Regensburg Center of Biomedical Engineering - RCBE
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Introduction
Shear induced multimerisation of von-Willebrand-factor (vWF) is supposed to play an important role in coagulation inside extracorporeal membrane oxygenators. However, there is no proof that links observed vWF structures to computed or measured flow conditions.
Methods
The structures of multimeric vWF fibers, observed in clinically used membrane oxygenators is examined using immunofluorescence microscopy (IFM) using Carstairs’ staining method (positive ethics committee vote). The flow around the membrane fibres inside the oxygenator is investigated in terms of shear rate, wall shear velocity and streamlines by using CFD (RANS, Carreau-Yasuda viscosity, geometry remodelled after high-resolution µCT-scans). By interpreting the histological and numerical results in this common context, indications for shear induced coagulation mechanisms can be identified.
Results
The fibre structures of multimeric vWF build regular but not exactly symmetric formations around the contact face (CF) between the crosswise stacked oxygenator fibres (OF), see fig.1B, vWF marked red. Annular around the CF arranged, cells are likely to be found, see fig.1B, nuclei marked blue.
The computed streamlines around the OF show attached flow around the circular fibres. However, the irregular arrangement of real OF produce considerable cross flow between the interconnected neighbouring channels, in contrast to previous 2D-simulations. Thus, the CF are washed around closely by blood, also from neighbouring channels. The wall shear velocity streamlines form regular, slightly asymmetric shapes around the contact faces. The occurring maximum shear rates are in the range of 1,000 1/s.
Discussion
The shapes of vWF structures found in clinically used oxygenators match the computational results in terms of wall shear velocity and streamlines well. The accumulation of cells close to the CF can also be explained by fluid mechanics, as there are small shear gradients and slow velocities. However, occurring shear rates between OFs are too low to trigger multimerisation of vWF. That raises the question where in the circuit the actual activation of vWF is started and how, at least partly chained, vWF multimeres are attracted towards the OF surface. A next step will be the investigation of the actual shear rate triggered (or mediated) multimerisation of vWF. Towards this end, microfluidic experiments with shear triggered coagulation will be performed. Also of big interest is the computation of the flow situation in the oxygenator in proximity to chaining threads, which have been ignored in computations so far. However, first a realistic representation of the effective viscosity in computations is needed, which is not available yet.
Modelling blood flow an shear induced coagulation in membraene oxygenators (MO) is challenging. The relevant geometry of oxygenator fibers (OF) and chaining threads is complex and spans several length scales. In relevant scales and regimes blood shows several significant non-Newtonian effects. Existing models are only capable of accounting for some, but not all relevant effects. Additionally, coagulation processes are influencing fluid properties and geometry significantly. Due to the enormous size of the discretised geometries highly detailed viscosity and coagulation properties of blodd flow in MOs. First step is to find a gemoetry dependent viscosity representation on basis of parametric micro channel experiments with anti-coagulated blood. Next step is a statistic coagulation model, based on micro channel experiments with human (re-calcified citrated) whole blood an evaluation of clinically used osygenators. Since shear rate dependent (i.e. viscosity dependet) coagulation in return influences the viscosity, a combined model with suitable implementation in a RANS framework is necessary. Towards this end, micro channel experiments with new and used single OFs triggering coagulation are performed. Structures of multimeric von Willebrand fibers (vWF), as indicator for shear induced coagulation, are compared to computed and measured flow conditions, using immunofluorescence microscopy, RANS-computations and µPIV, respectively. Preliminary examinations in clinically used MOs show good agreement between occurring structures of vWF, cell depositions and computed flow patterns (geometry form µCT-Scans). However, computed shear rates might be to low to actually trigger activation of vWF. The complex geometry of MOs results in huge meshes, which makes RANS with statistical modelling of viscosity and coagulation a reasonable approach. Towards this end, experimental data on micro channel level with evaluation on real application level is crucial. Especially regarding clotting processes, micro fluidic experiments are powerful research tool.
