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Implant-associated infections remain a challenge in biomedical engineering and prevention of such complications is a topical subject. For that, local drug delivery is associated with a number of advantages over systemic antibiosis. In this context, incorporation of antibiotic drugs into fibrous nonwovens is a promising approach for the generation of antiinfective implant envelopes or wrappings. Such materials can be manufactured in large scale and electrospinning process is suitable for a wide range of drugs to be incorporated. With regard to increasing numbers of pacemaker implantations and associated risk factors for infections, biodegradable ceftriaxone loaded poly(L-lactide)-co-poly(ethylene glycol) (PLLA-co-PEG) nonwovens have been characterised concerning the influence of the drug on morphology, thermal and mechanical properties and drug release behaviour. Our results show that the chosen material combination is promising for further approaches towards an antiinfective nonwoven pacemaker envelope.

Various manufacturing techniques are available for polymer stent fabrication. Polymer semi-finished products can be prepared using solvent based methods, e.g. dip coating, as well as thermal processes, e.g. extrusion. These different methods may lead to an altered polymer crystal structure, resulting in a different deformation mechanism during mechanical stress. For the material property characterization needed for implant development, the test specimens usually are prepared using laser-cut or die-cut methods. Due to these different preparation protocols, a change in polymer microstructure, causing a material property variation, may also result. For this purpose, comparison of laser-cut versus die-cut of PLLA films has been performed. PLLA films have been prepared by dip-coating and were evaluated with respect to structural, thermal, and mechanical properties. In this study, a combination of uniaxial tensile tests, SEM and DSC studies was used. The results of the mechanical tests showed drastic differences in the elongations at break of die-cut specimens compared to laser-cut ones. The results point out formation of complex crystal structures during the manufacturing process. By the use of SEM imaging and DSC measurements, we were able to attribute these changes to the different plastic deformation mechanisms.

Uniaxial tensile tests are the most common method for investigating the mechanical properties of materials. However, due to the small strength and size of certain materials, larger conventional universal testing machines are sometimes not suitable for performing elongation testing, so dedicated test setups are required. Therefore, the authors developed a testing device to measure the mechanical properties of small, flexible materials, e.g. fragile specimens of the capsular bag of the eye. Also different variants for specimen holders were designed and tested. Initial tests using eggshell membranes as a model material demonstrated the functionality of the test setup at different strain rates.

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.

A diagnostic medical tool is described that allows patients to non-invasively observe, describe and document their own retinal blood vessels using the Purkinje vascular entoptic test. We envision key applications of the Purkinje retinal image stabilization (PRIS) device in monitoring of diabetic retinopathy and cost-effective assessment of retinal visual acuity. To optimize our PRIS principle, we have developed a benchtop device with interchangeable light modules. The modular design is intended to provide maximum flexibility for determining appropriate PRIS stimulation parameters. In self-tests, we found that a pleasant entoptic perception occurs when a green luminous light spot (approx. 525 nm) moves on a circular path. The challenging part is to derive an objective diagnosis from a subjective phenomenon.

Dynamic mechanical properties of polymers for biomedical applications are crucial parameters for development and engineering of new medical devices. Here, the time-dependent material behavior is a key factor for durability. Varying the strain rate is a convenient implementation of time-dependency for uniaxial testing. This study investigates time-dependence of Poly(L-Lactide) (PLLA) through uniaxial testing with different strain rates and PLLA with different molecular weight. The results show strain dependence for elongation at break and yield stress, Young’s modulus however is not rate dependent. An increase in elongation at break is also seen with increasing molecular weight of PLLA. Plastic strain increases significantly only for PLLA with an intermediate inherent viscosity. Results show distinct time dependencies regarding strain rate for PLLA with slightly different inherent viscosities. For stent-related mechanical material characteristics, higher molecular weight PLLA seems to be advantageous. This study only considers base materials, although appropriate thermal, mechanical as well as chemical post processing approaches for further adjustment of different properties have already been shown. A combination of the best possible base material and a suitable post-processing should be targeted.

