Adhesives and sealants in medicine, dentistry and pharmacy - a review of materials and applications- Part I

TWI Bulletin, January/February 2002

Mehdi Tavakoli received a BSc in Chemistry and an MSc and PhD on Polymer Science and Technology at Aston University in Birmingham. He joined TWI in 1989 and has been working on new joining and associated technologies with particular interest in joining and coating of medical and implantable devices. He has over 20 years research, industrial problem solving and product development experience on polymeric materials and has published more than 40 papers and patents and is currently working as Technology Manager on polymers/adhesives at TWI.

The use of natural and synthetic polymers in a variety of medical applications has increased in recent years. As Mehdi Tavakoli reports, medical polymers with their diverse and unique specific properties offer many new applications as adhesives, sealants and coatings in medicine, dentistry and pharmacy.

The use of adhesives for joining medical and implantable devices was recently reviewed. ^[1-3] The purpose of this article is to provide a review of polymers, particularly adhesives and sealants that are suitable for tissue bonding, bone repair and those used in dentistry and pharmacy.

Tissue adhesives

For many years the closure of human skin has been achieved using needles and thread. Many types of suture materials, such as cotton wool-fibre, linen, animal sinews and more recently synthetic polymers such as nylon and dacron have been used with varying success. In recent years surgeons have become increasingly interested in replacing conventional sutures with tissue adhesives for several reasons: ^[5]

• Ability to both bond and seal the tissue, therefore preventing seepage of body fluids.
• Rapid bonding of tissue in seconds.
• Possibility of precision bonding without deformation of the tissue.
• Possibility for improvement in the repair of tissue affected by age and disease where suture methods are difficult.
• Ability to bond and seal tissues in inaccessible areas of the body and to reduce infection.
• Tissues ( eg facial skin) closed with adhesives may only leave invisible scars and do not cause 'zipper effect' (due to the needle puncture pattern on either side of the wound) which is associated with the use of sutures.

Butyl cyanoacrylates are typically used in tissue adhesives because of their lower volatility and non-toxicity compared to methyl and ethyl cyanoacrylates. Cyanoacrylate adhesives are usually stabilised using a weak acidic inhibitor. Moisture available on the skin or in the atmosphere can neutralise the inhibitor and start anionic polymerisation reactions.

Pressure-sensitive acrylic adhesives are used for contact with skin ^[6] in many applications like nicotine patches and wound dressings. The main types of acrylic resins used in these systems include; 2-ethylhexyl acrylate, isooctyl acrylate or n-butyl acrylate copolymerised with polar functional monomers such as acrylic acid, methacrylic acid, vinyl acetate, methyl acrylate, n-vinylcaprolactam, or hydroxyethyl methacrylate. It was shown ^[6] that functional comonomers increase cohesive strength, provide surface polarity, and enhance wear performance.

Degree of adhesion to skin, tackiness, adhesive transfer to skin, and wear performance of the adhesive are governed by glass transition temperature, molecular weight, and viscoelastic behaviour of the adhesive. It was concluded that wear performance behaviour of acrylic adhesive tapes on skin was governed by surface energy of skin and surface energy and viscoelastic behaviour of adhesive. Polar comonomers incorporated into the adhesive formulation increased interfacial interactions with the dynamic skin surface resulting in improved adhesion during sweating when the skin surface energy is higher.

Pressure-sensitive adhesives (PSAs) for medical applications are required to do far more than simply provide good adhesion to skin. One of the ideal requirements of medical adhesive tapes is to provide a controllable degree of adhesion to skin on demand - strong adhesion during use and ease of removal after use. This type of PSA can be used with little or no trauma to the patients. This is particularly important in elderly patients with fragile skin or repeated applications to the area of skin ( eg in ostomy devices).

Medical grade adhesives have been developed where their adhesion is 'switched off' on exposure to visible light. ^[7-8] A methacrylate functional PSA has been synthesised which, when blended with a visible-light curing photoinitiator, becomes light sensitive and can undergo crosslinking reaction by a free-radical mechanism of vinyl groups. This process lead to a considerable reduction (up to 90%) in peel forces of the adhesive and a change from a tacky to a less tacky, or even non-tacky, state, thereby providing the possibility of trauma-free removal.

One of the well known tissue adhesives for rapid closing of wounds and lacerations intended to replace sutures or staples is under the trade name of Indermil ^TM. ^[9] This is a clear, non-pigmented adhesive based on n-butyl cyanoacrylate. It is applied to a wound site after the edges have been carefully aligned next to each other by hand or by using skin-hooks. The adhesive polymerises within seconds to bond and seal the skin together. The application and effects of Indermil ^TM on closing of a wound in different stages of wound repair are shown in Fig.1.