BACKGROUND:
Shear-induced conformational changes of von Willebrand factor (vWF) may be responsible for coagulation disorder and clot formation inside membrane oxygenators (MOs) during extracorporeal membrane oxygenation (ECMO) therapy.
OBJECTIVE:
The aim was to identify vWF structures inside clinically used MOs and employ computational fluid dynamics to verify the corresponding flow conditions.
METHODS:
Samples from gas exchange membranes (GEM) from MOs were analysed for accumulations of vWF and P-selectin-positive platelets using immunofluorescence techniques. Streamlines and shear rates of the flow around GEMs were computed using a laminar steady Reynolds-Averaged-Navier-Stokes approach.
RESULTS:
Most samples were colonized with equally distributed leukocytes, integrated in thin cobweb-like vWF-structures. Only 25 % of the samples showed extended accumulations of vWF. Computed streamlines showed considerable cross flow between interconnected neighbouring channels. Stagnation points were non-symmetric and contact faces were washed around closely. The occurring maximum shear rates ranged from 2,500 to 3,000 1/s.
CONCLUSIONS:
If pronounced vWF structures are present, shape and extent match the flow computations well. Computed shear rates bear a critical degree of uncertainty due to the improper viscosity model. If flow conditions inside the MO were sufficient to affect vWF, a more consistent distribution of vWF across the samples should be present.
Die Aufmerksamkeit für Unternehmensgründungen hat in den letzten Jahren extrem zugenommen. Grundsätzlich muss ein Start-up in einem kompetitiven Umfeld erfolgreich sein, um bestehen zu können. Der Weg dorthin wird maßgeblich beeinflusst durch Planung und finanzielle Ressourcen, die die Gründer bereitstellen müssen. In der Medizinprodukteindustrie kommen zusätzlich große Hürden hinzu, die u. a. einen kurzen Produktlebenszyklus, lange Projektlaufzeiten, aufwendige klinische Studien und aktuell neue gesetzliche Verordnungen betreffen. Dieser Beitrag konzentriert sich zunächst auf mögliche Fördermittel und Beratung von Start-up-Projekten aus dem Hochschulbereich. Aus einer Analyse derzeit existierender Gründerwettbewerbe im Hinblick auf das Gesundheitswesen werden dem Leser entsprechende Adressen zum Einwerben von Fördermitteln geliefert. Darüber hinaus wird ein Pilot-Prozess vorgestellt, wie eine Ausgründungsberatung an der Hochschule Ulm im Studiengang Medizintechnik derzeit verläuft. Dies kann möglicherweise ein Anknüpfungspunkt für eine zukünftige Institutionalisierung von Spin-off-Vorhaben aus dem Hochschulbereich sein.
Epigenetic modifiers of the histone deacetylase (HDAC) family contribute to autoimmunity, cancer, HIV infection, inflammation, and neurodegeneration. Hence, histone deacetylase inhibitors (HDACi), which alter protein acetylation, gene expression patterns, and cell fate decisions, represent promising new drugs for the therapy of these diseases. Whereas pan-HDACi inhibit all 11 Zn2+-dependent histone deacetylases (HDACs) and cause a broad spectrum of side effects, specific inhibitors of histone deacetylase 6 (HDAC6i) are supposed to have less side effects. We present the synthesis and biological evaluation of Marbostats, novel HDAC6i that contain the hydroxamic acid moiety linked to tetrahydro-β-carboline derivatives. Our lead compound Marbostat-100 is a more potent and more selective HDAC6i than previously established well-characterized compounds in vitro as well as in cells. Moreover, Marbostat-100 is well tolerated by mice and effective against collagen type II induced arthritis. Thus, Marbostat-100 represents a most selective known HDAC6i and the possibility for clinical evaluation of a HDAC isoform-specific drug.
