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NMI Natural and Medical Sciences Insitute at the University of TübingenMarkwiesenstraße 5572770 Reutlingen / GermanyPhone: +49 (0) 7121 51530-0Telefax: +49 (0) 7121 [email protected]

Angewandte Forschung und Entwicklung an der Schnittstelle von Bio- und Materialwissenschaften

2006-2007Applied research and development at the junction of life sciences and material sciences

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Annual Report

NMI Natural and Medical Sciences Institute

Innovation Alliance Baden-Wuerttemberg

The NMI is a research institute of the Innovation Alliance Baden-Wuerttemberg.

This Alliance consists of 14 cooperating research facilities, which work in various scientifi c fi elds. Our Alliance partners are:

Hohenstein Institute for Clothing Physiology (BPI)www.hohenstein.de

Research Institute Precious Metals & Metals Chemistry (FEM) www.fem-online.de

Forschungsinstitut für Pigmente und Lacke e.V.; www.fpl.uni-stuttgart.de

Research Center for Information Technologies (FZI) at the Uni-versity of Karlsruhe (TH); www.fzi.de

Hahn-Schickard-Gesellschaft, Institut for Micro Assembling Technology; www.hsg-imat.de

Hahn-Schickard-Gesellschaft, Institut for Micro Technical com-ponents and systems; www.hsg-imit.de

Institut für Lasertechnologien in der Medizin und Meßtechnik an der Universität Ulm; www.uni-ulm.de/ilm

Institut für Mikroelektronik Stuttgart; www.ims-chips.de

Institute for Textile Chemistry and Chemical Fibers (German Institute for Textile and Fibre Research Denkendorf DITF); www.itcf-denkendorf.de

Institut für Textil- und Verfahrenstechnik (German Institute for Textile and Fibre Research Denkendorf DITF); www.itv-denkendorf.de

Centre for Management Research of the German Institute for Textile and Fibre Research; www.ditf-denkendorf.de/mr

Training, Testing and Research Centre - Competence in Lea-ther; www.lgr-reutlingen.de

Zentrum für Sonnenenergie- und Wasserstoff-Forschung Baden-Württemberg; www.zsw-bw.de

How to fi nd us

Coming from Stuttgart orStuttgart airport:Take the B27 highway from Stuttg-art or from the Stuttgart airport in the direction of Tübingen. After arriving in Tübingen, follow signs to Reutlingen. You are now on the B28 in the direction of Reutlingen.Exit the B28 at Jettenburg/Mähringen.At the fi rst intersection continue straight for approximately 1 kilometer. The NMI is located on the right.

Coming from Tübingen:Take the B28 highway towards Reutlin-gen and exit at Jettenberg/Mähringen. At the fi rst intersection continue straight for approximately 1 kilometer. The NMI is located on the right.

Coming from Reutlingen:Follow signs in the direction of Tübin-gen, taking the B28 highway to Tübin-gen. Exit at Jettenburg/Mähringen, keep right, crossing bridge over the B28. After the bridge take fi rst left into the Mark-wiesenstrasse. Follow the Mark-wiesen-strasse for approximately 1 kilometer.The NMI is located on the right.

NMIMarkwiesenstraße 5572770 ReutlingenPhone 0 71 21 5 15 30-0

Applied research and development at the junction of life sciences and material sciences

Pharma and biotechnology

Biomedical technology

Surface and interface technology

NMI overview

NMI Natural and Medical Sciences Institute at the University of Tübingen

NMI Natural and Medical Sciences Institute at the University of TübingenMarkwiesenstraße 5572770 Reutlingen / GermanyPhone: +49 (0) 71 21 5 15 30-0Telefax: +49 (0) 71 21 5 15 [email protected]

Managing director: as of 2008: R. Enzio Müller, PhD Prof. Dr. Hugo HämmerlePhone: +49 (0) 71 21 5 15 30-10 +49 (0) 71 21 5 15 [email protected] [email protected]

NMI Annual Report 2006–2007 3

Table of contents

2 NMI overview

4 Foreword6 Board of trustees and executive management7 Core competencies8 Sustainable growth8 Control instruments9 Competencies10 Networking11 Start-up companies12 Quality management12 Patents13 Public relations14 NMI Technologie Transfer GmbH

60 Staff61 Abbrevations62 Publications64 Projects

16 Pharma und Biotechnology

18 Functional genomics18 Gen transfer and cell function20 Molecular neurobiology22 Protein microarrays24 Cell biochips

26 Test systems for drug discovery26 Microsystems and nanotechnology27 Microelectrode array technology28 Microculture and analysis of neuronal cells and tissue29 Cell manipulation through microfluidics and electric field forces30 Electrophysiology of tissues and cells31 Characterization of ion channels

32 Bioanalytics/Peptide synthesis32 Bioanalytics33 Peptide synthesis

34 Biomedical technology

36 Micromedicine37 Intelligent implants38 BioFIB39 Microsystems for diagnostics

40 Regenerative medicine and biomaterials41 Biomaterials for regenerative medicine42 Regeneration of articular cartilage43 Regeneration of the spinal disc44 Nerve regeneration 45 Regeneration of blood vessels

46 Development of medical products47 Improvement of surface properties47 Qualification of cleanliness

48 Surface and interface technology

50 Microsystems and nanotechnology52 Sensor arrays with micro- and nanoelectrodes54 Manipulation and analysis in the nanoworld

55 Functional surfaces and layers55 Interface and microstructure analysis57 Layers

58 Bonding, adhesion and tribologic systems58 Bonding59 Tribologic systems

4 NMI Annual Report 2006–2007

NMI overview

After 13 years of leading the NMI it is time form me to say goodbye to my employees and customers.This is no easy task, due to the fact that they were great, exciting and challeng-ing years to be sure. I couldn’t have made a better choice in the year 1995 than accepting the job in Reutlingen.

2007 was the most successful year since the founding of the institute. The turno-ver was nearly 10 million euros, making 2007 the seventh consecutive year with an average growth of 14%. What could be more fitting than the trendy word “sustainable”? Other words also come to mind, such as enthusiastic, innova-tive, quality and customer-oriented, all of which distinguish the NMI as a reliable and highly valued service provider and business partner and explain the success of the institute.

By thanking individuals or praising ideas, I would run the risk of forgetting some-one or some important project. Instead, I would like to express my thanks to all of the employees not only for their out-standing contributions and enthusiasm, but also for their constructive criticism, tolerance and support throughout the years.

The NMI has had to display a high degree of intuition and flexibility due to the ever-changing economic and techno-logical environment that our customers deal with. For the NMI innovation means recognizing and developing today what our customers will need tomorrow. This also means that the institute’s goals and strategies must be constantly reviewed, re-evaluated and adapted to the mar-ket’s needs.

I would like to thank all the members of the Board of Trustees for their support in this endeavor.

My special thanks goes to my deputy, Prof. Dr. Hämmerle, for the many years of productive cooperation, mutual respect and loyalty. Together we made many important and far-reaching deci-sions for the institute.

I will leave the institute in 2008 and Prof. Dr. Hämmerle will be my successor. His expertise and years of successful work at the NMI as a scientist and deputy direc-tor will make a smooth and uncompli-cated transition possible. He can best guarantee the strategic position of the institute in the future and at the same time ensure that the institute will offer continuity as well as innovation.

I wish our sponsors, customers and busi-ness partners further success in their cooperation with the NMI. I wish my successor and my employees the best for the future and remain,

Very truly,

Foreword E. Müller

R. Enzio Müller, PhDManaging director

Enzio Müller


On February 1, 2008 I assumed the position of director of the NMI. As the deputy of Dr. Enzio Müller I have worked since 1998 on the strategic position-ing and positive development of the institute and believe I am therefore able to ensure its future success. The focus of my work in the next years will be to further develop our profile as a business-oriented research institute that sup-ports innovative processes in the health care industries and environment with its research and services.

The NMI does research at the interface of bio- and material sciences. In this capacity we have not only an excellent scientific background, but also inter-national renommée. In order to better serve the needs of the future, we plan to expand the competences of the mate-rial sciences and consolidate the current strong status of biotechnology. Our cen-tral focus will be the development of our core competence in biomedical tech-nologies. Biotechnology, micro and nan-otechnology and medical technology are fusing more and more. Neuroimplants, biosensors, biochips and coated implants are examples of important and growing product groups.

One important aspect of our transfer services is the incubator model, which has given rise to successful, even inter-nationally known high-tech companies in the last 10 years.

Because of the sustainable growth of last years, the NMI is no longer able to offer spin-off companies space on the premises. We are currently doing our utmost to create additional space, so that also in future the institute will be able to bring forth high-tech companies.

Our employees are the capital of the institute. Thanks to their expertise and flexibility, their ability to work in interdis-ciplinary cooperation, their creativity and enthusiasm, and their customer orien-tation, the NMI has been able to assert itself and grow in the face of challeng-ing competition and an ever-changing market.

We now plan to increase the perform-ance of our competence teams through structural changes, more individual responsibility and authority. Concrete measures to this goal will be imple-mented in 2008/2009.

We expect to play in the national league together with other business-oriented institutes and expand our excellence at the interface of bio- and material sci-ences while fulfilling our commitments to our customers to their greatest satis-faction.

I am convinced that the NMI has the potential to face future challenges and to offer excellent transfer services. Our goal shall be to even further refine the NMI as the gem among research insti-tutes of southwestern Germany.

Prof. Dr. Hugo HämmerleManaging director as of February 2008

Hugo Hämmerle

Foreword H. Hämmerle


NMI overviewBoard of trustees and executive management

Over the past two decades the NMI Nat-ural and Medical Sciences Institute has established an outstanding reputation for translating findings from basic research into industrial application.

The NMI is a foundation (non-profit organization) which functions as a hold-ing for the institute with the same name and for the company NMI Technology Transfer GmbH. The president of the foundation is also the director of the applied research institute NMI. He reports to an overview board which includes rep-resentatives from academic research, city and state government, chamber of com-merce, and industry.

Although administratively and finan-cially independent from the University of Tübingen, there is a very intense collabo-ration between researchers at the two institutions.

President and vice-president of the foundation(as of December 31, 2007)E. Müller, Ph.D., President of the foun-dation and Managing Director of the instituteProf. Dr. H. Hämmerle, Vice-President of the foundation and Deputy Managing Director of the instituteProf. Dr. D. Kern, Vice-President of the foundation and Vice-Chancellor of the University of Tübingen

Board of TrusteesProf. Dr. K.-P. Jäckel, Chairman of the Board of Trustees, BASF AG, Ludwig-shafenProf. Dr. H. Brunner, Vice-Chairman of the Board of Trustees, director of the Fraunhofer IGB, StuttgartB. Bosch, Mayor of the city of Reutlingen(represented by P. Rist, Assistant Mayor)Dr. A. Carter, MBA, Boehringer Ingel-heim GmbH, Ingelheim/RheinDr. B. Dengler, Ministry for Science and Art of Baden-WürrtembergProf. Dr. B. Engler, President of the Uni-versity of Tübingen represented by Prof. Dr. H. Müther, ProrektorDr. H. Gareis, Gelita AG, EberbachDr. S. Hock, ZF Friedrichshafen AGMinDir. G. Leßnerkraus, Ministry of Economy of Baden-WürttembergProf. Dr. mult. J. Löhn, Steinbeis Founda-tion for Economic Development, BerlinProf. D. P. Niess, Präsident, University of ReutlingenProf. Dr. H.P. Rodemann, University of TübingenDr. A. Siegel, Carl Zeiss AG, OberkochenDr. H. Stallforth, Aesculap AG & Co KG, Tuttlingen Prof. Dr. H. Weber, University of Tübingen Prof. Dr. E. Zrenner, University of Tübingen

From the left: Ira Digel (secretary), Hugo Hämmerle (Deputy Managing Director), Enzio Müller (Mana-ging Director) and Renate Roscher (secretary).


Biomedical technology Surface and interface technology

Functional genomics Neurotechnology and micromedicine

Microsystems and nanotechnology

Test systems for drug discovery

Regenerative medicine and biomaterials

Functional surfaces and layers

Bioanalytics/ Peptide synthesis

Development of medical products

Bonding, adhesion and tribologic systems

Testing in accredited fields according to DIN EN ISO/IEC 17025


Core competencies

Research at the NMI means applied research for key industrial fields of the 21st century. The NMI is positioned at the interface between life sciences and material sciences.

Our clients in the area of pharma and biotechnology recognize our skills in functional genomics, application of innovative systems for drug discovery support, safety pharmacology, peptide synthesis and bioanalytics. We elucidate the function of genes and proteins and their potential as targets for therapeu-tic agents by employing gene transfer technologies, interfering-RNA, protein microarrays, cell biochips and peptide technologies.

Microsystems in combination with bio-materials and cells play an important role in biomedical technology. A specific application in neurotech-nology and micromedicine which has received world-wide attention is the retina implant. This microsystem device was developed by the NMI with research-ers and clinicians at the Eye Clinic at the University of Tübingen, the Institute for Microelectronics Stuttgart and the Insti-tut for Physical Electronics (IPE) at the University of Stuttgart. A first clinical trial on blind patients conducted by the NMI spin-off Retina Implant AG produced very encouraging results.

Microsystem technology in combination with biological applications has entered the field of regenerative medicine. At the NMI nerve or cartilage regeneration as well as new three-dimensional biocom-patible scaffolds supporting cell growth have been research topics of high prior-

ity. This knowledge was instrumental for the development of new tissue engineer-ing products for companies, such as B/Braun, TETEC AG and Gelita AG.

Surface and interface technology at the NMI is a key technology which finds its applications in many projects for cli-ents in the fields of pharma, biotech-nology, biomedicine, medical products, tribology, bonding and other aspects of material sciences. Micro and nanostruc-tures for sensors and actuators, lab-on-the-chip and similar devices based on the integration of microfluidics with elec-tronics and biomaterials, optimization of surfaces of medical implants, these and many more examples can be found in this report, illustrating how interdis-ciplinary teams of scientists at the NMI translate basic research results into new processes and products.

Our three core competencies

Günther Beck, director of administration

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Funding from state ofBaden-Württemberg

Research grants frompublic sector

Revenues from industry

Landesstiftung


NMI overviewSustainable growth

above: The turnover of the NMI has increased by 15% per annum since the year 2000 (including the NMI TT GmbH).

below: The turnover for services for SMEs (small and medium-size enterprises) in Baden Wuerttemberg remained at a high level in the last 2 years.

The NMI is constantly growing. The annual growth rate of 15% over the last 7 years and the doubling of income from research grants and industrial contracts from 4.3 mil q in the year 2000 to 9 mil q in 2007, are the result of the high quality of our R&D and services, the dedication of our employees, and the trust of our clients.

As illustrated below, income from projects for industrial clients amounted to 3.6 mil q, out of which 1.7 mil. q were projects for companies in Baden Württemberg (BW). Income from public funding for research projects in coopera-tion with industrial partners (European Union, German Ministry of Education and Research, State of BW) amounted to 3.8 mil. q Furthermore, the NMI received

1.6 mil. q from the Ministry of Economic Affairs in BW, support which is needed to develop new technologies which are of interest to small and medium enterprises (SME) in BW.

In 2007 the NMI executed over 200 projects for SME in BW for a total volume of 1.3 mil. q Thus, the Institute fulfills the most important mission of the foundation, namely supporting innovation for indus-trial clients.

Research institute run as an enterpriseAs of the end of 2007 the NMI employed 122 people, of which 85% were scientific and technical personnel. Scientists and engineers representing various disciplines from life sciences to material sciences ensure a high degree of interdisciplinary competence. Thirteen competence teams report to the director. Each team has a team leader who is responsible for the cash flow of the group. The teams are part of six areas, namely cell biology, molecular biology, protein analytics, bioorganic chemistry/analytics, physical engineering/biophys-ics and surface/interface & microstructure analytics. Six area leaders coordinate the strategic and operational goals of the 13 team leaders.

The high degree of interdisciplinary work means that members of more than one team are frequently involved in the execu-tion of a given project.

The constant development and improve-ment of controlling instruments together with a quality management system have proved instrumental to increased qual-ity, efficiency and growth. In 2007 all area leaders participated and successfully completed the Essentials of Management Certificate Program at the Executive School of Management, University St.Gallen, Switzerland. This additional qualification strengthens the ability of the NMI to inte-grate economic and management aspects with technological competence, thus ensuring better quality and efficiency to the benefit of its clients.

Management Müller / Hämmerle

Support services

Quality management

Public relations

Technical support

Accounting andcontrolling

Personnel

Patents, contracts

Core competencies

Pharma andbiotechnology

Biomedicaltechnology


Cell biologyE. Guenther

B. SchloßhauerK. BenzE. GuentherB. Angres

Business unitArea leader

Structural organization of the NMI

Team leader

Protein analyticsM. Pawlak

T. JoosM. Templin

Surface / interface & microstructure analytics N.N.

W. DreherB. Schröder

Physical enginee-ring / biophysicsA. Stett

A. StettW. NischM. Stelzle

Bioorganic chemistry/ analyticsD. Stoll

D. Stoll

Molecular biology HJ. Volkmer

HJ. Volkmer


Competencies

The Competence teams

Cell biology:ElectrophysiologyProf. Dr. Elke Guenther, biologistRegenerative medicine IProf. Dr. Burkhard Schloßhauer, biochemistRegenerative medicine IIKarin Benz, engineerCellular test systemsDr. Brigitte Angres, biologist

Molecular biology:PD Dr. Hansjürgen Volkmer, biologist

Protein analytics:Assay developmentDr. Markus Templin, biologistBiochemistryDr. Thomas Joos, biochemist

Bioorganic chemistry / analytics:Dr. Dieter Stoll, chemist

Physical engineering / biophysics:BiophysicsDr. Alfred Stett, physicistPhysical engineeringDr. Wilfried Nisch, physicistPhysical chemistry and sensor technologyDr. Martin Stelzle, physicist

Surface / interface and microstructure analysis:Interface and microstructure analysisDipl.-Phys. Werner Dreher, physicistSurface technologyDr. Bernhard Schröder, physicochemist

Ruprecht-Karls-Universität Heidelberg

Universität zu Köln

Universität Regensburg

LMU München

FH Albstadt Sigmaringen

Unversität Würzburg

FH IPA Stuttgart

Universitätsklinikum Ulm

Stiftung Orthopädische Universitätsklinik Heidelberg

IMTEK Freiburg

Friedrich Schiller Universität Jena

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NMI overviewNetworking

Solutions for complex problems are best found by cooperating with compe-tent partners. For this reason we define and coordinate collaborative national and international projects in which we work together with partners from aca-demic and non-academic institutions, research foundations, industry and clin-ics. Through this interdisciplinary net-work we share know-how and allow our industry partners to benefit from the entire value chain, i.e. from basic research to product-to-market.

In the years 2006-2007 the NMI partici-pated in 52 national and international projects with over 130 partners from academic institutions as well as indus-try. The NMI had the lead or a central coordinating function in 16 such projects

with a total volume of approximately 73 mil. q, of which 42 million were from public grants and the remainder from industry. The NMI collaborates in numerous projects with academic and clinical researchers at the University of Tübin-gen, for example in the projects Retina Implant, Spinal Disc Regeneration, NanoKryoSims and Affinity-Regulated Artificial Synapse.For many projects the NMI has been able to attract partners from the USA, Israel, Switzerland and countries from the Euro-pean Union. The topics of these interna-tional cooperations vary from regenera-tive medicine, to Alzheimer’s disease, new methods for proteomics to biomar-ker identification for clinical diagnostics. The NMI furthermore coordinates the competence cluster BioChip Technolo-gies Baden-Württemberg.

We thank our academic partners for their cooperation in many successful projects.


Start-up companies

NMI as incubator for new enterprises

New high-tech enterprises are founded at sites which provide the best environ-ment for the entrepreneur. The NMI has provided a technological base for numerous start-up companies and coop-erates with them in R&D projects sup-ported through public funding. These new enterprises may utilize our know-how, skilled personnel, infrastructure and equipment to perform their R&D and product development, thus reduc-ing their need for capital investment and personnel while minimizing financial risks. This incubator concept has proven to be very successful. The strong commitments of the cities Tübingen and Reutlingen (founders of the TTR Technology Park Tübingen-Reutlingen), the BioRegio STERN, the BIOPRO Baden-Württemberg GmbH, the Attempto Service GmbH, the local Chamber of Commerce and the Univer-sity of Tübingen with its start-up com-pany program has contributed greatly to improve the prevailing conditions in the area. Start-up companies are thus able to find suitable space, consultancy, net-working and the right environment for a young enterprise.

CyBio Robotics GmbH(Previously accelab GmbH)

www.cybio-ag.com

Founded in 1998, accelab GmbH has become a well recognized enterprise for system integration in laboratory auto-mation. A team of 25 people, mainly scientific and technical personnel, devel-ops new automated systems and pro-vides routine services at the site of robot application.

