Julie Kornfield, Bob Grubbs Division of Chemistry & Chemical Engineering, Caltech

1. Dan Schwartz Ophthalmology, UCSF Robert Grubbs Chemistry, Caltech Sculpting Implants in situ: Light-Adjustable Intraocular Lens Julie Kornfield, Bob Grubbs Division of Chemistry & Chemical Engineering, Caltech Jagdish Jethmalani & Chris Sandstedt Calhoun Vision

2. Cataract Treatment: • extraction • replacement with an intraocular lens (IOL) • 14 million implants/yr. worldwide • Current IOLs: Cornea Retina Lens Pupil Sclera Motivation The Problem: Imperfections in wound healing and lens positioning create refractive errors (farsightedness, nearsightedness and astigmatism).

3. Clinical Need • Cataract surgery is the most commonly performed surgery in patients over 65 • 50% of patients require spectacles afterward • Defocus, Lateral Displacement, Post-Operative Astigmatism (Unpredictable Wound Healing), Rotation. • 98% of these are within ± 2 D.

4. Matrix Macromer [High mol. wt. poly(siloxane)] [Low mol. wt. poly(siloxane)] Design Principles for New Polymers Photopolymerizable end groups Photoinitiator (Light sensitive) ==> -Low glass transition temperature (-125 C) -Relatively rapid diffusionÆability to modify shape on large length scale -Non-volatile -Insoluble in water

5. hn hn Light-induced changes in shape and refractive index Spatially resolved irradiation "locking" ==> ==> Irradiation profile controlled by: - Transmission mask, - Spatial light modulator, or - Rastered laser - Once the desired shape is achieved, blanket irradiation makes it permanent

7. CCD Camera Test Sample 100 µm pinhole He:Ne Laser f=40 mm f=125 mm Ronchi Ruling 300 Lines/inch Simple Characterization of Lenses • Optical Quality • Controllable Shape Changes • Effective Photolocking • Permanent Shape After “Locking” • Prior to Adjustment, not altered by Ambient Light

8. Example of Power Change Ronchi Interferogram Before Irradiation: Lens quality matches current IOLs Ronchi Interferogram After Irradiation Irradiate 2 min with 2 mW/cm2 at 325nm, allow 3 hr for diffusion: Focal length reduced from 11mm to 4mm!

9. 0.00 -0.50 Diopters -1.00 -1.50 D 0 20 40 60 Adjustments occur Overnight • 12 hours after adjustment is performed, the desired lens power is achieved. • 48 hours after adjustment is performed, irradiation of the entire lens makes it permanent. time post irradiation (hours) Experiments performed at Calhoun Vision.

10. Biocompatibility of Material & Irradiation: in vivo evaluation in rabbit Two weeks after surgery and irradiation, the eye is “quiet”. Explanted lens for evaluation. Calhoun Vision and Dr. Nick Mamalis at the University of Utah, Salt Lake City, Utah

11. Adjustments in vivo are Precise and Predictable Animal-to-animal variability is small. Dose-response relationship measured in the lab holds in vivo, too. Calhoun Vision and Dr. Nick Mamalis at the University of Utah, Salt Lake City, Utah

12. Astigmatic adjustment Increase lens power Decrease lens power Precise Myopic, Hyperopic & Astigmatic Adjustments Control orientation & magnitude. Dose-Response Experiments performed at Calhoun Vision.

13. Standard Slit-Lamp Footprint User Friendly Software Texas Instruments Digital Micromirror Device Unlimited Flexibility for Lens Modifications Clinical Implementation Digital Light Delivery System Designed & Manufactured with Carl Zeiss Meditec AG Developed by Zeiss Meditec and Calhoun Vision.

