Professional Education / Organs and tissues
Learn.Share.Advance
Webinar: Organ Culture of Corneas and its Role in Eye Banking Economics Transcript
Host: Gary Rockl
…for HEMA Quebec in Quebec City, and I'm attached to the tissue bank and the ocular bank as well.
If you could keep your mic muted during the presentation, and at the end, for questions, if you would like to type in the chat that you have a question, or if you'd like to type the question itself, Dr. Pollock will then go ahead and address the questions one at a time. If we can keep the chat free of any other information just so that it's organized so that you can see the question or the person that would like to answer that ask the question. Feel free to obviously ask the question directly yourself [or you can type it] to have it read.
Barring that, I'll just give you a little bit of background information about what is going on and how this came about. Back about two years ago, CBS put on an ocular forum and a bunch of us attended. If you weren't there, this initiative was essentially centered around how to make the Canadian ocular system better. An individual named Heather Manchin attended and she's an Australian lady, very, very kind. I did a brief presentation for them at their, one of their lunch and learns, and at that time Doctor Pollock and I connected, and I started asking them questions about organ culture. And he very kindly answered more and more questions and sent more and more information. And it became apparent to me that there was just so much to learn. There was like a mouse nibbling on a giant wheel of cheese. I didn't have perspective about what it was that I was looking at. And one of the nice things, Doctor Pollock and the organization in Australia has been very gracious to come and speak to us, but they've gone through a transition from hypothermic to organ culture. And so, they have great perspectives to offer potentially on how this works and what we can do from it.
So without further ado, I'm going to introduce Doctor Pollock. Doctor Graham Pollock. He’s the Lions eye donation, the director of the Lions Eye Donation Service in Melbourne. He spent the past 30 years involved in eye banking at local and national [and] international levels. He's BSc honors GCUT MPH PhD OAM. Trained in pathology at the University of Melbourne. His association with donation and transplantation extends back to the 1980’s while working in organ preservation for transplantation. He completed his doctorate in this field at the University of Queensland and University of Cambridge. Graeme also holds a master’s degree in public health from Monash University in Health Administration, and a Post-Graduate Certificate in University Teaching from the University of Melbourne. His current interests include medical standards and guidelines in the field of eye banking. He is a past Chair of the Eye Bank Association of Australia and New Zealand, past-President of the Australasian Transplant Coordinators Association, a member of the Medical Advisory Board of the Eye Bank Association of America and a founding member of the Global Alliance of Eye Bank Associations. In [2019] he was awarded an Order of Australia for service to corneal transplantation and education. Wow, that’s quite amazing!
And I without further ado, I'm going to turn it over to Doctor Pollack to give his presentation on organ culture for us.
Presenter: Dr. Graham Pollock
OK. Thank you, Gary for that, for that great introduction. I feel like I don't need to even speak now after that.
Just let me share my screen for you and we'll, then we'll start the presentation. OK. Have we all got, have we all got that up, Gary? Is that coming through? Gary, you got that?
Host: Gary Rockl
No, it's not showing yet.
Presenter: Dr. Graham Pollock
Not showing?
Host: Gary Rockl
No. It did just a minute ago.
Presenter: Dr. Graham Pollock
Yeah, let me, uh, let me just try again.
Host: Gary Rockl
I did forget to mention one thing. This is being recorded and so for everybody's knowledge it will be available by CBS. I'm sure one of the logistics individuals from CBS will let us know how that's available and people that aren't able to attend could access it after the fact. It’s not up? OK. There we go.
Presenter: Dr. Graham Pollock
There we go. Got it. OK. Thank goodness for that. Alright. OK. Yeah. Thanks for the opportunity to chat.
Originally, what we were really looking at was to try and take away some of the mystery of organ culture for you all and what it is. But it's kind of extended into a discussion of how that might fit into your system. And I guess even to an extent some of the learnings that we had in Australia.
As Gary indicated, when we when we changed over to organ culture from hypothermic storage from my own eye bank in Melbourne, we changed over back in 2005, so we had about 15 years [of] experience of hypothermic storage and now we've had about 15 or so years of experience with organ culture storage now. And So what I want to cover today:
- What are some of the technical requirements with organ culture, trying to get into the nitty gritty and remove some of the mysteries of it.
- What are the benefits and some of the disadvantages of the organ culture system?
- Examine whether organ culture is right for your eye bank or right for your eye banking system if you like.
- And then to finish up with looking at how Australia approaches some of our national networking of eye banks, working towards the self-sufficiency and sustainability of corneas for transplantation across Australia.
I think as starting point, it's probably prescient to consider that that whilst where we talk about organ culture storage— in fact we even talk about hypothermic storage [of] corneas, really and that's the correct ISBT 128 terminology—we're still talking really about preservation of corneas in the same sense that you preserve hearts and livers and kidneys and whatever, in contrast to the type of storage that is conducted for most tissues. And because we're really talking about preservation rather than storage, it actually changes the dynamics of your system. Your operating, in fact, a little bit—eye banks [are] operating, in fact, a little bit more like an OPO, especially when it comes to allocation and distribution and internal processes, even rather than tissue banking for bones or heart valves are concerned.
So organ culture preservation has actually been around for quite some time. It was first developed by Doughman in Minnesota back in 1974. At least, he put together the original experiments towards organ culture. It's interesting that in fact this is around the same time that McCarey-Kaufman media emerged in the United States as well the first hypothermic corneal storage media. Prior to that, looking at preserving corneas literally on the on the whole globe in a in what was called a termed the moist pot. And you really had around about 24 hours from the time of the death of the donor until you needed to transplant that cornea.
The Doughman system didn't really take off because there were some inherent problems in the way it was originally designed. But both Neil Ehlers and Elizabeth Pels – Neil Ehlers in Denmark and Elizabeth Pels in Netherlands in Amsterdam— took the the pieces of the organ culture system and they developed it into something that was more practical and more readily usable and solves some of the issues that Doughman had had. And so the first organ culture of clinical corneas was conducted really in the mid 80s in primarily in Europe and certainly spread across Western Europe as the method of choice for the preservation of corneas, so that, for instance, in the UK, France, Netherlands, Italy, [and] most of Germany, pretty much the only system of corneal preservation that's used is actually organ culture preservation. And that's been around since the mid 80s. So this is, it's not something new. It's been around for a very long time now and it's and it's very, very well developed and very, very reliable.
