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An unfulfilled pregnancy is often due to impaired patency of the female Fallopian tubes. To circumvent tubal obstruction, cost-intensive in vitro fertilisation (IVF) is currently indicated. The only therapeutic treatment concepts available are transvaginal tubal lavage/catheterization or laparoscopy with minimally invasive or complex surgical tubal reconstruction, which are associated with side effects. The development of new and cost-effective non- or minimally invasive therapeutic concepts that can restore the patency of the Fallopian tubes would be key in the treatment of female infertility and can fulfil the desire to have children. Therefore, in the present work, ex vivo anatomical studies are carried out on various laboratory mammals (pigs, rabbits, guinea pigs). Using these animal models, it was also evaluated whether a sensor-ureterorenoscope can be inserted through the whole female reproductive tract to the Fallopian tubes. This device will be used for endoscopically guided implantation of a novel tubal microstent prototype via its tailor-made delivery system into the isthmus region of the Fallopian tubes in upcoming studies. This work serves to identify an optimal species for a longitudinal animal study, in which the feasibility as well as the tissue reaction to the implant will be evaluated.

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.

The radial strength of balloon expandable stents represents a key property for a successful recanalization of sclerotic blood vessels. This study focuses on the most commonly used method for investigation of radial strength and radial stiffness via segmented head test setup. A custom made user software was used for evaluation of the radial force curves considering requirements of international standards such as ASTM F3067. Contributing factors during measurement such as friction and test setup deformation as well as the single cycle and multi cycle approach were addressed and discussed.

The promising results of transcatheter aortic valve replacement (TAVR) over the past two decades indicate an expansion of the patient cohort toward patients with intermediate or low surgical risk. Since some complications of TAVR have already been minimized, subclinical leaflet thrombosis (SLT) has gained importance in recent years. SLT is manifested by a thrombotic layer on the prosthetic leaflets that gradually reduces leaflet motion. The resulting decrease in functionality of the TAVR causes a need for re-intervention. The origin of SLT and approaches to prevent SLT are still unexplored. For this reason, we have developed an in silicomodel that can be used during the design development process of TAVR devices to estimate the thrombosis risk of the implant. Based on passive scalar transport, hemodynamic metrics are used to quantify platelet activation and aggregation which are associated with the formation of thrombosis. In conjunction with a numerical simulation model considering the fluid-structure interaction between the blood mimicking fluid and the TAVR implanted in an aortic root, the thrombosis risk can be modeled. The simulation model can be used to calculate the three-dimensional flow structures within the native sinus and neo-sinus and also provides the ability to derive metrics to assess the risk of thrombosis. We demonstrated that this in silicomodel is a time-effective tool to assess thrombosis risk in TAVR product development.

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.

Biofluid mechanics play an important role in the study of the mechanism of cardiovascular diseases and in the development of new implants. For the assessment of hydrodynamic parameters, experimental methods as well as in-silico approaches can be used, such as particle image velocimetry (PIV) and Deep Learning, respectively. Challenges for PIV are the optical access to the region of interest, and time consumption for measuring and post-processing analysis in particular for three dimensional flow. To overcome these limitations state-of-the-art deep learning algorithms could be utilized to augment spatially coarse resolved flow fields. In this study, we demonstrate the use of Physics Informed Neural Networks (PINN) to augment PIV measurement data. To demonstrate a combined workflow, we investigate the flow of a Newtonian fluid through a simplified aneurysm under laminar conditions. Generation of synthetic PIV particle images of a single measurement plane and the corresponding PIV vector calculations were performed as the basis for the PINN algorithm. Based on the Navier-Stokes equations the PINN reconstructs the entire 3D flow field and pressure distribution inside the aneurysm. We observed qualitative agreements between ground through data and PINN predictions. Nevertheless, there are substantial differences in the quantitative, locally resolved comparison of the flow metrics, despite the generally tendency for the PINN algorithm to correctly augment the flow field.

