GOVERNMENT INTEREST

[001] This invention was supported, in part, by Grant Number Grant 5T32 DC005363-04 from the NIH. The government may have certain rights in the invention.

CROSS REFERENCE TO RELATED APPLICATIONS

[002] This application claims priority to United States provisional patent application 61/098,387, filed September 19, 2008, which is incorporated by reference herein in its entirety.

FIELD OF THE INVENTION

[003] This invention is directed to a controlled and sustained release delivery device or composition for pathologies associated with Rhinology- associated conditions and any pathology involving the digestive tract or upper or lower airway including all spaces lined by respiratory or digestive epithelium. Specifically, the invention is directed to a semi-rigid biodegradable stent, comprising: deacetylated Chitosan glycerophosphate (CGP) matrix; and an agent in the Chitosan glycerophosphate (CGP) matrix, wherein the degree of deacetylation provides a sufficient rigidity to the stent and the use of agent impregnated Chitosan glycerophosphate (CGP) constructs in sinonasal applications.

BACKGROUND OF THE INVENTION

[004] Allergic rhinosinusitis is an IgE mediated immune response which affects approximately 35 million Americans resulting in direct costs of up to $4.5 billion dollars. Topical steroid represent the most efficacious treatment for controlling symptoms of allergic rhinitis and are considered first line therapy for patients with more than mild intermittent symptoms. While topical steroid application allows for high therapeutic concentrations at the site of pathology with minimal systemic effects, success relies on patient compliance and optimal delivery technique which are often difficult to achieve. Even with correct technique, several studies have shown that the majority of medication is deposited in the anterior nasal vault where it is expelled without ever reaching the intended site of action. Patients who ultimately fail medical treatment may require functional endoscopic sinus surgery to achieve adequate ventilation however these patients still require topical treatments to maintain postoperative sinus patency. Some authors advocate the placement of silastic stents to prevent critical outflow stenosis and allow access for topical irrigations however these stents may become colonized with biofilms leading to further mucosal inflammation. These limitations have catalyzed a search for an implantable intranasal steroid delivery vehicle which could be placed directly on the involved mucosa as a biodegradable stent and would continuously elute steroid over a specified period of time obviating issues of compliance, application technique, and post-operative sinus ostial stenosis.

SUMMARY OF THE INVENTION

[005] In one embodiment, the invention provides a semi-rigid biodegradable stent, comprising: a deacetylated Chitosan glycerophosphate (CGP) matrix.

[006] In another embodiment, the invention provides a semi-rigid biodegradable stent, comprising: a deacetylated Chitosan glycerophosphate (CGP) matrix; and an agent in the Chitosan glycerophosphate (CGP) matrix.

[007] In one embodiment, the invention provides a semi-rigid biodegradable nasal implant, comprising: a deacetylated Chitosan glycerophosphate (CGP) matrix. [008] In one embodiment, the invention provides a semi-rigid biodegradable nasal implant, comprising: a deacetylated Chitosan glycerophosphate (CGP) matrix; and an agent in the Chitosan glycerophosphate (CGP) matrix.

[009] In another embodiment, the implant of the invention comprises a drug. In another embodiment the implant comprises a drug and one or more agents. In one embodiment, the implant comprises one or more agents. In another embodiment, the agent is a steroid. In one embodiment, the agent is an antibacterial agent. In another embodiment, the agent is an antimicrobial agent. In one embodiment, the agent is an antibiotic agent. In another embodiment, the agent is an antifungal agent. In another embodiment, the implant comprises an agent and another drug. [0010] In another embodiment, the invention provides a controlled release delivery composition for an otorhinolaryngology and otorhinolaryngology-associated pathology, Head and Neck associated pathology conditions, Rhinology associated conditions and any pathology involving the digestive tract or upper or lower airway including all spaces lined by respiratory or digestive epithelium, or their combination, comprising a chitosan- glycerophosphate (CGP) hydrogel and an agent, bio-materials and their combination. [0011] In one embodiment, the invention provides a method comprising: placing a semi-rigid biodegradable stent, within a body lumen, said stent comprises comprising: deacetylated Chitosan glycerophosphate (CGP) matrix; and an agent in the Chitosan glycerophosphate (CGP) matrix, wherein the degree of deacetylation provides a sufficient rigidity to the stent. [0012] In another embodiment, the invention further provides a method of treating an otorhinolaryngology and otorhinolaryngology- associated pathology, conditions, indications or their combination, Head and Neck associated pathology conditions, indications or their combination, or their combination, in a subject, comprising the step of inserting a the stent or implant a predetermined region in a subject. [0013] In one embodiment, the invention provides a method of inhibiting or suppressing an otorhinolaryngology and otorhinolaryngology- associated pathology, conditions, indications or their combination, Head and Neck associated pathology conditions, indications or their combination, or their combination, in a subject, comprising the step of inserting the stent or implant thereby inhibiting or suppressing an otorhinolaryngology and otorhinolaryngology- associated pathology. In one embodiment, the stents used in the methods provided herein, define a lumen while, in another embodiment, the implants described herein, may or may not have alumen defined by their structure.

[0014] In another embodiment, the invention provides a method of reducing symptoms or incidence of, associated with an otorhinolaryngology and otorhinolaryngology-associated pathology, conditions, indications or their combination, Head and Neck associated pathology conditions, indications or their combination, or their combination, in a subject, comprising the step of inserting the stent or implant, thereby reducing symptoms or incidence of, associated with an otorhinolaryngology and otorhinolaryngology-associated pathology. [0015] In one embodiment, the stent and/or implant compositions described herein, which are used in another embodiment, in the methods provided herein, are agent eluting stent or compositions.

[0016] In one embodiment, the agent used in the stents or implants provided herein, is a combination of agents or active pharmaceutical ingredients (API's). In another embodiment, the agent is a steroid. In one embodiment, the agent is a steroid and an antibacterial agent. In another embodiment, the agent is a steroid and an antimicrobial agent. In one embodiment, the agent is a steroid and an antibiotic agent. In another embodiment, the agent is a steroid and an antifungal agent

[0017] In another embodiment, the invention provides a method of producing an agent eluting implant comprising: forming a Chitosan glycerophosphate (CGP) matrix film, with an active ingredient incorporated therein, wherein the Chitosan glycerophosphate (CGP) matrix is deacetylated; cross linking the Chitosan glycerophosphate (CGP) matrix; and drying the Chitosan glycerophosphate (CGP) matrix, creating a semi-rigid stent, spacer, or implant. [0018] In one embodiment, the invention provides a method of treating, inhibiting or suppressing or ameliorating symptoms associated with rhinologic pathology in a subject, comprising inserting into a sinus pathway of the subject, an agent-eluting stent, agent eluting implant, whereby the stent, spacer, or implant comprising: deacetylated Chitosan glycerophosphate (CGP) matrix; and an agent dispersed in the Chitosan glycerophosphate (CGP) matrix, wherein the degree of deacetylation provides a sufficient rigidity to the stent, spacer, or implant and wherein the agent is effective in treating, inhibiting or suppressing or ameliorating symptoms associated with the rhinologic pathology.

[0019] In one embodiment, the rhinologic pathology is acute, subacute, or chronic sinusitis. In one embodiment, the sinusitis is allergic, viral, bacterial, or fungal sinusitis or their combination. In one embodiment, the sinusitis is associated with polyps. In one embodiment, the sinusitis is not associated with polyps. In one embodiment, the rhinologic pathology is any anatomical abnormality leading to obstruction or inflammation of the sinonasal cavity. In one embodiment, the rhinologic pathology is any benign or malignant neoplasm within the sinonasal cavity or a surrounding structures. In one embodiment, the surrounding structure is the skull base, pterygopalatine fossa, infratemporal fossa or their combination. In one embodiment, the rhinologic pathology is a pathology of the upper or lower respiratory tract. In one embodiment, the pathology of the upper or lower respiratory tract is any process involving the larynx, trachea, bronchi, bronchioli, alveoli, lungs or a combination thereof. In another embodiment, the invention provides a biodegradable nasal implant comprising: an effective concentration of a chitosan-glycerophosphate (CGP) impregnated with a therapeutic agent for a prolonged delivery of said agent in a nasal region. In an exemplary embodiment, said agent is an antibitic. In another embodiment, the invention provides a method of treating a disease in a subject, the method comprising the step of implanting a composition comprising an effective concentration of a chitosan-glycerophosphate (CGP) impregnated with a therapeutic agent for a prolonged delivery of said agent in a nasal region. In an exemplary embodiment, said agent is an antibitic and said disease is a bacterial disease. Other features and advantages of the present invention will become apparent from the following detailed description examples and figures. It should be understood, however, that the detailed description and the specific examples while indicating preferred embodiments of the invention are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

[0020] The invention will be better understood from a reading of the following detailed description taken in conjunction with the drawings in which like reference designators are used to designate like elements, and in which:

Figure 1 shows how CGP-Dex-Hydrogel degrades in a controlled Manner.16% of solid CGP- Dex-hydrogel remains after 4 days. The degradation of CGP-Dex-hydrogel is controlled and is tapered. The error bars represent the SEM (± 0.002 to 0.026);

Figure 2 shows CGP-Dex-Hydrogel release of dexamethasone in a Controlled Manner. Release of dexamethasone occurs for 4 days. The black bars represent the daily measurement and the gray bars the accumulation over the 4 days of testing. There is an initial bolus release of dexamethasone in the first 24 hours followed by a tapering off over the next three days so that by day 4 -100% of the available dexamethasone has been released. The error bars represent the SEM (+/- 0.004 to 0.115);

Figure 3 shows CGP-Dex-Hydrogel locally delivery of Dexamethasone into Perilymph. The release of dexamethasone into perilymph was detected for 5 days. There was a significant difference between dexamethasone levels detected in the treated ear and serum for all time points. (Day 1 and 3 p< 0.01 Day 5 p < 0.05) The error bars represent the SEM (+/- 0.002 to 0.509);

Figure 4 shows normal hearing following CGP-Dex-Hydrogel Placement. 4a) The solid line represents the pre-operative baseline ABR value of the sham surgery group. There was a 5 to 2OdB increase in hearing thresholds across frequencies in the immediate post-operative period (dashed line). By post-operative day 10, the hearing thresholds returned to baseline levels (dotted line). At the conclusion of the experiment, there was no statistical difference between pre-operative ABR values and those obtained 10 days after the sham surgery, (p < 0.05) 4b) The same pattern was observed in the CGP-Dex-hydrogel group. There was a 5 to 2OdB increase in hearing thresholds across frequencies in the immediate post-operative period (dashed line). By post-operative day 10, the hearing thresholds returned to baseline levels (dotted line). At the conclusion of the experiment, there was no statistical difference between pre-operative ABR values and those obtained 10 days after placement of CGP-Dex- hydrogel. (p < 0.05). Frequencies tested are in within the normal hearing range of mice. The error bars represent the SEM;

Figure 5 shows histologic images (H&E, 25x) showing stent degradation over 15 days with negligible surrounding inflammation;

Figure 6 shows a graph of dexamethasone levels in nasal lavage over 15 days (Rabbits 8,9 = O.lmg dexamethasone stent; Rabbits 10,11 = lOmg dexamethasone stent);

Figure 7 shows a graph of peripheral blood dexamethasone levels over 15 days (Rabbits 8,9 = O.lmg dexamethasone stent; Rabbits 10,11 = lOmg dexamethasone stent);

Figure 8 shows antibiotic concentration in the nasal lavage over a 4 day period demonstrating first order kinetics in the CGP+Vancomycin and CGP+Gentamicin arms;

Figure 9 shows CFU log reduction in the S. aureus arm by treatment modality. The reduction in the CGP+Vancomycin and Vancomycin Solution group were significantly greater than that of the saline group (p=0.018); and

Figure 10 shows CFU log reduction in the P. aeruginosa arm by treatment modality.

