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Aug 23, 2016

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Search terms: exosomes OR "extracellular vesicles" OR microvesicles OR microparticles. Direct link to the PubMed search here.

Macrophages alternatively activated by endometriosis-exosomes contribute to the development of lesions in mice.

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Macrophages alternatively activated by endometriosis-exosomes contribute to the development of lesions in mice.

Mol Hum Reprod. 2018 Nov 14;:

Authors: Sun H, Li D, Yuan M, Li Q, Zhen Q, Li N, Wang G

Abstract
STUDY QUESTION: Do exosomes play a role in the pathogenesis of endometriosis in a murine model?
SUMMARY ANSWER: Exosomes from endometriosis (EMS) can alternatively activate macrophages and thus contribute to the development of lesions in mice.
WHAT IS KNOWN ALREADY: The pathogenesis of endometriosis, an inflammatory disease, possibly involves peritoneal macrophages. Exosomes are recognized as a new communicator among cells and a key modulator in several inflammatory diseases.
STUDY DESIGN SIZE, DURATION: We performed in vitro and in vivo experiments to demonstrate the role of exosomes in modulating macrophages. RAW264.7 cells (macrophages) were used to examine the effects of exosomes on macrophages in vitro. An experiment was also conducted in vivo, as follows. Fifty C57BL/6 female mice were randomly allocated to five control and five experimental groups (n=5/group). The experimental group was injected i.p. with EMS-exosomes derived from eutopic stromal cells, starting on day-7 then every day for 1 week. )The control group received CON-exosomes from mice without endometriosis. Peritoneal macrophages were assessed over the next 6 days. On day 0, all mice were injected i.p. with endometrium to establish the endometriosis model. On day 14, all mice were sacrificed, ectopic lesions were counted and measured.
PARTICIPANTS/MATERIALS, SETTING, METHODS: Exosomes were isolated from endometrial stromal cells(ESCs) by ultracentrifugation and characterized through transmission electron microscopy, nanoparticle tracking analysis, and western blot. After treatment with exosomes, the polarization and phagocytic ability of the macrophages were detected by flow cytometry analysis.), immunofluorescent staining, and RT-PCR. C57BL/6 mice were utilized to establish an endometriosis model by i.p. injection of endometrial segments.
MAIN RESULTS AND THE ROLE OF CHANCE: After treatment with EMS-exosomes, the macrophages were polarized into an M2-like phenotype and their phagocytic ability decreased(p <0.05 versus treatment with CON-exosomes). The total weight and volume of the lesions in mice treated with EMS-exosomes significantly increased compared with those in mice treated with CON-exosomes (p<0.05). The infiltration of M2-like macrophages was enhanced in the EMS-exosome group (p <0.001 versus treatment with CON-exosomes).
LARGE SCALE DATA: N/A.
LIMITATIONS REASONS FOR CAUTION: Detection of endometriosis following exosome treatment was only performed in a murine endometriosis model. Clinical data and additional mechanism studies must be conducted to understand the role of exosomes in the pathogenesis of endometriosis.
WIDER IMPLICATIONS OF THE FINDINGS: This study emphasizes the importance of EMS-exosomes in the pathogenesis of endometriosis. Further investigations on the exosome signaling pathways may contribute to the development of effective treatments for endometriosis.
STUDY FUNDING/COMPETING INTEREST(S): This research was supported by grants (Nos. 81571417 and 81771552) from the National Science Foundation of China. The authors report no conflict of interest.

PMID: 30428082 [PubMed - as supplied by publisher]

Characterization and Therapeutic Uses of Exosomes: A New Potential Tool in Orthopedics.

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Characterization and Therapeutic Uses of Exosomes: A New Potential Tool in Orthopedics.

Stem Cells Dev. 2018 Nov 14;:

Authors: Vitha AE, Kollefrath AW, Huang CC, Garcia-Godoy F

Abstract
In recent years, regenerative medicine has directed its interests onto the use of stem cells to heal human tissue. One specific class of cells that has been employed in this field of research is mesenchymal stem cells. Due to difficulties with the usage of whole stem cells, researchers have turned to an alternative, the secretome of these mesenchymal stem cells. In recent years, research has explored numerous aspects of the mesenchymal stem cell secretome, especially the most promising aspect, exosomes. This review explores a variety of interest in exosomes including the classification and molecular composition, mechanisms for isolation, and the various biological functions. As more is discovered about these exosomes different diagnostic and therapeutic uses in the medical field have also been explored. A new field attempting to exploit these exosomes in clinical practice is orthopedics. While a significant deal of research has been carried out, even more is being discovered to allow utilization of these vesicles in clinical practice.

