Biomedical subjects

A Göpferich

Publications and source records attributed to A Göpferich.

At least 19 recordsLinked to original sources

PubMed2003

Monolithic glyceryl trimyristate matrices for parenteral drug release applications.

Monolithic lipid matrices were developed that allow parenteral drug release for days, weeks or even months. The cylindrical matrices consist of triglycerides or triglyceride/cholesterol mixtures and allow, due to their small dimensions, an application via injection. Pure triglyceride matrices showed less than 3%, triglyceride matrices containing 70% and more cholesterol less than 10% water uptake over 30 weeks. This swelling behavior would allow the use of such matrices even for sophisticated applications such as interstitial drug delivery to the brain where excessive swelling is highly undesirable. The drug release kinetics were found to depend strongly on the fatty acid chain length of the triglyceride and the cholesterol content of the matrices. Increasing the chain length from C(12) to C(18) allowed an increase in the release of pyranine, a low molecular weight model compound, from approx. 60 days to more than 120 days. Adding cholesterol to glyceryl trimyristate matrices made it possible to adjust the release within a time span varying from days to weeks. While matrices containing 50% cholesterol released pyranine within 8 days, cholesterol contents of 90% allowed a release of the dye for more than 3 weeks.

Arylsulfonates↗

PubMed2003

Monolithic triglyceride matrices: a controlled-release system for proteins.

Matrices made of glyceryl trimyristate as a bioerodible and biocompatible material were manufactured by compression in dimensions that would still allow an application via injection. Pyranine, as a low molecular hydrophilic compound with a low detection limit, and tetramethylrhodamine labeled bovine serum albumin (TAMRA-BSA), as a high molecular weight (66 kDa) protein compound, served as model drugs for release investigations. In vitro studies with pyranine revealed that release depends substantially on the gelatin content of the matrices, which proved to be a useful tool as a release modifier. The duration of the drug release period can be adjusted to a desired time interval ranging from days to weeks by choosing the right gelatin content. Moreover, results illustrated the importance of the molecular weight and the nature of the compound to be incorporated into such matrices, since investigations with TAMRA-BSA showed a more pronounced burst release and altered release profiles and periods. Experiments with hyaluronidase, which served as a model enzyme to assess the problem of protein integrity in such matrices, suggested that proteins may display sufficient stability during the manufacturing procedure of the cylinders or while in contact with the triglyceride matrices. In addition to in vitro investigations, a study in mice revealed that after 15 days of subcutaneous implantation the matrices showed a good in vivo stability. The main conclusion that could be drawn from these results was that triglycerides are a promising alternative to biodegradable polymers for the development of parenteral release systems for protein and peptide drugs.

Animals↗

PubMed2003

Poly(D,L-lactic acid)-poly(ethylene glycol)-monomethyl ether diblock copolymers control adhesion and osteoblastic differentiation of marrow stromal cells.

Biodegradable polymers, such as poly(lactic acid) (PLA) and poly(lactic-coglycolic acid) (PLGA), are attractive materials for tissue engineering because of their degradative and mechanical properties, which permit scaffolds to be tailored to the individual requirements of different tissues. Although these materials support tissue development, their chemical properties offer no control of cell adhesion or function because their surfaces become immediately masked by adsorbing serum proteins when the materials come into contact with body fluids. Furthermore, adhesion proteins undergo conformational changes and a decrease in bioactivity when adsorbed to hydrophobic materials, such as PLA. To overcome these limitations, we modified the properties of PLA by synthesizing a diblock copolymer with poly(ethylene glycol) (PEG), which is known to reduce the amount of adsorbed proteins and to modify their conformation. By altering the PEG content of these diblock copolymers we were able to control the adsorption of adhesion proteins and, because cell adhesion takes place only in the presence of serum proteins, to control cell adhesion and cell shape. Marrow stromal cell differentiation to the osteoblastic phenotype was strongly improved on PEG-PLA compared with PLA, PLGA and tissue culture polystyrene and led to a 2-fold increase in alkaline phosphatase activity and mineralization.

