Journal of Biomedical Materials Research Part A, 2012
Restenosis (renarrowing of the blood vessel wall) and cancer are two different pathologies that h... more Restenosis (renarrowing of the blood vessel wall) and cancer are two different pathologies that have drawn extensive research attention over the years. Antiproliferative drugs such as paclitaxel inhibit cell proliferation and are therefore effective in the treatment of cancer as well as neointimal hyperplasia, which is known to be the main cause of restenosis. Antiproliferative drugs are highly hydrophobic and their release from porous biodegradable structures is therefore advantageous. The release profiles of four antiproliferative drugs from highly porous polymeric structures were studied in this study in light of the physical properties of both the host polymers and the drug molecules, and a qualitative model was developed. The chemical structure of the polymer chain directly affects the drug release profile through water uptake in the early stages or degradation and erosion in later stages. It also affects the release profile indirectly, through the polymer's 3D porous structure. However, this effect is minor. The drug volume and molecular area dominantly affect its diffusion rate from the 3D porous structure and the drug's solubility parameter compared with that of the host polymer has some effect on the drug release profile. This model can also be used to describe release mechanisms of other hydrophobic drugs from porous structures. V
Restenosis (re-narrowing of the blood vessel wall) and cancer are two different pathologies that ... more Restenosis (re-narrowing of the blood vessel wall) and cancer are two different pathologies that have drawn extensive research attention over the years. Antiproliferative drugs such as paclitaxel inhibit cell proliferation and are therefore effective in the treatment of cancer as well as neointimal hyperplasia, which is known to be the main cause of restenosis. Drug-eluting stents (DES) significantly reduce the incidence of in-stent restenosis (ISR), which was once considered a major adverse outcome of percutaneous coronary stent implantations. Localized release of antiproliferative drugs interferes with the pathological proliferation of vascular smooth muscle cells (VSMC), which is the main cause of ISR. Conventional approaches to treating cancer are mainly surgical excision, irradiation, and chemotherapy. In cancer therapy, surgical treatment is usually performed on patients with a resectable carcinoma. An integrated therapeutic approach, such as the addition of a delivery system loaded with an antiproliferative drug at the tumor resection site, is desirable. This will provide a high local concentration of a drug, that is, detrimental to malignant cells which may have survived surgery, thus preventing re-growth and metastasis of the tumor. The present review describes recent advances in systems for controlled release of antiproliferative agents. It describes basic concepts in drug delivery systems and antiproliferative drugs and then focuses on both types of systems: stents with controlled release of antiproliferative agents, and drug-eluting particles and implants for local cancer treatment. The last part of this article is dedicated to our novel drug-eluting composite fiber structures, which can be used as basic stent elements as well as for local cancer treatment.
ISSN: (Print) 2159-2535 (Online) Journal homepage: http://www.tandfonline.com/loi/kbim20 Highly p... more ISSN: (Print) 2159-2535 (Online) Journal homepage: http://www.tandfonline.com/loi/kbim20 Highly porous drug-eluting structures Jonathan J. Elsner, Amir Kraitzer, Orly Grinberg & Meital Zilberman To cite this article: Jonathan J. Elsner, Amir Kraitzer, Orly Grinberg & Meital Zilberman (2012) Highly porous drug-eluting structures, Biomatter, 2:4, 239-270, DOI: 10.4161/biom.22838 To link to this article: http://dx.doi.org/10.4161/biom.22838
Drug-eluting medical implants are actually active implants that induce healing effects, in additi... more Drug-eluting medical implants are actually active implants that induce healing effects, in addition to their regular task of support. This effect is achieved by controlled release of active pharmaceutical ingredients (API) into the surrounding tissue. In this chapter we focus on three types of drug-eluting devices: drug-eluting vascular stents, drug-eluting wound dressings and protein-eluting scaffolds for tissue regeneration, thus describing both internal and external implants. Each of these drug-eluting devices also presents an approach for solving the drug release issue. Most drug-eluting vascular stents are loaded with water-insoluble antiproliferative agents, and their diffusion from the device to the surrounding tissue is relatively slow. In contrast, most drug-eluting wound dressings are loaded with highly water-soluble antibacterial agents and the issue of fast release must therefore be addressed. Growth factor release from scaffolds for tissue regeneration offers a new approach of incorporating high-molecular-weight bioactive agents which are very sensitive to process conditions and preserve their activity during the preparation stage. The drug-eluting medical implants are described here in terms of matrix formats and polymers, incorporated drugs and their release profiles from the implants, and implant functioning. Basic elements, such as new composite core/shell fibers and structured films, can be used to build new antibiotic-eluting devices. As presented in this chapter, the effect of the processing parameters on the microstructure and the resulting drug release profiles, mechanical and physical properties, and other relevant properties, must be elucidated in order to achieve the desired properties. Newly developed implants and novel modifications of previously developed approaches have enhanced the tools available for creating clinically important biomedical applications.
