Severe Ocular Surface Disease treatment, with Edward Holland, M.D.

0:00 Welcome to the Doctor podcast, Sicard File Show, where we dive into groundbreaking medical advancements with leading experts. This is episode #123 and I'm your host, Doctor Robert Sicard. Today we're honored to speak with Doctor Edward Holland, an internationally renowned ophthalmologist and Director of Cornea Services at the Cincinnati Eye Institute, as well as Professor of Ophthalmology at the University of Cincinnati. Doctor Holland is a pioneer in treating severe ocular surface disease, which we'll talk about in detail.

0:36 It's a condition that's causing corneal blindness that affects 10s of thousands of people annually due to birth defects, chemical burns or autoimmune diseases of the eye. Through the Holland Foundation for Site Restoration, which he started the only organization of its kind by the way, Dr. Holland is transforming lives by advancing Oculus surface stem cell transplantation and establishing centers of excellence across the USA and globally. His innovative Cincinnati protocol, which he developed, combines advanced surgical techniques with systemic immunosuppression, offering hope to patients with limited treatment options.

1:21 Join us as we explore how Doctor Holland and his foundation are breaking barriers to restore vision and improve quality of life for those with severe visual impairment. So thanks very much, Doctor Hall Ned, for taking time from your busy day to join us today on the Doctor Podcast program. We appreciate it. Well, thanks for having me. You know, it's a, it's a very, very important group of patients. I think one of the biggest unmet need and certainly in cornea, but in all of ophthalmology and I appreciate your interest in, in, in, you know, in allowing us to kind of tell the story.

1:59 Right. So I'm a cornea specialist as well and I've had patients with this condition and it's extremely difficult to treat and very frustrating. So I'm glad you're you're doing something about it that will be very helpful for 10s of thousands of patients. So to start, tell us what severe ocular surface disease is, what causes it, and what symptoms patients have, what problems patients have, and how it's extremely difficult to treat it. So if we talk about severe ocular surface disease, we're really talking about the conjunctival and cornea epithelium and you know, really wasn't well understood until around 1990 when the understanding of where regeneration of the uphill layer came from for the cornea.

2:47 And so if you look back at a lot of corneal transplant, you know, studies, they would look at success rates and they'd see that for keratoconus or corneal scarring or success rate was very, very good. And standard penetrating keratoplasic success rate in Stevens Johnson syndrome, chemical injuries, thermal injuries was terrible. And, and when I first started doing transplants, you know, in the mid 1980s, we kind of treated everybody the same. Everybody got a penetrating keratoplasty for coronal disease, but there's a group of patients that did poorly.

3:23 It was really the understanding of this anatomy and several of very good basic scientists and translational researchers, you know, made us understand that first of all, there are stem cells for the cornea that that are, are at the, the, the juncture between the conjunctiva and cornea called the limbus. And the basal layer of the limbus gives rise to daughter cells, which repopulate the ocular surface and give us that clear, transparent, healthy epithelium that allows our patients to see if we have a injury or a medical condition that affects those stem cells.

4:03 Then we don't have a source of that skin layer and scar tissue or the, the the tissue around the white part of the conjunctiva invade. And this tissue is thick and has blood vessels and is opaque. And of course, the patients don't see. And the second part of the story is we for for several decades concentrated on the limbal stem cells, but we also have to understand there are card conjunctival stem cell areas in the foreign disease and throughout the ocular surface that give rise to the special epithelial layer of the ocular surface around the white part of the eye, the sclera.

4:40 And so you know, we, we talk about limbal deficiency, but really it's conjunctival and limbal deficiency that give us this group of patients with severe ocular surface disease. In fact, it's the patients that lose the conjunctiva and they'll go on to lose the limbus and and their according to clarity, those are the most difficult patients. We have to manage the conjunctival plus limbal deficiency and there's categories of of conjunctival disease and categories of pure limbal disease. Right. And so these patients basically the the cornea normally is crystal clear, transparent, like a clear window pane.

5:18 When they have this severe ocular surface disease, the cornea turns hazy and cloudy. It's almost like looking through a frosted glass window instead of a clear window pane. Yeah. So two things happen. Let let you know we can talk about the the common diagnosis chemical injuries, thermal injuries are are you know kind of at the top of the list inherited disorders. And there's a condition called aniridia in which it's a dominantly inherited condition in which children are born with either partially or no iris.

5:52 And hence the the term aniridium was applied to these group of patients many decades ago. But they also have other things wrong with their eye. They have problems with cataract, glaucoma and retina development. But unfortunately what really causes them to lose the majority of their vision is their stem cells drop out in the second or third decade and their their cornea becomes opacified. So we have chemical injuries, thermal injuries, you know, inherited disorders. Then we have a lot of dermatologic conditions that cause scarring of the skin that lead to the same stem cell drop out that we see with with with with aniridia.

6:32 And then this category of patients are called ectodermal dysplasia with one big category of patients and then some of the what we call autoimmune disease. So reactions in the body that can cause scarring of of your joints or scarring of your muscles or skin can cause the same problem. And one of the one of the real common ones is Stevens Johnson syndrome, which is kind of a a typically allergic reaction that leads to a chronic inflammatory systemic condition. And these patients often are quite ill acutely and the worst patients are actually because they Slough their skin or managed in a burn unit but but they often recover and and become healthy again.

