Reference Work Entry

Handbook of Adhesion Technology

pp 1485-1503

Adhesion in Medicine

  • Robin A. ChiversAffiliated withConsultant in Medical Adhesives and Materials Email author 

Abstract

Adhesives are increasingly being used in medicine for repairing cuts and tears in the body as an alternative to mechanical fixation such as sutures. There are very strict regulations controlling the application of adhesives within the body and this means that there are only a limited number of chemistries which are approved for clinical use. The principal internal adhesives in current use are those based on fibrin, gelatin, and poly(ethylene glycol) (PEG) hydrogels and function largely as sealants, though do bond to the tissue surfaces. Cyanoacrylates are approved, mostly only for application to the surface of the skin for wound closure, but are quite widely used in a range of other applications. There are many requirements of an adhesive for internal use and this has led to large number of further systems being proposed. A number of those currently being evaluated for internal indications are described. Some are based on synthetic chemistry, some from biological sources such as marine creatures, and some are akin to welding or soldering.

Pressure-sensitive adhesives are widely used for securing dressings and devices to the skin surface. Most of these are now based on acrylic or silicone chemistries.

Keywords

Acrylate bone collagen cyanoacrylate fibrin formaldehyde gecko gelatin hemostasis hydrogel mussel pressure-sensitive adhesive protein sealant shellfish silicone skin solder surgery suture tissue urethane welding wound

Abstract

Adhesives are increasingly being used in medicine for repairing cuts and tears in the body as an alternative to mechanical fixation such as sutures. There are very strict regulations controlling the application of adhesives within the body and this means that there are only a limited number of chemistries which are approved for clinical use. The principal internal adhesives in current use are those based on fibrin, gelatin, and poly(ethylene glycol) (PEG) hydrogels and function largely as sealants, though do bond to the tissue surfaces. Cyanoacrylates are approved, mostly only for application to the surface of the skin for wound closure, but are quite widely used in a range of other applications. There are many requirements of an adhesive for internal use and this has led to large number of further systems being proposed. A number of those currently being evaluated for internal indications are described. Some are based on synthetic chemistry, some from biological sources such as marine creatures, and some are akin to welding or soldering.

Pressure-sensitive adhesives are widely used for securing dressings and devices to the skin surface. Most of these are now based on acrylic or silicone chemistries.

Keywords

Acrylate bone collagen cyanoacrylate fibrin formaldehyde gecko gelatin hemostasis hydrogel mussel pressure-sensitive adhesive protein sealant shellfish silicone skin solder surgery suture tissue urethane welding wound

Introduction

In simplest terms, the human body is made up of organs and tissues held together in a way which maintains their mechanical integrity and ability to function correctly. However, there are occasions when, due to accident, surgery or wear, some of these tissues or organs fail. In many cases, the body is capable of repairing naturally but sometimes needs assistance with this. Surgery has developed to such an extent that it is frequently possible to refasten or repair the failure such that the tissue can repair itself and regain its normal function, albeit in a scarred state. Initially, these surgical procedures consisted of provision of a mechanical fixation, but more recently a range of adhesive products and techniques have been developed to replace or augment these, analogously to the substitution of adhesives for nails, screws, bolts and rivets in engineering. This chapter aims to summarize the current state of this technology – adhesion and adhesives for repairing the human body. These may be adhesives for repair of internal organs, or for topical application to the skin, alone or on dressings. They are distinguished as adhesives for contact with body tissue, applied for the most part by medical professionals, though with one exception: dentistry is not included. The use of adhesives is well established in dentistry and will not be covered further here as it is the subject of Chap.​ 56.

There are a number of other aspects of adhesion in medicine which will only be touched on here. Adhesives are used widely in the manufacture of medical devices. Some of these applications require the adhesive to be in contact with body material, such as recirculating blood, and are therefore subject to some of the strict regulations which are imposed on products with body contact (Tavakoli et al. 2005). Other aspects of adhesion include the aggregation of cells and proteins onto foreign surfaces within the body, forming biofilms, the desired adhesion of cells in culture onto scaffolds for tissue engineering in the regeneration of organs, and the undesirable adhesion, known as “adhesions” between scarred tissues which can produce serious complications after surgery.

Mechanical Fastening

Traditionally, repair of damage to the body has been performed by surgeons using mechanical means. The most familiar of these is the suture, a thread of resorbable or non-resorbable polymer, which is stitched through soft tissue using a specially designed needle. Pulling the tissue edges together encourages the formation of a bond between them as the tissue regrows. When repair is complete, the surgeon may return to remove the sutures or they may degrade and eventually be excreted by the body. Suturing is usually fairly straightforward and medical professionals are trained in its use. It can also be easily removed and reapplied should there be a problem. It has the disadvantage, though, of only holding the tissue at discrete points, leaving less well-secured gaps between these which may be susceptible to leakage (see, e.g., Fig. 57.1a ). More recent developments in soft tissue fixation include metallic staples and barbed polymeric darts, and when fixation is required to hard tissue, there are ranges of interference screws available. Securing pieces of bone mechanically is usually done using plates, held in place with screws, or by the use of long intramedullary nails which can be inserted down the medullary canal in the long bones, and then held fast by transverse screws at the ends. Metallic repair means may be surgically removed after the tissue has healed, but are frequently left in place if they do not cause a problem for the patient.
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Fig. 57.1

Surgical repair of the dura. (a) Mechanical fastening, suturing, does not result in a watertight closure. (b) Adjunctive use of a patch to the closure seals the gap (Images provided courtesy of Tissuemed Ltd.)

