WO1994026203A1 - Apparatus and method for delivering laser radiation to a substrate - Google Patents

Apparatus and method for delivering laser radiation to a substrate Download PDF

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Publication number
WO1994026203A1
WO1994026203A1 PCT/GB1994/000976 GB9400976W WO9426203A1 WO 1994026203 A1 WO1994026203 A1 WO 1994026203A1 GB 9400976 W GB9400976 W GB 9400976W WO 9426203 A1 WO9426203 A1 WO 9426203A1
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WO
WIPO (PCT)
Prior art keywords
delivery head
laser
laser radiation
delivery
substrate
Prior art date
Application number
PCT/GB1994/000976
Other languages
French (fr)
Inventor
Bipin Chandra Muljibhai Patel
Original Assignee
British Technology Group Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by British Technology Group Limited filed Critical British Technology Group Limited
Priority to US08/532,719 priority Critical patent/US5738678A/en
Priority to EP94914473A priority patent/EP0696905B1/en
Priority to JP6525120A priority patent/JPH08509884A/en
Priority to DE69404297T priority patent/DE69404297T2/en
Publication of WO1994026203A1 publication Critical patent/WO1994026203A1/en

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61CDENTISTRY; APPARATUS OR METHODS FOR ORAL OR DENTAL HYGIENE
    • A61C1/00Dental machines for boring or cutting ; General features of dental machines or apparatus, e.g. hand-piece design
    • A61C1/0046Dental lasers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B90/00Instruments, implements or accessories specially adapted for surgery or diagnosis and not covered by any of the groups A61B1/00 - A61B50/00, e.g. for luxation treatment or for protecting wound edges
    • A61B90/04Protection of tissue around surgical sites against effects of non-mechanical surgery, e.g. laser surgery
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61CDENTISTRY; APPARATUS OR METHODS FOR ORAL OR DENTAL HYGIENE
    • A61C19/00Dental auxiliary appliances
    • A61C19/003Apparatus for curing resins by radiation
    • A61C19/004Hand-held apparatus, e.g. guns
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/18Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves
    • A61B18/20Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser
    • A61B18/201Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser with beam delivery through a hollow tube, e.g. forming an articulated arm ; Hand-pieces therefor
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00Surgical instruments, devices or methods, e.g. tourniquets
    • A61B2017/00017Electrical control of surgical instruments
    • A61B2017/00022Sensing or detecting at the treatment site
    • A61B2017/00057Light
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00Surgical instruments, devices or methods, e.g. tourniquets
    • A61B2017/00017Electrical control of surgical instruments
    • A61B2017/00115Electrical control of surgical instruments with audible or visual output
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00Surgical instruments, devices or methods, e.g. tourniquets
    • A61B2017/00017Electrical control of surgical instruments
    • A61B2017/00132Setting operation time of a device
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00Surgical instruments, devices or methods, e.g. tourniquets
    • A61B2017/00017Electrical control of surgical instruments
    • A61B2017/00137Details of operation mode
    • A61B2017/00154Details of operation mode pulsed
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00Surgical instruments, devices or methods, e.g. tourniquets
    • A61B2017/0023Surgical instruments, devices or methods, e.g. tourniquets disposable
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00Surgical instruments, devices or methods, e.g. tourniquets
    • A61B2017/00535Surgical instruments, devices or methods, e.g. tourniquets pneumatically or hydraulically operated
    • A61B2017/00557Surgical instruments, devices or methods, e.g. tourniquets pneumatically or hydraulically operated inflatable
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B2018/00005Cooling or heating of the probe or tissue immediately surrounding the probe
    • A61B2018/00011Cooling or heating of the probe or tissue immediately surrounding the probe with fluids
    • A61B2018/00017Cooling or heating of the probe or tissue immediately surrounding the probe with fluids with gas
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B90/00Instruments, implements or accessories specially adapted for surgery or diagnosis and not covered by any of the groups A61B1/00 - A61B50/00, e.g. for luxation treatment or for protecting wound edges
    • A61B90/06Measuring instruments not otherwise provided for
    • A61B2090/061Measuring instruments not otherwise provided for for measuring dimensions, e.g. length
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B90/00Instruments, implements or accessories specially adapted for surgery or diagnosis and not covered by any of the groups A61B1/00 - A61B50/00, e.g. for luxation treatment or for protecting wound edges
    • A61B90/36Image-producing devices or illumination devices not otherwise provided for
    • A61B90/37Surgical systems with images on a monitor during operation
    • A61B2090/373Surgical systems with images on a monitor during operation using light, e.g. by using optical scanners
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B90/00Instruments, implements or accessories specially adapted for surgery or diagnosis and not covered by any of the groups A61B1/00 - A61B50/00, e.g. for luxation treatment or for protecting wound edges
    • A61B90/39Markers, e.g. radio-opaque or breast lesions markers
    • A61B2090/3937Visible markers
    • A61B2090/3941Photoluminescent markers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B2218/00Details of surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B2218/001Details of surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body having means for irrigation and/or aspiration of substances to and/or from the surgical site
    • A61B2218/002Irrigation
    • A61B2218/006Irrigation for smoke evacuation
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B2218/00Details of surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B2218/001Details of surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body having means for irrigation and/or aspiration of substances to and/or from the surgical site
    • A61B2218/007Aspiration
    • A61B2218/008Aspiration for smoke evacuation

Definitions

  • the invention relates to laser treatment of substrates, and more specifically to an apparatus and method for delivering laser radiation to a substrate.
  • it concerns an apparatus and a method of producing cosmetic or prophylactic coatings for teeth utilising such an apparatus.
  • BACKGROUND TO THE INVENTION In attempting to prevent or reduce the incidence of tooth decay, and to inhibit decay after it has commenced, a number of compounds for forming highly durable coatings or fillings for teeth, and methods of using such compounds, have been considered in the past.
  • Protective/cosmetic coatings and restorative surfaces for teeth must be highly durable and cosmeticaily acceptable.
