WO2005035058A1

WO2005035058A1 - Mobile device for photodynamic diagnostics and therapy and methods

Info

Publication number: WO2005035058A1
Application number: PCT/HR2004/000035
Authority: WO
Inventors: Antun Persin; Kreso Tisaj; Hrvoje Zorc; Vitomir Stanisic; Roudnicky Dunja Soldo; Nenad Agatic; Martin Loncaric; Anton Radman
Original assignee: Rudjer Boskovic Institute
Priority date: 2003-10-10
Filing date: 2004-10-07
Publication date: 2005-04-21
Also published as: HRP20030817A2

Abstract

The invention is a mobile device for external photodynamic diagnotics and therapy and methods, which is completely computer controlled, which has a camera for storage of lesion photographs prior to therapy, during diagnostics, during therapy and after therapy, and which uses a light source in the form of a new type of cluster-lamp made of a considerable number of small light-emitting diode crystals, a reflector and a dioptre.

Description

MOBILE DEVICE FOR PHOTODYNAMIC DIAGNOSTICS AND THERAPY AND METHODS DESCRIPTION OF INVENTION Technical field The invention concerns a mobile device for external photodynamic diagnostics and therapy and methods. International classification: A61N 5/06

Solution to the technical problem for which patent protection is requested Solution to the technical problem for which patent protection is requested is a mobile device for external photodynamic therapy and diagnostics with methods. Technical background As already known, external photodynamic therapy is a method of medical treatment for pathological skin changes which utilizes photo-sensitizers and lights. Photo-sensitizers are mostly derivatives of porp yrine, while light sources used for photodynamic therapy are bulbs, lasers, arc lamps, fluorescent tubes and light-emitting diodes. Today, the most frequently used photo-sensitizer is the 5-aminolevulinic acid (abbr. 5-ALA); the abbreviation ALA-PDT is already accepted worldwide for photodynamic therapy which uses 5-aminolevulinic acid as photo-sensitizers. The reason for such a wide range of the use of 5-ALA in photodynamic therapy is the simplicity of its application.

