2. Tissue Engineering
“The application of the principles and methods of engineering and life sciences
toward the fundamental understanding of structure-function relationships in
normal and pathological mammalian tissue and the development of biological
substitutes to restore, maintain, or improve tissue function”
Skalak, R., & Fox, C. F. (1988). Tissue engineering: proceedings of a workshop, held at Granlibakken, Lake Tahoe,
California, February 26-29, 1988 (p. 343).
3. Tissue Engineering
They introduced a new field that is basically a combination
of engineering and biological science with motivation of
finding a solution for patients that suffer from organ failure.
Langer, R., & Vacanti, J. (1993, 01). Tissue engineering. Science, 260(5110), 920-926. doi: 10.1126/science.8493529
4. Motivation
The Need Is Real: Data. (n.d.). Retrieved June 24, 2014, from http://www.organdonor.gov/about/data.html
Mo RB St Im DA DC BP App Sy
5. Motivation
"Every 30 seconds, a patient dies from a disease that could
be treated with tissue replacement."
Dr. Anthony Atala
http://www.bioscaffold.com/
Mo RB St Im DA DC BP App Sy
6. Tissue Engineering is a combination of basic biological science, engineering
fundamentals, many clinical aspects and various relevant biotechnologies.
Required Backgrounds
Mo RB St Im DA DC BP App Sy
7. Tissue Engineering is a combination of basic biological science, engineering
fundamentals, many clinical aspects and various relevant biotechnologies.
- Biological Science:
Cell biology
Physiology
Embryology
Wound healing
Required Backgrounds
Mo RB St Im DA DC BP App Sy
8. - Clinical aspects:
Surgery and transplantation
Immunology
Pathology
Radiology
Medicine
Required Backgrounds
Mo RB St Im DA DC BP App Sy
10. - Engineering fundamentals:
Fluid dynamics
Transport phenomena
Material Science
Mechanics
Chemical kinetics
Required Backgrounds
Mo RB St Im DA DC BP App Sy
11. - Engineering fundamentals:
Fluid dynamics
Transport phenomena
Material Science
Mechanics
Chemical kinetics
This long list make it challenging to cover all aspects in a course. This course
will be an introductory course with focus on Engineering fundamentals and few
important aspects of biotechnology.
Required Backgrounds
Mo RB St Im DA DC BP App Sy
12. Steps
Murphy, S. V, & Atala, A. (2014). 3D bioprinting of tissues and organs. Nature Biotechnology, 32(8), 773–
785. doi:10.1038/nbt.2958
Mo RB St Im DA DC BP App Sy
13. Steps
Murphy, S. V, & Atala, A. (2014). 3D bioprinting of tissues and organs. Nature Biotechnology, 32(8), 773–
785. doi:10.1038/nbt.2958
Mo RB St Im DA DC BP App Sy
14. Steps
Murphy, S. V, & Atala, A. (2014). 3D bioprinting of tissues and organs. Nature Biotechnology, 32(8), 773–
785. doi:10.1038/nbt.2958
Mo RB St Im DA DC BP App Sy
15. Steps
Murphy, S. V, & Atala, A. (2014). 3D bioprinting of tissues and organs. Nature Biotechnology, 32(8), 773–
785. doi:10.1038/nbt.2958
Mo RB St Im DA DC BP App Sy
16. Steps
Murphy, S. V, & Atala, A. (2014). 3D bioprinting of tissues and organs. Nature Biotechnology, 32(8), 773–
785. doi:10.1038/nbt.2958
Mo RB St Im DA DC BP App Sy
17. Steps
Murphy, S. V, & Atala, A. (2014). 3D bioprinting of tissues and organs. Nature Biotechnology, 32(8), 773–
785. doi:10.1038/nbt.2958
Mo RB St Im DA DC BP App Sy
18. Step 1: Imaging
X-Ray
X-rays are a type of electromagnetic radiation, just like visible light.
An x-ray machine sends individual x-ray particles through the body. The
images are recorded on a computer or film.
● Structures that are dense (such as bone) will block most of the x-ray
particles, and will appear white.