  • a suitable vitreous dental coating composition is described, specifically a sol gel, xerogel or heat-consol1dated gel composition, comprising a hydrolysable silicic ester, 1-4 moles water per mole of silicon, a solvent and a filler.
  • a sol gel, xerogel or heat-consol1dated gel composition comprising a hydrolysable silicic ester, 1-4 moles water per mole of silicon, a solvent and a filler.
  • the surface of the tooth is first prepared by cleaning, then the composition is applied to the tooth surface in a thickness of a few microns, and then the composition is cured or consolidated by heat treatment.
  • This heat treatment stage is carried out by application of appropriate radiation energy. For this latter stage, it is important to safely deliver the correct amount of energy to the correct location in a sufficiently short time, preferably below or close to the thermal relaxation time of the tooth tissue, that is, within a few microseconds.
  • a suitable source of radiation energy for processing thin film of the type discussed above is a CO2 laser producing pulsed or continuous wave laser light tuned to lO. ⁇ m, since such laser light is strongly absorbed by the natural tooth.
  • Other laser radiation sources such as NdrYAG or argon lasers, with wavelengths in the near infra-red and visible ranges, can also be used.
  • an apparatus for delivering laser radiation to a substrate, said apparatus including: a laser radiation source delivery means to transmit the laser radiation from the source a delivery head to direct the laser radiation from the delivery means onto the substrate, having isolation means to isolate a selected target area from its surroundings by substantially preventing escape of laser radiation; and viewing means to enable an operator to view the selected target area.
  • the laser radiation source preferably comprises a C0 2 pulsed or continuous wave laser.
  • the laser radiation may be delivered by way of an articulated arm provided with laser light guiding means, such as a system of mirror elements or fibre optic means.
  • the delivery head comprises focusing means and at least one optical scanner deflector, to control the delivery of laser radiation to the substrate.
  • the delivery head preferably has a body part, the isolation means comprising a shield defined by a socket projecting from the body part and having means for selectively sealing around the target area.
  • the delivery head may have a tubular body, the isolation means comprising an extension piece with an end wall, the extension piece fitting onto the tubular body in sliding engagement therewith.
  • At least one section of the delivery head may be transparent to visible light, or an optical eyepiece can be incorporated in the delivery head.
  • video monitoring means may be provided.
  • Figure 1 shows the main components of a laser radiation delivery apparatus according to the invention
  • Figure 2 diagrammatically illustrates one embodiment of the delivery head of the apparatus of Figure 1 used to direct laser light onto the surface of a tooth;
  • Figure 3 shows an adapted version of the delivery head of Figure 2;
  • Figure 4 shows another embodiment of the delivery head;
  • Figure 5 diagrammatical ly i 1lustrates "the process of -scanning the surface of a tooth with the apparatus of the invention;
  • Figure 6 is a block diagram representing the various operational components of the apparatus, and the connections therebetween.
  • Figure 1 shows a laser energy delivery apparatus used to supply laser light to a tooth coating to be treated and comprising a laser light source 1, an articulated arm 2, a laser light delivery head 3 at the end of the articulated arm, and a control system 4.
  • the arrangement of the delivery head 3 on the articulated arm 2 is similar to that of a standard dental handpiece.
  • Laser Light Source The laser light source 1 contains a sealed, RF-excited C0 2 laser producing pulsed or continuous wave laser light at a wavelength of 10.6 ⁇ m.
  • a Nd:YAG laser (1.064 ⁇ m - near infra-red), an Er:YAG laser (2.94 ⁇ m - mid infra-red), an Ho. ⁇ AG laser (2.1 ⁇ m - mid infra-red), a CO laser (5 ⁇ m - mid infra-red), or a far infra-red C0 2 laser (9.6 ⁇ m).
  • a tunable C0 laser may be used to take advantage of the energy absorption of different wavelengths in the case of different materials.
  • energy absorption can be enhanced by the inclusion in the tooth coating material of chromophores, such as transition metal ions. Beam Del iverv
  • the articulated arm 2 acts as a laser light transmission tube, and in a known manner has reflective mirrors suitably mounted at the various joints to accurately direct a laser beam to the delivery head 3, whilst allowing the arm to be manoeuvred into different positions to access a target.
  • the beam may also be directed via fibre optic means, and although infra-red fibre optics appropriate for C0 2 laser wavelengths are not at present fully practicable (such wavelengths not being efficiently transmitted by standard silica-based fibres or hollow ceramic or metal waveguides), this transmission method is certainly suitable for other categories of laser light, such as that from the Nd:YAG laser.
  • the delivery head 3 receives the laser beam and delivers it to the surface to be treated via an opening 5.
  • a control system 4 is used by an operator to control the functioning of the apparatus, and is therefore connected to the laser source 1, to select the duration and various other criteria for the operation of the laser beam, and to the delivery head 3 to control the scanning operation described below.
  • the control system 4 is also provided with means for entering details such as patients' names and means for monitoring various aspects of the operation of the system.
  • the system is microprocessor-controlled and includes a VDU screen as part of the monitoring means.
  • Figure 2 shows the delivery head 3 receiving the beam of laser light, indicated by reference numeral 10. Because of lack of uniformity of energy of a CO2 laser beam over its entire cross section, it is not practical to irradiate the whole of an extended target area simultaneously, with different parts of the target area exposed to different parts of the beam cross section. For that reason the beam is focused to a small spot (10-500 ⁇ m in diameter, preferably between 50 and lOO ⁇ rn) by means of lenses 21, which are movable so as to focus the beam at the appropriate point, thereby effectively eliminating hot spots across the beam cross section and producing instead a single point heat source which can be scanned across the target area using optical scanner deflectors, operating in directions transverse to one another and controlled by way of control system 4.
