REFERENCE TO RELATED APPLICATIONS This application is a continuation-in-part of PCT Application No. PCT/EP2005/000360 filed on Jan. 15, 2005 entitled: Device For Removing Epithelial Cells From A Lens Capsule Bag Of A Human Or Animal Eye and claims priority to German Patent Application No. 10 2004 021 754.8 filed on Apr. 30, 2004, the entire disclosures of which are hereby incorporated by reference.
The invention relates to a method and to a device each for preventing or reducing proliferation or migration of epithelial cells at the inside of a lens-capsule bag of a human or animal eye.
In ophthalmology a known and frequently employed surgical procedure is to replace an eye's natural lens by an artificial (synthetic) one (“intraocular lens”). During this surgical intervention the natural lens is removed from its lens capsule bag (explantation), after which an intraocular lens is inserted (implantation) into the remaining lens-capsule bag (capsula lentis). The explantation of the natural lens in practice involves destruction and extraction of the lens tissue (phacolysis), in general by phacoemulsification, during which the lens is emulsified (liquefied) by shock waves generated by means of an ultrasonic probe or a laser (photolysis) and is then removed by suction. The synthetic intraocular lens can be a prefabricated, rigid body mounted in the capsule bag by way of a supporting means (haptic device), but can also be a soft, yielding body or even be injected into the capsule bag as a free-flowing mass. When a flexible or yielding intraocular lens is used, it can accommodate—i.e., adjust its optical focal length just as the natural lens does, by way of the ciliary muscles and the zonular fibres as well as the lens-capsule bag. The use of folding NYLIB-390700.1 lenses or injectable lenses enables the surgical incision to be reduced, in practice to only 3 mm. For the intraocular lens it is customary to use polymer materials that are transparent in the visible spectrum, in particular polymethyl methacrylate (PMMA) or silicone (polysiloxane elastomer) or acrylic.
Replacement of the natural eye lenses by a synthetic intraocular lens is at present employed only to eliminate a cataract, i.e. a cloudy lens. However, other cases for application are also possible, although more rarely encountered in practice: for example, an intraocular lens can be employed to adjust or correct the optical focal length, e.g. in cases of short-sightedness (myopia) or far-sightedness (hyperopia), or after accidents or injuries to the lens in which the lens-capsule bag itself is not irreparably damaged.
The document U.S. Pat. No. 5,324,282 A discloses a surgical instrument in the form of a needle for destroying tissue, which is designed to remove cataracts in optical surgery, i.e. to remove the lens of the eye by photolysis. This known instrument comprises a tubular outer wall with a longitudinal axis and a free end, as well as an optical fibre from a laser and an aspiration channel, each of which is longitudinally oriented and passes through the interior of the needle as far as its free end. At the free end of the needle a target made of titanium (Ti) is disposed, separated by some distance from the free end of the laser fibre, the fibre and the target being adjusted with respect to one another so that the laser beam from this fibre strikes the target. At the free end of the needle is also provided a tissue-aspiration port, disposed at an angle and laterally offset, into which the aspiration channel opens and which is disposed immediately adjacent to the target and the space between the end of the laser fibre and the target. By way of a suction pump a vacuum is created in the aspiration channel, by means of which the tissue to be destroyed is sucked up to the aspiration port and fractured, after which the individual fragments of the tissue are sucked away through the aspiration channel. When the tissue is in contact with or has been sucked against the tissue-aspiration port by the low pressure, laser pulses are shot out of the laser fibre and onto the target, the energy in these pulses being sufficient to produce an optical breakdown in the target material and hence generate a shock wave that strikes the tissue at the tissue-aspiration port and tears it into small pieces, which ate then sucked away through the aspiration channel. The laser light is preferably generated with a neodymium-YAG laser and has a wavelength of 1,064 nm. The laser pulses have a pulse duration of 8 ns and a pulse repetition rate of 20 pulses per second. Hence the laser energy is 100 mJ per second and the energy of each pulse, 5 mJ. Furthermore, there can also be provided within the needle a longitudinally oriented irrigating tube to conduct flushing fluid through an outlet disposed at the side.
