Institute of Applied Medical Engineering

Aachen, Germany

Institute of Applied Medical Engineering

Aachen, Germany
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Hussain A.F.,Institute of Applied Medical Engineering | Amoury M.,Institute of Applied Medical Engineering | Barth S.,Institute of Applied Medical Engineering | Barth S.,Fraunhofer Institute for Molecular Biology and Applied Ecology
Current Pharmaceutical Design | Year: 2013

In the past two decades, immense advances have been achieved in the engineering, production and purifying of recombinant proteins. These proteins are being widely utilized in many fields of biology, biotechnology and medicine, including diagnostic and therapeutic applications. These applications often require the modification or conjugation of these proteins with other molecules. Researchers are spending many efforts to develop and improve the methods of protein modifications. A main challenge they face is derivatizing proteins without affecting their structure and biological function. The conjugation methods available today include random and specific chemical modifications on endogenous amino acids or carbohydrate of the protein of interest. Other methods utilize self-labeling tags as fusion partners to the original protein enabling site-specific conjugation. SNAP-tag is one of the most promising self-labeling tags, which reacts specifically, rapidly and covalently with benzylguanine (BG) derivatives. SNAP-tag fusion proteins have been successfully used for imaging living cells. Recently, several studies have utilized the SNAP technology for generating antibody-based diagnostic and therapeutic tools. We here review these approaches and their possible impact on improving cancer targeting. © 2013 Bentham Science Publishers.


Kolberg K.,Institute of Applied Medical Engineering | Puettmann C.,Institute of Applied Medical Engineering | Pardo A.,Institute of Applied Medical Engineering | Pardo A.,University of Würzburg | And 3 more authors.
Current Pharmaceutical Design | Year: 2013

Over the past few years, the SNAP-tag technology has become a methodology with great potential in a variety of applications, e.g. the (specific) visualization of individual proteins and studies of protein interaction in living cells. Furthermore, the tag can be used for immunopurification and detection of recombinant proteins or site-specific coupling of recombinant proteins to surfaces. Next to the in vitro applications, it also enables detection of tagged proteins in vivo. This review gives an overview of the SNAP-tag technology in different fields of research and its potential for future developments. © 2013 Bentham Science Publishers.


PubMed | University of Lübeck, Fraunhofer Institute for Molecular Biology and Applied Ecology, University of Kiel, RWTH Aachen and Institute of Applied Medical Engineering
Type: Journal Article | Journal: Oncotarget | Year: 2016

Triple-negative breast cancer (TNBC) is a heterogeneous disease in which the tumors do not express estrogen receptor (ER), progesterone receptor (PgR) or human epidermal growth factor receptor 2 (HER2). Classical receptor-targeted therapies such as tamoxifen or trastuzumab are therefore unsuitable and combinations of surgery, chemotherapy and/or radiotherapy are required. Photoimmunotheranostics is a minimally invasive approach in which antibodies deliver nontoxic photosensitizers that emit light to facilitate diagnosis and produce cytotoxic reactive oxygen species to induce apoptosis and/or necrosis in cancer cells. We developed a panel of photoimmunotheranostic agents against three TNBC-associated cell surface antigens. Antibodies against epidermal growth factor receptor (EGFR), epithelial cell adhesion molecule (EpCAM) and chondroitin sulfate proteoglycan 4 (CSPG4) were conjugated to the highly potent near-infrared imaging agent/photosensitizer IRDye700DX phthalocyanine using SNAP-tag technology achieving clear imaging in both breast cancer cell lines and human biopsies and highly potent phototherapeutic activity with IC50values of 62-165 nM against five different cell lines expressing different levels of EGFR, EpCAM and CSPG4. A combination of all three reagents increased the therapeutic activity against TNBC cells by up to 40%.


Hussain A.F.,Institute of Applied Medical Engineering | Kampmeier F.,Institute of Applied Medical Engineering | Von Felbert V.,RWTH Aachen | Merk H.-F.,RWTH Aachen | And 2 more authors.
Bioconjugate Chemistry | Year: 2011

Cancer cells can be killed by photosensitizing agents that induce toxic effects when exposed to nonhazardous light, but this also causes significant damage to surrounding healthy cells. The specificity of photodynamic therapy can be increased by conjugating photosensitizing agents to antibodies and antibody fragments that bind specifically to tumor cell antigens. However, standard conjugation reactions produce heterogeneous products whose targeting specificity and spectroscopic properties can be compromised. In this study, we used an antibody fragment (scFv-425) that binds to the epidermal growth factor receptor (EGFR) as a model to investigate the use of SNAP-tag fusions as an improved conjugation strategy. The scFv-425-SNAP-tag fusion protein allowed the specific conjugation of a chlorin e6 photosensitizer modified with O(6)-benzylguanine, generating a homogeneous product that was delivered specifically to EGFR + cancer cells and resulted in significant, tumor cell-specific cytotoxicity. The impact of our results on the development of photodynamic therapy is discussed. © 2011 American Chemical Society.


