AU681376B2 - Light emitting diode source for photodynamic therapy - Google Patents

Description

WO 94/15666 PCT/US94/00506 LIGHT EMITTING DIODE SOURCE FOR PHOTODYNAMIC THERAPY 1 BACKGROUND OF THE INVENTION 2 1. Field of the Invention 3 This invention relates to photodynamic therapy and more 4 specifically to a light source for photodynamic therapy.

2. Acknowledqement 6 This invention was made with Government support under 7 Grant No. 1R43CA55446-1 awarded by the Department of Health and 8 Human Services. The Government has certain rights in the 9 invention.

3. Prior Art 11 Photodynamic therapy (PDT) is presently undergoing 12 extensive basic pre-clinical and clinical testing and development 13 both domestically and internationally. The general method of 14 performing PDT is now well known and described, for example, in U.S. Patents 4,968,715; 4,932, 934; and 5,028,621 to Dougherty, et 16 al.; and 5,002,962 to Pandey, et al. In PDT, photosensitizing 17 drugs such as hematoporphyrin derivatives are introduced into and 18 retained by the hyperproliferating cells or tissue such as 19 cancerous tissue and atheromas. With the exposure to suitable wavelengths of light the photochemical reaction of the 21 photosensitizer can lead to selective destruction of 22 photosensitizer-associated cells or tissue. PDT also holds 23 potential for a number of possible applications other than cancer 24 treatment such as for treating microvascular lesions and blood purging. To obtain the desired therapeutic response, all of these 26 applications require the delivery of sufficient light of 27 appropriate wavelength to the photosensitizer in vivo. The WO 94/15666 I PCT/US94/00506 1 activating light must be sufficiently intense at wavelengths 2 matching the absorption spectrum of the photosensitizer to initiate 3 the photochemical reaction. Secondly, these wavelengths need to 4 penetrate the host tissue to permit activation of the therapeutic reaction at the desired depth. Additionally, the light must be 6 able to be delivered to the treatment area in sufficient quantities 7 to permit treatment on a reasonable and effective time scale.

8 Prior art sources of illumination have been primarily 9 lasers. The reasons for this are the efficient deliverability of the laser light through flexible single optical fibers, the single 11 wavelength nature of the laser, the tunability of certain lasers, 12 and the ability to deliver sufficient effective power to permit 13 reasonable treatment times. All of these properties together have 14 permitted PDT to be administered endoscopically with the interstitial delivery of the light for the treatment of otherwise 16 inaccessible or large thick lesions. The use of lasers has not 17 been without drawbacks. These negative qualities of the laser 18 include high cost, low reliability, large size, complex operating 19 procedures and constant attention to the safety issues required when dealing with laser light.

21 Puliafito, et al. (Arch. Ophthalmology, Vol 105, March, 22 1987) disclose using laser diodes for Photodynamic therapy. There 23 are significant differences between LED's and laser diodes. A 24 Light Emitting Diode (LED) is a solid state electronic device capable of emitting light when an electric current is passed 26 through the device. LED-derived light is relatively broad band 27 (20-40nm) and is emitted in a wide output distribution pattern, and i-I WO 94/15666 I PCTIUS94/00506 1 lacks coherence. The light is produced at very low current levels 2 (20ma). All of these characteristics of LEDs serve to technically 3 differentiate them from laser diodes. The major advantage gained 4 by using a laser for PDT is the ability to couple significant light power into flexible optical waveguides. This is necessary for 6 applications requiring interstitial or endoscopic delivery of 7 treatment light for PDT. Laser diode systems which include a large 8 power supply and cooling system are very expensive.

9 There are a significant number of applications for PDT that do not require the use of a laser light source or the delivery 11 of light through light guides. In fact, the majority of the basic 12 pre-clinical and original trials of PDT using hematoporphyrin 13 derivative were done using non-laser light sources. For example 14 the treatment of cutaneous and subcutaneous skin lesions less than 1.0 cm thick can be treated using non-laser light sources. Skin 16 cancer incidence in the United States of America is o'er 550,000 17 new cases per year and rising. Even though a majority of these 18 cases can be easily treated with local resection or other methods, 19 there are a significant number involving multiple and/or recurrent lesions th&t could be more conveniently treated using PDT. The 21 clinical use of PDT in many of these cases would be limited, in 22 part, due to the need to use lasers. This is due to the high cost 23 and lack of availability of suitable lasers. There is truly a heed 24 for a low cost non-laser light source for use in PDT.

