Melt blending of poly(lactic acid) with biomedically relevant polyurethanes to improve mechanical performance.

Minimally invasive surgery procedures are of utmost relevance in clinical practice. However, the associated mechanical stress on the material poses a challenge for new implant developments. In particular PLLA, one of the most widely used polymeric biomaterials, is limited in its application due to its high brittleness and low elasticity. In this context, blending is a conventional method of improving the performance of polymer materials. However, in implant applications and development, material selection is usually limited to the use of medical grade polymers. The focus of this work was to investigate the extent to which blending poly-l-lactide (PLLA) with low contents of a selection of five commercially available medical grade polyurethanes leads to enhanced material properties. The materials obtained by melt blending were characterized in terms of their morphology and thermal properties, and the mechanical performance of the blends was evaluated taking into account physiological conditions. From these data, we found that mixing PLLA with Pellethane 80A is a promising approach to improve the material's performance, particularly for stent applications. It was found that PLLA/Pellethane blend with 10% polyurethane exhibits considerable plastic deformation before fracture, while pure PLLA fractures with almost no deformation. Furthermore, the addition of Pellethane only leads to a moderate reduction in elongation at yield and yield stress. In addition, dynamic mechanical analysis for three different PLLA/Pellethane ratios was performed to investigate thermally induced shape retention and shape recovery of the blends.

Development of a bioresorbable self-expanding microstent for interventional applications - an innovative approach for stent-assisted coiling.

OBJECTIVES: Stent-assisted coiling prevents coil migration in broad-based intracranial aneurysms. So far, only permanent metal stents are approved for intracranial use. Bioresorbable stents allow a new therapeutic approach that may prevent the need for lifelong anticoagulation. We developed a neurovascular bioresorbable microstent (NBRS) and compared it in vitro to the commercial Neuroform EZ stent. MATERIALS AND METHODS: The self-expanding NBRS design is oriented on the Neuroform EZ stent. Poly L-lactic acid (PLLA) was used to manufacture semi-finished products in a dipping process. For the compensation of the inferior material properties of PLLA, design adjustments were made. The NBRS were cut by means of femtosecond (fs) laser and were morphologically and mechanically compared in vitro to the Neuroform EZ stent. In vitro implantation of an NBRS was performed using a complex patient-specific 3D-printed aneurysm model. In addition, an in vitro coiling procedure to assess the stent's ability to support a coil package was conducted. RESULTS: The NBRS could be reproducibly manufactured and had high quality regarding surface morphology. The radial force at the indicated vessel diameter of 3.0 mm was slightly higher for the Neuroform EZ stent compared to the NBRS. The self-expansion ability of the NBRS could be proven. The kink behavior of the NBRS was comparable to that of the Neuroform EZ stent, so no vessel lumen size reduction is expected. The stents showed identical deformation under local compression of 25 % based on the initial diameter, resulting in maximum forces of 24 ±â€Š5 mN (Neuroform EZ) and 8 ±â€Š2 mN (NBRS). The implanted NBRS expanded uniformly, and proper vessel wall adaptation was observed. The NBRS has the ability to retain a coil package. CONCLUSION: This study reported a reproducible manufacturing process for the developed NBRS as well as mechanical and morphological in vitro tests. Furthermore, successful NBRS implantation into a complex patient-specific vessel model was presented as proof of concept. The promising results of this study, also considering the commercial Neuroform EZ stent, support the idea of fully biodegradable microstents for intracranial aneurysm treatment. KEY POINTS: · High-performance polymer-based self-expanding neurovascular microstents were manufactured with good reproducibility.. · The bioresorbable microstent meets the requirements to pass through narrow radii.. · Implantability in a patient-specific and close-to-physiology vascular in vitro model was proven..

Development of a testing device for external wrist bridging dynamic fixators used for distal radius fractures.