DETAILED DESCRIPTION OF THE INVENTION

[0021] In one embodiment, the invention provides a semi-rigid biodegradable stent, comprising: a deacetylated Chitosan glycerophosphate (CGP) matrix. In another embodiment, the invention provides a controlled release delivery composition for otorhinolaryngology and otorhinolaryngology- associated pathology, conditions, indications or their combination, Head and Neck associated pathology conditions, indications or their combination, or their combination, comprising a chitosan-glycerophosphate (CGP) hydrogel and an agent, bio-materials and their combination. In another embodiment, a composition as provided herein delivers an agent at a controlled rate for an extended time. In another embodiment, the composition is localized by spatial placement near where it is needed. In another embodiment, the composition targets a drug action by using techniques known to a person of skill in the art. In another embodiment, targeting comprises delivery of a drug to a particular organ. In another embodiment, targeting comprises delivery of a drug to a particular tissue. In another embodiment, targeting comprises delivery of a drug to a particular cell type.

[0022] In one embodiment, the invention provides a semi-rigid biodegradable stent, comprising: a deacetylated Chitosan glycerophosphate (CGP) matrix; and an agent in the Chitosan glycerophosphate (CGP) matrix. [0023] In another embodiment, the stent of the invention is placed in the maxillary sinuses of a subject suffering from a a rhinologic pathology. In another embodiment, the stent of the invention comprises a drug. In another embodiment the stent comprises a drug and one or more agents. In one embodiment, the stent comprises one or more agents. In another embodiment, the agent is a steroid. In one embodiment, the agent is an antibacterial agent. In another embodiment, the agent is an antimicrobial agent. In one embodiment, the agent is an antibiotic agent. In another embodiment, the agent is an antifungal agent. In another embodiment, the stent comprises an agent and another drug.

[0024] In one embodiment, the invention provides a semi-rigid biodegradable implant, comprising: a deacetylated Chitosan glycerophosphate (CGP) matrix. [0025] In one embodiment, the invention provides a semi-rigid biodegradable implant, comprising: a deacetylated Chitosan glycerophosphate (CGP) matrix; and an agent in the Chitosan glycerophosphate (CGP) matrix.

[0026] In another embodiment, the implant of the invention is placed in the maxillary sinuses of a subject suffering from a a rhinologic pathology. In another embodiment, the implant of the invention comprises a drug. In another embodiment the implant comprises a drug and one or more agents. In one embodiment, the implant comprises one or more agents. In another embodiment, the agent is a steroid. In one embodiment, the agent is an antibacterial agent. In another embodiment, the agent is an antimicrobial agent. In one embodiment, the agent is an antibiotic agent. In another embodiment, the agent is an antifungal agent. In another embodiment, the implant comprises an agent and another drug. [0027] In another embodiment, the invention provides a controlled release delivery composition for an otorhinolaryngology and otorhinolaryngology-associated pathology, Head and Neck associated pathology conditions, Rhinology associated conditions and any pathology involving the digestive tract or upper or lower airway including all spaces lined by respiratory or digestive epithelium, or their combination, comprising a chitosan- glycerophosphate (CGP) hydrogel and an agent, bio-materials and their combination. [0028] In one embodiment, the invention provides a method comprising: placing a semi-rigid biodegradable stent, within a body lumen, said stent comprises comprising: deacetylated Chitosan glycerophosphate (CGP) matrix; and an agent in the Chitosan glycerophosphate (CGP) matrix, wherein the degree of deacetylation provides a sufficient rigidity to the stent. [0029] In another embodiment, the invention further provides a method of treating an otorhinolaryngology and otorhinolaryngology- associated pathology, conditions, indications or their combination, Head and Neck associated pathology conditions, indications or their combination, or their combination, in a subject, comprising the step of inserting a the stent or implant a predetermined region in a subject.

[0030] In one embodiment, the invention provides a method of inhibiting or suppressing an otorhinolaryngology and otorhinolaryngology- associated pathology, conditions, indications or their combination, Head and Neck associated pathology conditions, indications or their combination, or their combination, in a subject, comprising the step of inserting the stent or implant thereby inhibiting or suppressing an otorhinolaryngology and otorhinolaryngology- associated pathology.

[0031] In one embodiment, the invention provides a method of reducing symptoms or incidence of, associated with an otorhinolaryngology and otorhinolaryngology-associated pathology, conditions, indications or their combination, Head and Neck associated pathology conditions, indications or their combination, or their combination, in a subject, comprising the step of inserting the stent or implant, thereby reducing symptoms or incidence of, associated with an otorhinolaryngology and otorhinolaryngology-associated pathology. [0032] This invention relates in one embodiment to a controlled and sustained release delivery device or composition, for pathologies associated with Rhinology-associated conditions and any pathology involving the digestive tract or upper or lower airway including all spaces lined by respiratory or digestive epithelium. In another embodiment, the invention is directed to a semi-rigid biodegradable stent, comprising: deacetylated Chitosan glycerophosphate (CGP) matrix; and an agent in the Chitosan glycerophosphate (CGP) matrix, and the use of agent impregnated Chitosan glycerophosphate (CGP) constructs in sinonasal applications.

[0033] In one embodiment, Chitosan refers to an amino-polysaccharide derived from the deacetylation of chitin which is found in crustacean shells and can be engineered to form a cationic polymer. When a polyol salt with a single anionic head such as glycerophosphate is mixed with the chitosan, a temperature dependent hydrogel results which undergoes a phase transition from liquid to gel at body temperature. These hydrogels are biodegradable, inert, and capable of reversibly binding a variety of large and small molecular weight pharmaceutical compounds. [0034] In another embodiment, a chitosan glycerophosphate hydrogel is able to continuously elute dexamethasone over a four day period in the mouse middle ear. In another embodiment, chitosan based hydrogel use in sinonasal applications mandates novel formulations which are capable of eluting steroid in certain embodiments, over a longer period of time and are engineered in another embodiment, into a semi-rigid sheet capable of acting as a biodegradable sinus stent.

[0035] Accordingly and in one embodiment, provided herein is a semi-rigid sheet capable of acting as a biodegradable stent, spacer, or implant comprising: deacetylated Chitosan glycerophosphate (CGP) matrix; and an agent dispersed in the Chitosan glycerophosphate (CGP) matrix, wherein the degree of deacetylation provides a sufficient rigidity to the sheet to act as a stent, spacer, or implant.

[0036] In one embodiment, the term "rigidity" refers to the property of the stent, spacer, or implant of resisting displacement or deformation when load is applied thereto. This ability to hold the appropriate space is important in one embodiment, to preserve adequate sinus pathway. Accordingly, when a stent, spacer, or implant exhibiting rigidity, e.g., a compression strength of on the order of from about 10 to about 10 ¹ centipoise (cP), the agent eluting stent, spacer, or implant used in the methods described herein, can be advantageously employed. In another embodiment, the term "rigidity" refers to the amount of deflection which a deacetylated Chitosan glycerophosphate (CGP) matrix displays when responding to a force. In one embodiment, rigidity is measured by holding a cylinder (or similar shape) of deacetylated Chitosan glycerophosphate (CGP) matrix in a horizontal direction. The extent to which the cylinder bends toward the earth under the force of gravity is used as a measure of the rigidity of the deacetylated Chitosan glycerophosphate (CGP) matrix. A very rigid deacetylated Chitosan glycerophosphate (CGP) matrix will not bend to any noticeable degree, while a matrix that exhibits little or no rigidity will display considerable bend.

[0037] In another embodiment, a composition as described herein delivers an agent at a controlled rate for an extended time. In another embodiment, the composition is localized by spatial placement near where it is needed. In another embodiment, the composition targets an agent action by using techniques known to a person of skill in the art. In another embodiment, targeting comprises delivery of an agent to a particular organ. In another embodiment, targeting comprises delivery of an agent to a particular tissue. In another embodiment, targeting comprises delivery of an agent to a particular cell type. In another embodiment the composition is applied as a stent, implant, or spacer to any area of the digestive tract or upper or lower airway including all spaces lined by respiratory or digestive epithelium either alone or as an agent delivery vehicle.

[0038] In another embodiment, the composition controls entry to the body according to the specifications of the required agent delivery profile. In another embodiment, the composition controls the rate and duration of delivery. In another embodiment, the rate and duration of delivery are designed to achieve desired concentration.

[0039] In another embodiment, the composition is a sustained release composition. In another embodiment, a sustained release composition releases an agent over extended time. In another embodiment, rate and duration are not designed to achieve a particular profile. [0040] In another embodiment, the composition of the invention reduced side effects because effective concentration of an agent is maintained. In another embodiment, the composition of the invention eliminates damage to non-target.

[0041] In another embodiment, the composition is in a chitosan-glycerophosphate (CGP) hydrogel form. In another embodiment, the chitosan-glycerophosphate (CGP) hydrogel serves as an agent reservoir. In another embodiment, the agent diffuses from the chitosan- glycerophosphate (CGP) hydrogel. In another embodiment, the chitosan-glycerophosphate (CGP) hydrogel comprising an agent of the invention is placed near or at the site of treatment.