It actually works on maintaining the cell metabolism of the endothelial cells of the cornea. And, you're actually incubating the corneas at a temperature anywhere between 28 to 37 degrees. It just depends on the eye bank on what temperature they stick at. In Melbourne, we actually use 34 degrees, 34 degrees being the temperature of (the normal temperature of) the of the cornea in situ.
So what's in the organ culture media that makes it so magical? it's actually very very simple. it's really just an extension of a cell culture media; the base of it is (equals) minimal essential media that is that's nicely pH buffered to maintain the pH very well. Again, depending on the eye bank you're looking at somewhere between 2% to 8% fetal bovine serum. From, of course, TSE-free herds. In a practical sense, what that means is I think everyone that's using organ culture in the world actually obtains their fetal bovine serum from Australia.
It has also in it antibiotics and antifungals. The antifungal is in interesting; since the mid-80s we've been putting amphotericin B in our organ culture media. And, of course, there's been a recent trend, because of the problems with some fungal endophthalmitis with lamellar corneal transplantation, particularly in America to start putting amphotericin B in hypothermic media. There's probably some good reasons though, that you don't need amphotericin B in hypothermic media, but you certainly need it in organ culture media.
And organ culture preservation is actually a two step part: there's then, before you actually use the cornea, there is a another media that you place the cornea in, which is exactly the same as the as the original organ culture media, but it contains a large amount of Dextran 500. The idea being to thin down the cornea before use, the corneas get quite edematous and plump whilst they're in the organ culture media. And again, the concentration of Dextran is, depending on the eye bank, is anywhere between 4% to 8%. So there's certainly some variables, but only in concentrations of Dextran and antibiotics and the fetal bovine serum that varies a little bit between eye banks if they make it up themselves, which we actually do.
There is a commercial organ culture media that is available from two firms in Europe. One is Eurobio that's based in France and the other is the Alchimia which is based in Italy. The. In fact my understanding is that Alchimia, from their eye banking product, they've actually now been bought by Moria, that's the French instrument firm that produces a lot of microkeratomes for eye banking, and that's actually, at least in Australia, allowed for some better distribution of the commercial media out of Italy, and in fact in Melbourne, we're looking at, instead of making up our own media, actually going across to the commercial media, even though it's slightly more expensive.
So if you look at – I'll just, I'll just run through the process very quickly of organ culture media—organ culture preservation, sorry. And then get back to some of the specifics along the way. Really as with the cornea, placing it in optisol, you're decontaminating the surface of the globe or decontaminating the cornea in situ, and the cornea is simply placed in the organ culture media at anywhere, as I said, between 28 degrees to 34 degrees. It's just a dry heat Incubator; this is a sealed system, so it's not in the CO2 incubator or an incubator that needs any relative humidity in it. So a very, very cheap, simple sort of incubator as long as [it’s] reliable on its temperature. And it can actually sit in that media for up to 30 days—30 days in our experience; some eye banks around the world will even go out to almost 50 days. And the cornea can still be used after that period of time.
So you're really looking at an extension of preservation time over hypothermic media. Hypothermic media probably, it's generally rated out to 14 days. You probably find the ophthalmologists really want to use those corneas by 7 days. In organ culture media, as I said, we can actually go out to 30 days. In a practical sense, operating in an eye bank (in our eye bank), the average time of storage is usually somewhere around about 18 to 19 days in storage.
During that storage period we actually monitor it for microbial growth at three to seven days, we take a sample and monitor for microbial growth because this is a very, very nutrient media and bugs will take off in it if they're in there. And once we have no bugs growing in there, or at least no bugs from our microbiological monitoring, the cornea is good to go for transplantation.
Before it's transplanted, it actually, as I said, goes into a secondary media, which is the thinning media that thins the cornea down. And once it's in that media, it is good for one to five days before you need to transplant. So notionally in our system, for instance, we can go from the preservation time, from the death of the donor until it's transplanted something like about 35 days. And there's also more microbiological monitoring once you've transferred into that other tissue.
Just to let you have a little bit of a view of placing the cornea into the media: I'm not sure whether you can see from that photo, but the cornea is actually suspended in the media on a suture that we just put through the rim of the cornea. That's just drawing the suture through the rib. And the other end of the suture goes up through the through the cap to hold it in place and all of that is then placed into the organ culture media and field and goes off to the incubator, like so.
In the case of some of the commercial medias, they also supply what's called a corneal float, which is [a] little simple plastic disc with a notch in it that actually attaches to the side of the cornea and it just allows the cornea to float a little bit under the surface of the media during its organ culture. Period. So it's actually quite a neat system as well.
As I said it, somewhere between three to seven days we take a sample of the media, and we actually place that media in blood culture bottles, which is a nice simple way of monitoring the microbiology of it.
These cultures can grow bugs, and it's essential that you monitor the media for the bugs. It's not actually possible to test the cornea itself, you're actually testing the media. It's of course not possible to have a sterile cornea. And so you're looking for a…trying to detect a level of growth of contaminants in the media that would compromise the transplantation of the tissue. In a practical sense, we find that monitoring through blood culture bottles, which is a very nice, simple, easy and rapid system to do this works very, very well in eliminating any corneas that would be compromised by a microbial contamination. And there's a range of information and publications there on the use of blood culture bottles just for this—that particular purpose.
Yes, you do get contamination in organ culture media and you can see in the first picture there that you often don't even need to monitor by blood culture bottles. You can see the contamination straight away just from visual inspection. The other interesting one that you have below, it's actually some Candida albicans that's growing attached to that cornea there. And so visually, I mean that that's obviously one that we've let grow quite a bit; that’s certainly not used for transplantation. But it demonstrates very nicely how you can pick up microbial contamination in these cultures and eliminate them from being transplanted.
