Development of Bone Targeting Drugs.

The skeletal system, comprising bones, ligaments, cartilage and their connective tissues, is critical for the structure and support of the body. Diseases that affect the skeletal system can be difficult to treat, mainly because of the avascular cartilage region. Targeting drugs to the site of action can not only increase efficacy but also reduce toxicity. Bone-targeting drugs are designed with either of two general targeting moieties, aimed at the entire skeletal system or a specific cell type. Most bone-targeting drugs utilize an affinity to hydroxyapatite, a major component of the bone matrix that includes a high concentration of positively-charged Ca(2+). The strategies for designing such targeting moieties can involve synthetic and/or biological components including negatively-charged amino acid peptides or bisphosphonates. Efficient delivery of bone-specific drugs provides significant impact in the treatment of skeletal related disorders including infectious diseases (osteoarthritis, osteomyelitis, etc.), osteoporosis, and metabolic skeletal dysplasia. Despite recent advances, however, both delivering the drug to its target without losing activity and avoiding adverse local effects remain a challenge. In this review, we investigate the current development of bone-targeting moieties, their efficacy and limitations, and discuss future directions for the development of these specific targeted treatments

Skeletal Myogenic Progenitors Originating from Embryonic Dorsal Aorta Coexpress Endothelial and Myogenic Markers and Contribute to Postnatal Muscle Growth and Regeneration

Skeletal muscle in vertebrates is derived from somites, epithelial structures of the paraxial mesoderm, yet many unrelated reports describe the occasional appearance of myogenic cells from tissues of nonsomite origin, suggesting either transdifferentiation or the persistence of a multipotent progenitor. Here, we show that clonable skeletal myogenic cells are present in the embryonic dorsal aorta of mouse embryos. This finding is based on a detailed clonal analysis of different tissue anlagen at various developmental stages. In vitro, these myogenic cells show the same morphology as satellite cells derived from adult skeletal muscle, and express a number of myogenic and endothelial markers. Surprisingly, the latter are also expressed by adult satellite cells. Furthermore, it is possible to clone myogenic cells from limbs of mutant c-Met-/- embryos, which lack appendicular muscles, but have a normal vascular system. Upon transplantation, aorta-derived myogenic cells participate in postnatal muscle growth and regeneration, and fuse with resident satellite cells. The potential of the vascular system to generate skeletal muscle cells may explain observations of nonsomite skeletal myogenesis and raises the possibility that a subset of satellite cells may derive from the vascular system

Skeletal muscle as an experimental model of choice to study tissue aging and rejuvenation.

Skeletal muscle is among the most age-sensitive tissues in mammal organisms. Significant changes in its resident stem cells (i.e., satellite cells, SCs), differentiated cells (i.e., myofibers), and extracellular matrix cause a decline in tissue homeostasis, function, and regenerative capacity. Based on the conservation of aging across tissues and taking advantage of the relatively well-characterization of the myofibers and associated SCs, skeletal muscle emerged as an experimental system to study the decline in function and maintenance of old tissues and to explore rejuvenation strategies. In this review, we summarize the approaches for understanding the aging process and for assaying the success of rejuvenation that use skeletal muscle as the experimental system of choice. We further discuss (and exemplify with studies of skeletal muscle) how conflicting results might be due to variations in the techniques of stem cell isolation, differences in the assays of functional rejuvenation, or deciding on the numbers of replicates and experimental cohorts

The action of obestatin in skeletal muscle repair: stem cell expansion, muscle growth, and microenvironment remodeling