Externally, the skin may be sutured or bandaged to give support during natural healing. However, crude adhesives, such as tar, have long been used to protect sites of severe damage.

Adhesives Technologies for Internal Applications

Overview

From the time of the introduction of the first adhesive used in an internal application, fibrin sealant, some clinicians have been seeking adhesive solutions to problems in the internal repair of the body, aiming to achieve excellent performance without the problems related to the use of the traditional mechanical means of repair such as localized fixation and the need for removal. Chemists and biologists have been keen to support them in this quest and have produced a wide range of different materials with the ability to bond one or more tissue types. Initial experimentation is performed on ex vivo tissue and many materials show some promise in that environment. The ability to bond is, naturally, essential, but is not the only requirement, and many systems which showed initial promise proved not to work when applied in vivo or gave too many undesirable side effects to be permitted for human use. Beyond that, other systems may be successful technically but not be of wide-enough application, or appeal to enough clinical users and purchasers, to be a commercial success and so may be withdrawn from the market. The technical, techno-commercial, and medical literature has many examples of initially promising materials which are not available for clinical use.

This section aims to describe some of the requirements for a tissue adhesive for internal application and then to give further details on the principal materials which are commercially available and clinically used (though not necessarily permitted in all countries). All materials are described generically as chemical species, without brand names and manufacturers’ details as these can frequently change and may also differ between countries, potentially leading to confusion. In addition, some of the more promising and distinct developments of potential novel surgical adhesives are described, though usually in less detail. There can be no guarantee that any of these will ever be successful, but it is to be hoped that some will and that further inventors may be inspired to come forward and test new ideas as the subject is still very much alive and there are still many unmet needs for this technology within the clinical community.

Requirements of an Adhesive for Internal Use

The body provides a very distinct environment in which to apply adhesives. There are therefore many special requirements placed on any material considered for this application. Internal use requires stricter provisions than for adhesives which are purely in contact with intact skin. First and foremost they have to be safe. Materials sticking to the body cannot contain chemicals which are toxic to the body or to the cells in their vicinity. In addition, the material must not cause sensitization either for the patient or for the user. Nor must it produce an immune response – rejection – from the body. Safety testing must be comprehensively performed before new chemicals are permitted in these applications.

As with any device or material intended for use in medicine, medical adhesives cannot be sold for clinical use without regulatory clearance from the relevant national authority. This is to ensure, as far as possible, the safety of the product for the designated indication or indications. Different countries impose different requirements on products, which also depend on the nature of the device or material and its intended use. These frequently require extensive testing, both preclinically on animals and clinically in carefully controlled studies on humans, as well as the provision of other safety data. Because of the different regulations, products may be found on sale in one country but restricted in others.

The material must not introduce organisms which might be harmful for the body or for the repair. It must therefore be intrinsically sterile (as produced) or capable of being adequately sterilized. Sterilization is performed by heat (autoclaving), chemical and heat (ethylene oxide), or ionizing radiation (gamma rays), all of which involve the application of much energy. This energy will often be sufficient to initiate chemical reactions, such as the curing of adhesives, so developers of medical adhesives have to include means of ensuring that the adhesives are protected from any possibility of this.

Clearly, a medical adhesive must be capable of reliable secure bonding of the tissue that is to be bonded. Not all tissue is the same. An early misapprehension in the development of medical adhesives was that one adhesive would work everywhere. Subsequent experience has proved that this is not the case. Different formulations have been developed for different tissue types. The moisture content, the fat content, and the protein and polysaccharide content differ, and bone also has mineral content (Duck 1990). It has been found that the strongest bonds occur when there is true chemical bonding to the substrate material (Wilson et al. 2005). Almost universally, the area to be bonded is wet, which is a challenge for many conventional adhesives, and even if it can be temporarily dried at the time of application, the bond will soon be wet again.

The bond must form rapidly as it is unsafe and inefficient for surgery to take longer than strictly necessary. In most cases, a surgeon will opt for a quick action rather than a prolonged surgery. However, it is possible for bonding to occur too rapidly, leading to fixation of an incorrect placement. Related is the concern over adhesive spills or leakage from the joint. It should ideally be possible to see and remove safely any adhesive which gets in the wrong place, though the nature of the adhesive and means of dispensing it should be designed so as to avoid this happening at all. Adhesive products are sometimes colored (usually with a shade of blue), so that they may be distinguished from the surrounding tissue. Figure 57.5 shows an example of this.

