Built for you

Gavril Abramovich Ilizarov could stake an easy claim to being the most industrious doctor ever to work in Siberia. Soon after he was posted to the village of Dolgovka in 1944, Ilizarov found that patients were scattered across the surrounding steppe – some reachable only by propeller aircraft. What’s more, he was alone. The nearest hospital was hundreds of miles away, along with a ready supply of medicines, painkillers and surgical tools.

Ilizarov’s workload was, unsurprisingly, heavy. Nothing brought this home more than the succession of ‘non-unions’ he treated, cases where villagers had sustained fractures so traumatic that sections of the bone were actually missing. Ilizarov’s medical textbooks recommended a treatment regimen of painkillers, bed rest and keeping the affected limb absolutely still. Recovery was slow, and painful. Ilizarov was convinced he could devise a better alternative.

Ilizarov’s solution was inspired by a shaft-bow harness, widely used in Siberia to ease the tension placed on horses carrying heavy carts. Ilizarov’s patients had a similar problem – put too much weight on the broken limbs too quickly and chances were the next thing to be heard was a sickening snap. So, the ambitious doctor read every orthopaedic textbook he could find and designed an external fixation apparatus that, when drilled into the two ends of limb, would take on the weight normally shouldered by the bone. What’s more, the device was adjustable; when the frame was slowly lengthened, the bone was encouraged to bridge the non-union, a process that came to be known as distraction osteogenesis.

The Ilizarov apparatus soon became the number one treatment for those seeking remedial action on their unfortunate shortage of bone, with a cavalcade of cancer sufferers, disabled gymnasts and vertically challenged air hostesses sporting the arresting framework of large screws and taut wires protruding from their skin. For all its resemblance to an instrument of torture, however, the Russian doctor’s invention was effective.

“You can produce up to 1mm per day of new bone with that technology,” explains Georg Duda, a professor at the Julius Wolff Institute for Biomechanics and Musculoskeletal Regeneration. Even so, Ilizarov’s technique has its drawbacks, including weakening the affected bone by drilling into it, not being able to wash the limb until the procedure is complete and having no guarantee of providing a seamless docking at the fracture site.

Duda is one of a team of researchers working on an alternative healing device that, they hope, will result in a more effective healing process. Known as a bone scaffold, this technique is intended to stimulate osteogenesis around a frame placed in the void of a fracture that, in time, is broken down of its own accord. For researchers like Duda, this new method should eliminate the need for multiple operations on the affected limb. The only point of serious disagreement lies in the material used. “We decided to go for a titanium scaffold because they are, in the end, stable model implants,” says Duda. “We want to have a setting in which a bone cell feels happy.”

An age old practice

While the concept of a scaffold to encourage osteogenesis may be relatively new, inserting an artificial bridge inside a fracture void is a practice that dates back centuries. While the principle was straightforward enough, not every material would be accepted by the body. Wood, for example, was considered by the Aztecs to be a suitable bridging device, as Spanish friar Bernardino de Sahagun discovered in the 1500s when he witnessed Mexican physicians jamming wooden sticks inside their patients’ medullary canals. Three centuries later, the opening of Africa and India to European commerce saw physicians graduate to using ivory, which afforded greater stability and degraded inside the body more slowly.

It was only by the early 1970s, however, that paediatric orthopaedic surgeon WT Green realised, after several failed experiments in cartilage regeneration in mice, that improvements in the speed and quality of osteogenesis might be achieved by implanting specially designed scaffolds into fracture voids. Unlike wood or ivory, these structures could be designed to imitate bone, providing pathways for fibroblasts and blood vessels to wrap themselves around the implant like ivy around a trellis, before degrading in time for the bone to completely fill in the former void.

While this method promised more efficient docking than an Ilizarov apparatus would allow, it was hardly as adaptable: each non-union is unique and every implant is carefully crafted to conform to the patient’s anatomy. The advent of advanced imaging technologies and the popularisation of 3D printing by the early 2010s, however, eliminated this problem. Not only can surgeons take a detailed image of the wound site and quickly design, print and sterilise a suitable scaffold, but researchers have much more leeway in experimenting with the materials that make up the structure to see which is the most effective and why.

For Duda, titanium is best. “They are, in the end, stable model implants,” the professor says of the scaffolds. Duda’s reasons are simple: when you’re repairing non-unions, “you don’t want to have any cracks”.

