|  |  |  | | | | | TERMSC | | | | | | | | | | | | | | | | | | | Efficient in vivo vascularization of tissue-engineering scaffolds. J Tissue Eng Regen Med. 2010 Sep 23; Authors: Hegen A, Blois A, Tiron CE, Hellesøy M, Micklem DR, Nör JE, Akslen LA, Lorens JB The success of tissue engineering depends on the rapid and efficient formation of a functional blood vasculature. Adult blood vessels comprise endothelial cells and perivascular mural cells that assemble into patent tubules ensheathed by a basement membrane during angiogenesis. Using individual vessel components, we characterized intra-scaffold microvessel self-assembly efficiency in a physiological in vivo tissue engineering implant context. Primary human microvascular endothelial and vascular smooth muscle cells were seeded at different ratios in poly-L-lactic acid (PLLA) scaffolds enriched with basement membrane proteins (Matrigel) and implanted subcutaneously into immunocompromised mice. Temporal intra-scaffold microvessel formation, anastomosis and perfusion were monitored by immunohistochemical, flow cytometric and in vivo multiphoton fluorescence microscopy analysis. Vascularization in the tissue-engineering context was strongly enhanced in implants seeded with a complete complement of blood vessel components: human microvascular endothelial and vascular smooth muscle cells in vivo assembled a patent microvasculature within Matrigel-enriched PLLA scaffolds that anastomosed with the host circulation during the first week of implantation. Multiphoton fluorescence angiographic analysis of the intra-scaffold microcirculation showed a uniform, branched microvascular network. 3D image reconstruction analysis of human pulmonary artery smooth muscle cell (hPASMC) distribution within vascularized implants was non-random and displayed a preferential perivascular localization. Hence, efficient microvessel self-assembly, anastomosis and establishment of a functional microvasculture in the native hypoxic in vivo tissue engineering context is promoted by providing a complete set of vascular components. Copyright © 2010 John Wiley & Sons, Ltd. PMID: 20865694 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | A dynamical study of the mechanical stimuli and tissue differentiation within a CaP scaffold based on micro-CT finite element models. Biomech Model Mechanobiol. 2010 Sep 24; Authors: Sandino C, Lacroix D The control of the mechanical stimuli transmitted to the cells is critical for the design of functional scaffolds for tissue engineering. The objective of this study was to investigate the dynamics of the mechanical stimuli transmitted to the cells during tissue differentiation in an irregular morphology scaffold under compressive load and perfusion flow. A calcium phosphate-based glass porous scaffold was used. The solid phase and the fluid flow within the pores were modeled as linear elastic solid material and Newtonian fluid, respectively. In the fluid model, different levels of viscosity were used to simulate tissue differentiation. Compressive strain of 0.5% and fluid flow with constant inlet velocity of 10 μm/s or constant inlet pressure of 3 Pa were applied. Octahedral shear strain and fluid shear stress were used as mechano-regulatory stimuli. For constant inlet velocity, stimuli equivalent to bone were predicted in 80% of pore volume for the case of low tissue viscosity. For the cases of high viscosity, fluctuations between stimuli equivalent to tissue formation and cell death were predicted due to the increase in the fluid shear stress when tissue started to fill pores. When constant pressure was applied, stimuli equivalent to bone were predicted in 62% of pore volume when low tissue viscosity was used and 42% when high tissue viscosity was used. This study predicted critical variations of fluid shear stress when cells differentiated. If these variations are not controlled in vitro, they can impede the formation of new matured tissue. PMID: 20865437 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | A multiphysics/multiscale 2D numerical simulation of scaffold-based cartilage regeneration under interstitial perfusion in a bioreactor. Biomech Model Mechanobiol. 