Guglielmo LanzaniCenter for Nano Science and Technology
Istituto Italiano di TecnologiaDept. of Physics, Politecnico di Milano
Oculus ReparoPolymer Nanoparticles for Rescuing
Vision in Blind Retinas
Center for Nano Science and Technology, Istituto Italiano di Tecnologia, Milan, ItalyMaria Rosa Antognazza, Greta Chiaravalli, Daniele Fazzi, Giovanni Manfredi, Sara Perotto. Alumni: Jonathan Barsotti, Sebastiano Bellani, Caterina Bossio, Eleonora Canesi, Andrea Desii, Michele Garbugli, Ester Giussani, Erica Lanzarini, Lucia Laudato, Francesco Lodola, Matteo Porro, Gabriele Tullii, Elena Zucchetti.
Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Genoa, ItalyFabio Benfenati, Elisabetta Colombo, Mattia Difrancesco, Stefano Di Marco, Ermanno D. Papaleo, Cyril Eleftheriou, Giulia Mantero, Mattia Nova, Anna Rocchi, Dmytro Shmal. Alumni: Mattia Bramini, Marco Dal Maschio, Paul Feyen, Diego Ghezzi,
ISMN-ISOF-IMM-CNR Bologna Italy Giovanna Barbarella, Valentina Benfenati, Francesca Di Maria, Stefano Ferroni, Mattia Zangoli
Ospedale Sacro Cuore – Don Calabria (Verona), ItalyMaurizio Mete, Angela Russo, Grazia Pertile
Department of Health Science, Nuclear Medicine, University of Genoa, 16132 Genoa, ItalyAmbra Buschiazzo, Vanessa Cossu, Gianmario Sambuceti, Flavia Ticconi
Department of Biotechnology and Applied Clinical Science, University of L’Aquila, Italy. Silvia Bisti, Mattia Di Paolo, Rita Maccarone
Animal Facility, National Institute Cancer Research, IRCCS AOU San Martino-IST, 16132 Genoa, ItalyMichele Cilli, Laura Emionite
IBFM-CNR, Milan, ItalyCecilia Marini
Innovhub-SSI, Silk Division, 20133 Milan, ItalyIlaria Donelli, Giuliano Freddi
ISTM-CNR Perugia, ItalyEdoardo Mosconi, Paolo Salvatori, Filippo De Angelis
Istituto Officina dei Materiali CNR-IOM SLACS Cagliari, Cittadella Universitaria, 09042 Monserrato (California), ItalyMaria Ilenia Saba, Alessandro Mattoni
Georgia Institute of Technology, Atlanta, Georgia United StatesJean-Luc 6fYdas,Hong Li
Department of Biology - University of Pisa, ItalyJosé Fernando Maya-Vetencourt
Multi disciplinary collaboration
I b]j Yfg]hUdegli Studi di Milano-Bicocca,Milan, ItalySergio Brovelli, Francesco Bruni, Beatriz Santiago Gonzalez
ISASI-CNR, Naple, ItalyAngela Tino, Claudia Tortiglione
Politecnico di Milano, ItalyChiara Bertarelli, Cosimo D’Andrea, Francesco Scotognella
Università degli Studi di Bari “Aldo Moro”Dr. R. Ragni, Dr. D. Vona, Dr. E. Altamura, Prof. G. M. Farinola
OUTLINE
• Motivation
• Retina Prosthesis
• P3HT and Nanoparticles Photophysics
• Optostimulation mechanism
Il più sofisticato organo di senso
“To suppose that the eye, with all its inimitable contrivances for adjusting the focus to different distances, for admitting different amounts of light, and for the correction of spherical and chromatic aberration, could have been formed by natural selection, seems, I freely confess, absurd in the highest possible degree.”
Charles Darwin
Guglielmo Lanzani
The Retina
Guglielmo Lanzani
Evolution Strategy
George Wald
Nobel Prize in Physiology or Medicine
1967
Octopus
Great salad
The Blind Spot
1 mm
blood vessel-free
Distribuzione spaziale dei fotorecettori
2.3 micron10 micron
Guglielmo Lanzani
A broad field of view
Guglielmo Lanzani
How the brain perceives the world
I fotorecettori rispondono alla luce
Peacock Mantis
Third among the global causes of visual impairment with a blindness prevalence of 8,7%.
