Ординатура / Офтальмология / Английские материалы / Corneal Endothelial Transplant (DSAEK, DMEK & DLEK)_John_2010

such as radial keratotomy, diurnal variation in IOP can lead to fluctuation in corneal refractive power by greater than one diopter (D).15

Metrics of Corneal Biomechanical

Properties

In the terminology of material science, the cornea is a complex composite (of collagen, other proteins, proteoglycans, water, and salts) with non-linear elastic and viscoelastic properties characterized by important local variation in organization in central versus peripheral and anterior versus posterior dimensions. Mathematical modeling of such a complex system is therefore quite difficult, but begins with identification of intrinsic properties of corneal tissue, as described below (Table 1-2).

TABLE 1-2: Descriptors of corneal biomechanical properties

1.Elasticity

2.Viscoelasticity

3.Hysteresis

4.ORA corneal resistance factor

5.Creep

6.Stress relaxation

7.Sheer strength

8.Ocular rigidity

9.PASCAL ocular pulse amplitude

Elasticity (Young’s modulus, E) is an indicator of material stiffness, with a higher modulus corresponding to a stiffer material. For example, a metallic rod would have a higher modulus than a wood rod (Figure 1-1). A perfectly elastic material returns to its original form, when an external stress is withdrawn, in a completely reversible and symmetric manner, i.e., along the same stress-strain pathway.16 Elasticity is traditionally measured ex vivo with an extensiometer that records the force generation required during steady axial elongation of a tissue sample. The slope of stress (force per unit area) over strain (the current length divided by the starting length) is calculated for a representative portion of the curve. A linear approximation can be obtained from the instantaneous slope of the stressstrain curve (tangent modulus) or as a chord between two points on the curve (secant modulus).

A limitation of extensiometer measurement of elasticity is that the range of in vivo corneal elasticity modulus in healthy or diseased tissue is unknown,17 and reports on animal and human tissues can span orders of magnitude.15,18 Additionally, while most biological soft tissues approximate linear elastic behavior when a small range of stresses are introduced, their overall elastic behavior is highly non-linear. Nevertheless, understanding elastic

Figure1-1: The influence of structural and material properties upon the ability to deform the cornea. Bending a single chopstick is usually easy. However, bending three of the same type of chopsticks at once is much more difficult (top row). Hence, a larger deformation will be generated for thinner corneas given the same applied force. This partially explains the underestimation of IOP in eyes with thinner corneas. In contrast, it requires greater pressure to applanate or indent a thicker cornea, which contributes to overestimation of IOP in eyes with thicker corneas. Similarly, much more force is required to bend a steel rod than a wood rod of the same dimensions (middle row). The difference in this case is the elastic properties of the material, specifically Young’s modulus. Steel has a much higher Young’s modulus (w200 000 MPa) than wood (w10 000 MPa); therefore, if all other parameters are the same, it is much harder to deform a steel structure than a wood structure. Corneal curvature is another variable that can affect the accuracy of IOP measurement, possibly because of the difference in the volume of the displaced fluid after a given area is flattened (bottom row).17

properties is important for evaluating the instantaneous response of the cornea to surgery and can affect its subsequent viscous behavior. Some studies have demonstrated, for example, a decrease in stiffness and increase in extensibility of keratoconic tissue relative to normal tissue.19 The elastic modulus was identified by Guirao20 in mathematical modeling as the most influential risk factor for posterior corneal steepening after keratorefractive surgery.

Viscoelasticity extends the biomechanical response of biological tissues into complex mathematical descriptions of viscous fluids, where elastic responses are time and rate dependant.21 Viscoelastic materials return to their pre-stress shape via different stress-strain pathways that depend upon loading rates. Viscoelastic properties can be described through metrics of hysteresis, stress relaxation and creep. Viscoelastic creep is a time-dependent elongation of tissue (or increasing strain) that occurs under a sustained or constant stress (such as IOP).21 The effect of creep is a reduction in effective tissue stiffness, which can lead to a decrease in resistance to stretch. Creep may be a precursor to ectasia, where stressed collagen fibrils undergo a

pathologic weakening without an initial change in length. Once the collagen fibrils are weakened, a gradual stretching then occurs under constant stress or IOP. Viscoelastic stress relaxation refers to a situation where strain is increased then held constant (no more tissue elongation) while a slow but quantifiable time-dependent relaxation of the load is observed (Figure 1-2).

