Hydrogel membrane for adhesion prevention

Abstract

To prevent unwanted scarring after surgery.SOLUTION: A biocompatible membrane comprising alginate and hyaluronate is provided. The membrane may be used to prevent unwanted scarring after surgery. The tissue adherence and the rate of bioresorption of the membrane may be modified through an external stimulus comprising a sequestering agent and a viscosity modifier.SELECTED DRAWING: None

Description

[Technical field]

[0001] Embodiments of the present invention were made with United States Government support under Grant No. DMR-0805298 awarded by the National Science Foundation (NSF). The United States Government includes certain rights in this invention.

[0002] FIELD OF THE DISCLOSURE Embodiments of the present invention relate generally to the field of medical devices, and specifically to devices that inhibit, reduce, or prevent scar formation. Embodiments of the present invention include a bioabsorbable membrane that can be inserted within the body between tissue and organs to prevent the adhesion of unwanted scar tissue. [Background technology]

[0003] Scar tissue attachment, also known as adhesions, is a frequent complication of surgical procedures. During surgical procedures, body tissues and organs can be intentionally or inadvertently injured. These injuries trigger a wound healing response that results in the formation of scars. Scarring becomes problematic when it causes scar tissue to form attachments between adjacent tissues or organs where they should not be. Adhesions can form in any anatomical location, including around the eyes, tendons, heart, spinal cord, peripheral nerves, sinuses, and between organs in the abdominal and pelvic cavities. For example, when a bowel is removed from the abdominal cavity, scar tissue may form adhesions between the bowel and the abdominal wall. These adhesions can cause pain and discomfort to the patient, impair the function of the affected organ, and prevent future surgery in the same anatomical area.

[0004] Anti-adhesion barriers are medical devices that surgeons use to inhibit, reduce, or prevent scar tissue adhesions. These devices are commercially available as membranes, gels, and solutions. During a surgical procedure, surgeons may choose to insert an anti-adhesion agent between damaged tissues or organs. Such devices work by physically separating damaged organs during a critical period of wound healing when the patient is most at risk of adhesions. Once that critical period has passed, the device is absorbed by the body. In general, membrane barriers are superior to gels and solutions, which are quickly absorbed by the body. However, even the most successful membranes are only partially effective and can suffer from brittleness and poor resorbability. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] International Publication No. 2009 / 108760 [Patent Document 2] International Publication No. 2012 / 048283 [Patent Document 3] International Publication No. 2012 / 048289 [Brief description of the drawings]

[0006] Features and advantages of embodiments of the present invention will become apparent from the appended claims, the following detailed description of one or more exemplary embodiments, and the corresponding drawings. [Figure 1] 1 includes a photograph of a hydrogel in accordance with one embodiment of the present invention. [Diagram 2] 1 includes a chart regarding swelling of a hydrogel in one embodiment of the present invention. [Diagram 3] 1 includes a series of photographs illustrating the mucoadhesive properties of one embodiment of the present invention. [Figure 4] In one embodiment of the present invention, a bilayer hydrogel is provided. [Diagram 5] A process for making a bilayer hydrogel in one embodiment of the present invention is provided. [Figure 6] In one embodiment of the present invention, a method 600 is included. Summary of the Invention [Problem to be solved by the invention]

[0007] In the following description, numerous specific details are set forth; however, embodiments of the present invention may be practiced without these specific details. Well-known circuits, structures, and techniques are not shown to avoid obscuring an understanding of this description. "One embodiment," "various embodiments," and the like refer to embodiments that include a particular feature, structure, or characteristic. However, not every embodiment necessarily includes the particular feature, structure, or characteristic. An embodiment may include some, all, or none of the features described in other embodiments. "First," "second," "third," and the like refer to different instances of a common object and similar object to the object being referred to. Such adjectives mean that the objects may not be in a particular order in time, space, ranking, or in any other manner. "Connected" means that elements are in direct physical or electrical contact with each other, and "coupled" means that elements cooperate or interact with each other, but the elements may or may not be in direct physical or electrical contact.

[0008] There is a need for anti-adhesion membranes with improved handling and greater efficacy by clinicians. Various embodiments of the present invention, discussed below, provide hydrated, resorbable and effective membranes. [Means for solving the problem]

[0009] In one embodiment, the membrane comprises two polysaccharides, alginate and hyaluronate. In one embodiment, the membrane comprises only alginate and hyaluronate, and little to nothing else. The proportion of each polymer in the membrane may vary from embodiment to embodiment. For example, in one embodiment, the alginate component may comprise 10%-95% of the dry weight (with the hyaluronate comprising the remainder of the membrane). In another embodiment, the membrane comprises 50%-75% of alginate by dry weight (with the hyaluronate comprising the remainder of the membrane). In one embodiment, the membrane comprises 60%-70% of alginate (with the hyaluronate comprising the remainder of the membrane).

[0010] In one embodiment, the alginate component may be a copolymer of mannuronate (M) and guluronate (G) chemical units. The alginate backbone may consist of these two units (e.g., MMMMMM, GGGGGG, and MGMGMG patterns). The ratio of M and G units in a particular alginate may depend, for example, on the plant source from which the alginate is collected in one embodiment. The alginate may be characterized by the ratio of M and G units. In one embodiment, the alginate component may be an alginate having a high proportion of M units (i.e., high M alginate), an alginate having a high proportion of G units (i.e., high G alginate), or a blend of high M and high G alginates. In one embodiment, a "high proportion" of units includes 50% or more, while in other embodiments, the value may be 60%, 70%, 80%, 90%, or more.

[0011] Alginates may be obtained in various salt forms. Alkaline metal (e.g. sodium and potassium) and magnesium alginates are water soluble. Alkaline earth metal (e.g. calcium, strontium, barium) alginates are water insoluble. Alginates may form insoluble salts with transition metals (e.g. iron and copper). The water insolubility of alginates may be due to ionic crosslinking of the G units of the alginate backbone by multivalent cations. In one embodiment, water soluble alginates may be used to prepare a solution for film casting. After casting, the alginates are converted to an insoluble salt form by ion exchange to obtain the final membrane. In one embodiment, sodium alginate is used for film casting and subsequently converted to calcium alginate after the membrane is obtained. Calcium, an element found throughout the body, can act as a crosslinker and is a suitable option from the standpoint of biocompatibility.

[0012] Hyaluronate is an alternating polysaccharide of N-acetylglucosamine and glucuronide chemical units. In various embodiments, polymers may be obtained from animal and microbial sources at a number of molecular weights. Hyaluronic acid (HA) may be obtained in its acid form, but has limited water solubility. Research and clinical hyaluronate stocks are dominated by salts, particularly the sodium salt. In one embodiment, hyaluronic acid sodium salt is used in membrane manufacture, for example, due to its commercial availability. Other salts are also obtained, but unlike alginate, these salts are water soluble.