Inkjet printing is a versatile tool for the precise positioning of droplets that is used in many application areas such as 3D printing, biotechnology or pharmacy. This work focused on comparing the inkjet printability of different drug solutions of celecoxib (CLX), a non-steroidal anti-inflammatory drug, to produce drug depots in medical implants. CLX was dissolved in dimethyl sulfoxide (DMSO), poly(ethylene glycol) diacrylate (PEGDA) and a mixture of DMSO and PEGDA in a ratio of 1:1. The pure solvents and the drug solutions were inkjet printed using a Nanoplotter 2.1 with the NanoTip J printhead (GeSiM mbH, Radeberg, Germany). The voltage was varied from 60 V to 150 V using a step size of 5 V. Droplet volume and the trajectory of the droplets were investigated. For DMSO, DMSO-CLX, DMSO-PEGDA and DMSOPEGDA- CLX, reproducible droplet formation occurred with a droplet volume of approximately 300 pl - 500 pl and not more than one satellite droplet in a voltage range between 60 V to 80 V. Inkjet printing of PEGDA and PEGDA-CLX was not reproducible in the range of 60 V to 150 V. DMSO, DMSOPEGDA, DMSO-CLX and DMSO-PEGDA-CLX showed a high inkjet printability. In contrast, inkjet printability of PEGDA and PEGDA-CLX was very limited.

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.

For the in vitro examination of the effects on cells and tissues of metal ions derived from implants by wear and corrosion, a system is needed to release metal ions in a controlled and sustained manner. As small concentrations may have an impact on biological systems, a corresponding slow release over a defined period of time is necessary. Here, a manufacturing method of polymeric Poly(L-lactic acid) (PLLA) films with incorporated cobalt ions via dip coating is reported. The establishment of two analytical methods for the detection and quantification of cobalt ions is shown. High performance liquid chromatography enables cobalt quantification over a concentration range of 0.33 μg/mL up to 33 μg/mL in sample solutions. Extraction and detection of cobalt ions from solvent cast PLLA-cobalt-films shows the feasibility of the manufacturing method. Initial biocompatibility tests with manufactured PLLA-cobaltfilms showed no effects on adipose derived primary mesenchymal stem cells (adMSCs).

Physical vapor deposition (PVD) sputtering is a promising technique for the generation of electrically conductive coatings on complex structured biomaterials, such as nonwovens, that can be used in implants. The ultra-thin coatings can fulfil a variety of purposes, such as drug depot or biosensor. The aim of our studies was to determine the feasibility of generating thin silver (Ag) coatings on complex structured poly-L-lactide (PLLA) nonwovens by sputtering and their morphological characterization. PVD sputter process was performed using a customized plasma chamber and a complex rotation of the tender electrospun PLLA nonwovens. Morphological analysis revealed a promising homogenous Ag coating, representing the structure of the nonwovens.

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.

Applications and requirements for biomedical test benches are often quite different, but there is always a need to monitor and usually to control processes. Commercially available development systems can be used to build simple laboratory setups up to industrial systems but are limited with respect to high costs and information for required validation. A test bench development kit is presented which ensures high compatibility for prospective developments, adaptations and embedding of sensors and actuators. The development kit is based on a printed circuit board built around the singleboard computer Raspberry PI. Supporting circuitry for power control, logics and special functions are implemented. Several types of peripheral devices can be connected via two serial bus standards (I2C, or RS-485). Current applications demonstrate the achieved level of automation and process control.

Nitinol became one of the most prominent materials for biomedical devices. The unique properties such as the shape memory effect and the superelasticity enabled new applications, particularly in the field of stent technologies. Due to their thermosensitivity, manufacturing processes are required that control the heat accumulation in the material. Here we investigate the femtosecond laser ablation of Nitinol supported by a water flow inside the processed tube. We show that laser absorption in the water prevents annealing of the Nitinol, even for high pulse energies. Furthermore, we investigate the groove profiles by scanning electron microscopy and observe minor improvements in the processed structure when using water flow inside the tube. The results show that water-supported femtosecond laser ablation can be used to optimize the fabrication of medical devices such as cardiovascular stents and to reduce processing times.