2010 Sep 24; Authors: Sacco R, Causin P, Zunino P, Raimondi MT In vitro tissue engineering is investigated as a potential source of functional tissue constructs for cartilage repair, as well as a model system for controlled studies of cartilage development and function. Among the different kinds of devices for the cultivation of 3D cartilage cell colonies, we consider here polymeric scaffold-based perfusion bioreactors, where an interstitial fluid supplies nutrients and oxygen to the growing biomass. At the same time, the fluid-induced shear acts as a physiologically relevant stimulus for the metabolic activity of cells, provided that the shear stress level is appropriately tuned. In this complex environment, mathematical and computational modeling can help in the optimal design of the bioreactor configuration. In this perspective, we propose a computational model for the simulation of the biomass growth, under given inlet and geometrical conditions, where nutrient concentration, fluid dynamic field and cell growth are consistently coupled. The biomass growth model is calibrated with respect to the shear stress dependence on experimental data using a simplified short-time analysis in which the nutrient concentration and the fluid-induced shear stress are assumed constant in time and uniform in space. Volume averaging techniques are used to derive effective parameters that allow to upscale the microscopic structural properties to the macroscopic level. The biomass growth predictions obtained in this way are significant for long times of culture. PMID: 20865436 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Lipase activation and stabilization in room-temperature ionic liquids. Methods Mol Biol. 2011;679:25-35 Authors: Kaar JL Widespread interest in the use of room temperature ionic liquids (RTILs) as solvents in anhydrous biocatalytic reactions has largely been met with underwhelming results. Enzymes are frequently inactivated in RTILs as a result of the influence of solvent on the enzyme's microenvironment, be it through interacting with the enzyme or enzyme-bound water molecules. The purpose of this chapter is to present a rational approach to mediate RTIL-enzyme interactions, which is essential if we are to realize the advantages of RTILs over conventional solvents for biocatalysis in full. The underlying premise for this approach is the stabilization of enzyme structure via multipoint covalent immobilization within a polyurethane foam matrix. Additionally, the approach entails the use of salt hydrates to control the level of hydration of the immobilized enzyme, which is critical to the activation of enzymes in nonaqueous media. Although lipase is used as a model enzyme, this approach may be effective in activating and stabilizing virtually any enzyme in RTILs. PMID: 20865386 [PubMed - in process] | | | | | | | | | | | | | | | | | | | | | | | | | HIF1-alpha functions as a tumor promoter in cancer associated fibroblasts, and as a tumor suppressor in breast cancer cells: Autophagy drives compartment-specific oncogenesis. Cell Cycle. 2010 Sep 4;9(17) Authors: Chiavarina B, Whitaker-Menezes D, Migneco G, Martinez-Outschoorn UE, Pavlides S, Howell A, Tanowitz HB, Casimiro MC, Wang C, Pestell RG, Grieshaber P, Caro J, Sotgia F, Lisanti MP Our recent studies have mechanistically implicated a loss of stromal Cav-1 expression and HIF1-alpha-activation in driving the cancer-associated fibroblast phenotype, through the paracrine production of nutrients via autophagy and aerobic glycolysis. However, it remains unknown if HIF1a-activation is sufficient to confer the cancer-associated fibroblast phenotype. To test this hypothesis directly, we stably-expressed activated HIF1a in fibroblasts and then examined their ability to promote tumor growth using a xenograft model employing human breast cancer cells (MDA-MB-231). Fibroblasts harboring activated HIF1a showed a dramatic reduction in Cav-1 levels and a shift towards aerobic glycolysis, as evidenced by a loss of mitochondrial activity, and an increase in lactate production. Activated HIF1a also induced BNIP3 and BNIP3L expression, markers for the autophagic destruction of mitochondria. Most importantly, fibroblasts expressing activated HIF1a increased tumor mass by ∼2-fold and tumor volume by ∼3-fold, without a significant increase in tumor angiogenesis. In this context, HIF1a also induced an increase in the lymph node metastasis of cancer cells. Similar results were obtained by driving NFκB activation in fibroblasts, another inducer of autophagy. Thus, activated HIF1a is sufficient to functionally confer the cancer-associated fibroblast phenotype. It is also known that HIF1a expression is required for the induction of autophagy in cancer cells. As such, we next directly expressed activated HIF1a in MDA-MB-231 cells and assessed its effect on tumor growth via xenograft analysis. Surprisingly, activated HIF1a in cancer cells dramatically suppressed tumor growth, resulting in a 2-fold reduction in tumor mass and a 3-fold reduction in tumor volume. We conclude that HIF1a activation in different cell types can either promote or repress tumorigenesis. Based on these studies, we suggest that autophagy in cancer-associated fibroblasts promotes tumor growth via the