Mesenchymal stromal cells and the repair of cartilage tissue

Articular cartilage has a limited intrinsic repair capacity, and thus defects are more likely to further degrade rather than undergo spontaneous self-repair. Whilst a number of surgical techniques have been developed to repair cartilage defects, their efficacy is generally poor and total joint replacement remains the gold standard, albeit last resort, treatment option. Cell-based therapies hold the greatest promise, as they appear uniquely capable of generating de novo cartilage tissue. Two approved therapies (ACI and MACI) are based on the premise that the transplantation of ex vivo expanded autologous chondrocyte populations, harvested from a non-load bearing region of the same joint, could be utilized to effectively regenerate cartilage tissue in the primary defect site. These therapeutic strategies are partially limited by our inability to harvest and expand adequate numbers of autologous chondrocytes that retain the appropriate phenotype. By contrast, the harvest and expansion of large numbers of mesenchymal stem/stromal cells (MSC) derived from tissues such as bone marrow and adipose is comparatively straightforward and has become routine in laboratories worldwide. Additionally, our understanding of the biochemical and biophysical signals required to drive the chondrogenic differentiation of MSC is rapidly increasing. It is conceivable that in the near future MSC expansion and differentiation technologies will offer a means to generate sufficient cell numbers, of an appropriate phenotype, for use in cartilage defect repair. In this chapter we review the relative potential of MSC and their likely contribution to cartilage regeneration.

An analysis for the causes of accidents of repair, maintenance, alteration and addition works in Hong Kong

This study unveils causes of accidents in repair, maintenance, alteration and addition (RMAA) work. RMAA work is playing an increasingly important role in developed societies, including Hong Kong. Safety problems associated with RMAA work in Hong Kong has reached an alarming level. In view of rapid expansion of the RMAA sector and rising proportion of accidents in the construction industry, there is a pressing need to investigate causes of RMAA accidents. Structured interviews were conducted with RMAA contractors to explore causes of accidents in the RMAA sector. A two-round Delphi method with 13 safety experts was subsequently employed to verify the interview findings and rank the relative degree of importance for various causes of accidents. Accidents happen in RMAA work due to intersection of reasons. One of the root causes of accidents in RMAA works is low safety awareness of RMAA workers; however, wider organizational and industrial factors are not negligible. This study sheds light on why accidents happen in the RMAA sector. Only when the factors leading to accidents are identified can effective measures be made.

Empirical study to investigate the difficulties of implementing safety practices in the repair and maintenance sector in Hong Kong

Repair, maintenance, minor alteration, and addition work (RMAA) has become more and more important in developed societies, but its safety performance is alarming. For example, RMAA projects accounted for 53.2% of the total construction market and the percentage of RMAA accidents to all construction accidents in the Hong Kong Special Administrative Region (HKSAR) increased considerably in 2007. The RMAA sector has a huge potential for safety improvement. This study aims to explore and evaluate the difficulties of implementing safety practices in RMAA work. The mixed methods approach was adopted, and semistructured interviews and a two-round Delphi survey were conducted for the data collection. Major difficulties were identified, including limited safety resources for small and medium enterprises (SMEs), difficulty in changing the mindset of RMAA workers, and difficulty in performing safety supervision. These obstacles for implementing safety practices in the RMAA sector, if successfully removed, could significantly improve the safety performance of the RMAA sector and the construction industry as a whole.

Safety management in repair, maintenance, minor alteration, and addition works : knowledge management perspective

Safety of repair, maintenance, alteration, and addition (RMAA) works have long been neglected because RMAAworks are often minute and only last for a short period of time. With rising importance of the RMAA sector in many developed societies, safety of RMAA works has begun to draw attention. Many RMAA contracting companies are small- and medium-sized enterprises (SMEs) that do not have comprehensive safety management systems. Existing safety legislation and regulations for new construction sites are not fully applicable to RMAAworks. Instead of relying on explicit and well-established safety systems, tacit safety knowledge plays an extremely important role in RMAA projects. To improve safety of RMAAworks, safety knowledge should be better managed. However, safety knowledge is difficult to capture in RMAA works. This study aims to examine safety management practices of RMAA contracting companies to see how safety knowledge of RMAA projects is managed. Findings show that RMAA contracting companies undertaking large-scale RMAA projects have more initiatives of safety management. Safety management of small-scale RMAA works relies heavily on the motivation of site supervisors and self-regulation of workers. Better tacit knowledge management improves safety performance. To enhance safety capability of RMAA contracting companies, a knowledge sharing culture should be cultivated. The government should provide assistance to SMEs to implement proper safety management practices in small-sized projects. Potentials of applying computer software technology in RMAA projects to capture, store, and retrieve safety information should be explored. Employees should be motivated to share safety knowledge by giving proper recognition to those who are willing to share.

