BB&T Contributing Editor

Tissue adhesives are a comparatively recent introduction and currently account for a relatively small but growing proportion of the wound closure market. It is estimated that as much as 40% of the global suture/staple market could eventually be accounted for by tissue adhesives and sealants. The perceived advantages of tissue adhesives over alternative methods include: speed and ease of use, reduced patient trauma (no anesthetic required), superior wound closure, reduced infection potential, improved cosmetic outcome, and low treatment cost.

In May, the FDA's Center for Devices and Radiological Health (CDRH) reclassified tissue adhesives for topical approximation of skin from Class III to Class II devices under the generic name "Tissue Adhesive for Topical Skin Approximation." This means that tissue adhesives will now be cleared for commercial distribution via a 510(k) submission rather than the more demanding premarket approval application (PMA).

Fibrin-based sealants achieve hemostasis and are moderately adhesive. These sealants are approved as hemostatic adjuncts to suturing. Internationally, they are used much more extensively as sealants and low-strength glues, as well as for their hemostatic properties.

The internal adhesive market is dominated by fibrin-based products, which are not very strong and require mixing to prepare. The two approved fibrin sealants that are sold in the U.S. are Tisseel from Baxter (Deerfield, Illinois) and Evicel from the Ethicon (Somerville, New Jersey) subsidiary of Johnson & Johnson (New Brunswick, New Jersey), which it licenses from Omrix Biopharmaceuticals (New York). Haemacure (Montreal) is developing the Hemaseel HMN fibrin sealant for the U.S. and international markets. CSL Behring (King of Prussia, Pennsylvania) markets Beriplast-P fibrin sealant in Europe. Vivostat (Alleroed, Denmark) and Thermogenesis (Rancho Cordova, California) market autologous fibrin sealants in Europe.

Cyanoacrylate adhesives bring added strength

Cyanoacrylates are used when greater adhesive strength is needed. They can be used in place of sutures and staples to close surgical incisions and are also being used to close minor cuts. Cyanoacrylates are fast-setting, high-tensile-strength polymers that bind with the skin's surface and, after setting, are flexible, durable, waterproof and transparent. They are the main type of high-strength surgical glues used worldwide.

These adhesives are approved in the U.S. for topical applications and for use in preventing post-surgical infections. In Europe, they are also approved for internal use.

Cyanoacrylates are marketed by several companies for external skin closure as a replacement for sutures in surgical procedures and for wound closure in accident situations. They produce cytotoxic compounds during the curing process which has delayed their development and clinical evaluation for internal surgical procedures.

The worldwide market for high-strength surgical glues is estimated to be $500 million and is poised for continued growth from the adoption of cyanoacrylates for a wider range of procedures and by enabling new procedures to be done more economically and with better outcomes. Also, there is growing recognition that these products play a role in reducing infection by protecting the surgical incision areas from bacteria. About 8% of wounds are infected in the hospital during surgical procedures. Adjunctive surgical closure and securement products have been shown to reduce infection levels.

Ethicon markets Dermabond adhesive (2-octyl cyanoacrylate), which came with its acquisition of Closure Medical (Raleigh, North Carolina). Dermabond 2-octyl cyanoacrylate can be used in place of sutures or staples to close wounds and incisions. It dries to form a strong, flexible bond and protective covering and it can get wet in the course of normal activities. Dermabond is sold in about 40 countries.

Closure Medical's Liquiderm adhesive is the first cyanoacrylate approved by the FDA for the over-the-counter adhesive bandage market. It uses the same proprietary technology as in Dermabond and competes against Nexcare Liquid Bandage from 3M (St. Paul, Minnesota).

Syneture (Norwalk, Connecticut), a subsidiary of Covidien (Mansfield, Massachusetts), sells Indermil, a n-butyl cyanoacrylate-based tissue adhesive for the closure of topical skin incisions and trauma-induced lacerations in areas of low skin tension with easily approximated wound edges. Indermil remains liquid until exposed to water water-containing substances such as tissue, after which it cures (polymerizes) and forms a film that bonds to the underlying surface. The adhesive seals skin in 30 seconds. It is supplied in a single-use 0.5 g plastic ampule. Indermil is manufactured by Henkel Loctite (Dusseldorf, Germany).

