Comparison of the international regulations for medical devices-USA versus Europe.

In May 2021, the new Medical Device Regulation in the EU came into force. While the US has a centralized governmental authority, the Food and Drug Administration (FDA), the EU implemented a system of different Notified Bodies responsible for the approval process of medical devices. Both regions have a similar system to classify medical devices based on their overall risks but specific devices, like joint prostheses, are classified differently in the US and the EU. Depending on the risk class, there are differences in the quality and quantity of clinical data required to obtain market approval. In both regions, it is possible to place a new device on the market based on the demonstration of equivalence to an already marketed device, but the MDR significantly increased the regulatory requirements for the equivalence pathway. While an approved medical device in the US in most cases only requires general post-market surveillance activities, manufacturers in the EU must continuously collect clinical data and submit specific reports to the Notified Bodies. In this article, we will compare the regulatory requirements between the US and Europe and provide an overview of similarities and differences.

Regulatory clearance: How are outcome measurements critical?

In May 2017 the European Medical Device Regulation (MDR) was published to replace the current Medical Device Directive (MDD) and the Active Implantable Medical Device Directive (AIMDD). After a transition period of 3 years (ending May 2020) the MDR will apply in the European Union (EU). With this new legislative framework, the requirements for placing new medical devices and keeping existing medical devices on the EU market will become more stringent. This is mainly due to the focus on clinical data for all medical devices regardless of their classification and the increased requirements on the post market surveillance system. In most cases, the MDR will require pre-market clinical studies for implantable medical devices and devices falling in the highest risk class (Class III). Since 2000 there has been a significant increase in the quantity and quality of publications in the fields of orthopaedic and orthopaedic trauma surgery. However, there is still a large number of medical devices without direct clinical data which rely on market experience and the established level of a specific technology or a group of devices. Due to this fact, and the fact that the new MDR is requiring sufficient clinical data for devices which shall stay on the market after May 2020, there is an increasing need for new clinical data sources reflecting the real-world use of medical devices.

Evaluation of Hybrid Surgical Access Approaches for Pulmonary Valve Implantation in an Acute Swine Model.

Percutaneous implantation of the pulmonary valve through peripheral vascular access can be limited due to poor venous access, low patient weight, hemodynamic or rhythmic instability, and size constraints related to the valve. In such cases, hybrid procedures may provide alternatives. Because the most commonly used median sternotomy is unsuitable for chronic trials in large animals, we evaluated several hybrid approaches for pulmonary valve replacement in a swine model. We tested the feasibility of hybrid pulmonary valve implantation in pigs by using inhouse-generated valves containing bare-metal or nitinol stents. Valves consisted of bovine jugular veins, bovine pericardial valves, or sprayed polyurethane valves. Access was achieved through median sternotomy, lower partial sternotomy, transverse sternotomy, or right lateral thoracotomy. The delivery device was introduced in a transventricular manner. Implantation took place under fluoroscopic and epicardial echocardiographic guidance. We achieved implantation of the stented valve in 12 (92.3%) pigs, of which 5 (41.7%) of the implanted valves were in an optimal position. Paravalvular leakage occurred in 2 trials (16.7%). Lower partial sternotomy provided the best trade-off between feasibility and minimized trauma for long-term animal trials. Here we describe our experience with hybrid pulmonary valve implantation in an acute large-animal (swine) model. We demonstrate the feasibility of the procedure in terms of surgical technique and the perioperative management and preparation of the field for a chronic trial.

A feasibility study of a multimodal stimulation bioreactor for the conditioning of stem cell seeded cardiac patches via electrical impulses and pulsatile perfusion.