7:18 But the long term sequelae is inflammation and scarring of the conjunctiva and the limbal stem cells. So when you lose your stem cells, you have no skin on the cornea. And without skin on the cornea, we see scarring and thinning kind of a, a reaction the eye has to save itself is to grow scar tissue into the cornea to try to prevent thinning and perforation. And that scar tissue, while prevents perforation of the cornea becomes, leads to moral pacification and, and, and blindness. So ultimately these corneas have dense scarring, you know, they kind of turn white.

7:58 And in the past, clinicians would think, well, I've got this scarred cornea, the acute episode's over, why don't we just do a transplant? But when you do a corneal transplant, the full thickness corneal transplant comes from the eye bank. And there could be some donor tissue skin on that donor cornea. But that ultimately sloughs in weeks to months and the patient has to grow back their own skin layer. And that's where a stem cell deficiency patient cannot do that. And the success rate, if you do a full thickness or a partial thickness coral transplant in total level deficiency, the success rate is 0.

8:38 Right. Yeah. I remember doing transplants in patients who had Stevens, Johnson and other conditions and and they always failed. And initially we didn't understand why. Now we know why. And fortunately, thanks to you, we now have a new excellent way to treat it. So now the The Holland Foundation for Site Restoration, which you started, is the only organization dedicated to addressing unmet need of corneal transplantation for severe ocular surface disease. Can you share what inspired you to establish this foundation and how its mission to create Centers of Excellence aims to change the landscape of care for these patients?

9:21 Yeah. And, and to be honest, I, I don't get credit, Robert, it really goes to a gentleman called Robert Dempsey. Robert Dempsey has been in industry and ophthalmology for many, many decades. He's been with the big ophthalmic companies, he's been with startup companies and he's a friend to a lot of ophthalmologists. And he was actually in visiting in Cincinnati and came over for dinner and we were just talking at the end of the evening. And he picked up my cornea textbook and kind of randomly open to the chapter of Oculus Surface Stem Cell transplantation.

9:57 This is kind of a crazy story. And he said, I didn't even, you know, tell me about this. You're you, you've written this chapter and there's a picture of a severe chemical injury. And then he flips the page and then there's this beautiful clear cornea. And he said, you know, how does one go from that diseased eye to that clear cornea with good vision? So I kind of told the story that we were talking about and I said that we have to, we have to find stem cells from either a deceased donor or a living relative and place them on the eye, rehabilitate the oxygen surface, then we can afford transplants.

10:31 And he was kind of saying, you know, he's known me for many, many years, but didn't really know that that was a big part of what I was doing because he knew me as kind of a consultant for his pharma companies he worked with. So he said, I'm so moved about what you do. I want to donate to your foundation. And I said, I said, Bob, I don't have a foundation. And then he said, shame on you. You should have a foundation because how many of these patients are being treated? And I said not even 1% of these patients being treated.

11:03 So Bob Dempsey that evening decided on his own and he dragged me with him to start the the the Holland Foundation for site restoration. So I give Bob credit. That's a great story. I happen to know about them. See. Well, when Zydra first came out, which is a treatment for dry eye disease, I worked with him and used to give talks about the Zyde ophthalmology. Yeah, he's an incredibly smart, nice guy, very innovative, and he's been a great addition to ophthalmology. The Cincinnati Protocol, which you created, is described as a management concept that integrates systemic immunosuppression collaboration with kidney specialists known as nephrologists and the dedicated transplant coordinator.

11:54 Can you take us through the key components of this Cincinnati Protocol and how it draws from kidney transplantation principles to improve outcomes for severe ocular surface disease? Yeah, Robert, I'd like to kind of talk about how we got there. So if we think back about, you know, the late 80s, we were doing full thickness transplants for for these patients, they're all failing. And then the discovery of the anatomy of the Oculus surface and the location of the stem cells and then several investigators and I didn't come up with the original procedures, but had these ideas we could.

12:29 And the original procedure was, was actually for unilateral disease, taking steps, taking stem cells or or tissue off the good eye and treating the bad eye. And, and actually baricare in the mid 60s at the very first World Cornea Congress. Now he didn't know where stem cells were located, but he had, he had the idea to do an autograft or cells from the good eye to the bad eye. And so that actually was the very first socket surface transplantation. But then the understanding of the anatomy and the evolution of different techniques.

13:06 And, and so really it's kind of come down to two basic technique. Well, I say 3 basic techniques, the patients with utilateral disease and they have a very good chance of rehabilitation because we can take cells off the fellow eye and transplant into the disease eye. So we call that a conjunctival limbal autographed. And why does it work so well? Well, obviously the patient can't reject their own tissue. And if the, if the, if the eye is managed properly preoperatively and the inflammation is managed and the eye is quiet, the success rate is outstanding.

13:41 The question we always get is, you know, what's the risk of the donor eye And you know, we we along with others have kind of modified the conjunct time limbal autograph to take about 40% of the limbal stem cells of the donor eye and transplant those cells. And we've never had a patient lose vision from that surgical procedure. So it's a safe procedure. Now, if the fellow I had any history of partial trauma, multiple surgeries, long term glaucoma drops, you know, contact lens wear can actually stress stem cells.