PMID: 30426846 [PubMed - as supplied by publisher]

BLTR1 and CD36 Expressing Microvesicles in Atherosclerotic Patients and Healthy Individuals.

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BLTR1 and CD36 Expressing Microvesicles in Atherosclerotic Patients and Healthy Individuals.

Front Cardiovasc Med. 2018;5:156

Authors: Sanden M, Botha J, Nielsen MRS, Nielsen MH, Schmidt EB, Handberg A

Abstract
Aims: Monocytes/macrophages play a crucial role in the development, progression, and complication of atherosclerosis. In particular, foam cell formation driven by CD36 mediated internalization of oxLDL leads to activation of monocytes and subsequent release of microvesicles (MVs) derived from monocytes (MMVs). Further, pro-inflammatory leukotriene B4 (LTB4) derived from arachidonic acid promotes atherosclerosis through the high-affinity receptor BLTR1. Thus, we aimed to investigate the correlation between different MMV phenotypes (CD14+ MVs) on the one hand, and arachidonic acid and eicosapentaenoic acid contents in different compartments including atherosclerotic plaques, plasma, and granulocytes on the other. Methods and Results: Samples from patients with femoral atherosclerosis and healthy controls were analyzed on an Apogee A60 Micro-PLUS flow cytometer. Platelet-poor plasma was labeled with lactadherin-FITC, anti-CD14-APC, anti-CD36-PE, and anti-BLTR1-AF700. Eicosapentaenoic acid and arachidonic acid content in different compartments in patients were analyzed using gas chromatography. Compared to controls, patients had lower levels of BLTR1+ MVs (p = 0.007), CD14+BLTR1+ MVs (p = 0.007), and CD14+BLTR1+CD36+ MVs (p = 0.001). Further, in patients CD14+ MVs and CD14+CD36+ MVs correlated inversely with arachidonic acid in granulocytes (r = -0.302, p = 0.039 and r = -0.322, p = 0.028, respectively). Moreover, CD14+CD36+ MVs correlated inversely with arachidonic acid in plasma phospholipids in patients (r = -0.315, p = 0.029), and positively with triglyceride in both patients (r = 0.33, p = 0.019) and controls (r = 0.46, p = 0.022). Conclusion: This is the first study of its kind and thus the results are explorative and only indicative. BLTR1+ MVs and CD14+CD36+ MVs has potential as markers of atherosclerosis pathophysiology, but this needs further investigation.

PMID: 30425991 [PubMed]

Effect of Endothelial Microparticles Induced by Hypoxia on Migration and Angiogenesis of Human Umbilical Vein Endothelial Cells by Delivering MicroRNA-19b.

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Effect of Endothelial Microparticles Induced by Hypoxia on Migration and Angiogenesis of Human Umbilical Vein Endothelial Cells by Delivering MicroRNA-19b.