Hysteresis, in general, is a property of physical and biological systems that do not instantly follow the forces applied to them but react slowly or do not return completely to their original state.21 Hysteresis describes a lag between making a change, such as increasing or decreasing power, and the response or effect of that change. Whereas a rubber band can be described as elastic because is springs back to its original shape at the same rate as when it is stretched, a putty exhibiting viscoelastic behavior quickly assumes a new shape when pushed upon but will not immediately return to its original shape when the mechanical pressure is released. Another example of hysteresis is a thermostat set at 80 degrees, which actually regulates the room temperature between 78 and 82 degrees. In broad terms, corneal hysteresis can be thought of as a metric of the ability of the cornea to absorb energy.

Shear strength describes stromal resistance to lamellar sliding and bending. The shear resistance provided by collagen interweaving and other matrix forces has been

estimated from metrics such as the interlamellar cohesive strength.7 Corneal shear strength is low relative to its tensile strength, but provides a mechanism for tensile load transfer between lamellae.9

Volumetric distension experiments provide a measure of whole globe stiffness, or ocular rigidity. The slope of a pressure-volume curve can be recorded during such experiments. Ocular rigidity is non-linearly dependent upon IOP and has been shown to increase with age.2 The utility of metrics describing ocular rigidity may be limited with respect to their impact on the understanding of corneal surgery, given the contributory role of the scleral and uveal tissue to ocular rigidity.

New Techniques for in vivo Measurement of Corneal Biomechanical Properties

While ex vivo diagnostic techniques, such as extensiometry, have provided valuable information on the biomechanical nature of normal and pathological corneas,22 a new era is dawning in biomechanical research with the development of techniques to measure structural and biomechanical properties in vivo. Imaging of the cornea can now be performed by confocal microscopy,23 very high frequency,24

and optical coherence technology (See Section 2: Corneal Imaging). Holographic interferometry uses optical comparison to evaluate corneal elasticity.25,26 Another method, dynamic corneal imaging, uses stepwise central indentation of the cornea and computer analysis of videokeratography images during indentation to assess corneal elastic properties in vivo.27 A commercially available device that uses a dynamic, bidirectional, airpuff applanation to measure in vivo IOP and corneal viscoelastic properties is the Ocular Response Analyzer ([ORA], Reichert Ophthalmic Instruments, Depew, New York, USA).28

Biomechanics and Intraocular

Pressure

Increasing attention has focused on the impact of corneal parameters, particularly central corneal thickness (CCT), on the measurement of IOP.29 IOP measurements have been demonstrated to vary with CCT using the Goldmann applanation,30 pneumotonometry,31 and non-contact tonometry.32 The deformation of the cornea during applanation is determined by an interaction of the external applied force with the intrinsic properties of the cornea. With the same applied force, a larger deformation will be produced for less rigid corneas. This partially explains the underestimation of IOP in eyes with thinner corneas. In contrast, it requires greater force to applanate a more rigid cornea, partially explaining the overestimation of IOP in eyes with thicker corneas. Additionally, alteration of corneal biomechanics by LASIK flap creation and excimer laser ablation affects the postoperative measurement of intraocular pressure (IOP) using Goldmann applanation tonometry (GAT). The impact of pachymetry on intraocular pressure readings has been recently highlighted by the Ocular Hypertension Treatment Study,36 which demonstrated an inverse relationship between CCT and the risk of developing glaucoma.

Goldmann tonometry is a static measurement, calculating IOP from the force applied during a steady state applanation of the cornea.37 Its design is based upon a number of assumptions, including that all corneas were of uniform thickness (i.e., 500 microns), that the eye’s volume was spherical and that the cornea behaved biomechanically as an infinitely thin and perfectly flexible membrane. Corneal biomechanics embody far more than central pachymetry alone, and include viscosity, elasticity, hydration, regional pachymetry and other factors.17 As an example, whereas corneas from patients with keratoconus are generally thinner than average and biomechanically

“floppy”, corneas from patients with Fuchs’ dystrophy are thicker than normal while they are also biomechanically similar to keratoconus.28 Other illustrative examples are the decrease in corneal rigidity following radial keratometry29 and hyperopic LASIK33 with subsequent drop in static applanation tonometry readings, yet little or no change in central corneal pachymetry. These examples highlight the complexity and potential flaws of simplistic attempts to linearly offset IOP based upon pachymetry alone.

