1- Introduction to Biomedical Nanotechnology
GBM8810 : Biomedical Nanotechnology
Michel Meunier
Content
1.1 What is nanotechnology?
1.2 Economical aspects of nanotechnology
1.3 Nanotechnology: Some history
1.4 Biomedical nanotechnology
1.5 Introduction to biomedical nanophotonics
and nanomagnetism
1.6 Research done by Michel Meunier and his team
1.7 Syllabus
2
Section 1.1
What is nanotechnology?
What is : Nano ?
Human
1-2 m
1000
1000
1000
1000
Skyscraper
1 km
Radius of the Moon
1700 km
Pinhead
1-2 mm
Bacteria
2-10 mm
1000
Diameter of the Sun
1 400 000 km
Nanoparticles
10 nm
1000
4
It’s all about the size!
2m
5 nm
4 x 108
If we were the
nanoparticle :
Soleil
14 x 108 m
2m
4 x 108
5
Introduction
-9
1 nm = 10 m
Nanotechnologies : 0.1 – 100 nm
It’s not a nano-kilometer = 1 mm !!!
Nanoscience:
(1) At least one dimension is expressed on the nm scale (0.1-100 nm)
(2) Special property specifically related to this dimension
Nanotechnologies:
Applications of these phenomena
Nano-engineering:
Design and synthesis of nanomaterials and nanosystems
Phenomenon at the nanoscale
Macroscopic effect
6
Nanotechnology: 21st century technology
2000-2100
7
The growth of nanotechnology
8
Dimension in nanotechnology
9
Magnitude
Genes
ADN
(10-100nm in
length)
(2nm width)
Atom
1Å
Genes
(10-100μm)
Virus
(2nm width)
1nm
Cells
(20-450nm)
10nm
100nm
1μm
10μm
100μm
Proteins
(5-50nm)
Brain
membrane
(<20nm)
10
Nanotechnology
11
When physics, chemistry and biology merge
Biomedical
Nanotechnologies
12
Bottom-up and Top-down
13
Section 1.2 Economical aspects of
nanotechnology
Applications of nanotechnology
15
Applications of biomedical nanotechnology
16
Applications of biomedical nanotechnology
17
Nanotechnology market
18
Nnaomaterials market
19
Nanotechnology in Medical devices
20
Approx: 6.5 B$ in 2030
21
Section 1.3 Nanotechnology:
Some history
Nanotechnology in the 4th century!
Example: Lycurgus cup (4th century)
Reflected light
Au (40 ppm) and Ag (300 ppm)
Ag-Au Alloy : 50-100 nm
Ag:Au ratio : 7:3
Transmitted light
Without knowing it, they used metallic nanoparticles and their
optical properties in the manufacture of art pieces!
23
Nanotechnology: Some history
Drexler’s Nano-robot
24
There’s plenty of room at the bottom!
December 29th 1959
Richard Feymann
1918-1988
Nobel Prize: 1965
I would like to describe a field, in which little has been
done, but in which an enormous amount can be done in
principle. This field is not quite the same as the others in
that it will not tell us much of fundamental physics but it is
more like solid-state physics in the sense that it might tell us
much of great interest about the strange phenomena that
occur in complex situations. Furthermore, a point that is
most important is that it would have an enormous number
of technical applications.
What I want to talk about is the problem of manipulating and
controlling things on a small scale.
What would happen if we could arrange the atoms one by one the
way we want them?
25
The phenomena at the NANO scale are different!
When we get to the very, very small world, we have a lot of new things
that would happen that represent completely new opportunities for
design. Atoms on a small scale behave like nothing on a large scale, for
they satisfy the laws of quantum mechanics. So, as we go down and
fiddle around with the atoms down there, we are working with
different laws, and we can expect to do different things. We can
manufacture in different ways. We can use, not just circuits, but some
system involving the quantized energy levels, or the interactions of
quantized spins, etc.
