Integrated Engineering for Life Sciences – Providing Customized Medical Solutions

As progress and innovation increasingly occur at the interface of once distinct scientific disciplines, comprehensive knowledge and integrated capa-bilities have become crucial for success.

This holds particularly true in a field as inter-disciplinary as Life Sciences. The traditional process of developing and launching outstanding products encounters new and complex challenges which requires the experience of people from diverse disciplines with different perceptions, working together to design novel solutions.

The Fraunhofer Life Sciences Engineering Group has understood and taken on those challenges. With a motivated and experienced team of professionals, we have at our disposal the port-folio of skills required for integrating engineer-ing and medical science technologies to develop complex and economically feasible products in a highly dynamic yet regulated environment. We are thereby able to rapidly deploy cutting-edge medi-cal technologies into outstanding products for our customers across the medical industry.

Interdisciplinary Expertise: Our Passion at Your Disposal

With our close cooperation with public and private research facilities that carry out basic research, we transfer those novel technologies into an industrial and economic context. We thereby create particu-lar value for

• medical clinicians by identifying and fostering promising, relevant applied research

• industrial R&D partners by launching new development partnerships

Our vision is to advance the state of medicine through the integration of engineering techno-logies and medical science. We invite you to join with us in that vision of translating medical needs into customized solutions.

Our service portfolio offers a wide range of professional expertise and technologies. We offer our customers integrated solutions comprising the whole value chain, ranging from applied product and process R&D to production ramp-up and commercialization. We understand that the ability to develop an outstanding product is challenged by increasing pressures to lower development cost and risk while addressing regulatory agency requirements.

We are aware of the complex interplay between clinical requirements and technological opportuni-ties and help you to synchronize the technological and medical development paths. With more than 280 highly qualified professionals located at the United States East Coast and in the heart of Central Europe, we possess the know-how, infrastructure and customer proximity which are required for the development of unique and successful solutions.

Our core strength is the application of advanced engineering to biological problems. We have numerous high precision technologies for devel-oping solutions for complex machining, handling, and process tasks that allow us to prototype unique solutions that we design. Utilizing the resources at our disposal, we develop customized, integrated products and processes, employing the latest computer-assisted procedures and methods.

Relying on this platform of core strengths, we specialize in two areas of the Life Sciences Sector: Medical Instruments and Devices and Automation of Biological and Biomolecular Processes:

Medical Instruments and Devices– Selection of suitable materials such as metals,

ceramics, fiber-reinforced plastics and glass considering their cytotoxic, hemocompatible, allergenic and mechanical properties

– Miniaturization into micro-electro-mechanical systems and nano-devices

– Development of minimally invasive medical tools (e.g. puncturing fiber-reinforced plastic syringes) and microinstruments (e.g. intra-cardiac blood pumps, suturing, high-precision implants)

– Development of minimally invasive and non-invasive metrology solutions (e.g. spectros-copy, confocal microscopy, Optical Coherence Tomography (OCT))

– Data and image processing

Automation of Biological and Biomolecular Processes

– Automation, integration, linking and scaling of complex biological process chains (e.g. automated cell culture, high throughput automation and lab-on-a-chip technologies)

– Integrated design and development of process-es and products – from design to operational production prototypes in compliance with regulatory standards such as GMP

– Extensive expertise in process engineering for optimizing, adapting and controlling all required machining steps for prototype fabri-cation

– Online process control for complex biological procedures

– Turnkey factory automation systems

Our Services

ObjectiveObtaining viable myocyte cells is a critical step in performing in vitro cardiac cell assays. Testing new drug candidates in this model heart system requires large numbers of myocytes to be pro-duced for high throughput screening. The isolation and production of myocyte cells for this screening is a highly labor-intensive and low yield process. Thus the goal of this project was to automate the manual process for isolation of myocyte cells from mouse hearts while maintaining viability and increasing throughput.

MethodologyWe developed a system that utilizes pressure-based liquid infusion with volumetric feedback control. The use of a pressure-based liquid dis-pensing manifold results in a lower cost, easier to use and more reliable system. The four reaction chambers feature oscillating mechanical agita-tors and allow up to four myocyte cultures to be processed at the same time. The system housing protects it from environmental factors. Custom-ized software was developed for system control with the appropriate interface hardware which is capable of accepting user supplied inputs for fluid extraction/replenishment quantities and processing times. This customized solution allows the user to modify the parameters as needed.