● Metal and contrast media (special dye used to highlight areas of the
body) will also appear white.
● Structures containing air will be black, and muscle, fat, and fluid will
appear as shades of gray.
http://www.nlm.nih.gov/medlineplus/ency/article/003337.htm
Mo RB St Im DA DC BP App Sy
21. Step 1: Imaging
Computed Tomography (CT)
Computed tomography (CT) is a type of imaging. It uses special x-ray
equipment to make cross-sectional pictures of subject.
CT scans are being used for
● Broken bones
● Cancers
● Blood clots
● Signs of heart disease
● Internal bleeding
● Tissue Engineering
http://www.nlm.nih.gov/medlineplus/ctscans.html
http://en.wikipedia.org/wiki/X-ray_computed_tomography
The Nobel Prize in Physiology or Medicine 1979 was awarded jointly to Allan M.
Cormack and Godfrey N. Hounsfield "for the development of computer assisted
tomography"
Mo RB St Im DA DC BP App Sy
23. Step 1: Imaging
micro-Computed Tomography (micro-CT)
X-ray microtomography, like tomography and x-ray computed
tomography, uses x-rays to create cross-sections of a physical object
that can be used to recreate a virtual model (3D model) without
destroying the original object. The prefix micro- (symbol: µ) is used to
indicate that the pixel sizes of the cross-sections are in the micrometre
range. These pixel sizes have also resulted in the terms high-
resolution x-ray tomography, micro–computed tomography (micro-CT
or µCT), and similar terms. Sometimes the terms high-resolution CT
(HRCT) and micro-CT are differentiated, but in other cases the term
high-resolution micro-CT is used.Virtually all tomography today is
computed tomography.
Example:
http://upload.wikimedia.org/wikipedia/commons/d/d8/3D_rendering_of_
a_micro_CT_scan_of_a_piece_of_dried_leaf..ogg
http://en.wikipedia.org/wiki/X-ray_microtomography
Mo RB St Im DA DC BP App Sy
24. Step 1: Imaging
Magnetic Resonance Imaging (MRI):
An MRI (magnetic resonance imaging) scan is an imaging test that uses powerful magnets and radio waves to
create pictures of the body. It does not use radiation (x-rays).
Single MRI images are called slices. The images can be stored on a computer or printed on film. One exam
produces dozens or sometimes hundreds of images.
http://www.nlm.nih.gov/medlineplus/ency/article/003335.htm
http://en.wikipedia.org/wiki/Magnetic_resonance_imaging
Mo RB St Im DA DC BP App Sy
25. Step 1: Imaging
MRI VS CT:
Both MRI and CT scans have their own advantages and limitations.
But an important advantage of MRI is that no ionizing radiation is used and so it is recommended over
CT when either approach could yield the same diagnostic information
Mo RB St Im DA DC BP App Sy
26. Step 1: Imaging
Generating 3D geometry from 2D images
Baghaie, A., & Yu, Z. (2014). Curvature-Based Registration
for Slice Interpolation of Medical Images. In Y. Zhang & J. S.
Tavares (Eds.), Computational Modeling of Objects Presented
in Images. Fundamentals, Methods, and Applications SE - 7
(Vol. 8641, pp. 69–80). Springer International Publishing.
doi:10.1007/978-3-319-09994-1_7
Mo RB St Im DA DC BP App Sy
27. Step 2: Design Approach
First Idea was to print stem cells on
a bio scaffold presented by Langer,
R., & Vacanti, J. at 1993
Which is called Biomimicry method
Langer, R., & Vacanti, J. (1993, 01). Tissue engineering. Science, 260(5110), 920-
926. doi: 10.1126/science.8493529
Mo RB St Im DA DC BP App Sy
28. Step 2: Design Approach
Biomimicry method or Scaffold-base method
Derby, B. (2012, 12). Printing and Prototyping of Tissues and Scaffolds.Science,
338(6109), 921-926. doi: 10.1126/science.1226340
Mo RB St Im DA DC BP App Sy
29. Step 2: Design Approach
Biomimicry method or Scaffold-base method
Bioscaffolding is the use of biocompatible and bioresorbable
materials to construct a 3d structure comparable to the
implant tissue area, in order to promote tissue regeneration
and injury recovery. The structure is seeded with native
differentiable cells and cell adhesion proteins in order to
encourage cell adhesion and tissue regeneration. The matrix
is also consistently porous, which further promotes cell
adhesion and differentiation at a controlled rate. The scaffold
must be designed to withstand and effectively transfer local
stresses evenly across the area of implantation during the
degradation period. Also, the degradation properties are
catered to match the cell differentiation rates and
extracellular matrix deposition rates of the implant site in
order to provide continuous support throughout the repair
process. Materials used for the scaffold construction must be
chosen appropriately to minimize adverse reaction and
maximize cell adhesion and differentiation.
