To the bone

After Dr Jacob van Meekeren successfully completed the first bone graft operation on the face of a wounded soldier, the practical possibilities seemed endless. But this was 1668, and his medical revolution soon hit a torrent of Calvinist superstition. Because he had used dog bone to treat his patient, the Dutch clergy accused Van Meereken of creating an inhuman monster. Worse, the procedure had worked so well it could not be reversed. The soldier – now part dog – was excommunicated from his local church.

Today, bone graft patients have no need to fret for their mortal souls, but plenty of more basic medical problems remain. Many forms of grafting require bouts of gruelling surgery, which can lead to dangerous side effects like nerve injury. An ageing population, meanwhile, makes finding quality bone for operations increasingly challenging. But with dynamic alternatives to bone grafts appearing all the time, doctors have the chance to make procedures safer and faster than ever before.

Autograft repair or replace?

Autografting – transferring tissue from one site to another on the same person – has been the gold standard in bone graft operations for decades. Up to a point, this is easy to understand. Autograft procedures are proven and reliable, mainly because they rely on living tissue. This keeps the bone cells alive and allows vertebrae to fuse. At the same time, using the patient’s own tissue, eliminates the risk of rejection. So-called allograft procedures are where bone is taken from a donor.

More generally, autograft procedures hit all three sweet spots needed for bone formation: osteoconductivity, osteoinductivity and osteogenesis. Each mechanism is important in its own way. Osteoconductivity refers to the ability of bone-forming cells in the grafting area to spread over a bone scaffold and replace it with new tissue. Osteoconductivity measures how well bone grafts can attract early-lineage cells, like stem cells, into bone-forming cells. Combining osteoconductivity and osteoinclusivity promotes osteogenesis – the actual process by which new bone is created.

But autograft procedures are not perfect: a lack of material means doctors often need to make several incisions into a single iliac crest, the area of bone around the hip where most autografts come from. “In many cases, you have to make a second incision at the local site of the patient’s iliac crest, and dig it out from there,” explains Salvatore Leo, co-founder and CEO of Royal Biologics, a New Jerseybased orthobiologics company. This is a particular difficulty in elderly patients, Leo continues. “In young patients, you are likely to have good bone. But when you get to patients who are maybe 60 or 70 years old, and you need to add bone graft for surgery, that bone isn’t always the best quality.”

This causes a number of problems, including discomfort for the patient. “There is site-pain morbidity associated with [autografts],” emphasises Leo. “This means that patients experience pain for several days after the procedure. It is an extra step, an extra incision [and] an extra set of stitches after the procedure.” The figures are disputed but, some studies suggest that autograft surgery causes chronic pain in as many as 25% of patients. Harvesting tissue from the iliac crest can sometimes spark serious side effects, including pelvic fractures and heavy bleeding.

Demineralised bone matrix

Given these challenges, it is unsurprising that scientists and medical companies have worked hard to come up with alternatives. Allografts, taken from human cadavers, are one option. Because samples are distributed across regional centres, doctors can access allograft tissue much quicker than autografts. Donors are already dead, so there are no worries about site pain morbidity either. Still, bone allografts come with their own disadvantages. Moving bone from one body to another can spread disease and cleaning tissue can seriously weaken it.

Caught between traditional autografts and allografts, many doctors have migrated towards a third option: bone graft substitutes. By deciding to abandon natural bone altogether, doctors are increasingly using alternatives. Over the past decade, researchers have experimented on everything from ceramics to proteins and coral. This movement makes sense: bone graft substitutes are often safer than traditional methods, while still retaining osteoinductivity and osteoconductivity.

The shift towards bone graft substitutes has helped create a new market in medicine. According to a report by Transparency Market Research, the global demand for alternative grafts was worth $1.5 billion in 2014, a figure expected to reach a massive $3.48 billion by 2023. The same study found that specific types of osteopathic surgery are growing just as fast. Spinal fusion treatment, which combats joint pain in the back, is due to rise by 4.4% by 2023.

