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Research_

Biomechanics, biomaterials and tissue engineering

Harnessing the body’s ability to heal itself

Tissue engineering uses multidisciplinary approaches to repair diseased or damaged tissues. Our projects encompass biomaterials, stem cells, computer modelling, molecular biology and animal models to achieve this goal.

The worldwide shortage of donor organs and drawbacks of surgical methods have created significant challenges in repairing and replacing diseased or damaged tissues and organs. This pressing need has led to the rise of ‘tissue engineering and regenerative medicine’, a multidisclinary field which aims to induce the body’s natural regenerative abilities and produce functional substitutes of biological tissue for clinical use.

The fundamental concept combines various tissue engineering elements, most often a scaffold as a supporting matrix in combination with living cells and/or bioactive molecules, to form a tissue engineering construct that repairs or regenerates the diseased or damaged tissue or organ.

Advances in medical technology have contributed to the world’s ageing population and increased life expectancies. Unfortunately, this has also caused a drastic increase in musculoskeletal conditions impacting bones, joints and tendons, which impose annual costs of $5.7 billion on the Australian healthcare system. The demand for bone graft substitutes is estimated to increase by 30 percent from 2013 to 2020.

Tissue engineering and regenerative medicine can provide a novel treatment regime based on the use of synthetic biomaterials, which may be constructed into three-dimensional implants and combined with biologics (such as cells and/or bioactive molecules). This will positively impact the quality of life of millions of people who are affected by musculoskeletal conditions globally.

Our research

Our work aims to develop optimal tissue engineered constructs for the repair and regeneration of different types of musculoskeletal tissues, including bone, cartilage and tendon. Our projects encompass knowledge and techniques from a wide range of disciplines, including materials science, engineering, computer modelling, nanotechnology, stem cells, cell and molecular biology, and animal models. Our ultimate goal is to translate our laboratory discoveries into therapeutic products that can improve the clinical treatment of musculoskeletal conditions.

Biomaterials-based solutions to repair and regenerate tissues

The aim is to develop synthetic biomaterial constructs with optimal properties for encouraging the regeneration of specific tissues such as bone, tendon and heart. The focus is on producing purely synthetic, off-the-shelf and market-ready grafts for clinical use in tissue reconstruction.

Our experts: Professor Hala Zreiqat, Associate Professor Colin Dunstan, Dr Jiao Jiao Li

Our industry partner: Allegra Orthopaedics

The current lack of appropriate bone substitute materials for spinal fusion applications is a major clinical problem. This project will develop a novel 3D-printed synthetic scaffold suitable for bone repair in spinal fusion, featuring both mechanical stability (for weight-bearing) and bioactivity (to regenerate the bone) – so far an extremely difficult combination to achieve. We have recently developed a novel bioactive ceramic, known as Sr-HT-Gahnite, with exceptional mechanical properties and bioactivity, and suitable for use in bone repair.

The aim is to produce 3D-printed Sr-HT-Gahnite scaffolds with optimised geometry, microstructure, and strength for use as bone substitutes in spinal fusion. The mechanical and biological properties of the scaffolds in spine fusion settings will be evaluated. This bone substitute will have potential to closely match individual patient needs and greatly improve long-term treatment efficacy.

Our experts: Professor Qing Li, Professor Hala Zreiqat, Mr Seyed-Iman Roohani-Esfahani (UNSW)

Industry partners: Allegra Orthopaedics

An inherent problem for bone scaffolds is the limited ability to induce tissue ingrowth and angiogenesis at the centre. Permeability and diffusivity are the main design factors that can address these limitations, in addition to conventional parameters such as pore size, porosity and interconnectivity. Permeability quantifies the ability of a porous scaffold to transmit fluid through its interconnected pores, while diffusivity indicates the spatial gradient of oxygen concentration within a scaffold. The effect of varying permeability and diffusivity on scaffold behaviour is largely unexplored, and their role in modulating cell behaviour is unclear.

We propose a unique method to design and fabricate bone scaffolds with optimised diffusivity and permeability, by altering strut and pore geometry through the combination of computational modelling and 3D printing. Designed scaffolds will be mechanically tested and their biological performance will be evaluated using bone-related cells. The outcomes of this project will improve implant design and produce bone substitutes with enhanced bioactivity and strength to achieve optimal tissue regeneration.

Our experts: Mr Young No, Professor Hala Zreiqat

Injectable biomaterials are useful in a range of tissue engineering applications, such as in contained or deep tissue defects, and allow administration by minimally invasive surgery. This research focuses on injectable cements and self-setting composite hydrogels that can handle the loading required for musculoskeletal tissues. We have developed a novel calcium silicate-based cement, which is currently being tested in preclinical animal models with collaborators in Shanghai Jiao Tong University.

