PRESSURE SENSORS

INCORPORATION BY REFERENCE

[0001] All publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

BACKGROUND

[0002] Intraocular lenses (“IOLs”) are typically permanent, plastic lenses that are surgically implanted inside of the eyeball to replace or supplement the eye's natural crystalline lens. They have been used in the United States since the late l960s to restore vision to cataract patients, and more recently are being used in several types of refractive eye surgery.

[0003] The natural crystalline lens is a critical component of the complex optical system of the eye. The crystalline lens provides about 17 diopters of the total 60 diopters of the refractive power of a healthy human eye. Most intraocular lenses used in cataract surgery may be folded and inserted through the same tiny opening that was used to remove the natural crystalline lens. Once in the eye, the lens may unfold to its full size. The opening in the eye may be as small as 2.5 mm in length, so that it heals itself quickly without stitches. The intraocular lenses may be made of inert materials or they may have a biocompatible coating that does not trigger rejection responses by the body.

[0004] In most cases, IOLs are permanent. They rarely need replacement, except in the instances where the measurements of the eye prior to surgery have not accurately determined the required focusing power of the IOL. Also, the surgery itself may change the optical characteristics of the eye. In most cases, the intraocular lenses implanted during cataract surgery are monofocal lenses, and the optical power of the IOL is selected such that the power of the eye is set for distance vision. Therefore, in most cases the patient will still require reading glasses after surgery lntraocular lens implants may be static multifocal lenses, which attempt to function more like the eye's natural lens by providing clear vision at a distance and reasonable focus for a range of near distances, for patients with presbyopia.

[0005] Recently, IOLs have been implanted in canines, mainly household pet dogs, after cataract extraction. Commonly affected breeds include the American cocker spaniel, poodle, Boston terrier, miniature Schnauzer, Bichon Frise, and Labrador retriever. Typically, genetic lenticular opacities are bilateral and slowly progressive. Rapidly progressive cataracts commonly occur in dogs with diabetes mellitus. Secondary lens-induced uveitis is a frequent finding that may complicate pre- and postoperative management (Cook, C,“Canine Cataract Surgery”, in Cataract & Refractive Surgery Today, 2008; pp 32). An exemplary intraocular lens 2 developed for implantation in canines is shown in figure 1. Figure 1, which is a hydrophilic posterior chamber intraocular implant (PCL) developed for canines (Manufactured by Bausch and Lomb). The dimensions of this intraocular lens and its intended site of implantation are given in Table 1.

[0006] Table 1. Dimensions and other specifications of a posterior chamber intraoocular lens (PCL) designed for canines.

[0007] A considerable number of patients needing to undergo cataract surgery have preexisting glaucoma. Glaucoma has been diagnosed in nearly 15% of the population in USA above age 80. The incidence of glaucoma rises with age, and is more prevalent in the African American and Hispanic population segment in USA. Many of these patients develop cataract at an earlier age (typically between 50 and 75 years of age), and undergo cataract extraction and in virtually all cases implantation of an intraocular lens. Many of these pseudophakes or aphakes, especially those with diabetes may develop glaucoma, including angle closure glaucoma caused by post operative inflammation.

[0008] Postoperative increase in intraocular pressure may be caused by residual viscoelastic gels left over after surgery, incursion of the vitreous caused by breach of the posterior capsule during cataract surgery, or iatrogenic damage to the iris, leading to pigment dispersion or the Ugh (uveitis-glaucoma-hyphema) syndrome. Moreover a certain percentage of persons who develop glaucoma at a relatively early age subsequently develop cataract and undergo cataract extraction and implantation of an intraocular lens.

[0009] Models based on UN world population projections predict that in the year 2020, 79.6 million persons will be afflicted with either open-angle glaucoma (OAG) or angle-closure glaucoma (ACG) with 5.9 million and 5.3 million projected to be bilaterally blind from these two conditions, respectively. (Kung, JS, et al,“Cataract surgery in glaucoma patient” in Middle east Afr J Ophthalmol, 2015; 22(1), pp 10-17.).

[0010] Occurrence of glaucoma after cataract surgery is especially prevalent in canines, partly because canines tend to experience a substantially higher level of postoperative inflammation subsequent to cataract surgery.

