Drug-eluting implants and uses thereof

Abstract

Described herein are exemplary embodiments and uses of implantable therapeutic and / or prophylactic agent delivery devices that may be comprised of one or more layers of collagen-alginate hydrogel.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 385,102, entitled "Drug Eluting Implants and Uses Thereof," filed November 28, 2022, the contents of which are incorporated herein by reference in their entirety.

[0002] The subject matter disclosed herein relates generally to compositions, materials, and methods for delivering compounds, such as therapeutic compounds, particularly over long periods of time. [Background technology]

[0003] Surgical site infections remain a significant concern following orthopedic procedures, particularly following surgeries such as joint replacements and other prosthetic implants. There are few commercially available devices, prophylaxis, and / or treatments for sustained antibiotic delivery in orthopedic, surgical, and other applications where internal long-term and / or recurrent infections are a problem.

[0004] Citation or identification of any reference in this application is not an admission that such reference is available as prior art to the present disclosure. Summary of the Invention

[0005] In some aspects, the devices and techniques described herein relate to an implantable device comprising one or more layers of moldable gel, each moldable gel of the one or more layers comprising an amount of collagen, an amount of alginate (wherein the collagen and alginate form an implantable moldable gel), and one or more therapeutic and / or prophylactic compounds dispersed throughout the moldable gel, wherein the moldable gel is configured to release the one or more therapeutic and / or prophylactic compounds over a period of time.

[0006] In some aspects, the devices and techniques described herein relate to implantable devices in which the amount of collagen and / or the amount of alginate is an effective amount.

[0007] In some aspects, the devices and techniques described herein relate to implantable devices in which the ratio of collagen to alginate is an effective ratio.

[0008] In some aspects, the devices and techniques described herein relate to implantable devices in which the alginate, collagen, or both are modified.

[0009] In some aspects, the devices and techniques described herein relate to implantable devices in which the alginate is at least partially oxidized.

[0010] In some aspects, the devices and techniques described herein are configured such that the alginate is about 1-50%, about 3-30%, about 5-30%, about 7-30%, about 10-30%, about 12-30%, about 15-30%, about 20-30%, about 25-30%, about 1-25%, about 3-25%, about 5-25%, about 7-25%, about 10-25%, about 12-25%, about 15-25%, about 20-25%, approximately 1-20%, approximately 3-20%, approximately 5-20%, approximately 7-20%, approximately 10-20%, approximately 12-20%, approximately 15-20%, approximately 1-15%, approximately 3-15%, approximately 5-15%, approximately 7-15%, approximately 10-15%, approximately 12-15%, approximately 1-12%, approximately 1-12%, approximately 5-12%, approximately 7-12%, approximately 10-12%, approximately 1-10%, 1-3%, approximately 5-10%, approximately 7-10%, about 1-7%, about 3-7%, about 5-7%, about 1-5%, about 3-5%, about 1-3%, about 3-50%, about 5-50%, about 7-50%, about 10-50%, about 12-50%, about 15-50%, about 20-50%, about 25-50%, about 30-50%, about 35-50%, about 40-50%, about 45-50%, about 30-45%, about 30-40%, about 30-35%, about 2 The implantable device is oxidized to 5-45%, about 25-40%, about 25-35%, about 20-45%, about 20-40%, about 20-35%, about 15-45%, about 15-40%, about 15-35%, about 10-45%, about 10-40%, about 10-35%, about 5-45%, about 5-40%, about 1-35%, about 1-45%, about 1-40%, or about 1-35%.

[0011] In some aspects, the devices and techniques described herein relate to implantable devices having a duration of at least 1-42 days or more, about 7-42 days, about 14-42 days, about 21-42 days, about 28-42 days, about 1-28 days, about 7-28 days, about 14-28 days, about 21-28 days, about 1-21 days, about 7-21 days, about 14-21 days, about 1-14 days, about 7-14 days, or about 1-7 days.