Project HighlightsAutomation of Biological and Biomolecular Processes

Results• Unique mixing chamber design improved cell

survival rate• Set up time is less than 20 min• Easily customizable protocols• Compact – fits in a standard bio-safety cabinet• Produces 3 million functional cells per reaction

chamber

Myocyte Cell Extractor

ObjectiveIn the field of drug discovery, assays must be automated to achieve the required high through-put analysis for screening new drug candidates. A large pharmaceutical company was interested in automating the loading of microtiter plates into a Luminescent Image Analyzer to increase the throughput of their screening assays. In addition, the design was required to have a small footprint to be compatible with the crowded laboratory environment.

MethodologyThe unique system reduces the number of part “handoffs” thereby reducing cycle time and dimensional foot print. The entire load/unload mechanism including the magazine are all attached to what became a new door on the imaging chamber. The load/unload mechanism is attached to the inside of the door. Microtiter plates are then picked from the queue using an arm/gripper assembly that actually holds the plate during imaging (like a CD/DVD load mechanism). Servo motors and pneumatics were utilized to reduce overall system cost. A bar code reader helps ensure traceability and scheduling of hundreds of samples daily.

Results• Capacity: 50 microtiter plates that can be

replenished on the fly• Changeover time < 10 sec.• 2 removable cassettes for remote loading• Unattended operation• Simple retrofit to existing systems• Bar code reader reduces errors in identification

and automated data collection

ObjectiveIn the post-human genome project era, the demand for large scale studies using nucleic acid arrays is increasing. Although prefabricated arrays for specific experimental purposes are commerciallyavailable, the ability to rapidly produce smaller custom arrays is of great utility to research groups. Thus, in collaboration with the Boston University Center for Genomic Research, we undertook the development of an instrument for low cost and rapid production of custom DNA arrays (several hundred to several hundred thousand sequences) for research purposes.

MethodologyWe built a prototype using a maskless lithography approach to enable photochemistry. This photo-lithography approach is based on the use of semiconductor technologies in a biochip setting. The prototype allows polymerization of user deter-mined nucleotides at preprogrammed locations and enables the researcher to create customized arrays with about 10,000 arbitrary elements, each oligonucleotide being up to 25 bases long in approximately 13 hours.

Results• Mask-less system with precision fluid deposition

enables researchers to create custom diagnostic chips.

• PC programmability enables researchers to change configurations easily

Automated Microtiter Plate Loader for High Throughput Assay Screening

Maskless DNA Array Synthesizer

Motivation and objectiveCurrently, the in vitro fabrication of human tissue structures is a labor-intensive process carried out under manual conditions. This limited scalability precludes a sufficient availability of inexpensive tissue engineered products used for in vitro testing of diverse substances and for transplants.Faced with a strongly increasing demand in diverse industries, the project aims at the development, ramp-up and commercialization of a production system automating a manual process for grow-ing non-vascular, three-dimensional in vitro skin test models. As a result, the throughput will be increased by one order of magnitude while taking down production costs per unit by one third. By abiding by GMP standards, the production system will not only allow for the fabrication of in vitro test systems, but also for permanent human skin transplants.

MethodologyWe are leading a research consortium which works on the biological and production issues which are relevant to the automation and parallelization of the process of human tissue growth. This involves aligning and re-engineering all manual processes to ensure compliance with GMP and automation standards, the design and construction of com-ponents, the adaption and transfer of novel tech-nologies such as micro-machining for biological applications as well as integrating isolated process steps into a fully functional process chain. We are further in charge of elaborating the commerciali-zation strategy for the entire production system as well as for the diverse product variants that can be manufactured on it.

Results• Process engineering in consideration of GMP and

automation constraints• Mass production of microstructured, biofunc-

tional substrate surfaces for enhanced isolation, selective enrichment and proliferation of cells such as keratinocytes and fibroblasts

• Development of stand-alone process modules (bioreactors for controlled cell isolation and expansion, skin model growth, online process control units, sluices)

• Development of novel cell handling techniques• Ramp-up and demonstration of a stable mass

production process for tissue engineered human skin test models

• Process chain optimization and target costing• Market surveys for the specification of customer

requirements (e.g. order patterns, tolerated delivery times, required product variants)

• Product commercialization (e.g. configuration of product variants and service spectrum, elaboration of licensing models)

Mass Customized Organ Replicates – Tissue Engineering on Demand

ObjectiveTo ensure the production of pharmaceuticals, such as vaccines, in sufficient quantities to meet the global demand, high throughput production in transgenic and virus infected plants is a feasible approach. We have therefore recently started the development of a fully automated production sys-tem to facilitate and scale up vaccine production within the next three years. In adhering to modular design principles, we envisage a flexible and easily configurable plant-based production platform that could revolutionize biopharmaceutical production of a diversity of drugs.

