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1.
Polymers (Basel) ; 13(2)2021 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-33477626

RESUMO

Local drug delivery has become indispensable in biomedical engineering with stents being ideal carrier platforms. While local drug release is superior to systemic administration in many fields, the incorporation of drugs into polymers may influence the physico-chemical properties of said matrix. This is of particular relevance as minimally invasive implantation is frequently accompanied by mechanical stresses on the implant and coating. Thus, drug incorporation into polymers may result in a susceptibility to potentially life-threatening implant failure. We investigated spray-coated poly-l-lactide (PLLA)/drug blends using thermal measurements (DSC) and tensile tests to determine the influence of selected drugs, namely sirolimus, paclitaxel, dexamethasone, and cyclosporine A, on the physico-chemical properties of the polymer. For all drugs and PLLA/drug ratios, an increase in tensile strength was observed. As for sirolimus and dexamethasone, PLLA/drug mixed phase systems were identified by shifted drug melting peaks at 200 °C and 240 °C, respectively, whereas paclitaxel and dexamethasone led to cold crystallization. Cyclosporine A did not affect matrix thermal properties. Altogether, our data provide a contribution towards an understanding of the complex interaction between PLLA and different drugs. Our results hold implications regarding the necessity of target-oriented thermal treatment to ensure the shelf life and performance of stent coatings.

2.
Biomed Mater ; 16(1): 015022, 2020 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-33022660

RESUMO

An ongoing challenge in drug delivery systems for a variety of medical applications, including cardiovascular diseases, is the delivery of multiple drugs to address numerous phases of a treatment or healing process. Therefore, an extended dual drug delivery system (DDDS) based on our previously reported cardiac DDDS was generated. Here we use the polymer poly(L-lactide) (PLLA) as drug carrier with the cytostatic drug Paclitaxel (PTX) and the endothelial cell proliferation enhancing growth factor, human vascular endothelial growth factor (VEGF), to overcome typical in-stent restenosis complications. We succeeded in using one solution to generate two separate DDDS via spray coating (film) and electrospinning (nonwoven) with the same content of PTX and the same post processing for VEGF immobilisation. Both processes are suitable as coating techniques for implants. The contact angle analysis revealed differences between films and nonwovens. Whereas, the morphological analysis demonstrated nearly no changes occurred after immobilisation of both drugs. Glass transition temperatures (Tg ) and degree of crystallinity (χ) show only minor changes. The amount of immobilised VEGF on nonwovens was over 300% higher compared to the films. Also, the nonwovens revealed a much faster and over three times higher PTX release over 70 d compared to the films. The almost equal physical properties of nonwovens and films allow the comparison of both DDDS independently of their fabrication process. Both films and nonwovens have significantly increased in vitro cell viability for human umbilical vein endothelial cells (EA.hy926) with dual loaded PTX and VEGF compared to PTX-only loaded samples.

3.
J Mech Behav Biomed Mater ; 91: 174-181, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30583263

RESUMO

Resorbable magnesium scaffolds are used for the treatment of atherosclerotic coronary vascular disease and furthermore, for vascular restoration therapy. Recently, the first-in-man clinical studies with Magmaris showed promising results regarding the target lesion failure as well as vasomotion properties after 12 and 24 month. The consistency of in vivo degraded magnesium alloys in a cardiovascular environment is qualitatively described in literature, but only little has been disclosed about the actual change in mechanical properties and the behavior of the magnesium alloy degradation products. In the present study, uncoated magnesium scaffolds 3.0 × 20 mm were implanted in coronary arteries of two healthy Goetinnger mini-swine. The scaffolds were explanted to evaluate the mechanical properties of the degraded magnesium scaffolds after 180 days in vivo. Ex vivo sample preparation and test conditions were adapted to a customized compression test setup which was developed to investigate the micro-scale scaffold fragments (width 225 ±â€¯75 µm, thickness 150 µm). As reference bare undegraded magnesium scaffold fragments were tested. Mechanical parameters relating to force as a function of displacement were determined for both sample groups. The undegraded samples showed no fracturing at the maximum applied force of 8 N, whereas the in vivo degraded test samples showed forces of 0.411 ±â€¯0.197 N at the first fracturing and a maximum force of 0.956 ±â€¯0.525 N. The deformation work, calculated as area beneath the force-displacement curve, of the in vivo degraded test samples was reduced by approximately 87-88% compared to the undegraded samples (5.20 mN mm and 40.79 mN mm, both at 7.5% deformation). The indication for a complete loss of structural integrity through a reduction of mechanical properties after a certain degradation time increases the chance to restore vascular function and physiological vasomotion in the stented vessel compartment.