The effect of molecular weight Mwon the polymorphous crystallization and melting behavior of poly(Llactide) PLLA (L206, L210 and L214) were systemically studied by differential scanning calorimetry (DSC). Melting and reorganization of conformationally disordered crystals (α′-phase) of PLLA are analyzed with respect to the cooling rate qcin a range between about 4 and 50 K/min and the heating rate qhin a range between about 5 and 200 K/min. It was shown that the α′- to α-crystalline phase transition prior to the dominant melting depends on cooling rate qcand Mw. Unlike very high-MwPLLA L214, for low-MwPLLA L206 crystallized at high qc, the α′-form crystals only partially transformed into the α-modification, and certain amounts of α′-form crystals melted directly without α′- to α-transition during the heating process. With increasing qc, the melting of PLLA L210 changed from phase-transition- and -melting mechanism to the common melt-recrystallization mechanism. It was also found that the polymorphism of PLLA significantly affected the crystallization kinetics. Consequently, the reorganization of α′-crystals into stable α- crystals could be inhibited by fast heating (qh> 150 K/min).

The increasing trend of minimally invasive therapy methods for widespread diseases in the cardiovascular system, in the field of ophthalmology, ear, nose, and throat medicine, or gynecology, leads to an extensive demand for innovative microdevice manufacturing technologies. Femtosecond (fs)-laser technology offers a wide range of applications in the field of cutting, milling, and surface structuring on the micro- and nanometer scale. Ophthalmic devices for glaucoma therapy have dimensions in the submillimeter range. Irrespective of this, there are high demands on the safety and efficacy of these implants. Within the current study, fs-laser-based manufacturing technologies for functional elements of a novel microstent for glaucoma therapy were developed, considering potential industrial scalability. We successfully developed a mounting mechanism for quick and reproducible manufacturing of a micromechanical valve mechanism for safe regulation of intraocular pressure. Furthermore, we successfully developed a fs-laser-based process for manufacturing grooves as part of a fixation mechanism for a stable device positioning inside the eye. The results show that fs-laser manufacturing represents a promising technology for manufacturers of medical microdevices, such as ophthalmic microstents.

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.

To simulate the specific material properties of thermoplastic polymers a suitable constitutive model is essential. The parallel rheological framework (PRF) model was calibrated and evaluated in this study as potential constitutive model for polymer stent application. Tensile as well as recovery tests with different loading rates were performed using PLLA specimens. In order to calibrate the constitutive model, the conducted material tests were simulated accordingly. The parameters of the model were iteratively varied to obtain good accordance of the simulation with the material tests. In contrast to elastic plastic material models, viscoelastic material behavior can be represented with the nonlinear viscoelastic-plastic PRF model. The generated and possibly further refined model can be used for the simulation of polymer stents.

Poly(N-isopropylacrylamide) (PNIPAM) hydrogels are one of the most commonly studied thermoresponsive biomaterials. In this work, we investigate ball milling as a method of producing PNIPAM nanogels and confirm that the temperature responsiveness is maintained in the nanogel form based on hydrodynamic diameter and zeta potential measurements.

In this study, DSC experiments were used to elaborate an annealing protocol for injection molded very high molecular weight (VHMW) PLLA with two molecular masses, 320,000 g/mol and 700,000 g/mol. The initial material obtained from the injection molding process was found to be highly amorphous and not in thermodynamic equilibrium state, as distinct cold crystallization and enthalpy relaxation were observed in DSC data. Thermal annealing to 85 °C for 60 - 90 min under controlled conditions using a DSC device showed to be sufficient to stabilize the polymer and increase the crystallinity to up to 50 %. Annealing did not result in any signs of thermal decomposition. The elaborated thermal treatment has been transferred to manual annealing of large specimen geometries for subsequent DMA analysis.

Besides visual assessment of the intra-vascular appearance, intravascular optical coherence tomography (IVOCT) enables precise diameter measurements within the coronary arteries. The current study presents an upgraded test setup allowing the investigation of the elastic properties of porcine coronary arteries ex vivounder pulsatile flow conditions. IV-OCT imaging was performed within the left circumflex artery of a porcine heart applying a normotensive and a hypertensive pressure regime at different pulse rates. Radial compliance was derived from the luminal diameter as well as intra-arterial pressure measurements. Test results show a significant reduction of radial compliance under pulsatile conditions, when compared to reference measurements under steady flow. The mean radial compliance decreased with increasing pulse rate, which can be attributed to the viscoelastic properties of the arterial wall.

