Close to the bone

C&I Issue 7, 2015

There are about 30m fractures/year in the US and Europe, around 10% of which either don’t heal well or never heal. These patients undergo several operations to try to repair or heal the fracture, often involving a bone graft. This is usually painful, costly and runs a high risk of infection, especially if it is donated from another person or an animal.

Researchers at Israeli company Regenecure are developing a polymeric membrane that they say can accelerate healing of severe fractures by 40%, without the need for a bone graft

The membrane, which is made of AMCA (ammonio methacrylate copolymer A PEG 400), is strong and flexible, drillable, and can be cut by scissors into any shape to fit the fracture size. Specifically designed for extreme fractures, it can be wrapped around the fracture or patched on using absorbable sutures.

The simple and easy-to-apply membrane enables a single-stage procedure that promotes guided bone regeneration. According to Moshe Tzabari, Regenecure’s ceo, because the AMCA membrane is positively charged, it attracts mesenchymal stem cells (MSCs), the adult stem cells found in bone marrow, and growth factors normally involved in healing to its surface where micropores help them adhere. In this optimal biological environment, the stem cells proliferate and differentiate to form osteoblasts that make new bone tissue until the gap is bridged.

‘On its own, our membrane can close a huge 3.5cm gap in only six months,’ Tzabari says. ‘And when combined with a graft, it takes only 14 weeks.’  Impregnating the material with the statin drug simvastatin shows even faster healing, he adds, although this has been done only in animals so far. Simvastatin is known to enhance the expression, in MSCs, of a protein involved in bone formation.

The membrane is currently marketed as BoneCure for use in animals, and is expected to be available for use in humans at the end of 2016 in Europe and 2018 in the US. The first applications will be in long bone fractures and trauma, but the company is also developing it for use on cranial fractures and for joint fusion. ‘[So far] the safety profile looks excellent,’ says Tzabari. ‘Natural healing is best but it does not always happen.’

As well as accelerating healing, Regenecure’s membranes reduce re-operation rate, improving patient experience/convenience and reducing overall healthcare costs.

Another healing technology that is set to do the same is FeyeCon’s Intelliplants.

Over the past few years, clean-tech company FeyeCon, based in The Netherlands, has been developing implantable smart materials that accelerate healing. The company, a global leader in carbon dioxide technology, is making Intelliplants specifically to speed the healing of bones and skin.

The implants are made of undisclosed biodegradable and biocompatible polymers that have a range of mechanical properties and biodegradation rates, making them suitable for different applications. According to Melanie Wijnands, FeyeCon’s marketing & communications manager, the company uses supercritical carbon dioxide — a state above a critical temperature and pressure at which CO2 has characteristics of both a gas and a liquid simultaneously— to make Intelliplants of different shapes and sizes, such as three-dimensional pieces for bone replacement or flat membranes for patching skin, and with varying flexibility, strength and porosity, depending on what’s needed.

The base material can also be impregnated with a number of different active ingredients for slow release at the site of injury. In the case of bone, for example, these would be growth factors to promote healing by stimulating cells to grow faster and in a more controlled way, and antibiotics to minimise the risk of hospital-induced infections upon implantation. The active ingredients are encapsulated inside certain other undisclosed materials and diffuse out at different rates according to how quickly the materials degrade, according to Wijnands.

However, it is not yet clear how effective they will be. ‘How much Intelliplants speed up healing depends on a lot of factors, such as how serious the injury is and what the person’s normal healing time is,’ says Wijnands.

Nevertheless, in addition to improving patient comfort and convenience, Intelliplants are expected to reduce overall healthcare costs by lessening the need for additional surgical procedures; reducing the risk of infection; and enabling patients to resume their normal lives relatively quickly.

Intelliplants have not yet undergone testing in the clinic; FeyeCon is currently looking for partners for clinical trials. As well as broken bones and skin wounds, Wijnands says the company is also considering developing Intelliplants for cosmetic purposes to rejuvenate or protect skin.

Taking a different approach to accelerate the healing of broken bones, industrial designer Deniz Karasahin of dk design in France/Turkey has designed Osteoid, a customised cast that incorporates the use of ultrasound.

