Melbourne Research Unit for Facial Disorders

Research

  • Current Research

    Currently the MRUFD has two main research themes that relate to bone and teeth respectively. A third theme on biomarkers, which pertains to both bone and teeth, is at an early stage of development. Being complementary at both the biological and clinical levels, these companion topics hold broad relevance across the orofacial spectrum. As such, current efforts are providing a strong foundation for future expansion into a variety of clinical areas.

    1. Surgical and biological manipulation of bone generation and shape

    The MRUFD maintains a strong interest in the biological behaviour of bone at several levels, ranging from the remodelling of facial bones following repositioning to the generation of new bone using distraction techniques in craniofacial syndromes.

    Distraction osteogenesis

     MRUFD DO research

    In the 1950's, the Russian surgeon, Illizarov, successfully lengthened shortened lower limbs using his novel technique of distraction osteogenesis. This technique was adapted to advance the bones of the facial skeleton in the early 1990s following several animal studies. Initially this involved lower jaw (mandibular) lengthening in patients with diminutive jaws (micrognathia). This application broadened to include advancement of the mid-face in cases of cleft lip and palate and the syndromic craniosynostoses. Many internal and external devices have since been trialled for regular clinical use. Protocols have been developed for the use of these techniques, leading to publications on this topic.

    Upper airway obstruction is an increasingly recognised condition in paediatric patients with craniofacial anomalies. The application of mini-internal devices to lengthen the mandible in neonates and infants with Robin Sequence and other micrognathic conditions was commenced early this century in conjunction with the Departments of Neonatology and Respiratory Medicine and our team was one of the first in the world to conduct a prospective series for investigation. Similarly, internal and external devices have been applied to young patients with obstructed airways due to hypoplastia of the mid-facial structures. Distraction osteogenesis in many of these patients has revolutionized their management by eliminating the need for tracheostomies, by removing the need for noctural supplemental oxygen and has led to earlier discharge from hospital and the more rapid establishment of feeding. Studies are continuing in these areas and further publications are being prepared.

    Protocols of management

    Repositioning components of the facial skeleton by performing traditional osteotomies has been well established for several decades but the advent of distraction osteogenesis has provided another tool for use in the management of cleft and craniofacial patients. Uncertainties remain about the response and stability of certain movements of the jaws in three dimensions using these techniques. Optimised protocols are evolving and are the subject of continuing investigation by A/Prof Heggie's team in the Department of Plastic and Maxillofacial Surgery.

    Bone regeneration

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    Skull repair using regenerated bone

    Major skeletal defects often require more bone for replacement than is available from the patient. The ability to grow ("culture") bone outside the body or at the site of the defect for repair of craniomaxillofacial defects is an aspiration for scientists worldwide. The new field of tissue regeneration challenges the hugely successful era of hard and soft tissue reconstruction based on flaps and free vascularised transfer. Enormous interest surrounds the use of stem cell technology to replace damaged tissues, ranging from bone and cartilage to cardiac muscle.

    Cranial defects resulting from various conditions have proved to be a challenge to the surgeon as the availability of sufficient bone to use for repair is not always possible. With the development of bone substitutes, stem cell research and agents that promote bone healing, investigation of ways to effectively avoid the use of patient donor sites has been undertaken by MRUFD. The successful use of fresh frozen irradiated allografted bone using the rabbit critical size cranial defect was published, and a similar outcome involving a resorbable polymer was reported by Dr. Peter Farlie and his team. The use of a decellularized connective tissue matrix was also investigated in the same model.

    2. Cause and prevention of Developmental Dental Defects

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    Hypomineralisation defects in incisors and a "6-year-old" molar

    Diagnostic profiling of Molar Hypomineralisation lesions 
      Diagnostic profiling of Molar Hypomineralisation lesions

    Capitalising on Prof. Hubbard's experience in the biology of enamel-forming cells and calcium regulation, a major research thrust of the MRUFD is to improve understanding of Developmental Dental Defects (DDDs = D3s). We hope to not only help improve treatment options but ultimately to achieve prevention of D3s in many cases, through understanding their causes. D3s have a disturbingly high prevalence, affecting about 20% of children worldwide. Consequently D3s bring high costs to patients and society, particularly through increased risk of dental decay and pain. The most common types of D3 are acquired during infancy, apparently as a result of injury to the tooth-forming cells. It remains unclear what causes such cellular injuries, although suspicions centre on environmental toxins and several factors associated with childhood illness. To tackle the D3 problem effectively through a translational approach, the MRUFD has initiated and spear-headed development of a cross-sector network (see More about The D3 Group). Focussing on what is considered the most pervasive problem, Molar Hypomineralisation (pictured), MRUFD has assembled new research teams comprising career scientists and clinicians working alongside each other. With seed funding from MRUFD, one such multidisciplinary team has undertaken a pioneering analysis of the molecular makeup of hypomineralised enamel. Their findings have given useful insights to the underlying disease mechanism, and provided protein profile information that could be useful for guiding diagnosis and treatment (read more). Other teams are applying a variety of biochemical, biophysical and structural approaches to clinical specimens and experimental models of D3 (read more at The D3 Group).