[0013] Hyaluronate is found throughout the connective tissues of the body, especially in the skin, cartilage, and lens fluid of the eye. It is a very large macromolecule that can reach a molecular weight of several million. It can bind to specialized proteins to form macromolecular complexes that are the structural framework for tissue growth and wound healing. The backbone of hyaluronate is highly negatively charged due to the prevalance of carboxyl functionality. Hyaluronate is unique in the body due to the combination of high molecular weight and high charge density. Due to these properties, hyaluronate can bind many water molecules, thereby maintaining tissue hydration and homeostasis.

[0014] Hyaluronate is biocompatible. Hyaluronate is present throughout the tissues of the body. Therefore, the immune system does not recognize it as foreign. Furthermore, hyaluronate is strongly associated with wound healing, especially scarless wound healing and fetal tissue growth.

[0015] HA may be crosslinked. Methacrylate groups are bonded to available carboxylic acid groups, and these groups are then bonded together by photocuring. However, photocrosslinked HA alone results in a film that is not rigid and easily fractures. To obtain a film with more structure and rigidity, alginate is added in one embodiment. Calcium may be used as a crosslinker, as it is biocompatible and the body has a system to regulate calcium levels. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] More specifically, in one embodiment, the membrane includes hyaluronate and alginate. In addition to these polymers, the membrane may contain a significant proportion of water and may be classified as a hydrogel. A hydrogel is a material that swells when exposed to excess water. At the molecular level, the hydrogel comprises a network of polymer chains dispersed in an aqueous medium. The hydrogel membrane of one embodiment is characterized by crosslinks that connect the individual polymer chains. The crosslinks allow the hydrogel to swell in water but prevent the hydrogel from completely dissolving. Because water itself is biocompatible, hydrogels tend to be biocompatible. Thus, hydrogels are attractive for clinical applications that place materials in contact with living tissue.

[0017] In one embodiment, alginate forms the framework of the membrane due to the ability of alginate to form a cross-linked gel in the presence of calcium. This cross-linked framework provides mechanical stability and shape to the membrane. The hyaluronate component is trapped within the alginate gel, but its release is limited by its larger size than the pores of the alginate gel. Hyaluronate is more hydrophilic than alginate, and therefore water swelling of hydrogel compositions with a high ratio of hyaluronate is greater. At low ratios of hyaluronate to alginate, the hyaluronate component is fully or partially entrapped within the cross-linked alginate matrix, limiting elution. However, at high ratios of hyaluronate to alginate, the cross-linked alginate may not be able to retain the elutable hyaluronate component. The hyaluronate component can be eluted by rinsing the membrane in water, for which hyaluronic acid has a strong affinity. When the hyaluronate is eluted, it leaves empty pores in the membrane that provide interconnected pathways for the diffusion of water. Thus, by altering the water content of the membrane, the physical properties of the membrane, such as flexibility and elasticity, are also altered. The elution of hyaluronate from the membrane during manufacture, by altering the porosity, can be used as a means to advantageously modify the physical properties of the membrane. Hyaluronate elution may also occur in vivo as a means to deliver hyaluronate to wound sites to take advantage of its pro-regenerative wound healing properties.

[0018] Figure 2 shows the water swelling ratio of alginate / hyaluronate membranes as a function of composition. The membranes are hydrophilic and absorb water. Increasing the ratio of hyaluronate in the membrane makes the membrane more hydrophilic and increases the water swelling capacity of the membrane.

[0019] In one embodiment, the membrane is prepared by solution casting, which includes: The water-soluble salt forms of alginate and hyaluronate must be dissolved in an aqueous mixture. A volume of the solution can then be dispensed into a mold. A suitable mold can be of any shape or size. The water in the solution can be evaporated to obtain a dry film that can be crosslinked by immersion in an aqueous solution of calcium salts. Once crosslinked, a hydrogel film is obtained that swells in water but does not dissolve. Crosslinking produces a hydrogel film that swells in water but does not dissolve. Similar techniques for obtaining cast films, such as spin casting, doctor blading with a casting knife, and extrusion, can produce films that do not require a water evaporation step. These films can be crosslinked with calcium without the need for a drying step.

[0020] Doctor blade is a tool used to create a wet film of a defined thickness. In one embodiment, the doctor blade is used after dispensing a volume of alginate / hyaluronate solution on a substrate. The doctor blade is then placed over the solution to spread the solution into a flat film of a defined thickness. The doctor blade removes excess solution, thereby producing a wet film of a defined thickness that covers the substrate.

[0021] Tissue anchor More specifically, liquid tissue anchor embodiments using a sequestering solution will now be discussed. The tissue anchor embodiments described below may be used in conjunction with the above embodiments or may be used independently of those embodiments.

[0022] One embodiment includes a method of treating an adhesion barrier or any implantable device comprised of a cross-linking component (such as calcium alginate) that can be decrosslinked by removing one or more cross-linking agents (e.g. calcium) with a sealing solution at the injury site that removes the cross-linking agent (such as calcium). One embodiment of the present invention can also be understood as a sealing solution per se (irrespective of the implant).

[0023] One embodiment of the sequestration solution includes a calcium chelating agent, while other embodiments are not so limited.

[0024] In one embodiment, the sequestering solution functions by disrupting crosslinks (see above discussion regarding crosslinking embodiments) within the implant. The disruption of crosslinks occurs by binding a sequestering agent to the crosslinking agent within the implant. In one embodiment, the sequestering agent binds to the crosslinking agent more strongly than the crosslinkable components of the implant bind, causing disruption. More specifically, the sequestering agent can sequester the crosslinking agent or ions, thereby lowering the overall energy of the system. This energy reduction relaxes the implanted device, reducing the mechanical integrity of the device. The device conforms to tissue geometry and becomes mucoadhesive due to the nature of hydrogen bonding. This mucoadhesion eliminates the need for other anchoring devices (e.g., sutures or tissue glues).

[0025] Figure 3 is a series of photographs showing the application of alginate and hyaluronate membranes to the intestine of a rat model for abdominal trauma. The membranes are flexible and can be easily placed in precise locations. A syringe applies any liquid tissue anchor that promotes tissue adherence and biosorption of the membrane.

[0026] Mechanically robust implants (e.g., alginate adhesion membranes) may remain in the body beyond the critical healing period (approximately two weeks), which can be problematic as the probability of an undesirable immune response increases if the implant is in the body for an extended period of time. In one embodiment, the sealing solution increases the rate of bioabsorption of the adhesive barrier. However, in one embodiment, the implanted device, when used with the sealing solution, completely resorbs within two weeks of the procedure. However, other embodiments may shorten or lengthen this period.

[0027] In various embodiments, suitable sequestering agents are salts of organic molecules that contain multiple anionic functional groups that can bind to the crosslinker (calcium, magnesium, cadmium, silver, zinc, silicon, oxidizing agents, protonic acids, compounds that can be metallated, etc.) Examples include citric acid, EDTA, EGTA, BAPTA, tetracycline, and phosphate salts.