  • a small spot (10-500 ⁇ m in diameter, preferably between 50 and lOO ⁇ rn)
  • the optical scanner deflectors may be galvanometer-based optical scanners (GBOSs), which are commonly used in applications which call for accurate positioning of a laser beam. As illustrated diagrammatically in Figure 2, they may alternatively be solid-state acousto-optical crystal devices 11 and 12, in which the optical properties of a suitable crystal (e.g. Te0 2 or LiNb0 3 ) are locally varied by a strong acoustic wave generated at radio frequencies, so as to deflect a beam of light. Acousto-optical devices of this kind are more compact than GBOSs.
  • GBOSs galvanometer-based optical scanners
  • the beam focusing lenses and scanners are contained within a tubular housing 13 which is closed off by an end wall 14 and which features a side aperture 15 through which the beam can be directed by means of an angled mirror 16 mounted on a pivot 21 within the tubular housing as shown in Figure 2.
  • the tubular housing 13 may be cylindrical, about 16cm in length, with a diameter of 1.8cm for the portion destined to be inserted into the patient's mouth.
  • the aperture is fitted with a joint 17 for coupling to a socket 18 which serves as a shield to isolate a tooth from its surroundings.
  • a socket 18 which serves as a shield to isolate a tooth from its surroundings.
  • the laser radiation used is potentially harmful and the isolation means provides protection for other parts of the patients' mouth, such as soft tissue and other teeth, nd also provides protection for the dentist or operator.
  • the isolation means provides protection for other parts of the patients' mouth, such as soft tissue and other teeth, nd also provides protection for the dentist or operator.
  • the socket 18 is of short, flexible, approximately tubular form of a plastics material, one end being adapted to be attached to joint 17 and provided at the other end with an elastic 0-ring 19 of a flexible material, to at least partially seal the tooth with the socket.
  • the 0-ring 19 may be inflatable to provide an air-tight seal, and alternatively or additionally the diameter of the socket may be adjustable to improve sealing.
  • the delivery head 3 can be manoeuvred to fit the socket 18 over the occlusal surface of a molar or premolar tooth 20 to aid in location and to stabilise the apparatus on the target and to prevent, or at least greatly reduce, the possibility of laser light reaching any other part of the patient's mouth.
  • the socket 18 also ensures that the delivery head is maintained at an optimum distance from the tooth surface.
  • the socket 18 is readily detachable and can be discarded and replaced after use to prevent the possibility of contamination from one patient to another.
  • the delivery head or its socket 18 is equipped with viewing means.
  • the socket may be transparent to visible light, or may feature a viewing port transparent to visible light, to assist in alignment of the delivery head and to enable an operator to view a selected target area on the tooth.
  • a transparent portion may be manufactured of glass or plastics material such as perspex, to be highly absorbent of radiation at that wavelength and thereby prevent escape of laser radiation.
  • an eyepiece may be incorporated as a lateral attachment to the tubular housing 13 to enable the operator to view the target area.
  • This may be a rotating, angled tubular eyepiece for ease of use.
  • a beam splitter or similar is included within the delivery head to deflect to the eyepiece a portion of the light reflected through the optical system from the target.
  • the eyepiece is designed to prevent transmission of radiation at the wavelength of laser light used for the curing process.
  • the delivery head 3 shown in Figure 2 is also provided with light detector means 22 and may also feature a sensor 23 and/or opto-electronic means 24, 25, which will be described further below.
  • FIG 3 the same delivery head is shown but in this case it is being used to cosmeticaily or prophylactical ly treat the visible surface 120 of an incisor, where the coating is applied to the front surface of the tooth.
  • An appropriately shaped alternative socket 118, with 0-ring seal 119, is fitted to joint 17 so as to provide a continuation of end wall 14, thereby reducing the danger of any laser light which travels past the tooth causing damage to any part of the subject's mouth.
  • mirror 16 is not required in this case and can be folded away as shown by means of hinge 21.
  • interchangeable disposable sockets may be used with the delivery head, selected to suit different teeth in different patients.
  • Figure 4 illustrates a section of an alternative delivery head, also to be used in treating the visible surface of an incisor, which features adjustment means to accommodate in an alternative manner the particular size of tooth to be treated and thus shield the tooth effectively.
  • the delivery head comprises an open cylindrical tube 30 on which a closely fitting tubular endpiece 31 can be fitted, the endpiece being closed by end wall 32 and having a side aperture 33 to receive the tooth.
  • the tubular endpiece is engaged by a clamping ring 34 and rotating locking ring 35.
  • rubber impression material 36 is mounted on the inner side of endwall 32 rubber impression material 36 is mounted.
  • the endpiece 31 can be telescoped along the tube 30 as indicated by the arrow to provide an opening that closely fits the size of the tooth.
  • the clamping means can then be operated to lock the two parts in position relative to one another, thus fixing the size of opening for the duration of the treatment process.
  • Tubular endpiece 31 may be of glass or another suitable transparent material. Focusing Means As explained above, to ensure the beam parameters at the tooth surface are appropriate for curing a sol-gel derived coating which has been applied to the tooth surface, it is required to focus the laser, beam relative to the surface to produce a spot with the required diameter. Since this spot is to be scanned over the - probably irregular - surface of the tooth, it may be necessary to instantaneously control the focusing during the scanning operation. If a relatively long focal length is selected then the process will be less sensitive to the exact position of the tooth surface, but some means of focus control will still be required.
  • the scanning system should be correctly aligned prior to beginning the curing process, and to this end visible laser radiation is directed along the same projected path of the C0 2 laser beam.
  • a light detector is arranged to receive light reflected from the irradiated surface.
  • a sensor device of an automatic focusing unit, or another photoelectrical detection element 22 is mounted behind the mirror 16, which for this purpose is a partially reflecting mirror, such that visible light reflected from the tooth surface passing through the partially reflecting mirror is detected by the element 22.
  • the light detector element can be used to provide a signal which is sent to the control system 4 and which can be used to indicate the presence of the tooth surface and to calculate Its distance from the light detector, this information being used to control the focusing of the C0 2 laser beam during the subsequent curing stage.