Hussain A.F.,Institute of Applied Medical Engineering | Tur M.K.,Justus Liebig University | Barth S.,Institute of Applied Medical Engineering | Barth S.,Fraunhofer Institute for Molecular Biology and Applied Ecology
Nucleic Acid Therapeutics | Year: 2013

Small interfering RNAs (siRNAs) silence gene expression by triggering the sequence-specific degradation of mRNAs, but the targeted delivery of such reagents remains challenging and a significant obstacle to therapeutic applications. One promising approach is the use of RNA aptamers that bind tumor-associated antigens to achieve the delivery of siRNAs to tumor cells displaying specific antigens. Wholly RNA-based constructs are advantageous because they are inexpensive to synthesize and their immunogenicity is low. We therefore joined an aptamer-recognizing alpha V and integrin beta 3 (αvβ3) integrin to a siRNA that targets eukaryotic elongation factor 2 and achieved for the first time the targeted delivery of a siRNA to tumor cells expressing αvβ3 integrin, causing the inhibition of cell proliferation and the induction of apoptosis specifically in tumor cells. The impact of our results on the development of therapeutic aptamer-siRNA constructs is discussed. © Copyright 2013, Mary Ann Liebert, Inc.


Graf F.,Institute of Applied Medical Engineering | Rossbroich R.,Institute of Applied Medical Engineering | Finocchiaro T.,Institute of Applied Medical Engineering | Steinseifer U.,Institute of Applied Medical Engineering
Artificial Organs | Year: 2016

One of the most critical components regarding the durability of the ReinHeart total artificial heart (TAH) is its biocompatible diaphragm, which separates the drive unit from the ventricles. Hence, a durability tester was designed to investigate its required 5-year lifetime. The aim of this study was to prove the validity of accelerated testing of the polyurethane diaphragm. The durability tester allows simultaneous testing of 12 diaphragms and mimics physiological conditions. To accelerate the time of testing, it operates with an increased speed at a frequency of 8 Hz. To prove the correctness of this acceleration, a servo-hydraulic testing machine was used to study the effect of different frequencies and their corresponding loads. Thereby the viscoelastic behavior of the polyurethane was investigated. Additionally, high-speed video measurements were performed. The force against frequency and the high-speed video measurements showed constant behavior. In the range of 1–10 Hz, the maximum resulting forces varied by 3%, and the diaphragm movement was identical. Frequencies below 10 Hz allow a valid statement of the diaphragm's mechanical durability. Viscoelasticity of the polyurethane in the considered frequency-range is negligible. The accelerated durability test is applicable to polyurethane diaphragms, and the results are applicable to TAH use. The reliability of the diaphragm for a lifetime of 5 years was found to be 80% with a confidence of 62%. Copyright © 2015 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.


Neidlin M.,Institute of Applied Medical Engineering | Steinseifer U.,Institute of Applied Medical Engineering | Kaufmann T.A.S.,Institute of Applied Medical Engineering
Journal of Biomechanics | Year: 2014

Neurological complication often occurs during cardiopulmonary bypass (CPB). One of the main causes is hypoperfusion of the cerebral tissue affected by the position of the cannula tip and diminished cerebral autoregulation (CA). Recently, a lumped parameter approach could describe the baroreflex, one of the main mechanisms of cerebral autoregulation, in a computational fluid dynamics (CFD) study of CPB. However, the cerebral blood flow (CBF) was overestimated and the physiological meaning of the variables and their impact on the model was unknown. In this study, we use a 0-D control circuit representation of the Baroreflex mechanism, to assess the parameters with respect to their physiological meaning and their influence on CBF. Afterwards the parameters are transferred to 3D-CFD and the static and dynamic behavior of cerebral autoregulation is investigated.The parameters of the baroreflex mechanism can reproduce normotensive, hypertensive and impaired autoregulation behavior. Further on, the proposed model can mimic the effects of anesthetic agents and other factors controlling dynamic CA. The CFD simulations deliver similar results of static and dynamic CBF as the 0-D control circuit. This study shows the feasibility of a multiscale 0-D/3-D approach to include patient-specific cerebral autoregulation into CFD studies. © 2014 Elsevier Ltd.