BACKGROUND: Stabilization of extra-articular distal radius fractures by wrist joint bridging (WB) dynamic fixation allows for early motion of the wrist, but relies on exact positioning of the device. In fact, physiological movement appeared to be compromised with even distinctly aberrant positioning of such device. To investigate this issue in more detail, we developed an in-vitro testing apparatus suitable for assessing the forces required for flexion and extension of the wrist. METHODS: The experimental set-up enables the transmission of the translational movement of the traverse of a universal testing machine into the main physiological movement (flexion and extension) of the wrist. An external WB dynamic fixator was assembled to an artificial saw bone wrist model prior and after performing a wedge-shaped osteotomy on the distal radius about 1.5 cm proximal to the joint line, i.e. generation of a fracture model. The functionality of the fixator was evaluated under either condition and the effect of misalignment of the external WB dynamic fixator was quantified by purposeful violation of the manufacture's instructions. Results were statistically analyzed using the generalized linear mixed model. FINDINGS: Significantly higher loading was noted as the degree of misalignment increased. The normalized force was significantly higher at a misalignment of 20° compared to 10° (10°: 4.13; 20°: 6.93, P < 0.001). INTERPRETATION: The proposed set-up turned out to allow highly reproducible and sensitive recording of the reaction forces during flexion and extension of the wrist and thus is feasible for the evaluation and comparison of different external WB devices.

Investigation of Stent Prototypes for the Eustachian Tube in Human Donor Bodies.

Chronic otitis media is often connected to Eustachian tube dysfunction. As successful treatment cannot be guaranteed with the currently available options, the aim is to develop a stent for the Eustachian tube (ET). Over the course of this development, different prototypes were generated and tested in ex vivo experiments. Four different prototypes of an ET stent and one commercially available coronary stent were implanted in the ET of seven human donor bodies. The position of the stents was verified by cone beam CT. The implanted ETs were harvested, embedded in resin and ground at 200 µm steps. Resulting images of the single steps were used to generate 3D models. The 3D models were then evaluated regarding position of the stent in the ET, its diameters, amount of squeezing, orientation of the axes and other parameters. Virtual reconstruction of the implanted ET was successful in all cases and revealed one incorrect stent placement. The cross-section increased for all metal stents in direction from the isthmus towards the pharyngeal orifice of the ET. Depending on the individual design of the metal stents (open or closed design), the shape varied also between different positions along a single stent. In contrast, the cross-section area and shape remained constant along the polymeric prototype. With the current investigation, insight into the behavior of different prototypes of ET stents was gained, which can help in defining the specifications for the intended ET stent.

Revisiting SFA stent technology: an updated overview on mechanical stent performance.

OBJECTIVES: The study investigated mechanical parameters of stent systems indicated for treatment of femoropopliteal (FP) arterial disease to support interpretation of clinical results and the related causalities. METHODS: Eight stent system types of same dimensions were investigated (n=2). Parameters were the profile of stent delivery system (SDS), radiopacity, trackability and pushability, bending stiffness (flexibility) and axial stiffness of expanded stents, length change during expansion, radial force, crush resistance, strut thickness and general surface condition. RESULTS: The trackability ranged from 0.237 to 0.920 N and the pushability was 47.9-67.6 %. The bending stiffness of SDS was between 108.42 and 412.68 N mm2. The length change during stent release to 5 mm was low, with one exception. The bending stiffness of the expanded stents was 2.73-41.67 N mm2. The normalized radial forces at 5 mm diameter ranged from 0.133 N/mm to 0.503 N/mm. During non-radial compression by 50 %, the forces were 3.07-8.42 N, with one exception (58.7 N). The strut thickness was 153-231 µm. CONCLUSIONS: Large differences occurred for flexibility, radial force and length change during expansion. The data should be used when choosing the proper device for restoring vascular function.

Development of a Novel Valve-Controlled Drug-Elutable Microstent for Microinvasive Glaucoma Surgery: In Vitro and Preclinical In Vivo Studies.

