Implants have been used for thousands of years, from documented cases of Egyptians replacing appendages with wooden prostheses, to the insertion of the first pacemaker in the 1950s, which lasted only 7 days. Since then, huge advancements to extend the lifespan of medical devices have been made and millions of procedures are performed each year, such as cochlear implants, cardiac valve replacements, orthopedic procedures, and reconstructive or cosmetic implants. One study has suggested that in North America, approximately 10% of individuals have some type of medical implant. However, medical devices undergo degradation within the body as both the host and the device age. The effect the body has on the device – and the effect that the aging device has on the body – are important mechanistic questions in this fast-growing industry, not only to improve how these devices function, but also to help mitigate the number of secondary procedures and complications that can arise.
The materials used to engineer medical implants need to withstand the highly electrolytic and oxidative environment of the body, remain chemically inert, maintain structural integrity under mechanical wear, and last for the entire life of an individual, all without inducing inflammation, hypersensitivity or cancer. There can also be additional constraints for certain implants depending on their intended function; for example, shunts, which contact the blood, must be designed so as not to induce thrombosis and fibrosis within the vessel.
Biomaterials fall into three main categories, namely metal alloys, polymers and ceramics. Each material has specific uses, advantages, and disadvantages based on their effects on and interactions with surrounding body tissues as well as their ability to withstand mechanical stress. In practice, materials are often used in conjunction to take advantage of the benefits of each material.
Titanium, chromium and cobalt are the most commonly used metal alloys and are typically used in load bearing implants such as knee and hip replacements and temporomandibular implants; they are also often used for the housing of cardiac implants, such as pacemakers. They are relatively inert but are subject to corrosion over time and have limited tissue integration capacity. Corrosion is an issue not only because the device integrity is compromised but also because it causes a release of small metal particles into the body. According to some studies, this can result in the activation of tissue resident macrophages and the induction of pro-inflammatory cytokines such as TNFα and IL-6. In addition, this can influence the surrounding tissue microenvironment and drive the release of pro-inflammatory cytokines and induced nitric oxide synthase (iNOS). Corrosion of metal surfaces can also result in systemic symptoms such as dermatitis and anemia. The inflamed tissue and released microparticles can then contribute to an osteolytic cycle on the load bearing surface, resulting in aseptic loosening of the bone away from the implant surface. This often results in patients requiring revision procedures. To combat these weaknesses, these devices are often coated with polymers such as polyurethane or silicone; however, wear of the coating itself remains an issue.
Silicone remains one of the most highly used polymers for medical implants. It is used for a variety of purposes, including tracheal, facial, reconstructive and cosmetic surgeries. Silicone is a siloxane polymer that can range from a liquid to a gel to an elastomer-type material depending on the polymer length. It is typically considered to be biologically inert and is posited to have a high level of tissue integration. When used as a scaffolding material, it is also thought to be highly bioactive, as tissue can integrate with the silicone scaffold.
It is not well understood how silicone breaks down in the body; however, there is some evidence that small microparticles may leak from implants. Although most commonly associated with breast implant leakage, “siliconosis” can occur due to any silicone implant and the risk increases as the device ages within the body. In recent literature, siliconosis has been described as an autoimmune syndrome induced by adjuvant (ASIA). It is hypothesized that macrophages and other phagocytic antigen presenting cells ingest silicone microparticles and traffic into surrounding tissues and lymph nodes. There is also interaction with TLRs, initiating assembly of the NALP3 inflammasome and activating both innate and adaptive immune cells. However, these reactions to silicone are rare and the development of rheumatic disease in association with silicone implants remains highly controversial. Many studies argue that removal of the implant results in resolution of the disease because the source of antigen has been removed. In addition, it is well documented that silicone implants have been linked to specific types of cancer. In France, the health administration mandates that all silicone breast implants come with a cancer warning. Cancers found in these patients are often rare lymphomas such as anaplastic large cell lymphoma (ALCL); however, both B and T cell lymphomas have been found at the site of breast implants, pacemakers and intraocular prostheses. It is posited that this may be correlated to long lasting chronic inflammation occurring at the implant site. Importantly, risk of developing silicone-associated secondary illnesses is influenced by genetic and environmental risk factors. Certain individuals may be more genetically susceptible to silicone related complications due to autoimmunity or cancer associated genes. While silicone may provide a constant source of antigen or alter the surrounding tissue microenvironment, altered gene expression contributes to the development of a chronic disease state. In addition, environmental risk factors such as smoking or transient infections may contribute to the disruption of immune homeostasis, potentially resulting in activation of a chronic immune response and in the development of ASIA or silicone associated cancers.
CERAMICS AND GLASS
Ceramics and glass are highly advantageous as biomaterials since they are stable in the body and do not break down even in response to repetitive friction forces. Some ceramics can also be bioactive, as their porous nature and chemical composition are conducive to host integration. They are commonly used for dental implants and non-load bearing orthopedic implants; however, widespread use remains challenging as these materials are rigid and susceptible to breakage due to sheering forces and cannot be used for load bearing applications. To circumvent fragility, composite materials have been developed that combine the rigidity of metal alloys with the stability and bioactivity of ceramics. In addition, these composite materials can be engineered to closely resemble natural bone by generating scaffolds or using specific coatings such as fibronectin. This encourages rapid integration of the bone and faster tissue healing in comparison with current ceramics. Eventually, composite materials could be designed to completely integrate with host tissue, rendering the host-implant interface indistinguishable.
