U.S. patent application number 16/659984 was filed with the patent office on 2020-02-13 for real time acoustic dosimetry for corneal collagen crosslinking.
The applicant listed for this patent is TECLens, LLC. Invention is credited to David E. Acker, Patrick David Lopath.
Application Number | 20200046554 16/659984 |
Document ID | / |
Family ID | 53673303 |
Filed Date | 2020-02-13 |
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United States Patent
Application |
20200046554 |
Kind Code |
A1 |
Lopath; Patrick David ; et
al. |
February 13, 2020 |
Real Time Acoustic Dosimetry For Corneal Collagen Crosslinking
Abstract
A change in the response of the cornea to ultrasonic energy
directed into the cornea is monitored during irradiation of the
cornea to bring about corneal crosslinking. Because the change in
ultrasonic response is correlated with the degree of crosslinking
achieved, a desired degree of crosslinking can be achieved by
terminating the irradiation when the change reaches a threshold.
The change in ultrasonic response can be determined by taking a
baseline measurement before irradiation and additional measurements
during irradiation using the same ultrasonic transducer (47). The
transducers may be carried on a device (30) resembling a contact
lens which overlies the eye and which transmits the light used in
the irradiation step to the eye.
Inventors: |
Lopath; Patrick David;
(Stamford, CT) ; Acker; David E.; (St. James,
NY) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
TECLens, LLC |
St. James |
NY |
US |
|
|
Family ID: |
53673303 |
Appl. No.: |
16/659984 |
Filed: |
October 22, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15856651 |
Dec 28, 2017 |
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16659984 |
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14751324 |
Jun 26, 2015 |
9883970 |
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15856651 |
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62096164 |
Dec 23, 2014 |
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62018255 |
Jun 27, 2014 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61F 2009/00844
20130101; A61N 5/062 20130101; A61B 8/485 20130101; A61F 9/0079
20130101; A61F 2009/00897 20130101; A61B 8/5207 20130101; A61B 8/10
20130101; A61F 2009/00872 20130101; A61F 2009/0088 20130101; A61F
2009/00842 20130101; A61B 8/0858 20130101; A61B 8/4236 20130101;
A61F 9/008 20130101 |
International
Class: |
A61F 9/008 20060101
A61F009/008; A61B 8/08 20060101 A61B008/08; A61B 8/00 20060101
A61B008/00; A61F 9/007 20060101 A61F009/007; A61B 8/10 20060101
A61B008/10; A61N 5/06 20060101 A61N005/06 |
Claims
1. A device for applying irradiation and ultrasound to an eye of a
subject comprising: (a) a housing having an inwardly-facing surface
adapted to rest on an anterior surface of the eye; (b) an optical
diffuser mounted to the housing, the diffuser having inner and
outer surfaces facing inwardly and outwardly; and (c) a ultrasonic
transducer mounted to the housing and disposed outward of the
diffuser so that the diffuser is disposed between the transducer
and the eye when the housing rests on the anterior surface of the
eye.
2. A device as claimed in claim 1 wherein the ultrasonic transducer
is coaxial with the diffuser.
3. A device as claimed in claim 1 wherein the housing includes a
peripheral portion facing inwardly, the peripheral portion defining
the inner surface of the housing and, the inner surface being
adapted to bear on the sclera of the eye and maintain the diffuser
and the transducer in alignment with the cornea.
4. A device as claimed in claim 3 wherein the peripheral portion is
adapted to maintain a space between the diffuser and the cornea.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a continuation application of
U.S. patent application Ser. No. 15/856,651, filed Dec. 28, 2017,
which is a divisional application of U.S. patent application Ser.
No. 14/751,324, filed Jun. 26, 2015, which application claims the
benefit of the filing date of U.S. Provisional Patent Application
No. 62/096,164, filed Dec. 23, 2014, and also claims the benefit of
the filing date of U.S. Provisional Patent Application No.
62/018,255, filed Jun. 27, 2014. The disclosures of the foregoing
applications are hereby incorporated by reference.
BACKGROUND OF THE INVENTION
[0002] The present invention relates to methods and apparatus for
corneal collagen crosslinking ("CCXL").
[0003] The vision of a human or other mammalian subject can be
modified by crosslinking the collagen within the cornea of the eye.
A photoactivated crosslinking facilitator such as riboflavin is
applied to the cornea. Light at a wavelength selected to activate
the crosslinking facilitator is applied. Where the crosslinking
facilitator is riboflavin, the light typically is ultraviolet or
blue light. The activated facilitator causes crosslinking of the
collagen within the cornea. The crosslinking changes the mechanical
properties of the cornea. For example, the crosslinking stiffens
the cornea. These changes can result in stabilization of
pathological conditions, such as keratoconus, or in alterations to
the shape of the cornea. This technique can be used to correct
defects in vision such as myopia, hyperopia, or astigmatism. For
myopia (nearsightedness), the center of the cornea is stiffened;
for hyperopia (farsightedness), an annulus around the periphery of
the cornea is stiffened. For more complicated corrections such as
astigmatism, custom patterns are used.
[0004] In some applications, the light is applied as a beam
directed into the eye from a device remote from the eye. In other
applications, the light is applied by a device which rests on the
eye. As disclosed in U.S. Patent Application Publication No.
2014/0379054 ("the '054 Publication") and U.S. Provisional Patent
Application No. 61/839,016 ("the '016 Provisional"), the
disclosures of which are hereby incorporated by reference herein,
light can be applied to the eye through a structure having a form,
size, and shape resembling that of a contact lens such as a scleral
contact lens. The structure may incorporate an optically dispersive
element. Light may be directed into the dispersive element and
dispersed so that the dispersed light passes into the eye from the
dispersive element. This arrangement has numerous advantages. For
example, the patient may be able to close his or her eye during the
treatment, so that the structure is disposed between the eyelid and
the eye.
[0005] CCXL changes the mechanical properties of the cornea by
creating chemical bonds between the protein layers in the corneal
stroma. These bonds (crosslinks) increase the stiffness of the
cornea in the region crosslinked. This increased stiffness changes
the balance between the cornea tension and the intraocular
pressure. Through mechanisms not completely understand in the
field, within a few days to weeks of CCXL therapy, physiologic
processes reshape the cornea. The amount of reshaping, and thus the
degree of curvature correction, is determined by a number of
treatment parameters, including the amount and rate of energy
delivery, the treatment time and the aperture of the treated area
on the cornea. The amount of reshaping also may be influenced by
factors such as the oxygen saturation of the cornea during
irradiation; the amount of crosslinking facilitator present in the
cornea during irradiation and physiological differences between
patients.
