Short Proposal

1. Cover Sheet
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Boltzmann Biotribology Institute Carinthia
1.1. Name of the Planned Institute (BBIC)

1.2. Coordinator and Applicants

The coordinator and the applicants accept the conditions set out in the guidelines for the
application for Ludwig Boltzmann Institutes and in the corresponding manual. They also accept
their responsibility for the compliance with all relevant legal regulations.

Coordinator

Name Prim. Priv. Doz. Dr. med. Dr. Ing. habil. Matthias Honl
Address St. Veiter Straße 47, 9020 Klagenfurt, AT
Telephone +43 463 538-24550
Email Matthias.Honl@kabeg.at

Date, Signature
14.2.2007

Applicants

Institutional Partner 1 Rush University Medical Center

To be identified, temp. Matthias Honl MD PhD, Vis. Prof. and
Contact Person
Faculty member
Department of Orthopaedic Surgery, 726 Academic Facility,
1653 W. Congress Pkwy., Chicago, IL 60612, US
Department
Tel.: +1 312 942 7128
e-mail: matthias_honl@rush.edu.
Institutional Partner 2 AO Research Institute Davos
Contact Person Prof. Dr. Erich Schneider
Clavadelerstraße 8, 7270 Davos Platz, CH
Department Tel. +41 81 414 24 41
e-mail: erich.schneider@aofoundation.org

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Institutional Partner 3 Paris-Lodron-University of Salzburg
Contact Person Univ.Prof.Mag.Dr. Erich Müller
IFFB Sport- and Science of Motion/ USI
Rifer Schlossallee 49, 5400 Hallein, AT
Department
Tel.: +43 662 8044 4851
e-mail: erich.mueller@sbg.ac.at
Institutional Partner 4 Paracelsus Private University Salzburg
Contact Person Univ.Prof.Dr. Felix Eckstein
Institute for Anatomy and Musculoskeletal Research
Strubergasse 21, 5020 Salzburg, AT
Department
Tel.: +43 662 442002 1240,
e-mail: felix.eckstein@pum.ac.at
Institutional Partner 5 Technical University Hamburg-Harburg
Contact Person Prof.Dr. habil Michael M. Morlock, PhD
Institute for Biomechanics Denickestraße 15, 21073 Hamburg,
DE
Department
Tel. ++49 +40 42878-3053
e-mail: morlock@tuhh.de
Institutional Partner 6 Alpe-Adria University
Contact Person Univ.Prof.Dr. Robert Neumann
Management of cooperative Network
Universitätsstraße 65-67, 9020 Klagenfurt , AT
Department
Tel. ++43 463 2700 4062,
e-mail: robert.neumann@uni-klu.ac.at

For additional Institutional Partners please use the space given below.

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2. Table of Contents

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1. Cover Sheet 1
1.1. Name of the Planned Institute 1
1.2. Coordinator and Applicants 1
2. Table of Contents 3
3. Short Summary (no more than 6 lines) 4
4. Executive Summary (no more than 1 page) 5
5. Profile of the Institute (no more than 6 pages) 6
5.1. Objectives (no more than 2 pages) 6
5.2. Partners (no more than 3 pages) 8
5.3. Size / Location(s) of the Institute (no more than 1 page) 11
6. Research Programme (no more than 10 pages) 12
6.1. State of Research (no more than 1 page) 12
6.2. Research Programme (no more than 7 pages) 13
6.3. Methodological Approach and Theoretical Background (no more than 2 pages) 18
7. Human Resources (no more than 2 pages) 20
8. Management and Organisation (no more than 2 pages) 22
8.1. Organisational Chart 22
8.2. IPR (Intellectual Property Rights) 23
9. Appendix 24
9.1. Costs / Financing 24
9.2. Letters of Intent (LoI) 25
9.3. CV and Track Record of the Key Personnel (no more than 3 pages per person) 25

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3. Short Summary (no more than 6 lines)
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The Boltzmann Biotribology Institute Carinthia will be a centre of excellence in translational
research related to degenerative joint diseases their prophylaxis and treatment. Research
questions will be addressed from the cell level to the in vivo organ level using an integrative
approach by applying existing and novel methods used in cell biology, tribology and in vivo
biomechanics.

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4. Executive Summary (no more than 1 page)
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The mission of the BBIC is to improve mobility and quality of life of those who suffer from
degenerative joint diseases. The overall goal of the Institute is to increase the understanding of
causes and consequences of degenerative joint diseases and establish a synergy between
research and clinical practice in a bench-to-bedside-to-bench approach. The location of the
Institute at the New LKH Klagenfurt, one of the most modern health centres of Europe, will
facilitate the translation of front-line research to the clinic.
The Institute will contribute to the body of traditional orthopaedic knowledge through
engineering practices and investigating new ideas that show potential for improving the physical
capabilities of those who suffer from musculoskeletal ailments. In particular, the Institute will
focus on degenerative joint diseases that may be caused by changes in the biological or
mechanical environment of the cell, tissue and/or joint. Since severe tissue degeneration
requires the replacement of a joint; either with artificial joints or with engineered tissue grafts,
both treatment options are a focus of the Institute. The suggested institute will apply a
combination of biology and engineering approaches spanning scales from the cell to the organ
level. This is needed to further the understanding of causes and consequences of degenerative
joint diseases and other forms of joint damage and to allow for the development of improved
and novel treatment methods for these conditions.

