PhD Proposal

Biomedical Engineering Depatrment

Faculty of Engineering
Helwan University
PhD Student: Hassan Mostafa Ahmed Hassan Fahmy Gabr __________________________________________

PhD Proposal
Assessment of Corneal Biomechanics Properties Post Refractive Surgery
1. Abstract:
A stable shape for corneas experiencing refractive surgery has to be sustained so as to elude post
refractive surgery de-compensation. This leads to visual complications and unsatisfactory procedure
recovery. Variation in corneal lamellae and collagen fibres is induced by recent LASER refractive
surgical procedures utilizing LASER ablation and disruption techniques. Conserving a steady
response of central apex flattening and peripheral steepening in an elastic cornea pre- and post-
procedure is the ultimate purpose of successful refractive surgery. Early diagnosis of ectatic corneal
disorders and better understanding of corneal pathogenesis is achieved by assessment of corneal
biomechanical properties.

Noninvasive prediction of corneal biomechanics and structural strength is not quite accurate pre- and
post-refractive surgery despite the great advance in assessment methods. This is due to the alteration
happening to the corneal structure post-refractive surgery. Patients who undergo radial keratotomy
(RK), photorefractive keratectomy (PRK), laser-assisted in situ keratomileusis (LASIK), or small
incision lenticule extraction (SMILE), should have their stress concentration maps, potential creak
zones, and potential errors in intraocular pressure (IOP) measurements determined for successful
post refractive surgery assessment. Developing a noninvasive and accurate method for estimating
corneal biomechanics post-refractive surgery will help identifying many corneal pre- and post-
operative pathogenesis.

Estimating biomechanical properties for normal and pathogenic corneal tissue pre- and post-
operative is the ultimate objective of this research. Accounting for its high localization; ultrasonic
estimation of soft tissue biomechanics will be used as non-invasive method for corneal tissue
biomechanical properties estimation. Designing an ultrasound probe that is capable of generating a
highly localized acoustic force inside thin corneal tissue, as well as picking up the minimal
displacement profile generated in response to this acoustic force is another objective of this research.
Displacement tracking method will be utilized for assessment of soft tissue mechanical properties
related to the investigated soft tissue. Ultrasound probe simulations will be carried out to optimize
the probe design. FEM simulations will take place to precisely estimate in-situ corneal tissue
biomechanics.

2. Introduction:
The cornea is the first and most powerful refractive surface of the optical system of the eye. The
production of an accurate image in the retinal receptors requires the cornea to be transparent and
have a suitable refractive power [1–3]. The structural integrity of the cornea can be altered in the
refractive surgery modifying its refractive properties. These procedures have been developed
empirically without detailed knowledge of corneal behavior. Measuring the change in corneal shape
1
PhD Proposal
Biomedical Engineering Depatrment
Faculty of Engineering
Helwan University
PhD Student: Hassan Mostafa Ahmed Hassan Fahmy Gabr __________________________________________

has been available in the past decade through computerized analysis of the reflection of
photokeratoscopic ring surface of the cornea (corneal topographer). Little is known about the
behavior of the internal structure of the cornea. Although the ultrastructure was analyzed by electron
microscopy, the role of each one of the layers has not been examined in detail. The tools to measure
and understand these processes arise from mechanical engineering and have been used in other
medical specialties, such as orthopedics, which evaluates quantitatively the requirements of the
prosthesis. Many of these methods are not suitable for soft tissue such as the cornea, but the general
principles can be applied.

The refractive power of the cornea depends on the curvature at its anterior and posterior surfaces, its
thickness, and the refractive index difference between the air and the aqueous humor. The radius of
curvature on the anterior surface of the cornea varies from the center (apex) toward the periphery. It
is steeper in the central and somewhat flattened at the periphery. Average values of 7.8 and 6.7 mm
from anterior to the posterior surface. Figure 1 shows the anatomy of human cornea.

Figure 1. Anatomy of human cornea.