Cytocentrics AG

www.cytocentrics.com

Founded in 2001, the NMI spin-off Cyto-cenrics AG is developing an automated microsytem for patch-clamp ion-channel analysis based on the integration of elec-trical and microfluidic components.

EMC Microcollections GmbH

www.microcellections.de

EMC was founded in 1996. Its compe-tence is in the field of bioorganic synthe-sis and immunochemistry. Furthermore the company has significant expertise in the field of medicinal chemistry and ana-lytics.

Kleindiek Nanotechnik GmbH

www.nanotechnik.com

Due to miniaturisation in semiconduc-tor technology, optics, micro-mechanics, medicine, gene- and bio-technology, highly precise positioning techniques are becoming increasingly important. This company has developed and offers high-precision micro- and nanopositioning systems.

Multi Channel Systems MCS GmbH

www.multichannelsystems.com

MCS is the world leader for microelec-trode array applications. It develops high-performance measuring instruments and

equipment in the field of electrophysi-ology for research groups and for the pharmaceutical industry. When it comes to extracellular recordings with micro-electrode arrays in vitro and in vivo, MCS instrumentation is the undisputed number one. The success of MCS is an example for the effective translation of NMI micro-electrode technologies into industrial practice.

Retina Implant AG

www.retina-implant.de

The Retina Implant AG was founded in 2003. The mission is to restore vision -albeit limited- in patients who have turned blind because of degeneration of the retina (retinitis pigmentosa). The product is a biocompatible chip with integrated photodiodes which, when implanted under the degenerated retina of blind patients, transforms incident light into electrical impulses. These in turn will stimulate the optic nerve and restore a certain degree of vision.First clinical trials have given very encouraging results.

TETEC AG

www.tetec-ag.de

With its products Novocart, Novocart Disc and Novocart 3D for the therapy of cartilage injury based on the autolo-gous chondrocyte transplantation (ACT) procedure, TETEC AG is the market leader in Germany. Founded in 2000 on the premises of the NMI, the company is now entering international markets. In 2007 it became a subsidiary of the B|Braun Aesculap AG & Co.KG.


NMI overviewPatents

Patents – the NMI is a motor for innovation

Quality management

“We consider our quality managementto be the basis for our work in research and development as well as in our test-ing labs. For this reason we not only maintain our quality management sys-tems, but also design and utilize them proactively so that we recognize defi-ciencies in a timely manner and can improve our work processes when nec-essary. Regular audits help us to proac-tively identify many possible sources of error and to take corrective measures. It is our goal to make use of QM to opti-mize our processes and critically assess and improve our work.“

The NMI quality managementmission statement

Accreditation document by the DAR.DAP-PL-3420.00

Current legislation mandates that the testing of medical products for registra-tion must be performed in accreditedlaboratories. This is true also for indus-trial products. A prerequisite for accredi-tation is the establishment of a qual-ity management system. The latter has been introduced at the NMI.All services provided to our clients are performed according to the QM system. Testing can be performed in accredited areas according to the European norm EN ISO/IEC 17025.

Testing in accredited fields according to DIN EN ISO/IEC 17025:Analysis of organic and anorganic sur-faces (for example metals, semicon-ductors, alloys, glass and ceramics for medical technology) by means of spec-troscopic and electron-microscopic meth-ods; various electrochemical analyses in aqueous solutions.

Our QM fulfills the ISO9001:2000 requirements.

Numerous companies are holders of pat-ents based on IP generated at the NMI. In many instances transfer of NMI rights to the start-up companies was essential to their success. This is the best proof of the NMI claim of being committed to technology transfer.The generation of IP and its translation into innovative industrial products takes the highest priority among the strategic goals of the NMI. During the past few years, 21 patents have been assigned to the NMI. The entire portfolio includes 48 families of patents, in many instances jointly with other researchers which col-laborated with the NMI.The transfer of patents into industrial applications is carried out by the NMI Technology Transfer GmbH, a company which is 100% owned by the NMI foun-dation.In addition to patent commercialization through transfer to a given company, the NMI also offers exclusive and non-exclu-sive licensing.

“Our QM fulfills the ISO 9001:2000 requirements“


Public relations

Contact:

Public relationsDr. Nadja GugelerPhone: +49 7121 [email protected]

BioChipNet DatabaseDr. Jutta BachmannPhone: +47 66 [email protected]

The NMI participates as an exhibitor at fairs, congresses and scientific meetings. These PR activities complement the vis-ibility achieved through scientific presen-tations at international meetings, publi-cations in peer reviewed journals, round table discussions, etc. The most effec-tive visibility, of course, is that achieved through satisfied clients spreading the news about the quality of our services.

The BioChipNet databaseBioChipNet is an international inter-net portal on microarrays which can be accessed free of charge. It is the “who is who” of the BioChip scene. It contains information with the respective links on new technologies, scientific break-throughs, scientific meetings, companies and press releases. A monthly newsletter deals with patent information, confer-ences, publications and book reviews. The BioChipNet link appears on all major internet sites of the biotech-community as the information source on microar-rays. Since 2005 BioChipNet offers a yearly biomarker workshop which is held at the NMI.

www.biochipnet.com

Events at the NMI

Nadja Gugeler Jutta Bachmann

Biomarker workshop: from technolo-gies to targets and biomarkersEvery year since 2005 the NMI has hosted an international biomarker work-shop. Scientists from academia and industry discuss their scientific findings and new technologies in the field of biomarkers. The format of the meeting allows for ample discussion time and networking.

MEA meeting 2006For the fifth time the NMI organized this microelectrode array (MEA) meeting. At the last 4-day meeting, 160 participants from 16 nations presented their research concerning MEA applications and MEA development.The next meeting will also take place in Reutlingen in July 2008.

www.nmi.de/meameeting2008

“Our QM fulfills the ISO 9001:2000 requirements“


A Subsidiary of the NMI

The principal mission of the NMI foun-dation is to apply the results of basic research into product or process devel-opment for industrial clients. Accord-ingly, the scientific personnel and infrastructure of the NMI is geared to performing applied R&D rather then rou-tine services. Due to the high demand for validated high quality services based on new technologies developed at the NMI, the foundation has established a subsidiary, the NMI Technology Transfer GmbH.

The portfolio of the NMI TT GmbH includes:• peptide synthesis• protein profiling• bioanalytics • electrophysiology screening (ion chan-

nels) for drug discovery • in vitro safety pharmacology• micro- and nanostructure analysis of

materials• mechanical analysis• coating of surfaces • small series production (e.g. biochips,

microelectrode arrays, coated stents)• consultancy• info-brokerage/databases

Custom synthesis of peptides“NMI Peptides” is the brand name for our customer-specific synthesis of peptides.

We have more than 10 years experi-ence in multiple peptide synthesis and, beyond synthesis, we offer comprehen-sive consultancy that is tuned to the needs of our customers. We manufac-ture and deliver with short turnaround time high quality peptides with guaran-teed degree of purity in 1 mg-1 g quan-tity.Chemists at the NMI TT GmbH are experts in the synthesis of difficult sequences, including coiled-coil struc-tures and poorly soluble peptides, such as amyloid sequences for Alzheimer’s disease research.

Peptides are important for applications in the fields of cell assays, enzyme assays, epitope mapping, immunization, surface modification, smart biomaterials, drug discovery, etc.. We offer: • individual peptides• multiple peptide collections• peptide pools• combined peptide libraries• peptide microarrays

A variety of peptide modifications can be synthesized, including:• phosphopeptides• lipopeptides• cyclopeptides, branched peptides• marked peptides (biotin, fluorophores,

etc.)

Contact: [email protected] www.nmipeptides.com

CoatingThe NMI TT GmbH coats implantable medical products with diamond-like car-bons and polymers.

BioanalyticsAnalysis of oligonucleotides, proteins, lipids, drug metabolism, including:• oligonucleotide (MS)• posttranslational modifications (glyco-,

lipo-, phosphor-)• protein identification (MS, gels, Edman

degradation)• phosphatidylcholine• drug metabolites

NMI Technology Transfer GmbH

Contact:

Peptide synthesis:Nils ClausenPhone: +49 7121 [email protected]@nmi.de

Coating:Dr. Bernhard Schröder Phone: +49 7121 [email protected]

Bioanalytics:Dr. Dieter StollPhone: +49 7121 51530-811 [email protected]

Protein profiling:Dr. Michael PawlakPhone: +49 7121 [email protected]

Preclinical safety pharmacology:Prof. Dr. Elke Günther Phone: +49 7121 [email protected]

Dr. Dietmar HessPhone: +49 7121 [email protected]


Protein profiling by RPMA technologyThe NMI TT GmbH offers protein profil-ing services for the analysis of protein expression in extremely small samples using the Reverse Phase Protein Micro Array (RPMA) platform. RPMA is used for biomarker research, screening in early drug discovery, in preclinical devel-opment and in clinical research. The technology is based on specific immu-noassays (analogous to the Western Blot) and allows the parallel analysis of dozens of analytes in hundreds of samples, with a throughput of up to 10,000 Western Blot lanes per day.

We offer:• multiplexed analysis of differential pro-

tein expression and signaling pathway mapping

• screening of phosphoprotein activation and inhibition

• effect of drug candidates on cellular proteins in cell cultures (drug profiling, IC50)

• biomarker screening for preclinical drug discovery (analysis of samples from cell culture studies and from tis-sues of animal studies), and for clinical studies (analysis of tissue biopsies, e.g. tumors)

At present we offer over 100 standard-ized immunoassays on our RPMA plat-form.

Preclinical safety pharmacologySafety pharmacology studies represent an important milestone in drug develop-ment.

The NMI TT GmbH has established the following screening systems:• manual and automated patch-clamp

analysis in heterologous ion channel expressing or in transfected cells, e.g. hERG potassium channels in CHO cells.

• automated two-electrode voltage clamp analysis of ion channels in oocytes.

• automated QT-screen in cardiac myocytes

• langendorff heart preparation• papillary muscle preparation• isolated organ

Consultancy servicesThe NMI TT GmbH also offers compre-hensive consultancy regarding biochip and micro-array technologies, market overview, who-is-who and product pipe-lines. This service has the goal of defin-ing the best possible solutions for our clients.

Info-brokerage and databasesBioChipNet is the leading information platform on biochip and micro-array technologies worldwide (www.biochip-net.de). The database is updated regu-larly by Dr. Jutta Bachmann. A monthly newsletter supplements this information service.

PatentsThe NMI TT GmbH seeks licensees for NMI patents.

(Top) Reverse Phase Protein Microarray (RPMA) of treated cell culture samples.(Bottom) Differential proten expression profile: effect of 5 different treatments (treated over control signal ratios) on 3 phospho-kinases (orange, red, green); signal below line = down-regulation (inhibition), signal above line = up-regulation (activation).

4-Antibody-AG, Basel / Switzerland4base lab GmbH, Reutlingen Advalytix AG, BrunnthalAlopex GmbH, KulmbachBachmann Consulting, Nesoddtangen / NorwayBayer AG, LeverkusenBeiersdorf AG, Hamburg Biocat GmbH, HeidelbergBiopharm GmbH, HeidelbergBoehringer Ingelheim GmbH & Co.KG, IngelheimCytocentrics AG, RostockDiagno Swiss, Monthey / Switzerland

Among our customers are:

The sequencing of the human genome represents a milestone in modern biol-ogy. For the pharmaceutical industry this opens many new opportunities for the identification of specific disease-asso-ciated genes and cellular targets. This will facilitate the drug discovery process and the treatment of many diseases. The major effort in this post-genomic era will reside in the identification, functional characterization and comparative analy-sis of all cellular proteins (so-called pro-teom) in healthy and diseased tissue.

In cooperation with pharma and biotech-nology companies, the NMI develops new procedures and system solutions for drug discovery.We are active in the following fields:• functional genomics• test systems for drug discovery• bioanalytics/peptide synthesis

Our services include:• cell-based assays• gene transfer systems• protein identification• protein microarray• electrophysiology• analysis and synthesis of peptides

and biomolecules



Ebidi GmbH, Ingolstadt EDI GmbH, ReutlingenFresenius SE, Bad Homburg Grünenthal GmbH, AachenHoffman - La Roche AG, Basel / SwitzerlandIbidi GmbH, MartinsriedIngenium Pharmaceuticals AG, Martinsried/PlaneggInvitrogen Corporation, Carlsbad, CA / USAJerini AG, Berlin Luminex Corp., Austin / USAMerck KgaA, DarmstadtMerz Pharma GmbH & Co. KgaA, FrankfurtMorphoSys AG, Martinsried / Planegg

From gene to protein to cell function

Gene transfer and cell functionWith viral vectors we can introduce gene sequences into cells. This allows induction or inhibition of expression of proteins and assessment of their role in cellular processes (p. 18).

Molecular neurobiologyOur research is focused on the functional characterization of neuronal proteins which regulate neurite growth and plas-ticity in the nervous system. This work could provide the rationale for new ther-apies for diseases of the nervous system (p. 20).

Protein microarraysA large number of proteins from a small tissue sample can be identified simul-taneously and with high sensitivity in a miniaturized assay at low cost (p. 22).

Cell biochipsThe proteins of the extracellular matrix influence cell function. We have devel-oped a multiple substrate array (MSATM) for the screening of cell-matrix interac-tions (p. 24).

Functional Genomics

In vitro technology platforms

Electrophysiology with tissuesand cellsWith microelectrode arrays (MEA) one can measure and analyze the propaga-tion of signals upon electrostimulation in vitro as well as the spontaneous activity of electrogenic cells. The system finds its application in the study of the effect of compounds on neurons and cardiac tissue or cells (p. 26).

Characterization of ion channelsMessenger RNA or cDNA coding for ion channels is injected into frog Xenopus laevis oocytes. The ion channel proteins are expressed and after one day drug effects can be measured by a robot. Patch-clamp measurements in cell cul-tures are performed to analyze the effect of drugs on ion channels such as the car-diac potassium channel (p. 30).

High-quality custom-made solutions

BioanalyticsHighly sensitive and specific analytical methods for research and quality control require expensive instrumentation and expert personnel. The NMI provides spe-cific problem solutions for its customers (p. 32).

Peptide technologyPeptides play an important role in research and clinical medicine. Weoffer rapid customer-specific synthesis of pure peptides at competitive prices (p. 33).

Test sytems for drug discovery Bioanalytics/peptide synthesis

mphasys GmbH, TübingenMulti Channel Systems MCS GmbH, ReutlingenNeuroProgen GmbH, Leipzig Nycomed AG, KonstanzN-Zyme BioTec GmbH, DarmstadtProQinase GmbH, FreiburgProteinLogic Ltd, Cambridge / GB sanofi-aventis, FrankfurtSchering AG, BerlinServier Inc., Neuilli-Sur-Seine Cedex / FranceUniLever, Vlaardingen / NetherlandsZeptosens AG, Witterswil / Switzerland


Functional genomics


Target identification and validation for drug discovery.

Molecular biology plays an important role in target identification and valida-tion in drug discovery. Putative disease-related genes are identified by compar-ing the genome of healthy and diseased individuals. Such genes can be trans-ferred into cells via viral or non-viral systems leading to the expression of the gene product, i.e. a specific protein. The analysis of the effects of this gene transfer on cellular functions sheds light on the physiological role of the pro-tein under consideration. The reverse approach is also used, namely the inhi-bition of expression of a specific gene (referred to as gene-knockdown). This

is achieved by applying so-called RNA-interference (RNAi) technology, a manip-ulation which leads to the reduction of a specific gene product, i.e. the protein. Specificity of gene-knockdown is given by the siRNA nucleotide sequence. The analysis of the effects of this transfection on cell function can provide information regarding the possible physiological role of the protein. Molecular biologists at the NMI are experts in gene transfer and gene silencing technologies. These methods find their application in drug discovery projects for pharma and biotechnology companies.

Frank Weise, molecular biology, project leader

Gene transfer, gene silencing and cell function

Contact:

PD Dr. Hansjürgen VolkmerPhone: +49 7121 [email protected]

Dr. Frank WeisePhone: +49 7121 [email protected]

From the left: Maria Thomas, Sven Basa, Martin Kriebel, Sibylle Glock, Hansjürgen Volkmer, Roswitha Fischer, Claudia Franz, Ursula Hagner, Karen Böhme, Frank Weise, Cornelia Fricke, Thomas Hees und Sabine Trinks.


(A) (B)

Recombinant adenoviruses containing the construct for a fluorescence protein are spotted as array on a chip. The chip is then incubated with cells. An enlarged spot (A) shows the cells on one spot; the same spot (B) under UV-light reveals the expression of the fluorescent protein gene transferred by the virus.

A new biochip for target identifica-tionThe NMI has developed a new biochip for the analysis of proteins as potential targets for drug discovery.Of particular interest are protein kinases, a class of enzymes which regulate mul-tiple cellular functions by phosphorylat-ing other proteins, thereby altering their activity. The human genome contains more than 500 protein kinase genes, and several human diseases have been correlated to malfunctioning of the regu-lation of kinase activity. For this reason protein kinases have become an impor-tant target for drug discovery.The functional characterization of these enzymes in their intact intracellular environment can be achieved by the aforementioned gene silencing method, in which specific siRNA is introduced into cells to reduce the concentration of a given protein kinase. The high number of human protein kinases has prompted researchers at the NMI to develop a chip for the study of the effect of hundreds of kinases on cells in parallel. To this goal, adenoviruses carrying the siRNAs under consideration are printed as indi-vidual spots on a chip. Thus one can generate arrays with different siRNA at different positions. Subsequent incuba-

tion of the chip with cells leads to infec-tion of the cells by the siRNA viral vector and to synthesis of many copies of siRNA in the transfected cell. This in turn causes gene-knockdown and reduction of the concentration of the corresponding gene product, i.e. of a specific kinase. The observation of the effects on the function of the trans-fected cells can then be attributed to the decreased concentration of a specific protein kinase, since it is known which type of siRNA was placed at which posi-tion on the array.

Automated target identificationTarget identification and validation stud-ies by gene transfer technology are very time-consuming. The procedure requires creation and purification of the appropri-ate DNA vectors, their incubation with cells to induce transfection, identifica-tion of the efficiently and stably trans-fected cells, and finally analysis of the effects of specific gene transfection on cellular parameters. This elaborate proc-ess is being carried out at the NMI with the help of robotics. With this laboratory automation, up to 5000 genes per week are examined in drug discovery studies for our clients from pharma and biotech companies.

Biomek NXP laboratory automation workstation

FKZ 0313180


Functional genomics


Recombinant proteins for peripheral nerve regenerationBiopharm GmbH in Heidelberg, the Free University of Berlin, the University of Würzburg and the NMI are developing a synthetic implant for peripheral nerve regeneration. The molecular biologists at the NMI are investigating the role of recombinant proteins on intracel-lular signal transduction and neuronal growth. Ultimately the goal will be to coat the implant with highly specific fac-tors which can promote regeneration of injured nerves.

Neurons isolated from the rat brain (hippocampus), visualized by antibodies against GAD65 highlighting inhibitory synapses (red).

Molecular neurobiology

Promemoria: memory research“Promemoria” is the title of a project funded by the EU in which the NMI - together with 16 European partners - is researching the formation of synapses in order to develop a therapy for Alzhei-mer’s disease. One aspect on which the NMI is focusing deals with the role of cell adhesion molecules on nerve growth and synapse formation.This European consortium has already developed one candidate drug which is currently being tested in phase II studies. The NMI was awarded a prize by the Dr. Willy and Bärbel Bischoff Foundation in 2007 for its contribution to Alzheimer’s disease research.

FKZ LSHM-CT-2005-512012

FKZ 0312116

FKZ 0313422

Pruss et al,. (2006)

Niere et al,. (2006)

Rat hippocampal neurons, cultivated in a 96-well format were immunostained using an antibody against MAP2 (microtubule-associated protein 2), a marker for dendrites.

Contact:

PD Dr. Hansjürgen VolkmerPhone: +49 7121 [email protected]

Hansjürgen Volkmer, head of molecular biology.


NAT assaysNAT (nucleic acid amplification technolo-gies) -based assays are characterized by high sensitivity as well as high specificity. Thus, NAT assays have a broad range of applications including analysis of donors (e.g. blood donors) for genotyping purposes, the detection of genetically modified organisms, and analysis of cell cultures for contamination by viruses or bacteria.

The NMI TT GmbH is developing in co-operation with the 4base lab GmbH a NAT-based detection system for the squirrel monkey retrovirus (SMRV). Cell cultures in Germany have recently been tested positive for the presence of this virus. This project aims at detection of the virus as well as identifying polymorphisms in the sequence of the virus.

The information on polymorphisms will be included in the development of the NAT assay.

Contact:

Dr. Cornelia Fricke Phone: +49 7121 [email protected]

A transfilter culture is sub-cultivated under sterile conditions. Such transfilter cultures are applied as in vitro test systems e.g. for the human lung. This cultivation method offers the following advantage: cells can be cultivated at a liquid-air interphase which models the physiological conditions of the human lung.

