Translating tissue engineering technology platforms into cancer research

Technology platforms originally developed for tissue engineering applications produce valuable models that mimic three-dimensional (3D) tissue organization and function to enhance the understanding of cell/tissue function under normal and pathological situations. These models show that when replicating physiological and pathological conditions as closely as possible investigators are allowed to probe the basic mechanisms of morphogenesis, differentiation and cancer. Significant efforts investigating angiogenetic processes and factors in tumorigenesis are currently undertaken to establish ways of targeting angiogenesis in tumours. Anti-angiogenic agents have been accepted for clinical application as attractive targeted therapeutics for the treatment of cancer. Combining the areas of tumour angiogenesis, combination therapies and drug delivery systems is therefore closely related to the understanding of the basic principles that are applied in tissue engineering models. Studies with 3D model systems have repeatedly identified complex interacting roles of matrix stiffness and composition, integrins, growth factor receptors and signalling in development and cancer. These insights suggest that plasticity, regulation and suppression of these processes can provide strategies and therapeutic targets for future cancer therapies. The historical perspective of the fields of tissue engineering and controlled release of therapeutics, including inhibitors of angiogenesis in tumours is becoming clearly evident as a major future advance in merging these fields. New delivery systems are expected to greatly enhance the ability to deliver drugs locally and in therapeutic concentrations to relevant sites in living organisms. Investigating the phenomena of angiogenesis and anti-angiogenesis in 3D in vivo models such as the Arterio-Venous (AV) loop mode in a separated and isolated chamber within a living organism adds another significant horizon to this perspective and opens new modalities for translational research in this field.

Establishment of a preclinical ovine model for tibial segmental bone defect repair by applying bone tissue engineering strategies

Currently, well-established clinical therapeutic approaches for bone reconstruction are restricted to the transplantation of autografts and allografts, and the implantation of metal devices or ceramic-based implants to assist bone regeneration. Bone grafts possess osteoconductive and osteoinductive properties, however they are limited in access and availability and associated with donor site morbidity, haemorrhage, risk of infection, insufficient transplant integration, graft devitalisation, and subsequent resorption resulting in decreased mechanical stability. As a result, recent research focuses on the development of alternative therapeutic concepts. The field of tissue engineering has emerged as an important approach to bone regeneration. However, bench to bedside translations are still infrequent as the process towards approval by regulatory bodies is protracted and costly, requiring both comprehensive in vitro and in vivo studies. The subsequent gap between research and clinical translation, hence commercialization, is referred to as the ‘Valley of Death’ and describes a large number of projects and/or ventures that are ceased due to a lack of funding during the transition from product/technology development to regulatory approval and subsequently commercialization. One of the greatest difficulties in bridging the Valley of Death is to develop good manufacturing processes (GMP) and scalable designs and to apply these in pre-clinical studies. In this article, we describe part of the rationale and road map of how our multidisciplinary research team has approached the first steps to translate orthopaedic bone engineering from bench to bedside byestablishing a pre-clinical ovine critical-sized tibial segmental bone defect model and discuss our preliminary data relating to this decisive step.