Purpose: Microinvasive glaucoma surgery (MIGS) has become an important treatment approach for primary open-angle glaucoma, although the safe and long-term effective lowering of intraocular pressure with currently available implants for MIGS is not yet achieved to a satisfactory extent. The study focusses on the development and in vitro and in vivo testing of a novel microstent for MIGS. Methods: A silicone elastomer-based microstent was developed. Implants were manufactured using dip coating, fs-laser cutting, and spray coating. Within the current study no antifibrotic drug was loaded into the device. Sterilized microstents were analyzed in vitro regarding pressure-flow characteristics and biocompatibility. Six New Zealand white rabbits were implanted with a microstent draining the aqueous humor from the anterior chamber into the subconjunctival space. Drainage efficacy was evaluated using oculopressure tonometry as a transient glaucoma model. Noninvasive imaging was performed. Results: Microstents were manufactured successfully and characterized in vitro. Implantation in vivo was successful for four animals with additional device fixation. Without additional fixation, dislocation of microstents was found in two animals. Safe and effective intraocular pressure reduction was observed for the four eyes with correctly implanted microstent during the 6-month trial period. Conclusions: The described microstent represents an innovative treatment approach for MIGS. The incorporation of a selectively antifibrotic drug into the microstent drug-elutable coating will be addressed in future investigations. Translational Relevance: The current preclinical study successfully provided proof of concept for our microstent for MIGS which is suitable for safe and effective intraocular pressure reduction and offers promising perspectives for the clinical management of glaucoma.

Accelerated Endothelialization of Nanofibrous Scaffolds for Biomimetic Cardiovascular Implants.

Nanofiber nonwovens are highly promising to serve as biomimetic scaffolds for pioneering cardiac implants such as drug-eluting stent systems or heart valve prosthetics. For successful implant integration, rapid and homogeneous endothelialization is of utmost importance as it forms a hemocompatible surface. This study aims at physicochemical and biological evaluation of various electrospun polymer scaffolds, made of FDA approved medical-grade plastics. Human endothelial cells (EA.hy926) were examined for cell attachment, morphology, viability, as well as actin and PECAM 1 expression. The appraisal of the untreated poly-L-lactide (PLLA L210), poly-ε-caprolactone (PCL) and polyamide-6 (PA-6) nonwovens shows that the hydrophilicity (water contact angle > 80°) and surface free energy (<60 mN/m) is mostly insufficient for rapid cell colonization. Therefore, modification of the surface tension of nonpolar polymer scaffolds by plasma energy was initiated, leading to more than 60% increased wettability and improved colonization. Additionally, NH3-plasma surface functionalization resulted in a more physiological localization of cell−cell contact markers, promoting endothelialization on all polymeric surfaces, while fiber diameter remained unaltered. Our data indicates that hydrophobic nonwovens are often insufficient to mimic the native extracellular matrix but also that they can be easily adapted by targeted post-processing steps such as plasma treatment. The results achieved increase the understanding of cell−implant interactions of nanostructured polymer-based biomaterial surfaces in blood contact while also advocating for plasma technology to increase the surface energy of nonpolar biostable, as well as biodegradable polymer scaffolds. Thus, we highlight the potential of plasma-activated electrospun polymer scaffolds for the development of advanced cardiac implants.

Vascular Response Toward an Absorbable Sirolimus-eluting Polymeric Scaffold for Vascular Application in a Model of Normal Porcine Carotid Arteries.