[0012] In some aspects, the devices and techniques described herein relate to implantable devices in which one or more layers of moldable gel are substantially homogeneous.

[0013] In some aspects, the devices and techniques described herein relate to implantable devices in which one or more layers of the moldable gel are heterogeneous.

[0014] In some aspects, the devices and techniques described herein relate to implantable devices further comprising one or more impermeable but degradable layers, each of which is sandwiched between two layers of moldable gel and / or forms an outer layer surrounding the one or more moldable gel layers and / or one or more other degradable layers.

[0015] In some aspects, the devices and techniques described herein relate to implantable devices in which one or more of the one or more impermeable but degradable layers are (a) biodegradable, (b) degradable in response to an external stimulus, or both (a) and (b).

[0016] In some aspects, the devices and techniques described herein relate to implantable devices wherein one or more therapeutic and / or prophylactic compounds are present in one or more layers of a moldable gel, respectively, in 1-70% by weight of the moldable gel layer, 1-65% by weight of the moldable gel layer, 1-60% by weight of the moldable gel layer, 1-55% by weight of the moldable gel layer, 1-50% by weight of the moldable gel layer, 1-45% by weight of the moldable gel layer, 1-40% by weight of the moldable gel layer, 1-35% by weight of the moldable gel layer, 1-30% by weight of the moldable gel layer, 1-25% by weight of the moldable gel layer, 1-20% by weight of the moldable gel layer, 1-15% by weight of the moldable gel layer, 1-10% by weight of the moldable gel layer, or 1-5% by weight of the moldable gel layer.

[0017] In some aspects, the devices and techniques described herein relate to implantable devices wherein the one or more therapeutic and / or prophylactic compounds are selected from the group consisting of anti-infective agents, chemotherapeutic agents, immunomodulatory agents, antipyretics, analgesics, antispasmodics, anti-inflammatory agents, antihistamines, radiosensitizers, chemotherapy sensitizers, anti-infective sensitizers, biological agents, bisphosphonates, or any combination thereof.

[0018] In some aspects, the devices and techniques described herein relate to implantable devices in which the one or more therapeutic and / or prophylactic compounds include an anti-infective agent.

[0019] In some aspects, the devices and techniques described herein relate to implantable devices in which the one or more therapeutic and / or prophylactic compounds include an antibiotic.

[0020] In some aspects, the devices and techniques described herein relate to implantable devices in which the one or more therapeutic and / or prophylactic compounds comprise an aminoglycoside or a derivative thereof.

[0021] In some aspects, the devices and techniques described herein relate to implantable devices in which the aminoglycoside is selected from paromomycin, tobramycin, gentamicin, amikacin, kanamycin, neomycin, and any combination thereof.

[0022] In some aspects, the devices and techniques described herein relate to implantable devices in which the one or more therapeutic and / or prophylactic compounds are each independently selected from an aminoglycoside or derivative thereof, a carbapenem or derivative thereof, a cephalosporin or derivative thereof, a glycopeptide or derivative thereof, a glycylcycline or derivative thereof, a lincomycin or derivative thereof, a macrolide or derivative thereof, a penicillin or derivative thereof, a quinolone or derivative thereof, a sulfonamide or derivative thereof, a tetracycline or derivative thereof, or any combination thereof.

