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1.
Int J Mol Sci ; 22(12)2021 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-34199303

RESUMO

The main purpose of new stent technologies is to overcome unfavorable material-related incompatibilities by producing bio- and hemo-compatible polymers with anti-inflammatory and anti-thrombogenic properties. In this context, wettability is an important surface property, which has a major impact on the biological response of blood cells. However, the influence of local hemodynamic changes also influences blood cell activation. Therefore, we investigated biodegradable polymers with different wettability to identify possible aspects for a better prediction of blood compatibility. We applied shear rates of 100 s-1 and 1500 s-1 and assessed platelet and monocyte activation as well as the formation of CD62P+ monocyte-bound platelets via flow cytometry. Aggregation of circulating platelets induced by collagen was assessed by light transmission aggregometry. Via live cell imaging, leukocytes were tracked on biomaterial surfaces to assess their average velocity. Monocyte adhesion on biomaterials was determined by fluorescence microscopy. In response to low shear rates of 100 s-1, activation of circulating platelets and monocytes as well as the formation of CD62P+ monocyte-bound platelets corresponded to the wettability of the underlying material with the most favorable conditions on more hydrophilic surfaces. Under high shear rates, however, blood compatibility cannot only be predicted by the concept of wettability. We assume that the mechanisms of blood cell-polymer interactions do not allow for a rule-of-thumb prediction of the blood compatibility of a material, which makes extensive in vitro testing mandatory.


Assuntos
Plaquetas/citologia , Comunicação Celular/efeitos dos fármacos , Monócitos/citologia , Monócitos/efeitos dos fármacos , Poliésteres/farmacologia , Plaquetas/efeitos dos fármacos , Adesão Celular/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Humanos , Agregação Plaquetária/efeitos dos fármacos , Água , Molhabilidade
2.
Materials (Basel) ; 10(12)2017 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-29168794

RESUMO

Titanium is widely used as a bone implant material due to its biocompatibility and high resilience. Since its Young's modulus differs from bone tissue, the resulting "stress shielding" could lead to scaffold loosening. However, by using a scaffold-shaped geometry, the Young's modulus can be adjusted. Also, a porous geometry enables vascularisation and bone ingrowth inside the implant itself. Additionally, growth factors can improve these effects. In order to create a deposit and release system for these factors, the titanium scaffolds could be coated with degradable polymers. Therefore, in the present study, synthetic poly-ε-caprolactone (PCL) and the biopolymer poly(3-hydroxybutyrate) (P(3HB)) were tested for coating efficiency, cell adhesion, and biocompatibility to find a suitable coating material. The underlying scaffold was created from titanium by Selective Laser Melting (SLM) and coated with PCL or P(3HB) via dip coating. To test the biocompatibility, Live Cell Imaging (LCI) as well as vitality and proliferation assays were performed. In addition, cell adhesion forces were detected via Single Cell Force Spectroscopy, while the coating efficiency was observed using environmental scanning electron microscopy (ESEM) and energy-dispersive X-ray (EDX) analyses. Regarding the coating efficiency, PCL showed higher values in comparison to P(3HB). Vitality assays revealed decent vitality values for both polymers, while values for PCL were significantly lower than those for blank titanium. No significant differences could be observed between PCL and P(3HB) in proliferation and cell adhesion studies. Although LCI observations revealed decreasing values in cell number and populated area over time on both polymer-coated scaffolds, these outcomes could be explained by the possibility of coating diluent residues accumulating in the culture medium. Overall, both polymers fulfill the requirements regarding biocompatibility. Nonetheless, since only PCL coating ensured the maintenance of the porous implant structure, it is preferable to be used as a coating material for creating a deposit and release system for growth factors.

3.
Int J Mol Sci ; 17(2)2016 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-26805825

RESUMO

Drug-eluting stents (DES) have reduced in-stent-restenosis drastically. Yet, the stent surface material directly interacts with cascades of biological processes leading to an activation of cellular defense mechanisms. To prevent adverse clinical implications, to date almost every patient with a coronary artery disease is treated with statins. Besides their clinical benefit, statins exert a number of pleiotropic effects on endothelial cells (ECs). Since maintenance of EC function and reduction of uncontrolled smooth muscle cell (SMC) proliferation represents a challenge for new generation DES, we investigated the effect of atorvastatin (ATOR) on human coronary artery cells grown on biodegradable polymers. Our results show a cell type-dependent effect of ATOR on ECs and SMCs. We observed polymer-dependent changes in IC50 values and an altered ATOR-uptake leading to an attenuation of statin-mediated effects on SMC growth. We conclude that the selected biodegradable polymers negatively influence the anti-proliferative effect of ATOR on SMCs. Hence, the process of developing new polymers for DES coating should involve the characterization of material-related changes in mechanisms of drug actions.


