Repairing skeletal damage could come with the press of a printer button, if Hala Zreiqat can realise the potential of her biomedical innovations.
The adult human skeleton is made up of 213 bones that give structure and protection to the body. Professor Hala Zreiqat is intimately acquainted with them.
Zreiqat and her team have created a synthetic substitute for this living tissue, along with futuristic technology that allows each replica bone to be printed on demand.
If you’ve ever broken a minor bone, such as a phalanx in your finger or toe, you’ve perhaps marvelled at its ability to heal itself. However, for large or challenging bone defects caused by injury, infection or disease, a complex grafting procedure is generally required to fix the problem.
Bone is the second most common transplant tissue after blood, and around 2.2 million of these surgeries are performed each year around the globe.
The grafts usually include metal components, such as plates and screws, to help support the remarkable load-bearing and shock-absorbing abilities of bone.
However, metal does not integrate with bone and can become encased by fibrous tissue during the regeneration process, resulting in serious complications.
“If you want to make a material for the purpose of building bone, it needs to have a composition that replicates your own bones’ properties,” Zreiqat said.
“The starting point is to understand the tissue you’re trying to replicate.”
Building bridges
For Zreiqat, who is Professor of Biomedical Engineering, Head of the Biomaterials Tissue Engineering Research Unit, and Director of the Australian Research Centre for Innovative BioEngineering at the University of Sydney, that starting point began in late 1991 when she arrived in Australia from Jordan and began knocking on the doors of universities to pursue her dream of medical research.
A chance meeting with Professor Rolfe Howlett, who was studying skeletal disease at the University of New South Wales, led to a full-time job at that institution, where she studied how biomaterials impacted bone development.
In 2006, Zreiqat was recruited to the University of Sydney to establish its first Biomaterials and Tissue-Engineering Research Unit.
She promptly assembled a team of engineers, molecular biologists and materials scientists, and set about developing a bone-strong synthetic substitute that was biologically compatible with living cells.
The first step was to develop a porous ceramic material infused with trace elements important in bone formation, such as calcium, silicon, strontium and zinc.
The material was structured to form a scaffold similar to real bone — a bit like a Lego block bridging the gap — with sponge-like pores that would allow blood and nutrients to penetrate.
These scaffolds encourage natural bone to grow; it generally takes about three months for healthy tissue to begin to form.
Within about a year, sufficient bone will have grown through the scaffold to replace the defect.
With its job done, the synthetic material degrades and is then excreted from the body through natural physiological processes.
“We have not scientifically looked at the mechanism by which it degrades,” Zreiqat said.
“It is ongoing research, because it is remarkable what happens to this material.”
Cut to the bone
Zreiqat said her team has recently commenced the first pre-clinical trial in sheep for one of the materials they have developed for intervertebral spinal fusion.
“The study is ongoing, and we will hopefully see the outcome by the end of the year,” Zreiqat said.
“What we know from our research is that the material, being synthetic, can rebuild critical-size defects, which are defects that normally would not heal on their own. It is remarkable for a synthetic material to do this and to also withstand the mechanical forces applied to it.”
Zreiqat is hesitant to “pre-empt anything that isn’t scientifically proven”, but she said the results of the pre-clinical trial are looking positive.
If successful, she said patients could soon have bespoke replacement bones printed futuristically on the spot.
The outcome of this trial will be closely observed by scientists in the burgeoning field of biomedical engineering.
Keeping biocompatible
Biocompatible materials are an area of interest for Professor Andrej Atrens from the University of Queensland’s School of Mechanical and Mining Engineering, who began studying the corrosive properties of magnesium more than two decades ago.
While his early focus was on applications in automotive and aeronautical industries, he has recently turned his attention to biocompatible magnesium alloy scaffolds for bone tissue engineering applications.
“Think of a bad bone break, where you’d need plates and screws to keep it all together while it heals,” Atrens said.
“The traditional approach has been to make them from stainless steel or titanium, but they are not needed once the bone has healed, and a secondary operation is often required to remove them. With magnesium, the advantage is that potentially it will naturally corrode in the body without a trace.”
Materials scientist and engineer Adam Jakus is also monitoring the work of Zreiqat and her team. Along with colleagues at Northwestern University in Chicago, he has created flexible bone implants, known as hyperelasatic bone, that can be 3D-printed using an ink made from hydroxyapatite, a mineral found naturally in bone, and PLGA, a polymer that binds the mineral particles together and gives the implants their elasticity.
Jakus said the 3D-printed hyperelastic bone has been tested in various animal models and has been scaled up for larger manufacturing. In 2016 — four years after the technology was developed — he founded the company Dimension Inx to commercialise both the hyperelastic bone and the broader 3D-painting technology.
“We have sold research-grade hyperelastic-bone 3D paint direct to customers and through a number of major 3D-printing companies since 2017 and have been actively working with major industry and clinical partners to co-develop clinical products based on hyperelastic bone and its variants,” Jakus said.