What the actual contamination that you get from all the corneas that you put through, at least in our system it's, it's less than 1%. So you don't actually lose many corneas through microbial contamination, and the great thing about it is that you have a built in microbiological surveillance during the during the storage period. What that means is that you can actually accept septicemic donors for donation of corneas because if the bugs are contaminated, being contaminated at all by the septicemia (infected by the septicemia), those bugs will actually grow in the culture and you can eliminate them from the pool. In reality we find that very, very few septicemic donors actually do end up growing any bugs. And so that's actually allowed us to expand our donor pool quite a bit by accepting septicemic donors.
We also—when you look at some of the studies that have been done over a period of time, this built in microbiological surveillance actually also assists in preventing postoperative infections. And so that whilst for hypothermic storage you have an endophthalmitis rate in—averaged across many studies of about 0.2%, in organ culture it's more like 0.1%, so it's actually very effective in reducing endophthalmitis and indeed in the recent outbreaks of fungal endophthalmitis. With lamellar surgery (DSAEK or DMEK surgery) I think almost all of those cases have been hypothermically stored media. I do know of one case in Australia where a fungal contamination did fake through that but open culture is a very safe system for reducing that risk. There’s actually a paper done by my colleagues in the in the NSW Tissue Bank which looks at some of the characterization of these contaminations in culture.
So at somewhere between 6 to 30 days…I'm talking about six days because by the time if you take your sample of media at three days, you want to wait a little while until you take your sample in the media to allow for any bugs to actually emerge in the media and then look at a three day result from your microbiological surveillance that's a minimum of six days before you can actually release the corneas for transplantation. So somewhere between 6 to 30 days the cornea is transferred into thinning media and then it can be used for transplantation, usually after a day to allow the cornea to thin down. And you're also doing another microbiological test at that moment.
The reason for the thinning media or transport media—it's alternately referred to as thinning or transport media–is, in the organ culture media, that cornea swells out to about a 1000 microns. So if you're looking at a normal cornea in hypothermic storage sitting somewhere between 500 and 600 microns, you can see it's quite swelling, and it's all due to stromal oedema because even though you have…still maintaining the metabolism of the cornea, the turnover is very, very slow, and so the endothelium certainly isn't as effective in continuing to remove the water from the corona. And, as I said, the thinning media contains about 3% to 12% Dextran depending on what bank is using it, and that Dextran will act oncotically to reduce the stromal oedema and thin those corneas out to make the most suitable for transplantation and also suitable for pre cutting for DSAEKs and also thinning them down to assist in the preparation of DMEK as well.
One of the things that also happens upon the point of transfer is, this is when we're actually doing our assessment of the cornea. In hypothermic storage, you're doing your assessment of the cornea usually by slit lamp and specular microscopy of the endothelium at the beginning of the preservation time. And all that is giving you is a snapshot of the morphology of the cornea before you start the preservation. The advantage of organ culture is you're doing your assessment at the end of the storage period, almost immediately before the cornea is actually transplanted.
It's—you say a light or a phase contrast microscopy to do it, and it also involves a Trypan Blue exclusion test. So you're actually also looking at the viability of the endothelial cells, not just the morphology. So you're looking at the cell density, the cell morphology as you do with the specular microscope, but you're also adding to that a cell viability assay. It actually involves just simply placing a concentration of Trypan Blue on the back of the cornea. You then wash it off, and you add a small amount of sucrose. I think it's 1.3% sucrose. What the sucrose does is it shrinks down the cells, just a tiny, tiny little bit so that you can actually see the cell margins under the microscope. And you can effectively count those cells, get a cell density measurement. You've actually got a wider field of view than you do on a specular microscope as well. So you're looking at a larger number of endothelial cells, and you can see [in] the photo on the right there, there's some Trypan Blue staining along, in that cornea. Yeah, that one, that cornea wouldn't be used for whatever reason that endothelium—parts of the endothelium aren’t viable.
So again, we've got with organ culture here a built-in viability assay so that you know that when you're transplanting the corneas, the cornea is actually viable. What that means is that you can safely extend your corneal ischemia criteria so that empirically, when you're retrieving full hypothermic storage, again depending on the local eye bank, you're probably looking at a death to preservation time of somewhere under 15 or 16 hours. When I first started, it used to be under 6 hours and that was kind of just an empirical safety net because you didn't actually know because there was no viability assay; all you had was the morphology of the cornea to know how long out you could go from death to preservation. The beauty of organ culture is that you could extend that death to preservation time out as long as you like. And in Germany in fact, they're routinely going beyond 24 hours up to 30 hours death to preservation time. And as long as the cornea is still viable, then at the end of your preservation period it's suitable for transplantation, so you're actually using an objective assessment of whether that cornea is suitable for transplantation or not. By being able to extend that corneal ischemic criteria also means that you're that you're expanding your donor pool quite a bit as well. In fact, in Denmark for example, for medical examiner’s/coroner’s cases, they're not actually allowed to retrieve until 24 hours after death. So if they were using a hypothermic system, there is some risk in those corneas, but by using an organ culture cornea, they can safely retrieve those corneas that have availability of that donor pool from the medical examiners, coroners cases and safely transplant those corneas.
So just if you compare the hypothermic and organ culture storage looking at some advantages and disadvantages: as far as graft outcomes are concerned, they're comparable. There's really no difference in all the studies that've ever been done. There's no difference in the outcomes of transplantation between the two techniques. Certainly hypothermic is simple, and it's fast; there's minimal handling. Organ culture and you can see is more complex, and you do need more support services to operate it. Although it's more complex, it's still not really complex. It's still relatively simple.
Again, your presentation times: hypothermic rated somewhere between 7 to 14 days. Organ culture in general, it's rated out to about 30 days in organ culture media and another five days in the thinning media.
For hypothermic, your tissue is available for direct use. You can retrieve a cornea straight into optisol, for example, and as long as you've got all r your communicable disease testing done and all your history checked, et cetera, you can transplant that cornea straight away. That's not the case with organ culture. It needs to go through a quarantine period, and it also needs to go through a reversed swelling period as well. So then they're not directly available for use.
