Cyanoacrylate Surgical Tissue Adhesives

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The medical community is searching for adhesives that swiftly bond human tissue, replace staples and sutures, are biocompatible, biodegradable, and do not interfere with the healing process. A tissue adhesive is one that surgeons can use to mend flesh without the complications of sutures or other mechanical fasteners.

Over the entire range of surgical adhesives, cyanoacrylates have arguably the best chance at satisfying the majority of surgical requirements. Cyanoacrylates have unique properties that set them apart from others and have been utilized for topical tissue repair and closure. For example, cyanoacrylate adhesives are replacing sutures in external applications, and they are the most widely used adhesives for bonding traumatized tissues. Cyanoacrylates are also being proposed and clinically tested in many internal surgical procedures.

Let's explore the main types of tissue glues used in clinical procedures and the criteria to select these adhesives so that they are widely accepted by the surgical community. Also, learn how cyanoacrylates have generated significant interest as tissue adhesives and appear to have great promise for further development.

Overview of Surgical Adhesives Alternatives

Sutures, staples, and clips are considered to be the standards for wound closure and tissue reconstruction in surgical procedures. However, surgical tissue adhesives have also been used for similar purposes. These include both synthetic and biologically-based types.

Due to the broad possible number of applications, there are many tissue adhesives that are currently used in clinical and experimental procedures. Each of these has an optimal clinical application depending on physical and chemical characteristics (bond strength, fluid or solid consistency, activation mechanism, etc.). The properties of some of these are described in the table below. Of these tissue glues, five main types are commercially available.

• Fibrin
• Cyanoacrylate
• Gelatin and thrombin products
• Polyethylene glycol polymers, and
• Albumin and glutaraldehyde products.

Several new materials are also under development, but these represent relatively new entities, and their commercialization is likely to be delayed by regulatory requirements. Today, when a high-strength surgical adhesive is required, the primary candidates are based on cyanoacrylate resins.

In all cases, these materials go from a liquid phase (during application) to a solid phase (during service) based on some mechanism. These mechanisms include chemical crosslinking, solvent evaporation or absorption, heat activation, light (laser) activation, and a variety of other energetic methods. The combination of formulation and activation mechanism will control how fast the adhesive/sealant sets.

Adhesives	Approximate Strength, kPa	Activation	Side Effects	Approximate Degradation Time in the Body, Weeks
Fibrin	13 (burst) 8 (tensile)	Chemical	Virus transmission Weak tensile strength	2
Cyanoacrylate	68 (tensile)	Chemical	Cytotoxic	8
Albumin Solder	67 (burst)	Infrared laser	Possible thermal damage Virus transmission	6
Chitosan adhesive films	15 (tensile)	Infrared laser	Possible thermal damage	2-12
Gelatin	12 (tensile)	UV light	UV damage	4

Tissue Adhesives Currently Used in Clinical Procedures

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Qualification for Surgery – What are the Key Considerations?

General Requirements for Surgical Adhesives

Five criteria are important in the use of surgical adhesives:

• Safety,
• Effectiveness,
• Usability,
• Cost, and
• Regulatory approval

Only products that satisfy all of these criteria will be recognized and widely accepted by the surgical community. The general requirements for surgical adhesives are listed in the table below, but most requirements will depend on the surgical procedure.

General Requirements of Surgical Adhesives

Chemical Curable from the liquid state (wettable and spreadable) through polymerization, chemical crosslinking, or solvent evaporation Rapidly curable under wet physiological conditions (e.g., blood) at body temperature The adhesive should provide sufficient tack for early fixation and opportunity for rearrangement Any exothermic or chemical process involved in the curing of the adhesive should not damage the surrounding tissue

Physical Once cured, the adhesive should mimic the mechanical performance of undamaged tissue Should not shrink excessively after application High bonding strength to tissues Tough but pliable

Clinical Should be simple to handle and be easy to store (long shelf-life) Viscosity, bond strength, working life, and strength development time should be suitable for the procedure Should be sterile

Biological Should not influence the healing process and the regrowth of new tissue where possible Adhesive product or degradation products should not affect the tissue (dermatitis, heat, and chemical sensitization, etc.) or histotoxicity Adhesive or degradation products should not be transferable through the body Non-toxic components and degradation products that are bioabsorbable or are metabolized in a reasonable time

Regulatory Should meet appropriate standards and regulations relevant for the procedure (e.g., United States Pharmacopoeia (USP) Class VI Standard and International Standards Organization (ISO) ISO-10993).

Surgical adhesives must be non-toxic, safe, and free from the risk of infectious transmission. Ideally, they should be bioabsorbable and not persist for a long time as a substance that is foreign to the body. Surgical adhesives should not hinder the healing processes. Due to toxicological concerns, not all substances are approved by the FDA or other regulatory agencies and some tissue adhesives are limited as yet to only external procedures.

Surgical adhesives should bond rapidly to the surrounding tissues in the presence of water or other bodily fluids and provide high adhesive strength. However, the working life and gel time should be long enough for the surgeon to apply the dressing without being rushed. Appropriate working life, gel time, and mechanical properties will be required for specific procedures.

