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

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

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

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

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

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

9. time post irradiation (hours) -1.50 -0.50 0.00 0204060  Diopters 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. Adjustments occur Overnight Experiments performed at Calhoun Vision.

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

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

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

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

14. Digital Mirror Device Projects Any Desired Intensity Profile To decrease lens powerTo Increase lens powerTo 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. Precise, predictable adjustments are achieved in patients. Results in Clinical Trials

17. Arbitrary Wavefront Correction 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. C. Sandstedt (Calhoun Vision)

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

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

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

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

22. USAF Target Images Calhoun Vision Diffractive LAL +3.2 D Add Distance Focus G4 E3Near Focus G4 E1 Alcon ReStor IOL (SN#: 893599.049) +3.5 D Add Distance Focus G4 E3 Near Focus G4 E2

23. Irradiation Patterns CylinderTetrafoil Non-linear Response = Complicated Profiles Currently empirical 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. Important Processes h 1 diffusion photopolymerization 0 2 swelling 3 global shape change

28. Important Processes: Relevant Parameters h M m     [A] G 0 Pertinent Material Properties External Stimulus (x,0)(x,0) incorporated via F (x,t)F (x,t) Deformation Gradient Tensor (x,t)(x,t)

29. Inter-Relationships among the Processes M m     [A] G 0 Material Specifications h (x,t)(x,t) r m (x,t) I (x,t)I (x,t) G (x,t)G (x,t) F (x,t)F (x,t) j m (x,t) External Stimulus I i (x,t) Internal Variables Global Shape Change D Each arrow is a physical (and, therefore, mathematical) relation

30. [A] Diffusion h r m (x,t) I (x,t)I (x,t) G (x,t)G (x,t) F (x,t)F (x,t) External Stimulus I i (x,t) Internal Variables Global Shape Change M m      (x,t) j m (x,t) D G0G0 Material Specifications 1) Diffusion

31. Swelling M m     [A] G 0 Material Specifications h r m (x,t) I (x,t)I (x,t) G (x,t)G (x,t) j m (x,t) External Stimulus I i (x,t) Internal Variables Global Shape Change D (x,t)(x,t) F (x,t)F (x,t) 2) Swelling

32. Global Shape Change M m     [A] G 0 Material Specifications h (x,t)(x,t) r m (x,t) I (x,t)I (x,t) j m (x,t) External Stimulus I i (x,t) Internal Variables D G (x,t)G (x,t) F (x,t)F (x,t) 3) Global Shape Change

33. 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 Conclusions & Future Directions Acknowledgements “That Man May See” Foundation Chartrand Foundation Calhoun Vision Robert Grubbs Chemistry, Caltech Dan Schwartz Ophthalmology, UCSF