Design of an Optimized Distal Optic for Non Linear Endomicroscopy

Claire Lefort

, Hussein Hamzeh

, Liu Wei

, David Sevrain

, Philippe Leproux

Frédéric Pain

and Darine Abi Haidar

2,3

Laboratoire XLIM, UMR 7252, CNRS, F-87060 Limoges, France

Laboratoire IMNC, UMR 8165- Université Paris-Sud, Orsay, France

Université Paris 7-DENIS DIDEROT, F-75012 Paris, France

Keywords: Nonlinear Endomicroscopy, Double-Clad Fibre, GRIN Lens, Zemax Simulations.

Abstract: The development of a nonlinear endomicroscope is justified by the need for a non-invasive diagnosis tool to

assess at the cellular level, in vivo and in live the presence of pathologies like cancer in a patient body. To

do so, an important effort has to be made in the miniaturization of the distal head of the endoscope. We

report in this paper our work on the characterization of a commercial gradient index (GRIN) lens, especially

its possible fluorescence emission and ability to image biological structures. We show that the fluorescence

of the peripheral glue of the GRIN lens does not have impact on the fluorescence images but can lead to

perturbations to measure fluorescence lifetime and emission spectrum. The axial and lateral resolutions are

obtained by imaging 1 μm diameter gold beads. The results show a good agreement with values from the

literature. Finally, we simulate an endomicroscope combining an appropriate double-clad fibre (DCF) with

the GRIN lens and a tubular piezoelectric scanner (PZT) scanning head. Variations of parameters values

like fibre tilt angle and distance between the DCF and the GRIN lens allow to discuss on the performances

of this device in terms of working distance (WD), magnification, field of view (FOV) and coupling

efficiency.

1 INTRODUCTION

Cancer is a family disease where abnormal cells are

proliferating. It is becoming more and more

widespread in the world. Cancer treatment is a

ticklish issue, depending on the development of the

cancerous tumour and its localisation in the patient's

body. Nowadays, the main hope of curing this

illness lies in surgery, often completed by chemical

treatments or radiotherapy (Miller, 1981). If this

global process is applied in the early stages of the

disease, the chances to heal a patient and extends his

hope of life considerably increase. Nevertheless,

surgery is a very invasive operation and there still

exists a risk of relapse associated with a new

proliferation of cancerous cells in the treated area.

This may be due to a non-complete removal of all

the cancerous cells, despite the use of combined

modality therapies.

Starting from this alarming observation,

particularly true in the case of cancers where it is not

possible to remove a large part of the tissues around

the cancer area like the brain cancer, there is an need

for a tool enabling a fast and accurate discrimination

between cancerous and healthy cells.

A way to achieve this goal consists in the

development of an endoscope with a microscopic

resolution. The first endomicroscopes, now

clinically used, are based on the confocal principle

with an excitation laser source in the visible range

(Salaün, 2010). This device allows to image

endogenous tissue components like elastin, in vivo

and in real time. However, some drawbacks can be

underlined, such as an imaging depth limited to at a

few tens of micrometres inside the target tissues,

mainly due to the strong scattering properties of

biological tissues, as well as the small number of

mean contrasts available from endogenous

fluorescent proteins under linear excitation.

To overcome this limitation, the current research

on endomicroscopy aims at developing two-photon

fluorescence (2PEF) imaging with femstosecond

pulse (150fs) excitation at high excitation rate

(80MHz) in the infrared (NIR) range (GU, 2014).

The interest of nonlinear imaging technique

compared to the confocal imaging is justified not

only by an increase in imaging depth due to IR

excitation (Cosignani 2012) but also by the

availability of a new mean of contrast thanks to the

second harmonic generation emitted by non-centro-

Lefort C., Hamzeh H., Wei L., Sevrain D., Leproux P., Pain F. and Abi Haidar D..

Design of an Optimized Distal Optic for Non Linear Endomicroscopy.

