Mesenchymal stem cells in osteoarthritis therapy : current status of theory, technology, and applications

Osteoarthritis (OA) is a chronic, non-inflammatory type of arthritis, which usually affects the movable and weight bearing joints of the body. It is the most common joint disease in human beings and common in elderly people. Till date, there are no safe and effective diseases modifying OA drugs (DMOADs) to treat the millions of patients suffering from this serious and debilitating disease. However, recent studies provide strong evidence for the use of mesenchymal stem cell (MSC) therapy in curing cartilage related disorders. Due to their natural differentiation properties, MSCs can serve as vehicles for the delivery of effective, targeted treatment to damaged cartilage in OA disease. In vitro, MSCs can readily be tailored with transgenes with anti-catabolic or pro-anabolic effects to create cartilage-friendly therapeutic vehicles. On the other hand, tissue engineering constructs with scaffolds and biomaterials holds promising biological cartilage therapy. Many of these strategies have been validated in a wide range of in vitro and in vivo studies assessing treatment feasibility or efficacy. In this review, we provide an outline of the rationale and status of stem-cell-based treatments for OA cartilage, and we discuss prospects for clinical implementation and the factors crucial for maintaining the drive towards this goal.

The Australian Grey Nomads : are they who we think they are? Enhancing formative research through the quantitative assessment of psychological constructs

Issue addressed: Measures of 'social identity' and 'psychological sense of community' were included within a broader formative research inquiry to gain insight into the identity characteristics and level of connectedness among older recreational road travellers (commonly known as Grey Nomads). The research sought to gain insights on how best to reach or speak to this growing driver cohort. ----- ----- Method: Participants included 631 older recreational road travellers ranging in age from 50 years to over 80 years. Data were obtained through three scales which were incorporated into a larger formative research survey; an identity hierarchy, the Three Factor Model of Social Identity and the Sense of Community Index. ----- ----- Results: Older recreational road travellers see themselves principally as couples, with social group identity being secondary. Although many identified to some degree with the Grey Nomad identity, when asked to self categorise as either members of the Broad Network of Recreational Vehicle Travellers or as Grey Nomads, the majority categorised themselves as the former. Those identifying as Grey Nomads, however, reported significantly higher levels of 'social identification' and 'sense of community'. ----- ----- Conclusion: The Grey Nomad identity may not be the best identity at which to target road safety messages for this cohort. Targeting travelling 'couples' may be more efficacious. Using the 'Grey Nomad' identity is likely to reap at least some success, however, given that many identified to some degree with this group identity. Those identifying as Grey Nomads may be more open to community participation or behaviour change given their significantly higher levels of 'social identity' and 'sense of community'.

Instability prolongs the chondral phase during bone healing in sheep

In this sheep study, we investigated the influence of fixation stability on the temporal and spatial distribution of tissues in the fracture callus. As the initial mechanical conditions have been cited as being especially important for the healing outcome, it was hypothesized that differences in the path of healing would be seen as early as the initial phase of healing. ----- ----- Sixty-four sheep underwent a mid-shaft tibial osteotomy that was treated with either a rigid or a semi-rigid external fixator. Animals were sacrificed at 2, 3, 6 and 9 weeks postoperatively and the fracture calluses were analyzed using radiological, biomechanical and histological techniques. Statistical comparison between the groups was performed using the Mann–Whitney U test for unpaired non-parametric data. ----- ----- In the callus of the tibia treated with semi-rigid fixation, remnants of the fracture haematoma remained present for longer, although new periosteal bone formation during early healing was similar in both groups. The mechanical competence of the healing callus at 6 weeks was inferior compared to tibiae treated with rigid fixation. Semi-rigid fixation resulted in a larger cartilage component of the callus, which persisted longer. Remodeling processes were initiated earlier in the rigid group, while new bone formation continued throughout the entire investigated period in the semi-rigid group. ----- ----- In this study, evidence is provided that less rigid fixation increased the time required for healing. The process of intramembranous ossification appeared during the initial stages of healing to be independent of mechanical stability. However, the delay in healing was related to a prolonged chondral phase.