Chin Med J (Engl). 2018 Nov 20;131(22):2726-2733

Authors: Liang HZ, Li SF, Zhang F, Wu MY, Li CL, Song JX, Lee C, Chen H

Abstract
Background: Microparticles (MPs) are small extracellular plasma membrane particles shed by activated and apoptotic cells, which are involved in the development of atherosclerosis. Our previous study found that microRNA (miR)-19b encapsulated within endothelial MPs (EMPs) may contribute to the upregulation of circulating miR-19b in unstable angina patients. Hypoxia is involved in atherosclerosis as a critical pathological stimulus. However, it still remains unclear whether the increase of miR-19b levels in EMPs is related to hypoxia and if the effect of miR-19b - wrapped within EMPs - stimulates hypoxia on vascular endothelial cells. This study aimed to explore the changes of miR-19b in EMPs induced by hypoxia as well as their effects on endothelial cells.
Methods: Human umbilical vein endothelial cells (HUVECs) were cultured in vitro and arranged to harvest EMPs in two parts: the first part consisted of EMPcontrol and EMPhypoxia and the second part included EMPvehicle, EMPNC mimic, and EMPmiR-19b mimic. Cell migration was detected by scratch migration and transwell chamber migration. Angiogenesis was assessed by tube formation assays. Furthermore, we predicted the target gene of miR-19b by bioinformatics analysis, and luciferase assay was used to verify the targeted gene of miR-19b. Data were analyzed by one-way analysis of variance. Student's t-test was used when two groups were compared.
Results: Compared with EMPcontrol- and EMPhypoxia-inhibited migration of cells by scratch migration assay (80.77 ± 1.10 vs. 28.37 ± 1.40, P < 0. 001) and transwell chamber migration assay (83.00 ± 3.46 vs. 235.00 ± 16.52, P < 0.01), the number of tube formations was markedly reduced by 70% in the EMPhypoxia group (P < 0.001) in vitro analysis of HUVECs. Meanwhile, a strong inhibition of migration and tube formation of HUVECs in the presence of miR-19b-enriched EMPmiR-19b mimic was observed. This effect might be due to the delivery of miR-19b in EMPs. Transforming growth factor-β2 (TGFβ2) was predicted to be one of the target genes of miR-19b, and we further confirmed that TGFβ2 was a direct target gene of miR-19b using the luciferase assay. The expression of TGFβ2 in HUVECs was inhibited by treatment with EMPhypoxia and EMPmiR-19b mimic.
Conclusions: MiR-19b in EMPs induced by hypoxia could reduce endothelial cell migration and angiogenesis by downregulating TGFβ2 expression, which may have inhibited the progression of atherosclerosis.

PMID: 30425199 [PubMed - in process]

The Use of Microfluidic Technology for Cancer Applications and Liquid Biopsy.

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The Use of Microfluidic Technology for Cancer Applications and Liquid Biopsy.

Micromachines (Basel). 2018 Aug 10;9(8):

Authors: Kulasinghe A, Wu H, Punyadeera C, Warkiani ME

Abstract
There is growing awareness for the need of early diagnostic tools to aid in point-of-care testing in cancer. Tumor biopsy remains the conventional means in which to sample a tumor and often presents with challenges and associated risks. Therefore, alternative sources of tumor biomarkers is needed. Liquid biopsy has gained attention due to its non-invasive sampling of tumor tissue and ability to serially assess disease via a simple blood draw over the course of treatment. Among the leading technologies developing liquid biopsy solutions, microfluidics has recently come to the fore. Microfluidic platforms offer cellular separation and analysis platforms that allow for high throughout, high sensitivity and specificity, low sample volumes and reagent costs and precise liquid controlling capabilities. These characteristics make microfluidic technology a promising tool in separating and analyzing circulating tumor biomarkers for diagnosis, prognosis and monitoring. In this review, the characteristics of three kinds of circulating tumor markers will be described in the context of cancer, circulating tumor cells (CTCs), exosomes, and circulating tumor DNA (ctDNA). The review will focus on how the introduction of microfluidic technologies has improved the separation and analysis of these circulating tumor markers.

PMID: 30424330 [PubMed]

Progress in Circulating Tumor Cell Research Using Microfluidic Devices.

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Progress in Circulating Tumor Cell Research Using Microfluidic Devices.

Micromachines (Basel). 2018 Jul 14;9(7):

Authors: Gwak H, Kim J, Kashefi-Kheyrabadi L, Kwak B, Hyun KA, Jung HI

Abstract
Circulating tumor cells (CTCs) are a popular topic in cancer research because they can be obtained by liquid biopsy, a minimally invasive procedure with more sample accessibility than tissue biopsy, to monitor a patient's condition. Over the past decades, CTC research has covered a wide variety of topics such as enumeration, profiling, and correlation between CTC number and patient overall survival. It is important to isolate and enrich CTCs before performing CTC analysis because CTCs in the blood stream are very rare (0⁻10 CTCs/mL of blood). Among the various approaches to separating CTCs, here, we review the research trends in the isolation and analysis of CTCs using microfluidics. Microfluidics provides many attractive advantages for CTC studies such as continuous sample processing to reduce target cell loss and easy integration of various functions into a chip, making "do-everything-on-a-chip" possible. However, tumor cells obtained from different sites within a tumor exhibit heterogenetic features. Thus, heterogeneous CTC profiling should be conducted at a single-cell level after isolation to guide the optimal therapeutic path. We describe the studies on single-CTC analysis based on microfluidic devices. Additionally, as a critical concern in CTC studies, we explain the use of CTCs in cancer research, despite their rarity and heterogeneity, compared with other currently emerging circulating biomarkers, including exosomes and cell-free DNA (cfDNA). Finally, the commercialization of products for CTC separation and analysis is discussed.

