Tuesday, February 12, 2008

New Wound Closures Get Seal of Approval

New Wound Closures Get Seal of Approval
By P. Driscoll
From January 2008 issue of MedMarkets, with excerpts from “Worldwide Wound Management, 2007-2016,” report #S145.

The market for surgical sealants is expected to grow in double digits over the next five years as aging populations drive increases in caseloads (see chart below). In addition, less morbidity and better outcomes are seen with the latest fibrin sealants, high-strength glues and adhesion prevention products, thus spurring increased adoption of these technologies over traditional wound closure methods.
There are several main categories of closure and securement devices in use in the OR: sutures and staples, tapes, hemostats, fibrin glues and sealants, adhesion prevention products, and soft tissue attachment products.
Some leading companies in the modern wound closure market established their leadership positions when the market consisted exclusively of sutures, staples and tapes; others are new entrants based on expertise in areas such as adhesives. While the fibrin sealant market segment is dominated by Baxter Healthcare and CSL Behring, the high-strength glue segment is led by U.S. Surgical (now part of Covidien), Ethicon, and Aesculap (a B. Braun company). Key players in the market for adhesion prevention products are Ethicon, U.S. Surgical and Genzyme. Market shares for these companies are shown in the charts, “Leading Companies in the Sealants Market by Market Share.”
Leading Companies in Sealants Market by Market Share

