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MATERIAL-RELATED APPROACHES TO PROMOTE
CELL FUNCTIONS PERTINENT TO NEOTISSUE FORMATION
FOR BIOMEDICAL APPLICATIONS
Rena Bizios, Ph.D.
Peter T. Flawn Professor
Department of Biomedical Engineering
The University of Texas at San Antonio
San Antonio, TX 78249
USA
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A Perspective of
Past Accomplishments and Current Advances
regarding
Biomaterials for Prosthetic Devices
as well as
some Thoughts and Comments regarding
Future Trends
pertinent to
Implant Biomaterials
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MEDICAL NEEDS
Need for substitutes for limbs, tissues and organs result from:
birth defects
trauma
age-related diseases
degenerative conditions
end-stage organ failure
etc.
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TISSUE/ORGAN GENERATION IN BIOLOGY
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* Reference: http://www.nidr.nih.gov/spectrum/NIDCR4/4grasec2.htm
EXAMPLES OF TISSUE REGENERATION *
Limbs and tails of salamanders and newts Antlers of deer
• Regeneration of tadpole tails
• Plugging holes in bat wing membranes
• Filling-in ear holes in rabbits, domestic cats, and bats
• Regrowth of the tips of mouse toes
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* Reference: Cover page of Science, Volume 276, Issue 5309 (4 April 1997)
The Myth of Prometheus*
• Prometheus stole fire from the
Gods of Olympus and gave it to
humans.
• Prometheus was punished by the
gods to have a portion of his liver
eaten each day by an eagle.
• The liver regenerated overnight
providing the eagle with an endless
food supply, and Prometheus with
eternal torture.
ORGAN REGENERATION IN HUMANS
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TISSUE REGENERATION IN HUMANS IS EXTREMELY LIMITED
Special cases:
Liver
Bone
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MATERIALS USED FOR PROSTHETIC DEVICES
PAST ….TO PRESENT
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DEVELOPMENT OF BIOMATERIALS
• In the past, “ordinary” materials were used for prosthetic devices
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http://humanrestore.com/wp-content/uploads/2011/02/wooden_toes
_from_egyptian_mummy_37143800.jpg
Reference: As found in “dvd.monstersand critics.com”
EXAMPLES OF ANCIENT AND LEGENDARY PROSTHETIC DEVICES
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Reference: Cover page of Science, Volume 295, Issue Number 5557, pg. 995 (8 February 2002)
DEVELOPMENT OF PROSTHETIC DEVICES
http://www.humanpl.us/wp-
content/uploads/2009/12/dean-kamen-arm.jpg 2009
Reference: Cover page of Science, Volume 295,
Issue Number 5557, pg. 995 (8 February 2002)
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Reference: Science, Volume 295, Issue Number 5557, pg. 995 (8 February 2002)
DEVELOPMENT OF PROSTHETIC DEVICES (continued)
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Reference: Advertisement in press (2007)
RECENT DEVELOPMENTS
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OSCAR PISTORIUS MAKES OLYMPIC HISTORY (400 meter qualifying heat; August 4, 2012)
2012 OLYMPIC GAMES, LONDON, UNITED KINGDOM
Building
http://www.bbc.co.uk/news/
(August 4, 2012)
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Types of Prostheses
• Mostly External
• Mechanical
• Electrical
• Temporary
• Intermittent Use
“TRADITIONAL” PROSTHETIC DEVICES
Reference: Cover page of Science, Volume 295,
Issue Number 5557 (8 February 2002)
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Characteristics/Specifications
• Mechanical
• Electrical
• “Combination”
• Internal
• Long-term
IMPLANTED PROSTHESES/DEVICES
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MATERIALS IN IMPLANTED PROSTHESES/ DEVICES
PAST…..TO PRESENT
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DEVELOPMENT OF BIOMATERIALS
• In the past, “ordinary” materials were used for prosthetic devices
• In the past, synthetic materials were chosen and used for various
biomedical applications by trial-and error approaches
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http://www.marketmanila.com/archives/s
ausage-casings-a-k-a-pigs-intestines
http://www.buycheapr.com/us/result.jsp?q=women+girdles
EXAMPLES OF “ORDINARY” MATERIALS USED FOR EARLY BIOMEDICAL APPLICATIONS
The first family of hollow-fiber dialyzers
(C-DAK, “Cordis Dow Artificial Kidney“)
http://www.fmc-ag.com/262.htm 2011
http://www.shubhanmedical.com/wp-content/
uploads/2010/09/MAQUET_Graft3.jpg
EXAMPLES OF CURRENT COMMERCIALLY AVAILABLE DIALYZERS AND VASCULAR GRAFTS
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DEVELOPMENT OF BIOMATERIALS
• In the past, synthetic materials were chosen and used for
biomedical applications by a trial-and error approach.