PMID: 30424286 [PubMed]

Self-Assembled Mucin-Containing Microcarriers via Hard Templating on CaCO₃ Crystals.

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Self-Assembled Mucin-Containing Microcarriers via Hard Templating on CaCO₃ Crystals.

Micromachines (Basel). 2018 Jun 19;9(6):

Authors: Balabushevich NG, Sholina EA, Mikhalchik EV, Filatova LY, Vikulina AS, Volodkin D

Abstract
Porous vaterite crystals of CaCO₃ are extensively used for the fabrication of self-assembled polymer-based microparticles (capsules, beads, etc.) utilized for drug delivery and controlled release. The nature of the polymer used plays a crucial role and discovery of new perspective biopolymers is essential to assemble microparticles with desired characteristics, such as biocompatibility, drug loading efficiency/capacity, release rate, and stability. Glycoprotein mucin is tested here as a good candidate to assemble the microparticles because of high charge due to sialic acids, mucoadhesive properties, and a tendency to self-assemble, forming gels. Mucin loading into the crystals via co-synthesis is twice as effective as via adsorption into preformed crystals. Desialylated mucin has weaker binding to the crystals most probably due to electrostatic interactions between sialic acids and calcium ions on the crystal surface. Improved loading of low-molecular-weight inhibitor aprotinin into the mucin-containing crystals is demonstrated. Multilayer capsules (mucin/protamine)₃ have been made by the layer-by-layer self-assembly. Interestingly, the deposition of single mucin layers (mucin/water)₃ has also been proven, however, the capsules were unstable, most probably due to additional (to hydrogen bonding) electrostatic interactions in the case of the two polymers used. Finally, approaches to load biologically-active compounds (BACs) into the mucin-containing microparticles are discussed.

PMID: 30424240 [PubMed]

Rapid Detection and Trapping of Extracellular Vesicles by Electrokinetic Concentration for Liquid Biopsy on Chip.

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Rapid Detection and Trapping of Extracellular Vesicles by Electrokinetic Concentration for Liquid Biopsy on Chip.

Micromachines (Basel). 2018 Jun 19;9(6):

Authors: Cheung LS, Sahloul S, Orozaliev A, Song YA

Abstract
Exosomes have gained immense importance since their proteomic and genetic contents could potentially be used for disease diagnostics, monitoring of cancer progression, metastasis, and drug efficacy. However, establishing the clinical utility of exosomes has been restricted due to small sizes and high sample loss from extensive sample preparation. Sample loss is particularly critical for body fluids limited in volume and difficult to access, e.g., cerebrospinal fluid. We present a microfluidic technique that locally enhances the concentration of extracellular vesicles extracted from MDA-MB-231 human breast cancer cell lines by using an ion concentration polarization (ICP)-based electrokinetic concentrator. Our design incorporates a trapping mechanism near the conductive polymer membrane; therefore, we can preconcentrate and capture extracellular vesicles simultaneously. Compared with standard fluorescence detection, our method increased the limit of detection (LOD) of extracellular vesicles by two orders of magnitude in 30 min. Our concentrator increased the extracellular vesicle concentration for 5.0 × 10⁷ particles/1 mL (LOD), 5.0 × 10⁸ particles/1 mL, and 5.0 × 10⁸ particles/1 mL by ~100-fold each within 30 min using 45 V. This study demonstrates an alternative platform to simultaneously preconcentrate and capture extracellular vesicles that can be incorporated as part of a liquid biopsy-on-a-chip system for the detection of exosomal biomarkers and analysis of their contents for early cancer diagnosis.

PMID: 30424239 [PubMed]

Fab on a Package: LTCC Microfluidic Devices Applied to Chemical Process Miniaturization.

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Fab on a Package: LTCC Microfluidic Devices Applied to Chemical Process Miniaturization.