We are also investigating other injectable biomaterial formulations with potential for filling bone defects, degenerative vertebral discs, and root canals. This project further involves developing synthetic tendons and ligaments for rupture repair. We have recently formulated a synthetic hydrogel-fibre composite, which will be tested in preclinical animal models in collaboration with Ulm University, Germany. 

Our experts: Ms Stephanie Yee, Associate Professor James Chong, Professor Hala Zreiqat

This research aims to develop and characterise a composite elastomer-nanoparticle patch for use in cardiac regeneration. The patch is made from elastomeric polyglycerol sebacate (PGS), a tough, biocompatible and biodegradable elastomer, which is embedded with beta-tricalcium phosphate nanoparticle platelets. The addition of the nanoparticles will improve fracture toughness of the patch. The mechanical and degradation properties of the patch have been optimised using different synthesis conditions and nanoparticle platelets have been successfully integrated into the PGS. Results are promising, with PGS patches containing nanoparticles showing significant increases in failure stress and strain compared to patches without.

Our experts: Ms Lin Jiang, Associate Professor Andrew Minett, Professor Hala Zreiqat

This research adopts an environmentally friendly method to prepare carbon nanotubes (CNTs) on the surface of carbon materials. This method produces nanoscale structures that not only enhance the strength between CNTs and carbon materials, but can also modify some properties of the carbon materials to extend their applications, including for high-energy storage batteries, high- temperature resistant materials, and biomedical materials. This research also involves preparing silicon materials on the CNT-carbon materials by an electroplating method to address carbon fibre lifespan issues. 

Stem cells and their interactions in tissue regeneration

The aim of this sub-theme is to elucidate the mechanisms by which stem cells interact with materials and the microenvironment. Biomaterials with different properties are used as a tool to mimic the natural environment in which cells reside in the body and a range of techniques are used to study the behaviour of the cells. This will provide us with the fundamental knowledge necessary to manipulate cells for use in regenerating tissues.

Our experts: Dr Miriam Jackson, Professor Hala Zreiqat

Our collaborator: Bill Keyes (INSERM)

Biomaterials play an important role in the regulation of adhesion and growth of a variety of cultured cell types. This research focuses on 'cellular senescence', a process that involves the permanent arrest of cell division and growth in response to various stressors. These cells remain metabolically active, but they stop dividing and undergo distinct, observable changes. Senescence causes loss of tissue-repair capacity, and senescent cells produce pro-inflammatory and matrix-degrading molecules. It has recently been suggested that these cells have a role in age-related bone loss. As such, they are promising therapeutic targets for the prevention of age-related degenerative conditions, including osteoporosis. Certain biomaterials can induce senescence-associated changes in cultured human cells, and this must be considered in the selection of a biomaterial for medical application.

This research aims to investigate the biomaterial properties that may contribute to cellular senescence and understand the mechanisms involved.

Our experts: Dr Yogambha Ramaswamy, Dr Zufu Lu, Ms Christina Viray, Professor Hala Zreiqat

Cells in the natural microenvironment of the body constantly encounter and respond to a myriad of signals to maintain appropriate biological functions. Much of the attention so far has been focused on understanding the importance of biochemical signals that cells respond to. However in recent years, the critical role of biophysical cues imparted either by the extracellular matrix or the adjoining cells is being additionally appreciated and explored.

This project focuses on engineering innovative artificial platforms using biomaterials to mimic various biophysical cues, as a tool to understand the molecular mechanisms by which cells sense and adapt to their biophysical environment. These artificial platforms can provide a broader understanding of the role of biophysical cues in stem cell differentiation, which can lead to new strategies for tissue engineering and regenerative medicine. They can also be used to explore the effects of biophysical cues on cancer metastasis and test the efficacy of novel drugs. 

Our experts: Dr Zufu Lu, Professor Hala Zreiqat

There is a great need for developing novel and effective approaches for the repair and regeneration of large bone defects non-union bone fracture. Stem cell-based bone tissue engineering techniques offer a promising approach for reaching this aim. Understanding and recreating a biochemical environment to control the differentiation of stem cells into the bone lineage is of great importance.

We have been able to mimic the signals in the bone microenvironment, including a mineral phase, a cellular phase, and a soluble factor phase. This provides a specific and balanced signalling network, which can control the commitment of stem cells into the osteogenic lineage for bone regeneration. However, the current challenge is to reveal the mechanisms by which these signals act in synergy to drive stem cell differentiation and behaviour.

Our experts: Ms Christina Viray, Dr Yogambha Ramaswamy, Professor Hala Zreiqat

Cancer is a leading cause of death worldwide. Current treatments for cancer are unable to completely cure the disease and pose high health risks for patients. As an alternative or complementary treatment to avoid such problems, cancer patients can undergo immunotherapy. Immunotherapy involves harnessing the body’s native immune system mechanisms, such as T cells, to combat the disease. T cells carry out cell-mediated immune responses and must be motile to search for antigen-presenting cells and tumour cells. T cell migration is regulated by biochemical, mechanical, and physical cues within their microenvironment to direct them to specific sites to carry out their roles. The influence of these cues on T cell migration is a field that is largely unexplored and is a promising therapeutic target.