Temporal tissue patterns in bone healing of sheep

Secondary fracture healing in long bones leads to the successive formation of intricate patterns of tissues in the newly formed callus. The main aim of this work was to quantitatively describe the topology of these tissue patterns at different stages of the healing process and to generate averaged images of tissue distribution. This averaging procedure was based on stained histological sections (2, 3, 6, and 9 weeks post-operatively) of 64 sheep with a 3 mm tibial mid-shaft osteotomy, stabilized either with a rigid or a semi-rigid external fixator. Before averaging, histological images were sorted for topology according to six identified tissue patterns. The averaged images were obtained for both fixation types and the lateral and medial side separately. For each case, the result of the averaging procedure was a collection of six images characterizing quantitatively the progression of the healing process. In addition, quantified descriptions of the newly formed cartilage and the bone area fractions (BA/TA) of the bony callus are presented. For all cases, a linear increase in the BA/TA of the bony callus was observed. The slope was greatest in the case of the most rigid stabilization and lowest in the case of the least stiff. This topological description of the progression of bone healing will allow quantitative validation (or falsification) of current mechano-biological theories.

Endochondral ossification in vitro is influenced by mechanical bending

Bone development is influenced by the local mechanical environment. Experimental evidence suggests that altered loading can change cell proliferation and differentiation in chondro- and osteogenesis during endochondral ossification. This study investigated the effects of three-point bending of murine fetal metatarsal bone anlagen in vitro on cartilage differentiation, matrix mineralization and bone collar formation. This is of special interest because endochondral ossification is also an important process in bone healing and regeneration. Metatarsal preparations of 15 mouse fetuses stage 17.5 dpc were dissected en bloc and cultured for 7 days. After 3 days in culture to allow adherence they were stimulated 4 days for 20 min twice daily by a controlled bending of approximately 1000-1500 microstrain at 1 Hz. The paraffin-embedded bone sections were analyzed using histological and histomorphometrical techniques. The stimulated group showed an elongated periosteal bone collar while the total bone length was not different from controls. The region of interest (ROI), comprising the two hypertrophic zones and the intermediate calcifying diaphyseal zone, was greater in the stimulated group. The mineralized fraction of the ROI was smaller in the stimulated group, while the absolute amount of mineralized area was not different. These results demonstrate that a new device developed to apply three-point bending to a mouse metatarsal bone culture model caused an elongation of the periosteal bone collar, but did not lead to a modification in cartilage differentiation and matrix mineralization. The results corroborate the influence of biophysical stimulation during endochondral bone development in vitro. Further experiments with an altered loading regime may lead to more pronounced effects on the process of endochondral ossification and may provide further insights into the underlying mechanisms of mechanoregulation which also play a role in bone regeneration.

CYR61 (CCN1) protein expression during fracture healing in an ovine tibial model and its relation to the mechanical fixation stability

