WO2008005276A2 - Growth factor delivery system containing antimicrobial agents - Google Patents

Abstract

The present invention features hydrogel drug delivery systems and methods of producing and using such systems for the treatment of wounds, infections, and other conditions. The systems are based on a hydrogel into which a low concentration of growth factor, e.g., epidermal growth factor, or an antibacterial, antifungal, antiparasitic, or antiviral compound is passively transferred from a dilute aqueous solution. When placed in contact with a wounded, infected, otherwise compromised tissue, the therapeutic agent passively transfers out of the contact lens to provide accelerated healing. The systems are applicable to ocular treatments.

Description

MEDICAL DEVICE/DRUG DELIVERY SYSTEM FOR THE HEALING OF WOUNDS AND THE PREVENTION OF INFLAMMATION AND

DISEASE

BACKGROUND OF THE INVENTION

In general, the invention relates to the fields of hydrogels, drug delivery systems, wound healing, reduction of pain and inflammation, and antibacterial, antifungal, antiparasitic, or antiviral therapy. Corneal wounds caused by injury, disease, or surgery represent a serious medical condition that may lead to loss of sight. For example, persistent epithelial defects can lead to stromal melting, which causes serious visual dysfunction. Wound healing of corneal mucosal tissue has taken on increased importance with the advent of laser corrective surgery to re-establish normal vision for people who do not wish to wear contact lenses or spectacles. These laser surgical methods are used to correct vision for nearsightedness (myopia), farsightedness (hyperopia), and astigmatism. The methods include laser in situ keratomileusis (LASIK), laser epithelial keratomileusis (LASEK), and photorefractive keratectomy (PRK). Surgical procedures and wounds can result in corneal epithelial defects, and inflammation and infection may also occur. These complications can lead to acuity regression, pain, or other adverse effects. Corneal defects from injury or other types of surgery, such as corneal transplants, may also result in these undesirable outcomes. Other disease states may also lead to non-healing defects. Wound healing is thus of critical importance for the outcome of surgery. Infection and disease may occur as a consequence of these types of surgery, or because of trauma related injury. SUMMARY OF THE INVENTION

The present invention features hydrogel drug delivery systems and methods of producing and using such systems for the treatment of wounds, infections, and other conditions. The systems are based on a hydrogel into which a growth factor and an antibacterial, antifungal, antiparasitic, or antiviral compound is passively transferred from a dilute aqueous solution. When placed in contact with wounded tissue or a site of infection or other condition, the therapeutic agent, e.g., growth factor, passively transfers out of the hydrogel to provide accelerated healing and a concomitant reduction in pain. The amount of a growth factor absorbed into the hydrogel may be ≤ 350 ppb, but this amount is effective in producing a therapeutic effect likely because the delivery system is localized and provides a sustained release of the factor. Higher concentrations of growth factor may also be employed. The systems are applicable to ocular wounds, infections, and conditions, especially after vision correcting surgery, as well as other wound treatments. Antibacterial, antifungal, antiparasitic, or antiviral compounds may be released in a similar fashion. These compounds are effective at treating various types of infections and other conditions.

In one aspect, the invention features a polymeric hydrogel that contains a substantially pure growth factor. Exemplary growth factors include epidermal growth factor, platelet derived growth factor, hepatocytic growth factor, human growth hormone, fibroblast growth factor, and combinations thereof. The concentration of the growth factor is, for example, between 0.005 and 350 ppb. Other exemplary concentrations include at most 1, 10, 25, 50, or 100 ppm. The hydrogel has a water content of, for example, between 10% and 90% by weight. Exemplary hydrogel materials include a tetrapolymer of hydroxymethylmethacrylate, ethylene glycol, dimethylmethacrylate, and methacrylic acid. Other examples of hydrogels include etafilcon A, vifilcon A, lidofilcon A, vasurfϊlcon A, and polymacon B. The hydrogel may also be a silicone hydrogel, e.g., balafilcon A, lotrafilcon A, galyfilcon A, acquafilcon, lenefilcon, or senofilcon. In addition, variations of these polymers formed by the use of different packing solutions (e.g., phosphate-buffered saline and boric acid) in the manufacturing process are also included. The hydrogel may be charged or not charged. In various embodiments, the growth factor is capable of being passively released into an environment, e.g., an ocular environment, under ambient or existing conditions. In other embodiments, the hydrogel may be shaped as a contact lens, e.g., one capable of correcting vision. Such a contact lens may be capable of correcting vision in the range of +8.0 to -8.0 diopters, and may have a base curve between 8.0 and 9.0. Hydrogels of the invention may further include other therapeutic compounds as described herein, e.g., an anti-inflammatory compound, such as dexamethasone, fluorometholone, rimexolone, or prednisolone, or an antibacterial, antifungal, antiparasitic, or antiviral compound. Exemplary antibacterial, antifungal, antiparasitic, and antiviral compounds and concentrations are described herein.

The invention further features a method for making a hydrogel drug delivery system by placing the hydrogel, e.g., a contact lens, in an aqueous solution containing a substantially pure growth factor as described herein, which is passively transferred to the hydrogel. This method may further include the steps of washing the hydrogel in an isotonic saline solution and partially desiccating the hydrogel prior to placement in the solution. The aqueous solution has, e.g., a pH between 6.9 and 7.4 and between 0.001 and 10 ng growth factor per μL. The concentration of growth factor in the hydrogel after soaking (i.e., after the medicated hydrogel is manufactured) is, for example, between 5 and 350 ppb. In one embodiment, the hydrogel is placed in the solution of growth factor for at least 30 minutes. The aqueous solution may further include another therapeutic compound as described herein, e.g., an anti-inflammatory compound, such as dexamethasone, fluorometholone, rimexolone, or prednisolone, or an antibacterial, antifungal, antiparasitic, or antiviral compound. In addition to or in alternative to providing a therapeutic effect, an antibacterial, antifungal, antiparasitic, or antiviral compound may be employed to prevent or reduce contamination with infectious organisms during manufacture, storage, or treatment. Sequential aqueous solutions may be employed to add multiple therapeutic agents to a hydrogel.