There are a number of non-laser light sources that could 26 potentially be used in certain PDT applications. The major 27 properties of these light sources that determine their WO 94/15666 W PCT/US94/00S06 1 applicability in PDT are: output spectrum; b) brightness or 2 intensity at a suitable wavelength; c) deliverability; d) size; 3 and e) cost. These non-laser light sources include arc lamps, 4 incandescent lamps, fluorescent lamps and light emitting diodes (LEDs). The lamp sources have a broad emission spectrum ranging 6 from ultraviolet to infrared. These broad spectrum sources require 7 the use of optical filtering-to remove the undesired wavelengths, 8 particularly the ultraviolet and infrared, due to the potential of 9 carcinogenic effects and heating respectively. In addition, the low brightness of these light sources at suitable wavelengths, 11 compared to lasers, make them all poor candidates for transmitting 12 sufficient power through small (less than 600 micron core), 13 flexible light guide to effect PDT. The best of these light 14 sources for brightness is the arc lamp due to the relatively high intensity and small size of the discharge arc. Even though such 16 technology shows promise for certain medical applications, 17 including PDT, it still suffers from problems such as the need for 18 extensive filtering, limitations on its use for large area 19 exposure, and the requirement for high voltage and the concomitant potential for arc lamp explosion.

21 LED technology, unlike the other non-laser light source 22 outlined above, has the advantage of small size, typically 0.3 mm 23 by 0.3 mm, limited emission spectrum band, typically 20 nm to 24 nm, high efficiency and low cost. The light power emitted from a single diode is relatively low however (approximately 4 milliwatts 26 to 5 milliwatts for the brightest red LEDs using the specified 27 driving currents) but its emission angle is low when compared, for 1. i ~Y- WO 94/15666 PCT/US94/00506 1 example, to the arc lamp so that its actual brightness is 2 reasonably good. The small size of the LED along with its high 3 efficiency give the potential of using an array consisting of S4 multiple LEDs in a single device to significantly increase deliverable power density over a large area. The low power output 6 has, however, delayed the acceptance of LED arrays ac a suitable 7 light source for PDT. The intensity can be increased by over- 8 driving the LEDs in the array. Such over-driving results in 9 heating which shortens the lifetime of the LED and causes a spectral shift in the output. LEDs are available in variety of 11 discrete packages as well as several one and two-dimensional array 12 packages. As used herein, an LED array means multiple LED's 13 integrally mounted in a single device. Commercially available 14 arrays, from manufacturers such as Mitsubishi, Hewlett Packard or Stanley Electric, combine a few LEDs in a single package but not 16 in high enough packing density or in geometrics suitable for PDT.

17 None of these prior art devices can provide sufficient power 18 density for effective PDT treatments, nor can they be easily 19 configured in the geometries necessary for the wide range of applications for surface illumination and PDT. It is desirable to 21 have a multiple integrated LED array with a power output suitable 22 for use in PDT.

23 SUMMARY OF THE INVENTION 24 It is an object of this invention to provide an array of multiple integrated LEDs useful for photodynamic therapy.

26 It is another object of the invention to provide an 27 inexpensive light source useful for photodynamic therapy.

I II WO 94/15666 SPCT/US94/00506 1 It is still another object of this invention to be able 2 to provide an LED array for photodynamic therapy that is capable 3 of illuminating the surface of various types of tissues.

4 It is yet a further object of this invention to provide an LED array for photodynamic therapy which enables accurate 6 wavelength and exposure control and permits accurate dosimetry.

7 It is another object of this invention to provide an 8 illuminating system for photodynamic therapy that is safe to both 9 the physician and the patient.