Reflecting these needs, the Institute will consist of three major complementary research pillars:
Cell Biology and Tissue Engineering; Tissue Mechanics and Tribology; In Vivo Joint Mechanics
and its Implication for Prophylaxis and Rehabilitation. The unique environment at the LKH
Klagenfurt will assure interaction between scientists and orthopaedic surgeons and provide
additional resources in other clinical disciplines including rheumatology, immunology, radiology,
endocrinology, pathology and physical therapy. A network of global partners at academic
institutions and in industry will provide knowledge, guidance and support to ensure research
excellence and promote commercialisation of medical products originating at the Institute.
Located in the heart of Europe, the New LKH Klagenfurt is a project of the century that will
establish a premier European health centre. The Department of Orthopaedics and Orthopaedic
Surgery, consisting of 18 consultants, specialized in Joint Replacement, Paediatrics
Orthopaedics, Foot and Ankle Surgery, Shoulder Surgery, Sports Medicine and Spine Surgery
are treating 3,000 in- and 15,000 outpatients per year. The cooperation with the private hospita,
Althofen, increases the total number of orthopaedic patients to 23,000. The LKH houses 25
medical departments chaired by academic persons. The research will be supported by their
knowledge and their equipment (e.g. MRI, CT, Positron Emission Tomography), facilities, and
their human resources.

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5. Profile of the Institute (no more than 6 pages)

5.1. Objectives (no more than 2 pages)

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The objective of the Institute is to provide a research environment spanning multiple
disciplines and scales to further the knowledge and understanding of biological and
biomechanical concerns in orthopaedic surgery by assessing biomechanical function (joint
kinematics and kinetics), joint structure (tissue mechanics of bone and cartilage), and
biological responses (biomarkers) and developing new treatment options. The training of
high quality graduate students and aides in the continuing education of consultants will be
integral part of the Institute.

Pillar 1: Cell Biology and Tissue Engineering

The objective of Pillar 1 is to develop a therapeutic approach at the cell and molecular level
for the preservation, repair and regeneration of the musculoskeletal tissues involved in the
degeneration of the injured and/or diseased joint. While the ultimate goal to prevent the
necessity for artificial implants, adverse tissue reactions following total joint replacement
(TJR) procedures will be another focus of the research program. Biomarkers as diagnostic
and/or efficacy tools will be included.
To avoid the use of an artificial implant, the regeneration of the degenerating tissues should
be guided directly in situ. Different matrices will be used as a delivery system of growth
factors to induce chondrogenesis or osteogenesis and promote local tissue growth.
Progenitor cells will potentially be added as they are known to differentiate into several
specific cell types including cartilage bone and muscle.
Although TJRs are successful in providing pain relief and joint function for patients with end
stage osteoarthritis, wear particles have been demonstrated to be largely involved in the
induction of periprosthetic osteolysis with subsequent failure of the implant. A better
understanding of the molecular mechanisms leading to this adverse biological response and
the control of these mechanisms will allow the preservation of the surrounding tissues and
reduce the implant failure rate.

Pillar 2: Tissue Mechanics and Tribology

The joints of the human body are under constant static and dynamic loading. These forces
are born by all of the tissues of the joint, and henceforth, each of the components of a joint is
specifically adapted for load-bearing. During degenerative processes such as osteoarthritis,
the extrinsic loads on joints are altered but intrinsic changes within the joint structures also
occur that may be associated with disease progression. Following TJR, artificial materials
must sustain these loads and motion while demonstrating minimal wear.
Therefore, the objectives of Pillar 2 are three-fold: (1) to determine the influence of altered
joint kinematics and kinetics as derived from Pillar 3 on natural and artificial joints and (2) to
develop methodologies for the assessment of intrinsic material properties of the natural,

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altered, or regenerated joint tissues, and (3) to develop systematic approaches that optimize
wear and minimize biological complications of orthopaedic interventions by applying physical
principles of friction, wear, and lubrication to natural and artificial joints.
While the primary focus will be directed towards the engineering of articular surfaces of
implant components within their biological environment, we will also apply 'tribological
thinking' to natural tissues in an attempt to better understand the effects of loading and
motion on living structures.

Pillar 3: In Vivo Joint Mechanics and Prophylaxis and Rehabilitation

The objective of Pillar 3 is to contribute to the understanding of in vivo joint mechanics in
healthy individuals and in patients with degenerative joint diseases and other forms of joint
damage and injury and to develop non-invasive treatment modalities for the prevention and
rehabilitation of these conditions. This group will complement efforts of the tissue mechanics
and tribology group by quantifying in vivo loading conditions in patients prior to and following
TJR thereby providing an objective outcome measure for these interventions. We will also
give feedback to both the tissue mechanics and tribology and the cell biology and tissue
engineering groups on in vivo joint loads during daily activities to establish physiological
loading conditions in wear testing settings and in in situ loading conditions.
In vivo joint mechanics describes the motion and loads at the joint level in the healthy subject
and patient during daily activities ranging from locomotion to stair ascending and descending
to squatting. The use of magnetic imaging and musculoskeletal modelling will allow the
estimation of joint contact forces. Novel techniques such as marker-less motion capture will
improve the feasibility of motion analysis as a diagnostic and evaluation tool in clinical
practice. A database of joint mechanics for large groups of healthy subjects and patients will
be established that will provide normative data for the healthy population and for patients
with degenerative joint diseases and other forms of joint damage and injury.
Outcome of in vivo joint rehabilitation methods ranging from surgical methods including
corrective osteotomy and joint replacement to non-invasive interventions such as footwear
modifications, physical therapy and gait retraining will be evaluated. Novel methods for the
prevention and rehabilitation of joint diseases and injuries for specific patient groups such as
ACL-deficient and meniscetomised knee patients or obese patients will be developed.