Suspicious pathological change on skin is covered by solution or cream containing 5-ALA, overlaid by a non-transparent covering which is left for 4-24 hours to take effect. During that time proto-porphyrine IX (PpIX) forms in the area of the skin beneath which 5-ALA has penetrated, much more prominently in the areas affected by pathological changes - tumours - than in healthy skin because tumour cells rid themselves of PpIX at a much slower rate than do healthy cells. PpIX is a photo-sensitizer which is beneficial both for diagnostics and therapy of pathological changes on skin. The maximum degree of absorption occurs at a wave length of about 407 nm, followed by gradually decreasing maximums at wave lengths of about 504 nm, 538 nm, 575 nm, and the lowest degree at about 635 nm. Diagnostics utilizes the highest maximum at about 407 nm. By illuminating the PpIX with light the wave length of which is about 407 nm, fluorescence of PpIX occurs in the red section of the spectrum, with a maximum level being reached at about 635 nm. Since the accumulation of PpIX in skin affected by pathological changes is considerably higher than is the case in healthy skin, the intensity of fluorescent light of pathological changes of skin is going to be several times stronger than the intensity of fluorescence of healthy skin. In other words, diagnostics are reduced to the observation of the red fluorescent light - skin areas with a pronounced fluorescence have suffered pathological changes. In the course of illumination with PpIX light of a wave length of about 407 nm, PpIX fluoresces, single-bond oxygen is released from the PpIX molecule and in the process the PpIX molecule is destroyed, but the released single-bond oxygen forms a strong bond with the surrounding molecular cells and oxidises them, which ultimately leads to their death. Since the concentration of PpIX in tumorous cells is several times higher than in healthy cells, selectivity is achieved regarding the destruction of tumorous cells, which is much higher than the destruction of healthy cells. This is the principle of photodynamic therapy by way of the PpIX photo-sensitizer in treating pathological changes on skin. Single-bond oxygen is also released when all other absorption maximums of PpIX are illuminated. Bearing in mind that the absorption maximums weaken as their wave length increases, and in order to achieve the same therapeutic effect, it is necessary to utilize the highest intensity of light for illumination of the lowest absorption maximum with a wave length of about 635 nm, and the lowest light intensity for the highest absorption maximum with a wave length of about 407 nm. However, the shorter the light wave length, the shallower its penetration into the skin: light with a wave length of 407 nm penetrates the skin to a depth of about 2mm, while the penetration of light with a wave length of 635 is over 1 cm. This means that the larger and deeper the tumours are in the skin, the greater the wave length of the light utilized has to be. The existing devices target two maximums: a short wave absorption maximum of about 407 nm for shallow tumours such as keratosis, or a long wave absorption maximum of about 635 nm for deeper tumours. Apart from the above described PpIX photo-sensitizer which forms in the tissue from 5-ALA, photodynamic therapy is also performed with other photo-sensitizers such as haematoporphyrin, the short wave and long wave absorption maximums of which are very close to the analogous PpIX maximums (long wave absorption maximum of haematoporphyrin is at 630 nm). The difference in relation to 5-ALA is that other photo- sensitizers must be introduced directly into the tissue. The existing portable illuminators for external photodynamic therapy based on halogen bulbs (for instance, Patent WO9852205), are cumbersome due to the low efficaciousness of a bulb during transformation of electric energy into light of the wave lengths optimal for photodynamic therapy. Bearing in mind that bulbs transform the majority of electric energy into infrared-thennal radiation, it is necessary to have ventilators and filters for the elimination - from the remaining visible spectrum - of infrared radiation, as well as optical filters in colour for the separation of the segment optimal for photodynamic therapy - usually in the red segment of the spectrum. Laser-based portable illuminators, the wave length of which tallies with one of the ^" photo-sensitizer absorption maximums - usually in the infra-red segment of the spectrum (for instance, Patent No. US5068515) - are the most expensive light sources for photodynamic therapy due to the high cost of the lasers themselves. Illuminators based on discreet light-emitting diodes are effective in the transformation of electric energy into light energy, but they are used for stationary illuminators since a number of light-emitting diodes are required if the intensity required for phototherapy is to be achieved (for instance, illumination lamps based on discreet light-emitting diodes produced by PHOTOCURE). A discreet light-emitting diode is a miniature lamp, 3 mm or 5 mm in diameter, whose light source is a small crystal of a light-emitting diode, its most common dimension being 0.3 mm x 0.3mm. Disclosure of invention The invention is a portable device for external photodynamic diagnostics and therapy which is fully computer controlled, which has a camera for storage of photographs of a lesion prior to therapy, during diagnostic process, during therapy and after therapy, and which uses a new type of lamp comprising a considerable number of light-emitting diode crystals, evenly and closely spaced in two dimensions on a base which conducts thenrial energy and insulates electric energy - as a light source. The crystals are encased in transparent optical material such as silicon or epoxy, or are hermetically sealed in a capsule with a glass window. This new source of light, consisting of a considerable number of small crystals of light-emitting diodes, was named "Cluster LED" (Light Emitting Diode). Since the light-emitting diodes emit light as a Lambert source - into the hemisphere, the cluster is fitted into a reflector of a suitable shape - most usually paraboloidal, which considerably reduces the divergence of radiated light. Further divergence reduction is achieved by placing an appropriately shaped dioptre in front of the reflector. This 95 combination of a cluster, reflector and dioptre creates a new type of lamp based on light- emitting diodes - a "cluster-lamp" of light-emitting diodes, or cluster LED lamp. This invention employs the "cluster LED lamp" as a light source for photodynamic therapy, since it is inexpensive, light and effective. Available on the market are highly efficient clusters which emit light in the violet segment of the spectrum, with a maximum emission

100 at 405 nm and a spectral half- width of less than 20 nm - which is ideal both for the ALA- photodynamic diagnostics and for ALA-photodynamic therapy of shallow tumours. Also available on the market are highly effective clusters that radiate in the red segment of the spectrum with a maximum emission at 635 nm and a spectral width of below 20 nm, which is ideal for ALA-photodynamic therapy of deeper tumours. Both clusters can be used for