The purpose of most tissue adhesives is to hold the tissue together so that fluids (e.g., blood) do not leak and it is able to heal naturally. Healing may be a slow process, taking several days, so the bond must last as long as the process, ultimately degrading as the tissue is able to regain the necessary strength. Healing, though, will only occur if the adhesive has not formed a barrier to its progress. Several medical adhesives are therefore applied as “patches” or “sleeves,” bridging the gap in tissue, while not penetrating between the tissue surfaces (Fig. 57.1b ). The breakdown products of the adhesive must be safe to the patient and not harmful to the repair process. In general, this requirement is more likely to be met by adhesives of a biological origin, but synthetic and semisynthetic adhesives may also be safe, or the small quantities of material and slow release rate may lead to breakdown products being present in such small concentrations as not to be a problem. In a few cases, it may be necessary for the medical adhesive to provide a permanent fixation, and not to degrade away, if the tissue is not capable of regeneration.

As has already been indicated, packaging and delivery of the adhesive is of key importance. The packaging must keep the material sterile and, for multicomponent materials, separate. It must be easy to use, and, to remove the possibility of cross-infection by multiple uses, contain the volumes needed to achieve a single repair on one patient, although a second application may be needed in some cases. Application must be foolproof, simple (surgeons’ hands may be required to perform many functions), and permit accurate delivery with minimal spillage. Where two components are concerned, the way in which they are mixed, for example, through a mixing nozzle, multi-jet spray, or by sequential delivery, must be reliable and not lead to problems, such as premature setting, clogging the delivery.

Categories of Adhesives

Medical adhesives may be categorized in various ways. Clinicians would probably choose listing by the indications for which they may be used. In this chapter, adhesives have been divided into different groups depending on the similarities of the chemistry and technology. There are separate sections below for adhesives which are produced entirely by synthetic chemistry and for those of biological origin. Naturally, there is some crossover where synthetic molecules are used with biological products, and some “biological” materials are being produced by identification of the functional components of a natural product and then reproducing these by a synthetic route. Laser welding and soldering are somewhat different means of producing adhesion between tissues and are covered in a separate section.

Synthetic Adhesives

Cyanoacrylates

Cyanoacrylates are widely used in a range of engineering applications where instant strong bonding is required when using a minimum of adhesive material. The adhesive only requires a small amount of water on the surfaces in order to set off the polymerization reaction that forms the bond. These features are clearly attractive in a medical context, so it is not surprising that the use of cyanoacrylates in surgery (of small blood vessels) was attempted before 1960. A number of problems were then discovered which have led to only slow adoption over the intervening years, though recently this has gathered pace, particularly after 1998, when the US Food and Drug Administration (FDA) first approved cyanoacrylate products for specific indications, initially external to the body and, more recently, for a few very specific internal conditions.

The fundamental structure of a cyanoacrylate is given in Fig. 57.2 . The R group can be one of many different species, though usually alkyl, giving rise to a large family of different molecules with different properties. The adhesive is a low viscosity liquid which cures by anionic polymerization, and the process is exothermic. The reaction can be set off by hydroxyl ions, or similar chemistry, such as hydroxyl or amine groups present in proteins in the tissue surface. Thus, cyanoacrylate is capable of bonding covalently to the tissue surface (Wilson et al. 2005) which contributes, along with its ease of penetration into the structure of the surface before curing, to the very strong bonds which it can make to most tissue types (Chivers and Wolowacz 1997). The choice of alkyl group in the molecule is very important. Domestic and industrial “superglues” are usually methyl or ethyl cyanoacrylates. These were initially tried in medical applications and found to be unsatisfactory. The curing reaction was too fast, leading to tissue necrosis due to overheating and the rate of subsequent degradation was also too rapid (Woodward et al. 1965). Larger alkyl groups were found to be more successful and the most commonly used medical cyanoacrylates are currently n-butyl-2-cyanoacrylate and octyl-2-cyanoacrylate. In addition to these molecules, formulations include stabilizers to permit sterilization and to reduce the likelihood of polymerization during storage, and thickeners, usually poly(methyl methacrylate) (PMMA) or polymerized cyanoacrylate. The hardness and inflexibility of cured cyanoacrylate can be reduced by the use of other additives. Low curing rates of the octyl- monomer, which otherwise has the advantage of giving a more flexible polymer, can be improved by adding accelerators at the point of delivery.
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Fig. 57.2

The structure of a cyanoacrylate monomer. R can be selected from many different species; see text for details

In the early days of their use, medical cyanoacrylate adhesives received bad publicity due to tissue damage at the site of use. This may have been due to the exothermic curing reaction but may also have been due to the degradation products of the polymer (Leonard et al. 1966). Cyanoacrylates degrade hydrolytically by a reverse Knoevenagel reaction to formaldehyde and alkyl cyanoacetate. Concerns about formaldehyde released into the body have led to many considering it as the major cause of the problem, and several routes have been attempted to reduce the likelihood of its release by altering the chemistry or adding agents to capture it (e.g., Leung and Clark 1994). However, as formaldehyde release is only a potential problem within the body, cyanoacrylates have become widely used and approved as a topical means of skin closure in accident and emergency situations, where the adhesive is delivered across the laceration (not in between opposing edges) using careful control of the flow. This process is shown in Fig. 57.3 . The result can be good secure holding of the wound, excellent sealing to provide a barrier to microbial ingress, and also a good cosmesis after the adhesive has sloughed off the surface and the wound is healed (Quinn et al. 1997). Figure 57.4 shows a comparison of wounds from laparoscopic surgery closed using sutures and using cyanoacrylate. It is only recently that the US FDA has approved this application as a Class III device, for topical use only, initially in 1998 for octyl-2-cyanoacrylate and later (in 2002) for n-butyl-2-cyanoacrylate (Mattamal 2005).
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Fig. 57.3