DOI: 10.5220/0005249700050012

In Proceedings of the 3rd International Conference on Photonics, Optics and Laser Technology (PHOTOPTICS-2015), pages 5-12

ISBN: 978-989-758-092-5

 2015 SCITEPRESS (Science and Technology Publications, Lda.)

symmetrical structures as collagen. This fact,

combined to the absence of confocal pinhole due to

the intrinsic localisation of the nonlinear

phenomenon in the focal plane of the focusing

device, promote a deeper imaging depth within a

few hundreds of micrometres

While nonlinear microscopy is now a very well

known and essential tool for biological tissues

characterization, its transposition to endomicroscopy

remains problematic. Indeed, endomicroscopy

requires several miniaturized elements like scanning

system or distal lens of focalization (Ducourthial,

2013). The laser excitation, coming from a Ti:

Sapph oscillator is classically delivered through an

optical fibre, flexible and with a small diameter

providing access to the internal hollow organs

(alveoli, kidney…). The choice of the optimal fibre

proves to be complex and must be realized taking

into account all other parameters of the global

system. The fibre has to be preceded by a shaping

module for the compensation of linear and nonlinear

effects occurring inside this material medium (Lelek

2007).

Currently, all the miniaturized parts of the

endomicroscope are problematic and prevent the

multiphotonic endomicroscope commercialisation.

This is particularly true for the distal lens. Named

“GRIN lenses” for gradient index lenses this

technology is based on the gradient of negative

refractive index of its material from the centre to its

outskirts, glued inside a cylinder of stainless steel.

Dimensions of classical GRIN lenses range between

0.35 to 2 mm in diameter and between 5 mm and

few cm in length, with a numerical aperture (NA) of

the object space between 0.2 and 0.8.

In this paper we present our study of GRIN

lenses in the context of the development of a

multiphotonic endomicroscope. The first part is

dedicated to the experimental study of a GRIN lens

alone. Background fluorescence induced in the

GRIN lens is studied under UV excitation beam,

mimicking the emitted multiphotonic fluorescence

or second harmonic generation coming from

biological samples. Then, the impact of the

background fluorescence of the GRIN lens on its

imaging ability, spectral detection and fluorescence

lifetime measurements is evaluated. The 2D lateral

resolution is experimentally measured using 1 µm

diameter gold beads. The second part of the paper is

dedicated to numerical simulations, using Zemax, of

the GRIN lens coupled to a specifically designed

double clad fibre (DCF) ideal for the assembly of a

multiphotonic endomicroscope (Lefort, 2014). Both

geometric ray tracing and Gaussian beam approach

were considered. Furthermore, the influence of the

relative position between the GRIN lens and the

DCF tip on the magnification, FOV, axial and lateral

resolutions is evaluated. Finally, choosing a

piezoelectric (PZT) stage as scanning device

(Myaing, 2006), the coupling of the DCF with the

PZT and the GRIN lens is characterized through the

variation of the image working distance, the

coupling efficiency of the fluorescence beam inside

the DCF, the size of the field of view (FOV) and the

axial and lateral resolutions.

2 GRIN LENS EXPERIMENTAL

CHARACTERIZATION

2.1 GRIN Lens Definitions

The GRIN lenses are all manufactured with a

medium having a continuously variable index of

refraction between the periphery and the centre of

the lens. This optic is glued to a biocompatible ring

of stainless steel.

In this study, we have chosen to characterize

a commercial GRIN lens (GT-MO-080-018-810,

Grintech, Jena, Germany), with a total length of 7.53

mm and a diameter of 1.4 mm. Figure 1 shows the

definitions of the image and object space and their

working distances (WD). The object space contains

the target biological sample and in the image space

lies the DCF delivering the NIR excitation beam and

collecting the multiphotonic signal emitted by the

biological sample.

Figure 1: a. Picture of the two GRIN lenses. b. Setup for

GRIN lens characterization from Grintech. c. Definitions

of the image and object spaces and the corresponding WD.

2.2 Background Fluorescence

2.2.1 Imaging the Background Fluorescence

Fluorescence imaging techniques need a previous

characterization of all the potential background

source of fluorescence, as the GRIN lens. To start

the characterization of the background fluorescence,

PHOTOPTICS2015-InternationalConferenceonPhotonics,OpticsandLaserTechnology

the GRIN lens is placed under the microscope

objective of a confocal microscope focusing a

krypton argon laser (Figure 1b). In this

configuration, the confocal microscope gives an

image of the image face of the GRIN lens Figure 2

presents the resulting observation of the image space

of the GRIN lens.