Micromachines (Basel). 2018 Jun 05;9(6):

Authors: Cobas Gomez H, Mansini Cardoso R, de Novais Schianti J, Marim de Oliveira A, Gongora-Rubio MR

Abstract
Microfluidics has brought diverse advantages to chemical processes, allowing higher control of reactions and economy of reagents and energy. Low temperature co-fired ceramics (LTCC) have additional advantages as material for fabrication of microfluidic devices, such as high compatibility with chemical reagents with typical average surface roughness of 0.3154 μm, easy scaling, and microfabrication. The conjugation of LTCC technology with microfluidics allows the development of micrometric-sized channels and reactors exploiting the advantages of fast and controlled mixing and heat transfer processes, essential for the synthesis and surface functionalization of nanoparticles. Since the chemical process area is evolving toward miniaturization and continuous flow processing, we verify that microfluidic devices based on LTCC technology have a relevant role in implementing several chemical processes. The present work reviews various LTCC microfluidic devices, developed in our laboratory, applied to chemical process miniaturization, with different geometries to implement processes such as ionic gelation, emulsification, nanoprecipitation, solvent extraction, nanoparticle synthesis and functionalization, and emulsion-diffusion/solvent extraction process. All fabricated microfluidics structures can operate in a flow range of mL/min, indicating that LTCC technology provides a means to enhance micro- and nanoparticle production yield.

PMID: 30424218 [PubMed]

Controlled Mechanical Motions of Microparticles in Optical Tweezers.

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Controlled Mechanical Motions of Microparticles in Optical Tweezers.

Micromachines (Basel). 2018 May 12;9(5):

Authors: Liu J, Li Z

Abstract
Optical tweezers, formed by a highly focused laser beam, have intriguing applications in biology and physics. Inspired by molecular rotors, numerous optical beams and artificial particles have been proposed to build optical tweezers trapping microparticles, and extensive experiences have been learned towards constructing precise, stable, flexible and controllable micromachines. The mechanism of interaction between particles and localized light fields is quite different for different types of particles, such as metal particles, dielectric particles and Janus particles. In this article, we present a comprehensive overview of the latest development on the fundamental and application of optical trapping. The emphasis is placed on controllable mechanical motions of particles, including rotation, translation and their mutual coupling under the optical forces and torques created by a wide variety of optical tweezers operating on different particles. Finally, we conclude by proposing promising directions for future research.

PMID: 30424165 [PubMed]

Spiral Microchannels with Trapezoidal Cross Section Fabricated by Femtosecond Laser Ablation in Glass for the Inertial Separation of Microparticles.

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Spiral Microchannels with Trapezoidal Cross Section Fabricated by Femtosecond Laser Ablation in Glass for the Inertial Separation of Microparticles.

Micromachines (Basel). 2018 Apr 09;9(4):

Authors: Al-Halhouli A, Al-Faqheri W, Alhamarneh B, Hecht L, Dietzel A

Abstract
The fabrication and testing of spiral microchannels with a trapezoidal cross section for the passive separation of microparticles is reported in this article. In contrast to previously reported fabrication methods, the fabrication of trapezoidal spiral channels in glass substrates using a femtosecond laser is reported for the first time in this paper. Femtosecond laser ablation has been proposed as an accurate and fast prototyping method with the ability to create 3D features such as slanted-base channels. Moreover, the fabrication in borosilicate glass substrates can provide high optical transparency, thermal resistance, dimensional stability, and chemical inertness. Post-processing steps of the laser engraved glass substrate are also detailed in this paper including hydrogen fluoride (HF) dipping, chemical cleaning, surface activation, and thermal bonding. Optical 3D images of the fabricated chips confirmed a good fabrication accuracy and acceptable surface roughness. To evaluate the particle separation function of the microfluidic chip, 5 μm, 10 μm, and 15 μm particles were focused and recovered from the two outlets of the spiral channel. In conclusion, the new chemically inert separation chip can be utilized in biological or chemical processes where different sizes of cells or particles must be separated, i.e., red blood cells, circulating tumor cells, and technical particle suspensions.

PMID: 30424104 [PubMed]

Modeling and Analysis of an Opto-Fluidic Sensor for Lab-on-a-Chip Applications.

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Modeling and Analysis of an Opto-Fluidic Sensor for Lab-on-a-Chip Applications.