The transport is interesting. Hypothermic, of course, has to be transported refrigerated organ culture can be transported at ambient temperatures. Ambience: interesting isn't it, though, because it depends on what part of the world what the ambient temperature is. But what I mean by that is you can transport these; you don't need the corneas to be refrigerated to transport them. That makes a big difference in your logistics of transportation around. And also, if you're sending corneas around the country, it also makes it a lot cheaper. And you don't need any microbiological tests for hypothermic, but you do for organ culture. But the advantage of that is that it's tolerant of septicemia, so you're expanding your donor pool by having septicemic donors.
With hypothermic, after a period of time, we've certainly found this with optisol, when you're going out beyond seven days, you can often get a lot of epithelial shoughing, and if you have any epithelial defects when you started with that cornea, they will remain, which is always, then, a slight risk that you might have precipitated an epithelial defect after transplantation, although that doesn't seem to happen very often. In organ culture, those epithelial defects will actually repair themselves and close over. So you have a very, very nice epithelial surface. It grows very, very nicely in organ culture.
The evaluation for hypothermic is noninvasive whereas in organ culture it is invasive. But, again, the advantage being that occurs at the end of preservation and it's a viability assay as well. The risk of endophthalmitis is less or culture. For DSAEK preparation, we find that it's actually easier to do pre-cut DSAEK if you're using hypothermic corneas. They're more stable in the thickness, and so you've got a better starting point for your cut. For organ culture, you need to d-swell the corneas before you cut, and it probably takes a little bit more skill to do it accurately. For DMEK preparation, again, you need to de-swell the tissue before you start to do a pre-strip on the on the DMEK, so you can actually see more clearly where you're at.
OK, so that kind of explains the technical aspects of organ culture, and hopefully that removes some of the mystery of it and presents you with some of the advantages and disadvantages. But to know whether organ culture is right for your particular system, it's probably necessary to have a look at the way your particular system, and indeed the way your particular health system operates. So just to have a look back at some of the economics of certainly the ecosystem of eye banking and distribution, if you like.
I can talk about demand, and demand is actually what the eye bank sees. It's what on our scheduled list at any particular time for any particular week. Oops, sorry, I’ve gone the wrong way…find that again. There we go. In comparison to need, a need is actually what the ophthalmologist sees or what the health system sees. There are there are plenty of patients out there that will be on an ophthalmologist’s list or an ophthalmologist’s watch list. You might need a transplant, you know, in a year or so. But the eye bank actually doesn't see that. So that's kind of the background need as distinct from the demand which is immediately what the eye bank sees.
Now, the thing about demand is that it varies with time. And some of the variables that make that variation, of course, is the variable access that you actually have to be able to do the transplant in the 1st place—so whether there’s surgeon availability or theatre availability or anesthetist availability. And such things will depend on—it can depend on the public or private mix that you have within your health system itself. Certainly, those sorts of availabilities and demand vary between the public and private systems, depends on the efficiencies of your health system as well to do the transplants and it's also going to vary during holiday periods; [during] long summer breaks, there is not very much demand for corneas. And of course, what demand isn’t met gets fed back into the need, so it cycles through.
And of course, to meet that demand you also have, though, variable donor cornea access that can vary over time. It can vary in having a whole bunch of donations in one week and none in the next, and it can vary depending on the geography of where you are in your particular nation. For example, you can have a good donor rate on the East Coast of Australia and a poor donor rate on the West Coast of Australia in any one particular time.
Donation, again depending on your system, is very hard to regulate, but you can take out some of the ups and downs of donation by extending your preservation through organ culture. For example, sharing between banks so that the East Coast having a good donor rate [is] sharing corneas with the West Coast that has a poor donor rate at any particular time. And you can also do it if you have very, very good control over your referrals. Which is the case in, certainly, across the United States with their conditions of participation rule. But that's certainly not necessarily the case in other in other nations. Within Australia itself there [are] even variations in that depending on what state or what city that you're operating in. So you can control your donation rate to a certain extent, but in other health systems that's not possible and it's quite unpredictable.
The skill, of course, is trying to match your donor rate with the demand at any particular time, which is going to vary, even depending on what time of the year it is. For example, at the moment in Victoria, where we have—I don't want to use it, but I'll use it anyway—a gut of corneas. We have more corneas than we can actually transplant at the moment. The reason for that is that we're now reached December. In December—festive season—interestingly enough, the community wants to donate, so you have a lot of donors coming in through the door. But at the same time, there's a slowdown in the transplantation rate, and so there's a there's a mismatch. Of course, at other times you can have, the demand increasing because you have more access, you have surgeons putting on more cases, and at the same time a decrease in the number of donors or in fact, the number of donors not increasing to meet the demand. So you can actually have periods where you're actually doing an increased number of transplants., but the wait time for the transplants is also increased.
People tend to think “Oh, you know why can't I get a cornea for transplantation at a particular time?” and they naturally think, “Oh, haven't you gotten any donors?” The situation often isn't that you haven't got any donors. In fact, often the [donor] rate is increasing. The problem is that the rate of demand is outstripping the rate of increase in donation. And conversely, as I said, you can have reduced access to transplantation, increased donation, and what that leads to, though, is increased waste. And when you have increased waste, you also have higher service fees because you're doing a whole lot of work not for the purpose of transplantation that still has to be funded, but your funding is generally through the number of transplants that you can perform, and so the increased workload but not increased transplantation leads to higher service fees. And also if you're if you're doing a whole lot of donation and not being able to get these things transplanted, there's a problem between…ethical problem and reputational and humanitarian cost problems as well.
So this gets back to one of the reasons that we changed initially in Melbourne and subsequently four of our 5 eye banks in Australia have changed over to organ culture. And the reason was, within our particular health system and our donation ecosystem, our donor rate does this from week to week, and if you have hyperthermic storage, and you only have one week to get those corneas transplanted, and yet demand remains relatively constant, you find in some weeks you have many, many more corneas than you scheduled for that particular week and you find yourself calling around trying to get these—all transplants performed, which again, if you're operating a public health system is a very, very big problem. Public hospitals are very, very reluctant to take on extra caseload because of the costs involved in doing it. When we were operating hypothermic storage, I was often called by the theatres that the Eye and Ear Hospital in Melbourne asking me what the hell [I am] I doing putting on all these extra surgery after hours. It costs a lot of money. And then the very next week I'd turn around and be cancelling schedule cases, which meant that that you had empty operating theatres because those scheduled cases weren't going ahead, which again, costs a lot of money. But when we examined the number of corneas that we were able to retrieve over a longer period of time, like over a month, we found that we had enough corneas to actually meet the demand within a given month. And the organ culture system let it overcome those variations of donations though, that you were then spreading out your distribution in a much smoother form.