BACKGROUND/OBJECTIVE: Ischemic heart disease is a major cause of mortality worldwide. Myocardial tissue engineering aims to create transplantable units of myocardium for the treatment of myocardial necrosis caused by ischemic heart disease - bioreactors are used to condition these bioartificial tissues before application. METHODS: Our group developed a multimodal bioreactor consisting of a linear drive motor for pulsatile flow generation (500 ml/min) and an external pacemaker for electrical stimulation (10 mA, 3 V at 60 Hz) using LinMot-Talk Software to synchronize these modes of stimulation. Polyurethane scaffolds were seeded with 0.750 × 106 mesenchymal stem cells from umbilical cord tissue per cm2 and stimulated in our system for 72 h, then evaluated. RESULTS: After conditioning histology showed that the patches consisted of a cell multilayer surviving stimulation without major damage by the multimodal stimulation, scanning electron microscopy showed a confluent cell layer with no cell-cell interspaces visible. No cell viability issues could be identified via Syto9-Propidium Iodide staining. CONCLUSIONS: This bioreactor allows mechanical stimulation via pulsatile flow and electrical stimulation through a pacemaker. Our stem cell-polyurethane constructs displayed survival after conditioning. This system shows feasibility in preliminary tests.

Is Transcatheter Aortic Valve Implantation of Living Tissue-Engineered Valves Feasible? An In Vitro Evaluation Utilizing a Decellularized and Reseeded Biohybrid Valve.

Transcatheter aortic valve implantation (TAVI) is a fast-growing, exciting field of invasive therapy. During the last years many innovations significantly improved this technique. However, the prostheses are still associated with drawbacks. The aim of this study was to create cell-seeded biohybrid aortic valves (BAVs) as an ideal implant by combination of assets of biological and artificial materials. Furthermore, the influence of TAVI procedure on tissue-engineered BAV was investigated. BAV (n=6) were designed with decellularized homograft cusps and polyurethane walls. They were seeded with fibroblasts and endothelial cells isolated from saphenous veins. Consecutively, BAV were conditioned under low pulsatile flow (500 mL/min) for 5 days in a specialized bioreactor. After conditioning, TAVI-simulation was performed. The procedure was concluded with re-perfusion of the BAV for 2 days at an increased pulsatile flow (1100 mL/min). Functionality was assessed by video-documentation. Samples were taken after each processing step and evaluated by scanning electron microscopy (SEM), immunohistochemical staining (IHC), and Live/Dead-assays. The designed BAV were fully functioning and displayed physiologic behavior. After cell seeding, static cultivation and first conditioning, confluent cell layers were observed in SEM. Additionally, IHC indicated the presence of endothelial cells and fibroblasts. A significant construction of extracellular matrix was detected after the conditioning phase. However, a large number of lethal cells were observed after crimping by Live/Dead staining. Analysis revealed that the cells while still being present directly after crimping were removed in subsequent perfusion. Extensive regions of damaged cell-layers were detected by SEM-analysis substantiating these findings. Furthermore, increased ICAM expression was detected after re-perfusion as manifestation of inflammatory reaction. The approach to generate biohybrid valves is promising. However, damages inflicted during the crimping process seem not to be immediately detectable. Due to severe impacts on seeded cells, the strategy of living TE valves for TAVI should be reconsidered.

In vitro biological and mechanical evaluation of various scaffold materials for myocardial tissue engineering.

A cardiac patch is a construct devised in regenerative medicine to replace necrotic heart tissue after myocardial infarctions. The cardiac patch consists of a scaffold seeded with stem cells. To identify the best scaffold for cardiac patch construction we compared polyurethane, Collagen Cell Carriers, ePTFE, and ePTFE SSP1-RGD regarding their receptiveness to seeding with mesenchymal stem cells isolated from umbilical cord tissue. Seeding was tested at an array of cell seeding densities. The bioartificial patches were cultured for up to 35 days and evaluated by scanning electron microscopy, microscopy of histological stains, fluorescence microscopy, and mitochondrial assays. Polyurethane was the only biomaterial which resulted in an organized multilayer (seeding density: 0.750 × 10(6) cells/cm(2)). Cultured over 35 days at this seeding density the mitochondrial activity of the cells on polyurethane patches continually increased. There was no decrease in the E Modulus of polyurethane once seeded with cells. Seeding of CCC could only be realized at a low seeding density and both ePTFE and ePTFE SSP1-RGD were found to be unreceptive to seeding. Of the tested scaffolds polyurethane thus crystallized as the most appropriate for seeding with mesenchymal stem cells in the framework of myocardial tissue engineering.

