GB1577645A - Apparatus for introducing a predetermined volume of enzyme solution into the lens of an eye - Google Patents

Description

(54) APPPARATUS FOR INTRODUCING A PREDETERMINED VOLUME OF ENZYME SOLUTION INTO THE LENS OF AN EYE (71) We, Novo LABORATORIES, 1NC.

of 59 Danbury Road, Wilton, Connecticut 06897, United States of America, a company organised under the laws of Connecticut, one of the United States of America, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: This invention relates to an apparatus for introducing a predetermined volume of enzyme solution into the lens of an eye.

The lens is an optically clear encapsulated disc-like structure which is suspended within the eye, behind the iris and in front of the vitreous. It supplies part of the optical refracting power of the eye. The lens becomes cataractrous when its nuclear and/or cortical and/or subcapsular regions become opaque, thus blocking the path of light entering the eye, thereby causing diminished vision. A cataract is simply a lens that has become cloudy.

There are, generally speaking, two types of cataracts, congenital and senile. Congenital cataracts, approximately 1% of all cases, are found in people under the age of 25 and characteristically are relatively soft. Senile cataracts, approximately 99% of all cases, are found in older people and characteristically are relatively hard.

The intracapsular technique of cataract surgery developed in the 1930's calls for making a large incision, 25 mm, approximately 1800 around the cornea for an entry into the anterior chamber of the eye. After breaking the suspensory ligaments which suspend the lens within the eye, the lens is removed by mechanical means such as forceps or suction. Removal of the lens may be facilitated by the use of alpha chymotrypsin to dissolve the ligaments that attach the lens to the ciliary body (the zonules).

Another method of surgery currently practiced is applicable only to congenital cataracts. If the cataract is extremely soft and liquid, the surgeon enters the anterior chamber of the eye through a small incision, then breaks the lens capsule and aspirates the contents thereof out using a thin needle and a normal syringe. If the lens contact is a little too hard to be aspirated in this manner, the surgeon makes several incisions in the anterior capsule and allows the aqueous humour of the anterior chamber to attack and soften the cataract. After several days the lens becomes soft enough to allow the above mentioned aspiration technique to be employed. This procedure works only for soft congenital cataracts and is not effective for hard senile cataracts.

Also, the surgeon cannot cut open a senile cataract and then wait (a long period) for the natural enzymes to work since the eye soon becomes severely inflamed due to the reaction of the lens material with the vascularized areas of the eye.

It has now been discovered that senile cataracts can be treated by introducing into a cataractous lens a solution of an exogenous lens digesting enzyme dissolved in a liquid carrier so as to soften the lens sufficiently to allow its removal by aspiration and irrigation techniques.

The object of this invention is to provide an apparatus for introducing such an enzyme solution into the lens of an eye and to seal the opening formed to block the egress of enzyme solution from the lens.

This invention provides an apparatus which comprises a) a liquid dispenser connectible to a reservoir of enzyme solution, b) a source of gas, c) a multiport valve comprising at least four ports and d) a cannula, said liquid dispenser, gas source and cannula being each connected to a different valve port, the fourth valve port being an exhaust port, said valve having therein two reversible channels each connectible to two of said ports with the gas source port connecting to the exhaust port and the liquid dispenser port connecting to the cannula port, the combined volume within said cannula and the valve port connected to the cannula corresponding to a single dosage volume of enzyme solution to be introduced into the lens and the volume of each valve channel being greater than the single dosage volume of enzyme solution to be introduced.

When using the apparatus of the invention the liquid dispenser is activated so as to pass enzyme solution from the reservoir through one channel in the valve into the cannula. Simultaneously gas is passed from the gas source through the second channel of said valve to the exhaust port. Then the valve is reversed so as to interpose the gas containing second channel in line between the liquid dispenser and the cannula. The gas trapped in said second channel then becomes a gaseous separator limiting continuous enzyme solution flow out of the channel to the volume already downstream of the gaseous separator. As mentioned above, this volume is adjusted to correspond to the volume of enzyme solution to be introduced into the lens.