Animals↗

PubMed2002

Polyanhydride degradation and erosion.

It was the intention of this paper to give a survey on the degradation and erosion of polyanhydrides. Due to the multitude of polymers that have been synthesized in this class of material in recent years, it was not possible to discuss all polyanhydrides that have gained in significance based on their application. It was rather the intention to provide a broad picture on polyanhydride degradation and erosion based on the knowledge that we have from those polymers that have been intensively investigated. To reach this goal this review contains several sections. First, the foundation for an understanding of the nomenclature are laid by defining degradation and erosion which was deemed necessary because many different definitions exist in the current literature. Next, the properties of major classes of anhydrides are reviewed and the impact of geometry on degradation and erosion is discussed. A complicated issue is the control of drug release from degradable polymers. Therefore, the aspect of erosion-controlled release and drug stability inside polyanhydrides are discussed. Towards the end of the paper models are briefly reviewed that describe the erosion of polyanhydrides. Empirical models as well as Monte-Carlo-based approaches are described. Finally it is outlined how theoretical models can help to answer the question why polyanhydrides are surface eroding. A look at the microstructure and the results from these models lead to the conclusion that polyanhydrides are surface eroding due to their fast degradation. However they switch to bulk erosion once the device dimensions drop below a critical limit.

Anhydrides↗

PubMed2002

Efficacy of BCNU and paclitaxel loaded subcutaneous implants in the interstitial chemotherapy of U-87 MG human glioblastoma xenografts.

Nude mice were challenged with human U-87 MG glioblastoma tumors to assess the efficacy of different cytostatics and different application protocols. While the intraperitoneal application of BCNU solutions (3 times 20 mg BCNU/kg) had no effect on tumor growth, the application of polymer matrices made of a physical mixture of poly(1,3-bis[carboxyphenoxpropane]-co-sebacic acid) 20:80 with poly(D,L-lactic-co-glycolic acid) loaded with 0.25 mg BCNU, slowed down the growth of tumors significantly. When the animals were treated with implants carrying 0.25 mg BCNU they responded to the treatment whether the tumor had been inoculated recently (9 days ago) or whether it was fully established (after 20 days). After its sensitivity was proven, the xenograft model was used to further investigate the efficacy of anticancer drugs and some treatment regimens using polymer implants. Thus the tumor model allowed to discriminate between the efficacy of different doses of BCNU. Only implants loaded with 0.75 or 1 mg of BCNU led to a substantial suppression of tumor growth over approximately 2 months. While BCNU was only able to suppress the growth of the tumor, the combination of BCNU with paclitaxel led to a complete remission in some animals. These preliminary results suggest that combinations of cytostatics might improve local chemotherapy of malignant glioma substantially. Based on our data it will be worthwhile to investigate implants that release drugs such as BCNU and paclitaxel closer. Amongst other factors we will try to elucidate the effect of repetitive doses of drugs using programmable implants.

Animals↗

PubMed2001

Lipid microparticles as a parenteral controlled release device for peptides.

To investigate the potential of physiological lipids as an alternative to synthetic polymeric materials such as poly(lactide-co-glycolide), peptide-containing glyceryl tripalmitate microparticles were prepared. A modified solvent evaporation method and a melt dispersion technique without the use of organic solvent were employed. Thymocartin (TP-4), an immunomodulating tetrapeptide and insulin were chosen as model peptides and incorporated as a solid or dissolved in 100 microl aqueous solution. The resulting microparticles were characterized with respect to particle size and morphology, biocompatibility, drug content (encapsulation efficiency) and in vitro release behavior. Electron spectroscopy for chemical analysis was used to investigate the adsorption of the model peptides to the lipid matrix material. The modified solvent evaporation as well as the melt dispersion method were suitable for the preparation of microparticles in the size range of 20-150 microm with an acceptable yield. The biocompatibility of the glyceryl tripalmitate microparticles after implantation into NMRI-mice was comparable to poly(lactide-co-glycolide) microparticles. The encapsulation efficiency for both model peptides was high (>80%) even at high theoretical loadings when the peptide was incorporated as a solution with the melt dispersion technique. The in vitro release behavior was substantially influenced by the physicochemical properties of the model peptides used in this study.