[0042] In another embodiment, the agent is physically blended with the chitosan- glycerophosphate (CGP) hydrogel. In another embodiment, the agent is dissolved or dispersed within the chitosan-glycerophosphate (CGP) hydrogel. In another embodiment, the agent is uniformly dissolved or dispersed within the chitosan-glycerophosphate (CGP) hydrogel. In another embodiment, the characteristics of the chitosan-glycerophosphate (CGP) hydrogel define an agent rate-controlling mechanism. In addition, the active compounds may be incorporated into sustained-release, pulsed release, controlled release or postponed release preparations and formulations.

[0043] Controlled or sustained release compositions include formulation in lipophilic depots (e.g. fatty acids, waxes, oils). Also comprehended by the invention are particulate compositions coated with polymers (e.g. poloxamers or poloxamines) and the compound coupled to antibodies directed against tissue- specific receptors, ligands or antigens or coupled to ligands of tissue-specific receptors.

[0044] In one embodiment, the composition can be delivered in a controlled release system. For example, the agent may be administered using intranasal delivery, intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other modes of administration. In one embodiment, intranasal delivery is used. In another embodiment, advantages resulting from intranasal delivery include rapid adsorption into the nasal mucosa due to the abundant presence of capillary vessels in the nose, rapid onset of action, avoidance of hepatic first-pass metabolism, utility for chronic medication, and ease of administration. In another embodiment, it is envisaged that nasal administration will provide for a fast onset of action, at a rate similar to that of injection and at a rate much faster than that of oral administration. Indeed, for the treatment of many acute conditions, nasal administration is advantageous over oral administration, since gastric stasis can further slow the onset of action following oral administration. In one embodiment, a pump may be used (see Langer, supra; Sefton, CRC Crit. Ref. Biomed. Eng. 15:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321 :574 (1989). In another embodiment, polymeric materials can be used. In another embodiment, a controlled release system can be placed in proximity to the therapeutic target, i.e., the ear nose or throat, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984). Other controlled release systems are discussed in the review by Langer (Science 249:1527-1533 (1990).

[0045] Aside from the delivery of medicaments, the irrigation of the nasal mucosa with liquids, in particular saline solutions, is commonly practised to remove particles and secretions, as well as to improve the mucociliary activity of the nasal mucosa. These solutions can be used in combination with active pharmaceuticals.

[0046] In another embodiment, the chitosan-glycerophosphate (CGP) hydrogel comprises a microbead structure. In another embodiment, the chitosan-glycerophosphate (CGP) hydrogel comprises a microtube structure or a polymeric hollow fiber. In another embodiment, the chitosan-glycerophosphate (CGP) hydrogel serves as an osmotic pump. [0047] In another embodiment, the chitosan-glycerophosphate (CGP) hydrogel is further surrounded by a polymer film that further controls the agent release rate. In another embodiment, the chitosan-glycerophosphate (CGP) hydrogel serves as an agent reservoir implant. In another embodiment, the chitosan-glycerophosphate (CGP) hydrogel comprises a rate control mechanism of solvent activation. In another embodiment, the chitosan- glycerophosphate (CGP) hydrogel absorbs fluids. In another embodiment, the chitosan- glycerophosphate (CGP) hydrogel is swollen. In another embodiment, swelling allows agent to migrate more easily. In another embodiment, water penetrates the chitosan- glycerophosphate (CGP) hydrogel thus forming pores and releasing the agent. [0048] In another embodiment, a composition comprising chitosan-glycerophosphate (CGP) hydrogel and an agent is administered parenterally. In another embodiment, a composition comprising chitosan-glycerophosphate (CGP) hydrogel and an agent is administered by an injection. In another embodiment, a composition comprising chitosan-glycerophosphate (CGP) hydrogel and an agent is administered subcutaneously. In another embodiment, a composition comprising chitosan-glycerophosphate (CGP) hydrogel and an agent is administered intramuscularly. In another embodiment, a composition comprising chitosan- glycerophosphate (CGP) hydrogel and an agent is administered intraperitonealy. In another embodiment, a composition comprising chitosan-glycerophosphate (CGP) hydrogel and an agent is administered intravenously. In another embodiment, a composition comprising chitosan-glycerophosphate (CGP) hydrogel and an agent is administered orally. In another embodiment, a composition comprising chitosan-glycerophosphate (CGP) hydrogel and an agent bypasses some routes of metabolic clearance. In another embodiment, a composition comprising chitosan-glycerophosphate (CGP) hydrogel and an agent substantially improves patients' compliance. [0049] In another embodiment, a composition comprising chitosan-glycerophosphate (CGP) hydrogel and an agent is accessible to an organ. In another embodiment, a composition comprising chitosan-glycerophosphate (CGP) hydrogel and an agent is accessible to a large surface area. In another embodiment, a composition comprising chitosan-glycerophosphate (CGP) hydrogel and an agent exhibits elevated absorption. [0050] In another embodiment, a chitosan-glycerophosphate (CGP) hydrogel releases an agent over a period of 2-4 hours. In another embodiment, a chitosan-glycerophosphate (CGP) hydrogel releases an agent over a period of 3-9 hours. In another embodiment, a chitosan- glycerophosphate (CGP) hydrogel releases an agent over a period of 5-15 hours. In another embodiment, a chitosan-glycerophosphate (CGP) hydrogel releases an agent over a period of 10-20 hours. In another embodiment, a chitosan-glycerophosphate (CGP) hydrogel releases an agent over a period of 15-30 hours. In another embodiment, a chitosan-glycerophosphate (CGP) hydrogel releases an agent over a period of 25-40 hours. In another embodiment, a chitosan-glycerophosphate (CGP) hydrogel releases an agent over a period of 30-45 hours. In another embodiment, a chitosan-glycerophosphate (CGP) hydrogel releases an agent over a period of 45-60 hours. In another embodiment, a chitosan-glycerophosphate (CGP) hydrogel releases an agent over a period of 50-70 hours. In another embodiment, a chitosan- glycerophosphate (CGP) hydrogel releases an agent over a period of 60-90 hours. In another embodiment, a chitosan-glycerophosphate (CGP) hydrogel releases an agent over a period of 90-120 hours.

[0051] In another embodiment, a chitosan-glycerophosphate (CGP) hydrogel releases an agent over a period of 5-7 days. In another embodiment, a chitosan-glycerophosphate (CGP) hydrogel releases an agent over a period of 6-10 days. In another embodiment, a chitosan- glycerophosphate (CGP) hydrogel releases an agent over a period of 10-15 days. In another embodiment, a chitosan-glycerophosphate (CGP) hydrogel releases an agent over a period of 15-20 days. In another embodiment, a chitosan-glycerophosphate (CGP) hydrogel releases an agent over a period of 20-30 days. In another embodiment, a chitosan-glycerophosphate (CGP) hydrogel releases an agent over a period of 30-45 days. In another embodiment, a chitosan-glycerophosphate (CGP) hydrogel releases an agent over a period of 45-90 days. In another embodiment, a chitosan-glycerophosphate (CGP) hydrogel releases an agent over a period of 90-120 days. In another embodiment, a chitosan-glycerophosphate (CGP) hydrogel releases an agent over a period of 100-200 days. In another embodiment, a chitosan- glycerophosphate (CGP) hydrogel releases an agent over a period of 200-370 days. [0052] In another embodiment, a chitosan-glycerophosphate (CGP) hydrogel releases an agent over a period of 1-1.5 years. In another embodiment, a chitosan-glycerophosphate (CGP) hydrogel releases an agent over a period of 1-2 years. In another embodiment, a chitosan-glycerophosphate (CGP) hydrogel releases an agent over a period of 1.5-3 years. [0053] In another embodiment, a chitosan-glycerophosphate (CGP) hydrogel composition of the invention comprises an agent or a bioactive agent. In another embodiment, the term agent comprises a bioactive agent. In another embodiment, a chitosan-glycerophosphate (CGP) hydrogel composition of the invention treats an Otorhinolaryngology-associated pathology. In another embodiment, the CGP comprising compositions described herein, treats Head and Neck associated pathology. In another embodiment, a chitosan-glycerophosphate (CGP) hydrogel composition of the invention prevents an Otorhinolaryngology-associated pathology, Head and Neck associated pathology or their combination. In another embodiment, a chitosan-glycerophosphate (CGP) hydrogel composition of the invention inhibits an Otorhinolaryngology-associated pathology, Head and Neck associated pathology or their combination. In another embodiment, a chitosan-glycerophosphate (CGP) hydrogel composition of the invention improves the condition of a patient affected with an Otorhinolaryngology-associated pathology, Head and Neck associated pathology or their combination.

[0054] Pathologies associated with the aerodigestive tract are unique in that they may be directly treated with topical medication without having to violate healthy tissue. Topical therapies are preferable to their systemic counterparts as they allow for increased agent concentrations at the site of treatment while minimizing systemic absorption with its attendant toxicity. Important concepts include adequate delivery, optimal dosing, degree of mucosal absorption, duration of action at local site, and side effect profile including systemic absorption. Topical treatments in the aerodigestive tract including but not limited to steroids, antibiotics, antifungals, antivirals, fibroblast inhibitors, antibiofilm agents, antiinflammatories, and immunologically active compounds have been explored in a variety of applications and have found to be of clinical benefit at all sites lined by respiratory epithelium. [0055] In one embodiment, the agent loading in the agent eluting stents described herein, which are used in the methods provided, and in yet another embodiment, comprises two or more active ingredients (pharmaceutical or excipients), is loaded at a loading of between about 0.1 and 50% (w/w CGP matrix). In another embodiment, the agent loading is between about 0.1 and 1% In another embodiment, the agent loading is between about 1 and 5%. In another embodiment, the agent loading is between about 5 and 10%. In another embodiment, the agent loading is between about 10 and 20%. In another embodiment, the agent loading is between about 20 and 20%. In another embodiment, the agent loading is between about 20 and 30%. In another embodiment, the agent loading is between about 30 and 40%. In another embodiment, the agent loading is between about 40 and 50% . [0056] In another embodiment, provided herein is a controlled release delivery composition for an otorhinolaryngology and otorhinolaryngology-associated pathology, Head and Neck associated pathology conditions, Rhinology associated conditions and any pathology involving the digestive tract or upper or lower airway including all spaces lined by respiratory or digestive epithelium, or their combination, comprising a chitosan- glycerophosphate (CGP) hydrogel and an agent, bio-materials and their combination. [0057] In another embodiment, the invention further provides a method of treating an otorhinolaryngology and otorhinolaryngology-associated pathology, conditions, indications or their combination, Head and Neck associated pathology conditions, indications or their combination, or their combination, in a subject, comprising the step of inserting a composition comprising a chitosan-glycerophosphate (CGP) hydrogel and an agent, bio- materials and their combination in a predetermined region in a subject. [0058] In one embodiment, provided herein is a method of inhibiting or suppressing an otorhinolaryngology and otorhinolaryngology- associated pathology, conditions, indications or their combination, Head and Neck associated pathology conditions, indications or their combination, or their combination, in a subject, comprising the step of inserting a composition comprising a chitosan-glycerophosphate (CGP) hydrogel and an agent , bio- materials and their combination in a predetermined region in a subject. [0059] In one embodiment, provided herein is a method of reducing symptoms associated with an otorhinolaryngology and otorhinolaryngology-associated pathology, conditions, indications or their combination, Head and Neck associated pathology conditions, indications or their combination, or their combination, in a subject, comprising the step of inserting a composition comprising a chitosan-glycerophosphate (CGP) hydrogel and an agent , bio- materials and their combination in a predetermined region in a subject. [0060] In another embodiment, provided herein is a method of producing a semi-rigid stent, spacer, or implant comprising: forming a Chitosan glycerophosphate (CGP) matrix film, with an active ingredient incorporated therein, wherein the Chitosan glycerophosphate (CGP) matrix is deacetylated; cross linking the Chitosan glycerophosphate (CGP) matrix; and drying the Chitosan glycerophosphate (CGP) matrix, creating a semi-rigid stent, spacer, or implant.

