Three-Dimensional Model of the Release and Diffusion of Paclitaxel in the Stent-Polymer-Wall-Lumen System of a Blood Vessel

Les stents sont utilisés en cardiologie interventionnelle pour garder ouvert un vaisseau malade. Les nouveaux stents sont recouverts d’un agent médicinal pour prévenir l’obstruction prématurée suite à la prolifération de cellules musculaires lisses (CML) dans la lumière du vaisseau. Afin de réaliser le taux nécessaire de largage de médicament pendant la période thérapeutique désirée, la tendance est aux largages biphasiques ou possiblement polyphasiques à partir d’un mélange de polymères dégradables. Blanchet-Delfour-Garon [7] ont introduit une équation différentielle ordinaire quadratique à 2 paramètres et Garon-Delfour [42] une équation différentielle partielle 3D quadratique à 2 paramètres pour caractériser la dynamique du largage du médicament pour chaque polymère. Les deux paramètres de ces modèles peuvent être obtenus expérimentalement à partir du protocole de mesures de Lao et al. pour des polymères purs et pour des mélanges de polymères en créant des conditions de réservoir infini. Ces équations constituent un outil pratique pour simuler numériquement et théoriquement le largage 3D d’un médicament imprégné dans une mince couche de polymère vers la paroi et la lumière du vaisseau sanguin aux fins d’évaluation et de design d’un stent. L’objectif principal de la recherche était de passer d’une surface plate de polymère à la surface courbe qui recouvre un véritable stent de géométrie complexe. En premier lieu, le modèle à diffusion linéaire (et les résultats) de Delfour Garon-Longo [31] pour un vaisseau modélisé par un cylindre droit ont été généralisés au cas d’un vaisseau avec surface cylindrique courbe en introduisant les conditions de transparence appropriées à l’entrée et à la sortie. Ce modèle a ensuite été utilisé pour obtenir les équations de la dose et de la concentration normalisée. En second lieu, les conditions de transparence et le largage quadratique ont été intégrés à l’équation aux dérivées partielles 3D de Garon-Delfour [42]. Ce deuxiéme modèle non linéaire a ensuite été utilisé pour étudier la concentration normalisée en fonction de l’épaisseur du polymère et de la constante de diffusion du milieu ambiant.Stents are used in interventional cardiology in order to keep a diseased vessel open. New stents are coated with a medicinal agent that prevents the early reclosing caused by the proliferation of smooth muscle cells (SMC). In order to obtain the desired release kinetics for the SMC-controlling drug during the required therapeutic period, the current strategy focuses on biphasic or possibly polyphasic release from blends of degradable polymers. BlanchetDelfour-Garon [7] introduced an ordinary differential equation with two parameters and Garon-Delfour [42] a partial differential equation with two parameters to model the release kinetics. The parameters are all obtained from experimental release curves of Lao et al. [60] for pure polymers and polymer blends under infinite sink conditions. They are practical tools to numerically and theoretically simulate the 3D drug release from a thin coating of polymer to the aggregated wall and lumen of the blood vessel in order to facilitate the design and evaluation of the coating. The primary objective of this research was to pass from the thin, flat midsurface coating to the thin coating of a realistic 3D stent with curved and complex surface. To begin, the linearly diffusive model (and the results) of Delfour-Garon-Longo [31] that were obtained for a vessel with flat surface were extended to the case of a vessel with curved surface by finding the appropriate boundary conditions. The resulting model was then analysed from the point of view of the dose and the normalised concentration. Secondly, the resulting boundary condition from the 3D partial differential equation of Garon-Delfour was introduced into the model. This second nonlinear model was then used to study the normalised concentration as a function of the thickness of the polymer and the diffusion constant of the surrounding mediu

Functional Polymers for Controlled Drug Release

This Special Issue focuses on the synthesis and characterization of hydrogels specifically used as carriers of biological molecules for pharmaceutical and biomedical employments. Pharmaceutical applications of hydrophilic materials has emerged as one of the most significant trends in the area of nanotechnology. To propose some of the latest findings in this field, each contribution involves an in-depth analysis including different starting materials and their physico-chemical and biological properties with the aim of synthetizing high-performing devices for specific use. In this context, intelligent polymeric devices able to be morphologically modified in response to an internal or external stimulus, such as pH or temperature, have been actively pursued. In general, hydrophilic polymeric materials lead to high in vitro and/or in vivo therapeutic efficacy, with programmed site-specific feature showing remarkable potential for targeted therapy. This Special Issue serves to highlight and capture the contemporary progress in this field. Relevant resources and people to approach - American Association Pharmaceutical Scientists (AAPS): web: www.aaps.org; email: (marketing division): [email protected]; (mmeting division): [email protected] - International Association for Pharmaceutical Technology (APV): web: apv-mainz.de; email (managing director)