[0028] In one embodiment, the strength of the sealing solution depends on the molar concentration of the sealing agent. For example, a solution formulated with a greater molar concentration of the sealing agent will break more crosslinks in the implant, and the rate of bioabsorption will increase accordingly. Thus, the concentration of the sealing agent in the sealing agent solution can be adjusted to obtain a desired rate of resorption of the implant in the body. For example, 300 mM citrate will provide one week of bioabsorption for an alginate / hyaluronate film crosslinked with 100 mM calcium chloride solution. Meanwhile, 100 mM citrate will provide two weeks of bioabsorption for an alginate / hyaluronate film crosslinked with 100 mM calcium chloride solution. Furthermore, without the sealing solution, the same film will survive for six weeks. This adjustment allows one implant to facilitate healing support for various indications. For example, hernia repair may require long-term support, such as six weeks, until fibroblast growth is sufficient. This time frame is in contrast to abdominal anti-adhesion, which requires bioabsorption in approximately two weeks.

[0029] In one embodiment, a surgeon can use a sealing solution during any surgical procedure in which an implant is used that is comprised of a cross-linking component (such as calcium alginate) that can be decrosslinked with a sealing solution to prevent unwanted tissue adhesion or unwanted scar tissue attachment. The surgeon applies the sealing solution to the surface of the implant with a suitable delivery device (e.g., syringe, spray, etc.). The sealing solution acts quickly to break down the unwanted cross-links (e.g., calcium). The treated implant then conforms to the contours of the underlying tissue and adheres more strongly.

[0030] In one embodiment, the sealing solution can be formulated with a thickening agent to facilitate application of the sealing solution to the wound site. The thickening agent increases the viscosity of the solution to produce a thick, syrupy liquid. The thickening agent increases the solution viscosity to produce a thick, syrupy liquid. The beneficial effect of the thickening agent is that a more viscous sealing agent is better trapped at the application site than a less viscous aqueous liquid. In one embodiment, the thickening agent is sodium hyaluronate, known for both its biocompatibility and its ability to thicken the solution.

[0031] For biocompatibility in various embodiments, the sequestration solution may contain salts to buffer pH and adjust osmolality, such as those commonly found in phosphate buffers.

[0032] One embodiment is an alginate barrier that is specifically cross-linked with calcium and treated with a corresponding calcium sequestrant solution. However, in other embodiments, the same method can be applied to other ions. For example, in various embodiments, the alginate barrier is cross-linked with cations such as barium, strontium, copper, iron, etc. The same sequestrants can be used to disrupt these cross-linkers.

[0033] Crosslinking of a material refers to an increase in the number of bonds between the material and itself or another material. The increase in bonds changes the refractive index of the entire material, distorting light passing through the material. In this embodiment, a sequestering solution is included that reduces bonds within the implant, so that the refractive index of the resulting implant changes with administration of the sequestering solution. For example, an alginate and HA adhesion barrier is translucent when crosslinked and becomes transparent when a calcium sequestering solution is applied. Figure 1 shows an example of a membrane (2 cm x 4 cm) containing alginate and hyaluronate. The surface of the membrane is thin, flexible, hydrophilic, translucent, and has a smooth, lubricating surface.

[0034] In one embodiment, the hydrogel membrane and sealing solution are provided in a kit. The kit would also include a delivery device suitable for applying the sealing solution to the wound site. A surgeon or other medical personnel in the operating room would use the kit to apply the membrane and the appropriate amount of sealing solution to the wound site. This approach allows the end user great flexibility in adjusting the membrane size and solution volume to suit the specific needs of the patient.

[0035] A sealing solution can be applied to the membrane hours, days, or weeks after implantation of the membrane. For example, a hydrogel membrane can be placed at a wound site to prevent unwanted scar tissue adhesions (e.g., flexor tendon repair). After a period of scar formation, usually 3-14 days, the membrane barrier is no longer necessary and therefore a sealing solution can be injected into the wound site to completely dissolve the membrane. This action aims to remove the membrane from the wound site, thus preventing an unwanted foreign body reaction. The sealing solution can be introduced by penetrating the surrounding tissue with a needle and syringe or by minimally invasive surgical means.

[0036] Multilayer Hydrogel One embodiment of the present invention is a polysaccharide-based bilayer hydrogel film in which one layer promotes regeneration and the second layer prevents the formation of unwanted scar tissue. For example, the hydrogels described in US Pat. Nos. 5,993, 6,141, 6,151, 6,163, 6,171, 6,182, 6,193, 7,196, 7,197, 8,198, 9,103, 9,104, 9,111, 9,112, 9,113, 9,121, 9,136, 9,143, 9,155, 9,166, 9,177, 9,187, 9,199, 10,194, 11,189, 12,196, 13,162, 14,177, 15,189, 16,197, 17,189, 19,199, 19,199, 20,199, 20,199, 21,199, 22,199, 23,199, 24,199, 25,199, 26,199, 27,199, 28,199, 29,200, 30,210, 31,220, 32,230, 33,240, 34,250, 35,260, 36,270, 37,280, 38,290, 39 ...

[0037] One embodiment includes a bilayered hydrogel that contains biopolymers that prevent scar tissue adhesions on one side and promote healthy regeneration on the other side. The anti-adhesion layer includes hyaluronate and alginate. The regeneration layer includes collagen and hyaluronate. The two layers are distinct and covalently bonded. One embodiment includes a collagen matrix that promotes cell attachment and proliferation.

[0038] The embodiments solve the problem of undesirable soft tissue adhesion as well as aid in the regeneration of damaged tissue to reduce critical healing times. Various embodiments provide anti-adhesive and regenerative layers using non-synthetic, all-natural components. One embodiment includes a biocompatible bilayer hydrogel composed of natural polysaccharides.

[0039] One embodiment is self-adhesive, eliminating the need for sutures or screws. One embodiment may be coupled (e.g., coated) with a mesh material to allow for better tissue bonding (e.g., suturing tissue to the mesh) and may be useful in a variety of procedures such as hernia repair, gallbladder removal, etc. More generally, an embodiment may be implanted in a variety of surgical procedures, including intraperitoneal surgery and / or procedures involving the abdomen, gynecological system, lungs, tendons, heart, neuroanatomy, etc.

[0040] In one embodiment, a membrane with alginate and a photoreactive derivative of hyaluronate (GMHA) was prepared according to the methods described, for example, in WO 02009 / 108760, WO 2012 / 048283, and WO 2012 / 048289, all of which are incorporated herein by reference. After preparation of the first membrane layer, the sample was dried under sterile conditions and a second layer of collagen and GMHA was cast on top. The two layers were chemically crosslinked and fused by treatment with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC). Bilayer formation was confirmed using confocal imaging of fluorescently labeled hyaluronate and collagen under immunostaining. Diamidino-2-phenylindole (DAPI) was used to characterize cell morphology in vitro. In vitro cell morphology and characterization showed that the collagen layer effectively provided an adhesive, proliferative substrate. The anti-adhesion layer effectively prevents cell proliferation and attachment.