14. Digital Mirror Device Projects Any Desired Intensity Profile To decrease lenspower To Increase lenspower To correct astigmatism

15. It works in rabbits, but does it work in people? Initial clinical experiments (on blind eyes) did not give the predicted adjustment. Why? Literature on the human cornea was inadequate: Transmission values from 30% to 75% were reported No information on lateral variations in transmission Careful experiments on human donor corneas: Transmission values from 56% to 58% were found Attenuation is greater near the perimeter

16. Results in Clinical Trials Precise, predictable adjustments are achieved in patients.

17. Greyscale image of a tetrafoil fourth-order Zernike correction, projected on a LAL using a digital mirror device 3-D rendering of the Fizeau interference fringes of the LAL 24 hrs after irradiation with the tetrafoil spatial intensity profile. Arbitrary Wavefront Correction C. Sandstedt (Calhoun Vision)

18. Restoring Distance & Near Vision From the Eye Sight website of student Kyle Keenan at Steton Hall University.

19. Strategies for “Built-in Bifocals” Diffractive lens on a Refractive lens Multizone lens

20. Irradiate to Add Multiple Zones 1.9 mm central region 0.5 mm ring +2.3 D Alternating Zones of ± 2 D 2.0 mm central region -2.5 D and 0.6 mm ring +2.8 D 1.8 mm central region 0.6 mm ring +2.8 D Experiments performed at Calhoun Vision.

21. Irradiate to Add a Diffractive Lens Irradiance Profile Phase Contrast Microscope Image Wavefront Image

22. USAF Target Images Calhoun Vision Diffractive LAL +3.2 D Add Distance Focus G4 E3 Near Focus G4 E1 Alcon ReStor IOL (SN#: 893599.049) +3.5 D Add Near Focus G4 E2 Distance Focus G4 E3

23. Irradiation Patterns • Non-linear Response = Complicated Profiles • Currently empirical Cylinder Tetrafoil Need for a theoretical model for systematic design.

24. Predicting Shape Change:Is this a previously solved problem? • Well known: • Polymerization reaction kinetics • Diffusion processes in non-deforming media • Solid deformation caused by external forces • Not so well known: • Deformation driven by diffusion

25. Some Interesting Features • Deformation without external force • Mechanical loading is determined completely within the object • The “load” is imposed by spatially-resolved chemical reaction • Free surface boundary condition • No material enters or leaves • Deformation arises from redistribution of material within the object

26. Diffusion and Deformation in Polymeric Gels • Stress-Diffusion Coupling Model (SDCM) • T. Yamaue and M. Doi (2004) • Restricted to situations in which an externally applied load on a rigid bounding surface drives fluid out of the gel • Mixture Theory approach • J. Shi, K. R. Rajagopal, and A. Wineman (1981) • Externally imposed pressure-drop across the material drives flow through a slab • Requires some ad hoc assumptions regarding constitutive equations and boundary conditions • Variational approach • S. Baek and A. R. Srinivasa (2004) • Gel is swollen in a bath; can be generalized to other choice of closed system • Provides rigorous underpinning for the requisite constitutive equations and boundary conditions.

27. photopolymerization 0 1 diffusion swelling 2 3 Important Processes hn global shape change

28. External Stimulus incorporated via f(x,0) Pertinent Material Properties Mmc f0[A] G0 F(x,t) Deformation Gradient Tensor Important Processes: Relevant Parameters hn f(x,t)

29. Inter-Relationships among the Processes Material Specifications hn Mmc f0[A] G0 External Stimulus Ii (x,t) D I(x,t) f(x,t) rm (x,t) jm (x,t) G(x,t) F(x,t) Global Shape Change Internal Variables Each arrow is a physical (and, therefore, mathematical) relation

30. Material Specifications Mmc f0 G0 D f(x,t) jm (x,t) Diffusion hn [A] External Stimulus Ii (x,t) 1) Diffusion I(x,t) rm (x,t) G(x,t) F(x,t) Global Shape Change Internal Variables

31. f(x,t) F(x,t) Swelling Material Specifications hn Mmc f0[A] G0 External Stimulus Ii (x,t) D I(x,t) rm (x,t) jm (x,t) G(x,t) 2) Swelling Global Shape Change Internal Variables

32. Global Shape Change Material Specifications hn Mmc f0[A] G0 External Stimulus Ii (x,t) D I(x,t) f(x,t) rm (x,t) jm (x,t) G(x,t) F(x,t) 3) Global Shape Change Internal Variables

33. Conclusions & Future Directions • Photosensitive Elastomers for Remote Manipulation • Enable wavefront corrections for static abberrations • Function in air, vacuum and aqueous media • Present interesting theoretical mechanics questions • May find application in “labs-on-a-chip” or space-based optics Acknowledgements Robert Grubbs Chemistry, Caltech Dan Schwartz Ophthalmology, UCSF “That Man May See” FoundationChartrand FoundationCalhoun Vision