[0006] As with any therapeutic energy delivery modality, it is
desirable to control the irradiation of the eye so as to deliver a
dose of radiation which will yield the desired procedural outcome,
such as a desired degree of reshaping. Because numerous factors
control the relationship between the light energy applied to the
cornea during irradiation and the amount of reshaping achieved, it
is difficult to achieve a precise degree of reshaping by selecting
a dose of energy in advance, based on a priori knowledge of a
relationship between dose and reshaping, and then simply applying
the selected dose.
[0007] The reshaping of the cornea after CCXL takes place over a
few days to weeks after the procedure. Thus, the real time
monitoring of corneal shape during irradiation cannot be used as a
measurement during the procedure to control the dose of UV
delivered.
[0008] It has been proposed to use Brillouin microscopy to monitor
properties of the cornea in conjunction with corneal crosslinking.
However, application of this approach in a clinical setting suffers
from significant practical difficulties.
[0009] Accordingly, further improvement would be desirable.
SUMMARY OF THE INVENTION
[0010] One aspect of the present invention provides methods of
corneal crosslinking. A method according to this aspect of the
invention desirably includes the step of irradiating a cornea in an
eye of a living subject with light to induce crosslinking of
collagen in the cornea. The method desirably further includes the
step of monitoring the crosslinking by directing ultrasonic energy
into the cornea and determining a response of the cornea to the
ultrasonic energy using one or more transducers. The steps of
directing ultrasonic energy and determining a response most
preferably are using the same one or more transducers to provide a
baseline response before commencement of the light applying step
and one or more additional responses during the light applying
step. The method desirably further includes the step of comparing
the additional responses to the baseline response and controlling
the irradiating step based at least in part on the results of the
comparison. For example, the controlling step may include
terminating the irradiation when a comparison between an additional
response and the baseline response indicates a change in the
response in excess of a threshold value. Most preferably, the one
or more transducers used to direct ultrasonic energy into the
cornea and to determine the response are mounted on a structure
which overlies the anterior surface of the eye and rests on the eye
during the irradiating and monitoring steps. The structure
desirably is adapted to transmit the light used in the irradiating
step. For example, the structure may be a structure such as that
described in the '054 Publication.
[0011] The various elastic moduli of the cornea are fundamental
material properties of the cornea. In conjunction with forces which
act on the cornea, such as intraocular pressure, the elastic moduli
determine the shape of the cornea. The elastic moduli change during
crosslinking, and thus change in the elastic moduli is correlated
with the degree of crosslinking. In preferred methods according to
this aspect of the invention, the response of the cornea to
ultrasonic energy, alone or in conjunction with other data, serves
as a "proxy" for one or more of the material properties of the
cornea, such as one or more of the elastic moduli. As referred to
herein, a "proxy" for one or more material properties is a value or
set of values which changes in a manner correlated to the material
properties. As properties of the collagen in the cornea such as the
elastic moduli of the collagen change during crosslinking, the
proxy indicates the degree of crosslinking. Thus, the baseline
response determined prior to irradiation is a proxy for the
original material properties, whereas each additional response is a
proxy for the material properties at a time during irradiation.
Comparison of the proxy determined during irradiation with the
original or baseline proxy gives an indication in the change in
material properties, and thus an indication of the degree of
crosslinking which has occurred. It is not essential to determine
the actual material properties. Moreover, because the same
transducer or transducers mounted on the same structure overlying
the eye are used for both baseline and additional measurements, the
same errors will affect both baseline and additional measurements.
Therefore, these errors will be substantially cancelled in the
comparison between the baseline and additional proxies.
[0012] As further discussed below, several different responses to
applied ultrasonic energy can be used. These include the spectrum
of backscattered ultrasonic energy, the time of flight of reflected
ultrasonic pulses; and the resonant frequency or period of the
cornea after it is displaced from its rest position by applied
ultrasonic energy.
[0013] Further aspects of the present invention provide methods of
measuring a physical property of the cornea in a living subject, as
well as devices and systems which can be used in such methods and
in the method of corneal crosslinking discussed above.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] FIG. 1 is a diagrammatic sectional view depicting elements
of a system according to one embodiment of the invention in
conjunction with an eye of a subject.
[0015] FIG. 2 is a fragmentary sectional view on an enlarged scale
depicting elements of the system shown in FIG. 1.
DETAILED DESCRIPTION
[0016] A system according to one embodiment of the invention
includes a device 30 having a structure adapted to overlie and rest
upon the anterior surface of the eye. The structure of the device
includes a housing 32 generally in the form and size of a scleral
contact lens having a central axis 33. The housing includes a
peripheral portion adapted to bear on the sclera 34 of the eye when
the device is in place on the eye as depicted in FIG. 1. When the
device is in place on the eye, the central axis 33 of the housing
is aligned with the cornea 38 of the eye and the axis 33 extends
inwardly toward the eye and outwardly away from the eye. The
structure further includes a diffuser 36 disposed in a central
portion of housing. As described in greater detail in the '054
Publication, the diffuser is formed from an optically dispersive
material such as a clear silicone polymer with particles such as
titanium dioxide dispersed therein. The diffuser may be in the form
of a layer or dome having an inner surface 37 facing toward the eye
when the structure is in place. The structure further includes a
fiber carrier 40 defining an aperture aligned with a portion of the
diffuser 36. In the particular embodiment depicted, the aperture is
in the form of a circular opening as, for example, about 6 mm in
diameter, although other sizes and shapes may be employed. As best
seen in FIG. 2, one or more optical fibers 44 extend within the
fiber carrier 40 and are in optical communication with the diffuser
36. The optical fibers 44 are connected via a transmission fiber or
fibers 46 (FIG. 1) to a light source such as a laser 48. The
foregoing features of the device may be as disclosed in the '054
Publication, and may also include the features disclosed in U.S.
Provisional Patent Application No. 62/095,416, filed Dec. 22, 2014
("the '416 Provisional"), the disclosure of which is hereby
incorporated by reference herein.
[0017] The device further includes an ultrasonic transducer 47
incorporating a layer 48 of a piezoelectric material, preferably a
polymeric piezoelectric material such as polyvinylidene fluoride
("PVDF") or other piezoelectric polymer, co-polymer, or composite.
An electrically conductive metallic film 50 such as an aluminum
film overlies an inner or front surface of the piezoelectric layer.