Of course, we also had the situation that we're about to encounter in fact coming up to Christmas, and Christmas in Australia is also the long summer break as well. There are very, very few transplants, really only urgent transplants that are done from the week before Christmas right through to almost the end of January in Australia. It varies a little bit by state, the shutdown. But again, when we had hypothermic storage, we had a lot of corneas that we couldn't get transplanted. These days we can hold a lot of corneas for the period until things start up again. And it also allows us to more easily export corneas to those countries that don't have such a shutdown and actually get the corneas transplanted as well. This, interestingly enough, is what Italy sees in August. They have— Italy has a shutdown during August; during that period Italy actually exports a lot of their corneas elsewhere.
There is another way to deal with those ups and downs, which is the system that the United States uses with their hypothermic storage system, and that is that you always have an excess of donation to what [your actual] need is. But of course, as I said that leads to a lot of waste. You actually then have to look at export markets and you're also giving yourself higher service fees for doing that as well.
So the benefits of organ culture can be summed up certainly by time and also the benefits to the issue itself. We find with organ culture that we have what we call less sport forward cases so we don't we don't need to rush transplants any longer, and at the same time we have less cancellations. In fact, we haven't cancelled any surgery in Australia for wanted a cornea now for something like 20 years. There's additional flexibility with your scheduling, so I don't know what it's like in Canada, but for some reason in Australia everyone wants to do their corneal transplants on Tuesdays and Thursdays, and no one wants to do their corneal transplants on a Friday. So, again, with hypothermic storage, with one week storage, that was a problem because you were loading up particular days of the week. With organ culture storage, it doesn't matter if you load up particular days of the week with your schedule, and also you have an earlier notification of availability. We're able to tell someone, one of our ophthalmologists who has a scheduled case on the 18th of December, for example, we can tell him now that that transplant is going to go ahead. We have a cornea for that transplant.
You also give yourself benefits of time in your suitability determination. There is a big issue in Australia over communicable disease testing, and part of it, it's been created by our Therapeutic Goods Administration which is our equivalent to the FDA that regulates the eye banking in Australia. One of the things that they more recently introduced (we had an exemption for a little while) was nucleic acid testing for all your HIV Hep. B Hep. C. Now, that sounds like a simple thing, but the TGA complicated a little bit because that testing has to be done only at TGA-licensed laboratories, and it also has to be done only by TGA-validated and licensed test kits as well. What that has led to is a lack of laboratories that can actually do our testing for us. In the case of South Australia and Western Australia, for example, the closest laboratory that can do the testing for them is in Melbourne. So from Perth to Melbourne is 5,000 kilometers away. So that's equivalent to I'm guessing Vancouver to Toronto or New Brunswick or something like that. Very big distance. Which creates a good deal of problems in getting your communicable disease testing done in time. Organ culture gives you that time to get it done.
It also gives you time if you're following up with family physicians on donor histories, which are notoriously difficult to get as far as time is concerned. And even if you're trying to track down a next of kin for the donor risk assessment interview, that can sometimes be difficult to track down the right person for that. So organ culture gives you all the time for that. And there's also a question they're asked some nations that still do HLA matching for their corneas as well. It's not routinely done around the world anymore, but if you were going to be doing HLA matching, that's given you extra time to do that as well.
The benefits to the tissue: you're looking at bug-free cornea, essentially, which is not the case for most corneas that go out—well, I shouldn't say most; that's not the case for probably around about 10% to 15% of corneas that go out hypothermically stored. And you're able to expand your donor pool and that's by having longer death to donation times because you've got that inbuilt viability assay, and you're also accepting bacteremia septicemia because you have the built microbiological assay.
So just to briefly sort of finish up, I thought it might be an idea for you to have a look at the networking system of eye banks that operates in a in Australia. Now, it's fair to say that the network doesn't operate because of organ culture, but organ culture makes it easier for it to operate.
Just to review Australia's geography and system, and in fact, I'm guessing a lot of this might sound a little familiar to the Canadian situation. I don't absolutely know that, but I'm guessing maybe a little. We’re of course a federation of States and territories and with a very, very large geography, but our population is concentrated in in the in these large cities. In each of the cities marked are where our eye banks are. I've included New Zealand in this over in Auckland because New Zealand is actually part of our eye bank association: it's the Australian and New Zealand Eye Bank Association, and we do share a lot of corneas out into Auckland as well, although Auckland isn't able to provide Australia a share in reverse because of regulations and also because of donor rates as well.
The funding and providing of tertiary Healthcare is actually a state responsibility. So the states actually run the public hospitals in Australia, it's not a federal responsibility. Federal responsibility is towards primary care, general practitioner level primary care. And our public, private mix of medicine is about 50/50. So, it’s certainly not dominated like private medicine such as United States, but it's not dominated by public medicine, say for instance the NHS in the UK. So it's a mix.
We have 5 eye banks in Australia. Two are actually run by this by the state health departments themselves, and three operate as non-government organizations which are under contract to their particular state for providing corneas to the public sector as well as their providing corners to the private sector. Four of them are now running organ culture and one runs hypothermic. The one that runs hypothermic is in Adelaide, which is our smallest eye bank and from a scalability point of view that works better for them.
We operate—all our funding is essentially on a fee per service basis. The level of our fee per service is actually assessed independently by the Commonwealth that sets what they consider to be a fair and reasonable service fee for us. The service fee does vary between states because the cost certainly varies between the states. So we have our five eye banks in Australia and essentially each of the eye banks looks after their own jurisdiction in supply and holds a local state waiting list, if you like. So all our distribution in Victoria, for example, is to Victorian ophthalmologists. We do also distribute to Tasmania that doesn't have an eye bank. And all the all the bookings that an ophthalmologist makes for their corneas in Victoria [are] made with the Victorian eye bank, and so on around Australia so that you have essentially a network of eye banks that's decentralized, that are that are working with their own local jurisdiction. And what that does mean is that the jurisdictional benefit is, is from the amount of input that the jurisdiction puts in into the eye bank.