At the atomic level, we have new kinds of forces and new kinds of
possibilities, new kinds of effects. The problems of manufacture and
reproduction of materials will be quite different. I am, as I said,
inspired by the biological phenomena in which chemical forces are
used in repetitious fashion to produce all kinds of weird effects.
(one of which is the author).
26
And the biomedical…
…….it would be interesting in surgery if you could swallow the
surgeon. You put the mechanical surgeon inside the blood vessel
and it goes into the heart and ``looks'' around. (Of course the
information has to be fed out.) It finds out which valve is the faulty
one and takes a little knife and slices it out. Other small machines
might be permanently incorporated in the body to assist some
inadequately-functioning organ.
Nanosurgeon !
27
Section 1.4 Biomedical
nanotechnology
Nanosurgeon: The fantastic voyage (1966)
Director: R. Fleische
Actors: Stephen Boyd
and Raquel Welch
A submarine is shrunken to microscopic size and injected
into the blood stream with a small crew to remove the
blood clot with a laser.
29
The nanotechnology approach
Nanoclinic
Magnetic materials:
-Position control
-Treatment
-Imaging (MRI)
Optical materials:
- Treatment
- Imaging (optics)
30
Nanomedicine
31
Theranostics
Therapy and diagnostics
Theranostics is the term used to describe
the proposed process of diagnostic
therapy for individual patients - to test
them for possible reaction to taking a
new medication and to tailor a treatment
for them based on the test results.[1] It is
formed by the combination of the terms
"Therapeutics" and "Diagnostics".
Drug delivery
Therapy
Diagnostic
A path to personalized
medecine !
32
Theranostics
33
Applications of nanomaterials in medicine
B.Y. Kim et al, «nanomedicine»,
The New England Journal of Medicine,
363, 2434, December (2010).
34
Important characteristics of nanomaterials
The structure and/or composition allows:
– To include a «cargo» (probes or therapeutic agents).
– Drug delivery activated by an external stimulus.
– Diagnostic (by contrast agents or others) which can
be activated by an external stimulus.
– Functionalization to facilitate the penetration of the
cell membrane by endocytosis.
– Functionalization to target cells or biological sites
expressing a specific receptor.
35
Biological constraints
At the biological level, the nanomaterial:
– Is not toxic.
– Is preferentially eliminated from the body by
biodegradation or excretion.
– Is non-immunogenic (does not stimulate an immune
response).
– Escapes in the blood from by the RES
(Reticuloendothelial system: eliminates foreign
objects).
36
Types of nanomaterials for nanomedicine
Organic
- Polymers
- Lipid-based
- Dendrimer
Inorganic
- Semiconductors
- Metallic
- Magnetic
- Dielectric (silica)
Combined/multifunctional
- PEBBLE (Probe Encapsulated By Biologically Localised Embedding)
- Nanoclinic
37
Materials for biomedical nanotechnology
38
Nanocarriers
39
Some organic nanomaterials
Dendrimers
M. Shi J. Mat Chem. (2009)
Lipid based nanocarriers
Li Gan Drug Discovery Today (2012)
40
Combined and multifunctional nanomaterials
Kopelman’s Group
PEBBLE: Probe Encapsulated By Biologically
Localised Embedding
It is a nanoscale device consisting of sensor
molecules entrapped in a chemically inert
matrix. It enables optical measurement of
changes in intracellular calcium levels, pH
and other biologically significant chemicals.
Prasad’s Group
Nanoclinics are ~30nm silica shells that
can encapsulate various optical,
magnetic or electrical probes as well as
externally activable therapeutic agents.
41
NBIC
The integration and synergy of the four technologies ( nano-bio-info-cogno = NBIC)
originate from the nanoscale, where the building blocks of matter are established.
This picture symbolizes the confluence of technologies that now offers the promise
of improving human lives in many ways, and the realignment of traditional
disciplinary boundaries that will be needed to realize this potential. New and more
direct pathways towards human goals are envisioned in working habits, in economic
activity, and in the humanities.
42
NBIC
43
Section 1.5 Introduction to
biomedical nanophotonics and
nanomagnetism
Photonics and magnetism
Light; photons (wavelength, impulsion, intensity, etc.)
