Publications by authors named "Hassan Niknejad"

43 Publications

ERRATUM: The biological mechanism involved in anticancer properties of amniotic membrane.

Oncol Rev 2021 Feb 5;15(1):536. Epub 2021 Mar 5.

Medical Nanotechnology and Tissue Engineering Research Center, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

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http://dx.doi.org/10.4081/oncol.2021.536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993017PMC
February 2021

Biofabrication of chitosan/chitosan nanoparticles/polycaprolactone transparent membrane for corneal endothelial tissue engineering.

Sci Rep 2021 Mar 29;11(1):7060. Epub 2021 Mar 29.

Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

We aimed to construct a biodegradable transparent scaffold for culturing corneal endothelial cells by incorporating chitosan nanoparticles (CSNPs) into chitosan/polycaprolactone (PCL) membranes. Various ratios of CSNP/PCL were prepared in the presence of constant concentration of chitosan and the films were constructed by solvent casting method. Scaffold properties including transparency, surface wettability, FTIR, and biocompatibility were examined. SEM imaging, H&E staining, and cell count were performed to investigate the HCECs adhesion. The phenotypic maintenance of the cells during culture was investigated by flow cytometry. Transparency and surface wettability improved by increasing the CSNP/PCL ratio. The CSNP/PCL 50/25, which has the lowest WCA, showed comparable transparency with human acellular corneal stroma. The scaffold was not cytotoxic and promoted the HCECs proliferation as evaluated by MTT assay. Cell counting, flow cytometry, SEM, and H&E results showed appropriate attachment of HCECs to the scaffold which formed a compact monolayer. The developed scaffold seems to be suitable for use in corneal endothelial regeneration in terms of transparency and biocompatibility.
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http://dx.doi.org/10.1038/s41598-021-86340-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007807PMC
March 2021

Human amniotic mesenchymal stem cells to promote/suppress cancer: two sides of the same coin.

Stem Cell Res Ther 2021 Feb 12;12(1):126. Epub 2021 Feb 12.

Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Cancer is a leading cause of death in both developed and developing countries, and because of population growth and aging, it is a growing medical burden worldwide. With robust development in medicine, the use of stem cells has opened new treatment modalities in cancer therapy. In adult stem cells, mesenchymal stem cells (MSCs) are showing rising promise in cancer treatment due to their unique properties. Among different sources of MSCs, human amniotic fluid/membrane is an attractive and suitable reservoir. There are conflicting opinions about the role of human amniotic membrane/fluid mesenchymal stem cells (hAMSCS/hAFMSCs) in cancer, as some studies demonstrating the anticancer effects of these cells and others suggesting their progressive effects on cancer. This review focuses on recent findings about the role of hAMSCs/hAFMSCs in cancer treatment and summarizes the suppressing as well as promoting effects of these cells on cancer progression and underling mechanisms.
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http://dx.doi.org/10.1186/s13287-021-02196-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881457PMC
February 2021

Proposed Mechanisms of Targeting COVID-19 by Delivering Mesenchymal Stem Cells and Their Exosomes to Damaged Organs.

Stem Cell Rev Rep 2021 02 11;17(1):176-192. Epub 2021 Jan 11.

Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

With the outbreak of coronavirus disease (COVID-19) caused by novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the world has been facing an unprecedented challenge. Considering the lack of appropriate therapy for COVID-19, it is crucial to develop effective treatments instead of supportive approaches. Mesenchymal stem cells (MSCs) as multipotent stromal cells have been shown to possess treating potency through inhibiting or modulating the pathological events in COVID-19. MSCs and their exosomes participate in immunomodulation by controlling cell-mediated immunity and cytokine release. Furthermore, they repair the renin-angiotensin-aldosterone system (RAAS) malfunction, increase alveolar fluid clearance, and reduce the chance of hypercoagulation. Besides the lung, which is the primary target of SARS-CoV-2, the heart, kidney, nervous system, and gastrointestinal tract are also affected by COVID-19. Thus, the efficacy of targeting these organs via different delivery routes of MSCs and their exosomes should be evaluated to ensure safe and effective MSCs administration in COVID-19. This review focuses on the proposed therapeutic mechanisms and delivery routes of MSCs and their exosomes to the damaged organs. It also discusses the possible application of primed and genetically modified MSCs as a promising drug delivery system in COVID-19. Moreover, the recent advances in the clinical trials of MSCs and MSCs-derived exosomes as one of the promising therapeutic approaches in COVID-19 have been reviewed.
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http://dx.doi.org/10.1007/s12015-020-10109-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799400PMC
February 2021

Fabrication of nanochitosan incorporated polypyrrole/alginate conducting scaffold for neural tissue engineering.

Sci Rep 2020 12 16;10(1):22012. Epub 2020 Dec 16.

Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

The utilization of conductive polymers for fabrication of neural scaffolds have attracted much interest because of providing a microenvironment which can imitate nerve tissues. In this study, polypyrrole (PPy)-alginate (Alg) composites were prepared using different percentages of alginate and pyrrole by oxidative polymerization method using FeCl as an oxidant and electrical conductivity of composites were measured by four probe method. In addition, chitosan-based nanoparticles were synthesized by ionic gelation method and after characterization merged into PPy-Alg composite in order to fabricate a conductive, hydrophilic, processable and stable scaffold. Physiochemical characterization of nanochitosan/PPy-Alg scaffold such as electrical conductivity, porosity, swelling and degradation was investigated. Moreover, cytotoxicity and proliferation were examined by culturing OLN-93 neural and human dermal fibroblasts cells on the Nanochitosan/PPy-Alg scaffold. Due to the high conductivity, the film with ratio 2:10 (PPy-Alg) was recognized more suitable for fabrication of the final scaffold. Results from FT-IR and SEM, evaluation of porosity, swelling and degradation, as well as viability and proliferation of OLN-93 neural and fibroblast cells confirmed cytocompatiblity of the Nanochitosan/PPy-Alg scaffold. Based on the features of the constructed scaffold, Nanochitosan/PPy-Alg scaffold can be a proper candidate for neural tissue engineering.
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http://dx.doi.org/10.1038/s41598-020-78650-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744540PMC
December 2020

The differentiation effect of bone morphogenetic protein (BMP) on human amniotic epithelial stem cells to express ectodermal lineage markers.