For his part, Leo and his team at Royal Biologics are focusing on demineralised bone matrix (DBM), one of the most intriguing forms of bone graft replacement. This involves taking allograft bone and removing the inorganic mineral, leaving a bone-like scaffold for new tissue to form. Leo explains the advantages of this technique by using a sweettoothed analogy.

“Imagine an M&M,” he says. “You have to take off the shell to get to the chocolate, which is the bone you want to grow. By demineralising bone, you are exposing more of the osteoinductivity.”

At the same time, DBM has robust handling characteristics, making it an excellent frame for bone formation. “Will it fit and conform [into] the unique shapes of bone?” asks Leo, rhetorically. “That is the key. You want it to remain in a good form.” In his experience, doctors have come to admire DBM for exactly these properties. “Doctors will always notice the handling characteristics of DBM first. They tell me it feels good and does not fall apart. It does not slide all over the place. Overall, DBM is a good scaffold that can help support bone formation.”

Premier DBMs

Though DBM is now a popular choice for bone graft surgery, downsides persist. Demineralising bone boosts osteogenesis, but DBM has typically not been as osteogenic as old-fashioned autographing. Doctors need to combine it with autograft bone for the best results. Fortunately, a new generation of ‘premier’ DBMs promises to close the gap, Leo explains. This involves combining DBM with osteogenic stem cells. “Medical companies are improving DBM by obtaining the bone graft from the donor within 24 to 72 hours,” he says . “By freezing it right away, they are basically obtaining the body’s live [stem] cells. A lot of these premier DBMs are frozen versions of regular DBMs, and they are guaranteed to have between 500,000 and a million cells [a] sample.” For Leo, this heralds “a new age of bone grafting. Everyone wants stem cells in their product. Everyone wants the most alive, most viable stem cells.” Several companies are now focused on just this approach; for example, DePuy Synthes recently released a new cryopreserved cellular allograft for use on a range of trauma procedures.

Meanwhile, Leo and his team are focusing on other areas of regenerative medicine. “There is a lot of potential for harvesting stem cells via the body’s own blood or bone marrow aspirate,” he explains.

“Rather than getting cells from a donor and putting them in a freezer, we would rather take bone marrow from a patient, add it to bone grafts and make a live cellular product. We want to harness the body itself – its own potential – and inject cells into tissue injuries or help on-bone formation. That is our vision.”

Although Royal Biologics is still tweaking the specifics, there is plenty to be hopeful about. Apart from being inexpensive – using bone marrow aspirate from individual patients cuts down on storage and transportation costs – this system is gentler on patients than allografts or autografts. Thanks to a special ‘minimally invasive’ syringe that collects blood directly from bone marrow, gathering cells is quick and painless. Even better, the same device allows doctors to draw other useful material alongside stem cells, including disease-busting white blood cells and platelets, encouraging stems cells to specialise.

Variety of substitutes

Away from Royal Biologics, researchers are working on a range of fascinating new bone graft substitutes. Scientists from the University of Kazan in Russia recently combined DBM with gene therapy to boost osteogenesis, for instance. Synthetic glass is another area of interest; one recent study showed that bioactive glass could dramatically increase the quality and amount of new bone when mixed with DBM. Leo’s company may have set its gaze elsewhere, but he understands how powerful these tools could be. “Bioactive glass helps in fusion,” he says. “Those [types of] glass can bond to tissue and are biocompatible with human bone. As it adheres to human bone, it works pretty well.”

With innovations like these marching ahead, it’s no surprise Leo is so excited about the long- term future of his industry. “Bone graft substitutes are huge in orthopaedics,” he emphasises. “This is a [massive] market.” He is likely to be proved more right as time goes on; for example, as an ageing population makes bone conditions like arthritis more common, the need for cheap and reliable orthopaedic aids seems certain to rise. Thankfully, for doctors and patients alike, priests have less power than they did and dogs are kept well away from the operating theatre.