Figure 2: Fluorescence image of the glue between the

GRIN lens and the stainless steel of protection by confocal

imaging.

The inhomogeneous fluorescence signal from Figure

2 probably result from fluorescent components in the

glue used to fix the GRIN lens to the steel ring. No

impact of the intrinsic fluorescence of the glue on

fluorescence images of biological samples was

observed.

2.2.2 Spectroscopic Analysis

The background fluorescence of the GRIN lens is

spectrally characterized. Figure 3 gives a

representation of the experimental setup.

Figure 3: Experimental setup for the spectral

characterization of the background fluorescence of the

GRIN lens.

This setup consists of a pulsed diode laser from

Picoquant at 405±10 nm (LDHP-C-405B,

Picoquant) coupled into one of the two fibres of a

bifurcated fibre. The laser power can be adjusted, as

well as the repetition frequency, which can be set

between 2.5 and 40 MHz The fibre guides the

excitation laser source to the GRIN lens image

space. A solution of Rhodamine B (RhB) is placed

in the object space of the GRIN lens. The backward

fluorescence, emitted by both the RhB and the GRIN

lens, is collected by the second core of the bifurcated

fibre and delivered to a spectrometer, preceded by a

long pass filter to reject the excitation laser beam. In

a first stage the GRIN lens is excited with 405 nm

laser source without the sample of RhB and without

the filter to measure the background fluorescence

emitted by the GRIN lens itself. The graph of Figure

4a is the emission spectrum of the background

fluorescence. It can be seen that this spectrum covers

a wide spectral range (around 400-700 nm).

The solution of RhB is then illuminated and

its fluorescence emission spectrum was collected by

the GRIN lens with a separation distance between

the lens and the fibre of 2 mm and less than 200 µm

(Figures 4b and 4c, respectively). Figures 4d and 4e

present the analysis of the total spectrum by

comparison with the spectrum obtained by the sum

of the fluorescence spectra of the glue of the GRIN

lens and the RhB solution. The latter was measured

using the bifurcated fibre alone so as to eliminate its

possible contribution to the fluorescence signal.

Figure 4: a. Emission spectrum of the background

fluorescence induced by the GRIN lens alone with a 405

nm laser excitation. b. RhB fluorescence emission

spectrum measured with a separation distance between the

fibre and the GRIN lens of 2mm and c. of less than 200

µm. d. Summary of the measured emission spectra and the

sum of the RhB and glue emission spectra. e. Calculation

of the difference between the sum of each spectral

component and the effective measured spectrum.

The contribution of the fluorescence from the glue

around the GRIN lens is now spectrally

characterized (Figures 4a, 4b and 4d). From

DesignofanOptimizedDistalOpticforNonLinearEndomicroscopy

comparison between figures 4b and 4c, it can be

shown that depending on the separation distance

between the fibre tip and the GRIN lens, the

contribution of the glue fluorescence is variable. At

a large separation distance between the GRIN lens

and the fibre tip (2 mm), the background

fluorescence significantly altered the RhB spectrum,

while the background fluorescence is hardly

noticeable when this separation distance is very

short, below 200 µm. This can be explained if one

considers the very short image space WD of the

GRIN lens (below 100 µm in air at 405 nm). It is

also remarkable from Figure 4d that the RhB

spectrum in blue recovers successfully the measured

spectrum using the GRIN lens. Figure 4e

corroborates this observation.

2.2.3 Lifetime Measurements with GRIN

Lens

The two previous sections have brought out the

presence of a background fluorescence perturbing

the spectral measurement or the imaging through the

GRIN lens in specific conditions. This section aims

to present the effect of the GRIN lens position, in

ideal conditions of object and image WD, on the

measurement of fluorescence lifetime in time

domain of the RhB.