The metallic film may be a film formed by vapor deposition on the
piezoelectric layer or a thin foil in contact with the
piezoelectric layer. The metallic film may be provided with a thin
layer of a coating to prevent oxidation of its surface as, for
example, a deposited SiO.sub.2 coating. The surface of the metallic
film abuts the rear or outer surface 39 of the diffuser. Desirably,
the metallic layer covers the entire outer surface 39 of the
diffuser. As further discussed below, the metallic layer acts both
as an electrode of transducer 47 and as a reflector for light.
[0018] A backing layer 52 abuts the rear or outwardly-facing
surface of the piezoelectric film 48 in a region of the film.
Backing layer 52 is formed from a material which desirably has
acoustic properties approximating those of air. Desirably, the
material is acoustically attenuative or "lossy" at acoustic
frequencies in the ranges discussed herein. The material of the
backing layer desirably has acoustic impedance lower than the
acoustic impedance of the piezoelectric layer and also lower than
the acoustic impedance of the diffuser. For example, the backing
may be a foam such as syntactic foam incorporating hollow
"microballoons" and an adhesive matrix. Desirably, the backing is
also electrically conductive. The microballoons may incorporate or
may be coated with an electrically conductive material such as
silver. Alternatively or additionally, the adhesive matrix may be
an electrically conductive polymer or may incorporate an
electrically conductive material as, for example, silver particles.
The electrically conductive backing layer 52 and the metallic film
50 serve as electrodes for the piezoelectric film 48 in the region
covered by the backing layer. Electrical connections schematically
indicated at 54 and 56 connect the electrodes 50 and 52 to a drive
circuit 58 (FIG. 1). As discussed further below, the drive circuit
58 is arranged to excite the piezoelectric film 48 to emit
ultrasound and to receive electrical signals generated by the
piezoelectric film responsive to ultrasound impinging on the
film.
[0019] Desirably, the ultrasonic transducer is a high-frequency
transducer, capable of operating efficiently at frequencies of 10
MHz or more, preferably 20 MHz or more, more desirably 50 MHz or
more, and most desirably 100 MHz or more.
[0020] The foam backing 52 helps to ensure acoustic isolation of
the transducer from the structure behind it. These balloons are
very low density. The low density foam created from the
microballoons does not load the acoustic transducer as much as the
front layers of the light guide and beyond. Thus, the larger real
load on the front of the acoustic transmitter enables a larger
forward transmitting voltage response (TVR) than rearward TVR, so
more energy is transmitted forward (in the inward direction
indicated in FIG. 2) than backward. This helps reduce the rear
reflections that must be attenuated, helping to prevent confounding
signals from reflecting off backing interfaces and returning to the
transducer. The ultimate goal of this foam backing is to
approximate air, which is highly attenuative at high frequencies.
In addition to poor coupling to (and thus power transfer from) the
transducer and limited ability to support high frequency
compressional waves, the very light backing foam also contains
scatters (microballoons and potentially silver particles from a
conductive epoxy used as the adhesive matrix) of various sizes on
the order of the acoustic wavelength. This scattering helps to
further attenuate any rearward waves before they can reflect back
to the transducer. The light foam (or air) backing has the added
benefit of improving the sensitivity of the transducer in receive
mode by enabling impinging waves that are returning from the region
of interest to dissipate most of their energy in the piezoelectric
material, as opposed to traveling through the sensor into the
backing.
[0021] The diffuser 36 constitutes the load on the front or
inward-facing side of the piezoelectric film. The material of the
diffuser has an acoustic impedance close to that of the polymeric
material of the transducer. The matching acoustic impedance
promotes efficient emission from the front or inward-facing surface
of the transducer, and efficient transfer to the transducer of
ultrasonic signals returning through the diffuser from the eye. The
transducer and optical elements of the device, including the
diffuser 36 and the aperture defined by fiber carrier 40 are
arranged so that at least part of the region exposed to ultrasonic
energy from the transducer lies within the region exposed to light
supplied by the optical elements. In the particular arrangement
shown, the transducer and is coaxial with the optical elements. The
optical elements are arranged to apply light to a circular region
of the cornea surrounding the central axis 33 of the device, and
the ultrasonic transducer is arranged to apply ultrasound to a
circular region surrounding the same axis.
[0022] The drive circuit 58 (FIG. 1) includes conventional
components for generating high-frequency electrical signal and
supplying the same to the transducer. The drive circuit also
includes conventional components for receiving electrical signals
from the transducer and providing representations of those signals.
For example, the drive circuit may include components such as
analog to digital converters, digital to analog converters, an
oscillator, amplifiers and filters.
[0023] A control circuit 60 is connected to drive circuit 58, so
that the control circuit can command the drive circuit and
transducer to apply ultrasound and so that the control circuit can
receive representations of signals generated by the transducer
responsive to ultrasound impinging on the transducer. The control
circuit 60 is also connected to light source 48 so that the control
circuit can control operation of the light source. The control
circuit may include a general-purpose computer having elements such
as a processor, a memory linked to the processor and input/output
elements. The memory desirably stores instructions operative to
cause the computer to execute the operations discussed below.
[0024] When the device 30 is in disposed on the eye in the
operative position shown in FIG. 1, there is a space 62 between the
anterior surface of the cornea 38 and the inner surface 37 of the
diffuser. This space 62 desirably is kept filled with a liquid
during operation of the device. The liquid desirably is transparent
to the light such as UV which will be applied by the device, and
desirably has acoustic impedance reasonably close to that of the
diffuser 36 and the cornea 38. For example, an aqueous liquid such
as a saline solution or the subject's natural tears may fill the
space. Preferably, the liquid disposed in space 62 desirably
contains a source of oxygen, as disclosed in U.S. Provisional
Patent Application No. 62/095,288, filed Dec. 22, 2014, ("the '288
Provisional") the disclosure of which is hereby incorporated by
reference herein. As disclosed in the '288 Provisional, the oxygen
source helps to maintain oxygen saturation of the cornea during the
crosslinking procedure, and thus promotes crosslinking. As also
disclosed in the '288 Provisional, pharmaceutically acceptable
perfluorocarbons can serve as a source of oxygen and be used as a
part or all of the liquid. Use of a perfluorocarbon liquid is
particularly advantageous where ultrasonic energy is to be applied
to the cornea. Perfluorocarbons are dense and transmit both UV
light and ultrasound well.