14:16 So we eliminate any long term contact lens wear. So conjunctile limbal R graph is the first one. But really the majority of patients we take care of have bilateral disease. And even if the the fellow eye has moderate disease versus severe disease, we we never touch the better eye. Just it's not worth the risk of of making that eye worse. So we basically have have two ideas we can take and the original idea was actually using a living relative and taking the conjunctive and limbus of, you know, one eye of the relative to the to the disease eye.

14:51 And, and when that was proposed kind of in the early 90s, I think a lot of surgeons were were were reluctant to operate in a healthy eye. And so the next operation came from using a deceased donor. So we can take a donor globe, we really can't get conjunctiva, but we can get plenty of limbal stem cells off the periphery of that donor cornea. And so actually in the early 90s, that kind of was was tried by many, many surgeons. But here's where the real failure occurred and it took as many years to figure it out.

15:26 As ophthalmologists, as cornea specialists, we really don't understand the art of systemic immunosuppression, right? No kidney surgeon would think about using a doing a kidney transplant and not using oral anti rejection medications. They would just, they wouldn't think of it. So in ophthalmology, some a lot of surgeons tried these procedures in the early 90s and they used a little bit of of of Prednisone, a common rapid anti-inflammatory and then maybe a short course of at that time the leading systemic anti rejection drug cyclosporin.

16:02 But really for three months was kind of the average and all the procedures failed. So there was this period between 1990 and, you know, about 1995 where I remember starting to do these procedures using a low dose protocol like that. And, and I, I will tell you, Robert, kind of every Cornell surgeon gave up. They just said the, the, the techniques flawed. It doesn't work. We're not going to do it. You know, I happened to be at the time at the University of Minnesota and I got to know the head of kidney transplantation, the head of general surgery, one of leading kidney transplant surgeons in the world.

16:41 And he was talking to me my my research and, and he was saying to me, why are you using such a short course of low dose? I mean, you know that he said to me, is the is the tissue vascularized? I said, yeah, unfortunately it is. He said there is no way that you could ever get that tissue to work and prevent rejection. So it was kind of in the mid 90s. And I think one of my major contributions to the field is at that point, even though, you know, you know, I didn't have the in depth training of, of a lot of transplant surgeons with immunosuppression, I had done another fellowship after my corona fellowship and, and Acura Immunology at the National Institutes of Health and did have experience with using a lot of these medications.

17:29 So I just decided at that time, I'm going to adopt what the kidney transplant surgeons are doing. I'm going to go all in and treat these patients 100% like, like kidney transplant patients. And it was interesting. We, we were doing it at Minnesota, but I couldn't get as much collaboration. You know, I, I couldn't get their team to kind of take over my team. And we, we, we had some success. But it was really when I moved to the University of Cincinnati and the Cincinnati Institute, and I reached out to the head of renal at the University of Cincinnati and I said, you know, I need help and if you will, will help me manage my patients.

18:09 I think we can really, you know, change the lives of a lot of people. It was really the year 2000 I moved here and it was the commitment of the University of Cincinnati nephrology department. And in fact, they at the beginning, they manage my patients. And we'll talk about the importance of a transplant coordinator, the the nurse who overseas all the care, the medications, the tracking of the labs, the side effects of the medications. So we were basically rolled into the renal program at the University of Cincinnati.

18:40 And that's when our success rate totally took a different trajectory. And that's what differentiate our program for the rest of the world is we were all in. And that is one of the main obstacles I think other cornea folks don't have. So Robert, what happened after about three years and I would meet with the renal team and we'd, we'd, you know, if they would change their protocol, we, we'd adapt and change ours. But he called me into his office and he said, listen, you're doing more akin surface transplants then we're doing kidney transplants.

19:12 So you need to build your own team. So go out there and find money and hire a transplant coordinator. And so we slowly rolled and built our own team and we've had a lot of good collaboration. We have a wonderful partner in Saint Elizabeth Hospital here in Northern Kentucky that helps us with our transplant coordinator. We still have tremendous collaboration with the renal department at UC and we were allowed to build something special. So the Cincinnati protocol is basically taking what a, a renal or a liver or heart transplation, what they would experience and modeling our patients experience with that.

19:52 So it starts with the transplant coordinator, right? So when you go, if you need a, a renal transplant, you know, you're going to meet with the surgeon, you're going to meet the nephrologist, but you spent a majority of your time with the transplant coordinator nurse who who is kind of overseeing all your care. And that's, that's what we have on our team and. Whereas in organ transplantation there are codes that Medicare, you know, you can charge Medicare or, or you know, commercial providers that will pay for a transplant coordinator.

20:25 Unfortunately in ophthalmology, we don't have that, you know, we, we don't have enough numbers to, to, to try to get that. So, so the transplant coordinator has to the source of his or her salary has to come from another source. It can't be the hours they, you know, they work and they can't build for their time. So we that's a workaround that we've we've really had to, to, to deal with when we talk about starting centers outside Cincinnati. Wow. You know, when I first heard about your foundation, I said wow, that's incredible.