Drug Delivery Systems↗

PubMed2001

Mathematical modeling of bioerodible, polymeric drug delivery systems.

The aim of this article is to give an introduction into mathematical modeling approaches of bioerodible controlled drug delivery systems and to present the most important erosion theories reported in the literature. First, important parameters such as degradation and erosion are defined and physicochemical methods for their investigation are briefly presented. Then, phenomenological empirical models as well as models based on diffusion and chemical reaction theory are discussed. Due to the significant chemical and physicochemical differences among individual bioerodible polymers used for controlled drug delivery systems, various mathematical models have been developed to describe the chemical reactions and physical mass transport processes involved in erosion-controlled drug release. Various examples of practical applications of these models to experimental drug release data are given. For those involved in the design and development of biodegradable drug delivery systems this will help to choose the appropriate mathematical model for a specific drug release problem. Important selection criteria such as the desired predictive power and precision, but also the effort required to apply a model to a particular system will be discussed. Furthermore, before models can be used for drug release predictions certain parameters such as drug dissolution or polymer degradation rate constants, have to be known. The number of parameters to be determined significantly differs between the models. The practical benefit of carefully choosing the right model is that effects of composition and device geometry on the drug release kinetics can be predicted which can reduce laborious formulation studies to a minimum.

Drug Delivery Systems↗

PubMed2001

Programmable biodegradable implants.

Pulsatile release implants were developed that release substances up to 58 days post implantation. With a cylindrical size of 2 mm diameter and 1.8 mm height the matrices can carry as much as 1 mg of drug and allow even for intracranial implantation into a rodent model. The matrices are made of materials that have been used for parenteral applications in humans before such as surface eroding polyanhydrides and bulk eroding poly(D,L-lactic acid) or poly(D,L-lactic acid-co-glycolic acid). The onset of drug release is controlled by the degradation of bulk eroding polymers which are known to exhibit a certain stability over a defined period of time and which start eroding after they reach a critical degree of degradation. The time of drug release onset was found to depend on the molecular weight and the chemical state of the carboxylic acid end of the polymer chain. For testing the onset of release in vivo a nude mouse model was developed where the release of Evan's blue could be observed visually after subcutaneous application. By combining individual matrices with different release onset, a therapeutic system can be composed that releases drugs after implantation at predetermined time points in a preprogrammed way. Potential applications for such matrices is vaccination and local tumor therapy.

Absorbable Implants↗

PubMed2001

Development and characterization of lipid microparticles as a drug carrier for somatostatin.

Somatostatin, a therapeutic peptide with a high therapeutical potential but a very short biological half-live was encapsulated within microparticles by a modified solvent evaporation method and a melt dispersion method without the use of organic solvent. As the use of synthetic polymer matrix materials often goes along with detrimental effects on incorporated peptides, we investigated the potential of physiological lipids such as glyceryl tripalmitate (Dynasan 116) as an alternative matrix material. The two preparation methods were evaluated with respect to surface topography, particle size distribution, encapsulation efficiency, in-vitro release behavior and modification of the resulting microparticles. Microparticles with a suitable particle size distribution for i.m. or s.c. injection could be prepared with both methods. The encapsulation efficiency of the peptide into glyceryl tripalmitate microparticles was substantially influenced by the preparation method and the physical state of the peptide to be incorporated. The melt dispersion technique and the incorporation of the drug as an aqueous solution gave the best results with actual drug loadings up to 9% and an encapsulation efficiency of approximately 90%. Microparticles prepared by the melt dispersion technique crystallized in the unstable alpha-modification. The peptide was released almost continuously over 10 days with no burst effect, 20-30% of the incorporated somatostatin was not released in the monitored time period.