Assuntos
Atorvastatina/farmacologia , Plásticos Biodegradáveis/farmacologia , Vasos Coronários/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Polímeros/farmacologia , Técnicas de Cultura de Células , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Doença da Artéria Coronariana/tratamento farmacológico , Vasos Coronários/efeitos dos fármacos , Stents Farmacológicos , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Humanos , Miócitos de Músculo Liso/citologia , Especificidade de Órgãos , Propriedades de Superfície
4.
Eur J Pharm Biopharm ; 96: 322-8, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26318979

RESUMO

Lately, drug-coated balloons have been introduced in interventional cardiology as an approach to treat occluded blood vessel. They were developed for the rapid transfer of antiproliferative drugs during the angioplasty procedure in stenosed vessels with the intent to reduce the risk of restenosis. In this study five different paclitaxel (PTX) balloon coatings were tested in vitro in order to examine how solvents and additives influence coating stability and drug transfer rates. PTX-coated balloons were advanced through a guiding catheter and a simulated coronary artery pathway under perfusion and were then inflated in a hydrogel acceptor compartment. The fractions transferred to the gel, remaining on the balloon and the PTX lost in the simulated coronary pathway were then analysed. The results obtained suggest that the solvent used for the coating process strongly influences the surface structure and the stability of the coating. Ethanol/water and acetone based PTX coatings showed the lowest drug transfer rates to the simulated vessel wall (both <1%) due to their high drug losses during the prior passage through the coronary artery model (more than 95%). Balloons coated with PTX from ethyl acetate-solutions showed smaller drug loss (83%±9%), but most of the remaining PTX was not transferred (mean balloon residue approximately 15%). Beside the solvent, the use of additives seemed to have a great impact on transfer properties. The balloon pre-treatment with a crosslinked polyvinylpyrrolidone (PVP) film was able to increase the PTX transfer rate from less than 1% (without PVP) to approximately 6%. The best results in this study were obtained for balloon coatings with commercially available SeQuent© Please balloons containing the contrast agent iopromide. For this formulation drug transfer rates of approximately 17% were determined. Fluorescence microscopic imaging could visualize the particulate transfer of labelled PTX from the balloon surface during dilatation. The findings of this study underline the importance of drug adhesion and coating stability for the efficiency of PTX transfer.


Assuntos
Absorção Fisiológica , Inibidores da Angiogênese/metabolismo , Angioplastia Coronária com Balão/instrumentação , Artérias Carótidas/metabolismo , Sistemas de Liberação de Medicamentos , Paclitaxel/metabolismo , Matadouros , Adesividade , Adsorção , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/análise , Inibidores da Angiogênese/química , Animais , Artérias Carótidas/química , Meios de Contraste/química , Composição de Medicamentos , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Excipientes/química , Técnicas In Vitro , Iohexol/análogos & derivados , Iohexol/química , Paclitaxel/administração & dosagem , Paclitaxel/análise , Paclitaxel/química , Perfusão , Povidona/química , Solventes/química , Propriedades de Superfície , Sus scrofa
5.
Int J Mol Sci ; 16(6): 13287-301, 2015 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-26068455

RESUMO

Degradable implant material for bone remodeling that corresponds to the physiological stability of bone has still not been developed. Promising degradable materials with good mechanical properties are magnesium and magnesium alloys. However, excessive gas production due to corrosion can lower the biocompatibility. In the present study we used the polymer coating polycaprolactone (PCL), intended to lower the corrosion rate of magnesium. Additionally, improvement of implant geometry can increase bone remodeling. Porous structures are known to support vessel ingrowth and thus increase osseointegration. With the selective laser melting (SLM) process, defined open porous structures can be created. Recently, highly reactive magnesium has also been processed by SLM. We performed studies with a flat magnesium layer and with porous magnesium implants coated with polymers. The SLM produced magnesium was compared with the titanium alloy TiAl6V4, as titanium is already established for the SLM-process. For testing the biocompatibility, we used primary murine osteoblasts. Results showed a reduced corrosion rate and good biocompatibility of the SLM produced magnesium with PCL coating.