Histoacryl is a topical and translucent skin adhesive that consists of monomeric n-butyl-2-cyanoacrylate which polymerizes in contact with tissue fluid. Histoacryl Blue contains a dye that makes it easier to see. It is packaged in a plastic ampule and is indicated for closure of minor wounds without suturing. The products are supplied in the U.S. by TissueSeal (Ann Arbor, Michigan) and Aesculap, a subsidiary of B. Braun (Melsungen, Germany and Bethlehem, Pennsylvania), its manufacturer.

GluStitch (Delta, British Columbia) sells Glu-Shield cyanoacrylate tissue adhesive. It is a liquid bandage that remains on the skin for several days even with gentle washing and showering. It is primarily indicated for the closure of uncomplicated linear or curvilinear lacerations with little or no tissue loss. It is usually used in areas of low tension since its holding power relative to sutures is about 20%. GluShield is offered as a multiuse kit as well as a single use product. It is sold as a single-use product under the GluSeal name.

PeriAcryl is a fast drying n-butyl cyanoacrylate that is indicated for use in the oral cavity as a securing agent for free gingival grafts and as a liquid dressing for donor sites, biopsy sites and for securing other types of dental dressings.

Advanced Medical Solutions (Cheshire, UK) markets in Europe, Australia and South Africa its LiquiBand Surgical S, which combines n-butyl-cyanoacrylate with the slower setting 2-octyl cyanoacrylate. It is indicated for closure of surgical wounds with easily approximated skin edges that are not under tension or flexion. It may be used in conjunction with, but not in place of, subdermal sutures. A foam pad applicator is used to apply a broad, occlusive liquid wound dressing. U.S. market clearance of LiquiBand Surgical S via a 510 (k) submission is expected by the end of this year.

Chemence Medical Products (Alpharetta, Georgia) is a newly created company that produces Derma+Flex, a cyanoacrylate gel adhesive that has a controlled flow rate. The company was spun out of Chemence (Corby, UK).

Adhesives under development

Nerites (Madison, Wisconsin) has biomaterials technology that is based on the research of Dr. Phil Messersmith, associate professor of biomedical engineering at Northwestern University's (Evanston, Illinois) department of biomedical engineering, on how marine mussels bind to surfaces underwater. His research has led to a class of adhesive proteins and coating compounds that are exclusively licensed to Nerites.

Mussels and other marine organisms secrete fluids (adhesive proteins) that undergo an in situ crosslinking or hardening that enables them to adhere to a variety of surfaces. One of the unique structural features of mussel adhesive proteins is the presence of L-3,4-dihydroxyphenylalanine (DOPA), an amino acid that is believed to play a dual role in adhesion and crosslinking.

Nerites' technology combines mussel adhesive proteins with a variety of polymers to create novel synthetic constructs for use as biologically compatible adhesives for tissue repair, as skin adhesives and device coatings. The company has shown that its tissue adhesives are non-immunogenic and non-cytotoxic and will bind tissues together in aqueous environments, including body fluids such as blood.

Nerites is developing a range of tissue adhesives for specific applications, such as an adhesive that stretches for use on the intestines and a high tensile strength and non-stretching adhesive for use on bones. Its lead product is licensed to an unannounced strategic partner and is being tested under a PMA program. It is expected to be approved in about one year.

The company is in active discussions with potential strategic partners for use of tissue-specific adhesives.

Nerites' Medhesive can be used after surgery on an internal organ, such as the heart, liver or kidney. Other potential applications include binding tissue-to-tissue and bone-to-bone, as well as binding implanted devices to skin, tissue or bone. Animal experiments are under way.

The company's adhesives are easier to handle than cyanoacrylates. They have a cure rate of 10 to 20 seconds and are resorbed. Cyanoacrylates provide great adhesion but are very brittle in relation to human tissue which is very elastic. Also, they do not resorb.