Calorimetry, Differential Scanning↗

PubMed2001

Retinal pigment epithelial cell adhesion on novel micropatterned surfaces fabricated from synthetic biodegradable polymers.

Novel synthetic biodegradable polymer substrates with specific chemical micropatterns were fabricated from poly(DL-lactic-coglycolic acid) (PLGA) and diblock copolymers of poly(ethylene glycol) and poly(DL-lactic acid) (PEG/PLA). Thin films of PLGA and PEG/PLA supported and inhibited, respectively, retinal pigment epithelial (RPE) cell proliferation, with a corresponding cell density of 352,900 and 850 cells/cm2 after 7 days (from an initial seeding density of 15,000 cells/cm2). A microcontact printing technique was used to define arrays of circular (diameter of 50 microm) PLGA domains surrounded and separated by regions (width of 50 microm) of PEG/PLA. Reversed patterns composed of PEG/PLA circular domains surrounded by PLGA regions were also fabricated. Both micropatterned surfaces were shown to affect initial RPE cell attachment, limit cell spreading, and promote the characteristic cuboidal cell morphology during the 8-h period of the experiments. In contrast, RPE cells on plain PLGA (control films) were elongated and appeared fibroblast-like. The reversed patterns had continuous PLGA regions that allowed cell-cell interactions and thus higher cell adhesion. These results demonstrate the feasibility of fabricating micropatterned synthetic biodegradable polymer surfaces to control RPE cell morphology.

Biodegradation, Environmental↗

PubMed2001

Insulin in tissue engineering of cartilage: a potential model system for growth factor application.

Investigation of novel experimental application systems for growth factors or other bioactive substances in tissue engineering is often limited by high costs of substances and would benefit from a defined and easily controllable model tissue system. Herein, we demonstrate a potential three-dimensional in vitro system using engineered cartilage as a model tissue and readily available insulin as a model drug. Previously it has been shown that insulin-like growth factor-I (IGF-I) has profound effects on tissue-engineered cartilage in vitro. Insulin is known to bind to the IGF-I receptor and to elicit significant responses in cartilage. In this study, bovine articular chondrocytes were seeded onto biodegradable polyglycolic acid (PGA) scaffolds and cultured for up to 7 weeks. Exogenous insulin (0.05-50 microg/ml) increased the growth rate and the glycosaminoglycan fraction of tissue-engineered cartilage, decreased the cell number in the tissue constructs, and improved the morphological appearance, with 2.5 microg/ml being the most favorable concentration. The observed effects of insulin were similar to effects of IGF-I (0.05 microg/ml) and were in agreement with the reported binding constants of IGF-I and insulin at the IGF-I receptor. Besides the possibility to employ insulin as a potent substance to improve tissue-engineered cartilage, the presented easily controllable in vitro system may be used in the future to evaluate experimental growth factor application devices using economically favorable insulin as a model protein.

Animals↗

PubMed2000

Biodegradable poly(D,L-lactic acid)-poly(ethylene glycol)-monomethyl ether diblock copolymers: structures and surface properties relevant to their use as biomaterials.

To obtain biodegradable polymers with variable surface properties for tissue culture applications, poly(ethylene glycol) blocks were attached to poly(lactic acid) blocks in a variety of combinations. The resulting poly(D,L-lactic acid)-poly(ethylene glycol)-monomethyl ether (Me.PEG-PLA) diblock copolymers were subject to comprehensive investigations concerning their bulk microstructure and surface properties to evaluate their suitability for drug delivery applications as well as for the manufacture of scaffolds in tissue engineering. Results obtained from 1H-NMR, gel permeation chromatography, wide angle X-ray diffraction and modulated differential scanning calorimetry revealed that the polymer bulk microstructure contains poly(ethylene glycol)-monomethyl ether (Me.PEG) domains segregated from poly(D,L-lactic acid) (PLA) domains varying with the composition of the diblock copolymers. Analysis of the surface of polymer films with atomic force microscopy and X-ray photoelectron spectroscopy indicated that there is a variable amount of Me.PEG chains present on the polymer surface, depending on the polymer composition. It could be shown that the presence of Me.PEG chains in the polymer surface had a suppressive effect on the adsorption of two model peptides (salmon calcitonin and human atrial natriuretic peptide). The possibility to modify polymer bulk microstructure as well as surface properties by variation of the copolymer composition is a prerequisite for their efficient use in the fields of drug delivery and tissue engineering.