[0061] In one embodiment, Chitosan refers to a copolymer of glucosamine and N-acetyl glucosamine linked by β 1-4 glucosidic bonds obtained by N-deacetylation of chitin. In another embodiment, the molecular weight and degree of deacetylation can be modified during its preparation to obtain tailor-made properties. In another embodiment, chitosan has free amine as well as hydroxyl groups, which can be modified to obtain different chitosan derivatives. In one embodiment, chemical cross -linking is carried out by interacting the Chitosan glycerophosphate (CGP) matrix with negatively charged species such as TPP to prepare cross-linked chitosan matrix. The interaction of chitosan with TPP leads to formation of biocompatible cross-linked chitosan sheet, which can be efficiently employed for creating a semi-rigid stent, spacer, or implant. In one embodiment, the agent loading, the degree of deacetylation and the degree of cross-linking are optimized for the application desired. Accordingly and in one embodiment, the agent load, degree of acetylation and cross linking for making a nasal stent for the treatment of allergic rhinosinusitis, is different than the agent load, degree of acetylation and cross linking for making a spacer for COPD associated disorder.

[0062] In one embodiment, the term "stent" encompasses any prosthetic device for implantation or insertion in a body passageway (e.g. a lumen). In another embodiment, the term "spacer" refers to a spacing device for use in fenestrations of the paranasal sinus, consisting in yet another embodiment of a sheath which forms a hollow body, surrounding an internal cavity.

[0063] In one embodiment, provided herein is a method of treating, inhibiting or suppressing or ameliorating symptoms associated with rhinologic pathology in a subject, comprising inserting into a sinus pathway of the subject, an agent-eluting stent, spacer, or implant, whereby the stent, spacer, or implant comprising: deacetylated Chitosan glycerophosphate (CGP) matrix; and an agent dispersed in the Chitosan glycerophosphate (CGP) matrix, wherein the degree of deacetylation provides a sufficient rigidity to the sheet to act as a stent, spacer, or implant and wherein the agent is effective in treating, inhibiting or suppressing or ameliorating symptoms associated with the rhinologic pathology.

[0064] The success of treatment of Rhinologic applications within the sinonasal cavity depend in one embodiment on a complex interplay of efficiency of delivery, patient performance and compliance, and the efficacy of the agent being used. In another embodiment, the operative status of the patient of critical importance as well, as certain areas of the sinus can not be accessed with intact native sinus parititions. In certain embodiments, even in the postoperative setting, persistent inflammation and iatrogenic mucosal injuries at sinus outflow tracts can lead to neoosteogenesis and circumferential stenosis leading to further disease and blocking access of topical medication. In the majority of medication is lost in the anterior nasal cavity and nasal vestibule where they are swept out of the nasal cavity without reaching their intended site of action. Patient compliance and performance also plays an important role in success of therapy. Most topical treatments require daily use at a minimum and often must be used for a prolonged course for benefit to be derived. This coupled with technically difficult application techniques and subjective treatment related discomfort lead to poor patient compliance with treatment regimens and subsequent treatment failure. In another embodiment rhinologic associated pathology is acute, subacute, or chronic sinusitis which can be characterized as allergic, viral, bacterial, or fungal, and may or may not be associated with polyps. In another embodiment rhinologic associated pathology is any anatomical abnormality leading to obstruction or inflammation of the sinonasal cavity. In another embodiment rhinologic associated pathology is any benign or malignant neoplasm within the sinonasal cavity or surrounding structures including but not limited to the skull base, pterygopalatine fossa, or infratemporal fossa. In another embodiment pathology of the upper or lower respiratory tract is any process involving the larynx, trachea, bronchi, bronchioli, alveoli, or lungs. [0065] In one embodiment, there is a need for for a non-immunogenic, biodegradable carrier for pharmacologic therapies which can be placed in any sinonasal cavity under direct visualization and will predictably elute medication over a specific period of time. Provided herein is a chitosan-glycerophosphate (CGP) hydrogel and an agent comprising an agent delivery vehicle with these characteristics. In another embodiment, CGP hydrogel are engineered by the techniques which is formed into a semi-rigid sheet which is capable of acting as an inert sinus stent in one embodiment, or a spacer, or a sinonasal implant which can be applied endoscopically and elutes an agent and spontaneously degrade over a predictable time period. [0066] In one embodiment, the provided structures apply to the entire aerodigestive tract in one embodiment, as well as the upper and lower respiratory tract in another embodiment for diseases such as asthma in one embodiment, or bronchitis, or COPD in other discrete embodiments for controlled or sustained delivery of agents such as corticosteroids in one embodiment, or beta2- agonists (long and short acting), leukotriene inhibitors, antibiotics, anticholinergics, and immunotherapy in other discrete embodiments of the agent eluted by the stents described herein.

[0067] In another embodiment, the Otorhinolaryngology-associated pathology is hearing loss. In another embodiment, the Otorhinolaryngology-associated pathology is vertigo. In another embodiment, the Otorhinolaryngology-associated pathology is a vestibular Disorder. In another embodiment, the Otorhinolaryngology-associated pathology is an ear infection. In another embodiment, the Otorhinolaryngology-associated pathology is Otitis Media. In another embodiment, the Otorhinolaryngology-associated pathology is a sinus infections or a sinus disease. In another embodiment, the Otorhinolaryngology-associated pathology is scaring or stenosis of openings within the ear and sinuses. In another embodiment, the Otorhinolaryngology-associated pathology is a cancer associted with the head and neck. In another embodiment, the Otorhinolaryngology-associated pathology comprises an abscess or an infections of the ear, nose, throat, head, neck, or a combination thereof. In another embodiment, the Otorhinolaryngology-associated pathology comprises otology pathology. In another embodiment, the Otorhinolaryngology-associated pathology comprises neurotology pathology. In another embodiment, the Otorhinolaryngology-associated pathology comprises rhinology pathology. In another embodiment, the Otorhinolaryngology- associated pathology comprises an allergy. In another embodiment, the Otorhinolaryngology-associated pathology comprises laryngology pathology. In another embodiment, the Otorhinolaryngology- associated pathology comprises bronchoesophagology pathology. [0068] In one embodiment, Head and Neck associated pathology is Branchial Cleft Cyst. Or in another embodiment, the Head and Neck associated pathology is a salivary-gland associated pathology, a thyroid- associated pathology, Verrucal Keratosis of the larynx or their combination in certain other embodiment. In one embodiment, Head and Neck- associated pathology, refers to any pathology associated with the head, neck or organs or tissue comprised in the head and neck, each of which, is a discrete embodiment to be treated with the methods and compositions described herein.