In vitro comparison of novel polyurethane aortic valves and homografts after seeding and conditioning.

The aim of the study was to compare the behavior of seeded cells on synthetic and natural aortic valve scaffolds during a low-flow conditioning period. Polyurethane (group A) and aortic homograft valves (group B) were consecutively seeded with human fibroblasts (FB), and endothelial cells (EC) using a rotating seeding device. Each seeding procedure was followed by an exposure to low pulsatile flow in a dynamic bioreactor for 5 days. For further analysis, samples were taken before and after conditioning. Scanning electron microscopy showed confluent cell layers in both groups. Immunohistochemical analysis showed the presence of EC and FB before and after conditioning as well as the establishment of an extracellular matrix (ECM) during conditioning. A higher expression of ECM was observed on the scaffolds' inner surface. Real-time polymerase chain reaction showed higher inflammatory response during the conditioning of homografts. Endothelialization caused a decrease in inflammatory gene expression. The efficient colonization, the establishment of an ECM, and the comparable inflammatory cell reaction to the scaffolds in both groups proved the biocompatibility of the synthetic scaffold. The newly developed bioreactor permits conditioning and cell adaption to shear stress. Therefore, polyurethane valve scaffolds may offer a new option for aortic valve replacement.

Transcatheter valve replacement: new concepts for microsurgery inside the heart.

OBJECTIVE: Transcatheter aortic valve implantation gained clinical relevance with an impressive and peerless power; however, the procedure induces unsolved complications such as paravalvular leakage, occlusion of coronary ostia, and vascular complications. The safe removal of bulky calcified valves will improve the outcome, well known through the open surgical procedure. In this article, a new stapler-based resection and implantation device as well as a new approach for valve isolation during normal heart cycle without extracorporeal circulation will be analyzed. METHODS: First, a novel stapler-based instrument for transapical aortic valve replacement [removal and implantation; stapler-based aortic valve replacement (StapAVR)] was constructed and analyzed in an aortic debris model. Artificial aortic valves (N = 20), containing fluorescent granules to simulate the calcification, were placed into an aortic model in anatomical supine position (DP) and right-sided lateral position (RP). With the StapAVR, resection before implantation was performed in a water-filled basin. Black light was used for debris visualization. The procedures have been digitally recorded and analyzed due to procedural times, and the debris amount in thoracic side branches. Second, an enhanced prototype of the pulmonary valve isolation chamber (PVIC) was analyzed in porcine in vitro (n = 10) and in vivo models (n = 1). This PVIC contains a microaxial pump (Impella; Abiomed, Aachen, Germany) in the central bypass channel. It was deployed through the right ventricular wall. Once the PVIC was in place, the pump was started before isolating the valve. The complete hemodynamic monitoring was digitally recorded. RESULTS: The deployment of the StapAVR in the correct position and the valve resection time took a mean (SD) of 95.8 (19) seconds in DP and 90.1 (18) seconds in RP. Fluorescent debris was found: in the left coronary artery, 22% in DP and 7% in RP; in the ascending aorta, 0% in DP and 11% in RP; in the aortic bulbous, 5% in DP and 10% in RP; in the left ventricle, 8% in DP and 14% in RP; in the brachiocephalic trunk, 4% in DP and 9% in RP; and in the descending aorta, 46% in DP and 1% in RP. Consecutive valved stent implantation was performed without complications. The PVIC deployment time in vivo was 5 minutes, replacements included. The total valve isolation time was 21 minutes, with a mean (SD) bypass flow of 2.1 (0.4) L/min. The oxygen saturation showed a median of 91% (range, 83%-97%), and the median arterial blood pressure was 69 mm Hg (systolic; range, 47-120 mm Hg) and 40mm Hg (diastolic; range, 32-56 mm Hg) without the use of inotropes or vasopressors. Electrocardiogram confirmed sinus rhythm during isolation. CONCLUSIONS: The resection of the artificial valves followed by valved stent implantation was possible with the StapAVR. In vivo, the procedure will be carried out under rapid pacing and sudden vacuum; however, the results of this in vitro debris model underline the need for isolation or filter devices during transcatheter aortic valve implantation to avoid embolization. Secondly, the use of the pump-advanced PVIC showed stable heart function for 21 minutes under isolated pulmonary valve conditions. This time will be adequate to remove bulky calcifications and to implant a valved stent. Improvements of both prototypes are ongoing. Nevertheless, the presented concepts showed promising application possibilities in the future.

