New Frontiers in Biomedical Systems: From...
Transcript of New Frontiers in Biomedical Systems: From...
New Frontiers in Biomedical Systems: From Bioinspired Design to
BioMEMS and Nanotechnology
Wole SoboyejoPrinceton Institute of Science and Technology of
MaterialsAnd Department of Mechanical and Aerospace
EngineeringPrinceton University
Princeton, NJ
Acknowledgments
• Glaucio Paulino (UIUC)• Dulce Rufino• Ken Chong (NSF) • Jorn Larsen-Basse (NSF)• Carmen Huber (NSF)
Acknowledgments• Challa Kumar (LSU/CAMD)• Carolla Leuschner (Pennington Biomedical)• Warren Warren (Princeton)• Sylvia Centano (Princeton)• Dr. Jikou Zhou (Princeton)• Dr. Min Huang (Princeton)• Chris Milburn (Princeton)• Steve Mwenifumbo (Princeton/Cambridge)• Lauren Hayward (Princeton)• Lara Ionescu (Princeton)• Omar Bravo (University of Puerto Rico)• Robert Bond (West Windsor/Plainsboro)
Outline of Presentation
• Background and Introduction• Bioinspired Design of FGMs• BioMEMS
– Implantable BioMEMS Structures • Nano-Bio-Technology
– Functionalized Nanoparticles for Cancer Cell Detection
• Summary and Concluding Remarks
Background and Introduction
• Biomedical design is often done without adequate inputs from biology
• Examples – dental implants that fail after a few years- BioMEMS and nano-structures from non-biocompatible materials
• Objective is to introduce some basic ideas in biomedical design at different scales
MECHANICAL PROPERTIES OF DENTAL MATERIALS/MULTILAYERS
Tooth Structure
Dental ceramic E: 50~200 GPa
Dentin-like polymer E=20 GPa
Dental cement E=5 GPa
Enamel E=65 GPa
Dentin E=20 GPa
Dentin-Enamel Junction (DEJ): Graded
Dental restoration
ELASTIC MODULUS DISTRIBUTION IN DENTIN-ENAMEL JUNCTION (DEJ)
Marshall et al. J Biomed Mater Res 54, 87-95, 2001
MAXIMUM PRINCIPAL STRESS DISTRIBUTION
Dental Restoration
1 mm
E=65 GPa
E=20 GPa
Natural Tooth
1 mm
E=20 GPa
E=65 GPa
MAXIMUM PRINCIPAL STRESS
ceramic
Max
imum
Prin
cipa
l Stre
ss (M
Pa)
Graded ceramic/polymer
0
20
40
60
80
100
120
140
0 50 100 150 200 250
ZircorniaGlass
Mark II
Dicor MGC
DicorEmpress 2
Elastic modulus of ceramic (GPa)
FGM
polymer
cement
ceramic
polymer
DIFFERENT YOUNG’S MODULUS DISTRIBUTION
0
10
20
30
40
50
60
70
80
0 20 40 60 80 100
Cement thickness (µm)
You
ng’s
mod
ulus
(GPa
)
20
25
30
35
40
45
50
55
Max
prin
cipa
l stre
ss (M
Pa)
I
IIIII
IV
V
I II III IV V
Different Young’s modulus distribution
E=20 GPa
E=72 GPa
Introduction to BioMEMS Systems
Drug Delivery System Implantable Blood Pressure Sensor
BioMEMS structures are micron-scale devices that are used in biomedical or biological applicationsAt this scale, a wide range of devices are being made (e.g. pressure sensors, drug delivery systems, and cantilever detection systems)Explosive growth in emerging markets – civilian and military applications expected to reach multi-billion dollar levels
Biocompatibility of Silicon MEMS SystemS
500 nm
Coated BioMEMS Structure 500 nm Ti Layer on Si
Si is not the most biocompatible materialCan be made biocompatible through the use of polymeric or Ti coatings.Polymeric coatings used on Si drug release systems.Ti coating approaches are also being developed.
Si
Ti
Ti
Ti
Ti
SURFACE CHEMISTRY – CELL SPREADING
Si - 50 nm Titanium
Si
30 minutes 60 minutes 120 minutes
HOS Cells
PROTEINS INVOLVED IN ADHESION
Adhesion between cells/substrate surfaces -focal contacts or adhesion plaques.Consist of integrins, microfilaments, and proteins.Integrins bind to the extracellular matrix or cell surface.
