U.S. patent application number 17/201961 was filed with the patent office on 2022-02-24 for performing a procedure based on monitored properties of biological tissues.
The applicant listed for this patent is The General Hospital Corporation, Intelon Optics, Inc.. Invention is credited to Dominik Jean Michel Beck, Niaz Karim, Giuliano Scarcelli, Jang Lawrence Hyun Yoo, Seok-Hyun Yun.
Application Number | 20220054004 17/201961 |
Document ID | / |
Family ID | |
Filed Date | 2022-02-24 |
United States Patent
Application |
20220054004 |
Kind Code |
A1 |
Yoo; Jang Lawrence Hyun ; et
al. |
February 24, 2022 |
PERFORMING A PROCEDURE BASED ON MONITORED PROPERTIES OF BIOLOGICAL
TISSUES
Abstract
A procedure is performed on at least one section of an ocular
component. At least one first electro-magnetic radiation is
provided to the section so as to interact with at least one
acoustic wave in the ocular component. At least one second
electro-magnetic radiation is produced based on the interaction.
Multiple portions of the second electromagnetic radiation are
received. Each portion was emitted from a different corresponding
segment of the section. A visco-elastic modulus of the section is
monitored based on the multiple portions during the procedure.
Feedback is applied to the procedure based at least in part on the
monitored visco-elastic modulus, including at least one of: (1)
guiding a trajectory of an incision based on different respective
monitored values of visco-elastic modulus for the segments, or (2)
determining a number of incisions to be made based on different
respective monitored values of visco-elastic modulus for the
segments.
Inventors: |
Yoo; Jang Lawrence Hyun;
(Los Angeles, CA) ; Beck; Dominik Jean Michel;
(Muttenz, CH) ; Scarcelli; Giuliano; (Washington,
DC) ; Karim; Niaz; (Weston, MA) ; Yun;
Seok-Hyun; (Belmont, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
The General Hospital Corporation
Intelon Optics, Inc. |
Boston
Los Angeles |
MA
CA |
US
US |
|
|
Appl. No.: |
17/201961 |
Filed: |
March 15, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15548264 |
Aug 2, 2017 |
10952608 |
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PCT/US16/50147 |
Sep 2, 2016 |
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17201961 |
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62213423 |
Sep 2, 2015 |
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International
Class: |
A61B 3/103 20060101
A61B003/103; A61B 3/10 20060101 A61B003/10; A61B 5/00 20060101
A61B005/00; G01J 3/44 20060101 G01J003/44 |
Claims
1. A method for guiding an invasive procedure performed on an eye
of a subject based on monitored properties of the eye, the method
comprising: providing at least one first electro-magnetic radiation
to the eye to interact with at least one acoustic wave in the eye,
wherein, at least one second electromagnetic radiation is produced
based on the interaction between the first electro-magnetic
radiation and the acoustic wave; receiving multiple portions of the
at least one second electro-magnetic radiation, each portion having
been emitted from a different corresponding segment of the eye;
determining a visco-elastic modulus of at least one section of the
eye based on the multiple portions; and communicating feedback
about the invasive relative to at least one of a width, depth,
length, curvature, number of incisions, or location of incision to
be used in the invasive procedure.
2. The method of claim 1, wherein the invasive procedure increases
stiffness of the eye.
3. The method of claim 2, wherein the invasive procedure comprises
collage crosslinking of a cornea of the eye.
4. The method of claim 1, wherein the invasive procedure reduces
stiffness of the first ocular component.
5-8. (canceled)
9. The method of claim 1, wherein the incision comprises a laser
incision that induces optical breakdown of a first ocular-component
based on cavitation bubble creation.
10. The method of claim 1, wherein the incision comprises a
mechanical incision that induces mechanical breakdown of a first
ocular component.
11. The method of claim 9, wherein the first ocular component
comprises a crystalline lens of the eye, and the invasive procedure
reduces stiffness of the first ocular component by inducing optical
breakdown of the crystalline lens.
12. The method of claim 1, wherein the invasive procedure uses an
optical source to provide a third electro-magnetic radiation to the
eye.
13. The method of claim 1, wherein the invasive procedure uses an
acoustic source to provide at least a portion of the energy in the
acoustic wave.
14. The method of claim 1, wherein the at least one second
electro-magnetic radiation is produced based on a Brillouin
scattering interaction.
15. The method of claim 14, wherein communicating feedback includes
applying real time feedback to guide the invasive procedure in real
time.
16. The method of claim 15, wherein guiding the invasive procedure
in real time includes determining a plurality of values of
visco-elastic modulus based on different respective values of a
spectral characteristic of each of the multiple portions of the at
least one second electro-magnetic radiation.
17. The method of claim 14, wherein communicating feedback includes
guiding the invasive procedure based on different respective
monitored values of visco-elastic modulus.
18. The method of claim 1, wherein determining the visco-elastic
modulus includes performing anisotropic monitoring of the
visco-elastic modulus.
19. The method of claim 1, wherein determining the visco-elastic
modulus includes computing a time-dependent evolution of a
spatial-dependent function of multiple discrete element values,
where each discrete element value is derived from a value of
visco-elastic modulus for at least one of the multiple segments,
and each discrete element value is updated at each of multiple
sequential times during the invasive procedure.
20. (canceled)
21. The method of claim 1, wherein determining the visco-elastic
modulus for a particular segment is determined based at least in
part on at least one of a spectral line width or spectral shift of
a spectrum of a corresponding portion of the at least one second
electro-magnetic radiation.
22-24. (canceled)
25. The method of claim 1, wherein determining the visco-elastic
modulus includes detecting the portions of the at least one second
electro-magnetic radiation using a polarization sensitive device to
determine characteristics of the portions of the at least one
second electro-magnetic radiation that are associated with
propagation direction of the acoustic wave.
26. The method of claim 1, wherein determining the visco-elastic
modulus includes detecting each of the portions of the at least one
second electro-magnetic radiation in a different location of a
two-dimensional sensor array.
27. The method of claim 1, wherein the visco-elastic modulus is
determined for each of a plurality of the segments, and is
represented as a parameter that includes a component representing a
viscous modulus and a component representing an elastic
modulus.
28. An apparatus for monitoring an invasive procedure to be
performed on eye of a subject, the apparatus comprising: a light
source configured to provide at least one first electromagnetic
radiation to interact with at least one acoustic wave in the eye of
the subject and produce at least one second electro-magnetic
radiation based on the interaction; imaging optics configured to
receive multiple portions of the at least one second
electro-magnetic radiation, each portion having been emitted from a
different corresponding segment of the eye; and a computer
configured to monitor a visco-elastic modulus; and an interface
configured to deliver feedback about the invasive procedure
including at least one of width, a depth, a length, a curvature, or
a location of where the invasive procedure is performed on the eye
of the subject.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application No. 62/213,423 filed Sep. 2, 2015, incorporated herein
by reference.
[0002] This application is related to, but does not claim priority
to, U.S. application Ser. No. 13/460,595, filed Apr. 30, 2012, and
U.S. Patent Application No. 61/480,885, filed Apr. 29, 2011, each
of which is incorporated herein by reference.
BACKGROUND
[0003] This description relates to performing a procedure based on
monitored properties of biological tissues.
[0004] Although Brillouin spectroscopy has been used for material
characterization, various issues have limited its use for imaging
biological tissues in certain contexts (e.g., in vivo imaging).
SUMMARY
[0005] In one aspect, in general, a method for performing a
procedure based on monitored properties of at least one ocular
component of an eye includes: performing a procedure on at least
one section of a first ocular component of the eye; providing at
least one first electro-magnetic radiation to the at least one
section of the first ocular component so as to interact with at
least one acoustic wave in the first ocular component, wherein at
least one second electro-magnetic radiation is produced based on
the interaction; receiving multiple portions of the at least one
second electro-magnetic radiation, each portion having been emitted
from a different corresponding segment of the at least one section
of the first ocular component; monitoring a visco-elastic modulus
of the at least one section of the first ocular component based on
the multiple portions during the procedure performed on the at
least one section of the first ocular component; and applying
feedback to the procedure based at least in part on the monitored
visco-elastic modulus, including at least one of: (1) guiding a
trajectory of an incision based on different respective monitored
values of visco-elastic modulus for the segments, or (2)
determining a number of incisions to be made based on different
respective monitored values of visco-elastic modulus for the
segments.
[0006] Aspects can include one or more of the following
features.
[0007] The procedure comprises a procedure that increases stiffness
of the first ocular component.
[0008] The procedure that increases stiffness of the first ocular
component comprises collagen crosslinking of a cornea of the
eye.
[0009] The procedure comprises a procedure that reduces stiffness
of the first ocular component.
[0010] The procedure that reduces stiffness of the first ocular
component comprises an incision.
[0011] Applying feedback to the procedure based at least in part on
the monitored visco-elastic modulus includes guiding a trajectory
of the incision based on different respective monitored values of
visco-elastic modulus for the segments.
[0012] Guiding the trajectory includes determining at least one of:
a radius of curvature of at least a portion of the trajectory, or a
length of the trajectory.
[0013] Applying feedback to the procedure based at least in part on
the monitored visco-elastic modulus includes determining a number
of incisions to be made based on different respective monitored
values of visco-elastic modulus for the segments.