At the apex, a wide range of variation of the radius of curvature of 7–8.5 mm is compatible with
good visual function, and in pathological conditions increases even more the spectrum. Short radii
result in refractive power and high myopia. Conversely, large rays give a low dioptric power and
farsightedness. Furthermore, the central corneal curvature is often not equal in all meridians. The
focus of the rays reflected by a point object does not form a point image on the retina. In these cases
occurs astigmatism (a, without; stigma, point). The curvature of the cornea changes somewhat with
age. It is more spherical in childhood and changes to the rule astigmatism (more curved horizontal
meridian) in adolescence. Then again it becomes more spherical in adulthood to turn against the rule
astigmatism (steepest vertical meridian) with senility. The thickness also varies from the center to
the periphery. This causes the difference in curvatures of the anterior and posterior surfaces. It has an
average value of 0.5 mm center, increasing toward the periphery at an average of 1.2 mm at the
limbus (limit of the cornea with sclera). The corneal thickness is determined largely by corneal
hydration that increases with increasing hydration and slightly with the age.

Gradual loss of the spherical shape of cornea happens in the Keratoconus disease process yielding a
conical shape of cornea [4], [5]. The Lack of sufficient in vivo clinical data as well as lack of proper

2
PhD Proposal
Biomedical Engineering Depatrment
Faculty of Engineering
Helwan University
PhD Student: Hassan Mostafa Ahmed Hassan Fahmy Gabr __________________________________________

clinical instrument monitoring the corneal pathological changes results in opaque nature of the
Keratoconus disease etiology.

Accurate measurement of intra-ocular pressure as well as early detection of corneal diseases can be
obtained from information held by corneal viscoelastic properties. Amongst these properties, the
corneal shape is essential for visual acuity. Cornea shape is affected by biomechanical properties
where it is made from load bearing collagen and is exposed to mechanical forces such as fluctuating
intraocular pressure arising from blood circulation.

Noninvasive estimation of these properties leads to local cornea stiffness estimation and results in
assessing more corneal pathologies like Keratoconus. In addition, it could highlight the mechanical
effects induced by corneal transplant using femtosecond laser or therapy based on
Riboflavin/UltraViolet-A Corneal Cross Linking (UVA CXL). In terms of glaucoma treatment, it is
very important to have a precise and stable IOP measurement because any fine tuning in corneal
elasticity could lead to a dramatic shift in IOP.

3. Background:
Scheimpflug imaging of corneal deformation in response to a rapid air-puff disturbance has been
proposed [6], [7], along with other imaging-based techniques including optical coherence
tomography (OCT) [8], [9], Brillouin microscopy [10], and high-frequency ultrasound [11].
Acoustic radiation force has also been used as an alternative to air-puff to apply a rapid and localized
force on the cornea [12–14].

Advances in ultrafast ultrasound scanners; utilizing high frame rates of several thousand frames per
second; leads to quantitative assessment of tissue viscoelastic properties locally. Amongst them,
tissue Young’s modulus (E) is the most important [15–18]. A recently developed method Supersonic
Shear Imaging (SSI) holds for isotropic homogeneous medium. This medium has the property of
directly relating the stiffness of the medium and the propagating shear wave speed. This theoretical
relation is stated by E = 3Cs2 where  is the tissue density (assumed to be constant in soft tissue,
typically 1000 kg/m) and Cs is the local propagation speed.

Ariza-Gracia et al. reported that the noncontact tonometry test is not sufficient to evaluate the
individual mechanical properties and a complete in vivo characterization of the preoperative cornea,
in which the anterior cornea presents compression in a range of 0–0.4 MPa individually [20].

Hollman et al. proposed an ultrasound elasticity microscope system for strain imaging of corneal
tissue with a compression plate on the corneal surface of ex vivo porcine eyes. This method provided
an image of the relative strain distribution rather than a quantitative estimate of Young’s modulus
[21].

3
PhD Proposal
Biomedical Engineering Depatrment
Faculty of Engineering
Helwan University
PhD Student: Hassan Mostafa Ahmed Hassan Fahmy Gabr __________________________________________

Tanter et al. acquired a quantitative measurement of the Young’s modulus ex vivo on porcine
corneas based on their proprietary Supersonic Shear Imaging (SSI) system, which is an innovative
ultrasound scanner with a very high frame rate [22].

