GB2446019A

GB2446019A - The enhancement of light penetration in tissues using chemical agents and ultrasound

Info

Publication number: GB2446019A
Application number: GB0701582A
Authority: GB
Inventors: Ruikang K Wang; Yonghong He
Original assignee: Cranfield University
Current assignee: Cranfield University
Priority date: 2007-01-27
Filing date: 2007-01-27
Publication date: 2008-07-30
Also published as: GB0701582D0

Abstract

The optical properties of biological tissues and, more specifically, to enhancing the light delivery efficiency into tissues, so that the light penetration depth can be improved for optical techniques currently applied to biomedicine. The optical techniques concerned may include optical imagining techniques, therapeutic techniques (including photodynamic therapy), laser surgery, and other optical diagnostic techniques that are based on light scattering, absorption, polarisation and the flourescence properties of tissues. In addition, the invention may also apply to the optical imaging based diagnostic techniques where the goal is to enhance the local imaging contrast within tissue.

Description

Enhancement of Light Penetration into Bio-tissues using Chemical Agents

Mediated with Ultrasound The present invention generally relates to controlling the optical properties of biological tissue and, more particularly, to the enhancement of light delivering efficacy into tissue in order to improve the light penetration depth for optical diagnostic. This can include imaging and therapeutic techniques (including photodynamic therapy), laser surgery, optical imaging, and optical diagnostic techniques based on light scattering, absorption, polarisation and the fluorescence properties of tissues. Furthermore the enhancement of image contrast for optical imaging based diagnostic techniques can be realised.

1. Background of the invention

There is a growing interest in the use of optical techniques for medical imaging, diagnosis and therapy. Techniques that use the intrinsic optical properties of biological tissues, such as light scattering, absorption, polansation and fluorescence, have many advantages over conventional x-ray tomography, MRI and ultrasound imaging in terms of safety, cost, contrast and resolution.

Some optical techniques are noted below: 1. Photodynamic therapy, where light is delivered directly to abnormal tissue whilst keeping the overlaying normal tissue intact.

2. Laser surgery, where the operation on the desired target lying deep within the tissue is often extremely difficult.

3. Optical imaging techniques that rely on the light scattering properties of tissue, for example optical coherence tomography, confocal microscopy, optical diffusion tomography where 1) the severe light scattering of tissue limits the optical imaging depth into the tissue and 2) the imaging contrast of the abnormal tissue is low.

4. Optical imaging techniques, relying on the fluorescence properties of tissue, for example fluorescence microscopy, life-time fluorescence imaging microscopy, and confocal fluorescence microscopy, where the emitted fluorescence from the deep tissues are either scattered or absorbed by the superficial tissue.

5. Optical spectroscopic techniques where severe light scattering of the superficial tissues often excludes its ability to detect the target lying deep within the tissue.

6. Luminescence techniques, for example chemiluminescence and bioluminescence imaging/diagnosis and sonoluminescence imaging where the emitted luminescence from the deep tissue is either scattered or absorbed by the superficial tissue.

7. Low intensity laser blood irradiation therapy, where light is delivered directly to blood by passing through the overlaying tissues.

The major problem facing current optical techniques is the limited light penetration depth in biological tissue, due to its highly scattenng nature. Biological tissues are optically inhomogeneous absorbing media. Multiple scattering and absorption are responsible for light beam broadening and eventual decay as it travels through a tissue, ultimately limiting the light delivery efficiency within tissue. For an example, in optical coherence tomography imaging of opaque tissues there is currently no evidence that a light penetration depth greater than 2 mm is possible and the optical imaging contrast of the localised tissue is low. Consequently, the light penetration depth and optical imaging contrast need to be improved in order to enhance the diagnostic capabilities of the optical coherence tomography when used with tissue.

Recently, an optical clearing technique was investigated, principally for overcoming the penetration limitation of these optical techniques. Previous studies have shown that osmotically active chemical agents are effective in changing the optical properties of both in vitro and in vivo tissue. Topical application of hyperosmotic solutions such as glycerol, propylene glycol, mannitol, glucose, or dextrose causes the turbid tissue, such as skin, sciera, and aorta, to become optically clear by creating a refractive index matching the environment within the tissue.

However, current optical clearing methods typically use a high refractive index and high osmotic chemical agents. The agents diffuse passively into the tissue, leading to a reduction in photon scattering. With the passive method, one cannot control the rate and area of the optical clearing, and the improvement of the light penetration is limited.

This provides a method for enhancing the penetration depth of light into tissues. In addition the invention provides a method for controlling the rate and the area of optical clearing of tissue, where the primary goal is to achieve a suitable therapeutic and/or diagnosis level for the aforementioned optical techniques.

