Patent Application
20150037262
This application claims priority to EP 12152866.5 filed on Jan. 27, 2012 in the name of Ecole Polytechnique Federate de Lausanne (EPFL), the content of which is incorporated by reference in its entirety in the present application.
The present invention relates to a support containing cavities (or reservoirs), preferably micro-cavities or micro-reservoirs, in direct contact with tissue (e.g., human or animal tissues) to which the support according to the invention is applied allowing direct transplantation of cells on said tissues.
More specifically, in one embodiment, the present invention relates to a contact lens which comprises at least one cavity forming a reservoir containing cells in suspension, said cavity or said cavities being in direct contact with the eye which allows direct transplantation of cells on the eye in a localized manner.
The number, the shape and the volume of the cavities may vary. Similarly one may consider different shapes of support so that it may be adapted to different types of tissues. This support can be achieved in different types of materials, and may be treated on its inner surface in contact with the tissues, e.g. coated with an adhesive substance like a surgical glue or another product according to needs.
Publication WO 2008/144340 describes a scleral lens for drug delivery. This scleral lens comprises a reservoir on the whole surface of the cornea, said reservoir containing a drug. This lens does not allow the delivery of the drug in a localized manner but only on the whole of the cornea.
Publication WO 2010/068281 describes a lens for delivering an active agent to the cornea of the eye of a patient. In this document, the lens comprises a carrier material to release the agent which is encapsulated within the lens.
Publication US 2009/269391 describes a contact lens comprising fibers that are used as a means to deliver drugs. The fibers are loaded with drugs and deliver them to the eye.
Publication WO 2009/03226 describes a system for administering an agent ophthalmically bioactive including a contact lens with microparticles or microgels of a crosslinked polymer dispersed therein, said microparticles or microgels having trapped a bioactive agent capable of migration by diffusion in the lacrymal film.
Publication US 2008/075757 describes a lens having a micro-emulsion of oil in water, with a bioactive agent which is ophthalmically encapsulated in the oil phase.
Publication WO 2006/084275 describes a system for delivering drugs using a polymeric hydrogel.
Publication DE 40 22 553 describes a product for the issuance of a substance on the cornea of a patient.
Publication DE 1964116 describes a lens with a reservoir in the shape of ridge which extends inside the lens along its periphery. Such a configuration does not allow targeted application of the product contained in the reservoir.
Publication US 2008/0107713 describes a contact lens with application areas of drugs distributed asymmetrically on the lens. More particularly, the lens includes a first lens made in a non-hydrophilic material and which contains the drug and a second lens on the concave surface of the first lens so as to take the drug in “sandwich”, the second lens being made of a hydrophilic material.
Other publications of the state of the art are: US 2008/317819, US 2008/107713, WO 2007/002671, US 2006/290882, US 2005/196428, WO 03/090662, US 2003/203001, EP0882996, JP 6273702, DE 4022553, U.S. Pat. No. 3,786,812, CN 2914127Y, EP 0347043, DE 1964116, WO 2008/131973, WO 2007/092550, WO 84/01297, U.S. Pat. No. 4,466,705, US 2008/212021, US 2006/152674, WO 2004 / 046768, U.S. Pat. No. 7,695,135, WO 93/07840, WO 2009/145842, WO 99/45869, WO 2010/105130, WO 2008/098299, U.S. Pat. No. 3,867,519, US 2010/069857, WO 2006/029332, U.S. Pat. No. 4,186,184, U.S. Pat. No. 3,961,628, WO 03/077794, U.S. Pat. No. 4,177,256, US 2010/210996, WO 00/66139, WO 95/01764, US 2005/275799, US 2005/013806, US 2005/177149, WO 2006/047788, JP 2002331025, WO 95/20969, US 2004/081643, WO 2010/33853, WO 03/030959, US 2005/070942, WO 01/30375, WO 03/077898, WO 98/53806, WO 03/030958, WO 02/06883, U.S. Pat. No. 6,541,028, US 2004/049268, U.S. Pat. No. 5,932,205, WO 2004/060348, WO 2011/031852, US 2007/106394, WO 2005/123035, WO 2006/102378.