20:56 He did that over a year and everything's running smooth. The story's fascinating because it took you many years, couple of decades, to get this all. It really did. It really did. An overnight success that took 20 years in the making. So why are corneal specialists around the country kind of resistant or hesitant to do this? You, you mentioned, now we, we get a feeling for this. Is it possible to replicate the Cincinnati Protocol, which took you many years to get going at at your center, and get other people around the country and around the world to do the same thing?

21:37 So it's interesting, Robert, when we first started publishing our better results and you know, and with living related matched tissue, our success rate could be depending on their diagnosis, because some diagnosis have a better, but somewhere between 50% for the worst diagnosis up to 85% for the best. And with with deceased donor tissue, a little less, maybe about 76, sixty, 75% because rejection is higher in a deceased donor than as a a living donor. So we always our first go to if we can is to find a relative and get some tissue matching.

22:16 But why aren't, you know, I think when we started publishing better results, there were a lot of skepticism, you know, like we don't know what he's doing, but I'm not sure his results are real because nobody else has results like him. And and there was a lot of it was for the early years. People didn't believe me, to be honest with you. But but I've traded enough fellows and enough people have been here to see my post op patients that are 6 months out, two years out, 10 years out, 15 years out, 20 years out to, to see that we have the success what I'm talking about.

22:54 So I think the barrier is, is, is, is number 1. I think a corneal surgeon just doesn't have the training to be, to be comfortable using full immunosuppression. And those who even tried to do it didn't do it the right way. They, you know, back in the 90s when they were having failure and rejection, they may have had a friend in rheumatology or a friend in oncology. But but systemic immune suppression for transplantation is very, very different from medications used in oncology and rheumatology. And really we've changed our protocol multiple time based on what University of Cincinnati real team does in terms of the testing we do preoperatively, which really the the work of we do preoperatively.

23:42 We do tests that nobody in ophthalmology uses like a panel reactive antibody test to determine what risk the patient has about receiving a transplanted tissue. It's routine in renal, never done in cornea. We do it routinely in all our patients, but we learned that from renal. So what is, is, you know, they, they don't, they don't have that partnership with nephrology. And sometimes it's hard to make #2 there is this responsibility. If you're the treating surgeon, you're ultimately responsible for the patients taking these medications.

24:18 And I think a lot of coronal surgeons remember systemic immune suppression from their medical school days when they saw maybe sick oncology patients or very sick diabetics who are getting renal transplants and how sick they were. But you have to understand the majority of our patients are young and healthy and they and the complications from these medications on a 25 year old with a chemical injury versus a six year old diabetic who has high blood pressure, high cholesterol, obesity, cardiac disease are very, very different.

24:54 But it's, it's hard to convince a cornea person, you know. And then the the third big obstacle is really understanding the role of the transplant coordinator. You know, we, we don't have somebody in the clinic we could just pull into that. You know, we have, as you know, we don't even have nurses anymore. We have technicians and you, you know, we need somebody with a nursing background and it really takes a outside funding source to to pay for, for her his salary. So, so with those obstacles, you know, I, I thought we could publish our results and, and, and convince people to go ahead and try this.

25:31 And, and really in discussions with Bob Dempsey and Dick Lindstrom and Steve Lane and members of our, of our board of directors, we really realize that we need to create a, a different way to reach coral surgeons. So instead of, you know, and we and we've published textbooks on techniques and management and, and everything we do is, is in the literature, it's in the peer reviewed literature, but we've decided the other pathways really, we need a passionate quarterback of the team. And, and that quarterback actually has to be a corneal surgeon, right?

26:07 So we need a corneal surgeon that'll say, all right, I'm all in. I believe what you do. I'm going to adopt the since I protocol, I'm going to find funding for a transplant coordinator and we're going to start this process. And so it really it's, it would be hard to convince a lot of senior corneal people to do it. They're kind of stuck in their way. So what we've done is look for these younger corneal surgeons who are brilliant and they're motivated and we've gone, you know, kind of region by region this country and found those who are interested.

26:41 And that's how we're going to build our center of his excellence around a passionate, dedicated, motivated quarterback coral surgeon. So these are people who finish their fellowships like 3-4 five years ago and are very busy but want to take on this challenge. Yeah, and, and you know, and a lot of them are at academic centers. So it really helps to have a passionate chairperson who, who believes too, because they'll, you know, and I'll, I'll say the you know, the first center we built Cincinnati was, you know, in terms of centers of excellence.

27:16 We're we're the first one. It was your visit California, Irvine. And, and the reason why was, you know, my old friend Roger Steiner, who was chair and unfortunately he passed a few years ago, but he, he saw me in a meeting and he had recently read one of our papers. And he's like, you know, and, you know, I, I practice in the Sensei metro area, but actually my office in my surgical centers in Kentucky, you know, people don't realize about 1/3 of Cincinnatians live over the river. And I'm here, the airport's very close to where my office is.

27:48 So Roger would say to me, how could you do this in Kentucky? And we can't do it at University of California, Irvine, you know, and, and I said, Roger, shame on you. And so it was Roger's willpower that really started to build that program. And, you know, the young surgeon that we built around Doctor Marjane Fareed, she's brilliant. She's dedicated, she's a great surgeon. And and she was, you know, really loyal to Roger. And Roger was her her great mentor. And she said, I am going to do this because I want to do it, but especially because Roger wants to do it.