• 2-arylamido methyl 1-propane sulphonic acid
• vinyl succinimide
• glycidyl acrylate
• 2-isocyanatoethyl methacrylate.

It was shown that these bio-adhesives can provide UV-induced rapid curing of about three minutes and improved adhesion values (180° peel strength of up to 4.6 N/m on porcine intestine samples). The photoinitiator used was based on hydroxycyclohexyl phenyl ketone (C ₁₀H ₁₆O ₂, Irgacure 184). It was also shown that the fully hydrated bio-adhesives exhibit high water uptake and equilibrium water content ranging from 20 to 100 wt%. It was suggested that the developed bio-adhesives have a strong potential for many medical applications, such as single-layered hydrogel wound dressings and as tissue adhesives.

The use of a new type of cyanoacrylate in neurosurgery, particularly in brain surgery, has also recently been reported. ^[11] The new adhesive contains a radio opaque agent which enables neurosurgeons to see the adhesive on an x-ray screen and apply the adhesive on the trouble spot, deep inside the brain, using minimally invasive surgical procedures without opening the skull. In this case the cyanoacrylate adhesive is used to treat a condition called arterio-venous malformation or AVM (clump of blood vessels in the brain). In some patients an AVM could burst, haemorrhaging blood into the brain and causing a stroke. During the treatment, the cyanoacrylate adhesive is delivered to the relevant spot in the brain ( Fig.2) using a catheter inserted into the patients groin inside the large artery. Neurosurgeons position one end of the catheter next to the AVM, put a small drop of surgical adhesive in the other end and push it along the tube with air pressure. The adhesive is delivered to the clump site and quickly polymerises as a result of moisture absorption from the surrounding area. As a result of curing of the adhesive, the whole clump converts to a small lump very rapidly which can no longer burst and cause a stroke. The treatment is performed in several hospitals in the UK.

Most recently, development of a new bio-adsorbable cyanoacrylate-based tissue adhesive containing bio-adsorbable copolymers has been reported. ^[12] The copolymers are preferably derived from:

Fibrin

Although the use of fibrin-based adhesives/sealants is very old, the first commercial products prepared from pooled plasma (plasma pooled from volunteers) only became available in the 1980s. The major challenges to suppliers of pooled fibrin adhesives/sealants have been: product availability, cost, ease of use, product consistency, regulatory approval and product safety. With respect to product safety, the risk of viral transmission remains the major concern. Potential applications for fibrin adhesive/sealant include their use as a biocompatible adhesive in plastic, reconstructive or in neurosurgery as well as prevention of fluid and blood loss from burns and traumatic injuries.

Muscle adhesive protein

Gelatine-resorcinol-formol

Bone adhesives

Materials and applications

Total joint replacements have improved the quality of life for thousands of people over the last quarter century. Debilitating diseases such as osteo and rheumatoid arthritis, avascular necrosis, bone cancer and trauma can be treated using prostheses. The surgery reduces or eliminates pain and patients dramatically regain mobility and functionality of their joints.

An up-to-date review of bone cements and related issues has recently been published. ^[13] Whereas the clinical objective of joint replacement is pain relief and increased joint motion, the engineering objective is to provide as physiologic a stress as possible to the remaining bone, so that the integrity and functionality of the bone and prosthetic materials are maintained over more than 10 years service life. Materials suited for joint replacements are those that are well tolerated by the body and can withstand cyclic loading in an aggressive environment.

The most common joint to be replaced in the UK is the hip joint with approximately 50 000 hip replacements performed each year. A normal hip joint is shown in Fig.3.

A hip joint consists of the ball shaped end of the femur fitting into a socket or acetabulum. Thus it is called a ball and socket joint and allows movement in all directions. A total hip replacement involves the removal of the femoral head at the base of the neck, the insertion of a femoral prosthesis and the enlarging of the acetabulum to receive an acetabular cup.

The mechanical properties of these materials along with those for poly(ethylene), acrylic bone cement and bone are shown in Table 1. The values of mechanical properties of bone are highly dependent on both source and conditions of testing and quoted values are approximate. It can be seen that the properties of PMMA cement are intermediate between those of cortical and cancellous bone.

Table 1: Mechanical properties of implant materials ^[16-17]

Bone fracture fixation and associated techniques

• Mechanical interlock, achieved by press fitting the implant, ^[18] by using PMMA as a grouting agent, ^[19] or by using threaded components. ^[19]
• Biological fixation using textured or porous surfaces which allow bone to grow into the interstices. ^[20]
• Direct chemical bonding between implant and bone eg coating the implant with HA. ^[21]

The most common method of securing prostheses, particularly in patients over 60 years of age, is to use autopolymerising PMMA bone cement. ^[22] This cement is mixed in surgery until it becomes a doughy consistency. It is inserted into the cavity between the prosthetic stem and the cortical bone of the femoral shaft, where completion of the polymerisation takes place. The implant is secured by mechanical interdigitation between the cement and (trabecular) bone, illustrated in Fig.4a.