Farnesylthiosalicylate (FTS) is a new specific nontoxic drug with a mild hydrophobic nature, whic... more Farnesylthiosalicylate (FTS) is a new specific nontoxic drug with a mild hydrophobic nature, which acts as a Ras antagonist and can therefore be used for stent applications as well as for local cancer treatment. FTS-loaded bioresorbable core/shell fiber structures were developed and studied in order to investigate the FTS release mechanism. These structures were composed of a polyglyconate core and a porous poly(d,l-lactic-glycolic acid) shell loaded with FTS, prepared using freeze drying of inverted emulsions. The effects of the emulsion's composition (formulation) and process kinetics on the FTS release from the coatings were studied with reference to the shell morphology and degradation profile. The FTS release profiles exhibited a burst effect accompanied by a release rate which decreased with time and lasted for 15-40 days. The process was found to affect the drug release profile via two routes: (1) Direct, through water uptake and swelling of the structure, leading to a FTS burst release. Degradation of the host polymer affects the FTS release rate at a later stage. (2) Indirect effect of the microstructure on the release profile, which occurs via an emulsion stability mechanism. The copolymer composition is the most important parameter affecting the release behavior in our system. Other parameters, including polymer content, O:A phase ratio and homogenization rate exhibited only minor effects on the FTS release profile. The controlled release of the new drug FTS is reported here for the first time.
Paclitaxel-eluting bioresorbable core/shell fiber structures for stent applications and local can... more Paclitaxel-eluting bioresorbable core/shell fiber structures for stent applications and local cancer treatment were developed and studied. These structures were composed of a polyglyconate core and a porous PDLGA shell loaded with the anti-proliferative agent paclitaxel, prepared using freeze drying of inverted emulsions. The investigation of these new composite fibers focused on the effects of the emulsion's composition (formulation) and process kinetics on the long-term drug release from the fibers, in light of the shell's morphology and degradation profile. Paclitaxel release from the porous shell was relatively slow due to its extremely hydrophobic nature. It exhibited three phases of release, which corresponded to the degradation profile of the host PDLGA. We found that the effect of the emulsion formulation on the release profile is more significant than the effect of the process kinetics. The copolymer composition had the most dominant effect on the drug release profile from the composite fibers. The polymer content also affected the release profile, whereas the drug content and the organic:aqueous phase ratio resulted in minor effects. Emulsions with a less hydrophobic nature are favorable for effective controlled release of the hydrophobic paclitaxel from the porous shell.
New core/shell fiber structures loaded with paclitaxel were developed and studied. These composit... more New core/shell fiber structures loaded with paclitaxel were developed and studied. These composite fibers are ideal for forming thin, delicate, biomedically important structures for various applications. Possible applications include fiber-based endovascular stents that mechanically support blood vessels while delivering drugs for preventing restenosis directly to the blood vessel wall, or drug delivery systems for cancer treatment. The core/shell fiber structures were formed by ''coating'' nylon fibers with porous paclitaxel-containing poly(DL-lactic-co-glycolic acid) structures. Shell preparation (''coating'') was performed by freeze-drying water in oil emulsions. The present study focused on the effects of the emulsion's formulation (composition) and processing conditions on the porous shell structure, which actually reflects the emulsion's stability and also the drug release profile from the fibers. In general, extremely porous ''shell'' structures were obtained with good adhesion to the core fiber. An increase in the emulsion's drug content and copolymer composition demonstrated a significant effect on pore size and distribution, because of enhanced emulsion instability, whereas the homogenization rate and duration had only a slight effect on the pores' microstructure. The thermodynamic parameters in the studied system are thus more important than the kinetic parameters in determining the emulsion's stability and the shell's porous structure.