A lung model for drug developmentThe European Lung Foundation has warned that lung diseases are becom-ing one of the major causes of death in Europe. In Great Britain lung diseases have already outpaced cardiovascular-related diseases as the leading cause of death. This illustrates the urgent need for new and effective drugs.

In cooperation with the EDI GmbH and the Novalung GmbH, the NMI is devel-oping an organotypic test system for potential new drug candidates aimed at the treatment of chronic inflammatory diseases of the human lung, e.g. asthma bronchiale or COPD (chronic obstruc-tive pulmonary disease). The test system consists of genetically modified human cells which possess an increased replica-tive life span while retaining a similar biological function as primary cells. The test system will be characterized in detail using molecular and cellular biological methods. The overall aim is the estab-lishment of a test system which allows an improved prediction of effectiveness and toxicity of potential new drug can-didates. Hopefully this will accelerate the development of new drugs for patients suffering from lung diseases.

FKZ 01GG0712

FKZ 720.830-4-15/3b

Cornelia Fricke, molecular biology, project leader


Functional genomics


Protein microarrays

A growing marketProtein microarrays are widely used in basic and applied research. Neverthe-less their market share is still growing. According to a recent report by BCC (September 2007) world-wide sales in 2006 amounted to 221 mil US $ and are predicted to reach 708 mil US $ 2013. The NMI offers its expertise to companies who want to participate in this rapidly expanding market.Furthermore, the NMI is a provider of extensive information on microarrays through the database BioChipNet (www.biochipnet.de) at no cost to the user. In collaboration with Dr. Jutta Bachman (Oslo, Norway) the database is constantly updated and covers microarray products and companies, new developments and technologies, applications, publications, conferences and press releases. This inter-net site is the leading portal for biochip technologies.

Protein arrays for clinical diagnostics and drug discoveryAutoimmune diseases such as rheu-matoid arthritis are diagnosed by the detection of autoantibodies in the blood of the patient. So far testing has been based on ELISA immunoassays. With the same accuracy, precision and reproduc-ibility one can detect these autoanti-bodies by microarray technology, the advantage being that much smaller sample size and fewer reagents are needed. There are many examples of the application of protein arrays in basic and applied research, in clinical research and in drug discovery, in particular in the measurement of biomarkers in body fluids and tissue extract.

Protein arrays for the detection of side effects of immunotherapeutics This is the topic of a project funded by the BMBF to promote innovation in drug discovery. The research partners of the NMI are the EDI GmbH in Reutlingen, Merck KgGa in Darmstadt, the Univer-sity Clinic in Ulm, and InterMed Dis-cover GmbH. The research approach is to establish human co-cultures for the detection of potential side effects of immunotherapeutics. Various human epithelial cells (from skin, intestine syno-vial fluid) are incubated with human blood which represents the complete immune system. At this point immuno-suppressant agents, ion channel block-ers, enzyme inhibitors, receptor antago-nists, antibiotics and antiviral compound are added and time/dose responses of the cells are measured using multiplex protein arrays and FACS analytics. This work will provide valuable information on the positive and adverse effects of drug candidates, including biologically active metabolites derived from bacteria, fungi and medical herb extracts.

Contact:

Dr. Thomas JoosPhone: +49 7121 [email protected]

Dr. Markus TemplinPhone: +49 7121 [email protected]

FKZ 035050

FKZ Jo687/2-1

Joos et al. (2006)

Thomas Joos, head of biochemistry.

Polystyrene microspheres internally dyed with spec-trally distinct fluorochromes define a set of signature beads (Bead Mix). Each set of signature beads carries a specific detection reagent (such as oligonucleotide probes, recombinant antigens or specific proteins) on its surface. Analytes contained in added samples bind to detection reagents on beads. A reporter coupled with another fluorochrome quantifies the reaction on the bead surface. The biomolecular interactions are quantified by the LX100 analyzer while passing the laser beams.


FKZ NMP4-CT-2003-505311

Templin et al. (2006)

Pawlak et al. (2007)

Markus Templin, head of assay development.

Contact:

Dr. Markus TemplinPhone: +49 7121 [email protected]

Assay developmentDuring the past years the NMI has focused on the development of numer-ous miniaturized multiplexed assay sys-tems for protein profiling. This allows the identification of new biomarkers obtained from cell cultures, serum or biopsy probes in preclinical drug discov-ery studies. Planar protein microarrays, microspheres (Luminex technology), and reverse phase protein microarrays are employed for parallel detection of over one hundred analytes in a single probe.

Research focusAn important question in modern drug discovery concerns the role enzymes and other proteins play in various intracellular signal transduction pathways. Compari-son of data obtained from normal and diseased states may point to the culprit of the disease and provide a rationale for selection of specific targets for drug discovery.

In collaboration with clinical researchers we are aiming at the identification and characterization of specific biomarkers as prognostic factors for a given disease state. Eventually the data from such studies may lead to robust standardised assays for clinical diagnostics.Other areas of research at the NMI involve the use of miniaturized protein array systems for the study of protein-protein interaction, for characterization of antibodies (epitope mapping, binding kinetics and determination of affinity constants, etc.). Thus the assay development group offers to its clients a variety of protein profiling test systems and will select the most suit-able of them, depending on the specific properties of the protein to be analyzed.

Protein microarrays for proteomics.The array consisting of 380 microspots allows the identification of collagen II produced by chondrocytes. Thirty-nine cell lysates were spotted and collagen detected with specific antibodies. The color intensities correlate with the concen-tration of collagen.


Pharma and biotechnologyFunctional genomics

Landesstiftung FRET in TIRFM

Kuschel et al. (2006)

Brigitte Angres, head of cellular test systems.

Contact:

Dr. Brigitte AngresPhone: +49 7121 [email protected]

The interaction of cells with their imme-diate extracellular environment is of great interest to researchers in the fields of regenerative medicine and drug dis-covery. The NMI develops technologies allowing the study of specific parameters of these interactions in planar and three-dimensional cell culture systems.

Multiple substrate arrays MSA™The multiple substrate array technology allows rapid screening of the interaction of cells with matrix proteins on a miniaturized scale. The proteins are spotted as array and the effects of individual proteins on cell adhesion, proliferation and differentiation can be observed. Additional content can be derived from the system by adding specific soluble biomolecules such as growth factors or drug candidates to the

medium. Green fluorescent protein tech-nology can also be applied to visualize the effect of matrix protein components or soluble factors in the medium on spe-cific cellular proteins.

Researchers at the University of Dres-den and at NeuroProgen in Leipzig col-laborate with the NMI in developing an appropriate matrix material to induce stem cell differentiation into neurons, with the goal of promoting regeneration in the brain.

HepatoSys is a research program that makes use of the MSA™ chip to study matrix protein effects on proliferation, differentiation and signal transduction of liver cells. The goal is to better under-stand the mechanism of liver regenera-tion.

Cells bind with different avidities to different extra-cellular proteins of the MSATM chip. Microscopic images of each microspot are taken for cell pheno-type analysis.

Arrays of extracellular matrix proteins are microspotted on glass microslides. Cells are incubated on the arrays and effects of extracellular matrix proteins on cell behaviour are subsequently analysed.

Test systems for the analysis of cell-matrix interaction

substrate 1,2,3, ... n

cell colonization

cellular assay: for example adhesion, phenotype, differentiation


The point of signal transduction from matrix to cell is the cell membrane. Here we are dealing with very subtle and specific protein-protein interactions. The analysis of this process is essential to understanding the points controlling cellular responses to their environment. Experimentally one can use fluorescent labels to tag a pair of proteins and use optical instrumentation to study their interaction. The adaptation of this so-called FRET-based technology (FRET: Föster energy transfer) to an automated screening system for drug discovery is a goal being pursued by the NMI and partners at the University in Aalen and funded by a grant of the State Founda-tion of Baden-Württemberg.

Signal transmission at the cell-matrix interface

Top view of a cell culture: specific cell adhesion sites are labeled with fluorescent proteins and visualised in optical sections of only 100 nm thickness by total internal reflection microscopy.

Focal adhesion kinase (FAK) and paxillin (Pax) are two central signaling proteins in focal adhesions. FAK and Pax are genetically fused to the fluorescent proteins ECFP, and EYFP respectively. The intracellular interaction of the two proteins can be monitored in live cells by measuring the Förster resonance energy transfer (FRET) between ECFP and EYFP. The low energy illumination of the protein complexes in an evanescent field of a totally reflected laser beam allows the detection of the fluorescent signals without cytotoxic side effects..

In still another project sponsored by a State Foundation of Baden-Württem-berg, the MSA™ chip is employed to study the ability of various synthetic peptides to promote cell adhesion and differentiation. This allows rapid identi-fication of active peptides which could later be used as substrates for regen-erative medicine and tissue engineering applications.

The numerous applications for the MSA™ chip make it a very powerful tool for the study of the interaction of cells with proteins and factors in their environment. The MSA™ chip is com-mercially available through the com-pany BioCat, Heidelberg.

evanescent field

plasma membrane

total reflection of the light


Pharma and biotechnology Test systems for drug discovery

Contact:

Dr. Alfred StettPhone: +49 7121 [email protected]

Simply the best: microelectrode array (MEA) technologies at the NMIThe NMI is the world leader in microelec-trode array development and applica-tions. Scientists at the institute have been instrumental to the propagation of this technology, which now has become an established method in electrophysiology.MEAs allow for simultaneous stimulation and recordings from cells and tissues. Brain slices, spinal cord preparation, neu-ronal cells, and cardiac cells are examples of applications of the MEA technology. The effects of specific agents on these tissues and cells can be analyzed with a millisecond timescale. Since the system makes it possible to attribute each signal to a certain set of electrodes, spatial res-olution, signal propagation in slices and

cell networks can be measured, in turn making it possible to address basic ques-tions related to neuronal networks.The system is very suitable for drug dis-covery studies, for instance in the thera-peutic areas of epilepsy, ischemia, schizo-phrenia and cardiovascular disease.

Microsystems and nanotechnology: innovations for pharma and biotech companies

Alfred Stett, head of biophysics

The nanostructure of the pin-like titanium nitride provides a large surface, a prerequisite for the electrodes’outstanding characteristics.

Microelectrode array (MEA) developed by the NMI for electrical stimulation and recording of electrical activity of living tissues. The amplifier contact pads to the 60 electrodes in the center of the chamber are aligned along the chip sides.

Brain slice (hippocampus) on a microelectrode array (MEA). The electrical activity can be recorded from 60 electrodes simultaneously, thus allowing the spa-tial and temporal analysis of the signal propagation within the brain slice.

A single titanium nitride electrode. The highly sensitive and long-term stable electrodes are manufactured at the NMI.

200 µm 10 µm 200 nm

1 cm


NMI – a pioneer of microelectrode array technology

The NMI is constantly involved in devel-oping new applications, such as MEAs on glass, flexible MEAs on polymer sub-strates, and MEAs integrated in microflu-idic systems. The microelectrode geom-etry and number (up to 1024 per array) can vary, as can the specific distribution of electrodes on the chip. The material composition can also be varied, depend-ing on the specific application. In one line: an array of technologies to meet the requirements of NMI partners.The chips are produced by NMI TT GmbH for Multi Channel Systems, which integrates them in appropriate measur-ing systems and sells them world-wide to academic and industrial researchers.Safety guidelines for new drugs allow in vitro analysis of drug effects on organs as long as the test systems closely reflect the in vivo situation with respect to those parameters which are crucial for safety. The NMI has therefore developed

robust and relevant protocols (p.30) for the measurement of electrophysiological parameters in nerve and cardiac tissue which are relevant to safety pharma-cology. Innovative MEA developmentsThe latest innovation is the perforated MEA on polyimide substrate connected to a microfluidic system. This facilitates the placing of brain slices onto the elec-trode field and, thanks to the perfora-tion, allows better perfusion and oxy-genation of the tissue.

Rat cortex brain slices on MEA (U. Egert, University of Freiburg).

FKZ 16SV2378

Egert et al, (2006)

Fejtl et al., (2006)

Stett et al., (2007)

Perforated MEA with electrode arrays for stimulation and for recording in different cell layers of hippo-campal tissue slices. The perforation comprises 28% of the relevant area. Electrode pitch in the recording region is 90 µm * 200 µm.



Systems for microculture and analysis of neuronal cells and tissue

Sensor and culturing device for neuronal cell and organotypical tissue culture. The highly transparent plastic foil (blue) with integrated microelectrodes for recording neuronal cell activity was bonded with an extruded plastics moulding (red). a) Both parts consist of gas-permeable plastic material and form a microchannel fluidic system for long term tissue culture. b) The plastics moulding is equipped with a sealable opening for placement of brain slices.

There is an increasing need for standard-ized screening systems for drug discov-ery in the treatment of central nervous system injuries and dysfunction. A plat-form for organotypic cultures integrated with optical and electrophysiological readout components would represent a significant innovation.In the research project “Neuroslide” funded by a grant from the BMBF, the NMI is developing a modular, integrated system for culturing and analyzing neu-ronal cell function. It is based on the automated microscope-platform iMIC of Till Photonics; it integrates the microelec-trode (MEA) platform of Multi Channel Systems with the flexibility of the ibidi culture system. The principal integration level is the Neuroslide culture chamber with microchannels and integrated micro-electrodes. It is made of a special plastic material suitable for microstructuring, is permeable to gas and has excellent opti-cal properties. This device allows laser manipulation of cells, fluorescence-based optical readout of specific cellular reac- Tissue culture vessels with self-contained micro-

channels and substrate-integrated microelectrode arrays deposited on gas-permeable thin plastic bottoms (BMBF project Neuroslide, FKZ 16SV2378). MEA-based biosensors can be used for studying phy-siological and pathological tissue conditions or for analyzing the effects of pharmaceuticals on specific tissue. The technique represents an alternative to time-consuming in vivo experiments in pre-clinical screening tests.

Project partner:

Multi Channel Systems MCS GmbH, Reutlingen

ibidi Integrated BioDiagnostics GmbH, Martinsried

TILL Photonics GmbH, Gräfelfing

FKZ 16SV2378

tions and electrophysiological stimulation and recording of neuronal activity.The system represents a fundamental improvement over the conventional MEA technology since it integrates microflu-idics with electronic and optical readout components, thus allowing the monitor-ing of several parameters of neuronal tissue activity at once. Such a Neuroslide could significantly facilitate the screening of new therapeutic agents for the treat-ment of CNS diseases.

Neuroslide

a) Microchannel with integrated electrodes

tissue slice

1 2

seal

b)

Test systems for drug discovery

Contact:



Cell manipulation through microfluidics and electric field forces

Drug metabolism and toxicity studies of drug candidates are crucial milestones in the development of effective and safe therapeutic agents. Predictive in vitro models for such studies are therefore of great interest to the pharmaceutical industry. Studies performed with tissue culture systems are of limited predictive value, since cells in culture dedifferenti-ate and lose many of their original func-tional and metabolic properties. Further-more, cells in tissues are in contact with other cell types and their behaviour is influenced by cell-to-cell signalling.

In order to overcome some of these limitations, the NMI has applied for and obtained funding for a research project entitled HepaChip. Partners in this

project are Keyneurotek AG in Magde-burg, BLS Bioservice in Munich, Micro-fluidic Chip Shop and the University of Leipzig.The HepaChip should allow for the assembly of cells into cell aggregates with a cell-type composition similar to that of the original organ. The micro-fluidic system enables the perfusion of these aggregates with tissue culture media in order to promote the forma-tion of three-dimensional organ-like structures. Furthermore, samples of the perfusate can be removed and analyzed by conventional HPLC-mass spectrom-etry. Once standardized, these on-the-chip microcultures can be used for drug discovery, toxicity and drug metabolism studies.

Manipulation of living cells by dielectrophoresis: cells sedimenting from medium above an electrode array are arranged in an array format.

Contact:

Dr. Martin StelzlePhone: +49 7121 [email protected]

Martin Stelzle, head of physical chemistry and sensor technology


Pharma and biotechnologyTest systems for drug discovery

Contact:

Prof. Dr. Elke GuentherPhone: +49 7121 [email protected]

Safety pharmacology for drug discovery

MEA cardiosensorCardiac activity is regulated by electrical impulses which are recorded and graphi-cally presented in the form of electro-cardiograms (ECG). The ECG has typi-cal characteristics and is therefore a very sensitive tool for the diagnosis of heart diseases such as arrhythmia. An important functional parameter is the so-called QT-interval, which represents the time interval between ventricular depolarization and repolarization. In some instances, adverse effects on cardiac activity have been observed in patients who were treated for diseases other than cardiac diseases. The potential of drugs to elicit this seri-ous and sometimes deadly side-effect is recognized in the ECG by a prolongation of the QT-intervals. For this reason it has become mandatory to show that drugs do not affect this parameter. The NMI pro-vides this safety pharmacology service to drug companies in conformance with the “Guidelines of the International Confer-ence on Harmonization (ICH)”.

The MEA cardiosensor is an automated system for QT-screening. It was developed by Multi Channel Systems MCS GmbH based on the microelectrode array tech-nology (p. 27-28). It consists of a 96-well platform integrated in an automated elec-trophysiological recording system which allows measuring the effects of drugs on heart cells in vitro, thereby revealing their potential to induce QT-interval prolonga-tion and arrhythmia.

MEA retina sensorFunctional changes of the retina in vitroLight incidence induces electrophysiologi-cal activity in the retina. This response is transmitted via the optic nerve to the visual cortex in the brain, where the signal results in visual perception. Electroretinography (ERG) refers to the process of detection and recording of the electrophysiological response of the retina to light and is used in the diagno-sis of eye retina malfunction. Abnormali-ties in retina function can also occur as a result of adverse side-effects of drugs. This retinal response to light and drugs can also be induced in vitro.

As a safety pharmacology service to pharmaceutical companies, the NMI per-forms microelectroretinograms in vitro on retina explants of rats or chickens by means of a MEA-retinasensor. The retina is placed on a microelectrode array inte-grated in an incubation chamber. The influence of added drugs on the elec-troretinogram is measured and presented in form of dose-response curves. In addi-tion to such safety applications, the MEA retina sensor is used in studies on the mechanism of drug action.

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Cardiomyocyte monolayer on MEA chip

Field action potential recordings of cardiomyocytes.Upper left: control, upper right and below: effects of the hERG channel blocker E4031 on rhythmic activity of cardiomyocytes in vitro.

QT well plate for parallel recording of field action potentials in 96 cardiomyocyte cultures.

Prolongation of the QT-interval in vitro of cardiomy-ocytes in response to increasing concentrations of quinidine (black: control).

wash-in of 1 µM E4031 sinus rhytm QT prolongation arrhythmia block of activity

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Characterisation of ion channels

Ion channel screening oftoad oocytesAfter injecting into the oocytes of clawed toads mRNA or cDNA coding for the ion channel of interest, the channel proteins are expressed and their function and pharmacology can be examined by the electrophysiological patch-clamp method.

The injection of nucleic acids into the oocytes as well as substance application and electrophysiological recordings of ion channel activity are done automatically by a robot, the Roboocyte. This ensures a high throughput and makes the proce-dure reproducible and inexpensive.

Patch-clamp analysisSeventy percent of all illnesses are treated with medication that affects the ion chan-nels. Any medication that has an effect can, however, also have side effects. In order to identify and evaluate these side effects, it is necessary to carry out phar-macological tests on certain ion chan-nels. One such ion channel is the hERG potassium channel, the malfunctioning of which may lead to dangerous cardiac irregularity. In the field of safety pharma-cology we carry out electrophysiological patch-clamp analysis of ion channels in cultivated primary cells or cell lines.

Upper: Roboocyte setup with 96 well plateLower: SCN5A without (green) and in presence of a blocking substance (red).The Robocyte enables a fast and efficient analysis of substance effects on ion channels.

hERG transfected CHO cells: left: adherent cell culture for manual patch clamping, right: cells on suspension for automated patch clamping

Cisaprid effect on hERG transfected CHO cells (auto-mated patch clamp recording)

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Pharma and biotechnologyBioanalytics/peptide technologie

Contact:

Dr. Dieter StollPhone: +49 7121 [email protected]

First Class: bioanalytics at the NMI

Success breeds recognition! In May 2007 the NMI and CureVac GmbH in Tübin-gen were awarded a prize by the VBU (German Association of Biotechnology Companies) for their excellent coopera-tion and for the outstanding research and development in the field of RNA immunotherapeutics. CureVac GmbH is a very successful start-up company which received the prestigious Dr. Rudolf Eberle Innovation Award in November 2007. The NMI supported CurVac by developing and validating analytical pro-cedures for RNA analysis.

The bioanalytics department at the NMI participates in projects which require the analysis and quantification of lipid metabolites, proteins in body fluids for proteomic research, and peptidic sub-trates of matrix metalloproteases.