EFFECT OF THE AGING BODY ON IMPLANTS
Not only do medical devices age in specific ways in the harsh environment of the body, but we age with our devices. As we age, cells become immunosenescent, are slow to respond, and are often functionally dysregulated. It has been documented that macrophages in older animals convert from an M2 to an M1 phenotype, resulting in chronic inflammation of the surrounding tissue. Due to implant aging and material leeching into the surrounding environment, as well as the chronic inflammatory response, changes are induced in the surrounding tissue microenvironment. These alterations cause tissue invasion of fibroblasts, resulting in fibrosis, limited tissue remodelling and changes to the extracellular matrix, and can have a variety of negative effects on implant success depending on the type of device. Given that a huge proportion of the aging population has or will receive implants, these cellular changes are an important consideration when engineering new implants.
While the field of biomaterial engineering is far from perfect, there are some amazing new advances that will hopefully limit the deterioration of aging biological devices. These include the use of nanotechnology to improve the surface integrity of titanium oxide, 3D-printed scaffolds seeded with stem cells to promote tissue integration and organ regeneration, and coatings modified using UV light to improve the integrity of certain materials.
Finding materials that meet all the criteria for use in a medical implant is uniquely challenging. Understanding mechanical and chemical wear, as well as what happens to components within the body as they break down, is critical to developing improved materials. In doing so, we can hopefully slow the clock on aging biomaterials, extending their lifespan well beyond our own.
- Vera-Lastra O., G. Medina, M. D. P. Cruz-Dominguez, L. J. Jara, and Y. Shoenfeld. 2013. Autoimmune/inflammatory syndrome induced by adjuvants (Shoenfeld’s syndrome): clinical and immunological spectrum. Expert Rev. Clin. Immunol. 9: 361–373.
- Mel, A. De, B. G. Cousins, A. M. Seifalian, F. Hampstead, N. H. S. Trust, P. Street, and L. Nw. 2012. Surface Modification of Biomaterials: A Quest for Blood Compatibility Interactions: Thrombogenicity. 2012.3.
- Jiri Gallo, Stuart B. Goodman, Yrjö T. Konttinen, Markus A. Wimmer, and M. H. 2013. Effects of aging upon the host response to implants. Acta Biomterials 9: 8046–8058.
- Gibon, E., L. Y. Lu, K. Nathan, and S. B. Goodman. 2017. Inflammation, aging, and bone regeneration. J. Orthop. Transl. 10: 28–35.6.
- Manivasagam, G., D. Dhinasekaran, and A. Rajamanickam. 2010. Biomedical Implants: Corrosion and its Prevention – A Review. Recent Patents Corros. Sci. 2: 40–54.7.
- Navarro, M., A. Michiardi, O. Castan, and J. A. Planell. 2008. Biomaterials in orthopaedics. J. R. Soc. 1137–1158.
- Parithimarkalaignan, S., and T. V. Padmanabhan. 2013. Osseointegration: An update. J. Indian Prosthodont. Soc. 13: 2–6.8.9.
- Mallela, V. S., V. Ilankumaran, and S. N. Rao. 2004. Trends in cardiac pacemaker batteries. Indian Pacing Electrophysiol. J. 4: 201–212.10.
- Dai, X., G. Hong, T. Gao, and C. M. Lieber. 2018. Mesh Nanoelectronics: Seamless Integration of Electronics with Tissues. Acc. Chem. Res. acs.accounts.7b00547.11.
- Joung, Y.-H. 2013. Development of Implantable Medical Devices: From an Engineering Perspective. Int. Neurourol. J. 17: 98.12.
- Bizjak, M., C. Selmi, S. Praprotnik, O. Bruck, C. Perricone, M. Ehrenfeld, and Y. Shoenfeld. 2015. Silicone implants and lymphoma: The role of inflammation. J. Autoimmun. 65: 64–73.13.
- Brown, B. N., M. J. Haschak, S. T. Lopresti, and E. C. Stahl. 2017. Effects of age-related shifts in cellular function and local microenvironment upon the innate immune response to implants. Semin. Immunol. 29: 24–32.14.
- Iwasa, F., N. Tsukimura, Y. Sugita, R. K. Kanuru, K. Kubo, H. Hasnain, W. Att, and T. Ogawa. 2011. TiO2 micro-nano-hybrid surface to alleviate biological aging of UV-photofunctionalized titanium. Int. J. Nanomedicine 6: 1327–1341.15.
- Bruno ME, Sittner M, Cabrini RL, Guglielmotti MB, Olmedo DG, T. D. In vitro age dependent response of macrophages to micro and nano titanium dioxide particles. J Biomed Mater Res A 103: 471–8.
- Bizjak, M., C. Selmi, S. Praprotnik, O. Bruck, C. Perricone, M. Ehrenfeld, and Y. Shoenfeld. 2015. Silicone implants and lymphoma: The role of inflammation. J. Autoimmun. 65: 64–7