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5.2. Partners (no more than 3 pages)
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The LKH Klagenfurt is the main hospital in the state Carinthia and one of the largest
hospitals over all of Austria, and the biggest hospital within the KABEG group. It provides first
class medical care to the south of Austria as well as parts of Italy and Slovenia (~78,000
inpatients and 300,000 outpatient treatments p.a.) The 1,500-bed hospital has been
established as an outstanding centre of excellence that houses respected orthopedic
surgeons with a special focus on spinal surgery, joint replacement, sports medicine and
pediatric orthopedics. In order to extend the excellent level of medical care, a concept has
been developed which focuses on implementing one of the most modern health centres of
Europe in Klagenfurt. The new hospital building will be finished 2009 and the sum of
investment is 350 billion €.

The KABEG, with its >7,000 employees, is Carinthia’s biggest healthcare provider. The aim
of the regional hospitals’ operating company is to guarantee a high standard of medical and
nursing care in its five regional hospitals (in total 2,724 beds; 138,000 in- and 552,000
outpatient treatments p.a.). The Institution of Public Law controls, as an incorporated
enterprise, the flow of money due to economic principles and objectives set by the state of
Carinthia. The Supervisory Board of the company consists of fifteen members, including
seven of the Carinthian provincial government (statutory members).

The State of Carinthia: Carinthia, the most southern province of Austria, is with its 9,533
square kilometers the fifth largest federal state of the country. The economical development
of Carinthia is extremely positive, as underlined by the prognoses of the Institute for
Advanced Studies Carinthia (IHS). According to HIS, the gross regional product (BRP) of
Carinthia is going to increase with plus 2.6 percent (2006) in excess of the gross domestic
product (BIP) of Austria.

The Rush University Medical Center, Chicago, US, is an academic medical centre that
encompasses a 613-bed hospital serving adults and children, the 61-bed Johnston R.
Bowman Health Center and Rush University. For nearly 170 years, Rush has been leading
the way in developing innovative and often life-saving treatments. This unique combination of
research and patient care has earned Rush national rankings in 11 specialty areas, as
reported in U.S.News & World Report’s 2006 “America’s Best Hospitals” issue. Ranked
among the very best orthopaedic programs in the country by U.S.News & World Report,
Rush is home to nationally respected orthopaedic surgeons who find great reward in the fact
that their research, discoveries and leading-edge therapies benefit patients .

The AO Research Institute was established as a non-profit institution by the founding

members of the Association for the Study of Internal Fixation (AO , Arbeitsgemeinschaft für
Osteosynthesefragen) in the 1950s. It is one of the leading research institutes in the field of
orthopedic surgery in Europe. The Mission of the AO Research Institute (ARI) is to contribute

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to the general scientific body of knowledge in the area of trauma and the diseased musculo-
skeletal system, to investigate the performance of surgical procedures and devices to
improve patient treatment, and to render services in the above areas to recipients within and
outside the AO Foundation. New focus areas are found in the fields of polymeric and
inorganic bone substitute materials, in fracture fixation of the osteoporotic patient, or in the
enhancement of bone defect regeneration using a combined approach in which conventional
load-bearing fixation devices are supplemented by biodegradable scaffolds, and
osteodynamic substances.

EndoLab GmbH offers a variety of technological services to develop and certify medical
products. The company is a spin-off from the Technical University of Munich and is closely
connected to several national and international research departments. The scope of
available implant tests is divided into anatomically orientated groups of application. The hip
implant section includes wear tests using a ISO hip joint simulator and multiple ISO and
ASTM tests to determine the fatigue properties of stemmed femoral components, acetabular
cups and balls. Screening tests for new implant materials are also available. The spine
implant section covers the demands of a fast growing medical market by new designed test
procedures.

DePuy designs, manufactures and distributes orthopaedic devices and supplies including
hip, knee, extremity, trauma, orthobiologics, and operating room products.
Acquired by Johnson & Johnson in 1998, DePuy is part of the Johnson & Johnson Medical
Devices & Diagnostics group. The company develops and markets products under the
Codman, DePuy Mitek, DePuy Orthopaedics and DePuy Spine brands. DePuy Orthopaedics
designs, manufactures, markets and distributes products for reconstructing damaged or
diseased joints and for repairing and reconstructing traumatic skeletal injuries. DePuy Mitek
products offer innovative devices in sports medicine for the treatment of soft tissue injuries.

Biomet, Inc. and its subsidiaries design, manufacture and market products used primarily by
musculoskeletal medical specialists in both surgical and non-surgical therapy. The
Company’s product portfolio encompasses reconstructive devices, including orthopaedic joint
replacement devices, bone cements and accessories, autologous therapies and dental
reconstructive devices; fixation products, including electrical bone growth stimulators, internal
and external orthopedic fixation devices, craniomaxillofacial implants and bone substitute
materials; spinal products, including spinal stimulation devices, spinal hardware and
orthobiologics; and other products, such as arthroscopy and softgoods and bracing products.

The Technical University Hamburg Harburg (TUHH) is one of the youngest universities in
Germany as well as one of the most successful. Between 1982 and today an attractive
architectural ensemble was created on the TUHH campus in the south of Hamburg.
Research work started in 1980 and in 1982/83 lecturing followed. Today around 100 senior
lecturers/professors and 1,150 members of staff (450 scientists, including externally funded
researchers) work at the TUHH. The Biomechanics Section was founded in 1991. The main

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purpose of the centre is to promote interdisciplinary research of engineering, biological and
medical sciences in the field of biomechanics of the musculo-skeletal system. Research
activities are present in several areas: Artificial Joint Replacement, Tissue Engineering,
Interaction between Implant and Bone, Endovascular Prostheses, Spine Biomechanics, and
Biomechanics of the Human Locomotors System.