28:23 So they had a center and, and we, we reached out with her and found somebody in nephrology that would be on her team. We then raise money through our foundation to, to hire her first transplant coordinator, which we've done. And she she has built that team. Now other parts of team are important in ophthalmology. You know, half the patients have LYB disease. If if you have a chemical injury, you get a burn of the eyelids, or if you have Stevens Johnson syndrome, you scar your eyelids. So you need an ocoplastic surgeon.

28:54 More than half the patients have glaucoma. So you need a dedicated glaucoma surgeon. And I will tell you these patients are probably the glaucoma surgeon's kind of worst nightmare. They're very challenging because their tissue is not normal. And then of course, you need a good retina specialist because of all the retina issues. So, so we have this ophthalmic team headed up by the corner specialist. We have this collaboration with Reno and then we have the transplant coordinator. And, and that's tying into to form what we call the SYSA protocol.

29:27 And you know, after that success, the next place we went to was the Massachusetts Eye and Ear Infirmary. Doctor Thomas Dolman and Dr. Jia yen had had, had talked with me after one of my lectures and we had, you know, I went to visit them and we had talked about, you know, how can we help set up that program there. And interesting enough, Doctor Thomas Dolman's grandfather, the, the, the famous Klaus Dolman, you know, invented the Boston carrot of prosthesis, the artificial cornea that has been used for these patients.

30:00 And I do think it has a role, but it, but it, they have a a lot of complications if you have severe Oculus surface disease. So I give Doctor Thomas Dolman credit to want to expand the way he he approaches these patients. And so our second, our third center was open at Harvard and they're up and running and doing patients and, and, and doing a fantastic job. Yeah. Now, I think you're opening centers in Tel Aviv and Israel also and in Toronto, Canada. Is that right? So we, we, one of my former fellows, Claire Chan is at the University of Toronto and, and she was, was doing kind of things on her own and we kind of put her, you know, into our protocol and she's kind of part of our educational group now.

30:47 And so Toronto is certainly online and she's a very busy Oculus Surface transplant surgeon. There's a very good group of, of surgeons in Tel Aviv. Unfortunately, the, the, the war has kind of slowed that progress down, but we'll, we'll definitely make that happen. We're working with surgeons in Tuscany in, in a big eye clinic in Gracetto, Italy. And they're going to be, they're going to be part of our group in the, in the, in the last year. We've now have a collaborative effort going on at the Woolmer Eye Institute at Johns Hopkins and then most recently had conversations with Will's Eye Hospital in Philadelphia.

31:30 The next hitter probably to, to really come online is going to be the University of Illinois Chicago with Doctor Ali Gillili and another one, a former resident of mine who's who's worked with me and, and we're getting them up and running and then and then University of Michigan. Wow, that's, that's awesome. What about Baskin Palmer? They they should get that too, no? Yeah, so far they haven't reached out. So, you know, they do some, a lot of ocular surface work down there and of course a incredible ophthalmology department and certainly would be happy to collaborate with with anybody who wants to collaborate.

32:09 So we think we have kind of figured out at least for now the best approach for these patients. We figure out what doesn't work, we figure out what's work. We've, we, we understand the importance of using the latest anti rejection protocols that were really and why renal Well, renal was the first, right Renal, you know, the first successful really kidney transplant program was kidney. And they are, they are kind of the leaders for everyone and we kind of follow their, their lead. And you know, we, we now categorize patients.

32:42 You think about a patient who had probably the 4th leading cause of why we have limbo stem cell failure is contact lens wear. Now there's 10s of millions of contact lens wearers and, and, and, and you know, 99.9% of them do well, but a small, small percent end up giving, getting liberal stem cell failure, believe it or not. And, and it's kind of a silent disease because while they're wearing their lenses, unless they have kind of annual check UPS and their ophthalmologist or optometrist kind of looks at their limbus, they'll miss it because their eyes really don't hurt until the loss of stem cells bring that bad skin layer toward the center of the cornea.

33:23 But but the rest of their eyes normal. So they're actually, they actually have the highest prognosis because we're dealing with just a single kind of threat to the eye. So let's say we take a patient like that with that diagnosis who has a relative that's a excellent match. I mean, that would be the lowest risk patient we'd have. And then let's go on the other side of it. We have a patient with either severe Stevens Johnson syndrome and chronically inflamed eye with eyelid scarring and glaucoma and they don't have a living relative.

33:57 We have to use deceased donor, they're at the highest risk. So we don't treat those patients all the same, right. We, we can use less anti rejection medication for shorter duration on the low risk patient. And we're going to use, you know, not only, you know, the maximum immunosuppression, but we're also going to do some treatment protocols for high risk patients using renal giving monoclonal antibodies pre op and post op. And again, these are things we all learned, but we, we kind of look at high risk, medium risk and low risk to kind of, you know, categorize our patients to how we're going to manage them post operatively.