The NMI is accredited according to the European norm DIN EN ISO/IEC 17025:2000.

As a service for biotechnology and pharma clients, the bioanalytics depart-ment performs quality control studies of biopharmaceuticals, of siRNA oligonu-cleotides, and of peptides and polymers to be used as biodegradable materials in regenerative medicine. In the field of medical products the NMI applies the most modern, precise and sensitive analytical methods to determine drug release kinetics from medical products (e.g. drug-coated stents). Any issues related to cleanliness and chemical sta-bility of implantable medical products are also addressed by chemical analysis procedures.

Equipment:• ESI/Apcl-qTOF mass spectrometer• ESI/Apcl triple quadruple

mass spectrometer• MALDI-TOF mass spectrometer• Capillary electrophoresis• HPLC systems coupled with MS (mass

spectrometers), MS/MS, UV, diode array UV, fluorescence or or evapora-tive light scattering detector

Dieter Stoll, head of bioorganic chemistry/analytics

Results of a mass spectrometry based screening of the MMP cleavage kinetics of different peptide substrates related to the type of aminoacid and its distance from the cleavage site.

Comparison of release kinetics of paclitaxel from different drug-eluting stents

Half period of digestion (h)

Peptide library of Ac-Aca-GPLGVRGK-Aca-Amide

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Contact:

Nils ClausenPhone: +49 7121 5 [email protected]


Peptides are important molecular tools in life science research and in medicine. They are used in immunology as anti-gens to generate antibodies or as probes for epitope mapping. Peptide vaccines are used in infectious diseases affecting animals and humans. Many new drugs under development are peptides. Insulin for diabetes is a peptide, as are many HIV/AIDS drugs. Many more examples could be given at this point to further illustrate the importance of peptides.

In collaboration with industrial and aca-demic partners, the NMI conducts many research projects in which peptides syn-thesized in-house are employed to inves-tigate the nature of antigen-antibody binding sites, to generate antibodies for microarray technology applications in biomarker research, and to deriva-tize biomaterials (smart biomaterials and 3D-scaffolds) in order to promote spe-cific cellular responses for applications in regenerative medicine.

Further information on bioanalytics and customer-specific synthesis of peptides can be found on p.14 of this report.

Peptide technology

CombiFlash Sq16x flash chromatography system for fast and automated peptide cleanup.

Determination of an antibody epitope using a peptide microarray

“Biomedical technology is an important future-oriented, high tech branch of industry that provides job security and prosperity in Germany while at the same time contributing to our health and to increased efficiency in our health care system.“

Prof. Dr. Olaf Dössel,German Society for

Biomedical Technology

Precision mechanics, mechanics, optics, material technology and textiles are the branches of industry which have traditionally been involved in medical technology. In the last years there has, however, been new focus on biotechnol-ogy with its specific insight into cell and tissue life.

We are convinced that the collaboration between traditional medical technology enterprises and modern biotechnology will give rise to economic and technical progress in biomedical technology, lead-ing to new innovation. Due to its inter-disciplinary structure, the NMI is able to take these developments into account and offer new and important impulses in the fields of• neurotechnology and micromedicine• regenerative medicine and biomaterials• development of medical products

The NMI carries out R & D and product development in the field of biomedical technology for the following companies:

accelab GmbH, KusterdingenAltimed JSC, Minsk / BelarusBIBraun Aesculap AG & Co.KG, TuttlingenBruker Daltonic GmbH, BremenBiopharm GmbH, HeidelbergCarl Zeiss SMT AG, OberkochenCellMed AG, AlzenauCybio GmbH, KusterdingenDr. Fenning Biomed, KirchzartenFriz Biochem, MünchenGelita AG, EberbachHL-Planartechnik GmbH, DortmundLabor Dr. Merk & Kollegen, OchsenhausenMediagnost GmbH, ReutlingenMikrogen GmbH, NeuriedNycomed AG, KonstanzPerkin Elmer Inc., Massachusetts / USAPlasmaelectronic GmbH, Neuenburg a.R.Retina Implant AG, ReutlingenTETEC AG, Reutlingen



Micromedicine Regenerative medicine and bio-materials


Chips for diagnostics and intelligent implants

Intelligent implantsThe development and production of intelligent implants is a great challenge. The NMI conducts research in the field of active and passive implants, with a focus on the development of neurotechnologi-cal implants for the eye, ear and brain (p. 36-37).

BioFIB The biocompatibility, biostability and functionality of implants, actuators and sensors are influenced by their sur-face properties. The latter determine the interactions at the point of contact between the biological tissue and the medical device. The NMI is developing procedures for the ultrastructural analy-sis of this interface (p. 38).

Microsystems for diagnosticsMicrosystem technology has entered the field of diagnostics. The NMI is devel-oping robust assay procedures for the detection of biological particles, viruses, proteins and DNA (p. 39).

A positive outlook for the patient

Biomaterials for regenerative medi-cineThe NMI is developing a new three-dimensional scaffold to support the function of implantable cells (p. 41).

Regeneration of articular cartilageThe focus is on the development of smart biomaterials for the ACT therapy of osteoarthritis (p. 42).

Regeneration of the spinal discResearchers at the NMI are investigat-ing the use of autologous intervertebral disc cells or mesenchymal stem cells for the therapy of spinal disc degeneration (p. 43).

Regeneration of injured nervesThe NMI develops implantable biode-gradable hollow fibre nerve guides to promote the regeneration of injured nerves (p. 44).

Vascular regenerationAtherosclerosis results in narrowing of coronary arteries and can lead to stroke and heart attack. Angioplasty with stenting is used to reduce symptoms of atherosclerosis. This procedure, however, results in injuries to the arterial wall, which in turn can cause restenosis and blood vessel occlusion. The NMI is inves-tigating whether repair of these injuries and prevention of restenosis can be achieved with stem cell technology and new types of vascular implants (p. 45).

New technologies and innovation guarantee growth

Functional surfacesImprovement of the surface properties of medical devices according to clients specifications is one of the specialties of the NMI (p. 47).

Cleanliness of medical productsSurgical instruments, endoscopes, cath-eters, etc. must meet highest functional and hygienic standards. This is particu-larly true for reusable medical devices. The NMI performs a variety of tests to demonstrate the effectiveness of clean-ing and sterilization procedures (p. 47).



Micro- and nanotechnology are among the top ten key medical technologies of this decade. Microsystem technology drives innovation in medical diagnostics, preventive medicine, patient monitor-ing and therapy. Once fully established and implemented, these technolo-gies will have an enormous impact on public health and healthcare costs. In 2005, the VDE estimated that the world market for micromedicine applications amounted to 12 bil q. In 2007, sales of products based on microsystem tech-nology for clinical diagnostics, such as lab-on-a-chip devices, amounted to 625 mil US $, a volume which could double by 2013 (BBC Research, Sept. 2007).

Contact:

Dr. Wilfried NischPhone: +49 7121 [email protected]


Micromedicine

Retina implant.

Functional diagram of the subretinal implant. Visual information is projected by the cornea and lens of the eye to a light-sensitive chip which replaces degenerated photoreceptors. Depending on the local contrast of the image, the retina is electrically stimulated by the electrodes. This results in spatially resolved activation of the retinal nerve cells, which is perceived by blind people as a phosphene pattern.(For more information visit www.retina-implant.de)

Titanium nitride electrode50 x 50 micrometers.

Stimulation pixel.

According to an estimate by the BMBF, the retina implant chip for patients with retinitis pigmentosa, now being devel-oped with the cooperation of the NMI, has a market potential of 1.5 bil $ US. These examples best illustrate the signifi-cance of micro- and nanotechnology for microsystem applications in clinical diag-nostics and micromedicine, two fields in which the NMI has been conducting research and product development for many years.


Neurotechnological implantsThe eye, ear and brain are the organs for which the NMI develops neurotech-nological implants in cooperation with industrial, academic and clinical research partners. A clinical pilot study with retina implants for patients with retinitis pig-mentosa launched by the Retina Implant AG, a spin-off of the NMI, has yielded very encouraging results. The NMI is conducting studies aimed at improving the long-term stability and biocompatibility of neurotechno-logical implants. For a particular type of ear implant, a so-called round-window implant consisting of several connected components, the goal is to ensure biostability and biocompatibility through special encapsulation technologies. Fur-thermore, a nanostructured surface has been developed which should allow for a better integration of the neuroimplant in the target tissue, thereby increasing the efficiency of neurostimulation.For EEG recordings in epilepsy the NMI develops cranial implants consisting of carbon microelectrodes integrated in a flexible polymer substrate. This type of microdevice is an example of an innova-tive microsystem in the field of micro-medicine. Further developments will lead to the production of implantable micro-devices which combine EEG recording with neurostimulation capability. Such intelligent active implants could detect the onset of an epileptic attack and sup-press its build-up through electrostimula-tion of the affected brain area.

Artificial synapseCurrently available neuroprosthetic devices deliver electrostimulation to muscle and nervous tissue at once. A more selective stimulation may be obtained with microstructured implants capable of delivering stimulating or inhibiting substances in very small quantities to selected target cell areas. The NMI is applying microfluidics and microstructuring technologies to create an intelligent implantable device which should mimic some aspects of the bio-logical synapse. Various prototypes capable of delivering discrete picoliter amounts of solution containing cer-tain neurotransmitters to cells in culture are currently under development at the NMI in collaboration with scientists at the HSG-IMIT in Villingen-Schwennigen and at the IMTEK at the University of Freiburg. One of these devices is based on the bubble-jet principle used for ink-jet printing.

Electrostimulation of cells and tissuesScientists at the NMI are investigating the effects of continuous electrostimu-lation of nervous tissue. In collabora-tion with the eye clinic at University of Tübingen and the Retina Implant AG it could be shown that in an animal model of retina degeneration continu-ous electrostimulation decreases the degenerative process. Additional studies with the above partners and research-ers of the IME at the University of Ulm are focused on developing a new type of retinal implant. The device is based on highly integrated electrode arrays which allow multilocal electrostimulation of the retina. The effects on spatial and time resolution and of perception of the sur-rounding environment will be examined.

Intelligent implants

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New materials and production processesThe development and production of pas-sive or active implants is a very challeng-ing task. Implants that remain in the body for months or years must be compat-ible with their biological environment and maintain their functional properties. A variety of reactions can occur at the interface between implanted material and host tissue, all of which can influence the stable integration and functionality of the device. Intelligent microimplants consist of various interconnected components and require energy supply for recording, telemetry or electrostimulation. Due to the complex composition of such micro-devices, the reactions at the points of contact with the biological environment at the site of implantation can be crucial to their stability and long-term function-ality.The NMI is permanently involved in the development of specific solutions to optimize the performance of active and passive implants for biomedical appli-cations. This involves the selection of appropriate biostable and biocompatible materials and surface coatings, such that the desired mechanical and tribological properties of long-term implants remain unaltered, thereby ensuring safety and functionality of the implanted device. The many years of microsystem research and product development for biomedical applications at the NMI have resulted in a considerable accumulation of expertise in microfluidics, micro- and nanostructur-ing, connecting and assembly technolo-gies. As part of these efforts, research at the NMI has focused on the modification of the surfaces properties of materials through coating with biological molecules in order to allow a better integration of implants into the host tissue.

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BioFIB: Preparation and analysis of the interface between medical implants and biological environment

“BioFib” refers to the application of the Focused Ion Beam (FIB) technology to the ultrastructural analysis of the inter-face between implanted material and host tissue. This point of contact is of great interest for a better understand-ing of those factors which influence the biostability and biocompatibility of implants, sensors and actuators. The NMI is developing procedures which allow the analysis of ultrastructures at the interface between the tissue and the implanted material. In this case, conven-tional methods used to prepare biologi-cal specimens for electron microscopy have to be adapted in order to avoid disruption of the cell-to-material contact points.

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The combination of conventional techniques for biological sample preparation with the possibility of site specific preparation in a CrossBeam® electron microscope allows us to prepare and image the interface between biological and technical materials.

Micromedicine

Contact:

Dr. Claus BurkhardtPhone: +49 7121 [email protected]

Zeiss CrossBeam® scanning electron microscope

Claus Burkhardt, physical engineering

Polyimide

Silicon oxide

Retina

Example: Retina tissue cultivated on a electrode. Top: Three dimensional cross sectionLower left: Organelle (bright) within the retinal pigment epithelium Lower right: Different layers from top to bottom: polyimide, silicon oxide, gold and retina

Gold

A scanning electron microscope with a built-in focused ion beam (CrossBeam®, Zeiss) is used for the three-dimensional representation of the ultrastructures at the interface between the biological moiety and the implant.


Microsystems for diagnostics

The application of microsystem technol-ogy accelerates and facilitates analyses in the field of clinical diagnostics. Mini-aturization allows performing assays on a single chip, which until now could only be carried out on a laboratory scale. Such disposable smart lab-on-the-chip devices are especially suited for point-of-care set-tings. These chips integrate means for sample preparation and analysis. Func-tions such as sample injection, on-chip reservoirs, droplet formation structures, fluidic pathways, reagent mixing areas and sites for optical detection of analytes may be integrated on the same chip.The NMI has expertise in the develop-ment and handling of such systems. This includes know-how in microfluidics, application of microsystem technologies, thin-layer surface coating techniques, rapid prototyping, numeric simulation, as well as knowledge of the biocompatibil-ity of materials, culturing and handling of cells and optical, electrochemical or bio-chemical analytical methods.

Bioseparation/pathogen diagnosticsIn order to detect small particles in body fluids or tissue extracts, separa-tion and enrichment procedures must be employed. Towards this goal the NMI, the Fraunhofer IBMT and the industrial part-ners Mediagnost GmbH and Evotec Tech-nologies AG have developed the NanoVir-Detect platform which uses microfluidics and dielectrophoresis for sample process-ing and particle enrichment. The system is compatible with highly sensitive analytical detection methods such as single mole-cule spectroscopy or impedance measure-ment. The technology has been applied

to the separation, accumulation and detection of antibody-loaded micro- and nanobeads as well as to the analysis of samples containing Hepatitis A viruses. More recently the NMI has joined efforts with Biorad GmbH and Boehringer Ingel-heim MicroParts GmbH in order to further develop the NanoVirDetect platform for the separation of cell organelles from cell homogenates.Another project deals with the detection of antibiotic resistance genes in bacteria in the urinary tract. In this case the micro-fluidic chip must integrate sample extrac-tion and injection, bacterial accumulation, lysis, DNA extraction and DNA analysis. This project is being carried out in coop-eration with the Stuttgarter Institute for Technical Biochemistry, the Eppendorf AG, Multi Channel Systems MCS GmbH, the Robert Bosch GmbH and the Robert Bosch Hospital.

Nanobiopore: highly sensitive electro-chemical sensorsNanobiopore is the name of a new tech-nology platform for electrochemical detection of DNA and proteins in body fluids. Nanostructured electrode arrays are produced at the NMI by means of a nanoparticle lithography process. The high sensitivity of the analyte detect-ion system is based on redoxrecycling. The nanostructured electrode array has already been tested for the direct meas-urement of analytes in serum. High sensitivity, robustness and low produc-tion costs should facilitate entry into the clinical diagnostics market. Partners in this project are HL Planartechnik GmbH, Mikrogen GmbH, Merck KGA, Friz Bio-chem GmbH, Multi Channel Systems GmbH and Dr. Fenning Biomed GmbH.

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Neugebauer et al., (2006)

Contact:


Sensor chip with 4 sensor elements.

Micrographs of a dielectrophoretic field cage structure in a NanoVirDetect microfluidic device recorded at four different times. Dielectrophoretic forces are employed to accumulate and trap microbeads loaded with antibodies in a field cage. Only if the sample contains the target antigen - hepatitis A viruses in the particular case of the experiment shown - will fluorescently labeled detection antibodies bind and the particle aggregate appear bright and be detected.

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SEM micrograph of a nanobiopore sensor electrode comprising 0,8µm pores. The insert shows a cross-section of the layer system prepared by focused ion beam etching.


Biomedical technologyRegenerative medicine and biomaterials

Regenerative medicine: a positive outlook for patientsThere are many examples of tissue regeneration in the animal kingdom. We all know the lizard, for instance, whose tail grows back if lost after being attacked by a bird. Human organs, in contrast, need the help of regenerative medicine to restore tissue after injury.Virtually any disease which results from malfunctioning, damaged or failing tissues and organs may be potentially cured through regenerative medicine therapies. One approach is tissue engi-neering: tissue structures are generated in vitro and then implanted into the patient to support or substitute the dam-aged organ. In a different therapeutic approach biomaterials in combination with various cell types including stem cells can be implanted in the degener-ated tissue.

It is generally accepted that regenera-tive medicine has a very strong growth potential. There have been reports estimating that its world-wide market volume for the year 2012 could reach 160 billion euros. One of the driving forces of this expansion is the growing number of elderly persons. For example, there is an increasing need for effective therapies for various types of impairment of the musculoskeletal system of elderly patients.

The NMI is focusing on developing new types of implants in which the interac-tion between cells and biomaterial on the one hand and cells and host tissue on the other hand are optimized. This approach is consistent with the key com-petence of the NMI at the interface of life sciences and material sciences.Over the past decade the NMI has already made significant contributions to the development of new therapies in regenerative medicine.

Contact:

Karin BenzPhone: +49 7121 [email protected]

Prof. Dr. Burkhard SchlosshauerPhone: +49 7121 [email protected]


Dr. Helmut Wurst Phone: +49 7121 [email protected]

Regenerative medicine at the NMI

BioRegioSTERN with a clear focus on regenerative medicine

nervous system

vascular system

biomaterials as sub-strates for enzymes

siRNA biomaterials

3D biomaterials

cartilage

bone


Biomaterials for regenerative medicineThe physiological activity of cells in a tissue is precisely regulated via complex communication mechanisms between the individual cells and their environment. Thus, soluble factors in the extracellular milieu and structural properties of the extracellular matrix are key regulatory elements of cell function and cell-to-cell interaction within a tissue.

In order to analyze these mechanisms, the NMI has developed a biocompatible polymer which, when admixed to cells, can be chemically activated to form a gel scaffold. This three-dimensional mater-ial supports cell growth without affect-ing specific cell functions. The polymer can also be functionalized by the addition of specific regulatory factors. This allows studying the behavior of cells in a three-dimensional structure in response to spe-cific biomolecules and drug candidates. For tissue engineering the development of a biocompatible matrix which can be colonized with certain cell types for subsequent implantation would be very useful.

Differentiation of mesenchymal stem cells in threedimensional cell culture The therapeutic potential of stem cells in modern regenerative medicine is gener-ally recognized. These cells can differ-entiate into various cell types, a process which can also be induced in vitro. Thus mesenchymal stem cells can be manipu-lated to differentiate into bone cells, car-tilage-generating chondrocytes, muscle and fat cells. With the support of the State Foundation of Baden-Württemberg, the NMI is conducting research on the effects of specific proteins or peptides on the differentiation of mesenchymal stem cells embedded in the aforementioned three-dimensional scaffold.

Contact:

Dr. Helmut WurstPhone: +49 7121 [email protected]

Dr. Brigitte Angres Phone: +49 7121 [email protected]

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Angres et al. (2007)

Left: confocal cross section of a 10-day old cyst (section across six cells) of kidney epithelial cells in a polyvinyl alcohol gel. Cellular surfaces and cell-cell contacts are visible due to the labeling of actin with GFP (Green Fluorescent Protein).Right: 7-day old culture of chondrocytes in albumin gels.

Helmut Wurst, bioorganic chemistry / analytics



Karin Benz, head of regenerative medicine II

Osteoarthritis is a very painful disease which affects 5 million people in Ger-many today. This number is increas-ing with the growing number of elderly people. It has been estimated that 200 million people are suffering world-wide from osteoarthritis. In Europe and the USA 350,000 patients receive a knee implant every year because of this ail-ment. At present there is no therapy for this degenerative disease.

During the last decade autologous chondrocyte transplantation (ACT) has been developed as a therapeu-tic approach to heal localized articular cartilage damage. Osteochondral tissue of the patient is removed from a non- load-bearing area near the site of injury, autologous chondrocytes are extracted from it and cultured in vitro and subse-quently reimplanted at the site of injury in order to regenerate cartilage tissue. Novocart-3D is a three-dimensional matrix developed by the NMI in coop-eration with partners for TETEC AG. It is used in the ACT therapy to incorporate autologous chondrocytes for subsequent reimplantation. So far more than one thousand patients have benefited from these three-dimensional autologous chondrocyte implants.


Contact:

Dipl. Ing. (FH) Karin BenzPhone: +49 7121 [email protected]

Collagens are the main components of the extra cellular matrix of all cartilage tissues. The amount of collagen in a tissue or a cell culture can be deter-mined by measuring the amino acid hydroxyproline which is characteristic for collagen. The more intensive the red color, the higher the amount of hydroxyproline in the sample (red = much, yellow = no hydroxyproline).