Cell Tissue Res 2021 Feb 22;383(2):751-763. Epub 2020 Sep 22.

Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Stem cells are a promising tool for treatment of a variety of degenerative diseases. Human amniotic epithelial stem cells (hAECs) have desirable and unique characteristics that make them a proper candidate for cell therapy. In this study, we have investigated the effects of BMP-4 (bone morphogenetic protein-4) and its inhibition on differentiation of AECs into ectodermal lineages. Analysis of AEC-derived ectodermal lineages (neurons and keratinocytes) was performed by using flow cytometry technique for Map2 and β-tubulin (as neuron markers), Olig2 and MBP (as oligodendrocyte markers), and K14 and K10 (as keratinocyte markers). The results of this study illustrated that noggin (as BMP antagonist), BMP4, and both BMP4 and heparin (together or separately) increased neural and keratinocyte marker expression, respectively. The expression of markers MAP2, olig2, and K14 in hAECs has been significantly decreased 21 days after exposure to differentiation medium (without growth factors) compared with isolation day, which supports the hypothesis that AECs can be dedifferentiated into pluripotent cells. Moreover, activation and inhibition of BMP signaling have no effects on viability of hAECs. The results of this study showed that BMP signaling and its inhibition are the key factors for ectodermal lineage differentiation of amnion-derived stem cells.
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http://dx.doi.org/10.1007/s00441-020-03280-zDOI Listing
February 2021

Recent Advances on Drug-Loaded Mesenchymal Stem Cells With Anti-neoplastic Agents for Targeted Treatment of Cancer.

Front Bioeng Biotechnol 2020 23;8:748. Epub 2020 Jul 23.

Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Mesenchymal stem cells (MSCs), as an undifferentiated group of adult multipotent cells, have remarkable antitumor features that bring them up as a novel choice to treat cancers. MSCs are capable of altering the behavior of cells in the tumor microenvironment, inducing an anti-inflammatory effect in tumor cells, inhibiting tumor angiogenesis, and preventing metastasis. Besides, MSCs can induce apoptosis and inhibit the proliferation of tumor cells. The ability of MSCs to be loaded with chemotherapeutic drugs and release them in the site of primary and metastatic neoplasms makes them a preferable choice as targeted drug delivery procedure. Targeted drug delivery minimizes unexpected side effects of chemotherapeutic drugs and improves clinical outcomes. This review focuses on recent advances on innate antineoplastic features of MSCs and the effect of chemotherapeutic drugs on viability, proliferation, and the regenerative capacity of various kinds of MSCs. It also discusses the efficacy and mechanisms of drug loading and releasing procedures along with and preclinical outcomes of antineoplastic effects of primed MSCs for clinical prospection.
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http://dx.doi.org/10.3389/fbioe.2020.00748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7390947PMC
July 2020

The Bottlenecks in Translating Placenta-Derived Amniotic Epithelial and Mesenchymal Stromal Cells Into the Clinic: Current Discrepancies in Marker Reports.

Front Bioeng Biotechnol 2020 13;8:180. Epub 2020 Mar 13.

Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Placenta-derived amniotic cells have prominent features for application in regenerative medicine. However, there are still discrepancies in the characterization of human amniotic epithelial and mesenchymal stromal cells. It seems crucial that the characterization of human amniotic membrane cells be investigated to determine whether there are currently discrepancies in their characterization reports. In addition, possible causes for the witnessed discrepancies need to be addressed toward paving the way for further clinical application and safer practices. The objective of this review is to investigate the marker characterization as well as the potential causes of the discrepancies in the previous reports on placenta-derived amniotic epithelial and mesenchymal stromal cells. The current discrepancies could be potentially due to reasons including passage number and epithelial to mesenchymal transition (EMT), cell heterogeneity, isolation protocols and cross-contamination, the region of cell isolation on placental disk, measuring methods, and gestational age.
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http://dx.doi.org/10.3389/fbioe.2020.00180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083014PMC
March 2020

Purified compounds from marine organism sea pen induce apoptosis in human breast cancer cell MDA-MB-231 and cervical cancer cell Hela.

Eur J Pharmacol 2020 Jun 25;877:173075. Epub 2020 Mar 25.

Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address:

Marine organisms are an important source of chemical compounds which are appropriate for use as therapeutic agents. Among them, Sea pens produce valuable chemical compounds being used as anti-cancer drugs. The aim of this study was to investigate anti-cancer property of extracted and purified compounds from marine organism Sea pen and evaluate their effects on inducing of apoptosis. The extracts were prepared from dried colony of Virgularia gustaviana. The compounds (3β)-Cholest,5en,3ol (cholesterol) (15 mg), Hexadecanoic acid (2.5 mg) and 2-Hexadecanol (10.7 mg) were identified by GC-MS and NMR. The cytotoxic effects of the compounds were evaluated on Hela and MDA-Mb-231 human cancer cell lines with MTT assay. Immunocytochemistry and Western Blot analyses were used to evaluate the expression of apoptosis related markers Caspase 3, Caspase 8, Bax and BCL2 in cancer cells after treating with three compounds. The purified compounds reduced viability of human breast cancer cell line MDA-MB-231 and human cervical cancer cell line Hela concentration-dependently. 2-Hexadecanol reduced significantly the viability of both cancer cell lines in comparison to the other purified compounds. Treatment of cancer cells with the three purified compounds increased the expression of caspase-3, caspase-8 and Bax proteins and decreased the relative Bcl-2/Bax ratio, demonstrating induction of apoptosis as possible mechanism of action. According to the results, three purified compounds inhibit the growth of cancer cells by inducing of apoptosis pathway; an effect which needs to be further investigated in the future studies.
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http://dx.doi.org/10.1016/j.ejphar.2020.173075DOI Listing
June 2020

The biological mechanism involved in anticancer properties of amniotic membrane.