The genetic basis of human height : the role of estrogen

Height is a complex physical trait that displays strong heritability. Adult height is related to length of the long bones, which is determined by growth at the epiphyseal growth plate. Longitudinal bone growth occurs via the process of endochondral ossification, where bone forms over the differentiating cartilage template at the growth plate. Estrogen plays a major role in regulating longitudinal bone growth and is responsible for inducing the pubertal growth spurt and fusion of the epiphyseal growth plate. However, the mechanism by which estrogen promotes epiphyseal fusion is poorly understood. It has been hypothesised that estrogen functions to regulate growth plate fusion by stimulating chondrocyte apoptosis, angiogenesis and bone cell invasion in the growth plate. Another theory has suggested that estrogen exposure exhausts the proliferative capacity of growth plate chondrocytes, which accelerates the process of chondrocyte senescence, leading to growth plate fusion. The overall objective of this study was to gain a greater understanding of the molecular mechanisms behind estrogen-mediated growth and height attainment by examining gene regulation in chondrocytes and the role of some of these genes in normal height inheritance. With the heritability of height so well established, the initial hypothesis was that genetic variation in candidate genes associated with longitudinal bone growth would be involved in normal adult height variation. The height-related genes FGFR3, CBFA1, ER and CBFA1 were screened for novel polymorphisms using denaturing HPLC and RFLP analysis. In total, 24 polymorphisms were identified. Two SNPs in ER (rs3757323 C>T and rs1801132 G>C) were strongly associated with adult male height and displayed an 8 cm and 9 cm height difference between homozygous genotypes, respectively. The TC haplotype of these SNPs was associated with a 6 cm decrease in height and remarkably, no homozygous carriers of the TC haplotype were identified in tall subjects. No significant associations with height were found for polymorphisms in the FGFR3, CBFA1 or VDR genes. In the epiphyseal growth plate, chondrocyte proliferation, matrix synthesis and chondrocyte hypertrophy are all major contributors to long bone growth. As estrogen plays such a significant role in both growth and final height attainment, another hypothesis of this study was that estrogen exerted its effects in the growth plate by influencing chondrocyte proliferation and mediating the expression of chondrocyte marker genes. The examination of genes regulated by estrogen in chondrocyte-like cells aimed to identify potential regulators of growth plate fusion, which may further elucidate mechanisms involved in the cessation of linear growth. While estrogen did not dramatically alter the proliferation of the SW1353 cell line, gene expression experiments identified several estrogen regulated genes. Sixteen chondrocyte marker genes were examined in response to estrogen concentrations ranging from 10-12 M to 10-8 M over varying time points. Of the genes analysed, IHH, FGFR3, collagen II and collagen X were not readily detectable and PTHrP, GHR, ER, BMP6, SOX9 and TGF1 mRNAs showed no significant response to estrogen treatments. However, the expression of MMP13, CBFA1, BCL-2 and BAX genes were significantly decreased. Interestingly, the majority of estrogen regulated genes in SW1353 cells are expressed in the hypertrophic zone of the growth plate. Estrogen is also known to regulate systemic GH secretion and local GH action. At the molecular level, estrogen functions to inhibit GH action by negatively regulating GH signalling. GH treated SW1353 cells displayed increases in MMP9 mRNA expression (4.4-fold) and MMP13 mRNA expression (64-fold) in SW1353 cells. Increases were also detected in their respective proteins. Treatment with AG490, an established JAK2 inhibitor, blocked the GH mediated stimulation of both MMP9 and MMP13 mRNA expression. The application of estrogen and GH to SW1353 cells attenuated GH-stimulated MMP13 levels, but did not affect MMP9 levels. Investigation of GH signalling revealed that SW1353 cells have high levels of activated JAK2 and exposure to GH, estrogen, AG490 and other signalling inhibitors did not affect JAK2 phosphorylation. Interestingly, AG490 treatment dramatically decreased ERK2 signalling, although GH did stimulate ERK2 phosphorylation above control levels. AG490 also decreased CBFA1 expression, a transcription factor known to activate MMP9 and MMP13. Finally, GH and estrogen treatment increased expression of SOCS3 mRNA, suggesting that SOCS3 may regulate JAK/STAT signalling in SW1353 cells. The modulation of GH-mediated MMP expression by estrogen in SW1353 cells represents a potentially novel mechanism by which estrogen may regulate longitudinal bone growth. However, further investigation is required in order to elucidate the precise mechanisms behind estrogen and GH regulation of MMP13 expression in SW1353 cells. This study has provided additional evidence that estrogen and the ER gene are major factors in the regulation of growth and the determination of adult height. Newly identified polymorphisms in the ER gene not only contribute to our understanding of the genetic basis of human height, but may also be useful in association studies examining other complex traits. This study also identified several estrogen regulated genes and indicated that estrogen modifies the expression of genes which are primarily expressed in the hypertrophic region of the epiphyseal growth plate. Furthermore, synergistic studies incorporating GH and estrogen have revealed the ability of estrogen to attenuate the effects of GH on MMP13 expression, revealing potential pathways by which estrogen may modulate growth plate fusion, longitudinal bone growth and even arthritis.

Integrating engineering education in the middle school mathematics curriculum

Many nations are experiencing a decline in the number of graduating engineers, an overall poor preparedness for engineering studies in tertiary institutions, and a lack of diversity in the field. Given the increasing importance of mathematics, science, engineering, and technology in our world, it is imperative that we foster an interest and drive to participate in engineering from an early age. This discuission paper argues for the intergration of engineering education within the elementary and middle school mathematics curricula. In doing so, we offer a definition of engineering education and address its core goals; consider some perceptions of engineering and engineering education held by teachers and students; and offer one approach to promoting engineering education within the elementary and middle school mathematics curriculum, namely through mathematical modeling.

Integrating engineering model eliciting activities in elementary school curricula

This paper argues for a future-oriented, inclusion of Engineering Model Eliciting Activities (EngMEAs) in elementary mathematics curricula. In EngMEAs students work with meaningful engineering problems that capitalise on and extend their existing mathematics and science learning, to develop, revise and document powerful models, while working in groups. The models developed by six groups of 12-year students in solving the Natural Gas activity are presented. Results showed that student models adequately solved the problem, although student models did not take into account all the data provided. Student solutions varied to the extent students employed the engineering context in their models and to their understanding of the mathematical concepts involved in the problem. Finally, recommendations for implementing EngMEAs and for further research are discussed.