To do so, the spectrometer of the setup described

in Figure 3 is replaced by a photomultiplier tube

(PMT) and a Time-Correlated Single Photon

Counting (TCSPC) module synchronized with the

excitation laser source. This method detects the

exponential decay of fluorescence based on an

accurate record of a single photon using a highly

sensitive photon detector. The delay time of

emission of a photon relative to the laser excitation

pulse corresponds to the time spent in the excited

state. Then, excitation is repeated several times to

maintain the condition that only one photon per

molecule is detected at each pulse. These

measurements are recorded as a photon counting

histogram representing the fluorescence decay time

and the instrument response function (IRF), using a

Time Harp 200 acquisition card (Pico- quant, Berlin

Germany). The IRF characterizes the timing

precision of TCSPC system and for an ideal system

it should be infinitely narrow. During spectral or

lifetime measurement the laser emission was

rejected using a 410 nm high pass filter from

(SR410, Semrock, USA) in order to detect

fluorescence. The lifetime decays were fitted to an

exponential model in order to extract the lifetime

information with a reasonable fit quality, assessed

by the residuals of the fitting. An exponential model

was chosen because it gives a good description of

the physics involved in the lifetime decay. Two

exponential models were tested to extract the

lifetime information: the multi-exponential tail fit

(no consideration of the IRF) and the exponential

reconvolution (taking into account the IRF) detailed

in equations (1) and (2).

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(1)

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(2)

Where:

I (t) represent the measured decay data,

– amplitude of the i

component, in counts,

– lifetime of the i

component that has to be

calculated.

IRF was measured using a mirror instead of the RhB

sample and the filter was replaced by an optical

density filter in order to let the attenuated laser beam

pass to the PMT for IRF detection. The IRFs

measurements of the fibre alone, the fibre coupled to

a 10x microscope objective and the fibre coupled to

the GRIN lens are shown and compared in Figure 5.

Figure 5: Lifetime measurements. a. Fibre alone. b. Fibre

and objective 10x. c. Fibre and GRIN lens.

Figure 6: Measured fluorescence decay (in blue) and

fitting model (in black). a. Lifetime of RhB without

considering the IRF. b. Lifetime fitting by reconvolution,

IRF deconvoluted with the decay data (in red). c.

Residuals randomly distributed across the fitting range.

PHOTOPTICS2015-InternationalConferenceonPhotonics,OpticsandLaserTechnology

The IRFs are similar in the three conditions, with a

FWHM around 0,65 ns. This proves that the GRIN

lens does not affect lifetime measurements.

Lifetime measurements and decay fits of the

fluorescence signal of the RhB solution were then

realized, using the two fitting methods previously

detailed. Figures 6a and 6b present the results of

fluorescence lifetime measurements of RhB with the

fitting curves.

The results of lifetime decays of RhB through the

different elements of the setup are summarized in

the Table 1.

Table 1: Lifetime decay fitting through the setup elements

using tail fitting without the IRF and reconvolution fitting

with the IRF.

Element of

the setup

Fit

method

A (counts)

τ (ns)

Fibre

Tail 1872.4±20.9 1.72±0.02

Reconv 14046 ± 94.7 1.67 ± 0.01

Objective

Tail 1638.5 ± 19.3 1.705 ± 0.015

Reconv 3345.3 ± 40.4 1.703 ± 0.014

GRIN lens

Tail 252.5 ± 9.41 1.628 ± 0.049

Reconv 1835 ± 29.6 1.616 ± 0.019

In the literature (Boens 2007), the mean lifetime data

of the fluorescence lifetime of a solution of RhB in

water at 20°C is

RhB,ref

= 1.72±0.02 ns. The fluorescence lifetime is

therefore not affected by the presence of the fibre

considering the tail fitting method, while the

reconvolution method is less relevant. Furthermore,

the fluorescence lifetime is not significantly

disturbed by the microscope objective if one takes

the experimental incertitude into account. Finally, it

can be seen that for the GRIN lens, both fitting

methods, lead to a decrease of the fluorescence

lifetime from 1.7 ns to about 1.62 ns. This may be

explained by the detection of fluorescence signal of

the glue of the GRIN lens, leading to an average

measurement of the lifetime of the RhB and the

glue. That point corroborates the previous

conclusions in section 2.2.1 and 2.2.2 on the

significant perturbation of the signal collected by the

GRIN lens due to the background fluorescence of

the glue.

