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Filter membranes (pore size 0.2 μm) are frequently used to perform a sterile filtration. To characterize the pore size of filter membranes, a method to determine the particle retention of nanoparticles was defined. The Dynamic Light Scattering method was first analysed and calibrated to correlate the particle concentration with absolute intensity of scattered light. Afterwards, standard particle suspensions with particle sizes of 0.150 μm and 0.239 μm were lead through an infusion filter and the particle retention of the filter was evaluated by the determination of the original and the filtrated particle concentration. The test filter retained 91% of the smaller and 98% of the larger particles. Evaluating the particle retention with Dynamic Light Scattering could be a time saving method with lesser effort compared to existing methods.

Polycarbonate-urethane-co-silicone (PCU-Sil) are gaining increasing interest in biomedical application, such as drug delivery systems, coatings and combination products, due to their adjustable mechanical properties. They can be easily processed using a wide range of methods. Biocompatibility can be improved by surface modifications, such as coupling drugs, proteins, antibodies or polymer layers, which extends the range of biomedical applications. To generate additional coupling, the first step would be the generation of functional groups on the polymer surface using surface activations, such as plasma activation. In this context, the assignment of the functional groups is important, which can be done by XPS measurements. Within this study the analysis of the generated functional groups after oxygen (O2) plasma activation of two PCU-Sils was performed. In addition, the stability of the generated surface modification was evaluated after 24 hours. It was surprising that the generated groups were differently stable and also different groups were generated or rearranged over time, which would not have been recognizable if only contact angle measurements were used.

For the use of polymers as biomaterials in the production of implants, several processing methods are needed. Besides injection molding or Fused Deposition Modeling as temperature based processes, also solvent based processes were performed such as solvent-casting and electrospinning. As fabrication of medical devices makes use of potentially hazardous or toxic solvents, they have to be extracted from the final medical device. For analyses of residual solvents different methods can be used e.g. gas chromatography (GC), coulometric elemental analysis or thermogravimetrical analyses (TGA). Here we present first results for the use of X-ray photoelectron spectroscopy (XPS) to yield elemental as well as spatial information on residual solvents in polymeric materials. Therefore we analysed PLLA as biodegradable electrospun polymer, TPC-ET as biostable polymer and a PLLA-iron composite as example of a polymer metal composite via XPS and etching processes. It was possible to determine residual halogen containing solvents in all tested polymers processed from polymeric solution. As discrimination between polymer and solvent was made possible by specific elements, XPS measurements may be a suitable tool to identify even small amounts of solvent. Thus XPS analyses will help to optimize polymer processing in order to remove residual solvents.

Hydrogels are 3D polymeric networks, which exhibit properties such as softness, viscoelasticity and their ability to absorb large amounts of water. These characteristics make them exceptionally suitable in biomedicine as e.g. tissue scaffolds, drug delivery systems, wound dressings or contact lenses. One of these hydrogels is the biocompatible, hydrophilic and photopolymerizable poly(ethylene glycol) diacrylate (PEGDA). It is used in different biomedical applications due to its tunable mechanical characteristics. In our study, the mechanical properties of different PEGDA hydrogel compositions with variyng molecular masses and contents of water/methanol, were investigated. Different compositions containing 20 m%, 30 m% or 40 m% of PEGDA4K(4,000 g/mol), PEGDA10K(10,000 g/mol) or PEGDA20K(20,000 g/mol) in ultrapure water/methanol (1:2) were produced. Dumbbell-shaped samples were prepared in molds via photopolymerization in a UV chamber. Lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP) was used as photoinitiator (0.5% w/w). The mechanical testing was performed using a uniaxial testing system. The obtained results showed averagely 78% higher tensile strength (σmax) values for 30 m% and 40 m% samples in comparison with 20 m% samples for all of the tested polymers. PEGDA20K30 m% samples showed the highest σmax among all of the samples with 12.8 MPa. All of the PEGDA20K samples exhibited the highest elongation at break (εB) values (up to 958%), whereas the lowest values were found for PEGDA4K(up to 105%). The obtained stress-strain curves for most of the samples were typical for deformable, amorphous polymers with a deformation upon reaching a critical stress point. The PEGDA materials showed variable mechanical characteristics according to changing molecular mass or polymer concentration. These promising results showed that it should be possible to compose scaffolds with desired mechanical stability according to the needed application.

