Yeshiva University Journal of Medicine and Dentistry

The study concludes by listing some of the factors that can lead to osteoporosis like chronic drug use, alcohol abuse, low calcium intake, ect. The results strongly indicate that  physicians should conduct a thorough analysis of the patient’s bone health before surgery,11 such as doing densitometric scanning and bone density testing.8 There should also be regular radiological surveillance of osteoporosis and conscious effort to improve it. Alternatively, if the physician judges that although the bone is osteoperotic, surgery is possible, then a longer implant is used.12

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As discussed, osteoporosis can be a cause of implant failure, yet are there genotoxic and cytotoxic effects on the molecular level? Does titanium metal also affect the bone and its surrounding tissues?

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Metal Medical Implant and Application

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Medical implants are devices or tissues that are inserted inside of the body used to improve one’s health and/or replace a function lost due to body malfunctions or accidents.13 These medical devices should be corrosion resistant, biocompatible, bio-adhesive, bio-functional, processable and available to be innocuous in bodily fluids.13 Some common materials are metals, ceramics, polymers, and composites. These materials are frequently used for cosmetic and health purposes.

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Another common metal medical implant is the titanium hip implant. These implants are used as a replacement for damaged or worn out hip joints. Just like a human hip joint, the titanium implant consists of a titanium stem which is inserted into the femur with a metal ball at the top that fits into a titanium socket that is implanted into the pelvis, right where the ball-and-socket of a healthy individual joint would typically meet.9 The implant thus has direct contact with the bone and the surrounding tissues, like muscle and connective tissue.14

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Metal Medical Implant and Application

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Titanium metal is a popular material used in medical implants since it abides to the appropriate characteristics mentioned earlier which is supposedly harmless in bodily fluids. This metal is especially corrosion resistant and has excellent biocompatibility. However, titanium is a rare and costly material in its pure form, thus titanium alloys, like Ti-6AI-4V are mostly used in the metal medical implant industry. These alloys are composed of 90% titanium and 6% aluminum, 4% vanadium and traces of oxygen.15 Regarding titanium joint replacements like hip implants, research also suggests similar potential risks as discussed.  A study done by Gajski et al., suggest that the wear of hip implants composed of  Ti6Al4V and CoCrMo can lead to debris that can accumulate in bone marrow and cause chromosome aberrations,  given that the rod is embedded in the femur and the rest of the implants is adjacent to soft tissues.16 The excess marrow space in osteoporosis patients may allow for a greater accumulation. The study focused on analyzing materials commonly used in total hip joint replacements, in vitro models, via investigation of cytotoxic and genotoxic effects on human peripheral blood lymphocytes. After performing several experiments, like chemical characterization, induction of DNA strand breaks, micronuclei assay, and more, the results indicated that there was no significant genotoxic effect on human peripheral blood lymphocytes.16 However, another test called particle morphology assessment that studies the physical properties and shape of particles, showed that the wear debris were very small, making them highly reactive to their surroundings since submicron particles have larger surface area. The wear debris can therefore easily interact with surrounding media and cause inflammatory responses and tissue damage. As a result of the wear debris, an interface between the bone and the implant is created. In turn, foreign- body granulation tissue response invades the available space causing inflammation which activates osteoclasts that ultimately break down the bone resulting in a progressive local osteolysis.17 This effect eliminates the anchoring of the implant in the previously healthy femoral bone. In osteoporosis patients, induced osteolysis occurs in addition to the initial significant interface between the bone and the metal, leading to a possible grave fracture.17 The study also mentions how this can increase metal ion levels in organ sites. Although the overall research suggests that there is no carcinogenic effect, some genotoxic tests are contradictory and the particle effect can also lead to negative effects, thus further parameters need to be addressed.16

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Another review done by Coen et al., focuses on studying the effects of the debris of a specific concentration while the previously discussed article tested the actual concentration of debris in blood lymphocytes which was found to have no/minimal genotoxic effect.18 In this study the initial stock solution had a dense titanium debris composition. The experiment consisted on culturing fibroblast cells in medium and exposing them to different concentrations of titanium debris which was extracted from a patient’s periprosthetic tissue who underwent revision total hip arthroplasty. The higher dilutions had a lower indication of unstable aberration compared to higher concentration. Results of this experiment suggested that titanium debris can cause chromosomal aberrations. They found that this chromosomal instability was transmitted to the progeny of human fibroblast cells. Although this article suggests that there were significant cytotoxic/genotoxic effects, it may be based on the fact that the cells were directly exposed to higher concentrations of titanium debris.18 As it was well researched, titanium metal has low corrosion rates and it would therefore be unlikely that the surrounding tissue be exposed to as high of a concentration. The verdict remains that, as the first article mentioned, the effects are negligible, however studies should be continuous on this topic.

The further section discusses these biological processes at a more biochemical level.

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Metal Medical Implant and Application

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Ti-6AI-4V, Titanium alloy is generally known to have low corrosion rates, good biocompatibility, and low toxicity.19 However, some studies have shown that the components of the alloy, like vanadium, can be more corrosive and can lead to illnesses like peripheral neuropathy, osteomalacia and Alzheimer’s disease.19 On the other hand, further studies suggest that titanium itself can corrode over time and ultimately cause severe inflammation to its surrounding tissues.20

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Essentially, corrosion due to possible oxidation causes the release of metal ions, which are cations, shown to be non-biocompatible with the human body, particularly, toxic to the genome. These metal ions can cause small deviations from normal levels of oxidative stress that occur naturally by oxidative phosphorylation for which homeostasis cannot be restored. This unhealthy amount of oxidation can lead to acute and chronic toxicity, like cancer.19 The corrosion of titanium oxide releases Ti4+ and 2O-2 into body fluids and tissues which offer easy access to DNA. Each of these ions react in particular ways that ultimately lead to DNA damage. The interactions of these ions and DNA will be discussed individually below.