• Eventually, such materials were designed to be
non-toxic
non-pyrogenic
non-allergenic, etc.
BUT STILL
they did not produce desired and controlled interactions
with the surrounding tissues, and
they did not trigger the normal healing process of tissues at the implant-tissue interface.
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Contrôle Corail seul
16 weeks 16 weeks 16 weeks 16 weeks4 weeksPost-operative
Résultats RadiographiquesCLINICAL EXAMPLE: Nonunion Bone Defects
Slide courtesy of Dr. A. Meunier
16 weeks 16 weeks Post-Operative 4 weeks
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EXAMPLES OF BONE IMPLANTS
Slide courtesy of
Dr. A. Meunier
orthopaedic (hip prosthesis dental
http://www.siteadmincp.com/
sites/site135/
site_images/IMPLANT_TOOTH.jpg
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BIOMEDICAL NEED AND CHALLENGE
How to promote tissue regeneration and formation
of normal, functional new tissue in vitro and in vivo.
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RATIONALE
for
RECENT APPROACHES and DEVELOPMENTS
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THE INJURED TISSUE SITE: WOUND HEALING PROCESS
T I S S U E I N J U R Y
Biological Fluids (blood; interstitial fluids)
Proteins
Cells
Tissues
Biological Fluids (blood; interstitial fluids)
Proteins
Cells
Tissues
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THE TISSUE/IMPLANT INTERFACE
Cells
Extracellular Matrix
Adhesive Proteins
Growth Factors
Cytokines
Biological Fluids
Devices
Synthetic Materials
Scaffolds
I
N
T
E
R
F
A
C
E
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COMPARISON
Biological Tissues
Cells
Extracellular Matrix
Adhesive Proteins
Growth Factors
Cytokines
Cues/Stimuli
(biochemical/biophysical)
Cells
Biomaterials
Ceramics
Metals
Plastics
Cues/Stimuli
(biochemical/biophysical)
“Engineered” Tissues
I
N
T
E
R
F
A
C
E
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ILLUSTRATION: PREPARATION OF A TISSUE ENGINEERING CONSTRUCT
Cell seeded scaffolds
Slide courtesy of Dr. C.M. Agrawal, UTSA
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RECENT DEVELOPMENTS
Bioinspired and Biomimetic Aproaches
Recent research activities have focused on engineering
synthetic biomaterials for bio-recognition (by cells and proteins)
and for specificity in order to achieve precise, defined , and timely
biological responses.
TISSUE MICROENVIRONMENT* BY DESIGN
*This term was adapted from: Lumelsky, N. L., “Commentary: Engineering of Tissue Healing and Regeneration”.
Tissue Engineering 13: 1393-1398 (2007).
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THE TISSUE/IMPLANT INTERFACE
Devices
Synthetic Materials
Scaffolds
Biological Fluids (blood; interstitial fluids)
Proteins
Cells
Tissues
I N T E R F A C E
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MECHANISMS OF MAMMALIAN CELL ADHESION
ON
SUBSTRATE SURFACES
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CELL FUNCTIONS PERTINENT TO
THE WOUND HEALING/TISSUE REGENERATION PROCESSES
• Adhesion (to substrates and to other cells)
• Morphology Changes
• Survival and Apoptosis
• Motility/haptotaxis
• Proliferation
• Synthesis and Deposition of an Extracellular Matrix
• Differentiation (if applicable)
• Cell-to-cell signaling
• etc.
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PROTEIN-BIOMATERIAL INTERACTIONS
Biomaterial
Proteins
Schematics courtesy of Professor D.A. Puleo,
University of Kentucky, Lexington, KY
Cells
Biomaterial
CELL ADHESION ON BIOMATERIALS
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BIOMATERIAL-RELATED APPLICATIONS
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PROMOTION OF DIRECTED MAMMALIAN CELL ADHESION
ON PATTERNED SURFACES
MODIFIED CHEMICALLY WITH PROTEINS
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EXPERIMENTAL APPROACHES: MICROCONTACT PRINTING
N1[3-(trimethoxysilyl)propyl]diethylenetriamine (DETA)
Octadecyltrichlorosilane (OTS)
Lattice Parameter, dLP 25, 35, 50 mm
Feature Width, w 7.9, 21.7, 43.3 mm
Coverage Fraction, h 10, 25, 50, 75%
dLP
w
Reference: Kam, L., W. Shain, J.N. Turner, R. Bizios, Biomaterials 20: 2343-2350 (1999).