     

    3. Biomonitoring of tooth and bone dynamics

    'Dipstick' biomarker test 
     "Dipstick" biomarker test

    Seeking better options for orofacial healthcare, MRUFD is well positioned to engage the biomarker arena having spear-headed the establishment of Proteomics & Metabolomics Victoria (read more about PMV). Medical applications of biomarkers are well established and receive widespread use (e.g. monitoring of proteins released from damaged cardiac muscle after a heart attack, PSA test for prostate cancer). However, many of these tests are prone to error as they rely on single biomarkers. Proteomics/metabolomics technology can reveal groups of useful biomarkers, opening the door to more powerful "multiplex" tests.

     

    Two biomarker projects of interest to MRUFD involve "real-time" monitoring of tooth and bone movement (as in orthodontics and distraction osteogenesis of jaws) and of dental development. Orthodontists usually move teeth slowly to minimise risks of damaging the tooth roots. This problem of root resorption can lead to loss of teeth and is only detectable at advanced stages using X rays. Several studies have explored using a biomarker to give early warning about root resorption and, in its absence, to move teeth more rapidly. Promising results have been obtained, but we believe multiplex tests will be required for clinical robustness. Maxillofacial surgeons often need to reshape the facial skeleton using a bone-stretching process called distraction osteogenesis, as outlined above. Currently the stretching is done at an empirical "rule of thumb" rate and surgeons receive little feedback on how individual treatments are progressing. An attractive prospect is to use biomarkers to monitor this process so that stretching rates can be optimised for each individual. Given that D3s (developmental dental defects) are a widespread and costly problem, an attractive prospect is to monitor immature teeth as they develop in infants. Ultimately this approach might enable interventions that avoid D3s and maximise enamel strength. The current lack of such tests means that D3s are usually discovered several years later when the tooth erupts into the mouth, which is too late for preventive measures.

    In both problem areas, there is a fundamental need to discover informative patterns of biomarkers. A second requirement is to develop clinical tests for monitoring these biomarker sets. Biomarkers generally comprise proteins or their fragments (peptides), or natural small molecules (metabolites) that can be revealed in large numbers by proteomics and metabolomics technologies, respectively. Computer analysis is then used to select informative biomarker sets that in turn are validated rigorously in the clinical context. PMV provides access to technology experts, major equipment and the education sector, and provides links with industry and government that could benefit subsequent commercialisation. A substantial market is likely to exist for multiplex biomarker tests that foster individualised healthcare strategies in the orofacial sector.

    Other Research Interests

    A variety of other research avenues of interest to the MRUFD will be pursued as appropriate funding and resources become available, including:

    • Using the new discipline of 'phenomics' (a type of reverse genetics) to investigate the genetic foundation of common craniofacial disorders
    • Interpretation and management of cleft palate speech disorders
    • Identification of cellular populations in neural crest tissue
    • Molecular foundations of facial anomalies (see below)

    Molecular foundations of facial development and abnormality

    Fig3.gifProf. Hubbard teamed up with Dr Peter Farlie (Murdoch Childrens Research Institute and Deputy Director, Research, Department of Plastic and Maxillofacial Surgery) to initiate a ground-breaking project investigating the molecular foundation of facial development. This research provides a new method of investigating the pathogenesis of abnormalities in facial development that lead to birth defects such as clefting disorders, cranial shape abnormalities (craniosynostoses) and absent teeth. By combining Dr. Farlie's experience in craniofacial embryology with Prof. Hubbard's skills in 'proteomics' (a cutting-edge technology involving the analysis of many proteins simultaneously), a new way of learning about the cells that form the lower face (including jaw and teeth) became possible. With seed funding from the MRUFD, this study progressed well and the early findings were published in a widely read multidisciplinary journal. Dr Firas Alsoleihat (a dental graduate from Jordan) joined this project and his extension of the proteomics studies and development of other new research avenues led to successful completion of a PhD in 2008. Many intriguing avenues exist for expanding these investigations.