Several physico-chemical modifications have been developed to improve cell contact with prosthetic oral implant surfaces. The activation with non-thermal plasmas was one option. Previous studies found that gingiva fibroblasts on laser-microstructured ceramics were hindered in their migration into cavities. However, after argon (Ar) plasma activation, the cells concentrated in and around the niches. The change in surface properties of zirconia and, subsequently, the effect on cell behavior is unclear. In this study, polished zirconia discs were activated by atmospheric pressure Ar plasma using the kINPen®09 jet for 1 min. Surfaces were characterized by scanning electron microscopy, X-ray photoelectron spectroscopy (XPS), and water contact angle. In vitro studies with human gingival fibroblasts (HGF-1) focused on spreading, actin cytoskeleton organization, and calcium ion signaling within 24 h. After Ar plasma activation, surfaces were more hydrophilic. XPS revealed decreased carbon and increased oxygen, zirconia, and yttrium content after Ar plasma. The Ar plasma activation boosted the spreading (2 h), and HGF-1 cells formed strong actin filaments with pronounced lamellipodia. Interestingly, the cells’ calcium ion signaling was also promoted. Therefore, argon plasma activation of zirconia seems to be a valuable tool to bioactivate the surface for optimal surface occupation by cells and active cell signaling.

Sterilization processes ensure sterility of drug delivery systems, but may negatively affect the properties of biomaterials and incorporated drugs by changing their physical, chemical, mechanical properties and drug release behaviour. Therefore, it is important to investigate their influence. In this study, the influence of ethylene oxide (EtO) sterilization on the drug loading and release behaviour of incorporated Diclofenac (DCF) in a Poly-L-lactide (PLLA) coating and Dexamethasone (DMS) in the silicone carrier is presented. Silicone samples containing DMS were coated with PLLA containing DCF varying in layer thickness (5, 10, and 20 μm). Half of the samples underwent EtO sterilization, the other half was not sterilized. All un-/sterilized sample surfaces were in view of the morphology and hydrophilicity examined. Furthermore, in vitro release studies of DMS and DCF were conducted. The sterilized sample surfaces showed no morphological and hydrophilicity changes. The DCF and DMS loadings were similar for the sterile and untreated samples. This also applied to the in vitro DMS release profiles apart from the end of the studies where slight differences were evident. The results indicate that both drugs loaded in the polymer coating and the silicone were not impaired by the sterilization process. Thus, EtO sterilization appears suitable for DMS containing silicone and DCF incorporated PLLA coatings as a dual drug delivery system.

Drug delivery systems (DDS) are suitable for controlled local drug release in order to ensure safety and effectiveness of medical treatment. The choice and characterization of biomaterials that can be used as a DDS is a challenging step in the administration of drugs. Novel 3D printing photopolymerization-based techniques create the possibility for designing individual, patient-tailored DDS. Poly(ethylene glycol) diacrylate`s (PEGDA`s) chemical and biological properties make it a suitable photopolymerisable resin for the creation of DDS. This study describes the in vitro release of the antiseptic drug chlorhexidine (CHX) from UV-cured PEGDA and its copolymers (butanediol diacrylate, pentaerythritol triacrylate and pentaerythritol tetraacrylate) samples. A substantial decrease in CHX release with increasing concentration of the copolymers in comparison to pure PEGDA was obtained only for butanediol diacrylate. For pentaerythritol triacrylate and pentaerythritol tetraacrylate only a tendency of decreased CHX release with increasing concentration was detected. Therefore, release profiles of the low molecular drug CHX from PEGDA samples could be modified by the addition of copolymers with a different number of acrylate groups and PEGDA can be considered as a promising candidate for the preparation of novel DDS.

For the development of combination products, the determination of the release kinetics of polymer-based drug delivery systems (DDS) is a central and often timeconsuming investigation. Classical methods are often unsuitable for large-scale screening of potential polymers for combination products. We present a rapid method based on surface plasmon resonance spectroscopy (SPR), using PEGDA700 (Poly(ethylene glycol) diacrylate, average molecular weight (Mn) 700) as an example. This method is capable of determinating the kinetics of drug association and subsequent release within minutes. The proportion of desorption and diffusion can be determined separately. Surface plasmon resonance spectroscopy (SPR) is a label-free and very sensitive optical technique, which allows for real-time observation of surface interactions. The prepared SPR chips were spin-coated with PEGDA700 and crosslinked via photoinduced polymerization. The association and dissociation kinetics of dexamethasone phosphate in swollen PEGDA700 have been studied at different concentrations. The maximum loading of the surface was also obtained by this method. The study of PEGDA presented here identified the wellestablished SPR-based spectroscopy as a potential tool in the development of combination products.