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CONTROLED ASTROGLIAL ADHESION ON MICROPATTERNED SURFACES
Reference: Kam, L., Doctoral Thesis, Rensselaer Polytechnic Institute, Troy, NY (1999).
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PROMOTION OF DIRECTED MAMMALIAN CELL ADHESION
ON PATTERNED SURFACES
MODIFIED CHEMCIALLY WITH PEPTIDES
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Extracellular Domain
Cytoplasm
Adapted from: Akiyama, S.K., K.M. Yamada, J. Biological Chemistry 260: 4492-4500 (1985)
HS-PG = Heparin Sulfate Proteoglycans
Plasma Membrane
SCHEMATIC ILLUSTRATION OF THE OSTEOBLAST ADHESION MECHANISMS
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Octadecyltrichlorosilane (OTS)
N1[3-(trimethoxysilyl)propyl]diethylenetriamine (DETA);
further modified with either RGDS or KRSR.
L = 10 mm
d = 10, 50, 100, or 200 mm L
L
L
L
d
MICROPATTERNED SURFACES CHEMICALLY MODIFIED WITH IMMOBILIZED PEPTIDES
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OSTEOBLAST CLUSTERING DEPENDENTS ON THE DIMENSIONS OF THE
MICROPATTERNS MODIFIED WITH KRSR
d = 10 mm d = 50 mm
d = 100 mm d = 200 mm
Reference: Hasenbein, M.E., T.T. Andersen, R. Bizios, Biomaterials 23: 3937-3942 (2002).
100 mm
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CELL ADHESION ON SUBSTRATES MODIFIED WITH IMMOBILIZED PEPTIDES
Light Micrographs
Reference: Hasenbein, M.E., T.T. Andersen, R. Bizios, Biomaterials 23: 3937-3942 (2002).
Fluorescence
Micrographs Light Micrographs
Fibroblasts
Osteoblasts
Arginine-Glycine-Aspartic acid-Serine (RGDS) Lysine-Arginine-Serine-Arginine (KRSR)
Fluorescence
Micrographs
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NEW SCIENTIFIC DIRECTIONS
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MICROENVIRONMENT BY DESIGN
Devices
Synthetic Materials
Scaffolds
Biological Fluids (blood; interstitial fluids)
Proteins
Cells
Tissues
I N T E R F A C E
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DEFINITIONS
• Nanophase/Nanostructured are materials characterized by
atomic domains spatially confined (grain size)
to less than 100 nm in at least one direction.
• Conventional (micron-size) are materials with grain sizes
greater than 100 nm.
Reference for the schematic:
Silver, F.H., D.L. Christiansen,Biomaterials Science and Biocompatibility,
Springer: New York, p.110, 1999.
Grain Growth
Crystal Nucleation
Grain boundary
impingement
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EXCITEMENT
AND
POTENTIAL
NANOSTRUCTURED BIOMATERIALS PROMOTE SPECIFIC
FUNCTIONS OF SELECT MAMMALIAN CELLS
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ENHANCED OSTEOBLAST ADHESION ON NANOPHASE CERAMICS
0
1000
2000
3000
4000
1 2 3 4
Grain Size (nm)
Cell
Den
sit
y
(cell
s/s
qu
are
cm
)
Alumina
24 4520 97
Titania
39 179
Hydroxylapatite
132 67
* * *
167 45
Glass
*
Culture media : DMEM supplemented with 10% fetal bovine serum.
Values are mean ± SEM; n = 3;
*p<0.01 (student t-test compared to respective conventional grain size ceramic).
Reference: Webster, T.J., C. Ergun, R.H. Doremus, R.W. Siegel, R. Bizios. Biomaterials 21: 1803-1810 (2000)
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COMPARISON OF CELL ADHESION ON NANOPHASE ALUMINA
0
1000
2000
3000
4000
Osteoblasts Fibroblasts Endothelial Cells
Ce
ll D
en
sit
y
(c
ells
/sq
ua
re c
m)
Glass (reference substrate)
167 nm grain size alumina
45 nm grain size alumina
24 nm grain size alumina
*
*
**
*‡
‡
Glass (reference substrate)
Culture medium = DMEM supplemented with 10% fetal bovine serum.