Thus, the injection of said volume of enzyme solution into the lens is followed by injection of a gas bubble into the track of the cannula as the cannula is withdrawn from the lens and out of the eye.

During this operation the initially gas containing channel may be filled with enzyme solution so that the apparatus is ready for a new operational cycle when the gas has been driven out of the cannula.

Since the volume of each channel is greater than the volume of enzyme solution to be introduced, there will be gas enough for the desired gas bubble despite the compression that takes place as the gaseous separator is forced through the cannula into the lens. Furthermore, there will be enough gas for spacing purposes so that excess enzyme is not introduced into the lens after the deposition of the gas bubble in the track of the cannula.

If a mishap occurs during the introduction of the enzyme, e.g. rupture of the posterior capsule, the liquid dispenser may be connected with a source of enzyme inhibitor and said inhibitor may be sent through the cannula into the affected portion of the eye.

For further understanding of this invention, reference is now made to the attached drawing, wherein: Figure 1 diagrammatically illustrates a cannula inserted in the lens of an eye; Figure 2 is a cross-section taken along line 2-2 of Figure 1; Figure 3 is an enlarged diagrammatic cross-section of the human lens capsule and its contents; and Figure 4 is a diagrammatic illustration of a preferred embodiment of an apparatus of the invention for supplying enzyme solution and then a gas bubble to the lens.

Referring now to Figure 3, it may be seen how the lens 10 is divided up into capsule 12, epithelium 14 and lens substance 16 which consists of lens fiber. The lens substance can be further described as made up of the cortex 18, the cortex being a layer of soft, young superficial fibers which lie directly beneath the capsule 12, and the nucleus, the nucleus 20 being the hard, closely packed cells at the center of the lens. Extending into lens 10 at the sides thereof are the zonules 22, the zonules being the suspensatory ligaments which retain the lens in place inside the eye.

Any exogenous material inserted into the lens can be physically compartmentalized within the lens substance 16 by the lens capsule 12, provided the material does not act to destroy or rupture the lens capsule.

If the opening made for insertion of the material is sealed, such material can be made to remain within the lens capsule 12 for an extended period of time. It is significant that lens capsule 12 has a biochemical composition which is substantially different from that of cortex 18 and nucleus 20 of the main lens substance. Exogenous enzymes that are capable of selectively digesting me tissue of nucleus and cortex yet leave lens capsule 12 whole exist.

Parenthetically, it may be noted that the macromolecular character of enzymes keeps them from permeating rapidly, if at all, through the reticular structure of the capsular membrane. Accordingly, selective enzymes introduced into the cortex and nucleous will become trapped therein, and over a period of time are capable of enzymatically degrading the senile lens substance.

The treatment of cataract by using an enzyme solution involves making a puncture 24 at the sclera or at the scleral-corneal juncture 26 large enough for a needle, as is illustrated in Figure 1, followed by introduction of a concentrated solution of exogenous enzymes. Then sufficient time is allowed for enzymtic digestion of the lens.

Subsequently, the liquefied lens is removed by conventional aspiration and irrigation techniques, employing for example the techniques described in the medical literature for removing congenital or soft cataracts.

As can be seen in Figure 3, nucleus 20 and cortex 18 which completely fill the lens capsule, are layered (somewhat like an onion) so that any enzyme containing liquid forced into the lens substance 16 permeates the entire lens largely along the layer lines.

Thus, the layered structure places virtually all of the cells in the nucleus and cortex into immediate contact with the enzymes in the liquid. A normal senile cataract will accommodate up to 20 microliters of liquid without increasing the intraocular pressure to a level where rupture of the capsule 12 occurs. Accordingly, introduction of a concentrated solution of exogenous enzymes directly into the lens focuses an enzymatic action exclusively upon cortical, nuclear and subcapsular cataractous material in VINO.