Analysis of the active ingredient distribution of medical devices is typically performed using Raman spectroscopy, a method that is fast and inexpensive [1]. In addition, it offers the advantage of non-destructive analysis without the need for special sample preparation. Assuming that all components are Raman-active and present in sufficient quantities, their distribution can be well represented. The drug distribution in dexamethasone-loaded polymer nonwovens was investigated in order to draw conclusions on the quality of the fleece batches and to make predictions for the release behavior. In the present study, dexamethasone (DMS), a glucocorticoid was used as the active ingredient. Qualitative and quantitative studies of the content of DMS in polymer films by means of Raman spectroscopy have already been carried out in the working group [2]. A representative square section was examined to describe the distribution of active ingredients. The required number of measurement points (spectra) was determined earlier [2].

Photopolymerizing, high-resolution 3D printing methods such as Stereolithography (SLA) or Digital Light Processing (DLP) are very promising for the manufacturing of drug-incorporated, patient specific implants. However, a drug-load may be limited by adequately solubility of the active pharmaceutical ingredient (API) in the photopolymer. Furthermore, a drug-load may affect the mechanical properties of the material negatively. Here, we investigate the DLP 3D printing of drugincorporated photopolymers. Polyethylene glycol diacrylate (PEGDA, Mn = 700 g/mol) is used as matrix polymer and Dexamethasone (DEX) is used for drug-loading (10 g/L and 20 g/L). Compressive properties, drug release and drug stability of 3D printed test samples were analyzed. DEX was found to be sparingly soluble in the PEGDA-based photopolymer. Not all drug particles can be dissolved at a concentration of 20 g/L and a slurry-like suspension is formed. Drug-incorporated photopolymers of 10 g/L (solution) and 20 g/L (suspension) were processed successfully via DLP. The higher the drug-load, the lower the compressive strength. Mechanical properties can be improved via a post-curing in a UV light curing box. Drug-incorporated 3D printed test samples show burst-release of DEX. The post-curing process does not affect drug release. DEX degrades in 3D-printed test samples significantly (~ 30 %) over a several days time period.

The use of biomaterials in medicine is becoming increasingly important. One of the main concerns is the foreign body associated infection caused by direct microbial contamination or clinical infections. The bacterial biofilm formation on biomaterials depends on their surface properties. Therefore, several anti-adhesive surface modifications were developed. Nevertheless, the demand for antimicrobial agents that prevent bacterial colonisation is still largely unmet. The immobilization of active antimicrobial agents, such as antibacterial peptides or enzymes, offers a potential approach to achieve long-lasting effectiveness. In this investigation, the hydrolytic enzyme papain with its published antibacterial activity was covalently immobilized on the well-established biodegradable biomaterial poly-L-lactic acid (PLLA). For the characterization of the enzymes on the PLLA surfaces, the protein content and enzyme activity were determined. A biofilm assay was performed to test the effect of the papain-modified PLLA samples on the biofilm-forming bacterial strain Clostridioides difficile, one of the most frequently occurring human nosocomial pathogens. The investigated hydrolytic enzyme papain could be immobilized by coupling via the crosslinker EDC to the PLLA surface. Detection was performed by determination of the amount of protein and the reduced biofilm growth after 24 h and 72 h compared to the reference.

In this study, initial experiments are presented regarding the suitability of polyester based nonwoven composite materials for guided tissue regeneration based on degradation. The in vitro degradation of poly(lactic-coglycolic acid)/polydioxanone and polycaprolactone/ polydioxanone mats has been performed under accelerated condition in alkaline glycine buffer at 50 °C for 21 days. The degradation of the materials has been characterized regarding total mass loss and macroscopic morphological changes, as well as determination of the molecular weight degradation via GPC experiments.

In recent years, nanofiber based materials have emerged as especially interesting for several biomedical applications, regarding their high surface to volume ratio. Due to the superficial nano- and microstructuring and the different wettability compared to nonstructured surfaces, the water absorption is an important parameter with respect to the degradation stability, thermomechanic properties and drug release properties, depending on the type of polymer [1]. In this investigation, the water absorption of different non- and plasma modified biostable nanofiber nonwovens based on polyurethane, polyester and polyamide were analysed and compared. Also, the water absorption by specified water wetting, the contact angle and morphology changes were examined. The results show that the water uptake is highly dependent on the surface modification and the polymer composition itself and can therefore be partially changed.

