Optical Nanotechnologies in Dermatology. R. Rox Anderson MD Professor, Harvard Medical School Director, Wellman Center for Photomedicine at M.G.H.

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Louisa Greene
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1 Optical Nanotechnologies in Dermatology R. Rox Anderson MD Professor, Harvard Medical School Director, Wellman Center for Photomedicine at M.G.H.

2 Disclosures Cytrellis consultant, equity Sebacia consultant Follica consultant, equity Living Proof consultant, equity Galderma consultant Photomedex consultant, equity Zeltiq research support Stratatech research support I receive royalties from Massachusetts General Hospital per institutional policy

Photomedex consultant, equity Zeltiq research support Stratatech research

3 Problems Worth Solving Tools & Know-how

4 Nanotechnology Feynman (1959, APS): swallow the doctor. Really small micro- and nano-surgical machines This hasn t worked, except in Hollywood Fantastic Voyage, 1966

5 Optical Nanoparticle Evolution First, there were tattoos Now, plasmonic particles Cancer treatment Acne treatment Glucose sensing I expect to see: Wavelength up-converting particles for therapies Photon generation from phonons, E fields, etc Nanoparticle transducers, e.g. photovoltaic, photochemical, induced aggregation/dispersion Light electrical; chemical; mechanical Nanoscale cosmetics, e.g. new coatings for skin

generation from phonons, E fields, etc Nanoparticle transducers, e.g. photovoltaic, photochemical,

7 A B C D 14 million Americans (and rising) have an unwanted tattoo Intracellular, insoluble nanoparticles Short (ns) laser pulses cavitation (steam bubbles) Cell death particle release removal by??? mechanisms Ultrashort (ps) pulses particle fragmentation a little bit better Pharma solutions untapped!? Phagocytosis, Lymphatic flow

8 Confinement of energy in a target Heat: τt d2/4κ for a 100 nm particle, τt 10 ns Pressure: τi d/v for a 100 nm particle, τi 100 ps In 3 separate studies 15 years ago, tattoos were more efficiently removed with ps lasers but no practical laser existed.

100 ps In 3 separate studies 15 years ago, tattoos were more

9 Brauer JA, et al. Successful and rapid treatment of blue and green tattoo pigment with a novel picosecond laser. Arch Dermatol 2012;148: Next: Femtosecond (10-15s) therapeutic lasers in derm

10 Freedom-2 Solution: Microencapsulated Resorbable Pigments Laser Targets Pigment within Microsphere Capsule Breaks Pigment Released And Resorbed Clear, protective microsphere encapsulates bioresorbable pigment Microspheres contain discrete absorption pigment that can be targeted by a specific laser wavelength Laser treatment causes capsule to break and the pigment is exposed Pigment resorbed by body

bioresorbable pigment Microspheres contain discrete absorption pigment that can be targeted by a

11 Microencapsulated Soluble Pigments SEM of tattoo ink capsules 1 mm TEM of tattoo ink capsules 500 nm 1 micron SEM of laser treated capsules 1 mm All components made from biocompatible materials: Polymer materials already used in a number of clinical applications Bioresorbable colorants are FDA approved for use in cosmetics, foods, drugs and medical devices

biocompatible materials: Polymer materials already used in a number of clinical

12 Encapsulated Ink is Stable In Vivo Day 7 Day 60 Freedom-2 Ink Percent Original Intensity India Ink Freedom-2 Ink Conventional Ink Day Encapsulated ink tattoos were as stable as conventional tattoos

Conventional Ink 100 80 60 40 20 0 0 10 20 30 40 50 60 70 80

13 Microencapsulated Ink: Removal with only Nd:YAG laser Percentage Efficacy of Removal Efficacy of Laser Treatments Before TX 11 weeks after one TX Weeks after Treatment p< Weeks after Treatment * 80 p<0.001 * India Ink Freedom 2 Ink The intensity of tattoos rapidly decreased in 2-4 weeks following laser treatment Encapsulated ink tattoos removed significantly better than India ink tattoos Some encapulated ink tattoos were apparently removed in 1 treatment

001 * 70 60 50 40 30 20 10 0 India Ink Freedom 2 Ink The intensity of tattoos rapidly decreased in 2-4 weeks following laser

14 Microencapsulated Ink is Safe Freedom-2 microencapsulated inks behave in vivo as conventional tattoo inks Histological and clinical evaluation following tattoo application and removal show: 100 mm Aggregates of polymeric microspheres within dermal cells No adverse skin reactions No allergic reactions No infections No inflammation No adverse systemic reactions

and removal show: 100 mm Aggregates of polymeric microspheres within dermal cells No