Noninvasive analysis of synthetic and decellularized scaffolds for heart valve tissue engineering.

Microcomputed tomography (µ-CT) is a nondestructive, high-resolution, three-dimensional method of analyzing objects. The aim of this study was to evaluate the feasibility of using µ-CT as a noninvasive method of evaluation for tissue-engineering applications. The polyurethane aortic heart valve scaffold was produced using a spraying technique. Cryopreserved/thawed homograft and biological heart valve were decellularized using a detergent mixture. Human endothelial cells and fibroblasts were derived from saphenous vein segments and were verified by immunocytochemistry. Heart valves were initially seeded with fibroblasts followed by colonization with endothelial cells. Scaffolds were scanned by a µ-CT scanner before and after decellularization as well as after cell seeding. Successful colonization was additionally determined by scanning electron microscopy (SEM) and immunohistochemistry (IHC). Microcomputed tomography accurately visualized the complex geometry of heart valves. Moreover, an increase in the total volume and wall thickness as well as a decrease in total surface was demonstrated after seeding. A confluent cell distribution on the heart valves after seeding was confirmed by SEM and IHC. We conclude that µ-CT is a new promising noninvasive method for qualitative and quantitative analysis of tissue-engineering processes.

Use of a special bioreactor for the cultivation of a new flexible polyurethane scaffold for aortic valve tissue engineering.

BACKGROUND: Tissue engineering represents a promising new method for treating heart valve diseases. The aim of this study was evaluate the importance of conditioning procedures of tissue engineered polyurethane heart valve prostheses by the comparison of static and dynamic cultivation methods. METHODS: Human vascular endothelial cells (ECs) and fibroblasts (FBs) were obtained from saphenous vein segments. Polyurethane scaffolds (n = 10) were primarily seeded with FBs and subsequently with ECs, followed by different cultivation methods of cell layers (A: static, B: dynamic). Group A was statically cultivated for 6 days. Group B was exposed to low flow conditions (t1=3 days at 750 ml/min, t2=2 days at 1100 ml/min) in a newly developed conditioning bioreactor. Samples were taken after static and dynamic cultivation and were analyzed by scanning electron microscopy (SEM), immunohistochemistry (IHC), and real time polymerase chain reaction (RT-PCR). RESULTS: SEM results showed a high density of adherent cells on the surface valves from both groups. However, better cell distribution and cell behavior was detected in Group B. IHC staining against CD31 and TE-7 revealed a positive reaction in both groups. Higher expression of extracellular matrix (ICAM, Collagen IV) was observed in Group B. RT- PCR demonstrated a higher expression of inflammatory Cytokines in Group B. CONCLUSION: While conventional cultivation method can be used for the development of tissue engineered heart valves. Better results can be obtained by performing a conditioning step that may improve the tolerance of cells to shear stress. The novel pulsatile bioreactor offers an adequate tool for in vitro improvement of mechanical properties of tissue engineered cardiovascular prostheses.

A Pulsatile Bioreactor for Conditioning of Tissue-Engineered Cardiovascular Constructs under Endoscopic Visualization.