[0069] In another embodiment, the terms active pharmaceutical ingredient, agent, and agent are used interchangeably. In another embodiment, the agent is a steroid. In another embodiment, the agent is an antibiotic agent. In another embodiment, the agent is an antiviral agent. In another embodiment, the agent is a fungicidal. In another embodiment, the agent is a neurological agent. In one embodiment, the agent is non-steroidal anti-inflammatory agent. [0070] In another embodiment, the agent is dexamethasone. In another embodiment, the agent is acetic acid. In another embodiment, the agent is acetic acid-aluminum acetate. In another embodiment, the agent is hydrocortisone. In another embodiment, the agent is hydrocortisone-acetic acid. In another embodiment, the agent is benzocaine. In another embodiment, the agent is benzotic. In another embodiment, the agent is floxin. In another embodiment, the agent is ciprodex. In another embodiment, the agent is cipro. In another embodiment, the agent is flunisolide. In another embodiment, the agent is fluticasone. In another embodiment, the agent is mometasone. In another embodiment, the agent is ipratropium. In another embodiment, the agent is beconase. In another embodiment, the agent is triamcinolone. In another embodiment, the agent is chlorhexidine gluconate. In another embodiment, the agent is doxycycline. In another embodiment, the agent is pilocarpine. In another embodiment, the agent is levocabastine. In another embodiment, the agent is sodium cromoglycate. In another embodiment, the agent is bacitracin zinc. In another embodiment, the agent is polymyxin B-sulfate. In another embodiment, the agent is chloramphenicol. In another embodiment, the agent is erythromycin. In another embodiment, the agent is a mixture of the above agents. In another embodiment, the agent is a therapeutically effective mixture of the above agents. [0071] In another embodiment, the agent is levocabastine HCl. In another embodiment, the agent is ciprofloxacin HCl. In another embodiment, the agent is ciprofloxacin HCl/hydrocortisone. In another embodiment, the agent is erythromycin. In another embodiment, the agent is framycetin sulfate. In another embodiment, the agent is gramicidin. In another embodiment, the agent is gentamicin sulfate. In another embodiment, the agent is gramicidin. In another embodiment, the agent is neomycin sulfate. In another embodiment, the agent is ofloxacin. In another embodiment, the agent is trimethoprim sulfate. In another embodiment, the agent is sulfacetamide sodium. In another embodiment, the agent is tobramycin trifluridine. In another embodiment, the agent is beclomethasone dipropionate. In another embodiment, the agent is betamethasone sodium phosphate. In another embodiment, the agent is budesonide. In another embodiment, the agent is clioquinol. In another embodiment, the agent is fluorometholone. In another embodiment, the agent is fluorometholone acetate. In another embodiment, the agent is prednisolone acetate. In another embodiment, the agent is triamcinolone acetonide. In another embodiment, the agent is diclofenac sodium. In another embodiment, the agent is flurbiprofen sodium In another embodiment, the agent is atropine sulfate. In another embodiment, the agent is cyclopentolate HCl. In another embodiment, the agent is dipivefrin HCl. In another embodiment, the agent is homatropine Hbr. In another embodiment, the agent is benzydamine HCl In another embodiment, the agent is antazoline phosphate. In another embodiment, the agent is naphazoline HCl. In another embodiment, the agent is phenylephrine HCl. In another embodiment, the agent is brimonidine tartrate. In another embodiment, the agent is timolol maleate. In another embodiment, the agent is betaxolol HCl. In another embodiment, the agent is dipivefrin HCl. In another embodiment, the agent is levobunolol HCl. In another embodiment, the agent is acetazolamide brinzolamide. In another embodiment, the agent is dorzolamide HCl In another embodiment, the agent is carbachol. In another embodiment, the agent is pilocarpine HCl. In another embodiment, the agent is bimatoprost. In another embodiment, the agent is latanoprost . In another embodiment, the agent is travoprost. In another embodiment, the agent is apraclonidine HCl. [0072] In another embodiment, the agent is an adrenocorticoids such as but not limited to betamethasone, cortisone, dexamethasone, hydrocortisone, methylprednisolone, paramethasone, prednisolone, prednisone, and triamcinolone. Exemplary analgesics include acetaminophen, aspirin, buprenorphine, butalbital, butorphanol, codeine, dezocine, diflunisal, dihydrocodeine, etodolac, fenoprefen, fentanyl, floctafenine, hydrocodone, hydromorphone, ibuprofen, ketoprofen, ketorolac, levorphanol, magnesium salicylate, meclofenamate, mefenamic acid, meperidine, meprobamate, methadone, methotrimeprazine, morphine, nalbuphine, naproxen, opium, oxycodone, oxymorphone, pentazocine, phenobarbital, propoxyphene, salsalate, and sodium salicylate. One exemplary analgesic adjunct is caffeine. Exemplary anesthetics include articane-epinephrine, bupivacaine, chloroprocaine, etidocaine, ketamine, lidocaine, mepivacaine, methohexital, prilocaine, propofol, propoxycaine, tetracaine, and thiopental. One exemplary analgesic-anesthetic is antipyrine-benzocaine. [0073] In another embodiment, the agent is an antibiotic such as but not limited to anti- bacterials, and anti-infectives include sulfonamides (e.g., sulfanilamide, sulfadiazine, sulfamethoxazole, sulfisoxazole, para-aminobenzoic acid, or sulfacetamide), trimethoprim- sulfamethoxazole, quinolones (e.g., ciprofloxacin, ofloxacin, or nalidixic acid), .beta. -lactam antibiotics such as penicillins or cephalosporins, aminoglycosides (e.g., kanamycin, tobramycin, gentamycin C, amikacin, neomycin, netilmicin, streptomycin, or vancomycin), tetracyclines, chloramphenicol, and macrolides (e.g., erythromycin, clarithromycin, or azithromycin). Non-limiting examples of suitable penicillins include penicillin G, penicillin V, methicillin, oxacillin, nafeillin, ampicillin, and amoxicillin. Non-limiting examples of suitable cephalosporins include cephalothin, cefdinir, cefozolin, cephalexin, cefadraxal, cefamandole, cefoxitin, cefaclor, cefonicid, cefoletan, cefotaxime, ceftizoxime, cefrtriaxone, cefditoren, and cefepine. Exemplary antibiotics useful for treating OM include penicillins such as amoxicillin and amoxicillin-clavulanate (Augmentin.RTM.); sulfa-based combinations such as erythromycin-sulfisoxazole (Pediazole), trimethoprim- sulfamethoxazole (Bactrim, Septra. RTM.); macrolides/azalides such as azithromycin (Zithromax.RTM.) or clarithromycin (Biaxin.RTM.); second-generation cephalosporins such as cefaclor (Ceclor.RTM.), cefprozil (Cefzil.RTM.), cefuroxime axetil (Ceftin.RTM.), or loracarbef (Lorabid.RTM.); and third generation cephalosporins such as cefdinir (Omnicef.RTM.), cefixime (Suprax.RTM.), cefpodoxime proxetil (Vantin.RTM.), ceftibuten (Cedax.RTM.), cefditoren (Spectracef,.RTM.), and ceftriaxone (Rocephin.RTM.). [0074] In another embodiment, the agent is an anti-emetic such as but not limited to buclizine, chlorpromazine, cyclizine, dimenhydrinate, diphenhydramine, diphenidol, domperidone, dronabinol, haloperidol, hydroxyzine, meclizine, metoclopramine, nabilone, ondansetron, perphenazine, prochlorperazine, promethazine, scopolamine, thiethylperazine, triflupromazine, and trimethobenzamine. Exemplary antifungals include amphotericin B, clioquinol, clotrimazole, fluconazole, flucytosine, griseofulvin, ketoconazole, miconazole, and potassium iodide. Exemplary anti-inflammatory agents include aluminum acetate, aspirin, betamethasone, bufexamac, celecoxib, dexamethasone, diclofenac, etodolac, flurbiprofen, hydrocortisone, indomethacin, magnesium salicylate, naproxen, prednisolone, rofecoxib, salsalate, sulindac, and triamcinolone. Exemplary anti-vertigo agents suitable for the invention include belladonna, dimenhydrinate, diphenhydramine, diphenidol, meclizine, promethazine, and scopolamine. Exemplary anti-viral agents suitable for the invention include acyclovir, amantadine, delavirdine, didanosine, efavirenz, foscamet, ganciclovir, indinavir, nelfinavir, ribavirin, ritonavir, zalcitabine, and zidovudine. Exemplary biological response modifiers include aldesleukin, interferon .alpha. -2a, interferon .alpha. -2b, interferon . alpha. -nl, interferon .alpha.-n3, interferon .gamma., and levamisole. Exemplary cytotoxic agents include podofilox and podophyllum. Exemplary immunizing agents include influenza virus vaccine, pneumococcal vaccine polyvalent, and immune globulin. An exemplary immunomodulator invention is interferon .gamma. Other pharmacologic agents suitable for the invention include betahistine (e.g., for treating the nausea, dizziness, and ringing in the ears that occur in Meniere's disease), prochlorperazine, and hyoscine. [0075] In another embodiment, the agent is chlorhexidine gluconate. [0076] In another embodiment, the composition comprises 0.5-40% (w/w) chitosan. In another embodiment, the composition comprises 1-5% (w/w) chitosan. In another embodiment, the composition comprises 2-8% (w/w) chitosan. In another embodiment, the composition comprises 5-10% (w/w) chitosan. In another embodiment, the composition comprises 8-12% (w/w) chitosan. In another embodiment, the composition comprises 12- 20% (w/w) chitosan. In another embodiment, the composition comprises 15-25% (w/w) chitosan. In another embodiment, the composition comprises 20-30% (w/w) chitosan. In another embodiment, the composition comprises 25-35% (w/w) chitosan. In another embodiment, the composition comprises 30-40% (w/w) chitosan. [0077] In another embodiment, the composition comprises 1-60% (w/w) glycerophosphate. In another embodiment, the composition comprises 1-5% (w/w) glycerophosphate. In another embodiment, the composition comprises 5-15% (w/w) glycerophosphate. In another embodiment, the composition comprises 10-20% (w/w) glycerophosphate. In another embodiment, the composition comprises 15-25% (w/w) glycerophosphate. In another embodiment, the composition comprises 20-30% (w/w) glycerophosphate. In another embodiment, the composition comprises 25-35% (w/w) glycerophosphate. In another embodiment, the composition comprises 35-45% (w/w) glycerophosphate. In another embodiment, the composition comprises 40-50% (w/w) glycerophosphate. In another embodiment, the composition comprises 50-60% (w/w) glycerophosphate. [0078] In another embodiment, the composition is in a solid form. In another embodiment, the composition is in a liquid form. In another embodiment, the composition is in a gel form. In another embodiment, the composition is in a semi-gel form. In another embodiment, the composition's form is determined by factors comprising the ratio of glycerophosphate to chitosan. In another embodiment, the composition's the agent release profile is determined by factors comprising the ratio of glycerophosphate to chitosan. In another embodiment, the higher the ratio of chitosan to glycerophosphate when the agent is hydrophilic, the longer is the agent release following the initial release. In another embodiment, the lower the ratio of chitosan to glycerophosphate when the agent is hydrophobic, the longer is the agent release following the initial release.

[0079] In another embodiment, by altering the composition of CGP-hydrogel the physical properties can be adjusted to fit various release strategies. In another embodiment, these properties comprise the diameter of pores in the matrix, the strength of the matrix and the rate of matrix degradation. In another embodiment, by altering the pore size, the initial volume of agent released is controlled as a bolus early in the treatment course. In another embodiment, the mechanical strength of the CGP-hydrogel is fortified by adjusting the proportions of the hydrogel components permitting the design of hydrogels with reduced susceptibility to degradation, thereby prolonging the release of agent. In another embodiment, susceptibility of CGP-hydrogel to degradation by lysozyme is also adjustable which further enables us to fine tune the agent release properties of this system for the specific requirements of a given clinical scenario.

