Most of the time, bone implants do what they’re meant to: fix into place and stay there, usually to replace damaged tissue or stabilise a fracture. It’s estimated that over 90% of hip, knee and dental replacements remain successful ten years after surgery.
But it’s not uncommon for implants to fail. Usually, this happens because the implant has loosened from the bone surrounding it. One major culprit is poor osseointegration: the bone didn’t grow into the implant enough to anchor it in place. Whether osseointegration goes smoothly depends largely on the implant’s surface properties. Through direct contact, the surface can influence how surrounding cells behave in ways that encourage bone growth. It must also have antibacterial properties to stave off infection, another common reason for implant failure that can also interfere with bone formation.
Thanks to studies done so far, some surface design elements that can be beneficial have been identified. For example, wettability allows cells to spread along the implant and more easily interact with it. Yet newer research has proposed surface modifications that could improve implant integration and survival to an even greater degree.
Altering surface microtopography
Over the years, benchtop experiments have shown that if you constrain cells physically, for example by changing the physical topography of a material they’re in contact with, you can get them to do different things, says professor of Biomedical Engineering and Surgery at Northwestern University, Guillermo Ameer. For instance, you can get stem cells from bone marrow to differentiate into osteoblasts, which work to form bone.
But prior to a landmark study published last June that Ameer was involved in, no-one had investigated the effects of micro-level implant surface modifications on bone growth in vivo without adding in any other factors to enhance tissue regeneration.
“Implants are getting better, the materials are getting better, but the infection rate is rising due to people getting older, more multidrugresistant bacteria, and so on.”
Jessica Bertrand
The researchers, made up of an interdisciplinary team from Northwestern University and the University of Chicago, identified a particular pattern using micropillars that caused bone to form sooner compared to an implant with a flat surface in mice.
“By basically squeezing the nucleus of the [stem] cell, we found that we could, just by pure physical means, alter how these cells are able to process their DNA in order to make more of a particular protein, or proteins,” Ameer explains. These proteins would “eventually tell the cell to become more bone-like or produce factors that would be more likely to induce bone formation”.
Having an implant that speeds up osseointegration is significant because growing bone takes time: sometimes weeks or months. And until it’s integrated, micromovements between the bone and implant can affect how well it’s able to fix in place.
“The faster you get the new tissue, the better off you’re going to be,” says Ameer.
Micropillar patterns could be combined with the current standard of creating roughness – forming pores in the implant surface that are visible to the human eye – to maximise effects on the bone. The bone interlocks with the implant as it grows into the pores, which has been found to both improve osseointegration and load bearing capacity.
However, the surface within those pores is still smooth. Micropillars, which would affect a monolayer or bilayer of cells at most, can interact with cells that land on the implant surface, says Ameer. “Those cells will see another degree of patterning, besides the roughness.”
Preventing infection
An implant can have the most optimal properties for osseointegration possible, but if an infection develops, it’ll likely fail. “This is a huge problem in endoprosthesis nowadays,” says Professor Jessica Bertrand, head of the Experimental Orthopaedics Research Unit at the Orthopaedic University Hospital Magdeburg. “The implants are getting better, the materials are getting better, but the infection rate is rising due to people getting older, more multidrug-resistant bacteria, and so on.”
Yet creating antibacterial implants is a twofold challenge: you need properties that keep infection at bay without interfering with the process of bone growth. In a paper published in January of this year, Bertrand and her colleagues found that an alloyed silver surface did both – and was more effective at repelling bacteria than a control titanium alloy. Titanium and its alloys are the most common materials used in orthopaedic implants.
“We tested different silver concentrations to be antibacterial on one hand… and on the other hand, that still keeps the osteoblasts alive to form bone on the surface,” Bertrand explains. They found that Staphylococcus aureus, one of the main bacteria responsible for orthopaedic implant infections, attached to their silver surface significantly less than it did with the control. Better still, there was no negative effect on osteoblasts, suggesting that the surface wouldn’t impede bone growth.
Interestingly, there was also drastically less formation of osteoclasts on the silver surface – cells that degrade bone – indicating that there would be increased bone formation. However, in vivo studies are needed to confirm this.
Antibacterial silver implants already on the market tend to work by releasing silver that is then taken up by bacteria. However, these particles can cause silver contamination, a condition that can turn the skin grey.
“In our case, the silver is alloyed, more or less in the surface layer, so it shouldn’t be released. And the surface should keep this antibacterial property even when it’s implanted for a longer time in the body,” Bertrand says. This is also likely why their surface doesn’t interfere with osseointegration as much as other silver-modified implants, she adds.
Bioactive coatings
Metals are widely used for implants due to their mechanical properties, yet often they are inert. To get around this, you could add bioactive coatings to their surface to change the environment that the bone cells are sensing. This can help to drive osseointegration, says biomedical engineer and senior lecturer at the University of Technology, Sydney, Jiao Jiao Li.
For instance, you can add certain trace elements already present within our bones, like zinc and magnesium, onto the surface. “Those have the inherent ability to cause bone formation,” says Li.
One method that holds promise is micro arc oxidation (MAO), where rough and porous oxide films are formed on the implant surface. MAO has been found to increase the rate of osteoblast formation while these coatings can be enhanced when other elements are added. For instance, incorporating hydroxyapatite (HA), a mineral present in our bones, can promote bone growth by controlling macrophage activity – cells that control inflammation when an injury heals.
In the early stages of healing, macrophages release signals that can kickstart the bone formation process. Though if they stay activated they’ll cause chronic inflammation, which can interfere with bone growth. This HA-modified coating switches the macrophages on after the implant is put in but deactivates them once a good amount of bone has formed by responding to an enzyme released by the bone cells.
You can also add coatings that directly trigger molecular pathways that bone cells use, Li explains. Here, there’s a broad category called layer-by-layer self-assembly, where layers of oppositely charged materials adhere to each other on top of a charged substrate. “You have thin layers of biological coating and they may be different materials,” she says. “It’s combinations of different materials to convey different effects.”
Collagen is of particular interest here as it’s naturally found in bone, and so can mimic the natural interface of the tissue. This can encourage osteoblasts to adhere to the implant surface and improve osseointegration.
However, it can be tricky to ensure that coatings like these will have a reliable effect. “Biological materials are variable – even one batch of collagen is going to differ from the next,” says Li. “There’s a preservation period as well, because biological materials can’t just sit on the shelf forever.”
Building better implants
In the US alone, demand for hip replacement revision is estimated to rise by 137% from 2005- 2030; for knee replacements, that figure is 601%. By 2060 in the UK, demand for hip and knee implants is set to grow by almost 40% since 2022.
Creating implants that have a better chance of survival could make a difference for thousands while alleviating the burden on health systems.
But ideally, one day we won’t need to use artificial implants at all, says Li. “Hopefully, we’ll at least be at the point in say five years where we’re able to generate human pieces of bone that are derived from your own stem cells.”
Ameer envisions a future of “smart regenerative systems”: creating scaffolds that would allow tissues and cells to regrow, and that could integrate with telemedicine to relay information about the microenvironment of that implant. It’s something he’s currently working on with his team at Northwestern University.
Yet while we wait for those developments to materialise, we need to keep doing what we’re doing, says Li. “We still need to work on our implants and our coatings.”
