then one week treatment of the selective rokinase inhibitor drops. And so the results, they showed that three of these eight patients showed a decrease in central corneal thickness, but all of these were the patients with fuchs and that only had central corneal edema. So their conclusion, although this is a small, non-randomized, not controlled study, was that there's maybe efficacy in patients with early phases of corneal endothelial dysfunction that mainly just had central corneal edema. They also looked at preventing post-ocular surgery corneal decompensation, so treated three patients that had iatrogenic damage to the decimase membrane that had corneal edema, and then they treated them with the rock and hemorrhoid drops and all had recovery of corneal transparency within two months, which they felt was sooner than it would normally take to, I guess, get resolution of corneal edema. Also, another modality looked at cell therapy, so transplanting cultured corneal endothelial cells. These can be derived from skin cells, donor corneal, storm cells, embryonic tissue, adipose tissue, bone marrow or neural crest cells. There are two main approaches kind of studied. Transplant sheets of cultural corneal endothelial cells, which is kind of similar process to desec and DMEC, so it has a similar surgical difficulty in technicality. And the second option, which is kind of more popular, more, used more often, is injecting a suspension of cultured corneal endothelial cells into the anterior chamber. And specifically in just, in animal models, safety efficacy was shown, and this was done with and without rock inhibitors. And most recently, I'm gonna talk about a study, a human clinical trial that was recently published, looking at safety and efficacy of injecting corneal endothelial cells, plus rock inhibitors, or infused with rock inhibitors in bolus carotopathy. This is uncontrolled, single group study with 11 patients. They were all diagnosed with pseudophagic bolus carotopathy, so all had more diffused corneal edema. All had increased corneal pachymetry, no detectable corneal endothelial cells in specular and decreased visual acuity. And all in or went kind of like a desmetorexist, but they just mainly removed abnormal material from central cornea with a silicon needle, and then they did injection of cultural endothelial cells, supplemented with a rock inhibitor. And their results at 24 weeks, all patients had an increase in corneal endothelial cell density, and then 10 out of the 11 patients, or 91%, had corneal thickness less than 630 micrometers. Results at two years, all 11Is had corneal transparency and decreased central corneal thickness compared to baseline. There's several limitations of this study, one being it's not controlled, not randomized and really small sample size, but in general it wasn't really obvious whether it was the endothelial cells or the rock inhibitor that produced these results. So kind of a conclusion, a lot of these modalities are in their infancy and being studied. So number one, the desmetorexists without graft implantation, also known as DEWEC or DSO, probably can't be recommended until there are more consistent results, more studies, larger studies. And there's a better way to stimulate and control endothelial cell repopulation, and kind of a better understanding of what determines success or failure in these patients. And in general, for all three things I talked about, having a randomized controlled clinical trial is needed to confirm and validate that it's safe and efficacious for these patients. And in general, endothelial caritoplasty is still a really great surgery, a great option for patients with great visual recovery. Kind of tough to beat at this point. Any questions?