Cyanoacrylate Technology: Stay Glued

Dr Tania Fernandez and Dr. Val BliskovskyThursday, January 2, 2003, 08:00 Hrs  [IST]

A new technology in surgical adhesives that could provide patients with the option of sutureless skin closure is fast catching up. An ideal adhesive should be safe, easy to apply, polymerise rapidly and eliminate the need for suture removal basically leaving you looking and feeling brand new. Well seems as if we have got close to this ideal concept. The cyanoacrylate technology has caught on surely but slowly and is gradually penetrating the market. It's not a new buzzword; it really is something that most households are familiar with. Cyanoacrylates maybe very simplistically defined as solvent free, synthetic adhesives. They are reactive monomer liquids that polymerize into a film when initiated by moisture or certain chemicals. A key property of cyanoacrylates is that the monomer liquid actually polymerizes directly on the surface where it is applied, creating a high quality and very tenacious polymer film. Cyanoacrylates typically fix within the minute and achieve full bond strength in 24 hours. These types of adhesives are familiar to the general public under brand names such as Super Glue and Krazy Glue. Cyanoacrylates were first manufactured in 1949 and were the first adhesives noted to have extreme inflammatory effects on tissues. Industrial adhesives based on cyanoacrylates were first introduced in 1958 and are widely used in the aerospace and automotive industries as well as in consumer products such as super glue. Does cyanoacrylate technology have its hold only in the US? The answer to that would be no. N-butyl-2-cyanoacrylate developed in the 1970s was the first adhesive to have negligible toxicity and good bonding strength. This adhesive was not labeled for use by the FDA but was used in Canada and numerous other countries for the past 20 years. However, despite this availability, the adhesives failed to gain widespread popularity. This was partially due to their sub optimal handling, application characteristics, variable outcomes and the histotoxicity associated with their use.The histotoxicity is related to the byproducts of polymer degradation, the length of the alkyl (R) group of the cyanoacrylate derivative and the rate at which degradation occurs. Butyl-2-cyanoacrylate which was approved for use in Europe and Canada and is less toxic than methyl-2- or ethyl-2-cyanoacrylate because of its slower rate of degradation. The disadvantages and disappointments of the earlier generations of cyanoacrylates resulted in the inability to take advantage of the processing advantages that these adhesives offer. Subsequent developments in cyanoacrylate technology have greatly expanded the performance of these adhesives and led to products that offer the ease of use of a cyanoacrylate coupled with the performance of a true structural adhesive. Putting cyanoacrylate technology to good use really began way back in 1982 when a small technology company called Tri-Point Medical Corporation (Raleigh, North Carolina, USA) began work on synthesizing cyanoacrylates for use in healthcare. Tri-Point scientists worked for years to customize the physical and chemical properties of cyanoacrylates in order to develop medical adhesive formulations that could be used to close and seal topical skin wounds and incisions. In the mid-80s the company began marketing its first product, Nexaband adhesive, for veterinary use. By the mid '90s, momentum was building around a proprietary technology for human use based on the unique properties of 2-octyl cyanocrylate. Properties such as high bond strength, microbial barrier, and controllable polymerization were found to yield superior product benefits such as speed of healing, reduction of pain and infection, and staying in place until healing is complete. The company was renamed Closure Medical Corporation. In March 1996, the Company entered into a renewable, eight-year supply and distribution agreement with Ethicon, a subsidiary of Johnson & Johnson (New Brunswick, New Jersey, USA), which provided Ethicon with exclusive worldwide rights to market, to distribute and sell Traumaseal, the Company's nonabsorbable wound closure tissue cohesive. In August of 1998 Closure Med received US Food and Drug Administration(FDA) approval for market release of Dermabond Topical Skin Adhesive which became the first and only cyanoacrylate technology to be approved for topical wound closure.Dermabond was actually Trauma seal renamed. The latter was marketed as a tissue cohesive though for some reason this concept did not catch on with the general public. Dermabond made its market appearance as a tissue adhesive. Closure Medical through years of consistent research found a way to consistently produce an extremely pure form of 2- Octyl Cyanoacrylate that was biocompatible and possessed the strength and flexibility to function as an excellent microbial barrier. Closure's innovative technology resulted in the