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Elevated intraocular pressure is the main risk factor for glaucoma and its adjustment to physiological levels can prevent progression of the disease. If conventional drop-based glaucoma therapy fails, surgical interventions such as trabeculectomy or the application of implants, which drain aqueous humour from the eye and thus reduce intraocular pressure, are used as final therapeutic procedures. These interventions are becoming increasingly minimally invasive and the drainage implants are getting steadily smaller, which is why these interventions are now called microinvasive glaucoma surgery (MIGS). Both, surgery and drainage implant-based glaucoma therapy are limited by wound healing processes and fibrosis that occlude the newly created drainage pathways for the aqueous humour. To suppress unwanted postoperative fibrosis coupled with an increased extracellular matrix production, cytostatics like mitomycin c or 5- fluorouracil are currently used, which are associated with side effects. Therefore, more specific antifibrotic agents are key for a durable functionality of the interventions in glaucoma therapy. In this study a specific active substance (pirfenidone, PFD) was added in a polymer matrix for controlled release. Previous studies have shown that the release of pirfenidone from a thermoplastic silicone polycarbonate elastomer, which could be used as a material for a glaucoma drainage implant, has been relatively fast. To decelerate the release the influence of the alternate polymers Poly-L-Lactide (PLLA) and Poly-D,LLactide (PDLLA) as alternative drug carriers was investigated. Furthermore, a reduction of the pirfenidone content was used to delay the release.

Degradable polymeric Biomaterials, such as polylactic acid, are widely used in medical field as bioresorbable implant coatings. More recently, stent covers, implantable tubes or wound dressings made from electrospun nanofibers have been developed. In order to tailor the material for specific applications, dedicated fine-tuning procedures are required. To modify fiber interconnection or porosity, solvents or their dilutions are applicable. In this work, the effect of differently diluted protic and aprotic-polar solvents on electrospun poly-L-lactic acid (PLLA) nonwovens was investigated via immersion or vapor exposure. Fiber adhesion was observed with protic solvents. Fiber destruction and increased polymer crystallinity was observed with aprotic polar solvents. The immersion duration revealed to be far more irrelevant than solvent dilution. None of the tested solvents affected molecular weight. This opens up significant research potential to replace halogenated solvents as a cornerstone of eco-friendly “green” electrospinning processes. The results of this study are suggesting that biomaterials with desired properties can be produced in a targeted manner.

One of the greatest challenges in the development of novel implants is to find materials that optimally interact with the tissue and support the function of the implant over a long period of time. Especially considering the fact that biomaterials are used in multiple applications in modern implants, a better understanding of the physiology of the tissue in contact with the material becomes more and more important. To better understand the cellular responses to biomaterials, it is furthermore necessary that the models used reflect the physiological conditions at the implant site. However, in most cases, immortalized cell lines instead of tissue-specific primary cells are used to study the biocompatibility of implant materials. When interpreting these results, it is important to consider that cell lines differ significantly from primary cells found in their native environment. In this study, we examined the morphological differences between a cell line and primary cells upon contact with various implant structures resembling implant prototypes. Using a mouse fibroblast cell line in comparison with primary porcine fibroblasts, we discuss the results with respect to the use of cell lines for biocompatibility testing of biomaterials. Our results suggest that to better estimate meaningful results regarding the compatibility of implant structures, key control experiments should always be performed with specific primary cells.

Implant-associated infections still must be considered as a major risk factor and represent a significant threat to the well-being of patients. The detection of such complications is often late, making therapy at this stage difficult. However, the common route of systemic antibiotic prophylaxis can be associated with numerous side effects on the patient or even lead to resistant strains of bacteria. In this context, local antibiotic drug load is a promising way to protect implants against pathogen adhesion and biofilm formation. This work addresses the incorporation of the antibiotic Doxycycline into a biodegradable nonwoven matrix as potential implant coating. While the nonwoven matrix itself displayed already inhibitory effects on Staphylococcus aureus (S. aureus) biofilm formation in vitro, this effect was even more pronounced by the incorporation of Doxycycline. Antibiotic loaded nonwovens display the possibility for local inhibition of biofilm formation. In the shape of an implant coating, this may further help to avoid implantassociated infections. Nevertheless, as pathogens vary in shape and type, further adjustments have to be performed to improve wide-ranging protective effects

Extrusion is a common manufacturing process for semi-finished polymer products in various biomedical applications. Extrusion enables processing of a wide range of biomaterials, as well as different cross-sectional geometries. Furthermore, feasibility of drug elution, as it is used for a variety of medical devices, for example microstents for minimally invasive glaucoma therapy, was assessed. The current study deals with manufacturing of polymeric microtubes by extrusion processing. Semi-finished products were made of biodegradable poly-L-lactide (PLLA) and a non-biodegradable polycarbonate-based silicone elastomer (SIL) and covered with a polymer/drug combination, with resveratrol as active ingredient. Three different concentrations of polymer/resveratrol were applied by means of spray-coating. The release behavior of active ingredient was analyzed in vitro at 37°C and showed a correlation between the amount of drug and release time. With higher drug content, a faster release was observed. In addition, the release from SIL was faster compared with PLLA.

