Use of Nanoparticles in Tissue Engineering and Regenerative Medicine

Advances in nanoparticle (NP) production and demand for control over nanoscale systems have had significant impact on tissue engineering and regenerative medicine (TERM). NPs with low toxicity, contrasting agent properties, tailorable characteristics, targeted/stimuli-response delivery potential, and precise control over behavior (via external stimuli such as magnetic fields) have made it possible their use for improving engineered tissues and overcoming obstacles in TERM. Functional tissue and organ replacements require a high degree of spatial and temporal control over the biological events and also their real-time monitoring. Presentation and local delivery of bioactive (growth factors, chemokines, inhibitors, cytokines, genes etc.) and contrast agents in a controlled manner are important implements to exert control over and monitor the engineered tissues. This need resulted in utilization of NP based systems in tissue engineering scaffolds for delivery of multiple growth factors, for providing contrast for imaging and also for controlling properties of the scaffolds. Depending on the application, materials, as polymers, metals, ceramics and their different composites can be utilized for production of NPs. In this review, we will cover the use of NP systems in TERM and also provide an outlook for future potential use of such systems

Impact of B2O3 and La2O3 addition on structural, mechanical and biological properties of hydroxyapatite

In this study, hydroxyapatite-B2O3-La2O3 composites (with ≤ 20 wt.% B2O3 and ≤ 2 wt.% La2O3) were synthesized via wet precipitation method and calcined at 1100 °C for 1 h. X-ray diffraction (XRD) analysis revealed the existence of the pure hydroxyapatite (HA) phase with high crystallinity. Characteristic absorption bands of HA were also observed in Fourier transform infrared spectra. Furthermore, scanning electron microscopy images demonstrated that the addition of B2O3 and La2O3 into HA enhanced the particle growth. Mechanical properties of the composites were studied by diametral tensile test and the results showed that incorporation of 10 wt.% B2O3 and 2 wt.% La2O3 led to a 39% increase in tensile strength (compared to the pure HA). In vitro cytocompatibility of HA-B2O3-La2O3 composites was investigated using Osteosarcoma Cell Lines (Saos-2). Incorporation of B2O3 and La2O3 into HA had no toxic effect towards the cells. Based on its tensile strength properties and biological response, composite of 88 wt.% HA, 10 wt.% B2O3 and 2 wt.% La2O3 was suggested as a promising composite for bone tissue engineering applications

Polyelectrolyte multilayer films as substrates for photoreceptor cells.

Reconstruction of extracellular matrix substrates for delivery of functional photoreceptors is crucial in pathologies such as retinal degeneration and age-related macular degeneration. In this study, we assembled polyelectrolyte films using the layer-by-layer deposition method. The buildup of three different films composed of poly(L-lysine)/chondroitin sulfate (PLL/CSA), poly(L-lysine)/poly(styrenesulfonate) (PLL/PSS), or poly(L-lysine)/hyaluronic acid (PLL/HA) was followed by means of quartz crystal microbalance measurements, optical waveguide light mode spectroscopy, confocal microscopy, and atomic force microscopy. The exponential growth regime and the diffusion of PLL chains from the bulk through the PLL/CSA, PLL/PSS, and PLL/HA films was examined. Evaluation of photoreceptor cell viability was optimal on one layer of PLL (PLL(1)), followed by 10 bilayers of PLL/HA [(PLL/HA)(10)] and 10 bilayers of PLL/CSA [(PLL/CSA)(10)]. The number of bilayers and the type of terminating layer also had a significant influence on the number of photoreceptor cells attached. Functionalized polyelectrolyte multilayer films were obtained by adsorbing basic fibroblastic factor (bFGF) or the insoluble fraction of interphotoreceptor matrix (IPM) on or within polyelectrolyte multilayers. bFGF and IPM adsorption on top of the (PLL/CSA)(10)/PLL polyelectrolyte films increased the number of photoreceptor cells attached and maintained the differentiation of rod and cone cells.journal articleresearch support, non-u.s. gov't2006 Janimporte

Study on physiochemical structure and in vitro release behaviors of doxycycline-loaded PCL microspheres

