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Biomaterials in Bone Tissue Engineering
Miqin ZhangMiqin ZhangProfessor of Dept of Materials Science and EngineeringProfessor of Dept of Materials Science and Engineering
Adjunct Prof. of Neurological Surgery, Radiology, and OrthopaediAdjunct Prof. of Neurological Surgery, Radiology, and Orthopaedics cs & Sports Medicine& Sports Medicine
University of WashingtonUniversity of Washington
Outline
Background in tissue engineeringStructure and function of boneMotivation and background in bone tissueengineering Biomaterials in bone tissue engineering
2
History of Tissue Engineering
4~ 25 years4Yannnas et al: artificial
skin from collagen and glycosaminoglycan (1980) Cima et al: chondrocytes
from PLGA (1991)4Langer and Vacanti
(1993) defined “tissue engineering”
L. Bonassar, CA Vacanti, Journal of Cellular Biochemistry Supplements, 30/31:297-303 (1998)
Possible Tissue-Engineered Devices
3
Host Response
Material Response
ParticulatesSwelling
and leaching
Corrosion Deformationand failure
4
Material/device-Living System Interaction
Integrin
RGDRGD RGDAdhesion Protein
Cytoskeletal connection
α β
Material/device
Material/device Material/device
(1) Proteinadsorption
(2) Cell
adhesion
Material/device
+ Biological System
Integrin
Cell membrane
RGDRGD RGDAdhesion Protein
Cytoskeletal connection
α β
Material/device
Material/device Material/device
(1) Proteinadsorption
(2) Cell
adhesion
Material/device
+ Biological System
Effects of Surface Properties on Living Systems
SurfaceCrystallinity
SurfaceComposition
Surface topo-graphy
Hydrophilic/hydrophobic Character
Surface Roughness
CellCell
Protein
OH
CO
OH
PEG
5
Most implants
Biofunctional
Biointerfaces
Bioinert
Tissue engineering
Resist non-specificprotein adsorption
Promote protein adsorption
Outline
Background in tissue engineeringStructure and function of boneMotivation and background Biomaterials in bone tissue engineering
6
Function of Bone
SupportProtection
Storage and productionLeverage
Composition of Bone
7
The Structure of Bone4 Bone organic composition: 95% type I collagen,
and 5% of proteoglycans and noncollagenousproteins
4Bone: cortical (compact) and cancellous (spongy)
Collagen fibers
Bone apatite
The Types and Locations of Bone Cells
8
Bone Remodeling
Outline
Background in tissue engineeringStructure and function of boneMotivation and background in bone tissueengineering Biomaterials in bone tissue engineering
9
Trauma, tumors, aging, osteoporosis ….
Causes of Bone Defects
Osteoposis: 15% of those 50-59; 70% of those over 89
Spine disorders: 80% of population
Bone Defects – Affect Everyone
10
Data from AAOS, NIH, NOF and http://www.usbjd.org
1 out of 7 Americans have musculoskeletal impairments.36.9 million Americans incur injuries every year.1 out of 2 women and 1 out of4 men over 50 suffer an osteoporosis-related fracture $300 billion every year
Musculoskeletal Conditions are Worsening!!!
Treatments of Bone Defects
Autograft Allograft Xenograft Tissue engineering
Material substitutes
1. Patient pain
2. Infection3. High cost
Metalspolymers
bioceramicsdo not
have goodproperties
1. Immunerejection2. Pathogens
1. Donor shortage
2. Infection3. Pathogens4 Immune
Rejection
Patient Otherpatient
Animal Biomaterial Promisingtherapy
11
Bone Tissue Engineering
Scaffolds gradually degraded and eventually eliminatedPatient-derived bone cells onto a macroporous man-made scaffolds to create completely natural new tissuesCommon cells: osteoblast, mesenchymal stem cells
Scaffold Cultivated cells
Cells on scaffold
Scaffold with cells implanted in bone
Criteria for Scaffold Materials
Excellent mechanical strengthCancerous bone (compressive stress 0.5-10 MPa) Three dimensional (3D) interconnected macroporous microstructures Controllable biodegradation and bioresorptionSuitable surface chemistryMalleableGood biocompatibility and biofunctionality
12
Biocompatibility of Porous Materials for Bone Tissue Engineering
Bioactive: form bond between tissues and materialsOsteoconduction: stimulate cell attachment and migration Osteoinduction: stimulate proliferation and differentiation of stem cellsOsteogenesis: produce bone independently
Resist non-specific protein adsorption
Biofunctional
Bioinert
Outline
Background in tissue engineeringStructure and function of boneMotivation and background in bone tissueengineering Biomaterials in bone tissue engineering• Porous ceramic scaffolds for load bearing bone• Polymeric materials for non-load bearing bone
13
I. Porous Scaffolds for load-bearingBone Tissue Engineering (hard tissue)Tissue Engineering (hard tissue)
Background:Background: Existing Porous Scaffolds Existing Porous Scaffolds
High mechanical strength ~ 14 MPalimited resources, expensiveuncontrollable microstructures
Can be converted intoHA
Coral
High mechanical strength Not bioactive and osteoconductiveneed surface coatings
Stainless SteelTitanium
Metals
Composition similar to boneβ-TCP > HA in degradationbioactive, osteoconductive~ 2MPa
HA & β-TCPCeramics
Hydroxyapatite (HA), tricalcium phosphate (TCP)
14
100 µm 15 KV
C
CP
P
100µm 15KV
Compressive yield stress: 5 MPaCompressive elastic modulus: 7 GPa
HA Scaffolds by a GelHA Scaffolds by a Gel--Polymer MethodPolymer Method
H. Ramay and M. Zhang, Biomaterials 24 (19), 2003
β-TCP and HA Nanofiber Nanocomposite Scaffolds
100 μm
200 μm
(a)
(b)
80 nm
Compressive stress 9.8 MPa – Human cancellous bone 2-10MPaH. Ramay and M. Zhang, Biomaterials, 25 (21), 5171-5180 (2004). Filed US patent.