[0011] The prevalence of the primary breed-related glaucomas has gradually increased from 0.29% (1964-1973); 0.46% (1974-1983); 0.76% (1984-1993); to 0.89% (1994-2002). Breeds that consistently featured among the highest 10 for glaucoma prevalence from four different periods (1964 to 2002) included American Cocker Spaniel, Basset Hound, Wire Fox Terrier, and Boston Terrier. During the last observation period (1994-2002), 22 different breeds had 1% or higher prevalence of the glaucomas. The highest prevalence of glaucomas in 1994-2002 by breed included: American Cocker Spaniel (5.52%); Basset Hound (5.44%); Chow Chow

(4.70%); Shar-Pei (4.40%); Boston Terrier (2.88%); Wire Fox Terrier (2.28%); Norwegian ElkHound (1.98%); Siberian Husky (1.88%); Cairn Terrier (1.82%); and Miniature Poodle (1.68%). A predominance of females with glaucoma occurred in the American Cocker Spaniel, Basset Hound, Caim Terrier, Chow Chow, English Cocker Spaniel, Samoyed, and perhaps the Siberian Husky, and a predominance of males in the Australian Cattle dog and St Bernard. Age affected the time for first presentation of the glaucoma in the pure-bred dog. In the majority of breeds the glaucoma was presented for initial diagnosis in dogs between 4 and 10 years of age (Gellat KN, and McKay, EO,“Prevalence of the breed related glaucoma in pure bred dogs in North America”, in Vet Ophthalmol, 2004; 7(2), pp 97).

[0012] Biros, et al, reported a study of 346 canine eyes, in which they monitored incidence of glaucoma as a function of eight variables, including breed, sex, post-operative hypertension, and intraocular lens placement. Of the 346 eyes, 58 (16.8%) developed glaucoma after surgery. At 6 months, 32 of 206 (15.5%) eyes examined had glaucoma; at 12 months, 44 of 153 (28.8%) eyes examined had glaucoma. Median follow-up time was 5.8 months (range, 0.1 to 48 months). Mixed-breed dogs were at a significantly lower risk for glaucoma, compared with other breeds. Eyes without IOL placement were at a significantly lower risk for glaucoma, compared with eyes with IOL placement. Eyes with hypermature cataracts were at a significantly higher risk for glaucoma, compared with eyes with mature or immature cataracts (Biros, et al,“Development of glaucoma after cataract surgery in dogs”, in J Am Vet Med Assoc., 2000; 216(11), pp 1780).

[0013] Therefore, regular and frequent monitoring of intraocular pressure is critically important during the immediate post-operative period following cataract surgery. In the long run, regular monitoring of intraocular pressure is required to track continued efficacy of pressure controlling medications and monitor compliance. Both of these needs require introduction of an implanted, intraocular pressure sensor that can wirelessly transmit data to an external unit without any involvement of the patient.

SUMMARY OF THE DISCLOSURE

[0014] One aspect of the disclosure is an intraocular lens, comprising: an optic and a plate haptic configured for four point fixation in the eye, optionally within a capsular sac; and an embedded intraocular pressure (“IOP”) sensor assembly, wherein the intraocular pressure sensor assembly is mounted on a transparent substrate, wherein the substrate is attached to an anterior surface of the intraocular lens, and wherein the optic is wholly or substantially free from obscuration.

[0015] One aspect of the disclosure is a method of manufacturing an IOL, comprising: providing an IOL that includes an optic and a plate haptic; positioning an intraocular pressure sensor above an anterior side of the plate haptic; optionally positioning a soft gel above the IOL sensor;

positioning a multilayer conformal barrier coating above the soft gel; and optionally positioning a biocompatible coating above the barrier coating.

[0016] One aspect of the disclosure is a method of folding an IOL for delivery, comprising: providing an IOL that includes an optic and a plate haptic, and a pressure sensor disposed on the plate haptic; and folding the IOL along at least one fold line that is on a first side of the pressure sensor, the fold line not passing through an optical axis of the optic. [0017] One aspect of the disclosure is an intraocular lens, comprising: an optic and at least one plate haptic, and a pressure sensor embedded in the plate haptic.

[0018] One aspect of the disclosure is an intraocular lens, comprising: an optic and at least one plate haptic; and an antenna extending around a periphery of the IOL.

BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 illustrates an exemplary intraocular lens developed for implantation in canines.

[0020] Figure 2 illustrates an earlier exemplary IOL with an attached sensor.

[0021] Figures 3A and 3B illustrate an earlier exemplary IOL with an attached sensor.

[0022] Figure 4 illustrates an exemplary rigid PCB.

[0023] Figure 5 illustrates an exemplary flexible and transparent PCB.

[0024] Figure 6 illustrates details of an exemplary microstructure and layering of a multi-layer film.

[0025] Figures 7A, 7B and 7C illustrate an exemplary plate haptic IOL with an embedded intraocular pressure assembly.

[0026] Figure 8 illustrates an exemplary layering of components for any of the IOLs herein.