Assuntos
Interface Osso-Implante , Materiais Revestidos Biocompatíveis/efeitos adversos , Magnésio/química , Poliésteres/química , Titânio/química , Animais , Células Cultivadas , Materiais Revestidos Biocompatíveis/química , Lasers , Magnésio/efeitos adversos , Camundongos , Osseointegração , Titânio/efeitos adversos
6.
Eur J Pharm Biopharm ; 93: 328-38, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25936852

RESUMO

In this study drug release from the CYPHER™ stent, the gold standard in drug-eluting stent therapy until the end of its marketing in 2011/2012, was systematically evaluated using different in vitro release tests. The test systems included incubations setups, the reciprocating holder apparatus (USP7), the flow-through cell apparatus (USP4) and the vessel-simulating flow-through cell (vFTC) specifically designed for stent testing. The results obtained show a large variability regarding the fractions released into the media after 7d ranging from 38.6% ± 4.5% to 74.6% ± 1.2%. The lowest fraction released was observed in the vFTC and the highest in an incubation setup with frequently changed media of a volume of 2 mL. Differences were even observed when using fairly similar and simple incubations setups with mere changes of the media volume, under maintenance of sink conditions, and of the vessel geometry. From these data it can be concluded, that in vitro release even from a slow releasing drug-eluting stent is greatly influenced by the experimental conditions and care must be taken when choosing a suitable setup. Comparison of the obtained in vitro release profiles to published in vivo data did not result in a distinct superiority of any of the tested methods regarding the predictability for the situation in vivo due to large differences in the reported in vivo data. However, this comparison yielded that the release observed in vitro using the 2 mL incubation setup and the reciprocating holder apparatus may be faster than the reported in vivo release. The results of this study also emphasize the necessity to use highly standardized release tests when comparisons between results from different experiments or even different labs are to be performed. In this context, the compendial methods are most likely offering the highest degree of standardization.


Assuntos
Fármacos Cardiovasculares/química , Stents Farmacológicos , Sirolimo/química , Tecnologia Farmacêutica/métodos , Fármacos Cardiovasculares/administração & dosagem , Química Farmacêutica , Cinética , Desenho de Prótese , Reprodutibilidade dos Testes , Sirolimo/administração & dosagem , Solubilidade , Propriedades de Superfície , Tecnologia Farmacêutica/normas
7.
Int J Mol Sci ; 16(4): 7478-92, 2015 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-25849656

RESUMO

To improve well-known titanium implants, pores can be used for increasing bone formation and close bone-implant interface. Selective Laser Melting (SLM) enables the production of any geometry and was used for implant production with 250-µm pore size. The used pore size supports vessel ingrowth, as bone formation is strongly dependent on fast vascularization. Additionally, proangiogenic factors promote implant vascularization. To functionalize the titanium with proangiogenic factors, polycaprolactone (PCL) coating can be used. The following proangiogenic factors were examined: vascular endothelial growth factor (VEGF), high mobility group box 1 (HMGB1) and chemokine (C-X-C motif) ligand 12 (CXCL12). As different surfaces lead to different cell reactions, titanium and PCL coating were compared. The growing into the porous titanium structure of primary osteoblasts was examined by cross sections. Primary osteoblasts seeded on the different surfaces were compared using Live Cell Imaging (LCI). Cross sections showed cells had proliferated, but not migrated after seven days. Although the cell count was lower on titanium PCL implants in LCI, the cell count and cell spreading area development showed promising results for titanium PCL implants. HMGB1 showed the highest migration capacity for stimulating the endothelial cell line. Future perspective would be the incorporation of HMGB1 into PCL polymer for the realization of a slow factor release.


Assuntos
Vasos Sanguíneos/efeitos dos fármacos , Neovascularização Fisiológica/efeitos dos fármacos , Osteoblastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Titânio/administração & dosagem , Animais , Vasos Sanguíneos/metabolismo , Adesão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Quimiocina CXCL12/metabolismo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Congelamento , Proteína HMGB1/metabolismo , Lasers , Camundongos , Camundongos Endogâmicos C57BL , Osteoblastos/metabolismo , Poliésteres/química , Polímeros/química , Porosidade , Próteses e Implantes , Propriedades de Superfície , Fator A de Crescimento do Endotélio Vascular/metabolismo
8.
PLoS One ; 10(3): e0116080, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25734818