[0014] The incision comprises a laser incision that induces optical
breakdown of the first ocular component based on cavitation bubble
creation.
[0015] The incision comprises a mechanical incision that induces
mechanical breakdown of the first ocular component.
[0016] The first ocular component comprises a crystalline lens of
the eye, and the procedure that reduces stiffness of the first
ocular component comprises laser induced optical breakdown of the
crystalline lens.
[0017] The procedure uses an optical source to provide a third
electro-magnetic radiation to the at least one section of the first
ocular component.
[0018] The procedure uses an acoustic source to provide at least a
portion of the energy in the acoustic wave.
[0019] The at least one second electro-magnetic radiation is
produced based on a Brillouin scattering interaction.
[0020] Applying feedback to the procedure includes applying real
time feedback to guide the procedure in real time.
[0021] Guiding the procedure in real time includes determining a
plurality of values of visco-elastic modulus for the segments based
on different respective values of a spectral characteristic of each
of the multiple portions of the at least one second
electro-magnetic radiation in less than 0.4 seconds.
[0022] Applying feedback to the procedure includes guiding the
procedure over the at least one section based on different
respective monitored values of visco-elastic modulus for the
segments.
[0023] The segments are distributed in three spatial dimensions to
provide anisotropic monitoring of the visco-elastic modulus.
[0024] A monitored value of visco-elastic modulus for each of
multiple segments is computed based on a numerical analysis that
provides a time-dependent evolution of a spatial-dependent function
of multiple discrete element values, where each discrete element
value is derived from a monitored value of visco-elastic modulus
for at least one of the multiple segments, and each discrete
element value is updated at each of multiple sequential times
during the procedure.
[0025] The numerical analysis comprises finite element
analysis.
[0026] A monitored value of visco-elastic modulus for a particular
segment is determined based at least in part on at least one of a
spectral line width or spectral shift of a spectrum of a
corresponding portion of the at least one second electro-magnetic
radiation.
[0027] The method further includes: performing the procedure on at
least one section of a second ocular component of the eye;
providing a portion of the at least one first electro-magnetic
radiation to the at least one section of the second ocular
component so as to interact with at least one acoustic wave in the
second ocular component, wherein at least one third
electro-magnetic radiation is produced based on the interaction;
receiving multiple portions of the at least one third
electro-magnetic radiation, each portion having been emitted from a
different corresponding segment of the at least one section of the
second ocular component; monitoring a visco-elastic modulus of the
at least one section of the second ocular component based on the
multiple portions of the at least one third electro-magnetic
radiation during the procedure performed on the at least one
section of the second ocular component; and applying feedback to
the procedure based at least in part on the monitored visco-elastic
modulus of the at least one section of the second ocular component;
wherein the multiple portions of the at least one second
electro-magnetic radiation are received through a spectrometer
configured to have a first extinction efficiency that isolates a
spectral characteristic of the at least one second electro-magnetic
radiation, and the multiple portions of the at least one third
electro-magnetic radiation are received through the spectrometer
configured to have a second extinction efficiency that isolates a
spectral characteristic of the at least one third electro-magnetic
radiation.
[0028] The second extinction efficiency is greater than the first
extinction efficiency, the number of received portions of the at
least one third electro-magnetic radiation is lower than the number
of received portions of the at least one second electro-magnetic
radiation, and the time over which each portion of the at least one
third electro-magnetic radiation is received is longer time over
which each portion of the at least one second electro-magnetic
radiation is received.
[0029] The first ocular component is a cornea of the eye, and the
second ocular component is a sclera of the eye.
[0030] Monitoring the visco-elastic modulus of the at least one
section of the first ocular component includes detecting the
portions of the at least one second electro-magnetic radiation
using a polarization sensitive device to determine characteristics
of the portions of the at least one second electro-magnetic
radiation that are associated with propagation direction of the
acoustic wave.
[0031] Monitoring the visco-elastic modulus of the at least one
section of the first ocular component includes detecting each of
the portions of the at least one second electro-magnetic radiation
in a different location of a two-dimensional sensor array.
[0032] The visco-elastic modulus is determined for each of a
plurality of the segments, and is represented a parameter that
includes a component representing a viscous modulus and a component
representing an elastic modulus.
[0033] In another aspect, in general, an apparatus for performing a
procedure based on monitored properties of at least one ocular
component of an eye includes: at least one first arrangement
configured to perform a procedure on at least one section of a
first ocular component of the eye; at least one second arrangement
configured to provide at least one first electro-magnetic radiation
to the at least one section of the first ocular component so as to
interact with at least one acoustic wave in the first ocular
component, wherein at least one second electro-magnetic radiation
is produced based on the interaction; at least one third
arrangement configured to receive multiple portions of the at least
one second electro-magnetic radiation, each portion having been
emitted from a different corresponding segment of the at least one
section of the first ocular component; and at least one fourth
arrangement configured to monitor a visco-elastic modulus of the at
least one section of the first ocular component based on the
multiple portions during the procedure performed on the at least
one section of the first ocular component; wherein the first
arrangement is further configured to apply feedback to the
procedure based at least in part on the monitored visco-elastic
modulus, including at least one of: (1) guiding a trajectory of an
incision based on different respective monitored values of
visco-elastic modulus for the segments, or (2) determining a number
of incisions to be made based on different respective monitored
values of visco-elastic modulus for the segments.
[0034] In other aspects, in general, apparatus and methods are
capable of providing biomechanical information about at least one
portion of ocular tissues in patients or animals in vivo with
spatial resolution. Brillouin light scattering generated from
within the tissues in the eye is used to obtain the biomechanical
information of the tissues. The spectral characteristics of the
scattered light is analyzed and processed to provide the
biomechanical information relevant to the health and illness of the
ocular tissues, such as the weakening of the corneal stroma or
age-related stiffening of the nucleus in the crystalline lens. A
probe beam is scanned across the tissue to obtain one, two, or
three-dimensional spectral data of Brillouin scattered light. The
obtained information is displayed in the form of images or
parameters derived from the measured spectral characteristics.
[0035] Aspects can have one or more of the following
advantages.
[0036] The techniques described herein relate to arrangements and
methods to obtain the biomechanical and physiological properties of
ocular components, including various ocular tissues and/or
structures, such as the cornea, sclera, and crystalline lens, in
the eye of a patient or a living animal to perform procedures for
diagnosis and/or treatment of ocular disorders, as well as basic
study and preclinical developments. The information is obtained
from the spectral analysis of Brillouin light scattering that is
associated with the hypersonic acoustic properties in the ocular
components.
[0037] The techniques enable noninvasive interrogation of the
biomechanical information that is relevant to and useful in
diagnosing ocular disorders, such as corneal ectasia and
presbyopia, as well as treating these problems. Thus, a
quantitative approach is provided for screening refractive surgery
patients, identifying candidates at risk, and optimizing ablation
patterns.
[0038] By using Brillouin scattering spectroscopy to monitor a
visco-elastic modulus of an ocular tissue during a procedure, that
procedure can be guided in real time using feedback from the
monitored visco-elastic modulus. The monitored visco-elastic
modulus can provide a measurement of biomechanical changes caused
by cellular processes associated with procedures such as surgical
procedures or other types of treatment procedures. Biomechanical
changes to an ocular component (or other biological tissue) may
include changes that affect their cellular structures (e.g.,
extracellular matrix, collagen fibers, astrocytes, keratocytes,
etc.).
[0039] Compared to other techniques for modeling ocular structures
using numerical analysis (such as finite element analysis), which
may be required to use inverse modeling to account for such
characteristics as intra-ocular pressure (IP), the techniques
described herein enable direct mapping of visco-elastic modulus in
the context of many material characteristics, including IOP,
without the need to necessarily perform additional computational
steps, such as inverse modeling.
[0040] Other features and advantages of the invention will become
apparent from the following description, and from the claims.
DESCRIPTION OF DRAWINGS
[0041] FIG. 1A is a schematic of an exemplary embodiment of the
Brillouin ocular analyzer.
[0042] FIG. 1B is a schematic of another exemplary embodiment of
the Brillouin ocular analyzer.
[0043] FIGS. 2A-2C illustrate exemplary strategies for scanning the
focus of a probe beam for analysis of the human eye.
[0044] FIG. 3 illustrates a schematic of an exemplary configuration
and principle of a spectrometer consisting of multiple VIPA etalons
cascaded in the cross-axis configuration.
[0045] FIG. 4A is a schematic of exemplary two-stage VIPA
spectrometer;
[0046] FIG. 4B illustrates the design and output beam profiles in
two exemplary apodization schemes.
[0047] FIG. 4C is a graph of an exemplary Brillouin shift of an
epidermal layer in hydrated conditions according to exemplary
embodiments of the present disclosure.
[0048] FIG. 5A illustrates a schematic and principle of a
single-VIPA spectrometer configured to interrogate multiple spatial
locations in the eye simultaneously.
[0049] FIG. 5B illustrates a schematic and principle of a
single-VIPA spectrometer using a line-focused probe beam.
[0050] FIG. 5C is a schematic diagram and an image illustrating an
exemplary principle of a single-VIPA spectrometer configured to
interrogate multiple spatial locations in the eye simultaneously;
according to exemplary embodiments.