[0080] In another embodiment, the composition comprises at least two different chitosan to glycerophosphate ratio. In another embodiment, the composition comprises two different chitosan to glycerophosphate ratio. In another embodiment, the composition comprises three different chitosan to glycerophosphate ratio. In another embodiment, the composition comprises four different chitosan to glycerophosphate ratio. In another embodiment, the composition comprises five different chitosan to glycerophosphate ratio. In another embodiment, the composition comprises six different chitosan to glycerophosphate ratio. [0081] In another embodiment, the invention provides a method of treating an Otorhinolaryngology-associated pathology in a subject, comprising the step of administering a composition comprising a chitosan-glycerophosphate (CGP) hydrogel and an agent, bio- materials and their combination in a predetermined region in a subject. In anther embodiment, the method comprises topical administration. In another embodiment, the method comprises trans-tympanic administration. In another embodiment, the method comprises intra-tympanic administration. In another embodiment, the method comprises intraperitoneal administration. In another embodiment, the method comprises intravenous administration. In another embodiment, the method comprises intramascular administration. In another embodiment, the method comprises intra-ear administration. In another embodiment, the method comprises administration into the Round Window Niche (RWN). [0082] In another embodiment, the method comprises administering the composition of the invention in a solid state. In another embodiment, the method comprises adminstering the composition of the invention in a liquid state. In another embodiment, the method comprises adminstering the composition of the invention in a gel form. In another embodiment, the invention provides that the composition's states of aggregation changes from a liquid to a semi-solid gel when maintained in a temperature of 36°C to 38°C. In another embodiment, the method comprises adminstering the composition in a semi-solid gel form. In another embodiment, the method provides that a semi-solid gel form is preserved in a subject's body temperature. [0083] In another embodiment, the method comprises topically administering the composition of the invention onto an affected area. In another embodiment, the method comprises locally injecting the composition of the invention under the integument of an affected area. [0084] In another embodiment, hydrogels of the invention are suitable for use in the subject methods because they are biocompatible, by which is meant that they are suitable for contact with a human tissue.

[0085] In another embodiment, the hydrogel further comprises macromolecular or polymeric materials into which water and small molecules can easily diffuse and include hydrogels prepared through the cross linking. In another embodiment, crosslinking may be either through covalent, ionic or hydrophobic bonds introduced through use of either chemical cross-linking agents or electromagnetic radiation, such as ultraviolet light, of both natural and synthetic hydrophilic polymers, including homo and co-polymers. In another embodiment, additional hydrogels of interest include those prepared through the cross- linking of: polyethers, e.g. polyakyleneoxides such as poly(ethylene glycol), poly(ethylene oxide), poly(ethylene oxide) -co- (poly (propyleneoxide) block copolymers; poly (vinyl alcohol); poly(vinyl pyrrolidone); polysaccharides, e.g. hyaluronic acid, dextran, chondroitin sulfate, heparin, heparin sulfate or alginate; proteins, e.g. gelatin, collagen, albumin, ovalbumin or polyamino acids; and the like. [0086] In another embodiment, the physical characteristics such as size, shape and surface area can affect the absorption and release characteristics of the hydrogel composition. In another embodiment, the hydrogel composition that is employed may be in a variety of configurations, including particles, beads, rods, sheets, irregular shapes and the like. In another embodiment, the hydrogel shape comprises greater surface area to total mass ratios. In another embodiment, the porosity of the hydrogel affects the absorption and release characteristics of the hydrogel.

[0087] In another embodiment, the amount of pharmacologic agent present in the composition is dependent on the type of pharmacologic agent and its known effective dosage. In another embodiment, as described hereinabove a composition can include any type of pharmacologic agent, including, e.g., an adrenocorticoid (corticosteroid, steroid), analgesic, analgesic adjunct, analgesic-anesthetic, anesthetic, antibiotic, antibacterial, anti- infective, antibiotic therapy adjunct, antidote, anti-emetic, anti-fungal, antiinflammatory, anti-vertigo, anti-viral, biological response modifier, cytotoxic, diagnostic aid, immunizing agent, immunomodulator, proteins, peptides, and other agents that may useful in treating ear disorders. Analgesic, analgesic adjunct, analgesic-anesthetic, anesthetic, antibiotic, antibacterial, anti-infective, antibiotic therapy adjunct, anti-fungal, anti-inflammatory, antiviral, and peptides are particularly useful. [0088] In another embodiment, a composition of the invention can include a plurality of pharmacologic agents, including two or more agents within the same class (e.g., two different antibiotics) or two or more agents of various types, depending on the effect desired. For example, to fight a bacterial infection, to reduce tissue inflammation, and to alleviate irritation, a composition can contain an antibacterial, an anti-inflammatory, and an anesthetic or analgesic. In another embodiment, those skilled in the art can identify pharmacologic agents and combine them as needed to achieve a desired effect.

[0089] To further tailor the binding properties of the hydrogel, in another embodiment, the hydrogel can be modified to provide for specific binding of one or more of the agents to the surface of the hydrogel. In another embodiment, the hydrogel comprises agents that act as water absorbents and/or precipitants, where such agents include ethanol, PEG 400, phosphate buffer and the like.

[0090] In another embodiment, Chitosan glycerophosphate is used to create a semi-rigid silastic like sheet which is malleable, inert, and capable of eluting steroid in one embodiment, for a period of over 15 days in another embodiment, when implanted intranasally. In one embodiment, this material is used to create a pharmacologically active sinus stent which spontaneously degrades over time. In another embodiment creation of the semi-rigid stent involves a chitosan cross-linking reaction with subsequent vacuum dehydration for the purposes of creating a semi-rigid stent, spacer, or implant.

[0091] Accordingly and in one embodiment, provided herein is a semi-rigid sheet capable of acting as a biodegradable stent spacer, or implant, comprising: deacetylated Chitosan glycerophosphate (CGP) matrix; and an agent dispersed in the Chitosan glycerophosphate

(CGP) matrix, wherein the degree of deacetylation provides a sufficient rigidity to the sheet.

[0092] In another embodiment, provided herein is a method of producing a semi-rigid stent, spacer, or implant comprising: forming a Chitosan glycerophosphate (CGP) matrix film, with an active ingredient incorporated therein, wherein the Chitosan glycerophosphate (CGP) matrix is deacetylated; cross linking the Chitosan glycerophosphate (CGP) matrix; and drying the Chitosan glycerophosphate (CGP) matrix, creating a semi-rigid stent, spacer, or implant.

[0093] In another embodiment, the hydrogel compositions employed in the subject methods can be prepared by methods known to those skilled in the art.

[0094] The term "about" as used herein means in quantitative terms plus or minus 5%, or in another embodiment plus or minus 10%, or in another embodiment plus or minus 15%, or in another embodiment plus or minus 20%.

[0095] The term "subject" refers in one embodiment to a mammal including a human in need of therapy for, or susceptible to, a condition or its sequelae. The subject may include dogs, cats, pigs, cows, sheep, goats, horses, rats, rabbits and mice and humans. The term "subject" does not exclude an individual that is normal in all respects.

[0096] The following examples are presented in order to more fully illustrate the preferred embodiments of the invention. They should in no way be construed, however, as limiting the broad scope of the invention.

EXAMPLES

Materials and Methods: Biodegradable Hydrogel Preparation [0097] The parameters for formulating the CGP-hydrogel loaded with dexamethasone were selected creating a model formulation for further testing (CGP-Dex-hydrogel). The CGP- Dex-hydrogel was moderately viscous, injectable, and underwent phase transition to a semisolid gel in about 15 minutes at 37°C. Preparations were made on the day in which they were to be used. Ninety-eight percent deacetylated chitosan (Biosyntech, Quebec) was dissolved in 0.2M acetic acid yielding a 3.4% (w/w) chitosan solution. To this solution, water soluble dexamethasone 0.7% (w/w) (D2915, Sigma, St. Louis MO.) and glycreophosphate (G6501, Sigma, St. Louis MO.) 9% (w/w) were added. CGP-hydrogel was prepared and maintained at room temperature until it was used.

In Vitro Matrix Degradation and Dexamethasone Release

CGP-Dex-Hydrogel Pellet Preparation:

[0098] In order to evaluate CGP-Dex-hydrogel agent release and matrix degradation in the in vitro setting, it was necessary to create uniform samples which could be handled and transferred. To achieve this purpose, solidified CGP-Dex-hydrogel pellets were created. Liquid CGP-hydrogel was allowed to solidify in 1-ml syringes at 37°C for two hours until solidified. The tips of the syringes were clipped off with a razor and columns of gel were gently extruded. By sectioning these gel columns at 0.1ml increments, hydrogel pellets were created.

Dexamethasone Release from CGP-Dex-Hydrogel:

[0099] An in vitro agent release study was designed to evaluate the release of dexamethasone from the CGP-dex -hydrogel pellets. Individual CGP-Dex-hydrogel pellets were placed into 2-ml microcentrifuge tubes, weighed, and immediately loaded with ImI Dulbecco's phosphate buffered saline (PBS). The microcentrifuge tubes were then incubated at 37°C on a shaker table at lOOrpm. Every 24 hours the pellets were gently removed from the PBS solution and placed into fresh sets of microcentrifuge tubes with ImI PBS and incubated as before. The PBS sample solution was collected, ImI of 50% ethanol was added and the samples were then stored at 4°C until analysis by UV spectrophotometry.

Degradation of CGP-Dex-Hydrogel:

[00100] To understand the relationship between the release of dexamethasone and the degradation of the CGP-Dex-hydrogel matrix, the conditions of the dexamethasone release experiment were repeated. However, the pellets were collected every 24 hours for 4 days. After collection the pellets were desiccated for 72 hours and weighed. The ratio of solid components remaining was derived by subtracting from the starting pellet weight, the water weight of each pellet which was calculated from the CGP-Dex-hydrogel formula. A ratio was calculated between the initial solid component weight and the ending solid component weight for samples obtained daily over a 4 day period. In Vivo Dexamethasone Release and Auditory Function Assessment

Experimental Animals:

[00101] To assess the CGP-Dex-hydrogel mediated release of dexamethasone in vivo and to assess the safety of this system in an in vivo setting, an animal model was constructed. C57BL/6J mice (Charles River, Wilmington, MA) of either sex and weighing 18 to 22g were used at 6 to 8 weeks of age. Animals care and use was in accordance with the Institutional Animal Care and Use Committee of the University of Pennsylvania. Anesthetic used for all experiments was tribromoethanol. In total, 25 mice were used. The mice were divided into two groups a CGP-Dex-hydrogel placement group (n=20) and a sham surgery group (n=5). Fifteen of the mice in the CGP-Dex-hydrogel placement group were used for quantification of dexamethasone. The remaining 5 mice from this group and the 5 mice from the sham surgery group were used to evaluate the impact of the surgical procedure and of CGP-Dex- hydrogel upon the auditory system.