RESUMO

Drug-coated balloons (DCB), which have emerged as a therapeutic alternative to drug-eluting stents in percutaneous cardiovascular intervention, are well described with regard to clinical efficacy and safety within a number of clinical studies. In vitro studies elucidating the correlation between coating additive and DCB performance are however rare but considered important for the understanding of DCB requirements and the improvement of established DCB. In this regard, we examined three different DCB-systems, which were developed in former studies based on the ionic liquid cetylpyridinium salicylate, the body-own hydrogel hyaluronic acid and the pharmaceutically well-established hydrogel polyvinylpyrrolidone, considering coating morphology, coating thickness, drug-loss, drug-transfer to the vessel wall, residual drug-concentration on the balloon surface and entire drug-load during simulated use in an in vitro vessel model. Moreover, we investigated particle release of the different DCB during simulated use and determined the influence of the three coatings on the mechanical behavior of the balloon catheter. We could show that coating characteristics can be indeed correlated with the performance of DCB. For instance, paclitaxel incorporation in the matrix can reduce the drug wash-off and benefit a high drug transfer. Additionally, a thin coating with a smooth surface and high but delayed solubility can reduce drug wash-off and decrease particle burden. As a result, we suggest that it is very important to characterize DCB in terms of mentioned properties in vitro in addition to their clinical efficacy in order to better understand their function and provide more data for the clinicians to improve the tool of DCB in coronary angioplasty.


Assuntos
Antineoplásicos Fitogênicos/química , Materiais Revestidos Biocompatíveis/química , Stents Farmacológicos , Hidrogel de Polietilenoglicol-Dimetacrilato/química , Líquidos Iônicos/química , Paclitaxel/química , Angioplastia Coronária com Balão , Materiais Revestidos Biocompatíveis/síntese química , Ácido Hialurônico/química , Líquidos Iônicos/síntese química , Microscopia Confocal , Microscopia Eletrônica de Varredura , Modelos Biológicos , Povidona/química , Propriedades de Superfície
9.
J Biomed Mater Res B Appl Biomater ; 102(2): 345-55, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24000221

RESUMO

Aiming at a speed up of the re-endothelialization process of biodegradable endovascular implants, novel approaches for the functionalization of poly(l-lactide) (PLLA) with anti-CD34 antibodies were established. We propose a three-step process involving PLLA surface activation with functional amino groups, attachment of a protein repelling peptide spacer, and covalent random or site-selective immobilization of the antibodies. Obtainable antibody surface densities and antigen binding capacities were thoroughly evaluated by means of enzyme-linked immunosorbent assay. Results indicate that a lower amount of anchoring sites on the antibody favors high coupling efficiency, while localization of the anchoring sites, facing the antigen binding moiety, strongly enhances the antigen capture capacity of the support. Besides minimization of physisorption and cell adhesion exemplarily shown with bovine serum albumin, avidin, and human umbilical vein endothelial cells, respectively, the inclusion of the protein-repelling spacer strengthened this effect, yielding antigen capture capacities exceeding values so far reported in literature. In contrast, the number of amino groups on the PLLA surfaces, which is indeed highly dependent on the applied activation procedure, does not seem to influence antibody coupling efficiency and antigen capture capacity considerably. This allows the choice of surface activation treatment, plasma or wet-chemical, regarding other processing parameters as for instance sterilizability or favored modification depth.


Assuntos
Anticorpos/química , Antígenos CD34 , Prótese Vascular , Proteínas Imobilizadas/química , Poliésteres/química , Desenho de Prótese , Animais , Bovinos , Humanos , Camundongos , Peptídeos/química
10.
Acta Biomater ; 10(2): 688-700, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24148751

RESUMO

Despite the development of new coronary stent technologies, in-stent restenosis and stent thrombosis are still clinically relevant. Interactions of blood and tissue cells with the implanted material may represent an important cause of these side effects. We hypothesize material-dependent interaction of blood and tissue cells. The aim of this study is accordingly to investigate the impact of vascular endothelial cells, smooth muscle cells and platelets with various biodegradable polymers to identify a stent coating or platform material that demonstrates excellent endothelial-cell-supportive and non-thrombogenic properties. Human umbilical venous endothelial cells, human coronary arterial endothelial cells and human coronary arterial smooth muscle cells were cultivated on the surfaces of two established biostable polymers used for drug-eluting stents, namely poly(ethylene-co-vinylacetate) (PEVA) and poly(butyl methacrylate) (PBMA). We compared these polymers to new biodegradable polyesters poly(l-lactide) (PLLA), poly(3-hydroxybutyrate) (P(3HB)), poly(4-hydroxybutyrate) (P(4HB)) and a polymeric blend of PLLA/P(4HB) in a ratio of 78/22% (w/w). Biocompatibility tests were performed under static and dynamic conditions. Measurement of cell proliferation, viability, glycocalix width, eNOS and PECAM-1 mRNA expression revealed strong material dependency among the six polymer samples investigated. Only the polymeric blend of PLLA/P(4HB) achieved excellent endothelial markers of biocompatibility. Data show that PLLA and P(4HB) tend to a more thrombotic response, whereas the polymer blend is characterized by a lower thrombotic potential. These data demonstrate material-dependent endothelialization, smooth muscle cell growth and thrombogenicity. Although polymers such as PEVA and PBMA are already commonly used for vascular implants, they did not sufficiently meet the criteria for biocompatibility. The investigated biodegradable polymeric blend PLLA/P(4HB) evidently represents a promising material for vascular stents and stent coatings.