The document U.S. Pat. No. 5,906,411 A discloses a further development of the instrument known from U.S. Pat. No. 5,324,282 A, in which the target has a stepped structure, such that each step has two surfaces, one of which is oriented perpendicular to the needle axis and the other parallel thereto; the sequence of steps rises from an outer side, at the outside wall of the needle, towards the tissue-aspiration port. As a result, in each step zone of the target, as the target material evaporates the shock wave thus produced is not blocked by another part of the target in the direction towards the aspiration port. With a neodymium-YAG laser pulses can be produced with repetition rates between 2 and 50 pulses per second and pulse energies between 2 and 15 mJ. The pulse duration can be set between 8 and 12 ns. Preferably the pulse repetition rate is set at between 2 and 6 pulses per second and the pulse energy, between 6 and 10 mJ. For a cataract operation between 200 and 800 pulses or shots are used.
A laser hand piece constructed like those in U.S. Pat. No. 5,324,282 A and U.S. Pat. No. 5,906,611 A, together with a digital control and supply device that comprises a laser for the laser pulses as well as a venturi pump for aspirating the tissue parts, has for years been successfully marketed by the firm of A.R.C. Laser GmbH and was successfully employed in a large number of operations. Here aspiration occurs by way of the laser hand piece and irrigation with an electrolytic flushing solution (BSS) is done by way of a second instrument, in a bimanual technique. The product is sold under the name “Lyla/Pharo”. For the actual eye operation employing this known device, various surgical techniques are used.
One problem with surgical explantation or phacolysis of the natural eye lens and the subsequent implantation of an artificial intraocular lens is the subsequent growth and proliferation of the epithelial cells that constitute the epithelium covering the inner surface of the lens-capsule bag. During this postoperative complication the newly formed epithelial cells migrate around the inserted artificial lens or even into it, eventually obscuring vision through the lens. This phenomenon is referred to as posterior capsule opacification (PCO), and when it follows a cataract operation it is also called a secondary cataract.
To alleviate this problem of postoperative proliferation of the epithelial cells in the capsule bag, various solutions have been suggested and employed. These can be subdivided as follows:
1. The removal of epithelial cells from the inner surface of the capsule bag during or after explantation of the eye lens and before implantation of the intraocular lens;
2. Preventing growth of the epithelial cells of the lens-capsule bag after implantation of the intraocular lens; and
3. Producing a hole or tear in the capsule bag by means of a laser, as a result of which the tissue of cells forming the epithelium is likewise torn apart (photodisruption, capsulotomy).
As another possibility it would be conceivable to remove the entire capsule bag together with the lens and to replace it by an implant, which suspends the lens from the ciliary muscles and enables accommodation of the lens. However, at present no such implants exist in practice.
The removal of the epithelial cells is undertaken either by taking them away with a surgical instrument, such as a needle, or else chemically by applying substances toxic to cells or biochemically by antibodies.
So that after implantation of an intraocular lens the growth of remaining epithelial cells of the lens-capsule bag over the intraocular lens can be prevented or at least minimized, various measures are known, for example the use of special intraocular lenses, the surfaces of which are provided with structures such as pits or projections over which the epithelial cells cannot very easily grow, or are coated with growth-inhibiting cytotoxic substances; alternatively, growth-inhibiting cytotoxic substances can be implanted in the capsule bag itself, or an implant with photoactivatable immobilising substances can be inserted, as proposed in DE 199 55 836 C1. In the case of the ophthalmological implant according to DE 199 55 836 C1 the pharmaceutical cytotoxic agent is released by photoactivation at a later time following the operation, at the earliest after the wound has completely healed, so as to kill off the epithelial cells on the lens and prevent the growth of new epithelial cells there. The chemical or biochemical removal of lens epithelial cells and prevention of their proliferation is described in EP 0 372 071 B1. The chemical removal of lens epithelial cells is furthermore described in Patent Abstracts of Japan 04352719 A.
A good survey of the known methods and devices for removing epithelial cells from the lens-capsule bag or of methods and substances to prevent growth of the epithelial cells can be found in the printed documents DE 199 55 836 C1 and EP 0 372 071 B1.