[0051] FIG. 5D is a schematic diagram and an image illustrating an
exemplary principle of a single-VIPA spectrometer that uses a
line-focused probe beam according to further exemplary
embodiments.
[0052] FIG. 6A shows an exemplary schematic of animal imaging.
[0053] FIG. 6B shows typical experimental data of Brillouin spectra
obtained with a two-state VIPA spectrometer at four different
locations in a murine lens in vivo: i, aqueous humor; ii, cortex;
iii, nucleus; and iv, vitreous humor.
[0054] FIG. 6C shows an experimentally obtained, axial profile of
the Brillouin frequency shift from the murine lens.
[0055] FIG. 6D illustrates an axial profile of the Brillouin
linewidth.
[0056] FIG. 6E depicts representative cross-sectional Brillouin
images of the murine lens.
[0057] FIG. 7A depicts a cross-sectional Brillouin imaging of a
bovine cornea.
[0058] FIG. 7B depicts an en face Brillouin image of the bovine
cornea.
[0059] FIG. 7C shows an exemplary axial profile of the Brillouin
shift in the bovine cornea.
[0060] FIG. 8A depicts cross-sectional Brillouin images of a
corneal tissue before and after cornea cross-linking.
[0061] FIG. 811 shows a marked difference between normal and
crosslinked cornea tissues in terms of the axial slope of Brillouin
shift in the stroma.
[0062] FIG. 5C shows a significant difference in the space-averaged
Brillouin modulus between the normal and cross-linked corneal
tissues.
[0063] FIGS. 9A-9E depict exemplary incisions that can be
guided.
DESCRIPTION
[0064] It has long been known that the lens tends to stiffen with
age. As the lens becomes hard, the muscle holding the lens cannot
alter its shape easily, and the person has increasing difficulty
focusing on close objects or loss of accommodation ability, a
condition called presbyopia. Presbyopia affects almost every person
over the age of 45. Nevertheless, clinicians do not have tools to
characterize the biomechanical alterations in the lens.
Furthermore, no drugs are available that can prevent, slow, or
reverse the progressive nature of this condition.
[0065] Cataract, opacity of the lens, is the leading cause of
blindness in the world. Age-related nuclear cataract is the most
common form, affecting more than 50% of U.S. residents 65 and
older. Despite its prevalence, the only standard of care for
cataract patients today is surgery, an invasive procedure, which is
usually performed after patients have suffered from deteriorating
vision for many years before they are eligible for the procedure.
About 1.5 million people in the U.S. (of the 87 million with
cataracts) receive cataract surgery annually, leaving more than 85
million people untreated for this condition. A drug that can treat
or prevent the damage of the lens proteins is being actively sought
for. However, our limited understanding of the mechanisms of
cataracts and the dearth of techniques capable of monitoring the
genesis of cataracts had impeded the drug development. Although the
detailed mechanisms underlying the cataract formation remain to be
further elucidated, it has been known that the opacity of the lens
can result from the denaturation of lens proteins. This structural
and physiological modification can alter the lens's elastic
properties. Therefore, the ability to measure lens elasticity in
patients may be useful for early diagnosis and development of
non-surgical interventions for cataracts.
[0066] In the cornea, the mechanical balance between corneal
stiffness and intraocular pressure is critical in maintaining the
appropriate shape and normal function of cornea. An abnormal change
in the mechanical properties of the cornea can therefore degrade
visual acuity and threaten vision. Corneal ectasia refers to a
bulging of the cornea, occurring when it is not strong enough
mechanically to withstand the intraocular pressure. Ectasia may
result from a degenerative disease called Keratoconus. Keratoconus
and Keratoectasia occur in 1 out of 1000 people among the general
population and are often a complication of LASIK surgery performed
in 1.5 million patients in the USA each year. All of these
conditions and procedures are intrinsically linked to ocular
mechanical properties, and from a diagnostic standpoint are
expected to alter, at a very early stage, the mechanical properties
of ocular tissues.
[0067] Ectasia is also one of the rare but serious adverse outcomes
after LASIK (laser-assisted in situ keratomileusis) surgery.
Currently about 1.5 million LASIK operations are performed annually
in the U.S. As LASIK becomes increasingly popular, the incidence of
post-LASIK ectasia has continued to increase. A promising
therapeutic approach to corneal ectasia is increasing the stiffness
of the stroma by crosslinking the naturally present collagen fibers
in the cornea, a procedure known as corneal collagen crosslinking
(CXL). The viscoelastic properties of the cornea are also known to
affect the tonometry measurement of intraocular pressure.
[0068] As a consequence, the biomechanical properties may be an
appropriate target for diagnosis and monitoring of onset and
progression of cataract and refractive disorders such as myopia,
hyperopia, astigmatism, and presbyopia as well as corneal
pathologies and treatments. For this reason, there has been a great
deal of interest in measuring the mechanical properties of the
lens, scleral, and corneal tissues for diagnosis and for monitoring
of treatments. However, current techniques cannot detect such
localized biomechanical changes in vivo in patients and animal
models, seriously frustrating our efforts to develop understanding
and treatment of the prevalent ocular problems.
[0069] Conventional techniques, from the traditional slit-lamp
microscopy to newer imaging technologies (computer
videokeratography, OCT, confocal microscopy, ultrasound, Scheimflug
photography) are excellent in imaging the structure of cornea,
sclera, conjunctiva, and crystalline lens but fail to provide their
physiological and biomechanical information. Current clinical
instruments, such as pachymetry (measuring thickness) and
topography (mapping surface curvature), have been limited in
screening patients at high risk of post-LASIK ectasia; patients
with normal appearing corneas have developed the complication.
[0070] Several techniques have been used to characterize the
mechanical properties of the cornea, sclera, and lens cx vivo and
in vivo. For example, comprehensive but destructive analysis has
been performed by spinning cup, mechanical stretchers,
stress-strain equipment or by inflation tests. Other mechanical
testing methods include laser induced optical breakdown based on
bubble creation and the ocular response analyze measuring corneal
hysteresis on the surface without spatial information. Ultrasound
is an attractive tool as it allows noninvasive methods such as
elastography. Of particular note is ultrasound pulse-echo
techniques and ultrasound spectroscopy, where pulsed or
continuous-wave acoustic waves are launched onto the cornea, and
the propagation speed and attenuation are measured to compute the
viscoelastic moduli of the tissue. However, the ultrasound-based
techniques have drawbacks of relatively low spatial resolution and
measurement sensitivity.
[0071] Brillouin light scattering in a tissue or any other medium
arises due to the interaction between an incident light and
acoustic waves within the matter. Consider a probe light with a
frequency .nu. and a wavelength .lamda., which is illuminated to
the sample. In spontaneous Brillouin process, the acoustic waves or
acoustic phonons are naturally present due to thermal fluctuations.
Such fluctuations propagate through the medium in the form of
acoustic waves. These acoustic waves generate periodic modulations
of the refractive index. Brillouin scattering can be generated by
at least one or many acoustic waves or acoustic phonons, which form
phase-matched index modulation.
[0072] FIG. 1A illustrates an exemplary embodiment of the
description. A first arrangement 100 provides a first
electromagnetic radiation 110, which is delivered to an eye 120. A
most appropriate form of the electromagnetic radiation 110 is light
in the visible or near infrared range. The first arrangement
includes a light source, which is typically a single-frequency
laser, a filtered Mercury lamp, or other types of light emitters
known in the art. The light source can have a wavelength between
530 nm and 1350 nm, but other wavelengths that are known to be safe
for use in the eye can be used. The linewidth of the light is
typically less than 1 GHz or more preferably less than 100 MHz, but
light sources with broader linewidth or multiple spectral lines may
be used in conjunction with appropriate arrangements.
[0073] The electromagnetic radiation 110 is directed to the eye 120
to probe various portions of ocular tissues, including but not
limited to the cornea 122 and the crystalline lens 124. In general,
an imaging lens 120 is used to focus the electromagnetic radiation
110 onto a small spot. The imaging lens 120 can be a spherical
convex lens, aspheric lens, objective lens, theta lens, or
cylindrical lens for line focusing.
[0074] To scan the axial position of the focus within the ocular
tissues, the imagining lens 130 may be mounted on a translation
stage 134. Alternatively, a tunable element that changes the
divergence of the probe light may be employed. To scan the
transverse position of the focus, a one- or two-axis beam scanner
140 is employed. The scanner 140 can be a galvanometer-mounted
mirror, MEMS mirror, translation stages, or spatial light
modulator.
[0075] The acousto-optic interaction in the tissue gives rise to
light scattering, generating second electromagnetic radiation.
Several mechanisms for light scattering are known in the art, which
includes Rayleigh and Mie scattering, Raman scattering, and
Brillouin scattering. While in general biological tissues support
all of these scattering mechanisms, Brillouin scattering is
directly associated with the acoustic waves in the medium. A
portion of the at least one second electromagnetic radiation can be
collected by the imaging lens 130. In an epi-detection
configuration, the interacting probe and Brillouin-scattered lights
travel in the nearly opposite directions. Alternatively, a
dual-axis configuration can be employed, where the probe and
scattered light for a finite angle.