15
Mechanisms for Increased Toughness
Wavy fracture surface– Area of crack surface
is increased
Clinching at crack tip– Clinching reduces the
applied stress intensity factor 10 μm
II. Porous polymeric scaffolds for non-load bearing bone
16
Polyglycolic acid (PGA)
Polylactic acid (PLA)
Poly- lactic-co-glycolic(PLGA)
Synthetic polymers
• Hydrophobic• Acidic
degradation products
More biocompatibleMinimal foreign body reactionHydrophilicSuitable surface chemistry
Chitosan
Natural polymer
Polymeric Porous Scaffolds
WeakSwelling
Soluble in strong acidDifficult to incorporate
drug
StrongStrong ironic bondingNo swellingNeutral pH: easy to incorporate drugs
Chitosan+ Alginate
Natural polymer
Why Chitosan-alginate Scaffolds?
Chitosan
17
Mechanical and Swelling Properties
3~4 times increase in mechanical strength and compressive modulus
C
Chitosan hybrid Chitosan
Chitosan composite scaffolds• Do not swell in PBS solution• Stable in neutral solution• Incorporation of proteins
without denaturization
0.0
0.1
0.2
0.3
0.4
0.5
0.6
Yiel
d S
treng
th (M
pa)
Chitosan Composite
0
2
4
6
8
10
You
ng's
Mod
ules
(MP
a)
Chitosan Composite
3 days 7 days
In vitro Study of Bone Mineralization
A large amount of minerals was formed on chitosan-alginate scaffold
18
In vivo Ectopic Animal Model
Z. Li, H. Ramay, K. Hauch, D. Xiao, and M. Zhang, Biomaterials, 26 (18), 3919-3928 (2005).
Compatibility of Chitosan-alginate Scaffolds
No fibroticlayer
Blood vesselformation
19
In vivo Study of Mineral Formation
4 weeks 8 weeks
Black stain indicates bone formation
In vivo Orthotopic Animal Model: Digit Bone In vivo Orthotopic Animal Model: Digit Bone Defect RepairDefect Repair
Chris Allan (MD, UW Orthopedics) (bone)Buddy Ratner (UW Bioengineering)Miqin Zhang (UW Materials Science and Engineering)
20
Richard Hopper (MD, Children Hospital) Miqin Zhang (UW Materials Science and Engineering)
In vivo Orthotopic Animal Model: In vivo Orthotopic Animal Model: Cranial defectsCranial defects
Micro CT results Micro CT results
All samples show defect closureThe CA scaffolds with BMP-2 have the best result on bone formation
4 weeks 16 weeks
ControlNo scaffolds
CA scaffolds+ MSC
CA scaffolds+Bone marrow
CA scaffolds+ BMP
21
III. Other novel biomaterialsfor bone tissue engineeringtissue engineering
Biomimic Extracellular Matrix
Extracellular matrix: proteoglycans and fibrous proteins with fiber diameters in the range of 50 to 150 nm
motor
Rotation Controller
motor
Transverse motor
High voltage
Polymer jets
15 kV20–50 kV
1 2 3 4
motormotor
Rotation Controller
motor
Transverse motor
High voltage
Polymer jets
15 kV20–50 kV
1 2 3 4
Chitosan40-500nm
Electronspinning
100 nm 100 nm 50 μm 500 nm100 nm100 nm100 nm 100 nm100 nm100 nm 50 μm50 μm50 μm 500 nm500 nm500 nm
DDD
N. Bhattarai, D. Edmondson, O. Veiseh, F. A. Matsen, and M. Zhang, Biomaterials,
26 (31), 6176-6184 (2005) 2006.
22
Various Electronspun Nanofibers
Gelatin
100 µm
TEM image of PLLA/Iron oxide nanoparticle
1 µm
50 75 1000
15
30
Diameter (nm)
N. Bhattarai, C. Li, D. Edmondson, M. Zhang, Advanced Material, 2006
0
2
4
6
8
10
CaCl2 treated fibers
Tens
ile M
odul
us (M
Pa)
As spun fiberAlginate
Polycaprolactone
10 µm
Silk fibroin2 µm
Polylactide(PLLA)
2 µm
Thermoreversible Hydrogel
<100C 370C
Gel + nanoparticlesprolonged drug releasefor months
0 500 1000 1500 2000 2500 30000
1
2
3
4
5
6
7
At 10°C
Time (second)
Vis
cosi
ty (P
a.S
)
At 37°C
Vis
cosi
ty (P
a.S
)
Time (second)
G2 G1 G3 G4
3000 2500 2000 1500 1000 500 0
0
1
2
3
4
5
6
7
G2 G1 G3 G4
N. Bhattarai, F. A. Matsen, and M. Zhang*, Macromolecular Bioscience, 5, 107-111 (2005).
23
Thermoreversible Hydrogel for Controlled Drug release
N. Bhattarai, H. R. Ramay, J. Gunn, F. A. Matsen, and M. Zhang, Journal of Controlled Release, 103,
609-624 (2005).
0 10 20 30 400
20
40
60
80
100
Cum
uliti
ve R
elea
se (%
)
Time (days)
1000 µg/ml 800 µg/ml 600 µg/ml 400 µg/ml 200 µg/ml
0 10 20 30 40 500
20
40
60
80
100
Cum
mul
ativ
e re
leas
e (%
)
Time (h)
A B C
Treatment of osteoporosis