Heart valve disease (HVD) is a globally increasing problem and accounts for thousands of deaths yearly. Currently end-stage HVD can only be treated by total valve replacement, however with major drawbacks. To overcome the limitations of conventional substitutes, a new clinical approach based on cell colonization of artificially manufactured heart valves has been developed. Even though this attempt seems promising, a confluent and stable cell layer has not yet been achieved due to the high stresses present in this area of the human heart. This study describes a bioreactor with a new approach to cell conditioning of tissue engineered heart valves. The bioreactor provides a low pulsatile flow that grants the correct opening and closing of the valve without high shear stresses. The flow rate can be regulated allowing a steady and sensitive conditioning process. Furthermore, the correct functioning of the valve can be monitored by endoscope surveillance in real-time. The tubeless and modular design allows an accurate, simple and faultless assembly of the reactor in a laminar flow chamber. It can be concluded that the bioreactor provides a strong tool for dynamic pre-conditioning and monitoring of colonized heart valve prostheses physiologically exposed to shear stress.

A novel pulsatile bioreactor for mechanical stimulation of tissue engineered cardiac constructs.

After myocardial infarction, the implantation of stem cell seeded scaffolds on the ischemic zone represents a promising strategy for restoration of heart function. However, mechanical integrity and functionality of tissue engineered constructs need to be determined prior to implantation. Therefore, in this study a novel pulsatile bioreactor mimicking the myocardial contraction was developed to analyze the behavior of mesenchymal stem cells derived from umbilical cord tissue (UCMSC) colonized on titanium-coated polytetrafluorethylene scaffolds to friction stress. The design of the bioreactor enables a simple handling and defined mechanical forces on three seeded scaffolds at physiological conditions. The compact system made of acrylic glass, Teflon®, silicone, and stainless steel allows the comparison of different media, cells and scaffolds. The bioreactor can be gas sterilized and actuated in a standard incubator. Macroscopic observations and pressure-measurements showed a uniformly sinusoidal pulsation, indicating that the bioreactor performed well. Preliminary experiments to determine the adherence rate and morphology of UCMSC after mechanical loadings showed an almost confluent cellular coating without damage on the cell surface. In summary, the bioreactor is an adequate tool for the mechanical stress of seeded scaffolds and offers dynamic stimuli for pre-conditioning of cardiac tissue engineered constructs in vitro.

Comparative analysis of adherence, viability, proliferation and morphology of umbilical cord tissue-derived mesenchymal stem cells seeded on different titanium-coated expanded polytetrafluoroethylene scaffolds.

Umbilical cord tissue comprises an attractive new source for mesenchymal stem cells. Umbilical cord tissue-derived mesenchymal stem cells (UCMSC) exhibit self-renewal, multipotency and immunological naivity, and they can be obtained without medical intervention. The transfer of UCMSC to the ischemic region of the heart may have a favorable impact on tissue regeneration. Benefit from typical cell delivery by injection to the infarcted area is often limited due to poor cell retention and survival. Another route of administration is to use populated scaffolds implanted into the infarcted zone. In this paper, the seeding efficiency of UCMSC on uncoated and titanium-coated expanded polytetrafluoroethylene (ePTFE) scaffolds with different surface structures was determined. Dualmesh (DM) offers a corduroy-like surface in contrast to the comparatively planar surface of cardiovascular patch (CVP). The investigation of adherence, viability and proliferation of UCMSC demonstrates that titanium-coated scaffolds are superior to uncoated scaffolds, independent of the surface structure. Microscopic images reveal spherical UCMSC seeded on uncoated scaffolds. In contrast, UCMSC on titanium-coated scaffolds display their characteristic spindle-shaped morphology and a homogeneous coverage of CVP. In summary, titanium coating of clinically approved CVP enhances the retention of UCMSC and thus offers a potential cell delivery system for the repair of the damaged myocardium.