This project involves the development of a synthetic 3D hydrogel in which the material properties can be independently altered. The material will be used as a platform to identify aspects of T cell migration at a molecular level, as influenced by physical and mechanical properties within the microenvironment, using mechanobiology-related analytical techniques and advanced microscopy. A deeper, systematic understanding of T cell migration will lead to the development of improved cancer therapies and immunotherapies.

Developing orthopaedic implants with improved long-term outcomes

The aim of this research is to develop optimised orthopaedic implants by introducing features that promote osseointegration, which is a structural and functional connection between the implant and living bone. This will result in the next generation of implant designs with reduced implant failure rates due to enhanced functionality and longevity, ultimately translating to an improved quality of life for patients.

Our experts: Professor Hala Zreiqat, Associate Professor Colin Dunstan

Our collaborators: Christopher Berndt (SUT), Cynthia Whitchurch (UTS), Seyed-Iman Roohani-Esfahani (UNSW)

Industry partners: Allegra Orthopaedics, Osseointegration International Pty Ltd, Peter Brehm GmbH

The short lifespan of orthopaedic implants is a major clinical problem, where failure often occurs within a few months as a result of infection, or within 10–15 years due to loosening. Most orthopaedic implants use titanium alloys (Ti-6Al-4V), which often cannot achieve sufficient integration with bone, and currently used hydroxyapatite coatings are prone to delamination and fragmentation. This work will develop our family of patented ceramics for use as novel implant coatings: Baghdadite, Sr-HT, and Sr-HT-Gahnite.

We will optimise the plasma-spraying process for coating deposition to produce high bonding strength while ensuring that the inherent bioactivity and antimicrobial properties of the ceramics are retained. These coatings will reduce the costs associated with revision surgery and greatly improve the recipients’ long-term quality of life.

Our experts: Dr Jiao Jiao Li, Professor Hala Zreiqat

Industry partner: Osseointegration International Pty Ltd

Osseointegration implants have been developed over the past two decades as a new technology for mobilising patients with lower-limb amputations, offering many benefits over traditional socket prostheses, including improved function and quality of life. Currently, artificial limbs for osseointegration implants are connected through traditional mechanisms used in the socket prosthesis system based on rigid screws and bolts that limit the versatility of the implant. As osseointegration implants become more common, there is a pressing demand for an ideal connector system designed specifically to meet the requirements of individual patients.

Our goal is to develop a unique and cost-effective connector system between osseointegration implant and artificial limb to allow quick and easy release for the recipient to rapidly attach and remove the artificial limb as required, and a fail-safe mechanism to prevent undesirable impact and strain passing through the implant site, and to protect residual bone from breakage in the event of a fall. This device will enhance the functionality and safety of osseointegration implants, and will assist in promoting their widespread use as an emerging technology to improve the treatment of lower limb amputees.

Our experts: Mr Seamus Thomson, Dr Jiao Jiao Li, Professor Hala Zreiqat

Industry partner: Osseointegration International Pty Ltd

Osseointegration is a new strategy to overcome the shortcomings associated with upper- and lower-limb amputations, which directly anchors a percutaneous load-bearing implant to osseous tissue. In this [ACCORDIAN, the goal of the clinical research is to contribute to the current understanding, development, and application of osseointegration to lower limb amputees. The goal of the laboratory component is geared towards improving the key aspects of osseointegration, and developing new technologies that employ its unique interface into the body.

Our experts: Associate Professor Colin Dunstan

Our collaborators: Professor Markus Seibel, Professor Hong Zhou

Bone tissue provides a fertile environment for cancer cells leading to the preferential metastasis of many cancers to bone including in particular breast cancer and prostate cancer. It is becoming apparent that bone tissue provides a receptive niche for cancer targeting to bone. The nature of the cell-to-cell interactions leading to targeting to bone of cancer cells is very important for full understanding and prevention of cancer metastasis to bone.

In particular this research has identified a role for vitamin D signalling directly on cancer cells and for changing the secretome of mesenchymal stem cells found in bone to promote cancer cell proliferation and the ongoing aim of this project is to identify the important components of the activated signalling pathways.

Our experts: Associate Professor Colin Dunstan

Our collaborators: Professor Michael Murray, Dr Tristan Rawling (UTS)

Treatment of breast cancer cells with analogues of omega three fatty acids is associated with either suppressed cell proliferation or reduced ability of breast cancer cells to migrate and to invade their way through matrix – a predictor of metastatic potential. Some analogues are able to potently inhibit tumour growth in vivo.  Ongoing research is evaluating the effects of chemical modulation of these analogues and determining their mechanisms of action on breast cancer.