OptMed (Woodmere, New York), a start-up, is developing a surgical adhesive based on methylidene malonate 2.1.2 (MM212), which has potential competitive advantages in the topical market as well as in the untapped market for deep tissue and internal surgical repair. The advantages of the MM212 chemistry over cyanoacrylate are that its degradation pathway produces non-toxic alcohols (ethanol/ethyl glycolate/ glycolic acid) and its flexibility allows for the design of polymers with significantly more tensile strength. The degradation is controllable from days to weeks.

The MM212 platform has been studied extensively as a surgical adhesive and for use in drug delivery by its original developers, Halisol (Paris) and the UPSA Group, now part of Bristol-Myers Squibb (New York). OptMed acquired the technology in 2007 and is currently developing MM212 adhesive for external wound closure. It plans to file a 510(k) application in the second half of 2009. The company also plans to begin evaluating several internal applications in animal models later this year.

Cohera Medical (Pittsburgh) is developing surgical adhesives. TissuGlu, its lead product, is a strong and resorbable surgical adhesive that is in preclinical trials. It is designed to adhere to tissues for preventing fluid accumulation in deep wounds. The patented technology was developed at the University of Pittsburgh by Drs. Eric Beckman and Michael Buckley, co-founders of Cohera. The company has been awarded a Phase 1 SBIR grant for the design and development of a bioresorbable bone adhesive for orthopedic use. Recently published data in Plastic and Reconstructive Surgery showed that TissuGlu prevents seroma formation in a canine abdominoplasty model.

Synthetic surgical sealants

Sutures and staples facilitate healing by joining wound edges and allowing the body to heal naturally. However, sutures and staples do not have inherent sealing capabilities and cannot consistently eliminate air and fluid leakage at the wound site. This is particularly the case when sutures and staples are used to close tissues containing air or fluids under pressure, such as the lobes of the lung, the dural membrane surrounding the brain and spinal cord, blood vessels, and the gastrointestinal tract.

Several companies market synthetic, polymer-based, surgical sealants, which form stronger adhesive bonds than fibrin sealants.

Baxter acquired worldwide marketing rights to CoSeal from Angiotech Pharmaceuticals (Vancouver, British Columbia). CoSeal is a self-polymerizing, adherent, completely synthetic surgical sealant. It is designed to rapidly seal tissue surfaces, suture lines and for use over staples without the need for tamponade or activation devices. CoSeal has been shown in clinical trials to reduce post-surgical adhesions.

CoSeal is used to form a seal by combining two specially processed polyethylene glycol polymers which yield a low-viscosity fluid that flows around irregular tissue surfaces and polymerizes within seconds. CoSeal crosslinks to itself and also bonds to the tissue it contacts to create an adherent and continuous gel-like seal over the site. It also has been shown to tightly adhere to synthetic grafts. It resorbs over several weeks.

Covidien markets DuraSeal surgical sealant, which came with its acquisition of Confluent Surgical (Waltham, Massachusetts). DuraSeal is sold in the U.S. and Europe. It quickly forms a watertight seal and prevents leakage of cerebrospinal fluid in neurosurgical procedures. The SprayGel adhesion barrier also came with the Confluent acquisition.

DuraSeal is a polyethylene glycol-based synthetic, absorbable hydrogel sealant delivered from a dual-syringe applicator. It can be stored at room temperature and is prepared in less than two minutes. After several weeks, the hydrogel breaks down into water soluble molecules that are absorbed and cleared through the kidneys. A unique feature of the DuraSeal sealant is its blue color which enables the surgeon to view the coverage of the material after application.

DuraSeal has the CE mark for additional sealant applications. It is currently sold in Europe for elective pulmonary resection as an adjunct to standard closure techniques of visceral pleural air leaks, and arterial and venous reconstructions to seal suture lines as an adjunct to standard closure techniques in vascular surgery. The company plans to file an IDE to do trials on DuraSeal in order to obtain approval in the U.S. for use in pulmonary and vascular reconstruction.