[0025] In a method according to one embodiment of the invention,
the transmission time of ultrasound within the cornea serves as a
proxy for the stiffness or elastic modulus of the cornea. In a
method according to this embodiment, the cornea is pre-treated by
exposure to a liquid containing a photoactivated crosslinking
facilitator such as riboflavin. As disclosed in the '288
Provisional, this liquid also may contain an oxygen source to
increase the oxygen saturation of the cornea prior to irradiation.
The liquid containing the facilitator is typically is confined on
the eye by a device. This device may be the device discussed above,
or may be another device such as a contact lens.
[0026] Once the cornea has been brought to the desired riboflavin
saturation, and the device discussed above is in place with a
suitable liquid disposed in space 62, but before irradiation of the
cornea, the control circuit 62 obtains an initial response of the
cornea based on travel time of ultrasound through the cornea. To do
so, the control circuit actuates the drive circuit 58 to apply very
brief pulses of a positive or negative potential to transducer 47.
Each pulse of the electrical potential desirably is a single, high
frequency content potential spike. Each pulse of the potential
causes the piezoelectric film 48 to vibrate and emit a brief pulse
of ultrasound having a broad bandwidth. The ultrasound pulses
travel along a forward path, in the inward direction through the
diffuser 36 and through the liquid in space 62 to the cornea 38. A
portion of each ultrasound pulse will be reflected at the anterior
or outward-facing surface 66 of the cornea, but the remainder of
the pulse will continue along the forward path to the posterior or
inward-facing surface 68 of the cornea, where another portion of
the pulse is reflected. The reflected pulses travel along a reverse
path, outwardly through the liquid in space 62 and the diffuser and
back to the transducer 47. As the pulses impinge on the
piezoelectric film 48, the transducer produces electrical signals
at frequencies corresponding to the frequencies of the ultrasonic
energy. These signals are received by the drive circuit 58 (FIG.
1).
[0027] Each pulse reflected from posterior surface 68 is delayed
relative to the corresponding pulse reflected from anterior surface
66. This delay is caused by the time required for the ultrasound to
travel forwardly from the anterior surface 66 to the posterior
surface 68, and the additional travel time required for the
reflected pulse for travel in the reverse direction from the
posterior surface to the anterior surface. Stated another way, the
delay or difference in arrival times between anterior surface
reflections and posterior surface reflections is equal to the
transmission time required for the ultrasound to travel twice
through the cornea. This transmission time is equal to twice the
thickness of the cornea divided by the speed of sound in the
material constituting the cornea. The speed of sound in the cornea
is directly related to the stiffness of the material constituting
the cornea and in particular to the Young's modulus (elastic
modulus in tension or compression). Therefore, this transmission
time is inversely related to the Young's modulus and directly
related to the thickness of the cornea. The control circuit 60, in
cooperation with the drive circuit 58, determines the transmission
time and records it as a baseline response of the cornea. The
transmission time may be recorded either directly as a value of
time or indirectly, after conversion of the transmission time to
some other representation. For example, the transmission time can
be converted to an estimated elastic modulus based an assumed or
measured thickness of the cornea, or converted to an estimated
thickness of the cornea based on an assumed elastic modulus.
Desirably, the process of determining the transmission time is
repeated using multiple transmitted pulses to arrive at an average
value of the baseline response.
[0028] After the baseline response has been obtained, the control
circuit actuates the light source 48 (FIG. 1) to direct light such
as UV light into the cornea through the device. As discussed in
greater detail in the '054 Publication and '416 Provisional, the
light passes through the transmission fiber 46 and to the fiber or
fibers 44 in the device, and then passes into the diffuser, in
directions generally toward the central axis 33. As the light
passes through the diffuser, it is dispersed. Some of the dispersed
light is directed inwardly toward the cornea. Dispersed light
directed outwardly will be reflected inwardly by the metallic
coating 50 (FIG. 2) overlying the outer surface of the diffuser,
and thus will be redirected inwardly toward the cornea. The
inwardly-directed light passes through the liquid in space 62 and
irradiates the cornea. This light, in conjunction with the
crosslinking facilitator present in the cornea, causes crosslinking
of collagen in the irradiated area of the cornea. The irradiation
step may use either continuously-applied light or light applied in
pulses, typically a few seconds to a few minutes long.
[0029] During the irradiation process, the control circuit actuates
the drive circuit and transducer 47 to acquire transmission times
as additional responses of the cornea. Each additional response is
acquired in the same manner as the baseline response discussed
above, using the same transducer. Here again, each additional
response represents the transmission time of ultrasound through the
cornea in forward and reverse directions. The ultrasound used in
acquiring the responses does not interfere with the light used in
the irradiation. Thus, the additional responses can be acquired
during the irradiation step, regardless of whether the irradiation
is continuous or pulsatile. If the irradiation is pulsatile, the
additional responses can be obtained during or between irradiation
pulses, or at times unrelated to the pulsing cycle, so that the
times when additional responses are acquired have a random
relationship to the irradiation pulses. Each additional response
may include averaged results from multiple pulses within an
interval which is short in comparison to the total length of the
irradiation process.
[0030] The control circuit compares each additional response to the
baseline response. For example, the control circuit may determine
the difference between the baseline transmission time and each
additional transmission time. This difference represents a change
in the properties of the cornea induced by the irradiation. When
the difference reaches a preselected threshold, the control circuit
terminates the irradiation. The threshold may be a function of the
baseline response. For example, the threshold may be a certain
percentage decrease from the baseline transmission time. The
computation of the difference between the additional transmission
time and the baseline transmission time may be performed
implicitly, without an explicit subtraction operation. For example,
the threshold may be stored in the control circuit as a value
representing the baseline transmission time minus the preselected
percentage decrease, and each additional transmission time may be
compared with this value. In this instance, if an additional
response is lower than this value, the control circuit terminates
the irradiation step. In some cases, a decrease in transmission
time on the order of 10-20% may correspond to the degree of
crosslinking needed to bring about a desired reshaping of the
cornea. Changes of this magnitude can be measured readily.
[0031] The additional responses are obtained in real time, during
the irradiation step, so that the system can control the
irradiation process based on the comparison as discussed above.
Because the difference in the response vis-a-vis the baseline
response arises directly from the effects of the crosslinking
process, this difference is closely correlated with the degree of
crosslinking achieved by the irradiation. Therefore, it is closely
correlated to the magnitude of change in the shape of the cornea
which will occur in the corneal reshaping process which occurs
after the irradiation step. For example, the relationship between
magnitude of shape change and the threshold can be compiled based
on experience with experimental subjects, and can be continually
updated as further experience is gained with clinical patients.