[0041] FIG. 4 includes images of a bilayer film containing alginate, hyaluronate, and collagen. The film was photographed by confocal laser scanning fluorescence microscopy. FIG. 4(A) and FIG. 4(B) respectively show the presence of fluorescently labeled hyaluronate in the anti-adhesion layer (containing hyaluronate and alginate) and in the regeneration layer (containing hyaluronate and alginate). FIG. 4(C) shows the adhesion morphology of human dermal fibroblasts attached to the regeneration layer. FIG. 4(D) shows that the cells adhere poorly to the anti-adhesion layer. FIG. 4(E) is a photograph showing the advantageous handling properties of the bilayer film. In summary, these images show that the regeneration layer provides an adhesive substrate for the cells and the anti-adhesion layer prevents cell attachment.

[0042] HA in FIG. 5 is a linear polysaccharide with repeating disaccharide units consisting of sodium D-glucuronate and N-acetyl-D-glucosamine. Natural glycosaminoglycans are components of skin, synovial fluid, and subcutaneous and interstitial tissues. HA is metabolically removed from the body and functions to protect and lubricate cells and maintain the structural integrity of tissues. The anionic carboxylic acid groups immobilize water molecules that give HA its viscoelastic and anti-cell adhesion properties. In various embodiments, the layers can be fused together using any suitable crosslinking technique. For example, photoinitiated crosslinking of film components grafted with polymerizable functionalities fuses the layers. Suitable chemical crosslinkers (e.g., EDC) may be used. Ionic crosslinking (e.g., calcium crosslinking of alginate components) may also fuse the various layers together. The surgical area remains visible even with the addition of a second layer.

[0043] Although Figure 5 illustrates crystal templating, other embodiments may include the same process, except that the embodiments omit the crystal templating related steps (e.g., steps 2 and 2 are not performed in some embodiments, but the remaining steps in Figure 5 are performed), and instead proceed with an anti-adhesion layer consisting essentially of HA and alginate.

[0044] Although bilayered hydrogels have been discussed, the embodiments are not limited to two layers, but instead may include 3, 4, 5, 6, 7, 8 or more layers. Any of the outer layers may be anti-adhesion with one or more regenerative layers disposed between the outer layers.

[0045] The embodiments are also not limited to HA / collagen and alginate / HA layers. For example, the anti-adhesion layer may be composed of any polymer or combination of polymers that presents a smooth, non-adhesive surface. The regeneration layer may be composed of any combination of polymers or proteins (e.g., laminin) that promote cell attachment and proliferation.

[0046] Therapeutic Drug Delivery One embodiment of the present invention is a biocompatible membrane comprising alginate and hyaluronate that releases a pharmaceutical active ingredient at the wound site. The active ingredient may be an antibiotic, anti-inflammatory, chemotherapeutic agent, an anti-scarring agent, and / or a pro-regenerative drug (e.g., growth factors or stem cells).

[0047] Scarring, inflammation, and bacterial infections are unwanted complications of surgical procedures. During surgical procedures, body tissues and organs can be intentionally or inadvertently injured. These injuries can trigger a wound healing response that leads to scarring and inflammation. Scarring becomes problematic when scar tissue attaches between adjacent tissues or organs where they would not normally be attached. Patients are susceptible to bacterial infections, especially around polymeric or metal implants that provide niches for bacterial growth.

[0048] In one embodiment, the membrane comprises alginate and hyaluronate with an encapsulated pharmacoactive ingredient. In one embodiment, the membrane essentially comprises alginate and hyaluronate with an encapsulated pharmacoactive ingredient. In one embodiment, the membrane loaded with drug is obtained by mixing alginate and hyaluronate with the active ingredient in solution, either in dispersed or microcrystalline form, and then using, for example, casting into a mold, spin coating, doctor blading, or other methods to obtain a planar membrane. The membrane can then be stabilized by crosslinking with a multivalent cation, such as, but not limited to, calcium. In some cases, the membrane can be further stabilized by replacing either the alginate or hyaluronate with its photoreactive derivative (which undergoes chemical crosslinking when exposed to an ultraviolet or visible light source). In one embodiment, the membrane can be prepared without the active ingredient and then subsequently loaded with the ingredient. For example, the membrane is allowed to absorb the active ingredient from the solution by immersing the membrane in a concentrated solution. In one embodiment, the membrane can be incubated with a solution of the active ingredient, which is covalently or electrostatically bound to the polymer that constitutes the membrane.

[0049] An embodiment includes a method of using one of the drug-loaded membrane embodiments to inhibit, reduce, or prevent scarring, inflammation, or bacterial infection. The membrane can be used in any anatomical area of ​​the body, such as the abdominal cavity, peritendinous space, sinus cavity, or other areas following a surgical procedure where there is a risk of unwanted scarring or inflammation. Similarly, the membrane can be placed near or around any implant that poses a risk of bacterial infection. An embodiment includes a method of using the drug-loaded membrane embodiment to deliver chemotherapeutic agents to a tumor or to a treatment site following tumor removal. In one embodiment, the invention is a method of using the drug-loaded membrane embodiment described above to deliver regenerative agents, such as growth factors or stem cells, that promote tissue repair and healing. The membrane can be used in both open and minimally invasive surgery.

[0050] In one embodiment, the drug-loaded membrane is treated with a stimulus, preferably a solution or gel, to improve the release characteristics of the membrane. For example, the solution can increase the rate of membrane dissolution and therefore the release rate of the encapsulated active pharmaceutical ingredient. Such a solution includes a chelating agent that sequesters multivalent cations that stabilize the membrane. In one embodiment, the solution consists essentially of a chelating agent that sequesters multivalent cations that stabilize the membrane. The solution can be applied after the membrane is placed at the wound or treatment site. However, in other embodiments, the solution can be applied to the membrane hours, days, or weeks after implantation of the membrane. Application of the solution at a later time allows the medical practitioner to tailor the drug release to the specific needs of the patient.

[0051] One embodiment includes a membrane that is intended to release the active ingredient at the wound site, thus avoiding the side effects of systemic delivery. Such an embodiment is biocompatible and bioabsorbable. An embodiment that includes a membrane can be easily cut and trimmed during a surgical procedure and is convenient for covering the injured surface of tissues and organs. Such an embodiment can be inserted into deep or superficial wounds to release the active ingredient that reduces or prevents scarring, inflammation, or bacterial infection.

[0052] Hydrogel membranes consist of a network of alginates and hyaluronates that swell in water. This network provides pores that can absorb active ingredients from concentrated solutions. The pores of the hydrogel membrane constitute interconnected pathways through which water can permeate. Initially, the pores are small, in the angstrom to nanometer range, and can only absorb small molecules such as solvents, salts, and organic metabolites. As water penetrates the membrane, the pores swell, increasing in size and volume. The fully expanded pores are in the nanometer to micrometer range and can accommodate the diffusion of peptides, proteins, and macromolecules.