[0076] The system may employ a beam splitter 142 to reflect and
transmit the first and second electromagnetic radiations. The beam
splitter 142 may have an equal 50/50 splitting ratio or unequal
splitting ratios for optimization of the efficiencies of signal
generation and collection. The beam splitter 142 may be a neutral
splitter with broad spectral bandwidth or a dichroic splitter based
on multilayer coating, interference, or diffraction. The portion of
the second electromagnetic radiation 144 is sent to a second
arrangement 150, which is configured to receive the at least one
portion 144 of the at least one second electro-magnetic
radiation.
[0077] In a preferred embodiment, the second arrangement 150
employs at least one spectral analysis unit, such as a
spectrometer, a monochromator, fixed or scanning spectral filters,
or other devices known in the art. The second arrangement 150 is
configured to measure various properties of the second
electromagnetic radiation 144, including but not limited to the
center frequency and width of its spectrum, as well as the
intensity and polarization of the electrical field. In particular,
the frequency difference between the at least one first
electromagnetic radiation 110 entering the tissues and the at least
one portion of the second electromagnetic radiation 144, which
includes the Brillouin scattered light, is of importance.
[0078] The frequency shift .nu..sub.B of the Brillouin scattered
light with respect to the probe light 110 is given by
v B = .+-. 2 .times. .times. n .times. .times. V .lamda. .times.
sin .times. .times. ( .theta. 2 ) ( 3 ) ##EQU00001##
[0079] Where n is the local refractive index in the interrogated
tissue, V is the speed of the acoustic wave in the sample, and
.theta. is the scattering angle, i.e. the angle between the
incident and the scattered light, such as in the dual-axis
geometry. In an epi-backward detection configuration, .theta.=.pi.
is a reasonably good approximation. In typical soft tissues, the
speed of the acoustic wave ranges from 1000 to 3000 m/s, and the
Brillouin frequency shifts are typically between 2 and 20 GHz,
depending on the wavelength.
[0080] The intrinsic spectral width or linewidth of the Brillouin
scattered light is given by:
.DELTA. .times. .times. v B = .alpha. .times. .times. V .pi. , ( 4
) ##EQU00002##
where .alpha. is the attenuation coefficient of the acoustic wave
in the sample.
[0081] The longitudinal complex elastic modulus, M=M'+iM'', where
the real part M' refers to the elastic modulus and the imaginary
part M'' is the viscous modulus is given by:
M'=.rho.V.sup.2; (5)
M''=2.rho.V.sup.3.alpha./.nu..sub..delta.. (6)
[0082] Therefore, the measurement of the spectral characteristics
of the Brillouin scattered light provides the information about the
biomechanical properties of the ocular tissue. The useful
information obtained by the Brillouin measurement includes but is
not limited to the acoustic speed, acoustic attenuation
coefficient, Brillouin elastic modulus, Brillouin viscous modulus,
and electrostriction coefficient. As is further described below, by
scanning the focus within the tissue different spatial locations
can be probed, which provides the information in a spatially
resolved manner. This spatial information can in turn be useful to
evaluate for the diagnosis of the mechanical integrity or health of
the ocular tissue.
[0083] The index of refraction and acoustic speed of a given
material are generally dependent on the local temperature and
pressure. This dependence may be harnessed for the analysis of
inflammatory or pathologic states in the eye via the measurement of
the temperature or ph-value in the aqueous and vitreous humors. The
magnitude of the Brillouin scattered radiation is related to the
coupling of acoustic and optical energy inside the sample, which is
related to the material properties, such as the electrostriction
coefficient.
[0084] FIG. 1B illustrates a modified embodiment that employs an
optical fiber 160 between the first arrangement 100 and the beam
scanner 140. Another optical fiber 162 can also be used to deliver
the Brillouin scattering light to the second arrangement 150. The
optical fiber 160 in the sample arm can be preferably a single-mode
fiber, but multi-mode, few-mode, or double-clad fibers may be used.
Preferably, the optical fiber 182 on the detection arm is a
single-mode or few-mode fiber. The optical fiber 162 can serve as a
confocal pinhole, allowing the selective collection of essentially
only the portion of the second electromagnetic radiation generated
from the focus of the probe light in the sample. This confocal
detection greatly facilitates the spatially resolved Brillouin
measurement with three-dimensional resolution. The principle of
confocal detection is well known in the art. Instead of the optical
fiber 162, a spatial filter, such as employing a pinhole, may be
used. It is desirable to minimize optical reflection at various
air-glass or air-tissue interfaces along the beam paths or prevent
the reflected light from entering the second arrangement 150 as
much as possible.
[0085] The system may further comprise a third arrangement 170,
which is configured to facilitate positioning the eye 120 with
respect to the at least one first electro-magnetic radiation, or
the probe light. Preferably, the third arrangement includes at
least one of the following features: a forehead rest, a chin rest,
an eye fixation beam, and a slit lamp. In particular, the human
interface 180 can employ a camera to measure at least one position
of the at least one first electro-magnetic radiation with respect
to the at least one ocular tissue. This type of beam guiding
arrangement can facilitate aiming the probe beam and provide the
position information of the focus, which can be used in making of
Brillouin images or the spatial map of the biomechanical properties
of the ocular tissue.
[0086] The system can further comprise a fourth arrangement 180
configured to display the information associated with the at least
one portion of the ocular tissue in the eye in vivo. The displayed
information may include but is not limited to the Brillouin
frequency shifts. Brillouin linewidth. Brillouin images, and the
hypersonic viscoelastic moduli, as well as parameters, such as the
mean values or slopes, calculated from the Brillouin images or the
spatial maps of the viscoelastic properties.
[0087] The system arrangement can further employ a fifth
arrangement 190 to provide at least one frequency reference.
Preferably, the fifth arrangement 190 is configured to receive at
least one portion of the first electromagnetic radiation through
the beam splitter 142 and reemit Brillouin scattered light with at
least one, preferably multiple spectral peaks. For example, the
frequency reference 190 comprises at least one reference material,
solids or liquids, with known Brillouin frequency shifts.
Alternatively, the frequency reference 190 can be a light source
emitting an electromagnetic radiation at a wavelength locked to the
wavelength of the probe light source 100. In both case, the
electromagnetic radiation from the frequency reference 190 is
directed to the second arrangement 150. An optical switch 192 can
be employed to gate the intensity of the electromagnetic radiation.
The reference frequency helps calibrating the spectral analysis
unit in the second arrangement 150, facilitating the spectral
analysis.
[0088] The Brillouin viscoelastic moduli defined in Equations (5)
and (6) represent the tissue properties at the hypersonic GHz
frequencies. Most soft tissues, including the corneal tissues and
crystalline lens, exhibit viscoelastic properties characterized by
frequency-dependent moduli. Slower relaxation processes have little
time to respond to fast mechanical or acoustic modulation, such as
GHz acoustic phonons, and thus hardly contribute to the "softness"
of the material. As a consequence, modulus tends to increase with
frequency. In addition, the propagation of acoustic phonons is
governed by the longitudinal modulus, which is typically much
higher than the Young's or shear modulus owing to the
incompressibility (i.e. Poisson's ratio .about.0.5) of water. The
two effects, finite relaxation time and low compressibility,
provide qualitative explanation for the observed large difference
in modulus between the Brillouin and standard mechanical tests.
[0089] In one study, we cut fresh porcine and bovine lenses at
various ages (from 1 to 18 months) into small pieces of the size
our mechanical equipment could handle. The mean Brillouin modulus
was calculated from the 3D measurement of Brillouin spectrum and
the estimated density and refractive index. As expected,
Brillouin-measured elasticity is much higher than the traditional
DC elasticity. Nevertheless, there seems to be a clear relationship
between Brillouin measurement and standard technique, which shows
that the Brillouin signature indeed provides information about the
elasticity of lenticular tissue. Comparison to Young's modulus
measured by a conventional stress-strain test revealed a remarkable
correlation between Brillouin (M') and quasi-static modulus (G')
for both porcine and bovine tissues (FIG. 2). High correlation
(R>0.9) was obtained in curve fit to a log-log linear
relationship: log(M)=a log(G')+b, where the fitting parameters were
a=0.093 and b=9.29 for porcine tissues and a=0.034 and b=9.50 for
bovine tissues.
[0090] Aspects of the techniques described herein make use of
Brillouin spectroscopy with optical scanning techniques to guide
various procedures. For example, the techniques can be used to
characterize features in an eye to guide a procedure involving an
incision in that eye (e.g., an incision in a cornea or limbus, or
other ocular tissue). For example, some of the characteristics of
an incision that can be guided using appropriate feedback include:
width, depth, length, curvature, number of incisions, and location
of incision(s). Some of the contexts in which this characterization
is useful include the following.
1. Incisions, such as Astigmatic Keratotomy (AK) or Limbal Relaxing
Incision (LRI) or Arcuate Incision (AI) to correct
[0091] a. Congenital Astigmatism
[0092] b. Residual corneal astigmatism at the time of or following
cataract surgery
[0093] c. Post-traumatic astigmatism
[0094] d. Astigmatism after corneal transplantation
[0095] e. Astigmatism after a keratorefractive surgical
procedure
2. Surgery involving primary incisions to access anterior or
posterior chambers of the eye (e.g., Cataract surgery)
[0096] a. Primary incision to access the anterior or posterior
chambers of the eye (e.g., a Limbal Incision, Corneal Inscision, or
Scleral Inscision)
[0097] b. Secondary incision--AK (LRI or AI) that corrects
induced+existing astigmatism [0098] i. Penetrating incision (e.g.,
Cut in cornea made from anterior surface including epithelial
layer) [0099] ii. Intra-stromal incision (e.g., Cut made within
stroma layer, such as cuts for: small incision lenticule extraction
(SMILE), pockets, guiding planes, access ports, etc.) 3. Surgery
involving access to the crystalline lens (e.g., Presbyopia surgery)
and creation of gliding planes for softening of the crystalline
lens
[0100] AK, which includes LRI or AI, is a surgical procedure used
to treat congenital astigmatism, residual corneal astigmatism at
the time of or following cataract surgery, post-traumatic
astigmatism and astigmatism after corneal transplantation.
