More than two-thirds of the $1.6 billion worldwide suture market is comprised of products for external use

Synthetic "super glues" that can bond biological tissues as securely as sutures will soon appear on the U.S. market, eclipsing the long-anticipated approvals of fibrin-based sealants. Biologically based sealants are also not far behind. All of these products, which can close external or internal incisions, depending on the indication for which they are approved, will compete in the $2.5+ billion worldwide wound closure market. Currently, this market is almost equally divided between sutures and surgical staplers. Given the sealants’ potential for replacing, or at the very least significantly diminishing, the use of traditional wound closure products, it is not surprising that the dominant players in the suture and stapling arena are positioning themselves through the formation of strategic alliances to seal up opportunities in this new generation of surgical glues.

Primer on Sealants
Surgical glues can make tissues adhere in a matter of minutes without the use of sutures or staples and then, depending on their degradability, slough off or become resorbed by the body once the underlying wound has healed. A variety of technologies are under development as tissue adhesives, including cyanoacrylates or "crazy glues," degradable polymers, and biological materials such as collagen. A product’s resorbability is largely what determines whether it is appropriate for   internal or external use. In general, nonresorbable sealants are indicated for topical use such as closure of skin lacerations; those that are biodegradable are being developed for internal wound closure. More than two-thirds the $1.6 billion worldwide suture market is comprised of products for external use, such as closing small skin incisions and/or lacerations, according to Alexander Arrow, MD, analyst at Wedbush Morgan Securities (Figure 20).

Figure 20: 1997E, Worldwide Suture Wound Closure Market

Note: The U.S. accounts for $550 million (34.3%) of this market.
Sources: U.S. Department of Health and Human Services 1995 data; Wedbush Morgan Securities

Synthetic-based materials, such as cyanoacrylates and polymers, typically act to seal off a fluid duct and/or air leak, or to seal together the edges of an incision. Biologically derived products, such as collagen or fibrin glues, have inherent hemostatic properties and act predominately to control bleeding. Figure 21 describes the major applications for surgical sealants in the various surgical specialties.

Figure 21: Major Indications for Surgical Sealants, by Specialty

Source: Medical Data International

Sealants to Supplant Sutures
JOHNSON & JOHNSON’s ETHICON division (Somerville, NJ) has been aggressively pursuing distribution partnerships with companies developing new tissue adhesive products. Recognized as the undisputed leader in the   wound closure industry, ETHICON has seen the overall market for sutures erode over the past decade, partly because of the growth of minimally invasive surgery, but also from pricing pressure as new competitors, most notably U.S. SURGICAL (USS; Norwalk, CT) gain increased share in this market.   ETHICON still retains approximately 80% of the $550 million U.S. suture market. The remainder of the market is evenly divided between SHERWOOD-DAVIS & GECK (St. Louis, MO) and USS, whose share is increasing, mostly at the expense of the former. ETHICON has signed an eight-year distribution agreement with CLOSURE MEDICAL (Raleigh, NC), whose product, Dermabond, was unanimously recommended for approval by the FDA’s General and Plastic Surgery Devices Panel in January.

Dermabond is the first synthetic cyanoacrylate product that will appear on the U.S market for closure of trauma-induced skin lacerations or small surgical incisions that would normally be closed with sutures, staples or adhesive strips. Cyanoacrylates have been commercially available in the U.S. since the 1960s, but were removed from the market due to concerns over carcinogenicity. However, products such as BRAUN’s Histoacryl have been on the European market for more than two decades. Histoacryl, which is an n-butyl- 2 cyanoacrylate monomer formulation colored by a blue dye, has been predominantly used in the emergency room for treating pediatric patients and traumatic skin incisions in adults.

Dermabond to Enter Market
CLOSURE’s Dermabond product contains a different chemical monomer, 2-octyl cyanoacylate, that is less brittle than BRAUN’s (Germany) topical adhesive. Dermabond is applied as a bridge over the opposing skin edges and forms a flexible seal over the wound. The material remains in place for seven to 10 days, and then sloughs off as the underlying skin cells regenerate.

Dermabond is packaged as a sterile liquid in single-use glass ampules that are housed in polymeric tubes. At one end of the tube is a bullet-shaped porous surface. To apply the glue, the doctor crushes the glass ampule, and the glue exits through the porous "bullet." While holding the edges of the wound together, the physician places the bullet on the patient’s skin and gently paints the glue onto the surface of the wound. Upon contact with the skin, Dermabond polymerizes to form an adhesive seal; within 45-60 seconds, the adhesive develops enough strength to hold the wound edges together without manual   pressure. During application, care must be taken not to place the adhesive in the wound bed or between its margins, which could lead to infection or impede the healing process.