A fundamental problem associated with the known methods and apparatus for removing the epithelial cells by means of or during a surgical intervention resides in the fact that in no case have the epithelial cells been completely removed, in particular because certain places, e.g. along the equator and immediately behind the iris, are not readily accessible to the surgeon and because the chemical agents that are used ought not to be too aggressive on account of the danger of also damaging the capsule bag and adjacent eye regions, as well as the problem that wound healing may be impaired. However, if epithelial cells remain in the lens capsule, the risk of proliferation is always present.
It is the objective of the present invention to disclose a new method and a new device for preventing or reducing proliferation or migration of epithelial cells at the inside of a lens-capsule bag of a human or animal eye, in which the above-mentioned disadvantages in the state of the art are at least partially alleviated or entirely avoided.
This objective is achieved in accordance with the invention by the features given in claim1 and claim12 respectively.
The invention is based on the consideration that for the detaching (or: removing, carrying away, detaching, separating, forcing off) of the epithelial cells from the inner wall of the lens-capsule bag pressure pulses in a fluid medium (a liquid) should be used, by filling the lens-capsule bag at least partly, but definitely in the region of the epithelial cells that are to be removed, with said liquid.
The invention is based on the further consideration that in order to prevent proliferation or migration of the epithelial cells at the eye's lens-capsule bag it is also possible to inhibit the cells by means of pressure pulses in the fluid medium while they remain at the wall of the lens-capsule. Inhibiting the epithelial cells means that the epithelial cells are affected or damaged by the pressure pulses to such an extent that they cannot grow or multiply any more or that, in other words, the epithelial cells become pignotic or inactive. Inhibited cells remaining at the lens-capsule bag may in some cases even form a barrier for other epithelial cells.
Both processes, detaching as well as inhibiting of the epithelial cells, can be used alone or also in combination, for instance at different regions of the lens-capsule bag.
In both processes, detachment and inhibiting of the epithelial cells, the pressures and/or the energy and the impulse transmitted by or through the medium are adjusted regarding their time course in such a way that although the epithelial tissue and its epithelial cells are separated (or: carried away, detached, removed) from the wall of the capsule bag, the capsule bag is not otherwise damaged; in particular, the wall of the capsule bag remains intact and no hole or tear is produced in the wall of the capsule bag by the fluid medium impacting against it.
Here a pressure pulse should be understood to be a temporally delimited pressure elevation, in particular a pressure current or pressure wave or shock wave, which spreads out within the fluid medium as far as the epithelial cells. In this process, in addition to energy transport and impulse transport, as in the case of a wave, material transport can also occur as in the case of a current or a pressure jet.
A method for preventing or reducing proliferation or migration of epithelial cells (or: epithelial tissue) at the inside (or: the inwardly directed surface) of a lens-capsule bag of a human or animal eye according to the invention comprises the steps of
a) generating pressure pulses in a fluid medium within the lens-capsule bag, such that the fluid medium is adjacent to or covers the epithelial cells, which pressure pulses impact on the epithelial cells,
b) detaching epithelial cells from the wall of the lens-capsule bag and/or inhibiting epithelial cells which remain at the wall of the lens-capsule bag by the impacting pressure pulses, so that the detached or inhibited epithelial cells are prevented from proliferating or migrating at the inside of the lens-capsule bag,
c) wherein the pressure pulses are so formed or selected that, during detaching or inhibiting of the epithelial cells, no hole or comparable damage is produced in the wall of the lens-capsule bag by the pressure pulses.
A device or apparatus for preventing or reducing of proliferation or migration of epithelial cells at the inside of a lens-capsule bag of a human or animal eye according to the invention comprises
a) means for generating pressure pulses in a fluid medium within the lens-capsule bag, such that the fluid medium is adjacent to or covers the epithelial cells,
b) wherein the pressure pulses are so formed or selected,
b1) that epithelial cells can be or are detached from the wall of the lens-capsule bag by the impacting pressure pulses and/or that epithelial cells which remain at the wall of the lens-capsule bag can be or are inhibited by the impacting pressure pulses, and, at the same time,
b2) no hole or comparable damage is produced in the wall of the lens-capsule bag by the pressure pulses.