paracrine production of recycled nutrients, which can directly "feed" cancer cells. Conversely, autophagy in cancer cells represses tumor growth via their "self-digestion". Thus, we should consider that the activities of various known oncogenes and tumor-suppressors may be compartment and cell-type specific, and are not necessarily an intrinsic property of the molecule itself. As such, other "classic" oncogenes and tumor suppressors will have to be re-evaluated to determine their compartment specific effects on tumor growth and metastasis. Lastly, our results provide direct experimental support for the recently proposed "Autophagic Tumor Stroma Model of Cancer". PMID: 20864819 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | VHL Inactivation Induces HEF1 and Aurora Kinase A. J Am Soc Nephrol. 2010 Sep 23; Authors: Xu J, Li H, Wang B, Xu Y, Yang J, Zhang X, Harten SK, Shukla D, Maxwell PH, Pei D, Esteban MA The ciliary hypothesis for cystic renal diseases postulates that most of these conditions result from abnormalities in the primary cilium, a microtubule-based structure that acts as a sensor for extracellular cues. Inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene predisposes to renal cysts and clear cell renal cell carcinoma. VHL plays a critical role in the formation of primary cilia in kidney epithelium, but the underlying mechanisms are poorly understood. Here, we demonstrate that VHL inactivation induces HEF1/Cas-L/NEDD9 and Aurora kinase A via the stabilization of hypoxia-inducible factors 1 and 2. Aurora kinase A is a mitotic kinase commonly upregulated in cancer that causes regression of the primary cilium by promoting histone deacetylase-dependent tubulin depolymerization of the ciliary axoneme. HEF1/Cas-L/NEDD9 is a component of focal adhesions that has a prominent role in inducing metastasis and that colocalizes with Aurora kinase A at the centrosome, thereby enhancing the harmful effect of Aurora kinase A on the cilium. Suppression of this pathway improved the formation of primary cilia and reduced cell motility in VHL-defective renal cancer cells. Our results highlight the gatekeeper role of VHL in the kidney epithelium. PMID: 20864688 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Perivascular Adipose Tissue-Derived Complement 3 Is Required for Adventitial Fibroblast Functions and Adventitial Remodeling in Deoxycorticosterone Acetate-Salt-Hypertensive Rats. Arterioscler Thromb Vasc Biol. 2010 Sep 23; Authors: Ruan CC, Chen QZ, Chen J, Guo SJ, Li XD, Zhu DL, Gao PJ OBJECTIVE: To examine the role of perivascular adipose tissue (PVAT)-derived factors in the regulation of adventitial fibroblast (AF) function in vitro and in vivo. METHODS AND RESULTS: PVAT is an active component of blood vessels. Bioactive substances released from PVAT play regulatory roles in vascular function. However, their effects on vascular AFs remain unclear. PVAT-conditioned medium stimulated AF migration using a transwell technique, and differentiation was evaluated by α-smooth muscle-actin induction. We identified the secretome of PVAT by liquid chromatography-tandem mass spectrometry. One of the major secretory proteins in PVAT is complement 3 (C3). The C3 antagonist and neutralizing antibody attenuated PVAT-conditioned medium-induced AF migration and differentiation. Similar to PVAT-conditioned medium, C3 recombinant protein stimulated AF migration and differentiation. We demonstrated that the effects of PVAT-derived C3 were mediated by the c-Jun N-terminal kinase pathway. Moreover, we found morphological changes in perivascular adipocytes and increased expression of C3 in PVAT that was tightly associated with adventitial thickening and myofibroblast clustering around PVAT in deoxycorticosterone acetate-salt-hypertensive rats. CONCLUSIONS: PVAT-derived C3 stimulated AF migration and differentiation via the c-Jun N-terminal kinase pathway. PVAT-derived C3 may contribute to adventitial remodeling in a deoxycorticosterone acetate-salt-hypertensive model. PMID: 20864665 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Smooth and textured silicone surfaces of modified gel mammary prostheses cause a different impact on fibroproliferative properties of dermal fibroblasts. J Plast Reconstr Aesthet Surg. 2010 Sep 21; Authors: Seyhan H, Kopp J, Beier JP, Vogel M, Akkermann O, Kneser U, Schwartz S, Hartmann A, Horch RE Our study addressed the question of whether surface properties of modern standard gel prostheses may have a measurable impact on the fibrogenic properties of cultured human dermal fibroblasts. Fibroblasts were isolated from breast implants by using the explant culture technique and incubated either on smooth or on textured silicone elastomere surfaces. Fibroblast