Safety climate and injury occurrence of repair, maintenance, minor alteration and addition works : a comparison of workers, supervisors and managers

Purpose The repair, maintenance, minor alteration and addition (RMAA) sector has been expanding in many developed cities. Safety problems of the RMAA sector have attracted the attention of many governments. This study has the objectives of comparing the level of safety climate of workers, supervisors and managers in the RMAA sector; and explaining/ predicting the impact of safety climate on injury occurrence of workers, supervisors and managers. Design/methodology/approach A questionnaire survey was administered to RMAA contracting companies in Hong Kong. Findings When comparing the safety climate perception of workers, supervisors and managers in the RMAA sector, the supervisors group had the lowest mean safety climate score. Results showed that a positive workforce safety attitude and acceptance of safety rules and regulations reduced the workers’ likelihood of having injuries. A reasonable production schedule led to a lower probability of supervisors being injured. Management commitment and effective safety management reduced the probability of managers being injured. Originality/value This study revealed variations of safety climate at the different levels in the organizational hierarchy and their varying influence on safety performance of the RMAA sector. Safety of RMAA works could be improved by promulgating specific safety measures at the different hierarchy levels.

Fatalities of repair, maintenance, minor alteration, and addition works in Hong Kong

This study examines fatalities of repair, maintenance, minor alteration, and addition (RMAA) works which occurred in Hong Kong between January 2000 and October 2011. A total of 119 RMAA fatalities were recorded. Particular emphasis was placed on fall from height accidents as they accounted for the vast majority of RMAA fatal accidents for the period. A cluster analysis was conducted on fall from height fatal cases. The cluster analysis clearly identified three groups of fall from height fatalities: (1) bamboo scaffolders aged between 25 and 34 who fell from external wall/facade in the beginning of weekdays; (2) miscellaneous workers aged between 45 and 54 who fell from other/unknown places in the end of weekdays; and (3) manual labour aged between 35 and 44 who fell at floor level/from floor openings in weekends. Unsafe process and improper procedures were the main unsafe condition leading to fatalities whereas safety belt not properly used was the main unsafe action leading to fatalities. Specific safety interventions were recommended for each of these groups to help avoid these fatalities.

Relationships between safety climate and safety performance of building repair, maintenance, minor alteration, and addition (RMAA) works

The importance of repair, maintenance, minor alteration, and addition (RMAA) works is increasing in many built societies. When the volume of RMAA works increases, the occurrence of RMAA accidents also increases. Safety of RMAA works deserves more attention; however, research in this important topic remains limited. Safety climate is considered a key factor that influences safety performance. The present study aims to determine the relationships between safety climate and safety performance of RMAA works, thereby offering recommendations on improving RMAA safety. Questionnaires were dispatched to private property management companies, maintenance sections of quasi-government developers and their subcontractors, RMAA sections of general contractors, small RMAA contractors, building services contractors and trade unions in Hong Kong. In total, data from 396 questionnaires were collected from RMAA workers. The sample was divided into two equal-sized sub-samples. On the first sub-sample SEM was used to test the model, which was validated on the second sub-sample. The model revealed a significant negative relationship between RMAA safety climate and incidence of self-reported near misses and injuries, and significant positive relationships between RMAA safety climate and safety participation and safety compliance respectively. Higher RMAA safety climate was positively associated with a lower incidence of self-reported near misses and injuries and higher levels of safety participation and safety compliance.

Determining safety climate factors in the repair, maintenance, minor alteration, and addition sector of Hong Kong

The accident record of the repair, maintenance, minor alteration, and addition (RMAA) sector has been alarmingly high; however, research in the RMAA sector remains limited. Unsafe behavior is considered one of the key causes of accidents. Thus, the organizational factors that influence individual safety behavior at work continue to be the focus of many studies. The safety climate, which reflects the true priority of safety in an organization, has drawn much attention. Safety climate measurement helps to identify areas for safety improvement. The current study aims to identify safety climate factors in the RMAA sector. A questionnaire survey was conducted in the RMAA sector in Hong Kong. Data were randomly split into the calibration and the validation samples. The RMAA safety climate factors were determined by exploratory factor analysis on the calibration sample. Three safety climate factors of the RMAA works were identified: (1) management commitment to occupational health and safety (OHS) and employee involvement, (2) application of safety rules and work practices, and; (3) responsibility for health and safety. Confirmatory factor analysis (CFA) was then conducted on the validation sample. The CFA model showed satisfactory goodness of fit, reliability, and validity. The suggested RMAA safety climate factors can be utilized by construction industry practitioners in developed economies to measure the safety climate of their RMAA projects, thereby enhancing the safety of RMAA works.