105 photodynamic diagnostics and for haematoporphyrine therapy. Using clusters which emit light in other segments of the spectrum, and which correspond to the absorption maximums of other sensitizers, this invention can also be used for photodynamic therapy with those photo-sensitizers. The invention comprises a string of such clusters of light-emitting diodes together

110 with pertaining reflective-dioptrical optics, emitting within the absorption maximum of photosensitizers, thus enabling photodynamic diagnostics and therapy, recording with an integral CCD camera, where the control of the diagnostic, therapeutic, lighting clusters, as well as of the CCD camera, is performed by a computer. Technical innovation of the invention

115 The technical innovation of the invention is that it meets all the parameters required for photodynamic diagnostics, therapy, recording of lesions in patients, and through it the full monitoring of patient medical treatment. Brief description of drawings Fig. 1 Cross-section of the light-emitting diode cluster

120 Fig. 2 Cross-section of the light-emitting diode cluster-lamp Fig. 3 Cross-section of the head of the mobile device Fig. 4 Overview of the entire mobile device Detailed description of at least one of the ways of realizing the invention with examples provided and with reference to the design drawing 125 Fig. 1 Presents the cross-section of the light-emitting diode cluster in order to obtain a clearer understanding of the execution of the invention. The light-emitting diode cluster (1) consists of a considerable number of small crystals of light-emitting diodes (2), which are arranged bi-dimensionally on a base that is electrically insulated and able to conduct thermal energy (3), and is itself fixed to a metal base (4). The crystals of light-emitting

130 diodes (2) are encased in transparent optic material (5), silicon or epoxy, but they can also be hermetically sealed in a capsule with a glass window. Electric energy supply for the light-emitting diode cluster (1) is fed via the contact (6) to which the light-emitting diode crystals are connected (2). The light-emitting diode cluster (1) is secured with screws to an appropriate cooler (7). A light-emitting diode cluster (1) is available on the market as a

135 ready-made light source with a maximum emission of wave lengths in different segments of the spectrum - visible, ultraviolet and infrared. The existing light-emitting diode clusters (1) emitting in the visible spectrum have maximums distributed along the entire spectrum - depending on the producer. At this point in time the market offers clusters with maximums in the visible spectrum at, for example, 405 nm, 430 nm, 450 nm, 467 nm, 505 nm, 520

140 nm, 525 nm, 590 nm, 596 nm, 620 nm, 630 nm, 635 nm, 660 nm, 690 nm, 700 nm, 760 nm; in the ultraviolet segment at, for example, 385 nm, 395 nm; in the infrared segment at, for example, 810 nm, 850 nm, 879 nm, 910 nm, 940 nm. There are also RGB clusters, and clusters emitting white light, with spectral half-widths ranging from 20 nm to 50 nm, depending on the emission wave length. The technology of light-emitting diodes is

145 undergoing intense development and improvements can be expected, on the one hand of their effectiveness and power, and on the other hand of emissions in other wave lengths of the spectrum - both in the visible and infrared segment, and particularly in the ultraviolet segment where development is in its initial stages. Wider selection of spectrum wave lengths makes it possible to construct an illuminator for external photodynamic therapy,

150 not only on the basis of ALA, but also of other photo-sensitizers. Fig. 2 Presents the light-emitting diode cluster lamp (10) comprising a light-emitting diode cluster (1), reflector (8) and dioptre (9). The reflector (8) can be made of metal or plastic with a steam-bonded reflective layer on the inside. The aim is to collect as much light emitted by the light-emitting diode crystals into the hemisphere as possible, and to

155 form a beam of as low a divergence and as high a homogeneity as possible. The most common form of the reflector is one of a rotational paraboloid, although it can also be spherical, conical or some other suitable form. Dioptre (9) serves to further reduce divergence and increase the homogeneity of the beam. Dioptre can be a lens, a spherical or a spherical plane, the Fresnel lens, axicon or a window. Almost all combinations of a

160 reflector (8) and dioptre (9), manufactured by producers of light-emitting diode clusters (1) in parallel with their products, can be used as well as own constructions. Fig. 3 Presents the head (32) of the mobile device for photodynamic diagnostic and therapy and methods, where a CCD camera (12) is fitted to the cooler (11), where the cluster-lamps (13) designed to provoke fluorescence in photo-sensitizers are positioned

165 circularly around the camera (12) and fitted by way of their base (14) to the cooler (11). Around them, by way of their base (16), are circularly fitted cluster-lamps for photodynamic therapy in a number sufficient for achieving the desired intensity of therapeutic light on the treated area of skin (22) within the given therapy field (23) of FI diameter.