Kaufmann T.A.S.,Institute of Applied Medical Engineering | Neidlin M.,Institute of Applied Medical Engineering | Busen M.,Institute of Applied Medical Engineering | Sonntag S.J.,Institute of Applied Medical Engineering | Steinseifer U.,Institute of Applied Medical Engineering
Journal of Biomechanics | Year: 2014

Stroke and cerebral hypoxia are among the main complications during cardiopulmonary bypass (CPB). The two main reasons for these complications are the cannula jet, due to altered flow conditions and the sandblast effect, and impaired cerebral autoregulation which often occurs in the elderly. The effect of autoregulation has so far mainly been modeled using lumped parameter modeling, while Computational Fluid Dynamics (CFD) has been applied to analyze flow conditions during CPB. In this study, we combine both modeling techniques to analyze the effect of lumped parameter modeling on blood flow during CPB. Additionally, cerebral autoregulation is implemented using the Baroreflex, which adapts the cerebrovascular resistance and compliance based on the cerebral perfusion pressure. The results show that while a combination of CFD and lumped parameter modeling without autoregulation delivers feasible results for physiological flow conditions, it overestimates the loss of cerebral blood flow during CPB. This is counteracted by the Baroreflex, which restores the cerebral blood flow to native levels. However, the cerebral blood flow during CPB is typically reduced by 10-20% in the clinic. This indicates that either the Baroreflex is not fully functional during CPB, or that the target value for the Baroreflex is not a full native cerebral blood flow, but the plateau phase of cerebral autoregulation, which starts at approximately 80% of native flow. © 2013 Elsevier Ltd.


Egger C.,Institute of Applied Medical Engineering | Maas J.,Institute of Applied Medical Engineering | Hufen T.,Institute of Applied Medical Engineering | Schmitz-Rode T.,Institute of Applied Medical Engineering | Steinseifer U.,Institute of Applied Medical Engineering
Artificial Organs | Year: 2013

Acquired von Willebrand Syndrome (AvWS) is known as a frequent bleeding complication in patients on ventricular assist device (VAD) support. Clinicians demand that the requirements for VADs with regard to hemocompatibility should also include low susceptibility for AvWS. Clinical AvWS diagnosis is known to be a complex, high-price, and time-consuming analysis. This article investigates an easy-to-handle, time-efficient, and inexpensive method for comparative AvWS investigations in vitro. Von Willebrand Factor activity level (vWF:Ac) and von Willebrand Factor antigen level (vWF:Ag) were chosen from the complete set of clinically established parameters. Blood plasma (human and porcine) was exposed to an inhomogeneous shear field in a shear-inducing test set up for up to 4h. Plasma samples were drawn after different load periods and analyzed for vWF:Ac and vWF:Ag. vWF multimer analysis of selected samples were used as reference for determination of high molecular weight multimer (HMWM) loss. AvWS was detected after 20min of shear load via vWF:Ac/vWF:Ag ratio and multimer analysis. A good correlation between the vWF:Ac/vWF:Ag ratio and HMWM loss (multimer analysis) was found for human plasma. AvWS characteristics of human and porcine plasma for analyzed samples were comparable. A correlation between vWF:Ac/vWF:Ag ratio and HMWM in porcine plasma could not be found. Results gained in this study indicate that vWF:Ac/vWF:Ag ratio is sensitive enough for comparative AvWS investigations in vitro with human blood. The applicability of the method suggested in this article for AvWS characterization in porcine blood needs to be investigated in further studies. The selection of analysis kits promises a less cost- and labor-intensive, time-consuming, and complex method for comparative AvWS investigations in vitro compared with AvWS diagnosis in patients. © 2013 Wiley Periodicals, Inc. and International Center for Artificial Organs and Transplantation.


PubMed | Institute of Applied Medical Engineering
Type: Journal Article | Journal: Artificial organs | Year: 2015

One of the most critical components regarding the durability of the ReinHeart total artificial heart (TAH) is its biocompatible diaphragm, which separates the drive unit from the ventricles. Hence, a durability tester was designed to investigate its required 5-year lifetime. The aim of this study was to prove the validity of accelerated testing of the polyurethane diaphragm. The durability tester allows simultaneous testing of 12 diaphragms and mimics physiological conditions. To accelerate the time of testing, it operates with an increased speed at a frequency of 8Hz. To prove the correctness of this acceleration, a servo-hydraulic testing machine was used to study the effect of different frequencies and their corresponding loads. Thereby the viscoelastic behavior of the polyurethane was investigated. Additionally, high-speed video measurements were performed. The force against frequency and the high-speed video measurements showed constant behavior. In the range of 1-10Hz, the maximum resulting forces varied by 3%, and the diaphragm movement was identical. Frequencies below 10Hz allow a valid statement of the diaphragms mechanical durability. Viscoelasticity of the polyurethane in the considered frequency-range is negligible. The accelerated durability test is applicable to polyurethane diaphragms, and the results are applicable to TAH use. The reliability of the diaphragm for a lifetime of 5 years was found to be 80% with a confidence of 62%.

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