In another aspect, the invention features a method for treating a wound, infection, or other condition. The method includes placing a hydrogel, as described herein, in contact with the wound of site of infection or condition, wherein the therapeutic agent, e.g., growth factor or antibacterial, antifungal, antiparasitic, or antiviral compound or combination thereof, is passively released from the hydrogel to treat the wound, infection, or condition. In one embodiment, the hydrogel further acts as a protective shield against mechanical abuse. In various embodiments, the wound, infection, or condition is in endothelial tissue, epithelial tissue, the lung, the skin, or the digestive tract. The hydrogel may be placed in a body cavity. In another embodiment, the method causes a reduction in pain compared to a wound not contacted with the medicated hydrogel. Exemplary infections are described herein. The hydrogel may passively release, for example, at least 0.01, 0.05, 0.1, 0.5, 1, 10, 15, or 20 μg of a growth factor, and the hydrogel may be placed in contact with the wound for at least 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 7.5, 10, 15, or 24 hours. The hydrogel may also passively release at least 0.01, 0.05, 0.1, 0.5, 1, 10, 15, 20, 50, 100s, or 1000 μg of other compounds, as described herein. The invention also features a method of delivering growth factors and/or antibacterial, antifungal, antiparasitic, or antiviral compounds by placing a polymeric hydrogel of the invention in contact with a replenishable bodily fluid that is in contact with a wound or site of infection or other condition; and allowing the therapeutic agent to release passively from the hydrogel into the replenishable bodily fluid. In this method, the release of the therapeutic agent from the hydrogel into the replenishable bodily fluid is accelerated compared to the release of the agent from the hydrogel into a non-replenishable bodily fluid. An exemplary wound or site is ocular, and an exemplary replenishable bodily fluid is tear fluid. This method may also be used to deliver anti-inflammatory or other compounds as described herein.

As described herein, an antibacterial, antifungal, antiparasitic, or antiviral compound or combination thereof may be employed in the hydrogel to prevent or reduce contamination with an infectious organism or to treat a secondary infection accompanying a wound or other condition.

As used herein, by "ambient conditions" is meant room temperature and pressure.

By "existing conditions" is meant in situ, as in the eye or other body system.

By "substantially pure" is meant having a purity of greater than 75% by weight. A growth factor of the invention is, for example, greater than 85%, 90%, 95%, or even 99% pure. Use of the term is intended to define purity from other biological compounds, e.g., proteins, carbohydrates, and lipids that are commonly associated with the growth factor in vivo.

By "treating" is meant the medical management of a patient with the intent that a prevention, cure, stabilization, or amelioration of the symptoms will result. This term includes active treatment, that is, treatment directed specifically toward improvement of the disorder; palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disorder; preventive treatment, that is, treatment directed to prevention of the disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the disorder. The term "treatment" also includes symptomatic treatment, that is, treatment directed toward constitutional symptoms of the disorder. The term further includes the promotion of wound closure or healing.

By "therapeutically effective amount" is meant an amount of a compound sufficient to produce a preventative, healing, curative, stabilizing, or ameliorative effect in the treatment of a condition, e.g., an eye wound.

By "wound" is meant an injury to any tissue. Examples of wounds include burns, lacerations, abrasions, bites, surgical wounds, puncture wounds, and ulcers.

By "ocular environment" is meant the tissues of and surrounding the eye, including, for example, the sclera, cornea, and other tissues of the ocular cavity.

By "replenishable bodily fluid" is meant a fluid produced by a mammal that is periodically replaced with new fluid. Examples of replenishable bodily fluids include tears, saliva, mucous, gastric fluids, and urine. All percentages described in the present invention are by weight unless otherwise specified.

Other features and advantages of the invention will apparent from the following description and the claims.

BRIEF DESCRIPTION OF THE DRAWING

Figures IA and IB are groups of the uptake (A) and release (B) of EGF from vasurfilcon A contact lenses.

DETAILED DESCRIPTION OF THE INVENTION This invention provides a polymeric drug delivery system including a hydrogel containing a growth factor, e.g., EGF. Allowing passive transference of the growth factor from a dilute aqueous solution into the hydrogel produces the delivery system. The hydrogel, when placed in contact with a wound, delivers a low concentration of the growth factor. The delivery of the growth factor is sustained over an extended period of time, which is of particular utility in environments, e.g., the eye, that are periodically flushed with bodily fluids, e.g., tears. This sustained delivery accelerates the wound healing process while avoiding potential damaging effects of localized delivery of high concentrations of compounds, e.g., from eye drops. Other therapeutic agents, such as antibacterial, antifungal, antiviral, or antiparasitic compounds, may be delivered as described herein.

Drug Delivery System Hydrogels. This invention may employ different polymer compositions that are useful in the treatment of a variety of tissues. For example, in the ocular environment, conventional soft contact lenses can be used and can be either ionic or non-ionic hydrogels containing between 10% - 90% water by weight and can have any base curve, e.g., from 8.0 to 9.0. The contact lenses may also have the ability to correct vision, for example, over a range of diopters of +8.0 to —8.0, including piano. Exemplary hydrogel contact lens materials include etafilcon A, vifϊlcon A, lidofilcon A, polymacon B, vasurfilcon A, and a tetrapolymer of hydroxymethylmethacrylate, ethylene glycol, dimethylmethacrylate, and methacrylic acid. Silicone hydrogel materials, e.g., balafilcon A, lotrafilcon A, galyfilcon A, acquafilcon, lenefilcon, and senofilcon, may also be employed. These materials may also be employed, in other physical forms, in treating other tissues. Other suitable hydrogel materials are known to those skilled in the art. The hydrogels may be insoluble or may dissolve over time in vivo, e.g., over one day or one week. The growth factor is passively delivered, for example, by diffusion out of the hydrogel, by desorption from the hydrogel, or by release as the hydrogel dissolves.