Fixation with bone cement creates bone-cement and cement-implant interfaces, and loosening may occur at either one. Problems may arise from intrinsic factors such as the properties of PMMA and bone, as well as the extrinsic factors such as the cementing techniques.

As an alternative to cemented fixation, in an attempt to improve the long term performance of hip replacements, particularly in young patients, uncemented fixation relies upon the biological tissues ingrowing into the porous outer layer of the prosthesis to achieve a mechanical interlock. Figure 4b shows a fully ingrown uncemented prosthesis. Bioactive ceramic coatings such as hydroxyapatite, are used to encourage bone ingrowth right into the porous coating.

Characteristics of bone cement

Poly(methylmethacrylate) is an amorphous polymer, hard and brittle at room temperature, with a glass transition temperature of 105-120°C. This forms the main matrix ingredient of bone cement. The greater proportion of the cured cement, approximately 70%wt, consists of preformed polymeric beads, which usually come in the form of a powder of PMMA. Benzoyl peroxide is also present in small amounts, up to 2wt% in the majority of powders, acting as the initiator for polymerisation. In order to obtain the doughy, easily manipulated material, the powder is mixed with the liquid component consisting primarily of methyl methacrylate (MMA) monomer, 97vol%. The structure of the methyl methacrylate monomer unit is shown in Fig.5a.

Despite alterations to the basic PMMA powder composition, the reaction mechanism which occurs remains the same. Polymerisation proceeds as a result of the redox reaction which occurs between the initiator benzoyl peroxide (BPO, Fig.5b) present in the polymer powder and the accelerator, N-N-dimethyl-p-toluidine (DMPT, Fig.5c) included in the monomer liquid.

Polymerisation of the monomer is an exothermic reaction and the temperature in the centre of the bone cement can exceed 100°C. A typical temperature versus time profile is displayed in Fig.6. Time is recorded from when the liquid monomer is added to the polymer powder. Setting times and peak temperatures are not included in Fig.5 since they vary greatly for each commercially produced cement.

The time relationship between the physical and chemical processes occurring are of importance to the orthopaedic surgeon. The surgeon has approximately seven minutes of working time to mix the cement and inject it through a cement gun into the body. Alterations in processing such as pressurisation, vacuum mixing, centrifugation or fibre reinforcement must be implemented within the constraint of this working time. Once injected, the cement must be able to penetrate into the interstices of trabecular bone.

On the temperature profile shown in Fig.5 the dough time is indicated. This is the time from initial mixing when the cement no longer adheres to a gloved finger placed into the mixture and is the time when surgeons can start to insert the cement. The working time is the period during which the bone cement mixture remains doughy or workable. The limit of this period, the time it takes for cement to reach the mid point between the peak and ambient temperature, is known as the setting time and is used as a comparison for differences in setting characteristics of the various commercial cements.

Commercial bone cements

There are a number of commercially produced bone cements used in surgery at present which include, Surgical Simplex P, Palacos R, CMW (Type 13), Zimmer (Regular and Low viscosity) and Sulfix. ^[14] For each of these cements, the powder to liquid ratio is approximately 2:1 by weight and is supplied in 40g packets of powder and 29g vials of monomer. The cements do not always contain pure PMMA beads and MMA monomer, but deviate significantly from this composition to provide the bone cement properties required. The various modifications include the addition of radiopaque material usually barium sulphate (BaSO ₄) or zirconium dioxide (ZrO ₂), the initiator BPO and the accelerator DMPT. In the case of CMW and Zimmer there is also the option of low viscosity for use with a cement gun. The cement compositions have been changed over the years and are usually a well guarded secret of the manufacturers, so the values quoted in Table 2 may not reflect the compositions of the cements used today.

Table 2: Composition of common commercial bone cements ^[15]

Some of the important cement mechanical properties are given in Table 3. These results were obtained by a variety of methods, thus making it difficult to obtain a comprehensive chart of all properties of interest which can be directly compared.

A new research project has started at TWI and Cambridge University ^[14] to develop and assess the new generation of bone cements. The main aim is to develop an injectable bone cement for fracture fixation. A range of methacrylate materials and bioactive fillers will be investigated with appropriate rheological, structural, mechanical and biological characterisation.

Table 3: Mechanical properties of common commercial bone cements (adapted from ref. ^[17] )

Acknowledgements

Adhesives and sealants in medicine, dentistry and pharmacy - a review of materials and applications - Part II

References