Micromachines (Basel). 2018 Mar 19;9(3):

Authors: Muniswamy V, Bangalore Muniraju C, Kumar Pattnaik P, Krishnaswamy N

Abstract
In this work modeling and analysis of an integrated opto-fluidic sensor, with a focus on achievement of single mode optical confinement and continuous flow of microparticles in the microfluidic channel for lab-on-a-chip (LOC) sensing application is presented. This sensor consists of integrated optical waveguides, microfluidic channel among other integrated optical components. A continuous flow of microparticles in a narrow fluidic channel is achieved by maintaining the two sealed chambers at different temperatures and by maintaining a constant pressure of 1 Pa at the centroid of narrow fluidic channel geometry. The analysis of silicon on insulator (SOI) integrated optical waveguide at an infrared wavelength of 1550 nm for single mode sensing operation is presented. The optical loss is found to be 5.7 × 10-4 dB/cm with an effective index of 2.3. The model presented in this work can be effectively used to detect the nature of microparticles and continuous monitoring of pathological parameters for sensing applications.

PMID: 30424068 [PubMed]

Determination of the Three-Dimensional Rate of Cancer Cell Rotation in an Optically-Induced Electrokinetics Chip Using an Optical Flow Algorithm.

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Determination of the Three-Dimensional Rate of Cancer Cell Rotation in an Optically-Induced Electrokinetics Chip Using an Optical Flow Algorithm.

Micromachines (Basel). 2018 Mar 08;9(3):

Authors: Zhao Y, Jia D, Sha X, Zhang G, Li WJ

Abstract
Our group has reported that Melan-A cells and lymphocytes undergo self-rotation in a homogeneous AC electric field, and found that the rotation velocity of these cells is a key indicator to characterize their physical properties. However, the determination of the rotation properties of a cell by human eyes is both gruesome and time consuming, and not always accurate. In this paper, a method is presented to more accurately determine the 3D cell rotation velocity and axis from a 2D image sequence captured by a single camera. Using the optical flow method, we obtained the 2D motion field data from the image sequence and back-project it onto a 3D sphere model, and then the rotation axis and velocity of the cell were calculated. After testing the algorithm on animated image sequences, experiments were also performed on image sequences of real rotating cells. All of these results indicate that this method is accurate, practical, and useful. Furthermore, the method presented there can also be used to determine the 3D rotation velocity of other types of spherical objects that are commonly used in microfluidic applications, such as beads and microparticles.

PMID: 30424052 [PubMed]

Fetal Bovine Serum-Derived Extracellular Vesicles Persist within Vesicle-Depleted Culture Media.

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Fetal Bovine Serum-Derived Extracellular Vesicles Persist within Vesicle-Depleted Culture Media.

Int J Mol Sci. 2018 Nov 09;19(11):

Authors: Lehrich BM, Liang Y, Khosravi P, Federoff HJ, Fiandaca MS

Abstract
It is known that culture media (CM) promotes cellular growth, adhesion, and protects explanted primary brain cells from in vitro stresses. The fetal bovine serum (FBS) supplement used in most CM, however, contains significant quantities of extracellular vesicles (EVs) that confound quantitative and qualitative analyses from the EVs produced by the cultured cells. We quantitatively tested the ability of common FBS EV-depletion protocols to remove exogenous EVs from FBS-supplemented CM and evaluated the influence such methods have on primary astrocyte culture growth and viability. We assessed two methodologies utilized for FBS EV removal prior to adding to CM: (1) an 18-h ultracentrifugation (UC); and (2) a commercial EV-depleted FBS (Exo-FBS™). Our analysis demonstrated that Exo-FBS™ CM provided the largest depletion (75%) of total FBS EVs, while still providing 6.92 × 10⁸ ± 1.39 × 10⁸ EVs/mL. In addition, both UC and Exo-FBS™ CM resulted in poor primary astrocyte cell growth and viability in culture. The two common FBS EV-depletion methods investigated, therefore, not only contaminate in vitro primary cell-derived EV analyses, but also provide a suboptimal environment for primary astrocyte cell growth and viability. It appears likely that future CM optimization, using a serum-free alternative, might be required to advance analyses of cell-specific EVs isolated in vitro.

PMID: 30423996 [PubMed - in process]

Hypoxic Microenvironment and Metastatic Bone Disease.

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Hypoxic Microenvironment and Metastatic Bone Disease.