The drug delivery system may be produced from a partially desiccated hydrogel (or equivalently a partially hydrated hydrogel). The desiccation step removes, for example, approximately 1%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, or 75% of the water in a hydrogel. Desiccation can occur, for example, by exposure of the hydrogel to ambient or humidity controlled air, by heating the hydrogel for a specific period of time, or by blowing dried gas, such as N₂, over the hydrogel. In one embodiment, the hydrogel is saturated with physiological (isotonic) saline prior to desiccation. The partially desiccated hydrogel is then soaked, e.g., for at least 30 minutes, in a dilute aqueous solution of therapeutic agent, e.g., at a pH between 6.9 to 7.4. The hydrogels may also be soaked for at least 1 hour, 6 hours, 12 hours, or 24 hours, or longer. The concentration of growth factor into which the hydrogel is placed is typically 10 ng/μL or less, e.g., at most 5 ng/μL, 1 ng/μL, 0.1 ng/μL, or 0.01 ng/μL. Higher concentrations may also be used, for example, to reduce the soaking time. The therapeutic agent is passively transferred into the hydrogel. This transfer may occur at least in part by rehydrating the hydrogel. Diffusion of the therapeutic agent into the water in the hydrogel may also occur. In alternative embodiments, a fully hydrated or fully desiccated hydrogel is placed in the soaking solution to produce the medicated hydrogel. Antibacterial, antifungal, antiviral, or antiparasitic compounds may be included in a hydrogel for their therapeutic effect on a patient and/or to prevent or reduce contamination by infectious organisms during manufacture, storage, and therapeutic implementation.

Desirably, the concentration of therapeutic agent transferred to the hydrogel is substantially lower than the solution in which the hydrogel is soaked. For example, the concentration of therapeutic agent in the hydrogel is at least 2^χ, 5^χ, or 10x less than that of the soaking solution. Some agents, however, may have a higher affinity for a hydrogel than aqueous solution, and such a hydrogel will have a higher concentration of agent than the solution in which it was soaked. The water content and type of hydrogel, time and conditions, e.g., temperature of soaking, composition of the soaking solution (e.g., ionic strength and pH), and type of agent employed also may influence the concentration of agent in the drug delivery system. Since the water content of the hydrogel also helps to determine the total amount of agent present in a hydrogel, it represents a variable by which to control the amount of agent delivered to a tissue. The production of a hydrogel containing a specified amount of agent can be accomplished by routine experimentation by one skilled in the art.

Growth factors. Growth factors are a heterogeneous group of proteins capable of stimulating growth and the multiplication of cells. Exemplary growth factors include epidermal growth factor, platelet derived growth factor, hepatocytic growth factor, human growth hormone, fibroblast growth factor, and combinations thereof. These growth factors may be natural, synthetic, or recombinant growth factors or growth factor derivatives from any animal, for example, humans, or any domesticated animal or pet species. Such growth factors also include biologically active growth factors and analogs. Peptide growth factors play important biological roles by regulating many of the processes involved in normal wound healing including migration, mitosis, and differentiation of cells. Growth factors are commercially available or may be isolated using methods known in the art. Exemplary hydrogels include between 5 and 350 ppb of growth factor, for example, between 5 and 250 ppb, 5 and 100 ppb, 5 and 50 ppb, or 5 and 10 ppb. The concentration of growth factor in the hydrogel may, however, be higher, e.g., at most 100, 75, 50, 25, 10, or 1 ppm. Other compounds. The hydrogels of the invention may also contain medicaments other than growth factors. These additional compounds include, without limitation, analgesics, anti-inflammatory drugs (e.g., dexamethasone, fluorometholone, rimexolone, and prednisolone and non-steroidal antiinflammatory drugs (such as ibuprofen and naproxen)), antibodies, meganins, self-proteins, pharmaceutical drugs, and antibacterial, antifungal, antiviral, or antiparasitic compounds. These other compounds may be administered in any suitable combination.

Exemplary antibacterial compounds include macrolides, such as erythromycin, telithromycin, azithromycin, and clarithromycin; penicillins, such as benzathine benzylpenicillin, benzylpenicillin, phenoxymethylpenicillin, ampicillin, amoxicillin, flucloxacillin, dicloxacillin, methicillinpiperacillin, ticarcillin, azlocillin, and carbenicillin, alone or in combination with clavulanic acid; tetracycline, oxytetracycline, doxycycline, or minocycline; the aminoglycosides, such as kanamycin, kanamycin A, kanamycin B, kanamycin C, tobramycin, dideoxykanamycin B, amikacin, gentamicin, gentamicin B, gentamicin C12, gentamicin Cl, gentamicin C2, gentamicin CIa, sisomicin, netilmicin, neomycin, paramomycin, lividomycin, ribostamycin, butirosin, streptomycin, streptomycin B, spectinomycin, apramycin, and isepamicin; cephalosporins, such as cefacetrile/cephacetrile, cefadroxil/cefadroxyl, cefalexin/cefalexine/cephalexin, cefaloglycin/cephaloglycin, cefalonium/cephalonium, cefaloridine/cephaloradine, cefalothin/cefalotin/cephalothin/cephalotin, cefapirin/cephapirin, cefatrizine, cefazaflur, cefazedone, cefazolin/cefazoline/cephazolin, cefradine/cephradine, cefroxadine, ceftezole, cefaclor/cefachlor, cefonicid/cefonicide, cefprozil, cefuroxime axetil, cefuzonam, loracarbef, cefamandole nafate, ceforanide, cefotiam, cefbuperazone, cefmetazole/sefmetazole, cefminox, cefotetan, cefoxitin/cefoxitine, cefcapene pivoxil, cefdaloxime pentexil tosilate, cefdinir, cefditoren pivoxil, cefetamet pivoxil, cefixime, cefmenoxime, cefodizim/cefodizime, cefoperazone, cefotaxime, cefpimizole, cefpodoxime proxetil, cefteram pivoxil, ceftibuten, ceftiofur, ceftiolene, ceftizoxime, ceftriaxone, moxalactam, ceftazidime, ceφiramide, cefsulodin, cefquinome, flomoxef, cefetecol ,cefclidin, cefclidine, cefepime, cefluprenam, cefoselis sulfate, cefozopran, cefpirome, cefaclomezine/cephachlomezine, cefaloram, cefaparole, cefcanel and cefcanel daloxate, cefedrolor, cefempidone, cefetrizole, cefivitril, cefmatilen, cefmepidium, cefovecin, cefoxazole/cephoxazole, cefrotil, cefsumide, ceftioxide, ceftobiprole, ceftobiprole medocaril, and cefuracetime; and quinolones, such as norfloxacin, ciprofloxacin, ofloxacin, enoxacin, ϊomefloxacin, levofloxacin, trovafloxacin, gatifloxacin, moxifloxacin, alatrofloxacin, gemifloxacin, binfloxacin, cinoxacin, enrofloxacin, pefloxacin, amifloxacin, pirfloxacin, fleroxacin, danafloxacin, difloxacin, sarafloxacin, nalidixic acid, sparfloxacin, and grepafloxacin. Antifungal compounds include polyenes, imidazoles, triazoles, allylamines, and echinocandins. Exemplary antifungal compounds are amorolfine, amphotericin B, anidulafungin, bifonazole, butenafine, butoconazole, caspofungin, clotrimazole, econazole, fenticonazole, fluconazole, flucytosine, griseofulvin, isoconazole, itraconazole, ketaconazole, mebendazole, micafungin, miconazole, naftifine, natamycin, nystatin, oxiconazole, posaconazole, ravuconazole, sertaconazole, sulconazole, terbinafine, thiabendazole, tiaconazole, and voriconazole.