MethodologyIn close collaboration with biologists we are responsible for the complete design, engineering and assembly of the first pilot production modulewith a specific biomass capacity. In following a modular approach, the production system will be easily reconfigurable for the requirements of other biopharmaceutical agents, thus enlarging the potential product scope. This involves the development of specialized equipment needed for the envisaged large-scale process as well as the construction of all of the required production modules, including validation, to gain regulatory approval and certification of the whole production process.

Results• Development of all components necessary to

implement required process steps, such as plant infiltration, seeding and harvesting

• Optimized nutrient supply, lighting and temper-ing for efficient and controlled plant cultivation

• Process engineering and technology transfer in compliance with GMP regulations

Innovative technologies to manufacture ground-breaking biopharmaceutical products in microbes and plants

ObjectiveThe major challenge of point-of-care clinical diagnostics of bacteria and viruses is to provide accurate detection with automated sample pre-paration. The field of clinical diagnostics is moving toward molecular diagnostics (e.g. PCR) which are the most sensitive and specific methodologies cur-rently available. However, PCR suffers from labor intensive sample preparation to isolate the nucleic acids and requires the physical separation of the sample preparation laboratory space to minimize contamination. Existing point-of-care clinical diagnostics (e.g. rapid strep test, home pregnancy kits, etc.) use antibody-based immuno-detection which enables simple test protocols, but lacks the sensitivity and specificity of molecular diagnostic techniques.

To address this challenge, we, in collaboration with Prof. Catherine Klapperich of Boston University, are developing an integrated lab-on-a-chip consum-able and prototype instrument that automates the sample preparation for bacteria and viruses from clinical samples, amplifies the nucleic acid and optically detects the presence or absence of the target. The plastic microfluidic chip (below) is approximately the size of a credit card.

MethodologyThe chip is designed to be low cost by keeping all active components in the instrumentation (valves, heating units, optics, etc.) and having a planar layout that enables low cost fabrication methods. The individual channel technology was integrated into a complete lab-on-a-chip by incorporating precision machining techniques and polymer-solvent activated thermal bonding for construction of a single plane low cost consumable. Our proto-type instrument automates the fluidic handling, thermal control and optical detection such that bacteria and viruses can be detected in a point-of-care setting while maintaining the highest level of sensitivity and specificity typical of a hospital’s clinical laboratory. The instrument prototype for automatic detection of bacteria in the sample was designed with a unique valveless switching fluidic control system.

Results• Integrated chip includes bacterial and mamma-

lian cell lysis, mixing reagents, isolation and concentration of nucleic acids, polymerase chain reaction, and fluorescence detection

• Instrumentation automates fluidics, thermal cycling and optical detection

• Low cost design for manufacturing

Project HighlightsMedical Instruments and Devices

Integrated Lab-on-a-chip for Clinical Diagnostics

Objectives Minimally invasive surgery is an efficient method of medical treatment, reducing physical stress during and after medical procedures for patients and simultaneously reducing health care costs.Due to the miniaturization of diagnostic, imaging and therapy systems, tissue areas in the patient’s body can now be reached, visualized and medicatedwhile minimizing external and internal trauma of the surrounding tissue. Yet, the feasibility of minimally invasive methods is still limited by major technical constraints. Because of the restricted field of view in the operating field, supporting external imaging processes such as magnetic resonance imaging (MRI) can be utilized. By requiring strong magnetic fields, however, MRI limits the use of metallic surgical instrumentation.

MethodologyAiming at enhancing the potential of MRI-sup-ported minimally invasive procedures for medical professionals, we are currently working on a mini-aturized, navigatable endoscopic catheter made of fiber-reinforced plastics (FRP). Being equipped with operational channels which can be flexibly used by distinct applicators, this integrated multifunctional tool stands out with regard to its platform nature. Hence, the versatile combination of diagnostic and therapeutic functionalities for tumor characteriza-tion and treatment becomes possible. Integratablefunctional modules comprise various imaging methods, temperature measurement, medication, irrigation, spectroscopy and measurements of oxygen saturation.

Results• Optimizing FRP manufacturing processes for

medical applications• Development of FRP medical instruments• Fabrication of FRP guide wires and multi-lumen

catheters• Metrology integration for diagnostic functionality

Development of applicators and guide wires for inter-ventional magnetic resonance imaging procedures

ObjectivesOptical Coherence Tomography (OCT) is a non-destructive imaging method that is well suited for identifying defects within the inner structure of tissue or matrix material. We have recently devel-oped novel devices which advance OCT techniques in minimally invasive medical therapies. We help our customers in testing and validating techno-logical solutions as well as in gaining accreditation for medical instruments and devices by developing integrated solutions ensuring product compliance with regulatory standards.