Oncol Rev 2020 Feb 18;14(1):429. Epub 2020 Feb 18.

Proteomics Research Center, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

The main role of amniotic membrane (AM), or amnion, is to protect the fetus from drying out and create an appropriate environment for its growth. AM is also a suitable candidate for the treatment of various diseases due to its unique characteristics. In recent years, a new line of research has focused on the anticancer properties of amnion and its potential use in cancer treatment. The and studies indicate the anti-proliferative and proapoptotic activities, as well as the angioregulatory and immunomodulatory properties of the amniotic membrane. However, the exact mechanism and molecular basis of these anticancer effects of AM are not fully elucidated. This paper presents an overview of the latest findings and knowledge about the anticancer effects of AM and its underlying molecular mechanisms, which is crucial for the application of amnion in cancer therapy.
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http://dx.doi.org/10.4081/oncol.2020.429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7036708PMC
February 2020

The in vivo effect of Lacto-N-neotetraose (LNnT) on the expression of type 2 immune response involved genes in the wound healing process.

Sci Rep 2020 01 22;10(1):997. Epub 2020 Jan 22.

Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Lacto-n-neotatraose (LNnT) oligosaccharide shows properties such as anti-inflammatory, type 2 immune response induction, induced angiogenesis, and anti-bacterial effects. Here, we hypothesized that the application of LnNT in the skin full-thickness wound can accelerate the healing process through its anti-inflammatory effect as well as induction of type 2 immune responses. In this study, we evaluated the cell viability of fibroblasts in the presence of LNnT. The full-thickness wound model was created by punch biopsy. The mice were treated intradermaly with LNnT at the concentrations of 100 and 200 µg or PBS as a control group. The wounds samples were compared based on the macroscopic and histological evaluations. The amount of collagen deposition and expression of genes involved in type 2 immunity were measured by the hydroxyproline assay and real time PCR method, respectively. Our results showed that LNnT had no negative effect on the cell viability of fibroblasts. LNnT increased the wound closure rate on day 7 post-wounding. H&E stain analysis revealed that mice treated with 200 µg LNnT exhibited better healing score, follicle formation, and lower epidermal thickness index. The mice treated with LNnT exhibited a lower collagen deposition on day 21 and higher collagen content on days 7 and 14 post-treatment. The LNnT groups also exhibited a lower number of neutrophils and a higher number of basal cells and fibroblasts. The expression rate of IL-10, IL-4, and IL-13 was higher in the LNnT groups. These results showed the high potential of LNnT for use in treatment of full-thickness wounds.
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http://dx.doi.org/10.1038/s41598-020-57860-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6976585PMC
January 2020

Substrate stiffness affects the morphology and gene expression of epidermal neural crest stem cells in a short term culture.

Biotechnol Bioeng 2020 02 20;117(2):305-317. Epub 2019 Nov 20.

NeuroBiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

According to the intrinsic plasticity of stem cells, controlling their fate is a critical issue in cell-based therapies. Recently, a growing body of evidence has suggested that substrate stiffness can affect the fate decisions of various stem cells. Epidermal neural crest stem cells as one of the main neural crest cell derivatives hold great promise for cell therapies due to presenting a high level of plasticity. This study was conducted to define the influence of substrate stiffness on the lineage commitment of these cells. Here, four different polyacrylamide hydrogels with elastic modulus in the range of 0.7-30 kPa were synthesized and coated with collagen and stem cells were seeded on them for 24 hr. The obtained data showed that cells can attach faster to hydrogels compared with culture plate and cells on <1 kPa stiffness show more neuronal-like morphology as they presented several branches and extended longer neurites over time. Moreover, the transcription of actin downregulated on all hydrogels, while the expression of Nestin, Tubulin, and PDGFR-α increased on all of them and SOX-10 and doublecortin gene expression were higher only on <1 kPa. Also, it was revealed that soft hydrogels can enhance the expression of glial cell line-derived neurotrophic factor, neurotrophin-3, and vascular endothelial growth factor in these stem cells. On the basis of the results, these cells can respond to the substrate stiffness in the short term culture and soft hydrogels can alter their morphology and gene expression. These findings suggested that employing proper substrate stiffness might result in cells with more natural profiles similar to the nervous system and superior usefulness in therapeutic applications.
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http://dx.doi.org/10.1002/bit.27208DOI Listing
February 2020

Inducing type 2 immune response, induction of angiogenesis, and anti-bacterial and anti-inflammatory properties make Lacto-n-Neotetraose (LNnT) a therapeutic choice to accelerate the wound healing process.

Med Hypotheses 2020 Jan 3;134:109389. Epub 2019 Sep 3.

Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address:

The healing process of non-healing and full-thickness wounds is currently facing some serious challenges. In such ulcers, losing a large part of skin causes a chronic infection due to the entrance of various pathogens in the wound bed. Moreover, poor vascularization, uncontrolled inflammation, and delayed re-epithelialization increase the healing time in patients suffering from such wounds. In this light, tissue engineering provides a wide range of strategies using a variety of biomaterials, biofactors and stem cells to decrease the healing time and restore the function of the damaged site. A suitable wound healing agent should possess some critical parameters such as inducing re-epithelialization, anti-inflammatory and anti-bacterial properties, and angiogenic capability. The Lacto-n-Neotetraose (LNnT) with chemical formula C26H45NO21 is an oligosaccharide present in human milk and soluble antigens extracted from Schistosoma mansoni eggs. It is reported that LNnT induces type 2 immune response (Th2 immunity). Th2 immunity promotes re-epithelialization, angiogenesis and wound contraction by recruiting the cells which produce Th2-related cytokines. Moreover, LNnT shows some special characteristics such as angiogenic capability, anti-inflammatory, and anti-bacterial effects which can address the mentioned challenges in the treatment of non-healing and full-thickness wounds. Here, we hypothesize that utilizing LNnT is an appropriate biofactor which would improve the healing process in full-thickness and non-healing wounds.
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http://dx.doi.org/10.1016/j.mehy.2019.109389DOI Listing
January 2020

pH-Sensitive Magnetite Nanoparticles Modified with Hyperbranched Polymers and Folic Acid for Targeted Imaging and Therapy.

Curr Drug Deliv 2019 ;16(9):839-848

Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Objective: A novel pH-sensitive superparamagnetic drug delivery system was developed based on quercetin loaded hyperbranched polyamidoamine-b-polyethylene glycol-folic acid-modified Fe3O4 nanoparticles ([email protected]).

Methods: The nanoparticles exhibit excellent water dispersity with well-defined size distribution (around 51.8 nm) and strong magnetisability. In vitro release studies demonstrated that the quercetinloaded [email protected] nanoparticles are stable at normal physiologic conditions (pH 7.4 and 37°C) but sensitive to acidic conditions (pH 5.6 and 37°C), which led to the rapid release of the loaded drug.

Results: Fluorescent microscopy results indicated that the [email protected] nanoparticles could be efficiently accumulated in tumor tissue compared with non-folate conjugated nanoparticles. Also, in comparison with free quercetin, the quercetin loaded [email protected] exerts higher cytotoxicity. Furthermore, this magnetic nanocarrier showed high MRI sensitivity, even in its lower iron content.

Conclusion: The results indicated that the prepared nanoparticles are an effective chemotherapy and diagnosis system to inhibit proliferation and monitor the progression of tumor cells, respectively.
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http://dx.doi.org/10.2174/1567201816666191002102353DOI Listing
April 2020

Potential Therapeutic Features of Human Amniotic Mesenchymal Stem Cells in Multiple Sclerosis: Immunomodulation, Inflammation Suppression, Angiogenesis Promotion, Oxidative Stress Inhibition, Neurogenesis Induction, MMPs Regulation, and Remyelination Stimulation.

Front Immunol 2019 20;10:238. Epub 2019 Feb 20.

Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Multiple sclerosis (MS) is an inflammatory and degenerative disorder of the central nervous system with unknown etiology. It is accompanied by demyelination of the nerves during immunological processes in the presence of oxidative stress, hypoxia, cerebral hypo-perfusion, and dysregulation in matrix metalloproteinases (MMPs). Human amniotic mesenchymal stem cells (hAMSCs) as pluripotent stem cells possess some conspicuous features which could be of therapeutic value in MS therapy. hAMSCs could mimic the cascade of signals and secrete factors needed for promoting formation of stable neovasculature and angiogenesis. hAMSCs also have immunomodulatory and immunosuppressive effects on inflammatory processes and reduce the activity of inflammatory cells, migration of microglia and inhibit recruitment of certain immune cells to injury sites. hAMSCs attenuate the oxidative stress supported by the increased level of antioxidant enzymes and the decreased level of lipid peroxidation products. Furthermore, hAMSCs enhance neuroprotection and neurogenesis in brain injuries by inhibition of inflammation and promotion of neurogenesis. hAMSCs could significantly increase the expression of neurotrophic factors, which prevents neurons from initiating programmed cell death and improves survival, development, and function of neurons. In addition, they induce differentiation of neural progenitor cells to neurons. hAMSCs could also inhibit MMPs dysregulation and consequently promote the survival of endothelial cells, angiogenesis and the stabilization of vascular networks. Considering the mentioned evidences, we hypothesized here that hAMSCs and their conditioned medium could be of therapeutic value in MS therapy due to their unique properties, including immunomodulation and inflammation suppression; angiogenesis promotion; oxidative stress inhibition; neurogenesis induction and neuroprotection; matrix metalloproteinases regulation; and remyelination stimulation.
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http://dx.doi.org/10.3389/fimmu.2019.00238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391358PMC
July 2020

Chitosan-gelatin porous scaffold incorporated with Chitosan nanoparticles for growth factor delivery in tissue engineering.

Carbohydr Polym 2018 Dec 9;202:315-322. Epub 2018 Jul 9.

Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Designing scaffolds capable of mimicking the 3D structure of the extracellular matrix (ECM) and deliver signaling factors to affect and control the cell response favorably, is of high importance in the field of tissue engineering. As polymeric nanoparticles are effective vehicles for delivering growth factors, this study aimed to fabricate and characterize a nanocomposite scaffold based on chitosan and gelatin, incorporated with chitosan nanoparticles loaded with basic fibroblast growth factor (bFGF) and bovine serum albumin (BSA). Nanoparticles, prepared by the ionic gelation method, were loaded with BSA-bFGF and introduced into chitosan-gelatin scaffolds to enhance their biological properties. Structural characterizations and biological assays showed that nanoparticles significantly affected the physical properties of the scaffold and could provide a sustained release of growth factor to enhance the proliferation of fibroblast cells significantly. These results are promising for improving the properties of chitosan-gelatin scaffolds in tissue engineering applications, especially where the delivery of angiogenic growth factor such as bFGF is needed.
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http://dx.doi.org/10.1016/j.carbpol.2018.07.023DOI Listing
December 2018

Inhibition of Inflammation, Suppression of Matrix Metalloproteinases, Induction of Neurogenesis, and Antioxidant Property Make Bryostatin-1 a Therapeutic Choice for Multiple Sclerosis.