  • This may be accomplished by means of the reflected He-Ne visible light detected by the light detector 22. This supplies a ⁇ proximity signal', and thereby fulfils a safety function to prevent the curing laser operating unless the tooth surface is within a certain range.
  • mechanical means such as a spring-loaded mechanical contact, may be provided in association with the socket itself to determine whether it is appropriately located.
  • a sensor such as a strain gauge 23 may be provided on the flexible socket 18 to detect deformation in the socket due to contact with the tooth, or a pressure sensor may be built into the coupling joint 17. Either sensor can furnish a signal to prevent or allow the firing of the curing laser.
  • an opto-electronic system may be used to detect the presence or absence of a tooth.
  • An LED 24 and a photo sensor 25 may be provided on opposite sides of the inside of the socket 18, a safety signal being provided only if the path of light between the LED and the photosensor is broken by the presence of a tooth.
  • a positive pressure is therefore preferably provided within the delivery head to reduce this risk.
  • an aspiration system may be provided in or adjacent to the socket to remove vapours produced during the curing process.
  • a stream of forced air may be provided in or adjacent to the socket to assist in drying of the tooth surface during the curing operation.
  • the He-Ne laser already described may be used to select the target area to be scanned.
  • the reflected light from the He-Ne laser can be monitored by appropriate detection means and the precise area to be scanned at the curing stage can be automatically determined, thus ensuring that a sufficient area of the tooth surface is irradiated whilst minimising the danger that the laser may be directed at an area beyond the edges of the tooth surface to be treated, such as the patient's gum tissue.
  • Figure 5 illustrates this technique.
  • the intensity of reflected light from the tooth surface is considerably greater than that from the surrounding light-absorbing gum tissue, and the distribution of reflected light intensity will therefore give an indication of the size and shape of the tooth surface. If the
  • He-Ne beam is scanned across an area A (larger than the area of the tooth surface) the intensity of the reflected signal can be compared with a threshold value. If the reflected light is above this value then tooth surface is present' (R ⁇ ) and if the reflected light is below this value then gum tissue is present
  • the control system 4 is set up to record the reflected light value R j or R G as a function of the instantaneous position of the scanning light spot, and this gives the shape and size of the tooth surface. This may then be de-magnified automatically to define a reduced area, shown in Figure 5 as shaded area S within the dotted line, which is then scanned by the gel-curing laser beam.
  • a scanning field smaller than the entire tooth surface is selected as, for safety reasons, it may not be desirable that the whole surface, right out to its very periphery, should be scanned by this more powerful laser beam.
  • the operator may select a predetermined shape from a repertoire of geometrical shapes stored by the control system 4, as being suitable for the tooth in question and fitting within the boundaries of the tooth as determined by the He-Ne scan. This shape may then be used to determine the actual area which is irradiated by the C0 2 laser. With this system the operator is able to view the tooth, by means of a viewing means including a display generated by means of the He-Ne scan. Alternatively charged-coupled devices (CCDs) can be built into the delivery head to provide means of visual inspection of the tooth and the proposed target area before the curing is carried out. Using the control system 4 the operator can select the area to be scanned and the scanning pattern to be used, either by freehand control or by the techniques discussed above. Identification of Consolidation
  • a detector may be provided in the delivery head to monitor the surface emissivity from the tooth, this giving a measure of the temperature attained at the surface and hence an indication of the degree of consolidation.
  • an infra-red diode, or an array of such diodes may be mounted in the head to measure the temperature or the distribution of temperature across the target zone.
  • a temperature of 200°C-800°C is needed in a total curing period of the order of 0.1 s.
  • a photodetection system may be used to examine the cured coating. If fluorescent chromophores (such as fluorescein) are added to the gel these will thermally decompose during the heat treatment.
  • the tooth surface can then be interrogated by means of a light beam, for example, the He-Ne laser beam, and the fluorescence measured, giving an indication of the presence of cured coating and of the degree and uniformity of consolidation. Operation
  • the delivery head is fitted with an appropriate socket, and the apparatus is manoeuvred to position the socket over the selected tooth after the tooth has been cleaned and the coating gel has been applied to the surface to be treated.
  • the tooth is then scanned with the He-Ne laser light and the size and shape of the target area is determined.
  • the operator selects the target area while viewing the tooth by any of the means already described.
  • the operator then starts the aspiration means and the positive pressure means for the delivery head, if required, and the curing operation can then be initiated, the C0 2 laser beam only being activated when the system has detected a safety signal from the proximity signal or otherwise.
  • the laser beam spot is then scanned across the selected target zone in a zig-zag, raster or other pattern, selected as required and to avoid hotspots, to deliver the correct amount of energy in the appropriate time to consolidate the gel coating to its glassy state.
  • the target zone may be scanned a number of times, first at low power (less than 5w) to drive off solvents, then at a higher power (around lOw) to fully effect the curing.
  • An appropriate high frequency tone can be used to indicate when the C0 2 beam is engaged.
  • the degree and uniformity of consolidation can then be checked as described above, and any non-uniformity is corrected by further irradiation.
  • FIG. 6 The block diagram of Figure 6 shows the various operational components and how they are interconnected.
  • a TEA-C0 2 laser may be used. This is capable of producing a beam with uniform energy distribution across the area of the beam, and therefore the beam can simply be directed to a selected target area and switched on for the desired time. The delivery of the beam would not therefore require focusing means, the irradiated area being up to, say, 1cm in diameter. Masking could be used to protect surrounding areas and prevent their being irradiated.

Abstract

The invention provides an apparatus and method for delivering laser radiation to a substrate (20, 120) involving a laser radiation source (1), delivery means (2) to transmit the laser radiation from the source, a delivery head (3) to direct the laser radiation from the delivery means onto the substrate. The delivery head has isolation means to isolate a selected target area from its surroundings by substantially preventing escape of laser radiation, and viewing means are provided to enable an operator to view the selected target area. The apparatus is specifically for application in curing restorative or prophylactic tooth coatings, such as vitreous dental compositions or sol gels.

