Biomaterials and Clinical Translation

David Williams is the current President of TERMIS. He is a Professor and Director of International Affairs at the Wake Forest Institute of Regenerative Medicine, Chairman of the South African medical technology company Strait Access Technologies Pty and a Master of the DeTao Academy in China.

The New Organ Initiative is hosted by the Methuselah Foundation.

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New Organ: What is your background?

David Williams: I’m trained as a materials scientist, but I worked for the last 45 years as a professor of medical engineering and in various aspects of the medical industry, mostly in Liverpool, and now at Wake Forest in North Carolina. Most of my professional life, I've been concerned with medical technology, especially implantable devices—hip replacements, heart valves, and many others—and the materials used for them.

About 10 years ago, I transitioned to incorporate regenerative medicine. The reason for this is that we’ve been pretty successful in working with implantable devices, but we’ve had a very limited range of options and functions. We can use synthetic materials to replace parts of the body that have failed for some reason, but we can only replace mechanical or physical functions. We can't replace biology. Therefore, we can’t address many of the really important diseases, especially degenerative conditions, where we need to restore biological or pharmacological functions. That’s where regenerative medicine comes in.

NO: Between the Wake Forest Institute for Regenerative Medicine (WFIRM), the Tissue Engineering & Regenerative Medicine International Society (TERMIS), the University of Liverpool, the journal Biomaterials, and more, you wear a lot of different hats within the regenerative medicine community.

Williams: Yes, I suppose I do. Most recently, after 40 years as an educator heading up a large research group and chairing the department at Liverpool, Dr. Anthony Atala asked me to come work with him at WFIRM as a professor of biomaterials and also as director of international affairs. So my role is to mentor and facilitate international collaborations.

In everything I’m doing, you’ll find that the words “international” and “global” figure strongly. That's my role at both TERMIS and WFIRM. And perhaps just as importantly, it’s my role as editor-in-chief of Biomaterials, the world's major journal in this area. I've taken Biomaterials to number one as a major journal, and I've done so internationally—encouraging, promoting, and sponsoring research work all over the world, including Asia and Africa. I think advancing this field is largely a global issue, and whether we’re doing research or educating or working in the commercial sector, we should look at it that way.

NO: I want to come back to your international work, but for the moment, let’s talk about biomaterials. What are they, and what kind of work are you doing with them?

Williams: I published a short paper recently called “The Biomaterials Conundrum in Tissue Engineering,” and to put it simply, I think we’ve mostly gotten it wrong. I’m not being too critical, because it was probably inevitable, but the early attempts at tissue engineering involved material scaffolds, and that’s where biomaterials come in. The scaffold is the form in which you’re going to develop an engineered organ, and the originators felt that they needed to get FDA approval for them. Therefore, they needed to use an FDA approved material, and although this was understandable, I think it was misguided.

The sole criteria for FDA approval for biomaterials used in implantable devices was that the material did no harm. It had to be known to be safe. You're never going to get a scaffold or template material to function properly if all it does is play safe. You need the material to actually stimulate cells through mechanical forces or growth factor delivery, and standard synthetic polymers were never going to do this reliably and routinely.

Because of this, I think we need totally different types of materials that try to replicate or represent the micro-environment of the cell. I’ve been shouting this from the rooftops for a long time now. It can’t be an engineered fabricated structure that looks nothing like the cell micro-environment, or we’ll never be able to make the cell regenerate the tissues that we want.

We do have a number of pretty good hydrogels that do this, especially biologically-based hydrogels. That’s why decellularized extracellular matrix (ECM) is getting so popular. I don't think we're there yet by any means, but there are some interesting approaches around. But the key is that we have to have a different mindset regarding how we develop our biomaterials, and the regulators have to have a different mindset regarding how they regulate them. We can't use the standard tests for safety that the FDA is saying that we still have to use, and that’s a big issue at the moment. For the most part, the regulators still want to play it too safe.

NO: Are you a voice in the wilderness on this, or are there others out there who see it the same way?

Williams: There are some very good labs that are doing what I'm suggesting, but far too many that are not. Sam Stupp in Chicago and Jeff Hubbell in Switzerland are two who are, and there are quite a few others. Steve Badylak’s work on decellularized ECM is also very good. So I’m certainly not alone. I'm just trying to make sure that the community is aware of it.

I do get frustrated sometimes. I was at a biomaterials meeting in Europe this year, and presentation after presentation and poster after poster talked about a minor modification to an old material that never worked anyway. We academics have to get over this barrier. Why spend dollars and student time working on old science that is never going to work? It’s easy to do, but it’s not going to get us anywhere.

NO: What do you see as the most promising approaches to biomaterials?

