Craniosynostosis is a developmental condition where children present premature fusion of the skull sutures. This condition affects one out of 2500 live births and can cause damage by limiting brain growth. Scientists based in Ireland are investigating the mechanisms that speed up bone formation in children diagnosed with craniosynostosis. This follows the identification of local microenvironmental changes as a key player in the abnormal activation of a series of genes involved in the accelerated bone formation in the prematurely fused sutures.
Clinicians at the National Paediatric Craniofacial Centre at Temple Street Children’s University Hospital, together with scientists at RCSI (Royal College of Surgeons in Ireland) and the Science Foundation Ireland funded AMBER (Advanced Materials and BioEngineering Research) centre, compared the behaviour of cells from prematurely fused sutures and cells from unfused sutures in order to understand how changes in the local physical environment of the skull directs the premature suture fusion.
Their study, published in Scientific Reports –a leading open access journal from the publishers of Nature - identified that cells from fused sutures have a greater sensitivity to changes in their local environment while also discerned the genetic mechanisms that control that behaviour. In particular, cells from fused sutures prematurely commit towards a bone forming cell type. These insights in the mechanisms by which changes in the physical environment promote the premature fusion of the skull sutures may provide the opportunity to develop new therapeutic strategies for bone repair.
Mr. Dylan Murray, Lead clinician at the National Paediatric Craniofacial Centre at Temple Street Children’s University Hospital commented, ‘This study was possible with the consent of the parents of the children we operate on in Temple Street who have the condition craniosynostosis. Whilst it will never be the case that a fused suture can be treated with medications to reopen them, there are many applications of this scientific breakthrough. An example of this is the possibility of impregnating bone scaffolds with these genes. This will help to stimulate new bone formation. This can be used instead of bone grafts.
Professor Fergal O’Brien, Head of the Tissue Engineering Research Group in RCSI, Deputy Director of AMBER and lead PI on the project noted ‘This is a great example of interdisciplinary research between clinicians and scientists. We are particularly grateful to the patients in Temple St and their families who supported this project’
Commenting on the significance of the research, Dr. Arlyng Gonzalez Vazquez, whom together with Dr. Sara Barreto are the joint-first authors on the study, said: ‘Our findings not only shed new light to understand the mechanisms that control the premature fusion of the skull suture in children with craniosynostosis but also provide new targets that can be incorporated into novel therapeutic target-specific biomaterials to enhance bone formation in patients suffering from severe fractures and bone degeneration’.
This work was supported by the Temple Street, Children’s Fund for Health, the Health Research Board, and the Irish Research Council.
RCSI is ranked in the top 250 institutions worldwide in the Times Higher Education World University Rankings (2017-2018). It is an international not-for-profit health sciences institution, with its headquarters in Dublin, focused on education and research to drive improvements in human health worldwide.
Prof. Daniel Kelly, Investigator at AMBER and Director of the Trinity Centre for Bioengineering has been announced as a recipient of the European Research Council’s (ERC) Proof of Concept Grants. This is the 3rd ERC grant awarded to Prof Kelly and the 12th ERC awarded to researchers in AMBER, the Science Foundation Ireland funded materials science centre based in Trinity College Dublin, since its launch in 2013. This funding will provide Prof. Daniel Kelly with €150,000 over 1.5 years and enable him to verify the innovation potential of ideas arising from his existing ERC funded projects, which focus on a novel implant for treating cartilage damage.
Prof. Kelly won the funding for his project entitled ‘ANCHOR’. The aim of ‘ANCHOR’ is to develop and commercialise a new medicinal product for cartilage regeneration. Cartilage damage is a relatively common type of injury, with the majority of cases involving the knee joint. Damage can occur due to injury or wear and tear, and if not satisfactorily treated can lead to osteoarthritis (OA). OA represents a significant economic burden to patients and society in the world, estimates are that 9.6% of men and 18.0% of women, aged over 60 years, have symptomatic osteoarthritis, with 80% of those having limitations in movement and 25% saying they cannot perform their major daily activities of life*. There is currently no cure and in the most serious cases, the entire joint may need to be replaced with an artificial joint, such as a knee replacement prosthesis.
Prof Kelly’s proposed product comprises a cartilage derived 3D scaffold which acts as a template to guide the growth of new tissue by recruiting endogenous bone marrow derived stem cells. What is unique about the therapy is that the scaffolds will be supported by an array of 3D printed biodegradable polymer posts that will anchor the implants into the bone underneath the cartilage. If successful, such an implant would form the basis of a truly transformative therapy for treating degenerative joint diseases like arthritis. The funding will also allow Prof. Kelly to employ a post-doctoral researcher.
Prof. Daniel Kelly, Principal Investigator at AMBER, said “At present the treatment options for OA are limited to surgical replacement of the diseased joint, with a prosthesis. Joint replacement prosthesis also have a finite lifespan, making them unsuitable for the growing population of younger and more active patients requiring treatment for OA. Our 3D printed polymer posts will anchor the implant into the bone and will be porous to stimulate the migration of stem cells from the bone marrow into the body of the scaffold. While various scaffolds like this have been available for some time, they have had limited success, partly because scaffolds need to be anchored securely due to the high forces experienced within the joint. Our 3D printed posts overcome this problem.”
Prof. Michael Morris, Director of AMBER, commented on the announcement, saying “I’d like to congratulate Professor Kelly on successfully securing his 3rd ERC award. He is doing ground-breaking work in his field that will really make a difference to society. This award demonstrates both the excellence and also the quality of the research team that has been built in AMBER.”
Prof Kelly’s project has resulted from outputs and expertise from his previous ERC Starting Grant and his current ERC Consolidator Grant. As part of the ERC Starting Grant STEMREPAIR, he developed a range of porous cartilage derived scaffolds. He is currently developing 3D printing strategies as part of his ERC Consolidator grant JOINTPRINT.