The Paracelsus Private Medical University received accreditation in November of 2002

through an internationally staffed accreditation committee. Subsequently, studies at the
Paracelsus Private Medical University began in September of 2003. Thus, this university is
Austria's first and Europe's second private medical school which offers studies in human
medicine. The renowned Mayo Medical School (Minnesota, USA) serves Paracelsus
University's model as well as partner university. The Mayo Medical School is part of the
Mayo Clinic, the largest private non-profit clinic in the United States.

The Department of Sport Science and Kinesiology at Paris-Lodron University of Salzburg,

Salzburg, has become one of the leading working groups in the area of biomechanics of
human performance in Europe. The special strength of this group lies in the development of
complex biomechanical systems for analysing human movement and joint loading during
various sports activities in the field. A special focus has been put on research in winter sport
activities. In 2004 the Austrian Christian Doppler Research Foundation has installed the
Christian Doppler Laboratory “Biomechanics in Skiing” at the department of Sport Science
and Kinesiology, which is funded with € 500.000 per year for a period of seven years.

Established in 1975, the Humanomed Center Althofen consisting of the Private Clinic
Althofen, the Orthopaedic Rehabilitation Center, the Metabolic- and Cardiovascular
Rehabilitation and a spa hotel. In total about 650 beds and over 500 employees and is
treating more than 14,000 patients a year. Key areas of the private hospital activity are
orthopaedics & orthopaedic surgery with a special focus knee, hip and shoulder as well as
neurosurgery and a spine surgery and ALTIS sports surgery and sports medicine. Since
1995, a public-private partnership between the LKH Klagenfurt (distance 18km) and the
Private Clinic Althofen is providing the highest level of care for postoperative and non-
surgical orthopaedic patients.

The Alpen-Adria-University Klagenfurt has been future oriented and dynamic from the day
it was founded. Today it is Carinthia’s leading educational and research institution. It opens
its doors to the whole world and thrives on interculturality and people whose minds know no
boundaries. Biztec is the interface between enterprises and the university for the
development and implementation of modern business technologies, methods and
management concepts. In a close cooperation with enterprises and research partners, we
develop modern business technologies, methods, and management concepts (e.g.
Knowledge Management, Network Management) and implement them according to the
special requirements of the involved organisations, institutions and partners.

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5.3. Size / Location(s) of the Institute (no more than 1 page)
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The BIC occupies approximately 260 m² of laboratory space and additional 100m² office
spaces and gait lab space on the same floor. In conjunction with the Sections of the
Department of Orthopaedic Surgery it will be located directly connected to the new hospital.
Additional laboratory space, cold and dark rooms, a tissue preparation room, will be provided
by the Department of Pathology.

Orthop. Surg.
BBIC

The Research Center is located in a shut down infirmary of the Orthopaedic Department, so
infrastructure is still functional and therefore immediate start of the research process is
guaranteed.

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6. Research Programme (no more than 10 pages)

6.1. State of Research (no more than 1 page)

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Osteoarthritis (OA) or other forms of joint damage are responsible for major health care
expenditures and disability burdens. It is one of the most prevalent chronic conditions and is
a leading cause of disability in Europe, Australia, Canada, and the United States.
Osteoarthritis is affecting an estimated 103 million across Europe, 3 million Australians, 6
million Canadians, and almost 43 million people in the US. With the aging of the baby
boomers, these numbers and the associated disabilities will quickly escalate. Projected data
exist for the US and it has been estimated that by 2020 arthritis will affect 60 million people,
and the activities of 12 million people may be limited by arthritis. Hence, primary TJR
projected climb is to 750,000 operations annually, while at the same time revision rates will
raise to 20%. The latter is related to a steady decrease of the patient’s age at the onset of
the disease as well as a longer life expectancy. Wear particles have been demonstrated to
be largely involved in the induction of periprosthetic osteolysis the primary reason for failure.
Wear reduction of implant materials as well as improved biocompatibility are therefore
important. This should increase the durability of TJR. Further, alternative treatment strategies
which delay and/or prevent TJR are warranted.
The pressures on and in cartilage are the manifestation of the applied load in the
environment of the cartilage matrix. Pressure and pressure-time cycling thus appear to be
"critically important for the maintenance of cartilage". As a result, the pressure cartilage
experiences appears central to the etiology of osteoarthritis, acting either directly, e.g.,
collagen fiber rupture or through mechanical/biological coupling, e.g., the influence of the
mechanical microenvironment on chondrocyte metabolism.

In order to provide well targeted solutions facilitating tissue regeneration (for example
through tissue engineering) an exact understanding of the interplay between biomechanics
and biology from the cell to the joint level is necessary. The role of joint mechanics in the
initiation and progression of knee osteoarthritis (OA) is well established. Existing
interventions including tibial osteotomy and footwear modifications have been shown to be
effective in altering the load distribution at the knee and to slow the rate of progression of
OA. Similarly, highly invasive joint replacements are able to restore function of severely
degenerated joints and recreate mechanical loading conditions close to normal thereby
substantially improving a patient’s mobility and quality of life. Early intervention will be the
key in the prevention of disastrous cartilage breakdown. Measurement of serum biomarkers
have been shown to have prognostic value in OA. Longitudinally detectable changes in
biomarker levels in blood develop as early as 10 days after a knee injury, long before bone or
cartilage changes are detectable by conventional approaches. On the cell level it has been
shown that chondrocytes remodel their matrix throughout life, and respond to biomechanical
stimuli by altering the biosynthesis and catabolism of matrix components.