[0101] In the case of cataract surgery, a primary incision is made
to enable access to crystalline lens and intraocular lens, and a
secondary incision or multiple incisions (AK) are made in the
cornea to change the refraction to correct astigmatism, both
pre-existing and that which may have been induced by the primary
incision. Two examples of AK incisions are those that are
penetrating, which cut into the stroma layer through the epithelial
layer and those that are intra-stromal, which only disrupt the
stromal part of the cornea by using an energy source (e.g., a
femtosecond laser) or a mechanical instrument (e.g., knives or
blades formed from steel, diamond, etc.). The techniques described
herein are not limited to only AKs, but may apply to other corneal
keratoplasties that include incisions, such as radial keratotomies,
or apply thermal energy, mechanical energy or chemical
cross-linking to change the shape of the cornea.
[0102] Surgical planning for AKs assess a combination of patient
data including patient age, refractive history, corneal topography,
pachymetry, and other imaging (e.g., optical coherence tomography
(OCT), wavefront aberrometry, keratometry, and/or corneal and
anterior chamber raytracing) findings in order to come up with
appropriate nomogram selection to guide the nature of the incision,
including incision length, depth, uniformity of depth, angle and
location. Nomograms are typically used in conjunction with surgical
systems such as femtosecond lasers, if done manually, AKs are
typically placed based on surgeon's experience. AK planning may be
done in both cases. In the techniques described herein, a Brillouin
modulus value or 2D or 3D Brillouin maps of Brillouin modulus
values within the cornea (e.g., modulus maps of the mid-peripheral
and peripheral areas) are created to provide guidance for the
location and characteristics of an incision that may have a variety
of objectives, including minimizing surgically induced astigmatism
(SIA), correcting existing astigmatism in the eye, or other
procedures that use incisions to change the cornea's refractive
properties. For example, depending on the mechanical status, such
as the modulus or stress, in the location where the incision is
made on cornea or corneal limbus, or possibly sclera, it is
expected that the outcome, e.g. change in astigmatism, will be
different. In one embodiment, one or multiple measurements of the
corneal modulus and/or scleral modulus can be completed at set
depths or/and intervals, which may include specific ratios (e.g.,
thickness of the cornea/desired # of measurements) or patterns
(e.g., modulus measurements taken at equidistant points through the
depth of the cornea), to optimize mapping of modulus gradients in
the cornea. Also the limbal region can be included in the
measurements as the "hinge" zone (transitional zone) between two
mechanically different tissue structures (rigid sclera and more
compliant cornea or vice versa).
[0103] In case of softening of the crystalline lens, one or
multiple intra-lenticular incisions are made to create gliding
planes or cut lines. This is expected to reduce the bulk stiffness
of the lens to make it softer so it can alter its shape while
accommodating and increase its refractive power by enlarging the
exterior surface curvature.
[0104] In some embodiments, the spectrometer used to isolate the
Brillouin spectral characteristic (i.e., the characteristic from
which the visco-elastic modulus is derived) has a configurable
spectral efficiency. An example of such a spectrometer, described
in more detail below, uses a configurable number of VIPA stages to
change the extinction efficiency. Some ocular components scatter
more light and require a higher extinction efficiency in order to
filter out enough noise to achieve a satisfactory signal-to-noise
ratio. But, a higher extinction efficiency also calls for a longer
time to collect the Brillouin generated light (e.g., using a long
integration time in a charge coupled device (CCD) detector). That
longer collection time for each CCD line means there are fewer
distinct mapping locations that can be scanned in a given time
period, and therefore a lower mapping resolution that can be
acquired in the time period (which may be as short as 0.4 second,
for example, for real time operation). So, there is a trade-off
between extinction efficiency and mapping resolution. But, for
certain ocular components, such as the sclera, a lower mapping
resolution (than a resolution of for the cornea, for example) is
acceptable. Any of a variety of detectors may be used as a
two-dimensional sensor array other than, or in addition to, a CCD
detector (e.g., CMOS, sCMOS, EMCCDs, etc.).
[0105] There may be specific locations (e.g., points, zones,
regions, layers, areas) within an ocular component, such as the
cornea or sclera, (e.g., in Z-axis) that represent the stiffness
profile most efficiently. A variety of different types of
biomechanical heat maps of an ocular component can be generated by
measuring equidistantly, for example, or by concentrating
measurements in certain areas. For example, maps may cover various
distributions of measurement concentration through the thickness of
the ocular component.
[0106] FIG. 2 show various examples illustrating how the focus 132
is scanned over the eye 120 to obtain the biomechanical information
at multiple locations in ocular tissues and thereby to obtain
Brillouin images. Various scan types are known in the art, which
includes axial line scan, lateral line scan, raster area scan,
three-dimensional scan, and random sampling scan.
[0107] In one example, the focus of the probe light is positioned
at a center of the cornea or the lens. When this on-axis focus 200
is scanned along the depth coordinate (i.e. Z axis), an axial
profile of the biomechanical information, or Brillouin axial
profile, is obtained. An off-axis axial profile is obtained by
using an off-axis focus 210 displaced from the optic axis of the
cornea or the crystalline lens. For corneal scan, far-off-axis
focus 220 can be used, in which case the iris blocks the probe
light from entering the crystalline lens.
[0108] In another examples, lateral line-scan or 2-dimensional
cross-sectional scan is achieved by moving a focus along a linear
trace 230. A 2-dimensional enface or 3-dimensional scan can be
achieved by moving the focus over an area in the X and Y
coordinates. A simple raster scan 240 or hexagonal scan 250 may be
used.
[0109] In epi-confocal detection, the axial and lateral span of the
focus determines the axial and lateral resolution of Brillouin
imaging, which is given by the numerical aperture (NA) of the
imaging lens 120. For a given NA, the axial resolution is higher in
a dual-axis configuration than the backward epi detection.
Appropriate NA for probing the cornea and crystalline lens
typically ranges from 0.1 to 0.9. For retinal examination, the
imaging lens 120 may not be employed, as the crystalline lens
itself can focus the probe beam onto the retina.
[0110] Thermal damage by optical absorption in the cornea, lens,
and retina is one of the primary considerations in eye safety. The
maximum light exposure level to the eye is relatively well known in
the literature. An optimal power level of the probe light should be
used for eye safety as well as for maximal signal-to-noise ratio.
For example, for a wavelength of 780 nm, approximately 0.5 to 3 mW
of continuous-wave power may be allowed for corneal and lens
examinations.
[0111] The spectral analysis unit in the second arrangement 150
should have a high spectral resolution, a high sensitivity and a
high extinction. This relatively low illumination power and the
relatively low cross-section of Brillouin scattering place a
stringent requirement on the sensitivity of the spectral unit
employed in the second arrangement 150. This places a stringent
requirement on the extinction of the spectral analysis unit.
[0112] As a spectral analysis unit, a scanning Fabry-Perot
interferometer may be used. The interferometer may be designed to
have a free spectral range of about 50 GHz and finesse of about
1,000 with either a single-pass or a multi-pass configuration.
Another alternative spectral analysis unit is a fixed spectral
filter with a bandpass, notch or edge type. Which measures the
magnitude of a certain frequency component. In this case, the
optical frequency of the first electromagnetic radiation may be
stabilized or locked with respect to the fixed filter. Other
possible embodiment for the second arrangement 150 includes
heterodyne detection based on the beating between the probe and
Brillouin scattered light.
[0113] One of the preferred embodiments for the spectral unit is a
spectrometer employing at least one virtually imaged phased army
(VIPA) etalon. A VIPA 300 disperses the spectrum of input light
into different angles or spatial points. A conventional VIPA with
uniform reflectance coatings has an extinction ratio of about 30 dB
in its spectral transfer function.
[0114] Cascading two or more VIPAs is a viable option to increase
contrast without hurting significantly the sensitivity of the
spectrometer. A single VIPA etalon 300 produces spectral dispersion
along one spatial direction, parallel to its coating direction,
while leaving unchanged the optical beam propagation in the
direction perpendicular to its coating direction. Multiple single
VIPA etalons can be cascaded in such a way that each VIPA's
orientation matches the spectral dispersion axis from the previous
stage interferometer. FIG. 3 illustrates the principle of
cross-axis cascading. The VIPA 300 in the first stage is aligned
along the vertical direction and the spectral pattern is dispersed
vertically. When the sample is not transparent or when there are
strong optical reflections, the elastic scattering component
increases dramatically. If the ratio between elastic scattering
(dark-green circles) and Brillouin scattering (light-green circles)
exceeds the spectral extinction of the spectrometer, a crosstalk
signal appears along the spectral axis (green line). This "stray
light" can easily overwhelm the weak Brillouin signal.