Description

APPARATUS AND METHOD FOR DELIVERING
LASER RADIATION TO A SUBSTRATE
INTRODUCTION
The invention relates to laser treatment of substrates, and more specifically to an apparatus and method for delivering laser radiation to a substrate. In particular it concerns an apparatus and a method of producing cosmetic or prophylactic coatings for teeth utilising such an apparatus. BACKGROUND TO THE INVENTION In attempting to prevent or reduce the incidence of tooth decay, and to inhibit decay after it has commenced, a number of compounds for forming highly durable coatings or fillings for teeth, and methods of using such compounds, have been considered in the past. Protective/cosmetic coatings and restorative surfaces for teeth must be highly durable and cosmeticaily acceptable.
In co-pending application WO-93/00878 a suitable vitreous dental coating composition is described, specifically a sol gel, xerogel or heat-consol1dated gel composition, comprising a hydrolysable silicic ester, 1-4 moles water per mole of silicon, a solvent and a filler. In a typical use of such a composition the surface of the tooth is first prepared by cleaning, then the composition is applied to the tooth surface in a thickness of a few microns, and then the composition is cured or consolidated by heat treatment. This heat treatment stage is carried out by application of appropriate radiation energy. For this latter stage, it is important to safely deliver the correct amount of energy to the correct location in a sufficiently short time, preferably below or close to the thermal relaxation time of the tooth tissue, that is, within a few microseconds.
A suitable source of radiation energy for processing thin film of the type discussed above is a CO2 laser producing pulsed or continuous wave laser light tuned to lO.δμm, since such laser light is strongly absorbed by the natural tooth. Other laser radiation sources, such as NdrYAG or argon lasers, with wavelengths in the near infra-red and visible ranges, can also be used.
The process described above has been successfully tested on extracted human teeth, but there are particular requirements associated with delivering the laser energy effectively and safely to a tooth in situ in a patient's mouth.
Lasers have been increasingly used in the medical arena with ever improving clinical results for a number of years now. The controllable, intense light beams can be used for example to cut or vaporise tissue in many aspects of specialised surgery. However, in the dental treatment process presently of interest, different problems arise due to the specific safety considerations. An effective delivery system must be capable of being accurately controlled whilst ensuring that the risks inherent in the use of lasers are reduced as far as possible. SUMMARY OF THE INVENTION
According to the invention, an apparatus is provided for delivering laser radiation to a substrate, said apparatus including: a laser radiation source delivery means to transmit the laser radiation from the source a delivery head to direct the laser radiation from the delivery means onto the substrate, having isolation means to isolate a selected target area from its surroundings by substantially preventing escape of laser radiation; and viewing means to enable an operator to view the selected target area.
The provision of suitable viewing means is important because, when the target is isolated by the delivery head of the device, viewing access for the operator would otherwise become obstructed or severely restricted. Provision of the viewing means obviates this difficulty and the operator can effectively monitor the operation of the system in use. The laser radiation source preferably comprises a C02 pulsed or continuous wave laser.
The laser radiation may be delivered by way of an articulated arm provided with laser light guiding means, such as a system of mirror elements or fibre optic means.
Preferably, the delivery head comprises focusing means and at least one optical scanner deflector, to control the delivery of laser radiation to the substrate.
To effectively fulfil the isolating function, the delivery head preferably has a body part, the isolation means comprising a shield defined by a socket projecting from the body part and having means for selectively sealing around the target area. Alternatively, the delivery head may have a tubular body, the isolation means comprising an extension piece with an end wall, the extension piece fitting onto the tubular body in sliding engagement therewith.
A number of different viewing means may be provided according to the present invention. At least one section of the delivery head may be transparent to visible light, or an optical eyepiece can be incorporated in the delivery head. Alternatively, or additionally, video monitoring means may be provided.
Additional features of the invention will be found in the more specific description and the drawings which follow. BRIEF DESCRIPTION OF THE DRAWINGS Embodiments of the invention will now be described, solely by way of example, with reference to the accompanying drawings, in which:-
Figure 1 shows the main components of a laser radiation delivery apparatus according to the invention; Figure 2 diagrammatically illustrates one embodiment of the delivery head of the apparatus of Figure 1 used to direct laser light onto the surface of a tooth;
Figure 3 shows an adapted version of the delivery head of Figure 2; Figure 4 shows another embodiment of the delivery head; Figure 5 diagrammatical ly i 1lustrates "the process of -scanning the surface of a tooth with the apparatus of the invention; and
Figure 6 is a block diagram representing the various operational components of the apparatus, and the connections therebetween.
SPECIFIC DESCRIPTION OF THE INVENTION
Figure 1 shows a laser energy delivery apparatus used to supply laser light to a tooth coating to be treated and comprising a laser light source 1, an articulated arm 2, a laser light delivery head 3 at the end of the articulated arm, and a control system 4. The arrangement of the delivery head 3 on the articulated arm 2 is similar to that of a standard dental handpiece. Laser Light Source The laser light source 1 contains a sealed, RF-excited C02 laser producing pulsed or continuous wave laser light at a wavelength of 10.6μm. Other wavelengths and types of laser source are possible, such as a Nd:YAG laser (1.064μm - near infra-red), an Er:YAG laser (2.94μm - mid infra-red), an Ho.ΥAG laser (2.1μm - mid infra-red), a CO laser (5μm - mid infra-red), or a far infra-red C02 laser (9.6μm). Alternatively a tunable C0 laser may be used to take advantage of the energy absorption of different wavelengths in the case of different materials. For laser wavelengths in the near infra-red and visible ranges, energy absorption can be enhanced by the inclusion in the tooth coating material of chromophores, such as transition metal ions. Beam Del iverv
The articulated arm 2 acts as a laser light transmission tube, and in a known manner has reflective mirrors suitably mounted at the various joints to accurately direct a laser beam to the delivery head 3, whilst allowing the arm to be manoeuvred into different positions to access a target. The beam may also be directed via fibre optic means, and although infra-red fibre optics appropriate for C02 laser wavelengths are not at present fully practicable (such wavelengths not being efficiently transmitted by standard silica-based fibres or hollow ceramic or metal waveguides), this transmission method is certainly suitable for other categories of laser light, such as that from the Nd:YAG laser. The delivery head 3 receives the laser beam and delivers it to the surface to be treated via an opening 5.