Clinical trials with Dermabond demonstrated that the cosmetic result was comparable to that obtained with suture closure, but a slightly higher rate of infection was noted when compared to controls. Although the data were not statistically significant, the FDA has required that the product’s labeling include a reminder that the wound be thoroughly cleaned prior to the application of Dermabond. One of the benefits of a topical adhesive over sutures and staples for skin closure is that local anesthesia is not required during application; the drawback, however, is that adequate rinsing of the incision may be compromised due to pain. ETHICON expects to launch Dermabond in the U.S. in mid-1998 at a retail price of $17-$20 for a single-use bottle. It will address the over 4 million skin lacerations treated each year in U.S. hospitals (Figure 22).

Figure 22: Estimated Annual Skin Laceration Treatment Procedures in the U.S.

Source: Medical Data International

Other advantages of tissue sealants over traditional wound closure methods lie in their easy, rapid, and essentially pain-free application once the wound is cleaned. And, since the material sloughs off, there is no need for subsequent removal. Figure 23 compares the various techniques for closing surgical incisions.

Figure 23: Advantages & Disadvantages of Common Wound Closure Techniques

Source: Singer, MD, et al., "Evaluation and Management of Traumatic Lacerations," published in The New England Journal of Medicine 337:1142-1148 (October 16, 1997)

For the internal wound closure market, CLOSURE has formed a separate business unit to develop a resorbable formulation of cyanoacrylate. The company has been issued a patent covering a formaldehyde-scavenging process, which allows the product to degrade in the body without producing a toxic reaction. The absorbable technology will also allow the material’s flexibility, setting time, viscosity and bond strength to be tailored to specific clinical applications. Targeted indications include blood and fluid leakage at the anastomosis site in coronary bypass grafting and bowel resection procedures.

CORDIS, another J&J company, has entered IDE clinical trials at 13 sites in the U.S. for use of an n-butyl-2 cyanoacrylate formulation for use in   sealing off arteriovenous malformations (AVMs) in neurosurgery. The product is being used in a randomized study comparing the glue to polyvinyl alcohol particles in AVMs that will be surgically resected. In Europe, BRAUN's Histoacryl is used off-label as an embolic agent in neurosurgical and other interventional procedures.

Additional Synthetic Sealants
SHERWOOD-DAVIS & GECK has tied up worldwide distribution rights to LOCTITE’s (U.K.) Indermil technology. Indermil uses the same chemical monomer as BRAUN’s Histoacryl, but it is a clear rather than blue solution and so does not stain or tattoo the skin. The product has been granted a CE mark and is currently sold in Europe through SHERWOOD’s subsidiaries. Currently it is in IDE studies in the U.S. as a topical skin adhesive. The product is applied through a cannula attached to an electronic pump that helps deliver the glue to precise surgical sites. The glue forms a strong bond within 60 seconds after the surgeon places it in drops along the incision’s edges. Unlike Histoacryl, this product can be used on a sterile field. Both SHERWOOD and ETHICON will be targeting the OR with their adhesive technologies. Indermil is expected to be launched in the U.S. in late 1998.  

By combining its expertise in absorbable polymers with LOCTITE’s technology, SHERWOOD is developing an absorbable version of Indermil to replace sutures and staples for closing internal wounds. Examples of internal applications for Indermil include liver lacerations and   tears to the tympanic membrane, hernia ruptures, episiotomies and trocar incision closure.

MEDLOGIC GLOBAL (Colorado Springs, CO) is developing a platform of products for tissue adhesion and drug delivery based on its proprietary cyanoacrylate technology. The company has three cyanoacrylate products in various phases of regulatory approval. The first, called SuperSkin, is a liquid adhesive designed to prevent the skin from breaking down and ulcerating. The product was cleared for marketing in December 1997 and is the first cyanoacrylate to receive approval for general medical use.

MEDLOGIC’s second product is LiquiBand, a transparent, cyanoacrylate-based topical adhesive that will compete with CLOSURE’s DermaBond and LOCTITE’s Indermil for needleless skin closure. The n-butyl-2 cyanoacrylate formulation of the product has been enhanced to improve its performance characteristics and tensile strength. MEDLOGIC was awarded a patent in late 1997 covering the use of a surgical adhesive combined with an antimicrobial agent in an effort to allay the long-standing concerns regarding the potential for entrapping infection in the wound under the layer of the adhesive material. Clinical trials for LiquiBand will begin later this year.