Individually tailored drug delivery systems (DDSs) are considered one of the most promising therapeutic tools for the creation of safe and effective treatments. DDSs as a novel approach should be beneficial in curing systemic as well as local ailments, where a high topical concentration of the drug and a reduction of side effects are desirable. It could also be favorable for patients requiring customized treatments, showing atypical profiles of drug metabolism. Development of particular drug delivery devices require the selection of a suitable scaffold material, which should exhibit proper mechanical and biological properties, but also enable adjustment of the drug release according to a specific need. Thus, it is extremely important to expand the knowledge concerning potential DDS components. Poly(ethylene glycol) diacrylate (PEGDA) according to its properties can be easily used as a DDS resin and shaped into a desired structure with the employment of techniques based on photopolymerization, including some novel 3D printing techniques. As a continuation of our previous works, in this paper drug release studies from conventionally prepared PEGDA scaffolds are presented. We have shown that in PEGDA materials, the release profile of the low molecular weight model drug acetylsalicylic acid can be altered by water content. PEGDA as a delivery material should be further investigated to specify its potential as a comonomer and a matrix for pharmaceutical agents.

The degradable polymer Polydioxanone (PDO) is used for medical implants since 1981. Manufacturers state a degradation timeframe of

In this work ion functionalized hydrogels as potent drug delivery systems are presented. The ion functionalization of the hydrogel enables the retention of ionic drug molecules and thus a reduction of burst release effects. Timolol maleate in combination with polymerized anionic 3-sulfopropylmethacrylate potassium and ibuprofen combined with cationic poly-[2-(methacryloyloxy)ethyl] trimethylammonium chloride are investigated in respect to their drug release profile. The results are showing an ion exchange depending release behavior instead of a diffusion-controlled drug release as it is known from common drug delivery systems. Furthermore, the suitability of such hydrogels for standard methods for sterilization is investigated.

The large pool of naturally occurring carbohydrates with their diversity in chirality and structure led to the idea of a systematic investigation of carbohydrate based ILs. To this end, we investigated the influence of different ether groups, mainly methyl or ethyl ether, on the secondary OH groups as well as different configurations on physical properties such as melting point, thermostability and especially the influence on cell toxicity. For this investigation we chose α- and β-methyl-, β-allyl- and β-phenyl d-glucopyranose as well as four 1-deoxy-pentoses. In order to be able to classify the results, more ionic liquids with different structural motives were examined for cytotoxicity. Here, we present data that confirm the biocompatibility of such ILs consisting of naturally occurring molecules or their derivatives. The synthesized carbohydrate based ILs were tested for their suitability as additives in coatings for medical applications such as drug-eluting balloons.

During the last years substantial effort was taken in order to provide an effective and safe pharmacotherapy that can be adjusted to the individual needs of patients. Stereolithography is a simple and accurate additive manufacturing technology. According to these characteristics, it may offer unique opportunities for the industrial fabrication of structured drug delivery systems (DDS), which can be tailored to individual needs. During the stereolithographic process photopolymerizable biomaterial is transformed, layer by layer, into the designed polymer DDS. Combined with inkjet printing in an innovative 3D building system it enables selective and precise incorporation of the drug depot into the basic body of the DDS. Poly(ethylene glycol) diacrylate (PEGDA), a hydrophilic and low-immunogenic compound, is a suitable material as drug depot in a photopolymerizable basic biomaterial for this purpose. By combination of PEGDA with other acrylates, the physical properties of the DDS can be adjusted towards the desired characteristics. Therefore, it should be possible to modify the drug release profile through the positioning of drug depots and the diffusion of the drug and adjust it for a wide range of applications. In this study we investigated basic biological and thermodynamic properties of conventionally photocured systems consisting of PEGDA and its coacrylates: 1,3-butanediol diacrylate and pentaerythritol triacrylate. Our preliminary outcomes demonstrate the hydrophilic character of the samples and the importance of a rinsing process. They also show that the addition of different amounts of co-monomers influence the glass transition temperature, which increases with increasing content of coacrylate. Therefore, PEGDA/comonomer composition can be used as a tool for the modification of drug release properties. Consequently, these materials may be regarded as interesting and promising components for DDS via novel additive manufacturing with the ability of highly controlled drug release.