BACKGROUND: Fully absorbable polymeric scaffolds, as a potential alternative to permanent metallic stents, are entering the clinical field. The aim of this study is to assess the in vivo biocompatibility of a novel Sirolimus-eluting (SIR) absorbable scaffold based on poly(L-lactide) (PLLA) and poly(4-hydroxybutyrate) (P4HB) for interventional application. METHODS: Absorbable PLLA/P4HB scaffolds either loaded with SIR coating or unloaded scaffolds were implanted interventionally into common carotid arteries of 14 female. Bare metal stents (BMS) served as control. Peroral dual anti-platelet therapy was administered throughout the study. Stented common carotid arteries segments were explanted after 4 weeks, and assessed histomorphometrically. RESULTS: The absorbable scaffolds showed a decreased residual lumen area and higher stenosis after 4 weeks (PLLA/P4HB: 6.56 ± 0.41 mm² and 37.56 ± 4.67%; SIR-PLLA/P4HB: 6.90 ± 0.58 mm² and 35.60 ± 3.15%) as compared to BMS (15.29 ± 1.86 mm² and 7.65 ± 2.27%). Incorporation of SIR reduced the significantly higher inflammation of unloaded scaffolds however not to a level compared to bare metal stent (PLLA/P4HB: 1.20 ± 0.19; SIR-PLLA/P4HB: 0.96 ± 0.24; BMS: 0.54 ± 0.12). In contrast, the BMS showed a slightly elevated vascular injury score (0.74 ± 0.15), as compared to the PLLA/P4HB (0.54 ± 0.20) and the SIR-PLLA/P4HB (0.48 ± 0.15) groups. CONCLUSION: In this preclinical model, the new absorbable polymeric (SIR-) scaffolds showed similar technical feasability and safety for vascular application as the permanent metal stents. The higher inflammatory propensity of the polymeric scaffolds was slightly reduced by SIR-coating. A smaller strut thickness of the polymeric scaffolds might have been a positive effect on tissue ingrowth between the struts and needs to be addressed in future work on the stent design.

An optimized 3D-printed perfusion bioreactor for homogeneous cell seeding in bone substitute scaffolds for future chairside applications.

A clinical implementation of cell-based bone regeneration in combination with scaffold materials requires the development of efficient, controlled and reproducible seeding procedures and a tailor-made bioreactor design. A perfusion system for efficient, homogeneous, and rapid seeding with human adipogenic stem cells in bone substitute scaffolds was designed. Variants concerning medium inlet and outlet port geometry, i.e. cylindrical or conical diffuser, cell concentration, perfusion mode and perfusion rates were simulated in silico. Cell distribution during perfusion was monitored by dynamic [18F]FDG micro-PET/CT and validated by laser scanning microscopy with three-dimensional image reconstruction. By iterative feedback of the in silico and in vitro experiments, the homogeneity of cell distribution throughout the scaffold was optimized with adjustment of flow rates, cell density and perfusion properties. Finally, a bioreactor with a conical diffusor geometry was developed, that allows a homogeneous cell seeding (hoover coefficient: 0.24) in less than 60 min with an oscillating perfusion mode. During this short period of time, the cells initially adhere within the entire scaffold and stay viable. After two weeks, the formation of several cell layers was observed, which was associated with an osteogenic differentiation process. This newly designed bioreactor may be considered as a prototype for chairside application.

Side-branch expansion capacity of contemporary DES platforms.

BACKGROUND: Percutaneous coronary interventions (PCI) of bifurcation stenoses are both complex and challenging. Stenting strategies share that the stents' side cells must be carefully explored and appropriately prepared using balloons or stents. So far, stent manufacturers have not provided any information regarding side-branch expansion capacity of their stent platforms. AIMS: Given that drug-eluting stent (DES) information regarding their mechanical capacity of side-branch expansion is not available, we aimed to evaluate contemporary DES (Orsiro, BIOTRONIK AG; Xience Sierra, Abbott Vascular; Resolute Integrity, Medtronic; Promus Premier Select, Boston Scientific; Supraflex Cruz, Sahajan and Medical Technologies) by their side-branch expansion behavior using in vitro bench testing. METHODS: In this in vitro study, we analyzed five commercially available DES (diameter 3.0 mm), measuring their side-branch expansion following inflation of different high-pressure non-compliant (NC) balloons (balloon diameter: 2.00-4.00 mm), thereby revealing the morphological characteristics of their side-branch expansion capacities. RESULTS: We demonstrated that all tested contemporary DES platforms could withstand large single-cell deformations, up to 4.0 mm. As seen in our side-branch experiments, DES designs consisting of only two connectors between strut rings did not only result in huge cell areas, but also in larger cell diameters following side-branch expansion compared with DES designs using three or more connectors. Furthermore, the stent cell diameter attained was below the balloon diameter at normal pressure. CONCLUSIONS: We recommend that the expansion capacity of side-branches should be considered in stent selection for bifurcation interventions.