Over the past decade, veno-venous extracorporeal membrane oxygenation (vvECMO) has been increasingly utilized in respiratory failure in patients. This study presents our institution´s experience focusing on the life span of ECMO systems reflecting the performance of a particular system. A retrospective review of our ECMO database identified 461 adult patients undergoing vvECMO (2010-2017). Patients that required more than one system and survived the first exchange >24 hours (n = 139) were included. Life span until the first exchange and exchange criteria were analyzed for all systems (PLS, Cardiohelp HLS-set, both Maquet Cardiopulmonary, Rastatt, Germany; Deltastream/Hilite7000LT, iLA-activve, Xenios/NovaLung, Heilbronn, Germany; ECC.O5, LivaNova, Mirandola, Italy). At our ECMO center, the frequency of a system exchange was 30%. The median (IQR) life span was 9 (6-12) days. There was no difference regarding the different systems (p = 0.145 and p = 0.108, respectively). However, the Deltastream systems were exchanged more frequently due to elective technical complications (e. g. worsened gas transfer, development of coagulation disorder, increased bleedings complications) compared to the other exchanged systems (p = 0.013). In summary, the used ECMO systems are safe and effective for acute respiratory failure. There is no evidence for the usage of a specific system. Only the increased predictability of an imminent exchange preferred the usage of a Deltastream system. However, the decision to use a particular system should not depend solely on the possible criteria for an exchange.
BACKGROUND:
Validation and verification of multibody musculoskeletal models sEMG is a difficult process because of the reliability of sEMG data and the complex relationship of muscle force and sEMG.
OBJECTIVE:
This work aims at comparing experimentally recorded and simulated muscle activities considering a numerical model for crosstalk. METHODS:
For providing an experimentally derived reference data set, subjects were performing elevations of the arm, where the activities of the contemplated muscle groups were measured by sEMG sensors. Computed muscle activities were further processed and transformed into an artificial electromyographical signal, which includes a numerical crosstalk model. In order to determine whether the crosstalk model provides a better agreement with the measured muscle activities, the Pearson correlation coefficient has been computed as a qualitative way of assessing the curve progression of the data sets.
RESULTS:
The results show an improvement in the correlation coefficient between the experimental data and the simulated muscle activities when taking crosstalk into account.
CONCLUSIONS:
Although the correlation coefficient increased when the crosstalk model was utilized, it is questionable if the discretization of both, the crosstalk and the musculoskeletal model, is accurate enough.
BACKGROUND: Validation and verification of multibody musculoskeletal models sEMG is a difficult process because of the reliability of sEMG data and the complex relationship of muscle force and sEMG. OBJECTIVE: This work aims at comparing experimentally recorded and simulated muscle activities considering a numerical model for crosstalk. METHODS: For providing an experimentally derived reference data set, subjects were performing elevations of the arm, where the activities of the contemplated muscle groups were measured by sEMG sensors. Computed muscle activities were further processed and transformed into an artificial electromyographical signal, which includes a numerical crosstalk model. In order to determine whether the crosstalk model provides a better agreement with the measured muscle activities, the Pearson correlation coefficient has been computed as a qualitative way of assessing the curve progression of the data sets. RESULTS: The results show an improvement in the correlation coefficient between the experimental data and the simulated muscle activities when taking crosstalk into account. CONCLUSIONS: Although the correlation coefficient increased when the crosstalk model was utilized, it is questionable if the discretization of both, the crosstalk and the musculoskeletal model, is accurate enough.
In recent years, musculoskeletal computation has become a widely used tool to investigate joint and muscle forces within the human body. However, the issue of muscle fatigue is not considered adequately in most models and is a challenging task. One aspect that needs to be examined is the interaction of muscles during an exhausting task. Therefore, an experimental study was designed to analyze the changes of back muscle recruitment pattern during such exercises.