Other properties such as hardness, flexibility, exotherm temperature, etc. are important considerations as they can cause discomfort to the patient. As with other surgical techniques, the use of surgical adhesives and sealants requires special training in order to attain full value and minimize complications.

Bond Strength of Cyanoacrylate Tissue Adhesives

Common tests used to determine the adhesive strength of cyanoacrylate tissue adhesives have been described by ASTM.

• ASTM F 2255, Standard Test Method for Strength Properties of Tissue Adhesives in Lap- Shear by Tension Loading.
• ASTM F 2256, Standard Test Method for Strength Properties of Tissue Adhesives in T-Peel by Tension Loading.
• ASTM F 2258, Standard Test Method for Strength Properties of Tissue Adhesives in Tension.
• ASTM F 2458, Standard Test Method for Wound Closure Strength.

Chivers and Wolowacz¹ provide a thorough review of the strength of adhesively bonded tissue joints. Bond strengths were strongly dependent on the adhesive type, with cyanoacrylate adhesives outperforming the others by at least an order of magnitude (shown in the table below).

Adhesive	Bond Strength, MPa
	Cartilage	Bone	Skin
n-Butyl-2-cyanoacrylate	1.0 (4) [1.4]	1.4 (2) [1.6]	1.2 (5) [1.8]
Gelatin-resorcinol-formalin (GRF)	0.15 (5) [0.23]	0.2 (1) [0.20]	0.07 (5) [0.12]
Fibrin	0.0049 (4) [0.0070]	0.011  (5) [0.019]	0.019 (6) [0.028]
Note: The mean is quoted first, followed by the number of specimens in parentheses and then the highest value measured is in square brackets.

Measured Bond Strength Between Different Tissue Types for Butt Joints¹
Several studies have been made with regard to a comparison of the bond strengths of surgical cyanoacrylate adhesives with the strength of conventional sutures. Early studies indicated that the initial strength of n-butyl-2-cyanoacrylate or 2-octyl-cyanoacrylate was not as strong as sutures and the breaking strength only equalized after several days.^2,3 However, more recent publications indicate that Dermabond and Histoacryl are both significantly stronger than SteriStrips (3M, St. Paul, MN, USA) but inferior to staples.^4,5

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Placement of Cyanoacrylate Surgical Adhesives

The use of cyanoacrylate adhesives in surgery is important because of their unique combination of chemical and physical properties. They are single component, catalyst-free adhesives capable of bonding at room temperature within just a few seconds. Cyanoacrylates require no external initiation, relying only on the small amounts of adsorbed water and chemicals on the tissue surface for cure. Unlike sutures, which leave small openings in the wound, cyanoacrylates form a continuous seal which efficiently distributes the load and leads to decreased scarring. These adhesives can also act as a liquid bandage to protect the wound and even act as a reservoir for antibacterial medication.

Unlike fibrin sealants, cyanoacrylates are not bioabsorbable and the body cannot break them down. The degradation products are cyanoacetate and formaldehyde. These products can accumulate in tissues and produce significant histotoxicity characterized by both acute and chronic inflammation. Fibrin glues are generally less toxic than cyanoacrylates; however, they are less strong, less available, and more expensive.

Using cyanoacrylates can avoid sutures – a great advantage when operating on young children. Cyanoacrylates are waterproof, flexible, and require no dressing on the wound. Cyanoacrylate adhesives have many different uses and considerable research is underway on the application of certain cyanoacrylate products as tissue adhesives in a drug delivery system. A more advanced review regarding the chemistry, method of preparation, and application of cyanoacrylate tissue adhesives is available.⁶

Early on in the development of cyanoacrylate surgical adhesives there were concerns about the compatibility of the adhesive with the human system and possible toxicological effects of the adhesive. Some cyanoacrylates produce toxic compounds as part of the curing process when used for securing tissue. This had delayed the development and clinical evaluation of these potentially useful materials for internal surgical procedures.

Recent research found that the cyanoacrylate adhesives broke down into relatively harmless by-products. More importantly, the rate of cyanoacrylate breakdown was about the same rate at which the wounds healed. Today, cyanoacrylate surgical adhesives, such as those based on octyl cyanoacrylate resins, are approved by the U.S. Food and Drug Administration for many surgical procedures in the United States. Cyanoacrylates are also widely used by physicians in Canada, Europe, and Japan.

Cyanoacrylates have generated significant interest as tissue adhesives and appear to have great promise for further development. Current cyanoacrylate tissue adhesives have several benefits and limitations in surgical applications (shown in the table below).