Front Pharmacol 2018 19;9:625. Epub 2018 Jun 19.

Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Multiple sclerosis (MS) is a neurodegenerative disease characterized by inflammation and myelin damage. Pro-inflammatory cytokines, oxidative stress, high level of matrix metalloproteinases (MMPs) activity and blood-brain barrier (BBB) damage, immune-mediated destruction of myelin and neuron loss are involved in the pathogenesis of MS. The currently approved treatments for MS include injectable drugs (interferon-β and glatiramer acetate), oral drugs (fingolimod), and monoclonal antibodies (natalizumab). The mentioned therapeutic choices are mostly focused on the inhibition of inflammation. Therefore, the search for a multi-target therapeutic choice remains unchallenged. It seems that a drug with anti-inflammatory, oxidative stress inhibitory, reduction of MMPs activity, and neurogenesis stimulatory properties may be effective for treatment of MS. In this regard, Bryostatin-1 as a macrolide and marine natural product has been selected as a therapeutic choice. Studies indicate that Bryostatin-1 has anti-inflammatory and antioxidant properties and decreases MMPs level and BBB damage. Furthermore, Bryostatin-1 has a neuroprotective effect and promotes neurogenesis and differentiation of oligodendrocyte progenitor stem cells as a critical step for remyelination/myelogenesis. Based on these properties, we hypothesized here that Bryostatin-1 is an effective treatment in MS.
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http://dx.doi.org/10.3389/fphar.2018.00625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6018466PMC
June 2018

Inducing Apoptosis of Cancer Cells Using Sea Pen Extract Which is Comparable to Cembrane Diterpene Sarcophine.

Iran J Pharm Res 2018 ;17(2):640-652

Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Marine Soft corals have frequently been studied in recent years because of their specific chemical compounds in tissue engineering and regenerative medicine. The aim of this study was to investigate anti-cancer property of extracted compound from and their effect on inducing of apoptosis. The extraction process was carried out with ethyl acetate for 5 days and the extract was separated by silica-gel column chromatography. The column was washed with n-hexane-ethyl acetate solvent at ratio of 10:0 to 0:10. Thin layer chromatography (TLC), High performance thin layer chromatography (HPTLC), high performance liquid chromatography (HPLC), and 13C NMR spectroscopy were used for qualitative identification of compounds. The viability of HeLa and MDA-MB-231 cancer cells was investigated using MTT assay at the concentrations of 25, 50, and 100 µL/mL of extracted compounds. Immunocytochemistry and Western Blot analyses were used to evaluate expression of apoptotic markers caspase-3 and caspase-8 in cancer cells after treating with effective fractions (based on viability of cancer cells) and the results were compared with Sarcophine. From ten isolated fractions (A-J), Retention time and Retention Factors (Rf) of fractions G, I, and J were the same as Sarcophine. Fraction G, I, and J dose-dependently decreased cancer cell viability compared to control group and Sarcophine. Treatment of cancer cells with the latest fraction increased expression of caspase-3 and caspase-8 demonstrating induction of apoptosis as possible mechanism of action. According to the results, the compounds extracted from inhibit the growth of cancer cells by inducing of apoptosis pathway; an effect which needs to be further investigated in the future studies.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985181PMC
January 2018

Amniotic membrane and its epithelial and mesenchymal stem cells as an appropriate source for skin tissue engineering and regenerative medicine.

Artif Cells Nanomed Biotechnol 2018 24;46(sup2):431-440. Epub 2018 Apr 24.

a Department of Pharmacology, School of Medicine , Shahid Beheshti University of Medical Sciences , Tehran , Iran.

One of the main goals of tissue engineering and regenerative medicine is to develop skin substitutes for treating deep dermal and full thickness wounds. In this regard, both scaffold and cell source have a fundamental role to achieve exactly the same histological and physiological analog of skin. Amnion epithelial and mesenchymal cells possess the characteristics of pluripotent stem cells which have the capability to differentiate into all three germ layers and can be obtained without any ethical concern. Amniotic cells also produce different growth factors, angio-modulatory cytokines, anti-bacterial peptides and a wide range of anti-inflammatory agents which eventually cause acceleration in wound healing. In addition, amniotic membrane matrix exhibits characteristics of an ideal scaffold and skin substitute through various types of extracellular proteins such as collagens, laminins and fibronectins which serve as an anchor for cell attachment and proliferation, a bed for cell delivery and a reservoir of drugs and growth factors involved in wound healing process. Recently, isolation of amniotic cells exosomes, surface modification and cross-linking approaches, construction of amnion based nanocomposites and impregnation of amnion with nanoparticles, construction of amnion hydrogel and micronizing process promoted its properties for tissue engineering. In this manuscript, the recent progress was reviewed which approve that amnion-derived cells and matrix have potential to be involved in skin substitutes; an enriched cell containing scaffold which has a great capability to be translated into the clinic.
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http://dx.doi.org/10.1080/21691401.2018.1458730DOI Listing
June 2019

Immunological compatibility status of placenta-derived stem cells is mediated by scaffold 3D structure.

Artif Cells Nanomed Biotechnol 2018 23;46(sup1):876-884. Epub 2018 Feb 23.

a Department of Pharmacology, School of Medicine , Shahid Beheshti University of Medical Sciences , Tehran , Iran.