Antiviral compounds include thiosemicarbazones, nucleosides and nucleotides, cyclic amines, phosphonic acid derivatives, protease inhibitors, nucleoside and nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and neuraminidase inhibitors. Exemplary antiviral compounds are abacavir, acyclovir, adefovir dipivoxil, amantadine, amprenavir, atazanavir, brivudine, cidofovir, delavirdine, didanosine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, fosamprenavir, foscarnet, fosfonet, ganciclovir, idoxuridine, indinavir, inosine pranobex, lamivudine, lopinavir, metisazone, moroxydine, nelfinavir, nevirapine, oseltamivir, penciclovir, pleconaril, ribavirin, rimantadine, ritonavir, saquinavir, stavudine, tenofovir disoproxil, tipranavir, trifluridine, tromantadine, valaciclovir, valganciclovir, vidarabine, zalcitabine, zanamivir, and zidovudine.

Exemplary antiparasitic compounds include albendazole, amphotericin, artemether, artesunate, atovaquone, atovaquone/proguanil, azithromycin, benznidazole, bithionol, chloroquine HCl and chloroquine phosphate, clarithromycin, clindamycin, crotamiton, dapsone, diethylcarbamazine citrate USP, diloxanide furoate, doxycycline, eflornithine, fluconazole, flucytosine, furazolidone, iodoquinol, itraconazole, ivermectin, ketoconazole, levamisole, malathion, mebendazole, mefloquine, meglumine antimonate, melarsoprol, metronidazole, miltefosine, niclosamide, nifurtimox, nitazoxanide, ornidazole, oxamniquine, paromomycin, pentamidine isethionate, permethrin, praziquantel- primaquine phosphate USP, proguanil. proguanil/atovaquone, propamidine isethionate, pyrantel pamoate, pyrethrins and piperonyl butoxide, pyrimethamine USP, quinacrine, quinidine gluconate, quinine dihydrochloride, quinine sulfate, rifampin, secnidazole, sodium stibogluconate, spiramycin, sulfadiazine, suramin sodium, tinidazole, triclabendazole, trimethoprim and sulfamethoxazole, and trimetrexate (see, e.g., "Drugs for Parasitic Infections" The Medical Letter August 2004). These other compounds may be delivered from a hydrogel, e.g., a contact lens, either individually or in combination with each other or growth factors or anti-inflammatory agents. Concentrations of antibacterial, antifungal, antiparasitic, and antiviral compounds that may be delivered are, for example, from 0.0001 ppm to 1000 ppm. These other compounds may also be used at reduced concentrations from their typically prescribed dosages. For example, these compounds may be delivered in concentrations of less than 100, 50, 25, 10, 1, 0.1, 0.01 , or 0.001 ppm at various sites (e.g., the eye) and under different conditions (e.g. ambient or existing). Treatment. To treat a wound, infection, or other condition, a drug delivery system of the invention may be placed in contact with a damaged or infected tissue. When the system is shaped as a contact lens, the lens may simply be placed in the eye normally in order to deliver the therapeutic agent. In order to effect accelerated healing of other wounds, infections, or other condition, the hydrogel may be part of a bandage or may be adhered (e.g., by adhesives or sutures) to the treated tissue. If the hydrogel is placed internally in a patient, the hydrogel is advantageously biodegradable.

Hydrogels may be considered to be disposable and may be replaced after a specified period of time, e.g., at least 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 7.5, 10, 15, or 24 hours. Alternatively, a hydrogel that has a depleted amount of therapeutic agent may be recycled by desiccating and soaking the hydrogel again.

Treatment Approaches

The invention may be used in conjunction with treating many types of wounds, infections, and other conditions, including, without limitation, those in ocular, oral, lung, digestive tract, skin, large intestine, small intestine, colon, and other endothelial, mucosal, or epithelial tissues. As stated above, the invention provides accelerated healing by delivering a therapeutic agent to an injured, infected, or otherwise diseased tissue. In certain embodiments, at least 0.001, 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 15, or 20 μg of the growth factor is released from the hydrogel. This delivery occurs by passive transfer down a concentration gradient and allows medications to be released into fluids of the body, e.g., ocular fluid. A growth factor stimulates proliferation of cells surrounding a wound to close the wound and replace damaged cells. Other therapeutic agents produce a therapeutic effect by various mechanisms, as is known in the art. Because the therapeutic agent is localized by the hydrogel, which provides greater control over release of the growth factor or drug, a lesser amount of agent may in many cases be needed to effect healing than if, e.g., topical solutions, such as eye drops are used. Accelerated healing may also reduce the pain and inflammation associated with a particular wound, infection, or other condition and may help prevent infection in wounded tissue. In addition, the hydrogel may also act as a physical barrier to provide protection from mechanical abuse and to prevent adherence of the healing tissue to adjacent tissues. The use of hydrogels of the invention may also allow patients to be treated using fewer applications than with traditional methods. For example, a patient treated using the hydrogels of the invention may be able to treated only once in a period of at least 48 hours.

In desirable embodiments, a hydrogel of the invention is used to treat a wound or site of infection or other condition that is in contact with a replenishable bodily fluid, e.g., tears or other heterogeneous ocular fluids. In these embodiments, the therapeutic agent is released from the hydrogel at a more rapid rate than the release of the therapeutic agent into a fixed volume of fluid because as the bodily fluid is replenished, the therapeutic agent released is flushed away from the site of application causing an increase in the relative rate of diffusion of the therapeutic agent out of the hydrogel. The replenishing action of fluids such as tears may also effectively increase the rate of diffusion of the therapeutic agent into the fluid and lead to earlier onset of therapeutic activity. For medicated hydrogels of the invention placed in contact with a non-replenishable bodily fluid (i.e., one where replacement is very slow or nonexistent on the time-scale of drug release), lower concentrations of a drug may be used since the drug is not flushed from the site as quickly as in a replenishable fluid.