Application of a cyanoacrylate adhesive to close a skin wound (Published with permission of MedLogic Global Ltd)

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Fig. 57.4

Comparison of wounds post laparoscopic surgery closed (a) using sutures and (b) with cyanoacrylate (Published with permission of MedLogic Global Ltd)

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Fig. 57.5

Use of a sprayed two-component hydrogel sealant during lung surgery. The sealant (in the lower middle of the picture) contains blue dye to enable the surgeon to see where it is and to judge the thickness of the application (Copyright © 2010 Covidien. All rights reserved. Used with the permission of Covidien)

Cyanoacrylates have been widely used experimentally in a great number of surgical procedures, particularly in eye and ear surgery, which are largely external to the body (Quinn 2005). One internal application has also been approved by the US FDA. This is for a formulation of which the major ingredient is n-butyl-2-cyanoacrylate. The application is for neurologic embolization in the skull (Mattamal 2005). It is, however, believed that cyanoacrylate adhesives are frequently used off-label for other internal conditions.

Modified Gelatin

An early commercial medical adhesive was made from gelatin, resorcinol and formaldehyde and is therefore known as GRF (Braunwald et al. 1966). The gelatin is a bioresorbable polymer which can be cross-linked with formaldehyde, and this may also crosslink to the tissue surfaces. Resorcinol can also be cross-linked by formaldehyde, making a stronger bond. However, on enzymatic degradation, the formaldehyde is released. The issues with formaldehyde which are perceived with cyanoacrylates are therefore also present here, but this has not stopped the material from being widely used, though not in the USA, particularly in aortic dissection repairs and also in liver and kidney surgery. The gelatin-resorcinol mixture is a viscous paste which has to be heated to 45°C before application and then mixed with an aqueous solution of formaldehyde, usually containing some glutaraldehyde as well, as it is delivered to the tissue.

Concerns about the formaldehyde have led to several modifications of this system. In a prominent commercial product, it is replaced by a mixture of glutardialdehyde (pentane-1,5-dial) and glyoxal (ethanedial) (Ennker et al. 1994a, b). This formulation is also used for aortic dissections.

A further alternative is to replace the gelatin with another protein, albumin, and an adhesive sealant is commercially available containing 45% albumin solution which is mixed with 10% glutaraldehyde solution as it is delivered to the repair site. This is successful particularly for hemostasis in cardiac and vascular surgery (Chao and Torchiana 2003).

Polyurethanes

Polyurethanes are formed from the reaction of diisocyanates and diols to make a prepolymer, usually a paste, which can then further polymerize in moist conditions to give a cross-linked strong material. As the body provides a moist environment for bonding, it is not surprising that many groups have attempted to make polyurethane adhesives for medical applications. Indeed, these were some of the earliest surgical adhesives to be explored and were considered particularly for bonding bone. Obviously, the materials have to be able to degrade to safe products, and therefore lactides and caprolactones have featured in the formulations. However, these have not made a commercial success, because of adverse reactions and because of difficulties in obtaining suitable reaction rates. Most are found to cure too slowly.

Recently, several new urethane systems have been developed with chain extenders derived from lysine or other hydrolyzable, bioresorbable molecules. These show promise for bonding layers of abdominal tissue together to reduce fluid accumulation (Gilbert et al. 2008) and for bonding small bones.

Synthetic Hydrogels

Much body tissue is effectively a hydrogel. Any adhesive used in the body has to be compatible with the high water content and mechanical properties of tissue, so it is not surprising that hydrogels have been widely used for tissue bonding and sealing. Many of these are based on poly(ethylene glycol) (PEG), which may be cross-linked by a number of means after derivatization to make these reactive, for example, with tetra-succinimidyl and tetra-thiol residues (Wallace et al. 2001), to give the necessary cohesive strength. Two-component systems have been commercialized for sealant applications, such as for incisions in the dura mater, lungs, and blood vessels (Bennett et al. 2003). The two components, PEG and a cross-linker, trilysine, both with reactive end groups and in separate solutions each with very low viscosity, are delivered together, often by spraying. The reaction is very rapid, producing a film which seals over the defect and bonds mechanically to the tissue surface by penetration of the precursors into its crevices, followed by curing. Figure 57.5 shows the result of application of such a system during lung surgery. The material breaks down over time in the body and the components are excreted.

Hydrogels may alternatively be cross-linked by derivitization with photocurable monomers. This has the advantage of curing only when the light is shone and the disadvantage of working only in “line of sight” of the light source (Sawhney et al. 1993).