DETAILED DESCRIPTION

[0027] The present disclosure is related to the field of IOLs. In particular, the present disclosure relates to IOL wherein one or more sensors is attached (directly or indirectly) to at least one of the optic and the haptic(s) surface of the IOL, ensuring that the sensor does not significantly affect the optical performance or stability of the IOL in the eye. Preferably, the sensor is an intraocular pressure sensor.

[0028] In this disclosure, an intraocular sensor module means a capacitative or piezoresistive sensor that may comprise a separate package, or be on die (fabricated on the same silicon substrate as the rest of the electronic components). An intraocular pressure sensor assembly means the intraocular sensor and all the electronics that are may be used to operate the sensor, including, without limitation a microcontroller, voltage amplifiers, resistors and capacitors, memory units, RFID modules, batteries, and so on.

[0029] The intraocular pressure sensor can be mounted (directly or indirectly) on an intraocular lens, preferably designed for implantation in the posterior chamber. Attachment of an intraocular pressure sensor to the body an IOL has several advantages relative to commonly prescribed sites of fixation of such a sensor in intraocular space, for example, in the sclera (making it an intrascleral implant), in the subconjunctival space, the superchoroidal region, the vitreous, or in or near the Schlemms canal. An exemplary advantage of a sensor embedded in an IOL is that, by being embedded in the body of an IOL, the sensor is safely away from ocular tissue that may be otherwise disrupted by touch of the sensor body, for example, the iris or the corneal endothelium.

[0030] If the sensor is embedded on the anterior side of the IOL body and the IOL is placed in the capsular sac, the sensor is covered by the anterior capsule, and provided another layer of isolation and protected from cellular deposits and growth. At the same time, it is surrounded by flowing aqueous humor so that the pressure recorded by the sensor is the true intraocular pressure. Sensors embedded in the sclera, the vitreous or the subconjunctival space do not record pressure of the free flowing aqueous humor, but of ocular tissue in mechanical contact with the aqueous humor. The sensed pressure for those devices is therefore dampened by the modulus and the viscoelastic properties of the ocular tissue that surrounds the sensor.

[0031] Earlier examples of a design of an IOL with an attached sensor are shown and labeled in Figure 2 and 3. Figure 2 shows an exemplary intraocular lens 4 with an intraocular pressure sensor 10 mounted on its surface. Antenna 6 can be made of copper or a gold-titanium alloy, coated with gold, and is mounted around the periphery of the optic, as shown. The IOL also includes electronics 8 in communication with at least one of the antenna 6 and the pressure sensor 10. Pressure sensor 10 extends into the optical zone of the optic, and the antenna extends around the periphery of the optic portion. Figures 3A and 3B show an exemplary intraocular pressure sensor assembly 14 positioned on the anterior surface of an exemplary canine posterior chamber IOL 12. Antenna 16 is also shown extending around the periphery of the optic portion of the IOL. Again, the pressure sensor assembly 14 extends into a portion of the optic zone of the optic. Exemplary non-limiting dimensions include an optic diameter of 6 mm and overall length of the IOL of 14 mm.

[0032] Earlier examples of IOLs with embedded sensors and an electronic package that operates such sensors have the advantages of being compact and operationally functional because they maintain a clear central optic of 3 mm or larger in diameter. At the same time, some of these earlier designs do obscure part of the IOL optic, thereby compromising peripheral vision of dogs.

[0033] The current disclosure solves this problem by using a state of the art

microelectromechanical assembly that utilizes a flexible, transparent PCB. Transparent PCBs are a recent development, and the initial development led to rigid, transparent PCBs, as example of which is shown in Figure 4. The exemplary transparent PCB of figure 4 can be made of

Aluminum oxide (Alumina, 99.9%). Its properties, as published by the manufacturer (Elite Advanced Technologies, Penang, Malaysia) are listed below Exemplary advantages of transparent Alumina PCB include transparency up to 80-90%; high operating temperature up to 350°C; low expansion coefficient strong thermal properties (e.g., 26-28 W/mK); multi-layer circuits are possible; hermetic packages possible; and 0% water absorption. Other types of transparent PCBs have also been commercialized, utilizing polyimide, polyethylene

terephthalate, polycarbonate or glass as substrates.