Covidien markets PleuraSeal lung sealant in Europe. It uses hydrogel technology to mechanically adhere to tissue crevices to create an airtight closure. It is intended for use as a surgical sealant during elective pulmonary resection as an adjunct for standard closure techniques of visceral pleural air leaks.

BioGlue and BioFoam from CryoLife

CryoLife (Kennesaw, Georgia) markets BioGlue, a polymeric surgical adhesive based on purified bovine serum albumin and glutaraldehyde, a cross-linking agent. Its tensile strength is four or five times that of fibrin sealants. It has FDA approval as an adjunct to sutures and staples for use in adult patients in open surgical repair of large vessels. BioGlue has expanded regulatory approval in Canada and Australia for use in soft tissue repair procedures which include cardiovascular, vascular, pulmonary and general surgical applications, such as repairing dura mater, reinforcing friable, diseased or damaged cardiac and vascular tissue.

BioGlue is available in 2 ml, 5 ml and 10 ml disposable syringes and cartridges. It is applied using either a reusable delivery "gun" or pre-filled disposable syringe. The product is stable at room temperature and does not require reconstitution. It forms a mechanical seal within 20 to 30 seconds, independent of the body's clotting mechanism, and reaches its maximum bonding strength in two to three minutes.

BioGlue is currently sold in 60 countries in Europe, Asia and Central and South America. CryoLife has a distribution agreement with Proxy Biomedical (Galway, Ireland) for use of BioGlue in its hernia repair kit.

The company also has a licensing and distribution agreement with BioForm Medical (San Mateo, California) for the development and commercialization of BioGlue for use in cosmetic and plastic surgery indications. The companies reported in June the receipt of the CE mark for the use of BioGlue for periosteal fixation following endoscopic browplasty (brow lift). The product will be distributed in Europe by BioForm under the name BioGlue Aesthetic Medical Adhesive.

CryoLife also is developing BioFoam, a patented protein hydrogel adhesive, as a tissue and organ sealant and as a hemostat. It is comprised of the same two components as BioGlue plus an expansion agent that causes the glue to expand to about five times its original volume upon application. It can be used to fill and seal open wounds.

The U.S. Department of Defense has provided funding for CryoLife to explore the use of BioFoam for limiting blood loss in soldiers injured in battle, described as battlefield trauma stabilization. Another application being pursued using the protein hydrogel technology is the BioDisc nucleus pulposus replacement, an in situ polymerizing hydrogel, for use in spinal disc repair and in trauma surgery.

Sealant development rolls on

Kuros Biosurgery (Zurich) is researching combinations in which synthetic biomaterials (e.g., a liquid thiol having an unsaturated group and a polyethylene glycol-based material) undergo a chemical reaction to form a hydrogel matrix after injection for use as sealants. It is initially focusing on a dural sealant, although it can potentially also be used as a sealant in thoracic, pleural and ocular surgery. Its dural sealant program is in preclinical studies and has shown favorable results. The company expects the product to be in clinical trials later this year.

Kuros also is investigating the potential of its biomaterial technology for use as an anti-adhesion barrier following spinal and abdominal/gynecological surgeries.

Lifebond (Caesarea, Israel) is developing a sealant and active convergence hemostat which incorporate a proprietary crosslinking gelatin. The adhesive sealant forms a network similar to the fibrin network of blood clots but has greater adhesive strength than blood-derived fibrin sealants. It will compete against CoSeal, BioGlue and fibrin sealants. Lifebond's convergence hemostat stops severe bleeding during surgery or after trauma. When it comes in contact with blood, it forms a biomimetic clot that rapidly closes the wound site.

NeoMend (Irvine, California) has a patented resorbable polymer hydrogel that the company is developing for wound sealing and adhesion prevention. ProGel surgical sealant, NeoMend's first product, is for use in closing intra-operative air leaks after lung resection surgery, the most common complication following lung surgery. It acquired the technology from 3M. ProGel is a two-part self-curing system that is similar to the product developed by Confluent Surgical.