[0053] The pores in the membrane may be formed by the elution of the hyaluronate component of the membrane. At low ratios of hyaluronate to alginate, the hyaluronate component is fully or partially encapsulated in the cross-linked alginate matrix, limiting elution, but at high ratios of hyaluronate to alginate, the cross-linked alginate may not be able to retain elutable hyaluronate. The hyaluronate component can be eluted by rinsing the membrane in water, for which hyaluronate has a strong affinity. As the hyaluronate is eluted, empty pores remain in the membrane, providing interconnected pathways for the diffusion of water and drug molecules. The elution of hyaluronate from the membrane occurs in vivo and can be used as a method of delivering hyaluronate to wound sites. This would be advantageous as a method to take advantage of the regenerative wound healing properties of hyaluronate.

[0054] In one embodiment, the membranes can be fabricated with interconnected pore networks on the scale of micrometers to hundreds of micrometers by crystalline templating, a method that creates a porous network by the nucleation and growth of crystals within a cast film. Such membranes can be fabricated with: casting a solution of alginate, hyaluronate and crystallizable molecules into a form or container; allowing the solvent to evaporate; growing crystals of the crystallizable molecules by spontaneous nucleation or by deliberate introduction of crystalline seeds; crosslinking the alginate and / or hyaluronate around the crystals; and They can be prepared by dissolving the crystals so that a porous network of the crystals is templated into the membrane. The crystal growth process ensures pore interconnectivity and results in a dendritic structure. This pore system structure favors the diffusion and release of the trapped drug molecules (e.g., interconnected pores allow greater diffusion of the drug into the hydrogel).

[0055] The solution from which the membrane may absorb drugs or other therapeutic agents from the solution may be an aqueous solution, since water is a suitable solvent to promote swelling of the hydrogel membrane and diffusion of the active ingredient into the pores. However, since many drugs have low solubility in water, the concentrated solution may be a mixture containing water and water-miscible solvents such as alcohols (e.g., methanol, ethanol, ethylene glycol), polar aprotic solvents miscible with water (e.g., acetone, dimethyl sulfoxide, dimethylformamide), acids, and / or bases. These mixtures have the effect of dissolving drugs that are poorly water-soluble and swelling the membrane. The proportion of water in these mixtures may range from 100% to 0% depending on the solubility characteristics of the particular drug.

[0056] The hydrogel membrane is not limited by the types of drugs that can be incorporated. In various embodiments, the hydrogel membrane may incorporate proteins, peptides, and small molecules. Embodiments may include chemotherapeutic agents, regenerative agents such as growth factors and stem cells, and drugs used to prevent or treat inflammation, infection, scarring, and adhesions. Embodiments may include an active ingredient selected from vancomycin, tobramycin, doxorubicin, mometasone furoate, and their hydrochloride salts. In one embodiment, the hydrogel membrane may also be formulated to release macromolecules such as vascular endothelial growth factor and sodium hyaluronate. The hydrogel membrane may be formulated with non-active ingredients (e.g., binders, surfactants, salts, etc.) that aid in the release of the active ingredient.

[0057] The drug-loaded hydrogel membrane may be used during surgical procedures. In one embodiment, the drug-loaded membrane may reduce scarring and inflammation on top of injured tissues and organs. The injured tissue may be an internal tissue where the membrane is inserted into a body cavity, or an external tissue where the membrane is applied locally to the injured area. In one embodiment, the drug-loaded membrane may be placed adjacent to an implant that may be at risk of causing bacterial infection at the surgical site. In one embodiment, the drug-loaded membrane may be placed near a tumor or at the site of tumor resection to release a chemotherapeutic agent.

[0058] In one embodiment, the hydrogel membrane, initially unloaded with drug, may be provided in a kit that includes a drug component that is combined with the membrane immediately prior to use. This method has the advantage that the membrane and drug can be stored separately. For example, a surgeon, nurse, or other medical personnel in a hospital, office, or operating room can open the kit, soak the membrane in a drug solution, and then apply the soaked membrane to the injury site. This method allows great flexibility to the end user, as they can mix and match membrane and drug combinations to meet the specific needs of the patient based on disease state, weight, age, and metabolism.

[0059] The timing of drug release from hydrogel membranes is determined by many factors. Among these factors are the amount of drug loaded, the membrane composition (e.g., the ratio of hyaluronate to alginate), the degree of crosslinking, and the water content of the membrane. For example, increasing the ratio of hyaluronate to alginate can decrease the crosslinking density of the membrane, thereby making it more permeable to the diffusion of the encapsulated drug. In another example, the water content due to swelling is correlated to the porosity of the membrane, so that membranes with higher water content may exhibit faster release.

[0060] In one embodiment, the release of the active ingredient from the membrane may be modified by the stimulus used. Such a stimulus may be a chelating agent in the form of an aqueous solution or gel that sequesters a bridging ion (e.g., calcium) that stabilizes the membrane. In one embodiment, such a stimulus in the form of an aqueous solution or gel may consist essentially of a chelating agent that sequesters a bridging ion (e.g., calcium) that stabilizes the membrane. Suitable chelating agents are salts of organic molecules with multiple anionic functional groups that can bind to calcium (or whatever bridging ion is used). Examples include salts of citric acid, EDTA, EGTA, BAPTA, tetracycline, and phosphates. The stimulus may be applied during a surgical procedure after the membrane is inserted inside the human body. In response to the stimulus, the membrane swells, increasing the pore size of the membrane and accelerating the diffusion rate of the active ingredient from the membrane to the wound environment. The pore size increases by at least 10 times and up to 1,000 times. A beneficial effect of the stimulation is that the release rate of the drug can be tailored to the patient's condition, such as weight, age, metabolism, or disease state. The stimulation can be delivered to the surface of the implanted membrane via a syringe, spray mechanism, or the like.

[0061] In other embodiments, the stimulus may be applied to the membrane hours, days, or weeks after implantation of the membrane. For example, a virtual membrane loaded with the antibiotic vancomycin can be inserted adjacent to the bone implant. The membrane exhibits antibiotic release. If a medical practitioner notices symptoms of infection around the bone implant, the medical practitioner can choose to stimulate the membrane to increase the release rate of the antibiotic and address the infection. After all the drug has been released, the medical practitioner can determine that the membrane, having served its purpose of delivering vancomycin, should be completely solubilized by the action of the stimulus, thus clearing the wound site of the presence of the foreign membrane. The stimulus can be introduced by a needle and syringe penetrating the surrounding tissue or by minimally invasive surgical means.

[0062] Many of the above embodiments combine a therapeutic agent with a porous hydrogel. One such porous hydrogel described above is a crystal-templated hydrogel. As an example, the embodiments found in US Patent Publication No. 20110008442 may be utilized with a therapeutic agent. That application, the contents of which are incorporated herein by reference, includes some embodiments in which the porous hydrogel is formed by crystal templating, and other embodiments in which the pores are not formed by crystal templating. The therapeutic agent described herein may include these pores in any of these embodiments.