Ocular Wounds. In one embodiment, the wound is an ocular wound, e.g., in corneal epithelial, endothelial, or retinal tissue. The invention is of particular utility after vision correcting surgery, such as LASIK, PRK, or LASEK or as a wound healing medical device/drug delivery system. Soft and collagen contact lenses may be utilized to minimize post-surgical epithelial trauma and provide a stable healing environment. PRK typically requires a therapeutic contact lens for 3-4 days, and post-operative therapeutic drops are often prescribed. In the present invention, the hydrogel may be shaped as a contact lens that acts as a reservoir for the therapeutic agent and can serve to protect the leading edge of wound healing from normal mechanical abuse. The therapeutic agent gradually delivered in a low concentration from the hydrogel obviates the need for therapeutic drops. Therapeutic drops often include high concentrations of drugs because the majority of the drop is excreted from the eye in a short period of time. These high concentrations can cause additional damage to a wound, which is avoided by the use of the present, localized time- release drug delivery system.

Ocular Infections. In another embodiment, the infection is an ocular infection. Exemplary ocular infections that are treated using the hydrogels of the invention include fungal infections such as, mycotic keratitis, e.g., caused by Acremonium spp., Aspergillus βavus, Aspergillus fumigatus, Aspergillus niger, Bipolaris spp., Candida albicans, Curvularia spp, Exserohilum spp., Fusarium oxysporum, Fusarium solani, or Lasiodiplodia theobromae; endogenous oculomycosis, e.g., candidiasis, cryptococcosis, coccidioidomycosis, blastomycosis, sporotrichosis, paracoccidioidomycosis, histoplasmosis, and aspergillosis; extension oculomycosis, e.g., caused by Rhizopus arrhizus. Other infections include parasitic infections, e.g., river blindness or those caused by F. tularensis, Toxoplasma gondii, Trypanosoma cruzi, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, Plasmodium falciparum, Leishmania spp., Acanthamoeba spp., Encephalito∑oon, Nosema, Microsporidium, or Septata spp., Giardia lamblia, Rhinosporidium seeberi, Loa loa, Dirofύaria immitis, Gnathostoma spp.,

Taenia spp., Toxocara spp., Echinococcus spp., and Dermatobia, Gasterophilus, Oestra, Cordylobia, Chrysomia, Wohlfahrtia, Cochliomyia, or Hypoderma spp.. Viral infections of the eye may be caused by CMV, herpes simplex, or herpes zoster, and bacterial infections of the eye may be caused by gonorrhea or Chlamydia spp., e.g., Trachoma. Conjunctivitis, e.g., Acanthamoeba, adenoviral follicular, chlamydial, diphtheritic, gonococcal, haemorrhagic, herpesviral, meningococcal, Newcastle, and zoster, may also be treated by the hydrogels of the invention.

Delivery of therapeutic agents may occur via a contact lens as described for ocular wounds.

A further understanding of the invention may be obtained from the following non-limiting examples.

Example 1. Production of a Drug Delivery System. An exemplary drug delivery system was prepared as follows. Contact lenses were removed from their package and rinsed with saline to remove contact lens packing solution. The hydrogel lens materials were allowed to desiccate for at least of one second. The hydrogel lens materials were placed into physiological saline that contained epidermal growth factor (EGF) at concentrations of 10 ng/μl or 5.0 ng/μl for at least 30 minutes. Lower concentrations may also be used. Longer passive transference times may also be used. Untreated or control lenses were placed in physiological saline without EGF.

Example 2. Healing of Ocular Tissue.

Ocular cells were placed into a sterile plastic dish. This dish contained a 5-mm disk. The purpose of the disk was to prevent cells from growing in the covered area. When the disk was removed, a 5-mm "wound" or "hole" was present. Contact lenses were then added to these cell sheets with the wounds. The lenses were left in contact with the cell sheets for a minimum of 30 minutes. Minimal medium was used to maintain the cell cultures. Cells were incubated at 35 ⁰C ± 2 ⁰C in 5% CO₂. Contact lenses with or without EGF were produced as in Example 1. The contact lenses used were polymacon B, vifilcon A, and lidofilcon A hydrogel polymers.

The cell sheets were then viewed over time, and the diameter of the hole was measured.

The results are expressed in terms of closure of the in vitro wound over time.

Epithelial Cells and Tissue. Epithelial (rabbit corneal epithelial cells) cells were seeded on a dish and contacted with control and EGF-containing contact lenses. At 48 hours there was a 25% difference in the closure rate between the EGF-treated cells and the non-EGF treated cells. At 72 hours, there was a 43% difference in the closure rate between the EGF-treated epithelial tissue and the controls. The hydrogel material that was used was vifilcon A, an ionic polymer with a water content of 55%. The polymer had been incubated with 10 ng/μL EGF for one hour at 4 ⁰C prior to use in the experiments. Closure rates were calculated by direct measurement of the diameter of the wound. Measurements were taken daily.

In a related series of experiments, a vifilcon A lens was incubated under the same conditions as above with 5.0 ng/μL of EGF and then contacted with an epithelial "wound" as above. At 48 hours, there was a 21% closure rate difference between controls and EGF treated hydrogel materials. At 72 hours, there was also a 21% difference in the closure rate. These results indicated that over a 72-hour period, the relative healing rates remained essentially the same for the treated and non-treated epithelial tissue, with the epithelial tissue treated with EGF always having an accelerated rate of healing.

The rate of wound healing increased with increased exposure of the hydrogel material to the wound. Further, compared to a wound not contacted with any lens, at 48 hours there was a 31% difference in the healing rates.

Healing for tissue exposed to a lens soaked in 10 ng/μL of EGF increased from

14% at 48 hours to 25% at 72 hours.