Values are mean ± SEM; n = 3; *p<0.01 (student t-tests compared to 167 nm grain size alumina);
‡ p<0.01 (student t-tests compared to fibroblast and endothelial cell adhesion
on respective grain size alumina).
Reference: Webster, T.J., C. Ergun, R.H. Doremus, R.W. Siegel, R. Bizios. JBMR 51: 475 - 483 (2000)
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0
1000
2000
3000
4000
Osteoblasts Fibroblasts Endothelial Cells
Ce
ll D
en
sit
y
(c
ells
/sq
ua
re c
m)
Glass (reference substrate)
167 nm grain size alumina
45 nm grain size alumina
24 nm grain size alumina
*
*
**
*‡
‡
Glass (reference substrate)
COMPARISON OF CELL ADHESION ON NANOPHASE ALUMINA
Culture medium = DMEM supplemented with 10% fetal bovine serum.
Values are mean ± SEM; n = 3;
*p<0.01 (student t-tests compared to 167 nm grain size alumina);
‡ p<0.01 (student t-tests compared to fibroblast and endothelial cell adhesion on respective
grain size alumina).
Reference: Webster, T.J., C. Ergun, R.H. Doremus, R.W. Siegel, R. Bizios. JBMR 51: 475 - 483 (2000).
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QUESTION
How are cell functions modulated by nanoscale-size features
on material surfaces?
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PROTEIN-BIOMATERIAL INTERACTIONS
Biomaterial
Proteins
Schematics courtesy of Professor D.A. Puleo, University of Kentucky, Lexington, KY
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Borosilicate glass 167 nm alumina 24 nm alumina
Reference: Webster, T.J., C. Ergun, R.H. Doremus, R.W. Siegel, R. Bizios. JBMR 51: 475-483 (2000).
Values are ± SEM; n = 3; *p<0.01 (compared to 167 nm alumina pretreated with the respective
protein);
‡ p<0.01 (compared to respective grain size alumina pretreated with albumin)
PROTEIN ADSORPTION ON ALUMINA
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Cells
Biomaterial
CELL ADHESION ON BIOMATERIALS
Schematic courtesy of Professor D.A. Puleo, University of Kentucky, Lexington, KY
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OSTEOBLAST ADHESION ON SELECT PROTEINS PRE-ADSORBED ON
NANOPHASE ALUMINA
Cell culture medium = DMEM without serum. FBS= fetal bovine serum.
Substrate were pretreated with protein (0.5 mg/ml).
Values are mean ± SEM; n = 3; *p< 0.01 (student t-tests compared to 167 nm grain size alumina);
‡ p< 0.01 (student t-tests compared to respective grain size alumina pretreated with albumin).
Reference: Webster, T.J., C. Ergun, R.H. Doremus, R.W. Siegel, R. Bizios. JBMR 51: 475-483 (2000)
0
1000
2000
3000
4000
1 2 3 4 5 6
Protein
Series1
Series2
167 nm grain size alumina
24 nm grain size alumina
Cell D
en
sit
y
(cells/s
qu
are
cm
)
*‡
*‡
*‡ *
‡
Albumin10% FBS Laminin Denatured
Collagen
Fibronectin Vitronectin
Glass (reference substrate)
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CONCLUSIONS
• Nanoscale features and/or grain sizes modulate the
type,
amount, and
conformation
of select adsorbed proteins.
• These protein interactions subsequently promote cell functions
(such as adhesion, etc.) of specific cells (selectivity).
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CONCERNS
regarding
NANOSTRUCTURED MATERIALS:
BIOSAFETY
Need to determine any detrimental effects of nanostructured materials
at the following levels:
• gene
• subcellular
• cellular
• tissue
• organ
• whole body (systemically)
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EVOLVING IDEAS FOR
NOVEL MATERIALS/BIOMATERIALS:
SCIENTIFIC DIRECTIONS OF PROMISE
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http://www.pbs.org/wgbh/nova/tech/making-stuff-smarter.html
MATERIALS RESPONSIVE TO ENVIRONMENTAL CONDITIONS (such as temperature, pH, etc.)
