Use of the Free Electron Laser for the Noninvasive Determination of Retinal Oxyhemoglobin Saturation by Near Infrared Reflectance Spectrophotometry

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1 Use of the Free Electron Laser for the Noninvasive Determination of Retinal Oxyhemoglobin Saturation by Near Infrared Reflectance Spectrophotometry Ref: Eye, M.C. Escher, 1946

2 Ref: Eye, M.C. Escher, 1946

3 Ref: Eye, M.C. Escher, 1946

4 Ref: Eye, M.C. Escher, 1946

6 Why Is It Important to Determine Retinal Oxygenation? Several Types of Ischemic Retinopathies: Arterial Occlusion Venous Occlusion Ocular ischemic syndrome Retinopathy of prematurity Diabetic retinopathy

7 2000 National Estimates of the Burden of Diabetes Diabetes Prevalence: Diagnosed Undiagnosed Total Diabetic Retinopathy Prevalence: 11.1 million 5.9 million 17.0 million (6.2% of US population) 65,000 diabetics per year develop proliferative DR Leading cause of blindness among 20 to 74 yr old Ref: National Diabetes Information Clearinghouse Research to Prevent Blindness

11 Ref: G.W. Robison, Jr. et al., 1995

12 Coagulation factors Arteriolar hyalinosis Occlusion of terminal arterioles radual Elevated PAI-1 Microthrombi formation Sudden Cotton-wool spots apillary losure Ref: Jacot et al., 1999 Capillary occlusion Areas of Non-perfusion Ischemia Hyperglycemia Hypoxic changes Protein Glycation AGEs VEGF Increased DAG PKCß 2 <ANG-1 >ANG-2 Polyol Pathway Loss of Peri-endothelial Cell contact Reduced angiostatic factors Angiogenesis Preretinal IRMA angiogenesis TIMPs EC Activated Proliferation MMPs ECM proteolysis Pericyte Degeneration (pericyte ghost) BM Thickening Functional changes In EC Microaneurysm Increased growth factors In vitreous Increased vascular Permeability (leakage) Edema Loss of structural support Loss of contractility Changes in Vascular Resistance/BF Hemorrhage Exudates Breakdown Of BRB Extravasation of Pr and growth factors

13 Incident light Backscatter

14 Favorable Attributes of the FEL Short pulsation of the emitted light» Minimizes total retinal irradiance» Compensates for eye movements

15 Vessel Oximetry Incident light Backscatter

16 Scattering Components of the Fundus Sclera RPE Choroid Internal limiting membrane

17 Focal length Approximately 23 mm n= Vitreous humor n = Diameter of Retinal Vessels: Veins: 212 um Arteries: 150 um Rate of flow: 34 ul/min Cornea n=1.377 A-V oxygen difference 2%

19 Vitreous 50% v/v Standard type A immersion oil n = % Mineral spirits n=1.438 n=1.476 Cornea f = 17.2 mm Plano-convex lens Retinal vessels Capillary pipette Internal diameter um Borosilicate glass n=1.472 Phantom retina Spectralon Diffuse reflection 22.6 mm Optical geometry Reflectance properties Rate of flow 34ul/min Aluminum Backing

Optical Absorption of Hemoglobin Molar Extinction Coefficient (cm-1/m) 1000000 100000

20 Optical Absorption of Hemoglobin Molar Extinction Coefficient (cm-1/m) Wavelength (nm) Oxyhemoglobin Deoxyhemoglobin

21 Optical Absorption of Hemoglobin Molar Extinction Coefficient (cm-1/m) High absorption Isobestic points Wavelength (nm) Oxyhemoglobin Deoxyhemoglobin

22 Optical Absorption of Hemoglobin Molar Extinction Coefficient (cm-1/m) Weaker absorption Single Isobestic point Reduced scattering Outside of visible range Wavelength (nm) Oxyhemoglobin Deoxyhemoglobin

23 Favorable Attributes of the FEL Broad tunability of the emitted light.» To rapidly scan a range of 70 to 100 nm» Alternate between visible and near-infrared Strong energy output in the near-infrared region of the spectrum (700 to 900 nm).» Where hemoglobin chromophore signal is attenuated

28 Derivation of Algorithm Consulted References R. Pittman and B. Duling (1975) described the relationship between spectral absorption and oxygen saturation of hemoglobin in microvasculature within visible range. A.P. Sheperd (1975) developed an empirically derived analytical expression relating OD and Hb concentration. Delori (1988) Determined contribution of fundus scattering to OD of hemoglobin at three wavelengths (555nm). Ferrari et al (1989) utilized DNIRS to noninvasively determine cerebral venous Hb saturation (sagittal sinus).

29 r 2 = 0.993

30 Dark Adapted High Oxygen Extraction Profile of Oxygen Tension Choroidal Vessels Outer Segment Choriocapillaris Inner Segment Retinal Photoreceptor Layer ROD Dark-Current Retinal Arteriole Retinal Capillaries

31 Light Adapted Low Oxygen Extraction Profile of Oxygen Tension Choroidal Vessels Outer Segment Choriocapillaris Inner Segment Retinal Photoreceptor Layer ROD Light-Current Retinal Arteriole Retinal Capillaries

32 RPE OS IS ONL OPL INL IPL GC Light-adapted Dark-adapted Ref: Padnick-Silver, Linsenmeier RA. IOVS 44(2): , Linsenmeier RA. J. Gen. Physiol. 88: , 1986

33 In Situ Schematics of Optical System Detector Electro-optic or Acousto-optic Deflector Device Polarizing Prism Output FEL LASER Source Power Supply Fiber optic laser light Fundus camera Deflected Beam

35 Y Regional Oxygen Map High O 2 Low O 2 X

36 Summary Presents the opportunity to study retinal metabolism in a yet unprecedented fashion. Technique may reveal subtle alterations in retinal metabolism that are not discernable with present routine function tests. Could promote a more rational physiologic basis for clinical intervention and delve into the pathogenic mechanisms and possible early diagnosis of diabetic retinopathy, and other retinal ischemic/vascular diseases. Collectively these retinopathies comprise the leading causes of blindness in the industrialized world.

37 Ref: Drawing Hands, M.C. Escher, 1948 THE END

PART 1: GENERAL RETINAL ANATOMY

PART 1: GENERAL RETINAL ANATOMY General Anatomy At Ora Serrata At Optic Nerve Head Fundoscopic View Of Normal Retina What Is So Special About Diabetic Retinopathy? The WHO definition of blindness is