Int J Mol Sci. 2018 Nov 09;19(11):

Authors: Hiraga T

Abstract
Hypoxia is a common feature of solid tumors and is associated with an increased risk of metastasis and a poor prognosis. Recent imaging techniques revealed that bone marrow contains a quite hypoxic microenvironment. Low oxygen levels activate hypoxia signaling pathways such as hypoxia-inducible factors, which play critical roles in the key stages of metastatic dissemination including angiogenesis, epithelial-mesenchymal transition, invasion, maintenance of cancer stem cells, tumor cell dormancy, release of extracellular vesicles, and generation of pre-metastatic niches. Hypoxia also affects bone cells, such as osteoblasts and osteoclasts, and immune cells, which also act to support the development and progression of bone metastases. Paradoxically, hypoxia and related signaling molecules are recognized as high-priority therapeutic targets and many candidate drugs are currently under preclinical and clinical investigation. The present review focuses on our current knowledge of the potential roles of hypoxia in cancer metastasis to bone by considering the interaction between metastatic cancer cells and the bone microenvironment. Current therapeutic approaches targeting hypoxia are also described.

PMID: 30423905 [PubMed - in process]

Decellularized bovine small intestinal submucosa-PCL/hydroxyapatite-based multilayer composite scaffold for hard tissue repair.

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Decellularized bovine small intestinal submucosa-PCL/hydroxyapatite-based multilayer composite scaffold for hard tissue repair.

Mater Sci Eng C Mater Biol Appl. 2019 Jan 01;94:788-797

Authors: Parmaksiz M, Elçin AE, Elçin YM

Abstract
This study involved the development of a multilayer osteogenic tissue scaffold by assembling decellularized bovine small intestinal submucosa (bSIS) layers, together with synthetic hydroxyapatite microparticles (HAp) and poly(ε-caprolactone) (PCL) as the binder. As a first step, the surface and mechanical properties of the developed scaffold was determined, after which the biocompatibility was evaluated through seeding with isolated rat bone marrow mesenchymal stem cells (BM-MSCs). Then, a 21-day culture study was performed to investigate the in vitro osteoinductive potential of the scaffold on BM-MSCs under standard and osteogenic culture conditions. The SEM findings indicated that a uniform multilayer and perforated structure was acquired; that the HAp microparticles were homogenously distributed within the structure; and that the PCL-bound laminar scaffold had structural integrity. Mechanical tests revealed that the scaffold maintained its mechanical stability for at least 21 days in culture, with no changes in the first-day maximum strength and maximum stress values of 625.123 ± 70.531 N and 6.57762 ± 0.742 MPa, respectively. MTT and SEM analyses together revealed that BM-MSCs preserved their viability and proliferated during a 14-day culture period on the multilayer scaffold. Immunofluorescence analyses indicated that cells on the scaffold differentiated into the osteogenic lineage, by the culture-time-dependent increase in osteogenic markers' expression, i.e. Alkaline phosphatase, Osteopontin, and Osteocalcin. It was also clear that, the osteoinductive effect by the composite scaffold on BM-MSCs could be achieved even without the use of any external osteogenic inducers.

PMID: 30423765 [PubMed - in process]

Towards the production of natural rubber-calcium phosphate hybrid for applications as bioactive coatings.

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Towards the production of natural rubber-calcium phosphate hybrid for applications as bioactive coatings.

Mater Sci Eng C Mater Biol Appl. 2019 Jan 01;94:417-425

Authors: do Nascimento RM, de Paula AJ, Oliveira NC, Alves AC, de Oliveira Aquino YML, Filho AGS, Rodrigues JEFS, Hernandes AC

Abstract
This paper assesses the morphological, structural and bio-physicochemical stability of natural rubber (NR) Hevea brasiliensis coatings incorporated with microparticles of calcium phosphate-based (CaP) bioactive ceramics. Optical and electronic spectroscopic imaging techniques were employed to successfully evaluate the NR encapsulation capability and the stability of the coating in a biologically relevant media for bio-related application, i.e., simulated body fluid (SBF). The chemical structure of the natural polymer, the microchemical environment at the NR-CaP interface and the morphology of the CaP clusters were fully characterized. Further, the response of the hybrid coating to SBF was evaluated by incubating the samples for 30 days. The hybrid coating formed on Si surface (inert substrate) exhibited both stability and biodegradability in different levels (time dependence), thus opening horizons for applications as coatings for both biomaterials and drug delivery systems.

PMID: 30423725 [PubMed - in process]

 

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