[0063] In one embodiment, the tissue anchor is used to deploy a therapeutic agent. For example, a hydrogel containing the therapeutic agent may be applied to the agent. The hydrogel may be applied to a patient and left in place. However, a stimulus may be applied to "tune" the hydrogel. For example, the hydrogel may include calcium crosslinks and a therapeutic agent. A calcium chelator may be applied to the calcium crosslinked hydrogel to (1) aid in the attachment of the hydrogel to the patient (e.g., to the tumor), (2) speed up or tune the dissolution time of the hydrogel (e.g., 1 hour or 1 week), and (3) tune the application time of the therapeutic agent (e.g., 1 hour or 2 weeks).

[0064] The embodiment may be combined with the multi-layer hydrogel described above. Thus, one embodiment includes a multi-layer hydrogel that can be used to deploy a therapeutic agent. The multi-layer hydrogel includes a first layer that provides a regenerative effect (e.g., a regenerative layer that includes collagen and hyaluronate) and a second layer that is an anti-adhesion agent (e.g., an anti-adhesion layer that includes hyaluronate and alginate), and further includes a therapeutic agent with holes in the second layer.

[0065] One embodiment includes a film that has four beneficial attributes for an adhesive barrier. The embodiment overcomes the traditional burden of adhesive barriers, poor handling characteristics, which have significantly hindered their market acceptance. The first attribute is the ability to include the barrier's function to be manipulated in a manner relevant to a surgical setting (e.g., open surgery, use of trocars for laparoscopic surgery, etc.). The second attribute is adhesion to tissue. If the barrier can remain where it is implanted, it not only provides site-specific tissue support, but also eliminates (or at least reduces) the need for suturing or other fixation steps. The third attribute is conformability. The final attribute is bioabsorbability. One embodiment of the present invention meets all four of these attributes.

[0066] One embodiment uses a technique that adds porosity and fibers to the hydrogel. Different crystals and different densities of biopolymers are used, providing flexibility for an easily tunable process, giving different polymer properties, different patterns, etc. In addition to this flexibility, the production of the hydrogel can be scaled up. In one embodiment, HA is photocrosslinked around the periphery of the crystalline network, and alginate is chemically crosslinked around the periphery of the crystalline network. Compressing the biopolymer into fibers enhances the strength of the film, while the porous network provides elasticity. Thus, the crystallization process gives the material unique fibers and pores that provide the necessary handling properties to an otherwise fragile material. The crystallization process is cheap, simple, time-saving, and does not require sophisticated equipment or technology. Film casting is no different from any other casting.

[0067] One embodiment may be applied wet, which is suitable for endoscopic procedures, eliminating the need to degrease the surgical area. The film is flexible and translucent, allowing visualization of the surgical field. Additionally, the surgical incision can be much smaller than with wettable implants. One embodiment of the film is also temporarily repositionable. For example, in one embodiment, upon initial placement in the surgical field, the film is easily repositionable. However, within 24 hours of placement, the film changes from a gel to a mucus. At this point, the film is no longer repositionable and strongly adheres to tissue. This change occurs due to replacement of calcium crosslinks in the film by endogenous sodium ions.

[0068] One embodiment of the present invention includes a membrane comprising alginate and hyaluronate. The membrane can be obtained by methods such as casting into a mold, spin coating, doctor blading, extrusion, etc. The membrane is stabilized by cross-linking with a multivalent cation, preferably calcium. The membrane is stabilized by cross-linking with a multivalent cation, preferably calcium. In some cases, the membrane can be further stabilized by replacing either the alginate or the hyaluronate with its photoreactive derivative, which undergoes chemical cross-linking when triggered by ultraviolet or visible light sources.

[0069] One embodiment of the present invention is a method of using the membrane described above to inhibit, reduce, or prevent scar tissue adhesions. The membrane can be used in any anatomical location of the body where there is a risk of scar tissue adhesions. In surgical procedures, the membrane can be placed between two adjacent organs or tissues. The membrane can be used in both open and minimally invasive surgery.

[0070] One embodiment of the present invention is a method of treating the above-mentioned membrane with an irritant, preferably a solution or gel, to change the membrane's properties. For example, the solution can enhance the membrane's tissue attachment or increase the rate of membrane absorption in the body. Such a solution contains a chelating agent (e.g., a calcium chelating agent) that binds multivalent cations that stabilize the membrane. The solution is applied during a surgical procedure after the membrane is inserted into the human body. In some cases, the solution may contain a viscosity modifier to facilitate the surgical procedure.

[0071] One embodiment of the present invention is the encapsulation of a pharmaceutical active ingredient in the above membrane comprising alginate and hyaluronate. The active ingredient may be an antibiotic, anti-inflammatory, chemotherapeutic agent, an anti-scarring agent, and / or a regenerative agent such as growth factors or stem cells. In one embodiment, the release of the active ingredient from the membrane may be modified using the above stimuli.

[0072] One embodiment of the present invention is a bilayer hydrogel membrane that includes two distinct layers, one layer that inhibits, reduces or prevents the deposition of scar tissue and the other layer that promotes wound healing, the two layers being joined together via chemical, ionic or physical bonds. EXAMPLES

[0073] The following examples relate to further embodiments.

[0074] Example 1 is a hydrogel film comprising the following: uncrosslinked hyaluronate and crosslinked alginate; and Calcium chelating agents where (a) the alginate is cross-linked with calcium; (b) the hydrogel film is planar and comprises a width, a length, and a thickness that is less than the width and length; (c) configured to increase the bioabsorbability of the hydrogel film in response to application of a calcium chelating agent to the hydrogel film;

[0075] In Example 2, the subject matter of Example 1 can optionally be configured such that a calcium chelator disrupts calcium cross-links within the hydrogel film.

[0076] In Example 3, the subject matter of Example 1 or 2 may optionally be such that the calcium chelating agent is selected from the group including citrate, EDTA, EGTA, and BAPTA.

[0077] In Example 4, the invention specific matters of Examples 1 to 3 are such that, in some cases, the concentration of the calcium chelating agent can be 0.05 to 1.0 molar.

[0078] In Example 5, the invention-specifying matter of Examples 1 to 4 can be a thickening agent in some cases.

[0079] In Example 6, the inventive features of Examples 1 to 5 may optionally include a thickening agent that includes sodium hyaluronate.

[0080] In Example 7, the inventive features of Examples 1 to 6 can be configured such that, in some cases, a thickener is added to increase the viscosity of the calcium chelating agent.

[0081] In Example 8, the inventive features of Examples 1-7 are such that, in some cases, the hydrogel film can consist essentially of hyaluronate and alginate.

[0082] In Example 9, the inventive features of Examples 1-8 are such that, in some cases, the hydrogel film may contain at least 1% and no more than 33% hyaluronic acid composition.

[0083] In Example 10, the inventive features of Examples 1 to 9 are optionally further characterized by a first hydrogel layer comprising an uncrosslinked hyaluronate and a crosslinked alginate; and A second hydrogel layer comprising collagen and hyaluronate. It may be composed of:

[0084] In Example 11, the invention-specifying matters of Examples 1 to 10 may be, in some cases, the first hydrogel layer is monolithic; the second hydrogel layer is monolithic, but not monolithic with the first hydrogel layer; and the first hydrogel layer and the second hydrogel layer are covalently bonded to one another; It is possible.