Strategies for improving safety performance of repair, maintenance, minor alteration and addition (RMAA) works

Purpose Managing and maintaining infrastructure assets are one of the indispensible tasks for many government agencies to preserve the nations' economic viability and social welfare. To reduce the expenditures over the life-cycle of an infrastructure asset and extend the period for which the asset performs effectively, proper repair and maintenance are essential. While repair, maintenance, minor alteration and addition (RMAA) sector is expanding in many developed cities, occurrences of fatalities and injuries in this sector are also soaring. The purposes of this paper are to identify and then evaluate the various strategies for improving the safety performance of RMAA works. Design/methodology/approach Semi-structured interviews and two rounds of Delphi survey were conducted for data collection. Findings Raising safety awareness of RMAA workers and selecting contractors with a good record of safety performance are the two most important strategies to improve the safety performance in this sector. Technology innovations and a pay-for-safety scheme are regarded as the two least important strategies. Originality/value The paper highlights possible ways to enhance safety of the rather under-explored RMAA sector in the construction industry.

A game theoretical approach to construction safety in the Repair, Maintenance, Alteration and Addition (RMAA) sector

Safety has long been a problem in the construction industry. Repair, maintenance, alteration and addition (RMAA) sector has emerged to play an important role in the construction industry. It accounted for 53% of the total construction market in Hong Kong in 2007. Safety performance of the RMAA words has been alarming. Statistics indicate that the percentage of fatal industrial accidents arising from RMAA work in Hong Kong was over 56% in 2006 while the remaining 44% was from new works. Effective safety measures to address the safety problems and improve safety performance of the RMAA sector are urgently needed. Unsafe behaviour has been attributed to one of the major causes of accidents. Traditional cost-benefit analysis of workers' safety behaviour seems to be inadequate. This paper proposes to adopt a game theoretical approach to analyse safety behaviour of RMAA workers. Game theory is concerned with the decision-making process in situations where outcomes depend upon choices made by one or more players. A game theoretical model between contractor and worker has been proffered. Mathematical analysis of this game model has been done and implications of the analysis have been discussed.

Evaluation of BMP-2 gene-activated muscle grafts for cranial defect repair

Large, osseous, segmental defects heal poorly. Muscle has a propensity to form bone when exposed to an osteogenic stimulus such as that provided by transfer and expression of cDNA encoding bone morphogenetic protein-2 (BMP-2). The present study evaluated the ability of genetically modified, autologous muscle to heal large cranial defects in rats. Autologous grafts (8 mm � 2 mm) were punched from the biceps femoris muscle and transduced intraoperatively with recombinant adenovirus vector containing human BMP-2 or green fluorescent protein cDNA. While the muscle biopsies were incubating with the vector, a central parietal 8 mm defect was surgically created in the calvarium of the same animal. The gene-activated muscle graft was then implanted into the cranial defect. After 8 weeks, crania were examined radiographically, histologically, and by micro-computed tomography and dual energy X-ray absorptiometry. Although none of the defects were completely healed in this time, muscle grafts expressing BMP-2 deposited more than twice as much new bone as controls. Histology confirmed the anatomical integrity of the newly formed bone, which was comparable in thickness and mineral density to the original cranial bone. This study confirms the in vivo osteogenic properties of genetically modified muscle and suggests novel strategies for healing bone. � 2011 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 30:1095–1102, 2012

Use of genetically modified muscle and fat grafts to repair defects in bone and cartilage