An object of the invention is to improve the known products and processes.
Another object of the invention is to provide a support such as a lens or another support that can be used in a simple and precise way to treat a patient, namely for the application of cells directly on tissue of the patient, typically on the patient's eye as in one of the embodiments of the invention.
The present invention is innovative especially in that it enables the application of a cell suspension (cells which are thus directly transplanted onto the target organ) and that said application has a precise location (determined by the arrangement of cavities of the device).
In an embodiment, the device for the application of a medium, such as the transplantation of cells in suspension, comprises a carrier with at least one micro-cavity for containing said medium in direct contact with the object on which the said medium is to be applied.
The carrier may comprise several micro-cavities.
In an embodiment, the carrier may comprise at least one channel for the supply of the micro-cavity or micro-cavities with medium.
In an embodiment, the device may further comprise at least one reservoir which allows continuous feeding of the micro-cavity or micro-cavities with medium over time.
In an embodiment the carrier may have the shape of a contact lens.
In an embodiment the carrier may comprise a plurality of cavities that are evenly distributed on the carrier or which are not evenly distributed on the carrier.
In an embodiment, the carrier may comprise protection means to protect the medium from the environment when the carrier is applied to a patient.
In an embodiment the protection means may be a ring or a plurality of cavities.
In an embodiment the cavity or the cavities may have a cylindrical shape, and/or a ring shape and/or have different volumes.
In an embodiment the device may comprise a sensor.
In an embodiment the sensor may be placed in the carrier.
In an embodiment, the sensor may be an indicator dye in the medium or microelectrodes.
In an embodiment the sensor may comprise a polymer or hydrogel pouch.
In an embodiment, in order to reconstitute the medium, the carrier may comprise at least an inlet connected to a medium concentrate chamber covered by a water permeable membrane.
In an embodiment, the inlet may further comprise a valve to build an overpressure in the chamber.
In an embodiment, the at least one cavity may contain as a medium cells in suspension for the transplantation of said cells.
In an embodiment, the device may comprise a plurality of cavities, wherein some cavities contain cells in suspension as a medium, and other cavities contain a growth inhibitor, and/or a growth factor, and/or inhibitors of blood vessels, and/or cell death inhibitors and/or a permeabilization agent.
In an embodiment, the sensor may be a pH, CO2 or metabolite concentration sensor.
In an embodiment, the carrier may be adapted for application to human tissue or human or animal body, such as the eye, the gingiva, skin, a wound or a burn or an internal organ.
In an embodiment, the invention concerns the use of a device as described herein for a direct application of a medium to a patient or to an animal.
The present invention will be better understood by the following detailed description and the accompanying figures, in which
The principle of the present invention is illustrated in
The result of the application of the lens 1 on the cornea of the eye 4 of a user 5 is illustrated in
In
The channels 6 may comprise a chamfer to facilitate refilling or not and may have any suitable shape (straight or not).
These channels 6 form a particularly interesting feature in that they may hold the carrier 1 (for example a lens) in position on the eye 5. By applying the principle of the invention, it is possible therefore to obtain a support/carrier 1 such as a lens or another equivalent carrier to apply in a very precise and localized manner a cell suspension on a patient. Once the support 1 is positioned appropriately with the cavity 2 placed at the desired location, the support 1 remains in place and the cavity 2 can be fed as long as necessary, without displacing the carrier 1, see
One of the advantages of the present invention is clear here. One can provide one or more cavities 2 in specific areas of the carrier 1 for a targeted application of cell suspension. In addition, various cavities 2 can contain different products for a complementary application, or mixed substances, once it has reached the target, that is to say the desired location.