Severe aortic valve stenosis has been successfully treated with minimally invasive transcatheter aortic valve replacement (TAVR) for more than 20 years. The therapy is applied to an increasing cohort of patients. Nevertheless, paravalvular leakage (PVL) remains one of the main complications after TAVR implantation reducing safety and efficacy of the implant. To improve TAVR performance, virtual patient cohorts can be used to generate a significant amount of data with biologically varying conditions comparable to clinically realworld data. For this purpose, in silico models need to be established which are used to evaluate the possible occurrence of PVL. When establishing in silico models, the question between simplification to reduce computational effort and still valid information from the model must always be clarified. Thus, we investigated the comparability between steadystate and transient PVL measurements as an input parameter for simulations in virtual cohorts. A clinically established TAVR was implanted into different annulus models and tested in a steady-state back-flow test bench and in a pulse duplicator system. As a result, leakage rates were compared and assumptions for the in silico models were derived. Although the trend of PVL is comparable in steady-state and transient conditions, absolute values differ making it difficult to extract generalized assumptions. Especially when PVL increased, e.g. in a larger implantation diameter or in an imperfect annulus, the variation also increased up to 50% of the measured value.

In spite of advances in the treatment of cardiovascular disease, there remains a significant need for high-quality evidence for clinical practice given the rising prevalence worldwide. Next to the increase of regulatory requirements, poor screening-to-recruitment ratios, lack of patient engagement, and long timelines for contracting and institutional review board (IRB) approval are leading to an outflow of clinical trials in the EU. Patient registries are a potentially rich source of data, especially for evaluating the course of rare diseases and effects of new treatments. In the sectors of regulatory assessments of medical devices they are greatly underused. Health-related real world data provide crucial support for regulatory decision-making, particularly post-market assessments of medical products. Registries can be used not only for observational studies, but also for conducting experimental study designs. Register-based randomized controlled trials (RRCTs) are of particular importance here, as they can combine the advantages of randomized controlled trials (RCT) and registers. The government's financial support and reduction of regulatory barriers to the implementation of registry-based RCT are incentive factors for manufacturers to let their medical devices (re-)certified. Furthermore, it is essential that the necessary criteria are already taken into account when setting up the German implant registry in order to enable future RRCTs. The presented work is an additional pleading for the use and extension of registries for all medical products.

Implantation of a shunt system is the most common neurosurgical procedure for the treatment of hydrocephalus. Hydrodynamic parameters of hydrocephalus shunt systems are valuable variables to address patients' needs. In this report, we present a test setup to evaluate hydrodynamic parameters of hydrocephalus shunt systems. The test setup was validated using a stainless steel capillary and compared with the analytical solution according to Bernoulli's equation. It was demonstrated that the experimental setup is able to model the pressure in a physiologically relevant range. The measured and averaged flow resistance was 2.96 mmHg/(ml min-1). According to the analytical solution of Bernoulli's equation, the flow resistance is 2.86 mmHg/(ml min-1). Therefore, the measured flow resistance is 3.5% higher than the analytical solution. Moreover, the nonlinear characteristic of the pressure drop at the inlet and outlet of the capillary plays a minor role compared to the friction of the tube flow. As a result, the increase in flow rate with increasing pressure load can be well approximated by a linear function for the low flow rates measured here. The experimental setup presented will be used in the future to characterize commercially available shunt systems under various hydrodynamic conditions.

Fallopian tube occlusions represent one of the most common causes of female sterility. As an innovative treatment approach for affected persons, we previously presented the concept of a novel polymeric, self-expanding, and bioresorbable microstent. As a basis for microstent development, knowledge of the mechanical properties of the anatomical target structure represents a crucial requirement. The current work describes a methodological approach for the experimental determination of radial Fallopian tube compliance using optical coherence tomography. It could be shown that a quantitative assessment of the mechanical properties of porcine Fallopian tube samples - as a whole anatomical structure including the Tunica mucosa, the Tunica muscularis, and the Tunica serosa - is possible, using the described test setup. Future investigations on human samples will allow for valuable information regarding the structural-mechanical properties of the Fallopian tube. Therefore, the current work offers perspectives for the development of a novel gynecological microstent for the treatment of Fallopian tube occlusions.

