By: 20 January 2025
Researcher in Focus Q&A with Dr Zhidao Xia

Zhidao (Dao) Xia is a Senior Lecturer of Regenerative Medicine at Swansea University Medical School. His research interests focus on the regeneration of skeletal tissue, mainly bone and cartilage, through the use of biomaterials, stem cells and controlled drug/growth factor delivery.

Dao specialises in the development of biodegradable materials and investigates the mechanisms of biodegradation as well as the interaction between biomaterials and the host tissue.

His interests also include the study of adverse tissue reactions and clinical complications associated with medical implants, with the aim of developing better biocompatible biomaterials. Additionally, Dao is also working on translational research and collaborates closely with industries to commercialise a patented 3-D printed biodegradable bone graft substitute. 

 

OPN: What drove you to choose a career in medical research and skeletal tissue regeneration?

ZX: I was originally trained as an orthopaedic surgeon in China before moving to Oxford in 1998 to study and work. In 2010, I joined Swansea University Medical School. During my time as an orthopaedic surgeon, I treated numerous cases of bone tissue loss caused by trauma, tumours, and spinal disorders. My experience at the Nuffield Orthopaedic Centre, Oxford University—where I completed my PhD and worked as a research fellow—greatly enhanced my knowledge of stem cell technology, tissue regeneration, and biomaterial interfaces. This experience inspired me to focus my research on bone regeneration.

Bone is a vital organ, providing mechanical support and protection to the body. Loss of bone tissue often leads to disability and can significantly impact a patient’s quality of life, placing strain on individuals and healthcare systems. While practising, I began working on bone graft materials, but I was dissatisfied with the options available at the time. Even with the materials used today, there remains considerable room for improvement.

In 1994, I published an article predicting that an ideal bone graft material should be calcium phosphate-based, biodegradable, and capable of transforming “from lifeless to living.” After 30 years, I believe I have finally discovered the bone graft material I envisioned.

 

OPN: You have recently developed a revolutionary bone graft substitute inspired by coral, which not only promotes faster healing but dissolves naturally in the body after the repair is complete. Could you tell us more about your research?

ZX: Coral has been used as a bone graft material since the 1970s, with significant success. Our team began using coralline hydroxyapatite for research and clinical applications in 2006. However, natural coral is an endangered species, and its harvest is now globally banned.

There are many artificial bone graft materials, such as hydroxyapatite and beta-tricalcium phosphate ceramics, bioglasses, calcium sulphate, metals, and plastics. However, none of these are truly biomimetic – mimic biological processes. For example, hydroxyapatite ceramics are sintered at over 1,000°C, while the natural hydroxyapatite formed in the body occurs at 37°C. This high-temperature processing results in ceramics that are non-biodegradable, with the calcium phosphate in the material only able to work as a scaffold without contributing to the host’s bone regeneration.

Let’s look back at the evolution of the skeletal system in life. What we find is through evolutions, there has been a change from exoskeletons to endoskeletons and a shift from materials such as chitin, silicon and calcium carbonate to calcium phosphate.

Processed coral, or coralline hydroxyapatite, is structurally and chemically closer to human bone due to its porous structure and calcium carbonate content. While human bone consists of only approximately 3-4% calcium carbonate, compared to 65-70% hydroxyapatite, it plays a vital role in bone metabolism.

Inspired by coralline bone graft substitutes, our team aimed to mimic the natural coral structure. Initial attempts using casting methods were unsuccessful, but with 3D-printing technology, we successfully produced a porous structure and replicated the chemical composition of hydroxyapatite and calcium carbonate.

 

OPN: What could your findings mean to help support the treatment of orthopaedic injury, and what will be the effect on patient experience?

 ZX: Enhancing bone formation is a significant challenge in clinical practice, particularly for large bone defects and fractures in ageing populations. There is a strong need for biomaterials that promote rapid bone regeneration and degrade in sync with natural bone turnover. If the material degrades too quickly, the bone may not form adequately; if too slowly, it may hinder healing. Additionally, some materials may contain toxic components that can lead to complications.

Our research presents a new biomaterial for orthopaedic surgery that can effectively repair bone defects. This material supports faster bone formation than most existing artificial grafts and is fully biodegradable. It has the potential to replace allografts for non-weight-bearing defects, as well as applications in spinal and dental settings, and even prevent non-union of fractures.

The material is autoclavable for sterilisation and easy for surgeons to handle. It consists only of natural bone minerals formed under physiological conditions, ensuring an unlimited supply of raw materials with no ethical concerns or toxicity risks. Patients can expect faster recovery, fewer complications, and reduced costs compared to current alternatives.

 

OPN: What is planned for the next stage of your research?

ZX: Future research will focus on understanding the biological behaviour of the material and the molecular mechanisms that underpin rapid bone formation. This project, which is partially supported by a Royal Society International Exchange grant with Johns Hopkins Medical School, will involve continuous collaboration with national and international partners to explore the roles of hydroxyapatite and calcium carbonate in bone formation.

In terms of product development, the project is at the scale-up stage. To achieve regulatory approval and the necessary manufacturing licenses, further pre-clinical evaluations are required. The steps include:

  • Producing the material in ISO 13485-compliant facilities.
  • Testing physicochemical properties to ensure quality assurance.
  • Assessing biocompatibility in comparison to conventional bone graft substitutes.
  • Consulting with the FDA for 510K compliance.
  • Applying for FDA 510K and HMRA approvals for clinical use.