The formation of new blood vessels is a prerequisite for bone healing. CYR61 (CCN1), an extracellular matrix-associated signaling protein, is a potent stimulator of angiogenesis and mesenchymal stem cell expansion and differentiation. A recent study showed that CYR61 is expressed during fracture healing and suggested that CYR61 plays a significant role in cartilage and bone formation. The hypothesis of the present study was that decreased fixation stability, which leads to a delay in healing, would lead to reduced CYR61 protein expression in fracture callus. The aim of the study was to quantitatively analyze CYR61 protein expression, vascularization, and tissue differentiation in the osteotomy gap and relate to the mechanical fixation stability during the course of healing. A mid-shaft osteotomy of the tibia was performed in two groups of sheep and stabilized with either a rigid or semirigid external fixator, each allowing different amounts of interfragmentary movement. The sheep were sacrificed at 2, 3, 6, and 9 weeks postoperatively. The tibiae were tested biomechanically and histological sections from the callus were analyzed immunohistochemically with regard to CYR61 protein expression and vascularization. Expression of CYR61 protein was upregulated at the early phase of fracture healing (2 weeks), decreasing over the healing time. Decreased fixation stability was associated with a reduced upregulation of the CYR61 protein expression and a reduced vascularization at 2 weeks leading to a slower healing. The maximum cartilage callus fraction in both groups was reached at 3 weeks. However, the semirigid fixator group showed a significantly lower CYR61 immunoreactivity in cartilage than the rigid fixator group at this time point. The fraction of cartilage in the semirigid fixator group was not replaced by bone as quickly as in the rigid fixator group leading to an inferior histological and mechanical callus quality at 6 weeks and therefore to a slower healing. The results supply further evidence that CYR61 may serve as an important regulator of bone healing.

Towards a classification of criterion referenced assessment models in mathematics courses : student and academic perspectives

We present the findings of a study into the implementation of explicitly criterion- referenced assessment in undergraduate courses in mathematics. We discuss students' concepts of criterion referencing and also the various interpretations that this concept has among mathematics educators. Our primary goal was to move towards a classification of criterion referencing models in quantitative courses. A secondary goal was to investigate whether explicitly presenting assessment criteria to students was useful to them and guided them in responding to assessment tasks. The data and feedback from students indicates that while students found the criteria easy to understand and useful in informing them as to how they would be graded, it did not alter the way the actually approached the assessment activity.

Long-term effects of hydrogel properties on human chondrocyte behavior

Hydrogels provide a 3-dimensional network for embedded cells and offer promise for cartilage tissue engineering applications. Nature-derived hydrogels, including alginate, have been shown to enhance the chondrocyte phenotype but are variable and not entirely controllable. Synthetic hydrogels, including polyethylene glycol (PEG)-based matrices, have the advantage of repeatability and modularity; mechanical stiffness, cell adhesion, and degradability can be altered independently. In this study, we compared the long-term in vitro effects of different hydrogels (alginate and Factor XIIIa-cross-linked MMP-sensitive PEG at two stiffness levels) on the behavior of expanded human chondrocytes and the development of construct properties. Monolayer-expanded human chondrocytes remained viable throughout culture, but morphology varied greatly in different hydrogels. Chondrocytes were characteristically round in alginate but mostly spread in PEG gels at both concentrations. Chondrogenic gene (COL2A1, aggrecan) expression increased in all hydrogels, but alginate constructs had much higher expression levels of these genes (up to 90-fold for COL2A1), as well as proteoglycan 4, a functional marker of the superficial zone. Also, chondrocytes expressed COL1A1 and COL10A1, indicative of de-differentiation and hypertrophy. After 12 weeks, constructs with lower polymer content were stiffer than similar constructs with higher polymer content, with the highest compressive modulus measured in 2.5% PEG gels. Different materials and polymer concentrations have markedly different potency to affect chondrocyte behavior. While synthetic hydrogels offer many advantages over natural materials such as alginate, they must be further optimized to elicit desired chondrocyte responses for use as cartilage models and for development of functional tissue-engineered articular cartilage.

Development of an automated safety assessment framework for construction activities

This paper presents an ongoing research project concerning the development of an automated safety assessment framework for earthmoving and surface mining activities. This research seeks to determine data needs for safety assessment and investigates how to utilize collected data to promote more informed and efficient safety decision-making. The research first examined accidents and fatalities involved with earthmoving and surface mining activities—more specifically, those involving loading, hauling, and dumping operations,—investigated risk factors involved with the accidents, and finally identified data needs for safety assessment based on safety regulations and practices. An automated safety assessment method was then developed using the data needs that had been identified. This research is expected to contribute to the introduction of a fundamental framework for automated safety assessment and the systematic collection of safety-related data from construction activities. Implementation of the entire safety assessment process on actual construction sites remains a task for future research.