Source: MedMarket Diligence, LLC

Fibrin—The Body’s Sealant
Fibrin sealants are the most useful surgical hemostats because they can be used to clot blood but are also valuable for sealing around suture lines for organ transplants, mastectomies, and various resection procedures, as well as to prevent leakage of fluids and gases. A number of companies, including Harvest Technologies, Plasmaseal, ThermoGenesis, and Interpore Cross Medical, have developed active mixes of growth factors to aid repair and devices capable of preparing autologous fibrin and platelet formulations that can be used as sealants.
In July 2007, ThermoGenesis announced that the FDA had approved the CryoSeal FS system, the company’s autologous fibrin sealant, as an adjunct to hemostasis in liver resection surgery. The product was already cleared for sale throughout the European Community (CE Mark) for any type of surgery. The CryoSeal FS system, an automated device with a companion sterile blood processing disposable, is used to prepare fibrin sealants from plasma in about an hour. The system produces a surgical sealant by harvesting, from a patient’s plasma, wound healing proteins including fibrinogen and Factor VIII, and the activating enzyme thrombin. When combined at the bleeding wound site, the two components form an adhesive gel that helps stop bleeding and bonds tissue.
Thrombin is a predecessor of fibrin in the clotting cascade and is involved in converting (soluble) fibrinogen to (insoluble) fibrin. It is used in combination with fibrin for accelerated hemostasis.
On January 10, 2008, Omrix Biopharmaceuticals announced that the FDA had granted an expanded indication for general hemostasis in surgery for Evicel liquid fibrin sealant (human). Evicel is the first liquid fibrin sealant to be indicated as an adjunct to hemostasis for use in patients undergoing surgery when control of bleeding by standard surgical techniques is ineffective or impractical. Ethicon is Omrix’s marketing partner and will actively promote Evicel for a wide range of surgeries.
High-Strength Medical Adhesives
Fibrin-based wound closure products achieve hemostasis and have moderate adhesive properties that can help sutures to keep wound edges in apposition. Where greater adhesive strength is required, cyanoacrylate products are the main form of high-strength surgical glue approved for human clinical use. They are replacing sutures in many procedures but do not represent the ideal alternative to suturing, an ideal technology that is still sought by researchers. Cyanoacrylate glues used for external skin closure are approximately five times less strong than sutures, and cyanoacrylates produce cytotoxic compounds as part of the curing process when used for securing torn or excised tissue. This has delayed the development and clinical evaluation of potentially useful materials for internal surgical procedures. Nonetheless, cyanoacrylate glues are marketed actively by a number of companies for topical wound closure in accident/emergency situations and in surgical closure.
Leading products in this category include Dermabond, which is developed by Closure Medical and marketed by Ethicon. Dermabond is marketed in about 40 countries under EU- and FDA-approval for topical wound closure. For Ethicon, Dermabond represents the culmination of a five-year joint development program with Closure Medical that started in 1996.
Closure Medical, which is now incorporated into Ethicon, also developed Omnex vascular sealant, a high-strength adhesive that received the CE mark in 2005.
Post-Surgical Adhesion Prevention
Post-operative adhesions tend to arise when internal connective tissues are exposed to air and instrumentation during the surgical procedure and any irritation caused to internal organs. Abdominal surgery often leads to some form of adhesion formation, as does cardiovascular surgery. There are roughly 8 million–9 million abdominal surgeries, more than 2 million gynecologic surgeries, and 9 million cardiovascular surgeries every year, with about 1.7 million procedures associated with some risk of critical adhesion formation. Thus there is enough risk for adhesions from these procedures to encourage the use of adhesion prevention products in approximately 10% of the cases over the next decade.
Among companies that have led the growth in adhesion prevention products are Johnson & Johnson/Ethicon with its Interceed brand, and Genzyme Biosurgery, which launched Seprafilm approximately five years after the J&J product. Interceed (made out of neutralized oxidized regenerated cellulose by the company’s Noramco chemical synthesis business) and Seprafilm both provide a bioresorbable protective layer between tissues susceptible to adhesion formation.
Other contenders in this field include Omrix Biopharmaceuticals, which has developed an anti-adhesion product named Adhexil; an IND for Adhexil was filed in December 2006. Meanwhile, SyntheMed has developed the Repel-CV bioresorbable adhesion barrier; the company announced favorable results from a pivotal trial in neonatal patients in September 2006.
When Angiotech acquired Cohesion Technologies, it inherited the Adhibit sprayable adhesion prevention product. In April 2006, the company announced data from a 71-patient human clinical study (conducted in the EU) designed to assess the safety and efficacy of Adhibit for preventing adhesions in patients undergoing a myomectomy procedure. The trial data indicated that the use of Adhibit reduced post-operative adhesion. Baxter Healthcare has been granted exclusive worldwide (excluding the United States) marketing and distribution rights to Adhibit.
In July 2007, Protein Polymer Technologies (PPTI) announced it had entered into an agreement with an unnamed multinational biotechnology device company in which PPTI will provide genetically engineered protein polymer biomaterials for use in the prevention of post-surgical adhesions. PPTI believes its protein polymer materials can improve the outcome of abdominal and gynecological surgery by substantially reducing adhesions.
PPTI is also in discussions with several U.S. and international biotechnology and medical device companies, which are evaluating PPTI’s surgical sealant and drug delivery product applications. These products are intended to aid in the closure of surgical incisions and tissue trauma reducing, for example, the incidence of post-operative bleeding and the local delivery of therapeutic agents.
Market Potential
The commercial importance of wound closure and adhesion prevention products is directly linked to clinical need, which is reflected in the numbers of procedures that can benefit from improved closure and adhesion-prevention technology.
Approximately 10 million cardiovascular procedures in the United States have the potential to benefit from improved hemostasis, sealants and glue products. In an estimated 1.5 million procedures, these products can make a major contribution to the work of the surgeon in carrying out a safe procedure with minimal risk from blood transfusion and complications associated with loss of blood. Procedures that fall into this category include open heart bypass procedures with vein harvesting and many heart revascularization procedures, aortic valve replacements, mitral valve replacements, carotid endarterectomy, femoral distal bypass, and femoral popliteal bypass.