Journal of Biomedical Materials Research Part A, 2012
Restenosis (renarrowing of the blood vessel wall) and cancer are two different pathologies that h... more Restenosis (renarrowing of the blood vessel wall) and cancer are two different pathologies that have drawn extensive research attention over the years. Antiproliferative drugs such as paclitaxel inhibit cell proliferation and are therefore effective in the treatment of cancer as well as neointimal hyperplasia, which is known to be the main cause of restenosis. Antiproliferative drugs are highly hydrophobic and their release from porous biodegradable structures is therefore advantageous. The release profiles of four antiproliferative drugs from highly porous polymeric structures were studied in this study in light of the physical properties of both the host polymers and the drug molecules, and a qualitative model was developed. The chemical structure of the polymer chain directly affects the drug release profile through water uptake in the early stages or degradation and erosion in later stages. It also affects the release profile indirectly, through the polymer's 3D porous structure. However, this effect is minor. The drug volume and molecular area dominantly affect its diffusion rate from the 3D porous structure and the drug's solubility parameter compared with that of the host polymer has some effect on the drug release profile. This model can also be used to describe release mechanisms of other hydrophobic drugs from porous structures. V
Restenosis (re-narrowing of the blood vessel wall) and cancer are two different pathologies that ... more Restenosis (re-narrowing of the blood vessel wall) and cancer are two different pathologies that have drawn extensive research attention over the years. Antiproliferative drugs such as paclitaxel inhibit cell proliferation and are therefore effective in the treatment of cancer as well as neointimal hyperplasia, which is known to be the main cause of restenosis. Drug-eluting stents (DES) significantly reduce the incidence of in-stent restenosis (ISR), which was once considered a major adverse outcome of percutaneous coronary stent implantations. Localized release of antiproliferative drugs interferes with the pathological proliferation of vascular smooth muscle cells (VSMC), which is the main cause of ISR. Conventional approaches to treating cancer are mainly surgical excision, irradiation, and chemotherapy. In cancer therapy, surgical treatment is usually performed on patients with a resectable carcinoma. An integrated therapeutic approach, such as the addition of a delivery system loaded with an antiproliferative drug at the tumor resection site, is desirable. This will provide a high local concentration of a drug, that is, detrimental to malignant cells which may have survived surgery, thus preventing re-growth and metastasis of the tumor. The present review describes recent advances in systems for controlled release of antiproliferative agents. It describes basic concepts in drug delivery systems and antiproliferative drugs and then focuses on both types of systems: stents with controlled release of antiproliferative agents, and drug-eluting particles and implants for local cancer treatment. The last part of this article is dedicated to our novel drug-eluting composite fiber structures, which can be used as basic stent elements as well as for local cancer treatment.
ISSN: (Print) 2159-2535 (Online) Journal homepage: http://www.tandfonline.com/loi/kbim20 Highly p... more ISSN: (Print) 2159-2535 (Online) Journal homepage: http://www.tandfonline.com/loi/kbim20 Highly porous drug-eluting structures Jonathan J. Elsner, Amir Kraitzer, Orly Grinberg & Meital Zilberman To cite this article: Jonathan J. Elsner, Amir Kraitzer, Orly Grinberg & Meital Zilberman (2012) Highly porous drug-eluting structures, Biomatter, 2:4, 239-270, DOI: 10.4161/biom.22838 To link to this article: http://dx.doi.org/10.4161/biom.22838
Drug-eluting medical implants are actually active implants that induce healing effects, in additi... more Drug-eluting medical implants are actually active implants that induce healing effects, in addition to their regular task of support. This effect is achieved by controlled release of active pharmaceutical ingredients (API) into the surrounding tissue. In this chapter we focus on three types of drug-eluting devices: drug-eluting vascular stents, drug-eluting wound dressings and protein-eluting scaffolds for tissue regeneration, thus describing both internal and external implants. Each of these drug-eluting devices also presents an approach for solving the drug release issue. Most drug-eluting vascular stents are loaded with water-insoluble antiproliferative agents, and their diffusion from the device to the surrounding tissue is relatively slow. In contrast, most drug-eluting wound dressings are loaded with highly water-soluble antibacterial agents and the issue of fast release must therefore be addressed. Growth factor release from scaffolds for tissue regeneration offers a new approach of incorporating high-molecular-weight bioactive agents which are very sensitive to process conditions and preserve their activity during the preparation stage. The drug-eluting medical implants are described here in terms of matrix formats and polymers, incorporated drugs and their release profiles from the implants, and implant functioning. Basic elements, such as new composite core/shell fibers and structured films, can be used to build new antibiotic-eluting devices. As presented in this chapter, the effect of the processing parameters on the microstructure and the resulting drug release profiles, mechanical and physical properties, and other relevant properties, must be elucidated in order to achieve the desired properties. Newly developed implants and novel modifications of previously developed approaches have enhanced the tools available for creating clinically important biomedical applications.