Although ultrasound-stimulating technology for facilitating bone regeneration has been around for about 20 years, what is revolutionary is that Karasahin has combined it with 3D scanning and printing technology.

It is not possible to use ultrasound to stimulate bone healing within a conventional plaster cast because the use of ultrasound intensifies oedema or excess water fluid, causing the limb to swell. Because a plaster cast is solid and physically restricting throughout, this can cause considerable pain for the patient. The alternative would be to drill holes into the cast while the patient is wearing it but this, too, is neither practical nor desirable.

Karasahin’s Osteoid cast is made of acrylonitrile butadiene styrene (ABS), a common thermoplastic polymer. After 3D scanning the patient’s limb, a personalised cast is 3D printed in a trellis design incorporating large gaps. As well as making the cast lighter, the gaps enable low intensity pulsed ultrasound to be applied directly to the skin. They also allow the limb to expand as necessary, reducing oedema accumulation and therefore pain, explains Karasahin.

It takes only single 20 minute daily sessions of ultrasound to increase the healing process by up to 38% and increase the heal rate up to 80% in ‘non-union’ fractures that still haven’t healed after three to six months, according to Karasahin, who expects Osteoid to be on the market by the end of 2015.

Whether or not it will become mainstream, however, remains to be seen. The ABS material would currently cost around $50 for a typical cast, and the 3D printing would probably be less than $10, depending on the machine. However, at the moment it would take around six hours to produce one cast.  ‘I foresee hospitals either needing 3D printers or working with 3D printing hubs [to supply Osteoids],’ says Karasahin.

Other groups, meanwhile, are trying to promote faster wound healing through the use of sodium nitrite. This industrial inorganic compound is used in a wide range of applications, including as a food additive to prevent botulism; in the treatment of cyanide poisoning; in photography; and as a corrosion inhibitor.

Tony Giordano, ceo of pharma company TheraVasc in Ohio, US, says that in studies of diabetic animals, sodium nitrite significantly improved wound healing in ischemic limbs – those with an inadequate blood supply – while having no negative effects on normal tissue.

In the first human trial of TV1001SR, TheraVasc’s orally-dosed slow-release formulation of therapeutic sodium nitrite, the wounds in diabetic patients who were given TV1001SR healed, in contrast to those who didn’t receive the nitrite.

The patients who received TV1001SR also reported less pain, and TV1001SR is now being developed for diabetic neuropathy. Nevertheless, the earlier, wound-healing findings still stand.

Giordano explains that the nitrite promotes angiogenesis or the formation of new blood vessels, stimulating blood flow to the wound. This brings with it the body’s regeneration components, such as immune cells and growth factors, to promote healing at the site. It is not entirely clear why angiogenesis is stimulated in ischemic tissue only. ‘[It could be] either because in ischemic tissue different enzymes are produced that convert nitrite to nitric oxide, or, when oxygen is low, nitrite is converted to nitric oxide and [so] stimulates angiogenesis,’ he suggests.

Caterina Minniti, director of the Sickle Cell Center in New York, US, and her research group is investigating the use of topical sodium nitrite to promote healing of chronic leg ulcers in patients with sickle cell anaemia.

A Phase 1 trial confirmed that application of topical sodium nitrite was associated with a significant increase in cutaneous blood flow around the wound, and the ulcers in patients who received the highest concentrations of the formulation healed completely. Topical sodium nitrite, a known nitric oxide donor, enhances blood flow in ulcers and has known bacteriostatic effects, say the researchers (

Although nitric oxide is known to promote wound healing, it was difficult to deliver it to wounds in a sustained way until an NIH pharmacy developed a stable form of sodium nitrite, according to Minniti. Once on the wound, it is reduced inside the hypoxic tissue to deliver NO.

If successful in clinical trials, Minniti’s cream - or something like it – would most likely be used to clean a wound of bacteria and increase blood flow to it, before application of a more sophisticated treatment. Nevertheless, it represents a first step towards an effective healer of any type of wound, the need for which is ‘tremendous’, she adds. ‘In North America, wounds are increasing and healing is estimated to be a $62bn industry, [yet] nothing really works.’

Emma Dorey is a freelance science writer based in Brighton, UK

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