The invention also provides a method for enhancing the penetration of light into tissues, which does not harm the optical technique or damage the tissues.

The invention also provides a simple, efficient, reproducible and economical method for enhancing the penetration of light within tissues and for controlling the optical properties of tissues.

The invention provides a method for controlling the optical properties of the localised tissue, where the primary goal is to enhance the contrast for optical imaging techniques

2. Description of the invention

The present invention is a method where the combination of biocompatible chemical agents, including synthetic agents (for example nano-and micro-particles),and ultrasound is used to control the optical properties of tissue, thereby controlling the light energy distribution within tissues when optical therapeutic, surgical or diagnostic techniques are being performed.

The present invention uses the biocompatible chemical agents to be topically applied onto the targeted tissues, (or perfused through the blood stream or injected into the tissue) while the delivery of light is mediated by the ultrasound. On one hand (generally applied), the application of agents will make the tissue become optically clear, thereby reducing the light scattering of tissue for any wavelength applied.

However, (particularly when applied to the optical imaging techniques) such an application can make the localised tissue become optically more opaque, or more clear; thereby enhance the optical imaging contrast for the localised tissue. The use of ultrasound is to control the delivery of the agents into the tissue; hence the clearing procedure for the tissue can be purposely controlled either fast or slow, on the bulk or localised tissue.

The wavelength range of the light is between 300 mn and 3000 nm, and can include laser light, wide-band light, fluorescence, chemiluminescence, bioluminescence, sonoluminescence and even ordinary light.

The chemical agents are biocompatible nano-or micro-particles that can be selected from inorganic compounds, organic compounds, synthetic particles and any combinations of such, including optical contrast agents and fluorescence agents, which have the capability of modifying the optical properties of biotissue.

Ultrasound has a frequency greater than 20 KHz. In general, the frequency range of ultrasound is between 20 kHz and 10 MHz, with intensities between 0 and 4 W/cm 2.

Intensity is decreased as the frequency is decreased, to prevent side-effects with the tissues. The preferred range of frequencies is between 20 KI-lz and 1.0 MHz and the preferred range of intensities is between 2 and 4 W/cm 2. Exposure is for between 0.1 and 30 minutes, for most medical uses. The ultrasound may be pulsed or continuous.

However, the frequency, intensity and time of exposure are dependent on the diffusion characteristics of the agents and the nature of the tissues at the site of exposure. One way of determining the maximum limit of exposure is to measure tissue temperature, from which the dose of treatment can be decreased or stopped when the temperature of the tissues rising by one to two degrees.

The specific embodiment of the ultrasound device is not important. Probes, baths and boxes are all potentially available, depending on where the ultrasound is to be applied.

A number of devices are commercially available.

3. Example

An ultrasonic transducer (MASSA, TR-89/B), 18 millimetres in diameter, transmitted vertically an ultrasonic wave into the coupling medium. The ultrasonic transducer was driven by an amplified 40KHz sinusoidal signal from a function generator (Thuriby Thandar Instruments, TG2 15), amplification was achieved by the use of a power amplifier (BMA, Ltd, 1OL). Measurements with an ultrasonic receiver (MASSA, TR-891B) showed that the pressure at the location of the tissues was proportional to the peak-peak voltage applied to the transducer. When the peak-peak voltage was 50 V, the peak ultrasonic pressure at the location of the tissues was 0.03 bars.

An optical coherence tomography system was used for this example to measure the light distribution of the tissues, in which a broadband light source with the central wavelength at 1300 nm and a bandwidth of 52 nm was employed with an output power of 1.5 mW. The system had an imaging resolution of 14 micrometers in free space. Imaging was performed by directing low coherence light at the sample and detecting reflections from various internal structures, by the use of an fibre-optic integrated scanning system.

The chemical agent chosen for this example was glycerol with a 50% concentration.

The tissue chosen for this example was porcine stomach tissue, because the imaging depth was severely limited by the high scattering properties of this tissue; within I mm using the optical coherence tomography technique. The tissue was overlaid onto a high reflecting surface. The reflectance from the reflecting surface before and after the application of chemical agents, with ultrasound, was measured.