growth was observed 4 weeks following incubation. Expression of transforming growth factor (TGF)-β1 was measured after cell culture. Incubated fibroblasts on textured surfaces showed a fivefold lower growth rate during all experiments. TGF-β1 expression was lowered in smooth surface fibroblasts compared with textured surface cultures. Our results show that smooth and textured silicone surfaces of modified gel breast implants have a different impact on the fibroproliferative properties of dermal fibroblasts. These preliminary results seem promising and we aim to further perform qualitative and quantitative analyses of the inflammatory processes in the environment of the implant and their link to the TGF-β pathway. PMID: 20864424 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | In situ thermal gelling polypeptide for chondrocytes 3D culture. Biomaterials. 2010 Sep 21; Authors: Choi BG, Park MH, Cho SH, Joo MK, Oh HJ, Kim EH, Park K, Han DK, Jeong B In the search for a cell-instructive or cell-interactive artificial extracellular matrix, synthetic hydrogels have been extensively investigated to apply three-dimensional (3D) cell culture and tissue engineering. Here, we are reporting a reverse thermal gelling l/dl-polyalanine block copolymer aqueous solution for chondrocyte 3D culture. The polymer aqueous solution undergoes sol-to-gel transition as the temperature increases, thus forming a 3D cell encapsulating scaffold in situ at 37 °C. In particular, the fraction of the β-sheet structure of the polyalanine dictated the population and thickness of fibrous nanostructure of the hydrogel, which in turn affected the proliferation and protein expression of the encapsulated chondrocytes. As an injectable tissue engineering system of chondrocytes, very promising results were confirmed for nude mice, using the current polypeptide aqueous solution. This paper not only provides important clues in designing an artificial extracellular matrix but also proves the significance of thermal gelling polypeptide as a minimally-invasive tissue engineering scaffold. PMID: 20864172 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | An alginate-based hybrid system for growth factor delivery in the functional repair of large bone defects. Biomaterials. 2010 Sep 21; Authors: Kolambkar YM, Dupont KM, Boerckel JD, Huebsch N, Mooney DJ, Hutmacher DW, Guldberg RE The treatment of challenging fractures and large osseous defects presents a formidable problem for orthopaedic surgeons. Tissue engineering/regenerative medicine approaches seek to solve this problem by delivering osteogenic signals within scaffolding biomaterials. In this study, we introduce a hybrid growth factor delivery system that consists of an electrospun nanofiber mesh tube for guiding bone regeneration combined with peptide-modified alginate hydrogel injected inside the tube for sustained growth factor release. We tested the ability of this system to deliver recombinant bone morphogenetic protein-2 (rhBMP-2) for the repair of critically-sized segmental bone defects in a rat model. Longitudinal μ-CT analysis and torsional testing provided quantitative assessment of bone regeneration. Our results indicate that the hybrid delivery system resulted in consistent bony bridging of the challenging bone defects. However, in the absence of rhBMP-2, the use of nanofiber mesh tube and alginate did not result in substantial bone formation. Perforations in the nanofiber mesh accelerated the rhBMP-2 mediated bone repair, and resulted in functional restoration of the regenerated bone. μ-CT based angiography indicated that perforations did not significantly affect the revascularization of defects, suggesting that some other interaction with the tissue surrounding the defect such as improved infiltration of osteoprogenitor cells contributed to the observed differences in repair. Overall, our results indicate that the hybrid alginate/nanofiber mesh system is a promising growth factor delivery strategy for the repair of challenging bone injuries. PMID: 20864165 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Incorporation of biomaterials in multicellular aggregates modulates pluripotent stem cell differentiation. Biomaterials. 