Electrospun poly(L-lactide) (PLLA) nonwoven represent potential options for biodegradable medical implants. They can be manufactured with high reproducibility and do offer the potential for chemical modification to alter matrix properties. In our study, we investigate the mechanical, thermal and morphological properties of PLLA fiber matrices. Fibrous nonwovens were fabricated from polymer solution by needle electrospinning. The polymer solutions were loaded with Triton X-100 (TX- 100), formic acid and tetraethyl ammonium chloride (TEAC) with respect to polymer weight. Morphology of the PLLA nonwoven scaffolds was examined with SEM. We performed uniaxial tensile tests and differential scanning calorimetry (DSC). Different concentrations of the additives TEAC, formic acid and Triton X-100 lead to strong changes regarding mechanical and thermal properties of the electrospun PLLA fiber matrices. In comparison with mechanical properties of established biological tissue materials, the results indicate the suitability for medical applications.

Current research activities focus on personalized, comfortable and safe products for systemic or local drug application in patients. Poly(ethylene glycol) diacrylate is in particular interest as a drug delivery material, as it shows appropriate biological properties such as hydrophilicity and low toxicity. Additionally, as an easily photopolymerizable compound it can be also utilized for the production of scaffolds with the use of different techniques such as stereolithography. Even though it is often used as a biomaterial or as a copolymer in many photopolymer systems for drug delivery, thermomechanical analysis and basic understanding are rare. Therefore, we investigated the tensile stress and the glass transition temperature of pure PEGDA and of its copolymers with 1,3-butanediol diacrylate or pentaerythritol triacrylate, as a function of the photoinitiator (PI) or acrylate concentration. Additionally, we demonstrated that the washing procedure decreases the tensile stress values. We showed, that by the means of composing PEGDA with these, it is possible to influence thermomechanical properties of the sample. Our outcomes have revealed, that there is no clear influence of the PI concentration on the thermomechanical properties. However there is an influence of the monomer concentration. Therefore, it should be possible to modify drug release profiles in future experiments.

Polycarbonate urethane and polyether urethane nonwovens as promising representatives of novel polymer heart valve materials were analysed regarding the susceptibility to calcification in comparison to porcine pericardium and polyamide 6. The applied method represents an accelerated calcification out of a metastable solution in short time with significant precipitates on the reference material. As our results show, urethane based nonwoven structures exhibit considerably lower susceptibility to calcification compared to pericardium as widely established material for leaflet design.

Three-dimensional (3D) printing has become a popular technique in many areas. One emerging field is the use of 3D printing for the development of 3D drug delivery systems (DDS) and drug-loaded medical devices. This article describes a novel concept for the fabrication of timecontrolled drug delivery systems based on stereolithography combined with inkjet printing. An inkjet printhead and an UV-LED light source have been integrated into an existing stereolithography system. Inkjet printing is used to selectively incorporate active pharmaceutical ingredients (API) during a stereolithographic 3D printing process. In an initial experimental study, poly (ethylene glycol) diacrylate (PEGDA) was used as polymer whereas 2-Hydroxy-4´-(2- hydroxyethoxy)-2-methylpropiophenone (Irgacure 2959) and Lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP) were used as photoinitiators. Basic structures could be manufactured successfully by the new hybrid 3D printing system.

Sirolimus incorporated nonwoven polymer matrices were fabricated via electrospinning. Release kinetics considering different fiber diameters and layer thicknesses were investigated. In vitro drug release profiles were evaluated by measuring the drug concentration in an established drug release medium (0.9% saline solution with additives, not buffered) at predetermined time points. Furthermore, an NH3-plasma pretreatment was examined to ensure complete wetting from the beginning of the study. In comparison to thin drug-loaded PLLA spray coatings it was shown that the release of sirolimus is diffusion- and degradation-controlled regardless of the surface-to-volume ratio, though fiber diameters or a hydrophilization can affect its release kinetics.