Derby, B. (2012, 12). Printing and Prototyping of Tissues and Scaffolds.Science,
338(6109), 921-926. doi: 10.1126/science.1226340
http://www.bioscaffold.com/
Mo RB St Im DA DC BP App Sy
30. Step 2: Design Approach
Biomimicry method or Scaffold-base method
http://www.nlm.nih.gov/medlineplus/ency/imagepages/1078.htm
Mo RB St Im DA DC BP App Sy
31. Step 2: Design Approach
Biomimicry method or Scaffold-base method
Gerlach, J. C., Johnen, C., Ottoman, C., Bräutigam, K.,
Plettig, J., Belfekroun, C., … Hartmann, B. (2011, April 1).
Method for autologous single skin cell isolation for
regenerative cell spray transplantation with non-cultured cells.
The International Journal of Artificial Organs. IJAO. Retrieved
from http://www.artificial-organs.com/article/method-for-
autologous-single-skin-cell-isolation-for-regenerative-cell-
spray-transplantation-with--non-cultured-cells-ijao-d-10-00181
Mo RB St Im DA DC BP App Sy
32. Step 2: Design Approach
Biomimicry method or Scaffold-base method
Ahn, S., Lee, H., Lee, E. J., & Kim, G. (2014, 12). A direct cell
printing supplemented with low-temperature processing
method for obtaining highly porous three-dimensional cell-
laden scaffolds. Journal of Materials Chemistry B. doi:
10.1039/c4tb00139g
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33. Step 2: Design Approach
“Could we direct write living cells?”
asked by primary investigators and
Defense Advanced Research Program Agency (DARPA)
program manager sometimes in the mid to late 1990s
Ringeisen, B. R., Othon, C. M., Barron, J. A., Young, D., & Spargo, B. J. (2006, 12). Jet-based methods to
print living cells. Biotechnology Journal, 1(9), 930-948. doi: 10.1002/biot.200600058
Mo RB St Im DA DC BP App Sy
34. Step 2: Design Approach
Self-assembly method
Jakab, K., Norotte, C., Marga, F., Murphy, K., Vunjak-Novakovic, G., &
Forgacs, G. (2010). Tissue engineering by self-assembly and bio-printing of
living cells. Biofabrication, 2(2), 022001. doi:10.1088/1758-
5082/2/2/022001
Mo RB St Im DA DC BP App Sy
35. Step 2: Design Approach
Self-assembly method
Prediction Models
Cellular Particle Dynamics (CPD)
Cellular Potts Model (CPM)
I. Kosztin, G. Vunjak-Novakovic, and G. Forgacs,
“Colloquium: Modeling the dynamics of multicellular systems:
Application to tissue engineering,” Rev. Mod. Phys., vol. 84,
no. 4, pp. 1791–1805, Dec. 2012.
F. Graner and J. Glazier, “Simulation of biological cell sorting
using a two-dimensional extended Potts model,” Phys. Rev.
Lett., vol. 69, no. 13, pp. 2013–2016, Sep. 1992.
Mo RB St Im DA DC BP App Sy
36. Step 2: Design Approach
Self-assembly method
Prediction Models Cellular Particle Dynamics (CPD)
I. Kosztin, G. Vunjak-Novakovic, and G. Forgacs,
“Colloquium: Modeling the dynamics of multicellular systems:
Application to tissue engineering,” Rev. Mod. Phys., vol. 84,
no. 4, pp. 1791–1805, Dec. 2012.
