Product Development in Surgical Glues

Surgical closure and securement products range from simple suture products to sophisticated biomaterial aids for hemostasis, sealant activity, and for adhesion prevention. Within the hemostasis field, products have the objective of rapidly achieving hemostasis and acting to seal in the presence of high pressure blood flow or air flow.

Screen Shot 2014-04-23 at 3.49.13 PMDevelopment Timelines
Natural hemostats such as gelatin, collagen and thrombin were first developed as hemostatic agents, followed by mixes and fibrin sealants. More recently, companies have introduced synthetic sealants and hemostats that accelerate the process of blood clotting and provide a stronger seal that will withstand greater pressures. These products employ various synthetic polymer chemistry systems. Glues are required to secure tissue firmly under substantial forces. In extreme cases such as musculoskeletal repair, these glues need to withstand high tension and pressure forces. Fibrin and other sealants are not strong enough for these applications and have been used as adjuncts to sutures and staples. Cyanoacrylate glues have sufficient strength for most procedures but are not yet cleared for use in the majority of internal applications due to toxicity concerns. They also lack sufficient flexibility for use in many procedures.

Efforts are progressing to develop new biomaterials capable of gluing tissues with high strength, low toxicity, and sufficient flexibility to avoid breakage of the bond. In addition, cyanoacrylate manufacturers are examining the possibility of improving cyanoacrylate technology to overcome the existing challenges of toxicity and brittleness. Despite this huge challenge, one or both of these two approaches are likely to establish new products in the next decade. In addition, the evidence of research work suggests it should be possible to create a glue technology that incorporates hemostatic properties to further enhance the role of this technology.

Apart from fibrin-based sealants and cyanoacrylate-based high-strength glues, there are three other main categories of closure/attachment products in use or in development at present.

Collagen and Thrombin Combination
Screen Shot 2014-04-23 at 3.54.26 PMCollagen is a major protein found in most mammals; the form of collagen that is generally used for wound sealant and closure is a white water-soluble fiber containing several key amino acids. In most sealants, collagen forms a matrix on which thrombin (but also fibrin, polyethylene glycol (PEG) polymers, or other compounds) are attached. The role of the collagen matrix is to channel blood with its various clotting proteins to the compounds attached to the matrix (thrombin, etc.), triggering a clotting cascade.

Polyethylene Glycol Polymer (PEG)
Screen Shot 2014-04-23 at 3.55.52 PMPolymers such as polyethylene glycol polymer (PEG) can absorb fluids and are the basis for products to seal and join tissues. CoSeal (Angiotech Pharmaceuticals, marketed by Baxter BioSurgery) and FocalSeal (Genzyme) are two products of this type. They are completely synthetic and offer quick sealing of the wound with the flexibility to expand and contract. Because these sealants are synthetic, they do not pose the risk of viral infection spreading from one person to another.

Albumin Cross-Linked with Glutaraldehyde
Screen Shot 2014-04-23 at 3.58.05 PMAlbumin, the protein that forms egg white, is one of the strongest natural adhesives in the market. Albumins are water-soluble and will coagulate when heated or combined with certain acids. When combined with glutaraldehyde, albumin forms a strong adhesive for internal surgery. The albumin/glutaraldehyde compound forms a cross-link with the tissues to be bonded that can even be stronger than the underlying tissues. In fact, the compound has been shown to withstand pressures of 500 mm–800 mm of mercury, which is more than four times normal human blood pressure.

CryoLife’s BioGlue is a widely used albumin/glutaraldehyde glue. It begins to set within 20–30 seconds of application and reaches its ultimate bonding strength within two minutes.

It is unlikely that any one formulation of tissue glue will be adequate for all applications. For example, fixing fragments of bone after significant bone trauma is likely to require an adhesive with a different modulus and strength to that required for adherence of pericardium during cardiovascular surgery. It is also likely that the sealant and hemostatic properties of these two products will need to be different. For example, to stick pericardial tissues together, the surgeon will be concerned with avoiding surgical adhesions and excessive fibrosis that might lead to problems during revision surgery. In the example of bone repair, rapid rehabilitation and avoidance of non-unions during fracture healing is a major challenge: this would suggest looking for a glue that encourages osteoblast activity and does not form an impenetrable barrier for cellular in- growth, but which can also tolerate the static and dynamic forces put upon bone.

Recently, new technologies have appeared on the market to address the need for adhesion prevention. These products have been formulated to be approvable by the FDA through device regulation routes; thus, in addition to providing a physical barrier, these products also may have some subsidiary active mechanism to achieve their objective.