170 Fitted to the cooler (11) around them, by way of their base (18), are cluster-lamps (17) emitting white light which illuminate the treated skin area (22) so that sufficient light be provided for camera recording (12). Fitted by way of supports (20) at the outermost edges of the cooler (11) are pointers (19). Pointer (19) beams cross in the centre of the given field of therapy (23) - the speck diameter being S - thus visually defining the given

175 distance D between the head (32) and the treated surface (22). Within the head (32) are cooling ventilators (21), as well as the necessary electronics: (25) for supplying the cluster- lamps for diagnostics; (26) for supplying the cluster lamps for therapy; (27) supplying the cluster-lamps for illumination; (28) for supplying the pointers (19); (29) for supplying the ventilator (21). The electronic elements are linked to the control electronics (31),

180 positioned outside the head (32), via a connector (30). Fig. 4 Presents an overview of the whole mobile device for photodynamic diagnostics and therapy and methods, where the head (32) is fitted to a mechanical arm (33) which can be translated into a wheeled casing (34), within which lie the control electronics (31) and the source of power supply (35), which are mutually interlinked as

185 well as being linked to the pertaining electronic elements (25)-(29) within the head (32). The outside computer is linked to the CCD camera (12), and with the control electronics (31), by way of which the entire device for photodynamic diagnostics and therapy and methods is controlled (36). Method of industrial or other application of the invention The method of industrial or other application of the invention is visible from the description of the invention.

E SHEET RULE 26)

Claims

CLAIMS Mobile device for photodynamic diagnostics and therapy and methods (36), intended primarily for photodynamic diagnostics and therapy based on ALA, but which can also be used with other photo-sensitizers such as haematoporphyrin, mTHPC and other adequate photo-sensitizers, is characterized in that its source of light is a light-emitting diode cluster (1) which emits those wave lengths that can be found around the absorption maximum of the photo-sensitizer and uses them for photodynamic diagnostics and therapy, to which a reflector (8) with a dioptre (9) is fixed, and together they form a cluster-lamp (10), where there is the head (32) of the mobile device for photodynamic diagnostics and therapy and methods, within which there is a CCD (12) camera fitted to a cooler (11), and where the cluster-lamps (13) for provoking fluorescence in photo sensitizers are arranged circularly around the camera (12) and fitted to the cooler (11) by their base (14), around them fitted by their base (16) are cluster-lamps for photodynamic therapy in a number sufficient for achieving the desired intensity of therapeutic light on the treated area of the skin (22) within the given field of therapy (23) of FI diameter, and arranged around them and fitted by their base (18) to the cooler (11) are cluster-lamps (17) emitting white light and serving to provide sufficient light in order to ensure that the treated skin area (22) can be recorded by camera (12), while fitted to the outermost edges of the cooler (11) by way of supports are pointers (19), the pointer beams (19) cross in the centre of the given field of therapy (23) in the speck - the diameter of the speck being S - thus providing visual definitions of the given distance D between the head (32) and the surface treated (22), while located within the head are cooling ventilators and the pertaining electronics: (25) for supplying the cluster-lamp for diagnostics; (26) for supplying the cluster-lamps for therapy; (27) for supplying the illumination cluster-lamp; (28) for pointer (19) supply; (29) for ventilator (21) supply; where all these electronic elements are linked via a connector (30) to the control electronics (31) outside the head (32), where the head (32) is fitted to a mechanical arm that can be translated into a wheeled casing (34) within which lie the control electronics (31) and the power supply (35) which are mutually interlinked, as well as being linked with the pertaining electronics (25)-(29) located within the head (32), where the outside computer is linked to a CCD camera (1-2), as well as to the control electronics (31) by way of which it controls the entire device for photodynamic diagnostics and therapy and methods (36).