Female sterility is caused by Fallopian tube occlusions in one of three cases. Current treatment methods achieve unsatisfying pregnancy rates and are associated with high costs or significant psychological and physiological stress. Our previously described microstent technology opens up new therapeutic possibilities to restore the lumen of the Fallopian tube without surgery. In this work, a Finite Element Analysis model of a physiologically relevant loading of the device is presented. Therefore, microstent radial force was analysed as a function of the device diameter up to a minimum diameter of 1.4 mm, which was found after microstent implantation ex vivo. A bilinear constitutive material model considering isotropic hardening was used for modeling of the microstent. The Finite Element Analysis results were validated using corresponding results of experimental investigations. In this context, a maximum deviation of 15% between experimental radial force and the corresopnding simulation results (1.33 N vs. 1.13 N) was found. Maximum von Mises stresses of approximately 88 MPa were determined. A good agreement between simulation and experiments was found. Therefore, future simulations will be carried out as a basis for microstent design optimisation.

Laser-induced periodic surface structures (LIPSS) provide the possibility to functionalize the surface of various materials, which can be used to control the wettability of metal surfaces or influence cell adhesion. LIPSS thus offer great potential for application on implant surfaces if their fabrication process is compatible with standard implant fabrication techniques. Here we demonstrate an easy-to-use two-step fabrication method for stents with different types of LIPSS. The separation between the fabrication of the stent structure and the surface structuring process allows the implementation of any stent structure finishing technique without affecting the LIPSS. The suggested fabrication method may be a step further in implementing laser machining-based surface functionalization in commercial implants.

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.

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.

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.

Computational fluid dynamics (CFD) has enormous potential for the development of novel cardiovascular implants. In particular, the evaluation of the thrombogenic potential of implants is gaining importance. For this purpose, the numerical model must represent the essential properties of the real system, i.e., an implant in the human blood circulation, in a suitable form. Due to its complexity, the model building process is crucial for the successful application of the model. Currently, there is no structured guideline for the application of numerical flow simulation to which model developers can refer. Based on NASA and ASTM, we present key aspects of the model building process using CFD for stent flow as an example.

The implantation of a transcatheter aortic valve replacement (TAVR) in patients with severe aortic stenosis improves pathologic blood flow through the aortic valve, but still alters hemodynamics in comparison to a healthy native aortic valve. The hemodynamic characteristics of TAVR are associated with hypo-attenuating leaflet thickening and prosthetic leaflet thrombosis, which may reduce the durability of TAVR. For this reason we developed a numerical model to identify pro-thrombotic regions of TAVR based on the velocity field. In silico models have already been proven to be an effective tool for device optimization in other medical device applications. However, when using an in silico model, it is important to validate the model assumptions with experimental data or analytical solutions to confirm the accuracy of the model. In this study, we present an approach to validate a complex numerical Fluid Structure Interaction (FSI) model used to simulate leaflet kinematics and flow in the vicinity of a TAVR. Based on the recommendation of ISO 5840 (2021), a combined validation of the kinematic and fluid dynamic parameters was performed for this purpose. The leaflet kinematic was investigated via high-speed recordings and evaluated based on the Geometric Orifice Area (GOA). The velocity field of the TAVR was determined experimentally using Particle Image Velocimetry (PIV). The evaluation of the GOA showed a good agreement of the in silico model with the in vitro data for the systolic duration. The occurring velocities were qualitatively compared during peak systole for three planes and showed similar flow characteristics. The maximum velocity was 1.1 m/s in the in vitro and in silico model. Based on the results, it can be assumed that the numerical FSI model of the TAVR can be used for thrombosis risk assessment.

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.

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.

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.

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.