A further series of experimental systems use an aminated star PEG cross-linked with dextran aldehydes. The aldehyde not only cross-links the PEG but also bonds chemically to the tissue surface, so varying the aldehyde content can give a range of bond strengths. It is claimed that this chemistry can thereby be tailored to create adhesives for different tissue types (Artzi et al. 2009).

Several workers have been attempting to mimic the performance of fibrins without the need to use blood-based materials with their attendant risks. These formulations include gelatin cross-linked with a calcium-independent microbial transglutaminase (McDermott et al. 2004) and other gelatin-based materials.

Other Synthetic Adhesive Materials

Most of the adhesives discussed here for surgical use are delivered in the form of one or more fluids which cure (react) on the tissue surface to produce a bond and also cross-link to develop cohesive strength. An alternative approach is to make a dry film which already has mechanical integrity and which is coated with materials which react on contact with the wet tissue surface to give a strong bond (Thompson 2009). This therefore has some similarities with the wound dressings which are discussed later in this chapter, but there are numerous differences as these commercial “patches” are intended for internal application for sealing leaks of fluid, for example, air leaks in the lungs and cerebrospinal fluid leaks through the dura. An example of this latter application is shown in Fig. 57.1b . A resorbable biocompatible film of poly(DL-lactide-co-glycolide) is coated with a layer of a terpolymer of polyvinylpyrrolidone (PVP), polyacrylic acid (PAA) and N-hydroxysuccinimide (NHS). This layer becomes rapidly hydrated on making contact with the tissue surface due to the presence of PVP. The PAA gives tack to the film, producing rapid adherence to the tissue, while the NHS is capable of covalent bonding to the tissue surface. A patch like this will degrade in the body over time with the degradation products being excreted, so leaving no residue.

Bone contains inorganic material, mostly calcium-containing minerals such as hydroxyapatite. Bone defects are often surgically filled with cements made of a variety of calcium phosphates which are found to enhance the healing of the bone. The bonding of the filler to the bone is mostly by mechanical interlocking, and therefore not very strong, but it has been found that some magnesium-containing mineral compounds can be used as adhesives, making stronger bonds to help with the initial fixation of the bone. These have been used, for example, in the fixation of bone-tendon grafts for the reconstruction of the anterior cruciate ligament (ACL) (Gulotta et al. 2008).

Glass ionomer cements have been used for some years in dentistry for bonding restorations to teeth. It has been found in certain circumstances that these can also be used for bonding bone, though as the current formulations contain acrylic polymers, these are not resorbable and can only be used in situations where the bond is intended to be permanent and not replaced by regrowth of the tissue. One such commercial application is for repair of the tiny bones in the ear (Tysome and Harcourt 2005).

Biological Adhesives

Fibrin

Fibrin adhesives have been used for longer than any other tissue adhesive, being first applied in the mid-twentieth century, although they were not sold commercially until 1978. Frequently referred to as fibrin sealants as their ability to seal leaks is more significant than their mechanical strength, they are widely used in a variety of surgical procedures, and more so in recent years after the approval by the US FDA of one product in 1998 for certain indications and a second product in 2003 (Spotnitz et al. 2005).

Fibrin adhesives contain several constituents. These are fibrinogen, thrombin, factor XIII and calcium ions (usually as calcium chloride) as well as fibrinolytic inhibitors, such as aprotinin, tranexamic acid, or aminocaproic acid (Sierra 1993). The fibrinogen and factor XIII are typically prepared from human blood sources, usually pooled from carefully screened donors and then treated to inactivate any viruses present (MacPhee 1996) either by cryoprecipitation and freeze drying or by solvent detergent cleaning, heat pasteurization and nanofiltration (Spotnitz et al. 2005). The thrombin and aprotinin are sometimes from human and sometimes from bovine sources. Recombinant processes are being sought for these materials. Some products contain the components as lyophilized powders and solutions that have to be mixed just prior to application, while others are supplied as a liquid to be stored at or below −18°C and then gently thawed before use. Fibrinogen may also be obtained by extraction from the patient’s own blood. This is known as autologous fibrin, and is prepared during surgery by taking blood before the operation and centrifuging it to extract fibrinogen. This is naturally somewhat time consuming but has the advantage of eliminating any chance of virus transmission. The viscosity of the preparation and low strength of the resulting adhesive are limitations of material from this source.

The chemistry of the process of formation of the adhesive material from the ingredients is given in Fig. 57.6 and resembles the final stages of the coagulation (clotting) of blood. Essentially, the thrombin cleaves fibrinopeptides A and B from the fibrinogen molecule to leave fibrin. This polymerizes to form a soft clot, which is cross-linked by the transglutaminase factor XIIIa, which is produced by the action of thrombin on factor XIII in the presence of calcium ions (Marx 1996; Webster and West 2001). The initial soft clot formation is relatively quick but produces a weak material. The cross-linking is a slower process, taking typically about 2 h, giving rise to a considerable increase in strength by formation of covalent bonds and possibly contributing some bonding to collagen in the tissue surfaces (Marx 1996; Donkerwolke et al. 1998). In addition, the cross-linking stabilizes the clot to proteolytic degradation by plasmin. It has been found that different concentrations of the different components can affect the time to cross-link and the strength of the resulting bond (Marx 1996). However, as the materials are of natural origin, it is not always possible to control the ratios precisely.
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Fig. 57.6

Schematic of the formation of fibrin adhesive from its ingredients. This occurs in-situ at the time of use

As a pure biological adhesive resembling blood clots, the fibrin adhesive is able to break down naturally in the body on a timescale resembling that for the tissue to heal (Lontz et al. 1996). Degradation typically occurs in about 2 weeks (Lauto et al. 2008).