Duda’s scaffolds adhere to the constraints imposed by the patient’s anatomy as far as 3D printing will currently allow. First, the individual’s limb will undergo a CT scan. Then, says Duda, the team makes “a custom model scaffold that self-optimises toward an elasticity that is suitable for the bone defect in the patient,” using a software tool that optimises the thickness and the angle of the struts inside the implant.

The aim is to harness the endogenous healing capacity of the patient’s body by inserting a scaffold that provides the ideal medium for bone repair according to their individual anatomy. After that is achieved, the scaffold is then created using a 3D printer, placed in the non-union and stabilised with a plate fixation.

“We have treated, so far, 21 patients using this method,” says Duda – not all successfully. After the first few operations, Duda and his colleagues began to realise that rigidity of the scaffold had a major effect on the rate of repair at the fracture site. “Bone healing requires a lot of nutrition,” he explains, delivered by a reliable blood supply to the wound site. Therefore, “you actually need to have a little bit of a pumping effect” delivered by the scaffold. The softer that is, the more easily blood vessels can begin winding themselves around the structure and the faster the healing progresses.

Of course, a softer bridge in the fracture void – as those unfortunate Aztec warriors no doubt discovered – means a greater risk of the patient refracturing the affected limb. So, in early operations, Duda and the team erred on the side of caution by making the scaffold more rigid. When it became apparent that healing was taking much longer than expected, “Then we decided to go for much softer scaffolds,” says Duda. The structure the team are using now is “basically a ninth of the stiffness”.

Difference in opinion

Not all researchers have settled on titanium as the best scaffold material. There was the team from John Hopkins University who, in 2016, chose a mixture of polycaprolactone – a type of biodegradable polyester – and triturated cow knee bones; the combined Sino- American team who suggested creating lightweight open-cell scaffolds from the spines of sea urchins; and the researchers from Washington State University who claimed a rise in the rate of regrowth of between 30–45% by coating a ceramic scaffold with curcumin, a substance derived from turmeric.

The truth is, the medical research community is not in agreement on the absolute superiority of any one material. Christabelle Tonna, for one, believes that ceramic implants can exhibit very high tensile strength. They can also crack under pressure.

“While ceramic materials generally exhibit very high strengths, their brittle nature is not as attractive when used for the filling of bone defects in load-bearing regions within our skeleton,” says the research support officer from BioSA, another project investigating scaffold materials at the University of Malta. Funded by the Malta Council for Science and Technology, Tonna and her colleagues are exploring the effectiveness of a mixture of metallic compounds to build the scaffold.

“While the iron makes up the bulk of the material, the addition of manganese lends additional strength while also making the scaffold antigerromagnetic, as is required for most medical implants,” explains Tonna. “The addition of silver is then aimed at the increase of the corrosion rate of the bulk material.”

Currently, BioSA is focusing on studying how the mixture of alloys affects the corrosion rate of the scaffold while osteogenesis takes place. “Different application sites may require different rates of degradation to accommodate the loads applied and the size of the defect,” explains Tonna. “Therefore, we cannot aim for a specific degradation rate but rather find ways to adjust this characteristic as necessary.”

Tonna remains guarded on precisely what level of success has been experienced in this area. “We cannot divulge further information due to intellectual property protection,” she says. However, BioSA is confident that it’s edging closer to providing a scaffold that dramatically reduces the intrusive nature of popular non-union treatments.

“One of the biggest benefits of developing a functional degradable bone scaffold is the possibility of eliminating the need for a second surgery for implant removal, after the scaffold has served its temporary function,” says Tonna. “This in itself eliminates not only the pain and consequences of any surgical intervention but also eases the additional financial burden on the recovering patients.”

Let the body do what it does best

Duda feels similarly encouraged. The success of the team’s research has led to an exploration of whether the approach in healing non-unions might also be applicable in maxillofacial surgery. “We’re really curious to see if what works basically in large bone defects after trauma also works as well in large bone defects after tumour resection,” he says.

Fundamentally, Duda believes the work is harnessing the natural propensity of bodies to heal even the most serious fractures. In the end, metal frames are not what’s needed to get bones to stitch themselves back together. “Sometimes, instead of supporting that endogenous healing capacity, we actually injure it,” says Duda. What is more effective is, instead, giving the body a little support in doing what it does best: repairing the fracture and restoring freedom of movement to the patient.