The LED light source of the present invention is novel 11 because it teaches how to use the characteristics of the LED to an 12 advantage over the laser diode for applications of PDT which do not 13 require interstitial or endoscopic light delivery. The wide output 14 distribution pattern, small size, and minimal cooling requirements of the LED allow large arrays of the devices to be constructed 16 which cumulatively are capable of producing a total output light 17 power exceeding that of laser diodes. This opens up applications 18 for large surface area illumination (such as is needed in 19 dermatology) for which laser diode systems are inadequate.

These and other objects of the invention will soon become 21 apparent as we turn now to a brief description of the drawings.

22 23 BRIEF DESCRIPTION OF THE DRAWINGS 24 Figure 1 is a schematic representation of an LED system suitable for illumination of surfaces for photodynamic therapy.

WO 94/15666 PCT/US94/00506 1 Figure 2 schematic diagram of the front panel of the LED 2 array driver showing the displays for controls for exposure power 3 and coolant temperature display.

4 Figure 3 is a cross-sectional view of the LED handpiece configured for flat surface illumination.

6 Figure 4 is a top view of the LED puck configured for 7 flat surface illumination.

8 Figure 5, which is a detailed top view of the area shown 9 in Figure 4 enlarged for ease of viewing, shows the top surface of the LED puck showing the machine holes and indicating the LED die.

11 Figure 6 is a cross-sectional view of the LED handpiece 12 for illumination of cylindrical surfaces.

13 Figure 7 shows the LED sleeve for cylindrical surface 14 illumination.

Figure 8 is a schematic diagram of a preferred embodiment 16 of the light output and wavelength detector.

17 DESCRIPTION OF THE PREFERRED EMBODIMENT 18 It is the combination of small size and high efficiency 19 that make the LED a potentially useful light source for PDT. The small size of the LED allows them to be fabricated in high density 21 into applicators of various shapes for the direct contact treatment 22 of cutaneous lesions. The shape may be circular, rectangular (or 23 any curvilinear surface) for treating skin lesions or cylindrical 24 for the treatment of cervical cancer. Planar arrays of LED's may be bent or Zolded to form various curvilinear surfaces to conform 26 to the surface being treated. To be useful, the LED's must be 27 overdriven to produce useful power outputs. The heat generated WO 94115666 PCT/US94/00506 1 during over-driving must be removed by cooling the LED in order to 2 control the wavelength and increase the lifetime of the LED.

Z Turning now to Figure 1, we see a schematic view of the LED system 4 configured for flat surface illumination and generally indicated at the numeral 10. The system consists of the LED array driver 11, 6 the flat surfaced LED handpiece 12, the flat surfaced LED puck 13 7 and the closed loop chiller 14. The detailed controls of the front 8 panel of the system are shown in Figure 2 of the array driver 11, 9 and shows the displays for the controls of exposure 21, power 22, the coolant temperature display 23 and the power supply 24.

11 An LED handpiece configured for flat surface illumination 12 12 is shown in cross section in Figure 3. The stainless steel 13 housing 31 and threaded retaining ring 32 are connected to the 14 system ground 33 and provide one electrical connection to the LED puck 13. The heat sink 34 is connected to the LED supply voltage 16 35. This provides the second electrical connections to the LED 17 puck as well as removing the heat generated in the puck. The heat 18 sink is electrically insulated from the housing by the DELRIN® 19 insulator 36. The coolant tubes 37 provide a flow of cooling water from the chiller to the heat sink. The light output power and 21 wavelength detector 38 (shown in greater detail in Figure 8) 22 detects the amount of light being delivered to the patient by 23 sensing the light through the light sense channel 39.

24 An LED puck configured for f.at surface illumination is shown in Figure 4. The puck, generally indicated at 13, comprises 26 a gold plated insulated copper and fiberglass laminate sheet 41 27 bonded to a flat copper substrate 42. Holes are machined through 3 WO 94115666 PCT/US94/00506 1 the copper laminate to the surface of the copper substrate. The 2 LED puck is coated with a clear epoxy potting material 43 to 3 protect the LED device and provide a smooth clean surface for 4 patient contact.

Figure 5, shown as detail A of Figure 4, is an enlarged 6 view of the top surface of the LED puck showing the machined holes 7 and indicating the LED die 51 bonded to the copper substrate 42 8 with electrically and thermally conductive epoxy 52. The figure 9 also shows the gold bonding wire 53 attached between the top contact of the LED die and the surface _f the copper laminate 41 11 using common integrated circuit assembly techniques.