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6.2. Research Programme (no more than 7 pages)
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The research programme of the Institute will consist of a number of projects in each of the
three pillars. While each pillar stands for a particular program and represents resources and
know-how unique to the field of research, specific projects are set up independently of this
structural organisation. In fact, they will be laterally interwoven drawing resources from all
three pillars. This guarantees that information can be easily shared among the three pillars
and facilitates maximum collaboration between the team members of traditionally relatively
independent acting research entities. Our group strongly believes that considerable progress
in the treatment of degenerative joint disease will only be possible using an interdisciplinary
approach. This requires the integration of information from medicine, biology, biochemistry,
biomechanics, and traditional engineering concepts. The specific set-up of the research
program allows such an approach. For example, in the Cell Biology & Tissue Engineering
pillar methodologies from tribology (Pillar 2) and mathematical modelling (Pillar 3) are used.
In the following, project areas are described. Specific projects will be outlined in the full
application.

Cell Biology and Tissue Engineering

Project area 1.1: The goal of project area 1.1 is to identify the influence of compression and
articular motion on cartilage homeostasis, as fundamentals for future tissue regeneration
studies. We will address the contributions of dynamic loading, articular motion and kinematic
and kinetic loading parameters in the presence of growth factors and other mediators on
gene expression, cell stimulation and metabolism. Analysis will include measurements of
cell viability and function as well as gene expression of matrix components and histological
analyses. Thus, we contend that basic knowledge about the effect of various mechanical
stimuli (compressive load, shear load, articular fluid transport) on the cell metabolism of
cartilage will be accumulated which will have an immediate impact on cartilage homeostasis.
Several specific questions will be addressed, e.g.

• What is the relative contribution of dynamic loading with respect to cell viability and
gene expression?
• What is the specific contribution of articular motion (versus simple compressive
loading)? Do contact zone kinematic profiles matter?
• What is the specific role of growth factors in the presence of external loads?

During the course of this project basic knowledge about the effect of various mechanical
stimuli (compressive load, shear load, articular fluid transport) in the presence of growth
factors on the cell metabolism of cartilage will be accumulated which will be utilized for other
research endeavours of cartilage repair; for example, functional tissue-engineering.

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Project area 1.2: Tissue engineering involves the use of cells, scaffolds, and/or regulators to
grow functional tissue ex vivo. The regulators have traditionally been growth factors, but for
the development of load-bearing tissues such as articular cartilage, mechanical factors may
also play an important role and are therefore considered in this proposal.
One goal of project area 1.2 is to identify suitable matrices that can be used as a delivery
system of growth factors. These are thought to induce chondrogenesis or osteogenesis and
promote local tissue growth. Candidate materials must be biocompatible and accommodate
cell adhesion, proliferation, and matrix synthesis. In the past, various growth factors (i.e.
fibroblast growth factor-2, transforming growth factor-β, insulin-like growth factor-1, and
osteoprogenitor factor-1) have been used to modulate chondrocyte phenotype, proliferation,
and biosynthesis rates.
Another goal is the identification of the most appropriate cell-scaffold constructs. Here we
will try to work with mesenchymal stem cells which can be derived from the bone marrow
stroma. It has been shown that these can differentiate into chondrocytic cells in vivo;
however, the in vitro differentiation process of MSC into chondrocytes is not yet fully
controllable and will be the focus of our research. Besides the use of growth factors,
considerable evidence suggests that the mechanical environment can influence
chondrogenesis.

Project area 1.3: The goal of this project area is to identify the molecular pathways leading to
wear-particle induced osteolysis following a TJR. Although macrophages are a key cell
initiator of a cascade of events that finally leads to osteolysis, other cells, such as
osteoblasts, osteoclasts or fibroblasts, also play a role in periprosthetic osteolysis. For
example, it has been reported that particles directly stimulate fibroblasts to release high
levels of collagenease and stromelysin, which can degrade the organic components of bone.
Also, the ability of osteoblasts to synthesize collagen and make bone seems to be
compromised when these cells are exposed to particles.
Previous studies proposed models for periprosthetic osteolysis in which wear particles are
phagocytosed by macrophages, resulting in the activation of nuclear transcription factor-
kappaB and the production of TNF-α, which induces fibroblast proliferation and tissue fibrosis
and recruits and/or activates osteoclasts to resorb adjacent bone. Other studies suggest that
particle-induced macrophage release of TNF-α and IL-6 does not require phagocytosis but is
dependent on tyrosine and serine/threonine kinase activity. Finally, other mechanisms have
also been proposed as mediators of aseptic loosening, such as micro motion of implants that
did not achieve adequate initial fixation or elevated hydrodynamic pressure produced by high
fluid pressures surrounding the migrating prosthesis. However, the progression from the
stage of early migration of the implant to clinical loosening has still unknown causes, of which
particles may be one.
Ongoing work in the field of signaling pathways leading to periprosthetic osteolysis will
continue to advance our understanding of the mechanisms of periprosthetic bone loss and
allow us to define potential targets for therapeutic intervention.

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Tissue Mechanics and Tribology

Project area 2.1 focuses on natural tissues. In order to support pillar 1, mechanical field
values which influence the biological response of tissues and tissue engineered constructs
need to be determined. The goal of this project area is therefore to identify novel approaches
that allow the characterization of the necessary mechanical field parameters. We will
facilitate this task through the integration of numerical modelling (finite element approach)
into experimental testing. The construction and consecutive improvement of computer
programs of articular cartilage and cell-seeded scaffolds will allow us to characterise the
constitutive behaviour of matrix-cell composites. This in turn is important to identify the most
appropriate mechanical stimulation protocol for tissue engineered constructs (Pillar 1) or to
provide recommendations for rehabilitation protocols for injured or diseased joints (Pillar 3).
A mixed media multilevel finite element approach with bimodular anisotropic nonlinear elastic
or viscoelastic solid content will be used. Constitutive parameters governing the numerical
model will be determined from the experiments. Conformation of numerically calculated
mechanical fields (stress, strain, pressure gradients as a measure for fluid flow, etc.) will be
matched with spatial patterns of biochemical or biological quantities.