By using the channels 6 as illustrated in
In some embodiments all cavities 2 may have at least one channel 6 for filling or refilling with a product, in other embodiments only one or some cavities may have at least one such channel. It is therefore possible to design different embodiments where some selected cavities may be refilled and others not on the same carrier depending on the product used. Some cavities may even be filled optionally, for example after the carrier has been placed on a patient depending on the evolution (to increase the concentration of a product or for any suitable subsequent purpose).
The shape of the cavities 2 can be selected at will, for example circular or oblong, “banana” or other. One may also choose a shape related to the application of the carrier 1 or to the zone where the carrier 1 is to be applied on a patient.
As said above, the carrier 1 of
In
In
The reservoir 7, 7′ is held in position through the forces of surface tension. If necessary, it is possible to add a holding means, such as a surgical adhesive or any other equivalent means to enhance the attachment of the reservoir 7, 7. The choice of a retaining means may be linked to the application in question.
The advantage of the invention is to apply a medium 3 for example a suspension in a localized and precise manner. As indicated above, the lens, and more generally the carrier 1 used to apply the medium 3 may include one cavity 2, or more than one cavity 2, which is (are) located at the selected/required place for applying said medium.
In addition, the use of channels 6 allows refilling of the microcavities 2 either directly or by using the additional reservoir 7.
In the case of the presence of several cavities 2, they may be supplied by the same medium 3 or different media 3 for different effects and/or complementary effects or by any other desired product.
The reservoirs 7, 7′ as illustrated in
When changing the reservoir 7 according to the procedure illustrated in
As one skilled in the art will understand, the principle of the invention allows many variants that may be tailored to the intended use/application of the invention.
The ring 12 may be in any suitable material for the intended application of the device (not limited to a lens). Preferably the material is a biocompatible one, for example a metal or a synthetic material.
Taking advantage of the fact that the device may comprise more than one cavity 11 (2) the device can be functionalized to improve homogenous and rapid coverage of the grafted area of a patient by appropriate arrangement of the cavities 11/2 on the carrier 1/10.
Accordingly, as also described hereabove and applicable to said embodiments, the device may comprise in one embodiment a central cavity 11 containing the medium 3, for example cells to be transplanted and more external cavities 11 forming an outer ring containing growth factors of chemo attractants that will diffuse through the stroma. Thus the grafted cells will be attracted to the periphery and will cover homogenously and rapidly the area to be healed. This embodiment is illustrated in
In another embodiment illustrated in
In the case of transplantation in a severely damaged environment the transplanted cells not only need to grow and cover the wounded area but they firstly need to survive. To answer this need, the device carrier may comprise some cavities containing cells, some other containing growth factors, small molecules promoting proliferation and some containing cell death inhibitors etc. As one will readily understand from the above description, the present invention allows many different configurations of carrier with cavities and media being applied to a patient.
In some embodiments, the carrier may be built with numerous cavities 2 in such a way to create gradients of media 3 being applied such as cell suspension, growth factor, cell death inhibitors etc. . . .
This gradient may be achieved by different constructions illustrated in
In the embodiment of
In the embodiment of FIGS. 15A to 15CB, another version is shown which applies a gradient of concentration of medium 3 via the cavities 2 of the carrier 31.
In
In
An advantage of using an increase of density of cavities 2 or of the cavitie's volume rather than to increase the concentration of the medium is that there is no need to change the medium over time to achieve this effect. Of course, in certain circumstances it may be better to change the concentration of the medium.
In
It is of course understood that when using several different chemical substances for the creation of gradients in the carrier, the gradients of the individual substances can be controlled individually and hence combined arbitrarily (same, opposing or arbitrarily different directions and geometries).A skilled person will recognize the many combination possible with the principle of the invention and the combination of features of embodiments.
In the case of chemical permeabilization, the carrier 36 (for example a contact lens) comprises at least one cavity 2 for cells in suspension as a medium 3, and other cavities (in this example two cavities 2′) which form distinct permeabilization cavities 2, 2′, the surface epithelium can be removed or permeabilized in the vicinity of the cavities 2′ containing the permeabilization agent, eventually allowing the cells in the main cavity 2 to reach the interior of the cornea 4 of the eye 5.