And you also get no duplication of effort, so that we're not seeing Opthamologists book a cornea with an eye bank in New South Wales and book another—book that very same cornea for an eye bank in Victoria and just see who comes up with the cornea first, so there's no double booking of corneas […].
This system is more efficient in transportation. Not only from the cost of transporting corneas across a very large country between the population centres that are a long way away from one another, but this is this is actually old data. Now it goes back to 2012, and largely represents when we were operating hypothermic storage. But one of the interesting things that we found is that a cornea that was transplanted in a different state from where it was procured did not do as well as if it was transplanted locally. There's a little bit of conjecture about why this may have occurred: whether it's the transportation standards or (which it almost certainly wasn't), whether there's some other confounders that are going on here to produce this result. But we don't know if that result is continued with organ culture corneas, but one thing was certain: that if you can, you're always better off procuring and transplanting the cornea locally. Although networking, of course, allows you to more equitably distribute corneas across your nation.
Also, of course, when you're working locally, your data collection and your outcomes are more easily monitored. But then all of that goes—because it's all nationally networked—it all goes into a national pooling of data. And there's no competition between eye banks between states for finding ophthalmologists. So that system is very, very different from the system in the United States, of course, where it's more free for all. And no doubt part of the reason for this also is 50% of what we do is public medicine.
In practice, with the sharing of corneas, we've always of course, if someone requires an urgent cornea, say there's an urgent cornea required WA and they don't have anything locally available, it's the cornea is available from another eye bank somewhere. A brief example of this actually, is that WA had their microkeratome that they were using to cut their pre-cuts for DSAEKs out of action, and their replacement microkeratome also broke down, and they had all these schedules for precut corneas available. They couldn't–they had the corneas, but they couldn't actually cut the corneas, so corneas precut corneas from other states were provided to WA to meet their schedules for that. The other issue with the with the networking is that you can have, for instance, an eye bank such as in this instance New South Wales with more corneas than they can use, and at the same time Victoria with not enough corneas to make their schedules, so each eye bank can call across to the other eye bank both by saying “we have corneas available for transplant if you require them” or indeed in this scenario Victoria saying “Hey, can anyone supply us with a cornea at our eye bank.” so there's a an exchange of corneas between the eye banks that enables the equity of access across Australia. And by using that that system, it's also meant that Australia is now up for about the past 10 years—the past 20 years now there's been—if you lived in Perth, you had exactly the same access to being transplanted as if you lived in in Sydney. So there's equitable distribution of corneas across the nation. Oh yeah, that's just the diagram; I already explained that.
But to summarize the organ culture system, it's very well proven. It's been around for 40 years or so now. It has some very distinct benefits in comparison to hypothermic storage. The technique is not complicated, but it does require more scientific expertise and staff training. But that's easier than you might imagine. Importantly, it's adoption: it's not changing one preservation media for another, it's changing from one system of eye banking to another. And the degree of benefit that you derive from using organ culture, it needs to be looked at in the context of your eye banking economics, your eye banking ecosystem:
- What sort of pathology support have you got?
- What donor rates have you got?
- What are your referral systems?
- How do you schedule and distribute corneas?
- What are the demographics of your transplantation?
- How are you funded? and
- What's your public/private mix?
These all play into that, the eye banking economics and the and the ecosystem that you're working in, to determine what sort of system hypothermic or culture would work better for what for what you're trying to do. And I'll be happy to take any questions.
Host: Gary Rockl
Thank you so much, Doctor Pollock. That was very enlightening. I think, just as a comment before we get any questions—I'll get to you in a second, Christine—one of the comments I have, I think a lot of what you said is mirrored in our system here. There are some obvious differences in terms of how funding works and scheduling et cetera, but when you talked about donation versus utilization and timing and stuff like that, that I think was really relevant for the discussion that happened back at the Ocular Forum. A lot of people brought the same issues up, that availability can be really robust at one month or one week or whatever and there's no need for the corneas, and then the next week there's no donation and this puts a real strain especially on hypothermic situations.
So, I'm going to use my position as a moderator to ask the first question: Would it be possible in your opinion to run a hybrid system where you have some hypothermic and some organ culture? Now I noticed most eye banks in the world pick one or the other, and this is maybe based upon history or is this a logistical thing that is just a nightmare to try and to work that kind of stuff out?
Presenter: Dr. Graham Pollock
Our own eye banking in Melbourne, we actually do run a hybrid system, so it's only about 5% of what we do is hypothermic though, and 95% is open is organ culture. So that's within our eye bank itself. Some of the reasons that we might utilize just hypothermic media is the faster turn-around time, OK? And there can be a variety of reasons why you might want that faster turn-around time from the death until the transplantation, and it's not to do with the quality of the tissue, it's to do with the availability of like a certain type of tissue, for example. An example of that might be, for DMEK tissue, for example. Generally, generally what you want (and what the ophthalmologists want depending on their experience) is tissue that's over 50 or 55 years of age. And if you've got a case coming up—and I don't know that we're actually ever in this situation—but if you've got a case coming up where what you have in organ culture is all corneas that are under 55 years of age, but then you suddenly have donor a few days beforehand that is over 55, you want to be able to use that cornea for that particular DMEK case.
So that's when you tend to use hypothermic storage, because it's a faster general type. From our point of view, though, when I was talking about the communicable disease testing, even though we have…our laboratory is across the road. But because it's not a routine pathology laboratory that has a high volume through it, because in Australia those routine pathology laboratories that have a high volume do not want to be TGA licensed because it adds to their cost and also what we do isn't commercially viable for them. The turnaround time on our on our communicable disease testing can be extended so that they y guarantee that it'll be under seven days, but it might, it might be 7 days, so if we have something in optisol that we need to be pushed through quickly, we actually have to make a special appeal to the laboratory to specially push this through. And if they especially push the test through, it costs them more money to do it and they charge us more to do it as well. Yeah.