LiquiShield, a postsurgical wound dressing, is MEDLOGIC’s third product under development. This material is designed for use with traditional sutures and staples; it is applied after the wound is closed to provide a waterproof barrier that promotes healing, reduces the risk of infection and eliminates the need for daily wound dressing changes. LiquiShield will be approved via a 510(k). To expand its research and development efforts in drug delivery, in late 1997 MEDLOGIC acquired GEL SCIENCES (Cambridge, MA), a biotechnology firm specializing in materials science and hydrogel polymers.

Polymeric Sealants
Another group of synthetic materials under evaluation as surgical adhesives is bioresorbable polymers. FOCAL (Lexington, MA) is pioneering this area with their proprietary polyethylene glycol hydrogel technology that is applied as a liquid and then polymerizes into a solid gel inside the body upon the application of light. FOCAL’s first product, FocalSeal-L, is under evaluation for internal use for sealing air leaks following lung surgery. A 60-patient randomized, multicenter, controlled clinical study recently completed in Europe showed superior efficacy to sutures and staples in controlling air leaks. The product is currently in IDE studies in the U.S., and a PMA application is expected to be submitted to the FDA by year’s end. European launch of FocalSeal-L is anticipated in the second quarter of this year and will be distributed by ETHICON. FOCAL has retained distribution rights in North America.

FOCAL’s second product, FocalSeal-S, is a faster-resorbing hydrogel that will be used for sealing dural tissue following spinal and neurosurgery. A preclinical report published in the February issue of the Journal of Neurosurgery showed that FocalSeal-S prevented leakage of dural tears in 100% of the dogs in which it was tested, compared to a leak rate of 35% when only sutures were used. The product is applied in two phases. First, a primer is brushed onto the exposed dura and the sealant is applied. Then, a light is focused on the sealant, causing it to polymerize in 40-60 seconds to form a clear, flexible, solid seal over the site. European clinical trials for FocalSeal-S are slated for mid-1998.

Other potential applications of FOCAL’s technology include reinforcement of suture and staple lines to prevent leakage of blood and fluid in cardiovascular and gastrointestinal surgery. It is estimated that sealants are used 70% of the time for bleeding control and used for sealing of fluid and air leaks in the remaining cases (Figure 24).

Figure 24: Uses for Surgical Sealants

Source: Medical Data International

Biological Glues
In the biological adhesive arena, CRYOLIFE (Atlanta, GA) is preparing for a European launch of BioGlue, a composite of bovine serum albumin and glutaraldehyde, for treating acute aortic dissections and strengthening vascular anastomoses. The product, which can set up within seconds, is designed to bind biological and prosthetic materials together in areas of inactive bleeding. It appears to function more as   a glue rather than a hemostatic agent and may be used to attach vessels together without the need for sutures. The company plans to submit an IDE application for BioGlue this month for use in acute aortic dissections (also see MedPro Month VIII[2]:62, 1998).

A second product under development at CRYOLIFE is FibRx, a light-activated fibrin adhesive composed of human fibrinogen and thrombin—which happen to be the components of a blood clot. The product is formulated with an inhibitor that retards the reaction between the clotting agents prior to application at the surgical site. To use FibRx, the surgeon sprays or squirts it onto the incision and exposes it to light, which causes the inhibitor to evaporate so the fibrinogen and thrombin can form a clot. The company will submit an IND at the end of June 1998 and will apply for human testing of FibRx as a hemostatic agent. The company is seeking a partner for international distribution.

Hemostatics vs. Sealants
Most biologically derived sealants adhere to tissue by participating in the normal clotting cascade. Fibrin glues, for example, are generally used to control bleeding or to reinforce suture or staple lines rather than to make tissues adhere, thus functioning more as hemostatic agents than glues. Moreover, fibrin glues are most effective in areas of inactive bleeding. Several new technologies are under development that offer the potential for use in diffuse bleeding sites.

FUSION MEDICAL TECHNOLOGIES (Mountain View, CA) has developed a promising material that combines collagen with thrombin to form a gel that can adhere to tissue in sites of active bleeding and result in hemostasis. The product, called FloSeal Matrix, is composed of pellets of bovine collagen that are coated with thrombin. Mixed prior to use, these components create a matrix that generates a strong clot in the wound to halt bleeding. Topical thrombin alone will form a clot over the area of bleeding, but if there is underlying blood flow, the clot will simply wash away downstream and rebleeding occurs. FloSeal Matrix adheres to the underlying wound surface, swells from the absorption of blood or fluids, and forms a   structural matrix which exerts pressure on the bleeding site. The pellets act as a kind of dam to seal off a bleeding site or vessel puncture, remaining in place at the root of the bleeding to encourage active flow between the particles until a clot is formed and bleeding ceases. The sealant, which is delivered via a syringe, is resorbed after 30 days.