Taking advantage of the localized action provided by microcavities 2, 2′, one can treat the corneal surface epithelium locally by conditions that result in the local removal of the surface epithelium. This can be achieved by means of application of solutions of permeabilizing agents in at least some of the cavities 2′. These permeabilizing agents can be tensides (such as benzalkonium salts), enzymes (such as Trypsin or collagenases), chelating agents (such EDTA), photodynamic agents (such as gamma-aminolevulinic acid and derivatives which are processed to photoactive porphyrins by the cells) as well as combinations of these agents. The permeabilization allows transplantion of cells directly to the surface of the stroma. It is possible to use hydrogels in the permeabilization cavities to avoid unintended mixing of the cells (medium 3) and the permeabilization agent prior to transplantation.
Of course, all the teachings and configurations of previous embodiments described above may be applied here to the embodiments of
For example, the carrier 38 may be provided with sensors 39, 39′ allowing quantifying different aspects of the cellular metabolism and growth transplantation. For instance, pH, carbon dioxide, oxygen or glucose concentration may be used to define the time points when a medium change is needed. The sensors 39, 39′ may use any operating principle compatible with the spatial restraints, but typically electrical or optical mechanisms may be used.
For instance, microelectrodes 39, 39′ embedded in the carrier and reaching the medium may be used for sensing pH, glucose or oxygen; readout systems for electrical measurements embedded in contact lenses are available as well.
In another variant, optical sensing is based on substances which change optical properties as a function of an analyte concentration.
Accordingly, the carrier 43 (for example a contact lens) comprises a cavity 2 with a medium 3 to be applied to a patient on the cornea 4, the cavity comprising a side extension 44 which is used to allow reading of the dye reaction. To this effect, the carrier 43 comprises an optical background 45 suitable for an optical readout.
In an embodiment , the side extension 44 comprises an optical background 45 and also a polymer or hydrogel pouch 46 containing indicator substances for the reaction in accordance with the principle of the present invention.
Of course, as mentioned, a carrier may comprise one single sensor or a plurality of sensors of the same type or of a different type to detect/monitor different variables and elements, according to circumstances. Many variants are thus possible in the frame of the present invention.
An example of a readout system that may be used in the present context for electrical sensing is the one developed by the Company named Sensimed (www.sensimed.ch), as disclosed in the application WO 03/001991. In particular, one may combine the signal processing and readout systems described therein with microelectrodes measuring metabolites, oxygen tension, pH or carbon dioxide concentrations.”
The result of the sensing may be used to determine whether the medium 3 has to be re-supplied and/or exchanged and/or adapted in accordance with a result sought. Such refilling, exchange and/or adaptation may be carried out with the embodiments of the invention described hereunder.
Upon transplantation, it is important that the cells are in a controlled environment. Several solutions are possible to provide the cells with nutrients for a time period suitable for successful implantation (typically, about 10 days) prior to exposure to the native environment when removing the device. Possible solutions are the following:
Possible embodiments and variants are described in more detail hereunder.
In
In
Taking advantage of the fact that the size of device's cavity 2 can be chosen, as described hereabove in relation to the different embodiments of the invention, one may construct two different carriers, i.e. lenses: a first seeding lens 70 (corresponding to lens 1) with the appropriate cavity 2 volume to seed the desired amount of cells (as the medium 3), and a second lens 71 with a larger cavity 72 to allow for a good cell 3 growth.
The transplantation procedure can be the following:
First step (
Second step (
Applications of the present invention are numerous. As mentioned earlier, one may use this support in the form of contact lens but this should not be construed as a limitation of the present invention.
