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By Eric J. Beckman, Bevier Professor Engineering, Department of Chemical Engineering, University of Pittsburgh; Co-Director, Mascaro Center for Sustainable Innovation; Co-founder, Cohera Medical Inc.
On February 4 of this year, the U.S. Food and Drug Administration approved TissuGlu, the primary product being developed by Cohera Medical Inc., as the first internal tissue adhesive authorized for use in the United States. The approval this year is the culmination of over eight years of laboratory and clinical developments by the company that Michael Buckley (oral and maxillofacial surgeon) and I spun out of the University of Pittsburgh in late 2005. I myself spent three years working full-time on TissuGlu’s development during an entrepreneurial leave from the University (2007-2009) and hence played an active role in the rollercoaster ride that working at a startup involves.
The technology that became TissuGlu was a somewhat serendipitous development, in that Dr. Buckley and I were researching an entirely different project; it was Michael who noted that surgeons (at that time) did not possess an approved adhesive for use internally that was both strong and safe – it was the identification of this business opportunity that led us to postpone the initial project (as it runs out forever) and devote full time to creation of an adhesive.
TissuGlu is designed to adhere flaps of tissue (such as created during abdominoplasty) to reduce fluid accumulation and in many cases eliminate the need for post-operative drains. The adhesive is applied dropwise during surgery using a single-use applicator, cures in approximately 30 minutes, and then resorbs slowly into benign fragments as the patient heals.
Needless to say, successfully creating anything molecular that is designed to be used inside the human body means that safety of the ingredients, the cured product, and the degradation fragments is paramount. TissuGlu is a urethane prepolymer adhesive; a urethane system was chosen because it can be employed as a single-part product (no mixing or other preparation in the clinical setting), cures through contact with moisture, and can covalently bond to functional groups commonly found at tissue surfaces (allowing for good adherence). Urethanes are potentially valuable as biomaterials because their structure allows for a reasonably confident prediction as to how they will hydrolyze.
Industrial and consumer urethane adhesives often employ aromatic isocyanates as building blocks; the known tendency of these to revert to aromatic diamines during degradation precludes their use in a surgical adhesive, and hence we chose the ethyl ester of lysine di-isocyanate to construct TissuGlu; because this material was not readily available commercially, the company developed a scalable manufacturing process in parallel to product development and clinical work.
Typically, urethane prepolymers are synthesized in the presence of a metal catalyst (often tin, but other metals such as zirconium can be used) – these are all cytotoxic to varying degrees and hence the manufacturing of the product proceeds in the absence of catalyst – a slower process but a safer product.
In addition to safety, the product design had to meet certain other criteria to render it attractive to surgeons and patients alike. The adhesive should cure relatively quickly (minutes) yet not too quickly to allow surgeons time to re-approximate tissue if needed. The viscosity of the material should be sufficiently low that it could be delivered from the applicator easily, yet if it were too thin it could “run” on tissue surfaces that are often anything but horizontal. The latter is a classic example of a potential design trade-off; if we add a diluent to reduce viscosity (a plus), the presence of the diluent could make the glue too runny and also slow cure time (owing to simple dilution). Our solution was a volatile diluent (non-toxic, non-flammable) that evaporated quickly upon contact with the 37C tissue.
Design of the applicator, though not a “chemical” issue, was a crucial part of the design, partly because competing products (many of which were two-part) employed relatively clumsy devices that required significant training and clogged readily. While a reusable applicator might have been desirable from a green perspective, potentially serious safety issues surrounding the collection, reconditioning, resterilization, and reuse of the device prompted the company to opt for single-use. In the end, the applicator resembles a glue gun; its ergonomic design allows clinicians to learn to use the product in minutes. Preparation in the operating room requires simply opening the package and flipping a single switch from red to green.
TissuGlu passed all of the preclinical testing required by the European Union and demonstrated safety in a 40-patient human clinical trial in Germany in 2009-2010. This led to E.U. approval in 2011 (the CE Mark); TissuGlu has since been used in over 1500 patients without any device-related safety issues. Approval in the U.S. required an additional series of preclinical tests (including carcinogenicity) that again demonstrated the product’s safety. Following two clinical trials in the U.S., the FDA General and Plastic Surgery Devices Panel of the Medical Devices Advisory Committee voted on August 1, 2014 to recommend TissuGlu for eventual approval; after discussions on indication, labeling, and patient brochure, the product received its approval.
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