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
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
Skull repair using regenerated bone
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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
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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
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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
Prof. 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.