Alternative techniques that dynamically derive IOP from the corneal movement in response to a rapid air pulse simultaneously assess and compensate (to varying degrees) for the effect of the cornea’s viscous and elastic qualities on IOP measurement. Reichert’s ORA28 utilizes a metered collimated air pulse to applanate the cornea and an infrared electro-optical system to record inward and outward applanation events. The air-pulse deforms the cornea through an initial applanation event (peak 1), then beyond into concavity and then gradually subsides, allowing the cornea to rebound through a second applanation (peak 2) (Figure 1-3). Corneal hysteresis (CH) is defined as the difference between the applanation pressure at peak 1 (P1) and peak 2 (P2), so that CH = P1–P2. This dynamic assessment of corneal biomechanical properties yields metrics of both the cornea’s viscous and elastic qualities. Whereas corneal hysteresis may reflect mostly corneal viscosity, corneal resistance factor (CRF, defined by a linear function of P1 and P2) may predominantly quantify corneal rigidity. The equation used to determine CRF is: CRF = P1– 0.7 × P2.

Pascal Dynamic Contour Tonometry (PDCT, Swiss Microtechnology AG; Port, Switzerland) employs a concave

Figure 1-3: The waveform generated from the ocular response analyzer identifies the pressure difference, or hysteresis, during inward (peak 1) and outward (peak 2) applanation events during non-contact tonometry.43

tip to “contour match,” rather than applanate, a convex segment of the central cornea and, thus, may be relatively independent of the effects of CCT or surgical intervention on IOP assessment.38-40 The instrument dynamically records over 100 IOP measurements per second, measuring IOP fluctuations throughout the cardiac cycle and digitally displaying the average diastolic IOP. Ocular Pulse Amplitude (OPA), the difference in IOP between systole and diastole (IOP systolic – IOP diastolic), is also reported and may be a marker for overall ocular rigidity,2 although it is also affected by ocular blood flow.

Clinical Applications of Hysteresis

and Corneal Biomechanics

Corneal hysteresis in normal eyes has been reported to range from 5.0 to 18.7, with a mean hysteresis of 9.6 to 12.7 mm Hg.28,41,42 Hysteresis values did not show a statistical difference in a cohort of 21 normal patients between right and left eyes, with a mean difference of 0.4 mm Hg (p>0.08).42 Hysteresis values appear to be relatively insensitive to diurnal effects (Figure 1-4), although intrasubject variations have been observed. The correlation of CCT with CH and CRF was 0.59 and 0.62, respectively.41 Lower hysteresis was associated with visual field progression in a glaucomatous population.43

Corneas with keratoconus (Figure 1-5), Fuchs’ dystrophy and post-refractive surgery demonstrate a general decrease in corneal hysteresis compared to corneas in normal eyes.28 The low corneal hysteresis in the Fuchs’ eyes is seen despite unusually thick, but edematous, corneas. However, the large 99% confidence interval of corneal hysteresis seen in normal controls has considerable overlap with diseased

Figure 1-5: Distribution of hysteresis values in 339 normal (blue) and 60 keratoconic (red) eyes. Mean hysteresis for normal and keratoconic eyes was 9.6 mm Hg and 8.1 mm Hg, respectively.28

and post-surgical corneas, limiting its diagnostic value as a single metric in individual cases. What may turn out to allow better diagnostic differentiation are the significant changes seen in applanation waveform in diseased or postsurgical corneas. Keratoconic and post-LASIK corneas appear to have similar applanation signal morphology, indicating reduced or low corneal viscoelastic properties in both cases (Figure 1-6). Investigations to quantify morphologic characteristics of the ORA waveform are now underway that attempt to extract additional corneal biomechanical information. Corneal hysteresis may be useful as a qualification factor for LASIK in corneas that have similar CCT but display significantly different waveform properties. Thus, the ORA waveform, along with the derived biomechanical metrics of corneal hysteresis and resistance factor, may provide a more complete characterization of corneal biomechanical properties than corneal thickness alone and is perhaps a better tool for assessing refractive surgery qualification and outcomes.