[0085] In Example 12, the subject matter of Examples 1-11 is optionally supplemented with a third hydrogel layer comprising additional uncrosslinked hyaluronate and additional crosslinked alginate.

[0086] Here, the third hydrogel layer is monolithic but not monolithic with the second hydrogel layer, the third hydrogel layer and the second hydrogel layer are covalently bonded to each other, and the second hydrogel layer may be between the first hydrogel layer and the third hydrogel layer.

[0087] In Example 13, the inventive features of Examples 1 to 12 are such that, in some cases, the alginate can be crosslinked around the uncrosslinked hyaluronate.

[0088] In Example 14, the inventive features of Examples 1-13 may optionally include a therapeutic agent selected from the group including drugs, pharmaceutical preparations, peptides, proteins, medicines, hormones, and polymers.

[0089] In Example 15, the inventive features of Examples 1-14 can be configured such that, in some cases, the hydrogel film can be configured to increase the release rate of the therapeutic agent in response to the application of a calcium chelating agent to the hydrogel film.

[0090] In Example 16, the inventive features of Examples 1-15 are further modified such that, optionally, the alginate can be crosslinked around the therapeutic agent.

[0091] In Example 17, the inventive features of Examples 1-16 are such that, in some cases, the hydrogel film can be configured such that increasing the content of hyaluronate in the hydrogel film increases the release rate of the hydrogel film with respect to the therapeutic agent.

[0092] In Example 18, the subject matter of Examples 1-17 can optionally be a therapeutic agent selected from the group including drugs, pharmaceutical preparations, peptides, proteins, medicines, hormones, and polymers.

[0093] In Example 19, the inventive features of Examples 1-18 are such that, in some cases, the hydrogel film can be configured such that mucoadhesiveness of the hydrogel film is increased in response to application of a calcium chelating agent to the hydrogel film.

[0094] In Example 20, the inventive features of Examples 1-19 can be configured such that, in some cases, the hydrogel film has increased transparency in response to the application of a calcium chelating agent to the hydrogel film.

[0095] In other embodiments, the thickness of the hydrogel film is 5-30 μm. However, in other embodiments, the thickness of the hydrogel film is 5, 10, 15, 20, 25, 35, 40, 45, or 50 μm or less. In other embodiments, the thickness of the hydrogel film is 5-10, 10-15, 15-20, 20-25, 25-30, 30-40, 50-60, 70-80, or 90-100 μm. In other embodiments, the thickness of the hydrogel film is 250 μm or less.

[0096] Example 21 is a hydrogel film consisting essentially of crosslinked alginate that is crosslinked around uncrosslinked hyaluronate to encapsulate the uncrosslinked hyaluronate within the crosslinked alginate; Blocking agent and A kit comprising: (a) the alginate is ionically cross-linked; (b) the hydrogel film is flat; (c) the hydrogel film is configured such that bioabsorbability of the hydrogel film is increased in response to application of the sealing agent to the hydrogel film; and (d) the sequestering agent is configured to sequester ions; Kit Including:

[0097] In Example 22, the invention-specifying matters of Example 21 may be, in some cases, The hydrogel film is a first hydrogel layer comprising uncrosslinked hyaluronate and crosslinked alginate; a second hydrogel layer comprising a therapeutic agent selected from the group consisting of drugs, pharmaceutical agents, peptides, proteins, medicines, hormones, and polymers; Includes; (a) the first hydrogel layer is monolithic; (b) the second hydrogel layer is monolithic, but not monolithic with the first hydrogel layer; (c) the first hydrogel layer and the second hydrogel layer are chemically bonded to each other; (d) the second hydrogel layer is adhesive; and (e) The first hydrogel layer can be anti-adhesion.

[0098] In Example 23, the invention-specifying matters of Examples 21 and 22 may be, in some cases, the hydrogel film comprises a therapeutic agent selected from the group including drugs, pharmaceutical agents, peptides, proteins, medicines, hormones, and polymers; and The hydrogel film can be constructed such that the release rate of the hydrogel film for a therapeutic agent is increased in response to application of a sequestering agent to the hydrogel film.

[0099] In Example 24, the invention-specifying matters of Examples 21 to 23 may be, in some cases, The hydrogel film can be configured such that mucoadhesive properties associated with the hydrogel film are enhanced in response to application of a sealant thereto.

[0100] FIG. 6 includes a method in one embodiment.

[0101] Block 605 includes applying a hydrogel film to the subject, the hydrogel film including uncrosslinked hyaluronate and crosslinked alginate, and the alginate being crosslinked with calcium.

[0102] Block 610 includes: (a) to enhance the bioabsorbability of the hydrogel film in response to application of a calcium chelating agent to the hydrogel film; (b) to tailor the release rate of the hydrogel film for a therapeutic agent contained within the hydrogel in response to application of a calcium chelating agent to the hydrogel film; and / or (c) enhancing mucoadhesiveness of the hydrogel film in response to applying a calcium chelating agent to the hydrogel film; The step includes applying a calcium chelating agent to the hydrogel.

[0103] Block 607 is optional. Block 607 includes applying a thickening agent to the calcium chelating agent to increase the viscosity of the calcium chelating agent. This may be done before or after the calcium chelating agent is applied to the hydrogel.

[0104] In one embodiment, the hydrogel film comprises a first hydrogel layer comprising an uncrosslinked hyaluronate and a crosslinked alginate; a second hydrogel layer comprising collagen and hyaluronate; According to such an embodiment, block 605 may include applying a second layer of hydrogel to the patient's wound.

[0105] In one embodiment, the calcium chelator in FIG. 6 is replaced with a sequestrant, and the cross-linked calcium is based on ion-based cross-links that more generally correspond to sequestrants.

[0106] Another embodiment includes a method comprising applying a hydrogel film to a subject, the hydrogel film comprising uncrosslinked hyaluronate and crosslinked alginate, the alginate being crosslinked with calcium; The hydrogel film is planar and includes a width, a length, and a thickness that is less than the width and length. The method further includes applying a calcium chelating agent to the hydrogel such that bioabsorbability of the hydrogel film increases in response to application of the calcium chelating agent to the hydrogel film. The method further includes applying a calcium chelating agent to the hydrogel one or more days after application of the hydrogel to the patient. In one embodiment, the method further includes applying a thickening agent to the calcium chelating agent to increase the viscosity of the calcium chelating agent. In one embodiment, the hydrogel film comprises a first hydrogel layer comprising uncrosslinked hyaluronate and crosslinked alginate; a second hydrogel layer comprising collagen and hyaluronate; The method further includes applying a second hydrogel layer to the wound of the patient. Another embodiment includes rolling the hydrogel film into a roll, the outer surface of which includes the first hydrogel layer. The embodiment includes contacting the first hydrogel layer with a trocar, introducer, or tube, and introducing the hydrogel film into the patient without the hydrogel film sticking or adhering to the trocar, introducer, or tube. In one embodiment, the hydrogel film includes a therapeutic agent selected from the group including drugs, pharmaceutical agents, peptides, proteins, medicines, hormones, and macromolecules. The method may include providing a calcium chelator to the hydrogel film to adjust the release rate of the hydrogel film for the therapeutic agent. In one embodiment, the method may include providing a calcium chelator to the hydrogel film to increase mucoadhesiveness of the hydrogel film.