Biocompatible Materials↗

PubMed1999

Modulation of marrow stromal cell function using poly(D,L-lactic acid)-block-poly(ethylene glycol)-monomethyl ether surfaces.

The adhesion of marrow stromal osteoblasts and the adsorption of fetal bovine serum (FBS) proteins to end-capped poly(D,L-lactic acid) 50:50 (PLA50) of molecular weight 17,000 (PLA5017), non-end-capped PLA50 of molecular weight 11,000 (PLA5011h), and a diblock copolymer made of poly(ethylene glycol)-monomethyl ether of molecular weight 5,000 and PLA50 of molecular weight 20,000 (Me. PEG5-PLA20) were investigated. Cell attachment and proliferation on both PLA50 polymers were equally good. The block copolymer did not allow the proliferation of cells. However, the attached cells were highly differentiated and metabolically active in contrast to the cells on PLA50. Moreover, surface analysis studies using electron spectroscopy revealed that FBS proteins adsorbed well from aqueous solutions to the PLA50 surfaces while they adsorbed substantially less to the block copolymer. These results suggest that Me.PEG-PLA block copolymers may be used to regulate protein adsorption and, therefore, cell adhesion by varying the block composition of the copolymer.

Adsorption↗

PubMed1999

Retinal pigment epithelial cell function on substrates with chemically micropatterned surfaces.

Model substrates with desired chemical micropatterns were fabricated using a microcontact printing technique. The substrate surfaces contained organized arrays of circular glass domains with a diameter of either 10 or 50 microm surrounded and separated by regions modified with octadecyltrichlorosilane (OTS) self-assembled monolayers (SAMs). The effects of surface patterning on in vitro cell attachment, proliferation, morphology, and cytoskeletal organization were evaluated using a human retinal pigment epithelium (RPE) cell line. Both micropatterns affected initial RPE cell attachment, limited cell spreading, and promoted the characteristic cuboidal cell morphology throughout the culture period. In contrast, RPE cells on plain glass control were elongated and appeared fibroblast-like prior to confluence. In addition, cells seeded at 30,000 cell/cm2 on the patterned surfaces maintained a normal pattern of actin and cytokeratin expression, and formed confluent monolayers within 4 days of culture. The cell density increased about 30-fold on both micropatterns by day 7. These results show that it is feasible to control RPE cell shape and expression of differentiated phenotype using micropatterned surfaces.

Actins↗

PubMed1999

pH and osmotic pressure inside biodegradable microspheres during erosion.

PURPOSE: To measure changes in pH as well as osmotic pressure in aqueous pores and cavities inside biodegradable microspheres made from polymers such as poly(D,L-lactic acid) (PLA) and poly(D,L-lactic acid -co- glycolic acid) (PLGA). METHODS: The internal osmotic pressure inside eroding PLA microspheres was analyzed with differential scanning calorimetry (DSC) in a temperature range of 10 to--25 degrees C. The osmotic pressure was calculated from the melting peaks of the aqueous phase using purity analysis. For pH determination, PLGA microspheres were loaded with a pH-sensitive spin probe which allowed the determination of pH by electron paramagnetic resonance (EPR). RESULTS: The osmotic pressure in PLA microspheres increased to 600 mOsm within four days and decreased to 400 mOsm after two weeks. The pH in PLGA microspheres in this study was < or =4.7. Basic drugs such as gentamicin free base or buffering additives led to a pH increase. In no case, however, did the internal pH exceed a value of 6 within 13 hours. CONCLUSIONS: DSC and EPR are useful techniques to characterize the chemical microenvironment inside eroding microspheres. This data in combination with detailed information on peptide and protein stability could allow in the future to predict the stability of such compounds within degradable polymers.

