A sticky situation - bone adhesives
David Farrar, Science Manager for Biomaterials at Smith & Nephew Research Centre, York, UK, gives an update on the development of bone adhesives.
If we break a favourite vase at home, we reach for a tube of glue to fix the complex set of fragments confronting us. So why not apply this principle to bones in the body?
There are a number of reasons why surgeons might want to use a glue to fix a broken bone instead of the conventional metal plates, nails, pins and screws. A glue would provide a simple and quick method of fixing fractures, particularly highly comminuted fractures where there may be many small fragments that are difficult to fix by conventional means.
An adhesive would also be invaluable for fixing fractures around articulating surfaces, where reduction using metal implants can be difficult without interfering with the joint’s functioning. Furthermore, a fracture fixed by a biodegradable glue would not require removal of metal implants, while a bone adhesive could also be a useful adjunct to such implants, allowing the surgeon to pre-assemble the pieces of the jigsaw, but still apply metalwork to carry the load.
So it is surprising that there are no real products that describe themselves as bone adhesives. There are many cements and void fillers but none of these claim any adhesive properties. The best known of these products is poly(methyl methacrylate) (PMMA) bone cement that has long been used for attaching implants such as hip and knee replacements into bone. However, this material just acts as a grout between the implant and bone and any attempts to use it to glue bones have generally been unsuccessful.
Developing a glue represents a particular challenge. Some of the requirements include -
- High level of adhesion to wet surfaces, often in the presence of other contaminants, such as fats and proteins.
- Easy to prepare and apply.
- Rapid setting time.
- Non-toxic and biocompatible.
- Biodegradable in a controlled manner and/or otherwise does not prevent bone healing.
- Sterilisable and with adequate shelf-life.
When these requirements are taken into account few, if any, available adhesive systems are suitable.
Previous developments in bone adhesives can be roughly classified into two groups – synthetic and biologically-derived and/or inspired.
Biological adhesives, including fibrin glue and gelatine-resorcinol-formaldehyde, tend to have good biocompatibility and biodegradability, but relatively low adhesion to bone. They have been more successful as soft-tissue adhesives and sealants.
More recently, a promising approach has been to develop adhesives that are derived from or inspired by ‘glues’ produced by marine animals, such as mussels, or so-called sandcastle glue produced by the marine worm P. californica. However, this research is at an early stage and is not ready to be implemented.
Synthetic adhesives that have been considered for bone include PMMA, cyanoacrylates, polyurethanes, epoxy resins and calcium phosphate cements. These tend to have better adhesion strength, but often poor biocompatibility, and many are not biodegradable. Again, some of the more recent developments in polylactide-methacrylate composites and magnesium-based cements appear more promising, but are at early stages.
The Smith & Nephew Research Centre in York, UK, is currently involved in a collaborative project funded by the UK’s Technology Strategy Board, which explores glass-ionomer cements modified for orthopaedic use.
Glass-ionomer cements (GICs) comprise a polyacid component, typically poly(acrylic acid) with a bioactive glass. The polymer and glass are initially in powder form and, when mixed with water, the carboxylic acid groups on the polymer dissociate and metal ions are released from the glass into the acid solution. Here, the metal ions interact with the acid groups on the polymer chain creating crosslinks. The cement then sets to form a hard composite material.
Importantly, for developing a bone adhesive, the acid groups on the polymer are able to bind onto other positively charged ions, such as calcium, which is found in the hydroxyapatite mineral phase of the bone (see diagram).
Unfortunately, GICs have drawbacks for use as bone adhesives. The glass components contain aluminium, which is released from the cement and aluminium is thought to interfere with normal bone healing, rendering such materials undesirable for applications in orthopaedics. Also, the cements currently used are not biodegradable. This is a problem for a bone adhesive where we do not want the glue to permanently block bone healing. The Novel Bioadhesive Cement (BIOAD) team, a consortium to develop a bone glue, has therefore had to reformulate GIC with modified glass and polymer components.
Another challenge is in handling setting properties. Unlike glues squeezed out of a tube, GICs require proper mixing of the powder and liquid components. This takes some time, and the surgeon requires the cement to have adequate working time during which he mixes and applies it. Surgeons will not tolerate long periods of waiting while the glue sets once the pieces of bone have been brought together – this is particularly true if the fracture is highly comminuted with many fragments requiring fixation. The BIOAD team has therefore also been exploring ways of presenting and delivering the cement, by activating the adhesive in situ.
The challenges of developing a bone adhesive have turned out to be even greater than envisaged at the start of the project, however, significant progress has been made, such as developing an aluminium-free formulation and exploring the use of a biodegradable polymer component. With this, and other developments going on in different labs around the world, it is an interesting time for research in this area.
David Farrar, Smith & Nephew Research Centre, York Science Park, Heslington, York, YO10 5DF, UK. Tel: +44 (0) 1904 451000. Email: firstname.lastname@example.org