Cardiovascular diseases are among the most common diseases with high mortality, including aortic valve stenosis and insufficiency. Minimally invasive implantation of transcatheter aortic valve prosthesis (TAVI) has become the standard procedure for patients with increased risk for open surgery. It is commonly accepted that the long-term outcome of aortic valve replacement depends on hemodynamic performance. This motivates the analysis of the velocity field in the vicinity of the TAVI. Computational fluid dynamics (CFD) methods have been established in the past, but show limitations in terms of computational effort when rapid design optimization or patient-specific decision making in real time is required. In this study we show the usage of PINNs for predicting fluid flow through a TAVI device. We also show a method of enforcing boundary conditions for this specific problem. Due to the physics involved in the training process, this principle does in theory not require additional training data. To validate the method, we performed CFD simulations that solved the Navier-Stokes equations be means of finite volume methods. Besides the good estimation of the main flow components, discrepancies between CFD and PINN results are present. Nevertheless, the flow structures have certain similarities in the coarse spatial localization of the vortex patterns occurring in flow around the TAVI device.

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

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.

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.

Absorbable stents made of poly-L-lactic acid (PLLA) exhibit inferior mechanical properties compared with metal based devices. Therefore, design optimization by means of finite element analysis (FEA) plays an important role in development of high performance absorbable stents. In the present study, three different meander structures made of PLLA material were compared in terms of their radial resistive force (RRF) using FEA. Material tests were performed to obtain input parameters of PLLA for the simulation. FEA was carried out to simulate the RRF and the length change of the meander structures as a function of the diameter. In addition, the numerical results were compared to the experimental outcome using corresponding meander based stents performing radial testing with a segmented head mechanism. Comparable high stresses occurred in the Ubends of the examined stent designs. In designs with a large radius of curvature less stress was observed while crimping. One meander structure developed comparatively higher structural resistance against radially acting forces, due to its curved strut design. In general, FEA revealed consistent results compared to the experimental investigations.

Patients undergoing transcatheter aortic valve replacement (TAVR) may suffer severe clinical complications, caused by paravalvular leakage (PVL) which is defined as leakage between TAVR and aortic annulus. PVL is often facilitated by a severely calcified annulus. This limits the expansion of a self-expandable TAVR stent. To assess TAVR performance in terms of leakage, measurement of regurgitation fraction in a pathophysiological annulus is recommended according to ISO 5840. For this purpose, a configuration of a circular annulus with a calcification nodule has been proposed in the recently published ISO 5840. The impact of the proposed pathophysiological annulus model on the expansion of self-expandable TAVR stents and on the regurgitation fraction was investigated in this study. For this purpose, two commercially available selfexpandable TAVRs (Evolut R and Portico) were implanted in a calcified annulus model. Circular expansion of the TAVR stents was investigated based on μCT scans of the implanted TAVR. The calcification-induced area in which retrograde flow can occur during diastole was detected. These results were then compared with the experimentally determined regurgitation fraction obtained from pulse duplicator tests. The results of the μCT scans showed a continuous leakage area in the region of the annulus for the Evolut R compared to a locally larger leakage area of the Portico, which, however, reattaches to the annulus in the distal inflow region. The hydrodynamic measurements confirmed a smaller leakage in the pathological annulus for the Portico. In summary, it can be assumed that a continuous leakage area in the TAVR stent inflow region encourages the PVL of TAVR.