Nanoclinic
Light; photons
Localised
diagnostic
Localised
treatment
Heat, electrons
Chemical reactions
Bubbles
Magnetic field (gradient, alternative)
45
Section 1.5.1 Introduction to
biomedical nanophotonics
Quantum dots
Nanocrystals from a few nm to tens of nm
can be synthesized.
Different size of CdSe nanocrystals
TEM: Transmission Electron Microscopy
Video: http://www.nibib.nih.gov/HealthEdu/ScienceEdu
47
Quantum dots for biomedical applications
Imaging of three
types of QDs
48
Metallic nanostructures
TEM
Colloidal solution
Au
nanospheres
AuAg alloy nanospheres
(increase of the [Au])
Au nanorods
Au nanorods
(increase of the aspect
ratio )
Ag nanoprisms
Ag nanoprisms
(increase of the side sizes)
49
Controlled drug release - 1
Principle: Trapping drug molecules in nanostructures that are
sent into the body. The drug can then be released locally by
irradiating specific regions with a laser.
A.
A. We produce gold nanocages
B.
0 ml 0.2 ml 0.5 ml 0.6 ml 0.8 ml 1.0 ml 1.6 ml
0.8
Extinction
wnloaded from informahealthcare.com by Ecole Polytechnique-Crea on 01/09/12
For personal use only.
1.0
0.6
0.4
0.2
➢ Hollow structure
➢ Porous surface that
lets the drug through TEM image of gold nanocages
0.0
400
600
800
1000
Wavelength (nm)
Extinction spectrum
Figure 1. A. Phot ograph and (B) UV--visible spect ra of gold nanocages t un
t he amount (volume list ed above each t race) of chloroauric acid added i
f rom [26] . C. Transmission elect ron microscopy (TEM ) image of silver nan
gold nanocages. M odif ied w it h permission f rom [17] . D. Scanning elect r
TEM inset .
➢ Possibility of an
infrared resonance
Modified with permission from [44] .
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Controlled drug release -B. 2
O
O
Br
Br
O
A.
B.
O
O
S
S
O
B. We cover the nanocages with NIPAAm
a polymer PMDETA
that changes
H O/MeOH
conformation at high temperature
NIPAAm Overnight, RTCuBr
PMDETA
O
CuBr
HN
HN
AAm
Trapped drug
Laser off
O
H2O/MeOH
Overnight, RT
+
H2N
Laser on
AAm
H2N
Laser on
O HN
O
Br
n
m
H2N
O
H2N O
O
Laser off
Br
O
2
+
O
O HN
S
O
S
Br
O
O
S
O
S
n
NH OO
m
NH2
O
n
n
pNIPAAm Br m
O
NH O
O
D.
Transition from Hydrophilic➔Hydrophobic @39 oC
Hydrophilic phase
100
D.
5
Drug delivery
3
2
100
We use80a pulsed laser (790 nm for 2 to 5
min) in the near
80 infrared to locally increase
the temperature
of the gold nanocages, the
60
phase changes , thus releasing the drug.
Cell viability (%)
4
Cell viability (%)
Concentration ( M)
S
O
.
0
S
1
Hydrophobic phase
0
2
4
6
60
40
8
10
C-1
C-2
2 min
5 min
51
Controlled drug release - 3
Drug release over time
C1 : Control
C2 : Laser without nanocages
2 min : Nanocages+laser for 2 min
5 min : Nanocages+laser for 5 min
Release of a chemotherapy drug (Dox: Doxorubicin)
Breast cancer cells
52
Hyperthermia treatment - 1
Principle : The use of nanostructures
that absorb radiation from a laser to
locally increase the temperature of
the human body and induce cell
death.
A.
Cobley, Au, Chen & Xia
C.
B.
0 ml
30 nm
0.8
Extinction
althcare.com by Ecole Polytechnique-Crea on 01/09/12
al use only.
We can use :
0.2 ml 0.5 ml 0.6 ml 0.8 ml 1.0 ml 1.6 ml
1.0
D.