Shih et al. designed a dual confocal ultrasound transducer for both the excitation and detection of
tissue movement and obtained a high-resolution strain image based on qualitative acoustic radiation
force imaging techniques [23].

Urs et al. reported the use of acoustic radiation force imaging as non-invasive method for evaluating
corneal biomechanical changes induced by cross-linking therapy [24]. In addition to ultrasound
elastography, several other techniques have been proposed in recent years.

Liu’s group described a quantitative ultrasound spectroscopy method for in vivo characterization of
corneal biomechanical properties [25].

4. Wider Objectives:
a. Developing an accurate, noninvasive and in-situ measurement technique for corneal
viscoelasticity that will facilitate the understanding of the pathogenesis and early diagnosis of
ectatic corneal disorders.
b. Calculating the biomechanical properties for cornea pre- and post-refractive surgeries so as to
assess the quality of the procedure and to early identify the pathologic changes.
c. Developing an alternative method to measure in-vivo and in-situ IOP precisely.

5. Statement of Proposed Research:

The proposed research is constituted of three major stages to reach its final output. These three
stages are optical coherence tomography and FEM, scatterrers model and Acoustic Radiation Force
Impulse (ARFI) imaging stages.

A. Optical Coherence Tomography (OCT) and Finite Element Model (FEM) stage:

In this stage, a full 3D surface layered model for cornea shall be obtained so as to be fed to the FEM
to build the general geometric shape of the cornea. The 3D surface layered model is obtained by
applying recent digital image processing techniques on 2D full stack of B-mode OCT ocular anterior
segment images. The output 3D layered model is fed to Finite Element Analysis (FEA) software in
order to create FEM corresponding to cornea structure.

The FEM is then given the biomechanical properties of corneal tissue so that it exhibits the same
behavior of living eye. ARFI map is imported to simulate the applied acoustic impulse on the cornea.
Output displacement, stresses and strains are exported from the FEA software to Matlab software for
subsequent imaging and calculation procedure.

4
PhD Proposal
Biomedical Engineering Depatrment
Faculty of Engineering
Helwan University
PhD Student: Hassan Mostafa Ahmed Hassan Fahmy Gabr __________________________________________

B. Scatterrers Model stage:

This stage is dedicated to generate scatterrers phantom; that is coincident with the cornea model; in
order to be used by the ultrasound probe to simulate the normal ultrasound (US) B-mode imaging
procedure. This stage has two outcomes; the first is to optimize the US probe design to obtain
optimum B-mode images of proper axial, lateral and temporal resolution; and the second outcome is
to have a reference frame for the ARFI imaging procedure in order to estimate the biomechanical
properties of the corneal tissue.

C. Acoustic Radiation Force Impulse (ARFI) imaging stage:

It is at this stage where the acoustic force 2D map is generated and optimized for being applied to
the FEM. The ARFI map is generated by using FOCUS tool; a tool used by Matlab software to
simulate the acoustic pressure from US probe. This ARFI is generated according customized US
probe, so optimization of the probe is essential in the previous stage in order to have both proper
pressure field and optimum US image.

5
PhD Proposal
Biomedical Engineering Depatrment
Faculty of Engineering
Helwan University
PhD Student: Hassan Mostafa Ahmed Hassan Fahmy Gabr __________________________________________

The proposed research can follow the presented diagram.

2D OCT US probe design 2D Corneal

stack parameters anatomy image

3D Complete Complete US probe Obtain corresponding

Simulated 2D ARFI design scatterrer phantom
FEM
map
model

Apply Tissue Obtain Reference

Properties Frame

Complete
FEM
model

Simulated Update
Scatterres
FEM
Phantom

Elastography
Images Stack

Corneal Tissue
Estimated
Biomechanics

6
PhD Proposal
Biomedical Engineering Depatrment
Faculty of Engineering
Helwan University
PhD Student: Hassan Mostafa Ahmed Hassan Fahmy Gabr __________________________________________

6. Methods of Procedures:
The proposed research methodology for utilizing these previous stages can be stated by the
following steps:

1. Obtaining a 3D surface layered model of cornea based on corneal optical coherence tomography
(OCT) imaging modality.
2. Generating a Finite Element Model (FEM) corresponding to corneal tissue based on the 3D
surface layered model.
3. Assigning the corneal tissue biomechanical properties obtained from relevant literature survey.
4. Ultrasound probe design and ARFI map generation.
5. Scatterrers model generation using anatomical corneal phantom image obtained from
corresponding survey.
6. Reference frame imaging using the designed US probe parameters and the corneal phantom
image.
7. Applying ARFI map to the FEM and obtaining relevant output of displacement profiles for the
whole model.
8. Exporting the 2D displacement map to the scatterrers model and re-imaging the scatterrers model
using ARFI imaging technique.
9. Estimating the displacement profiles for the corneal structure in order to calculate the corneal
biomechanical properties.

7. Plan Time Table:

Task Estimated Time Period
1. Literature Survey - One month.
2. OCT Data Collection - One month.
3. Obtaining 3D Surface Layered Model. - One month.
4. FEM generation and biomechanical properties - One month.
assigning.
5. Preliminary Results for Shear Wave Speed and - One month.
Young’s Modulus from FEM.
6. Ultrasound Probe Design. - One month.
7. Scatterrers Model generation. - One month.
8. Preliminary Results from Scatterrers model - One month.
using optimized US probe.
9. Estimation of Biomechanical Properties for - One month.
Normal Corneal Tissue.
10. Estimation of Biomechanical Properties for - Two months.
Abnormal Corneal Tissue.
11. Review of the presented research and future - One month.
work.

7
PhD Proposal
Biomedical Engineering Depatrment
Faculty of Engineering
Helwan University
PhD Student: Hassan Mostafa Ahmed Hassan Fahmy Gabr __________________________________________

8. Facilities and Equipment:

N/A

9. Budget:
N/A

10.References:
[1] R. Moses, W. Hart(h), Fisiologia del Ojo. Aplicacion clinica. (Adler. Panamericana, Bs.As.
1988).
[2] R. Berne, M. Levy, Fisiologia. (Panamericana, Bs. As., 1986).
[3] D. Schanzlin, J. Robin, Corneal Topography. Measuring and Modifying the Cornea (Springer,
New York, 1992).
[4] Y. S. Rabinowitz, “Keratoconus,” Surv. Ophthalmol., vol. 42, no. 4, pp. 297–319, Jan./Feb.
1998.
[5] J. H. Krachmer, R. S. Feder, and M. W. Belin, “Keratoconus and related noninflammatory
corneal thinning disorders,” Surv. Ophthalmol., vol. 28, no. 4, pp. 293–322, Jan./Feb. 1984.
[6] N. Q. Ali, D. V. Patel, and C. N. McGhee, “Biomechanical responses of healthy and
keratoconic corneas measured using a noncontact scheimpflug-based tonometer,” Invest.
Ophthalmol. Vis. Sci., vol. 55, no. 6, pp. 3651–3659, May 2014.
[7] Y. Hon and A. K. Lam, “Corneal deformation measurement using Scheimpflug noncontact
tonometry,” Optometry Vis. Sci., vol. 90, no. 1, pp. e1–e8, Jan. 2013.
[8] M. R. Ford, A. S. Roy, A. M. Rollins, and W. J. Dupps, “Serial biomechanical comparison of
edematous, normal, and collagen crosslinked human donor corneas using optical coherence
elastography,” J. Cataract Refractive Surg., vol. 40, no. 6, pp. 1041–1047, Jun. 2014.
[9] M. Singh et al., “Evaluating the effects of riboflavin/UV-A and rosebengal/ green light cross-
linking of the rabbit cornea by noncontact optical coherence elastography,” Invest.
Ophthalmol. Vis. Sci., vol. 57, no. 9, pp. OCT112–OCT120, Jul. 2016.
[10] G. Scarcelli, R. Pineda, and S. H. Yun, “Brillouin optical microscopy for corneal
biomechanics,” Invest. Ophthalmol. Vis. Sci., vol. 53, no. 1, pp. 185–190, Jan. 2012.
[11] K. W. Hollman, R. M. Shtein, S. Tripathy, and K. Kim, “Using an ultrasound elasticity
microscope to map three-dimensional strain in a porcine cornea,” Ultrasound Med. Biol., vol.
39, no. 8, pp. 1451–1459, Aug. 2013.
[12] M. Tanter, D. Touboul, J.-L. Gennisson, J. Bercoff, and M. Fink, “High-resolution
quantitative imaging of cornea elasticity using supersonic shear imaging,” IEEE Trans. Med.
Imag., vol. 28, no. 12, pp. 1881–1893, Dec. 2009.
[13] Y. Qu et al., “Acoustic radiation force optical coherence elastography of corneal tissue,” IEEE
J. Sel. Topics Quantum Electron., vol. 22, no. 3, May/Jun. 2016, Art. no. 6803507.
[14] E. Mikula, K. Hollman, D. Chai, J. V. Jester, and T. Juhasz, “Measurement of corneal
elasticity with an acoustic radiation force elasticity microscope,” Ultrasound Med. Biol., vol.
40, no. 7, pp. 1671–1679, Jul. 2014.
8
PhD Proposal
Biomedical Engineering Depatrment
Faculty of Engineering
Helwan University
PhD Student: Hassan Mostafa Ahmed Hassan Fahmy Gabr __________________________________________