This relationship can be stored in the control system as, for
example, as a lookup table. The physician may specify a desired
shape change, and the control system may select the appropriate
threshold using the stored relationship.
[0032] The comparison between the baseline response and the
additional response cancels out systematic errors. For example,
misalignment between the transmission direction of the ultrasound
and the thickness dimension of the cornea may exaggerate or
diminish the measured transmission time. In the method discussed
above, the transmission time is measured using the same transducer,
mounted on a structure remains in fixed place on the eye throughout
both the baseline and additional measurements. Thus, any error in
the transmission time will affect both the baseline response and
the additional response. The thickness of the cornea, as well as
the elastic modulus, may change during irradiation as a result of
the crosslinking. The transmission time measurement does not
discriminate between change in elastic modulus and change in
thickness. However, because both effects are correlated with
crosslinking, the correlation between change in transmission time
and degree of crosslinking is still valid.
[0033] Desirably, the wavelength of the ultrasound used in the
transmission time measurement is small in comparison to the
thickness of the cornea. Desirably, the ultrasound has a frequency
of at least 20 MHz, more desirably at least 50 MHz, and most
desirably at least 100 MHz Transducers formed from thin layers of
piezoelectric polymers are well suited to operation at these
frequencies. Moreover, the entire transducer, including the
polymeric film and the backing element, may be on the order of less
than a millimeter to a few millimeters thick. The transducer is
thus well-suited to incorporation in a device resembling a contact
lens. The leads connecting the electrodes of the transducer to the
drive circuit typically introduce some inductance into the
electrical system. However, the transducer has substantial
capacitance. Desirably, the inductance and capacitance are selected
so that the electrical impedance of the transducer and leads taken
together matches the output impedance of the drive circuit
component used to excite the transducer and matches the input
impedance of the drive circuit component that receives electrical
signals from the transducer.
[0034] The pulses used for measuring transmission time should be as
brief as possible while still providing as high an amplitude as
possible reflected pulses with an adequate signal to noise ratio.
For example, each pulse may approximate a pulse of two cycles at 50
to 100 MHz. Because the bandwidth of a pulse is directly related to
the pulse length, such a pulse will have a broad bandwidth.
[0035] A further embodiment of the invention may use the same
device as discussed above, and the same process of treating the
cornea with a crosslinking facilitator and providing a liquid in
the space 62 between the device and the eye of the subject. The
system used in this method also incorporates a light source, and
drive circuit as discussed above, as well as a control circuit
similar to the control circuit discussed above connected to the
drive circuit and light source. In this embodiment, however, the
drive circuit is arranged to determine the natural frequency or
period of vibration of the cornea in the manner discussed below as
a response of the cornea which is related to the degree of
crosslinking.
[0036] The natural frequency, f.sub.0, of any vibrating system is
related to the stiffness of through:
f.sub.0.varies. (k/m) (Formula 1)
where k is the stiffness constant and m is the effective mass of
the system. The Young's modulus or elastic modulus of a material
can be thought of as k for a unit area and unit length. The cornea
can be thought of as membrane. As the elastic modulus increases,
the stiffness of the membrane increases, and the natural frequency
of vibration of the membrane increases. It has been estimated that
crosslinking which is effective to correct vision and treat
keratoconus will increase the elastic modulus of the cornea on the
order of about 50% to 80%. Applying Formula 1 above, an 80%
increase in the elastic modulus translates to about a 35% increase
in f.sub.0.
[0037] To acquire a measurement of the natural frequency or period
of vibration, the control circuit first commands the drive circuit
and transducer to apply a pulse of ultrasound, desirably at a
frequency above about 20 MHz, such as 50-100 MHz or more, to a
location on the cornea. This pulse is referred to herein as a "push
pulse." Desirably, the push pulse is gated by a square wave, so
that the amplitude of the ultrasound increases rapidly at the
inception of the pulse and decreases rapidly at the end of the
pulse. The push pulse propagates in a longitudinal direction into
the cornea. In the particular embodiment depicted, where the
transducer is centered on the central axis 33 of the device, the
pulse may propagate inwardly along the axis. The inwardly
propagating pulse is attenuated to some degree by the cornea. As
the pulse is attenuated by the cornea, it transfers momentum to the
cornea, and thus applies a longitudinal force to the cornea. This
force displaces the part of the cornea where the pulse is applied
in the longitudinal direction. Stated another way, the pulse acts
to apply a force having a component perpendicular to the surface of
the cornea. The magnitude F of this force is given by:
F=2.alpha.I/c (Formula 2)
where .alpha. is attenuation, I is intensity and c is the
longitudinal speed of sound.
[0038] The force deforms the cornea, effectively pushing the cornea
inwardly at the location where the push pulse is applied. Stated
another way, the force applied by the push pulse mechanically
excites the cornea by deforming it from a rest position. When the
push pulse ends, the cornea rebounds. The cornea will rebound and
oscillate at its natural frequency. Transverse waves (waves
propagating in a direction approximately perpendicular to the
direction of the wave amplitude) propagate out from the location
where the push pulse was applied. The propagation pattern resembles
the propagation of ripples on a pond. This is the classic "step
function response" of a membrane, although in this case, the
membrane (the cornea) is curved.
[0039] The control circuit commands the drive circuit and
transducer to apply a succession of monitoring ultrasound pulses to
a location on the cornea after termination of the push pulse, while
the cornea is rebounding, and to acquire signals representing the
ultrasound reflected from such location responsive to each
monitoring pulse. The monitoring pulses may be applied to the same
location as the push pulse, or to a different location. Where the
device depicted in FIGS. 1 and 2 is employed, the same transducer
used to form the push pulse is also used to provide the monitoring
pulses, and thus the monitoring pulses will be applied to the same
location as the push pulse. The transverse waves propagating in the
cornea will cause the location where the monitoring pulses are
applied to move inwardly and outwardly, towards and away from the
transducer. This motion will cause a Doppler shift in the frequency
of the reflected ultrasound from the monitoring pulses. If the
location is moving toward the transducer when the monitoring pulse
is reflected, the frequency will be shifted upwardly. If the
location is moving away from the transducer, the frequency will be
shifted downwardly. The reflected monitoring pulses are received by
the transducer and converted to electrical signals. The control
circuit acquires a series of frequencies of the reflected
monitoring pulses over time. This series will have a periodic
variation, and the period of this variation will correspond to the
period of the natural vibration of the cornea. This period can be
detected, for example, by determining the time between successive
maxima or successive minima in the frequency of reflected
ultrasound. The frequency of the natural vibration is the inverse
of this period.