Furthermore, according to the invention, an apparatus for removing epithelial cells (or: epithelial tissue) from the inside (or: the inwardly directed surface) of a lens-capsule bag of a human or animal eye, comprises
a) means for generating pressure pulses in a fluid medium within the lens-capsule bag, such that the fluid medium is adjacent to or covers the epithelial cells that are to be removed,
b) wherein the pressure pulses are so formed or selected that
b1) the epithelial cells can be or are detached from the wall of the lens-capsule bag by the impacting pressure pulses, and at the same time
b2) during removal of the epithelial cells no hole or comparable damage is produced in the wall of the lens-capsule bag, in particular by the pressure pulses.
The method and the device according to the invention are preferably used during or after a cataract operation at the eye and significantly reduce the risk of a secondary cataract or PCO.
Advantageous designs and further developments of the device in accordance with the invention will be apparent from the claims dependent on claim1.
In the following the invention is explained further with reference to exemplary embodiments.
A cataract operation as a rule comprises the following procedural steps:
First a surgical instrument, for instance a cannula, is used to open the front of the capsule bag, as a rule producing an opening that measures 4.5 to 5.5 mm (a process sometimes called “capsulorrhexis”). Afterwards, two incisions are made in the cornea, as a rule on opposite sides, in particular at the limbus, for a photolytic laser hand piece on one side and an irrigation hand piece on the other.
By introducing a flushing fluid, e.g. BSS, the lens of the eye is detached from the capsule bag and hence mobilised (hydrodisection). By means of the irrigation instrument a flushing fluid, in general likewise BSS, is filled into the capsule bag and builds up a pressure that in particular prevents the back wall of the capsule bag from coming too close to the laser hand piece, while simultaneously cleaning the capsule bag. By means of the laser hand piece, which for example can be a laser hand piece from the firm of A.R.C. Laser GmbH as mentioned above or can be constructed according to the documents U.S. Pat. No. 5,324,282 A or U.S. Pat. No. 5,906,611 A cited above, the lens of the eye is successively broken down photolytically by laser pulses striking a target and thereby producing shock waves, and sucked away. In this procedure the eye lens, in particular its nucleus, which is treated at the end of the procedure, can be moved by means of the irrigation tool so as to optimise its position relative to the laser hand piece. By means of a plurality of laser pulses and the shock waves thereby triggered, the tissue of the lens is broken clown piece by piece and the individual tissue fragments can be sucked away through the laser hand piece by means of the pump. Subsequently, after the natural eye lens has been completely removed, an artificial lens is inserted into the capsule bag. The surgeon works with both instruments, one in each hand (bimanual technique).
According to the invention, either before the artificial lens has been inserted or preferably after insertion of the artificial lens, which then closes off the opening in the front part of the capsule bag that was produced by the capsulorrhexis, epithelial cells are cleaned out of the inside of the capsule bag by removal from the wall of the lens-capsule bag by means of pressure pulses and preferably flushing off with the flushing liquid such as BSS.
For this purpose, in one embodiment a modified photolysis device from A.R.C. GmbH can be used to produce the pressure pulse for detaching or removing or forcing away the epithelial cells. In this case the same laser hand piece can be used as was used for explantation of the eye lens. However, no low pressure is produced in the aspiration channel, i.e. the pump is not connected to the laser hand piece. This measure serves to adapt the properties of the laser apparatus, so that instead of being directed towards destruction of the lens tissue they are made suitable for the more sensitive situation of removing epithelial cells from the capsule bag. In particular, it is necessary to prevent the device and the introduction of pressure pulses into the capsule bag from damaging the wall of the capsule bag.