[0034] None of these transparent substrates, however, meets the necessary requirements that the PCB material be flexible, transparent, biocompatible and function as an excellent barrier material, providing isolation from water, ions, and small and large proteins. These requirements are met by using Paralyne C or Grapahene as substrates. One example is a transparent PCB developed by COAT-X, located in La Chaux-de-Fonds, Switzerland. An example, as shown on their Website, is shown in Figure 5, which shows an example of a transparent, flexible PCB, developed by COAT-X. In one embodiment, the film is a multilayer structure 20 (see figure 6), comprised of a polymer film 24 with barrier properties such as Paralyne -C interspersed with layers of ceramic 22 such as SiOx. The ceramic material is the relatively thinner horizontal layers, and the polymeric material is represented as the relatively thicker horizontal layers. The film can be formed either as a free standing film, or a conformal coating to provide a hermetic seal around an implant or a portion of an implant, as disclosed in the following patents, incorporated by reference herein for all purposes, including methods of manufacture and methods of application to other materials - US Pat. No. 8,313,811; US Pat. No. 8,313,819; and US Pat. No. 8,361,591. Any and all methods of manufacturing and deposition described in these references are fully incorporated herein and can be used to manufacture any of the flexible components onto the IOLs herein. Additional details of the exemplary multilayer ceramic- polymer stack utilizing SiOx and Paralyne- C shown in figure 6 can be found in A. Hogg, et ah, “Protective multilayer packaging for long-term implantable medical devices”, in Surf. Coat. Technol. (2014), http://dx.doi.Org/10.1016/j.surfcoat.2014.02.070, which is incorporated by reference herein for all purposes.

[0035] Figure 6 shows details of exemplary microstructure and layering of these multi-layer films, illustrating permeation and diffusion by the arrows. The structure of the film can be used to alter or control the permeation and diffusion. Their effect on permeation and diffusion properties of these films have been discussed by Dr. Andreas Hogg in his Ph.D. thesis.

(Development and Characterization of Ultrathin Layer Packaging for Implantable Medical Devices), published in the website of COAT-X. ( http ;//coat-x .corn/), which is incorporated by reference herein for all purposes.

[0036] Figures 7A, 7B and 7C are top, side, and front views of an exemplary plate haptic IOL with an embedded intraocular pressure assembly. The IOL in figures 7A, 7B and 7C is a plate haptic IOL that is adapted to be foldable, and exemplary folding lines are shown as the two dashed lines.

[0037] Figs. 7A-7C illustrate exemplary IOL 40, which includes optic portion 42 and plate haptic portion 44. IOL also includes an intraocular pressure sensor assembly that includes sensor module 46 and electronics module 48, which are in electrical communication via electrical connectors 52. The IOL also includes antenna 50, which extends around the periphery of the IOL as shown, and is in electrical communication with connectors 52. Exemplary dimensions between the folding lines and sensor module 6 are .1 mm to .6 mm, such as .2mm to .45 mm, such as .35 mm.

[0038] As can be seen in the side views on figures 3B and 3C, sensor module 46 and electronics module 46 are embedded in the plate haptics of the IOL.

[0039] The multilayer barrier film has been utilized to populate the electronic module, for example, comprising a microcontroller, an intraocular pressure sensor, a memory, and an RFID module on the haptic of the plate haptic IOL. The location of the printed circuitry shown in figure 7 is an example and is not intended to be limiting. The antenna 50 and the conductive bus 52 may be disposed along the periphery of the IOL body, enabling the deployment of a substantially longer antenna loop, relative to the earlier designs shown in Figures 2 and 3.

[0040] The overall length of the loop antenna can be in the range of 20.0 mm - 30.0 mm, preferably in the range 22.0 mm to 26.0 mm. The antenna can be made of a wire of, for example, a diameter of 100 microns (such as in a range of 25-200 microns), and is preferably mounted on the anterior surface of the intraocular lens. Alternatively, the antenna can be comprised of a thin plate of gold or Nitinol coated with Gold, of thickness in the range of 10-50 microns and width in the range of 100 - 250 microns. The advantage of utilizing Nitinol in the antenna is that use of Nitinol improves the unfolding characteristics of the haptic subsequent to implantation through a small incision. The antenna and all other electrical elements may be bonded to the transparent multilayer film that is bonded to the surface of the intraocular lens, preferably the anterior surface. The antenna and the conductive bus may be directly deposited (e.g., via physical or chemical vapor deposition) on the transparent multilayer film. The overall thickness of the multilayer film can be about 10-100 microns (preferably, 20-75 microns).

[0041] Preliminary tests with a piezoresistive intraocular pressure sensor (received from Bosch) indicate that the sensor retains greater than 90% of its sensitivity when it is covered by a layer of a silicone (polysiloxane) polymer, then over-coated with the multilayer coating shown in Figure 6. Encapsulation of the sensor so that the sensor does not cause any adverse reaction in the eye is a challenge, since any encapsulation that provides excellent and durable barrier properties and is also endowed with a biocompatible surface may be expected to isolate the sensor from the hydrostatic and hydrodynamic pressure of the aqueous humor and therefore result in a loss of the sensitivity or response of the sensor, and may also introduce an undesirable time lag in the sensing process.