Preliminary results of a study performed at four sites in Canada and The Netherlands on 35 patients with FloSeal Matrix in 20 different types of surgeries showed that the product achieved hemostasis in 97% of all cases. Approximately 86% of the patients in this series had impaired coagulation resulting from drugs or disease. U.S. clinical trials of FloSeal Matrix will begin this month.

Treating Active Bleeding
Most sealant technologies, including fibrin glues, are not recommended for use at sites of active bleeding, yet many clinicians—particularly cardiac and vascular surgeons—need a product that can control bleeding in these situations. For this reason, FUSION is initially focusing on these two surgical specialties, which together have an estimated worldwide market size of over $45 million (Figure 25). Another potentially lucrative market for FUSION’s product is for femoral artery closure, which represents another 2.5 million procedures. In addition, the company is developing a second platform of liquid adhesives that are strong and biocompatible glues designed to work on a relatively dry surface and will be applicable in   bowel and ENT procedures as well as neurosurgery. The two surgical sealant platforms address large markets estimated at $650 million worldwide.

Figure 25: 1998E, Market for Surgical Sealants in Cardiac & Vascular Surgery

Source: Presentation by Philip Sawyer, President of FUSION MEDICAL TECHNOLOGIES, at MDI’s November 1997 "Biomaterials of the Future" conference

FUSION has ceased the manufacturing and marketing of RapiSeal, a collagen-based biodegradable patch used for sealing air leaks of the lung, due to the low number of procedures for which the product is indicated. RapiSeal, which was the first sealant to be launched in the U.S., required the application of electrosurgery to make it stick to tissue. In a presentation at MDI’s "Biomaterials of the Future" conference in November 1997, company representatives emphasized the fact that these products must be easy to use, or surgeons will not take advantage of them.

COLLAGEN CORPORATION's spin off, COHESION (Palo Alto, CA), has developed a collagen and thrombin composite for use as a hemostatic agent in sites of diffuse bleeding. The product, known as CoStasis, is a sprayable material that is comprised of bovine fibrillar collagen and bovine thrombin suspended in   calcium chloride, that is provided premixed in a syringe. At the time of surgery, fibrinogen taken from the patient is mixed with the collagen/thrombin suspension, which provides the fibrinogen that is cleaved by the thrombin to form a collagen-reinforced hemostat. CoStasis is currently in human trials in Europe.

Protein Engineering
PROTEIN POLYMER TECHNOLOGIES (PPT; San Diego, CA) is developing tissue adhesives and sealants based on its proprietary protein-engineering technology. By creating synthetic genes using recombinant DNA technology, the company is able to precisely direct the assembly of small protein building blocks into high molecular weight polymers, which can be processed into fibers, gels, sponges, hydrogels and coatings. The polymers used in the tissue adhesives and sealants under development combine synthetic engineered silk and elastin proteins that, when mixed with an organic crossing-linking agent, form an exceptionally strong, quick-setting, flexible, biocompatible adhesive matrix that is as firm as a cyanoacrylate adhesive, and can be made to resorb. The adhesives are designed for internal wound closure applications.

PPT is currently involved in optimizing the functional performance of the material in animals to assess ability to close wounds, ease of use, increases in wound strength over time and biocompatibility. A study performed in guinea pigs showed that the product, when applied intraincisionally with the wound edges approximated, will epithelialize at seven days and healing and absorption of the material are well advanced at 28 days. The incision is essentially indistinguishable from controls, including the strength needed to tear the incision apart. PPT had an R&D agreement with ETHICON for development and commercialization of tissue adhesives and sealants for wound closure and related surgical applications, but this was recently terminated. The company is about to begin discussions with other potential partners. Figure 26 provides a summary of selected surgical sealants under development.

Figure 26: Selected Surgical Sealants Under Development

Source: Medical Data International

Most sealant technologies, including fibrin glues, are not recommended for use at sites of active bleeding

Protein-engineering technology is being used to develop tissue adhesives and sealants for internal wound closure applications

Copyright © 1998 Medical Data International

This article was published in the March 1998 issue of MedPro Month, Medical Data International's monthly
newsletter that provides critical insight and strategic business information to healthcare executives around the world.
For more information on MedPro Month, visit
www.medicaldata.com