12 Figure 6 shows a cross sectional view of the LED 13 handpiece for illumination of cylindrical surfaces, generally 14 indicated by 60. The stainless steel housing 31, threaded retaining ring 32, coolant tubes 37, the photodiode detector 34 and 16 the insulator 36 function the same as in the flat surface 17 illuminating handpiece. The heat sink 61, the light sense channel 18 62 and the LED sleeve 63 are now shaped appropriately for insertion 19 into the cervical canal or rectum.

Figure 7 shows an LED sleeve configured for cylindrical 21 surface illumination 63. The copper laminate 71, copper substrate 22 72 and LED 73 are assembled in a similar manner to the flat surface 23 LED puck except the geometry is out of a tube instead of a disk.

24 The light output power and wavelength detector is shown in greater detail in Figure 8. The light transmitted through the 26 light sense channel 39 (Figure 3) is focused jy the collimating 27 lens 81 and split into two equal light beams by the beamsplitter WO 94/15666 PCTAU594/00506 1 82. The light power in one beam path is filtered by a filter 93, 2 and measured by the photodiode 85. The unfiltered photodiode 84 3 measures the light power in the other light beam path. Assuming 4 that proper calibration is done to compensate for the different optical losses in each path, the total optical power and 6 verification of the wavelength can be accomplished with this 7 technique. It is clear that this device could also be configured 8 with a flexible light guide (not shown) built into the handpiece 9 which would then deliver the sampled light energy to the light power output and wavelength detector shown in Figure 8 which could 11 conveniently be installed in the LED array driver 11.

12 In summary, it has been shown that an LED array can be 13 configured to provide power and wavelength outputs suitable for 14 PDT. In order to achieve the required power levels, it is necessary to over-drive the LED's. The additional current required 16 for over-driving generates heat at the diode junction which results 17 in: a red-shift and broadening of the output light; and a 18 shorter lifetime. To overcome these problems, the LED array is 19 mounted on a puck enabling the LED array to be cooled to control the bandwidth and wavelength of the output light and increase the 21 lifetime of the array. In practice, the output wavelength depends 22 on the diode's junction temperature. Monitoring the wavelength 23 permits adjustment of the coolant temperature and flow rate to 24 maintain the junction at the desired temperature.

The foregoing preferred embodiment of the LED system for 26 photodynamic therapy provides a low cost, high power excitation 27 source for PDT which can be produced in a variety of shapes used i WO 94/15666 PCT/US94/00506 1 in a wide variety of applications. This device will allow PDT to 2 become viale treatment modality for many more cancer patients 3 inasmuch as it will now be cost effective for the physician's 4 office or small clinic. Although the invention has been described in terms of particular embodiments and applications, one of 6 ordinary skill in the art in the light of this teaching, can 7 generate additional embodiments and modifications without departing 8 from the spirit of or exceeding the scope of the claimed invention.

9 F7- example, single LED chips may be fabricated into an array by depositing them directly onto a chilled substrate by techniques 11 currently used in hybrid circuit fabrication. Accordingly, it is 12 to be understood that the drawings and descriptions herein are 13 preferred by way of example to facilitate comprehension of the 14 invention and should not be construed to limit he scope thereof.

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Claims (1)

1. A non-coherent light source operable for administering therapeutic treatment light to adjacent cissue for photodynamic therapy, said light source comprising, in combination: an electrically conductive cooling means comprising a thermally conductive slab having a tissue-facing surface and a coolant fluid channel therewithin, said coolant fluid channel being operable for circulating a coolant fluid therethrough; a plurality of light emitting diodes arrayed upon said tissue-facing surface and wherein each light emitting diode of said plurality of light emitting diodes has first and second electrical connectors and wherein said first electrical connector is in direct electrical connection with said slab; an LED driver comprising an electrical energy source having first and second output connectors and wherein said first output connector is in electrical communication with said slab and said second connector is in electrical communication with said second S 25 electrical connector. DATED this twelfth day of May 1997 OPDT SYSTEMS, INC. By their Patent Attorneys S. 5555