[0115] In a two-stage VIPA, the second etalon 310 is placed
orthogonally to the first one 300. The spectral pattern exiting the
first stage enters the second etalon through the input window. Both
etalons disperse light, in orthogonal directions, so the overall
spectral axis of the two-stage device lies along a diagonal
direction, at 135.degree. from the horizontal axis if the etalons
have identical dispersive power. The second etalon 310 will
separate Brillouin signal from crosstalk because, although
spatially overlapped after the first stage, their frequencies at
each spatial location are different. So, after the second stage,
while the Brillouin spectrum lies on a diagonal axis, crosstalk
components due to the limited extinctions of the etalons are
separated and mostly confined to the horizontal and vertical
axis.
[0116] Besides spatial separation of signal and stray light, the
two-stage spectrometer also allows selective spectral filtering. An
appropriate aperture mask 320 can be placed at the focal plane of
the first VIPA 300, where a highly resolved spectral pattern is
formed. Examples of the mask 320 are a slit or a rectangular
aperture. This mask allows unwanted spectral components to be
blocked and only the desired portion of the spectrum to pass to the
second VIPA 310. For optimal performance, it is often desirable to
maintain only two Brillouin peaks (Stokes and anti-Stokes from two
adjacent orders) and have a vertical mask cut off all elastic
scattering peaks. This greatly reduces crosstalk in the
second-stage VIPA 310 and helps avoid saturation of the pixels in a
CCD camera placed afterward, which are illuminated by strong
unfiltered elastic scattering light.
[0117] This cross-axis cascade can be extended to a third stage. In
a three-VIPA spectrometer, a third VIPA 330 is oriented
perpendicular to the spectral axis of the preceding two stages, so
that the Brillouin spectrum can enter through the input window of
the VIPA 330. A second mask 340 is employed to further reduce
crosstalk. Due to the combined dispersion of the three etalons, the
overall spectral axis is further rotated, at about 170.degree. if
all the etalons have the same dispersive power.
[0118] Following the same cascading principle, a multiple VIPA
interferometer of N stages can be built. The k-th VIPA is oriented
at an appropriate angle to accept the spectrum dispersed through
the preceding k-1 stages. The building block of each stage is
modular, comprised of a cylindrical lens C.sub.k, an etalon
VIPA.sub.k, a spherical Fourier transform lens S.sub.kf with focal
length f.sub.k, a mask and a spherical relay lens S.sub.k,k+1 of
focal length f.sub.k,k+1.
[0119] In the first stage, the VIPA is oriented along the direction
.nu.1 at an angle .theta..sub.1 with respect to the horizontal axis
(.theta..sub.1=90.degree. in our experiment), and its spectral
dispersion direction, d1, is parallel to .nu.1 with
.psi..sub.1=.theta..sub.1. In the double-VIPA interferometer, the
second etalon is aligned along .nu.2 at an angle
.theta..sub.2=.omega..sub.1.+-..pi./2, perpendicular to the
spectral direction of the first stage d1 (.theta..sub.2=180.degree.
in our experiment). After the two etalons, the spectrum emerges at
an angle .psi..sub.2 along spectral dispersion direction, d2. In a
three-stage interferometer, the third VIPA must be oriented
perpendicular to d2, at an angle
.theta..sub.3=.psi..sub.2.+-..pi./2. This arrangement results in a
final dispersion direction s3 at an angle .psi..sub.3.
[0120] For each stage, the dispersion angle, .PHI..sub.k, imposed
on a beam of wavelength .lamda..sub.k by the k.sup.th VIPA
interferometer was previously derived in both plane-wave and
paraxial approximations. The focal length f.sub.k of the spherical
lens, S.sub.kf, after the VIPA determines the linear dispersion
power, s.sub.k, of the k.sup.th stage: s.sub.k=.phi..sub.k*f.sub.k.
Since telescopes are used to link two subsequent VIPA stages, the
overall linear dispersion also depends on the magnifications
introduced by such optical systems. Namely, each k.sup.th stage
introduces a magnification M.sub.k=f.sub.k/f.sub.k-1 on the
spectral pattern obtained by the previous k-1 stages, so that the
effective linear dispersion, s'.sub.k, due to the k.sup.th stage is
given by: s'.sub.k=s.sub.k*M.sub.N*M.sub.N-1* . . . * M.sub.k+1.
Therefore, along the overall spectral axis, the total linear
dispersion, S.sub.N, of an N-stage multiple VIPA interferometer is
calculated to be: S.sub.N>=sqrt(.SIGMA..sub.1.sup.N
s'.sub.k.sup.2), which suggests a theoretical improvement in
spectral resolution. When all the spectral dispersions are equal,
i.e. s'.sub.1=s'.sub.2= . . . =s'.sub.N=s, the total dispersion
becomes S.sub.N= {square root over (N)}s.
[0121] Knowing the spectral dispersion and the optical
magnification introduced by each stage, the overall dispersion axis
can be computed. It can be shown:
.psi..sub.k+1-.psi..sub.k=tan.sup.-1(s'.sub.k+1/S.sub.k).fwdarw.tan.sup.-
-1(1/ {square root over (k)}); (7)
.theta..sub.k+1-.theta..sub.k=tan.sup.-1(s'.sub.k/S.sub.k-1).fwdarw.+tan-
.sup.-1(1/ {square root over (k-1)}). (8)
Here, the expressions marked with arrows apply in the case equal
dispersion and unit magnification for all stages.
[0122] In terms of extinction, a single VIPA spectrometer has
extinction, C proportional to its finesse squared:
C.about.4F.sup.2/.pi..sup.2, for an input beam with Airy profile.
After N VIPA etalons of equal finesse F, the spectral extinction or
contrast improves, in principle, to:
C.about.(4F.sup.2/.pi..sup.2).sup.N.
[0123] We experimentally compared the extinction performance of
single-stage, two-stage and three-stage VIPA spectrometers by
coupling the single mode laser light directly into the spectrometer
and placing a CCD camera in the focal planes of S.sub.1f, S.sub.2f,
and S.sub.3f, respectively To overcome the limited dynamic range of
the CCD, we recorded the spectrum at various optical power levels,
with calibrated neutral density (ND) filters of optical densities
in the range from 0 to 7. Subsequently, the full dynamic range
spectrum was reconstructed by rescaling the recorded raw spectra
according to the respective attenuation levels. The single-stage
VIPA shows an extinction level of about 30 dB over a wide frequency
range between 5 and 25 GHz. The extinction is improved to 55 dB
with two stages and to nearly 80 dB with three VIPA etalons in the
middle of the frequency range. It might be possible to improve the
extinction up to 90 dB by minimization of aberrations in the
optical system and improvements of beam shape or profile.
[0124] Besides the cross-axis cascading, another approach to
improve the extinction ration of a VIPA etalon is to make the
intensity profile of the VIPA output close to a Gaussian shape, a
technique known as apodization. FIG. 4A shows an embodiment of a
spectrometer using apodized VIPA etalons. In this embodiment, a
spatial filter 360 with a spatially varying transmission profile is
used just after the first VIPA etalon 300. The filter 360 converts
the otherwise exponential beam profile to a rounded shape, such as
a truncated Gaussian profile. After the second VIPA etalon 310,
another linear variable filter 365 is employed. The spectrally
dispersed output is then imaged on to a detection unit 370. The
detection unit is typically a two-dimensional camera based on
charge-coupled device (CCD) or a linear detector array.
[0125] FIG. 4B illustrates the role of the apodization filter 360.
An input light 380 enters the etalon 300 and is converted to an
output beam 380 consisting of a phased array. Normally, in the
absence of the filter 360, the intensity of this output beam 380
has an exponential profile 384. The transmission profile of the
filter 360 may have a linear, exponential, or more complex
nonlinear gradient along the length. The variable filter 360 with
an appropriately designed transmission profile converts the
exponential profile 384 to a more round, Gaussian-like profile 388.
Passing through a Fourier-transform lens in front of the detection
unit 370, the rounded profile produces significantly less crosstalk
or higher extinction ratio than conventional VIPA etalons. With a
linear variable filter, an extinction ration of greater than 40 dB
is typically achievable.
[0126] In another embodiment of apodization, a VIPA etalon 390 is
made with a gradient coating on the exit surface 394, such that its
reflectivity and transmission is varied spatially, producing a
rounded, Gaussian-like intensity profile 396. For example, with a
single VIPA with its reflectivity of the coating 394 is linearly
varied from 99.9% to 90%, an extinction ratio of approximately 59
dB can be achieved in principle assuming a constant phase profile.
Gradient reflectivity generally results in a spatially varying
phase profile. A linear phase chirp may not affect the extinction
much and can be compensated for by employing a wedge. With 15
evaporated coating layers, the reflectivity can be made to vary
from 92% to 98.5 over 15 mm along the surface 394 can yield a
lambda/100 deviation from a wedge. With more layers, a higher
reflectivity gradient from 92% to 99.5% can be achieved at the
expense of increased nonlinear phase variation of about
lambda/40.
[0127] The system arrangement can be configured to interrogate
multiple spatial points simultaneously in the ocular tissues. FIGS.
