Interview with Michael Hiles, Cook Biotech: “Biological scaffolds are limited only by imagination”

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This week, we extend our conversation on scaffolds used in tissue engineering by featuring an exclusive interview with Dr. Michael Hiles, the Vice President for Research and Clinical Affairs at Cook Biotech Incorporated. Cook Biotech is a company that develops extracellular matrix (ECM) technologies for implantable and topical medical devices.

Dr. Hiles is an expert on biomaterials and biological scaffolds as they are used in tissue engineering applications. Dr. Hiles received his BS and MS degrees in Electrical Engineering from Purdue and his Ph.D. in Veterinary Physiology and Pharmacology from the Veterinary Medical School at Purdue and holds over 30 patents. In his extensive career, he has published articles that span a broad array of tissue engineering topics, including catheter-based medical instrumentation, pharmacological intervention in acute animal disease, composition and structure of biomaterials, and biomechanics of soft tissues. Mike has provided his expert opinion on the current state of biological scaffolds.

Cook Biotech is a major developer of ECM-based biological tissue grafts – or scaffolds. Can you tell us a little bit about your company and the main sources of tissue graft materials that you work with?

ECMs can come from many species, including humans, and are used as tissue grafts in animals and people, but the processing and safety of each are not equivalent. For example, cadaveric grafts can convey fatal diseases and animal tissues need to be proven free of viruses and TSEs. Fortunately, the acellular animal tissues have proven to be quite compatible with humans and definitely safer and more ethical than cadaveric tissue. We currently work with several tissue ECMs from a porcine source. Most of our work is with the strong, growth factor rich, plentiful submucosa of the small intestine.

How have your tissue grafts been used? Can you tell us a little about some of your main products and applications?

Our grafts based on small intestinal submucosa (SIS) have been used to repair nearly every soft tissue in the body, from the dura mater directly on the brain to stimulating closure of venous ulcers on the foot. Our main products are used to repair large ventral hernias, common inguinal hernias, colorectal fistulas, chronic wounds, and for dental, plastics, and nerve repair procedures.

What are the most important requirements for a successful biological scaffold?

A successful biologic scaffold must interact with the body on macroscopic and cellular levels to be not only truly biocompatible but also be cell-friendly, tissue conductive, non-immunogenic, sterile, and possess the necessary handling characteristics to give surgeons confidence in using it. Unsuccessful biologic scaffolds behave more like synthetics, harbor infections, or are outright rejected by the body. We take a great deal of care to preserve the natural ECM because we have seen that this environment is important for healing.

Obviously you have had a lot of clinical success with your scaffold technology. Is this a trend you are seeing – in other words, are biological scaffolds finding a more straightforward path to approval?

Although we have seen literally millions of patient uses of SIS without rejection in tissues all over the body and in countries all over the world, the pathways to approval and regulations in general for new uses are murkier and more unnecessarily burdensome than ever. Most regulatory agencies are finding ways to exclude biologic scaffolds because their compositions cannot be fully defined, because their secondary or tertiary mechanisms of action are complex interactions with the body, or simply because they erroneously fear animal tissues are somehow inherently unsafe. Many aspects of regulation are driving up costs at a time when price pressures are also knocking biologic grafts out of many procedures.

Recurrence is often mentioned as a major issue with implanted tissue grafts. What are the main causes of elevated recurrence with certain grafts and what are strategies that companies are employing to reduce recurrence?

A successful outcome with a biologic graft can only result when there is a proper balance between patient, procedure, and product. Most recurrences, adverse events, or other complications are often blamed on the product when improper technique or patient selection may have been the root cause. This is not to say that recurrence is never a fault of the product. Overtly infected surgical fields and hyperactive metabolic states can cause premature graft degradation and recurrence, and improper material selection or graft design can cause graft failures. For example, highly elastic materials like dermis are not suited for applications that require long term strength with dimensional stability because they tend to stretch over time and form new tissue that is also stretchy. Thus, two strategies to reduce recurrence are to start with more structural ECMs and then teach practitioners how best to implant them.

The complexity of tissues is obviously a major challenge to developing functional grafts. Can you name a few tissue-specific challenges that you have encountered?

As a first example, although SIS isn’t as highly thrombogenic as pure collagen, it doesn’t seem to work well by itself for small diameter vascular grafts because the grafts thrombose before they can fully heal. We spent a lot of time, money, and effort trying to make this work and couldn’t. Secondly, because our source material is intestine, levels of bacterial endotoxin in the raw material can be very high. Dura mater replacement and contact with the CNS require a very low endotoxin load, and although difficult, we managed to get there and have a very successful dura product.

What are, in your opinion, the main general hurdles that accompany the development of new tissue graft products?

We’ve already touched on a few of the hurdles, such as increasing regulatory burden and tissue-specific designs, and other hurdles include viral validations and best practices determinations. If you don’t understand the chemical, biological, and mechanical needs of your intended use, then you won’t be able to make an effective product design. If you can’t prove that your source materials are safe, you won’t be helping anyone, and if you can’t help surgeons learn the best ways to use your products, you’ll end up with many more unhappy customers and poor patient outcomes than are acceptable.

Biological grafts have come a very long way. What is, in your opinion, the yet untapped potential of biological scaffolds looking ahead?

Scaffolds are perhaps the most important part of tissue engineering, and as we move more and more into the realms of cellular therapies, I think we will find that co-delivering cells with a matrix will make a much better product. Thus, biologic grafts in the form of combination products have a very large and untapped potential in virtually all tissues that can be accessed with a needle or a catheter. Further, we have learned that ECM can convert cancer cells into less pathologic phenotypes, that ECM itself can be used as vaccine adjuvants, and that drugs and cytokines can be preferentially bound and protected from degradation by ECMs. The limits of ECM utility are truly limited only by imagination!

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