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.

The characterization of mechanical properties of materials used in biomedical applications is essential for performance evaluation. In addition to quasi-static tests, dynamic tests extend the range of methods and allow predictions of failure, as well as information on durability. Appropriate specimen grips according to the test sample geometry are crucial for a reliable examination of mechanical testing and therefore valid experimental data. In particular, the investigation of polymers is challenging, as properties show major differences depending on temperature and applied loading rate. This could result in slipping or tearing of samples in the specimen grip area. Numerical simulations of reference grips, as well as alternative custom designs, were performed evaluating damage due to the clamping process and to provide appropriate specimen grips for future dynamic-mechanical investigations of materials with variable properties. Both the results of the numerical simulation and preliminary tests with 3D-printed prototypes show a distinct improvement in specimen clamping. Plastic deformation and local stress peaks were reduced while maintaining the same tightening torque.

Patients with cardiac arrhythmias are currently treated with conventional transvenous rhythm implants. Complications are frequently associated with intracardiac implanted leads primary insulated by silicone and polyurethane. However, experiences show that polyurethanes in particular are susceptible to various degradation mechanisms including hydrolysis, environmental stress cracking (ESC) and metal ion induced oxidation (MIO). In vivo, pacemaker leads are exposed to a complex thermal, chemical, mechanical and biological loading. The current study focusses on in vitro analyses to assess the biostability of Pellethane 2363 55D and the silicone MED 4765 as cardiac pacemaker lead insulations. Degradation processes were simulated in vitro in a load-free state and under static mechanical loading by subjecting a coaxial lead design to bending radii from 3 mm to 19 mm. Physiological environmental conditions were mimicked using a physiological saline solution and a tempered oxidative solution. Surface morphological and thermal analyses were performed before and after in vitro testing by means of scanning electron microscopy (SEM) and differential scanning calorimetry. Melting temperatures of silicones around 40°C were measured, before and after in vitro testing, respectively. Pellethane insulation layers had two endothermal melting regions at 100°C and 170°C before and a third melting region at 45°C after in vitro testing. The additional melting peak may indicate a change of thermal material properties due to degradation. SEM images showed degradation phenomena similar to in vivo studies, varying in severity and depending on the bending radius. Thus, the relevance of mechanical loading for in vitro replication of clinically relevant lead insulation degradation was demonstrated.

Electrospun fibers based on synthetic and natural polymers represent a promising approach in order to mimic the mechanical stability and the required cell-polymer interaction of the natural extracellular matrix (ECM), . In this biomedical context, the biodegradable medical grade poly-llactide (PLLA) and the natural gelatin are already well established. However, to obtain a stabilized structured PLLA/gelatin blend, crosslinking of gelatin is required. In this study, the influence of the post processed crosslinking via Glutaraldehyde (GTA) vapor and GTA solution on the morphological and physicochemical properties of the blend, as well as on the in vitrorelease of previously incorporated dexamethasone (DMS), was investigated. The addition of gelatin decreased the fiber diameter and increased the surface hydrophilicity, which is furthermore unaffected by the crosslinking process. The in vitrorelease of DMS was decisively changed by both, the addition of gelatin and the subsequent crosslinking processes. For all modified samples, a very rapid burst release of DMS was detected within the first 24 h, which is crucial for biomedical applications such as tumor therapy.