Placenta-derived amniotic epithelial cells (AECs), a great cell source for tissue engineering and stem cell therapy, are immunologically inert in their native state; however, immunological changes in these cells after culture and differentiation have challenged their applications. The aim of this study was to investigate the effect of 2D and 3D scaffolds on human lymphocyte antigens (HLA) expression by AECs. The effect of different preparation parameters including pre-freezing time and temperature was evaluated on 3D chitosan-gelatine scaffolds properties. Evaluation of MHC class I, HLA-DR and HLA-G expression in AECs after 7 d culture on 2D bed and 3D scaffold of chitosan-gelatine showed that culture of AECs on the 2D substrate up-regulated MHC class I and HLA-DR protein markers on AECs surface and down-regulated HLA-G protein. In contrast, 3D scaffold did not increase protein expression of MHC class I and HLA-DR. Moreover, HLA-G protein expression remained unchanged in 3D culture. These results confirm that 3D scaffold can remain AECs in their native immunological state and modification of physical properties of the scaffold is a key regulator of immunological markers at the gene and protein expression levels; a strategy which circumvents rejection challenge of amniotic stem cells to be translated into the clinic.
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http://dx.doi.org/10.1080/21691401.2018.1438452DOI Listing
August 2019

Induction of antimicrobial peptides secretion by IL-1β enhances human amniotic membrane for regenerative medicine.

Sci Rep 2017 12 5;7(1):17022. Epub 2017 Dec 5.

Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Due to antibacterial characteristic, amnion has been frequently used in different clinical situations. Developing an in vitro method to augment endogenous antibacterial ingredient of amniotic epithelial and mesenchymal stem cells is desirable for a higher efficacy of this promising biomaterial. In this study, epithelial or mesenchymal side dependent effect of amniotic membrane (AM) on antibacterial activity against some laboratory and clinical isolated strains was investigated by modified disk diffusion method and colony count assay. The effect of exposure to IL-1β in production and release of antibacterial ingredients was investigated by ELISA assay. The results showed that there is no significant difference between epithelial and mesenchymal sides of amnion in inhibition of bacterial growth. Although the results of disk diffusion showed that the AM inhibitory effect depends on bacterial genus and strain, colony count assay showed that the extract of AM inhibits all investigated bacterial strains. The exposure of AM to IL-1β leads to a higher level of antibacterial peptides secretion including elafin, HBD-2, HBD-3 and cathelicidic LL-37. Based on these results, amniotic cells possess antibacterial activity which can be augmented by inflammatory signal inducers; a process which make amnion and its epithelial and mesenchymal stem cells more suitable for tissue engineering and regenerative medicine.
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http://dx.doi.org/10.1038/s41598-017-17210-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5717175PMC
December 2017

Design and fabrication of GelMA/chitosan nanoparticles composite hydrogel for angiogenic growth factor delivery.

Artif Cells Nanomed Biotechnol 2018 Dec 24;46(8):1799-1808. Epub 2017 Oct 24.

b Department of Pharmacology, School of Medicine , Shahid Beheshti University of Medical Sciences , Tehran , Iran.

The cellular microenvironment plays a crucial role in improving cell response and function of an engineered tissue. Scaffolds mimicking the native ECM and capable of releasing growth factors are great candidates for tissue engineering applications. Gelatin methacryloyl (GelMA) hydrogel, a photocrosslinkable biomaterial possessing tunable properties, has been widely used in tissue engineering. It has been suggested that incorporating micro/nano carriers in GelMA could provide a sustained release of growth factors. Specifically, chitosan nanoparticles can be used for growth factor delivery due to its biocompatibility, easy method of synthesis, and preventing the biomolecule from degradation. In this study, GelMA/chitosan nanoparticles composite hydrogel was developed to deliver an angiogenic growth factor (bFGF). The hydrogel was prepared by photopolymerization and its chemical and physical properties were characterized. Its degradation and swelling characteristics were also evaluated. The size of nanoparticles was evaluated and the profile of bFGF release from the hydrogel and its effect on the viability of fibroblast cells was studied. The results showed that GelMA/chitosan nanoparticles can significantly promote cell proliferation due to its biocompatible structure and providing a sustained profile of bFGF release. This hydrogel scaffold can be used for efficient delivery of bFGF in various applications and especially for angiogenesis.
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http://dx.doi.org/10.1080/21691401.2017.1392970DOI Listing
December 2018

The effect of cryopreservation on anti-cancer activity of human amniotic membrane.

Cryobiology 2017 02 9;74:61-67. Epub 2016 Dec 9.

Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Nanomedicine and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address:

Human amniotic membrane (AM) is an appropriate candidate for treatment of cancer due to special properties, such as inhibition of angiogenesis and secretion of pro-apoptotic factors. This research was designed to evaluate the impact of cryopreservation on cancer cell death induction and anti-angiogenic properties of the AM. Cancer cells were treated with fresh and cryopreserved amniotic condition medium during 24 h and cancer cell viability was determined by MTT assay. To evaluate angiogenesis, the rat aorta ring assay was performed for both fresh and cryopreserved AM within 7 days. In addition, four anti-angiogenic factors Tissue Inhibitor of Matrix Metalloproteinase-1 and 2 (TIMP-1 and TIMP-2), Thrombospondin, and Endostatin were measured by ELISA assay before and after cryopreservation. The results showed that the viability of cultured cancer cells dose-dependently decreased after treatment with condition medium of fresh and cryopreserved tissue and no significant difference was observed between the fresh and cryopreserved AM. The results revealed that the amniotic epithelial stem cells inhibit the penetration of fibroblast-like cells and angiogenesis. Moreover, the penetration of fibroblast-like cells in both epithelial and mesenchymal sides of fresh and cryopreserved AM was observed after removing of epithelial cells. The cryopreservation procedure significantly decreased anti-angiogenic factors TIMP-1, TIMP-2, Thrombospondin, and Endostatin which shows that angio-modulatory property is not fully dependent on proteomic and metabolomic profiles of the AM. These promising results demonstrate that cancer cell death induction and anti-angiogenic properties of the AM were maintained within cryopreservation; a procedure which can circumvent limitations of the fresh AM.
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http://dx.doi.org/10.1016/j.cryobiol.2016.12.001DOI Listing
February 2017

Design and construction of multifunctional hyperbranched polymers coated magnetite nanoparticles for both targeting magnetic resonance imaging and cancer therapy.