2010 Sep 21; Authors: Bratt-Leal AM, Carpenedo RL, Ungrin MD, Zandstra PW, McDevitt TC Biomaterials are increasingly being used to engineer the biochemical and biophysical properties of the extracellular stem cell microenvironment in order to tailor niche characteristics and direct cell phenotype. To date, stem cell-biomaterial interactions have largely been studied by introducing stem cells into artificial environments, such as 2D cell culture on biomaterial surfaces, encapsulation of cell suspensions within hydrogel materials, or cell seeding on 3D polymeric scaffolds. In this study, microparticles fabricated from different materials, such as agarose, PLGA and gelatin, were stably integrated, in a dose-dependent manner, within aggregates of pluripotent stem cells (PSCs) prior to differentiation as a means to directly examine stem cell-biomaterial interactions in 3D. Interestingly, the presence of the materials within the stem cell aggregates differentially modulated the gene and protein expression patterns of several differentiation markers without adversely affecting cell viability. Microparticle incorporation within 3D stem cell aggregates can control the spatial presentation of extracellular environmental cues (i.e. soluble factors, extracellular matrix and intercellular adhesion molecules) as a means to direct the differentiation of stem cells for tissue engineering and regenerative medicine applications. In addition, these results suggest that the physical presence of microparticles within stem cell aggregates does not compromise PSC differentiation, but in fact the choice of biomaterials can impact the propensity of stem cells to adopt particular differentiated cell phenotypes. PMID: 20864164 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Characterization of the degradation mechanisms of lysine-derived aliphatic poly(ester urethane) scaffolds. Biomaterials. 2010 Sep 21; Authors: Hafeman AE, Zienkiewicz KJ, Zachman AL, Sung HJ, Nanney LB, Davidson JM, Guelcher SA Characterization of the degradation mechanism of polymeric scaffolds and delivery systems for regenerative medicine is essential to assess their clinical applicability. Key performance criteria include induction of a minimal, transient inflammatory response and controlled degradation to soluble non-cytotoxic breakdown products that are cleared from the body by physiological processes. Scaffolds fabricated from biodegradable poly(ester urethane)s (PEURs) undergo controlled degradation to non-cytotoxic breakdown products and support the ingrowth of new tissue in preclinical models of tissue regeneration. While previous studies have shown that PEUR scaffolds prepared from lysine-derived polyisocyanates degrade faster under in vivo compared to in vitro conditions, the degradation mechanism is not well understood. In this study, we have shown that PEUR scaffolds prepared from lysine triisocyanate (LTI) or a trimer of hexamethylene diisocyanate (HDIt) undergo hydrolytic, esterolytic, and oxidative degradation. Hydrolysis of ester bonds to yield α-hydroxy acids is the dominant mechanism in buffer, and esterolytic media modestly increase the degradation rate. While HDIt scaffolds show a modest (<20%) increase in degradation rate in oxidative medium, LTI scaffolds degrade six times faster in oxidative medium. Furthermore, the in vitro rate of degradation of LTI scaffolds in oxidative medium approximates the in vivo rate in rat excisional wounds, and histological sections show macrophages expressing myeloperoxidase at the material surface. While recent preclinical studies have underscored the potential of injectable PEUR scaffolds and delivery systems for tissue regeneration, this promising class of biomaterials has a limited regulatory history. Elucidation of the macrophage-mediated oxidative mechanism by which LTI scaffolds degrade in vivo provides key insights into the ultimate fate of these materials when injected into the body. PMID: 20864156 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | The All-on-4 Shelf: Maxilla. J Oral Maxillofac Surg. 2010 Oct;68(10):2520-7 Authors: Jensen OT, Adams MW, Cottam JR, Parel SM, Phillips WR All-on-4 treatment is facilitated by bone reduction to create prosthetic restorative space, establish maximum anterior posterior spread of implants, and to avoid pneumatized sites. Unlike a reduction alveloplasty for denture placement, the All-on-4 shelf enables optimal surgical prosthetic management of implant placement for the fixed hybrid prosthesis. PMID: 20863943 [PubMed - in process] | | | | | | | | | | | | | | | | | | | | | | | | | Hydrophobic Nanopillars Initiate Mesenchymal Stem Cell Aggregation and Osteo-Differentiation. Acta Biomater. 