CGP-Dex-Hydrogel Placement Procedure:

[00102] In preparation for detection of dexamethasone in murine perilymph after CGP-Dex- hydrogel placement, a procedure for placement of CGP-Dex-hydrogel was devised. On the left side, a 2cm post-auricular incision was made and dissection was carried out along the external auditory canal to the bulla. A 1 mm diamond burr was used to create a single burr hole through the bulla just posterior and inferior to the facial nerve. Through this control- hole, the intact stapedial artery and the round window niche and membrane were visualized. Twenty five mice underwent the surgical procedure to this point. For five of the mice (sham surgery group) the incision was then closed and the animals were allowed to recover. For the remaining 20 mice, CGP-Dex-hydrogel was injected directly onto the RWM filling the RWN. The injection was accomplished with the use of a custom-made flame-pulled glass syringe needle using a microcapillary tube flame-puller. The skin incisions were closed with 4-0 silk, and the animals were returned to the animal facility after they fully recovered from the anesthetic agent.

Perilymph and Serum Harvesting Procedures:

[00103] Fifteen of the animals which underwent surgical placement of CGP-Dex-Hydrogel were separated into three groups of 5 animals each for sample harvesting on post-operative days 1, 3 and 5. At the time of sample collection, mice were deeply anesthetized. A cardiac puncture was performed to obtain blood for serum agent concentration analysis. The skin overlying the skull was removed and the external auditory canals were transected. Using a pick and fine forceps the tympanic membrane of the left ear was gently removed. The stapes and oval window were exposed after removing the malleus and incus. Perilymph was collected in previously prepared microcapillary tubes which had tips drawn to approximately 20μm. The tip of the glass microcapillary tube was used to gently displace the footplate of the stapes laterally. The tip of the microcapillary tube was then advanced a few micrometers through the annular ligament and into the scala vestibule. Via capillary action, within a few seconds a target volume of 0.2 to 0.3 μl of perilymph was collected into the capillary tube. Following this, each animal was euthanized by cervical dislocation. Perilymph was transferred to microcentrifuge tubes and weighed to within O.Olmg. One mg of perilymph corresponded to 1 μl of perilymph. Samples were stored at -80 ⁰ C until they were analyzed.

[00104] In order to obtain perilymph samples for analysis, a procedure to collect consistent small sample sizes of perilymph was created. Special attention to collection methods is necessary to insure the quality of data generated. This is because in mice one must consider the potential which exists for contamination of perilymph samples with cerebrospinal fluid. This contamination can potentially occur because of an existing anatomical communication with the CSF space, the cochlear aqueduct. In mice and lower mammals, the cochlear aqueduct remains patent, this is not normally the case for humans. To prevent skewed data as a result of contamination we devised a way to rapidly harvest perilymph in consistent volumes which was well below the average volume of the perilymphatic space in our murine model.

Dexamethasone Concentration in Perilymph and Serum::

[00105] To elucidate whether dexamethasone was released into murine perilymph after surgical placement of CGP-Dex-hydrogel and the time-based release kinetics, we analyzed the harvested perilymph samples by liquid chromatography (LC) and mass spectroscopy (MS). Also, to prove that the concentration of dexamethasone was elevated in the local environment compared to systemic distribution, serum samples were also analyzed by LC/MS for comparison. Harvested perilymph and serum samples were analyzed using a Finnigan LTQ linear ion trap mass spectrometer (Thermo Fisher Waltham, MA) equipped with an electrospray ionization source. LC separations were conducted with a Zorbax 300Extend-C18 column (125 A, 3.5μ, 150 x 2.1 mm Ld., Agilent Santa Clara, CA) using a linear gradient of 5 mM ammonium acetate in water-methanol with a flow rate of 250 μl/min. Perilymph and serum samples were added with flumethasone (F9507 Sigma St. Louis, MO) as an internal standard. The sample cleanup was performed with liquid-liquid extraction using ethyl acetate. LC-MS/MS analyses were conducted using positive electrospray ionization in the monitoring MRM mode using following ion transitions: mJz 393.2 → 373.1 (dexamethasone), m/z 411.2 → 391.1 (flumethasone).

Auditory Function Assessment

[00106] To address the safety of CGP-Dex-hydrogel and the procedure to apply the hydrogel an assessment of auditory function using the auditory brainstem response (ABR) was performed to compare thresholds at three timepoints: pre-operative, immediate post-operative (post-op day 2) and late post-operative periods (post-op day 10). ABRs were recorded using a Tucker Davis System II (Tucker-Davis Technologies, Alachua, FL). Ten mice were divided into two groups, a CGP-Dex-hydrogel group (n=5) and sham surgery group (n=5). One animal was lost from the sham surgery group before testing on the final day of the experiment. Mice were anesthetized and electrodes were placed at the vertex (active), in the neighborhood of the left postauricular bulla (reference), and in the flank (ground). The acoustic stimulus, generated by the TDT SigGen system consisted of 10msec tone pips at 16.OkHz, 24.OkHz, 32.OkHz, and 40.OkHz presented at a rate of 20/sec Responses were averaged over 500 stimuli and intensity increments were set at 5dB. Threshold was determined to be halfway between the intensity at which an observable response could be detected and the next lower intensity at which no response was visible. Absolute stimulus intensities were calibrated to obtain the sound pressure level in dB relative to 20μPa. [00107] Chitosan glycerophosphate (CGP) sheets were produced with varying degrees of deacetylation (70-100%) and analyzed for structural integrity.

[00108] Two cm sheets of 91.7% deacetylated CGP were mixed with either 0.1 or 10 grams of dexamethasone and implanted in 12 rabbit maxillary sinuses. Nasal lavage and peripheral blood samples were tested for dexamethasone levels by enzyme linked immuno-sorbent assay (ELISA) over 15 days. Sinuses were examined histologically on post-operative days 3, 7, and 15 for persistence of the stent and degree of inflammation as compared to CGP alone.

Statistical Analysis

[00109] Statistical analysis was performed with Statmost (Dataxiom Software, Los Angeles, CA). The data presented represent the mean of each group +/- standard error of the mean. The statistical test of significance was the Mann- Whitney U test. A conservative probability (P) value less than 0.01 was considered to be statistically significant.

EXAMPLE 1: IN VITRO MATRIX DEGRADATION AND DEXAMETHASONE RELEASE

[00110] Degradation of CGP-Dex-Hydrogel: In vitro experiments demonstrated that 92% of the solid hydrogel matrix remained at 24 hours and then slowly degraded to 16% of the original solid component by day 4. These experiments were duplicated and the average results were plotted (Fig.l). Results were consistent between experiments with 2.6% < SEM > 0.02%.

[00111] Dexamethasone release from CGP-Dex -hydrogel: Sustained release of dexamethasone was observed over 4 days in vitro. In the first 24-hour period there was an initial bolus release of dexamethasone followed by a tapering of agent release until 100% of the agent was released by day 4. The experiment was repeated and the average results were plotted (Fig.2). The initial bolus release of dexamethasone is likely due to the release of dexamethasone from the voids formed in the hydrogel matrix while the gel was solidifying. The dexamethasone released over the next 3 days represents agent that was interacting more tightly with the matrix through non-covalent molecular interactions. Results were consistent between experiments with 11.4% < SEM > +/- 0.04%.

EXAMPLE 2: IN VIVO DEXAMETHASONE RELEASE AND AUDITORY

FUNCTION ASSESSMENT

[00112] CGP-Dex-Hydrogel Placement Procedure: Twenty five animals successfully underwent the procedure; 20 received CGP-Dex-hydrogel and 5 received no hydrogel injection (sham surgery). There were no surgical complications, the animals recovered normally and there were no infections. Following recovery and for the duration of the experiments, no animals exhibited signs of distress nor were there were no observable pathologic changes in behavior, such as log rolling or circling, indicating that both vestibular and auditory functions were preserved. [00113] Perilymph and Serum Harvesting Procedures: The mean volume of perilymph harvested was 0.22μl +/- 0.07μl. There were no statistical differences between groups or between the averages of all samples (p > 0.05). Day 1 : 0.25μl +/- 0.07μl; Day 3: 0.20μl +/- 0.06μl; Day 5: 0.22μl +/- 0.07μl. The volume of serum harvested for each animal was 5μl. [00114] Dexamethasone Concentration in Perilymph and Serum: Dexamethasone was detected in the perilymph of treated ears. The average dexamethasone concentration within the perilymph peaked at 24 hours at 3.2ng/μl and declined in a linear fashion over the 5 days of the experiment to 1.3ng/μl. These values remained elevated compared to serum (Fig.3). There was statistical significance between detected dexamethasone levels of the treated ear and serum of animals for all time points (Day 1 and 3 p< 0.01 Day 5 p < 0.05). [00115] Auditory Function Assessment: There was an initial increase in ABR thresholds followed by recovery of auditory function in both the sham surgery and the CGP-Dex- hydrogel placement groups. (Figs. 4a and 4b). The pure-tone average at pre-treatment testing across all 4 frequencies tested for the sham surgery group (n= 5) and CGP-Dex-hydrogel groups (n=5) respectively were 46.7 and 50.2 dB SPL. Measurement at post-operative day 2 showed a 15.1 and 15.8 dB SPL elevation in hearing threshold for the sham surgery and CGP-Dex-hydrogel groups. By post-operative day 10, the hearing thresholds returned to baseline levels 47.2 for the sham surgery group (n=4) and 49.5 for the CGP-Dex-hydrogel group (n=5). There was no statistical difference between post-operative day 10 measurements and the pre-treatment baseline levels p > 0.05. There was no statistically significant difference between hearing thresholds of the sham surgery and CGP-Dex- hydrogel groups at any tested frequency with the exception of the measurement at 4OkHz where there was a slight difference (p < 0.05). One animal from the sham surgery group was lost due to anesthetic overdose at the time of testing on post-operative day 10.

EXAMPLE 3: CGP STENTS EFFECTIVENESS AS SINUSAL STENTS FOR TREATMENT OF RHINOSINUSITIS

[00116] This example demonstrates that a chitosan based hydrogel is capable of acting as an agent delivery vehicle, its use in sinonasal applications mandate novel formulations which are capable of eluting steroid over a longer period of time and can be engineered into a semirigid sheet capable of acting as a biodegradable sinus stent.