One of the key aspects in the development of novel implants is to find suitable materials and understand the mechanisms that occur when a material is exposed to the tissues of the human body. These mechanisms are commonly referred to as the biocompatibility of the material. A better understanding of the tissue-material interactions becomes more urgent as biomaterials are used in wide-ranging applications like modern medical devices. However, most biomaterials used for implants are opaque, resulting in difficulties for the microscopical evaluation during in vitro biocompatibility testing. Particularly, cell morphology and adhesion capabilities of cells can provide insights in the interactions between implant materials and tissues at the implant site. To improve our capabilities in biocompatibility testing of novel biomaterials we applied a new method to quantitatively assess cellular parameters on opaque samples using fluorescence microscopy and bio-image analysis.

The novel concept of stenting the Eustachian tube was established to provide an effective and safe therapy of Eustachian tube dysfunction. Biodegradable polymer stents are being developed to restore impaired tube function. As the supporting effect may be required for different time periods, PLA-co-PEG copolymers, PLLGA, PDLLA and PDS, having shorter degradation times compared to PLLA, were evaluated as potential stent materials. Since tensile tests and thermal analyses of solvent cast films from PLA-co-PEG copolymers showed comparable properties to PLLA, stent samples were manufactured from these materials. Mechanical stent testing revealed an increase of elastic recoil and slight decrease of collapse pressure compared to PLLA. In a short term accelerated degradation study a considerable percentage molar mass reduction and an increasing degree of crystallinity depending on PEG content was found. Based on the results obtained, the tested polymers offer a promising, faster degradable alternative to the established stent material PLLA.

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.

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.

Electrospun fiber nonwoven materials of different polymer classes provide promising perspectives in almost all fields of application, including medical science. In this paper we present the fiber generation of selected biostable polymers (PBT, TPC-ET, PA 6.12 and PVDF) by direct electrospinning, as an extremely powerful tool for manufacturing of new superfiber implant materials. This initial study includes the variation of some relevant process parameters, such as polymer concentrations or electrode spacing. The influence on fiber morphology, tensile strength and biocompatibility is shown. The results presented indicate that the choice and combination of materials is crucial for the application on load-bearing implants, independent of the processing technology and thus of the fiber bonding, delamination or fiber strength.

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

Primary open angle glaucoma represents an eye disease that usually is associated with an increased intraocular pressure (IOP). Implants for micro-invasive glaucoma surgery (MIGS) are gaining importance as a promising option for IOP lowering. Currently available devices are implanted into the eye ab interno based on a clear corneal incision and drain aqueous humour into the schlemm’s canal, suprachoroidal or subconjunctival space. Fibrosis is known as a major limitation for long term success and often leads to the necessity of an additional medication or a surgical re-intervention. The current work focusses on the development of an antifibrotic drug-eluting coating for a minimally invasive implantable glaucoma microstent. Tubular microstent base bodies manufactured from a polycarbonate based silicone elastomer were spray-coated with a chloroform based mixture of the same polymer and the antifibrotic drug pirfenidone (PFD, P2116, Merck KGaA, Germany) in a polymer/drug ratio of 85/15% (w/w). Coating mass of 89 μg according to a drug loading of 1.96 μg mm-2 was aspired. Coating mass was measured using an ultramicrobalance (XP6U, Mettler-Toledo International, Inc., Switzerland). Glaucoma microstent prototypes with a drugeluting coating mass of (84 ± 19) μg (n = 12) were manufactured. Characterization by means of scanning electron microscopy (Quattro S, Thermo Fisher Scientific, FEI Deutschland GmbH, Germany) yielded a reproducible smooth surface of the coating. High performance liquid chromatography (KNAUER Wissenschaftliche Geräte GmbH, Germany) was used for analysis of drug release behaviour in 0.9% NaCl solution at 37°C. The in vitro PFDrelease is characterized by an initial burst phase of approximately 6 h followed by a more retarded release phase. The entire drug was released within 36 h (n = 3). Sterilization processing has a minor impact on drug release kinetics. Appropriate drug stability after sterilization could be proven. Future studies will focus on the antifibrotic properties of drug-eluting glaucoma microstents in animal studies.

