New Frontiers in Biomedical Systems: From Bioinspired Design to - - PowerPoint PPT Presentation

New Frontiers in Biomedical Systems: From Bioinspired Design to BioMEMS and Nanotechnology

Wole Soboyejo Princeton Institute of Science and Technology of Materials And Department of Mechanical and Aerospace Engineering Princeton 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

Maximum Principal Stress (MPa)

Graded ceramic/polymer

20 40 60 80 100 120 140 50 100 150 200 250

Zircornia Glass Mark II Dicor MGC Dicor Empress 2

Elastic modulus of ceramic (GPa)

FGM

polymer cement ceramic polymer

DIFFERENT YOUNG’S MODULUS DISTRIBUTION

10 20 30 40 50 60 70 80 20 40 60 80 100

Cement thickness (µm) Young’s modulus (GPa)

20 25 30 35 40 45 50 55

Max principal stress (MPa)

I II III 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 applications

• At 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 material
• Can 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 2

wh 6Qµ τ =

Shear Assay Results

104 Ti-Coated Silicon 82 Silicon 81 Ti-Coated Polystyrene 70 Polystyrene

Adhesion Strength (Pa) Adhesion Strength (Pa) Material Material Shear Stress at detachment for 2 Day HOS cultures

2 6 wh Qµ τ =

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-Grooves 2 µm Micro-Grooves

MEMS-Enhanced Trileaflet Valve

Our Approach to Early Cancer Detection and Treatment!

CAMD

LP conjugates LP conjugates LP conjugates LP conjugates LP conjugates LP conjugates LP conjugates LP conjugates LHRH LHRH LHRH LHRH LHRH LHRH LHRH LHRH

Magnetic core Polymer shell with lytic peptide conjugates

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 accumulation 68% of nanoparticles in tumor Distribution of iron in other tissues is being mapped

TEM Imaging of Cancer

LHRH-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
• f 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)