Degrading the cataract in situ, as is herein contemplated, imposes requirements for high levels of enzymatic unit activity and of selectivity. Fortuitously, highly selective enzymes exist. With high purity forms of enzymes, such as for example crystalline enzymes, concentrated (aqueous) solutions of mixed enzymes can be formulated, for example 10% wt/wt solutions.

Accordingly, the above-described 20 microliter limit allows introduction of as much as 2 mg of pure enzyme into the lens substance. Since a normal lens will weigh about 200 mg, the enzyme to substrate ratio of about 1:100, readily obtainable, constitutes a high enzyme: substrate ratio, particularly since the layered nature of the lens places virtually all of the lens cells into essentially direct contact with the enzyme solution.

The exogenous enzyme will become deactivated within a few days; and by then, the (softened or liquefied) cataractous lens is ripe for removal.

As can be seen from Figures 1 and 2, the lens degrading solution is delivered by a microcannula 30 attached to a suitable microliter four port valve 32 from a scleral or scleral-corneal juncture puncture directly into nucleus 20, introducing for example 15 microliters of a 5% wt/wt enzyme solution.

The outside diameter of the microcannula, for example, may be approximately 200 microns or as small as structural strength considerations permit. (The tip may be electronically tapered). Large diameter cannulas tend to rent and/or rip the lens capsule during penetration thereof, and substantially smaller diameter cannulas do not possess sufficient rigidity to cleanly penetrate into the lens substance. Use of a tracked micromanipulator to reduce lateral motion of the cannula upon entering the lens is recommended but is not considered essential. With the tid of an operating microscope, a 200 micron microcannula can be adequately inserted into the center of the lens manually. (Complete restriction of lateral motion by the cannula once positioned in the lens is essential, however, for maintaining a good gas bubble seal within the needle track as will be discussed below).

As has already been pointed out, the enzyme containing solution injected into the lens by a manual or pneumatic driven syringe system is an amount of fluid which can be accommodated by an average human lens, i.e. not more than about 20 microliters, and, e.g., only 6 microliters. The distribution pattern of the injected fluid may be observed by incorporating a soluble, inert dye such as dichloroindophenol or a fluorescent dye such as fluorescein into the injection fluid.

Injection of the solution into the central portion of the lens is followed by injection of a tiny gas bubble into the track of the cannula as the cannula is withdrawn from the lens and out of the eye. This tiny air bubble serves to seal the small puncture site 25 in the lens capsule and, thus, to block the egress of enzyme solution from the lens until normal intralenticular pressure is restored.

The composition of the digestive mixture and the intralenticular incubation time is adjusted to achieve a high level of liquefaction or softening of the lens nuclear and cortical region. Termination of the lens liquefaction process and protection of other intraocular structures, in the event of escape of the enzymatic digestive agent from the lens capsule, can be achieved by introduction of specific enzyme inhibitors into the nucleus 20 of the eye through the same cannula.

Enzyme inhibitors may also be introduced into the anterior chamber 28 of the eye in the event of enzyme leakage thereinto, or even as a precaution against such leakage. High molecular weight (or macromolecular) inhibitors will not permeate into the lens capsule, and therefore, do not interfere with the enzymatic digestion of the lens cortex and nucleus. Low molecular weight inhibitors can diffuse through the lens capsule and may be used to terminate enzymatic digestion, both external and internal to the lens itself.

The introduction of a predetermined amount of enzyme solution and the subsequent introduction of a gas bubble to seal the opening or puncture site in the lens capsule are effected by using the apparatus illustrated in Figure 4. As will appear from Figure 4, the mechanical assembly used for injection of the enzyme into the lens consists of three principal parts: precision liquid dispensing units 50, distribution valve 32 and the microcannula 30. Each of these three components is described as follows.

The pneumatically, hydraulically, or mechanically driven precision liquid dis penser 50 may be an electronically actuated, ratchet drive microliter dispensing assembly, such devices being well known to the art and need not be discussed here. The distribution valve 32 is a miniature four-terminal port valve containing a two-channel 90" distribution plug 62 with channels 64, 66 machined to tight specification so as to prevent leakage.