A control system 4 is used by an operator to control the functioning of the apparatus, and is therefore connected to the laser source 1, to select the duration and various other criteria for the operation of the laser beam, and to the delivery head 3 to control the scanning operation described below. The control system 4 is also provided with means for entering details such as patients' names and means for monitoring various aspects of the operation of the system. The system is microprocessor-controlled and includes a VDU screen as part of the monitoring means. Delivery Head
Figure 2 shows the delivery head 3 receiving the beam of laser light, indicated by reference numeral 10. Because of lack of uniformity of energy of a CO2 laser beam over its entire cross section, it is not practical to irradiate the whole of an extended target area simultaneously, with different parts of the target area exposed to different parts of the beam cross section. For that reason the beam is focused to a small spot (10-500μm in diameter, preferably between 50 and lOOμrn) by means of lenses 21, which are movable so as to focus the beam at the appropriate point, thereby effectively eliminating hot spots across the beam cross section and producing instead a single point heat source which can be scanned across the target area using optical scanner deflectors, operating in directions transverse to one another and controlled by way of control system 4. The combination of small spot size and controlled scanning makes uniform heat treatment of the target area possible, which is necessary for producing a consistent, flawless glassy surface. The optical scanner deflectors may be galvanometer-based optical scanners (GBOSs), which are commonly used in applications which call for accurate positioning of a laser beam. As illustrated diagrammatically in Figure 2, they may alternatively be solid-state acousto-optical crystal devices 11 and 12, in which the optical properties of a suitable crystal (e.g. Te02 or LiNb03) are locally varied by a strong acoustic wave generated at radio frequencies, so as to deflect a beam of light. Acousto-optical devices of this kind are more compact than GBOSs.
The beam focusing lenses and scanners are contained within a tubular housing 13 which is closed off by an end wall 14 and which features a side aperture 15 through which the beam can be directed by means of an angled mirror 16 mounted on a pivot 21 within the tubular housing as shown in Figure 2. Typically, the tubular housing 13 may be cylindrical, about 16cm in length, with a diameter of 1.8cm for the portion destined to be inserted into the patient's mouth.
The aperture is fitted with a joint 17 for coupling to a socket 18 which serves as a shield to isolate a tooth from its surroundings. The purpose of this shield 1s to minimise the possibility of laser radiation escaping to the surroundings during operation of the laser curing apparatus. The laser radiation used is potentially harmful and the isolation means provides protection for other parts of the patients' mouth, such as soft tissue and other teeth, nd also provides protection for the dentist or operator. In the embodiment illustrated in
Figure 2 the socket 18 is of short, flexible, approximately tubular form of a plastics material, one end being adapted to be attached to joint 17 and provided at the other end with an elastic 0-ring 19 of a flexible material, to at least partially seal the tooth with the socket. The 0-ring 19 may be inflatable to provide an air-tight seal, and alternatively or additionally the diameter of the socket may be adjustable to improve sealing.
The delivery head 3 can be manoeuvred to fit the socket 18 over the occlusal surface of a molar or premolar tooth 20 to aid in location and to stabilise the apparatus on the target and to prevent, or at least greatly reduce, the possibility of laser light reaching any other part of the patient's mouth. The socket 18 also ensures that the delivery head is maintained at an optimum distance from the tooth surface. The socket 18 is readily detachable and can be discarded and replaced after use to prevent the possibility of contamination from one patient to another. According to the invention, the delivery head or its socket 18 is equipped with viewing means. For example, the socket may be transparent to visible light, or may feature a viewing port transparent to visible light, to assist in alignment of the delivery head and to enable an operator to view a selected target area on the tooth. In the case of a C02 laser such a transparent portion may be manufactured of glass or plastics material such as perspex, to be highly absorbent of radiation at that wavelength and thereby prevent escape of laser radiation.
Alternatively, an eyepiece (not shown) may be incorporated as a lateral attachment to the tubular housing 13 to enable the operator to view the target area. This may be a rotating, angled tubular eyepiece for ease of use. A beam splitter or similar is included within the delivery head to deflect to the eyepiece a portion of the light reflected through the optical system from the target. The eyepiece is designed to prevent transmission of radiation at the wavelength of laser light used for the curing process. The delivery head 3 shown in Figure 2 is also provided with light detector means 22 and may also feature a sensor 23 and/or opto-electronic means 24, 25, which will be described further below.
In Figure 3 the same delivery head is shown but in this case it is being used to cosmeticaily or prophylactical ly treat the visible surface 120 of an incisor, where the coating is applied to the front surface of the tooth. An appropriately shaped alternative socket 118, with 0-ring seal 119, is fitted to joint 17 so as to provide a continuation of end wall 14, thereby reducing the danger of any laser light which travels past the tooth causing damage to any part of the subject's mouth. It is to be noted that mirror 16 is not required in this case and can be folded away as shown by means of hinge 21.
Clearly other interchangeable disposable sockets may be used with the delivery head, selected to suit different teeth in different patients.