Integrating Engineering Experiences within the Elementary Mathematics Curriculum

Engineering education for elementary school students is a new and increasingly important domain of research by mathematics, science, technology, and engineering educators. Recent research has raised questions about the context of engineering problems that are meaningful, engaging, and inspiring for young students. In the present study an environmental engineering activity was implemented in two classes of 11-year-old students in Cyprus. The problem required students to use the data to develop a procedure for selecting among alternative countries from which to buy water. Students created a range of models that adequately solved the problem although not all models took into account all of the data provided. The models varied in the number of problem factors taken into consideration and also in the different approaches adopted in dealing with the problem factors. At least two groups of students integrated into their models the environmental aspect of the problem (energy consumption, water pollution) and further refined their models. Results provide evidence that engineering model-eliciting activities can be successfully integrated in the elementary mathematics curriculum. These activities provide rich opportunities for students to deal with engineering contexts and to apply their learning in mathematics and science to solving real-world engineering problems.

The Queensland study of melanoma : Environmental and genetic associations (Q-MEGA); Study design, baseline characteristics, and repeatability of phenotype and sun exposure measures

Cutaneous malignant melanoma (CMM) is a major health issue in Queensland, Australia, which has the world’s highest incidence. Recent molecular and epidemiologic studies suggest that CMM arises through multiple etiological pathways involving gene-environment interactions. Understanding the potential mechanisms leading to CMM requires larger studies than those previously conducted. This article describes the design and baseline characteristics of Q-MEGA, the Queensland Study of Melanoma: Environmental and Genetic Associations, which followed up 4 population-based samples of CMM patients in Queensland, including children, adolescents, men aged over 50, and a large sample of adult cases and their families, including twins. Q-MEGA aims to investigate the roles of genetic and environmental factors, and their interaction, in the etiology of melanoma. Three thousand, four hundred and seventy-one participants took part in the follow-up study and were administered a computer-assisted telephone interview in 2002-2005. Updated data on environmental and phenotypic risk factors, and 2777 blood samples were collected from interviewed participants as well as a subset of relatives. This study provides a large and well-described population-based sample of CMM cases with follow-up data. Characteristics of the cases and repeatability of sun exposure and phenotype measures between the baseline and the follow-up surveys, from 6 to 17 years later, are also described.

Introducing Engineering Education in the Middle School

This paper first describes a new three-year, longitudinal project that is implementing engineering education in three middle schools in Australia (grade levels 7-9). This important domain is untapped in Australia. Hence, as a starting point, we conducted a context analysis to help situate engineering education in a school system. We report on this analysis with respect to findings from one of two literature-based surveys that gathered middle-school student responses in mathematics (n=172) and science (n=166) towards understanding their dispositions for engineering education. ANOVA indicated gender differences for 3 out of 23 items in both mathematics and science. In addition, the majority of students agreed or strongly agreed with 17 of the 23 survey items, however, there were some differences between mathematics and science. We conclude the paper with some recommendations for establishing engineering education in schools, including the development of partnerships among engineering and education faculties, school systems, and industry to develop contemporary engineering resources to support school-level mathematics, science, and technology.

Integrating engineering education within the elementary and middle school mathematics curriculum

Many nations are experiencing a decline in the number of graduating engineers, an overall poor preparedness for engineering studies in tertiary institutions, and a lack of diversity in the field. Given the increasing importance of mathematics, science, engineering, and technology in our world, it is imperative that we foster an interest and drive to participate in engineering from an early age. This discussion paper argues for the integration of engineering education within the elementary and middle school mathematics curricula. In doing so, we offer a definition of engineering education and address its core goals; consider some perceptions of engineering and engineering education held by teachers and students; and offer one approach to promoting engineering education within the elementary and middle school mathematics curriculum, namely through mathematical modeling.

QoS-Based Web Service Scheduling Accommodating Inter-Service Dependencies Using Minimal-Conflict Hill-Climbing Repair Genetic Algorithm

In the filed of semantic grid, QoS-based Web service scheduling for workflow optimization is an important problem.However, in semantic and service rich environment like semantic grid, the emergence of context constraints on Web services is very common making the scheduling consider not only quality properties of Web services, but also inter service dependencies which are formed due to the context constraints imposed on Web services. In this paper, we present a repair genetic algorithm, namely minimal-conflict hill-climbing repair genetic algorithm, to address scheduling optimization problems in workflow applications in the presence of domain constraints and inter service dependencies. Experimental results demonstrate the scalability and effectiveness of the genetic algorithm.