Of more than 9 million musculoskeletal surgical operations worldwide, a large number (approximately 4 million) involve minimally invasive arthroscopy or are closed fractures in which hemostats, sealants and glues cannot be used. However, open trauma cases, knee reconstruction, total knee replacement, some hip reconstruction procedures, and all spine fusion procedures have the potential to benefit from improved appropriate use of hemostat, sealants and glues. Some of these procedures cause the patient to lose substantial quantities of blood. Effective use of sealants/hemostats can prevent loss of time during surgery, reduce the requirement for replacement blood products, and significantly improve rehabilitation due to reduced morbidity.
Also there are 450,000 fusions and 432,000 discectomies performed in the United States each year. Particularly in the case of fusion, patients may require replacement of up to half the blood in their bodies. These procedures can take up to six hours to perform, and effective hemostasis can significantly improve cost effectiveness by saving surgical theater time and related costs, improving recovery and outcomes for the patient (e.g., reduced risk of infection) and reducing morbidity.
There are approximately 2.5 million joint reconstruction procedures worldwide. Although minimally invasive procedures have reduced the burden of these procedures, reconstructive surgery is likely to increase with the growth of the aging population and with increased recreational activity. These procedures can benefit from improved use of closure and hemostatic products. Typically, tourniquets are used to prevent excessive bleeding during many of these procedures; it is assumed that lack of blood flow results in morbidity of tissue and delayed recovery as well as leading to increased complications, although the reduced need for blood transfusion is thought to outweigh these disadvantages. The introduction of effective sealants and hemostats offers the possibility of selectively reducing bleeding at sites of reconstruction without the concomitant effect of increased morbidity.
It seems realistic to expect that a new category of procedure-enabling high-strength glue products will evolve and enable gluing of ligaments, tendon and bone in the orthopedic arena. Although there are a number of cement and bone graft substitute materials that have glue-like characteristics, none yet have the weight-loading potential or the torque-strength characteristics to meet the demand to fix bone fragments together without hardware support.
Gynecological and urological procedures include transurethal prostate resections, bladder surgery, prostatectomy, hysterectomy and surgical resection of adhesions, as well as cesarean sections. Hemostasis and sealing in these procedures is critical to prevent complications that can result from excessive bleeding. Neurosurgery (4 million procedures annually in the United States) is highly vulnerable to the effects associated with healing: inflammation, angiogenesis, and generation of fibrous tissue—all attributes of normal tissue repair—cause problems for neural tissue. Effective hemostasis and sealing of blood can avoid these traumatic effects and are vital to reduce morbidity.
Most traumatic wounds offer potential to be appropriately treated with hemostats, sealants and glues. Many lacerations can be adequately treated with high-strength glue products; this would avoid a secondary visit to a medical center for removal of sutures with associated costs. For example, conservative estimates of ER costs for closure of a small bleeding trauma laceration with sutures, (including local anesthetic, antibiotic cream and suture removal kit) are approximately $75 before labor and time are included. Further, in U.S. acute care hospitals, 5%–10% of patients develop hospital-acquired (nosocomial) infections, many of them in wounds. The cost per wound ranges from $3,000 to $27,000.
Revenue Implications
Fibrin-Based Sealants: The world market for fibrin-based sealants and similar products is estimated to be worth roughly $1.5 billion per annum, with annual growth rates in low double figures. Most fibrin and similar sealant products were first used for internal surgical hemostasis and sealant effects. This is now changing with the realization that appropriate hemostasis and gluing of surgical wounds results in reduced infection rates and better cosmesis. Growth rates in the synthetic and biological adhesives segment of the market will be relatively modest because these technologies have the most potential in niche opportunities, competing with established use of autologous and allogeneic fibrin products from major established players and a number of new device suppliers, as well as future recombinant human fibrin producers such as PPTI.
Fibrin sealant usage worldwide is forecast to increase steadily during the coming years, driven by such factors as the requirement to use these materials in new procedures and an increasing caseload.
One market in which these products are of special interest is Japan, where the loss of blood and avoidance of transfusion are extremely emotive issues. Growth rates here for autologous products and sealants not derived from blood may be delayed by long approval mechanisms, but will be rapid once these products appear on the Japanese market. In addition, this growth rate will be supported by the sales of new devices for the preparation of autologous fibrin sealants.
High-Strength Glues: Cyanoacrylate products are the primary form of high-strength surgical glues approved for human clinical use in the worldwide market. A number of new materials are under development for internal use in particular, but these represent new chemical entities and their commercialization is likely to be delayed by regulatory requirements.
Even though cyanoacrylate glues are not the ideal replacement for sutures, such a perfect replacement has yet to be fully developed, leaving room for cyanoacrylate glues to replace conventional sutures in many procedures over the next 10 years. To that end, cyanoacrylate glues are marketed actively by a number of companies for topical wound closure in accident/emergency situations and in surgical closure.
The $500 million world market for high-strength surgical glues is growing vigorously and expected to more than double in value over the next five years, driven by increased incidence of surgery, greater adoption of cyanoacrylate and newer adhesive products for internal surgical applications, and the need for improved, fast-acting and easy-to-use products for use in minimally invasive procedures. Also, it is increasingly recognized that these products have a role to play in reducing infection and improving cosmesis of superficial surgical wounds, which will also drive the value of this market segment.
Adhesion Prevention
The market for products to prevent post-surgical adhesions is driven by the introduction of new technologies, by impressive data on product effectiveness, by increasing caseload and by growing acceptance of this type of product. World sales of products in this category are forecast to increase by solid double-digit annual growth rates from a value around $700 million to something approaching $1.5 billion in five years’ time.

