1

Frank P. Luyten, MD, PhD

Division of Rheumatology, UZ Leuven

Skeletal Biology & Engineering Research Center

Prometheus, KU Leuven, 2015

Engineering for Health: ICT & Nanotechnology

2

CASE: 45 YEAR-OLD PATIENTPRESENTS WITH ARTHRITIS

New Technologies in Patient Care

3

Diagnostic work out…

• Anamnesis: inflammatory

• Clinical examination: synovitis/swelling right knee, discrete swelling both wrists

4

INFECTIOUSINFLAMMATORY (RA, SPA..) CRYSTALARTHROPATHY (GOUT, CPPD)

DD

5

INFECTIOUS ?

• Puncture knee: 20 cc liquid…

– analysis: cell count, cell type, glucose,

– Analysis: microscope: Gram staining, crystals ?

– Cultures…

• Point of need/care ? Minilabs….see JVH

6

DD INFLAMMATORY ARTHRITIS

SF: 12.000 cells, no crystals, no bugs, glucose normal

7

Subacute oligo-arthritis

• DD

– Spondylarthropathy: Psoriatic arthritis, reactive arthritis, IBD associated arthritis

– Rheumatoid arthritis

• Labo: Not really urgent, but reliable: RF, anti CCP

antibodies, CRP, ESR…

• (X-rays)

• Patient files ? – Frequently limited, get access to files over internet

– Access to Xrays and original images: Pacsonweb

8

CHRONIC ARTHRITIS: IDENTIFICATION OF PATIENT AT RISKRESPONSE TO TREATMENT

RF +, Anti CCP +: most probable diagnosis “Early RA”

9

Treatment & Management

• Treatment: precision medicine

– Disease activity: clinical & biochemical parameters

– Prognostic biomarkers

– Genetic profile

• Conclusion: high risk profile, induction/remission….

10

Tight disease management

• Response to treatment: preventing joint damage, stop non efficacious expensive treatments: clinical, biochemical, biomarkers…

• Toxicology: follow up of liver tests, kidney function…

11

Follow up Function

• Activities of Daily Live (ADL), recreational & professional activities

– Subjective: Patient questionaires online

– Objective measures in specific cases (old…): mobility sensors, remote sensing

12

Sensor-based Platform for the Accurate and Remote monitoring of Kine(ma)tics Linked to E-health

(SPARKLE)

IDO KULeuven funded project, 2014-2018

General aims

o Improve assessment of movement-

related functioning in

musculoskeletal diseases and beyondo joint mobility, movement-evoked

pain, motor control, activity capacity

and activity performance, physical

activity

o Innovate patient-centered

management in these diseases

o Develop a human model to study

interactions between disease

processes and mechanical tissue

loading

Consortium: UZLEUVEN, ESAT-MICAS,

ESAT-STADIUS, GROUP-T, FABER,

BIOMECH

13

Smart

algorithms

Novel outcome

measures

Sensor node

Access point

RF

Personal computer

Tablet

Smartphone

Data

logger

and

storage

Wireless Body Area

Network (WBAN)Motion/EMG

Feedback

Patient

Care provider

T. Swinnen

Sensor-based platform for the remote monitoring of kine(ma)tics linked to e-health (SPARKLE)

14

REGENERATIVE MEDICINE

Some years later: 50 year old, heavilydamaged knee….???

15

15

Disease control

Adapt lifestyle

NSAIDS

DMARDS

Biologicals

Regenerative solutions to bridge the gapS

eve

rity

of sym

pto

ms

Time: duration of symptoms

Regeneration Replacement

Joint replacement

Joint revision

GAP

16

The New Frontier: A Biological Joint

Lopa & Madry, TE 2014

17

Extrinsic Repair

• Stem cells: progenitors, embryonic, iPS(induced pluripotent stem cells)

• Combination products: stem cells, growthfactors, smart scaffolds

• Engineered Bioartificial Tissues

18

FROM BENCH TO BEDSIDE

Path of Development

19

Animal models

• Ectopic nude mouse/rat model• Standard in vivo potency assay

• Orthotopic (nude) mouse/rat model• Critical tibial load-bearing defect (5mm)• Integration with host bone

• Orthotopic, load-bearing rabbit model• Large tibial bone defect (2 cm)• 2 types of external fixators• Clinical size, training & process

robustness

• Orthotopic, load-bearing sheep tibial critical size defect & non union model

• Defects of 3-5 cm, young and adult• ‘Patient’ – fit standard of care

20

MANUFACTURING CHALLENGES REQUIRINGTECHNOLOGY DEVELOPMENTS

New Frontier: 3D living implant

21

Fundamental

research

Applied research

(TE)

Industry

Socio-economical reality

University

Market

Focus on application, brigde ‘gap’ Large ‘gap’

Organised valorisation strategy Ad hoc valorisation

Added value KULeuven know-how No focus

Increase succes rate No critical mass

?

PROMETHEUS

Clinical problem

Pre-clinical model

to bridge the gap

Translational Research

22

Enabling technologies

• Microfluidics

• Bioreactors

• Biosensors

• Non invasive imaging

• 3D Bioprinting

• Computational modeling

23

From laboratory to industrial scale expansion

1.8

m

120 flasks T-175 yield 400

million cells. Traditional 2D cell

culture requires routine manual

interventions daily.

A hollow fiber bioreactor, provides a cell

culture surface area, which is equivalent to the

surface area of 120 T-175 flasks. Bioreactor

culture requires a single manual intervention.

“Miniaturization”

24

From 2D to 3D: Bioreactor design evolution

Bioprocess monitoring and control

1st Generation 2nd Generation 3rd Generation

Incubator Incubator Benchtop incubator

25

66 micron 150 micron

Fabrication of 3D microaggregation platform

3-11-2015

26

Mass transport: Oxygen biosensor

3 november 2015 All rights reserved © 2012, KULeuven 26

• Oxygen sensing nanobeads

– Online

– Non-interfering

– Spatial resolution

– Versatile

Alexa Fluor 488 Ruthenium complex

Nile Blue Overlay

1 2

31 2

3

27

Perfusion bioreactor-spatial optimization

*Papantoniou et al. Biotechnol & Bioeng., 2014.

28

Neo-tissue growth modeling

Culture time

• Study interdependence between neo-tissue growth kinetics

and local environment

• Link to process-scale conditions

• Optimize culture protocols

29

NanoCT

QUANTITATIVE:3D image analysis

QUALITATIVE:Virtual 2D histology

+ and / or

Neo-tissue formation in cultured TE constructs

Contrast agents

Hexabrix®

Photo-tungstic acid (PTA)

03/11/2015 29

Contrast-enhanced nanoCT

30

3 november 2015 All rights reserved © 2013, KULeuven 30

Large animal studies: feasibility

31www.kuleuven.be/prometheus

PrometheusDivision of Skeletal Tissue Engineering

32

Acknowledgements

• Skeletal Biology and Engineering Research Center: www.uzleuven.be/rheumatology

• Prometheus:interdisciplinary platform www.kul.be/prometheus

• Stem Cell Institute Leuven (SCIL-Verfaillie): www.kul.be/scil