The World Health Organization assesses that 50 million persons suffer from AMD symptoms and 14 million persons are blind or severely visually impaired because of AMD.
It is the primary cause of visual deficiency in industrialized countries.
Motivation | Prosthesis | Photophysics | Mechanism
Age-related macular degeneration (AMD)
Retinitis Pigmentosa
Early Symptoms:Decreased night vision, loss of peripheral (side) vision
Late Symptoms:Vision loss, blindness
Inherited disease
1 in 3-4000 people1,5 M people worldwide
Motivation | Prosthesis | Photophysics | Mechanism
Organic Semiconductors Motivation | Prosthesis | Photophysics | Mechanism
IDEAMotivation | Prosthesis | Photophysics | Mechanism
Poly 3 hexhyl Thiophene Rods and Cones
Spectral Response
S n
Motivation | Prosthesis | Photophysics | Mechanism
20
• Motivation
• Retina Prosthesis
• P3HT and Nanoparticles Photophysics
• Optostimulation mechanism
P3HT NANOPARTICLES
P3HT nanoparticles
S n
Chem. Soc. Rev., 2018 10.1039/C7CS00860K
1 µm
10 µm
Motivation | Prosthesis | Photophysics | Mechanism
F. Benfenati
Maurizio Mete Grazia Pertile Grazia Pertile
Motivation | Prosthesis | Photophysics | Mechanism
Nanoparticles in retina
Microinjection
OCT Retina reattachment
No washout over time
P3HT-NPs
Wide retina coverage
P3HT-NPs
Nature Nanotechnology 15 (8), 698-708 (2020)
Motivation | Prosthesis | Photophysics | Mechanism
Pre
Post
30 DPI
240 DPI
Rescue of pupillary reflex in RCS rats subretinally microinjected with in P3HT-NPs
Nature Nanotechnology 15 (8), 698-708 (2020)
Light-Dark Test (5 lux)
Rescue of visually driven behavior in RCS rats subretinally microinjected with in P3HT-NPs
Nature Nanotechnology 15, 698 (2020)
Motivation | Prosthesis | Photophysics | Mechanism
Time Spent in the DarkEscape Latency
Light-evoked metabolic activation of V1 is rescued in dystrophic RCS rats injected with P3HT nanoparticles
240 DPI
Motivation | Prosthesis | Photophysics | Mechanism
VEPs
RCS
Long-Evans
1.0
0
1
0.1
VEP
ampl
itude
Spatial frequency (c per deg)
How to measure visual acuity ?Motivation | Prosthesis | Photophysics | Mechanism
Visual AcuityNature Nanotech 15 (8), 698-708 (2020)Motivation | Prosthesis | Photophysics | Mechanism
• Motivation
• Retina Prosthesis
• P3HT and Nanoparticles Photophysics
• Optostimulation mechanism
P3HT in contact with electrolyte
A
SC
NeAVCε2
2 2=−
ITO
PEl
Nitrogen
Air
Liquid+light
Cexp=180 nF
d < 15 nm
Cg = 17,8 nF(Mott-Schottky)
Nature Photonics 7, 400 (2013), J. Phys. Chem. C 118, 6291(2014)
Surface Polarization Drives Photoinduced Charge Separation at the P3HT / Water Interface