0.6
0.4
0.2
0.0
400
600
800
1000
Wavelength (nm)
Nanoparticles
Nanorods
100 nm
Nanocages
Figure 1. A. Phot ograph and (B) UV--visible spect ra of gold nanocages t uned t o a range of specif ic w avelengt hs by cont rolling
53
Hyperthermia treatment - 2
810 nm,
~ 20 ps,
82 MHz
Without nanocages
Nanocages
Target
goldIllumination.
nanocages t o cancer cells5
f ormin
phot otIllumination.
hermal dest ruct ion and drug delivery
5 ing
min
P=1.5W/cm2
P=1.5W/cm2
5 minutes
E.
C.
Cellular damage (%)
A.
Living cells
(Calcein; Green
Fluorescence)
With Au cages
Without Au cages
60
50
40
30
20
10
0
informahealthcare.com by Ecole Polytechnique-Crea on 01/09/12
or personal use only.
0
B.
D.
Cellular damage (%)
Dead cells
(Ethidium
homodimer;
Red
fluorescence)
F.
1
3
4
5
2
Power density (W/cm 2)
6
With Au cages
Without Au cages
40
35
30
25
P=4.77W/cm2
20
15
10
0
0
500 mm
2
10
6
8
4
Time of laser exposure (min)
Colbey et al Expert Opin. Drug Deliv. (2010) 7(5)
Figure 3. Qualit at ive and quant it at ive analysis of t he phot ot hermal ef f ect of gold nanocages in vit ro. A, B. The cells54
w ere
incubat ed w it h gold nanocages and illuminat ed f or 5 min at a pow er densit y of 1.5 W/cm 2 and examined w it h a f luorescence
mm3
Hyperthermia: In-vivo treatment
FIG. 4. Experiment using 8.5 mL/gm. Tumor volume change at
baseline was 41.3, 49.6 and 50.3 mm3 in GNS+L, S+L and C groups. At
day 21 tumor was absent in 14 of 15 tumors in treated group. C
tumors tripled in volume and there was no difference between S+L
and C at day 21 (182.7 and 182.2 mm3).
GNS+L: Gold Nano Shell + Laser
S+L: Only laser
C: Control
Laser diode 820nm , 4W/cm2, 3 min, 18h after injection
Core-Shell : 110nm diameter, 10nm shell
Temperature reached de 65oC
Lal, S. et al. Nanoshell-enabled photothermal cancer
therapy: impending clinical impact. Accounts of chemical
research(41)12, 1842-1851, 2008
55
Nanosurgery by laser: Therapy
Light nanoscapel
Nanosurgery of living cells for
transfection
- J. Baumgart…..M. Meunier,
Biomaterials, 33, 2345 (2012)
- E. Boulais, R. Lachaine et M.
Meunier,(2012)
Schematic representation of the different stages of the
application of the light nanoscapel to perform cell
transfection
56
Neuroscience
The Brain: The last frontier!
Imaging the Brain !
MRI
Imaging the Brain!
Optical
Electrical stimulation of neurons
Optical stimulation of neurons
57
Neuronal stimulation with functionalized AuNPs
Before stimulation
Stimulated region
Calcium signal (ΔF/F)
5 µm
5 µm
5 µm
Time points of stimulations
Highly localised stimulation possible (Orange and Blue regions unaffected)
Repeated stimulations possible
58
F. Lavoie-Cardinal...M. Meunier, Sci Rep. 2016
58
In-vivo transfection: Opthalmology
- Laser + nanoparticles: Virus-free technique
- To develop a new technique to deliver small
interfering RNA (siRNA) into retinal cells
- Treatment of Age related Macular degenerescence
AuNP
Laser
Collaborateurs: HMR
Prof P. Sapieha
Prof S. Costantino
Dr. Ariel Wilson
Rodent retina
M. Meunier et al Patent 16/168,982 (2019)
59
In-vivo laser mediated siRNA delivery
350mW
700mW
700mW
Confocal microscopy of in-vivo optoporated rat retinal cells
- Kv1.1-AuNPs, Cy5-siRNA (red, fluorescently labeled siRNA)
- Laser (100 fs pulses, 800nm, 80 MHz)
A, Wilson …M. Meunier, NanoLetters (2018)
~60% success rate
60
Gold nanoparticles based COVID detection
COVID-19
61
Section 1.5.1 Introduction to
biomedical nanomagnetism
Nanomagnetism in biomedical applications
The human body is transparent to magnetic fields. We
are not limited to the optical penetration limit.