The development of therapeutic strategies for skeletal muscle diseases, such as physical injuries and myopathies, depends on the knowledge of regulatory signals that control the myogenic process. The obestatin/GPR39 system operates as an autocrine signal in the regulation of skeletal myogenesis. Using a mouse model of skeletal muscle regeneration after injury and several cellular strategies, we explored the potential use of obestatin as a therapeutic agent for the treatment of trauma-induced muscle injuries. Our results evidenced that the overexpression of the preproghrelin, and thus obestatin, and GPR39 in skeletal muscle increased regeneration after muscle injury. More importantly, the intramuscular injection of obestatin significantly enhanced muscle regeneration by simulating satellite stem cell expansion as well as myofiber hypertrophy through a kinase hierarchy. Added to the myogenic action, the obestatin administration resulted in an increased expression of VEGF/VEGFR2 and the consequent microvascularization, with no effect on collagen deposition in skeletal muscle. Furthermore, the potential inhibition of myostatin during obestatin treatment might contribute to its myogenic action improving muscle growth and regeneration. Taken together, our data demonstrate successful improvement of muscle regeneration, indicating obestatin is a potential therapeutic agent for skeletal muscle injury and would benefit other myopathies related to muscle regeneration

A multi-viewpoint feature-based re-identification system driven by skeleton keypoints

Thanks to the increasing popularity of 3D sensors, robotic vision has experienced huge improvements in a wide range of applications and systems in the last years. Besides the many benefits, this migration caused some incompatibilities with those systems that cannot be based on range sensors, like intelligent video surveillance systems, since the two kinds of sensor data lead to different representations of people and objects. This work goes in the direction of bridging the gap, and presents a novel re-identification system that takes advantage of multiple video flows in order to enhance the performance of a skeletal tracking algorithm, which is in turn exploited for driving the re-identification. A new, geometry-based method for joining together the detections provided by the skeletal tracker from multiple video flows is introduced, which is capable of dealing with many people in the scene, coping with the errors introduced in each view by the skeletal tracker. Such method has a high degree of generality, and can be applied to any kind of body pose estimation algorithm. The system was tested on a public dataset for video surveillance applications, demonstrating the improvements achieved by the multi-viewpoint approach in the accuracy of both body pose estimation and re-identification. The proposed approach was also compared with a skeletal tracking system working on 3D data: the comparison assessed the good performance level of the multi-viewpoint approach. This means that the lack of the rich information provided by 3D sensors can be compensated by the availability of more than one viewpoint

Crossroads between peripheral atherosclerosis, western-type diet and skeletal muscle pathophysiology: emphasis on apolipoprotein E deficiency and peripheral arterial disease

Atherosclerosis is a chronic inflammatory process that, in the presence of hyperlipidaemia, promotes the formation of atheromatous plaques in large vessels of the cardiovascular system. It also affects peripheral arteries with major implications for a number of other non-vascular tissues such as the skeletal muscle, the liver and the kidney. The aim of this review is to critically discuss and assimilate current knowledge on the impact of peripheral atherosclerosis and its implications on skeletal muscle homeostasis. Accumulating data suggests that manifestations of peripheral atherosclerosis in skeletal muscle originates in a combination of increased i)-oxidative stress, ii)-inflammation, iii)-mitochondrial deficits, iv)-altered myofibre morphology and fibrosis, v)-chronic ischemia followed by impaired oxygen supply, vi)-reduced capillary density, vii)- proteolysis and viii)-apoptosis. These structural, biochemical and pathophysiological alterations impact on skeletal muscle metabolic and physiologic homeostasis and its capacity to generate force, which further affects the individual’s quality of life. Particular emphasis is given on two major areas representing basic and applied science respectively: a)-the abundant evidence from a well-recognised atherogenic model; the Apolipoprotein E deficient mouse and the role of a western-type diet and b)-on skeletal myopathy and oxidative stress-induced myofibre damage from human studies on peripheral arterial disease. A significant source of reactive oxygen species production and oxidative stress in cardiovascular disease is the family of NADPH oxidases that contribute to several pathologies. Finally, strategies targeting NADPH oxidases in skeletal muscle in an attempt to attenuate cellular oxidative stress are highlighted, providing a better understanding of the crossroads between peripheral atherosclerosis and skeletal muscle pathophysiology