Simultaneous electrokinetic and hydrodynamic injection of rapamycin (sirolimus) with off-line and online sample preconcentration techniques and using MEKC has been studied. Compared to conventional hydrodynamic injection, a 168-fold improvement in the signal was obtained with a combination of simultaneous electrokinetic and hydrodynamic injectionand field enhanced sample injection in conjunction with a sweeping technique called sequential stacking featuring sweeping. However, the coupling of the developed electrophoretic method and solid-phase microextraction allowed the signal intensity to increase more than 231 times. In this approach, the injection of the sample at negative polarity (anode at the detector end) into the capillary and the MEKC separation was achieved within 5 min using an electrolyte (composed of 10 mM sodium tetraborate and 40 mM SDS) when ultraviolet (UV) detection was performed at 280 nm. Thus, by combining the application of the sequential stacking featuring sweeping supported by the solid-phase microextraction clean-up procedure, the detection limit (LOD) for rapamycin in a serum sample was significantly decreased, and was set at 25 ng/mL. The proposed combined simultaneous electrokinetic and hydrodynamic injection with field enhanced sample injection -sweeping technique following MEKC separation of sirolimus in human serum could be an effective tool in biomedical and clinical applications.

Resveratrol is a member of stilbenoids with promising anti-atherosclerotic properties. This hallmark makes it an extremely interesting candidate for local drug delivery to damaged tissue adjacent to the implant in order to reduce implant-related complications. For the regulatory approval drug-eluting medical devices have to be thoroughly tested for safety, efficacy and interactions with the surrounding tissue, including tests for sensitization among others. Studies for sensitization help to estimate the risk for an allergic reaction upon prolonged exposure to a chemical compound. Due to increased social and regulatory demand for replacement of animal experiments by in vitro approaches a number of reliable predictive non-animal tests have been developed. Here, we assessed the skin sensitization potential of resveratrol by the direct peptide reactivity assay (DPRA), one of the first non-animal tests adopted by the OECD.

Insertion of a cochlear implant (CI) into the scala tympani evokes electrode insertion trauma that can result in mechanical damage of the lateral and medial wall and causes ingrowth of fibrous tissue on the implant surface. In consequence, it is of great clinical interest to modify the silicone surface of CI electrodes in order to inhibit and minimize the overgrowth by connective tissue. In this case, the covalent coupling of bifunctional polymers on common CI silicone surfaces is a versatile method to influence the implant cell interaction, but is still a challenge due to the chemically unreactive properties of silicone. We present a sophisticated method to apply a biodegradable polymer coating, such as polylactide or polyhydroxybutyrate, on silicone surfaces to generate a drug delivery system using a covalently bound intermediate layer. The adhesive coatings were applied via spincoating processes with different adherence to the intermediate layer. Changes in surface morphology were investigated by comparison of pure silicone and coated silicone. Specific polymer bands of the infrared spectra were detected by IR spectroscopy. Results indicate a complete coating with polylactide or polyhydroxybutyrate. The presented method is a versatile tool for the coating of silicone CI electrodes with degradable polymer layers.

The generation of electrospun nonwovens from polyimide (PI) is challenging as the fibers are prone to distinct delamination. In consequence, the resulting nonwoven material has particularly low structural integrity and loose fibre interlocking, demanding for a follow-up treatment, such as high temperature thermal treatment. In this work, a facile method for a post-processed treatment of PI nonwoven is presented in order to obtain a mechanically stable material while maintaining the characteristics of the electrospun nonwoven. The procedure was performed using a solution of EDA in methanol at 37 °C and ambient pressure to achieve a modified fiber interaction. Overall, the developed protocol opens new possibilities in the processing of PI into delamination-free nonwovens. Potential adverse effects of a high temperature thermal treatment are being avoided, and new applications in the field of medical devices may become accessible.

On the protection of animals used for scientific purposes, the EU Parliament adopted Directive 2010/63/EU. The essential factor is the 3R principle: Replacement, Reduction and Refinement. In 2013, the third amendment to the German Animal Welfare Act was revised and adapted to the European Directive. The majority of animals in science are used in basic research, as well as in translational and applied research. In medical research, animal experimentation is conducted to clarify previously unknown life processes and basic biological relationships, in order to improve diagnostics and treatment of human diseases. Before an animal experiment can be performed, it must be reported to and approved by the responsible authorities. The planned research project must be justified scientifically, and it must be demonstrated that the personnel and spatial/ technical prerequisites are in place to successfully complete the project. If all conditions are met, the approval can be granted, but may be subject to conditions. The guiding principle of essentiality also affects the procedure of the experiments: The number of animals used and the pain, suffering and damage caused to these animals must be limited to what is absolutely necessary. In this context, the 3R principle has to be applied. To obtain reliable results, it is essential that the laboratory animals are in normal physiological conditions and free of pain and fear. Scientific interest and animal welfare are therefore not in opposition, but rather mutually dependent. In our GLP (Good Laboratory Practice) laboratory we test new drug release systems for different biomedical applications in rabbits after careful selection of the animal model. Stress during animal experiments must be avoided as far as possible. Providing pain-killers and ensuring the best possible husbandry and care conditions are crucial for the animal’s wellbeing and absence of pain and anxiety. In the present work we report our different experience in a GLPcertified biomaterial test laboratory.