Assuntos
Plaquetas/citologia , Comunicação Celular/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/citologia , Miócitos de Músculo Liso/citologia , Polímeros/farmacologia , Stents , Biomarcadores/metabolismo , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Plaquetas/ultraestrutura , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Materiais Revestidos Biocompatíveis/farmacologia , Glicocálix/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/enzimologia , Humanos , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Selectina-P/metabolismo , Adesividade Plaquetária/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Reologia/efeitos dos fármacos , Estresse Mecânico , Propriedades de Superfície
11.
Nanotoxicology ; 8 Suppl 1: 118-27, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24289310

RESUMO

Abstract To examine gold nanoparticle reprotoxicity, bovine spermatozoa were challenged with ligand-free or oligonucleotide-conjugated gold nanoparticles synthesized purely without any surfactants by laser ablation. Sperm motility declined at nanoparticle mass dose of 10 µg/ml (corresponding to ∼14 000 nanoparticles per sperm cell) regardless of surface modification. Sperm morphology and viability remained unimpaired at all concentrations. Transmission electron microscopy showed an modification dependant attachment of nanoparticles to the cell membrane of spermatozoa, but provided no evidence for nanoparticle entrance into sperm cells. A molecular examination revealed a reduction of free thiol residues on the cell membrane after nanoparticle exposure, which could explain the decrease in sperm motility. Sperm fertilising ability decreased after exposure to 10 µg/ml of ligand-free nanoparticles indicating that agglomerated ligand-free nanoparticles interfere with membrane properties necessary for fertilisation. In conclusion, nanoparticles may impair key sperm functions solely by interacting with the sperm surface membrane.


Assuntos
Ouro/química , Nanopartículas Metálicas/toxicidade , Espermatozoides/efeitos dos fármacos , Adsorção , Animais , Bovinos , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Masculino
12.
Mater Sci Eng C Mater Biol Appl ; 33(7): 4244-50, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23910339

RESUMO

Drug-coated balloons (DCB), which have emerged as therapeutic alternative to drug-eluting stents in percutaneous cardiovascular intervention, are well described with regard to clinical efficiency and safety within a number of clinical studies. In vitro studies elucidating the correlation of coating method and composition with DCB performance are however rare but considered important for the understanding of DCB requirements and the improvement of established DCB. In this context, we evaluated the applicability of a pipetting, dip-coating, and spray-coating process for the establishment of DCB based on paclitaxel (PTX) and the ionic liquid cetylpyridinium salicylate (Cetpyrsal) as novel innovative additive in three different compositions. Among tested methods and compositions, the pipetting process with 50 wt.% PTX resulted in most promising coatings as drug load was less controllable by the other processes and higher PTX contents led to considerable drug crystallization, as visualized by electron microscopy, accelerating PTX loss during short-term elution. Applying these conditions, homogeneous coatings could be applied on balloon catheter, whose simulated use in an in vitro vessel model revealed percental drug losses of 36 and 28% during transit and percental drug transfers of 12 and 40% under expansion for coatings applied in expanded and folded balloon condition, respectively. In comparison to literature values, these results support the high potential of Cetpyrsal as novel DCB matrix regarding low drug loss and efficient drug transfer.