[0040] To facilitate determination of the frequency of the
reflected ultrasound, each monitoring pulse desirably has a narrow
bandwidth, and thus includes numerous cycles of the ultrasound.
Where frequencies such as those discussed above for the push pulse
are employed, a narrow-bandwidth pulse can have a duration which is
only a small fraction of the period of the natural vibration of the
cornea. Therefore, numerous monitoring pulses can be applied during
each period of the natural vibration. The relative speed of sound
difference between the transverse wave velocity V.sub.s and the
longitudinal wave velocity V.sub.l (V.sub.l>10V.sub.s) means
that many monitoring pulses can be launched at (and received from)
a single transverse wave as it moves toward and away from the
transducer. The monitoring pulses may have lower power than the
push pulse.
[0041] The control circuit actuates the drive circuit and
transducer in the manner discussed above to acquire a period or
frequency of the natural vibration as a baseline response of the
cornea before commencement of the irradiation, and to acquire a
series of additional responses, each including the period or
frequency of the natural vibration at a time during the
irradiation. Here again, the change in the response is determined,
and the control circuit commands the light source to terminate the
irradiation when the change reaches a predetermined threshold.
[0042] A system and method according to a further embodiment of the
invention may use a device and system components as discussed
above. In this embodiment, however, the control circuit uses the
frequency spectrum of backscattered ultrasound from the cornea as
the response of the cornea. He, Xiaoyin and Jun Liu, A Quantitative
Ultrasonic Spectroscopy Method for Noninvasive Determination of
Corneal Biomechanical Properties, Investigative Ophthalmology &
Visual Sci., Vol. 50, No. 11 (November 2009), pp. 5148-54,
(hereinafter the "He Article") the disclosure of which is
incorporated by reference herein, discusses the use of ultrasonics
for the measurement of an aggregate elastic modulus and other
physical properties of the cornea. The He Article uses an iterative
approach applied to the backscattered power spectra of an
ultrasound signal directed at a cornea. The He Article demonstrates
that the properties of a cornea prepared in the laboratory can be
measured in vitro with a precisely designed (and aligned), acoustic
pulse and the requisite signal processing to evaluate changes in
spectral content of that acoustic signal as it is reflected from,
and transmitted through, the cornea.
[0043] Data representing the back scatter power spectrum optionally
can be converted to values of corneal materials properties such as
aggregate elastic modulus. One or more of these values, or a
combination of these values, may serve as the response of the
cornea which is used as a proxy for the material properties.
Alternatively, the spectral data can be can be used as the response
or proxy for the materials properties. Here again, a baseline value
of the response is obtained before the irradiation step, and one or
more additional values of the response are obtained during
irradiation. The control circuit terminates the irradiation when
the change in the response reaches a predetermined threshold.
[0044] The He Article endeavors to determine the absolute material
properties of the cornea, comparing the acoustic power spectra
determined results against direct measurements by iterating through
established models of wave propagation and absorption as a function
of frequency. However, He's acoustic processes is based on an
idealized analytical approach that is not exceedingly easy to
translate to a clinical environment. For example, different
wavelengths of ultrasound will refract at different angles through
interfaces. Therefore, a very slight misalignment of the (assumed)
acoustic plane wave and the apex of the curved cornea imparts
spectral shifts into the acoustic signature of the pulse that are
geometric in origin (as opposed to the material property
generated). He's technique requires great care in alignment that is
not possible in the clinical setting, even in an on-eye transducer.
Thus, in practice, the values of material properties determined
using a device and system as discussed above may differ from the
true or "absolute" values of these properties.
[0045] However, as discussed above, active CCXL dosimetry feedback
control does not require the determination of the absolute material
properties. Where the difference in the response between the
baseline and additional response is employed, the comparison
between baseline and additional values will cancel out these
systematic errors. To assure such cancellation, it is desirable to
use the same transducer or transducers to acquire both the baseline
and additional responses, and to keep the transducer or transducers
as a whole in a fixed position on the eye throughout the process.
Even if the response does not accurately reflect the absolute
material properties, the difference between baseline and additional
responses will still correlate with the degree of crosslinking.
[0046] Stated another way, one method to achieve this "relative"
approach is to determine the approximate values of the cornea
material properties or proxies for such properties using the He
technique, but ignoring the departures from theory in the actual
measurement (such as the likely misalignment of the impinging
acoustic wave and the cornea and any deviations from a perfect
plane wave generated by the transducer). These sources of
systematic error will be identical in the both measurements. In one
example, change in the acoustic spectrum is used as a proxy for
change in corneal material properties. Thus, values representing
spectral change are used directly as the look-up values. Theory
shows that, all else being equal between two measurements, the
material properties determine the power spectral shifts. Thus, the
assumed material properties may not have to be determined, as the
characteristic of the power spectrum itself may serve as a proxy
for the material properties altered by CCXL, and thus as a proxy
for the ultimate cornea shape outcome.
[0047] The intraocular pressure may influence the responses
acquired in the methods discussed above. Thus, changes in the
intraocular pressure between the time a baseline response is
acquired and the time an additional response is acquired during
irradiation may influence the comparison between baseline and
additional responses. To further eliminate sources of potential
error in the any of the embodiments discussed above, the
intraocular pressure may be measured during irradiation. The
control circuit may combine the measured intraocular pressure the
measured response of the cornea acquired by any of the methods
discussed above to produce a "composite proxy value" that
incorporates both mechanical properties changes and
pressure-induced shape changes. One approach to monitoring the
intraocular pressure is to use an on-lens pressure sensor system
similar to Mansouri (Mansouri et. al., A Minimally Invasive Device
for the Monitoring of 24-hour Intraocular Pressure Patterns, US
Ophthalmic Review 6(1):10-14 (2013), the disclosure of which is
incorporated by reference herein.
[0048] In the embodiments discussed above, the transducer is a
single-element transducer. However, for monitoring treatment of
certain complex conditions such as some astigmatisms, a more
complex transducer arrangement may be used. The transducer may be
fabricated as a two-dimensional ("2D") ultrasonic array. Such an
array can be used to provide measurements at multiple locations on
the cornea. For example, multiple measurements may be used where
different doses of UV are delivered to different locations on the
cornea is a complex or custom CCXL correction. In one embodiment,
the 2D array of transducer elements are patterned to match a 2D
array of masking elements used to block the UV in certain region to
affect a specific corneal shape change.