Endothelial Cells and Tissue. Wounds caused in endothelial tissue

(bovine corneal endothelial cells) were also healed by release of EGF from a vifilcon A lens. The lens, soaked in 10 ng/μL of EGF as above, showed a 73% difference in healing rates at 48 hours compared to a control. At 72 hours, the

EGF-treated tissue had completely healed. In the control group, less than half

(43%) of the tissue had healed. The same lens material exposed to 5 ng/μL of

EGF showed a 31 % difference in closure rate at 48 hours between the EGF treated group and the controls. At 72 hours, 53% of the tissue had healed in the

EGF treated group, compared to 43% in the control.

Lidofilcon A hydrogel (non-ionic, water content = 70%) materials were evaluated for their ability to deliver EGF to endothelial tissue to close wounds.

The concentration of EGF used in the soaking solution was 10 ng/μL. At 48 hours, the EGF treated tissue showed a 54% increase in the healing rate (wound closure rate) as compared to controls. At 72 hours, there was a difference of

44%.

A third material, polymacon B, that is non-ionic and has a water content of 38%, was also evaluated for the ability to deliver EGF to wounds. The lenses were prepared using a soaking solution of 10 ng/μL of EGF. At 48 hours, the wound was 60% closed in the treated group and 27% closed in the non-treated group. At 72 hours, the difference in closure between the treated and untreated groups was 62%. In the EGF treated group at 72 hours, the wound had closed by 80%, while in the untreated group, the wound had closed by 46.8%.

Example 3. Uptake and Release of EGF. The amount of uptake and release of EGF from a contact lens depends on the water content or composition of the lens or both. Data were collected on the uptake and release of EGF from two types of lenses, lotrafilcon A (24% water) and vasurfilcon A (74% water). Both of these lenses are non-ionic. For uptake studies, thirty lenses of each type were placed in 25 mL of a solution containing 40 ppm of EGF. For release studies, the lenses produced by the uptake study were placed in 25 mL of solution not containing EGF after desiccation for 10 - 30 seconds. For both types of study, the amount of EGF in the solution was then measured at defined time intervals. For vasurfilcon A, about 75% of the EGF in solution was taken up by the lenses after 6 hours (Figure IA), at which point the lenses appeared to be in equilibrium with the solution, and about 37% of the EGF taken up was released after 7 hours (Figure IB), at which point the lenses appeared to be at or near equilibrium. The release data indicate that contact lenses can deliver a sustained dosage of EGF over a period of time. For lotrafilcon A, surprisingly, no measurable amount of EGF was taken up or released by the lenses. Based on a purely diffusional theory of uptake, at least some growth factor would have been expected to be taken up in the water in the lotrafilcon A contact lens. Two possible explanations for the differential uptake of EGF by the two polymers studied are 1) a water content higher than 24% is needed for uptake of EGF and 2) the lotrafilcon A polymer is chemically (thermodynamically) or structurally (kinetically) unfavorable for the entry of EGF. Example 4. Animal Tests.

Contact lenses containing EGF, EGF and dexamethasone (an antiinflammatory steroid), and human growth hormone (HGH) were tested in a rabbit model for efficacy and toxicity. New Zealand white rabbits were anesthetized, and then both eyes were abraded with a needle. A control contact lens was placed in the left eye, and a medicated contact lens was placed in the right eye of each rabbit for up to 4 hours prior to euthanasia. Control contact lenses (etafilcon A, an ionic lens with 58% water content) were washed with phosphate-buffered saline (PBS) prior to insertion. Medicated contact lenses (etafilcon A) were prepared by briefly drying the lens and then soaking it in 400ppb, 4 ppm, or 10 ppm EGF or 400 ppb HGH in PBS for 24 hours. In another experiment, lenses were soaked in 200 ppb EGF and 12.5 ppm dexamethasone for 25 hours. No toxicity was observed in the rabbits at any concentration of EGF tested. Rabbits were visually scored on a 0-4 scale (0 being the best and 4 being the worst) for corneal edema (which is a measure of wound healing), inflammation, and exudate production.

EGF (lenses soaked in 400 ppb EGF) released from hydrogel contact lenses (right eye) healed wounds at an accelerated rate when compared to control eyes (left eye) for the first two hours after treatment. Data from four rabbits are shown in Table 1.

In another experiment, in addition to being abraded, the rabbit eyes were treated with a solution of lipopolysaccharide from E. coli Ol 11 :B4 (1 mg/mL) to induce inflammation. Lenses soaked in 200 ppb EGF and 12.5 ppm (see above) dexamethasone controlled inflammation and caused increased wound healing (right eye) compared to control eyes (left eye). EGF controlled healing of wounds even if there was an increase in inflammation.

Rabbit eyes (right eye) treated with HGH released from a contact lens (400 ppb soak) had increased wound healing and reduction in inflammation compared to control eyes (left eye) in rabbits. In addition, no toxicity was observed to the ocular tissue

The following tables summarize the experimental data. In each box, the visual score is given for each animal, where 3/4, > 1+ indicates that three out of four animals in the group had a visual score of 1+.

4.0 m EGF. Three animals in this rou . One animal died at 3.0 hr.

The third animal had no edema or toxicity at time of death in the EGF treated eye. There was a 1+ edema and 0+ toxicity in the untreated eye.

Treatment of soft contact lenses with sterile, endotoxin tested, freeze- dried, recombinant human EGF does not appear to cause toxicity and does appear to increase the rate of corneal wound healing in an established, published model of corneal abrasion in rabbits.

Example 5. Human Testing.

The following table summarizes a series of human experiments in which humans with various conditions were treated with SofLens™ 66 (alphafilcon A) contact lenses that had been soaked in a solution of 400 ppb, as described herein.

Other Embodiments

Modifications and variations of the described methods of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific desirable embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention, which are obvious to those skilled in the art, are intended to be within the scope of the invention. All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually to be incorporated by reference. Other embodiments are within the claims.

What is claimed is:

Claims

1. A hydrogel having a water content of between 10% and 90% comprising (i) a polymer, (ii) a substantially pure growth factor, and (iii) an antibacterial, antifungal, antiparasitic, or antiviral compound.

2. The hydrogel of claim 1, wherein said hydrogel comprises an antibacterial, antifungal, antiparasitic, or antiviral compound

3. The hydrogel of claim 1, wherein said growth factor is selected from the group consisting of epidermal growth factor, platelet derived growth factor, hepatocytic growth factor, human growth hormone, fibroblast growth factor, and combinations thereof.