2.3 GRIN Lens Resolution

The resolution of the whole imaging system (10x

microscope objective + GRIN lens) is characterized

using 1μm diameter gold beads through the confocal

microscope. Those beads are assumed to be point

sources and the axial and lateral profiles of their

images are fitted by a Gaussian function depicted in

Figures 7a, 7b and 7c. The fitting was applied in

order to calculate the full width half maximum

(FWHM), considered as the optical resolution of the

system.

Figure 7: Beads profile measurements and their Gaussian

fits. a. Lateral resolution in x (μm). b. Lateral resolution in

y (μm). c. Axial resolution in z (μm).

The lateral resolution is 1 µm in x and 1 µm in y, in

good agreement with the best performances

described in the literature (Gu, 2014).

3 NUMERICAL SIMULATIONS

A numerical simulation of the GRIN lens in the

context of the manufacturing of an optimized

nonlinear endomicroscope is proposed. These

simulations are led simultaneously for NIR

nonlinear excitation and collection of the

multiphotonic signal emitted by the target. The

GRIN lens is coupled to the scanning system and the

optical fibre. The simulated fibre, a DCF, delivers

the nonlinear excitation by the core and collects the

multiphotonic emission by the inner cladding. This

DCF is simulated with ideal parameters for

delivering the multiphotonic excitation through a

small core diameter (5 µm) single mode at 800 nm

with a small NA (0.04) and a large inner cladding

diameter (200 µm) to collect the maximum of

multiphotonic signal from the GRIN lens thanks to a

large NA (0.3).

3.1 Simulation of the PZT Scanning

The scanning system is a tubular piezoelectric

scanner (PZT). This device consists in a small

tubular piezoelectric actuator governed by four

electrodes grouped in two pairs, with an optical fibre

positioned inside the actuator and electrically glued

at its tip. This layout allows driving the fibre tip,

exceeding the PZT for several tens of millimetres by

DesignofanOptimizedDistalOpticforNonLinearEndomicroscopy

application of a specific waveform (triangular or

sinusoidal) with a specific frequency, for each pair

of electrodes. This results in a circular scanning

pattern of the extremity of the fibre. The amplitude

is adjustable so that the position of the fibre tip can

be set on all the surface of a circle. The focalization

of the excitation beam on different parts of the target

relies on the relative position of the fibre with the

GRIN lens, as illustrated in Figure 8.

Figure 8: Complete scheme of the endomicroscope distal

end containing the DCF to guide the excitation and

collection signals, the PZT for scanning and the GRIN

lens for the focalization and the collection.

The use of the PZT scanning system on the fibre tip

imposes an angle between the fibre tip and the GRIN

lens, resulting in several consequences. First of all,

the object WD varies in function of the fibre angle.

Moreover, the coupling efficiency between the

excitation beam and the GRIN lens, linked to the

DCF core diameter and its NA is necessarily

modified by the tilt angle of the DCF. Figures 9a and

9b resume the related simulations.

Figure 9: a. Evolution of the object WD with the

inclination of the fibre tip due to the PZT scanning system.

b. Evolution of the coupling efficiency of the excitation

beam with the DCF angle.

Figure 9a shows a decrease of the object WD with

the fibre angle, revealing the fact that the fibre tip is

not really a plan, but a semi-sphere. This parameter

is not a major drawback but it should be considered

for the interpretation of the obtained images.

Concerning the coupling efficiency between the

excitation beam and the GRIN lens (Figure 9b), an

increase of the fibre angle leads to an important

decrease of the coupling. Indeed, 10% are lost for an

angle of 1.1° and more than 60% are not coupled for

1.4°. A direct consequence of this situation is the

reduction of the field of view in the object space.

It can be noticed that the PZT scanning system is

interesting by its small diameter ideal for a distal end

miniaturization. But several perturbations on the

detected image have to be taken into account to

interpret the images.