Wound healing after implant surgery represents a spontaneous repair process that, when disturbed, can lead to a pathological situation known as fibrosis, characterized by excessive proliferation, increased extracellular matrix deposition, and scarring of the tissue. Tissue-specific cell culture models simulating physiological or pathophysiological cell responses are valuable research tools in the field of fibrosis, among others. In such in vitro systems, endpoint measurements are typically used to assess cell viability and/or proliferation. However, this approach is usually time consuming, costly and often leads to the destruction of the sample. Additionally, these conventional in vitro systems provide only a single snapshot of the respective sample at the end of the experiment. Therefore, we aimed to evolve the fibrotic disease in vitro model established by Stahnke et al. To this end, we chose a time-resolved, non-invasive approach based on cell impedance measurements and bright-field microscopy that allows continuous monitoring of the cells. Such measurements can be directly conducted using the xCELLigence RTCA eSight system. This system was used to characterize the cellular responses of the fibrosarcoma cell line HT-1080 and primary fibroblasts isolated from the Tenon’s capsule of human donors to TGF-β1, a key cytokine involved in the pathogenesis of fibrosis. The data shows that compared to Tenon’s fibroblasts the response of HT-1080 cells to TGF- β1 is less pronounced and only detectable within a narrow time frame. Thus, HT-1080 do not appear to be a suitable cell culture model for the assessment of antifibrotic implant coatings.

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.

Electrospinning, a standard technique for producing nonwoven fabrics, is widely used in the biomedical field. Due to local electric fields, fiber deposition is influenced by 3D surface structure of metallic collectors. For complex shaped structures, predicting the deposition and orientation of the fibers remains challenging. Investigations on well-defined structures permit a more detailed insight. In this study, metal blocks with round, slit and square holes of various sizes and depths were fabricated and covered with a thin layer of polymer fibers. The fiber arrangement of the layer was investigated by different microscopic methods. Analysis of the results showed less deposition on round holes and well-bridged aligned fibers on gaps which were less than four times wide as deep. Experimental results confirmed the theoretical predictions. Considering these findings, further work can be addressed to specific collector design to attain targeted fiber deposition.

Involuntary female infertility represents a sensitive issue, which is frequently caused by an impaired patency of the Fallopian tube. Current treatment options, such as in vitro fertilisation (IVF) or tubal reconstruction, are related to high costs or surgical risks. Therefore, a need for an alternative highly safe and effective minimally invasive therapy option is assumed. The current work presents a proof-of-concept for a novel microstent in combination with a delivery system for treatment of proximal Fallopian tube occlusions. For this purpose, a microstent prototype was implanted into a porcine Fallopian tube ex vivo using the presented delivery system. The results of the procedure were analyzed using a micro-computed tomography (μ-CT). Based on the μ-CT imaging, critical parameters of the microstent, such as radial patency, were assessed. The microstent implantation leads to an increased opening area of the Fallopian tube. Additionally, the microstent does not impair the anatomical shape of the tube epithelium and adapts well to the anatomical path. In further studies, the functionality of the Fallopian tube will be examined after microstent implantation in vivo.

Heart valve tissue engineering aims at creating living valves through colonization of scaffolds with patient’s own cells. Various cell sources have been explored focusing mainly on endothelialization of the scaffold surface. Endothelial like cells, such as endothelial progenitor cells (EPCs), which can be isolated from peripheral blood or bone marrow could be a suitable option. In this study we investigated cell colonization potential of ovine EPCs (OEPCs) on thermoplastic silicone-based polyurethane (TSPU) polymer scaffolds. TSPU nonwovens with and without vascular endothelial growth factor (VEGF) functionalization were used. SEM images showed that by day 3 the cells were growing as patches on the surface of both polymer groups. The cell patches continued growing and started covering more of the nonwoven surface. On day 7 the cells had almost covered the scaffold surface. The cells were more uniformly distributed as monolayer on the functionalized TSPU compared to the non-functionalized nonwovens. Live/Dead staining provided bright green fluorescence on the samples, indicating metabolically active alive cells. These static cell seeding experiments demonstrated that functionalized TPSU nonwovens support endothelialization. The feasibility of TPSU nonwovens as heart valve prosthesis scaffold could be further explored with animal studies in an ovine model.