That is, the wall of the capsule bag is relatively thin. As a result, after the natural eye lens has been removed, the lens-capsule bag cannot retain its shape, so that even after the flushing fluid has been introduced the capsule bag may nevertheless collapse at least partially, so that there is a risk of damage by the laser hand piece (instrument) used to remove the epithelial cells. However, it has been found that the relatively strong shock waves or pressure pulses generated by the A.R.C. laser hand piece are as a rule harmless to the capsule-bag wall when the tension in the latter is sufficiently reduced, so that it can yield to the pressure by changing its shape. Therefore the capsule wall should be prevented from being under tension, or to a certain extent stiff, when it is struck by the shock wave for removing or forcing away the epithelial cells. Accordingly, a considerable danger would arise if the aspiration function of the laser apparatus were turned on or left activated and the capsule-bag wall were pulled against the opening of the hand piece and then, while it is in this state, the shock were to impact against the capsule-bag wall. Furthermore, even on account of the low pressure used for aspiration the capsule-bag wall could be sucked in so as to produce a tear or an opening in it. In order to avoid any complications, irrigation is provided through the laser hand piece.
In general the pulse repetition rate for the laser pulses, i.e. the number of laser pulses applied per unit time, for instance per second, is kept so low that after a laser pulse and the shock wave thereby produced have occurred, the capsule-bag wall can swing and move back into a relaxed state before the next laser pulse and associated shock wave, so that when the next laser pulse arrives it is not still in the deformed position in which it is under (maximal) tension and hence susceptible to tearing. That is, the capsule bag should, so to speak, be able to oscillate along with the repeated pressure pulses.
In initial experiments employing the modified A.R.C. laser device, i.e. without use of an aspiration means, it proved possible with the Nd-YAG laser present in the device, with laser light at the wavelength 1,064 nm, to remove lens epithelial cells such as are present in the capsule bag completely from substrates to which they had been applied, e.g. plastic substrates or millipore substrates for cultures.
A shock wave generated by a single laser pulse with pulse energy 7 mJ caused epithelial cells to be removed in a region having the following areas, given the following distances between the cells and the tip of the laser hand piece.
|
|
| Distance: | |
| epithelial cells to laser tip | Area from which epithelial cells removed |
|
| 1 mm | 6.3 mm2 |
| 1.5 mm | 5.9 mm2 |
| 2 mm | 7.2 mm2 |
| 2.5 mm | 6.2 mm2 |
| 3 mm | 5.3 mm2 |
| 4 mm | 4.3 mm2 |
| with an angle of incidence equal to 45°, and |
| 1 mm | 7.6 mm2 |
| 1.5 mm | 6.7 mm2 |
| 2 mm | 7.5 mm2 |
| 2.5 mm | 6.8 mm2 |
| 3 mm | 7.0 mm2 |
| 4 mm | 1.3 mm2 |
| with an angle of incidence equal to 90°. |
|
Therefore in the first measurement series the cleared area obtained with a distance of 1 mm was almost approximately 6.5 mm2, whereas with the larger distance of 4 mm the area in which the epithelial cells were removed was reduced by about 20 percent.
When the laser pulse energy was raised to 10 mJ, the following measured values were obtained:
|
|
| Distance: | |
| epithelial cells to laser tip | Area from which epithelial cells removed |
|
| 1 mm | 10.7 mm2 |
| 1.5 mm | 12.1 mm2 |
| 2 mm | 10.3 mm2 |
| 2.5 mm | 7.5 mm2 |
| 3 mm | 9.6 mm2 |
| 4 mm | 7.9 mm2 |
| with an angle of incidence equal to 45°, and |
| 1 mm | 7.0 mm2 |
| 1.5 mm | 6.0 mm2 |
| 2 mm | 5.7 mm2 |
| 2.5 mm | 7.1 mm2 |
| 3 mm | 7.0 mm2 |
| 4 mm | 5.5 mm2 |
| with an angle of incidence equal to 90°. |
|
When the pulse energy was 10 mJ the ablation region, in which the epithelial cells were completely removed, was about 11 mm2for a distance between cells and laser-hand piece tip of 1 mm. For a distance of 4 mm from laser-hand piece tip to the cells, the area in which epithelial cells were removed was reduced by about 60 percent.
Even if measurement errors (standard deviations) are taken into account, a dependence of area on distance can be inferred that is not necessarily such that a decrease in the ablation area is the consequence of increasing distance and hence reduced pressure of the pressure wave. In each case there is at least one local maximum, for example in the region of a distance of 1.5 mm to 2 mm. Furthermore, a dependence on pulse energy and angle of incidence can be discerned, such that a higher pulse energy need not necessarily lead to a larger ablation area.