Mo RB St Im DA DC BP App Sy
37. Step 2: Design Approach
Self-assembly method
Prediction Models Cellular Particle Dynamics (CPD)
I. Kosztin, G. Vunjak-Novakovic, and G. Forgacs,
“Colloquium: Modeling the dynamics of multicellular systems:
Application to tissue engineering,” Rev. Mod. Phys., vol. 84,
no. 4, pp. 1791–1805, Dec. 2012.
r = position vector of the CP
= friction coefficient
F_1 = the force (due to intracellular interactions) exerted by
CPs inside the nth cell
F_2 = the force (due to intracellular interactions) exerted by
CPs in all the other cells in the system
f = is a manifestation of molecular fluctuations at the coarse-
grained CP level
Mo RB St Im DA DC BP App Sy
38. Step 2: Design Approach
Self-assembly method
Prediction Models Cellular Potts Model (CPM)
Thomas, G. L., Mironov, V., Nagy-Mehez, A., & Mombach, J.
C. M. (2014). Dynamics of cell aggregates fusion:
Experiments and simulations. Physica A: Statistical
Mechanics and Its Applications, 395, 247–254.
doi:10.1016/j.physa.2013.10.037
Mo RB St Im DA DC BP App Sy
39. Step 2: Design Approach
Self-assembly method
Prediction Models Cellular Potts Model (CPM)
F. Graner and J. Glazier, “Simulation of biological cell sorting
using a two-dimensional extended Potts model,” Phys. Rev.
Lett., vol. 69, no. 13, pp. 2013–2016, Sep. 1992.
type associated with cell
surface energy between spins
Lagrange multiplier
the area of the cell
A the target area for the cells of type
Mo RB St Im DA DC BP App Sy
40. Step 2: Design Approach
Cellular Potts Model (CPM)
F. Graner and J. Glazier, “Simulation of biological cell sorting
using a two-dimensional extended Potts model,” Phys. Rev.
Lett., vol. 69, no. 13, pp. 2013–2016, Sep. 1992.
Self-assembly method
Prediction Models
Mo RB St Im DA DC BP App Sy
41. Step 2: Design Approach
Mini-tissues
Mironov, V., Visconti, R. P., Kasyanov, V.,
Forgacs, G., Drake, C. J., & Markwald, R. R.
(2009). Organ printing: tissue spheroids as
building blocks. Biomaterials, 30(12), 2164–74.
doi:10.1016/j.biomaterials.2008.12.084
Mo RB St Im DA DC BP App Sy
42. Step 4: Cell Selection / Differentiated cells
In this method the differentiated cells will be selected for tissue engineering
purposes but here we will focus on cell differentiation process by it self
Mo RB St Im DA DC BP App Sy
43. Step 4: Cell Selection / Differentiated cells
Compartmental models
Continuous process
Mo RB St Im DA DC BP App Sy
44. Step 5: Bio-printing
Binder, K. W., Allen, A. J., Yoo, J. J., & Atala, A. (2011,
12). Drop-On-Demand Inkjet Bioprinting: A Primer.
Gene Therapy and Regulation, 06(01), 33. doi:
10.1142/S1568558611000258
Mo RB St Im DA DC BP App Sy
45. Step 5: Bio-printing
InkJet (Drop on Demand & continuous flow)
Faulkner-Jones, A., Greenhough, S., King, J. A., Gardner, J.,
Courtney, A., & Shu, W. (2013). Development of a valve-
based cell printer for the formation of human embryonic stem
cell spheroid aggregates. Biofabrication, 5(1), 015013.