Project area 2.2 focuses research projects related to cartilage tribology. Tribology has been
defined as the science of interacting surfaces during motion and comprises the areas of
wear, friction and lubrication. The goal of the project area is the identification and critical
evaluation of artificial materials which are suitable to articulate against cartilage.
Specific projects will include the development of wear tests and wear outcome parameters;
thereby, using altered and normal loading conditions as identified in Pillar 3. An environment
closer to in situ of the natural cartilage is likely to alter the tribological system characteristics
and may provide more accurate and insightful results. We hope that this will be helpful to
screen new materials for cartilage friendly repair in vitro successfully.

Project area 2.3 will take a system approach to improve and better understand the
tribological stresses at artificial joints. The goal of this project area will be to identify important
system parameters which govern the wear of artificial joints. The specific aims will include
the development of wear resistant materials which behave less inflammatory due to reduced
wear rates and a more biocompatible release of wear particles. The biologic answer of
generated wear particles will be tested in Pillar 1.
In order to address these tasks, various steps in joint simulation will be taken. Starting from
pin-on-disk devices to specific joint simulation apparati, which model the full complexity of the
particular joint, the acting wear mechanisms will be identified. This allows a targeted
approach to adjust the material properties of the articulating bodies in contact, so that the
material loss is minimized.

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In Vivo Joint Mechanics and Prophylaxis
Project Area 3.1: A number of interventions are currently used to treat osteoarthritis. The
type of interventions mostly depends on the severity of the disease where non-invasive
methods are usually favoured in mild cases, and severe cases warrant surgical interventions
such as corrective osteotomy or TJR. However, non-invasive interventions such as bracing,
footwear modifications or physical therapy programmes often have poor patient compliance,
and the life-time of surgical intervention such as TJR is limited. Therefore, the goal of this
project area is to improve existing interventions and develop novel interventions for the
prevention and rehabilitation of degenerative joint diseases. We will develop a
musculoskeletal model to determine joint contact forces in healthy subjects and in patient
populations.
The musculoskeletal model will allow the estimation:

• of joint contact forces in healthy subjects and in patient populations

• of joint contact forces with different prevention and rehabilitation interventions at the
primary joint
• of joint contact forces at secondary joints thereby evaluating the consequences of
interventions

Project area 3.1 will provide normative and individual subject and patient data for projects in
Pillar 2.

Project Area 3.2 will focus on the functional outcome of existing and novel interventions for
the prevention and rehabilitation of degenerative joint diseases through experimental
evaluation. Some interventions for degenerative joint disease are effective only for some
patients. To date, the reason for this outcome difference is not well understood. In this
project area, we will quantify joint loading pre- and post-intervention to objectively measure
the outcome of interventions. Specifically, we will address the following questions:

• Can we identify patient groups who will most likely benefit from the treatment with a
specific intervention?
• What is the short-term, medium-term and long-term effectiveness of these
interventions?
• Can existing designs be improved?

What are the requirements for novel interventions?

Project area 3.2 will provide feedback on the effectiveness of specific interventions to Pillar 2,
and intervention designs will be improved accordingly.

Project Area 3.3 will deal with identifying risk factors for the development of degenerative
joint disease and investigate why these factors contribute to the development of the disease.
For instance, obesity is the main single risk factor for the initiation of knee osteoarthritis at a

Ausschreibung 2006 16
young age. Yet, it is unclear whether the main contributors for this relationship are
mechanical or biological in nature. For instance, joint mechanics in an obese person is not
well understood, and it has recently been shown that joint kinematics in obese persons differ
from those of a normal-weight person. Clearly, joint loading plays a critical role in the
development of the disease. The goal of this project area is to identify risk factors for
‘abnormal joint loading and subsequent development of degenerative joint diseases.
A database of imaging, kinematic, and kinetic data as well as life style and physical
functioning data and blood samples will be established for healthy subjects. This database
will form the basis for prospective studies by allowing the extraction of pre-injury or pre-
disease characteristics for different patient populations. Information originating from this
project area will be critical for the development of prevention interventions.
Project area 3.3 will provide information on cytokine and enzyme concentrations in
populations at risk for developing degenerative joint diseases. This information will be utilized
by Pillar 1 where the effect of elevated or diminished concentrations of specific proteins and
peptides on cell metabolism and gene expression will be evaluated.

The central paradigm of skeletal mechanobiology is that mechanical forces modulate

morphological and structural fitness of the skeletal tissues-bone, cartilage, ligament and
tendon. In modern mechanobiology the central question is how these same load-bearing
tissues are produced, maintained, and adapted by cells as an active response to biophysical
stimuli in their environment. In a human joint, the stimuli, but as well the destroying factors
are load, motion, friction, lubrication and finally wear. Both artificial and natural joints are
underlying these factors, which justifies applying our knowledge to artificial and biological
joint replacement strategies. Our collaborators will make it possible to simulate and apply the
physical principles and the performance of implants, tissue transplant surgical procedures
rehabilitation- and prevention programmes; in order, to achieve the objectives of our
institution.