The measured pressure of the pressure pulses decreased with distance from the laser tip, as expected, and was for example between 190 bar at 1 mm distance and 20 bar at 4 mm distance (for 12 mJ laser-pulse energy).
At both levels of pulse energy (7 mJ and 10 mJ) the removal of the cells from the substrate surface was complete, and the ablation zone had sharp edges. Similar results were obtained with cell-culture substrates having flexible membranes with biomechanical properties resembling those of the capsule bag.
It was also found out that even when the pulse energy was reduced to 5 mJ or less down to 1 mJ per laser pulse there still a considerable reduction of proliferation and migration of epithelial cells and thus a significantly reduced risk of secondary cataract although at least a portion of the epithelial cells remained at the lens-capsule bag. The remaining epithelial cells, although they looked intact under the microscope, were not able to grow, multiply or migrate any more and seemed to become pignotic or inactive, in some cases even forming a barrier for other or new epithelial cells which barrier could not be overcome.
Although these initial experiments were carried out with a modified version of the existing A.R.C. laser system, which is actually intended to be used for another purpose, and even with these experiments an extremely promising removal of epithelial cells was achieved, it would nevertheless be more advantageous to use improved instruments, specialized for the removal of epithelial cells.
For instance, it would of course be possible to employ other laser types such as gas lasers or solid lasers of every kind as well or in addition, in particular if the shock waves are still produced by laser pulses that strike a target but also with another kind of pulse generation; however, it is also conceivable to construct the instrument so that it is flexible and hence can be brought close enough to otherwise inaccessible sites that are difficult to reach by way of the opening in the front of the capsule bag. For example, the tip of the laser hand piece along with the target and the optical fibre for transmitting the laser pulses to the target could be integrated into an endoscope that is flexible, with which in addition an optical imaging is possible so that the treated sites in the lens-capsule bag can be visually monitored.
Furthermore, other instruments and devices for generating pressure pulses in the liquid within the capsule bag can also be used to detach the epithelial cells, for instance piezoelectric, in particular piezoceramic, devices or those that operate by spark discharge in the medium, or also generators of pressure shock waves or pressure pulses that comprise membranes driven electromagnetically or inductively, e.g. by way of a coil. The pressure-pulse generators can be disposed in the region of the instrument that is inserted into the capsule bag, or else outside of the capsule bag in a separate unit that is connected to the instrument by way of a transmission line.
For transmitting the laser pulses, electrical driving signals or the pressure pulses themselves, the instrument is connected to a supply and driving unit by way of a tube or a cable through which the transmission lines pass. In this case the instrument and the tube are discarded after an operation, i.e. they are single-use products.
The repetition rate of the pressure pulses in the device is in particular limited, preferably already in the operating unit, to maximally 10 Hz, i.e. 10 pulses per second, in particular to at most 4 Hz. In principle, however, higher frequencies are also possible. No low-frequency limitation is required, and pulse repetition rates can be set to 1 Hz or below. The pressure pulses can be shock waves or pressure waves or also pressure currents or jets that are associated with the transport of material.
The frequency spectrum of the pressure wave prior to the generation of a shock wave by nonlinear effects can vary from the region of a few Hz into the region of 100 kHz, so that in addition to sonic oscillations in the audible range, ultrasonic waves or oscillations arc possible. In the case of ultrasonic shock waves, in particular the means of producing ultrasonic shock waves that are known in the area of lithotripsy and other fields can be adapted to the requirements present here.
It is likewise conceivable, in particular in the case of low pulse or pressure energies and/or when the distances from the epithelial cells are small, to employ ultrasonic oscillators or platelets that operate at higher frequencies, namely ultrasonic frequencies, in order to clean or “polish” the inside of the capsule bag.
The energy or intensity of the pressure pulses for removal of epithelial cells from the lens-capsule bag is in general selected higher than for inhibiting the epithelial cells remaining at the lens-capsule bag, for instance at least 50 percent higher.