In the case of patients suffering from osteoarthritis, researchers at the NMI have shown that chondrocytes can be cultured in vitro to yield cells with prop-erties which are not significantly differ-ent from those of cells used in the above ACT procedure. It is likely, however, that in osteoarthritis the straightforward ACT approach must be further developed to include components which address the extracellular milieu in the diseased joint.

This leads to the concept of smart bio-materials, i.e. materials with proper-ties which go beyond those of a simple scaffold for cell support. In collabo-ration with B|Braun Aesculap AG & Co.KG, Gelita AG and TETEC AG, the NMI has developed a new biodegrad-able gelatine-based cell support mate-rial containing specific biologically active factors. These are subsequently released at the site of implantation in the patient, thereby creating a more favorable milieu for the implanted cells. This material is to be tested in patients who are candi-dates for the classical ACT treatment. If successful, the material will be tested in patients with osteoarthritis.

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Regeneration of articular cartilage


In 1999 the German economy incurred a loss of more than 17 billion € due to back pain-related sick leave. The most fre-quent cause of back pain is the degen-eration of the spinal disc. Two thirds of all patients are 30-50 years old, one third is female.

The spinal disc is a cartilage tissue which differs from articular cartilage. The inte-rior of the disc has an aqueous gelatine-like consistency and is surrounded by fibrous tissue. Thus the disc acts as an intervertebral shock absorber. With age spinal disc degeneration can occur and the consistency of the disc changes, so that its protective effect against pres-sure diminishes. This, in conjunction with improper posture caused by weak back muscles, can lead to back pain and movement impairment.

The NMI is conducting research aimed at reducing spinal disc degeneration by

A: A cross section through a bovine intervertebral disc shows their two components, the inner gelati-nous core (nucleus pulposus, NP), which is surroun-ded by a fibrous ring (annulus fibrosus, AF). B: The orientation of the collagen fibers can be seen in the histological section. C: Within the nucleus pulposus, the type II collagen, a main component of the extra cellular matrix is randomly distributed (red staining). The nuclei of the nucleus pulposus cells appear blue. D: In higher magnification proteoglycan-rich areas can be seen around the cells (orange staining with safranin O).

Regeneration of the spinal disc

cell therapy. Autologous spinal disc cells extracted from samples of the patient’s disc are cultivated and embedded in a gelatine-like matrix. Upon subsequent injection of the embedded autologous cells into the degenerated disc, new cartilage formation should restore disc function.

Whenever surgical intervention is required, e.g. in the case of a severe pro-lapse, spinal disc cells can be extracted from the excised tissue and cultivated in vitro. These autologous spinal cells can be reimplanted in the degenerated disc in a three-dimensional matrix biomat-erial. New cartilage formation should restore disc functionality.

Alternatively, mesenchymal stem cells can be induced to differentiate into spinal disc cells which, when injected into the disc, could promote its regen-eration.

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Project partner:

Tetec AG, Reutlingen

Orthopedic University Clinic, Heidelberg

Orthopedic University Clinic, Tübingen

A B

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Contact:

Prof. Dr. Burkhard SchloßhauerPhone: +49 7121 [email protected]

Glia cells (blue spots) can be successfully seeded onto polymer filaments (not stained) within nerve guide tubes. These cells support axon (green) regrowth.

Bridging the gap: nerve guide for nerve regeneration

Worldwide over 100,000 patients with peripheral nerve injury must undergo neurosurgery. Healing is possible, since peripheral nerves have the potential to regenerate, as long as the guiding nerve tract is not destroyed by injury. Since this is generally not the case, nerve tracts removed from other sites of the patient are applied at the injury, or synthetic hollow fibres are employed as nerve guides. The regenerating nerve extends through such biodegradable nerve guides and eventually innervates its target, e.g. an injured nerve in the lower arm tract could regenerate and restore motion in the hand. At present, however, these nerve guides only allow nerve regenera-tion over short distances.

Together with cooperation partners, the NMI has developed a new generation of biodegradable nerve guides. The strategy

was to create implants which promote rapid vascularization in order to pro-vide the regenerating nerve inside the hollow fibre with blood-borne nutrients and oxygen. Furthermore, the regenerat-ing nerve consists of thousands of nerve fibres - so-called axons - which should rapidly grow in the direction of the tissue to be innervated. Thus the strategy was to develop hollow nerve guides with a multiplicity of longitudinal microstruc-tured filaments on the inside in order to provide a substrate for the uni-directional growth of axons. Further improvement of axonal growth was obtained by placing glia cells on these filaments.

This research and development work is conducted by the NMI in collaboration with the Occupational Accident Clinic (Berufsgenossenschaftliche Unfallklinik) in Tübingen, the ITV in Denkendorf and Gelita AG.

Burkhard Schloßhauer, head of regenerative medicine I.


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e.g.

Schlosshauer et al., (2006)

Dreesmann et al., (2007)

Outgrowing axons in cell culture. The different colours highlight functionally different proteins within axons.


Progressive time dependent vascularization (from left to right) induced by the smart biomaterial implant (arrow), analyzed on the chorion-allantois membrane of a fertilized chicken egg.

Regeneration of blood vessels

Smoking, cholesterol and diabetes are some of the culprits in the develop-ment of atherosclerosis. The formation of atherosclerotic plaques can ultimately lead to impaired blood flow and occlu-sions of vital vessels, such as the coron-ary arteries. In the therapeutic inter-vention to open the vessel, a balloon catheter carrying a metal stent is guided through the artery to the occluded site and expanded against the arterial wall. This causes the stent to expand and to anchor onto the artery. Upon removal of the balloon catheter free blood flow is restored, whereby the implanted stent supports the arterial wall. While the procedure is very successful, it causes injury to the arterial wall. This in turn can cause restenosis, i.e. arterial tissue can grow through the net-like stent wall into the lumen and cause an occlusion. To prevent this reaction, drug eluting stents are now routinely employed.To prevent restenosis, the NMI is taking a different approach based on the strate-gies of regenerative medicine.The idea is to use the self-healing capac-ity of the body. The focus is placed on circulating stem cells which can promote regeneration of injured blood vessels.

In the field of regenerative medicine and tissue engineering therapeutic interven-tion based on biocompatible implants plays an important role. Integration of the implant in the tissue could be opti-mized by improving blood supply. For this purpose the NMI is developing cell and tissue culture systems in combi-nation with smart biomaterials in order to test their regenerative effects on vas-cular cells.The findings will be translated into regenerative medicine applications.

Another model for the study of blood vessel regeneration employed at the NMI is based on the fertilized chicken egg. By applying three-dimensional bioma-terial scaffolds to the surface of the egg, one can evaluate the effect on the proliferation of endothelial cells. These cells constitute the inner wall of blood vessels, i.e. the side facing the blood. Endothelial cells are essential for vascular regeneration.



Bernhard Schröder, head of surface technology

MITT Kompetenzzentrum Minimal Invasive Medizin & Technik Tübingen - Tuttlingen e.V.

Abbott Vascular Instruments GmbH, RangendingenAdelhelm LubriCoat GmbH, EningenAesculap AG & Co. KG, TuttlingenAlcon Pharma GmbH, FreiburgAltimed JSC, Minsk / BelarusAlumedica GmbH, GeisingenAMO, Advanced Medical Optics Surgical Systems Services GmbH, EttlingenAngiomed GmbH &Co, KarlsruheAppliedsensor GmbH, Reutlingen Arthesys sA., Gennevilliers / FranceBayer Material Science AG, LeverkusenBIBraun AG, BerlinBerchtold GmbH & Co. KG, TuttlingenBiedermann Motech GmbH, Villingen-SchwenningenBissinger GmbH, TeningenBoehringer Ingelheim Pharma KG, BiberachBorer Chemie AG, Zuchwil / SwitzerlandBrasseler GmbH, LemgoBredent GmbH, Senden

Peter Brehm Chirurgie-Mechanik, Weisendorf BSL Bioservice Scientific Laboratories GmbH, PlaneggCampus GmbH, HomburgChristoph Miethke GmbH & Co. KG, PotsdamCranium Telemetrics GmbH, Hannover DeguDent GmbH, HanauDentaurum J.P. Winkelstroeter KG, IspringenDENTSPLY Friadent, MannheimDisetronic Medical Systems AG, Burgdorf / SwitzerlandEBRO Electronic GmbH & Co. KG, IngolstadtEPFLEX Feinwerktechnik GmbH, Dettingen Erbe Elektromedizin GmbH, TübingenESKA Implants GmbH & Co., LübeckEthicon Endo-Surgery, INC., Cincinnati / USAEurocor GmbH, BonnEUROflex G. Rau GmbH, PforzheimForestadent Bernhard Förster GmbH, Pforzheim

Früh Verpackungstechnik AG, Fehraltorf / SwitzerlandGeister Medizintechnik GmbH, TuttlingenGeorg Leibinger Medizintechn. Apparate-bau GmbH, MühlheimGimmi GmbH, TuttlingenG. Rau GmbH, PforzheimHAMO AG, Pieterlen / SwitzerlandHeine Optotechnik GmbH & Co. KG, HerrschingHeinz Kurz GmbH, DußlingenHenke-Sass, Wolf GmbH, Tuttlingenicotec ag, Altstätten / SwitzerlandIIP Technologies GmbH, BonnImplantcast GmbH, Buxtehude inpac Medizintechnik GmbH, BirkenfeldInstitut Straumann AG, BaselIntegra ME GmbH, TuttlingenInvatec S.R.L., Roncadelle / ItalyJakoubek Medizintechnik GmbH, LiptingenJenaValve Technology GmbH, MünchenJotec GmbH, HechingenKapp GmbH, Dürbheim

Some of the companies which we assist in their product development are:


Contact:

Dr. Bernhard Schröder Phone: +49 7121 [email protected]

Technical progress leads to innova-tion and growth

Ninety-three percent of German compa-nies active in the field of medical tech-nology are small or medium enterprises with limited resources to conduct R&D. In order to support these companies in their effort to remain competitive in global markets, competence clusters between academic institutions, institutes for applied research such as the NMI, and university clinics have been formed. New production processes and new materials are being tested; new qual-ity standards are being introduced to enhance the physicochemical and func-tional properties of medical products, their long term stability, biocompatibility and cleanliness.

The NMI is an expert service provider in the field of medical products, offering:• improvement of surface properties, in

particular coatings and passivation• qualification of cleanliness • improvement of long-term

functionality • mechanical and electrochemical

characterisation• analytics and bioanalytics

Stainless steel coronary stent (scanning electron microscope) diameter 1.5 mm.


Improvement of surface properties

In order to improve the functional prop-erties of medical devices, the NMI devel-ops specific surface coating procedures which alter physico-chemical properties such as hydrophobicity, hydrophylicity,hardness, roughness, etc. Among the procedures which we employ are: electrophoretic coating, galvanic coating (e.g. hard gold for endoscopes), coating with diamon-like carbon (DLC), coating with polymers (e.g. polyzene), with drugs, electropolishing, etc.

“We develop coating procedures accord-ing to the specifications of each cus-tomer. The products are tested to assure the quality of the coating with respect to its adhesion and stability under mechani-cal loading, ultrastructure, chemical com-position, etc. The validated coating pro-cedure is transferred to the client.“

Dr. Bernhard Schröder,head of surface technology

Qualification of cleanlinessWhat is clean?

It goes without saying that cleanliness and hygiene are basic concepts for man-ufacturers and users of medical products. Surgical instruments, endoscopes, cath-eters, etc. must meet the highest func-tional and hygienic standards. A simple solution is to manufacture and employ only disposable products. However, in view of the ever increasing costs of medi-cal care, there is a strong demand for reusable products. This is only possible if the effectiveness of cleaning and sterilisa-tion procedures can be demonstrated.

In cooperation with 22 German and Swiss manufacturers of medical implants, the NMI has analyzed a variety of mate-rials. In these studies it was found that the most reliable analytical procedures are XPS and SEM, since they allow direct analysis of the surface. Other methods based on the elution of the surface and subsequent analysis of the eluate are less reliable, since they are based on the assumption that the solvent is able to remove all contaminants from the sur-face of the material.

Contact:

Dr. Rudolf ReichlPhone: +49 7121 [email protected]

Karl Storz GmbH & Co., Tuttlingen Keramed Medizintechnik GmbH, MörsdorfKlocke of America Inc., Florida, USAKreidler Medizintechnik GmbH, WurmlingenLightCut GmbH, PforzheimMathys Medizintechnik AG, BettlachMeCo GbR, Sarstedt / Hannovermedical & precision technology GmbH, Annaberg-BuchholzMepro GmbH, Nonnweiler-OtzenhausenMesotec Gesellschaft für medizinische Sen-sortechnik mbH, HannoverMetrax GmbH, RottweilMinitubes ZAC Technisud, Grenoble / FranceMITT Kompetenzzentrum Minimal Invasive Medizin + Technik Tübingen-Tuttlingen, e.V., TübingenMondeal Medical Systems GmbH, TuttlingenMTI Technische Instrumente GmbH, TuttlingenNormed Medizintechnik GmbH, TuttlingenObtech Medical AG, Zug / Switzerland

Occlutech GmbH, JenaOertli Instrumente AG, Berneck / SwitzerlandOHST Medizintechnik AG, RathenowPeter Brehm Chirurgie-Mechanik, WeisendorfPFM AG, KölnPlasma Ionic GmbH, BesigheimPolyzenix GmbH, UlmPreciswiss AG, Hünenberg / SwitzerlandQualiMed Innovative Medizinprodukte GmbH, WinsenRaith GmbH, DortmundReger Medizintechnik GmbH, DailingenREMED GmbH, FriedeburgRetina AG, ReutlingenRichard Wolf GmbH, KnittlingenRoche Diagnostic GmbH, MannheimSanofi-Aventis Deutschland AG, Frankfurt Sektion für Minimal Invasive Chirurgie der Universität Tübingen, TübingenSignus Medizintechnik GmbH, AlzenauSmith & Nephew Orthopaedics AG, Aarau / Switzerland

Rudolf Reichl, surface and interface analysis

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Smith & Nephew Orthopaedics GmbH, TuttlingenSMP GmbH, TübingenSQ Products AG, Steinhausen / SwitzerlandSteripac GmbH, CalwStratec Medical Ltd, Oberdorf / SwitzerlandStryker Trauma AG, Selzach / SwitzerlandSulzer Metco AG, Wohlen / SwitzerlandSurface Contacts GmbH, SaarbrückenSurgical Innovations Ltd, Leeds / GBSynthes GmbH, Oberdorf / SwitzerlandTechno-Coat Oberflächentechnik GmbH, ZittauTontarra Medizintechnik GmbH, WurmlingenTranslumina GmbH, HechingenTuttnauer Europe b.V., Breda / NetherlandsUlrich GmbH & Co. KG Medizintechnik, Ulm-JungingenUromed GmbH, Osteinbeck

ADA Abgaszentrum der Automobilindustrie, WeissachBalTec AG, Balzers / LiechtensteinBrucker Daltonic GmbH, KarlsruheCarl Zeiss NTS GmbH, OberkochenCytocentrics CCS GmbH, ReutlingenDaimler AG, StuttgartEvotec Technologies GmbH, HamburgFVA Forschungsvereinigung Antriebstechnik e.V., FrankfurtGambro GmbH, Planegg-Martinsried Greiner Bio One AG, FrickenhausenKleindiek Nanotechnik GmbH, ReutlingenMAN AG, NürnbergMediagnost GmbH, ReutlingenMulti Channel Systems MCS GmbH, ReutlingenNascatec GmbH, Stuttgart Robert Bosch AG, StuttgartSartorius AG, Göttingen Schaeffler AG, SchweinfurtUMS GmbH, München Voith Turbo GmbH&Co.KG, Crailsheim Walter AG, Tübingen Wittenstein GmbH, Verl ZF Friedrichshafen AG, Friedrichshafen

We collaborate with the following enterprises and organisations:

Understanding the processes which take place at the surface and interface of materials plays an important role in material sciences. At the NMI knowl-edge in this fields finds its application not only in material sciences, but also in biotechnology and biomedicine. Surface, interface and microstructure analysis is essential for the development and vali-dation of quality control standards and for damage analysis of materials. Our competence in surface and interface technology is the result of many years of research and practical experience related to those physical and chemical processes that are essential to the production of layers, of micro- and nanostructures, as well as to the analysis of materials, surfaces and interfaces. In collaboration with competent industrial and academic partners, we work in the following areas:

• microsystems and nanotechnology• functional surfaces and layers• bonding, adhesion and tribology




Functional surfaces and interfaces

Adhesive bonding and friction

Innovations to manipulate and analyze molecules, cells and tissues

Microsystems and nanotechnologyThe market for microsystem- and nano-technology products is growing at a fast rate. The NMI offers R&D and small series production of biocompatible micro- and nano-devices for research and medical applications (p. 50-52).

Microelectrode arraysMicroelectrode arrays for electrical stimulation and recording of cells and tissues in vitro and in vivo find their application in drug discovery, biotechnol-ogy and neurotechnology. The produc-tion of stable and biocompatible devices for electrophysiological applications represents a considerable technological challenge (p. 53).

Microfluidic systemsLab-on-a-chip and BioMEMS are chang-ing the face of biological and medical sciences. A system for the separation, accumulation and analysis of biological micro- and nanoparticles has been devel-oped (p. 53).

Nanoworkbench and BioFIBIon-beam technology (FIB: Focused Ion Beam) inside a scanning electron microscope allows rapid prototyping of 3-D-nanostructures and repairs in nano-scale. This new technology is integrated in the CrossBeam workbench, opening new perspectives in micro- and nanotechnology (p. 54).

NanoCryoSIMS(Nano Cryo Secondary Ion Mass Spec-troscopy)With cryopreparation, nanoanalytics and FIB we are developing a new process for the preparation, structural and chemical analysis of the interface between mate-rial and cells or tissues (p. 54).

The world of microstructures

Interface and microstructure analysisEquipped with state-of-the-art instru-mentation for chemical and ultrastruc-tural characterization of materials, researchers of the interface/microstruc-ture analytics department of the NMI play a central role in many projects. Their knowledge of the processes influenc-ing the surface properties of materials is applied to the development, optimiza-tion and quality control of various classes of products for medical diagnostics, bio-medicine and medicine (p. 55).

Functional surfaces and layersOur clients request that we improve the surface qualities of their products. This includes increasing the resistance to wear and corrosion, preventing certain reactions between the surface of the product and components of its environ-ment, creating a biocompatible surface for biomedical applications, etc. Depend-ing on the product specifications, we apply new coating procedures such as DLC (diamond like carbon), polymers and biomolecules. Stainless steel passiva-tion technology for surgical instruments is also an important aspect of our work (p. 56).

Bonding, adhesion and friction are processes taking place at the inter-face of materials

Bonding and adhesionNew technologies are in demand. The NMI has knowledge of the properties of bonding materials as well as of the surface material properties required for bonding. This allows selection of the appropriate adhesive while taking into account the physicochemical characteris-tics of the surface of the components to be bonded (p. 58).

TribologyTribology is the discipline which studies friction between two surfaces moving against each other. There is a great deal of empirical expertise concerning the interactions of materials and lubricants. The molecular mechanisms of these processes, however, are poorly under-stood. The NMI applies modern methods of chemical, micro- and nanostructure analysis to characterize the interface of tribological systems (p. 59).




Thin film PVDEquipment for production of small series of micro- chips for biotechnological applications

Small, smaller, smallest:From micro to nano

During the past 15 years there has been an enormous sustainable growth of products based on microsystem technol-ogy, in particular in the field of informa-tion technology. In 2007 alone, sales from German companies amounted to 70 bil €, corresponding to 25% of the world-wide market. More recently, microsystem technology has become involved in the field of life sciences: microarrays, microimplants, lab-on-the-chip, BioMEMS, sensors, stimulators, drug delivery, etc. Each of these names stands for highly innovative microsystem technology products which are continu-ously changing the world of biologi-cal research, drug discovery, biomedical technology, medicine and clinical diag-nostics, fields which have always been the main focus of the NMI.As with all technologies, the drive for innovation never ends. Thus micro isn’t enough, nano is now the goal. The

evolution of microsystem technology towards nanotechnology is very rapid. A recent study (September 2007) by Ernst & Young identifies five major areas for nanotechnology products: drug-delivery (39%), diagnostics, medical implants, medical materials (19% each), instru-mentation (17%), and therapeutics (5%).

“The NMI develops micro- and nanosys-tems for products in bio- and biomedical technology and medicine. Our strength is our ability to handle a variety of mate-rials which are biocompatible and biosta-ble and can be processed into micro- and nanostructures.”

Wilfried Nisch, Head of physical engineering

Contact: Dr. Wilfried NischPhone: +49 7121 [email protected]

Clean room nano lab with spray coating device, electron beam lithography system and UV nanoimprinter.