Since the bond strength of fibrin adhesives to tissue is not very high (Chivers and Wolowacz 1997), the material is usually used as an adjunct to mechanical fastening such as sutures, hence frequently being referred to as a sealant. It has the advantage of excellent hemostasis and is hence very useful in applications where blood leakage is a problem. In the USA, regulatory approval has been given for several applications where its primary purpose is for hemostasis during surgery on internal organs such as the spleen and liver. It is, however, also used for controlling blood loss during many types of surgery, including orthopedic, and is excellent for sealing blood vessels after suturing and before the blood is readmitted. It may be used for sealing other vessels which do not contain blood, such as lymphatic vessels and the dura containing cerebrospinal fluid, and can be applied to air leaks in the lung, although the low strength of fibrin means that special care has to be taken in preparing and monitoring the seal. As an adhesive, fibrin has found application in plastic surgery, where it can be used to attach skin grafts to the underlying tissue, though care has to be taken to ensure that it does not act as a barrier to tissue integration under the graft. In these various applications, the bond is most effective if the tissue surfaces are as dry as possible when the fibrin is used, and care must be taken that the bond not be disrupted while cross-linking as pre-cross-linked fibrin can be effective as an antiadhesive (Spotnitz et al. 2005). One of the first applications of fibrin adhesive, one which is still used, is in nerve anastomosis.

An additional application of fibrin is as a delivery means for a variety of pharmaceuticals such as antibiotics, because of its ability to adhere to tissue and so deliver the drug locally, as well as its safe degradation pathways (MacPhee et al. 1996; Webster and West 2001).

Modified Fibrin

Attempts have been made by several workers to overcome the limitations of fibrin adhesives while maintaining the basic fibrin chemistry. These retain the basic components, unlike those synthetic mimics which have been mentioned above. One way of doing this is to mix fibrillar type I collagen into the fibrinogen/factor XIII solution. When formulated correctly, this enhances the viscosity of the initial solution and therefore its ability to stay at the site where needed, though still permitting easy delivery. In addition, the stiffness and strength of the cross-linked adhesive are enhanced, giving the material greater toughness and ability to withstand loads in use. Effectively it is a fibre-reinforced composite (Sierra 1996). This technology has been commercialized in a number of formats including: collagen and thrombin to mix with the autologous fibrinogen thus enhancing the otherwise poor properties of autologous fibrin adhesives, collagen fleece coated with lyophilized fibrin adhesive components ready to soak to activate as a patch, and collagen (gelatin) with thrombin which acts as a hemostat with the patient’s own blood (Oz et al. 2003).

Adhesives from Shellfish

The ability of shellfish, such as mussels and barnacles, to stick to underwater structures and remain stuck despite considerable mechanical disturbance, such as due to waves and tides, has long attracted scientists looking for candidate adhesives suitable for medical application where the substrates are wet, the temperature may be up to or over 37°C, and there is mechanical stress. Since many synthetic adhesives suffer from an inability to stick underwater, an adhesive material which clearly works in wet conditions becomes particularly attractive. Many shellfish-based systems have been assessed, but the most studied has been the byssus, or attachment thread, of the common mussel, Mytilus edulis (Waite 1987; Silverman and Roberto 2007). Adhesives (known as mussel adhesive proteins or MAPs) can be extracted from the mussels, but it takes a huge number to produce sufficient material for commercial use. Various groups have worked on the identification and synthesis of the essential components of the natural protein in an attempt to be able to produce a MAP without resorting to mussels. It has been found that one of the protein residues essential for bonding (initial chemisorption to the surface and then cross-linking of the adhesive) is 3,4-dihydroxy-L-phenylalanine (DOPA). Any material which resembles MAP will contain this. Genetic engineering may be a route to large-scale production of suitable proteins, but so far this has not succeeded in producing DOPA-containing MAPs. Synthetic analogs are being developed by several groups, for example, Yu and Deming (1998) prepared simple copolypeptides of DOPA with L-lysine which, when mixed with certain oxidizing agents, gave good bond strengths to several nonbiological surfaces. An alternative approach has been developed (Lee et al. 2006; Burke et al. 2007), in which the DOPA residues are chemically coupled to PEG molecules and crosslink these rapidly when mixed with suitable strong oxidizing agents. The PEG makes up about 80–95% of the formulation. Concern about the oxidizing agents required has led to two further developments: a DOPA-containing block copolymer gel which exhibits a sol-gel transition between room and body temperature and a DOPA-containing monomer (with an acrylate group) which can be photopolymerized (Lee et al. 2006).