Figure 4 illustrates a section of an alternative delivery head, also to be used in treating the visible surface of an incisor, which features adjustment means to accommodate in an alternative manner the particular size of tooth to be treated and thus shield the tooth effectively. The delivery head comprises an open cylindrical tube 30 on which a closely fitting tubular endpiece 31 can be fitted, the endpiece being closed by end wall 32 and having a side aperture 33 to receive the tooth. The tubular endpiece is engaged by a clamping ring 34 and rotating locking ring 35. On the inner side of endwall 32 rubber impression material 36 is mounted. The endpiece 31 can be telescoped along the tube 30 as indicated by the arrow to provide an opening that closely fits the size of the tooth. The clamping means can then be operated to lock the two parts in position relative to one another, thus fixing the size of opening for the duration of the treatment process. Tubular endpiece 31 may be of glass or another suitable transparent material. Focusing Means As explained above, to ensure the beam parameters at the tooth surface are appropriate for curing a sol-gel derived coating which has been applied to the tooth surface, it is required to focus the laser, beam relative to the surface to produce a spot with the required diameter. Since this spot is to be scanned over the - probably irregular - surface of the tooth, it may be necessary to instantaneously control the focusing during the scanning operation. If a relatively long focal length is selected then the process will be less sensitive to the exact position of the tooth surface, but some means of focus control will still be required. It is also desirable that the scanning system should be correctly aligned prior to beginning the curing process, and to this end visible laser radiation is directed along the same projected path of the C02 laser beam. An He-Ne (Helium-Neon) laser with a wavelength of 633μm, which is also contained in the source 1, is used for this purpose, providing an 'aiming beam' of visible light which is arranged, by means of a combining beam splitter (not shown), such that the aiming beam follows the same path as the curing radiation. Further reference to this arrangement is made below under the heading 'Scanning System'.
Within the delivery head 3 or the source 1 a light detector is arranged to receive light reflected from the irradiated surface. In Figure 2, for example, a sensor device of an automatic focusing unit, or another photoelectrical detection element 22 is mounted behind the mirror 16, which for this purpose is a partially reflecting mirror, such that visible light reflected from the tooth surface passing through the partially reflecting mirror is detected by the element 22. The light detector element can be used to provide a signal which is sent to the control system 4 and which can be used to indicate the presence of the tooth surface and to calculate Its distance from the light detector, this information being used to control the focusing of the C02 laser beam during the subsequent curing stage. Safety Measures It is highly desirable from the point of view of safety that the curing laser radiation is not delivered until the delivery head is correctly positioned, for example until the socket 18 in Figure 2 is correctly located.over the tooth to fully isolate it from the rest of the patient's mouth, particularly from the surrounding soft tissues.
This may be accomplished by means of the reflected He-Ne visible light detected by the light detector 22. This supplies a proximity signal', and thereby fulfils a safety function to prevent the curing laser operating unless the tooth surface is within a certain range. Alternatively, mechanical means, such as a spring-loaded mechanical contact, may be provided in association with the socket itself to determine whether it is appropriately located. A sensor such as a strain gauge 23 may be provided on the flexible socket 18 to detect deformation in the socket due to contact with the tooth, or a pressure sensor may be built into the coupling joint 17. Either sensor can furnish a signal to prevent or allow the firing of the curing laser. As a further alternative, an opto-electronic system may be used to detect the presence or absence of a tooth. An LED 24 and a photo sensor 25 may be provided on opposite sides of the inside of the socket 18, a safety signal being provided only if the path of light between the LED and the photosensor is broken by the presence of a tooth.
During use of the system, there is a danger of small amounts of vapour and debris produced by the heat treatment process entering the delivery head and reaching the optical and mechanical components within. A positive pressure is therefore preferably provided within the delivery head to reduce this risk. Additionally an aspiration system may be provided in or adjacent to the socket to remove vapours produced during the curing process. Moreover, a stream of forced air may be provided in or adjacent to the socket to assist in drying of the tooth surface during the curing operation.
Scanning System The He-Ne laser already described may be used to select the target area to be scanned. For this purpose, the reflected light from the He-Ne laser can be monitored by appropriate detection means and the precise area to be scanned at the curing stage can be automatically determined, thus ensuring that a sufficient area of the tooth surface is irradiated whilst minimising the danger that the laser may be directed at an area beyond the edges of the tooth surface to be treated, such as the patient's gum tissue.
Figure 5 illustrates this technique. The intensity of reflected light from the tooth surface is considerably greater than that from the surrounding light-absorbing gum tissue, and the distribution of reflected light intensity will therefore give an indication of the size and shape of the tooth surface. If the
He-Ne beam is scanned across an area A (larger than the area of the tooth surface) the intensity of the reflected signal can be compared with a threshold value. If the reflected light is above this value then tooth surface is present' (Rγ) and if the reflected light is below this value then gum tissue is present
(RQ). The control system 4 is set up to record the reflected light value Rj or RG as a function of the instantaneous position of the scanning light spot, and this gives the shape and size of the tooth surface. This may then be de-magnified automatically to define a reduced area, shown in Figure 5 as shaded area S within the dotted line, which is then scanned by the gel-curing laser beam. A scanning field smaller than the entire tooth surface is selected as, for safety reasons, it may not be desirable that the whole surface, right out to its very periphery, should be scanned by this more powerful laser beam.
As an alternative, once the tooth shape has been determined, the operator may select a predetermined shape from a repertoire of geometrical shapes stored by the control system 4, as being suitable for the tooth in question and fitting within the boundaries of the tooth as determined by the He-Ne scan. This shape may then be used to determine the actual area which is irradiated by the C02 laser. With this system the operator is able to view the tooth, by means of a viewing means including a display generated by means of the He-Ne scan. Alternatively charged-coupled devices (CCDs) can be built into the delivery head to provide means of visual inspection of the tooth and the proposed target area before the curing is carried out. Using the control system 4 the operator can select the area to be scanned and the scanning pattern to be used, either by freehand control or by the techniques discussed above. Identification of Consolidation
It is desirable that the operator is able to check whether the coating has been fully cured by the laser treatment. A detector may be provided in the delivery head to monitor the surface emissivity from the tooth, this giving a measure of the temperature attained at the surface and hence an indication of the degree of consolidation. For this purpose an infra-red diode, or an array of such diodes, may be mounted in the head to measure the temperature or the distribution of temperature across the target zone. For adequate curing of sol-gel derived coatings a temperature of 200°C-800°C is needed in a total curing period of the order of 0.1 s.