Assuntos
Angioplastia com Balão , Cateterismo , Cetilpiridínio/química , Cetilpiridínio/síntese química , Materiais Revestidos Biocompatíveis/síntese química , Modelos Teóricos , Paclitaxel/farmacologia , Materiais Revestidos Biocompatíveis/química , Simulação por Computador , Humanos , Microscopia Eletrônica de Varredura , Tamanho da Partícula , Silicones
13.
Biomed Tech (Berl) ; 58(5): 417-27, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23979120

RESUMO

Implants providing controlled, local release of active substances are of interest in different medical applications. Therefore, the focus of the present article is the development of implant-associated diffusion- or chemically controlled local drug delivery (LDD) systems based on biodegradable polymeric drug carriers. In this context, we provide new data and review our own recently published data concerning the drug release behavior of diffusion-controlled LDD systems in relation to the kind of polymer, drug content, coating mass/thickness, and layer composition. We demonstrate that polymers allow a wide range of control over the drug release characteristics. In this regard, we show that the glass transition temperature of a polymer has an impact on its drug release. Additionally, the blending of hydrophobic, semicrystalline polymers with amorphous polymers leads to an increase in the rate of drug release compared with the pure semicrystalline polymer. Moreover, the percentage loading of the embedded drug has a considerable effect on the rate and duration of drug release. Furthermore, we discuss chemically controlled LDD systems designed for the release of biomolecules, such as growth factors, as well as nanoparticle-mediated LDD systems. With our own published data on drug-eluting stents, microstents, and cochlear implants, we highlight exemplary implant-associated LDD systems designed to improve implant performance through the reduction of undesirable effects such as in-stent restenosis and fibrosis.


Assuntos
Implantes Absorvíveis , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Stents Farmacológicos , Polímeros/síntese química , Difusão , Desenho de Fármacos , Teste de Materiais , Desenho de Prótese
14.
J Mater Sci Mater Med ; 24(11): 2589-600, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23846839

RESUMO

Within the context of novel stent designs we developed a dual drug-eluting stent (DDES) with an abluminally focussed release of the potent anti-proliferative drug sirolimus and a luminally focussed release of atorvastatin with stabilizing effect on atherosclerotic deposits and stimulating impact on endothelial function, both from biodegradable poly(L-lactide)-based stent coatings. With this concept we aim at simultaneous inhibition of in-stent restenosis as a result of disproportionally increased smooth muscle cell proliferation and migration as well as thrombosis due to failed or incomplete endothelialisation. The especially adapted spray-coating processes allowed the formation of smooth form-fit polymer coatings at the abluminal and luminal side with 70% respectively 90% of the drug/polymer solution being deposited at the intended stent surface. The impacts of tempering, sterilization, and layer composition on drug release are thoroughly discussed making use of a semi-empirical model. While tempering at 80 °C seems to be necessary for the achievement of adequate and sustained drug release, the coating sequence for DDES should be rather abluminal-luminal than luminal-abluminal, as reduction of the amount of sirolimus eluted luminally could then potentially minimize the provocation of endothelial dysfunction. In vitro proliferation and viability assays with smooth muscle and endothelial cells underline the high potential of the developed DDES.


Assuntos
Stents Farmacológicos , Ácidos Heptanoicos/administração & dosagem , Pirróis/administração & dosagem , Sirolimo/administração & dosagem , Atorvastatina , Varredura Diferencial de Calorimetria , Proliferação de Células , Células Cultivadas , Ácidos Heptanoicos/farmacologia , Humanos , Técnicas In Vitro , Microscopia Eletrônica de Varredura , Peso Molecular , Pirróis/farmacologia , Sirolimo/farmacologia
15.
PLoS One ; 8(12): e83992, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24391863

RESUMO

Drug-coated balloons are medical devices designed to locally deliver drug to diseased segments of the vessel wall. For these dosage forms, drug transfer to the vessel wall needs to be examined in detail, since drug released into the blood is cleared from the site. In order to examine drug transfer, a new in vitro setup was developed combining the estimation of drug loss during advancement to the site of application in a model coronary artery pathway with a hydrogel compartment representing, as a very simplified model, the vessel wall. The transfer of fluorescent model substances as well as the drug paclitaxel from coated balloons to the simulated vessel wall was evaluated using this method. The model was suitable to quantify the fractions transferred to the hydrogel and also to qualitatively assess distribution patterns in the hydrogel film. In the case of fluorescein sodium, rhodamin b and paclitaxel, vast amounts of the coated substance were lost during the simulated passage and only very small fractions of about 1% of the total load were transferred to the gel. This must be attributed to good water solubility of the fluorescent substances and the mechanical instability of the paclitaxel coating. Transfer of the hydrophobic model substance triamterene was however nearly unaffected by the preliminary tracking procedure with transferred fractions ranging from 8% to 14%. Analysis of model substance distribution yielded inhomogeneous distributions indicating that the coating was not evenly distributed on the balloon surface and that a great fraction of the coating liquid did not penetrate the folds of the balloon. This finding is contradictory to the generally accepted assumption of a drug depot inside the folds and emphasizes the necessity to thoroughly characterize in vitro performance of drug-coated balloons to support the very promising clinical data.