development and commercialization of four revolutionary products: Dermabond for professional topical wound closure, Soothe-n-Seal for oral care, Band Aid Brand Liquid Bandage for consumer wound care and Nexaband for veterinary wound care. They now partner with worldwide market leaders in five of their target markets. The strategic global partners include Ethicon, Inc. (a Johnson & Johnson Company), J&J Consumer Products Company, J&J Wound Management, Colgate Oral Pharmaceuticals and Abbott Laboratories. In April 2000 with Ethicon Inc., Dermabond adhesive captured the operating rooms with a focus on four specialties; Cardiovascular, OB/GYN, Plastic and reconstructive surgery and Neurology. A major milestone was in January 2002 when FDA approval was received for its marketing as an adhesive that acts as a barrier to microbial penetration. The market potential for Dermabond is fascinating. Each year globally, there are 90 million wound closure procedures, representing a market of $2.6 billion - $1.8 billion in sutures and $800 million in staples.Currently, DERMABOND adhesive is distributed in over 30 countries, including the US, Japan, and many European countries. Conquering the goal of having medical adhesives for use in the oral cavity for wound or ulcer protection is a technological achievement of the highest order.Soothe-N-Seal has a market of 40 million households in the United States alone. Soothe-N-Seal adhesive was the first and only cyanoacrylate medical device approved by the FDA for the over-the-counter market to treat canker sores. The first product in the oral care platform, Soothe-N-Seal a registered trademark of Colgate-Palmolive Company. A major opportunity exists to provide medical devices directly for the home medicine cabinet. This market is called consumer wound care. Liquiderm represents a very significant advancement in wound care technology. Liquiderm adhesive is marketed as Band-Aid Brand Liquid Bandage.In pre-clinical studies it was found that Liquiderm adhesive stops bleeding, speeds wound healing, reduces pain associated with minor cuts and abrasions. and provides a superior barrier to bacteria that cause infections versus traditional adhesive bandages." It is the first and only cyanoacrylate medical device approved by the FDA for the consumer adhesive bandage market. In the animal world, the Nexaband product line of veterinary adhesives was developed to meet a wide range of veterinary needs. In July 2001, the Company entered into an agreement providing Abbott Laboratories, Inc. with worldwide supply, distribution and development rights to the Nexaband product line. The potential surgical applications for Closure's cyanoacrylate adhesives are endless. Last year a Cooperative Research and Development Agreement of Closure Med with the Walter Reed Army Medical Center and the Uniformed Services University of the Health Sciences, USA was initiated to conduct animal research for the development of a treatment for emphysema - a chronic lung condition estimated to affect 10 million people globally. Closure's innovative research and development team is actively working to develop a novel, exciting and minimally-invasive technique to treat this deadly problem and to achieve bronchial occlusion without the need for open chest surgery - possibly resulting in reduced patient mortality and a significant reduction in procedure costs.It is hoped that the new Closure adhesives - Endobronchial Lung Volume Reduction (ELVR) would seal off diseased portions of the lung and allow the remaining lung to function more effectively. The Internal Products Development (IPD) group at Closure is developing several biocompatible cyanoacrylate formulations that have potential to be used for internal tissue bonding, sealing, and achieving hemostasis in internal applications. Through collaborations with leading research institutions, the formulations are being evaluated using in-vivo models to assess potential surgical use in a broad range of soft and hard tissue applications. These formulations and future absorbable products will require further development, clinical trials and regulatory clearance or approval prior to commercialization. Other companies in the race include MedLogic(MedLogic Global Corporation, Plymouth, England) which has developed a portfolio of cyanoacrylate-based products to meet multiple medical needs. The Company has also developed and patented methods for introducing antimicrobial agents into cyanoacrylate-based adhesives in order to reduce the risk of infection. These antimicrobial agents are introduced into the liquid prepolymer and after application to the skin, are slowly released through the cyanoacrylate film over a sustained period of time. MedLogic has developed six cyanoacrylate-based products now in various stages of market release, product/clinical testing and regulatory review. Two products, LiquiBand and LiquiShield (formerly known as SuperSkin), have recently been introduced in the UK.However none of these have been