3.2 Optimization of the Distance

between the DCF and the GRIN

Lens

The separation distance between the DCF and the

GRIN lens is a critical parameter. Indeed, the focal

point position and thus the object WD, the

magnification properties, the coupling efficiency and

the field of view (FOV) are the main parameters that

may vary with this distance. They are simulated here

and the results are summarized in Figure 10 for a

distance ranging between 0 mm and 3 mm.

Figure 10: Numerical simulations of the influence of the

separation distance between the fibre tip and the GRIN

lens on several parameters. a. Object WD. b.

Magnification. c. FOV. d. Coupling efficiency.

As expected, the object WD decreases when the

separation distance between the fibre and the GRIN

PHOTOPTICS2015-InternationalConferenceonPhotonics,OpticsandLaserTechnology

lens increases. Consequently, the focal point is under

control of this parameter and can be adjusted

between 10 and 100 µm, the highest penetration

depth reachable by the excitation beam. The

magnification and the FOV decrease slowly when

the separation distance increases. For example, the

FOV, which is very small at the origin (less than 75

µm) declines to about 73.25 µm at 3 mm

Finally, the coupling efficiency of the

multiphotonic signal emitted by the sample after the

collection by the GRIN lens is not modified

whatever the distance between the fibre and the

GRIN lens. This results from the big inner cladding

diameter of 200 µm with the highest possible NA of

0.3. That optimized parameter is crucial for the

efficient collection of very weak multiphotonic

endogenous signals.

To conclude, these simulations show that if an

axial scanning is needed, moving the separation

distance between the fibre and the GRIN lens is a

way to operate. Nevertheless, one has to expect an

important decrease of the object WD as well as a

modification of the magnification and the FOV.

4 CONCLUSIONS

In the context of the miniaturization of a distal head

of an endomicroscope, GRIN lenses are commonly

used. The aim of this article is to characterize a

commercial GRIN lens. The performances of the

GRIN lens to make images of brain tissues were

tested under a confocal microscope. The presence of

a fluorescent signal emitted by the outlying glue all

around the effective area of the lens was revealed,

and the imaging of glial cells of mouse brain showed

no influence on the resulting fluorescent image of

the sample. Starting from this observation, the

importance of this background fluorescence was

evaluated by spectral analysis and fluorescence

lifetime measurements. Both of them were showing

a non-negligible part of this fluorescence that can be

easily identified by its spectrum and by its lifetime.

The GRIN lens resolutions were then established

to around 1 µm for lateral resolution and 16 µm for

axial resolution, in accordance with the values

usually presented in the literature.

Finally, numerical simulations of an

endomicroscope including this GRIN lens coupled

to a homemade DCF fixed with a PZT scanning

system were led. The limitations of the use of this

PZT were highlighted: the focal plan is necessarily

not plan but curved and the coupling efficiency of

the excitation beam between the DCF and the GRIN

lens is dramatically reduced to less than 40% of

coupling when the fibre angle exceeds 1.4°.

Furthermore, the separation distance between the

DCF and the GRIN lens influenced the position of

the focal point in the object plan. This observation

presents a way to perform an axial scanning system,

which is still a limiting point for obtaining 3D

images. Nevertheless, a modification of the

separation distance induces a reduction of the FOV

and of the magnification. The best simulated FOV

obtained with the GRIN lens is 75 µm square, very

small and far from the ideal situation usually asked

by the surgeons of 1 mm square.

All these limitations have to be carefully thought

for the experimental use of the GRIN lens. It

remains that GRIN lens technology is the only one

allowing a distal lens with a diameter smaller than

0.5 mm, a decisive advantage in nonlinear

endomicroscopy.

ACKNOWLEDGEMENTS

This work has been highly supported by INCA Plan

Cancer with Physicancer program grants “MEMBO”

& “MEVO” and the Institut National de Physique

Nucléaire et de Physique des Particules (IN2P3).

This work was supported by the L’Oreal

Foundation, thanks to the French National Program

“For Woman in Science”, distinguishing Claire

Lefort for her work on endomicroscopy.

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