Background on the European Research Council’s (ERC) Proof of Concept Grants
All Principal Investigators in an ERC frontier research project, that is either on going or has ended less than 12 months before 1 January 2017, are eligible to apply for an ERC Proof of Concept Grant. The Principal Investigator must be able to demonstrate the relation between the idea to be taken to proof of concept and the ERC frontier research project (Starting, Consolidator, Advanced or Synergy) in question. Proof of Concept Grants are up to €150 000 for a period of 18 months.
A team of researchers from AMBER, the Science Foundation Ireland funded materials science centre based in Trinity College Dublin, have made a breakthrough in the area of material design – one that challenges the commonly held view on how the fundamental building blocks of matter come together to form materials. Professor John Boland, Principal Investigator in AMBER and Trinity’s School of Chemistry, researcher Dr. Xiaopu Zhang, with Professors Adrian Sutton and David Srolovitz from Imperial College London and University of Pennsylvania, have shown that the granular building blocks in copper can never fit together perfectly, but are rotated causing an unexpected level of misalignment and surface roughness. This behaviour, which was previously undetected, applies to many materials beyond copper and will have important implications for how materials are used and designed in the future. The research was published today in the prestigious journal, Science*. The Intel Corp. Components Research Group also collaborated on the publication.
Electrical, thermal and mechanical properties are controlled by how the grains in a material are connected to each other. Until now, it was thought that grains, which are made up of millions of atoms, simply pack together like blocks on a table top, with small gaps here and there. Professor Boland and his team have shown for the first time that nano-sized grains in copper actually tilt up and down to create ridges and valleys within the material. Nanocrystalline metals such as copper are widely used as electrical contacts and interconnects within integrated circuits. This new understanding at the nanoscale will impact how these materials are designed, ultimately enabling more efficient devices, by reducing resistance to current flow and increasing battery life in hand-held devices.
Professor John Boland, Principal Investigator in AMBER and Trinity’s School of Chemistry, said, “Our research has demonstrated that it is impossible to form perfectly flat nanoscale films of copper and other metals. The boundary between the grains in these materials have always been assumed to be perpendicular to the surface. Our results show that in many instances these boundaries prefer to be at an angle, which forces the grains to rotate, resulting in unavoidable roughening. This surprising result relied on our use of scanning tunnelling microscopy which allowed us to measure for the first time the three-dimensional structure of grain boundaries, including the precise angles between adjacent grains.”
He added, “More importantly, we now have a blueprint for what should happen in a wide range of materials and we are developing strategies to control the level of grain rotation. If successful we will have the capacity to manipulate material properties at an unprecedented level, impacting not only consumer electronics but other areas such as medical implants and diagnostics. This research places Ireland yet again at the forefront of material innovation and design.”
Professor Boland is Dean of Research at Trinity, a fellow of Trinity College and a fellow of the American Association for the Advancement of Science. He was the Laureate of the 11th ACSIN Nanoscience Prize (2011) and was awarded a prestigious ERC Advanced Grant in 2013.
* Zhang X, Han J, Plombon JJ, Sutton AP, Srolovitz DJ, Boland JJ. Nanocrystalline copper films are never flat. Science 28 July 2017
The porous, ‘sponge’-type molecules have an enormous internal surface area
This allows their use as ‘molecular flasks’ or ‘molecular containers’ that change the reactivity and properties of encapsulated molecules
Scientists from Trinity College Dublin and AMBER, the Science Foundation Ireland-funded materials science research centre hosted in Trinity College Dublin, have created ‘molecular cages’ that can maximise the efficiency of converting molecules in chemical reactions, and that may in future also be used as sensors and drug-delivery agents. The cages can be packed with different molecules, many of which have a specific task or functionality. Incredibly, a teaspoon of powder containing these cages provides a greater internal surface area to boost reactivity and storage capacity than would be provided by an entire football field (4000 m2/g).
This enormous intrinsic surface area relative to the weight of the structure in combination with the solubility offers great promise for energy conversion, while the structure blueprint (hollow, with sub-cages) allows different molecules to be discretely contained within. This latter feature is key in increasing the potential uses for these ‘metal-organic-organic polyhedra’ (MOP), because it means materials can be packed so as to react only when specific conditions present themselves.
One such example is in bio-sensing and drug-delivery, with a biological cue required to kick-start a chemical reaction. For example, a drug could be encapsulated in one of these MOP in the knowledge that it would only be released at the specific target site, where a specific biological molecule would trigger its release.
The researchers behind the breakthrough, which has just been published in leading international journal Nature Communications, also hope to develop light-active porous, metal-organic materials for use in green energy. The dream would be to create a molecule that could simply use light to convert energy – essentially replicating the way plants produce energy via photosynthesis.
Professor in the School of Chemistry at Trinity College Dublin, and Investigator in AMBER, Wolfgang Schmitt, led the research. He said: “We have essentially created a molecular ‘flask’ or better ‘sponge’ that can hold different molecules until a specific set of conditions spark them into life.”
“Hollow cage-type molecular structures have attracted a lot of scientific attention because of these features, but as the number of potential applications has grown and the target systems and environments become more complex, progress has been hampered by the lack of structures with sufficiently large inner cavities and surface areas.”
“The MOP we have just created is among the largest ever made, comprising a number of internal sub-cages, providing numerous different binding sites. The nano-sized compartments can potentially change the reactivity and properties of molecules that are encapsulated within the confined inner spaces and, as such, these cages can be used to promote distinct chemical reactions. Thus, these molecules have the potential to mimic biological enzymes.”
The journal article describes the structure of the new cage molecule, which is composed of 36 copper atoms and is made up of 96 individual components. The article can be read at Nature Communications.