Assuntos
Angioplastia com Balão/instrumentação , Materiais Revestidos Biocompatíveis , Vasos Coronários/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Paclitaxel/farmacologia , Simulação por Computador , Humanos , Hidrogel de Polietilenoglicol-Dimetacrilato
16.
Curr Pharm Biotechnol ; 14(1): 76-90, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23092260

RESUMO

Beyond their originally sole mechanical function, current drug-eluting stents (DES) implement the concept of local drug delivery for the re-opening of stenotic arterial vessels, and for prevention of in-stent restenosis as one of the major limitations of conventional bare metal stents (BMS). Current DES consist of a permanent metallic stent platform and an active agent being released from a drug-incorporated polymer coating or a porous stent surface. Although DES have impressively demonstrated their capability of reducing in-stent restenosis, their safety remains under debate due to potential risks, such as delayed healing, late thrombosis and hypersensitivity demanding further development. Current advancements in the stent design address the stent platform, the pharmacologically active substance and/or the drug carrier. For instance, novel biocompatible absorbable stent platforms and drug carriers are developed and novel drugs with a differential effect on vascular endothelial and smooth muscle cells, providing efficient inhibition of muscle cells without altering the endothelial cell function, are identified. Moreover, biofunctionalization of the stent's surface with capture molecules for endothelial progenitor cells are under investigation in order to achieve an in situ endothelialization of the implant. In this context, this review paper discusses the current advances in coronary stent technology with a special focus on novel stent platforms, drugs and stent coatings for the prevention of restenosis and improvement of biocompatibility.


Assuntos
Reestenose Coronária/prevenção & controle , Stents Farmacológicos , Desenho de Prótese , Animais , Materiais Revestidos Biocompatíveis , Sistemas de Liberação de Medicamentos , Humanos , Imunossupressores/administração & dosagem
17.
J Nanobiotechnology ; 8: 21, 2010 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-20731831

RESUMO

BACKGROUND: Bio-conjugated nanoparticles are important analytical tools with emerging biological and medical applications. In this context, in situ conjugation of nanoparticles with biomolecules via laser ablation in an aqueous media is a highly promising one-step method for the production of functional nanoparticles resulting in highly efficient conjugation. Increased yields are required, particularly considering the conjugation of cost-intensive biomolecules like RNA aptamers. RESULTS: Using a DNA aptamer directed against streptavidin, in situ conjugation results in nanoparticles with diameters of approximately 9 nm exhibiting a high aptamer surface density (98 aptamers per nanoparticle) and a maximal conjugation efficiency of 40.3%. We have demonstrated the functionality of the aptamer-conjugated nanoparticles using three independent analytical methods, including an agglomeration-based colorimetric assay, and solid-phase assays proving high aptamer activity. To demonstrate the general applicability of the in situ conjugation of gold nanoparticles with aptamers, we have transferred the method to an RNA aptamer directed against prostate-specific membrane antigen (PSMA). Successful detection of PSMA in human prostate cancer tissue was achieved utilizing tissue microarrays. CONCLUSIONS: In comparison to the conventional generation of bio-conjugated gold nanoparticles using chemical synthesis and subsequent bio-functionalization, the laser-ablation-based in situ conjugation is a rapid, one-step production method. Due to high conjugation efficiency and productivity, in situ conjugation can be easily used for high throughput generation of gold nanoparticles conjugated with valuable biomolecules like aptamers.

18.
J Biomed Opt ; 15(3): 036015, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20615017

RESUMO

Gold nanoparticles (AuNPs) have the potential to become a versatile biomarker. For further use of AuNPs labeled with functionalized molecules, their visualization in biological systems by routine laboratory tools such as light microscopy is crucial. However, the size far below the diffraction limit affords specialized parameters for microscopical detection, which stimulated the current study, aimed to determine from which size onward AuNPs, either in dispersion or cell-associated, can be reliably detected by standard confocal microscopy. First, gold colloids of size-restricted fractions are examined in dispersion. At a minimum particle size of 60 nm, detection appears to be reliable. Particle counts in dilution series confirm these results by revealing single particle detection of 60-nm colloids. Second, AuNPs are visualized and quantified in cells, which interestingly cause a phase shift in the reflection of AuNPs. Gold mass spectroscopy confirms the number of AuNPs counted microscopically inside cells. Furthermore, it demonstrates for the first time a very high diffusion rate of 15-nm particles into the cells. In conclusion, the results back the suitability of confocal microscopy for the quantitative tracking of colloidal and intracellular gold nanoparticles sized 60 nm.