doi:10.1088/1758-5082/5/1/015013
Mo RB St Im DA DC BP App Sy
46. Step 5: Bio-printing
InkJet (Drop on Demand & continuous flow)
Tasoglu, S., & Demirci, U. (2013, 12). Bioprinting for
stem cell research. Trends in Biotechnology, 31(1), 10-
19. doi: 10.1016/j.tibtech.2012.10.005
Mo RB St Im DA DC BP App Sy
47. Step 5: Bio-printing
InkJet (Drop on Demand)
Tasoglu, S., & Demirci, U. (2013, 12). Bioprinting for
stem cell research. Trends in Biotechnology, 31(1), 10-
19. doi: 10.1016/j.tibtech.2012.10.005
Mo RB St Im DA DC BP App Sy
48. Step 5: Bio-printing
Microextrusion (Continous flow)
Murphy, S. V, & Atala, A. (2014). 3D bioprinting of tissues and
organs. Nature Biotechnology, 32(8), 773–785.
doi:10.1038/nbt.2958
Mo RB St Im DA DC BP App Sy
49. Step 5: Bio-printing
Microextrusion (Continous flow)
Ozbolat, I. T., & Yu, Y. (2013, 12). Bioprinting Toward
Organ Fabrication: Challenges and Future Trends. IEEE
Transactions on Biomedical Engineering,60(3), 691-699. doi:
10.1109/TBME.2013.2243912
Mo RB St Im DA DC BP App Sy
50. Step 5: Bio-printing
Laser-assisted
Odde, D. J., & Renn, M. J. (2000, 12). Laser-guided direct
writing of living cells.Biotechnology & Bioengineering, 67(3),
312. doi: 10.1002/(SICI)1097-0290(20000205)67:33.3.CO;2-6
Mo RB St Im DA DC BP App Sy
51. Step 5: Bio-printing
Laser-assisted (LIFT)
Serra, P. (2006, 12). Laser-induced forward Transfer: A
Direct-writing Technique for Biosensors
Preparation.Journal of Laser Micro/Nanoengineering,1(3),
236-242. doi: 10.2961/jlmn.2006.03.0017
Mo RB St Im DA DC BP App Sy
52. Step 5: Bio-printing
Laser-assisted (modified-LIFT)
Guillemot, F., Guillotin, B., Fontaine, A., Ali, M., Catros,
S., Kériquel, V., ... Amédée-Vilamitjana, J. (2011, 12).
Laser-assisted bioprinting to deal with tissue
complexity in regenerative medicine. MRS Bulletin,
36(12), 1015-1019. doi: 10.1557/mrs.2011.272
Mo RB St Im DA DC BP App Sy
53. Step 5: Bio-printing
Laser-assisted
Guillemot, F., Guillotin, B., Fontaine, A., Ali, M., Catros, S.,
Kériquel, V., ... Amédée-Vilamitjana, J. (2011, 12). Laser-
assisted bioprinting to deal with tissue complexity in
regenerative medicine. MRS Bulletin, 36(12), 1015-1019.
doi: 10.1557/mrs.2011.272
Mo RB St Im DA DC BP App Sy
54. Step 6: Application
Application: Maturation
Cell Sorting
Jakab, K., Norotte, C., Marga, F., Murphy, K., Vunjak-
Novakovic, G., & Forgacs, G. (2010, 12). Tissue engineering
by self-assembly and bio-printing of living
cells.Biofabrication, 2(2), 022001. doi: 10.1088/1758-
5082/2/2/022001
Mo RB St Im DA DC BP App Sy
55. Step 6: Application
Application: Maturation
Tissue Fusion
Jakab, K., Norotte, C., Marga, F., Murphy, K., Vunjak-
Novakovic, G., & Forgacs, G. (2010, 12). Tissue engineering
by self-assembly and bio-printing of living
cells.Biofabrication, 2(2), 022001. doi: 10.1088/1758-
5082/2/2/022001
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56. Mo RB St Im DA DC BP App Sy
Syllabus
Week 2 X-Ray / CT / MRI
Week 3 Image processing /
Volume Rendering
Week 4 Quiz / Project 1
Week 5 Biomaterial Scaffolds
Week 6 CPD & CPM
Week 7 Quiz / Project 2
Week 8 Cell Differentiation *
Week 9 InkJet bio-printer
Week 10 Laser-assisted bio-printer
Week 11 Post-printing processes
Week 12 Final Project presentation
Class attendance 10%
Quiz 1/Project 1 20%
Quiz 2/Project 2 20%
Final Project 50%