The experimental results are shown in Figures 1, and 2. Figure 1(a) and Figure2(a) are the optical coherence tomography (OCT) images captured from the porcine stomach tissue without the application of the chemical agent or ultrasound. Figure 1 is a series of OCT images captured from the stomach tissue after the topical application of chemical agent alone at 0, 5, 10, 20, 40, and 60 minutes, respectively. Figure 2 is a series of OCT images captured from the stomach tissue after the combined used of ultrasound and topical application of chemical agent at 0, 3, 6, 10, 15 and 20 minutes, respectively. The line shown in the Figure 2 is the surface of the transducer. It is clear from the Figure that the light penetration depth after the application of glycerol is enhanced, but due to the diffusion characteristics of glycerol to the tissue, this process cannot be controlled. Because the diffusion of glycerol into stomach tissue is low, the duration for the enhancement of light penetration is long. However, with the exposure of ultrasound to the chemical applied stomach tissue, the duration of enhancement of light penetration would be controlled. With this example, the exposure of ultrasound shortened the time duration of the optical clearing effect of glycerol on the tissue. The time duration of optical clearing can be controlled by altering the intensity, frequency, sound-wave shape (or combination of above), of the ultrasound used. In other words, the optical properties of tissue can be controlled purposely by the use of this method.

In summary, this example demonstrate that the combination of ultrasound and chemical agents is an effective method of controlling the optical properties of tissues and enhancing the penetration depth of light into tissues. The intensity, frequency, wave shape and the time of application of the ultrasound and the selection of chemical agents can be optimised to suit the different optical techniques and the individual situations. Although this invention has been described with reference to specific embodiments, it is not restricted to them. It is understood that modifications and variations of the method for using ultrasound energy and chemical agents to enhance passage of light into tissues may occur to those skilled in the art. It is intended that all such modifications and variations be included with in the scope of the appended claims.

Claims

4. Claims 1. A method for controlling the optical properties of

bio-tissue with the combined use of the ultrasound and chemical agents, comprising of the following steps: (a) selecting of the chemical agents having the capability of altering the optical properties of biotissue of any type; (b) applying the said agents (diluted if desired) onto the tissue; (c) applying ultrasound to the said tissue at a frequency of between 20 kHz and 10MHz and an intensity of between 0 and 4 W/cm 2; (d) varying the frequency and intensity over time to diffuse the said agents at a optimal rate into the said tissue without delay or damage to the tissues, wherein the optimal rate is determined by measurements of the duration and the dose of an optical treatment;
2. This method of claim 1 wherein step (b) and step (c) turn over.
3. The method of claim 1 further comprising the selection of the said agents from inorganic cOmpounds, organic compounds, synthetic particles and any combinations thereof, including optical contrast agents and fluorescence agents, wherein the said agents has the effect of modifying the optical properties of the said tissue after diffusing into tissues.
4. The method of claim 1 further comprising suspension of the said agents mixed in an aqueous solution or gel of any type.
5. The method of claim 1 wherein the light is ultra violet light, visible light and near infrared light, with a wavelength of between 300 nm and 3000nm, either narrow or broadband.
6. The method of claim 1 wherein the light is a laser beam for any therapeutic, diagnostic or imaging purpose, for example laser surgery, photodynamic therapy and optical diagnostic techniques.
7. The method of claim 1 wherein the light is a broadband source for any therapeutic, diagnostic or imaging purpose, for example photodynamic therapy and optical diagnostic techniques. The latter includes for example optical coherence tomography and optical coherence microscopy.
8. The method of claim I wherein the light is fluorescence for any diagnostic or imaging purpose, for example fluorescence microscopy and confocal fluorescence microscopy.
9. The method of claim 1 wherein the light is luminescence, including chemilurninescence, bioluminescence and sonoluminescence, for any diagnostic or imaging purpose.
10. The method of claim I wherein the agent is applied topically onto the tissue.
11. The method of claim I wherein the agent is applied into the tissue through the perfusion of blood stream.
12. The method of claim I wherein the agent is applied by the injection into the tissue.
13. The method of claim I wherein the ultrasound frequency is applied at between 20 k}iz and 1 MHz and an intensity of between 0 and 4 W/cm 2.
14. The method of claim I wherein the ultrasound is applied continuously.
15. The method of claim I wherein the ultrasound is pulsed.
16. The method of claim I wherein the ultrasonic beam is focused.
17. The method of claim I wherein the ultrasonic beam is column-shaped.
18. The method of claim 1 further comprising measuring the temperature of the tissue where the ultrasound is applied.
19. The method of claim 18 wherein the ultrasound is applied at a frequency and intensity over a period of time which does not cause an increase in tissue temperature of more than 2 0C.
20. The method of claim 1 further comprising measuring the light energy distribution in the tissue during or immediately after exposure of the ultrasound.
21. The method of claim 1 further comprising determining the rate of and the area of the light distribution for a specific chemical agents at specific frequencies, intensities and times of ultrasound application, wherein the delivery of agents are subsequently controlled by the said ultrasound at the frequency, intensity and time of application determined to yield a specific light distribution in the tissues