[0049] In a 2D ultrasonic array to control CCXL, the individual
elements would not necessarily have to be physically separated from
each other (mechanically isolated to prevent acoustic crosstalk as
is done in imaging transducer by creating fine slices between
elements). The elements could simply be defined by patterning
individual electrodes on one of the surfaces of a unitary
piezoelectric element as, for example, by screen printing the
individual electrodes. In one embodiment, the front electrode 50
shown in FIG. 2 may serve as the common (ground) electrode for the
transducer elements so as to provide an unbroken reflector for UV
light. In this embodiment, the backing element 52 would be made
from a non-conductive material to maintain electrical isolation.
The rear or outwardly-facing surface of the piezoelectric film 48
would be provided with a 2D array of individual electrodes, and
each such individual electrode would be separately connected to the
drive circuit.
[0050] The elements of a 2D array can be individually excited and
"read" through the addressable electrodes, whether disposed on the
front surface or rear surface of the piezoelectric material. The
individual electrodes are electrically isolated from one another
using a patterned conductor created with a technique such as screen
printing. One method to connect to these rear addressable electrode
is to pattern a fine conductive lead to each element, allowing
electrical access to each element (including those "interior" to
the array) from outside the footprint of the array. Alternatively,
the elements could be accessed by some type of electrical via
system that either penetrates the backing layer, or is incorporated
as part of the backing layer.
[0051] The ability to pattern acoustic elements (as opposed to
slicing to separate individual elements) is possible for two
reasons. First, piezo-plastics tend to be very lossy, thus they
attenuate energy rapidly, and prevent the acoustic excitement
through shear waves of an area much larger than the area excited
electronically (they are also lossy to compressional waves, helping
with creation of a broadband signal). Acoustic isolation will
confine the collection of pixel dosimetry data (i.e., data
collected separately for each individual location on the cornea) to
roughly only the pixel in question (i.e., the location aligned with
the individual emitting element). Even with a lossy material
between elements, some crosstalk between elements of the array is
probable. However, unlike imaging systems, the elements of the 2D
acoustic dosimetry array would be driven with time multiplexing,
meaning that they would be excited one at time. In this sense, it
is not truly an "acoustic array," but rather a collection of
individual elements. Imaging systems drive all the elements of the
acoustic array at the same time, shifted only slightly in phase to
affect beam steering. Crosstalk is a significant problem for
steered beams, but will have negligible effect on a 2D "collection
of elements" for dosimetry data collection.
[0052] In one method of manufacturing the transducer 47 shown in
FIGS. 1 and 2, lightly backed plastic transducer, microballoons,
either conductor-coated or non-conductive, are mixed with an
adhesive matrix that may be a conductive (silver loaded) epoxy, or
some other adhesive, or a combination thereof, to obtain the target
light, attentive set of properties. Once cured, this foam is then
processed into sub-millimeter layer that is adhered to the
piezoelectric layer using one of a few possible methods. One
approach to bonding the foam layer is to use a non-uniform pressure
technique after E. Papadakis (U.S. Pat. No. 3,664,902) to achieve
the extremely thin bond lines required in high frequency
ultrasound. Another technique is to adhere only an annular ring
outside of the active area, allowing a thin air layer that may
further control back reflections. Creating a bond outside of the
active area can be done by making the rear electrode on the
piezoelectric layer (the electrode that will be in contact with the
foam) larger than the front electrode, and adhering the foam around
this extra perimeter, with potentially a few other small conductive
contact points across the active area. Finally, this entire
acoustic stack can be thermally and/or mechanically formed to
obtain the desired curvature. It can then be assembled to the
housing 32 along with the active components of the UV delivery
system.
[0053] In the embodiments discussed above, the acoustic dosimetry
elements are mounted in an on-eye CCXL device. However, this is not
essential. An on-eye device incorporating acoustic dosimetry
elements can be positioned on the eye and light such as UV light
effective for crosslinking can be applied to the eye by an external
or "standoff" light-applying device. In this case, the on-eye
device may have an opening or transparent area for transmission of
the light from the light-applying device to the eye.
[0054] In the embodiment discussed above with reference to FIGS. 1
and 2, the irradiation is applied to a circular region at the
center of the cornea, and the ultrasonic transducer is aimed at
this region. This arrangement is used to treat myopia. Where the
irradiation is intended to treat hyperopia, the irradiation may be
applied to an annular region of the cornea. In this case, the
ultrasonic transducer or transducers desirably are aimed at the
annular region.
[0055] In the embodiment discussed above with reference to FIGS. 1
and 2, a single transducer is used to transmit and receive all of
the ultrasonic energy used in acquiring the responses of the
cornea. However, the device may include plural transducers. For
example, a device using the natural vibration frequency as the
response may include one transducer for applying the push pulses,
another transducer for applying the monitoring pulses, and yet
another transducer for receiving the reflected monitoring pulses.
In yet another arrangement, the monitoring pulses may be replaced
by continuous monitoring ultrasound emitted by one transducer, with
the reflected ultrasound being received by another transducer.
[0056] The features of the individual embodiments discussed above
may be combined with one another. For example, measurements of the
transmission time of ultrasound may be used in conjunction with
measurements of the natural frequency or period of vibration of the
cornea. Likewise, measurement of the spectrum of backscattered
ultrasound can be combined with one or more of the other modalities
discussed above. For example, the various responses can be combined
with one another to yield a composite value, and that value can be
used as a proxy for the material properties of the cornea.
[0057] In the embodiments discussed above, the change in the
response of the cornea is determined by comparing additional and
baseline responses. However, the techniques and systems discussed
above also can be used to acquire individual measurements of
material properties of the cornea, without using the comparison
technique.
[0058] The following paragraphs further describe certain aspects of
the invention:
[0059] A method of measuring the physical properties of a cornea in
the eye of a living subject comprising:
[0060] (a) mechanically exciting the cornea;
[0061] (b) monitoring vibrations of the cornea after termination of
the excitation; and
[0062] (c) determining a natural period or frequency of vibration
of the cornea based on the monitoring.
[0063] A method as recited in paragraph [0059] wherein the step of
mechanically exciting the cornea includes applying a force to the
cornea having a component perpendicular to the surface of the
cornea.