In this study 38 subjects (27 male, 11 female, height = 177±8.5 cm, weight = 74.0±13.6 kg) participated. Each subject had to perform three static and three dynamic exhausting exercises where the back muscles were loaded with subject specific forces using a dynamometer adapter especially designed for the trunk muscles. To collect the muscle activity, twelve surface electromyography sensors were applied on the back, and four on the abdominal muscles. Muscle activity and fatigue were analyzed by calculating the maximum voluntary contraction normalized signal and the median frequency. At first the fatigue of m. erector spinae and m. multifidi was analyzed, since these muscles carry the main load during the exercises. Subsequently the activity of the m. trapezius, m. rectus abdominis and m. obliquus externus were investigated to determine recruitment patterns. To gain more detailed information of these patterns a numerical model was built using the AnyBody Modeling System™. Analyzing the measurements, we can observe an increasing muscle activity during isokinetic exercises while the force is constant. Since the activity in the simulation is defined as the current force output divided by the strength of the muscle, the strength parameter was scaled down based on the measured data, assuming a linear force – activity correlation, and using a numerical algorithm considering the influence of cross talk.
The results show, that changes in recruitment pattern can be divided into three major subgroups. Prior to total exhaustion, some of the subjects show additional activation of muscles in the trapezius region, while other subjects show an additional activation of abdominal muscles, increasing the intra-abdominal pressure which supports the spine. In the third group an activation in both regions can be observed.
The numerical simulations show an increasing activity of abdominal muscles as well as muscles in the upper back. Especially the m. latissimus dorsi shows a significantly higher activity.
The results lead to the conclusion that prior to total exhaustion, additional muscles are recruited to support the main muscles. It was shown that abdominal muscles are activated to support back muscles by pressurizing the trunk cavity to delay total exhaustion as long as possible. In conclusion, the results show that changes in muscle recruitment pattern need to be considered when introducing muscle fatigue to musculoskeletal models.
The number of spinal fusion surgeries is steadily increasing and biomechanical consequences are still in debate. The aim of this study is to provide biomechanical insights into the sagittal balance of the spine and to compare spinal load before and after spinal fusion.
METHOD:
The joint reaction forces of 52 patients were analyzed in proximo-distal and antero-posterior direction from the levels T12-L1 to L5-S1 using musculoskeletal simulations.
RESULTS:
In 104 simulations, pre-surgical forces were equal to post-surgical. The levels L4-L5 and T12-L1, however, showed increased spinal forces compression forces with higher sagittal displacement. Improved restauration of sagittal balance was accompanied by lower spinal load. AP shear stress, interestingly decreased with sagittal imbalance.
CONCLUSION:
Imbalanced spines have a risk of increased compression forces at Th12-L1. L4-L5 always has increased spinal loads. These slides can be retrieved under Electronic Supplementary Material.
Background
Iliac crest bone harvesting is a frequently performed surgical procedure widely used to treat bone defects. The objective of this study is to assess the biomechanical quantities related to risk for pelvic fracture after harvesting an autologous bone graft at the anterior iliac crest.
Methods
Finite element models with a simulated harvest site (sized 15 × 20 mm, 15 × 35 mm, 30 × 20 mm and 30 × 35 mm) in the iliac wing are created. The relevant loading case is when the ipsilateral leg is lifted off the ground. Musculoskeletal analysis is utilized to compute the muscle and joint forces involved in this motion. These forces are used as boundary conditions for the finite element analyses. Bone tissue stress is analyzed.
Results
Critical stress peaks are located between the anterior superior iliac spine (ASIS) and the anterior edge of the harvest site. Irrespective of the graft size, the iliac wing does not show any significant stress peaks with the harvest site being 20 to 25 mm posterior to the ASIS. The harvest area itself inhibits the distribution of the forces applied on the ASIS to extend to the posterior iliac wing. This leads to a lack of stress posterior to the harvest site. A balanced stress distribution with no stress peaks appears when the bone graft is taken below the iliac crest.
Conclusion
A harvest site located at least 20 to 25 mm posterior to the ASIS should be preferred to minimize the risk of iliac fatigue fracture.