5A and 5B illustrate two examples. A multiple foci 400 of the probe
light are formed, and the Brillouin scattered light 402 from each
focus is relayed and coupled to the VIPA etalon 390 through free
space or a fiber array 410. The spatio-spectral pattern 420
projected on the detection unit is then processed to provide the
biomechanical information about the ocular tissue interrogated.
[0128] Another method to interrogate multiple spatial points is to
use a line focus 430. The Brillouin scattered light 432 produced
from the line focus 430 is relayed and coupled to the etalon 390.
The spatio-spectral pattern 420 projected on the detection unit is
used to generate the information about the ocular tissues.
[0129] Other spectral modalities such as Raman and fluorescence
spectroscopy can be performed simultaneously with Brillouin
spectroscopy. The combined modalities could provide more
comprehensive information about the biochemical and structural as
well as biomechanical and physiological properties of ocular
tissues. Since fluorescence. Raman and Brillouin spectrum occupy
different region of the electromagnetic spectrum, the second
arrangement 150 may be configured to separate these spectra and
analyze them simultaneously. Using various spectral dispersive
elements, such as gratings and dichroic mirrors, the spectra
associated with different emission mechanisms can be easily
separated and analyzed. The separated spectra can be projected onto
a single detection unit such as a CCD camera after proper
equalization of their intensities. Alternatively, the spectra can
be directed to different detection units.
[0130] We conducted a proof-of-principle experiment and feasibility
study of the present description. We developed two prototype
instruments consisting of a light source, imaging optics, a
spectrometer, and a computer. The light sources for the two
prototypes are a frequency-doubled diode-pumped Nd-YAG laser
emitting a 532-nm wavelength with a linewidth of 1 MHz and a
grating-stabilized single longitudinal mode laser diode emitting at
780 nm with a linewidth of about 100 MHz. Light is focused on a
sample through a 35 mm or a 11 mm focal length lens. In the
prototypes, we used a beam scanner and a motorized translation
stage to move the sample. We employed the epi-detection
configuration so that scattered light is collected through the same
lens. A single mode fiber was used as confocal pinhole.
[0131] Light is then coupled into the VIPA spectrometer for high
spatial separation of the spectral components in the plane of an
Electron-Multiplied CCD camera. The spectrometer employed a 3 nm
bandpass filter to block fluorescence light. The optical design
used for the prototype is a combination of a two-stage VIPA
spectrometer and a variable attenuation neutral density filter. The
spectrometer features a spectral resolution of about 1 GHz, an
extinction ratio of about 75 dB, and a total insertion loss of 7 dB
with a finesse of about 40.
[0132] To test the possibility of measuring the lens elasticity in
vivo, we performed Brillouin imaging on laboratory mice 500
(C57BL/6 strain), as illustrated in FIG. 6A. We focused the probe
beam 510 into the eye of the mouse under anesthesia. As the animal
was moved by a motorized stage, the optical spectrum of scattered
light was recorded. FIG. 6B shows unprocessed data recorded by the
camera in the spectrometer at different depths along the ocular
optic axis of the lens, featuring the spectral pattern in the
anterior cortex (i), lens nucleus (ii), posterior cortex (iii), and
vitreous humor (iv). Each spectrum was acquired in 100 ms. FIG. 6C
shows a plot of the Brillouin frequency shift measured as a
function of depth in the region spanning from the aqueous humor
through the lens to the vitreous. FIG. 6D exemplifies an axial
profile of the width of the Brillouin spectrum over depth. From
these curves, several diagnostic parameters can be derived, such as
the peak Brillouin shift at the center of the nucleus, peak
Brillouin linewidth, average frequency shift across the lens,
etc.
[0133] FIG. 6E show cross-sectional Brillouin elasticity maps,
where the color represents the measured Brillouin frequency shift.
The image areas are 1.7.times.2 mm.sup.2 (XY), 1.8.times.3.1
mm.sup.2 (YZ), and 2.times.3.5 mm.sup.2 (XZ), respectively. With a
sampling interval of 100 .mu.m, it took .about.2 s to scan each
axial line (20 pixels), .about.50 s for a cross-sectional area
(20.times.25 pixels), and .about.20 min over an entire 3D volume.
These images visualize the gradient of modulus increasing from the
outer cortex to inner nucleus.
[0134] Using in vivo Brillouin microscopy, we investigated the
natural age dependence of the lens modulus. The peak Brillouin
shift observed at the center of the lens nucleus in a mouse at 18
month old was 16 GHz, whereas the shift in a younger mouse at 1
month old was 11.5 GHz. We extended the study to 12 mice of
different ages to find an evident trend of age-related stiffening.
Next, we imaged one mouse every week for two months and obtained
consistent age-related data. Our results indicate a quantitative
(linear-log) relationship between the hypersonic elastic modulus
and the animal age. This result suggests the first in vivo data
evidencing an age-related stiffening of lenses in mice.
[0135] We performed Brillouin imaging on bovine eyes ex vivo. FIG.
7A depicts a Brillouin image of the anterior segment of the bovine
eye. The transverse and axial resolution of the probe beam was 1
and 5 .mu.m, respectively. The Brillouin frequency shift is encoded
in color. The depth-resolved cross-sectional image (XZ) indicates
that the Brillouin frequency decreases gradually from the
epithelium 600 through the stroma 604 to the endothelium 608. The
Brillouin frequency of the aqueous humor 612 is consistent with
that shown in FIG. 6C. The variation of the elastic modulus along
the depth seems to correlate with the morphological structure of
the cornea. The Brillouin modulus doesn't seem to vary much along
transverse dimensions in normal cornea. FIG. 7B shows an en face
(XY) image of the cornea optically sectioned at a flat plane.
[0136] FIG. 7C shows a laterally averaged axial profile (along the
X-axis) obtained from the central 0.5-mm wide portion of the
cross-sectional image in FIG. 7A. Several features were observed,
such as a steep slope of the Brillouin frequency over depth in the
epithelium (620) and the anterior part of stroma, a mild and
apparent decreasing slope in the central part (622), and a rapid
decreasing slope 624 in the innermost layers of the stroma toward
the endothelium).
[0137] We can therefore define three slopes (anterior, central and
posterior) for each sample that characterize the axial behavior of
corneal stiffness. In the anterior region, defined as the depth
between 80 and 180 .mu.m, we measured an average slope (620) to be
1.09.+-.0.26 GHz/mm. In the central region, defined as the depth
between 300 and 600 .mu.m, we measured the average slope (622) to
be 0.36.+-.0.06 GHz/mm. And, in the posterior region over the depth
between 680 and 780 .mu.m, we measured the average slope 624 to be
2.94.+-.0.18 GHz/mm. The difference between the three slope
measurements was highly statistically significant with p-values of
<0.001 for the three comparisons calculated with unpaired
two-tailed t-test Another characteristic parameter that can be
quantified is the mean Brillouin shift 630, or the space average
over the entire depth.
[0138] Using the infrared prototype system we performed the first
in vivo study of cornea and lens in a human subject. We have
verified that the features we had seen in animal studies are also
present in humans, and the instrument is sensitive to detect the
elasticity of human cornea and lens. The axial profile acquired
with a continuous-wave power of 0.7 mW shows a decreasing Brillouin
frequency from anterior to posterior cornea and a gradual increase
in stiffness from the aqueous humor to the lens nucleus.
[0139] We tested the potential as a monitoring tool for corneal
procedures. We tested if Brillouin biomechanical imaging is
sensitive to corneal stiffness changes induced by therapeutic
procedures known as corneal collagen crosslinking (CXL). CXL is a
promising technique that promotes the formation of covalent bonds
between collagen fibers inside corneal stroma through a
photosensitizing agent and light irradiation. Enhancing the amount
of crosslinks between collagen fibers leads to a stiffer corneal
stroma. We performed the CXL procedure on bovine corneal samples. A
photosensitizer (Riboflavin) was diffused into the stroma of the
cornea after removal of the epithelium and was activated by
illuminating blue light. FIG. 8A shows Brillouin cross-sectional
images of bovine cornea samples in three different states: intact
(left), after removal of epithelium (middle), and after the
crosslinking procedure (right). It is apparent that the
crosslinking procedure greatly has enhanced Brillouin modulus in
the stroma. Shrinking of tissue after crosslinking is well
documented.
[0140] Using Brillouin parameters we can quantify the effect of CXL
procedure. Using analogous procedure to the one described
previously, we obtained corneal axial profiles before and after the
CXL. We found that CXL resulted in a dramatic increase in the
downward slope (622 in FIG. 7C for a normal tissue) of Brillouin
frequency over depth in the stromal region. FIG. 8B shows the
increase of the central slope (absolute value) for control versus
treated samples (N=4). The difference was statistically significant
with a p-value of <0.0001 in unpaired two-tailed t-test. FIG. 8C
shows a statistically significant increase of the mean Brillouin
modulus averaged along the depth profile. The increase in the
treated tissues was about 10%.
[0141] Finally, performed Brillouin analysis on surgically
extracted human corneas from healthy donors and keratoconus
patients undergoing corneal transplants. We found that a
statistically significant difference in both the central slope and
mean Brillouin modulus.