Results [00117] The 91.7% deacetylated CGP formulation was found to have optimal silastic-like properties and remained present with moderate degradation and negligible inflammation through post-operative day 15 (Figure 5). Dexamethasone levels were dependent on initial stent concentration and were detectable in nasal lavage and blood samples through postoperative day 15 and decayed over time. O.lg dexamethasone stent: (lavage: Day 0 3.94+/- 1.34ng/mL, day 15 0.09+/-0.03ng/mL; blood Day 3 1.54+/-0.02, Day 15 1.55+/-0.22). 1Og dexamethasone stent: (lavage: Day 0 7.70 +/-0.97ng/ml, Day 15 2.53 +/-1.71ng/ml; blood: Day 3 2.51 +/-0.15ng/mL, Day 15 1.70 +/-0.36ng/mL) (Figures 6 and 7).\

EXAMPLE 4: ANTIBIOTIC IMPREGNATED CGP IMPLANT

[00118] The inventors of the instant application have found that placement of a single antibiotic impregnated CGP implant in the setting of an acute gram positive or gram negative bacterial sinusitis resulted in a greater log reduction of CFU than daily antibiotic irrigation and lead to complete sterilization of the lavage within 4 days. [00119] Topical antibiotic treatments for sinusitis have gained popularity in recent years however their clinical efficacy has yet to be fully elucidated. Given the limited access of irrigations to obstructed or anatomically intact sinuses, an alternative method of topical antibiotic distribution would be beneficial. Topical sinonasal antibiotic treatments offer the potential for delivery of high concentrations of drug to the site of disease while minimizing systemic exposure and absorption. While multiple studies have demonstrated a benefit associated with these treatments, their precise role in the therapeutic algorithm remains unclear. One of the confounding issues of this mode of therapy is the variable and often unpredictable penetration of the antibiotic solution into the region of interest. Several studies have demonstrated that the majority of treatment solution is lost in the nasal vestibule while the remainder has relatively poor penetration into the frontal and sphenoid sinuses.

[00120] The purpose of this study is to utilize a rabbit model of acute bacterial gram positive and gram negative sinusitis to study the elution kinetics and efficacy of CGP loaded with one of two classes of antibiotics as compared to topical saline and antibiotic irrigations alone.

Experimental Details

[00121] Study Design: This was a prospective study of the treatment of acute bacterial sinusitis in a rabbit model using an antibiotic eluting implant. There were two arms to this study consisting of a S. aureus infection treated with Vancomycin and a P. aeruginosa infection treated with Gentamicin. Within each arm, 6 rabbits with bilateral infections were utilized for a total of 12 experimental sinuses. Each arm was comprised of 3 treatment groups performed in duplicate including saline irrigation alone, an 80μg/mL antibiotic solution, or a lcm ² antibiotic loaded CGP implant. Daily bacterial colony forming units (CFU' s) were measured in the nasal lavage for each sinus over a four day period. The log reductions between each treatment group were then compared to one another using a Student's t-test.

[00122] Animal Model: The New Zealand white rabbit is a widely accepted animal model of sinusitis. Twelve Pasteurella-free, female, New Zealand white rabbits (2-4kg) were used after a 1 week acclimatization period. Each rabbit was caged independently and had free access to standard pelleted food and water. The protocol was approved by the University of Pennsylvania Institutional Animal Care and Use Commmittee (Protocol# 801513).

[00123] Surgical Technique: The surgical technique proceeded as previously described ⁴ . Briefly, following standard anesthesia, prepping, and draping, a 3cm midline sagittal incision was made over the nasal dorsum down to the level of the periosteum. Medial based periosteal flaps were raised bilaterally exposing the dorsal maxillary bone. A 4mm diamond otologic drill was used to expose the maxillary sinus mucosa which was then incised using a no. 15 blade. A 0.5cm x 0.2cm cotton pledget with a lcm string attached was used to obstruct the natural ostium and a small amount of Vet Bond (3M, St Paul, MN, USA) was used to reinforce the pledget. After confirming an air tight occlusion, 0.2mL containing 4.0 x 10 ⁸ CFU of wild type P. aeruginosa or S. aureus was instilled into the sinus. The periosteal flaps were replaced and the skin was closed with a running 4-0 nylon suture.

[00124] One week was allowed to cultivate a robust acute infection, a second surgical procedure was then performed to assess the experimental treatments. The sagittal incision and periosteal flaps were reopened and the pledgets were removed. The presence of a successful infection was confirmed by the presence of purulence within the sinus. In the CGP group, a lcm ² implant was then placed into the sinus lumen under direct visualization. A 0.32 cm diameter catheter was then implanted through a stab incision over the cranial vertex. The catheter was tunneled subcutaneously and the tip was inserted into the prior sinusotomy. Following closure of the skin flaps, the catheter was irrigated and patency was confirmed by the egress of the lavage fluid at the ipsilateral nare. [00125] Treatment groups: The three groups within each arm consisted of daily treatments of 3mL of irrigation. The first group received saline alone. The second group received an 80μg/mL solution of either Gentamicin(Fluka, St Louis, MO) or Vancomycin (Sigma- Aldrich, St Louis, MO). The third group received saline in addition to a lcm ² implant composed of chitosan glycerophosphate (BioSyntech, Quebec, Canada) which was loaded with 25mg of either Gentamicin or Vancomycin.

[00126] Objective Measures: During each irrigation, the nasal lavage was collected for quantification of antibiotic concentration and colony forming units(CFUs). Typically 2- 2.5mL of the irrigant was collected as lavage fluid from the ipsilateral nare. Thirty minutes following each irrigation 2mL of venous blood was sampled from the marginal ear vein for determination of peripheral blood antibiotic levels.

[00127] Antibiotic levels in the nasal lavage and peripheral blood were measured using a Synchron LX 20 system (Beckman Coulter, Fullerton, CA) with a lower limit of detection of 3.5μg/mL for Vancomycin, and 0.5μg/mL for Gentamicin. [00128] To measure CFUs, the nasal lavage was immediately diluted 1 :50, pelleted via centrifugation at 3500 rpm for 10 minutes, and resuspended in the original volume of saline to prevent any bactericidal effect from the residual antibiotic within the lavage. The suspension was then plated and colony forming units/mL were then calculated from serially diluted samples using a standard plate count method.

Results

[00129] Antibiotic elution: In both the S. aureus and P. aeruginosa group, the implant exhibited first order elution kinetics over the four day period(Figure 1). The CGP+ Vancomycin lavage concentrations were as follows: Day 1 : 232.0+/-37.9μg/mL; Day 4: 34.7+/-8.4μg/mL. The Vancomycin irrigation lavage concentrations were as follows: Day 1: 67.1+/-l l.lμg/mL; Day 4: 74.2+/-4.2μg/mL. The CGP+Gentamicin lavage concentrations were as follows: Day 1: 390.8+/-99.0μg/mL; Day 4: 4.1+/-1.3μg/mL. The Gentamicin irrigation lavage concentrations were as follows: Day 1 : 76.6+/-1.7μg/mL; Day 4 88.6+/- 8.9μg/mL. The serum concentrations were below the limits of detection in all experimental conditions throughout the entire duration of the treatment period.

[00130] Colony Forming Unit determination: Within the S. aureus group, the CFU log reduction using CGP+Vancomycin(-2.57+0.21) was greater than Vancomycin irrigation(- 1.66+0.5, p=NS), and significantly greater than saline alone(2.46+0.97; p=0.018)(Figure T). Within the P. aeruginosa group, the CFU log reduction using the CGP+Gentamicin(- 4.62+0.74) was greater than Gentamicin irrigation(-4.09±0.70) and saline alone(- 1.90+0.90) however the results were not significant(Figure 3). In all rabbits receiving the CGP+ Antibiotic implant, no viable bacteria were present in the lavage by day 4. [00131] The treatment of sinonasal pathology provides a unique opportunity to directly access the site of disease through a natural orifice. While topical treatments have met with some clinical success, their full potential is tempered by the pragmatic limitations of intranasal delivery. A new generation of biodegradable polymers offer the potential to overcome these problems while simultaneously providing continuous drug elution and obviating issues of patient compliance and technique. Despite this promise, the optimal polymer has yet to be identified as idiosyncratic characteristics such as half life and immunogenicity must be compatible with the therapeutic goal.

[00132] The inventors of the instant application have investigated the role of antibiotic eluting hydrogels in the treatment of acute bacterial sinusitis. Given the potential advantages of site specific, continuous local delivery of drug at levels well above the minimum inhibitory concentration(MIC), this represents an exciting area of investigation with important clinical applications. This study was also designed to compare both mechanical debridement alone and the more traditional topical antibiotic irrigations with the novel implantable chitosan hydrogel. The choice of antibiotic concentrations in the irrigant was based on the most commonly described solutions. The finding that approximately sixty percent of each irrigation volume was immediately lost in the nasal lavage echoes the clinical scenerio in which only a fraction of the irrigant actually reaches the site of disease. [00133] Given that the hydrogel elution kinetics are based on molecular size, charge, and polarity, it was important to study two different types of antibiotic to ensure that our findings could be translated across antimicrobial class. The inventors of the instant application have found that in both cases, the elution curve revealed predictable first order kinetics in which the local concentration remained above the MIC for at least three days. Furthermore, while the lavage concentrations in the antibiotic solutions were higher than those of the antibiotic impregnated implant for the latter 2-3 days of the experiment, a trend towards a greater log reduction with the implant was evident. This may be attributed to the fact that in the implant group, the sinus lumen was continuously bathed in Vancomycin or Gentamicin laden fluid while in the antibiotic solution group, the local concentration likely decreased rapidly over time due to clearance and dilution. This too echoes the clinical scenerio in which mucociliary action will act to clear any non-mucoadherent topical therapy within 20-30 minutes. While concerns over toxicity related to continuous antibiotic administration are valid, the inventors of the instant application have found that serum levels were undetectable throughout the experiment suggesting that this mode of treatment is likely clinically safe. [00134] The results show that there was a trend towards a greater log reduction in the implant group. In the S. aureus arm both the solution and implant both achieved a statistically greater log reduction than saline alone. The study further shows that the antimicrobial effect is not simply related to the mechanical action of the irrigation. This has been demonstrated by the finding that a pseudomonal maxillary sinus infection in the rabbit can resolve within 7 days without any treatment. [00135] The elaboration of drug eluting hydrogels has provided a novel potential therapeutic intervention in the treatment of sinus disease. This is the first study to demonstrate both the elution kinetics and efficacy of an antibiotic eluting implant in an animal model acute sinusitis. The ability to treat bacterial sinusitis with the single application of a biodegradable hydrogel represents an exciting advance in the field of topical nasal therapy and may overcome many of the limitations associated with current techniques. [00136] Having described preferred embodiments of the invention with reference to the accompanying drawings, it is to be understood that the invention is not limited to the precise embodiments, and that various changes and modifications may be effected therein by those skilled in the art without departing from the scope or spirit of the invention as defined in the appended claims.