4. The hydrogel of claim 1, wherein said growth factor is epidermal growth factor or human growth hormone.

5. The hydrogel of claim 1, wherein said polymer comprises a tetrapolymer of hydroxymethylmethacrylate, ethylene glycol, dimethylmethacrylate, and methacrylic acid.

6. The hydrogel of claim 1, wherein said growth factor is capable of being passively released into an environment under ambient conditions.

7. The hydrogel of claim 6, wherein said environment is an ocular environment.

8. The hydrogel of claim 1, wherein said growth factor is capable of being passively released into an environment under existing conditions.

9. The hydrogel of claim 8, wherein said environment is an ocular environment.

10. The hydrogel of claim 1, wherein said hydrogel is shaped as a contact lens.

11. The hydrogel of claim 10, wherein said hydrogel is capable of correcting vision.

12. The hydrogel of claim 11, wherein said hydrogel is capable of correcting vision in the range of +8.0 to —8.0 diopters.

13. The hydrogel of claim 10, said hydrogel having a base curve between 8.0 and 9.0.

14. The hydrogel of claim 1, wherein said polymer comprises an ionic polymer.

15. The hydrogel of claim 1, wherein said polymer comprises a non- ionic polymer.

16. The hydrogel of claim 1, wherein said polymer is etafilcon A, vifilcon A, polymacon B, lidofilcon A, or vasurfilcon A.

17. The hydrogel of claim 1 , wherein said polymer is balafilcon A, lotrafilcon A, galyfilcon A, acquafilcon, lenefilcon, or senofilcon.

18. The hydrogel of claim 1 , further comprising an anti-inflammatory compound.

19. The hydrogel of claim 18, wherein said anti-inflammatory compound is dexamethasone, fluorometholone, rimexolone, or prednisolone.

20. The hydrogel of claim 1, wherein said antibacterial compound is benzathine benzylpenicillin, benzylpenicillin, phenoxymethylpenicillin, ampicillin, amoxicillin, flucloxacillin, dicloxacillin, methicillinpiperacillin, ticarcillin, azlocillin, carbenicillin, tetracycline, oxytetracycline, doxycycline, minocycline, kanamycin, kanamycin A, kanamycin B, kanamycin C, tobramycin, dideoxykanamycin B, amikacin, gentamicin, gentamicin B, gentamicin C12, gentamicin Cl, gentamicin C2, gentamicin CIa, sisomicin, netilmicin, neomycin, paramomycin, lividomycin, ribostamycin, butirosin, streptomycin, streptomycin B, spectinomycin, apramycin, isepamicin, cefacetrile/cephacetrile, cefadroxil/cefadroxyl, cefalexin/cefalexine/cephalexin, cefaloglycin/cephaloglycin, cefalonium/cephalonium, cefaloridine/cephaloradine, cefalothin/cefalotin/cephalothin/cephalotin, cefapirin/cephapirin, cefatrizine, cefazaflur, cefazedone, cefazolin/cefazoline/cephazolin, cefradine/cephradine, cefroxadine, ceftezole, cefaclor/cefachlor, cefonicid/cefonicide, cefprozil, cefuroxime axetil, cefuzonam, loracarbef, cefamandole nafate, ceforanide, cefotiam, cefbuperazone, cefmetazole/sefmetazole, cefminox, cefotetan, cefoxitin/cefoxitine, cefcapene pivoxil, cefdaloxime pentexil tosilate, cefdinir, cefditoren pivoxil, cefetamet pivoxil, cefixime, cefmenoxime, cefodizim/cefodizime, cefoperazone, cefotaxime, cefpimizole, cefpodoxime proxetil, cefteram pivoxil, ceftibuten, ceftiofur, ceftiolene, ceftizoxime, ceftriaxone, moxalactam, ceftazidime, cefpiramide, cefsulodin, cefquinome, flomoxef, cefetecol ,cefclidin, cefclidine, cefepime, cefluprenam, cefoselis sulfate, cefozopran, cefpirome, cefaclomezine/cephachlomezine, cefaloram, cefaparole, cefcanel and cefcanel daloxate, cefedrolor, cefempidone, cefetrizole, cefivitril, cefinatilen, cefmepidium, cefovecin, cefoxazole/cephoxazole, cefrotil, cefsumide, ceftioxide, ceftobiprole, ceftobiprole medocaril, and cefuracetime; and quinolones, such as norfloxacin, ciprofloxacin, ofloxacin, enoxacin, lomefloxacin, levofloxacin, trovafloxacin, gatifloxacin, moxifloxacin, alatrofloxacin, gemifloxacin, binfloxacin, cinoxacin, enrofloxacin, pefloxacin, amifloxacin, pirfloxacin, fleroxacin, danafloxacin, difloxacin, sarafloxacin, nalidixic acid, sparfloxacin, or grepafloxacin.

21. The hydrogel of claim 1 , wherein said antifungal compound is amorolfine, amphotericin B, anidulafungin, bifonazole, butenafine, butoconazole, caspofungin, clotrimazole, econazole, fenticonazole, fluconazole, flucytosine, griseofulvin, isoconazole, itraconazole, ketaconazole, mebendazole, micafungin, miconazole, naftifϊne, natamycin, nystatin, oxiconazole, posaconazole, ravuconazole, sertaconazole, sulconazole, terbinafine, thiabendazole, tiaconazole, or voriconazole.

22. The hydrogel of claim 1, wherein said antiviral compound is abacavir, aciclovir, adefovir dipivoxil, amantadine, amprenavir, atazanavir, brivudine, cidofovir, delavirdine, didanosine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, fosamprenavir, foscarnet, fosfonet, ganciclovir, idoxuridine, indinavir, inosine pranobex, lamivudine, lopinavir, lysozyme, metisazone, moroxydine, nelfinavir, nevirapine, oseltamivir, penciclovir, pleconaril, ribavirin, rimantadine, ritonavir, saquinavir, stavudine, tenofovir disoproxil, tipranavir, trifluridine, tromantadine, valaciclovir, valganciclovir, vidarabine, zalcitabine, zanamivir, or zidovudine.