Mitral regurgitation (MR) is the second most frequent indication for heart valve surgery and catheter interventions. According to European and US-American guidelines, transcatheter mitral valve repair in general and transcatheter edge-to-edge repair (TEER) in particular may be considered as a treatment option for selected high-risk patients. However, the biomechanical impact of TEERdevices on the mitral valve (MV) has not yet been fully understood. To address this problem, a 3D-Fluid-Structure Interaction (FSI) framework utilizing non-linear Finite Element Analysis (FEA) for the MV apparatus and Smoothed Particle Hydrodynamics (SPH) for the pulsatile fluid flow was developed and validated against in vitro data. An artificial MV-model (MVM) with a prolapse in the A2-P2 region and a custom-made TEER device implanted in the A2-P2 region were used for the in vitro investigations. In accordance with ISO 5910, projected mitral orifice areas (PMOA), flow rates as well as atrial and ventricular pressures were measured under pulsatile flow conditions before and after TEER device implantation. For the FSI-model, the MVM geometry was reconstructed by means of microcomputed tomography in a quasi-stress-free configuration. Quasi-static tensile test data was utilized for the development of linear- and hyperelastic material models of the chordae tendineae and leaflets, respectively. The fluid flow was modelled assuming an incompressible, homogenous Newtonian behaviour. Time-varying in vitro transmitral pressure loading was applied as a boundary condition. In vitro investigations show that TEER device implantation in the A2-P2 region effectively reduces the regurgitation fraction (RF) from 55 % to 13 %. Moreover, the comparison of experimental and numerical data yields a deviation of 2.09 % for the RF and a deviation of 0.40 % and 6.47 % for the maximum and minimum PMOA, respectively. The developed FSI-framework is in good agreement with in vitro data and is therefore applicable for the characterization of the biomechanical impact of different TEER devices under pulsatile flow conditions.

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.

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.

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.

Biomaterial research efforts focus on the development of biomaterials that mimic the natural extracellular environment. In addition, different strategies are applied to render materials for blood-contacting devices nonthrombogenic through surface modifications that would suppress activation of platelets, coagulation and the complement system. A confluent thin layer of endothelial cells lines all blood vessels and produces factors responsible for inhibition of coagulation, thrombosis and neointimal hyperplasia. Thus, the ability to rapidly form a healthy endothelium upon implantation represents a desired property of biomaterials used for cardiovascular devices. In this study we used advanced in vitro methods to investigate the biocompatibility of a biodegradable and a permanent electrospun nanofiber fabric, poly-L-lactic acid and polycarbonate-based silicone elastomer respectively, with the focus on endothelialization and hemocompatibility.

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.

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.

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.

Bioresorbable nanofiber nonwovens with their fascinating properties provide a wide range of potential biomedical applications. Modification of the material enables the adjustment of mechanical and biological characteristics depending on the desired application. Due to the nanosized fiber network, post-production structuring is very challenging. Within this study, we use femtosecond laser technology for structuring permeable and resorbable electrospun poly-L-lactide (PLLA) membranes. We show that this post-production process can be used without disturbing the fiber network near the structured areas. Furthermore, the modification of the water permeability and mechanical characteristics due to the laser structuring was investigated. The results prove femtosecond laser technology to be a promising method for the adjustment of the membrane properties and which in consequence can help to optimize cell adhesion, enable revascularization and open up applications of nanofiber membranes in personalized medicine.

Paravalvular leakage (PVL), defined as the leakage between the aortic annulus and a transcatheter aortic valve replacement (TAVR), is verifiably associated with short- and long-term clinical outcome, especially with increased mortality. Therefore, with the ambition to reduce or even prevent PVL of next generation TAVR, it is necessary to extend the hemodynamic understanding of PVL.