Host: Gary Rockl
Thank you. Christine, you had a question?
Participant:
Yeah. I actually had a couple, but [the] first one is with respect to costs: it seems like the organ culture would have additional costs associated with it. What is the difference between a cost for preparing the hypothermic versus the organ culture?
Presenter: Dr. Graham Pollock
Well, we don't prepare any of the hypothermic, so we purchase all our hypothermic (optisol, or whatever). If you if you manufacture the organ culture media yourself, and we of course end up having to manufacture these under the close watchful eye of the Therapeutic Goods Administration, but because it's an in-house manufacturer of media it actually doesn't have to be licensed, but you can certainly manufacture all the organ culture media yourself for a good deal cheaper than you can for the purchase of hypothermic media. However, if you go over to the commercial media that's available, for instance, from Alchimia, you're probably—in media—you’re looking at twice the cost, in media; however–and also you have to consider that, depending on who's doing your microbiology contamination testing, there's an additional cost there of that sort of pathology that you're not having with your hypothermic media. Many eye banks in the world actually use the BACT test system for their microbiology monitoring and they actually purchased their own BACT test system to do it. So it works out quite cheap.
But the other side of that, though, is that most of your fixed costs [are] in eye banking labor costs, and that we know that our consumable costs make up a small proportion of our overall cost compared to our labor costs. You do get some savings in labor costs through it because you're not employing those extra people that have to look after your schedules and cancels and distribution so much. And also, depending on the way your referral system operates, you're not requiring as many people to operate your referral system. Because you actually don't have to be as busy with your donations to ensure that you've got an excess of corneas all the time. You actually operate you donation system to match what the demand is going to be at any particular time. You don't need as much staff for that, though probably what you're what you're paying for extra in support services with pathology, and if you went commercially, the extra cost of consumables, it's you're probably offsetting a little bit in labor costs.
Participant:
That's a really good point because, yeah, we do export. We have a—well, usually; it's not the case right now because we're importing from the United States like crazy—but we usually are the main exporter within Canada. We provide a lot of tissues from our eye bank.
The other thing I was going to ask you is you made a comment about graft survival and there not being a lot of change, and I was just going to ask you about your 21-22 Report from your registry. It looks like for DMEK there's very little, like one system is better earlier on and the other system seems to have more graft survival in the in the later dates, but for PK and especially for DSAEK: for DSAEK there seems to be a fairly big difference between graft survival, in that the optisol corneas do better. And so, I was just wondering if you could comment on that if that's your experience?
Presenter: Dr. Graham Pollock
Yeah, you're talking about the figures from the Australian Corneal Graft registry?
Participant:
Yeah, yeah.
Presenter: Dr. Graham Pollock
Yeah, you still see—because the Australian corneal graft registry is a large cohort of all comers, to put it…it’s not a tight case control study or anything like that; it's a large cohort study. You find that a lot of the, again, a lot of those figures on DSAEK survival, they're actually including transplants that were done in the early days of DSAEK that have been followed, and so when there was certainly undoubtedly a learning curve for DSAEK in Australia. The recent results of DSAEK in Australia are improving quite a bit, but if you haven't look—and it's and it deidentified—but if you have a look at the graft survival produced by eye bank by per state, and you have four states that are that are now running organ culture (although the 4th state has only been running organ culture for about a year), so you've got three—on those figures, three states that have been running organ culture for 10 years or more and two states that have been running hypothermic, and the outcomes across DSAEK, DMEK, PK, they don't vary between states. They're exactly the same. They're all aligned. So you've got one system that -- so you have that internal comparison within the same health system of what your outcomes are between hypothermic and normothermic as well?
Participant:
Alright. Thank you. That's helpful.
Host: Gary Rockl
I have a question: from your perspective, when prepping the corneas, like do doing any pre cutting or anything, you mentioned the deswelling, so you have obviously technicians that have done both in some areas. Do they find that it's more difficult to work with this tissue? Is this something that that comes up quite often when they make a transition?
Presenter: Dr. Graham Pollock
Yeah, yeah it is. I know that when I used to do—I don't do DSAEK cuts anymore, but when I was when I was doing them—I'd always prefer to be doing it on an optisol cornea than an organ culture cornea because you would measure the thickness of the cornea before you cut. And with an optisol cornea, it was always pretty predictable that you were going to come in somewhere between 500 to about 550 microns, and it all ends up being pretty routine.
You get the organ culture corneas on there, and you measure the pre-cut thickness. Then it can vary since you've got to make a few more decisions about what cutting edge you need, what that's going to do, et cetera. Interestingly enough though that because you're cutting thicker corneas, therefore you use a deeper cut head to target, say you're targeting 100…
Host: Gary Rockl
Uh oh. We've lost the sound.
Yeah, yeah. There we go.
Presenter: Dr. Graham Pollock
It's back. I think someone got a bit bored with me because they muted me!
Host: Gary Rockl
It was Christine. We’ll blame Christine.
Participant:
Oh, come on Gary!
Presenter: Dr. Graham Pollock
You can prove—you can still reliably hit your target. But what's interesting is we know that even once you've hit your target, that lamella from an organ cultured cornea will continue to thin, so that once you've cut it, it might be 100 microns, but once the surgeon is actually placing it into the eye, it's, you know, 70 microns. And then postoperatively it's even less; though it can actually prove to be beneficial, but it's more difficult to do.
I think the bottom line, though, is that the father of both DSAEK and of DMEK—now lives in the Netherlands—who developed the system, it's all done on organ cultured corneas.
Host: Gary Rockl
I did read a paper that they did the DMEK on non-deswelled (I don't even know if there's a word there), but they didn't reduce the swelling.
Presenter: Dr. Graham Pollock
They didn't reduce the swelling. Yeah, you can do that from a transplantation point of view because of course the swelling isn't going to be in your Descemet’s membrane endothelium; it doesn't matter whether it's a hypothermic or organ culture corneas, you're still going to get 12 microns thickness. The difficulty is, though, in if you don't deswell the organ cultured cornea it's more difficult to visualize where you're at when you're trying to pre-strip and it's just simply a transparency issue, yeah.
Host: Gary Rockl
Christine, you had another question.