[0142] All of these experimental results indicate the usefulness of
this description in clinical and preclinical ophthalmology as well
as basic eye research. The Brillouin ocular analyzer may be proven
to be a useful diagnostic tool, facilitating early diagnosis,
screening of at-risk patients, monitoring therapeutic responses,
developing novel approaches for treatment, and understanding
pathogenesis.
[0143] The mechanical properties of the crystalline lens, sclera,
and cornea play an important role in several medical problems, such
as cataracts, presbyopia and corneal ectasia. In turn, these
disorders and age are known to alter the mechanical properties of
the tissues. This description enable us to obtain the information
relevant to the biomechanical and physiological states of various
tissues in the eye noninvasively in living patients and animals,
providing useful information for understanding, diagnosing and
treating the medical problems. In this description, the mechanical
properties of the ocular tissues are obtained from the spectrum of
light reemitted from ocular tissues via Brillouin scattering. This
information is useful for diagnosis and treatment of ocular
disorders in the clinical settings, as well as in basic and
preclinical stages.
[0144] The techniques described herein can be used in an algorithm,
including algorithms based on numerical analysis, such as finite
element analysis (FEA), which uses the local or global Brillouin
modulus values. Such numerical analysis enables material
information on a localized level to be used, where each element in
the FEA model, corresponding to a segment of an ocular component,
is able to have individual visco-elastic modulus values assigned.
Without such localized material information, elements of an FEA
model (e.g., a voxel in a 3D array of elements) may need to assign
a single material constant throughout a modeled region, which would
not be as useful for dynamically guiding a procedure based on such
an FEA model. Even if assigned material constants could be updated
based on in-situ measurements, it is still more useful to have a
high resolution dynamically evolving model where each individual
element is updated based on monitored properties of the ocular
component(s). In addition to the Brillouin modulus, other
information including geometric information, such as corneal
topography, curvature, thickness, physiological information such as
intra ocular pressure, and incision parameters can be input to the
FEA engine generating the numerical model. The algorithm may
generate an output, which may include a stress-strain map or local
stress value. The analysis output may be used to simulate varied
incisions (e.g. location, length, angle, and depth) and predict the
refractive impact of the incisions. The algorithm can provide a
biomechanics-based stress-strain maps that can be used in a
nomogram to help achieve the desired surgical outcome or refractive
result.
[0145] FIGS. 9A-9E depict exemplary incisions that can be guided
using the techniques described herein. FIGS. 9A and 9B depict
incisions into the cornea with a laser and a mechanical means,
respectively. FIG. 9C shows an incision into the sclera, which can
have an effect on the corneal structure. FIG. 9D depicts a limbal
relaxing incision (LRI). FIG. 9E shows the deformation of the
finite element model mesh of the cornea at the location of the
incision.
[0146] There may be challenges that need to be overcome to obtain
the peripheral measurements of the cornea. A measurement instrument
can be configured to make it easier and/or more efficient to take
such measurements, either in a specific system for peripheral
measurements or in a system that can toggle between central
measurements and peripheral measurements. For example, an oblique
angle at which the treatment laser is incident can be taken into
account.
[0147] Aspects of the techniques described herein can be applied to
Brillouin scanning measurement of modulus or stiffness of sclera
for diagnosis and prognosis of a condition, such as myopia or
glaucoma, for example, to optimize the treatment pathway for that
condition.
[0148] The sclera, also known as the white of the eye, is the
opaque, fibrous, protective, outer layer of the eye containing
collagen and elastic fiber. In humans the whole sclera is white,
contrasting with the colored iris. Changes in the shape of the eye
have been shown to contribute to the development of myopia.
Investigation has also been performed to determine if or by how
much scleral compliance or stiffness contributes to the development
and progression of myopia. Corneal contribution of
compliance/stiffness has been said to be small. Axial myopia is
attributed to an increase in the eye's axial length. Curvature
myopia is attributed to the curvature of one or more refractive
surfaces of the eye, especially the cornea. In the case of either
axial myopia or curvature myopia, it is unclear how properties of
the sclera influence the curvature and/or irregularity of the
refractive surfaces of the eye. Studies in the field have examined
how properties such as thickness of ocular tissues, may
statistically differ between high myopes and emmetropic healthy
controls. Some studies claim that the development and progression
of myopia is due to an increase of vitreous chamber depth, which
may be related to elongation of the sclera or scleral ectasia.
Although the definition of pathologic myopia has not been
standardized, the commonly used criteria for pathologic myopia
include myopic refractive error (spherical equivalent (SE)) greater
than 6.00 D or 8.00 D or an axial length greater than 26.5 mm.
[0149] Myopia may also be closely linked with scleral deformation,
and sclera biomechanics has been speculated to be a factor for
predicting myopia. Despite known treatment pathways, pathologic or
progressive myopia patients comprising approximately 4% of myopic
population still have not optimized treatment pathways. Myopia
treatment includes vision correction through glasses, contact lens,
refractive surgeries, and medical therapy with atropine. In vivo
high spatial resolution measurement of the elastic modulus of
sclera is now enabled by the techniques described herein.
[0150] The techniques described herein use the measurement of
Brillouin scattering to assess biomechanical properties of the
sclera and other ocular components, which facilitates potential
prognosis for developing conditions including axial myopia,
curvature myopia, and pathological myopia. In certain embodiments,
local Brillouin modulus is taken both from the surface of the
sclera and within the sclera. Reflectivity of the sclera can be
taken into consideration requiring the setup described in the
Appendix to be modified according to a number of potential
parameters, including the wavelength of the light source and
extinction of the spectrometer. Also, since the sclera scatters
light relatively strongly (in comparison to the cornea, crystalline
lens, and vitreous), accessing Brillouin modulus from inside of the
sclera, at varying depths, is a challenge. Potential approaches to
overcome this include the use of Brillouin spectrometer instrument
with sufficiently high extinction ratio, typically over 65 dB or
ideally over 80 dB, to reduce the elastic scattering from the
sclera. The scattering in the sclera is wavelength dependent. A
spectral range above 1000 nm in wavelength or around 1300 nm or
1550 nm may be advantageous because the reduced scattering from the
sclera. Additional embodiments may include an optical probe, which
may employ a waveguide or a fiber-optic setup, for delivering the
probe light to the sclera and capture the Brillouin scattered
signal from the sclera.
[0151] Additional embodiments may include one or more Brillouin
measurements of the sclera, at varying surface or depth locations
or both, may be combined through numerical methods, for example, as
averages or ratios to create a scleral biomechanics (e.g., a
coefficient). Such a coefficient may be compared to and numerically
combined, through a variety of methods, with other biomechanics
measures taken from additional ocular tissues, including but not
limited to the cornea. The measurements can include an array of
simultaneous or non-simultaneous measurements.
[0152] In embodiments that jointly measure and assess biomechanical
properties of the sclera and the cornea, the ratio or comparison
between different measures from these two tissues may be
particularly useful because it may provide insights to how the
deformation of corneal or scleral tissues, and the transitional
zone between sclera and cornea and conjunctiva (which covers the
sclera up to the cornea) and cornea, will progress over time. Not
only progression over time, but also assessment of the status of
this zone can help to better understand keratoconus, ectasia and
other corneal irregularities. The techniques described herein can
also be used to measure the stiffness of conjunctiva, a thin layer
around sclera to provide additional stiffness, and feedback into
the algorithm to determine the progression of myopia, corneal
disorders and irregularities, or even pre-disposition for ectasia
and keratoconus.
[0153] In other embodiments, local Brillouin modulus is taken both
from within the crystalline lens, which facilitates potential
guidance for treatments of the crystalline lens, for example, in
conjunction with presbyopia or extraction of the crystalline lens
in case of cataract surgery.
[0154] Brillouin microscopy can also be used to measure the
propagation speeds and damping coefficient of not only longitudinal
but also transverse acoustic waves. From the measured data, the
anisotropic mechanical or visco-elastic properties of tissues can
be determined. For each measurement, the polarization states of
Brillouin scattered light with respect to the polarization state of
the input light, and also with respect to the symmetry axis of the
sample, can be determined. For example, the symmetry axis can be
the orientation(s) of collagen fibers in the cornea. For such
isotropic samples, by symmetry no transverse (shear) acoustic modes
should be detectable in the back scattering geometry. When the axis
is tilted, symmetry is broken and the shear waves can be measured.
For this measurement, the input light is typically polarized by
using a linear, or circular, polarizer, and the scattered light is
detected through a polarization sensitive detector containing, for
example, one or more polarizers and/or polarization splitters. The
instrument may also employ an arrangement to vary the relative
orientation of the beam axis with respect to the sample. The
arrangement may include a beam tilt probe.
[0155] The techniques can also be applied to other procedures. The
biomechanical information from the cornea and/or sclera can provide
information that is useful to determine patient-specific optimal
protocols for intervention. The intervention or treatment of myopia
includes scleral crosslinking or drugs such as atropine.
[0156] Measurements of the bulbar sclera can be part of the
monitoring of scleral crosslinking or impact of drugs such as
atropine.
[0157] Measurement of the posterior sclera might be possible by
accessing the sclera through the pupil non-invasively to monitor
the same processes.
[0158] Monitoring of various ocular components can be useful to
guide not only noninvasive but also invasive procedures such as
vitreo-retinal procedures like pars-plana vitrectomy or retinal
laser treatments to name a few.
[0159] Other embodiments are within the scope of the following
claims.
* * * * *