2010 Sep 20; Authors: Brammer KS, Choi C, Frandsen CJ, Oh S, Jin S Surface engineering approaches that alter the physical topography of a substrate could be used as an effective tool and as an alternative to biochemical means of directing stem cell interactions and their subsequent differentiation. Here within we compare hydrophobic micro- vs. nanopillar type fabrication techniques for probing mesenchymal stem cell (MSC) interaction with the surface physical environment. The roles played by the topography of the nanopillar in particular influenced MSC growth and allowed for regulatory control of the stem cell fate. The nanopillar induced large 3-D cell aggregates to form on the surface which had up-regulated osteogenic specific matrix components. The ability to control MSC differentiation, using only the topographical factors, has a profound effect on both MSC biology and tissue engineering. This study aims to highlight the importance of the physical material carrier in stem cell based tissue engineering schemes. PMID: 20863916 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Micrometer-sized iron oxide particle labeling of mesenchymal stem cells for magnetic resonance imaging-based monitoring of cartilage tissue engineering. Magn Reson Imaging. 2010 Sep 20; Authors: Saldanha KJ, Doan RP, Ainslie KM, Desai TA, Majumdar S PURPOSE: To examine mesenchymal stem cell (MSC) labeling with micrometer-sized iron oxide particles (MPIOs) for magnetic resonance imaging (MRI)-based tracking and its application to monitoring articular cartilage regeneration. METHODS: Rabbit MSCs were labeled using commercial MPIOs. In vitro MRI was performed with gradient echo (GRE) and spin echo (SE) sequences at 3T and quantitatively characterized using line profile and region of interest analysis. Ex vivo MRI of hydrogel-encapsulated labeled MSCs implanted within a bovine knee was performed with spoiled GRE (SPGR) and T(1Ï) sequences. Fluorescence microscopy, labeling efficiency, and chondrogenesis of MPIO-labeled cells were also examined. RESULTS: MPIO labeling results in efficient contrast uptake and signal loss that can be visualized and quantitatively characterized via MRI. SPGR imaging of implanted cells results in ex vivo detection within native tissue, and T(1Ï) imaging is unaffected by the presence of labeled cells immediately following implantation. MPIO labeling does not affect quantitative glycosaminoglycan production during chondrogenesis, but iron aggregation hinders extracellular matrix visualization. This aggregation may result from excess unincorporated particles following labeling and is an issue that necessitates further investigation. CONCLUSION: This study demonstrates the promise of MPIO labeling for monitoring cartilage regeneration and highlights its potential in the development of cell-based tissue engineering strategies. PMID: 20863643 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | The healing of bony defects by cell-free collagen-based scaffolds compared to stem cell-seeded tissue engineered constructs. Biomaterials. 2010 Sep 21; Authors: Lyons FG, Al-Munajjed AA, Kieran SM, Toner ME, Murphy CM, Duffy GP, O'Brien FJ One of the key challenges in tissue engineering is to understand the host response to scaffolds and engineered constructs. We present a study in which two collagen-based scaffolds developed for bone repair: a collagen-glycosaminoglycan (CG) and biomimetic collagen-calcium phosphate (CCP) scaffold, are evaluated in rat cranial defects, both cell-free and when cultured with MSCs prior to implantation. The results demonstrate that both cell-free scaffolds showed excellent healing relative to the empty defect controls and somewhat surprisingly, to the tissue engineered (MSC-seeded) constructs. Immunological analysis of the healing response showed higher M1 macrophage activity in the cell-seeded scaffolds. However, when the M2 macrophage response was analysed, both groups (MSC-seeded and non-seeded scaffolds) showed significant activity of these cells which are associated with an immunomodulatory and tissue remodelling response. Interestingly, the location of this response was confined to the construct periphery, where a capsule had formed, in the MSC-seeded groups as opposed to areas of new bone formation in the non-seeded groups. This suggests that matrix deposited by MSCs during in vitro culture may adversely affect healing by acting as a barrier to macrophage-led remodelling when implanted in vivo. This study thus improves our understanding of host response in bone tissue engineering. PMID: 20863559 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Advanced Drug Delivery of N-Acetylcarnosine (N-Acetyl-beta-alanyl-Lhistidine), Carcinine (Beta-alanylhistamine) and L-carnosine (Beta-alanyl-L-histidine) in Targeting Peptide Compounds as Pharmacological Chaperones for Use in Tissue Engineering, Human Disease Management and Therapy: From in vitro to the Clinic. Recent Pat Drug Deliv Formul. 