The revolution in biomaterials
Where are the greatest challenges for materials scientists and engineers to be found? Professor Paul Hatton and Katie-Jo Harwood argue the case for biomaterials and explain the evolution of materials in medicine and dentistry.
Biomaterials is one of the most important and challenging areas for materials scientists and engineers. They must provide functional solutions that last for decades, often in difficult to access locations and where they might experience sustained mechanical loading and interaction with a biological environment with complex defence mechanisms intended to destroy foreign substances. They are used successfully in a wide range of clinical applications and modern medicine and dentistry would be impossible without a diverse array of ceramics, glasses, polymers, metals and composites with properties that assist them in performing the role of replacement body part when used correctly.
For many centuries, materials used to repair or replace human tissues were largely discovered by trial and error, or even luck. Until Victorian times, the majority of materials used in medicine and dentistry were obtained from nature – plants, animals and human corpses, often simply taken as direct substitutes for what was missing in the patient. Carved whalebone, ivory, wood, and cadaver teeth were all employed to provide body parts or to assist early clinicians in their practice. Dentists, in particular, were often in need of cadaver teeth for the manufacture of early dentures – it is well-documented that the dentition salvaged from the victims of the Battle of Waterloo flooded the European dental market in 1815. While these natural materials provided some utility, they were associated with many problems, including a foul smell as the dead tissues provided an excellent habitat for putrefying microorganisms. In addition, while dentistry had developed a long and sometimes successful partnership with this limited palette of materials, medicine and deeper surgery remained a largely unmet need on account of the need for other scientific advances.
The Victorian era heralded the first real advances in the development of synthetic materials for medicine and dentistry, paving the way for the future application of indwelling medical devices, such as the first use of metal plates for internal fracture fixation by Sir William Lane at the end of the 19th Century. Lane worked in a number of hospitals in London before his pioneering work on the use of bone plates. While infection rates were reported to be low, the primitive steel available to Lane suffered from corrosion (it would take a further 18 years for Harry Brearley to discover stainless steel, and longer still before this was adopted for surgery). Synthetic dental materials evolved sufficiently in Victorian times to effectively eradicate the use of natural materials and cadaver teeth, with dental amalgam eventually becoming established as a restorative material to replace tooth tissue damaged by caries in the 1850s and aesthetic porcelain crowns appearing at the end of the century (see page 40 for more on this topic).
After the Victorians
Scientific advances and an expanding clinical knowledge base increasingly informed innovation in biomaterials and accompanying surgical procedures, although luck, accompanied by a willingness to learn from personal observation, still had a part to play in the identification of new biomaterials. One remarkable example was the discovery of poly(methyl methacrylate), or PMMA, as an ophthalmic material by Harold Ridley. An eye surgeon in London during the Second World War, he noted that when aircrew were injured by shards of Perspex – a trade name for the high quality, transparent PMMA produced for aircraft – from shattered canopies, their eyes did not exhibit inflammation and a classical foreign body reaction. Ridley was sufficiently convinced by these observations to persuade St Thomas’ Hospital to undertake a series of cataract operations using intraocular lenses manufactured from Perspex. While it took many years to perfect the technique and persuade the medical community, intraocular lens implantation is now one of the most common ophthalmic surgical procedures.
During this period, the first mechanical heart valve was produced using a ball-in-cage design and implanted by Charles Hufnagel in 1952. The cage was formed using PMMA and the ball was nylon. This was followed by the surgical placement of the first implantable pacemaker in 1958 – a cumbersome device encased in epoxy resin. Shortly afterwards, the orthopaedic surgeon John Charnley pioneered low-friction arthroplasty using a stainless steel femoral component and a high molecular weight acetabulum, all held in place with a PMMA bone cement. This pioneering work had not gone well initially – one major setback was the selection of poly(tetrafluorethylene) or PTFE to manufacture the acetabular component, which failed because of its poor wear resistance. The choice of PMMA as a bone cement was, however, successful.
Changing the game
While this was a period of tremendous innovation that gave medicine and dentistry many of the medical devices in use today, it was beginning to dawn on the research and clinical communities that there was a need for improved biomaterials that could interact with the human body in some way that improved their performance, rather than simply space-filling in a way that did not irritate or harm the recipient. Moreover, medical ethics were also beginning to change – there is no doubt that many of the breakthroughs of the early 20th Century relied upon clinical interventions that would be classed as human experimentation today.
Clinicians always had a key role in biomaterials and related surgical innovation, but now scientists and engineers were increasingly playing a part. Alan Wilson and Brian Kent published their first description of a dental glass-ionomer cement (GIC) in 1971, arguably the first time a restorative dental material had been developed intentionally, using a scientific approach at the laboratory bench. The GICs actually interacted with tooth tissue in beneficial ways – for example, they adhered naturally to the mineralised tooth surface and they released fluoride that could protect teeth from caries.
By the 1980s, the concept of a biomaterial interacting with the body to produce a clinical benefit became firmly established. The bone bonding properties of hydroxyapatite, the mineral component of bone and tooth tissue, had been known for some time but it was too brittle for most devices and was difficult to process. The orthopaedic surgeon Ronald Furlong worked with an interdisciplinary team to overcome these challenges and implanted the first hydroxyapatite coated hip in 1985. Hydroxyapatite-coated implants could be placed without the use of PMMA bone cements, achieving stability by promoting local bone tissue recovery that locked the device in place.