Other Adhesive Technologies

The use of biological molecules has a number of potential advantages in resorption and biocompatibility, though not necessarily in immunogenicity. There is therefore an interest in finding and developing new adhesive systems from biological sources. Many of these are still in the research stage, far from commercialization, and are summarized below to give an idea of the range of ideas being considered.

Attempts are being made to produce proteins (resembling silk and elastin) using recombinant technology from synthetic genes. In this way, specific molecular structures can be constructed to have the desired biological effects, such as good elasticity and bonding to tissue surfaces in the body, while, it is claimed, not having the potentially undesirable side effects which can be shown by wholly natural materials (Cappello 1991).

A number of organisms produce adhesive materials that serve them in a variety of ways, including defense, attack, and to help create protection. As they are naturally produced, they are biocompatible and usually naturally degrade to safe molecules. They are also able to stick in wet environments. Several of these materials have been assessed for use as medical adhesives with promising results.

The sticky secretion from the back of frogs from the genus Notaden has been explored by workers in Australia (Graham et al. 2006). This exudate was extracted by stimulating the backs of the frogs and tested in peeling on ex vivo meniscal tissue. Bond strengths exceeded those produced by GRF and fibrin adhesives but not n-butyl-2-cyanoacrylate, and it was found that the adhesive functioned primarily as a pressure-sensitive adhesive (PSA) in that the strength was largely unaffected on breaking and reforming the joint.

Shellfish are not the only organisms using adhesives to ensure that they remain in place despite battery from waves and tides. Red and brown algae also produce adhesives, based on polyphenols, which can bond nonspecifically to both hydrophobic and hydrophilic surfaces under water. These have also been investigated, and synthetic analogues have been made which can successfully mimic this performance and are postulated as a soft tissue adhesive (Bitton and Bianco-Peled 2008).

A glycoprotein secreted by spiders onto webs to help catch prey is being considered as a possible biological adhesive for surgery (Choresh et al. 2009).

A challenge with any of these is the ability to obtain sufficient for commercial use. These materials are usually made by the organism in very small quantities and harvesting in bulk would be difficult. Preferred approaches are therefore either to identify the essential active molecules and synthesize these (as with mussel adhesion) or to find a way of producing these by using genetic engineering processes.

The mechanism of reversible adhesion used by geckos to walk on walls and ceilings is of interest to several research groups which would like to develop applications using synthetic mimics of this. Unfortunately, gecko adhesion, which is the result of van der Waals interactions between large number of nanoscale pillars and a surface, has been found not to be very effective in the wet, reducing its potential in medical applications. A possible way of overcoming this is being developed in which the nanoscale pillars, made of poly(dimethyl siloxane) (PDMS), are coated with a synthetic mimic of mussel adhesive: poly(dopamine methacrylamide-co-methoxyethyl acrylate) (Lee et al. 2007). The inventors believe that this could have applications as a temporary adhesive for use in the wet in medical settings.

Laser Welding and Soldering

The use of light to activate adhesives has been mentioned above offering the advantage that the time of activation is precisely controlled, but the disadvantage of only working in the beam of light. Alternative applications of “light” (including infrared and ultraviolet radiation) have been developed for the clinical bonding of tissue. These are known as welding when light alone is used and soldering when a material is cured with the light (Bass et al. 1996; Lauto et al. 2008).

When tissue is heated, the proteins in it coagulate to form a hard sticky mass. This is similar to the cooking of egg-white. A laser can provide a precise beam of infrared radiation to the edges of two pieces of soft tissue and can weld these together. This is a quick procedure and does not produce the damage that sutures can, but a hazard of this is that the tissue may become too hot and cells could be damaged. This can be reduced by applying a chromophore, which can preferentially absorb the radiation, converting it to heat. For the usual medical infrared laser wavelength of 808 nm, indocyanine green (ICG) is an approved, safe molecule with a maximum absorbance at the same wavelength.

Clinicians have generally found it preferable to apply a solder, a viscous solution of a protein such as albumin or fibronectin (Bass et al. 1996; Chivers 2000; Lauto et al. 2008). When mixed with ICG, this solder is applied over the tissue edges to be bonded and the area is irradiated with an infrared laser beam which is usually pulsed to reduce the net power delivered to the tissue. The enhanced absorption of the ICG enables the solder to reach the coagulation temperature of 65–70°C well before the tissue has become warm, and the proteins are believed to intermingle with the collagen in the tissue to give a relatively strong repair which can degrade naturally over a clinically acceptable timescale. Concerns over the difficulty of applying a runny liquid and keeping it in place and the possibility of it being diluted by water at the surgical site have led to the development of solid solders, strips and patches of high (>53%) albumin concentration, which can be laid on the tissue surface or placed as a short tube over a cut vessel to be resealed and then irradiated to create the bond. As an alternative to proteins, a similar material has recently been created using chitosan, a polysaccharide (Lauto et al. 2008).

Other, solder-free welding techniques have been reported. One uses Rose Bengal dye activated by laser light at a wavelength of 514 nm, and another a dye made of 1,8 naphthalimide which can be activated by blue light and bonds to tissue seemingly without any heating.