Nanoclinic
Magnetic NPs
• Can be handled remotely (without
contact) by applying external
magnetic fields. (In some cases, this
can eliminate the need for
"targeting.")
• Imaging: observe the magnetic
response spatially (example: MRI)
or by scanning a focused field.
• Design personalized treatments for
a given patient: hyperthermia,
embolization, etc.
63
Localized hyperthermia
Michele K. Lima-Tenorio et al, Inter. J. of Pharmaceutics, 493, 313-327 (2015)
64
Magnetic nanoparticles in MRI imaging
Fig. 7.
Ex vivo optical imaging and in vivo MR imaging of brain tumors for a mouse treated with
Cy5.5 labeled SPIONs (left) and an untreated mouse (right). Optical spectrum gradient bar
corresponds to increasing fluorescent intensity. Color gradient bar for MR images
corresponds to increasing r2 values. (Veiseh O, et al. Cancer Research. 2009; 69(15):6200).
65
Section 1.6 Research done by
Michel Meunier and his team
Laser Processes and Plasmonics Laboratory
(LP2L)
BioNanoPhotonics Laboratory (BNPL)
Michel Meunier
Fellow of SPIE, OSA, CAE
LP2L - BNPL
Mission
Develop and Model New:
-
Ultrafast laser processes
Nanomaterials for biomedical nanotechnologies
Bioplasmonic devices
Nanotherapy approaches
Nanodiagnostics approaches
Infrastructure
- Plasmonics systems
- Spectroscopy and imaging: (AFM, NSOM,…)
- Cell culture and biochemistry facilities
- In-vivo facilities (Coll: HMR; CHUM; Ste-Justine)
- Ultrafast lasers facilities: (45fs, 120fs) Topaz, Dazzler
- Other lasers: Nd:YAG
www.polymtl.ca/lp2l/
Été 2012
270m2 ; 5M$
LP2L
Laser Processing and Plasmonics Laboratory
Nanomedicine Engineering
Fundamentals
aspects
Physics of plasmonic
nanostructures
Imaging plasmonics
NPs
Physics of ultrafast
laser interaction with
plasmonic
nanostructures
Quantum Raman
Design,
optimisation and
engineering
Plasmonic devices
Biosensors
Plasmonic Nanomaterials
Optical imaging system
Applications
in medicine
Opthalmology
(H.Maisonneuve-Rosemont)
Pathology (Cancer)
(CHUM; Photon Etc, ORS, Vega
BioImaging; Roche)
Laser nanosurgery system
Oncology Therapy
(CHUM, UBC)
Gene/Drug delivery
Gene therapy (UBC)
69
Nanomedicine Engineering
Academic
$$$
FRQ-NT
CIHR
NSERC
TransMedTech
NMIN
CQDM
Axelys
GBM8810E Biomedical
Nanotechnology
Hospital
Collaborators
LP2L
Nanomedicine
Engineering
TransMedTehch
Biomedical
nanophotonic
platform
Academic
Collaborators
(Poly and ULB)
Industrial
Collaborators
Commercial
VegaBioImaging
70
Plateform on Biomedical Nanophotonic
https://www.polymtl.ca/transmedtech/recherche-et-developpement/plateformestechnologiques/nanotech/nanophotonique-biomedicale
- Our mission is to develop diagnostic and therapeutic technologies based on
plasmonic and optical properties of colloidal nanoparticles.