We report a novel technology for the rapid healing of large osseous and chondral defects, based upon the genetic modification of autologous skeletal muscle and fat grafts. These tissues were selected because they not only possess mesenchymal progenitor cells and scaffolding properties, but also can be biopsied, genetically modified and returned to the patient in a single operative session. First generation adenovirus vector carrying cDNA encoding human bone morphogenetic protein-2 (Ad.BMP-2) was used for gene transfer to biopsies of muscle and fat. To assess bone healing, the genetically modified (“gene activated”) tissues were implanted into 5mm-long critical size, mid-diaphyseal, stabilized defects in the femora of Fischer rats. Unlike control defects, those receiving gene-activated muscle underwent rapid healing, with evidence of radiologic bridging as early as 10 days after implantation and restoration of full mechanical strength by 8 weeks. Histologic analysis suggests that the grafts rapidly differentiated into cartilage, followed by efficient endochondral ossification. Fluorescence in situ hybridization detection of Y-chromosomes following the transfer of male donor muscle into female rats demonstrated that at least some of the osteoblasts of the healed bone were derived from donor muscle. Gene activated fat also healed critical sized defects, but less quickly than muscle and with more variability. Anti-adenovirus antibodies were not detected. Pilot studies in a rabbit osteochondral defect model demonstrated the promise of this technology for healing cartilage defects. Further development of these methods should provide ways to heal bone and cartilage more expeditiously, and at lower cost, than is presently possible.

Reduced excision repair cross-complementing 1 expression associates with enhanced papilloma formation and fibroblast transformation after genetic disruption of secreted protein acidic and rich in cysteine

SPARC (secreted protein acidic and rich in cysteine)/ osteonectin/BM-40 is a matricellular protein implicated in development, cell transformation and tumorigenesis. We have examined the role of SPARC in cell transformation induced chemically with 7,12-dimethylbenz[a]anthracene (DMBA) and 12- tetradecanoylphorbol-13-acetate (TPA) in embryonic fibroblasts and in the skin of mice. Embryonic fibroblasts from SPARCnull mice showed increases in cell proliferation, enhanced sensitivity to DMBA and a higher number of DMBA/TPA-induced transformation foci. The number of DMBA-DNA adducts was 9 times higher in SPARCnull fibroblasts and their stability was lower than wild-type fibroblasts, consistent with a reduction in excision repair cross-complementing 1 the nucleotide excision repair enzyme in these cells. The SPARCnull mice showed an increase in both the speed and number of papillomas forming after topical administration of DMBA/TPA to the skin. These papillomas showed reduced growth and reduced progression to a more malignant phenotype, indicating that the effect of SPARC on tumorigenesis depends upon the transformation stage and/or tissue context. These data reinforce a growing number of observations in which SPARC has shown opposite effects on different tumor types/stages.

Mechanistic insights into RAD51-associated protein 1 (RAD51AP1) action in homologous DNA repair

Homologous recombination catalyzed by the RAD51 recombinase is essential for maintaining genome integrity upon the induction of DNA double strand breaks and other DNA lesions. By enhancing the recombinase activity of RAD51, RAD51AP1 (RAD51-associated protein 1) serves a key role in homologous recombination-mediated chromosome damage repair. We show here that RAD51AP1 harbors two distinct DNA binding domains that are both needed for maximal protein activity under physiological conditions. We have finely mapped the two DNA binding domains in RAD51AP1 and generated mutant variants that are impaired in either or both of the DNA binding domains. Examination of these mutants reveals that both domains are indispensable for RAD51AP1 function in cells. These and other results illuminate the mechanistic basis of RAD51AP1 action in homologous DNA repair.

Human single-stranded DNA binding protein 1 (hSSB1/NABP2) is required for the stability and repair of stalled replication forks

Aberrant DNA replication is a primary cause of mutations that are associated with pathological disorders including cancer. During DNA metabolism, the primary causes of replication fork stalling include secondary DNA structures, highly transcribed regions and damaged DNA. The restart of stalled replication forks is critical for the timely progression of the cell cycle and ultimately for the maintenance of genomic stability. Our previous work has implicated the single-stranded DNA binding protein, hSSB1/NABP2, in the repair of DNA double-strand breaks via homologous recombination. Here, we demonstrate that hSSB1 relocates to hydroxyurea (HU)-damaged replication forks where it is required for ATR and Chk1 activation and recruitment of Mre11 and Rad51. Consequently, hSSB1-depleted cells fail to repair and restart stalled replication forks. hSSB1 deficiency causes accumulation of DNA strand breaks and results in chromosome aberrations observed in mitosis, ultimately resulting in hSSB1 being required for survival to HU and camptothecin. Overall, our findings demonstrate the importance of hSSB1 in maintaining and repairing DNA replication forks and for overall genomic stability.