 

OPN: How does the future look in the treatment of bone injury?

ZX: Over the past two decades, significant resources have been invested in stem cell-based therapies, including tissue engineering and gene therapy, yet few products have reached clinical use. This highlights the need for a re-evaluation of tissue regeneration strategies.

Stem cells naturally exist within the body and remain functional even in older individuals. Recent research indicates that tissue regeneration is not only locally controlled but is also regulated by the central nervous system. Therefore, creating an environment that promotes natural regeneration is critical.

The hydroxyapatite/aragonite biomaterial we developed supports this approach by fostering rapid bone formation. Our studies show that this process is driven by bone-forming cells on the bone surface and in the marrow, occurring within just 14 days of implantation. Unlike external stem cell therapies, this material capitalises on the body’s inherent regenerative capabilities.

Natural bone formation is also closely regulated by the central nervous system. Future biomaterials should facilitate nerve innervation to enhance controlled self-regeneration. Currently, 10% of fractures result in non-union, often due to rigid fixation, tissue damage during surgery, or implant-induced inflammation. The hydroxyapatite/aragonite material may prevent non-union by enhancing bone formation at the early stages following fracture and internal fixation.

 

OPN: What’s the best part of your job?

ZX: The best part of my job as a faculty member at Swansea University Medical School is the academic freedom I have to develop projects of personal interest and collaborate with international partners from around the world. This supportive environment has greatly contributed to the success of this project.

 

OPN: … and the worst?

ZX: Regarding our specific project, we face two main challenges. First, while the material we developed matches the strength of trabecular bone found in the body, it does not fully replicate the strength needed for repairing damaged bone. This means additional fixation is required, which is an important factor to consider. Second, the process of product translation and commercialisation is highly specialised and presents significant challenges for academic staff to manage effectively.

 

OPN: What has been the highlight of your career so far?

ZX: Our previous work on coral was published by the BBC in 2013, marking an important milestone in our research journey and establishing the groundwork for the outcomes reported here. This ongoing work represents the highlight of my career. If the material we have developed gains approval for its clinical benefits, it will truly fulfil my dream for the future.

 

OPN: Are you planning to attend or speak at any medical conferences or events in 2025?

ZX: I am the chair of the local organising committee for the 2nd Oxford-ICMRS Forum on Translational Medicine in Musculoskeletal Disorders 2025. I also plan to attend the Bone Research Society Annual Meeting in Edinburgh and the American Society for Bone and Mineral Research in Seattle.

 

OPN: If you didn’t work in the health industry, what would you be?

ZX: If I hadn’t pursued a career in health, I might have become a chemist. Chemistry was my favourite subject in high school and it also plays a critical role in understanding skeletal formation and metabolism.

Higher life forms, such as mammals, do not use silicon as their primary skeletal composition. While bioglasses that incorporate silicon are used as bone graft substitutes and are known to support the formation of connective tissue matrices, silicon accounts for only about 0.1% of bone weight, indicating that it cannot directly form bone structures.

Calcium carbonate, on the other hand, is widely used by marine organisms like shellfish, corals, and squids for their exoskeletons or endoskeletons. In human bones, calcium carbonate constitutes about 3-4% of the mineral content. Despite its presence, pure calcium carbonate has limitations as a biomaterial; in acidic conditions within the body, it degrades rapidly and releases CO₂, which is a metabolic waste.

Calcium phosphate tells a dramatically different story. Hydroxyapatite, the main form of calcium phosphate in the body, is the primary mineral in bones. Unlike synthetic hydroxyapatite ceramics, natural hydroxyapatite in bones dissolves under acidic conditions. Upon dissolution, phosphate is not a waste product like calcium carbonate; instead, it is an essential chemical for life. Phosphorus plays a pivotal role in energy metabolism, enzyme activity, protein synthesis, and the formation of DNA and RNA. This underscores why higher life forms, including mammals, evolved to use calcium phosphate for their skeletons, allowing for efficient metabolic processes and phosphate storage.

Interestingly, in hydroxyapatite, phosphate and carbonate ions are interchangeable—up to 40% of phosphate can be replaced by carbonate. Carbonate-substituted hydroxyapatite is more soluble than pure hydroxyapatite, which explains the full biodegradability of the hydroxyapatite/aragonite material we developed. This is why we believe that a combination of hydroxyapatite with calcium carbonate will be an ideal biomaterial for bone graft substitutes.

There are still many unresolved chemical questions regarding bone mineralisation, resorption, and regeneration. The introduction of artificial bone graft substitutes adds to the complexity of this knowledge, but it also makes the field very exciting. These challenges represent the most fascinating aspects of our research.

 

OPN: What would you tell your 21-year-old self?

ZX: Expanding your knowledge through learning is vital, but to succeed, you must focus on a specific direction, take action, and never give up.

 

OPN: How do you think the future looks within the field of orthopaedic surgery and treatments, and what are your predictions for 2025 and the next decade?

ZX: Science and technology continue to transform orthopaedic surgery, with AI and innovative biomaterials playing increasingly important roles. Nevertheless, the fundamental aspects of patient care and surgical skills will remain central to achieving successful outcomes.

 

Image submitted by the author