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Due to selective permeability of the membranes, the Ti4+cations enter the cell through ion channels and are released in the body fluids and tissues surrounding the metal implant and the positively charged species reacts with the negatively charged backbone of DNA and its electron donor base pairs. The metal cation can interact completely with DNA bases leading to DNA breakage. Alternatively, the metal ion can partially bond to water molecules found in body fluids, creating a complex ion that can hydrogen bond to DNA.19 Water bonded to a metal ion, a complex ion, significantly influences strong hydrogen bonding leading to the rupture of hydrogen bonding between base pairs and ultimately, significant DNA breakage.19

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As for the interaction of O2 with DNA, oxidative damage can take place and disrupt  the double helix structure.21 The production of ROS, reactive oxidation species, can result from homolytic breakage of the oxygen atoms after the dissociation from the metal ion occurring through corrosion in biological systems.21 Additionally, this oxygen ion can gain a single unpaired electron and become a free radical. Because the ROS are unselective and extremely unstable, they will react with the electron donor base pairs resulting in the formation of 8-hydroxyguinine.19 Subsequently to a radical substitution reaction, another homolytic fission can take place creating a radical OH group bonded to base pairs which can react un-selectively with all the components of the DNA molecule. Purines and pyrimidines will be damaged and lose their original structures. This rearrangement eventually alternates DNA physiologically.19 The mutations resulting from this malfunction cannot be repaired by checkpoint proteins, for instance DNA polymerase, given that the proteins have also been inhibited by metal ions.19

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The further section discusses in more detail the direct damage these processes cause and how DNA is damaged.

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Analysis of DNA Damage in Association with Metal Corrosion

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Essentially, DNA stores all genetic information. Once it is damaged or altered, error in DNA structure occurs, ultimately causing mutations that can have a detrimental effect on the cell’s function.19 In the case that this damage causes multiple abnormalities in the sequence of DNA, the cell proliferates uncontrollably and ultimately causes cancer.19 However, cells have several mechanisms that intend to repair the damage, but in case that the damage is too severe to repair, these mechanisms trigger cell death, also known as apoptosis.19 If these mechanisms are inhibited or do not function properly, the risk of disease increases since there is an accumulation of failed to repair errors in DNA structure or sequence. With all of this said, minimizing risks and attenuating factors that are responsible for DNA damage is vital to prevent diseases and malfunction of cellular repair mechanisms.19

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Micronucleus assays and comet assays were performed to prove these genotoxic effects. The micronucleus assay evaluates DNA breakage and genetic alterations.19 These malfunctions are monitored through the frequency of micronucleated cells. In an experiment, the frequency of micronucleation was determined in 1000 binucleated cells with a well-preserved cytoplasm. After observation, there was a difference in binuclei only at particularly higher concentrations, 75% and 100%, at the third treatment 25 and 26, respectively, compared to the control indicated to be 15.19 The comet assay, another method of DNA damage determination, evaluates DNA breakage using electrophoresis. The number of DNA breaks are reflected through the comparison of the comet’s head and tail intensity. The comet assay indicated that vanadium creates DNA breakage in the liver, kidney, lungs, and spleen.22

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Other methods of study were used to detect DNA damage indirectly given the relationship between metal ions and DNA damage.23 A study done by Sedarat et al. (2001) used absorption spectroscopy to monitor the release of metallic ions from the Ti-6AI-4V alloy over a period of 96 days in a solution that simulated the composition of body fluids.23 The study by Sedarat et al. (2001) showed that aluminum and titanium had a constant release of ions during the 96 days. However, vanadium released ions only on the first 6 days.23 Additionally, a study performed by Vendittoli et al (2010), looked at the blood concentrations that showed various ions from these metallic devices.14  The ion concentration in individuals with metal implants was significantly greater than individuals without the devices.14 Although corrosion and ion release may occur, compiled results judge that the benefits of titanium implants surpass the  overall effects.5

To avoid the problems discussed above, it is important to be aware of any unusual pain in the hip, groin or thigh, in the case of a hip replacement and report to a doctor for  revision. Limited mobility, fever, inflammation may also be symptoms related to a failed replacement.24

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Conclusion

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Although life can get busy, it is imperative to make physical health a priority and incorporate activities that promote it in daily life. From patients with osteoporosis to those that already house a titanium medical implant, bone health monitoring should always be done, especially that implant survival rates have become as high as 15 years or longer. Complications with implants would require invasive revisions that can give opportunity for infections to arise. Consuming foods rich in calcium, vitamin D, protein and engaging in   professionally taught physical activity consisting of weight-bearing exercise, all contribute to a better bone health.25 Improving the lifestyle that this generation has instilled in many, that consists of bad habits like, smoking, alcohol consumption, insufficient hours of sleep and drug misuse, can lead to better outcomes with metal implants and most importantly make the research on these implants worthwhile. While advancements in medical research that contribute to longevity are impressive, it is our responsibility to deal with the downsides that may arise from these innovations.