-
Besides supporting researchers, this platform offers a wide spectrum of services
(e.g., fabrication of plasmonic nanoparticle, design of optical devices, and
provision of different ultrafast lasers for theranostic applications).
- These newly developed technologies, supported by TransMedTech, respond to
the growing needs in healthcare for a fast and accurate diagnosis facilitating
personalized therapy.
71
VegaBioImaging
A cancer Diagnostics Company
Enabling quantitative , multi-target and fast protein testing in
biopsies
This technology responds to the growing needs in healthcare for fast
and accurate diagnosis and personalized therapies.
http://vegabioimaging.com/
72
LP2L Personnel
Prof Michel Meunier
STAFF (5)
Research associate: Dr. Sergiy Patskovsky
Research associate: Guillaume Ortiz
Postdoc: Isabelle Largillière
Postdoc: Leonidas Agiotis
Technician: Yves Drolet
STUDENTS (4PhD, 2M, 1B)
Jennyfer Zapata (PhD) (with Isabelle Brunette, MD)
Jie OuYang (PhD) (with Denis Seletsky)
Flavie Martin (PhD)
Amélie Baron (PhD)
Charline Courbon (M)
Marjolaine Malgérie (M)
Marie-Ève Lapointe (B)
73
Nanomedicine Research: Mission
Nanomedicine Engineering
Development of new and efficient nanotherapies and nanodiagnostics to address
challenging medical problems and to improve the quality of life of patients
In collaboration with researchers, medical doctors and industries:
Development of enabling technologies such as:
Laser technologies for medicine
Nanophotonics medical devices
BioImaging
Laser triggered gene/drug nanodelivery
Portable optical nanobiosensors
Quantum plasmonics sensors
74
General Objectives of projects
General objectives
Develop and model new plasmonic nanostructures and ultrafast laser
nanoprocesses for theranostic biomedical applications, such as
imaging, biodetection and therapy.
NanoPatho
Develop a quantitative and multiplex immunolabeling protocol and diagnostic tool
for clinical cytology samples using immunoplasmonic NPs markers
NanoEye
Develop an efficient laser gene therapy method and system for the front
and the back of the eye for ocular diseases
NanoCancer
Develop an efficient laser trigger nanotherapy
NanoBiosensors
Develop an efficient quantum sensor and biosensor
75
Collaborations
Universities
Industry
Networks
Funding agencies
Hospitals
76
Looking for graduate students
Looking for graduate students
Master-Research
PhD
Topic:
Biomedical nanotechnology
- for cancer diagnostics
- for laser therapy
77
Section 1.7 Syllabus
Syllabus
Goal: Introduction to nanophotonics and nanomagnetism for
biomedical applications
CONTENT
Lectures: 41 hours
Mid-term exam and final exam: 4 hours
Laboratories/ homework/Review: 7 hours
Total: 52 hours
4h/week X 13 weeks= 52 hours
EVALUATIONS
Laboratories/Homeworks: (40%) team of 3 students
Mid-term exam (30%) (individual)
Final exam: 40% (individual)
79
GBM8810E: Content
Course
presentation
Introduction to biomedical
nanotechnology (4h)
Simulation lab
PART A
Optical properties of
nanomaterials (9h)
Homework-1
PART B
Synthesis of nanomaterials (7h)
Homework-2
PART C
Biomedical nanophotonics (11h)
Homework-3
Synthesis lab
Functionalisation lab
Imaging lab
Hyperthermia lab
Part D
Biomedical Nanomagnetism (7h)
PART E
Carbon-based Nanoparticles (3h)
Homework-4
80
Prerequisites
• GBM3805 or equivalent
• Mathematics: Algebra, calculus, differential equations
• Modern physics: notions in quantum mechanics;
photons and electrons; energy states in atoms and
molecules;
• Materials: metals and semiconductors; Drude; Notions in
optical and magnetic properties of solids;
• Electromagnetism: Maxwell’s equations; electric and
magnetic fields.
• Optics: Electromagnetic waves; lasers.
• Thermodynamics: Heat transfer
• Biochemistry
81
• Cell biology