The Role of Biodegradable Poly-(L-lactide)-Based Polymers in Blood Cell Activation and Platelet-Monocyte Interaction.

The main purpose of new stent technologies is to overcome unfavorable material-related incompatibilities by producing bio- and hemo-compatible polymers with anti-inflammatory and anti-thrombogenic properties. In this context, wettability is an important surface property, which has a major impact on the biological response of blood cells. However, the influence of local hemodynamic changes also influences blood cell activation. Therefore, we investigated biodegradable polymers with different wettability to identify possible aspects for a better prediction of blood compatibility. We applied shear rates of 100 s-1 and 1500 s-1 and assessed platelet and monocyte activation as well as the formation of CD62P+ monocyte-bound platelets via flow cytometry. Aggregation of circulating platelets induced by collagen was assessed by light transmission aggregometry. Via live cell imaging, leukocytes were tracked on biomaterial surfaces to assess their average velocity. Monocyte adhesion on biomaterials was determined by fluorescence microscopy. In response to low shear rates of 100 s-1, activation of circulating platelets and monocytes as well as the formation of CD62P+ monocyte-bound platelets corresponded to the wettability of the underlying material with the most favorable conditions on more hydrophilic surfaces. Under high shear rates, however, blood compatibility cannot only be predicted by the concept of wettability. We assume that the mechanisms of blood cell-polymer interactions do not allow for a rule-of-thumb prediction of the blood compatibility of a material, which makes extensive in vitro testing mandatory.

Methodology for comprehensive cell-level analysis of wound healing experiments using deep learning in MATLAB.

BACKGROUND: Endothelial healing after deployment of cardiovascular devices is particularly important in the context of clinical outcome. It is therefore of great interest to develop tools for a precise prediction of endothelial growth after injury in the process of implant deployment. For experimental investigation of re-endothelialization in vitro cell migration assays are routinely used. However, semi-automatic analyses of live cell images are often based on gray value distributions and are as such limited by image quality and user dependence. The rise of deep learning algorithms offers promising opportunities for application in medical image analysis. Here, we present an intelligent cell detection (iCD) approach for comprehensive assay analysis to obtain essential characteristics on cell and population scale. RESULTS: In an in vitro wound healing assay, we compared conventional analysis methods with our iCD approach. Therefore we determined cell density and cell velocity on cell scale and the movement of the cell layer as well as the gap closure between two cell monolayers on population scale. Our data demonstrate that cell density analysis based on deep learning algorithms is superior to an adaptive threshold method regarding robustness against image distortion. In addition, results on cell scale obtained with iCD are in agreement with manually velocity detection, while conventional methods, such as Cell Image Velocimetry (CIV), underestimate cell velocity by a factor of 0.5. Further, we found that iCD analysis of the monolayer movement gave results just as well as manual freehand detection, while conventional methods again shows more frayed leading edge detection compared to manual detection. Analysis of monolayer edge protrusion by ICD also produced results, which are close to manual estimation with an relative error of 11.7%. In comparison, the conventional Canny method gave a relative error of 76.4%. CONCLUSION: The results of our experiments indicate that deep learning algorithms such as our iCD have the ability to outperform conventional methods in the field of wound healing analysis. The combined analysis on cell and population scale using iCD is very well suited for timesaving and high quality wound healing analysis enabling the research community to gain detailed understanding of endothelial movement.

Influence of Drug Incorporation on the Physico-Chemical Properties of Poly(l-Lactide) Implant Coating Matrices-A Systematic Study.