2010 Sep 24; Authors: Babizhayev MA, Yegorov YE A pharmacological chaperone is a relatively new concept in the treatment of certain chronic disabling diseases. Cells maintain a complete set of functionally competent proteins normally and in the face of injury or environmental stress with the use of various mechanisms, including systems of proteins called molecular chaperones. Proteins that are denatured by any form of proteotoxic stress are cooperatively recognized by heat shock proteins (HSP) and directed for refolding or degradation. Under non-denaturing conditions HSP have important functions in cell physiology such as in transmembrane protein transport and in enabling assembly and folding of newly synthesized polypeptides. Besides cellular molecular chaperones, which are stress-induced proteins, there have been recently reported chemical, or so-called pharmacological chaperones with demonstrated ability to be effective in preventing misfolding of different disease causing proteins, specifically in the therapeutic management of sight-threatening eye diseases, essentially reducing the severity of several neurodegenerative disorders (such as age-related macular degeneration), cataract and many other protein-misfolding diseases. This work reviews the biological and therapeutic activities protected with the patents of the family of imidazole-containing peptidomimetics Carcinine ( -alanylhistamine), N-acetylcarnosine (N-acetyl- -alanylhistidine) and Carnosine ( -alanyl-l-histidine) which are essential constituents possessing diverse biological and pharmacological chaperone properties in human tissues. PMID: 20863274 [PubMed - as supplied by publisher] | | | | | | | | | | | | | | | | | | | | | | | | | Off-label use of rhBMP-2 for reconstruction of critical-sized mandibular defects. N Y State Dent J. 2010 Jun-Jul;76(4):32-5 Authors: Glied AN, Kraut RA Techniques for reconstructing segmental defects of the mandible have traditionally relied upon autogenous tissue transfer. Tissue engineering has brought about the promise of de novo bone formation and the possibility of reconstruction of these defects without the drawbacks of traditional techniques. Bone morphogenic proteins (BMP) have presented themselves as the most promising in this field. We present three cases where reconstruction of critical-sized mandibular defects was attempted using recombinant human BMP-2. PMID: 20863038 [PubMed - in process] | | | | | | | | | | | | | | | | | | | | | | | | | Impact of nuclear organization and dynamics on epigenetic regulation in the central nervous system: implications for neurological disease states. Ann N Y Acad Sci. 2010 Sep;1204 Suppl:E20-37 Authors: Qureshi IA, Mehler MF Epigenetic mechanisms that are highly responsive to interoceptive and environmental stimuli mediate the proper execution of complex genomic programs, such as cell type-specific gene transcription and posttranscriptional RNA processing, and are increasingly thought to be important for modulating the development, homeostasis, and plasticity of the central nervous system (CNS). These epigenetic processes include DNA methylation, histone modifications, and chromatin remodeling, all of which play roles in neural cellular diversity, connectivity, and plasticity. Further, large-scale transcriptomic analyses have revealed that the eukaryotic genome is pervasively transcribed, forming interleaved protein-coding RNAs and regulatory nonprotein-coding RNAs (ncRNAs), which act through a broad array of molecular mechanisms. Most of these ncRNAs are transcribed in a cell type- and developmental stage-specific manner in the CNS. A broad array of posttranscriptional processes, such as RNA editing and transport, can modulate the functions of both protein-coding RNAs and ncRNAs. Additional studies implicate nuclear organization and dynamics in mediating epigenetic regulation. The compartmentalization of DNA sequences and other molecular machinery into functional nuclear domains, such as transcription factories, Cajal bodies, promyelocytic leukemia nuclear bodies, nuclear speckles, and paraspeckles, some of which are found prominently in neural cells, is associated with regulation of transcriptional activity and posttranscriptional RNA processing. These observations suggest that genomic architecture and RNA biology in the CNS are much more complex and nuanced than previously appreciated. Increasing evidence now suggests that most, if not all, human CNS diseases are associated with either primary or secondary perturbations in one or more aspects of the epigenome. In this review, we provide an update of our emerging understanding of genomic architecture, RNA biology, and nuclear organization and highlight the interconnected roles that deregulation of these factors may play in diverse CNS disorders. PMID: 20840166 [PubMed - in process] | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | Regenerative Medicine , September 2010, Vol. 5, No. 5, Pages 687-690.
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