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

The development of strategies for fibrosis prevention is a perpetual cutting the edge challenge, especially in ophthalmologic fistulating surgery. Stenosis of liquid draining implants but also fibrotic activation of implant-associated tissues are major clinical examples for fibrosis induced implant failure. Implant coating or incorporation of antifibrotic agents offer a promising approach to minimise failure rates. Nintendanib is a drug that has been successfully used for the treatment of ideopathic pulmonary fibrosis since 2015. In this study, we evaluated the suitability of Nintedanib for ophthalmic therapeutic treatment. Therefore, the antifibrotic potential of the active substance was tested with a fibrotic cell culture model on primary fibroblasts of the Tenon (hTF) in vitro. The concentration of 10μM Nintedanib demonstrated a marginal effect on cell viability but coincidently diminished cell proliferation remarkably. Both, immunocytochemical and Western blot analyses revealed a significant inhibitory effect of Nintedanib on the TGF-β1 induced expression of the extracellular matrix (ECM) components fibronectin and collagen. Moreover it supressed the expression and formation of stress fibres of the fibrotic marker protein alpha smooth muscle actin (α-SMA).

In vitro wound healing assays are a suitable application to verify the efficiency of pharmaceuticals or growth factors that will be incorporated in or immobilized to e.g. electrospun biomaterials for wound dressings or other biological devices in advance. Thereby, various factors like culture conditions or cell density influence the specific cell proliferation. Hence, to establish a wound healing assay for various cell types, a stepwise adaptation of cell numbers was done for better estimation and comparison of cell density for the validation of the influence of drugs on the wound healing process. Cell proliferation of different tissue relevant cell types was evaluated by impedance measurements and live cell imaging. Cell numbers could be successfully adapted for assay specific cell densities. In general, a universal comparison of biological or chemical materials and agents in vitro may require the creation of appropriate ISO or OECD standards for a consistent and cell specific adaptation or demand of initial cell density.

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.

Implant devices for micro invasive glaucoma surgery (MIGS) are gaining increasing acceptance in clinical ophthalmic use. The implant requirements are defined in international standards, such as ANSI Z80.27-2014 and the 2015 Guidance for Industry and Food and Drug Administration Staff “Premarket Studies of Implantable Minimally Invasive Glaucoma Surgical (MIGS) Devices”. The exact fluid-mechanical characterization represents a crucial part of the development and approval of innovative implant devices for MIGS. The current work describes the development and preliminary validation of a versatile test facility for pivotal characterization of glaucoma drainage devices. The test setup enables a pressurization of test specimens by means of two water columns. For measurement of pressure and volume flow, a pressure transducer and a total of three liquid flow meters were implemented into the test setup. Validation was conducted by experimental pressureflow characterization of standardized tubes and a comparison to theoretical results according to Hagen Poiseuille's law for stationary laminar flow of a Newtonian fluid in a tube with a circular cross section. Ultrapure water at (35 ± 2) °C was used for the analyses. The developed test setup potentially enables pressure-flow characterization of test specimens in a wide flow range of 0 μl min-1 ≤ Q ≤ 5.000 μl min-1. The preliminary test facility validation showed a good agreement of measured and theoretical volume flow characteristics as a function of the pressure difference, in the currently investigated flow range of Q < 80 μl min-1. The developed test facility is suitable for pivotal in vitro characterization of glaucoma drainage devices. Future investigations will focus on the final validation of the whole flow range and on the use of the test facility for fluid-mechanical characterization of self-developed prototypes of glaucoma microstents as well as commercially available glaucoma drainage devices.

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.

We present a thermal processing device, equipped for local heating and welding of biomaterials, e.g. electrospun nonwovens or polymer films. Depending on the application and choice of materials, we aim to determine appropriate processing parameters for permanent and non-permanent welds. Due to the modular device structure, applicationspecific heating tools can be used. Process temperature up to 250 °C is feasible.