Local drug delivery has become indispensable in biomedical engineering with stents being ideal carrier platforms. While local drug release is superior to systemic administration in many fields, the incorporation of drugs into polymers may influence the physico-chemical properties of said matrix. This is of particular relevance as minimally invasive implantation is frequently accompanied by mechanical stresses on the implant and coating. Thus, drug incorporation into polymers may result in a susceptibility to potentially life-threatening implant failure. We investigated spray-coated poly-l-lactide (PLLA)/drug blends using thermal measurements (DSC) and tensile tests to determine the influence of selected drugs, namely sirolimus, paclitaxel, dexamethasone, and cyclosporine A, on the physico-chemical properties of the polymer. For all drugs and PLLA/drug ratios, an increase in tensile strength was observed. As for sirolimus and dexamethasone, PLLA/drug mixed phase systems were identified by shifted drug melting peaks at 200 °C and 240 °C, respectively, whereas paclitaxel and dexamethasone led to cold crystallization. Cyclosporine A did not affect matrix thermal properties. Altogether, our data provide a contribution towards an understanding of the complex interaction between PLLA and different drugs. Our results hold implications regarding the necessity of target-oriented thermal treatment to ensure the shelf life and performance of stent coatings.

Smart releasing electrospun nanofibers-poly: L.lactide fibers as dual drug delivery system for biomedical application.

An ongoing challenge in drug delivery systems for a variety of medical applications, including cardiovascular diseases, is the delivery of multiple drugs to address numerous phases of a treatment or healing process. Therefore, an extended dual drug delivery system (DDDS) based on our previously reported cardiac DDDS was generated. Here we use the polymer poly(L-lactide) (PLLA) as drug carrier with the cytostatic drug Paclitaxel (PTX) and the endothelial cell proliferation enhancing growth factor, human vascular endothelial growth factor (VEGF), to overcome typical in-stent restenosis complications. We succeeded in using one solution to generate two separate DDDS via spray coating (film) and electrospinning (nonwoven) with the same content of PTX and the same post processing for VEGF immobilisation. Both processes are suitable as coating techniques for implants. The contact angle analysis revealed differences between films and nonwovens. Whereas, the morphological analysis demonstrated nearly no changes occurred after immobilisation of both drugs. Glass transition temperatures (Tg ) and degree of crystallinity (χ) show only minor changes. The amount of immobilised VEGF on nonwovens was over 300% higher compared to the films. Also, the nonwovens revealed a much faster and over three times higher PTX release over 70 d compared to the films. The almost equal physical properties of nonwovens and films allow the comparison of both DDDS independently of their fabrication process. Both films and nonwovens have significantly increased in vitro cell viability for human umbilical vein endothelial cells (EA.hy926) with dual loaded PTX and VEGF compared to PTX-only loaded samples.

Three-dimensional imaging and three-dimensional printing for plastic preparation of medical interventions.

Three-dimensional (3D) imaging has been available for nearly four decades and is regarded as state of the art for visualization of anatomy and pathology and for procedure planning in many clinical fields. Together with 3D image reconstructions in the form of rendered virtual 3D models, it has helped to better perceive complex anatomic and pathologic relations, improved preprocedural measuring and sizing of implants, and nowadays enables even photorealistic quality. However, presentation on 2D displays limits the 3D experience. Novel 3D printing technologies can transfer virtual anatomic models into true 3D space and produce both patient-specific models and medical devices constructed by computer-aided design. Individualized anatomic models hold great potential for medical and patient education, research, device development and testing, procedure training, preoperative planning, and fabrication of individualized instruments and implants. Hand in hand with 3D imaging, medical 3D printing has started to revolutionize medicine in certain fields and new applications are developed and introduced regularly. The demand for medical 3D printing will likely continue to rise, as it is a promising tool for plastic preparation of medical interventions. However, there is ongoing debate on the appropriateness of medical 3D printing and further research on its efficiency is needed. As experts in 3D imaging, radiologists are not only capable of advising on adequate imaging parameters, but should also become adept in 3D printing to participate in on-site 3D printing facilities and randomized controlled trials on the topic, thus contributing to improving patient outcomes via personalized medicine through patient-specific preparation of medical interventions.

Impact of strut dimensions and vessel caliber on thrombosis risk of bioresorbable scaffolds using hemodynamic metrics.