J Colloid Interface Sci 2017 Mar 10;490:64-73. Epub 2016 Nov 10.

Department of Tissue Engineering, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Nanomedicine and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Magnetic drug targeting is a drug delivery strategy that can be used to improve the therapeutic efficiency on tumor cells and reduce the side effects on normal cells and tissues. The aim in this study is designing a novel multifunctional drug delivery system based on superparamagnetic nanoparticles for cancer therapy. Magnetic nanoparticles were synthesized by coprecipitation of iron oxide followed by coating with poly citric acid (PCA) dendritic macromolecules via bulk polymerization strategy. It was further surface-functionalized with poly(ethylene glycol) (PEG) and then to achieve tumor cell targeting property, folic acid was further incorporated to the surface of prepared carriers via a facile coupling reaction between the hydroxyl end group of the PEG and the carboxyl group of folic acid. The so prepared nanocarriers ([email protected]) were characterized by X-ray diffraction, TEM, TGA, FT-IR, DLS and VSM techniques. The room temperature VSM measurements showed that magnetic particles were superparamagnetic. Transmission electron microscopy and dynamic light scattering were also performed which revealed that size of nanocarriers was lying in the range of 10-49nm. Quercetin loading and release profiles of prepared nanocarriers showed that up to 83% of loaded drug was released in 250h. Fluorescent microscopy showed that the cellular uptake by folate receptor-overexpressing HeLa cells of the quercetin-loaded [email protected] nanoparticles was higher than that of non-folate conjugated nanoparticles. Thus, folate conjugation significantly increased nanoparticle cytotoxicity. Also, T-weighted MRI images of [email protected] nanoparticles showed that the magnetic resonance signal is enhanced significantly with increasing nanoparticle concentration in water and they also served as MRI contrast agents with relaxivities of 3.4mMs (r) and 99.8mMs (r). The results indicate that this multifunctional nanocarrier is a significant breakthrough in developing a drug delivery vehicle that combines drug targeting as well as sensing and therapy at the same time.
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http://dx.doi.org/10.1016/j.jcis.2016.11.014DOI Listing
March 2017

Different Light Transmittance of Placental and Reflected Regions of Human Amniotic Membrane That Could Be Crucial for Corneal Tissue Engineering.

Cornea 2016 Jul;35(7):997-1003

*Department of Tissue Engineering and Regenerative Medicine, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; and †Nanomedicine and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Purpose: Because of long-term incorporation of amniotic membrane (AM) into corneal stroma after transplantation as a scaffold for stem cell delivery, the variation in haziness is a major factor that influences visual quality. The aim of this study was to evaluate probable sources of transparency variation in fresh and freeze-dried AM and compare the obtained results with transparency of rabbit corneas.

Methods: Amnions were extracted from placental and reflected regions of placentas from elective Cesarean sections. The effects of removing epithelial cells and spongy layer on transparency and thickness of fresh and freeze-dried AMs and rabbit cornea were evaluated. The epithelial surface of AMs was evaluated with histological analysis and scanning electron microscopy.

Results: The reflected region of intact AM was thinner and more transparent than the placental region. From histological analysis, the main source of difference between placental and reflected regions of amnion is related to epithelial cells. The process of acellularization improved light transmission of the AM in both placental and reflected regions and also omitted variation between transparency of reflected and placental regions of AM. Freeze-drying of intact AM did not improve transparency because of scattering of light by cellular debris; however, removing the epithelial layer before freeze-drying resulted in optimized light transmission similar to transparency of rabbit cornea.

Conclusions: The amniotic epithelial cells play a major role as a source of variation in light transmission properties of amnion. From the results, epithelial-denuded freeze-dried AM was found to be a suitable scaffold to be applied in corneal tissue engineering.
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http://dx.doi.org/10.1097/ICO.0000000000000867DOI Listing
July 2016

Induction of apoptosis, stimulation of cell-cycle arrest and inhibition of angiogenesis make human amnion-derived cells promising sources for cell therapy of cancer.

Cell Tissue Res 2016 Mar 5;363(3):599-608. Epub 2016 Feb 5.

Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Amniotic membrane (AM), the nearest layer of fetal membranes to the fetus, contains two types of cells with unique characteristics that make them excellent candidates for clinical applications. Amniotic epithelial and mesenchymal cells have low immunogenicity, anti-inflammation, anti-fibrosis and anti-bacterial properties and no ethical issues. Although amniotic cells have stem cell properties and express transcription factors specific for pluripotent stem cells, they are not tumorigenic after transplantation. In the last decade, a new line of research has been initiated with a focus on the anti-proliferative effects of amniotic epithelial and mesenchymal cells on tumor growth. Amnion-derived epithelial and mesenchymal cells inhibit tumor growth and invasion through three pathways: the induction of apoptosis, the stimulation of cell-cycle arrest and the inhibition of angiogenesis. In this review, the various aspects of the anti-cancer properties of amnion-derived cells and the underlying mechanisms are discussed with emphasis on the translation of the cell therapy of cancer from experimental into clinical practice.
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http://dx.doi.org/10.1007/s00441-016-2364-3DOI Listing
March 2016

The effects of cryopreservation on angiogenesis modulation activity of human amniotic membrane.

Cryobiology 2015 Dec 23;71(3):413-8. Epub 2015 Oct 23.