Assuntos
Coloide de Ouro/química , Espaço Intracelular/química , Nanopartículas Metálicas/química , Microscopia Confocal/métodos , Análise de Variância , Animais , Bovinos , Linhagem Celular Transformada , Centrifugação , Células Endoteliais/citologia , Coloide de Ouro/análise , Espectrometria de Massas , Tamanho da Partícula , Reprodutibilidade dos Testes , Espectrofotometria Ultravioleta , Ressonância de Plasmônio de Superfície
19.
Langmuir ; 26(10): 6892-7, 2010 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-20394393

RESUMO

The generation of nonoxidized magnetic alloy nanoparticles is still a challenge using conventional chemical reduction methods. However, because these nanoparticles are currently attracting much attention, alternative methods are required. In this context, the applicability of femtosecond laser ablation, which has evolved as a powerful tool for the generation of colloidal metal nanoparticles, has been investigated using the example of Ni(48)Fe(52) and Sm(2)Co(17) ablation in cyclopentanone. Besides stability and size measurements, the focus has been placed on the analysis of the elemental composition of nanoparticles, which proved the preservation of the stoichiometry of the target in Ni-Fe nanoparticles but not in Sm-Co. It is assumed that this is due to a greater difference in the heat of evaporation of the bulk alloy components in Sm-Co than in Ni-Fe. Hence, the successful generation of magnetic alloy nanoparticles is possible for alloys composed of elements with similar heats of evaporation. This one-step approach allows the fabrication of nanomagnetic polymer composites (e.g., with application prospects in microtechnology such as microactuators).


Assuntos
Ligas/química , Ciclopentanos/química , Lasers , Magnetismo , Nanopartículas Metálicas/química , Polímeros/química , Tamanho da Partícula , Propriedades de Superfície
20.
Cytometry A ; 77(5): 439-46, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20104575

RESUMO

Gold nanoparticles (GNPs) have interesting optical properties, such as exceptionally high quantum yields and virtually limitless photostability. Therefore, they show the potential for applications as biomarkers especially suitable for in vivo and long-term studies. The generation of GNPs using pulsed laser light rather than chemical means provides nanoparticles, which are remarkably stable in a variety of media without the need of stabilizing agents or ligands. This stabilization is achieved by partial oxidation of the gold surface resulting in positively charged GNPs. However, little is known about cellular uptake of such ligand-free nanoparticles, their intracellular fate, or cell viability after nanoparticle contact. The current work is aimed to explore the response of a bovine cell line to GNP exposure mainly using laser scanning confocal microscopy (LSCM) supported by other techniques. Cultured bovine immortalized cells (GM7373) were coincubated with GNP (average diameter 15 nm, 50 microM Au) for 2, 24, and 48 h. The detection of GNP-associated light scattering by the LSCM facilitated a clear distinction between GNP-containing cells and the negative controls. After 48 h, 75% of cells had visibly incorporated nanoparticles. No colocalization was detected with either Rab5a or Lamp1-positive structures, i.e., endosomes or lysosomes, respectivley. However, transmission electron microscope analysis of GNP-coincubated cells indicated the nanoparticles to be positioned within electron-dense structures. Coincubation at 4 degrees C did not inhibit nanoparticle uptake, suggesting diffusion as possible entrance mechanism. Although the assessment of cell morphology, membrane integrity, and apoptosis revealed no GNP-related loss of cell viability at a gold concentration of 25 microM or below, a cytotoxic effect was observed in a proliferation assay after exposing low cell numbers to 50 microM Au and above. In conclusion, this study confirmed the cellular uptake of ligand-free gold nanoparticles during coincubation apparently without using endocytic pathways.


Assuntos
Endossomos/metabolismo , Células Endoteliais/metabolismo , Ouro/metabolismo , Nanopartículas Metálicas/química , Animais , Transporte Biológico , Bovinos , Linhagem Celular , Sobrevivência Celular , Células Endoteliais/citologia , Células Endoteliais/ultraestrutura , Proteínas de Fluorescência Verde/metabolismo , Lasers , Ligantes , Nanopartículas Metálicas/ultraestrutura , Microscopia Confocal , Propídio/metabolismo , Frações Subcelulares/metabolismo , Ressonância de Plasmônio de Superfície , Fatores de Tempo
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