34:34 Right. The interesting you meant you mentioned about contact lenses. I've had about 3 or 4 patients who develop stem cell damage from contact lenses. Fortunately I caught them pretty early. Stop the lenses, but it can take them a year, 2-3 years. Yeah. You know, it's interesting because because all these patients can be caught on time if someone just look at their superior limits, that's where they fell first. But many of the patients, they can order their contacts online, they don't go in for annual exams anymore.

35:05 And the reason why we're seeing it is because there, there were these lenses for years. Their, their eyes don't really hurt. And by the time we get them, they have, you know, 360° limbal failure and they're, they're in trouble. And it's always bilateral. Now it may be a bit asymmetric, but most of the patients have bilateral visual loss. Right. And they get frustrated because they always want to start wearing their lenses once they're a little bit better. But I tell them you can't do that so. That's.

35:33 Now, what's your foundation's website? I'm going to post it with this video interview so that people can access it. Our web our website is Holland Holland Foundation for sight.org. OK. One, one word, yes. OK, I'll make sure I include that. Now you have some interesting and inspiring patients stories like that of Kurt Kozak whose vision was transformed through ocular surface stem cell transplantation. Can you share some other memorable patients stories that illustrate the life changing impact of your work and the Cincinnati protocol?

36:17 Yeah, a couple patients really stand out. One is was a a gentleman that was in the Middle East wars. He was serving in Afghanistan and there was an explosion and he got a chemical thermal burn to both eyes. And you know, actually several of his platoon died in that that accident and he was air back to Germany. You know, he got acute management, which was very good, but then sent to one of the military hospitals with totally opaque corneas. And really you can only see light and dark and, you know, very, very frustrated, you know, as, as you can imagine and receive the Purple Heart for his, his, his work, his duty to this country.

37:04 So unfortunately, the military hospital looked at the cornea and did a corneal transplant, a regular corneal transplant, which failed. He then, you know, then was discharged out of the Army and went back home to southern Georgia, where he has eight children, 8 kids. And he went to a very famous university in that area, southeast United States. And they did a coral transplant in his other eye, which of course failed. And he went back home. And you can understand his, his frustration now. He's, he's had two transplants and, and you know, they're both institutions are told there's nothing to do.

37:40 You just have to live with blindness. So he went to a another university where they told him he could have this artificial cornea. And again, artificial corneas, especially the Boston kernel prosthesis is a wonderful device. But patients with severe arc of surface disease have a severe dry eye and abnormal skin. And, you know, they need to maintain that skin layer right against the, the plastic, you know, optic of this artificial cornea. Well, well, you know, he melted it and, you know, and end up getting infected and actually lost the eye to an infection inside the eye.

38:18 So now he goes back home, he has one eye, 8 kids and is sitting there and, and is angry at the world, which I don't blame him. And so his wife wouldn't give up. His wife said, this is, this is, you know, I, I can't believe we can't offer my husband more than this. And she went back to one of the universities she went to and she said, you've got to tell me where to go. We, I, I don't believe that there's nothing to do. And the doctor there said, well, there's this one guy and said, hey, that might be able to help you.

38:49 So he came in and I'll tell you, I walked in the room and he was such an angry man and he wouldn't let me examine him. He was swearing at me like it's a waste of his time. His wife was crying and his eight kids, they were breaking my equipment in the exam room. They were all over. It was like a nightmare. So I called his wife out into the hallway. I said, listen, I understand your husband's anger, frustration. I don't blame him. But I also have an idea based on his medical records, I think we have a very good chance of, of, of getting his vision back.

39:26 But I need you to go in and change his attitude because I need him to be on board. He, he, he can't think he's going to fail. So she went back in the room and and two hours later she called me back into the room. Two hours. Two hours and I walked in and he was, he was. Yes, Yes, Doctor. No, Doctor. Whatever you say, doctor. I'll do whatever need you know, He, he totally had to add to adjustment. Long story short, he got, he got his vision back. He's got 2030 vision. He drives his car. He he has two children that are, are competing for the US Olympic wrestling team.

40:03 They're in that they're in that Youth League. They're outstanding athletes as as he was. And it's just, it's just a great story because it was his wife, his wife that wouldn't give up. You know, she's, I don't believe there's nothing left for my husband. Wow, she's a tough wife. I would have loved to be on the wall during those two hours. Yeah, yeah. That's that's a fantastic story. We had a another young man from Kansas and believe it or not, he was a wine maker. Now people wonder why you're making wine in Kansas, but prior to Prohibition, Kansas was a leading wine producing state in the US.

40:42 You know, obviously, yeah, obviously California, Washington, Oregon's kind of surpassed him. But they still make decent wine. And he was, he was doing a demonstration at a big mall and had a kind of kind of an explosion of the equipment that he was using and burned both of his eyes. And a young guy with a six month old daughter and he, he went to a couple places. They said there's nothing to do. Your eyes are too severely burned and you know, we don't think you're going to get your vision back. And so he did find a corneal surgeon in, in Kansas City.

41:20 Now, this guy's only about a month out from his injury. And he, he went to the doctor and said, listen, we're going to do a stem cell transplant and a corneal transplant. You're going to get your vision back in a couple weeks. And the, the day before the surgery, I got a phone call from his local optometrist saying, could you see my, And it turned out to be, that's his brother-in-law. By the way, can you see my brother-in-law for a second opinion because he's scheduled for surgery. And I said, I'm, I'm happy to see me.