SHAPE-MEMORY ALLOYS: Thermosensitive Materials
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A material made from the pig small intestinal submucosa (SIS)
EXAMPLE OF A BIO-DERIVED EXTRACELLULAR MATRIX (ECM)
http://www.nibib.nih.gov/publicPage.cfm?section=gallery&action=desc&page=3&photo=6
Image courtesy of Dr. Stephen Badylak, University of Pittsburgh. Grant EB000506
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Optical microscope images of a polymer nanocomposite taken (a) 2, (b) 10, (c) 20,
(d) 40, (e) 60 and (f) 90 seconds after a cut is made on the surface of the nanocomposite.
http://www.deakin.edu.au/itri/cmfi/research/areas/self-healing.php
SELF-HEALING POLYMERS AND NANOCOMPOSITES: AN EXAMPLE
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PROTEIN-ENGINEERED BIOMATERIALS*
*Reference: Sengupta, D. S.A. Heilshorn. “Protein-Engineered Biomaterials: Highly tunable tissue engineering
scaffolds”. Tissue Engineering, Part B 16, 285 (2010).
FIG 2. Schematic of the iterative protein-engineered biomaterial design strategy.
(1) Design a DNA template for the protein engineered biomaterial
(2) Encode into a recombinant plasmid
(3) Use the plasmid to transfect the host cell of choice,
(4) Translate the genetic message and express the engineered protein
(5) Purify the protein
(6) Process to fabricate a protein engineered scaffold
(7) The scaffold is analyzed using in vitro and in vivo methods,
providing information about how to improve the properties
of the scaffold, thus prompting biomaterial redesign and
modification of the encoding DNA template.
1
2 3
4
5 6
7
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NEW SCIENTIFIC DIRECTIONS
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Reference: Cover page of Science, Volume 276,
Issue Number 5795 (29 September 2006)
BIOMATERIALS AS
DELIVERY VEHICLES FOR:
• STEM CELLS
• GROWTH FACTORS
• GENES
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References: Gerstenfeld, L.C., Cullinane, D.M., Barnes, G.L., Graces, D.T., Einhorn, T.A., J Cell Bioc 88:873-874 (2003)
STAGES OF BONE FRACTURE REPAIR
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LIMITATIONS, CHALLENGES, AND OPPORTUNITIES
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SCHEMATIC ILLUSTRATION OF THE COMPONENTS AND STRUCTURE OF BONE
Reference: http://www.octc.kctcs.edu
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CURRENT LIMITATIONS IN TISSUE ENGINEERING
• Vascularization
• Innervation
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SCIENTIFIC CHALLENGES AND RESEARCH OPPORTUNITIES
• The current knowledge of the biology/physiology of functional tissue
formation is incomplete but is critically needed.
• Improved and/or thorough understanding of the wound healing
process in health and in disease is needed.
• The function of cells (including stem cells) pertinent to new tissue
formation needs to be elucidated and incorporated in implant
biomaterials.
.
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CLOSING REMARKS
• The field of implant biomaterials is at another “historic cross-road”of
potential and promise.
• Further developments require establishment of scientific
fundamentals pertinent both to implant biomaterials and to
cells/tissues/organs.
• Success requires interdisciplinary, multidisciplinary, creative, and
novel approaches which incorporate cutting-edge knowledge of
processes and conditions pertinent to physiology and pathology.
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ACKNOWLEDGMENTS
Former Graduate Students
at Rensselaer Polytechnic Institute
Dr. Kay C Dee
Ms. Meredith E. Hasenbein
Dr. Lance C. Kam
Dr. David A. Puleo
Dr. Thomas J. Webster
Colleagues
Ms. C. Charniga and Dr. H. Kimelberg, Department of Neurosurgery, Albany Medical College, Albany, NY.
Dr. J.N. Turner and Dr. W. Shain, Wadsworth Labs, NY State Health Department, Albany, NY.
Dr. T.T. Andersen, Department of Biochemistry, Albany Medical College, Albany, NY.
Dr. R.W. Siegel and Dr. R.H. Doremus, Department of Materials Science & Engineering, Rensselaer Polytechnic Institute, Troy, NY.
Nanophase Technologies, Inc., provided the nanophase alumina and titania
powders used in the respective studies of nanostrucutred ceramics
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THANK YOU
for
YOUR ATTENTION
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CASE STUDY*
• L.S., a 66-year old man, had a piece (about three-eights of
an inch long) cut off his right, middle finger by a gas-powered
model airplane propeller.
• The injury was treated using ACell Powder Wound Dressing
(ACell, Inc., Jessup, MD) every two-days. This powder (a
substance derived from pig bladder extract) had been used
for healing and tissue regeneration in animals (specifically,
horse ligaments) and had also received federal government
approval for use in humans.
• The finger regained its original length within 4 weeks.
• The finger looked like the normal finger within 4 months.
• A year later, the finger felt calloused but had tactile
sensation; it had a slight scar at the end; the nail grew at
twice the speed of the other finger nails.
* Reference:www.mysanantonio.com/news/metro/stories/MYSA0