Alternatively a photodetection system may be used to examine the cured coating. If fluorescent chromophores (such as fluorescein) are added to the gel these will thermally decompose during the heat treatment. The tooth surface can then be interrogated by means of a light beam, for example, the He-Ne laser beam, and the fluorescence measured, giving an indication of the presence of cured coating and of the degree and uniformity of consolidation. Operation
In operation of the system, the delivery head is fitted with an appropriate socket, and the apparatus is manoeuvred to position the socket over the selected tooth after the tooth has been cleaned and the coating gel has been applied to the surface to be treated. This isolates the tooth, and hence the selected target area, from its surroundings. The tooth is then scanned with the He-Ne laser light and the size and shape of the target area is determined. Preferably, the operator selects the target area while viewing the tooth by any of the means already described. The operator then starts the aspiration means and the positive pressure means for the delivery head, if required, and the curing operation can then be initiated, the C02 laser beam only being activated when the system has detected a safety signal from the proximity signal or otherwise. The laser beam spot is then scanned across the selected target zone in a zig-zag, raster or other pattern, selected as required and to avoid hotspots, to deliver the correct amount of energy in the appropriate time to consolidate the gel coating to its glassy state. The target zone may be scanned a number of times, first at low power (less than 5w) to drive off solvents, then at a higher power (around lOw) to fully effect the curing. An appropriate high frequency tone can be used to indicate when the C02 beam is engaged. The degree and uniformity of consolidation can then be checked as described above, and any non-uniformity is corrected by further irradiation.
The block diagram of Figure 6 shows the various operational components and how they are interconnected.
As an alternative to the small spot scanning system described above, a TEA-C02 laser may be used. This is capable of producing a beam with uniform energy distribution across the area of the beam, and therefore the beam can simply be directed to a selected target area and switched on for the desired time. The delivery of the beam would not therefore require focusing means, the irradiated area being up to, say, 1cm in diameter. Masking could be used to protect surrounding areas and prevent their being irradiated.

Claims

1. Apparatus for delivering laser radiation to a substrate, said apparatus comprising a laser radiation source; delivery means to transmit the laser radiation from the source; a delivery head to direct the laser radiation from the delivery means onto the substrate, having isolation means to isolate a selected target area from its surroundings by substantially preventing escape of laser radiation; and viewing means to enable an operator to view the selected target area.
2. Apparatus according to Claim 1, in which the laser radiation source comprises a C02 pulsed or continuous wave laser.
3. Apparatus according to Claim 1 or Claim 2, in which the delivery means comprises an articulated arm provided with laser 1 ight guiding means.
4. Apparatus according to any preceding claim, in which the delivery head comprises focusing means and at least one optical scanner deflector.
5. Apparatus according to any preceding claim, in which the delivery head has a body part and the isolation means comprises a shield defined by a socket projecting from the body part, having means for selectively sealing the socket around the target area.
6. Apparatus according to Claim 5 in which the sealing means is inflatable and capable of providing a substantially air-tight seal .
7. Apparatus according to Claim 5 or 6, in which the socket is detachably connected to the delivery head.
8. Apparatus according to any one of Claims 1-4, in which the delivery head has a tubular body and the isolation means comprises a sliding extension piece with an end wall, the extension piece fitting onto the tubular body in sliding engagement therewith.
9. Apparatus according to any preceding claims in which the viewing means comprises at least one section of the delivery head transparent to visible light.
10. Apparatus according to any one of claims 1-8, in which the viewing means comprises video monitoring means.
11. Apparatus according to any preceding claim, including a He-Ne laser radiation source for use in focusing and/or monitoring of the position of the laser beam.
12. Apparatus according to Claim 11 in which the He-Ne laser is associated with means to provide a visual display of the substrate target area.
13. Apparatus according to any preceding claim in which the delivery head is provided with a means for indicating the proximity of the substrate.
14. Apparatus according to any preceding claim in which gas transfer means is provided in connection with the delivery head for aspirating the delivery head and/or providing a positive gas pressure thereto.
15. Apparatus according to any preceding claim in which a safety device is associated with the delivery head to prevent operation of the laser in the absence of a received signal indicating correct positioning of the delivery head with respect to the substrate.
16. Apparatus according to any preceding claim for use in heat treatment of a curable composition applied to a tooth surface.
17. Apparatus according to Claim 16 including means for identifying the degree of consolidation of the composition.
18. Apparatus according to any preceding claim in combination with a control system to control and monitor the operation of the apparatus.
19. A method for delivering laser radiation to a substrate to which a curable composition has been applied, comprising use of the apparatus of any preceding claim.
UK 05/94
PCT/GB1994/000976 1993-05-07 1994-05-06 Apparatus and method for delivering laser radiation to a substrate WO1994026203A1 (en)

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US08/532,719 US5738678A (en) 1993-05-07 1994-05-06 Apparatus and method for delivering laser radiation to a substrate
EP94914473A EP0696905B1 (en) 1993-05-07 1994-05-06 Apparatus for delivering laser radiation to a substrate
JP6525120A JPH08509884A (en) 1993-05-07 1994-05-06 Device and method for delivering laser radiation to a substrate
DE69404297T DE69404297T2 (en) 1993-05-07 1994-05-06 DEVICE FOR DELIVERING LASER RADIATION TO SUBSTRATES

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US5738678A (en) 1998-04-14
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GB9309397D0 (en) 1993-06-23
IL109594A (en) 1996-10-31
DE69404297D1 (en) 1997-08-21
EP0696905B1 (en) 1997-07-16
DE69404297T2 (en) 1997-10-30
EP0696905A1 (en) 1996-02-21
IL109594A0 (en) 1994-08-26
JPH08509884A (en) 1996-10-22
GB9408998D0 (en) 1994-06-22

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