Biopolymers in Drug Delivery and Regenerative Medicine

Biopolymers including natural (e.g., polysaccharides, proteins, gums, natural rubbers, bacterial polymers), synthetic (e.g., aliphatic polyesters and polyphosphoester), and biocomposites are of paramount interest in regenerative medicine, due to their availability, processability, and low toxicity. Moreover, the structuration of biopolymer-based materials at the nano- and microscale along with their chemical properties are crucial in the engineering of advanced carriers for drug products. Finally, combination products including or based on biopolymers for controlled drug release offer a powerful solution to improve the tissue integration and biological response of these materials. Understanding the drug delivery mechanisms, efficiency, and toxicity of such systems may be useful for regenerative medicine and pharmaceutical technology. The main aim of the Special Issue on “Biopolymers in Drug Delivery and Regenerative Medicine” is to gather recent findings and current advances on biopolymer research for biomedical applications, particularly in regenerative medicine, wound healing, and drug delivery. Contributions to this issue can be as original research or review articles and may cover all aspects of biopolymer research, ranging from the chemical synthesis and characterization of modified biopolymers, their processing in different morphologies and hierarchical structures, as well as their assessment for biomedical uses

Smart and Functional Polymers

This book is based on the Special Issue of the journal Molecules on “Smart and Functional Polymers”. The collected research and review articles focus on the synthesis and characterization of advanced functional polymers, polymers with specific structures and performances, current improvements in advanced polymer-based materials for various applications, and the opportunities and challenges in the future. The topics cover the emerging synthesis and characterization technology of smart polymers, core?shell structure polymers, stimuli-responsive polymers, anhydrous electrorheological materials fabricated from conducting polymers, reversible polymerization systems, and biomedical polymers for drug delivery and disease theranostics. In summary, this book provides a comprehensive overview of the latest synthesis approaches, representative structures and performances, and various applications of smart and functional polymers. It will serve as a useful reference for all researchers and readers interested in polymer sciences and technologies

Synthesis and Applications of Biopolymer Composites

This book, as a collection of 17 research articles, provides a selection of the most recent advances in the synthesis, characterization, and applications of environmentally friendly and biodegradable biopolymer composites and nanocomposites. Recently, the demand has been growing for a clean and pollution-free environment and an evident target regarding the minimization of fossil fuel usage. Therefore, much attention has been focused on research to replace petroleum-based commodity plastics by biodegradable materials arising from biological and renewable resources. Biopolymers—polymers produced from natural sources either chemically from a biological material or biosynthesized by living organisms—are suitable alternatives for addressing these issues due to their outstanding properties, including good barrier performance, biodegradation ability, and low weight. However, they generally possess poor mechanical properties, a short fatigue life, low chemical resistance, poor long-term durability, and limited processing capability. In order to overcome these deficiencies, biopolymers can be reinforced with fillers or nanofillers (with at least one of their dimensions in the nanometer range). Bionanocomposites are advantageous for a wide range of applications, such as in medicine, pharmaceutics, cosmetics, food packaging, agriculture, forestry, electronics, transport, construction, and many more

Combinatorial design and development of biomaterials for use as drug delivery devices and immune adjuvants

There are several challenges associated with current strategies for drug and vaccine delivery. These include the need for multiple-dose administrations, which can hinder patience compliance, the requirements for specific storage conditions due to the fragile structure of protein-based molecules, and the need for additional excipients to enhance protein stability or adjuvant the immune response. This work has focused on the development of a high throughput, combinatorial approach to optimize degradable polymeric biomaterials, specifically polyanhydrides, to overcome these challenges associated with drug and vaccine delivery. We have developed high throughput techniques to rapidly fabricate polymer film and nanoparticle libraries to carry out detailed investigations of protein/biomaterial, cell/biomaterial, and host/biomaterial interactions. By developing and employing a highly sensitive fluorescence-based assay we rapidly identified that protein release kinetics are dictated by polymer chemistry, pH, and hydrophobicity, and thus can be tailored for the specific application to potentially eliminate the need for multiple-dose treatments. Further investigation of protein/biomaterial interactions identified polymer chemistry, pH, hydrophobicity, and temperature to be integral factors controlling protein stability during fabrication of the delivery device, storage, and delivery. Amphiphilic polymer chemistries were specifically identified to preserve the structure of both robust and fragile proteins from device fabrication to release. Our investigations of cell/biomaterial interactions revealed that all nanoparticle and polymer film chemistries studied were non-toxic at concentrations expected for human use. Furthermore, cellular activation studies were carried out with antigen presenting cells co-incubated with the polymer libraries which indicated that polymer films do not possess immune stimulating properties; however, the nanoparticles do, in a chemistry dependent manner. Combining these insights with informatics analysis, we discovered the molecular basis of the pathogen-mimicking behavior of amphiphilic polyanhydride nanoparticles. Specific molecular descriptors that were identified for this pathogen-mimicking behavior include alkyl ethers, % hydroxyl end groups, backbone oxygen content, and hydrophobicity. These findings demonstrated the stealth properties of polyanhydride films for tissue engineering and the pathogen-mimicking adjuvant properties of the nanoparticles for vaccine delivery. Finally, host/biomaterial interactions were studied, which indicated that polymer chemistry and administration route affect nanoparticle biodistribution and mucoadhesion. Amphiphilic nanoparticles were identified to reside longest at parenteral administration routes and adhere best to mucosal surfaces. These results point to their ability to provide a long-term antigen depot in vivo. In summary, the studies described in this thesis have created a rational design paradigm for materials selection and optimization for use as drug delivery vehicles and vaccine adjuvants, which will overcome the challenges associated with administration frequency, protein instability, and insufficient immune stimulation