Valve body 65 is correspondingly provided with four ports 67, 69, 71, 73 and is machined to fit plug 62 without leakage.

The valve 32 and the components therein fill the port 73 and cannula 30 with a predetermined fixed volume of the enzyme (e.g. 1, 3 or 5 microliters). (As a practical matter, porting plug 74 has no separate volume because cannula 30 is extended through porting plug 74).

Channels 64, 66 are of predetermined volume which, desirably, is from 2- 10 times the combined volume of port 73 and cannula 30 and may for example each be ten microliters. Thus when plug 62 is rotated to place channels 64, 66 into the position shown in Figure 4, enzyme solution drawn from reservoir 51 is pumped by dispenser 50, e.g. a metering microliter power syringe, through line 53 into channel 66, porting plug 74 and cannula 30. At the same time, filtered air or an inert gas flows from an inlet to port 67, through channel 64 and out by way of port 69. When the surgeon is ready to operate, the distribution plug 62 is then rotated through 1800 replacing the channel 66 containing a volume of enzyme solution, e.g. a 10 microliter volume, with the gas containing volume of channel 64. During delivery of enzyme solution to the lens dispenser 50 is driven forward, e.g. in one microliter pulse, gradually compressing the inline air pocket inside channel 64 until the port 73 and cannula 30 are cleared of enzyme solution.

Further activation of dispenser 50 drives air out of cannula 30 to produce the small gas bubble that seals the needle tract of the cannula.

As is readily apparent, the combined volume of enzyme solution inside port 73 and cannula 30 is intended to be the quantity of enzyme required for operating on a lens, i.e. the dosage unit. The 2-10:1 by volume ratio of gas in the valve channel 64 to the dosage unit volume provides enough gas for the desired bubble, despite the compression that occurs as the gas pocket is forced through cannula 30 into the lens and enough gas for spacing purposes so that excess enzyme is not introduced into the lens after the bubble has been discharged from the cannula.

In any event, the enzyme solution pumped into lens 10 creates for itself a pocket which frequently is shaped like an open umbrella whose stem is the cannula track. The puncture opening made by the cannula constitutes a narrow channel cap able of being sealed by the gas bubble, particularly when the cannula is partially withdrawn so that the gas is pumped directly into the cannula track. Experience (i.e. animal test studies) has indicated that the enzyme solution soon diffuses throughout the softer lens regions. Apparently, intraoccular pressures are restored rather rapidly, without even initially, sufficient pressure being generated by the enzyme solution-containing pocket to force the gas bubble out of the cannula track.

If desired, the enzyme solution dosage unit may be made smaller. The above procedure can then be repeated in a different region of the lens, for example, 2 x 3 microliter portions, instead of a 1 x 6 microliter dose. Introduction of multiple dosage units allows the surgeon to create an immediate distribution of enzyme solution throughout the lens.

If perchance a mishap occurs during the procedure, e.g., rupture of the posterior capsule, inhibitor can be introduced into the enzyme delivery system through port 67 and the plug 62 rotated appropriately to directly send the inhibitor through cannula 30 into the affected portion of the eye.

A suitable cannula is a 32 gauge stainless steel tube 8 inches long mounted in an appropriate porting plug 74 fitting which attaches to the distribution valve 32 at port 73. The outside diameter of the cannula is typically 0.009 inch and its internal holdup volume is less than 1 microliter. The most satisfactory needle point style is a short bevel 22 slant with an electronically tapered tip. Fittings available commercially are designed to have negligible dead volume and, therefore, variation in the volume of enzyme solution to be delivered is controlled by predetermining the hold-up volume of the terminal port 73 of the distribution valve 32. The entire assembly may be presterilized, conveniently, cold sterilized by chemical means, then rinsed with a sterile solution before the enzyme solution is quickly loaded into the assembly.

e.g. loading within 3 minutes. When competently handled, the assembly herein described will reproducibly deliver a selected volume of enzyme solution into the lens with virtually no leakage into the anterior chamber.