Drug Delivery Systems (DDS) are frequently operating in a surrounding liquid environment, such as blood in the case of drug-eluting stents or perilymph in the case of cochlear implants. However, there is also a demand for systems with sustained drug release in predominantly dry environments, mostly consisting of ambient air. Examples are the treatment of diseases located in the middle ear or the paranasal sinuses. On the one hand, due to the lack of transportation media, the functionality of a polymer/drug combination for delayed release would be limited in such environments. On the other hand, these environments are generally equipped with mucus membranes. Hence, a somewhat humid surrounding is ensured. In this study, a concept of a hydrogel equipped DDS for drug delivery through the round window membrane is presented, addressing two objectives. First objective is to ensure the drug transport by serving as a diffusion channel. For instance the route to the drug target destination, the round window membrane, can be provided by a hydrogel. The second objective is to ensure the adhesion to the membrane. Two promising approaches are presented in this study: The photo induced immobilisation of PEGDA700, as well as the immobilisation of chitosan on poly(l-lactid) (PLLA). For both approaches PLLA specimen had to be modified with oxygen plasma followed by activation for crosslinking with subsequent immobilisation of the hydrogel. With these methods a layer thickness of at least 5 μm was achieved. All steps were characterized with contact angle measurements. After the immobilization of the hydrogel, the swelling factor, as well as the layer thickness was examined.

Implants that feature a drug delivery system loaded with antifibrotic active drugs provide a promising approach to address postoperative complications caused by fibrosis. This study is intended to clarify whether Actinomycin D has an impact specifically on components of the extracellular matrix (ECM) and its formation in human primary fibroblasts of the Tenon capsule (hTF). Furthermore, the suitability of this agent in poly(N-vinylpyrrolidone)- poly(methylmethacrylate)(PVP-co-PMMA) as a drug delivery model is evaluated in drug incorporation and release studies. RT-qPCR revealed a significant downregulation of the fibrotic marker genes ACTA2, COL1A1 and FN1 in cells stimulated with TGF- β1 and additionally treated with Actinomycin D. However, these findings could only be confirmed on α- SMA protein level. collagen I and Fibronectin synthesis stayed unaffected. The diffusion based incorporation of Actinomycin D into the polymer model proved to be very effective. The release of the agent was retarded with a slightly prolonged kinetic. These findings make Actinomycin D a promising antifibrotic agent in ophthalmic implant surgery.

Plasma enhanced chemical vapor deposition is a promising process for the generation of tailor-made polymer coatings on medical devices in order to improve their implant/ host interaction. The ultra-thin coatings can fulfil a variety of purposes, depending on the monomers used, the process conditions and the location of the coated implants in the human body. In addition, even complex geometries can be coated easily and without the application of solvents. Particularly hydrophilic and hydrophobic plasma polymer coatings can improve biocompatibility, especially in blood contact. Furthermore, the selection of the monomers used enables the generation of specific functional groups for further surface immobilization of drugs, such as proteins, by chemical crosslinking. The release of toxic residues from polymeric implants, such as monomers, additives or degraded components, can also be avoided. The aim of our investigation was the generation of plasma polymer films, their characterization and application as coatings for biodegradable metallic biomaterials in order to retard the degradation process. Metallic biomaterials, in various forms are frequently used in orthopaedics, dentistry, cardiovascular and neurosurgical equipment, because of their tensile strength, fracture toughness, fatigue strength and electrical conductivity. Plasma polymerization was performed using the monomers hexamethyldisiloxane and allylamine. The resulting plasma polymers were analysed in an accelerated degradation test. Both plasma polymers appear to be promising, while polyHMDSO appears to degrade over time and polyallylamine indicates to be stable.