Bioresorbable scaffolds (BRS) promise to be the treatment of choice for stenosed coronary vessels. But higher thrombosis risk found in current clinical studies limits the expectations. Three hemodynamic metrics are introduced to evaluate the thrombosis risk of coronary stents/scaffolds using transient computational fluid dynamics (CFD). The principal phenomena are platelet activation and effective diffusion (platelet shear number, PSN), convective platelet transport (platelet convection number, PCN) and platelet aggregation (platelet aggregation number, PAN) were taken into consideration. In the present study, two different stent designs (thick-strut vs. thin-strut design) positioned in small- and medium-sized vessels (reference vessel diameter, RVD=2.25 mm vs. 2.70 mm) were analyzed. In both vessel models, the thick-strut design induced higher PSN, PCN and PAN values than the thin-strut design (thick-strut vs. thin-strut: PSN=2.92/2.19 and 0.54/0.30; PCN=3.14/1.15 and 2.08/0.43; PAN: 14.76/8.19 and 20.03/10.18 for RVD=2.25 mm and 2.70 mm). PSN and PCN are increased by the reduction of the vessel size (PSN: RVD=2.25 mm vs. 2.70 mm=5.41 and 7.30; PCN: RVD=2.25 mm vs. 2.70 mm=1.51 and 2.67 for thick-strut and thin-strut designs). The results suggest that bulky stents implanted in small caliber vessels may substantially increase the thrombosis risk. Moreover, sensitivity analyses imply that PSN is mostly influenced by vessel size (lesion-related factor), whereas PCN and PAN sensitively respond to strut-thickness (device-related factor).

Mechanical behavior of in vivo degraded second generation resorbable magnesium scaffolds (RMS).

Resorbable magnesium scaffolds are used for the treatment of atherosclerotic coronary vascular disease and furthermore, for vascular restoration therapy. Recently, the first-in-man clinical studies with Magmaris showed promising results regarding the target lesion failure as well as vasomotion properties after 12 and 24 month. The consistency of in vivo degraded magnesium alloys in a cardiovascular environment is qualitatively described in literature, but only little has been disclosed about the actual change in mechanical properties and the behavior of the magnesium alloy degradation products. In the present study, uncoated magnesium scaffolds 3.0 × 20 mm were implanted in coronary arteries of two healthy Goetinnger mini-swine. The scaffolds were explanted to evaluate the mechanical properties of the degraded magnesium scaffolds after 180 days in vivo. Ex vivo sample preparation and test conditions were adapted to a customized compression test setup which was developed to investigate the micro-scale scaffold fragments (width 225 ±â€¯75 µm, thickness 150 µm). As reference bare undegraded magnesium scaffold fragments were tested. Mechanical parameters relating to force as a function of displacement were determined for both sample groups. The undegraded samples showed no fracturing at the maximum applied force of 8 N, whereas the in vivo degraded test samples showed forces of 0.411 ±â€¯0.197 N at the first fracturing and a maximum force of 0.956 ±â€¯0.525 N. The deformation work, calculated as area beneath the force-displacement curve, of the in vivo degraded test samples was reduced by approximately 87-88% compared to the undegraded samples (5.20 mN mm and 40.79 mN mm, both at 7.5% deformation). The indication for a complete loss of structural integrity through a reduction of mechanical properties after a certain degradation time increases the chance to restore vascular function and physiological vasomotion in the stented vessel compartment.

[Development of an Oculopressor to Evaluate the Efficiency of Glaucoma Drainage Devices]. / Entwicklung eines Okulopressors zur Evaluation der Funktionalität von Glaukomdrainage-Implantaten.