Links:Advanced Medical Solutions (Winsford, U.K.; http://www.admedsol.com/)Aesculap (Center Valley, PA; http://www.aesculap.com/)Angiotech (Vancouver, Canada; http://www.angiotech.com/)B. Braun (Melsungen, Germany; http://www.bbraun.com/)Baxter Healthcare (Deerfield, IL; http://www.baxter.com/)Chemence (Corby, U.K.; http://www.chemence.com/)Closure Medical (Raleigh, NC; http://www.closuremed.com/)Covidien (Norwalk CT; http://www.covidien.com/)CSL Behring (King of Prussia, PA; http://www.cslbehring.com/)Daiichi Sankyo (Montvale, NJ; http://www.daiichius.com/)Ethicon (Somerville, NJ; http://www.ethicon.com/)GEM (See Synovis Life Technologies)Genzyme Biosurgery (Cambridge, MA; http://www.genzyme.com/)GluStitch (Delta, Canada; http://glustitch.com/)Harvest Technologies (Plymouth, MA; http://www.harvestech.com/)Interpore Cross Medical (Irvine, CA; http://www.interpore.com/)Johnson and Johnson (Somerville, NJ; http://www.ethus.jnj.com/)Kaketsuken (Kumamoto, Japan; http://www.kaketsuken.or.jp/)MedLogic Global (See Advanced Medical Solutions)Nissui Pharmaceutical (Tokyo, Japan; http://www.nissui-pharm.co.jp/)Omrix Biopharmaceuticals (Kiryat Ono, Israel; http://www.omrix.com/)Pharming Group (Leiden, The Netherlands; http://www.pharming.com/)Plasmaseal (San Francisco, CA; http://www.plasmaseal.com/)Protein Polymer Technologies (San Diego, CA; http://www.ppti.com/)Synovis Life Technologies (St. Paul, MN; http://synovislife.com/)SyntheMed (Iselin, NJ; http://www.synthemed.com/)SysCore (E-mail: Helmut.Kranzmaier@cnc-communications.com)ThermoGenesis (Rancho Cordova, CA; http://www.thermogenesis.com/)U.S. Surgical (Norwalk, CT; http://ussurg.com/)
Acute Wounds fibrin fibrin sealant hemostasis hemostats market data medtech sealants surgery surgical sealants Surgical wounds sutures Wound closure wound management

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