Surgical treatments of arterial occlusive disease with fully absorbable polymeric scaffolds, as a potential alternative to permanent metallic stents, are increasingly penetrating the clinical field. An addition part of the management of patients suffering from vascular diseases is the administration of statins. In this study, absorbable x-ray marked PLLA-based polymer scaffolds and permanent bare-metal stents (BMS) were implanted interventionally into both common carotid arteries (CCA) of 6 healthy female pigs via the left common iliac artery (8F-sheath). The pigs were administered dual antiplatelet drugs oral starting 3 days before the procedure until the end of the study. In Addition, the pigs received atorvastatin orally, beginning 5 days prior to surgery and lasting until the study ended. Stented CCA segments were explanted after 4 weeks, and processed for quantitative histomorphometry, and estimation of vascular inflammation and injury scores. Polymer scaffolds showed a decreased residual lumen area and higher stenosis after 4 weeks (6.41 ± 0.83 mm² and 40.52 ± 5.01%) as compared to the bare-metal reference stent (15.17 ± 0.896 mm² and 7.80 ± 0.88%). After 4 weeks, inflammation score were higher in the polymer group (1.30 ± 0.37) compared to the BMS group (0.42 ± 0.18). In contrast, the BMS showed a slightly elevated vascular injury score (0.85 ± 0.12), as compared to the polymer (0.60 ± 0.23) group. In this preclinical model, the new absorbable polymeric scaffolds showed similar technical feasibility and safety for vascular application as the permanent metal stents. Although no positive trends were observed with oral treatment with atorvastatin, further optimization with a dual-loaded coating is still reasonable. In addition, reduced strut thickness of the polymer scaffolds would have potential to positively impact tissue ingrowth between struts and should be considered in future work on stent design.

Electrospinning is used for producing nonwovens for medical polymer-based implants, such as prosthetic valves or covered scaffolds. In this study, nonwovens for prosthetic venous valves are investigated regarding their morphology and mechanics in physiological medium. Spinning molds were developed based on previous venous valve leaflet designs, 3D printed in different sizes and covered with electrospun nonwovens. Samples were stored in a physiological 0.9% saline at 37°C to investigate the influence of fiber rearrangement and swelling in medium for several weeks. Two different nonwovens of thermoplastic silicone-based polycarbonaturethane (TSPCU) were compared. Tensile test results show that storage in medium has a relevant influence on the mechanical properties. SEM images of TSPCU show substantially increased fiber diameters after 8 days stored in medium. After detaching the valve leaflet nonwovens from the molds, shrinkage of the material of approximately 12% was detected. A suitable valve size could be identified for joining with the stent structure into an interventional prosthetic venous valve. The results demonstrate the influence of storage conditions on the morphological and mechanical properties of electrospun TSPCU nonwovens. For development and dimensioning of venous valve leaflets, this change in mechanical behavior and possible shrinkage of the material has to be considered.

Titanium represents an important biomaterial for implantable medical devices. During medical device manufacturing by means of welding, implant structures are partially exposed to high temperatures. Additionally, active implants such as pacemakers can heat up during operation. Therefore, numerical studies of heat propagation within titanium structures represent an essential tool to assess functionality and safety of medical devices. The current study focusses on the development of a method for experimental validation of numerical heat transfer analysis of biomaterials such as titanium. Numerical heat transfer analysis was performed using the software Abaqus. A finite-element model was established including material properties such as density, thermal conductivity und specific heat capacity. Temperature distribution among a locally applied thermal load was calculated. Furthermore, effects such as convection were considered. For validation, an experimental setup was implemented according to the numerical calculation using a local heating tool. Heat propagation in the sample was determined, respectively. Radiation-based heat determination was performed using an infrared thermographic camera aligned parallel to the sample surface. Contact-based heat determination was performed using thermocouples fixed to the surface at defined distances from the point of local heat input. For evaluation of numerical and experimental results, temperature- time curves were compared for five distinct measuring points, respectively. While infrared thermography offers the advantage of non-contact measurements, difficulties may arise from the definition of correct emissivity and challenging sample surface characteristics, such as metallic reflectance and surface texture. The thermocouple-based temperature measurement shows a high sensitivity to local temperature changes, but it is not always suitable due to the influence on the sample by thermocouple fixation. Infrared thermography and thermocouple based temperature measurements represent suitable procedures for experimental validation of numerical heat transfer analysis of titanium. An individual decision for the most suitable method must be made considering the specific sample and its further application.

Poly(N-isopropylacrylamide) hydrogels are a popular temperature sensitive biomaterial. Bulk hydrogels can be quickly and easily processed into microgels using a ball mill. However, there is no information on whether the mechanical milling process affects critical PNIPAM characteristics. In this work, we compare swelling and thermo-responsive properties for a series of PNIPAM gels in bulk and microgel forms.