The two components of ProGel are human serum albumin and polyethylene glycol that has reactive groups at both ends of the polymer chain which serve as crosslinking agents upon mixing. Curing starts immediately upon mixing and the sealant reaches full strength in two minutes. There is no dependence on clot formation as with a fibrin sealant. ProGel provides a seal 10 times stronger than fibrin glues. NeoMend also is conducting feasibility tests for use of ProGel as a dermal filler and as an advanced wound dressing for burn and pressure ulcers.

NeoMend has completed a U.S. pivotal trial of ProGel used on lung surgery patients, with 77% of lungs sealed vs. 16% for the control group. In June, the FDA's Anesthesiology and Respiratory Therapy Devices Advisory Panel recommended that the agency approve ProGel. The panel's recommendation was conditional on the company conducting a post-approval study to gather more safety data.

The company's second product will be ProGel-AB, a sprayable surgical sealant that can seal oozing, bleeding and non-bleeding wounds as well as prevent adhesion formation.

Pre-clinical studies of ProGel AB demonstrated good anti-adhesion results for both open and laparoscopic surgeries. The company claims that there is no product available today for use during laparoscopic surgery.

Tissuemed (Leeds, UK) is marketing in Europe its TissuePatch3 surgical sealant. It was launched at the European Association for Cardio-Thoracic Surgery annual meeting in Geneva, Switzerland, in September 2007. It is an entirely synthetic self-adhesive film (does not contain human albumin) that is highly conformable to uneven surfaces.

TissuePatch3 is designed for use as an adjunct to sutures and staples for preventing blood, air and fluid loss and to avoid post-surgical complications in thoracic and general surgery. It has a fused multilayer structure that contains reactive polymers for chemical bonding to tissue surface (the free carboxylic acid groups on the polymer react with the amino group on tissue surfaces to form amide linkages), and a non-adhering backing material for ease of handling and prevention of post-surgical adhesions. The patch is absorbed in about 50 days.

Covalent Medical (Ann Arbor, Michigan) is in the pre-clinical phase of development of its CovaBOND sealant. The technology is based on a protein gel adhesive that is designed to combine four characteristics important in the surgical environment: speed, ease of use, strength and biocompatibility. Cova-BOND is comprised of two components, a protein solution and a proprietary crosslinker, which are delivered via a double-barreled syringe using assorted vortex mixing tips. It is intended as a sealant to be used in addition to sutures and staples as well as a high-strength glue to replace sutures during minimally invasive surgery.

Protein Polymer Technologies (San Diego) reported in July 2007 that it had entered into an agreement with a multinational pharmaceutical and medical device company to supply genetically engineered protein polymer biomaterials for use as surgical sealants.

Tenaxis Medical (Mountain View, California) is in clinical trials in Europe for ArterX, its vascular sealant. The company was founded in 2004 to bring high-performance surgical sealants to the vascular and general surgical markets. ArterX has a higher tensile strength than fibrin sealants and is used as an adjunct to sutures by being applied over the suture line. It cures in 15 seconds. It is made from bovine collagen and uses a proprietary crosslinking agent that covalently binds to proteins in both the sealant and human tissue for superior strength.

Tenaxis also has a gastrointestinal sealant and an anti-adhesion product under development.

Drs. Chris Elvin and Alan Brownlee at CSIRO, Australia's Commonwealth Scientific and Industrial Research Organisation, have developed PhotoSeal, a tissue sealant that is created by using a white light source to photochemically crosslink fibrinogen and two commercially available metal-based chemicals. PhotoSeal sets up fifty times faster than fibrin sealants (15 to 20 seconds versus 15 to 20 minutes) and forms a seal that is five times stronger. It can be stored at room temperature, unlike fibrin glues which remain frozen prior to use.

Berlin Heart (Berlin, Germany) markets Gluetiss in Europe. It is a biologically based adhesive comprised of two solutions in ready-to-use applicators. The glue component is a gelatin-resorcinol solution, and the hardening component is a glutaraldehyde/ glyoxal solution The optimum mixing glue:hardener ratio is 10:1. Gluetiss is approved for use in vascular surgery, especially for closing type A and B aortic dissections.