Participant:
Sorry, nobody else had their hands up. I just had a question about whether or not you do preloaded DMEK because we're moving towards preloaded, and how does that work with organ culture?
Presenter: Dr. Graham Pollock
We've started doing that in Melbourne now. We've been doing it for about three years, but we're the only eye bank in Australia that's currently doing it. And the up the uptake in Australia has actually been slow for preloaded. it's gradually growing but there's not a great willingness amongst the ophthalmologists for a need to do it. But preloaded works just fine with organ culture corneas. The only issue that we do find is the S-stamp or the F-stamp (whatever you need) in organ culture media does seem to fade a little faster than it does if you're using a hypothermic media. And by the time the surgeon is using it, the stamp can sometimes be more difficult to see, but that's really the only difference.
Participant:
Is there a difference in the media that you use, or is it the same as you would for regular DMEK that you've pre stripped?
Presenter: Dr. Graham Pollock
Yeah, same as the regular DMEK, so it actually sits in that thinning transport media. Yeah, once you've done it, that's how it goes out.
Participant:
All right. Thank you.
Host: Gary Rockl
I have a question about the media that you use, fetal bovine serum, in the actual product. Has there been any research done in replacing that as a…?
Presenter: Dr. Graham Pollock
Yeah, I think it was Alchimia themselves that actually produced a fully synthetic media commercially, but because the—the initial reason for doing that, I think from a from a marketing point of view, was concerned over BSE, you know. And/or a notional concern, if you like. Especially of course, when all the fetal bovine serum comes from pure Australian herds. Yeah, we’re untainted here, so...
Host: Gary Rockl
So far.
Presenter: Dr. Graham Pollock
Yeah, well, we’re tainted in other ways. So they put it out on the market, they produced it. I think the general consensus was that the quality of the corneas through it weren't as good, and the cost to the media was far, far higher. And so, I don't think they ended up selling very much of it. And I'm not too sure, but I think it may have even been withdrawn from the market.
Host: Gary Rockl
I have another question about change over. You mentioned that one of the banks has gone from hypothermic to organ culture just in the very recent time. Was the changeover dramatic and difficult for them, or was it something that was easy? Like, because you have a lot of experience with it yourself in Melbourne, was their changeover smooth? How did they, how did it…?
Presenter: Dr. Graham Pollock
That particular eye bank—What can I say?—tends not to be as open in their communications as others; I honestly don't know, but I would suggest that they had some difficulties, but I think that's less the difficulties inherent in the organ culture system itself, it's more probably inherent in their organizational abilities of that particular eye bank itself, yeah.
Host: Gary Rockl
So I've heard from people in Europe and other places that use Oregon culture that recommends not going in that direction in France and other places, and in Germany, where they say “avoid it if you can.”
Presenter: Dr. Graham Pollock
Organ culture?
Host: Gary Rockl
This is their sentiment. But you're on the other side of this coin here, and I wanted your perspective. From their perspective, they feel like it's more difficult, it's not as good from a surgeon standpoint; your opinion seems to be that no, that's not the case.
Presenter: Dr. Graham Pollock
Yeah.
Host: Gary Rockl
Have you talked to people in Europe and is that opinion…?
Presenter: Dr. Graham Pollock
I think, you know, Germany tends to run a hybrid system themselves, and again, Germany is a federation of states as well. And so you're going to find certain, you know, there's a certain degree of parochialism, as you undoubtedly know, between provinces and like even in Australia, there's a certain amount of parochialism, and once you're hooked on one system, you tend to insist that your system is the best, and so it can often depend on who you're talking to that in that respect.
Look, there's no doubt hypothermic storage is easier to do, but I also have no doubt that for our particular system, and the way our eye banking ecosystem operates, and especially considering, we have enough donors, but we only just have enough donors. And if we were operating a hypothermic system we would find problems with our distribution, and problems in equitable distribution across Australia as well. As for the tissue itself, I honestly believe that it's safer. It's certainly safer from a from a postoperative infection point of view, absolutely, and from the handling point of view, it probably depends on the individual surgeons from what they like.
We did have some concerns when we swapped over about how our surgeons would feel about the tissue, because, you know, is it going to handle differently, you don't think it's as good a quality, or whatever. We were actually surprised when we changed over because for most of our surgeon—mind you, having said that, a lot of our surgeons do their corneal fellowships in the UK which is on culture—but from but most of our surgeons when we swapped over said [they] actually prefer the organ cultured corneas. And I've certainly had comments even from—we've had quite a few fellows, of course, from Canada through our system as well, and we've certainly heard comments from those fellows that they prefer the organ cultured corneas over Hypothermic corneas.
Host: Gary Rockl
This is this is good to hear. That question, especially when I discussed with people in Europe, it always kind of gets brought up and I can hear the inherent bias obviously when people—like you said, when people are used to dealing with a way, that's the system they prefer because they understand it and that other one looks different.
Presenter: Dr. Graham Pollock
Yeah, I mean my position is, I ran a hypothermic bank for 15 years, and I've run an organ culture bank for 15 years, and I'm not—there's no right or wrong system. The right system is the one that's right for you, OK? And in our ecosystem, the right system for us is organ culture. But for someone else, it's going to be hypothermic.
Host: Gary Rockl
Yeah, very good point. So are there any more questions out there? Have we exhausted all the…?
I want to really thank you, Doctor Pollock; that was very enlightening, and you've put a ton of questions in my mind—and hopefully other people, to look—we certainly need to rethink some of what we're doing in Canada to approach our needs. Being so close to the US I believe we've become reliant sometimes, and COVID certainly brought to the Forefronts supply security as a major concern we need to address. So this is giving us more information and more ammunition to tackle this.
So thank you very much for volunteering to do this, and I want to thank Kyle and Lori and everyone at Canadian Blood Services for helping set this up. It was very gracious of you to give me the infrastructure and the invites, and to the people at the Canadian Ophthalmological Society for letting us use their e-mail service to send out invitations.
Thanks again, everyone. And I do appreciate it, Doctor Pollock again, thank you very much. Take care.
Presenter: Dr. Graham Pollock
Thank you very much. Bye, bye.