In this interview, Hazel Fermor (Lecturer in Musculoskeletal Regenerative Medicine, University of Leeds; Leeds, UK) discusses the challenges and applications of decellularized tissue in cartilage repair.
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What interests you in this area?
There is a huge patient demand for effective treatments; I’m sure all of us know someone who has got osteoarthritis. The ability to develop an earlier intervention regenerative therapy, so the people do not develop that disease in the first place, is really important to me. Regenerating tissues rather than waiting for people to have gone through many years of pain and disability before having to have a complete toe—joint replacement seems like the best idea to me.
What progress have you made on developing this early intervention?
I am really lucky to work as part of a great group at Leeds who are developing some brand new novel technology based on decellularizing natural tissue. Instead of starting from scratch, we use what nature has already made and simply remove the cells from those natural tissues which would otherwise cause rejection. That leaves us with an extracellular matrix composed of proteins and sugars, laid down in the same natural structure and composition as a biological tissue. When you go on to implant this, you do not get an immune response, as you’ve basically got a like-for-like implant.
These have been shown to be really successful in lots of different applications, so it is a platform technology that we can apply to different tissues of the body. At the moment, decellularized dermis is being used to treat diabetic foot ulcers really successfully. Because we have seen that level of success in pioneering products, we have more confidence to develop a later stage product. That’s where I come in, working on musculoskeletal interventions and developing processes to decellularize cartilage and bone. We are hoping that these will be just as successful as the precursor products.
What are some of the challenges in decellularizing natural tissue?
There are many challenges in decellularizing natural tissue and some of them come as a surprise. You think the tissue because it is part of your joints and is load and weight bearing, you think it is a very strong robust tissue. When you take it out of an animal or human patient and try to process it in the lab, you might find that it is not quite as robust as you expect. One of the fun parts of my PhD was watching cartilage dissolve before my very eyes and thinking, right, we are going to have to come up with an alternative method. Therefore, although the process actually sounds simple, optimizing each and every step for the individual tissue is a real challenge. We need to make sure that we keep processes as simple as possible, so they can be easily translated to our industry partners and are not too costly to produce, but that there are robust and effective methods to produce those decellularized scaffolds.
Can you share any details on your process?
We have the process patented but there are a number of different groups working on decellularization of natural tissues. There are many different ways you can go about it but the basic principle is washing out cells; we use washing-up liquid essentially, which is a really plain and simple process applied in a very specific way which causes the least damage that we can to those matrix components or proteins.
What stage is this process at?
We have been working on developing decellularized osteochondral scaffolds for many, many years now and I think we are just about getting to the stage where we are ready to go into large animal studies. We have been very lucky to receive funding from the IKC, which was an industry partnered award with Tissue Regenix Group PLC.
We are now looking at doing early preclinical studies implanting these osteochondral devices into the knees of sheep to see whether they work. Luckily, because we have already got industry involvement on the project, we hope that if we are successful with these preclinical studies, we can progress those rapidly to achieve actual patient benefit.
What will the challenges be in moving the tissue forward into large animals and then into patients?
There are quite a lot of challenges involved with anything to do with translation of technology and luckily I have got some excellent technology and translation specialists around me guiding me through the process. Making sure that you are doing things to the appropriate quality standards is always challenging. Something that works for you in the lab does not necessarily work when you translate it to industry, so that will be a major challenge making sure that we can produce these scaffolds on a larger scale to good manufacturing processes.
Further down the line from that there are additional problems in getting a product on the market. Just because they work very well in animal studies, and maybe you get some really good early-stage clinical data, it is challenging getting surgeons to adopt those technologies. Hopefully by engaging with that community early on in the project and getting input from clinicians, we make sure that we are developing a product that they actually want to use at the end of the day. We hope the results will speak for themselves and we will have surgeons queueing up around the corner for them.
When the tissue is implanted in the joint, will it be seeded with any cells?
The way that we are trying to translate this technology is as a completely acellular scaffold; that way we do not have to worry too much about the regulations around pharmaceutical products or ATMPs. If we are working purely with an acellular scaffold that can be implanted directly into the patient, the idea is that those are repopulated with the patient’s own cells over time. We are showing with animal models of tendons that you get a really good recellularization of these tissues without putting any additional biochemical factors or cells in, which is advantageous because it means that it is a cheaper product and it is quicker to get it into the market to help patients.
What do you think is the future of decellularized scaffolds in surgery patient treatment?
The ultimate goal is that these would be off-the-shelf products that would replace the need for autografts. At the moment, when people have an ACL rupture, they have a hamstring graft or a patellar ligament graft. We hope we would completely remove the need for those autologous therapies, because those cause major issues.
There are so many directions it could be taking. We’ve focused on a small number of functional tissues but there is no scope to what we cannot decellularize. As regulations catch up with us and as work with stem cells becomes more universally accepted, there is obviously potential for these regenerative scaffolds to be used in so many other applications.
Why is a multidisciplinary environment important?
I think I am very lucky to work in such a multidisciplinary environment, and have support from friends and senior academics in biology and engineering. I also work closely with translation and innovation experts on my doorstep from industry, the NHS and the clinic. It really helps to bring a lot of information into those very basic concepts of projects and make sure that from the very beginning of a research project, you are considering a lot of end user challenges. It means that you are not wasting everyone’s time and that hopefully you are addressing the problem with a lot more information, so that you don’t go off down a rabbit hole and lose sight of what the important parts of the project actually are.