23. The hydrogel of claim 1; wherein said antiparasitic compound is albendazole, amphotericin, artemether, artesunate, atovaquone, atovaquone/proguanil, azithromycin, benznidazole, bithionol, chloroquine HCl and chloroquine phosphate, clarithromycin, clindamycin, crotamiton, dapsone, diethylcarbamazine citrate USP, diloxanide furoate, doxycycline, eflornithine, fluconazole, flucytosine, furazolidone, iodoquinol, itraconazole, ivermectin, ketoconazole, levamisole, malathion, mebendazole, mefloquine, meglumine antimonate, melarsoprol, metronidazole, miltefosine, niclosamide, nifurtimox, nitazoxanide, ornidazole, oxamniquine, paromomycin, pentamidine isethionate, permethrin, praziquantel, primaquine phosphate USP, proguanil, proguanil/atovaquone, propamidine isethionate, pyrantel pamoate, pyrethrins and piperonyl butoxide, pyrimethamine USP, quinacrine, quinidine gluconate, quinine dihydrochloride, quinine sulfate, rifampin, secnidazole, sodium stibogluconate, spiramycin, sulfadiazine, suramin sodium, tinidazole, triclabendazole, trimethoprim and sulfamethoxazole, or trimetrexate.

24. The hydrogel of claim 1 , wherein said substantially pure growth factor is present at a concentration of between 5 and 350 ppb.

25. The hydrogel of claim 1, wherein said hydrogel is capable of producing a therapeutic effect after vision correcting surgery, trauma, or burn.

26. The hydrogel of claim 1, wherein said antibacterial, antifungal, antiparasitic, or antiviral compound prevents or reduces contamination by an

infectious organism during manufacture, storage, or treatment.

27. A method for making a hydrogel drug delivery system, said method comprising (i) placing a hydrogel in an aqueous solution of between

0.01 and 10 ng of a substantially pure growth factor per μL, wherein growth factor is passively transferred into said hydrogel in a therapeutically effective amount and (ii) placing said hydrogel in an aqueous solution of an antibacterial, antifungal, antiparasitic, or antiviral compound, wherein said antibacterial, antifungal, antiparasitic, or antiviral compound is passively transferred into said hydrogel in an effective amount, and wherein the solutions in (i) and (ii) may or may not be the same solution.

28. The method of claim 27, wherein the concentration of growth factor passively transferred to said hydrogel is between 5 and 350 ppb.

29. The method of claim 27, wherein said growth factor is selected from the group consisting of epidermal growth factor, platelet derived growth factor, hepatocytic growth factor, human growth hormone, fibroblast growth factor, and combinations thereof.

30. The method of claim 27, wherein said growth factor is epidermal growth factor.

31. The method of claim 27, wherein said aqueous solution has a pH between 6.9 and 7.4

32. The method of claim 27, wherein said hydrogel is shaped as a contact lens.

33. The method of claim 27, wherein said hydrogel is placed in said solution for at least 5 minutes.

34. The method of claim 27, wherein said aqueous solution of (i) or (ii) further comprises an anti-inflammatory compound.

35. The method of claim 34, wherein said anti-inflammatory compound is dexamethasone. fluorometholone, rimexolone, or prednisolone.

36. The method of claim 27, wherein, prior to placing said hydrogel in said aqueous solution of (i) or (ii), said hydrogel is at least partially desiccated.

37. The method of claim 27, wherein said antibacterial, antifungal, antiparasitic, or antiviral compound is present in a therapeutically effective amount.

38. The method of claim 27, wherein said antibacterial, antifungal, antiparasitic, or antiviral compound is present in an amount effective to prevent or reduce infection contamination of said hydrogel during said method, storage of said hydrogel, or treatment with said hydrogel.

39. A method for treating an infection comprising placing a hydrogel of claims 1-25 in contact with a site of infection, wherein said growth factor and said antibacterial, antifungal, antiparasitic, or antiviral compound are passively released from said hydrogel to treat said condition.

40. A method for treating a wound comprising placing a hydrogel of claims 1-25 in contact with said wound, wherein said growth factor and said antibacterial, antifungal, antiparasitic, or antiviral compound are passively released from said hydrogel to treat said wound.

41. The method of claim 39-40, wherein said hydrogel passively releases at least 0.01, 0.05, 0.5, 1, 10, 15, or 20 μg of said growth factor.

42. The method of claim 39-40, wherein said hydrogel is placed in contact with said site or wound for at least 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 7.5, 10, 15, or 24 hours.

43. The method of claim 39-40, wherein said growth factor is selected from the group consisting of epidermal growth factor, platelet derived growth factor, hepatocytic growth factor, human growth hormone, fibroblast growth factor, and combinations thereof.

44. The method of claim 39-40, wherein said growth factor is epidermal growth factor.

45. The method of claim 39-40, wherein said site or wound is in an eye and said hydrogel is shaped as a contact lens.

46. The method of claim 39-40, wherein said hydrogel further acts as a protective shield against mechanical abuse.

47. The method of claim 39-40, wherein said site or wound is in endothelial tissue.

48. The method of claim 39-40, wherein said site or wound is in epithelial tissue.

49. The method of claim 39-40, wherein said site or wound is a lung, skin, or digestive tract wound.

50. The method of claim 39-40, wherein the hydrogel is placed in a body cavity.

51. The method of claim 39-40, wherein said passively released growth factor causes a reduction in pain compared to said site or wound when not contacted with said polymeric hydrogel.

52. The method of claim 39-40, wherein said site or wound is in the sclera or cornea.

53. The method of claim 39-40, wherein said site or wound is the result of vision correcting surgery.

54. The method of claim 53, wherein said vision correcting surgery is LASIK, PRK, or LASEK, corneal transplant.

55. A method of delivering a therapeutic agent, said method comprising the steps of:

(a) placing hydrogel of claims 1-25 in contact with a replenishable bodily fluid in contact with a wound or site of infection or condition; and

(b) allowing said growth factor and said antibacterial, antifungal, antiparasitic, or antiviral compound to release passively from said hydrogel into said replenishable bodily fluid, wherein the release of said growth factor and said antibacterial, antifungal, antiparasitic, or antiviral compound from said hydrogel into said replenishable bodily fluid is accelerated compared to the release of said growth factor and said antibacterial, antifungal, antiparasitic, or antiviral compound from said hydrogel into a non-replenishable bodily fluid.