Benefits

Limitations

Simple cure mechanism Rapid strength development No measuring or mixing required High tensile-shear strength (approximately an order of magnitude greater than other surgical adhesives) Excellent adhesion to a wide variety of substrates including human tissues and graft materials High strength possible on polyolefins and fluorocarbons using primers Available in FDA approved, USP Class VI, and ISO 10993 compliant formulations

Significant reactivity results in short shelf-life Due to reactivity, precautions are needed for application and delivery Limited gap cure Soluble in polar solvents Relatively high material cost Toxic byproducts (e.g., formaldehyde) can form on degradation causing inflammation (additive scavengers can reduce this risk) Heat produced from the curing reaction can cause inflammation N-butyl-cyanoacrylate is relatively rigid (octyl cyanoacrylate has significantly higher flexibility)

Benefits and Limitations of Cyanoacrylate Adhesives in Surgical Procedures⁶

Types of Cyanoacrylates

The two primary types of cyanoacrylates used as tissue adhesives are:

• N-butyl-2-cyanoacrylate (Histoacryl, B. Bruan, Tuttlingen, Germany; Glubran 2, GEM S.r.l., Viareggio, Italy; Trufill, Cordis Neurovascular, Inc., Bridgewater, NJ, USA, and others) and
• 2-Octyl-cyanoacrylate (Dermabond, Ethicon, Raleigh, NC, USA, and others).

Dermabond and Trufill are approved by the FDA for superficial wound closure and are used by emergency room physicians, dermatologists, and plastic surgeons for external tissue adhesives. The 2-octyl-cyanoacrylate (OCA) is about three times stronger and more flexible than N-butyl-2-cyanoacrylate.⁷

Bond strengths of cyanoacrylate adhesives are dependent on specific formulation, the nature of the substrate(s), and the application/curing method utilized. Although n-butyl-2-cyanoacrylate is effective in closing superficial lacerations under low tension, it has several limitations. Studies have shown wound breaking strength in wounds repaired with n-butyl-2-cyanoacrylate to be equal to that in wounds repaired with sutures at 5-7 days; however, on day 1 the breaking strength with the tissue adhesive is only approximately 10-15% of that in a wound sutured with 5-0 monofilament. After polymerizing, the adhesive becomes brittle and is subject to fracturing when used in skin creases or long incisions. This restricts the use of adhesive to areas of relatively low tension, thus limiting their use.

The 2-octyl-cyanoacrylate adhesive (Dermabond) has greatly improved flexibility due to its internal plasticization, and several researchers have reported bond strength to tissue to be greater than n-butyl-2-cyanoacrylate.^8,9 However, there is debate regarding this due to differences in test procedures, substrates, etc. It may be possible that n-butyl-2-cyanoacrylate has a greater tensile strength while 2-octyl-cyanoacrylate has greater shear strength. Generally, more rigid adhesives perform better in tension while more flexible systems perform better in shear.

Applications of Cyanoacrylates

The value of cyanoacrylate adhesives was easily identified through many early medical trials. Cyanoacrylate adhesives proved valuable in sutureless surgery. Cyanoacrylate adhesives used for external skin closure are approximately three to five times stronger than sutures. The first major applications were rejoining veins, arteries, and intestines. Bleeding ulcers could also be sealed with a coating of adhesive through an endoscope without surgery. The seal would protect the ulcer from stomach acids while healing proceeded.

Cyanoacrylate adhesives were also useful in sealing and reinforcing suture lines in more conventional surgical procedures. In cosmetic surgery, the use of cyanoacrylate to replace or supplement sutures greatly reduced scarring. Skin grafts using cyanoacrylate adhesives were found to heal with much less scarring than those done with stitches. Cyanoacrylates also proved to be valuable in surgery related to vision. These adhesives were used to seal punctures or lesions in the eyeball. Corneal transplants were made safer and easier to perform.


Probably the most valuable use of cyanoacrylates is as hemostatic agents. These are used to control bleeding in surgery. Early in the investigation of cyanoacrylate adhesives for medical purposes, it was found that a thin coating of cyanoacrylate sprayed on the bleeding surface almost instantly stopped the loss of blood. This was considered to be a life-saving procedure since the bleeding has always been considered to be a serious problem in surgery.

The most notable test for cyanoacrylate adhesives as hemostatic agents came during the Vietnam War. Often seriously wounded soldiers would die from loss of blood before surgeons could make needed repairs. This was especially true for wounds of the chest or abdomen. Medical technicians found that a simple spray of cyanoacrylate stopped the bleeding almost immediately and included tubes of cyanoacrylate adhesive in their first aid kits.

Development Path of Cyanoacrylate Surgical Adhesives 

The use of cyanoacrylates in surgery has been restricted over the years due to:

• Application and physical properties not being suitable for specific procedures and
• Concerns about histotoxicity

The current commercially available cyanoacrylate surgical adhesives are only approved for external use in regions such as the US.

The development of surgical cyanoacrylate adhesives should aim at satisfying the unmet needs of both internal and external applications. Physicians need more advanced materials that are precisely deliverable, easily controlled, maintain a clear field of vision, and work reliably and promptly.

• For external applications, increased viscosity to a gel form, antimicrobial properties, and stronger strength and flexibility would be valued improvements.
• For internal procedures, the development of adhesives with lower toxicity and faster degradation rates would be of significant benefit.

In both external and internal applications, improvements may be possible in the easiness with which cyanoacrylate adhesives can be prepared and applied with a polymerization rate that can be controlled by the surgeon. Such improvements will be required before cyanoacrylate adhesives gain full surgeon acceptance and regulatory approval for the majority of surgical procedures.

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Adhesive Ingredients Used in the Medical Industry

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