The loading situation of the aortic valve is complex, complicating the identification of innovative approaches for heart valve leaflet materials, e.g. for transcatheter aortic valve implantation (TAVI). Materials engineering experiments allow for screening of materials but especially for durability testing, the consideration of physiological loads is vital/critical for the suitability-assessment of innovative leaflet materials. For this reason, a framework structure for the testing of leaflet materials in physiological loading (TAVI-Mimic) was developed. The exemplary use case for the TAVI-Mimic was a test for calcification propensity of pericardium during durability testing. The TAVI-Mimic was designed as a fourparted frame, based on previous work of our group. The leaflet material can be attached between inner and outer shells without sewing. In a second step, the TAVI-Mimic was optimized regarding radial load-deformation in comparison to a commercial TAVI by means of finite element analysis (FEA) and hydrodynamic characterization in a pulse duplicator system. Mechanical properties dependent on water uptake of different materials for 3D-printing of the TAVI-Mimic were investigated. After optimization, TAVI-Mimics were equipped with glutaraldehyde-fixated pericardial tissue and prototypes were calcified by using a heart valve durability tester and a metastable calcification-liquid, developed in earlier studies. The development of the TAVI-Mimic using FEA and experiments was successful, leading to a radial load dependent deformation of 0.6 mm which correlates with commercial TAVI. Two methacrylic photopolymers were identified for 3D-printing of the TAVI-Mimic and prototypes attached with pericardial tissue were manufactured. Pericardium TAVI-Mimics were calcified in vitro for one week and an average calciumphosphate precipitate of 0.34- 0.54 mg/cm² was measured. The optimization of the TAVR-Mimic led to an improved load-dependent behaviour compared to a commercial prosthesis while testing. The calcification method, combining the TAVI-Mimic, the metastable calcification solution and the durability tester enabled a successfully calcification of pericardial tissue, approaching the in vivo situation.

It is commonly accepted that hemodynamic situation is related with cardiovascular diseases as well as clinical post-procedural outcome. In particular, aortic valve stenosis and insufficiency are associated with high shear flow and increased pressure loss. Furthermore, regurgitation, high shear stress and regions of stagnant blood flow are presumed to have an impact on clinical result. Therefore, flow field assessment to characterize the hemodynamic situation is necessary for device evaluation and further design optimization. In-vitro as well as in-silico fluid mechanics methods can be used to investigate the flow through prostheses. In-silico solutions are based on mathematical equitation’s which need to be solved numerically (Computational Fluid Dynamics - CFD). Fundamentally, the flow is physically described by Navier-Stokes. CFD often requires high computational cost resulting in long computation time. Techniques based on deep-learning are under research to overcome this problem. In this study, we applied a deep-learning strategy to estimate fluid flows during peak systolic steady-state blood flows through mechanical aortic valves with varying opening angles in randomly generated aortic root geometries. We used a data driven approach by running 3,500 two dimensional simulations (CFD). The simulation data serves as training data in a supervised deep learning framework based on convolutional neural networks analogous to the U-net architecture. We were able to successfully train the neural network using the supervised data driven approach. The results showing that it is feasible to use a neural network to estimate physiological flow fields in the vicinity of prosthetic heart valves (Validation error below 0.06), by only giving geometry data (Image) into the Network. The neural network generates flow field prediction in real time, which is more than 2500 times faster compared to CFD simulation. Accordingly, there is tremendous potential in the use of AIbased approaches predicting blood flows through heart valves on the basis of geometry data, especially in applications where fast fluid mechanic predictions are desired.

The assessment of particulate matter generated during a simulated use is requested by international standards for approval of cardiovascular devices. The particle suspension was generated during a simulated use test procedure of a commercially available coronary stent delivery system and analyzed by Dynamic image analysis (DIA) using FlowCAM 8000. Four parameters were analyzed: the diameter, the aspect ratio value, the circularity and the intensity. The results revealed that 53% of the particles were larger than 25 μm. The particle shapes were inhomogeneous with a wide ranging aspect ratio of 0.03 to 0.95. Around 83% had an intensity value of more than 140 grey scales and appeared translucent.

Many catheters and vascular implants are coated to increase biocompatibility or to reduce friction during catheter based implantation. Several regulations require assessment of coating durability over the implant’s life time. An in vitro method for stent testing is presented to measure released particulate matter at defined inspection intervals. The method was validated using polystyrene microspheres with a size of 10, 25 and 50 μm to check for particle recovery (n=6). Two cleaning steps followed. Particle counting was performed by light obscuration method. The recovery rate was 103±5% (10μm), 94±4% (25 μm) and 78±12% (50 μm), respectively, meeting the requirements of FDA guidance documents (i.e. FDA 1545). Less than 3% of the particles were found in the cleaning solutions. The method using a fixed volume during stent loading can be adapted to all durability testers where tubes are used to fix the stents (radial pulsatile, bending, axial compression, torsion).