WOS: 000347695200020This study aimed to develop drug delivery system of doxycycline-loaded polycaprolactone (PCL) microspheres. The investigated microsphere formulation can be considered for local application in bone infections and degenerative joint diseases, which generally require long-term treatments via systemic drugs. PCL-14 kDa and 65 kDa were used in microsphere preparation. Before release, the microspheres were characterized by scanning electron microscopy, differential scanning calorimetry, and X-ray photoelectron spectroscopy. The mean particle size of microspheres was in the range of 74-122 mu m and their drug loadings ranged between 10 and 30%. In vitro release profiles were described using the Higuchi and the Korsmeyer-Peppas equations. Diffusion model was applied to experimental data for estimating diffusion coefficients of microspheres; calculated as between 4.5 x 10(-10) and 9.5 x 10(-10) cm(2)/s. Although long-term release from microspheres of PCL-14 kDa obeyed diffusion model, PCL-65 kDa microspheres showed this tendency only for some period. Modeling studies showed that the drug release mechanism was mainly dependent on loading and molecular weight differences. Release behavior of PCL-65 kDa microspheres, however, might be better represented by derivation of a different equation to model for the total release period. (c) 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015, 132, 41768Middle East Technical UniversityMiddle East Technical University [METU-BAP-R07-02-12]The authors would like to acknowledge the financial support provided by Middle East Technical University (Project No: METU-BAP-R07-02-12). The authors are also grateful to Dr. Utku Kanoglu for valuable contributions to the modeling studies

Half generations magnetic PAMAM dendrimers as an effective system for targeted gemcitabine delivery

WOS: 000389150700011PubMed ID: 27725272Tumor-specific delivery of anticancer drugs by magnetic nanoparticles will maximize the efficacy of the drug and minimize side effects, and reduce systemic toxicity. The magnetic core of these nanoparticles provides an advantage for selective drug targeting as they can be targeted to the tumor site and accumulated in cancer cells by means of an external magnetic field. Magnetic nanoparticles can be coated with Polyamidoamine (PAMAM) dendrimer and loaded with drugs. However, biomedical applications of PAMAM dendrimers are limited due to their toxicity associated with their multiple cationic charges due to terminal -NH2 groups. Modifying the positively charged end groups with negatively charged -COOH groups, is a satisfactory strategy for obtaining less toxic PAMAM dendrimers. Gemcitabine being an analogue of deoxycytidine, is an effective anticancer drug. However, clinical benefits of Gemcitabine are limited due to its short biological half-life. The aim of this study was to obtain an effective, less toxic targeted delivery system for Gemcitabine. Half generations, between G4.5 and G7.5, of PAMAM dendrimer coated magnetic nanoparticles (DcMNPs) were synthesized and conjugated with Gemcitabine. TEM images showed nanoscale size (12-14 nm) of the nanoparticles. The zeta-potential analysis indicated a decreased negativity of surface charge in drug bound dendrimer compared to the empty nanoparticles. Gemcitabine was effectively conjugated successfully onto the surface of half-generations of PAMAM DcMNPs. It was observed Gemcitabine did not effectively bind to Generations G4 and G5. The highest drug loading was obtained for DcMNPs with Generation 5.5. Empty nanoparticles showed no significant cytotoxicity on SKBR-3 and MCF-7 cells. On the other hand, Gemcitabine loaded nanoparticles were 6.0 fold more toxic on SKBR-3 and 3.0 fold more toxic on MCF-7 cells compared to free Gemcitabine. Gemcitabine loaded on Generation 5.5 DcMNPs showed a higher stability than free Gemcitabine. About 94% of the drug was retained over 6 weeks period, at pH 7.2. Due to their targetability under magnetic field, stability, size distribution, cellular uptake and toxicity characteristics the dendrimeric nanoparticles obtained in this study can be useful a delivery system for Gemcitabine in cancer therapy. (C) 2016 Elsevier B.V. All rights reserved

Characterization and Evaluation of Triamcinolone, Raloxifene, and Their Dual-Loaded Microspheres as Prospective Local Treatment System in Rheumatic Rat Joints