Electrospinning (ES) is a suitable and cost effective method to mimic the chemical composition, morphology, and functional surface of natural tissues, for example of the nervous, dermal, vascular, and musculoskeletal systems. This technique is a versatile tool to obtain tailored fibrous scaffolds from various polymer materials. By varying the diameter, porosity, orientation, layering, surface structuring, mechanical properties and biodegradability of the fibers the properties can be adapted for specific applications ranging from implantable medical devices to wound repair and protective clothing. Especially the combination of different polymer types offers a high potential. In this study electrospun two-component nonwoven structures of thermoplastic copolyester elastomer (TPC-ET) and bioresorbable polylactide (PLLA) were fabricated, using different ES setups. A comparative evaluation in terms of porosity, thermal and mechanical properties as well as required fabrication effort, was performed. Nonwovens made from polymer blends and coaxial spun core-sheath fibers showed similar tensile strength, which was higher than dual electrospun fabrics. Porosity was found to be in the range of 80 - 90%. By modifying the polymer solution and process parameters multicomponent nonwoven structures with tailored properties and drug release profiles can be manufactured.

Paravalvular leakage (PVL) has a crucial impact on clinical outcomes of transcateheter aortic valve replacements (TAVR), especially the mortality increases dramatically with high-grade PVL. Furthermore, the calcification of the aortic annulus has a decisive influence on the PVL of TAVR. Therefore, we developed a technical model of a calcified aortic annulus and used it for the investigation of PVL in steady-state back-flow conditions. We investigated an Evolut PRO (Medtronic, Minneapolis, MN, USA), implanted the TAVR at different depths in the aortic annulus model ranging between 0 mm and -6 mm and characterized PVL in steady-state retrograde flow from 0 mmHg up to a maximum achievable pressure. The used test bench and detailed test method was described in previous studies. The aortic annulus model exhibits three elevations symmetrically distributed around the circumference. Depending on the degree of calcification the elevations reached 1 mm to 3 mm into the lumen. For the Evolut PRO bioprosthesis, a decreasing PVL was measured with increasing implantation depth. At an implantation depth of 0 mm (inflow of TAVR and annulus model at same height) maximum PVL was measured. Minimum PVL was measured at a height of -6 mm. Furthermore, even a small calcification of 1 mm led to a large increase in PVL. This trend continued with increasing height of the calcification. The maximum regurgitation of (2,025.21 ± 12.47) ml (n = 3 measurements) was measured at a pressure of 6 mmHg in the annulus model with 3 mm calcification. A test method to quantify PVL depending on annular calcification was successfully developed. Additionally, the influence of implantation depth on PVL was characterized. Due to the technical operating principle of the test bench, only a limited increase in pressure was possible when large PVL occurred. In this respect, the test bench must be optimized in the future.

The selection of appropriate test conditions is of critical importance in mechanical testing of biomaterials. In particular the definition of dynamic test conditions is requiring high efforts. In this work, a thermoplastic semicrystalline polymer was characterized regarding mechanical properties by dynamic mechanical analysis (DMA). Timetemperature- superposition (TTS) of dynamic mechanical data provides an efficient method for the experimental design of follow-up studies. Our focus was to provide test conditions for cyclic tests, which correspond to viscoelastic materials. The results show, that the test temperature for dynamic mechanical fatigue tests, as an indicator of mechanical modification for viscoelastic materials, should necessarily remain below the onset temperatures of storage modulus and loss modulus. Moreover, changes in material characteristics due to varying frequencies should be considered when constructing a master curve for the evaluation of test frequencies. Therefore, TTS is particularly beneficial for the rapid determination of test parameters for accelerated material examination.

For the investigation of in vitro drug release, methods have been used in which samples of drug delivery systems are immersed in release medium. The medium is used to measure drug concentration via chromatography or photometry. These systems are suitable to investigate the drug release of different systems or to simulate tissue environments. When considering predominantly humid regions, e.g. for drug release into the cochlea through the round window membrane by a drug delivery system placed at that membrane, reproducible in vitro determination of drug release becomes particularly challenging. In this study the development of a system is reported that allows the investigation of the in vitro drug release simulating such conditions.