“We are also working at Dimension Inx now to obtain clearance for the first hyperelastic bone product. We expect to receive this clearance in the next one to two years, and, hopefully, that will soon be followed by a number of other product clearances.”
Jakus is familiar with Zreiqat’s pursuit of unique compositions and methods for tissue repair and regeneration. He describes her approach as “very refreshing”.
“It is too often the case in this field that researchers keep using the same traditional materials over and over again, 3D-printed or not, and expect different and much improved results,” he said.
“Additionally, a lot of the published research out there doesn’t do comprehensive in vivo experiments or, if they do, it is for a very short period of implant time.”
This is not how research should work, Jakus said.
“I am excited to not only see these new compositions being investigated by Professor Zreiqat and her team, but also that they are creating porous implants from them and evaluating them over long periods of time in animal models,” he adds.
“This is exactly what the biomaterials and broader biofabrication community needs.”
Theory into practice
The ceramic materials developed in Zreiqat’s lab can now be made by a custom-designed 3D printer.
While many of the printed scaffolds can fit in the palm of your hand, Zreiqat said there are endless possibilities for size and form. In addition to orthopaedics, their application extends to dental and maxillofacial surgeries.
“How big a bone can we print?” she asks.
“We are trying now to see if we can print a whole mandible. Provided we have the appropriate equipment, we can print any bone in the human body.”
How does the innovation work in practice?
“The patient will be scanned, and a precisely designed implant will be 3D-printed for use in surgery,” Zreiqat said.
“Everything needs to be clinically validated.
“I can also say that we can print complex geometric scaffolds, and this is a huge progress in our area and has just been achieved in my lab.”
Military precision
Had Zreiqat followed her early career ambition to become an interior designer, a scientific breakthrough of this scale might not have occurred.
Born in Jordan, she grew up in Bethlehem, West Bank, and said interior design courses were not offered at the university in her home country at the time.
“Interior design has a scientific basis, so I was probably always attracted to science,” she said.
Zreiqat studied biology at the University of Jordan in Amman, sponsored by a scholarship from the Royal Medical Services. After graduation, she worked as a scientific officer — and a first lieutenant dressed in regulation army greens — at the King Hussein Medical Centre.
She went on to run a cardiac diagnostic lab at the Queen Alia Heart Institute, and, while she describes the job as “amazing”, it didn’t “fulfil my vision, which was in medical research”.
“I don’t know why I wanted to do medical research, but I knew that I’d do all I could to pursue the dream,” she said.
Zreiqat considered moving to the UK to follow her dream but, having spent a year there, she was discouraged by the weather.
“I didn’t see the sun at all that year,” she said.
An uncle lived in Australia and that seemed like a brighter option. However, she was presented with some unexpected challenges when she resumed her career.
“The culture shock that I first experienced in Australia was the inequality between women and men,” she said.
“I couldn’t believe it.”
Expanding opportunity
In addition to revolutionising treatments for bone defects, Zreiqat, who received the New South Wales Premier’s Award for Woman of the Year in 2018, is championing opportunities for women and working to transform the way girls view STEM subjects.
Last year, she helped form an education network called Bio Challenge, which encourages high school students to develop innovative solutions for complex medical problems with the help of mentors working in academia and the biomedical industry.
“It’s about getting young schoolkids to see what’s happening in research and to show them that biology leads to innovation, that engineers and biologists can work together, and that mathematics can lead to discoveries applied to medicine,” Zreiqat said.
“Our commitment should be to the scientists, engineers and mathematicians of the future.”
Zreiqat describes the gender disparity in STEM subjects as “alarming”.
“Only 35 per cent of STEM students in higher education globally are women,” she said.
“This requires our collective action and voice. Teachers need to be educated that when you teach maths and science, you must give equal opportunities to all students to excel, regardless of gender.”
Future-focused
For STEM careers to thrive in Australia, scientific research must be fostered and supported.
“The most important thing to me is that the government maintains the brains that we have here,” she said.
“Yes, we can fund them to go out and see the world, but we have to bring them back and we have to ensure that there is career progression. We have to promote and foster younger people and give them security so they can flourish and develop and invent.”
Zreiqat said she went through many years of insecure work in Australia before being offered a permanent place in academia.
“Our work is creative, and you need the space to think,” she said.
“Any unnecessary disturbance or stress will impact our productivity.”
Funding may present a challenge to retaining talent, but the novel developments coming out of Zreiqat’s lab are helping to attract the finest scientific minds and ultimately progressing the biotechnology sector in Australia.
In addition to synthetic bone structures, the team has created tendons and ligaments using synthetic material, which could be in use within five years. They are also developing three-dimensional organ-like cell masses, known as organoids, and are working with 3D-printing technology to create human organs.
“We are trying to 3D-print and recapitulate what’s happening in the body,” Zreiqat said.
“Our cells live in an extracellular matrix and for us to reproduce their function, we need to recapitulate it in the lab and in tissue implants.”
When it comes to science, Zreiqat said, she “assumes nothing and follows the evidence”.