[0042] These problems have been solved by adding a layer of an inert soft gel, for example, a soft silicone gel, such as Silastic, available from Dow Corning, or Siluron, available from Geuder Corporation, Germany, then depositing the multilayer coating of figure 6 on top of the soft gel encapsulant. Preliminary tests indicate that this encapsulation package does not materially decrease sensor sensitivity. Tests clearly indicate that deposition of a material that has a bulk modulus exceeding 1 MPA adversely affects the response characteristics of the sensor. Therefore, the inventive designs herein meet this mechanical constraint while still providing the required biocompatibility and isolation of the sensor.

[0043] The implant comprising the IOL and the embedded intraocular pressure sensor, coated with the multilayer coating disclosed by Hogg is preferably coated with an organic

biocompatible coating that is designed to minimize adhesion of cortical and endothelial cells that are remnants of the crystalline lens that is removed prior to implantation of the IOL. Preferably, this coating minimizes stimulation of the inflammation cascade in the eye. The coating can be a multilayer amphiphilic or hydrophilic coating, with a gradation of cross-link density, glass transition temperature and bulk modulus. Its microstructure is that of a scaffold, with an inner layer with the highest cross-link density, and an outer layer of lowest cross-link density. The coating is applied via photopolymerization and comprises polyethylene glycol segments terminated with acrylate or methacrylate groups.

[0044] The plate haptic IOLs disclosed herein (e.g., in figures 7A and 7B) can be configured to engage the capsular equator at four points, and is therefore quite resistant to rotational displacement. It may not be vaulted, but a vault of up to 7 degrees is acceptable. A vault further separates the intraocular sensor assembly from the iris. The overall length of the IOL can be between 11.5 and 12.7 mm, preferably 12.5 mm. In exemplary figure 7A the exemplary length is shown as 12.3 mm. The IOL is preferably implanted in a folded state, preferably along lines bordering (on at least one side of) the electronic modules and the sensor module, such as is shown in figure 7 A. Such a folding pattern will enable the IOL to be delivered through a 3.3 mm incision. The haptic portions of the IOL can also be adapted to be more preferential to folding along the folding lines to facilitate folding in particular areas on both sides of the electronics modules and the sensor module.

[0045] One major advantage of the IOL designs herein over earlier designs is that it provides a full diameter optic, 6.0 mm in diameter. Alternative designs may be provided that have an optic of diameter from 5.0 mm to 6.5 mm, with an outer diameter of 6.0 to 7.5 mm. A second major advantage is that the IOLs herein allow an antenna of total length in the range of 20.0 to 25.0 mm, more than three time the length provided by previous designs.

[0046] The edge of the preferred plate haptic IOL is preferably designed to have a square profile. Since the edge of the optic has a thickness in the range of 50-150 microns, the overall thickness of the edge bearing the antenna coil will be in the range 150 - 525 microns, preferably 200-400 microns. This increase in edge thickness and a barrier on the anterior surface may eliminate migration of residual cortical and equatorial cells left over after phacoemulsification and cleaning of the capsular sac prior to lens implantation to the posterior capsule, and thus helps inhibit posterior capsular opacification (“PCO”).

[0047] Exemplary biocompatible coatings have been disclosed previously. Preferably it is made of a hydrogel material, and comprises two or more layers. The inner layers of this coating is preferably infused with pharmaceuticals, including an anticlotting agent, an antifibrotic agent, a corticosteroid and some other medicaments that downregulate expression of inflammation mediators such as cytokines. The multilayer coating, similar in molecular structure to an extracellular matrix prevents adhesion of giant cells, or polymorphic macrophage.

[0048] Figure 8 illustrates an exemplary layering of components for any of the IOLs herein. The sensor can be disposed above an anterior side of an IOL. An optional gel can be applied above the sensor or other sensor components. The multilayer barrier coating can then be positioned, which can be covered by an optional biocompatible coating.

[0049] As used herein, when this application refers to the optic being wholly or substantially free from obscuration, it generally refers to almost completely free of obscuration. There may be some obscuration in the most peripheral region of the optic. For example, in a top view, “substantially free” as used herein can mean that not less than 90% of the surface area is free of obscuration, or not less than 95%, or not less than 96%, or not less than 97%, or not less than 98%, or not less than 99%. For example, in figures 7A-7C, antenna 50 may extend slightly over the optic zone of the optic, but insignificantly.