[0064] A method as recited in paragraph [0060] wherein the step of
applying a force includes directing a push pulse of excitation
ultrasonic energy into the anterior surface of the cornea so that
the excitation ultrasonic energy deflects the cornea from a steady
state position.
[0065] A method as recited in paragraph [0061] wherein the step of
monitoring vibrations includes directing monitoring ultrasonic
energy toward the anterior surface of the cornea and detecting
reflected monitoring ultrasonic energy.
[0066] A method as recited in paragraph [0061] wherein the step of
monitoring vibrations further includes determining a Doppler shift
in the reflected monitoring ultrasonic energy.
[0067] A method as recited in paragraph [0062] or paragraph [0061]
wherein the monitoring ultrasonic energy has a frequency of at
least 20 MHz.
[0068] A method as recited in paragraph [0062] or paragraph [0063]
wherein the monitoring ultrasonic energy has a frequency of at
least 50 MHz.
[0069] A method as recited in paragraph [0062] or paragraph [0063]
wherein the monitoring ultrasonic energy has a frequency of at
least 100 MHz.
[0070] A method as recited in paragraph [0062] wherein the step of
determining a natural period or frequency of vibrations of the
cornea includes determining a time between a maximum positive
Doppler shift and a maximum negative Doppler shift in the reflected
monitoring ultrasonic energy.
[0071] A method as recited in paragraph [0062] wherein at least two
of the steps of directing an excitation pulse, directing monitoring
ultrasonic energy and detecting reflected monitoring ultrasonic
energy are performed using a single ultrasonic transducer.
[0072] A method as recited in paragraph [0068] wherein all three of
the steps of directing an excitation pulse, directing monitoring
ultrasonic energy, and detecting reflected monitoring ultrasonic
energy are performed using a single ultrasonic transducer.
[0073] A method as recited in paragraph [0062] wherein the step of
directing monitoring ultrasonic energy includes directing a
succession of pulses of monitoring ultrasonic energy toward the
anterior surface of the cornea.
[0074] A method as recited in any of paragraphs [0062]-[0069]
wherein the step of directing monitoring ultrasonic energy includes
directing continuous wave ultrasonic energy toward the anterior
surface of the cornea from a first transducer and the step of
detecting the reflected ultrasonic energy is performed using a
second transducer.
[0075] A method as recited in any of paragraphs [0061]-[0063]
wherein the excitation ultrasonic energy has a frequency of 20 MHz
or more.
[0076] A method as recited in any of paragraphs [0061]-[0063]
wherein the excitation ultrasonic energy has a frequency of 50 MHz
or more.
[0077] A method as recited in any of paragraphs [0061]-[0063]
wherein the excitation ultrasonic energy has a frequency of 100 MHz
or more.
[0078] A method as recited in any of paragraphs [0062]-[0068]
further comprising directing brief pulses of ultrasonic energy into
the cornea, detecting echoes of the brief pulses from a posterior
surface of the cornea, and determining a parameter related to
transmission time of the pulses and echoes through the cornea.
[0079] A method as recited in paragraph [0075] further comprising
detecting echoes of the brief pulses from an anterior surface of
the cornea, the step of determining a parameter related to
transmission time including determining differences between arrival
times of the echoes from anterior and posterior surfaces.
[0080] A method as recited in any one of paragraphs [0075] and
[0076] wherein the brief pulses and at least one of the monitoring
ultrasonic energy and the excitation ultrasonic energy are
generated by a single transducer.
[0081] A method of corneal crosslinking comprising:
[0082] (a) irradiating the cornea with light to induce crosslinking
of collagen in the cornea;
[0083] (b) monitoring the crosslinking by a method as recited in
any one of the preceding claims; and
[0084] (c) controlling the irradiating step based at least in part
on the natural period or frequency determined in the monitoring
step.
[0085] A method as recited in paragraph [0078] wherein monitoring
step is performed repeatedly and the controlling step includes
terminating the irradiating step when the natural frequency or
period has changed by a threshold amount.
[0086] A method as recited in paragraph [0079] wherein the
repetitions of the monitoring step include one or more baseline
monitoring steps performed before the irradiating step and the
threshold amount is a function of a baseline natural frequency or
period determined in the baseline monitoring steps.
[0087] A method as recited in any of paragraphs [0078]-[0080]
further comprising treating the cornea with an agent which
facilitates crosslinking, wherein the irradiating step includes
applying light at a wavelength which activates the agent.
[0088] A method as recited in any of paragraphs [0078]-[0081]
wherein the irradiating step is performed by applying pulses of
light and the monitoring step is performed during intervals between
pulses.
[0089] A method as recited in any of paragraphs [0078]-[0081]
wherein the monitoring step is performed while the cornea is being
irradiated with light.
[0090] A method of monitoring a physical property of the cornea in
a living subject comprising:
[0091] (a) applying a structure over the anterior surface of the
eye;
[0092] (b) directing brief pulses of ultrasonic energy into the
cornea;
[0093] (c) detecting echoes of the brief pulses from a posterior
surface of the cornea; and
[0094] (d) determining a transmission time of the pulses and echoes
through the cornea.
[0095] A method as recited in paragraph [0084] further comprising
detecting echoes of the brief pulses from an anterior surface of
the cornea, the step of determining a transmission time of the
pulses and echoes through the cornea including determining delays
between echoes from the anterior surface and echoes from the
posterior surface.
[0096] A method as recited in paragraphs [0084] or [0085] further
comprising applying light to the cornea through the structure, and
repeating the determination of transmission time so as to determine
a baseline transmission time before commencement of the light
applying step and one or more additional transmission times during
the light applying step, and determining differences between the
additional transmission times and the baseline transmission
time.
[0097] A method as recited in paragraph [0086] further comprising
terminating the light applying step when a difference between an
additional transmission time and the baseline transmission time
exceeds a threshold value.
[0098] A method as recited in paragraph [0087] wherein the
threshold value is a function of the baseline transmission
time.
[0099] A method as recited in paragraph [0088] wherein the
threshold value is proportional to the baseline transmission
time.
[0100] A method of corneal crosslinking comprising irradiating the
cornea in the eye of a living subject and simultaneously applying
ultrasound to the cornea and determining one or more responses of
the cornea to the applied ultrasound.
[0101] A method as recited in paragraph [0090] wherein the step of
applying ultrasound to the cornea is performed by actuating a
transducer mounted on a housing overlying the eye.
[0102] A method as recited in paragraph [0091] wherein the step of
irradiating the cornea is performed by directing light into a
diffuser mounted on the housing.
* * * * *