41:49 He, he came out. So Robert, one of the rules we have in, in, in, in chemical injuries and thermal injuries is that we never operate early on these patients. You know, a chemical injury takes a year, maybe 18 months for the eye to quiet down South. There's no way we would operate. We want to, we want to quiet the eye. We want to get the eye healthy and get the acute in the in the same thing with other, you know, the autoimmune diseases. We want to treat the autoimmune disease 1st and then thinking about doing the Oculus surface transplantation second.

42:20 So I said to him, I said to him, we, we have a chance of getting your vision back. And he said, OK, I know you do a lot of these. We read up on you. When can we start? I said I'll see you in a year, you know, I mean, I'll see you in four months to to do a check up to make sure you don't have glaucoma thing. But we're not doing surgery for a year. So he hung in there. He cancelled the surgery with the other surgeon and it was interesting. His first surgery was a an Oculus surface stem cell transplant.

42:51 Now when we take, we took living cells off his sister, but his injury was so severe we had to combine it with the deceased donor. So when we combine because we didn't want to use both of her eyes for one eye because she he had two eyes injured, we need we can only use 40% for one eye and then we combine the deceased donor to give us 360° of tissue. That's actually what's called the Cincinnati procedure, that operation where we combine donors. So obviously, he still didn't see because he had opaque cornea.

43:23 And then he came back, you know, we took care of him and three months later, he got his coronal transplant. But when we couldn't see through that cornea, we put the new cornea on. He had a white cataract. So he still didn't have vision. So now I told him, we need another few months before I get your cataract out. And so one of the nurses was saying to him, you know, your daughter now, she's almost two years old, You know, he said, yeah, I have not seen my daughter in almost two years. But I said to him, when we take this cataract, you're going to see your daughter that day.

43:53 You know, that that's one of the more rewarding things about you're seeing when you can get vision right back. And you've done it with coronal transplants. But so he took his cataract out, you know, and then, you know, he saw his daughter that night for the first time and, you know, it was really moving it. And the nurse said and asked him, are you going to have any more children? And he said, you know, this blindness has been so traumatic. I have this beautiful young daughter. We're not having any more kids.

44:20 We're happy with our child. So then six months later, we start operating on his fellow eye. And he comes in and the nurses were saying, you know, I've been talking to your wife and she told me she's pregnant. So, you know, after he got vision back and he got the confidence that he could be, you know, someone with vision to take care of his children and to, to work again, you know, they decided. So the next child they named Holland, that was, that's, that's the child's name, which was there's probably nothing more rewarding than a patient can do.

44:56 You know, I remember that his wife, his wife said to me, we, we really are, would like to, you know, honor you by naming our, our, our son after you. And I said, well, Edward's kind of an old fashioned name. Nobody gets named Edward anymore. She goes, no, no, we don't like Edward. We like the name Holland for his first name. So and they've gone out, they've gone out and they have more children since then. And our vision of both eyes, wonderful family back working, you know, and it's, it's a very, it's a pleasure to see them every time they come in.

45:27 Yeah, that's such a heart warming story. That's, I'm going to share that with us. Let me ask about these transplant coordinators. You mentioned there's no funding for that and you have a foundation that helps you with that. But what do other corneal surgeons and other academic institutions do? Does your foundation help to support transplant coordinators all over the country, all over the? World so, so one of the things we realize is, you know, to get a program off the ground, you know, we talked about the quarterback and we we can identify young talented coral surgeons, but you know to tell them they have to go out and depending on where they are in in the country, you know, a, a nurse's salary can be 100 to $200,000 a year.

46:14 I mean, so to to tell them they're going to have to go find a transplant coordinator and we'll help you get started. You know, so really was Bob Dempsey's idea that listen, the first financial support we're going to give you is to hire you. And we did a, you know, most of these programs we start with a part time transplant coordinator because they're not that busy yet. We are going to fund, you know, a 2/5, typically one to two days a week FTE transplant coordinator and our foundation is going to help you find that person and pay their salary.

46:49 So typically it's been, it's been different from different programs, but usually they'll find a renal transplant coordinator and they'll take one to two days of her or his or her time, put them on their team. And you know, we, it's, it's part of this collaboration with renal. You know, so first of all, those transplant coordinators are already trained. They, they, you know, they know how to manage these patients, you know, and think about what they do well, even healthy patients are doing well, have to have all their labs checked, right?

47:18 The side effects or medications can be toxicity to the kidney, the liver, the bone marrow. And so we have labs at minimum 4 * a year, but often more often than that. And then they have nuisance side effects like, you know, headaches or upset stomach and, and you know, so we have to adjust the meds and sometimes we have to switch them. So, you know, if a coral surgeon gets busy, he can't, he can't take every phone call or e-mail about diarrhea. You know, it has to, So having this person to be really the, the, the first person to interact and handle, you know, my transplant coordinator have been with me now for 12 years.

47:59 I think. I mean, she, she handles 9090% of the issues that come up now we and a lot of things I can do myself because we've been doing so long, but we still e-mail, you know, our partner at University of Cincinnati, I'm at Goble who's had a renal there. And we'll have an issue where, you know, we a patient can't take one of the medications. We want to switch the medications, You know, when do we do it? How do we do it? What's the dosing? So or the, the pre op diagnosis of the, of the patient, they may have some medical issues that we're unsure of will be, you know, we e-mail that person.

