View presentation from Professor John Fisher

Institute of Medical &
Biological Engineering
Biological Scaffolds for Tissue Repair
From Research Laboratory to Clinical Product
Eileen Ingham,
Professor of Medical Immunology
and
John Fisher CBE, FREng, FMedSci
Director Institute of Medical and Biological Engineering
University of Leeds
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Engineering ‘50 active years after 50’ through multi-disciplinary
research, innovation, knowledge creation and translation.

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HEALTHCARE COMPLIANCE: PORTFOLIO OF INTERESTS AND DISCLOSURES
Research funding and support
EPSRC, MRC, BBSRC, TSB, Wellcome Trust, ARUK, ORUK, ERC EU, NIH, NIHR,
DePuy Synthes, Invibio, JRI, Ceramtec, Mathys, Corin, Vascutek, Tissue Regenix, NHSBT
Director of institute of Medical and Biological Engineering
Director of WELMEC - Centre for Excellence in Medical Engineering
Director of IKC - Innovation and Knowledge Centre in Medical Technologies
Director of RegeNer8, Centre for Translational Regenerative Therapies
Director of EPSRC Doctoral Training Centre for Tissue Engineering and Regenerative Medicine
Co Director LMBRU - Leeds Musculoskeletal Biomedical Research Unit
Co Director OETC Osteoarthritis Experimental Treatment Centre
Consultant to DePuy International
Consultant to Invibio Biomaterials
Consultant to Tissue Regenix
Director of Marketing Leeds
EPSRC Council Member

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THREE ELEMENTS OF TISSUE REGENERATION
Stem Cells
Scaffolds and
Architecture
Molecular Drivers
to Stimulate Cells
Biological Scaffolds for Tissue Repair
which recruit patients own stem cells
Translated as Class 3 device which recruits patients own stem cells
Costs ten times less than an advanced medical product or cell therapy

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• Fifty active years after fifty - active ageing population
• Musculoskeletal and cardiovascular system
• Degeneration from early middle age
• Increased functionality – active ageing
• Degeneration OA
• Diabetes vascular disease
CLINICAL AND MARKET NEEDS
• Require functional (biomechanical) scaffold
• Markets growing globally - 35% per annum in Asia
• Medtech is 27% of manufacturing GDP in Singapore
• Global need for reduction in unit cost of healthcare
• Ten percent of population will need a repair or replacement
at some point during their life times

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FUNCTIONAL BIOLOGICAL SCAFFOLDS: THE CONCEPT
Source material matches
tissue requiring repair
or replacement
dCELL
process
removes
cells/DNA
Biological
Scaffold
Regenerates
and repairs
with patients
own
stem cells
0.1 mm
Scaffold source
is
human tissue
or
animal tissue
Blue stained cells
Cells cause rejection
of tissue when
transplanted
“immunogenic”
Red/Pink stained scaffold
Mainly collagen /elastin
Not immunogenic
Tissue physical properties

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CHARACTERISTICS OF FUNCTIONAL BIOLOGICAL SCAFFOLDS
• Provide a biologically and immunologically compatible environment for
tissue repair - attract and support tissue regeneration, through patients
own cells, An acellular therapy
• Provide low cost regenerative solutions by recruiting patients own cells
• Replicate tissue specific multi-scale structure and architecture and multiscale
biomechanical function and biocompatibility
• Convert macro-scale forces and stresses to appropriate micro cell level
strains, that stimulate appropriate cell differentiation pathways and tissue
regeneration

Force/Width (N/m)
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MULTI SCALE TISSUE SPECIFIC BIOMECHANICAL BIOCOMPATIBILITY
Micro-scale scaffold structure & architecture determines cell strain and function-
Macro
forces and
biomechanics
Scaffold architecture and structure
determines
Micro scale -local cell - strain field
Drives
scaffold - cell
strain / interactions
Model
anisotropic
scaffold
160
120
80
40
Fixed Aortic
Fixed Pulmonary
Fresh Aortic
0
0 5 10 15 20 25 30 35 40
Strain (%)
Each tissue has its
own unique
scaffold
architecture
Micro-scale strain
drives cell
differentiation

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dCELL BIOLOGICAL SCAFFOLD BIOPROCESS
‣ Start with animal/ human tissue to be replaced
‣ Remove cells and immunogenic components
‣ Retain extracellular matrix structure and histioarchitecture
‣ Retain biomechanical properties and function
‣ Regenerate in vivo with recipients endogenous cells
Based on hypothesis that tissue specific scaffold architecture will
generate micro-biomechanical stimuli to drive appropriate cell function