[0107] Other embodiments include a method comprising applying a hydrogel film to a subject, the hydrogel film comprising uncrosslinked hyaluronate and crosslinked alginate. The alginate is ionically crosslinked, and the hydrogel film is planar and comprises a width, a length, and a thickness that is less than the width and length. The method further comprises applying a sealing agent to the hydrogel such that the bioabsorbability of the hydrogel film increases in response to application of the sealing agent to the hydrogel film. In one embodiment, the method further comprises applying a thickening agent to the sealing agent to increase the viscosity of the sealing agent. In one embodiment, the hydrogel film comprises a first hydrogel layer comprising uncrosslinked hyaluronate and crosslinked alginate; a second hydrogel layer containing a therapeutic agent; The method further includes applying a second hydrogel layer to the wound of the patient. Another embodiment includes rolling the hydrogel film into a roll, the outer surface of which includes the first hydrogel layer. The embodiment includes contacting the first hydrogel layer with a trocar, introducer, or tube to introduce the hydrogel film into the patient without the hydrogel film sticking or adhering to the trocar, introducer, or tube. In one embodiment, the hydrogel film includes a therapeutic agent selected from the group including drugs, pharmaceuticals, peptides, proteins, medicines, hormones, and polymers. The method may include providing a sequestering agent to the hydrogel film to adjust the release rate of the hydrogel film for the therapeutic agent. In one embodiment, the method may include providing a sequestering agent to the hydrogel film to increase mucoadhesion of the hydrogel film.

[0108] Other embodiments do not include a kit, but instead simply include a hydrogel. Such embodiments include an uncrosslinked hyaluronate and a crosslinked alginate both contained within a hydrogel film, with the proviso that: (a) the alginate is cross-linked with calcium; (b) the hydrogel film is planar and comprises a width, a length, and a thickness that is less than the width and length; (c) The hydrogel film is configured such that the bioabsorbability of the hydrogel film is increased upon application of a calcium chelating agent to the hydrogel film. Such a calcium chelating agent would be configured to disrupt calcium cross-links within the hydrogel film. In one embodiment, the hydrogel film consists essentially of a hyaluronate salt and an alginate salt. In one embodiment, the hydrogel film comprises at least 1% and no more than 33% hyaluronic acid composition. In one embodiment, the hydrogel film comprises a first hydrogel layer comprising uncrosslinked hyaluronate and crosslinked alginate; a second hydrogel layer comprising collagen and hyaluronate; In one embodiment, the first hydrogel layer is monolithic; the second hydrogel layer is monolithic, but not monolithic with the first hydrogel layer; and The first and second hydrogel layers are covalently bonded to one another. In one embodiment, the hydrogel film comprises: a third hydrogel layer comprising additional uncrosslinked hyaluronate and additional crosslinked alginate; The third hydrogel layer is monolithic but not monolithic with the second hydrogel layer, the third hydrogel layer and the second hydrogel layer are covalently bonded to each other, and the second hydrogel layer is between the first hydrogel layer and the third hydrogel layer. In one embodiment, the alginate is crosslinked around the uncrosslinked hyaluronate. In one embodiment, the hydrogel film includes a therapeutic agent selected from the group including drugs, pharmaceuticals, peptides, proteins, medicines, hormones, and macromolecules. In one embodiment, the hydrogel film is configured such that the release rate of the hydrogel film of the therapeutic agent increases in response to application of a calcium chelator to the hydrogel film. In one embodiment, the alginate is crosslinked around the therapeutic agent. In one embodiment, the hydrogel film is configured such that the release rate of the hydrogel film of the therapeutic agent increases in response to increasing the content of hyaluronate in the hydrogel film. In one embodiment, the hydrogel film is configured to increase mucoadhesiveness relative to the hydrogel film in response to application of a calcium chelating agent to the hydrogel film. In one embodiment, the hydrogel film is configured to increase transparency in response to application of a calcium chelating agent to the hydrogel film. In one embodiment, the hydrogel film comprises a thickness of 5 to 30 μm. In one embodiment, the calcium chelating agent described in this paragraph is replaced with a sequestering agent, and the cross-linked calcium is based on ionic cross-linking more generally corresponding to the sequestering agent.

[0109] While the present invention has been described with respect to a limited number of embodiments, those skilled in the art will recognize numerous modifications and variations therefrom. It is intended that the appended claims cover all such modifications and variations as fall within the spirit and scope of the present invention.

Claims

1. 1. A hydrogel composition comprising: (a) an uncrosslinked hyaluronate; (b) cross-linked alginate; and (c) a cation-containing cross-linking agent for cross-linking the cross-linked alginate; A hydrogel composition comprising: a chelating agent for chelating said cation; A hydrogel composition system comprising: the hydrogel composition is non-crystalline, non-templated, and is comprised in a hydrogel film having a thickness of 5 to 30 micrometers; Hydrogel composition system.

2. 10. The hydrogel composition system of claim 1 comprising an uncrosslinked alginate, wherein: The cross-linked alginate comprises calcium alginate, the uncrosslinked alginate comprises sodium alginate; and The cross-linking agent comprises calcium, Hydrogel composition system.

3. The hydrogel composition system according to claim 1 or 2, wherein the uncrosslinked hyaluronate salt comprises sodium hyaluronate.

4. The hydrogel composition system of claim 1 or 2, wherein the uncrosslinked hyaluronate comprises hyaluronic acid.

5. The hydrogel composition system according to any one of claims 1 to 4, wherein the concentration of the chelating agent is 100 mM or more.

6. The hydrogel composition system of any one of claims 1 to 5, further comprising at least one of a drug, a pharmaceutical agent, a peptide, a protein, a medicine, a hormone, a polymer, or a combination thereof.

7. The hydrogel composition system of any one of claims 1 to 6, wherein the hydrogel composition is mucoadhesive.

8. the crosslinking agent comprises at least one of magnesium, cadmium, silver, zinc, silicon, an oxidizing agent, a protonic acid, or a combination thereof; The hydrogel composition system of any one of claims 1 to 7, wherein the chelating agent comprises at least one salt of citric acid, EDTA, EGTA, BAPTA, tetracycline, phosphate, or combinations thereof.

9. A kit system comprising a delivery device and the hydrogel composition system according to any one of claims 1 to 8.

10. The kit system of claim 9 , wherein the delivery device comprises a syringe.

11. 11. The kit system of claim 9 or 10, wherein the hydrogel film comprises a width, a length and a thickness, wherein the thickness is less than the width and less than the length.

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