15 Microencapsulated Ink met with Bizarre Economic Failure FDA declined to regulate it. Startup company viewed the tattoo artist, not the tattoo recipient, as primary customer Believe it or not, tattoo artists are conservative conformists Permanent, painful, and risky Launched in boutique shops only The second mouse gets the cheese.?

customer Believe it or not, tattoo artists are conservative conformists Permanent,

16 Plasmon Resonance Au or Ag nanorods, spheres, shells

17 Von Maltzahn G, et al. Computationally guided photothermal tumor therapy using long-circulating gold nanorod antennas Cancer Res. 2009;69:1-9

18 Plasmonic Gold-Ab Nanoparticles: highly selective targeting of T Cells Au Mab (CD8) Cavitation in CD8+ cells after a 30 ps, 532 nm laser pulse Selective CD8+ cell death Pitsillides CM et al. Selective cell targeting with light-absorbing microparticles and nanoparticles. Biophysical Journal 2003; 84:

19 Light-activated nanoparticles vs light-activated drugs 10,000 times more energy efficient Any EMR wavelength region (no quantum energy limitation) Extreme selectivity for target cells Sub-cellular targets possible, and untapped. Little or no metabolism Device, or at least device-like Free pass at the FDA: just call it a tattoo

selectivity for target cells Sub-cellular targets possible, and untapped.

20 Wanted: Dead or Barely Alive Analogy to laser hair removal Can SGs be selectively inactivated?

21 Selective Transfollicular Penetration of Optical Particles ~ nm in Diameter 1. Superimposition of transmission and fluorescent images, in vitro penetration of 320 nm particles in porcine skin after massage. Nanoparticles an efficient carrier for drug delivery into the hair follicles, Lademann, et al., European J of Pharmaceutics and Biopharmaceutics, v. 66, Toll, et al., Penetration Profile of Microspheres in Follicular Targeting of Terminal Hair Follicles, JID, Rolland et al., Site-specific drug delivery to pilosebaceous structures using polymeric microspheres, Pharm Res, 1993

22 Core-shell microparticles: Light Absorbers 150 nm

23 Acne treatment with gold coated particles Clean skin Apply particles topically Massage to deliver them into follicle Remove residual from skin surface Treat with laser at the absorption peak wavelength, combined with skin surface cooling Penetration assist Laser Au nanoshells Formulation Preferential heating and inactivation of sebaceous gland and associated follicle

24 PENETRATION INTO SGS (SWINE) Two Photon Induced Photoluminescence (TPIP) James Tunnel, UT Austin

25 GOLD PARTICLES IN A PHOTOTHERMALLY DESTROYED SEBACEOUS GLAND Courtesy: James Tunnell, PhD, UTAustin Former SG Gold nanoshells (ORANGE)

26 Swine skin: Au nanoshells nm laser exposures (45 J/cm2, 30 ms) cause follicular damage Laser Only 45 J/cm2 Vehicle Only + Laser Shells + Laser

27 Clinical Studies (Poland) A. Owczarek, et al. Phase I: 12 Full-Face Completed enrollment, follow-ups ongoing Phase II: 22 Split-Face Completed enrollment, follow-ups ongoing 27

28 Clinical 2.5 Inflammatory Lesion Data p = 0.03 (n=25) Tx1 Tx2 Tx3 Treatment Period (2 week interval) (n=21) (n=14)

29 Clinical 2.5 Non-Inflammatory Lesion Data (n=25) (n=20) (n=14)

30 02-10-JG-A Non-Polarized, Right Side -72% versus 12W -53% versus 16W Baseline 12W 16W

31 Cosmetics Everyone has the right to improve their looks. There is no clear line between cosmetic and medical concerns in dermatology. The separations between drugs, devices and cosmetics are bogus.

33 Nanoscale Cosmetics Cosmetics by definition are optical Currently we have Light-Scattering particles Light-Absorbing particles and dyes We do not have optical wave interference cosmetics (nanoscale)

34 Incoming Light Back-scattered Light Shows skin color, colortexture and translucence Surface Reflectance - 5-7% for ϑ = 0 - Shows texture & oiliness - Dominates in black skin epidermis dermis fat

35 Anderson RR. Polarized light examination and photography of the skin. Arch Dermatol 1991;127:

36 Anderson RR. Polarized light examination and photography of the skin. Arch Dermatol 1991;127:

37 Reflectance Spectrum of Light from Human Skin UV Infrared Celtic Surface Reflectance African

38 A quarter-λ antireflection coating on skin would suppress surface reflectance, but has never been built. Air (n = 1.0) Antireflection Coating ~100 nm thick AR coating (n ~ 1.25) Stratum corneum (n ~ 1.55)

39 How to build an AR coating for skin? Thickness ~ 100 nm Refractive index ~ 1.25 (very low) Substantive to the skin surface Gas Solid

40 Thanks

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