Connected by proteins to the microfilaments (actin cytoskeleton).
Talin and vinculin -two main proteins responsible for this connection.
ADHESION - IMMUNO-FLUORESCENCE (IF) STAINING
Actin
Vinculin
IF staining - used to view focal adhesions (actin and vinculin).
Tagged anti-bodies bind to specific protein of a cell.
Focal adhesions of specific cells can be quantitatively measured.
Qualitative assessment of cell alignment and growth can be achieved on a multi-cell scale (contact guidance).
Schwarzbauer et. al, 2002
Cell Attachment on PS/Ti Surfaces
Cell Spreading on PS/Ti Surface 3D View of Attached Cell
SHEAR ASSAY MEASUREMENT OF CELL ADHESION
Shear Flow Schematic
Cell Detachment
Shear stress for detachment is given by
Where Q - flow rate & µ -dynamic viscosity
Considering initial onset of detachment to correspond to “adhesion” strength:
τ = 70 Pa Polystyrene (PS)
τ = 81 Pa Ti Coated PS
2wh6Qµτ =
Shear Assay Results
104Ti-Coated Silicon
82Silicon
81Ti-Coated Polystyrene
70PolystyreneAdhesion Strength (Pa)Adhesion Strength (Pa)MaterialMaterial
Shear Stress at detachment for 2 Day HOS cultures
26whQµτ =
Determined as wall shear stress given by:
Micro-Groove Geometry and Cell/Surface Interactions
• Cells can undergo contact guidance when in contact with micro-grooved geometries
• This depends on the size of the grooves relative to the size of the cells• Contact guidance has implications for wound healing and scar tissue
formation
100 µm
Cell
30 µm
Cell
12 µm Micro-Grooves2 µm Micro-Grooves
MEMS-Enhanced TrileafletValve
Our Approach to Early Cancer Detection and Treatment!
CAMD
LP conjugates
LP conjugates
LP conjugatesLP conjugates
LP conjugates
LP conjugates LP conjugates
LP conjugates
LHRH
LHRHLHRH
LHRH
LHRH
LHRH LHRH
LHRH
Magnetic core
Polymer shellwith lytic peptideconjugates
CAMD
Wet Chemical Synthesis of Nano-particles
Metallic, polymeric and metal-polymer Nano-particles using bottom-up approaches
Novel Micro reactor technology for scale-up and controlled synthesis
Synchrotron radiation based X-ray absorption Spectroscopic characterization
Capability to attach bio-molecules
Nanoparticles in tumor: Prussian blue Used to Stain Paraffin Embedded Histological Sections
Targeted Destruction of Prostate Cancer in Balb/c athymic nude mice
CAMD
PC-3.luc Xenograft bearing male nude mice were used
LHRH bound nanoparticles effectively bind to tumor
Use of Nano-LHRH results in accumulation68% of nanoparticles in tumor
Distribution of iron in other tissues is being mapped
TEM Imaging of CancerLHRH-SIOP in Tumor SIOP in Tumor
Fundamentals of Magnetic Resonance Imaging (MRI)
• Hydrogen atoms in water have a property called spin
• MRI generates a magnetic pulse that aligns all of the spins in a certain direction
• The magnetic resonances of the nuclei will cause differences in how they return to their normal spin state
• The MRI machine records the energy released as they realign at different times and generates an image
• A set of images are generated at certain small time intervals after the pulse sequence
Initial MRI Experiments: Cherry Tomato and Grape
• Injected grapes with saturated saline solution of nanoparticles
• Observed contrast at the location of the injection (nanoparticles)
The iron creates a magnetic field in the water, thus creating a blind spot (dark) for the MRI
MRI Imaging of Cancer
MRI Imaging of Cancer –multiCRACED Magnetic Anisotropy
Summary and Concluding Ramarks
• Overview of some recent work on bio-inspired design, bioMEMS and bionanotechnology
• Bioinspired FGM design proposed for crown/dentin interface (need to fabricate structures & test idea)
• Nano-scale titanium coatings designed for implantable biocompatible BioMEMS structures
• LHRH-coated magnetite particles provide opportunities for early detection of breast & prostate cancer
• Significant opportunities for mechanics and materials research – modeling, adhesion, detection of cancer
• We welcome your involvement in the ongoing Americas program (americas.princeton.edu – no www)