Bayram, Cem/0000-0001-8717-4668;WOS: 000340277700020PubMed: 24939720In this study, injectable microspheres were developed for the local treatment of joint degeneration in rheumatoid arthritis (RA). Microspheres loaded with triamcinolone (TA), a corticosteroid drug, and/or raloxifene (Ral), a cartilage regenerative drug, were prepared with a biodegradable and biocompatible polymer, polycaprolactone (PCL). Microspheres were optimized for particle size, structural properties, drug release, and loading properties. In vitro release of Ral was very slow because of the low solubility of the drug and hydrophobic nature of PCL. However, when coloaded with TA, both drugs were released at higher amounts compared with their single forms. Smallest particle sizes were obtained in dual drug-loaded microspheres. In vitro cytotoxicity tests showed biocompatibility of microspheres. In vivo bioefficacy of these microspheres was also examined in adjuvant-induced arthritis model in rats. In vivo histological studies of control groups showed development of RA with high median lesion score (5.0). Compared with control and intra-articular free drug injections, microsphere treatment groups showed lower lesion scores and better healing outcomes in histological evaluations. Results suggest that a controlled delivery system of TA and RAL by a single injection in inflamed joints holds promise for healing and suppressing inflammation. (c) 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2396-2405, 2014Middle East Technical UniversityMiddle East Technical UniversityWe thank to Middle East Technical University for financially supporting the study

Loading of Gemcitabine on chitosan magnetic nanoparticles increases the anti-cancer efficacy of the drug

WOS: 000379653600013PubMed ID: 27181067Targeted delivery of anti-cancer drugs increase the efficacy, while decreasing adverse effects. Among various delivery systems, chitosan coated iron oxide nanoparticles (CsMNPs) gained attention with their biocompatibility, biodegradability, low toxicity and targetability under magnetic field. This study aimed to increase the cellular uptake and efficacy of Gemcitabine. CsMNPs were synthesized by in situ co-precipitation and Gemcitabine was loaded onto the nano particles. Nanoparticle characterization was performed by TEM, FTIR, XPS, and zeta potential. Gemcitabine release and stability was analyzed. The cellular uptake was shown. Cytotoxicity of free-Gemcitabine and Gem-CsMNPs were examined on SKBR and MCF-7 breast cancer cells by XTT assay. Gemcitabine loading was optimized as 30 mu M by spectrophotometric analyses. Drug release was highest (65%) at pH 4.2, while it was 8% at pH 7.2. This is a desired release characteristic since pH of tumor-tissue and endosomes are acidic, while the blood-stream and healthy-tissues are neutral. Peaks reflecting the presence of Gemcitabine were observed in FTIR and XPS. At neutral pH, zeta potential increased after Gemcitabine loading. TEM images displayed, Gem-CsMNPs were 4 nm with uniform size distribution and have spherical shape. The cellular uptake and targetability of CsMNPs was studied on MCF-7 breast cancer cell lines. IC50 value of Gem-CsMNPs was 1.4 fold and 2.6 fold lower than free-Gem on SKBR-3 and MCF-7 cell lines respectively, indicating the increased efficacy of Gemcitabine when loaded onto nanoparticles. Targetability by magnetic field, stability, size distribution, cellular uptake and toxicity characteristics of CsMNPs in this study provides a useful targeted delivery system for Gemcitabine in cancer therapy. (C) 2016 Elsevier B.V. All rights reserved

Brown Tumor of the Thoracic Spine : First Manifestation of Primary Hyperparathyroidism

Brown tumors also called as osteoclastomas, are rare nonneoplastic lesions that arise in the setting of primary or secondary hyperparathyroidism. Parathyroid adenomas or hyperplasia constitute the major Brown tumor source in primary hyperparathyroidism while chronic renal failure is the leading cause in secondary hyperparathyroidism. Most of the patients with the diagnosis of primary hyperparathyroidism present with kidney stones or isolated hypercalcemia. However, nearly one third of patients are asymptomatic and hypercalcemia is found incidentally. Skeletal involvement such as generalized osteopenia, bone resorption, bone cysts and Brown tumors are seen on the late phase of hyperparathyroidism. The symptoms include axial pain, radiculopathy, myelopathy and myeloradiculopathy according to their locations. Plasmocytoma, lymphoma, giant cell tumors and metastates should be ruled out in the differential diagnosis of Brown tumors. Treatment of Brown tumors involve both the management of hyperparathyroidism and neural decompression. The authors report a very rare spinal Brown tumor case, arisen as the initial manifestation of primary hyperparathyroidism that leads to acute paraparesis