Wilfried Nisch,head of physical engineering


Contact:


Dr. Claus Burkhardt Phone: +49 7121 515 [email protected]

Microsystems for life sciencesComponents based on micro- and nano-system technology have become integral parts of innovative products such as medical devices, robots, instruments for measurement and control of automated processes, scientific instrumentation, optics, electronics and manufacturing system engineering.

Thin layer- and microstructure technologies0ne of our specialities is the develop-ment and validation of processes suitable for the production of microstructured medical products and for biotechnol-ogy applications. With our equipment and clean room infrastructure, we can deposit thin layers on rigid and flex-ible substrates, which are integral parts of microsystems for biotechnological or biomedical application. Physical vapour deposition (PVD) and plasma-enhanced chemical vapour deposition (PECVD) are the methods of choice. With photoli-thography followed by plasma or chemi-cal etching, we can expose substrates to generate microstructures with a reso-lution down to 2 µm. Prototypes with nanostructures as small as 100 nm can be produced by electron-beam lithogra-phy or with the focused ion beam (FIB).

Microfabrication and productionof small seriesIn addition to the development of new micro- and nanotechnology processes, we apply our know-how to the produc-tion of small series. This requires the combination of different technologies in order to integrate various materials and functionalities in complex systems.An example of such process develop-ment and small series production is a novel bonding-adhesion procedure, which can be used to cover microflu-idic systems. This process is suitable for a variety of substrate lid combinations. In particular, it allows the production of microfluidic systems with integrated electrodes on both sides of the channels.

UV - Nanoimprinter

This is required in systems for the dielec-trophoretic separation and enrichmentof particles. Since the bonding process does not employ solvents and operates at low temperature, it allows the immo-bilization of functional biocomponents in microstructures and lid application with-out distroying the biological activity of these components.

Nanostructuring technologyThis technology is very flexible and well suited for rapid prototyping since the nanostructures can be created directly from CAD plans. In order to expand these capabilities towards small series production of nanostructure systems, the NMI laboratories are equipped with nanoprinters, which can structure 4-inch diameter substrates. This fabrica-tion process employs UV-nanoprinting together with UV-induced polymer hard-ening.

Shadow mask technologyMicrosystems for biological applications are usually made of plastic, a relatively inexpensive material. Many devices require integration of microfluidics with microelectrodes, sensors and other com-ponents. Conventional photolithogra-phy, however, is an expensive fabrication process and requires chemicals which may not be compatible with certain plas-tic materials. For this reason, the NMI has developed a less expensive fabrica-tion process in which sputter and vapour deposition through a shade mask placed

above the plastic material allows for the creation of microstructures resembling the shadow mask patterns, while avoid-ing the use of higher temperatures and chemicals which would not be compat-ible with the plastic substrates.

Hybrid nanostructuring technologyConventional procedures allow for the fabrication of nanosystems with highly precise structural patterns. In the case of larger surfaces, e.g. those of filtration membranes and sensors, such nano-structuring technologies would, how-ever, be too expensive. Yet, in many cases, the precise location of structures provided by these technologies is not essential. What counts is the dimen-sion of the nanostructures. This can be achieved at relatively low cost by a self-organization process relying on block co-polymers or particles to generate nanostructures on a given surface. The parameters which influence this self-organization process are the subject of several R&D projects at the NMI.

Shadow mask technology



Microelectrode arrays (MEAs)

Microelectrode arrays find their applica-tion in drug discovery, in biotechnology and in medical devices (e.g. implants for muscle and nerve stimulation). Not only must such devices fulfil specific technical criteria, but they must also be biocom-patible and exhibit long-term stability.At the NMI we employ a variety of sput-ter procedures to generate microelec-trode arrays with specific properties. For instance, we produce titaniumnitride or iridium microelectrodes with a large inner surface, such that a high charge can be transmitted to tissues or cells, without concomitant electrode polarisa-tion or electrochemical reactions at the interface between cell and electrode. Such electrodes exhibit excellent signal-to-noise ratios. Serial production of MEAs for Multi Channel Systems MCS GmbH takes place at the NMI TT GmbH.

Biostability of layers

Implants and devices for micromedicine which reside in the body for prolonged time periods must be biocompatible, stable and resistant to corrosion. This guarantees their safety and functionality.In cooperation with Plasmaelectronic GmbH and Retina Implant AG and with public BMBF funding, we are developing a process based on nanoscaled layers for the biocompatible and hermetic encap-sulation of microimplants. The quality of the encapsulation is evaluated on the basis of water vapour permeation rates (smaller then 10-8 g/d/cm2) and imper-meability to ions.

Stimulation electrodes with iridium/iridiumoxide on top of an CMOS retina implant chip

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Contact:


Multi layer of parylene/SiOxCy and analysis of the layer system


Computer modelling and simulation

The conception and production of a microsystem is a very involved process. Iterative trial and error approaches, therefore, can become very costly. For this reason scientists at the NMI apply computer modelling and simulation from the very beginning, i.e. well before the translation of the product idea into the product design and prototype produc-tion. “Multiphysics” simulation is the approach used to evaluate the effects of various physical phenomena related to microfluidics, electric fields and forces, surface properties, etc. on the functional properties of the microsystem. This com-puter simulation and modelling makes it possible to anticipate certain problems or advantages, thus leading to a more rational approach to microsystem design and production.

Flexibility and precision: production processes for microfluidic systems with integrated electrodes

The NMI develops microfluidic systems for the separation, enrichment and detection of biomolecules and particles in fluid samples. Photolitography is used to generate microchannels and inte-grated microelectrodes on glass chips. Prototypes are produced in a clean room with the help of highly precise CAD/CAM micromilling robots. For the con-nection of various components of a microdevice, the NMI has developed a dedicated bonding procedure, which connects single elements with micro-meter precision. The bonding procedure uses very thin layers of adhesive which can be light-cured when applied to glass, silicon or plastic substrates.

Functional coatings for BioMEMS

BioMEMS stands for Biomedical Micro Electro Mechanical Systems. The fron-tiers of micro- and nanotechnology are changing the face of medicine. Researchers are building microelectro-mechanical systems or BioMEMS, i.e. devices so small that they measure only a few micrometers. These devices are expected to find broad application in fields ranging from diagnostics, tissue engineered products, cell-based drug screening tools, and basic molecular biol-ogy tools. Research projects at the NMI bring together MEMS, biomaterials and bio-medical analysis with life sciences and medical research. Functional coatings with silanes to modify wettability of flu-idic components, coating of glass and silicon surfaces with copolymers carrying polyethylene glycol side chains to reduce protein adsorption, computer simula-tion and CAD for new BioMEMS, CAD/CAM fabrication of microforms and sili-cone stamps--these are examples of the surface chemistry and technical expertise of the NMI supporting its clients in the development of new products.

Contact:


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Neugebauer et al. (2006)

Microfluidic systems for lab-on-a-chip

Chemical stimulation of cells on a nanoporous membrane by application of a tiny droplet contaning the stimulant to the bottom surface of the membrane. The calculation provides spatio- temporal distribution profiles and considers diffusion, flow and evaporation effects.

adhesive bonding machine



Contact:

Dr. Claus BurkhardtPhone: +49 7121 [email protected]

Manipulation and analysis in the nanoworld

Nanoworkbench

Rapid prototyping and repair of3-D nanostructures can only be per-formed under observation in an elec-tron microscope. The so-called nano-workbench allows construction of 20-50 nanometer structures in a high-resolution field-emission scan-ning electron microscope by means of electron beam litography, ion etching, and additive nanolitography through electron beam induced deposition of metallo-organic compounds from the gas phase. The nanostructures can be manipulated through microlevers driven by a nanomotor (e.g. for transmission electron microscope analysis). With this nanoworkbench one can create all sorts of nanostructures, such as electrodes and carbon nanotubes.

BioFIB

The structures at the point of contact between medical implants and tissue are of great interest for a better understand-ing of the functional properties of these implants.Electron microscopy is a helpful tool for ultrastructural analysis. It has, however, been very difficult to analyse the inter-face between cells and material. Using a combination of classical tissue prepara-tion methods for electron microscopy and the CrossBeam® electron micro-scope, we have been able to repre-sent the ultrastructure at the interface between cells and material.

Nano-Cryo-SIMSFurther improvements of the BioFIB methodology can be expected from our efforts to develop a Nano-Cryo Sec-ondary Ion Mass Spectrometer for the analysis of biological probes. The aim of this research is to be able to detect anorganic and organic building blocks of nanostructures without creating prepara-tion artefacts. This goal is pursued in a cooperative project with Bruker Daltonic GmbH, Carl Zeiss NTS GmbH, Baltec AG and the University of Tübingen.The idea is to integrate in a CrossBeam® electron microscope an ion-trap mass-spec and a freeze-fracture device.

View inside of the specimen chamber of a Cross-beam electron microscope (sample, SEM, FIB, detectors and mass spectrometer)

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Microsystems & nanotechnology

Claus Burkhardt an der CrossBeam® Workstation.

Three cells (osteoblast) on silicon substrate – the cross section shows clearly cell-cell and cell-substrate contacts

Freeze fracture of retina tissue. SEM image. The sample was plunge-frozen in liquid propane and freeze-fractured in vacuum. The fracture shows from left to right: pigment layer, light receptors (rods and cones) and bipolar cells



Coronary stents with an antihrombo-genic surface, biostable passivation of a neuroimplant, biocompatible electrodes, insulating layers on BioChips, control of wetting in a microdispensing system, suppression of protein adsorption in microfluidic systems, coating of sur-faces to promote cell adhesion... these are just examples of the many projects in which the NMI know-how in surface and interface technology finds its practi-cal application. A common theme is the surface modification in order to achieve a specific cell or tissue interaction with the material. A detailed understanding of the pro-cesses that influence and alter the sur-face of materials during product manu-facturing or subsequent use is of primary importance to the producer. The NMI has the most modern equipment and uses validated procedures to analyze the physicochemical properties of surfaces, down to the atomic level.

Particulate matter and nanoparticles: a hot topic in public health

Airborne particles are pollutants which affect our respiratory function. Measures to improve air quality require knowledge of the size and physicochemical prop-erties of particles, their origin and the various ways of propagation (emission and imission). The NMI investigates these processes by applying modern micro- and nanostructure analysis in coopera-tion with the Ministry of Environment of Baden-Württemberg and the Univer-sity of Stuttgart. Furthermore, it applies these analytical tools in projects aimed at reducing automotive particle emission.

NMI instrumentation for physical and chemical characterization of sur-faces• surface topography and dimensional

accuracy are analyzed by: light microscopy, scanning electron

microscopy (REM, ESEM), profilometry, atomic force microscopy (AFM), confo-cal laser scanning microscopy (CLSM), transmission electron microscopy (TEM), scanning tunnel microscopy (STM).

• surface chemistry and atomic composi-tion are analyzed by:

photoelectron spectroscopy (XPS), secondary ion and secondary neu-tral particle mass spectroscopy (SIMS, SNMS), Raman spectroscopy, optical spectroscopy (UV/VIS/IR) and Fourier- transformed infrared (FTIR) spectros-copy, electron energy loss spectros-

Contact:

Dipl.-Phys. Werner DreherPhone: +49 7121 [email protected]

Nanoparticles of diesel on a sample carrier.

200 nm

Interface and microstructure analytics

Werner Dreher, head of interface and microstructure analytics

copy with transmission electron microscopy (EELS/TEM), energy dispersive x-ray (EDX/TEM), EDX environmental scanning electron microscope (EDX ESEM), x-ray fluorescent analysis (XRFA).

• inner solid-state properties are analyzed by: cross-section analysis (SEM, EDX) under

visual control in the CrossBeam® work-bench (p. 46).

Some of the above-mentioned analytical methods are performed in accredited labo-ratories according to DIN EN ISO/IEC 17025. The QM system is applied to all methods, regardless of the accreditation status.

Dreher et al. (2007)



Technologies for medical productsThrough selective surface modifications with organic or inorganic coatings or ion implantation procedures, we can obtain materials with specific properties for use in medical products.

Passivation of stainless steelIn the field of medical technology, phar-maceuticals and food processing, many machines and instruments are made of stainless steel. Cleaning, disinfection and sterilization, however, can cause consid-erable wear and damage to the stainless steel surface. To protect the surface from corrosion, high-tech stainless steel alloys enriched with chromium and chromium oxides are used. When these materials are subjected to various oxidizing solu-tions, a protective passivation layer is formed on the outer surface. The NMI applies interface analysis to verify the quality of passivation.

Testing of the passivation layerThe producers of stainless steel surgi-cal instruments can add value to their products by certifying the quality of the passivation layer. To this purpose, the NMI carries out testing according to its accreditation guidelines and to the standards 90120403B-STD (XPS) and 90120441B-STD (SEM).

Laser printing on stainless steelLaser printing for the labelling of medi-cal products can alter the physicochemi-cal properties of the surface and lead to corrosion at the site of the laser engrav-ing. The NMI applies surface analysis methods to obtain information that can be used to optimize the laser printing procedure.


Cr2p photoelectron spectrum of a passivation layer

Contact:

Dr. Rudolf ReichlPhone: +49 7121 [email protected]


Geuder AG, HeidelbergHager & Meisinger GmbH, NeussHAMO AG, Pieterlen / SwitzerlandHenke-Sass, Wolf GmbH, TuttlingenJakoubek Medizintechnik GmbH, LiptingenKarl Leibinger Medizintechnik GmbH & Co. KG, MühlheimKarl Storz GmbH & Co. KG, TuttlingenKaVo Dental GmbH, BiberachKompetenzzentrum MITT e.V., TübingenMH LOG, Belp / SwitzerlandMKK GmbH, Oldenburgnopa instruments Medizintechnik GmbH, TuttlingenOHST Medizintechnik AG, RathenowOlympus Winter & Ibe GmbH, HamburgPeter Brehm Chirurgiemechanik, WeisendorfPlasmaelectronic GmbH, NeuenburgPlasma-Ionic GmbH, BesigheimRichard Wolf GmbH, KnittlingenRudolf Medizintechnik GmbH, Fridingen Schaeffler KG, HerzogenaurachSchweickhardt GmbH & Co.KG, Tuttlingen

Acti-Med AG, Freiensteinau Adelhelm LubriCoat GmbH, EningenAdolf Schweickhardt GmbH&Co.KG, TuttlingenBIBraun Aesculap AG & Co.KG, TuttlingenBerchtold Medizinelektronik GmbH, TuttlingenBoehringer Ingelheim Pharma KG, BiberachBoner Galvanotechnik, VS-SchwenningenBorer Chemie AG, Zuchwil / SwitzerlandBSL Bioservice Scientific Laboratories GmbH, PlaneggDeguDent GmbH, HanauDentaurum J.P. Winkelstroeter KG, IspringenEisold Instruments GmbH, BalgheimEPflex Feinwerktechnik GmbH, DettingenEUROflex G. Rau GmbH, PforzheimFacility Service GmbH, HeilbronnF. Hoffmann-La Roche Ltd., BaselGebr. Brasseler GmbH & Co.KG, LemgoGeister Medizintechnik GmbH, TuttlingenGIMMI GmbH, Tuttlingen

Seemann GmbH, HausenSmith & Nephew, Aarau, Hamburg, TuttlingenSMP GmbH, Tübingensteripac GmbH, CalwStryker, Freiburg, Kiel, SelzachSurface Contacts GmbH, SaarbrückenSynthes GmbH, Oberdorf / SwitzerlandTechno-Coat Oberflächentechnik GmbH, ZittauThyssen Krupp Nirosta GmbH, KrefeldTontarra Medizintechnik GmbH, WurmlingenTrokamed GmbH, GeisingenTRUMPF Laser GmbH & Co.KG, SchrambergTRUMPF Laser Marking Systems AG, Grüsch / SwitzerlandUKT, TübingenUlrich GmbH & Co.KG, Ulm

The NMI is a process developer for the following companies:

The need for interdisciplinary cooperation

A core competence of the NMI is the modification and functionalization of surfaces for medical technology and bio-technology products. The development of functional layers requires intensive cooperation between experts in biologi-cal and material sciences.

Surface modification with diamond- like carbon (DLC)Surface modifications through DLC find their application in a variety of fields such as medical technology, engine con-struction and the textile industry (e.g. needles). The DLC layer creates a hard, yet elastic, surface which is abrasion and corrosion resistant, chemically inert, has particularly good tribological properties, is biostable, biocompatible, does not promote thrombus formation (e.g. for stents) and prevents leakage of atoms from the product material into body fluids (e.g. prevention of allergy caused by leakage of nickel from implants).

In our plasma-enhanced chemical vapour deposition (PECVD) plant we can adjust the process parameters so that also objects of complex geometry can be uniformly coated. Furthermore, specific coating characteristics such as thermo-stability, adhesive properties, colour and electrical conductance can be influenced. We develop customer-specific coating processes, which are then transferred to the client. Alternatively, we can perform serial coating of products in-house.

Contact:

Dr. Bernhard SchröderPhone: +49 71 21 5 [email protected]

Nitinol stent coated with DLC (diamond-like carbon). Interference colours result from the different thick-ness of the carbon layers (50-80 nm).

Layers



Physicochemical processes at the inter-face of two materials govern the bond-ing, adhesive and tribologic properties of interacting bodies. Empiric approaches have always been at the basis of tech-nical solutions in these fields. The NMI is involved in studies aiming to provide a theoretical foundation which should allow us to describe and anticipate the effects of various parameters on bond-ing, adhesion and friction. This will allow a more rational approach to the manu-facturing of medical products, engineer-ing of drive systems and components, chemical composition of adhesive and lubricants, etc.

Although a very ancient technology, bonding is much less frequently used than welding or soldering. This is sur-prising, since almost all materials can be bonded under conditions which do not alter the material characteristics of the bonded components. Physicochemical processes at the inter-face of two materials govern the prop-erties of adhesive bonding. Empiric approaches have always been the basis of technical solutions in these fields.

The NMI is involved in studies aimed to provide a theoretical foundation, which should allow us to describe and antici-pate the effects of various parameters on bonding. This will allow a more rational approach to the manufacturing of many products.

The NMI has expertise in the systematic selection of bonding systems, surface preparation for bonding, examination of bonding strength and other parameters. To better meet the specific needs of its clients, the NMI cooperates with several institutes and manufacturers of bonding materials whenever problem solutions require additional expertise.

Bonding technology at the NMI:• preparation of the material surface• mechanical characterization and selec-

tion of appropriate bonding material• selection of the appropriate application

conditions of the bonding material• physicochemical and mechanical char-

acterization of the interface between bonded components

• studies on the effects of light, humid-ity, temperature, mechanical stress (vibration, pressure load, tension, tor-sion, etc.) on bonding.

Contact:

Dr. Bernhard SchröderPhone: +49 7121 [email protected]

Torsion pendulum for the measurement of the mechanical properties of adhesives.

Bonding

Bonding, adhesion and tribologic systems


Afton Chemical Corporation, Richmond / USADaimlerChrysler AG, UlmDegussa Evonic AG, Hanauebm-papst GmbH & Co. KG, St. GeorgenEnayati GmbH, BirkenfeldFollmann & Co., MindenFuchs Petrolub AG, MannheimFVA ForschungsvereinigungAntriebstechnik e.V., Frankfurt Getrag GmbH, UntergruppenbachKaVo Dental GmbH & Co. KG, BiberachKHS Steiert, SimonswaldMaxon Motor GmbH, SexauMetabo GmbH, NürtingenMyonik GmbH, Leutkirch

Some of the companies which we assist in product development are:

OSK-Kiefer GmbH, EttlingenPMDM GmbH, Villingen-SchwenningenRobert Bosch GmbH, GerlingenRobert Bosch GmbH, Stuttgart and ReutlingenSchaeffler KG, HerzogenaurachDr. Tillwich GmbH Werner Stehr, HorbUzin Utz AG, UlmVautid-Verschleiß-Technik, OstfildernVoith Turbo GmbH, HeidenheimWalter AG, TübingenZAG Zyklotron AG, KarslruheZiemann GmbH, LudwigsburgZIKA Leime und Klebstoffe L. Zimmermann GmbH & Co, PfullingenZF Friedrichshafen AG, Friedrichshafen

Contact:

Dr. Peter BeckmannPhone: +49 7121 [email protected]

Tribology (greek Tribos = friction) is the science which examines the reactions which take place at the interface of two bodies moving against each other under load. It examines friction, wear and lubri-cation. The physicochemical processes are poorly understood. The NMI exam-ines the interactions between the lubri-cants (different oils with various addi-tives) and the surfaces of the moving bodies under load by means of chemi-cal, interface and microstructure analy-sis. The application of methods for the chemical and microstructure analysis of interfaces is essential to the understand-ing of tribological processes. Researchers at the NMI examine at the ultrastructural level, i.e. at a depth of 2 µm, the sur-face of gears and bearings, which have been subjected to prolonged load under various conditions. The results provide insight into the molecular events leading to material fatigue and damage.