Adhesives for External Application to the Skin

Although cyanoacrylates are now being widely used in the clinic for the closure of skin incisions, as described above, the principal adhesives used on the external surface of the body are pressure-sensitive adhesives. These are the only significant adhesives used on the body in which the application is frequently not made by a clinician, as they are on first aid dressings and other products for home use.

Pressure-sensitive adhesives (PSAs) have long been used to hold tapes, dressings (Fig. 57.7 ), and other devices (e.g., electrodes and ostomy pouches) onto the skin. A further application of PSAs for skin contact is to deliver pharmaceutical agents by a transdermal route. Unlike most other applications of adhesives mentioned here, these are purely for topical use and are normally only in contact with intact skin. This greatly simplifies the regulatory process and permits a wide range of materials to be used in comparative safety. There are nevertheless some people who are sensitive to chemicals which may be used in adhesives and care must be taken to watch out for this in clinical practice.
https://static-content.springer.com/image/chp%3A10.1007%2F978-3-642-01169-6_57/MediaObjects/978-3-642-01169-6_57_Fig7_HTML.jpg
Fig. 57.7

High performance wound dressings can be held securely in place on the skin using a pressure sensitive adhesive (Image copyright by Smith & Nephew April 2010)

Early PSAs were usually rubber based, containing natural rubber which needs to be modified by the addition of tackifiers, lanolin, and mineral filler to optimize performance. A traditional tackifier is colophony resin (gum rosin), another natural material. A disadvantage of these materials is that they are very poor at handling moisture. These adhesives have to be physically modified, usually by perforation, so that there is not an excessive moisture build-up under a dressing coated with rubber-resin adhesive. Other disadvantages include the lack of resistance to shear, and a tendency to fail in the adhesive mass (cohesive failure), resulting in adhesive residues being left on the skin around a dressing while being worn, and after removal. A variety of materials have since been used to make more “skin-friendly” adhesives with better mechanical and moisture-handling capabilities. These include, principally, acrylics and silicones, but there are also poly(vinyl ether)s and poly(vinyl pyrrolidone)s for certain specialist applications (Webster and West 2001). Formulations are continually being developed to attempt to improve these further.

The process of assessing a PSA for use on skin is extremely complex and relies a lot on subjective assessment. Many properties must be considered and have been widely discussed in the literature (Satas and Satas 1989; Chivers 2001). These include the ability to stick securely and yet be easily and safely removed, the ability to stay in place for several days despite the movement of the underlying skin, and the ability to handle moisture and to “breathe” with the skin. Naturally the adhesive is not used alone and must perform successfully when coated on a suitable backing material, usually a film or fabric.

The ability to stick is obvious, as patient health, wound protection and cleanliness can be compromised by a lifting dressing. In contrast, a skin PSA must be able to be removed easily, minimizing discomfort to the patient and risk of damage to skin which may be fragile, as well as ensuring that the adhesive residue is not left on the skin. Peeling frequently removes a layer of dead skin cells from the skin surface. It is not known whether this contributes to the discomfort of dressing removal, but it can compromise the ability of the dressing to be repositioned as it can mask the adhesive. Frequent removal of dressings from the same site can cause reddening and even damage to the skin. For that reason, adhesives and systems have been developed which make removal easier (Chivers 2001). Some skin-friendly solvent products are available to help with this, particularly in difficult cases such as ostomy.

Shear of the adhesive is also undesirable as it can lead to dressings sliding from the site of attachment and leaving sticky residues exposed on the skin. These can fasten to clothing or bedding.

As already mentioned, the moisture handling is important, since human skin loses moisture in the form of water vapor at, typically, 200–500 g/m2/24 h and inability of any skin covering to cope with this leads to maceration, overhydration, of the skin. In extreme cases the dressing can come off if too wet, which it may also become if immersed in water, since the adhesives cannot stick in very wet conditions. Various ways of handling moisture are available – the formulation of the adhesive can help, but how it is spread on the backing is also important. Gaps may be deliberately produced in the adhesive film – by pattern spreading or perforations.

Developers of new formulations for medical PSAs have a range of in vitro testing methods which they use to help to evaluate these requirements. Ultimately, though, the performance of PSAs on skin is so subtle and subjective that only testing using the correct backing and on humans from the target population will give a true assessment of the acceptability of a new material.

Conclusions

Adhesives technology has two main applications in medicine as considered in this chapter: for internal fixation of tissues usually after surgery, and for use on the skin, primarily to hold dressings in place. There are many differences between the requirements of the technology for these applications.

Internal application is very carefully regulated as there is a need for extreme caution on safety grounds. Adhesives for this have to pass a series of tests before approval, and this may not be universal. Many chemical and biological systems have been tried and several are now in widespread clinical use. The appeal of an adhesive over the current mechanical means of fastening tissue has led many developers to attempt to create new materials from a range of sources. Some of these may be successful, but there is a long way to go in many cases.

Adhesive technology for external application is, by contrast, mature and many successful systems are available as the regulatory requirements are fewer. This has not stopped developers working to improve the existing products, and indeed to modify them for use on further dressing types and for other applications, such as for transdermal drug delivery.

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© Springer-Verlag Berlin Heidelberg 2011
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