Delivery Systems

Screen Shot 2014-04-23 at 4.01.16 PM
Source: CryoLife

In parallel with new products, in several instances new delivery systems have had to be developed. Surgeons also experiment with these products in an effort to produce superior results. A surgeon may, for example, mix a sealant with a few ml of saline to gain greater control over product application. Development of these delivery systems may be driven by several factors, such as: to improve the speed and ease of surgical procedures; to facilitate complex procedures that would otherwise be less successful; to better access a particular tissue; or to avoid premature mixing of two components, thus providing better control of the gluing process. New delivery systems have evolved to spray liquid hemostat solutions such as thrombin onto surgical sites to improve speed of hemostasis. Fibrin sealant is supplied as two powders that need to be solubilized and then mixed immediately prior to application to the surgical site. This has led to the development of a number of sophisticated medical delivery devices, and companies like Baxter aredeveloping single component systems that are already solubilized for immediate use in the surgical theater.

Cyanoacrylate adhesive for surgical closure is a topical-only treatment that eventually sloughs off the top surface of the wound. The product is applied to the surface of the skin to form a glue film that secures apposition of the cut edges of the incision. Currently, the cyanoacrylate is supplied in a device that aids the curing of the adhesive and ensures its safe handling and application.

Several fairly sophisticated delivery systems for new sealant and glue products have been developed or are currently under development. As new procedures are developed for cyanoacrylate and new glues, new devices will be required to aid the procedure. The devices will contribute an increasing proportion of the value associated with the gluing process.

Sophisticated surgical instruments are being developed to facilitate the application in each new indication for new high-strength glue products. High-strength glues are increasingly being utilized to repair vascular joints in coronary bypass operations. Customized instrumentation is designed to hold vessels in place and facilitate the application of exact amounts of adhesive and to avoid subsequent delays from leakage, or imperfect integration of the grafted tissues.


Source: MedMarket Diligence, LLC; Report #S190, “Worldwide Surgical Sealants, Glues, Wound Closure and Anti-Adhesion Markets, 2010-2017.”

Opportunities for med/surg sealants, glues, hemostats driven by type of clinical benefit, competition

Advanced products for the closure, sealing, hemostasis and other endpoints for medical and surgical wounds generate varying degrees of clinical benefit based on the manner and extent to which they enable management of different wound types.  Degrees range from the acute need end of “important and enabling” to the less clinically necessary “aesthetic and perceived benefits”:

  • Important and enabling: Important to prevent excessive bleeding and transfusion, to ensure safe procedure, and to avoid mortality and to avoid complications associated with excessive bleeding and loss of blood.
  • Improved clinical outcome: Reduces morbidity due to improved procedure, reduced surgery time, and prevention of complications such as fibrosis, post-surgical adhesion formation, and infection (includes adjunct to minimally invasive surgery).
  • Cost-effective and time-saving: Immediate reduction in surgical treatment time and follow-up treatments.
  • Aesthetic and perceived benefits: Selection is driven by aesthetic and perceived benefits, resulting in one product being favored over a number of medically equivalent treatments.

These benefits are clearly different on a clinical specialty-by-specialty basis.  The numbers of targeted or prospective procedures also vary considerably by specialty. As a result, wound closure and securement products have the following categorized potential use worldwide:

Source: “Surgical Procedures with Potential for the Use of Hemostats, Sealants, Glues and Adhesion Prevention Products, Worldwide “; Report #S190.


Surgical sealants, glues, sutures/clips, hemostats outside the U.S.

See the updated, published 2012 Report #S190, “Surgical Sealants, Glues, Sutures, Other Wound Closure and Anti-Adhesion, Worldwide Markets, 2012-2017.”

The world market for the securement products, encompassing wound closure/sealing, hemostasis and anti-adhesion) is currently valued at more than $9.7 billion. This total market is growing at a steady 6.7% compound annual rate, though growth rates for individual regions vary.

Average growth in the world closure and securement products market also reflects differing conditions in individual countries, ranging between 3% CAGR for less developed economies and considerably higher for the United States.

Below is illustrated the market value and compound annual growth rate of the closure and securement market for countries outside the U.S. (the U.S. dominates the world market, largely dwarfing non-U.S. markets).

 

Securement-size-growth

 

Source: MedMarket Diligence Report #S180; “Worldwide Surgical Sealants, Glues, Wound Closure and Anti-Adhesion Markets, 2008-2015.”

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Steady growth in wound management products

Wound management, with its diverse products, well established base and growth prospects, not only for the advanced product segments but also for its tradiitional products, is an attractive area for medical technologies, drawing many active market participants.

The need for effective and improved technologies for acute and chronic wounds continues to be high, driven by the demographics of the aging population, the increasing sensitivity of healthcare systems to high costs such as chronic wounds and other forces.  The industry has responded by developing and introducing more complex types of wound products focused on shortening wound healing times and costs.

The largest single category of wound management products is already in physical wound management, encompassing negative pressure wound therapy, hyperbaric oxygen, hydrotherapy, electrical stimulation, electromagnetic stimulation, ultrasound, laser and others.  This category will also demonstrate some of greatest growth in wound management over the next several years. Other areas of significant growth include the use of growth factors, and foam and alginate dressings.

Illustrated is the global wound management market by product segment for 2008 and 2017.

Wound-by-segment-2008-2017

Source: MedMarket Diligence, LLC; Report #S247.