MethodologyWe have recently developed an automated read-out device which allows for reliably processing data from a fiber-optic, endoscopic OCT scanning probe with high precision and speed. Thanks to an integrated calibration software controller, the device can be easily dismantled and sterilized after each application without the need for troublesome and time-consuming readjustments. As a result of the modular architecture of the whole system, a technology transfer to various medical metrology applications is viable.

In another project, we developed OCT methods for application in in vivo therapy monitoring in close collaboration with university hospitals. Research was aimed at enabling doctors to evaluate the healing process of arthritis patients after replace-ment of cartilage with tissue engineered collagen.

Results• In vivo and in vitro tissue diagnostics and

monitoring• Miniaturization of (fiber-optic) metrological

solutions such as OCT-based image processing and analysis and integration into stand-alone minimally invasive systems for medical applications

• Automation, control and integration of inter-dependent, complex single components into a working device meeting required reliability standards

Application of Optical Coherence Tomography (OCT) in Medical Diagnostic Imaging

About Fraunhofer Life Sciences Engineering GroupThe Fraunhofer Life Sciences Engineering Group has offices in Boston, Massachusetts, USA and in Aachen, Germany. We provide applied research, advanced engineering designs, and build custom prototype devices and fully functional instruments and automation systems. We have experience from all fields of production technology including process technology, production machines, tech-nology management as well as metrology and quality management.

Thanks to our access to the Fraunhofer-Gesellschaft´s large industrial expert network and to our location at the prestigious Boston Uni-versity (BU) and Aachen University of Technology campuses, we possess the know-how, infrastruc-ture, technical resources and customer proximity that are required to fulfill unique and challenging application requirements. In our world class labora-tories and fabrication facilities we can thus realize comprehensive solutions and develop new manu-facturing technologies, customized stand-alone electromechanical products and turnkey auto-mation systems for a myriad of technical markets. Our clients comprise industrial companies of all sizes and all sectors of industry.

The Fraunhofer Life Sciences Engineering Group addresses the distinctive needs and constraints at the intersection of life sciences and engineering. Through collaborations with academic institutions, such as our formal Alliance with Boston Uni-versity in the area of Medical Devices, Diagnostics, and Instrumentation, we work together closely with scientists, engineers, and clinicians at Boston University’s main and medical school campuses and local area hospitals. In this way, we facilitate the accelerated translation of advanced biomedical research into products ready for commercialization and use in clinical applications.

Our core strengths in the areas of Medical Instru-ments and Devices and Automation of Biological and Biomolecular Processes provide a unique resource for your industrial R&D, design and automation needs.

For further information please visit our website:www.fraunhofer.org/lse

About Fraunhofer-GesellschaftResearch of practical utility for private and public enterprises lies at the heart of all activities pursued by the Fraunhofer-Gesellschaft. Having developed and leveraged revolutionary technologies such as the MP3 format, its services are solicited by customers and contractual partners in industry, the service sector and public administration.

At present, Fraunhofer-Gesellschaft maintains more than 80 research units worldwide. The majority of the 13,000 staff are qualified scientists and engineers, who work with an annual research budget of $2.1 billion. Of this sum, more than $1.6 billion is generated through contract research.

About Us

Fraunhofer USA Center for Manufacturing Innovation CMIat Boston University15 Saint Mary’s StreetBrookline, Massachusetts 02446-8200USA www.fhcmi.org

Alexis Sauer-Budge, Ph.D.Phone: +1 (617) 353-18 95Fax: +1 (617) 353-18 96Email: asauerbudge@fraunhofer.org

Bill MosolgoManager, Sales & Marketing Phone: +1 (617) 358-19 89Fax: +1 (617) 353-18 96Email: bmosolgo@fraunhofer.org

Fraunhofer Institute for Production Technology IPTSteinbachstrasse 1752074 AachenGermanywww.ipt.fraunhofer.de

Dipl.-Phys. Dipl.-Wirt. Phys. Joerg SaxlerPhone: +49 (0) 2 41/89 04-1 61Fax: +49 (0) 2 41/89 04-61 61Email: joerg.saxler@ipt.fraunhofer.de

Contact Information

Fraunhofer Center for Manufacturing Innovation CMI15 Saint Mary’s StreetBrookline, Massachusetts 02446-8200USA www.fhcmi.org

Fraunhofer Institute for Production Technology IPTSteinbachstrasse 1752074 AachenGermanywww.ipt.fraunhofer.de