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BIO- PROCESS RESEARCH CAPABILITIES AND TRANSLATION
10mM Tris hypotonic buffer pH 8.0
Aprotinin and EDTA 24h 4 o C
0.1% SDS in hypotonic buffer
Aprotinin and EDTA 24h RT
PBS + Aprotinin 24h 4 o C
DNAse and RNase 3h 37 o C
PBS + Aprotinin and EDTA 24h 4 o C
Sterilisation peracetic acid 0.1% 3h
Tissue Characterisation
Decellularisation
Histology
Biochemistry
Immunocytochemistry
Biomechanics
In vitro biocompatibility
In vivo biocompatibility [mice]
Pre-Clinical in vitro testing
Large animal functional model
Clinical trials
Product
Translation partners NHSBT and Tissue Regenix PLC

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NEW TECHNOLOGIES - NEW SIMULATIONS AND PRE-CLINICAL TESTING
A new purpose built whole joint tribological and biomechanical simulator for
the natural knee and regenerative interventions
In vitro simulation
Single station tribological simulator
Natural tissue

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BIOLOGICAL SCAFFOLDS;
Heart valves
Vascular patches
Dermis
Blood vessels
Meniscus
Ligament
Tendon
Bone
Bone ligament bone
Bone meniscus bone
Bone and cartilage
THE PRODUCT PIPELINE:
clinical product
clinical product
clinical trial
large animal studies
large animal studies
development
development
research
research
research
research

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CARDIAC VALVES
Native
Acellular
Native
Acellular
Explanted [7 valves] after 6 months in RVOT juvenile sheep

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CARDIAC VALVES:
CLINICAL STUDIES
Recent successful clinical
studies in aortic position
•Decellularised aortic valve
allografts aortic position
da Costa et al. Ann Thorac Surg
2010;90:1854-61

Failure Strain (%)
UTS(MPa)
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DCELL VASCULAR PATCH
Vascular patch for
blood vessel repair
50
45
40
35
30
25
20
15
10
5
0
Mean Failure Strain
FRESH PERICARDIUM
DECELLULARISED
PERICARDIUM
Mean Ultimate Tensile Strength
45
40
35
30
25
20
15
10
5
0
FRESH PERICARDIUM
DECELLULARISED
PERICARDIUM

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VASCULAR PATCH IN SHEEP MODEL
Study to compare biological scaffolds with
current therapies
H&E
N=3 3 months
N=6 6 months
FVII
PSR
Acellular porcine pericardium excellent
regenerative capacity
aSMA
Elastin

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TISSUE REGENERATION IN VIVO BIOLOGICAL SCAFFOLD - VASCULAR
Regeneration of dCELL
Biological scaffold as
Vascular Patch
repair with host cells
Animal study

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CLINICAL TRANSLATION VASCULAR PATCH
Tissue Regenix
dCELL® Vascular Patch
Manufacture, scale-up, quality, ISO standards
Safety, regulatory approval
Clinical trial
CE Mark August 2010
Now distributed in EU

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BIOLOGICAL SCAFFOLDS FOR VASCULAR GRAFTS
• Bioprocess for small/medium diameter
vascular grafts
• New process patent;
Acellular vascular graft
• dCELL porcine internal carotid artery
outperformed ePTFE in 28 day sheep
model
• Long term animal studies

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BIOLOGICAL SCAFFOLDS FOR MSK DISEASE
DCELL MENISCUS
dCELL meniscus
Biological scaffold
Empty cell
spaces.
Histo architecture
maintained 19

Deformation (mm)
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BIPHASIC MECHANICAL PROPERTIES - INDENTATION
Meniscal indention (3mm)
2.5
2
1.5
1
0.5
0
-0.5
Fresh
Decell
0 20 40 60 80
Time (min)
Transalated for commercial development

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BIOLOGICAL SCAFFOLD FOR LIGAMENT REPLACEMENT
Development of bioprocess for porcine
superflexor, a biological scaffold graft for ACL
replacement
Biomechanical properties retained
Translated to TRG for commercial development

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DCELL LIGAMENT SCAFFOLD, REGENERATION IN VITRO
Cells Surface of scaffold at 1 week
Cells Centre of scaffold at 3 week
Centre of scaffold at 3 weeks
Tenocytes
Tenocytes
Tenocytes
Tenocytes
21 Days
Surface

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REGENERATIVE BIOLOGICAL SCAFFOLDS - A PLATFORM TECHNOLOGY
Heart valves
clinical
Vascular patches
clinical
Dermis
clinical
Blood vessels
animal studies
Meniscus
animal studies
Ligament
development
Tendon
development
Bone
research
Bone and cartilage OCG research
Bone ligament bone research
Bone meniscus bone research
Tissue Regenix PLC - Aim Listed Company NHS National Blood and Tissue Service

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THANK YOU FOR LISTENING
Queen’s Anniversary Prize for Higher and Further Education 2012
Innovative joint replacements and regenerative technologies to improve quality of life