Surgical sealants, glues and hemostats: developmental timelines

UPDATE: See October 2010 Report #S180, “Worldwide Surgical Sealants, Glues, Wound Closure and Anti-Adhesion Markets, 2008-2015.

(Below is an excerpt from “Surgical Sealants, Glues and Wound Closure Worldwide Market, 2009-2013.”)

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 stronger 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 adjunctive 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 enhance the role of this technology even further.

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

Collagen 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)

Polymers such as PEG can absorb fluids and are the basis for products to seal and adhere tissues. CoSeal (Angiotech Pharmaceuticals) 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. As these sealants are synthetic, they do not pose the risk of viral infection spreading from one person to another.

Albumin Cross-Linked with Glutaraldehyde

Albumin, 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 the most 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 different 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 to avoid 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, and this would suggest a glue that encourages osteoblast activity and does not form an impenetrable barrier for cellular in-growth.

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. Lifecore Biomedical’s Lubricoat, for example, is manufactured from iron cross-linked hyaluronic acid. In addition to creating a thick viscous hydrogel material (its primary function), it is thought that the iron content may have an active effect in preventing formation of scar tissue.

Delivery Systems

A number of delivery systems have been developed to improve the speed and ease of surgical procedures and to facilitate complex procedures that would otherwise be less successful. For example, new products 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 devices for delivery and companies like Baxter are developing single component systems that are already solubilized for immediate use in the surgical theater.

Likewise, the application of cyanoacrylate adhesive for surgical closure has been approved by the FDA on the basis that this is a topical-only treatment that eventually sloughs off the top surface of the wound. These products are 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.

In addition, a number of sophisticated delivery systems for new sealant and glue products have been developed and are under development. We expect this trend to increase as new procedures are developed for cyanoacrylate and new glue systems; new devices will be required to aid the procedure and these devices will contribute an increasing proportion of the value associated with the gluing process.

Also, sophisticated surgical instruments will be required to facilitate the application of each specific indication for new high-strength glue products. For example, the use of high-strength glue products to repair vascular joints in coronary bypass operations is likely to need instrumentation to hold vessels in place and apply exact amounts of adhesive to specific surfaces to create optimal adhesion and to avoid subsequent delays from leakage, or imperfect integration of the grafted tissues.

Source: MedMarket Diligence, LLC; Report #S175.

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