FDA approved. FDA approval for cyanoacrylate technology is not restricted to the 2-octyl series. In September 2000, FDA approved Trufill n-BCA Liquid Embolic Treatment System. For presurgical embolisation of cerebral arteriovenous malformations. (AVMs: a tangle of abnormally connecting arteries and veins). Although AVMs occur in less than one percent of the population, there is risk of severe neurologic deficit or death if they are left untreated. Trufill is marketed by Cordis Neurovascular, Inc. (CNV) and is a unit of Cordis Corporation, a Johnson & Johnson company. Trufill n-BCA Liquid Embolic System is an artificial embolization device, comprised of Trufilln-Butyl Cyanoacrylate (n-BCA), Trufill Ethiodized Oil and Trufill Tantalum Powder. These components are combined to form a mixture that is injected through a microcatheter to embolize AVMs prior to surgical resection. Although the mixture is liquid during delivery, it hardens to form a solid material on contact with blood at the site of the AVM in the brain. Cyanoacrylates are too far from sales figures for classic blockbusters like erythropoetine or granulocyte colony stimulating factor to excite the investing community nor can they cause an excitement in hi-tech community similar to first recombinant protein products. However, they may eventually become household names and this is what makes them special. We were very taken up with the Liquid Bandage. They are reasonably simple and provide an obvious convenience that rest assured after using LiquiBand once, you will never return to traditional bandages. Minor wounds and scratches can be very annoying. They are prone to repeated irritation especially when you bend fingers, elbows or knees, when you are checking the oil in your car or adjusting the chain of your bike or simply cooking or washing dishes. Regular bandages protect you well when you are not doing anything but get dirty and wet when you do something. And what are the benefits of wet and dirty bandages? To take them off is a totally unpleasant procedure.If you are dealing with water frequently, for example fishing or swimming, the majority of these bandages are worthless. This year we both managed to fall from bikes and acquire unpleasant wounds and scratches. Luckily it did not happen at the same time and so when one poor victim of a healthy lifestyle was wounded, the other one was increasing revenues of first aid products manufacturers and nearby pharmacies by testing different products. Generally all these products worked well but with the usual problems mentioned above.Different bandages from different manufacturers, including "waterproof" ones, as well as the newest membranes, were tested and proved useless for real swimming. The best one held for no longer than 20 min and apparently that is as far as it can get with traditional technology. Our first attempt to use one of the liquid bandages available on the market was very disappointing. To our surprise it reminded us of nail polish and smelt and behaved correspondingly. The idea of having acetone put on your wounds is not necessarily the most attractive one but one of us was adventurous enough to try it. The nail polish-like layer was broken the next day and did not protect anything. The acetone smell persisted even after 24 hours and a kind of allergic reaction was initiated.After repeated washes with water, soap and finally with a bottle of specially purchased "acetone nail polish remover" the damage was fixed. At this stage stochastic approach to the wound treatment was finally replaced by a more scientific approach, this being more appropriate for two PhDs working in the biomedical field. ClosureMed was recommended to us a long time ago by a friend, an intelligent and knowledgeable biotech investor, as a highly professional team with excellent products.It was the perfect time to check if the Liquid Bandage finally hit OTC (Over the Counter) market and really delivered its promises.Indeed, that was the very week when the first lots were supplied to CVS Pharmacy, Safeway and other stores in the US. Of the 8 pharmacies that we visited only one had it, the others had already sold their inventory. We finally found a box for about $10 with enough components for 10 treatments.It is really easy, you just put the polymer on the spreader which contains catalyze of polymerization and apply it to the wound. After all the initial experiences we were not very optimistic but as technocrats we decided to trust in technology, decent manufacturer and FDA approval.Everything worked remarkably well.In about a minute a thin, elastic layer was formed. It never reminded us of its existence, there was no smell, no allergic reaction. It held perfectly for hours in chlorine-rich swimming pools, under the heat of 40oC and direct sun.Finally when the wound healed the polymer and fibrin covering it went off unnoticed. Whoever tries this product will never return to the old style bandages.

--The authors are Research Scientists based in the USA