The assessment of the coating integrity of cardiovascular implants such as catheters and stent systems is of crucial importance for device approval. Released particles may represent a potential health risk for the patients. Thus, an analysis of the particles released at simulated in-vivo conditions depending on their size and number is required by international standards (ISO, ASTM) as well as national authorities. In this study, an automated test bench for online particle measurement is presented. For software controlled automation, sensor data transmission and solenoid valves were implemented. A user interface was created for setting test parameters and data recording. The setup was validated by investigating standard particles as well as those released during the simulated application of non-industrial coated balloons. The measurement data were compared with results generated using the previous manual test routine. The results show an improvement in the reproducibility of the measurements, which can be attributed to the simplified handling for the user.

Continuous adaptation of international standards for medical devices requires recurrent modification of test benches. A universal control unit using an open software environment is presented to simplify the maintenance of various test benches. Our developed control unit is equipped with a Raspberry Pi 4, with standard communication interfaces and application-specific electronic assemblies. The software is based on Node-RED, a browser-based editor. A measuring setup was adapted for a flow perfusion system. Our control unit simplifies the handling of the flow perfusion system by controlling a hydraulic pump and all required valves. A software programmed PID algorithm adapts the speed of the pump to adjust the pressure automatically. Actuators like proportional pinch valves are handled to control volumetric flow and pressure within the circulation. Consequently, the user directly observes changes inside the system. The measured data are stored and are available for documentation.

Proximal occlusion of the Fallopian tube is one of the most common causes of female infertility. Due to the occlusion, the passage of the fallopian tubes is no longer given. Basically, there are two options for patients affected by this condition: cost-intensive in vitro fertilization (IVF) or surgery. The pregnancy rates of approximately 50% achieved with current treatment options are not satisfying. In this work, we present a Finite Element Analysis (FEA) model of a previously reported optimized microstent design for minimally invasive therapy of proximal tubal occlusion. Based on experimental investigations, the material model was set up and the simulation was validated. Comparison of the mechanical performance as an application related critical load case was in a good agreement. In this work, the proof of concept for the FEA model and the material model were carried out. In the future, the simulation will be used for further load cases such as the investigation of the bending stiffness and radial force and for the design optimization.

Optical coherence tomography (OCT) as imaging method is widely used in ophthalmology, oncology and cardiology. For intravascular imaging the OCT is used for pre-interventional as well as post-procedural assessments. Within the current study a test setup for ex vivo determination of the compliance of porcine coronary arteries via OCT is described. Diameter measurements based on OCT imaging were performed during consecutive pressurization of a porcine coronary artery from 40 to 200 mmHg in a physiological environment. The test results indicate that the radial compliance depends on the specific segment of the artery as well as the pressure range considered. The revealed compliance data can be used for numerical simulations of the vascular tissue as well as for optimization of in vitro test setups for pulsatile testing of vascular implants.

Catheters are widely used for therapeutic and diagnostic purposes in various medical applications. Along with frictional properties as well as the catheter profile the catheter stiffness mainly affects the deliverability and thus, the handling properties of the catheter. Within this study the bending stiffness of proximal and distal catheter samples was investigated with a custom made test setup. In particular, the influence of the catheter clamping length on the test results is discussed. Bending stiffness was calculated directly from the measured force, deflection and clamping length considering the test setup compliance. Measurements were performed three times at five positions in circumferential direction. Measured bending stiffness ranged from 629 ± 31 Nmm² to 733 ± 58 Nmm² for the proximal samples and from 30 ± 5 Nmm² to 98 ± 30 Nmm² for the distal samples, respectively. Bending stiffness varied depending on the free catheter length and the reaction force measured. The maximum reaction force decreased with increasing free catheter length leading to a higher measurement uncertainty. However, when considering the same free catheter length quantitative results were similar within the group of proximal and distal samples, respectively.