Assuntos
Implantes Absorvíveis , Magnésio/química , Magnésio/metabolismo , Fenômenos Mecânicos , Animais , Vasos Coronários , Teste de Materiais , Suínos
4.
Drug Deliv Transl Res ; 8(3): 719-728, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29532357

RESUMO

The successive incorporation of several drugs into the polymeric bulk of implants mostly results in loss of considerable quantity of one drug, and/or the loss in quality of the coating and also in changes of drug release time points. A dual drug delivery system (DDDS) based on poly-L-lactide (PLLA) copolymers combining the effective inhibition of smooth muscle cell proliferation while simultaneously promoting re-endothelialization was successfully developed. To overcome possible antagonistic drug interactions and the limitation of the polymeric bulk material as release system for dual drugs, a novel concept which combines the bulk and surface drug immobilization for a DDDS was investigated. The advantage of this DDDS is that the bulk incorporation of fluorescein diacetate (FDAc) (model drug for paclitaxel (PTX)) via spray coating enhanced the subsequent cleavable surface coupling of vascular endothelial growth factor (VEGF) via the crosslinker bissulfosuccinimidyl suberate (BS3). In the presence of the embedded FDAc, the VEGF loading and release are about twice times higher than in absence. Furthermore, the DDDS combines the diffusion drug delivery (FDAc or PTX) and the chemical controlled drug release, VEGF via hydrolysable ester bonds, without loss in quantity and quality of the drug release curves. Additionally, the performed in vitro biocompatibility study showed the bimodal influences of PTX and VEGF on human endothelial EA.hy926 cells. In conclusion, it was possible to show the feasibility to develop a novel DDDS which has a high potential for the medical application due to the possible easy and short modification of a polymer-based PTX delivery system.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Sistemas de Liberação de Medicamentos , Proteínas Imobilizadas/administração & dosagem , Paclitaxel/administração & dosagem , Polímeros/administração & dosagem , Fator A de Crescimento do Endotélio Vascular/administração & dosagem , Antineoplásicos Fitogênicos/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Células Endoteliais/efeitos dos fármacos , Fluoresceínas/administração & dosagem , Fluoresceínas/química , Humanos , Proteínas Imobilizadas/química , Paclitaxel/química , Polímeros/química , Propriedades de Superfície , Fator A de Crescimento do Endotélio Vascular/química
5.
Acta Biomater ; 10(12): 5081-5089, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25204522

RESUMO

As it has been demonstrated that bioactive substances can be delivered locally using coated surgical suture materials, the authors developed a vascular endothelial growth factor (VEGF)-releasing suture material that should promote vascularization and potentially wound healing. In this context, the study focused on the characterization of the developed suture material and the verification of its biological activity, as well as establishing a coating process that allows reproducible and stable coating of a commercially available polydioxanone suture material with poly(l-lactide) (PLLA) and 0.1µg and 1.0µg VEGF. The in vitro VEGF release kinetics was studied using a Sandwich ELISA. The biological activity of the released VEGF was investigated in vitro using human umbilical vein endothelial cells. The potential of the VEGF-releasing suture material was also studied in vivo 5days after implantation in the hind limb of Wistar rats, when the histological findings were analyzed. The essential results, enhanced cell viability in vitro as well as significantly increased vascularization in vivo, were achieved using PLLA/1.0µg VEGF-coated suture material. Furthermore, ELISA measurements revealed a high reproducibility of the VEGF release behavior. Based on the results achieved regarding the dose-effect relationship of VEGF, the stability during its processing and the release behavior, it can be predicted that a bioactive suture material would be successful in later in vivo studies. Therefore, this knowledge could be the basis for future studies, where bioactive substances with different modes of action are combined for targeted, overall enhancement of wound healing.


Assuntos
Indutores da Angiogênese/administração & dosagem , Vasos Sanguíneos/crescimento & desenvolvimento , Implantes de Medicamento/administração & dosagem , Células Endoteliais/fisiologia , Neovascularização Fisiológica/fisiologia , Suturas , Fator A de Crescimento do Endotélio Vascular/administração & dosagem , Indutores da Angiogênese/química , Animais , Vasos Sanguíneos/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Difusão , Implantes de Medicamento/química , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Humanos , Técnicas In Vitro , Masculino , Ratos , Ratos Wistar , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/química
6.
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
7.
Sci Rep ; 3: 1130, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23350037

RESUMO

Beta-pleated-sheet crystals are among the most stable of protein secondary structures, and are responsible for the remarkable physical properties of many fibrous proteins, such as silk, or proteins forming plaques as in Alzheimer's disease. Previous thinking, and the accepted paradigm, was that beta-pleated-sheet crystals in the dry solid state were so stable they would not melt upon input of heat energy alone. Here we overturn that assumption and demonstrate that beta-pleated-sheet crystals melt directly from the solid state to become random coils, helices, and turns. We use fast scanning chip calorimetry at 2,000 K/s and report the first reversible thermal melting of protein beta-pleated-sheet crystals, exemplified by silk fibroin. The similarity between thermal melting behavior of lamellar crystals of synthetic polymers and beta-pleated-sheet crystals is confirmed. Significance for controlling beta-pleated-sheet content during thermal processing of biomaterials, as well as towards disease therapies, is envisioned based on these new findings.


Assuntos
Seda/química , Animais , Bombyx/metabolismo , Varredura Diferencial de Calorimetria , Cristalização , Fibroínas/química , Transição de Fase , Estrutura Secundária de Proteína , Temperatura de Transição
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