ACS Energy Lett. , 2016, 1 (2), pp 454–463
P. Salvatori, E. Mosconi, M. Saba, A. Mattoni, H. Li, J-L. Brédas, F. De Angelis
Motivation | Prosthesis | Photophysics | Mechanism
Nanoparticle Absorption
Aggregates ~24%
Exciton bandwidth W=33 meV
I. Bargigia et al. ChemBioChem 2018, 19, 1 – 6
Motivation | Prosthesis | Photophysics | Mechanism
0,4 0,8 1,2 1,6 2,0 2,4 2,8
103
2x103
3x103
4x103
5x1036x1037x103
Inte
nsity
(a.u
)
q (Å-1)
200nm ai=0-1° 200nm ai=0.15°
100
010
-20 0 20 400,0
0,5
1,0
KRK Living Cell Water
Time (ps)
#5 αi=0.15°
#4 αi=0.1°
#7 αi=0.05°d100=1.67nm P3HT lamellar stackingd010=0.38nm P3HT π-π stacking
GIWAXS of P3HT NPs (200nm) spry coated on silicon TRPL
L L ~ 12 nm20
0nm
Fabiola Liscio CNR-IMM Bologna (I)
• Motivation
• Retina Prosthesis
• P3HT and Nanoparticles Photophysics
• Optostimulation mechanism
30 DPI 240 DPIP3HT NPs do not promote photoreceptor survival in dystrophic retinas
50 μm
Motivation | Prosthesis | Photophysics | Mechanism
Experimentum crucis
Nature Nanotechnology 15 (8), 698-708 (2020)
10 W/cm2
Office (500 Lux) ~ 25 mW/cm2
Sun Light 104-105 luxTV studio 103 luxOffice 500 luxMoonlight 1 lux
ILLUMINANCE [lux=lm/m2]
Motivation | Prosthesis | Photophysics | Mechanism
Photo-excitation mechanisms
CAPACITIVE FARADAIC
THERMAL CHEMICAL
𝑖𝑖𝑚𝑚 = 10 𝜇𝜇𝜇𝜇
𝐽𝐽𝑚𝑚 = 1𝑘𝑘𝜇𝜇𝑐𝑐𝑐𝑐2
𝑄𝑄𝑚𝑚 = 10𝜇𝜇𝜇𝜇𝑐𝑐𝑐𝑐2
𝑄𝑄𝑚𝑚 = 1𝜇𝜇𝜇𝜇𝑐𝑐𝑐𝑐2
A A-
𝐼𝐼 = 1W𝑐𝑐𝑐𝑐2
Motivation | Prosthesis | Photophysics | Mechanism
𝑧𝑧 = 𝑡𝑡𝑡𝑡𝑡𝑡 × y ≈ 𝑡𝑡 × y ≅ 1,22 𝜆𝜆2p y = 7 � 10−4 𝑐𝑐𝑐𝑐
a=π z2
I (corneal) = 20 lux= 20 lm/m2
λ=555 nm2p=0.1 cm (pupil diameter)
Pupil reflex
𝑃𝑃 = 𝐼𝐼 × 𝜋𝜋𝑝𝑝2
𝐼𝐼𝑅𝑅 =𝑃𝑃𝜋𝜋𝑧𝑧2
= 𝐼𝐼𝑝𝑝2
𝑧𝑧2≈ 15
𝑐𝑐W𝑐𝑐𝑐𝑐2 ≪ 1
W𝑐𝑐𝑐𝑐2
y=1 cm
Motivation | Prosthesis | Photophysics | Mechanism
∆𝑇𝑇 =𝐼𝐼0𝜋𝜋𝑅𝑅𝑁𝑁𝑁𝑁2
4𝜋𝜋𝑘𝑘𝑟𝑟𝐼𝐼0: light intensity (1 mW/cm2)𝑅𝑅𝑛𝑛𝑛𝑛: Nanoparticle radius (175 nm)𝑘𝑘: thermal conductivity of water (0.6 W/mK)𝑟𝑟: distance from nanoparticle centre
𝑟𝑟Nanoparticle heating:
At the particle surface: ∆𝑇𝑇~10_7 K
In VIVO thermal effect can be ruled out
Motivation | Prosthesis | Photophysics | Mechanism
Guglielmo Lanzani
Photo-excitation mechanisms
CAPACITIVE FARADAIC
THERMAL CHEMICAL
𝑖𝑖𝑚𝑚 = 10 𝜇𝜇𝜇𝜇
𝐽𝐽𝑚𝑚 = 1𝑘𝑘𝜇𝜇𝑐𝑐𝑐𝑐2
𝑄𝑄𝑚𝑚 = 10𝜇𝜇𝜇𝜇𝑐𝑐𝑐𝑐2
𝑄𝑄𝑚𝑚 = 1𝜇𝜇𝜇𝜇𝑐𝑐𝑐𝑐2
A A-
𝐼𝐼 = 10𝑐𝑐W𝑐𝑐𝑐𝑐2
Motivation | Prosthesis | Photophysics | Mechanism
Future Perspectives
Transferring to human experimentation
Cure degenerative blindness
Future perspectivesin brain stimulation
Transformational potential:Novel approach for neuronal stimulation and for the cure of retina and brain diseases
ORGANIC NANOPARTICLES
Funding
Premio Nazionale Innovazione
Mr. Monti
Ra.Mo
OLIMPIA
Fondazione 13 Marzo
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