Modeling Based Upon

Biomechanical Metrics: Implication for Surgical Planning

Models of the cornea have taken many forms, including complex computational models that integrate structural, biomechanical and optical corneal properties.44 Dupps and

Figure 1-6: ORA applanation signal in keratoconic and post-LASIK eyes shows depressed applanation peak amplitudes and altered applanation peak widths. A: Case 1-4 are from keratoconic eyes.

B:preand post-LASIK waveforms show a decrease in hysteresis postoperatively, along with reduced applanation peak amplitudes.

C:waveform post penetrating keratoplasty shows marked alternation in the applanation signal, with increased noise during the applanation events.28

Wilson16 have proposed a strategy (Figure 1-7) for such modeling. By comparing these models to clinical experiments, useful models can be created, which can significantly improve our understanding of corneal biomechanics and allow us to better predict refractive effect after corneal transplant procedures.45 Results of finite element simulations indicate that significant changes in corneal refractive power could be introduced if refractive

Figure 1-8: Major biomechanical loading forces in the cornea and a model of biomechanical central flattening associated with disruption of central lamellar segments. A reduction in lamellar tension in the peripheral stroma reduces resistance to swelling and an acute expansion of peripheral stromal volume results. Interlamellar cohesive forces and collagen interweaving, whose distribution is greater in the anterior and peripheral stroma and is indicated by grey shading, provide a means of transmitting centripetal forces to underlying lamellae. Because the central portions of these lamellae constitute the immediate postoperative surface, flattening of the optical surface occurs, resulting in hyperopic shift. The degree of flattening is associated with the amount of peripheral thickening. This phenomenon is exemplified clinically by PTK-induced hyperopic shift but is important in any central keratectomy, including PRK and LASIK. Simultaneous elastic weakening of the residual stromal bed may occur, and the threshold for inducing irreversible (plastic) or progressive (viscoelastic) steepening (or ectasia) is a matter of great clinical concern.16

procedures (Figure 1-8) are combined with corneal transplants. This requires high precision resections of corneal grafts, which may improve with the application of femtosecond laser technology.46 Treatment of the cornea with riboflavin and UVA to increase collagen crosslinking47 may also allow us to modulate the stiffness of the cornea before or after corneal transplant procedures.

Conclusion

A review of the histology of corneal fibrils indicates evidence for inextensibility, under a wide range of physiologic conditions, which appears to be the basis for stability of refraction and corneal curvature. Given the major biomechanical loading forces of the normal cornea, surgical disruption of the central corneal lamellae may lead to central corneal flattening and peripheral thickening.1 Studying the dynamics of corneal shape changes that occur in response to collimated air pulses (via the Ocular Response Analyzer) may provide a basis for understanding the biomechanical effects of incisional and lamellar corneal surgery. The in vitro interactions of corneal fibroblasts and a fibrillar collagen substrate48 can be combined with advanced structural and functional in vivo diagnostic imaging techniques to develop mathematical models of the

wound healing and viscoelastic features of the normal and post-surgical cornea. As our understanding of these processes improves, so will our ability to offer rational interventions and strategies for further improving the predictability of keratorefractive surgery and minimizing its complications.

References

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19.Edmund C. Corneal topography and elasticity in normal and keratoconic eyes. A methodological study concerning the pathogenesis of keratoconus. Acta Ophthalmol Suppl 1989; 193:1-36.

20.Guirao A. Theoretical elastic response of the cornea to refractive surgery: risk factors for keratectasia. J Refract Surg 2005; 21:176-85.

21.Dupps WJ. Biomechanical modeling of corneal ectasia. J Refract Surg 2005;21:186-90.

22.Andreassen TT, Simonsen AH, Oxlund H. Biomechanical properties of keratoconus and normal corneas. Exp Eye Res 1980;31:435-41.