Electrospinning is a method for producing fibrous polymer scaffolds that can be applied in drug delivery systems as well as for polymer-based implants. Biodegradable polymers for the purpose of cardiac tissue engineering are often applied as fibrous scaffolds for morphological mimikry of natural matrices but also drugeluting approaches are very promising. Hydrolytic degradation is one of the key parameters for successful application. The focus of our investigations is on monitoring accelerated in vitro degradation of electrospun nonwoven scaffolds. In the presented study degradation of poly(Llactide) is accelerated by alkaline hydrolysis. The process is characterized by weight loss, loss of molecular mass, surface morphology and thermal behavior of nonwoven samples, showing a fast degradation of the fibrous material within two weeks.

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.

The analysis of device drug content typically is carried out by means of chromatographic methods such as high performance liquid chromatography (HPLC) or liquid chromatography-mass spectrometry (LCMS). These approved methods are particularly fast, cost-efficient and ubiquitous in chemical-analytical laboratories. However, these quantitative methods necessitate the drug being eluted, which represents a destructive process. A novel alternative to these well-established methods [1, 2] is the Raman spectroscopy, which is fast and cost-efficient, as well [3]. Additionally, it offers the advantage of nondestructive analysis without the need for a special sample preparation. Within the current investigation we applied Raman spectroscopy for the qualitative and quantitative analysis of dexamethasone (DMS), a glucocorticoid, incorporated in a silicone matrix. The investigation was conducted in a rectangular area on the sample surface. The required number of measuring points (spectra) was determined. Calibration was performed with samples containing different amounts of DMS. The evaluation of Raman spectra is based on the analysis of the peak areas of the bands at 795 rel. cm-1(silicone) and 1,663 rel. cm-1(DMS). Remarkably, next to a precise overview of DMS distribution, an exact and reproducible quantification of incorporated DMS could be obtained.

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.

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.

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.

Drug coated balloons (DCB) are used in the therapy of coronary as well as peripheral artery disease. The success of drug transfer to the vessel wall depends on the excipient used in combination with paclitaxel as antiproliferative drug. Although in-vivo studies show very good results with this technology, there is a lack of in-vitro test methods for characterization of various DCB available on the market. This study describes a method to gain information about the drug transfer and the particle release of three different DCB based on cetylpyridinium salycate (Cetpyrsal), hyaluronic acid and iopromide within a porcine in-vitro model. The Cetpyrsal-based DCB showed promising results with the highest drug transfer while producing the lowest number of particles.

The particle generation of medical implants and drug coated balloons (DCB) is evaluated by simulating the implantation process and collecting the released particle material. In addition to size and particle counts their material composition is of interest. Raman spectroscopy and micros-copy are established methods for chemical identification. For the manual analysis of the particles different filter or rather background materials are suitable because different require-ments in height and intensity of the spectra can be compen-sated by the user. The aim of this study was to find suitable background materials for automatic particle identification.

Chemical identification of particles increasingly gains importance concerning regulatory affairs of medical devices. Particle numbers of samples very easily add up to orders larger than 1.000. Therefore an automated particle measurement is absolutely worthwhile. As a method of chemical identification Raman spectroscopy combined with microscopy is commonly used. The challenge is to distinguish small particles in a range of a few microns on a surface from the background. Different specimen holder made of glass, polymer (e.g. polycarbonate) or metal are commonly used. After the choice of suitable background parameters such as magnification, optical resolution, focal plane and brightness have to be optimized. The used software for Raman microscopy offers the possibility to select particles for the subsequent measurement. Therefore the xand y-coordinates of particles have to be added to a list manually and separately. This so called point list can be processed automatically. However, this procedure is very laborious and requires a high degree of user interaction especially in case of large particle numbers. Furthermore the software offers the possibility to perform a so called area scan, where a defined surface of the the specimen will be spectroscopically analyzed. The measurements are performed in defined distances on a grid, e.g. every 10 micrometer in xand y-direction. The choice of this tool leads to a large number of measuring points associated with an unwanted long measuring time. By means of the freely accessible software ImageJ an alternative path was found to relate xand y-coordinates to every particle. These coordinates can be imported into the point list of the software for Raman microscopy. Afterwards a Raman spectrum for every particle can be measured without further high effort in time.