Ausschreibung 2006 17
 Variation in Mechanics
or Kind of Activity
Load and Motion within
Joints
(Rush University)

Orthopedic Departments
LKH and Althofen
Load and Motion of
Variation to wear or Articular Surfaces
damag damage (Motion Analysis, Erich
Cell Biology and Tissue Mueller)
Engineering

Tissue Mechanics and

Tribology

Joint and Cartilage In vivo Joint Mechanics

Mechanobiology
Cell metabolism, response
to mechanical stimuli
(Tissue Lab, Erich
Schneider)
and Rehabiltation
Variation of Joint
Mechanics
And Joint Lubrication
(Modelling and Mechanical
Testing Michael Morlock)

Joint Replacement
Wear
In vivo cartilage
morphology
(Quantiative MRI Felix
Eckstein)

Figure: Scientific partners’ involvement.

Ausschreibung 2006 18
6.3. Methodological Approach and Theoretical Background (no more
than 2 pages)
Hilfe
Cell Biology and Tissue Engineering

A common struggle of in vitro cartilage studies is the maintenance of a viable (i.e. alive)
tissue state over time. In order to keep the chondrocytes within the cartilage alive and
metabolically active, a precise replication of in vivo conditions regarding temperature, CO2
and humidity, and load is warranted. An environment closer to in situ of the natural cartilage
is likely to alter the tribological system characteristics and may provide more accurate and
insightful results. Therefore, a novel 4-station simulator will be used to closely simulate the
movements and loading characteristics of natural joints. The new system provides joint
specific biomechanical stimuli and has been used already for various studies related to tissue
engineering and metabolic changes of articular cartilage.
Assays will include cell survival and histological assessments, metabolic activities by
radiolabelling techniques, proteoglycan accumulation, and release determination,
immunohistochemistry to assess matrix proteins and cytokines of interest. The release of
matrix fragments and cytokines into the media will be checked as well. Furthermore,
cytokines, MMPs, and aggrecanases could be determined using Western blotting and ELISA
techniques if it becomes necessary.
Like cartilage, bone provides mechanical support during posture and ambulation, and bone
alterations represent a sine qua non of OA. The subchondral bone of OA joints appears to
have increased BMD relative to unaffected normals and to exhibit altered metabolic activity
early in the disease course. Therefore, bone will be included into the analysis and structural
changes may be accessed with micro-CT.
Regarding artificial materials the effect of wear particles and possible treatment interventions
will be studied using tissue cultures.

Tissue Mechanics and Tribology

The wear and failure of TJR components is a function of relative motion and load. The
relative motion and load depend on factors such as the type of activity performed, the
frequency and duration of activities, the individual gait pattern and the geometric boundary
conditions of the implant. Currently, there is a large discrepancy between the damage
patterns of simulator tested and retrieved components.
To better understand the wear mechanisms and subsequent failure of natural cartilage and
TJR components, joint mechanics as determined in Pillar 3 will be applied. The various
testing apparati in use will be capable in simulating such dynamic conditions. Experimental
testing will be supplemented by numerical analyses. Evaluation of results will include
histological, immunohistochemical and ELISA techniques for natural tissues, as well as

Ausschreibung 2006 19
microstructural analyses of artificial materials using light- and electron microscopy
techniques. Wear particles will be characterized regarding size, shape and composition.
Tissue properties of healthy and altered tissues will be obtained through a combined
approach of experimental material testing and numerical analyses (finite element methods).
Novel tools like the characterization of local in-plane displacements determined by gray-scale
correlation of two consecutive video frames will be utilized to determine spatial strain
conditions.

In Vivo Joint Mechanics and Rehabilitation

Resultant joint moments and joint forces will be quantified using established techniques. In
particular, the point cluster technique, high-speed infrared cameras, a force plate and
pressure insoles will be used in combination with anatomical models and an inverse
dynamics approach to compute resultant joint moments and forces at the major joints of the
human body. Magnetic resonance imaging will be used to obtain subject and patient specific
joint geometries. Established segmentation approaches will be used to gain detailed
information on bone and soft tissue geometry and lines of action of major muscles of the
human body. Muscle forces of the major muscles of the human body will be estimated using
surface electromyography and geometric information of lever arms from imaging data and a
Hill-type muscle model. Resultant joint moments and forces, joint geometry and estimated
muscle forces will be used as input into a full body musculoskeletal model to estimate joint
contact forces in the major joints of the human body.
The establishment of a large database for prospective studies requires data collection with
high through-puts. A novel technique for markerless motion capture will be used to collect
kinematic and kinetic data to be entered into the database. This technique reduces the time
for data collection to approximately 10 to 15 minutes per subject or patient.
Serum samples will be collected, frozen and stored for future analysis. Cytokine and enzyme
concentrations will be quantified using commercial ELISA kits.

Ausschreibung 2006 20
7. Human Resources (no more than 2 pages)
Hilfe
The integration of the partner organizations is warranted by the Institute of Business
Technologies (BizTech) of the Alpe-Adria University of Klagenfurt and the business
administrator, who will be part of the team from the early beginning. The challenge is the
coordination of the knowledge intensive network.

Start-up phase(1st year)

Goal: Constitution of the Institute, Infrastructure, first short time projects and publications,
presentation of the Institute on scientific basis, management of knowledge between partners,
and making contacts generally

Markus Wimmer, Dr. Ing. - Director, 100% Time on BBIC

Matthias Honl, Prim. PD Dr. med Dr. Ing. - Clinical Director, 20% Time on BBIC (*u. b.)
Georg Lajtai , Prim . Univ. Doz. Dr. med. - Key Researcher, 15% Time on BBIC (*u. b.)
Bernd Graf, Prim. Dr. med. - Key Researcher, 5% Time on BBIC (*u. b.)
Karsten Schwieger, Dr. Ing.- Group Leader and Key Researcher, 100% Time on BBIC
NN, Business Administrator , 100% Time on BBIC
Josef Schwarz, Directors Assistant, 20% Time on BBIC
NN, Secretary, 80% Time on BBIC
NN, Biostatistician, 10% Time on BBIC
Thomas Kruppa, Dr. med., Postdoc, 30% Time on BBIC (*u. b.)
Stefan Schauss, Dr. med., Postdoc, 30% Time on BBIC (*u. b.)
NN, Technician, 100% Time on BBIC
NN, Technician, 100% Time on BBIC