Finding a third archetypal technical system in architectural phenomenology

Within the scope of phenomenology and in order to understand architecture, the role of the technical system is as important as those of the purpose of the building or its form. Mass construction and skeletal construction relate to the architectural theory concepts stereotomy and tectonics respectively, which are suitable for describing the fundamental structural and constructive form of architecture. These two systems became established as man built his first shelters and, so far, represented opposite sides of the building industry’s possibilities. The development of new construction techniques and the relationship between research and technology have a great impact on architecture, although new processing methods and materials may not necessarily cause genuine tectonic changes. The technical dimension of architecture is analysed in this work describing how technical elements are built from materials, and then organised in systems. First, the paper examines the division of technical systems in two categories (massive systems and skeletal systems); then it studies timber’s modern production technologies and subsequently the paper critically analyses how these influence the architectural form. The paper concludes that a third archetypal technical system can be perceived with the assembly of surface elements, joining both the multifunctional aspect of the massive systems and the flexibility of the skeletal systems, this third category being fundamental in phenomenological terms

Using Networks To Understand Medical Data: The Case of Class III Malocclusions

A system of elements that interact or regulate each other can be represented by a mathematical object called a network. While network analysis has been successfully applied to high-throughput biological systems, less has been done regarding their application in more applied fields of medicine; here we show an application based on standard medical diagnostic data. We apply network analysis to Class III malocclusion, one of the most difficult to understand and treat orofacial anomaly. We hypothesize that different interactions of the skeletal components can contribute to pathological disequilibrium; in order to test this hypothesis, we apply network analysis to 532 Class III young female patients. The topology of the Class III malocclusion obtained by network analysis shows a strong co-occurrence of abnormal skeletal features. The pattern of these occurrences influences the vertical and horizontal balance of disharmony in skeletal form and position. Patients with more unbalanced orthodontic phenotypes show preponderance of the pathological skeletal nodes and minor relevance of adaptive dentoalveolar equilibrating nodes. Furthermore, by applying Power Graphs analysis we identify some functional modules among orthodontic nodes. These modules correspond to groups of tightly inter-related features and presumably constitute the key regulators of plasticity and the sites of unbalance of the growing dentofacial Class III system. The data of the present study show that, in their most basic abstraction level, the orofacial characteristics can be represented as graphs using nodes to represent orthodontic characteristics, and edges to represent their various types of interactions. The applications of this mathematical model could improve the interpretation of the quantitative, patient-specific information, and help to better targeting therapy. Last but not least, the methodology we have applied in analyzing orthodontic features can be applied easily to other fields of the medical science.</p

Development of a Novel Device for the Perfusion Driven Decellularization of Skeletal Muscle

Decellularization of skeletal muscle is a process that removes cellular components of skeletal muscle tissue while leaving behind the intact extracellular matrix (ECM). Skeletal muscle ECM is currently being studied as a biologic scaffold for repairing volumetric muscle loss (VML) because the removal of cells greatly reduces the antigenicity of the donor tissue. Decellularization usually relies on passive diffusion of detergents, surfactants and/or osmotic solutions to strip cells from the ECM. However, passive diffusion alone is usually not sufficient for complete removal of cells from the interior of large pieces of skeletal muscle using detergents, such as sodium dodecyl sulfate (SDS). The goal of this study was to develop a device that not only removes cells by perfusion from the interior of skeletal muscle, but also monitors the progress of decellularization in real-time. The device, based around a Raspberry Pi, is a standalone system that does not require a desktop computer or expensive software packages. Different flow rates (0.1, 1.0 and 10 mL/hr) along with different concentrations of SDS (0.2% and 1.0%) were tested. Decellularization progress was monitored and logged to an online spreadsheet. The device was found to be capable of decellularizing the medial gastrocnemius of a rat in under 10 hours. Complete decellularization was validated using fluorescent imaging. Perfusion decellularized muscle samples were found to have no significant differences in collagen or sulfated glycosaminoglycan (sGAG) content when compared to samples that were decellularized using current passive diffusion protocols. The ECM obtained through the use of this device is currently being used for the repair of VML in a rat model