Gears, cogwheels and bearings undergo wear and tear because of high or low temperatures, friction, corrosion, dirt infiltration, poor lubrication, etc. Event-ually this can lead to very costly system failures. In a project funded by the state of Baden-Württemberg, the NMI is developing new coating procedures to improve the tribological properties of these moving components.

Many small and medium enterprises require praxis-oriented solutions. There-fore, the NMI collaborates with the Research Association for Drive Engineer-ing (FVA Forschungsvereinigung Antrieb-stechnik), the Institute for Tribology at the University of Manheim, the Institute for Materials and Electrotechnology at the University of Ulm and the Research Centre for Cogwheel and Gear Con-struction at the Technical University of Munich.

Peter Beckmann, interface analytics

FKZ 16SV1644

FVA 459/DFG HD 133 9/29-1

FKZ 4-4332.62-NMI/16

Beckmann et al. (2007)

Problem solving in tribology


Staff

Total staff(12/31/07)

44 scientists 12 Ph.D. students 13 undergraduates 3 trainees 12 engineers 19 technicians 9 assistants 10 administration assistants and secretaries

Dieter Martin, engineerDr. Meike Moschallski, engineerEnzio Müller, Ph.D., biochemistDr. Wilfried Nisch, physicistDr. Angelika Oehmig, biologistDr. Michael Pawlak, biophysicistDr. Oliver Pötz, biochemistDr. Rudolf Reichl, physicistProf. Dr. Burkhard Schloßhauer, biochemistHeiko Schmid, biologistDr. Nicole Schneiderhan-Marra, biochemistMonika Schrenk, chemistDr. Bernhard Schröder, chemistDr. Martin Stelzle, physicistDr. Alfred Stett, biophysicistHeiko Steuer, biologist Dr. Dieter Stoll, chemistDr. Sabine Sturany, biologistDr. Markus Templin, biologistDr. Maria Thomas, biochemistPD Dr. Hansjürgen Volkmer, biologistClementine Warres, engineerDr. Frank Weise, biochemistSimon Werner, engineerDr. Helmut Wurst, biologistSusanne Zibek, engineer

Scientists and engineers

Dr. Brigitte Angres, biologistDr. Peter Beckmann, physicistKarin Benz, engineerDr. Karen Böhme, biologistStefanie Breisch, engineerSandra Buckenmaier, biologistDr. Claus Burkhardt, physicistNadine Burkharth, biologistNils Clausen, pharmacistDr. Timm Danker, biologistWerner Dreher, physicistDr. Stefan Fennrich, medical scientistClaudia Franz, biologistDr. Cornelia Fricke, biologistDr. Reinhard Galneder, physicistMatthias Gerhardt, engineerBerthold Gierke, biologistProf. Dr. Elke Guenther, biologistDr. Nadja Gugeler, biologistKatja Gutöhrlein, physicistinProf. Dr. Hugo Hämmerle, biologistReiner Hajosch, engineerMichael Hartmann, engineerThoralf Herrmann, physicistDr. Dietmar Hess, biologistDr. Gerhard Heusel, physicistSybille Höppe, engineerDr. Thomas Joos, biochemistPhilipp Kammerlohr, engineerCornelia Kazmaier, engineerKatja Kirschbaum, biologistKarin Klaß, engineerThomas Knorpp, biochemistDr. Udo Kraushaar, biologistDr. Martin Kriebel, biologistUrsula Lakner, master biomedical sciencesKatrin Luckert, biochemistSteffen Lutz, engineerAdil Malik, physicist


Abbrevations

ACT Autologe Chondrocyte TransplantationBMBF Federal Ministry of Education and ResearchBW Baden-WürttembergCVD Chemical Vapour DepositionDLC Diamant Like CarbonDNA DesoxyribonucleinacidEKG ElektrocardiogrammESI MS Elektrospray-Ionisation-MassspektrometryFACS Array Fluorescent Activated Cell Sorting ArrayFHIGB Fraunhofer for Interfacial Engineering and BiotechnologyFIB Focused Ion BeamFRET-Technik Fluoreszense-Resonance-Energy-Transfer-TechniqueFTE Full Time EquivalentsGDF-5 Growth Differentiation Factor 5hERG Human Ether-a-gogo Related Gene-potassium channelHPLC High Performance Liquid ChromatographyHTS High Throughput ScreeningKMU = SME Small and Medium EnterprisesMALDI TOF Matrix Assisted Laser Desorption/Ionisation Time of FlightMS MassspectrometryPECVD Plasmaenhanced Chemical Vapour DepositionPVD Physical Vapour DepositonRNA RibonucleinacidRPA Reverse Phase ArrayshRNA Short Hairpin RNAsiRNA Small Interfering RNATIRF-Mikroskopie Total Internal Reflection FluorescenceUV Ultraviolett


Publications 2006

Grom, F., J. Kentsch, T. Müller, T. Schnelle and M. Stelzle (2006). „Accumulation and trapping of hepatitis A virus particles by electrohydrodynamic flow and dielectrophoresis.“ Electrophoresis 27: 1386-1393.

Hartmann, M., A. Toegl, R. Kirchner, M. F. Templin and T. O. Joos (2006). „Increasing robustness and sensitivity of protein microarrays through mictroagitation and automation.“ Analytica Chimica Acta 564: 66-73.

Heeren, A., C. Burkhardt, H. Wolburg, W. Henschel, W. Nisch and D. P. Kern (2006). „Preparation of nanostructured Tita-nium surfaces for investigations of the interface between cell monolayers and Titanium.“ Microelectronic Engineering(83): 1602-1604.

Kentsch, J., S. Breisch and M. Stelzle (2006). „Low tempera-ture adhesion bonding for BioMEMS.“ Journal of Microme-chanics and Microengineering 16: 802-807.

Kuschel, C., H. Steuer, A. N. Maurer, B. Kanzok, R. Stoop and B. Angres (2006). „Cell adhesion profiling using extracellular matrix protein microarrays.“ Biotechniques 40(4): 523-31.

Lietz, M., L. Dreesmann, M. Hoss, S. Oberhoffner and B. Schlosshauer (2006). „Neuro tissue engineering of glial nerve guides and the impact of different cell types.“ Biomaterials 27(8): 1425-36.

Lietz, M., A. Ullrich, C. Schulte-Eversum, S. Oberhoffner, C. Fricke, H. W. Muller and B. Schlosshauer (2006). „Physical and biological performance of a novel block copolymer nerve guide.“ Biotechnol Bioeng 93(1): 99-109.

Neugebauer, S., U. Müller, T. Lohmüller, Joachim P. Spatz, M. Stelzle and W. Schuhmann (2006). „Characterization of Nanopore Electrode Structures as Basis for Amplified Electro-chemical Assays.“ Electroanalysis 18(19-20): 1929-1936.

Niere, M., B. Braun, R. Gass, S. Sturany and H. Volkmer (2006). „Combination of engineered neural cell adhesion molecules and GDF-5 for improved neurite extension in nerve guide concepts.“ Biomaterials 27: 3432-3440.

Pruss, T., E. U. Kranz, M. Niere and H. Volkmer (2006). „A regulated switch of chick neurofascin isoforms modulates ligand recognition and neurite extension.“ Mol Cell Neurosci 31(2): 354-65.

Ruttger, A., J. Mollenhauer, R. Loser, M. Gutschow and B. Wiederanders (2006). „Microplate assay for quantitative determination of cathepsin activities in viable cells using deri-vatives of 4-methoxy-beta-naphthylamide.“ Biotechniques 41(4): 469-73.

Santiago, R., E. Guenther, K. Carroll and E. P. Junkins, Jr. (2006). „The clinical presentation of pediatric thoracolumbar fractures.“ J Trauma 60(1): 187-92.

Schlosshauer, B., L. Dreesmann, H. E. Schaller and N. Sinis (2006). „Synthetic nerve guide implants in humans: a compre-hensive survey.“ Neurosurgery 59(4): 740-7; discussion 747-8.

Schumann, C., K. Triantafilou, J. Kamenz, H. Hanke, M. Triantafilou, S. Wittemann, T. Joos, V. Hombach, E. Marion Schneider and P. M. Lepper (2006). „Septic shock caused by Streptococcus pneumoniae in a post-splenectomy patient successfully treated with recombinant human activated protein C.“ Scand J Infect Dis 38(2): 139-42.

Sinis, N., H. E. Schaller, C. Schulte-Eversum, B. Schlosshauer, M. Doser, K. Dietz, H. Rosner, H. W. Muller and M. Haerle (2006). „[Tissue engineering of peripheral nerves].“ Handchir Mikrochir Plast Chir 38(6): 378-89.

Steffensky, M., K. Steinbach, U. Schwarz and B. Schlosshauer (2006). „Differential impact of semaphorin 3E and 3A on CNS axons.“ Int J Dev Neurosci 24(1): 65-72.

Weissenstein U., Schneider M.J., Pawlak M., Cicenas J., Eppenberger-Castori S., Oroszlan P., Ehret S., Geurts-Moespot A., Sweep F.C. and Eppenberger U. (2006) „Protein Chip Based Assay for Simultaneous Quantitative Monitoring of Cancer Biomarkers in Tissue Extracts.“Proteomics 6(5), 1427-1436

Wilding, P., T. O. Joos , L. J. Kricka and L. Shi (2006). „Guidlines for terminology for microtechnology in clinical laboratories.“ Pure Appl. Chem. 78(3): 677-684.

Publications 2007

Boeuf, S., E. Steck, K. Pelttari, T. Hennig, A. Buness, K. Benz, D. Witte, H. Sultmann, A. Poustka and W. Richter (2007). „Subtractive gene expression profiling of articular cartilage and mesenchymal stem cells: serpins as cartilage-relevant differentiation markers.“ Osteoarthritis Cartilage 16(1):48-60.

Burkarth, N., M. Kriebel, E. U. Kranz and H. Volkmer (2007). „Neurofascin regulates the formation of gephyrin clusters and their subsequent translocation to the axon hillock of hippocampal neurons.“ Mol Cell Neurosci 36(1): 59-70.

Dreesmann, L., M. Ahlers and B. Schlosshauer (2007). „The pro-angiogenic characteristics of a cross-linked gelatin matrix.“ Biomaterials 28:5536-5543.

Funk, D., C. Fricke and B. Schlosshauer (2007). „Aging Sch-wann cells in vitro.“ Eur J Cell Biol 86(4): 207-19.

Hansen, R. K., C. Christensen, I. Korshunova, M. Kriebel, N. Burkarth, V. V. Kiselyov, M. Olsen, S. Ostergaard, A. Holm, H. Volkmer, P. S. Walmod, V. Berezin and E. Bock (2007). „Identification of NCAM-binding peptides promoting neurite outgrowth via a heterotrimeric G-protein-coupled pathway.“ J Neurochem (in press).

Meyer, T., P. Sartipy, F. Blind, C. Leisgen and E. Guenther (2007). „New cell models and assays in cardiac safety profi-ling.“ Expert Opin Drug Metab Toxicol 3(4): 507-517.

Nielsen, R. H., R. Stoop, D. J. Leeming, M. Stolina, P. Qvist, C. Christiansen and M. A. Karsdal (2007). „Evaluation of cartilage damage by measuring collagen degradation pro-ducts in joint extracts in a traumatic model of osteoarthritis.“ Biomarkers: 1-9.

Saturno G., Pesenti M., Cavazzoli C., Rossi A., Giusti, A., Gierke B., Pawlak M. and Venturi M. (2007) Expression of serine/threonine protein kinases and related factors in normal monkey and human retinas: the mechanistic understanding of a CDK2 inhibitor induced retinal toxicity. Toxicologic Pathology 35, 972-983.

Scharstuhl, A., B. Schewe, K. Benz, C. Gaissmaier, H. J. Buhring and R. Stoop (2007). „Chondrogenic Potential of Human Adult Mesenchymal Stem Cells is Independent of Age or Osteoarthritis Etiology.“ Stem Cells 25(12):3244-51.

Schröder, B. and R. Kaufmann (2007). „50 Hz Fatigue Testing of Large Diameter Stent Grafts.“ Medical Device Technology 2(18): 58-60.

Sinis, N., H. E. Schaller, S. T. Becker, B. Schlosshauer, M. Doser, H. Roesner, S. Oberhoffner, H. W. Muller and M. Haerle (2007). „Long nerve gaps limit the regenerative potential of bioartificial nerve conduits filled with Schwann cells.“ Restor Neurol Neurosci 25(2): 131-41.

Stett, A., A. Mai and T. Herrmann (2007). „Retinal charge sensitivity and spatial discrimination obtainable by subretinal implants: key lessons learned from isolated chicken retina.“ Journal of Neural Engineering 4: 7-16.

Stoop, R., D. Albrecht, C. Gaissmaier, J. Fritz, T. Felka, M. Rudert and W. K. Aicher (2007). „Comparison of marker gene expression in chondrocytes from patients receiving autologous chondrocyte transplantation versus osteoarthritis patients.“ Arthritis Res Ther 9(3): R60.

Stoop, R. (2007) Smart Biomaterials of Tissue Engineering of Cartilage. Injury (in press).

Storn, V., M. Kirschbaum, B. Schlosshauer, A. F. Mack and C. Fricke (2007). „Electrical stimulation-induced release of ß-endorphin from genetically modified Neuro-2a cells. (in press).“ Cell Transplantation

Zibek, S., A. Stett, P. Koltay, M. Hu, R. Zengerle, W. Nisch and M. Stelzle (2007). „Localized functional chemical stimulation of te 671 cells cultured on nanoporous membrane by calcein and acetylcholine.“ Biophys J 92(1): L04-6.

Conference articles, lectures und abstracts 2006 (samples)

Angres, B., H. Steuer, M. Wagner, P. Weber and H. Schne-ckenburger (2006). „Total Internal Reflection Energy Transfer (TIRET) Microscopy for Analysis of Focal Adhesions in Living Cells.“ Biophotonics and New Therapy Frontiers Proc. SPIE, Vol.6191: 81-87.

Angres, B., C. Kuschel, H. Steuer, A. N. Maurer, R. Stoop, M. Lietz and B. Schlosshauer (2006). Multiple Substrate Array: Screening of Extracellular Matrix Proteins for Effects on Cell Adhesion and Phenotype. . Strategies in tissue engineering, Würzburg, Cytotherapy 8, Suppl. 2, p. 41.

Beckmann, P., Dreher, W., Görlach, B., Holweger, W. (2006). Grenzflächenanalytische Untersuchungen zur Wechselwir-kung von Schmierstoffen mit technischen Grenzflächen. Vortrag 14. Arbeitstagung Angewandte Oberflächenanalytik, Kaiserslautern.

Burkhardt, C., H. Wolburg, K. Kohler, H. Schmid, R. Stoop and W. Nisch (2006). In-situ preparation of bio-technical interfaces by FIB-SEM microscopy. Proceedings MEA Meeting 2006, Reutlingen, BioPro edition, Vol. 3, p. 163-164, ISBN 3-938345-02-0.

Dreesmann, L., M. Lietz, S. Oberhoffner, A. Ullrich, M. Dauner and B. Schlosshauer (2006). Neuro Tissue enginee-ring: artificial bands of Büngner and associated cell interac-tions in vitro. FENS, Wien, Abstr. Vol. 3, A088.3, p. 225.

Egert, U., S. Okujeni, W. Nisch, K. H. Boven, R. Rudorf, N. Gottschlich and A. Stett (2006). Optimized Oxygen Availabi-lity and Signal-to-Noise Ratio in Brain Slice Recordings with Perforated Microelectrode Arrays. Proceedings MEA Meeting 2006, Reutlingen, BioPro edition, Vol. 3, p. 174-177, ISBN 3-938345-02-0

Fricke, C. and B. Schlosshauer (2006). Comparison of phar-macological effects on angiogenesis by immortalized versus non-immortalized cells. 3rd annual meeting Cell-based assays for HTS, Philadelphia, USA.

Fricke, C., Storn, V., Kirschbaum, M., and Schlosshauer B.(2006) Neuro tissue engineering: stimulated secretion of analgetic peptides;Biostar Kongress 2006; Stuttgart

Fricke, C., Funk, D., Shahr, A., Zamostiano, R., Barbio, I, and Schlosshauer, B. (2006) INTENSE: Nasal Stem Cells for Spinal Cord Regeneration and the Development of Drug Test Systems; Biostar Kongress 2006; Stuttgart

Gerhardt, M. and A. Stett (2006). Simulation of extra-cellular stimulation of bipolar cells with monopolar and dipolar electrode configurations. Proceedings MEA Meeting 2006, Reutlingen, BioPro edition, Vol. 3, p. 93-94, ISBN 3-938345-02-0.

Guenther, E., K. Henes, S. Pankow, K. H. Boven and T. Meyer (2006). Assessment of drug effects on myocyte function in vitro. Proceedings MEA Meeting 2006, Reutlingen, BioPro edition, Vol. 3, p. 136-139, ISBN 3-938345-02-0..

Hartmann, M., A. Toegl, R. Kirchner, M. F. Templin and T. O. Joos (2006). „Increasing robustness and sensitivity of protein microarrays through mictroagitation and automation.“ Analytica Chimica Acta 564: 66-73.

Kraft, A., T. Herrmann and A. Stett (2006). Electroretinogram recordings with MEAs from explanted rat retina (rat uERG). Proceedings MEA Meeting 2006, Reutlingen, BioPro edition, Vol. 3, p. 97-98, ISBN 3-938345-02-0.

Kriebel F, Wittemann S, Hsu HY, Joos T, Weiss M, Schneider EM.(2006) Caspase-3 activation, Bcl-2 contents, and soluble FAS-ligand are not related to the inflammatory marker profile in patients with sepsis and septic shock. Ann N Y Acad Sci. 2006 Dec;1090:168-76.

Müller, U., J. Kentsch, W. Nisch, S. Neugebauer, W. Schuh-mann, S. Linke, M. Kaczor, T. Lohmüller, J. Spatz and M. Stelzle (2006). NanoBioPore – a novel platform for sensitive electrochemical biosensors. Deutsch-Japanischer Biochip Workshop, Tokyo, Kanasawa.

Publications


Pawlak M. (2006) AMT – Advances in Microarray Technolo-gies, Amsterdam (NL), Making It Small: Protein Profiling using Novel Reverse Phase Arrays.

Reichl R (2006) Qualifizierung der Endreinigung nach der Fertigung bei Implantaten, eingeladener Vortrag auf der DIF-Fachkonferenz „Kunststoffe in der Medizintechnik“, Würzburg.

Reichl R (2006) Oberflächentechnologien und ihre Prüf-barkeit“ eingeladener Vortrag auf der Tagung der SAQ Fachgruppe Medizinprodukte „Wie sauber müssen / können Medizinprodukte nach der Herstellung sein?“, Olten.

Schmid, H., T. Herrmann, K. Kohler and A. Stett (2006). Zelluläre Reaktionen bei anhaltender elektrischer Netzhautsti-mulation. Poll R. Füssel J. (ed): Dresdner Beiträger zur Medi-zintechnik, Band 1:1. Dresdner Medizintechnik-Symposium, 189-194. TUDpress, Dresden, ISBN 3-938863-85-4.

Schmid, H., T. Herrmann, M. Gerhardt, H. Sailer, A. Stett and K. Kohler (2006). Organotypic retinal cultures on Micro Elec-trode Arrays: Validation of the stability of the in vitro system and cellular alterations induced by prolonged electrical stimu-lation. Proceedings MEA Meeting 2006, Reutlingen, BioPro edition, Vol. 3, p. 99-100, ISBN 3-938345-02-0.

Schwenger, D. and A. Stett (2006). Electrical stimulation of the receptive field of ganglion cells in degenerated retina of RCS rats. Proceedings MEA Meeting 2006, Reutlingen, BioPro edition, Vol. 3, p. 88-89, ISBN 3-938345-02-0.

Stelzle, M. (2006). Micro- and nanosystems for manipulation and sensing of (biological) particles and molecules. Physics of Sensors and Detection Systems International Workshop, JRC, Ispra.

Stett, A. and D. Schwenger (2006). „Spatial Sensitivity of Ganglion Cells in RCS Rat Retina to Subretinal Electrical Stimulation With Line Electrodes.“ Invest. Ophthalmol. Vis. Sci.(47): E-Abstract 3170.

Stoll, D and Clausen, N. (2006) Vortrag „Grundlagen der Peptidchemie „Fa. Roche Pharmaceuticals, Basel, Schweiz (Einladung).

Vaz Nürnberger, J., D. Albrecht, B. Gonser, A. Döttinger, M. Templin and R. Stoop (2006). P111 MMP-an cytokine-concentrations in synovial fluid of patients suffering from unilateral or primary osteoarthritis do not differ from those with post-traumatic cartilage degeneration of osteochondro-sis dessicans. OARSI. Prag. 14: S71.