The technology of pharmaceutical drug delivery systems (DDS) as an individual and adjustable tool for drug administration has been intensively developed in the last years. Additive manufacturing (AM) techniques, such as stereolithography, are a promising approach towards DDS scaffold manufacturing. Stereolithography, by using layerby- photo-polymerisation, creates DDS scaffolds with highly controlled 3D geometry. Combined with inkjet printing it allows a very precise positioning of the drug depot in the basic scaffold and therefore also a better control of the drug release. Furthermore, this hybrid AM technique also allows for the creation of a multi-drug DDS with a several drug depots localized in desired positions within the scaffold. Determination of the scaffold and drug depot material properties is one of the initial steps for such novel DDS development. Basic characteristics, such as stiffness, elasticity or glass transition temperature (Tg), are important for designing and adapting the material for biomedical application. The photosensitive poly(ethylene glycol) diacrylate (PEGDA) can be easily formed into a desired biocompatible scaffold geometry via stereolithography. In this study we have focused on the evaluation of PEGDA (Mn=700 g/mol) as a pure and copolymer system in combination with other acrylates (butanediol diacrylate, pentaerythritol triacrylate) as possible materials for DDS using this novel hybrid AM technique. Irgacure 2959, a biocompatible photoinitiator (PI), was used as a radical starter for photopolymerisation. Samples varying in PI and coacrylate concentration were prepared by conventional photopolymerisation. Physico-chemical analyses of the samples were performed and several parameters, such as stiffness, elongation at break and glass transition temperatures, were determined.

Local drug delivery systems (DDS) have become a favourable approach for the treatment of numerous diseases. Biomedical imaging techniques such as ultrahigh field magnetic resonance imaging (UHF-MRI) offer unique insight into DDS biodegradation in vivo. We describe the establishment of a 7 Tesla MRI routine for longitudinal in vivo examinations of a subconjunctival DDS for the treatment of glaucoma in a rabbit model. In initial in vitro examinations the T2-relaxation times of the polymeric DDS components were assessed. Imaging of enzymatically degraded depot samples in vitro did not reveal changes in sample morphology or T2-relaxation time. Ex vivo investigations with an enucleated porcine eye showed good correlation of anatomical MRI and histological data. In longitudinal in vivo studies in rabbits, we repeatedly scanned the depot in the same animal over the course of 5 months with an in-plane resolution of 130 µm at scan times of less than 30 minutes. The degradation was quantified using volumetric analysis showing a volume reduction of 82% between 3 and 21 weeks after depot implantation. We have thereby demonstrated the feasibility of our UHF-MRI protocol as a non-invasive imaging routine for qualitative and quantitative, longitudinal evaluation of biodegradable subconjunctival DDS.

Polymer nanoparticles (NP) are of escalating interest for their application as immune stimulatory pharmaceutics. The production of nanosized carrier systems is currently being widely investigated, but commonly used techniques, such as the double emulsion technique, are limited by shortcomings of low encapsulation efficiency and poor control over size distribution. In this study, the electrospray technique was successfully implemented and optimized to produce monodisperse 200-nm poly(lactide-co-glycolide) (PLGA) NP. For cytomegalovirus (CMV) pp65 and IE-1 peptides, a consistent encapsulation efficiency of approximately 85% was achieved. In vitro stimulation of peripheral blood mononuclear cells (PBMCs) from CMV+ donors using electrosprayed pp65489-503 peptide-loaded NP revealed a significantly increased proliferation rate and frequency of antigen-specific CD8+ T cells as compared to the soluble peptide. The results of this study demonstrate the suitability of the electrospray technique for production of monodisperse PLGA NP with high drug encapsulation efficiency as promising peptide-based vaccine carriers.

Implant-based drug delivery necessitates a rigorous quantitative assessment and quality control of the drug release behavior. In this context, a fast simultaneous UV-VIS spectrometer quantification method was developed for an antibiotic dual drug system. Particular challenges arose from interfering spectra, as well as different solubility and stability of the drugs. The test system used here consists of the antibiotics Minocycline and Rifampin, which are used as an antibiotic combination approach in a growing number of device applications, such as impregnation of venous or urethral catheters. Two suitable wavelengths for this test system were identified. At a wavelength of 475 nm only Rifampin shows an absorption maximum, which was used to determine the concentration of Rifampin in the mixture. At 245 nm both antibiotics have a local extremum, a maximum for Minocycline, and a minimum for Rifampin. The developed UV-VIS spectrometer method for Rifampin and Minocycline dissolved in Sörensen buffer showed good results for small concentrations of Minocycline. For stability tests, a mixture of both antibiotics (1:1) was stored at 37°C for up to 144 h in NaCl solution (0.9%), and in Sörensen buffer, respectively. At defined time points, UV-VIS spectra were recorded, and feasibility of this quick simultaneous quantification method for these two widely used antibiotics was demonstrated.