Advances in Nanogels

In the last two decades, nanogels have emerged as very promising and versatile biomaterials suitable for a wide range of applications. Their features, such as large surface areas, the ability to hold molecules, flexibility in their size and their water-based formulations, have earned them great recognition as drug delivery systems for various in vivo applications, confirming their potential. On the other hand, because of their tuneable and versatile characteristics, nanogels have been investigated in recent years for applications in various fields other than biomedicine. In view of this variety of possible applications of nanogels, in this Special Issue, we extend our knowledge on the topic of their possible uses described in literature, taking stock of the state-of-the-art for all possible nanogel applications and their synthesis methods

Biocompatible polymeric materials for regenerative medicine applications

networks are prepared by the interaction of chitosan with poly(methacryloylglycylglycine), which is a synthetic polymer belonging to the class of poly(acrylamides) and is being widely investigated for drug delivery applications. A comprehensive study of the prepared biomaterials including their degradability are done and presented. To recapitulate, the research activity in the present Doctorate Thesis involves the following topics: · Chitosan – A Versatile Material for Regenerative Medicine applications · Statistical Approach of Chitin Deacetylation. · Chitosan-Based Beads for Controlled Release of Proteins · Hybrid Nanoparticles Based on Chitosan and Poly(Methacryloylglycylglycine) · Synthesis and Characterization of Semi Interpenetrating Polymer Network Hydrogel Composed of Chitosan and Poly(methacryloylglycyl glycine

Nanostructured titania coatings for drug-eluting medical implants

Medical implants delivering drugs are used to ensure efficient medication at body sites, at which the conventional administration of drugs is insufficient. The application of drug-delivery coatings is a beneficial concept for implants exposed to mechanical loads, such as orthopedic implants or cardiovascular stents. Many of the commercially available coated stent-implants are designed to release a drug locally and at a predefined rate out of a polymer matrix in order to prevent the re-blocking of the artery. The polymer matrices of such so-called drug-eluting stents (DES) can either be bio-degradable or inert. In spite of their successful drug-release capability, they often fail with regard to biocompatibility and long-term chemical and mechanical stability. The aim of the project is to create a novel, nanostructured, ceramic drug-delivering coating for stents, which exhibits an improved performance as compared to the one of conventional DES-implants. The present work addresses the processing and characterization of a nanoporous coating, its drug-loading and release behavior as well as its cytocompatibility. A nanostructured titania (TiO2) coating was deposited on either 316L stainless steel or silicon wafer supports by a multi-step dip coating process involving TiO2-nanoparticle and polymer template suspensions. A subsequent sintering step burned the polymer template particles to create drug reservoirs in the thin coating, which has a thickness of 1.2 µm. These drug reservoirs have a diameter of 1 µm and are surrounded by a porous ceramic structure. This surrounding ceramic structure exhibits a mean pore width of 76 nm and has an open porosity of 50 % as was determined by small angle neutron scattering and mercury intrusion porosimetry. The presence of the drug reservoirs further increases the porosity and hence the drug-load capability of the coating. In addition, the coating was characterized with regard to the specific surface area by the Brunauer-Emmett-Teller (BET)-method, the crystal phases of TiO2 by X-ray diffraction (XRD) and the elemental composition by X-ray photoelectron spectroscopy (XPS). From cardiovascular DESs, therapeutical agents, which either reduce the activation of the immune system or inhibit cell growth, are released into the coronary artery tissue to prevent the local re-blocking of the artery. In the present study, the cell growth inhibiting drug paclitaxel (PTX) was successfully loaded into the highly porous titania coatings by a low-pressure, solvent evaporation technique. The pharmaceutical was accumulated in the drug reservoirs, in the pores of the surrounding ceramic structure and on top of the coating. The total quantity of loaded drug could be varied by changing the coating's structure or the parameters of the drug-loading process. The maximum quantity of PTX incorporated into the coatings was comparable with the amount of PTX in the commercially available TaxusTM DES of 1 µg/mm2. The in vitro release tests of PTX from the coatings into ultra pure water revealed a slow, continuous liberation of the therapeutical agent. After one month of testing, only 11 % of initially incorporated drug were released. The obtained release profile is similar to the one of a PTX-eluting stent. Further release tests of PTX from the titania coatings into bovine plasma were performed and the findings compared to a release profile of the TaxusTM stent. In vitro cytotoxicity tests were accomplished, in which isolated, primary, bovine endothelial cells were brought in direct contact to the non-PTX-loaded titania coatings. First results indicate that the nanostructured TiO2-coatings on wafer and 316L stainless steel supports are cytocompatible. A technology platform has been established, which comprises the characterization of the titania coatings, the loading and quantification of PTX as well as the cytotoxicity evaluation. Factors affecting each of these issues were identified. The findings of the present study will contribute to optimize the nanostructured, ceramic drug-eluting coating for its implementation in DESs and to adapt it to various biomedical applications