Farnesylthiosalicylate (FTS) is a new specific nontoxic drug with a mild hydrophobic nature, whic... more Farnesylthiosalicylate (FTS) is a new specific nontoxic drug with a mild hydrophobic nature, which acts as a Ras antagonist and can therefore be used for stent applications as well as for local cancer treatment. FTS-loaded bioresorbable core/shell fiber structures were developed and studied in order to investigate the FTS release mechanism. These structures were composed of a polyglyconate core and a porous poly(d,l-lactic-glycolic acid) shell loaded with FTS, prepared using freeze drying of inverted emulsions. The effects of the emulsion's composition (formulation) and process kinetics on the FTS release from the coatings were studied with reference to the shell morphology and degradation profile. The FTS release profiles exhibited a burst effect accompanied by a release rate which decreased with time and lasted for 15-40 days. The process was found to affect the drug release profile via two routes: (1) Direct, through water uptake and swelling of the structure, leading to a FTS burst release. Degradation of the host polymer affects the FTS release rate at a later stage. (2) Indirect effect of the microstructure on the release profile, which occurs via an emulsion stability mechanism. The copolymer composition is the most important parameter affecting the release behavior in our system. Other parameters, including polymer content, O:A phase ratio and homogenization rate exhibited only minor effects on the FTS release profile. The controlled release of the new drug FTS is reported here for the first time.
Paclitaxel-eluting bioresorbable core/shell fiber structures for stent applications and local can... more Paclitaxel-eluting bioresorbable core/shell fiber structures for stent applications and local cancer treatment were developed and studied. These structures were composed of a polyglyconate core and a porous PDLGA shell loaded with the anti-proliferative agent paclitaxel, prepared using freeze drying of inverted emulsions. The investigation of these new composite fibers focused on the effects of the emulsion's composition (formulation) and process kinetics on the long-term drug release from the fibers, in light of the shell's morphology and degradation profile. Paclitaxel release from the porous shell was relatively slow due to its extremely hydrophobic nature. It exhibited three phases of release, which corresponded to the degradation profile of the host PDLGA. We found that the effect of the emulsion formulation on the release profile is more significant than the effect of the process kinetics. The copolymer composition had the most dominant effect on the drug release profile from the composite fibers. The polymer content also affected the release profile, whereas the drug content and the organic:aqueous phase ratio resulted in minor effects. Emulsions with a less hydrophobic nature are favorable for effective controlled release of the hydrophobic paclitaxel from the porous shell.
New core/shell fiber structures loaded with paclitaxel were developed and studied. These composit... more New core/shell fiber structures loaded with paclitaxel were developed and studied. These composite fibers are ideal for forming thin, delicate, biomedically important structures for various applications. Possible applications include fiber-based endovascular stents that mechanically support blood vessels while delivering drugs for preventing restenosis directly to the blood vessel wall, or drug delivery systems for cancer treatment. The core/shell fiber structures were formed by ''coating'' nylon fibers with porous paclitaxel-containing poly(DL-lactic-co-glycolic acid) structures. Shell preparation (''coating'') was performed by freeze-drying water in oil emulsions. The present study focused on the effects of the emulsion's formulation (composition) and processing conditions on the porous shell structure, which actually reflects the emulsion's stability and also the drug release profile from the fibers. In general, extremely porous ''shell'' structures were obtained with good adhesion to the core fiber. An increase in the emulsion's drug content and copolymer composition demonstrated a significant effect on pore size and distribution, because of enhanced emulsion instability, whereas the homogenization rate and duration had only a slight effect on the pores' microstructure. The thermodynamic parameters in the studied system are thus more important than the kinetic parameters in determining the emulsion's stability and the shell's porous structure.
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