Clinical thinking was starting to change, with the advent of new biomaterials that appeared to interact with the body to promote healing or other beneficial effects. It was also increasingly recognised that the best materials in the body were usually the patient’s own tissues, and interventions that conserved healthy tissues were therefore desirable. These observations informed the collective thinking of engineers, scientists and clinicians, and eventually gave rise to the twin concepts of tissue engineering and regenerative medicine. The essential goal of both of these approaches was to stimulate the body to re-form or reproduce healthy functional tissues to replace the damaged or diseased parts that were no longer functioning and/or had become painful. The modern field of biomaterials is therefore more complex than ever before, combining materials science with a diverse range of subjects including information technology, cell biology, nanotechnology, and clinical practice in order to develop and, ultimately, bring to market improved devices.
Redesigning the eye
The eye is one area where the challenges of biomaterials can be clearly identified. In an increasingly ageing population, maintaining healthy vision has become a major area of research and investment. In the past few decades, significant strides have been made in the development of a wide-ranging number of ocular implants, ophthalmic biomaterials and other biomedical devices that can actively correct and restore vision deficiencies caused by the effects of age, disease and trauma.
It is estimated that, in the UK, one in every 30 people will suffer some form of vision loss, and, on a global scale, more than 39 million people are registered blind (although this figure is likely to be higher, as a large number of cases in developing nations go unreported). The leading cause of blindness worldwide is cataract, with vision defections caused by diseases and trauma that affects the cornea second, and age related macular degeneration third in number of diagnoses. The development of ophthalmic biomaterials that could be used to treat such ailments is an ever-expanding field of research that could improve the quality of life for millions of people worldwide. However, the human eye is a complex organ, comprising a number of intricate components that are responsible for allowing light to refract and for images to be transported via electrical signals to the brain. As such, creating biomaterial-based contacts that could replace or restore lost functions of the eye presents a particularly challenging endeavour.
Materials that are traditionally used in other areas of the body such as metals and composites, while being appropriate in terms of their biocompatibility and sterilisation, are physically unsuitable for many ophthalmic applications. Most modern ophthalmic biomaterials research efforts are aimed primarily at a wide range of polymers, both synthetic and naturally occurring.
It is now widely accepted that cellular invasion and vascularisation (blood vessel formation) are desirable characteristics for full orbital implants, as they actively discourage bacterial colonisation and allow the treatment of infections. Therefore, modern implants are now largely based on porous materials such as polyethylene. Porous implants have a failure rate of around 10% after surgical implantation, but it has been suggested that this figure can be lowered even further by effectively wrapping the implant in autologous donor tissue.
In recent years, R&D has focused on a number of different manufacturing techniques that can produce a range of hydrogels and thin films that would be suitable for ophthalmic applications. Hydrogels are favourable because of their transparency, high water content and mechanical flexibility, but they have relatively low refractive indexes and therefore make poor substitutes for certain native tissues. Solvent-casting, melt moulding, freeze drying and phase separation have also been explored as a means of producing suitable ophthalmic biomaterials with some success. Electrospinning is a particularly promising manufacturing technique that can provide highly porous networks with potential for use as either cell delivery vehicles, or as part of a wider drug delivery system. However, one of the biggest issues associated with any of those production techniques is the inherent hydrophobicity of polymer materials.
Cells generally prefer hydrophilic surfaces, and so despite the advantages polymers present for ophthalmic applications (such as mechanical strength, flexibility and controllable degradation), they are still intrinsically flawed in their ability to stimulate cellular attachment. Despite this, polymers still represent an excellent material selection for ophthalmic biomaterials, and so research has shifted to focus on the functionalisation of polymers to improve their cellular affinities.
With the exception of contact lenses, most ophthalmic biomaterial alternatives are still very much in the early stages of development. Of these, the most successful clinically is undoubtedly the intraocular lens. Cataracts, despite being one of the biggest global issues impairing vision, are one of the most easily treatable. Cataract extractions and subsequent intraocular lens implantations are among the most frequent ophthalmic surgical procedures performed, with more than 1.6 million completed in the USA every year.
Outside of implantable devices, ophthalmic biomaterials have branched out to include those designed for the purpose of drug delivery. In situ forming gels, microparticulates and nanoparticles in particular are being extensively developed to facilitate the controlled release of drugs to damaged areas of the eye. Osmotic mini-pumps, biodegradable polymer matrices and biodegradable scleral plugs are also undergoing increased development for these systems. As elsewhere in biomaterials, much current research focuses on encouraging the regrowth of a patients own native tissues, with the idea being that it will reduce the need for revision surgeries and extensive after-patient care and, most significantly, prevent an immune reaction to implanted devices.
As the world’s population ages further and research and development becomes more advanced, many clinicians and scientists can foresee a future in which ophthalmic biomaterials will play a key role in treating vision loss. As such, it is critical to carefully consider the challenges that developing ophthalmic biomaterials presents so that scientists, engineers and clinicians can work together towards developing protocols and systems that can help restore sight.
Biomaterials and medical devices today represent a remarkable success story, where millions of people worldwide benefit from longer and healthier lives as a result of the endeavours of these scientists and clinicians. Modern biomaterials are provided by a high quality manufacturing industry that turns ideas and laboratory discoveries into medical advances that are remarkably safe and effective to use. The modern innovation community is a complex ecosystem, in many ways far removed from the descriptions of pioneering individuals mentioned here.
Undoubtedly, however, we still need more innovation. Materials science has a significant part to play in this process, and biomaterials still provide many advantages over more complex and potentially risky approaches to tissue repair and regeneration. That said, progress will not be made without both investment and the recruitment of the brightest talent into our innovation ecosystem.