[15] M. Tanter, J. Bercoff, L. Sandrin, and M. Fink, “Ultrafast compound imaging for 2D motion
vector estimation: Application to transient elastography,” IEEE Trans. Ultrason., Ferroelect.,
Freq. Contr., vol. 49, no. 10, pp. 1363–1374, Oct. 2002.
[16] J. Bercoff, S. Chaffï, M. Tanter, L. Sandrin, S. Catheline, M. Fink, J.-L. Gennisson, and M.
Meunier, “In vivo breast tumors detection using transient elastography,” Ultrasound Med.
Biol., vol. 29, no. 10, pp. 1387–1296, 2003.
[17] J. Bercoff, M. Tanter, and M. Fink, “Sonic boom in soft materials: The elastic Cerenkov
effect,” Appl. Phys. Lett., vol. 84, no. 12, pp. 2202–2204, 2004.
[18] J. Bercoff, M. Tanter, and M. Fink, “Supersonic shear imaging: A new technique for soft
tissues elasticity mapping,” IEEE Trans. Ultrason., Ferroelect., Freq. Contr., vol. 51, no. 4, pp.
396–409, Apr. 2004.
[19] Imaging Corneal Biomechanical Responses to Ocular Pulse Using High-Frequency
Ultrasound.
[20] Ariza-Gracia, M. A., Zurita, J. F., Pinero, D. P., Rodriguez-Matas, J. F. & Calvo, B. Coupled
biomechanical response of the cornea assessed by non-contact tonometry, A simulation study.
PLoS One 10, e0121486 (2015).
[21] Hollman KW, Emelianov SY, Neiss JH, Jotyan G, Spooner GJ, Juhasz T, Kurtz RM,
O’Donnell M. Strain imaging of corneal tissue with an ultrasound elasticity microscope.
Cornea 2002;21:68–73.
[22] Tanter M, Touboul D, Gennisson JL, Bercoff J, Fink M. High-resolution quantitative imaging
of cornea elasticity using supersonic shear imaging. IEEE Trans Med Imaging 2009;28:1881–
1893.
[23] Shih C, Huang C, Zhou Q, Shung KK. High-resolution acousticradiation- force-impulse
imaging for assessing corneal sclerosis. IEEE Trans Med Imaging 2013;32:1316–1324.
[24] Urs R, Lloyd HO, Silverman RH. Acoustic radiation force for noninvasive evaluation of
corneal biomechanical changes induced by crosslinking therapy. J Ultrasound Med
2014;33:1417–1426.
[25] Liu J, He X, Pan X, Roberts CJ. Ultrasonic model and system for measurement of corneal
biomechanical properties and validation on phantoms. J Biomech 2007;40:1177–1182.

11.Appendices:
N/A