Zibek, S., T. Göttsche, M. Hu, P. Koltay, R. Zengerle, C. Tatzel, A. Stett and M. Stelzle (2006). Towards chemical stimulation of cells: the artificial synapse project. Poll R. Füssel J. (ed): Dresdner Beiträge zur Medizintechnik, Band 1:1. Dresdner Medizintechnik-Symposium, 195-198. TUDpress, Dresden. ISBN 3-938863-85-4.

Zrenner, E., D. Besch, K. U. Bartz-Schmidt, F. Gekeler, V. P. Gabel, C. Kuttenkeuler, W. Nisch, H. Sachs, H. Sailer, A. Stett, B. Wilhelm and R. Wilke (2006). Subretinal chronic multi-elec-trode arrays in blind patients: function testing and pattern recognition. Proceedings MEA Meeting 2006, Reutlingen, BioPro edition, Vol. 3, p. 90, ISBN 3-938345-02-0

Conference articles, lectures und abstracts 2007 (samples)

Angres, B.M., Benz, K., Sturany, S., Stoll, D., Platz, B. and Wurst, H. (2007). Modifiable hydrogel reagents for 3D cell culture. Mol. Biol. Cell 18 (suppl), abstract 1191. (CD-ROM).

Beckmann P., Dreher, W. (2007) Auswirkungen von Oberflächenbearbeitung und Schmierstoff auf Gefüge und chemische Zusammensetzung. Vortrag 48. Tribologie Fachtagung, Göttingen. Proceedings Band I, Nr. 14, ISBN 978-3-00-022603-8.

Dreesmann, L., M. Lietz, M. Weimar and B. Schlosshauer (2007). Fibroblast impact on Schwann cells and axonal growth. In: Proceedings of the 7th Meeting of the German Neuroscience Society 31st Göttingen Neurobiology Confe-rence, Thieme Verlag Stuttgart-New York, Neuroforum 2007, 1 Suppl.

Deher, W., Warres, C. (2007) 11th ETH Conference on Combustion Generated Nanoparticles, Zürich, August 13th-15th, Poster.

Dreher, W. (2007) „QUANTAX am CrossBeam“ „FIB (Focused Ion Beam) und Elementanalyse“, Kolloqium Berlin Adlershorst: Neue Entwicklungen in der EDX-Analyse am Rasterelektronenmikroskop - 4. Generation stickstofffreier Silizium Drift Detektoren (SDD).

Guenther E., Henning H., Wenzlaff H., Kohler K., Schmid S. (2007) Light-dependent regulation of NMDA receptor contribution to excitatory synaptic currents in ganglion cells of the rat retina. ERM 1, P13, p12.

Guenther E., Danker T., Pankow S., Meyer M. (2007) Microelectrode-based biosensors and their applications in drug screening and safety pharmacology. 5th Ion Channel Retreat. P11.

Hajosch, R., Dreesmann, L., Ahlers, M., Schlosshauer, B. (2007) Vortrag:Development of a gelatin nerve implant. Jahrestagung der deutschen Gesellschaft für biomedizinische Technik, Aachen.

Joos TO. (2007) Advances in proteomics in cancer research.Expert Rev Proteomics. 2007 Jun;4(3):347-9. Conference report. PMID: 17552917.

Müller, U., W. Nisch, M. Pawlack, B. Gierke, S. Breisch, C. Burkhardt, R. Rudorf, S. Neugebauer, W. Schuhmann, S. Linke, M. Kaczor, T. Lohmüller, J. Spatz, M. Motz, J. Sorsa, S. Hecke, G. Hartwich and M. Stelzle (2007). NanoBioPore: A novel nano-porous electrode system to enhance biosensor sensitivity. NSTI Nanotech, Santa Clara.

Pawlak M. (2007) Protein Array Workshop (Genoptics), ENS Cachan, Paris (F), 29. Reverse Phase Protein Arrays for Throughput Sample Profiling.

Reichl R (2007) Qualifizierung der Endreinigung nach der Fer-tigung bei Implantaten“, eingeladener Vortrag BIOSERVICE-Seminar „Aktuelle Anforderungen an biologische Prüfungen von Medizinprodukten“, München.

Reichl R (2007) Qualifizierung der Endreinigung nach der Fertigung bei Implantaten“, eingeladener Vortrag auf dem Vortragsforum „Medizintechnik“ der EUROMOLDin der Medizintechnik“, Frankfurt.

Schlosshauer, B. (2007) Vortrag: Entwicklung von Nervenleit-schienen. Berufsgenossenschaftliche Unfallkliniken, Wien.

Schlosshauer, B. (2007) Vortrag: Tissue engineering of nerve implants. 3. World Congress Regenerative Medicine, Leipzig.

Schlosshauer, B., Dreesmann, L., Rupp, M., Ahlers, M. (2007) Development of a pro-angiogenic nerve guide implant. Conference June 13-16, REGENERATE – TERMIS NA, Toronto, Canada.

Stett, A., T. Herrmann, K. Gutöhrlein, R. Rudorf, K. H. Boven and W. Nisch (2007). Improving of signal-to-noise ratio of electrophysiological recordings from explanted retinas by using perforated microelectrode arrays. Mikrosystemtech-nik Kongress, Berlin, Proceedings p. 425-427, VDE Verlag, Offenbach.

Stett, A., H. Schmid, T. Herrmann and K. Kohler (2007). „Inhibition of Apoptosis of Retinl Cells by Prolonged Electrical Stimulation of Organotypic cultures of Adult RCS Rat Retina.“ Invest. Ophthalmol. Vis. Sci.(48): E-Abstract 3705.

Stoll, D (2007) QC Analytik von RNA, 3. Tübinger Massen-spektrometrie Seminar, Universität Tübingen), (Einladung)

Vaz Nürnberger, J., D. Albrecht, B. Gonser, A. Döttinger, M. Templin and R. Stoop (2007). P63 MMP-and cytokine-concentrations in synovial fluid of patients suffering from unilateral of primary osteoarthritis do ot differ from those with post-traumatic cartilage degeneration of osteochondro-sis dessicans. Joint Meeting of the Netherlands and German societies for Materix Biology, Münster.

Zahnd C, Wyler E, Schwenk JM, Steiner D, Lawrence MC, McKern NM, Pecorari F, Ward CW, Joos TO, Plückthun A.(2007) A designed ankyrin repeat protein evolved to picomolar affinity to Her2. J Mol Biol. 2007 Jun 15;369(4):1015-28. Epub 2007 Mar 20.

Zrenner, E., R. Wilke, T. Zabel, H. Sachs, K. U. Bartz-Schmidt, F. Gekeler, B. Wilhelm, U. Greppmaier and A. Stett (2007). „Psychometric Analysis of Visual Sensations Mediated by Subretinal Microelectrode Arrays Implanted Into Blind Retinitis Pigmentosa Patients.“ Invest. Ophthalmol. Vis. Sci.(48): E-Abstract 659.

Book chapters and non-reviewed articles 2006 (samples)

Angres, B., C. Kuschel, H. Steuer and A. Blondiau (2006). „Charakterisierung von Zell-Matrix-Interaktionen mit Protein-Microarrays.“ Laborwelt 7(3): 37-39.

Fejtl M., Stett A., Nisch W., Boven KH., Möller A. (2006). On Micro Electrode Array revival: its development, sophistication of recording, and stimulation. In: Taketani M., Baudry M. (eds): Advances in Network Electrophysiology Using Multi Electrode Arrays; p. 24-37. Springer, Berlin 2006; ISBN: 0-387-25857-4

Guenther E., Herrmann T., Stett A. (2006). The Retinasensor: An In vitro Tool to Study Drug Effects on Retinal Signaling. In: Taketani M., Baudry M. (eds): Advances in Network Electrophysiology Using Multi Electrode Arrays; p. 321-331. Springer, Berlin 2006; ISBN: 0-387-25857-4

Joos, T. O. and H. Berger (2006). „The long and difficult road to the diagnostic market: protein microarrays.“ Drug Discov Today 11(21-22): 959-61.

Templin, M.F., Stoll D., Pawlak M. and Joos T.O. (2006) Protein micorarrays: Neue Systeme für die Proteomforschung. GIT Labor-Fachzeitschrit 10, 890-892.

Book chapters and non-reviewed articles 2007 (samples)

Angres, B. and H. Schneckenburger (2007). Protein-Protein-Wechselwirkungen in lebenden Zellen beobachten. Biospektrum: 22-24.

Benz, K., Mollenhauer, J. (2007) Gelenkknorpel, Arthrose und zelluläre Reparatur. Trauma und Berufskrankheit, 9(4), 246-251.

Pawlak M., Templin, M.F., Stoll D. and Joos T.O. (2007) Protein micorarrays: new tools for proteomic applications. Chemistry Today (Chimica oggi) 25(2), 62-65.

Schlosshauer, B. (2007). Blood-Retina Barriers. Handbook of Neurochemistry and Molecular Neurobiology 3rd Edition Vol.11 Neural Membranse and Transport (Eds. A. Lajtha and M.E.A. Reith) Springer Publishers, New York, 486-506.

Zrenner, E. and Haemmerle H. (2007). Sehchips - Hoffnung für Blinde. Spektrum der Wissenschaft, Dossier 6/07: 40-45.

Doctoral dissertations 2006/2007

Bauerdick, S. (2006). Entwicklung und Untersuchung eines Feldemitter-Kathodenarray mit einzeln adressierbaren, im fokussierten Elektronenstrahl direkt abgeschiedenen Emissi-onsspitzen. Dissertation, Eberhard-Karls-Universität, Tübingen

Dreesmann, L. (2007). Zelluläre Mechanismen beim Neuro-Tissue Engineering. Institut für Zoologie. Stuttgart, Universität Hohenheim: 137

Maurer, A. M. (2006). Interaktion von Chondrozyten mit Komponenten der extrazellulären Matrix - Einfluss von Erkrankung und Dedifferenzierung. Molekular- und Zellbiolo-gie. Mannheim, Hochschule Mannheim: 119.

Lietz, M. (2006). Schwann Zellen als integraler Bestandteil eines biohybriden Nervenleitfaser-Implantates. Fakultät für Biologie. Tübingen, Eberhard Karls Universität: 127.

Vaz Nürnberger, J. (2007). Smart Biomaterials for the Tissue Engineering of Articular Cartilage. Fakultät für Biologie. Tübingen, Eberhard Karls Universität: 138.


Projects supported by the

BMBF (Federal Ministry of Education and Research)

01EZ0709 pathIdent: PCR-freie Genotypisierung der Chinolon-Resistenz von E.coli zur Schnelldiagnostik bakteriel-ler Harnwegsinfektionen

01GG0712 Attodicil: Teilprojekt Celltest; Immortalisierte humane Endothelzellen und Bronchialepithelzellen für ein organotypisches Testsystem der Lunge

01GG0729 HepaChip: Dielektrophoretisch assemblierte organotypische Leberkokulturen zur toxicologischen und pharmakologischen Substanztestung (2008)

01GN0111 Mikrostrukturierte bioresorbierbare Leitkanäle mit Gliazellen für die Nervenregeneration.

01KP0401 Retina Implant III, Pilotstudie.

0311962 TENNIS: Tissue Engineering von NeuroImplantaten zur Schmerztherapie.

0312035A Nanodendroden: Mikroimplantate mit dendri-tischen 3D-Nanoelektroden als elektrotechnisch/biologische Gewebeschnittstelle

0312116 Neurotrophe Wachstumsfaktoren: Optimierte rekombinante Substratmoleküle für die neuronale Regene-ration.

0313081E HepatoSys - Plattform Zellbiologie: Teilprojekt: „Stabilisierung von Hepatozytenkulturen durch definierte extrazelluläre Matrix“

0313135 Langzeitverträglichkeit der funktionellen elek-trischen Netzhautstimulation zur Wiederherstellung von Sehvermögen.

0313141 SMART Biomaterials: Gelatine-basierende „Smart Biomaterials“ für die Knorpelregeneration.

0313144A BioProfile: Bioresorbierbare Kollagenleitfasern für die Nervenregeneration.

0313176C PSP Postgenomic Screening Platform: Modulare Technologieplattform für komplexe biologische Assays.

0313180C BioChancePlus: ASK-Chip: Entwicklung eines Adenoviralen siRNA Kinom Chip.

0313400C BioProfile: Knorpelerkrankung Bioartifizieller Oberflächenersatz zur Behandlung von degenerativen Knor-pelerkrankungen.

0313422 BioDisc: Nasale Stammzellen für die Rückenmarks-regeneration und Entwicklung von Pharmatestsystemen.

313447B BioChancePlus: AIONAS: Automatisierte Ionenkanal-Assays mit stnadardisierten transienten Suspen-sionskulturen.

0313649C BioChancePlus: Entwicklung einer biotechnischen Plattform für elektrophysiologische Gewebe-Assays zur in-vivo-nahen Wirkstoffuntersuchungen.

0313698 BioProfile: 3D-Zellbiologie: Intelligente Biomateri-alien für Zellkultur und Regenerative Biologie.

0313728B BioProfile Stuttgart/Neckar-Alb: Büngner-Bänder: NeuroTissue Engineering von regenerativen Büngner Bändern

0313755 Bandscheibenregeneration

0313756 Cryoion: Etablierung von validierten Cryokulturen für die automatisierte Ionenkanalanalyse von Primärzellen

0313905 Einheilung Gefäßstents

0313907A BioChancePLUS-3: Adhäsionsbarrieren

0313975B ERA NET EuroTransBio-1: Screeningsysteme zur Identifikation allergener Substanzen

13N8606 : NanoBioPore: Hochsensitive elektrochemische Sensoren mittels Nanopartikellithographie für die medizi-nische Diagnostik und Wirkstoffsuche.

13N8652 Nano-Kryo-Bio-Sims: Nano-Kryo-Sekundärionen-Massenspektrometrie für biologische Proben.

13N8955 Funaschi: Funktionelle nanostrukturierte Schichtsy-steme für elektrisch aktive Mikroimplantate.

13N9122 Nanohybrid: Hybride Nanostrukturierungsverfah-ren mittels selbstorganisierender funktioneller Partikel und Copolymere

16SV1644 M-A-P.: Entwicklung von Hochleistungs-Mikro-Antrieben mit neuen pulver-basierten Fertigungsverfahren.

16SV1744 MIMP: Multiwell-Microsensor-Plate für zell-basierte Wirkstoffuntersuchungen.

16SV1769 MiProzeF: Mikrofluidischer Prozessor für zelluläre Funktionsanalyse.

16SV2378 Neuroslide: Mikrosystem-basiertes Kultur- und Analysesystem zur kontrollierten elektrischen und optischen Manipulation und funktionellen Langzeitanalyse von neuro-nalen Zell- und Gewebekulturen

16SV2391 microPrep: Mikrofluidische Probenvorbereitung komplexer biologischer Extrakte und Partikel.

KA 0048601 QT-Verlängerung: AFC3 Entwicklung eines schnellen und preiswerten Test systems zur Untersuchung des Einflusses bestimmter Wirkstoffe oder Wirkstoffkombinati-onen auf die Herztätigkeit.

State of Baden-Württemberg

24-720.431-1-7/2 Bio-Disk: Autonomes Bioanalysesystem für diagnostische Anwendungen auf Basis eines Zentrifugalan-triebs.

4-4332.62-NMI/17 Technologien für medizinische Produkte mit verbesserten funktionellen Eigenschaften.

4-4332.65-NMI/15 Chip-basierende Genom-, Proteom- und Zellomanalyse für die regenerative Medizin.

720.830-3-15 Implantierbare Energieversorgung (Retina Implantat).

720.830-3-2 Entwicklung von Verfahren und Methoden zur GMP-konformen Herstellung und analytischen Charakterisie-rung von RNA Fragmentn

720.830-4-15/3b NAT-Assay: Entwicklung eines NAT-Assays zur Detektion von Squirrel Monkey Retrovirus (SMRV)-Konta-minationen in Zellkulturen.

Landesstiftung Baden-Württemberg (State Foundation of Baden-Württemberg)

Artificial Synapse: Nanofluidicsystem zur lokalen Substanz-applikation mittels nanoporöser Membran mit schaltbarer Permeabilität.

FRET in TIRFM: Räumlich und zeitlich hochauflösende Detektion von Protein-Protein-Interaktionen in Zelladhäsions-komplexen.

Retina Implantat: Adaptive neuroelektronische Schnittstellen für aktive Netzhautimplantate.

2-4662.62-NMI/24 Nanoskalige Randschichten: Erzeugung und Charakterisierung nanoskaliger Randschichten zur Reibungs- und Verschleißminderung

P-LF-Biomat/28 MatriXELECt: Zellbasiertes Verfahren für die Selektion von Faktoren zur Biologisierung von Materialien (2008).

European Union

EU026008 Proteom Binders

EU036644 DIALOK

LSHM-CT-2005-512012 Promemoria: Lernen – Gedächtnis – Alzheimer’sche Erkrankung.

NMP4-CT-2003-505311 NABIS

Other projects

Helmholtz Gemeinschaft e.V. Affinity-regulated artificial synapses

AIF KF0304101UL6 Gene Silencing Stents

FVA 459/DFG H0 133 9/29-1 Einfluss der Graufleckigkeit auf die Grübchentragfähigkeit einsatzgehärteter Zahnräder.

DFG Jo687/2-1 Neurofibromatose

The NMI thanks the Federal Ministry of Education and Research (BMBF), the Ministry of Economic Affairs of Beden-Württemberg, the Landesstiftung foundation Beden-Württemberg and the European Union for support of the above projects.

Projects

Innovation Alliance Baden-Wuerttemberg

The NMI is a research institute of the Innovation Alliance Baden-Wuerttemberg.

This Alliance consists of 14 cooperating research facilities, which work in various scientifi c fi elds. Our Alliance partners are:

Hohenstein Institute for Clothing Physiology (BPI)www.hohenstein.de

Research Institute Precious Metals & Metals Chemistry (FEM) www.fem-online.de

Forschungsinstitut für Pigmente und Lacke e.V.; www.fpl.uni-stuttgart.de

Research Center for Information Technologies (FZI) at the Uni-versity of Karlsruhe (TH); www.fzi.de

Hahn-Schickard-Gesellschaft, Institut for Micro Assembling Technology; www.hsg-imat.de

Hahn-Schickard-Gesellschaft, Institut for Micro Technical com-ponents and systems; www.hsg-imit.de

Institut für Lasertechnologien in der Medizin und Meßtechnik an der Universität Ulm; www.uni-ulm.de/ilm

Institut für Mikroelektronik Stuttgart; www.ims-chips.de

Institute for Textile Chemistry and Chemical Fibers (German Institute for Textile and Fibre Research Denkendorf DITF); www.itcf-denkendorf.de

Institut für Textil- und Verfahrenstechnik (German Institute for Textile and Fibre Research Denkendorf DITF); www.itv-denkendorf.de

Centre for Management Research of the German Institute for Textile and Fibre Research; www.ditf-denkendorf.de/mr

Training, Testing and Research Centre - Competence in Lea-ther; www.lgr-reutlingen.de

Zentrum für Sonnenenergie- und Wasserstoff-Forschung Baden-Württemberg; www.zsw-bw.de

How to fi nd us

Coming from Stuttgart orStuttgart airport:Take the B27 highway from Stuttg-art or from the Stuttgart airport in the direction of Tübingen. After arriving in Tübingen, follow signs to Reutlingen. You are now on the B28 in the direction of Reutlingen.Exit the B28 at Jettenburg/Mähringen.At the fi rst intersection continue straight for approximately 1 kilometer. The NMI is located on the right.

Coming from Tübingen:Take the B28 highway towards Reutlin-gen and exit at Jettenberg/Mähringen. At the fi rst intersection continue straight for approximately 1 kilometer. The NMI is located on the right.

Coming from Reutlingen:Follow signs in the direction of Tübin-gen, taking the B28 highway to Tübin-gen. Exit at Jettenburg/Mähringen, keep right, crossing bridge over the B28. After the bridge take fi rst left into the Mark-wiesenstrasse. Follow the Mark-wiesen-strasse for approximately 1 kilometer.The NMI is located on the right.

NMIMarkwiesenstraße 5572770 ReutlingenPhone 0 71 21 5 15 30-0

NMI Natural and Medical Sciences Insitute at the University of TübingenMarkwiesenstraße 5572770 Reutlingen / GermanyPhone: +49 (0) 7121 51530-0Telefax: +49 (0) 7121 [email protected]

Angewandte Forschung und Entwicklung an der Schnittstelle von Bio- und Materialwissenschaften

2006-2007Applied research and development at the junction of life sciences and material sciences

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Annual Report

NMI Natural and Medical Sciences Institute

Documents

Annual Report - NMI€¦ · Annual Report NMI Natural and ... 24 Cell biochips ... one or some important project. Instead, I would like to express my thanks to all