(* u. b. = unsalaried basis)

Consolidation phase (2nd year)

Goal: Development of Human Resources and infrastructure of laboratories, long-term

projects in collaboration with strategic partners, development of the knowledge network
between the LBI and the regional and international partners. Periodical meetings of the
partners to reflect and coordinate the research status will be organised.
Personnel added:
Anne Mündermann, PhD - Group Leader and Key Researcher, 100% Time on BBIC
Lars Mündermann, PhD – Key Researcher, 100% Time on BBIC
Candidate identified, PHD - Group Leader and Key Researcher, 100% Time on BBIC

Ausschreibung 2006 21
NN, PhD Candidate, Junior Researcher, 100% Time on BBIC
NN, PhD Candidate, Junior Researcher, 100% Time on BBIC
NN, Postdoc, Researcher, 100% Time on BBIC
NN, Postdoc, Researcher, 100% Time on BBIC

Full performance phase (3rd year)

With the beginning of the third year 16 full time employees should be working within three
cross-linked laboratories
NN, PhD Candidate, Junior Researcher, 100% Time on BBIC
NN, PhD Candidate, Junior Researcher, 100% Time on BBIC
NN, PhD Candidate, Junior Researcher, 100% Time on BBIC
NN, Technician, 80% Time on BBIC

The human resource development of the Institute will be indicated as a three-column-model:

Key Researcher: intensive exchange of knowledge within the cooperative network guided by
professional knowledge networking and management, buildup and development of ideal
working conditions for key research items and periodical exchange and reflection of
experiences and results of research.
Junior Researcher: further education in setting up, performing, analyzing and presenting of
scientific projects aided by the key researchers, theoretical seminars and periodical visits of
scientific meetings, education in the capacity of managing of research institutions and
acquisition of correct behavior within knowledge dominated networks.
Column combination of research and clinics: the education in use of research results in the
clinical everyday life is warranted by the close connection of the research area to the clinical
center and presents a focal point in developing our personnel.

Ausschreibung 2006 22
8. Management and Organisation (no more than 2 pages)

8.1. Organisational Chart

Ausschreibung 2006 23
8.2. IPR (Intellectual Property Rights)
Hilfe
In order to appropriate adequatelly the results, the proposer is responsible for managing all
intellectual property rights that result from the research activity of the institute. These rights
include especially patents, designs, copyrights as well as trademarks and may concern
orthopaedic implants and materials, technical test procedures as well as scientific knowledge.
Where knowledge is capable of industrial or commercial application, it must be protected.
Intellectual Property protection is not mandatory in all cases, though the decision to not
protect knowledge must be made in consultation with the other contractors.
The proposer will inform his partners about these conditions. If the proposer assesses it
necessary a contract stating the aforementioned conditions will be concluded.
IPR joint ownership arises in two specific cases:
Where two or more contractors have jointly carried out work generating the knowledge, and
their respective share of the work cannot be ascertained and, in the BBIC-specific
cooperative or collective research actions.
Joint owners have to agree among themselves on the allocation and the terms of exercising
the ownership of the knowledge. As far as allocation is concerned, the joint owners may
agree, for instance, that patent applications will be filed and maintained by only one of them
(possibly subject to appropriate licensing rules or other provisions). The shares of any
revenues should be defined clearly in an agreement between the relevant parties (either in
the consortium agreement or in a separate agreement) if they are not to be divided equally.

The proposer will instruct the BBIC Business Administrator to take the necessary measures
with specialised IP law firms in order to register any possible IP rights with respect to the
research activity. The proposer will inform Ludwig Boltzmann Gesellschaft about any
successfully registered IP rights related to the research activity.

With the permission of the proposer, the acquired IP rights should be licensed to one or more
industrial companies (KABEG LKH Klagenfurt, Biomet, Depuy, Endolab etc.). Each of these
relationships will be stipulated in individual license contracts. The content of those contracts
will be drafted in cooperation with specialized IP law firms. The goal is to allow the industrial
partners a real rate of return of their investments into the BBIC research programme.
In conclusion proposer's IPR strategy is adequate to fully appropriate the research results.
Moreover, the distribution of roles between the proposer and his partners is suitable to limit
the risk of any conflicts to a minimum.

Ausschreibung 2006 24
9. Appendix
Please do not copy Costs / Financing-Sheets, LoIs or CVs into this word document; use this
form only for additional comments.

9.1. Costs / Financing

Hilfe

Ausschreibung 2006 25
9.2. Letters of Intent (LoI)
Hilfe
Biomet, Depuy, Humanomed, Kabeg, Klagenfurt University, Salzburg University, PMU, State
of Carinthia
Rush University: To protect Dr. Wimmers directors position we did not request the letter from
a Chairman or CEO so far.

9.3. CV and Track Record of the Key Personnel (no more than 3 pages
per person)
Hilfe
• Felix Eckstein
• Bernd Graf
• Matthias Honl
• Thomas Kruppa
• Georg Lajtai
• Michael Morlock
• Erich Müller
• Anne Mündermann
• Lars Mündermann
• Bella Mustermann Tissue expert female, currently anonymous because of employer
• Stefan Schauss
• Erich Schneider
• Karsten Schwieger
• Markus Wimmer

Ausschreibung 2006 26
Ausschreibung 2006 27