Williams: Let me first make clear that even though I'm a biomaterials scientist, I don’t believe that we will always need biomaterials as part of regenerative medicine. There are a number of different approaches and therapies out there, for which a variety of different materials may be appropriate. However, if we do want to create solid organs and achieve reasonable dimensions to tissues, they will have to have some sort of structure, and I think we can only get that by using materials that are capable of elaborating that structure.

I mentioned Sam Stupp in Chicago, who uses peptide hydrogels, and works in both the musculoskeletal and the neural areas. I think his approach is very sound. I work with some groups in China who have made good progress in peripheral nerve regeneration using a combination of materials and growth factors and other bio-molecules. The overall principle, though is that we need a systems approach. It's not just one issue, but putting many different pieces together that gives the best opportunity for a cell to regenerate the cellular matrix and then for it to be integrated into the host.

NO: In terms of advancing state-of-the-art biomaterials science, what would you like to see happen that's not happening? What activities would really move things forward?

Williams: One of the biggest questions now has to do with suitable models for evaluation prior to “first in human.” It's a huge issue. We know that we can use both biomaterials-based therapy or cell therapy in mice, and we can do it in rats or in rabbits. But the first thing you notice is that you get different results in these different types of small animals, and when you go to a large animal, you get even greater variations in the results, especially in vascularity.

We need an appropriate large animal model that will be sufficiently predictive of performance in the clinic to allow regulators and funders to say, "Yes, go ahead and do it.” Without that, we're never going to be able to commercialize, because any company involved in this will have to follow the proper regulatory rules, and those are just too burdensome at the moment.

For example, the great work that has been done to date on the bladder and the trachea by people like Tony Atala and Paolo Macchiarini has been done under regulatory approval, but not as a commercial entity. And doing these transplants as orphan procedures is not necessarily going to translate into commercial success. The companies that are making money in regenerative medicine, I think, are those that are scaling up on the cell manufacturing side, companies like Mesoblast in Australia.

So far, we don't actually have a business model or a real clinical translation model that is going to allow for-profit companies to make their profit by treating a significant number of patients. We'll do it one by one, but to translate that into companies actually coming in, investing, and making money at scale in the manufacturing of tissue is a huge issue. We should never forget the role that health economics plays in all of this.

NO: Do you think we’re more likely to see clinical commercialization success in other countries? In other words, are economic conditions more favorable elsewhere? And if so, will those successes increase the odds of more favorable conditions in the U.S.?

Williams: It's too difficult to predict that at this stage. Let me give you an example. Ten years ago, when I was back in my lab in Liverpool, we worked on a tissue engineering approach to treating diabetic foot ulcers. We were working with a company and we had a system that was looking pretty good. But it was costing 20,000 euros to develop one product for one person, and that was just never, ever going to work.

From a health insurance point of view, the answer is, "We'll just put a new bandage on every week. You can have a band-aid.” And I'm not diminishing the impact of diabetic foot ulcers, but that was not the life-threatening issue that New Organ is trying to deal with. That’s why here in the U.S., I think we've got huge problems. It’s not simply ObamaCare or the Affordable Care Act. It's the way in which the insurance provider is now in charge. I think it’s going to be very difficult as long as their priorities are focused on short-term benefits. As far as I can see, long-term solutions are not really in the best interests of many insurers right now, and so the overall health economics in the U.S. are working against us rather than for us at the moment.

In order to change that reality, we have to persuade real decision makers that “Yes, there really is a future in this.” And there are very significant early costs required in order to get to that point. Pre-clinically, for example, we’re nearly there now in the treatment of patients with acute myocardial infarction (heart attack). There are some good cell therapies, as well as some tissue engineering approaches that look as though they may work.

I can also give you a couple of examples from the medical technology area. You may remember the artificial heart, and especially the heart assist devices? They can certainly be successful, but when the hardware and the first-year costs of these treatments amount to almost $500,000, and it saves one life for a year or two, that's obviously a big health economics issue. It’s the same when you look at the treatment of peripheral vascular disease (when a patient has clotted arteries in the leg). To avoid an amputation, we can put in vascular grafts, and I work with Peter Zilla in South Africa who developed a technology 10 years ago to seed those vascular grafts with endothelial cells from the patient. This improved the performance significantly, and he published paper after paper showing the improved patency rate (i.e., freedom from obstruction). He believes that this is the first type of tissue engineering, which I think it really was, and it improved patients’ lives enormously. But it was just too expensive for any hospital to take it up. You had to take the patient in, harvest her endothelial cells, and then grow them in the graft for several weeks. It just wasn't going to happen.

Examples like these lead me to conclude that health economics presents a very significant immediate barrier to what we’re trying to do. It’s still unclear to me what a successful business model in regenerative medicine is going to look like.