Algorithms↗

PubMed1998

Labelling peptides with fluorescent probes for incorporation into degradable polymers.

Two peptides, atrial natriuretic peptide (ANP) and salmon calcitonin (sCT) were conjugated with a fluorescent, amine-reactive probe 5-(and 6-)carboxytetramethylrhodamine,-succinimidylester (5-(6)-TAMRA-SE). The labelling reaction was followed by HPLC and found to be complete after 2 h. The labelled peptides were purified by gel filtration chromatography and characterised by [1H]NMR, UV/VIS and fluorescence spectroscopy. NMR-spectra confirmed the conjugation of dye to the peptides. Two absorption maxima between 500 and 600 nm were recorded in the UV/VIS-spectra. The fluorescence spectra were found to be pH-dependent, which allowed the measurement of pH in aqueous solution. The labelled peptides were encapsulated into poly(lactic acid) (PLA) microspheres using a double emulsion technique. Probe attachment permitted location of the peptides in the polymer.

Atrial Natriuretic Factor↗

PubMed1997

Erosion of composite polymer matrices.

The erosion of composite polymer matrices made of slow and fast eroding polymers was investigated. These matrices can be used as implants that release drugs in a preprogrammed way. To understand the mechanism of drug release, the erosion of cylindrical polymer matrices made of several layers of different polymers was investigated. A layer of poly(D,L-lactic acid) was used to separate a core and a mantle consisting of poly(1,3-bis[p-carboxyphenoxy]propane-co-sebacic acid) 20:80. The investigation of the erosion mechanism revealed that erosion is a two-phase process. Wide angle X-ray diffraction and differential scanning calorimetry proved that the crystalline polymer parts of the polyanhydride layers above and below the polylactide erode one after the other. Concomitantly, sebacic acid accumulates periodically inside the matrix and leaves it in two phases. This agrees well with the release of brilliant blue and carboxyfluorescein, two model compounds, from such implants when incorporated into the polyanhydride layers. It can be concluded that the core of the composite implant erodes with a delay of 10-14 days because the polylactide protects it against premature erosion. Theoretical erosion models that were developed to simulate erosion support the proposed mechanism.

Biocompatible Materials↗

PubMed1997

Erosion of biodegradable block copolymers made of poly(D,L-lactic acid) and poly(ethylene glycol).

Biodegradable block copolymers made of poly(ethylene glycol) monomethylether (Me.PEG) and poly(D,L-lactic acid) (PLA) were investigated for their erosion properties. Wide angle X-ray diffraction (WAXD) and differential scanning calorimetry (DSC) investigations prior to erosion revealed that despite the low content of crystallizable Me.PEG of 10%, Me.PEG5-PLA45 is a partially crystalline polymer. The erosion of the polymer was investigated using cylindrical polymer matrix discs with a diameter of 8 mm and a height of 1.5 mm. WAXD and DSC spectra obtained from eroded polymer matrix discs suggest that both polymer blocks separate completely during erosion. The crystallinity of Me.PEG5-PLA45 was found to increase during erosion, which is probably due to the improved mobility of Me.PEG inside the polymer with a progressive degree of degradation. The erosion kinetics were found to be similar to that of PLA or poly(lactic-co-glycolic acid). During erosion the polymer matrix weight of dried samples remains constant for 11 weeks after which erosion sets in rapidly. From this observation one can conclude that the impact of the relatively small Me.PEG chains on Me.PEG5-PLA45 erosion is not pronounced. This is beneficial for all those applications that require the stability of the polymer matrix and in which the Me.PEG chain is intended to bring about other effects such as the modification of the surface properties of PLA polymers.

Biocompatible Materials↗