PURPOSE: Evaluation of the long-term efficiency of MIGS implants is still challenging, due to the lack of standardized clinical studies of stand-alone procedures. Moreover, the different mechanisms of the various glaucoma drainage devices are not adequately considered. The current study focusses on the development of a method for oculopression to evaluate the efficiency of glaucoma drainage devices. METHODS: Explanted porcine eyes were subjected to pressure or weight load using three oculopressors with different modi operandi. The time-dependent intraocular pressure was measured using an anterior chamber maintainer. The Honan Balloon exerts variable pressure onto the eye via an air bellows, whereas the Taylor oculopressor applies a defined weight loading on the eye. A novel oculopressor with a weight loading of 60 g was developed and manufactured by means of 3-D-printing. RESULTS: The intraocular pressure changes observed during the experiments were similar for all tested oculopression devices, varying only in the absolute pressure values. The Honan Balloon was not suitable for the intended purpose, due to poor standardisation of the applied pressure. Oculopression using a defined weight appeared more suitable. The Taylor oculopressor, however, created intraocular pressure values of up to 203.3 ± 38.4 mmHg, which precludes its use with glaucoma patients. On the basis of these data, the new oculopression device was used in a preliminary trial with healthy human subjects, thereby preparing its use in a clinical trial. CONCLUSIONS: Oculopression represents a potentially suitable tool to analyse the efficiency of glaucoma drainage devices. Commercially available oculopression devices are not directly applicable for this task. Difficult handling, high intraocular pressure, and lack of standardisation complicate the use for glaucoma patients. These difficulties were overcome with the newly designed oculopressor that facilitates a well defined increase in intraocular pressure. The device is currently being used in a clinical study to evaluate the efficiency of MIGS implants.

Development of a biodegradable antifibrotic local drug delivery system for glaucoma microstents.

To prevent implant failure due to fibrosis is a major objective in glaucoma research. The present study investigated the antifibrotic effects of paclitaxel (PTX), caffeic acid phenethyl ester (CAPE), and pirfenidone (PFD) coated microstent test specimens in a rat model. Test specimens based on a biodegradable blend of poly(4-hydroxybutyrate) biopolymer and atactic poly(3-hydroxybutyrate) (at.P(3HB)) were manufactured, equipped with local drug delivery (LDD) coatings, and implanted in the subcutaneous white fat depot. Postoperatively, test specimens were explanted and analyzed for residual drug content. Fat depots including the test specimens were histologically analyzed. In vitro drug release studies revealed an initial burst for LDD devices. In vivo, slow drug release of PTX was found, whereas it already completed 1 week postoperatively for CAPE and PFD LDD devices. Histological examinations revealed a massive cell infiltration in the periphery of the test specimens. Compact fibrotic capsules around the LDD devices were detectable at 4-36 weeks and least pronounced around PFD-coated specimens. Capsules stained positive for extracellular matrix (ECM) components. The presented model offers possibilities to investigate release kinetics and the antifibrotic potential of drugs in vivo as well as the identification of more effective agents for a novel generation of drug-eluting glaucoma microstents.

Novel approach for a PTX/VEGF dual drug delivery system in cardiovascular applications-an innovative bulk and surface drug immobilization.

The successive incorporation of several drugs into the polymeric bulk of implants mostly results in loss of considerable quantity of one drug, and/or the loss in quality of the coating and also in changes of drug release time points. A dual drug delivery system (DDDS) based on poly-L-lactide (PLLA) copolymers combining the effective inhibition of smooth muscle cell proliferation while simultaneously promoting re-endothelialization was successfully developed. To overcome possible antagonistic drug interactions and the limitation of the polymeric bulk material as release system for dual drugs, a novel concept which combines the bulk and surface drug immobilization for a DDDS was investigated. The advantage of this DDDS is that the bulk incorporation of fluorescein diacetate (FDAc) (model drug for paclitaxel (PTX)) via spray coating enhanced the subsequent cleavable surface coupling of vascular endothelial growth factor (VEGF) via the crosslinker bissulfosuccinimidyl suberate (BS3). In the presence of the embedded FDAc, the VEGF loading and release are about twice times higher than in absence. Furthermore, the DDDS combines the diffusion drug delivery (FDAc or PTX) and the chemical controlled drug release, VEGF via hydrolysable ester bonds, without loss in quantity and quality of the drug release curves. Additionally, the performed in vitro biocompatibility study showed the bimodal influences of PTX and VEGF on human endothelial EA.hy926 cells. In conclusion, it was possible to show the feasibility to develop a novel DDDS which has a high potential for the medical application due to the possible easy and short modification of a polymer-based PTX delivery system.