Modeling object identification and tracking errors on image-based safety assessment of earthmoving operations

Object identification and tracking have become critical for automated on-site construction safety assessment. The primary objective of this paper is to present the development of a testbed to analyze the impact of object identification and tracking errors caused by data collection devices and algorithms used for safety assessment. The testbed models workspaces for earthmoving operations and simulates safety-related violations, including speed limit violations, access violations to dangerous areas, and close proximity violations between heavy machinery. Three different cases were analyzed based on actual earthmoving operations conducted at a limestone quarry. Using the testbed, the impacts of device and algorithm errors were investigated for safety planning purposes.

Assessment reform and educational change in Australia

This chapter addresses the changing climate of assessment policy and practice in Australia in response to global trends in education and the mounting accountability demands of standards-driven reform. Queensland, a State of Australia, has a tradition of respecting and trusting teacher judgment through the practice of, and policy commitment to, externally moderated school-based assessment. This chapter outlines the global trends in curriculum and assessment reform, and then analyzes the impact of international comparisons on national policy. The creation of the Australian Curriculum, Assessment and Reporting Authority (ACARA) together with the intent of establishing a standards-referenced framework raises tensions and challenges for teachers’ practice. The argument for sustaining confidence in teacher-based assessment is developed with reference to research evidence pertaining to the use of more authentic assessments and moderation practices for the purposes of improving learning, equity and accountability. Evidence is drawn from local studies of teacher judgment practice and used to demonstrate these developments and in so doing illuminate the complex issues of engaging the demands of policy while sustaining confidence in teacher assessment.

A hierarchical security assessment model for object-oriented programs

We present a hierarchical model for assessing an object-oriented program's security. Security is quantified using structural properties of the program code to identify the ways in which `classified' data values may be transferred between objects. The model begins with a set of low-level security metrics based on traditional design characteristics of object-oriented classes, such as data encapsulation, cohesion and coupling. These metrics are then used to characterise higher-level properties concerning the overall readability and writability of classified data throughout the program. In turn, these metrics are then mapped to well-known security design principles such as `assigning the least privilege' and `reducing the size of the attack surface'. Finally, the entire program's security is summarised as a single security index value. These metrics allow different versions of the same program, or different programs intended to perform the same task, to be compared for their relative security at a number of different abstraction levels. The model is validated via an experiment involving five open source Java programs, using a static analysis tool we have developed to automatically extract the security metrics from compiled Java bytecode.

Adhesion of perichondrial cells to a polylactic acid scaffold

The number of chondrogenic cells available locally is an, important factor in the repair process for cartilage defects. Previous studies demonstrated that the number of transplanted rabbit perichondrial cells (PC) remaining in a cartilage defect in vivo, after being carried into the site in a polylactic acid (PLA) scaffold, declined markedly within two days. This study examined the ability of in vitro culture of PC/PLA constructs to enhance subsequent biomechanical stability of the cells and the matrix content in an in vitro screening assay. PC/PLA constructs were analyzed after 1 h, 1 and 2 weeks of culture. The biomechanical adherence of PC to the PLA scaffold was tested by subjecting the PC/PLA constructs to a range of flow velocities (0.25-25 mm/s), spanning the range estimated to occur under conditions of construct insertion in vivo. The adhesion of PC to the PLA carrier was increased significantly by 1 and 2 weeks of incubation, with 25 mm/s flow causing a 57% detachment of cells after 1 h of seeding, but only 7% and 16% after I and 2 weeks of culture, respectively (p < 0.001). This adherence was associated with marked deposition of glycosaminoglycan and collagen. These findings suggest that pre-incubation of PC-laden PLA scaffolds markedly enhances the stability of the indwelling cells. (C) 2003 Orthopaedic Research Society. Published by Elsevier Science Ltd. All rights reserved.