Analysing preservice teachers' potential for implementing engineering education in the middle school

Engineering is pivotal to any country's development. Yet there are insufficient engineers to take up available positions in many countries, including Australia (Engineers Australia, 2008). Engineering education is limited in Australia at the primary, middle and high school levels. One of the starting points for addressing this shortfall lies in preservice teacher education. This study explores second-year preservice teachers' potential to teach engineering in middle school, following their engagement with engineering concepts in their science curriculum unit and their teaching of engineering activities to Year 7 students. Using a literature-based pretest-posttest survey, items were categorised into four constructs (ie. personal professional attributes, student motivation, pedagogical knowledge and fused curricula). Results indicated that the preservice teachers' responses had not changed for instilling positive attitudes (88%) and accepting advice from colleagues (94%). However, there was statistical significance with 9 of the 25 survey items (p<0.05) after the preservice teachers' involvement in engineering activities. Fusing engineering education with other subjects, such as mathematics and science, is an essential first step in promoting preservice teachers' potential to implement engineering education in the middle school.

Tissue engineering of articular cartilage with biomimetic zones

Articular cartilage damage is a persistent and increasing problem with the aging population, and treatments to achieve biological repair or restoration remain a challenge. Cartilage tissue engineering approaches have been investigated for over 20 years, but have yet to achieve the consistency and effectiveness for widespread clinical use. One of the potential reasons for this is that the engineered tissues do not have or establish the normal zonal organization of cells and extracellular matrix that appears critical for normal tissue function. A number of approaches are being taken currently to engineer tissue that more closely mimics the organization of native articular cartilage. This review focuses on the zonal organization of native articular cartilage, strategies being used to develop such organization, the reorganization that occurs after culture or implantation, and future prospects for the tissue engineering of articular cartilage with biomimetic zones.

Addressing Challenges for Internationalisation and Mobility in Engineering Through CDIO Standards

There is a growing need for international transparency of engineering qualifications, and mechanisms to support and facilitate student mobility. In response, there are a number of global initiatives attempting to address these needs, particularly in Europe, North America and Australia. The Conceive-Design-Implement-Operate (CDIO) Initiative has a set of standards, competencies, and proficiency levels developed through a global community of practice. It is a well-structured framework in which best-practice internationalisation and student mobility can be embedded. However, the current 12 CDIO Standards do not address international qualifications or student mobility. Based on an environmental scan of global activities, the underpinning principles of best practice are identified and form the basis of the proposed 13th CDIO Standard — “Internationalization and Mobility”.

An extended CDIO syllabus framework with preparatory engineering proficiencies

The CDIO Initiative has been globally recognised as an enabler for engineering education reform. With the CDIO process, the CDIO Standards and the CDIO Syllabus, many scholarly contributions have been made around cultural change, curriculum reform and learning environments. In the Australasian region, reform is gaining significant momentum within the engineering education community, the profession, and higher education institutions. This paper presents the CDIO Syllabus cast into the Australian context by mapping it to the Engineers Australia Graduate Attributes, the Washington Accord Graduate Attributes and the Queensland University of Technology Graduate Capabilities. Furthermore, in recognition that many secondary schools and technical training institutions offer introductory engineering technology subjects, this paper presents an extended self-rating framework suited for recognising developing levels of proficiency at a preparatory level. The framework is consistent with conventional application to undergraduate programs and professional practice, but adapted for the preparatory context. As with the original CDIO framework with proficiency levels, this extended framework is informed by Bloom’s Educational Objectives. A proficiency evaluation of Queensland Study Authority’s Engineering Technology senior syllabus is demonstrated indicating proficiency levels embedded within this secondary school subject within a preparatory scope. Through this extended CDIO framework, students and faculty have greater awareness and access to tools to promote (i) student engagement in their own graduate capability development, (ii) faculty engagement in course and program design, through greater transparency and utility of the continuum of graduate capability development with associate levels of proficiency, and the context in which they exist in terms of pre-tertiary engineering studies; and (iii) course maintenance and quality audit methodology for the purpose of continuous improvement processes and program accreditation.

Stakeholder impact analysis of infrastructure project management in developing countries : a study of perception of project managers in state-owned engineering firms in Vietnam

Construction projects can involve a diverse range of stakeholders and the success of the project depends very much on fulfilling their needs and expectations. It is important, therefore, to identify and recognize project stakeholders and develop a rigorous stakeholder management process. However, limited research has investigated the impact of stakeholders on construction projects in developing countries. A stakeholder impact analysis (SIA), based on an approach developed by Olander (2007), was adopted to investigate the stakeholders' impact on state-owned civil engineering projects in Vietnam. This involved the analysis of a questionnaire survey of 57 project managers to determine the relative importance of different stakeholders. The results show the client to have the highest level of impact on the projects, followed by project managers and the senior management of state-owned engineering firms. The SIA also provides suggestions to project managers in developing and evaluating the stakeholder management process.