The cannula described above is suitable for all lens types which have been encountered during test studies. The rabbit lens is approximately the consistency of a normal human cataract, and no difficulty has been experienced in making direct injections in the nuclear region of this type of lens.

In the case of the cat which has an extremely dense nuclear region and in the tests on the hard human cataract, no difficulty has been observed in penetrating the nuclear region with this cannula. However, with extremely dense lens centers the enzyme is best placed in the more peripheral areas of the nucleus or softer cortical regions.

WHAT WE CLAIM IS: 1. An apparatus for introducing a predetermined volume of enzyme solution into the lens of an eye, which apparatus comprises a) a liquid dispenser connectible to a reservoir of enzyme solution, b) a source of gas, c) a multiport valve comprising at least four ports and d) a cannula, said liquid dispenser, gas source and cannula being each connected to a different valve port, the fourth valve port being an exhaust port, said valve having therein two reversible channels each connectible to two of said ports with the gas port connecting to the exhaust port and the liquid dispenser port connecting to the cannula port, the combined volume within said cannula and the valve port connected to the cannula corresponding to a single dosage volume of enzyme solution to be introduced into the lens and the volume of each valve channel being greater than the single dosage volume of enzyme solution to be introduced.

2. An apparatus according to Claim 1, wherein the ratio of the channel volume to that of the single dosage is in the range of 2-10 to 1.

3. An apparatus according to Claim 1 or 2, wherein the liquid dispenser is connectible to a source of enzyme inhibitor.

4. An apparatus according to Claim 1, 2 or 3, wherein the liquid dispenser is a microliter power syringe.

5. An apparatus according to any one of the preceding claims, wherein the cannula is a stainless steel tube having an outside diameter of about 0.009 inch.

6. An apparatus for introducing a predetermined volume of solution into the lens of an eye, substantially as hereinbefore described with reference to, and as shown in, Figure 4 of the accompanying drawings.

**WARNING** end of DESC field may overlap start of CLMS **.

Claims (6)

**WARNING** start of CLMS field may overlap end of DESC **. extremely dense nuclear region and in the tests on the hard human cataract, no difficulty has been observed in penetrating the nuclear region with this cannula. However, with extremely dense lens centers the enzyme is best placed in the more peripheral areas of the nucleus or softer cortical regions. WHAT WE CLAIM IS:

1. An apparatus for introducing a predetermined volume of enzyme solution into the lens of an eye, which apparatus comprises a) a liquid dispenser connectible to a reservoir of enzyme solution, b) a source of gas, c) a multiport valve comprising at least four ports and d) a cannula, said liquid dispenser, gas source and cannula being each connected to a different valve port, the fourth valve port being an exhaust port, said valve having therein two reversible channels each connectible to two of said ports with the gas port connecting to the exhaust port and the liquid dispenser port connecting to the cannula port, the combined volume within said cannula and the valve port connected to the cannula corresponding to a single dosage volume of enzyme solution to be introduced into the lens and the volume of each valve channel being greater than the single dosage volume of enzyme solution to be introduced.

2. An apparatus according to Claim 1, wherein the ratio of the channel volume to that of the single dosage is in the range of 2-10 to 1.

3. An apparatus according to Claim 1 or 2, wherein the liquid dispenser is connectible to a source of enzyme inhibitor.

4. An apparatus according to Claim 1, 2 or 3, wherein the liquid dispenser is a microliter power syringe.

5. An apparatus according to any one of the preceding claims, wherein the cannula is a stainless steel tube having an outside diameter of about 0.009 inch.

6. An apparatus for introducing a predetermined volume of solution into the lens of an eye, substantially as hereinbefore described with reference to, and as shown in, Figure 4 of the accompanying drawings.