48:36 So you know, the renal doc doesn't really need to see the patients. He needs to understand their management issues. And so we still collaborate many times a week with our with our partner in renal. It's amazing that you have the time and energy and and patience to do all this 'cause you, you're a well known world famous cornea specialist to begin with even before undertaking this. How have you managed to to do this and what personally drives you to tackle this challenging and underfunded area of ophthalmology?

49:13 Well, I, I, I always give credit to one of the, my, my, you know, great mentor in, in ophthalmology was Richard Lindstrom at University of Minnesota. And Dick, Dick had this idea what, you know, when I was a resident, he, you know, he asked me, you know, to come back and join him. And, and I would have been the 4th cornea person, but in the middle of my cornea fellowship at the University of Iowa, he called me and said, you know, we got three guys that all kind of do the same. We're all general cornea and really high risk coral transplant, you know, immunology I think is the future.

49:44 And so I want you to do another fellowship to learn. You know what, I always joke with Dick, you know, I'm, I'm young and poor and out of money and, and, but we, you know, he always points out, not only did he get me help me get a fellowship at National High Institute, but he also put me on the tenure track at Minnesota with a salary while I was a fellow. So Dick, Dick really was, he was a very clever guy. So, but we didn't. So back then, that was 1987 when I joined, we didn't know about stem cells.

50:16 So we promoted a high risk corneal transplant program. We wanted to take rejected corneas and all we did was put them on medication that prevent rejection. And so if patients had just pure rejection problems, so let's say you had a keratoconus patient, you did a corneal transplant and they rejected a couple times. We could get that patient with systemic anti rejection meds and they do great. But we had a bigger population that didn't do well. And those were the chemical injuries, the thermal injuries.

50:48 Stevens Johnson paid because we didn't know what we, you know what we didn't know. And so we were treating them all the same. And really because we, I had done lots of quorum transplants and these patients with limbal deficiency and they all failed. I had a big population of patients that I was really, I was obliged to try to fix. So I kind of transitioned to saying, OK, let me figure out how to do waka surface stem cell transplants and make them work. And that was a long, you know, I, I, you know, I'd say we learned a lot at Minnesota.

51:23 We learned a lot more with the collaboration I have here in Cincinnati. And, you know, it took us a while to figure it out, but our sensei protocol is, is the way to manage these patients. And you know, by default, I, I just had them. And then once you start publishing, as you know, Robert, on a topic, the patients find you and and courted people. Courted people are happy to get rid of them, you know. Very different role to manage. Yeah, so, and we're happy to have them. And it's really been my passion for the majority of my career.

51:57 That's great. So I want to thank you and congratulate you for doing this incredible work that nobody else has done. I assume you want people to donate to the Holland Foundation for site restoration, so I'll we, we. We would love that. You know, we, we use, we, we need to raise money to, you know what we, what we found out in all these programs when we give the starting salary for a transplant coordinator, when the program gets busy, that that person becomes self funded. You know, we don't need a right.

52:31 We don't need to fund their salary forever. It's three to five years that person is covered. But we have, you know, patients need for travel and, and, and you know, another, another kind of story that we have a disconnect with if you're going to donate your kidney to your brother, his insurance will pay for your tissue typing to see if you're a match, right? So they're going to do tissue typing on you and your brother. And there's a code for that. We don't have that in ophthalmology. We can do tissue typing on the recipient patient, but their siblings, that's, that's out of their pocket and that's somewhere, you know, 1500 dollars, $1800 per donor.

53:12 And so that's another obstacle on the financial side. So, yeah, yeah, you know, donations are greatly appreciated. You know, our, our goal is to create multiple centers regionally in the United States to get these patients referred in. And you know, we've really, you know, this last year has really taken off. You know, our goal that we have a annual meeting. You know, we had about the first two years our annual meeting for August surface stem cell transplant here in Cincinnati. Yeah, we had about 20 surgeons this year.

53:45 We're going to have, it looks like 25 new surgeons that that that were not involved in our educational program last year are going to be coming this year. In addition to having formalized courses at the American County of Ophthalmology and American Society of Academic Refractive Surgery on this exact treatment management. Great. Well, I'll make sure to post the website for your foundation and hopefully that'll get you millions or 10s of millions of dollars and then we can open a center in every state so that patients don't have to travel all over the country to get their.

54:22 We need one in New York City. Yeah. Now think about that. You know, greatest city in America and we take care of a lot of New York patients. They now can go to Boston. But we need we need a passionate corneal surgeon to start a program in New York City. Help me. Help me do that, Robert. Well, I'm on the medical board of the New York Eye Bank for site restoration, so I'm going to make sure that everybody gets the word there. And after this is posted, I'll make sure I'll send an e-mail so everybody can watch it and hopefully you'll get a few corneal transplant physicians interested and get the New York City area started that.

55:02 'D be great. All right. Well, thanks again very much for taking the time to educate us about this extremely important topic that's been neglected for a long time. I really appreciate it. Thank you.