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Sealants and adhesives on course to seize the wound closure pie

See the updated, published 2012 Report #S190, “Surgical Sealants, Glues, Sutures, Other Wound Closure and Anti-Adhesion, Worldwide Markets, 2012-2017.”

One of the hallmarks of the market for surgical sealants, glues and adhesives is that these products are steadily gaining greater and greater share of a market — medical and surgical wound closure — that is itself growing at a steady rate.

Barriers to entry to this market are not significant for medical products.  The products are biological, chemical and combinations of both, and may include syringes, dual mixing vials (for product activation) and other delivery devices.  Therefore, there has been a steady stream of market entrants over the past few years, a trend that we expect will continue.

Worldwide Shares of Wound Closure Market by Type, 2010 and 2015

Sealants-closure-pies

Source: Report #S180

In the 2010 and 2015 breakdown of the “wound closure” market (see side-by-side pie charts), one can consider that fibrin and other sealants plus high strength medical adhesives potentially might target the entire pie, gaining full share of the market that is held by both mechanical closures and staples and sutures.  In reality, sealants and adhesives are unlikely to fully displace use of sutures, staples and other traditional products in wound closure, but may capture a great majority of the caseload.  Furthermore, many closures using sutures, staples and clips procedures that remain may call for the adjunctive use of sealants and adhesives to ensure tighter seal of the wound, hasten tissue healing and provide other benefits.


For more details of this market, see MedMarket Diligence Report #S180: “Worldwide Surgical Sealants, Glues, Wound Closure and Anti-Adhesion Markets, 2008-2015.”

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Sutures, staples, clips and other wound closure still active in development

See the updated, published 2012 Report #S190, “Surgical Sealants, Glues, Sutures, Other Wound Closure and Anti-Adhesion, Worldwide Markets, 2012-2017.”

In our analyses of the market for surgical sealant, glues, wound closure, hemostasis and ant-adhesion products (Report #S180), we highlight that a major force in the development of these new products is in manufacturers driving innovation to enable the products to displace traditional wound closure products, especially sutures, staples and clips.

Given the size of this “mechanical closure” market, at over $5 billion annually, manufacturers in this space are not idly standing by while novel wound closure technologies poach their caseload.  A healthy number of companies are actively developing and marketing novel wound closure products that still fall in this traditional category of wound closure:

Source: MedMarket Diligence, LLC; Report #S180.

 

Companies represented here (many involved in development of multiple wound closure product types) include: 3M, Abbott Vascular, Angiotech Pharmaceuticals, ArthroCare , B. Braun/Aesculap, BSN Medical, Cardiva Medical, Covidien, CSMG Technologies (Live Tissue Connect), Incisive Surgical, Innovasa, Johnson & Johnson (Ethicon), Kinetic Concepts, Morris Innovative, NeatStitch, Resorba, St. Jude Medical, Synovis Life Technologies, Teleflex Medical, Wound Care Technologies, and Zimmer.

This does not include the companies active in the area of medical/surgical tapes in a range of types; fabric, film, island, bandage, impregnated and others.

High Strength Medical and Surgical Glues

See the updated, published 2012 Report #S190, “Surgical Sealants, Glues, Sutures, Other Wound Closure and Anti-Adhesion, Worldwide Markets, 2012-2017.”

Cyanoacrylate products are the main form of high-strength surgical glue that is 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.  While sutures will be replaced by cyanoacrylate glues in many procedures over the next 10 years, this will only occur after some technical challenges are overcome. For example, 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 these potentially useful materials for internal surgical procedures. However, cyanoacrylate glues are marketed actively by a number of companies for topical wound closure in accident/emergency situations and in surgical closure.

Given the current size of the global market for high strength glues (at over $700 million) and the potential for this market to expand as products overcome the challenges of strength and toxicity, a respectable number of competitors compete in this space and many are working on further developing cyanoacrylate-based and other high strength adhesives (including fibrin-based and other “bio-glues”) to not only garner greater share of the existing market but to also erode the market for sutures and other mechanical wound closure products (e.g., clips and staples).

Source: MedMarket Diligence Report #S180, “Worldwide Surgical Sealants, Glues, Wound Closure and Anti-Adhesion Markets, 2010-2015.”

Ethicon (J&J), Covidien and B. Braun (Aesculap) hold the major positions in the market for high strength medical and surgical adhesives, but their positions are at risk, and will continue to be at risk, as long as the unmet need exists for stronger, more compatible glues.  Some of the many products on the market and in development in the area of high strength glues include SurgiSeal, DermaSeal, FloraGuard, LiquiBand, SkinLink, Histoacryl, Gluetiss, Autologous biological glue, Chemence USP Class VI adhesives, TissueGlu, Indermil, Glubran2, Glubran Tiss, GluSeal, GluSite, PeriAcryl, GluShield, Dermabond, InteguSeal, Epiglu, Surgical Tissue Sealants (STS) and others.