The preferred application of device according to the present invention is the use of a contact lense as described to transplant corneal epithelial stem cells. Indeed, many patients suffer from deficient vision due to damaged (chemical or thermic burns) or absent (limbal stem cell deficiency) corneal epithelium. Today, these conditions are treated by transplantation of cornea or limbal grafts. Transplantation of cells in suspension, thanks to the device described herein, facilitates and accelerates the transplantation procedure for the surgeon. Moreover, the technique described herein makes creation of an artificial epithelium in culture under expensive GMP conditions superfluous. Indeed, the surgeon can directly transplant cells obtained from the healthy contralateral eye, or a donor eye. Accordingly, the use of the present invention in this application is particularly advantageous.
Applications of the present invention are however numerous. Examples include:
The device of the present invention may potentially be used in a variety of other applications on the eye. For instance one can transplant genetically modified cells (for example for the correction of heritable corneal dystrophies) or non-epithelial cells (stromal, multipotent etc).
These applications may of course be combined among them.
With some adaptation, the device can be used for internal organs as well as mentioned earlier in the present application and illustrated in
The device generally has to be fixed to the organ surface by a mechanical method. Most commonly, this will be surgical sutures, fibrin glue or some form of mechanical bandage.
The principle of the present invention is still used in other applications and with different carriers as described below.
For example:
These applications may of course be combined among them.
Permabilization for transplantation to deep layers may be employed as needed (see the above description of this embodiment).
The size of the device, and volume capacity of the permeabilization and cell cavities should be adapted to the organ at hand and to the desired application.
Depending on the surgical procedure, it may be necessary to temporarily immobilize the cells, for example by a spontaneously liquefying hydrogel (e.g. surgical fibrin gels+plasmin or ca-alginate gels+alginate lyase).
Further example of target applications include among others: transplantation of genetically modified autologous hepatocytes to the superficial layers of the liver for correction of inborn errors of hepatic metabolism; transplantation of hormone-producing cells into the dermis for correction of endocrine diseases; transplantation of genetically corrected muscle satellite cells to muscle tissue for the treatment of heritable muscular dystrophies; application of immune cells to solid tumors for cancer therapy.
Any suitable material (including biocompatible) may be used to form the support. In the case of the lens, for example be used and a method of the PDMS mold. One may also use flexible silicone or other suitable material depending on the application.
In one embodiment, one may use a lens that is adjustable to light (“light adjustable lens,” Calhoun Vision LAL, Pasadena, Calif.), in which the power or correction of the lens can be adjusted after implantation in the eye.
The inner surface of the support, that is to say one that will be in contact with the user/patient or animal (e.g. in the case of eye lens) may receive a specific treatment such as adding a surgical glue or other.
The transplantation technique described herein allows the use of cells in suspension. One therefore avoids a cell culture on a lens or another media as proposed in other known devices. This makes transplanting easier and faster.
This device has the advantage of having pockets/cavities of small to large sizes the location of which may be chosen. This allows the control of the location and of the quantity of cells applied to the target tissue.
The realization of the device is done directly by molding, a simple process that does not necessitates reworking.
As mentioned above, the principle according to the invention may be used in many applications and may be designed for application to human tissue or a human organ, such as the eye, gums, skin, injury or burns etc . . . This device may be useful for veterinary use in similar applications.
As one understands, the embodiments of the present invention are for illustrative purposes and should not be construed as limiting. Other embodiments are possible using equivalent means within the scope of the present invention.
The described embodiments allow many different constructions in accordance with the principles detailed above. The invention is not limited to a use with a lens but many different applications may be envisaged with an appropriate carrier/support suitable for the intended use or application.
The different embodiments described above are not exclusive and they may be combined together (in part or totally).
The size, shape and volume of the cavities may be varied according to circumstances and/or to adapt to the intended use and application, the aim being to apply the desired medium at the desired location in the desired concentration to achieve the desired effect. The disposition of the cavities may be symmetrical or asymmetrical.
| Number | Date | Country | Kind |
|---|---|---|---|
| 12152866.5 | Jan 2012 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/IB2013/050721 | 1/28/2013 | WO | 00 |