Department of Tissue Engineering, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address:

Amniotic membrane (AM), as the innermost layer of placenta, has side dependent effects on the angiogenesis. Cryopreservation is a necessary process to avoid the challenging problems of fresh tissues; a procedure which makes the AM ready-to-use. Since the cryopreservation can influence the AM characteristics for experimental and clinical purposes, in this study the effects of cryopreservation were evaluated on angiogenesis modulation activity of the AM compared to fresh tissues in an animal model. The AM was implanted mesenchymal side up or epithelial side up in a rat dorsal skinfold chamber. The length and number of branches of formed capillaries were measured via intravital microscopy after 7 days. The amount of IL-8 (interleukin-8) and TIMP-2 (Tissue Inhibitor of Matrix Metalloproteinase-2) as two factors in amniotic cells which have great impacts on angiogenesis were evaluated using ELISA assay. The epithelial surface of cryopreserved AM had inhibitory effects on vessel formation. The cryopreserved amniotic mesenchymal side increased the vessel length and sprout. The result of cryopreserved AM on angiogenesis was similar to that of fresh tissues. The levels of IL-8 and TIMP-2 in cryopreserved samples were significantly less than fresh AMs which shows that angio-modulatory properties are not limited to the effects of amnion epithelial and mesenchymal stem cells and the other components such as extracellular matrix may contribute in angio-modulatory effects. These promising results show that inducing and inhibitory effects of the AM, which make it an appropriate candidate for different clinical situations, were maintained after cryopreservation.
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http://dx.doi.org/10.1016/j.cryobiol.2015.09.008DOI Listing
December 2015

Blood compatibility of human amniotic membrane compared with heparin-coated ePTFE for vascular tissue engineering.

J Tissue Eng Regen Med 2017 06 19;11(6):1701-1709. Epub 2015 Jul 19.

Department of Tissue Engineering, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Amniotic membrane (AM), a placenta-derived natural biomaterial, has several characteristics which make it a potential substitute for blood vessels. However, there are no reports on the effects of the AM on blood components. The aim of this study was to evaluate the blood compatibility of the epithelial and mesenchymal surfaces of the amnion for potential use in vascular tissue engineering. The activation of intrinsic and extrinsic pathways of the clotting system, haemolysis and platelet adhesion were studied and the results were compared with heparin-coated expanded polytetrafluoroethylene (ePTFE) as a standard synthetic vascular graft. Prothrombin time (PT), activated partial thromboplastin time (aPTT), clotting time (CT) and haemolysis (%) tests showed that both the epithelial and mesenchymal sides of the AM are haemocompatible. Platelet aggregation and P-selectin production from the platelets showed that the epithelial surface of the AM has less induction of platelet activation than ePTFE. The results of scanning electron microscopy (SEM) demonstrated that platelets in contact with ePTFE had a higher rate of adhesion than with the epithelial and mesenchymal surfaces of the AM. Moreover, the morphological distribution of the platelets showed that the majority of platelets were round, while a large number of cells on ePTFE were dendritic. These results suggest that the AM which contains epithelial and mesenchymal stem cells has appropriate haemocompatibility to be employed in vascular tissue engineering, especially as a vein substitute. Copyright © 2015 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/term.2064DOI Listing
June 2017

Extract of fetal membrane would inhibit thrombosis and hemolysis.

Med Hypotheses 2015 Aug 1;85(2):197-202. Epub 2015 May 1.

Department of Tissue Engineering, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

The innermost layer of fetal membranes is amnion which has anti-adhesive, anti-inflammation and viscoelastic properties, as well as low immunogenicity. Amniotic membrane has been employed in variety of clinical fields as a natural biomaterial. Amniotic epithelial cells possess stem cell characteristics and capability to differentiate into endothelial cells. The basement membrane of amnion is an extracellular matrix enriched scaffold to support adhesion of endothelial cells. The matrix of amniotic membrane contains two kinds of glycosaminoglycans including perlecan (a heparan sulfate proteoglycan) and hyaluronic acid which both inhibit blood coagulation. Moreover, the other ingredients of amniotic membrane such as pigment-epithelium derived factor (PEDF), IL-10, MMP-9 inhibit platelet aggregation. Based on some biochemical and biomechanical evidences, we hypothesized in this paper that amniotic membrane could prevent thrombosis and hemolysis; therefore, has the capability to be applied in blood contacting devices and implants.
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http://dx.doi.org/10.1016/j.mehy.2015.04.030DOI Listing
August 2015

Comparison of Different Crosslinking Methods for Preparation of Docetaxel-loaded Albumin Nanoparticles.

Iran J Pharm Res 2015 ;14(2):385-94

Nanomedicine and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

In the last step of desolvation method for preparation of albumin nanoparticles, glutaraldehyde (GA) is added to stabilize the newly formed nanoparticles. Due to undesirable effects of GA, the objective of this study was to evaluate alternative methods of crosslinking including ultraviolet (UV) irradiation, adding of glucose and combination of both methods. The nanoparticles were prepared by desolvation procedure. Final particle size, zeta potential, FTIR, scanning electron micrograph, cellular uptake and cell toxicity of nanoparticles crosslinked with UV and/or glucose were compared with commonly crosslinked nanoparticles with GA. Moreover, drug release and stability parameters of docetaxel-loaded albumin nanoparticles were investigated. Size of all nanoparticles prepared by different methods was in the same range (100-200 nm). Zeta potential showed the same results except for those treated with UV. The results of FTIR assay were the same for all groups. Although crosslinking by UV or glucose alone resulted in cytotoxic effects, combination of UV and glucose had less cytotoxic effects compared to GA. Cellular uptake of nanoparticles crosslinked with UV + glucose and GA showed similar results. The release of docetaxel from UV + glucose and GA crosslinked nanoparticles showed the same biphasic release. These data support the idea that crosslinking with a combination of UV and glucose can be a promising alternative method for production of docetaxel-loaded albumin nanoparticles with the advantage of omitting toxic GA.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403054PMC
April 2015