23.Sherwin T, Brookes NH. Morphological changes in keratoconus: pathology or pathogenesis. Clin Exp Ophthalmol 2004;32: 211-7

24.Reinstein DZ, Silverman RH, Raevsky T, Simoni GJ, Lloyd HO, Najafi DJ, Rondeau MJ, Coleman DJ. Arc-scanning very high frequency digital ultrasound for 3D pachymetric mapping of the corneal epithelium and stroma in laser in situ keratomileusis. J Refract Surg. 2000;16:414-30

25.Smolek MK. Holographic interferometry of intact and radially incised human eye-bank corneas. J Cataract Refract Surg 1994; 20:277–86.

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28.Luce DA. Determining in vivo biomechanical properties of the cornea with an ocular response analyzer. J Cataract Refract Surg 2005:31:156-62.

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Introduction

The cornea forms the transparent anterior part of the eye. It protects the contents of the eye and serves as the major refractive element in it. The principal layers of the cornea are the epithelium, Bowman’s layer, stroma, Descemet’s membrane, and the endothelium (Figure 2-1). The basis of understanding corneal physiology is to address the physiological importance of the corneal epithelial, endothelial barrier and metabolic pump functions. If either limiting layer is compromised, the cornea will increase in thickness, become edematous and show decrease in transparency. Loss of the corneal endothelial barrier will result in a much greater corneal edema than with loss of the epithelial barrier. This chapter addresses the fundamentals of corneal physiology to provide a foundation for understanding the normal as well as the pathological corneal conditions.

Figure 2-1: The cornea is a layered structure consisting of the epithelium (E), Bowman’s layer (Bw), stroma (St), Descemet’s membrane (De), and the endothelium (En).

Corneal Thickness and Hysteresis

Corneal thickness is one of the important parameters of corneal health. Pachymetry is a useful tool in both cornea and glaucoma practices. Thin cornea can indicate keratoconus or other ectasic diseases, whereas a thickened cornea usually correlates with endothelial dysfunction and secondary corneal edema. Applanation tonometry underestimates the intraocular pressure in eyes with thin corneas and overestimates it in thick corneas.1-3 The early measures of corneal thickness using manual optical

pachometers reported an average corneal thickness of 520 micrometers.4-7 Nowadays, because of practicality issues, automatic acoustic pachometers became the gold standard for measuring the corneal thickness despite calibration uncertainties.

The corneal hysteresis phenomenon is a result of viscoelastic dampening in the cornea, i.e., the tissue’s ability to absorb and dissipate energy (See also Chapter 1, Corneal Hysteresis and Biomechanics of the Normal Cornea). Studies have shown that subjects whose corneas exhibit low corneal hysteresis, which can be thought of as having a “soft” cornea, are probable candidates for a variety of ocular diseases and complications. This parameter can be measured by the Ocular Response Analyzer from Reichert (Depew, NY),8 which utilizes a patented applanation process. Hysteresis, as an indicator of the viscoelastic properties of the cornea, can be used to enable a more accurate tonometry measurement.9-12 Clinical research has shown that this measurement may be a valuable tool for identifying and classifying conditions such as corneal ectasia, Fuchs’ dystrophy as well as glaucoma.13

Physiology of the Corneal

Epithelium

The corneal epithelium serves as a barrier between the environment and the corneal stroma. Through its interaction with tear film, it forms a smooth refractive surface on the cornea.

Barrier Function

The barrier is formed as a balance of cell shedding; basal cell division and the renewal of basal cells maintain epithelial cells by centripetal migration of new basal cells originating from limbal stem cells. The epithelial cells move from the basal layer to the surface of the cornea, progressively differentiating until the superficial cells form two layers of flattened cells. These are encircled by tight junction known as zonula occludens which serve as a semipermeable, highly resistant membrane. This barrier prevents the movement of fluid from tears into the stroma and also protects the cornea and intraocular structures from infection by pathogens.14

Refractive Function

The microvilli on the surface of the most superficial epithelial cells are covered with a glycocalyx that interacts with the mucin layer of the tear film. This leads to smoothening of the surface of the cornea forming the smooth optical surface required for clear vision.15