[0023] In some aspects, the devices and techniques described herein are directed to a method for treating urinary tract infections in which (a) the aminoglycoside comprises paromomycin, tobramycin, gentamicin, amikacin, kanamycin, and neomycin, or any combination thereof; (b) the carbapenem comprises doripenem, meropenem, ertapenem, and cilastatin / imipenem; or (c) the cephalosporin comprises cefadroxil, cephradine, cefazolin, cephalexin, cefepime, cefraroline, loracarbef, cefotetan, cefuroxime, cefprozil, loracarbef, (d) the glycopeptide includes vancomycin, dalbavancin, oritavancin, telvancin, or any combination thereof; (e) the glycylcycline includes tigecycline; (f) the lincomycin includes clindamycin or lincomycin; (g) the macrolide includes telithromycin; (h) penicillin is amoxicillin, ampicillin, bacampicillin, carbenicillin, piperacillin, ticarcillin, amoxicillin / clavulanic acid, ampicillin / sulbactam, or any combination thereof; or (i) penicillin is amoxicillin, ampicillin, bacampicillin, carbenicillin, piperacillin, ticarcillin, amoxicillin / clavulanic acid, ampicillin / sulbactam, or piperacillin / sulbactam. (i) the quinolone includes lomefloxacin, norfloxacin, ofloxacin, moxifloxacin, ciprofloxacin, levofloxacin, gemifloxacin, moxifloxacin, cinoxacin, nalidixic acid, enoxacin, grepafloxacin, gatifloxacin, trovafloxacin, sparfloxacin, or any combination thereof;(j) the sulfonamide includes sulfamethoxazole / trimethoprim, sulfasalazine, sulfasoxazole, or any combination thereof; (k) the tetracycline includes, for example, doxycycline, demeclocycline, minocycline, doxycycline / salicylic acid, doxycycline / omega-3 polyunsaturated fatty acid, and tetracycline; or (1) the implantable device includes any combination of (a) to (k).

[0024] In some aspects, the devices and techniques described herein relate to implantable devices, wherein the implantable devices are effective in treating and / or preventing microbial infection, microbial growth, biofilm formation, or any combination thereof.

[0025] In some aspects herein, kits are described that include the implantable devices of the present disclosure.

[0026] In some aspects herein, methods are described that involve inserting or otherwise delivering an implantable device according to the present disclosure into a surgical site or wound in a subject in need thereof.

[0027] In some aspects, the technology described herein relates to methods wherein the surgical site or wound is within or near a joint of a subject, at or near the site of a foreign body implanted in a subject, or at or near the site of a skin or other soft tissue graft.

[0028] In some aspects, the technology described herein relates to methods in which a subject has or is at risk of developing a surgical site infection, an implant foreign body site infection, or a wound site infection.

[0029] In some aspects, the technology described herein relates to methods in which a subject has or is at risk of developing a microbial infection.

[0030] In some aspects, the technology described herein relates to methods wherein the microbial infection comprises a bacterial infection, a yeast infection, or both.

[0031] In some aspects, the technology described herein relates to methods wherein the bacterial infection is a chronic bacterial infection, a resistant bacterial infection, or both.

[0032] In some aspects, the technology described herein relates to methods wherein the bacterial infection comprises a biofilm.

[0033] In some aspects, the technology described herein relates to methods, wherein the bacterial infection is caused by bacteria of the species Staphylococcus, Streptococcus, Pseudomonas, Enterococcus, Escherichia, Acinetobacter, or any combination thereof.

[0034] In some aspects, the technology described herein relates to methods, wherein the bacterial infection is caused by Staphylococcus aureus.

[0035] In some aspects, the technology described herein relates to methods in which the implantation occurs during the first surgical procedure performed on the subject.

[0036] In some aspects, the technology described herein relates to methods in which the implantation occurs during a secondary surgical procedure performed on the subject.

[0037] In some embodiments, the technology described herein relates to methods wherein implantation occurs within 0.5 to 72 hours of a traumatic non-surgical wound to the subject.

[0038] In some aspects, the technology described herein relates to methods wherein the wound is a burn or other trauma requiring skin grafting.

[0039] In some aspects, the technology described herein relates to methods wherein the implanted foreign body is a penile implant, a soft tissue implant, a replacement joint or portion thereof, a fixation implant, or any combination thereof.

[0040] In some aspects, the technology described herein relates to methods in which (a) the soft tissue implant comprises a breast implant, a calf implant, a buttocks implant, or a cheek implant; (b) the fixation implant comprises a screw, a plate, a cage, a rod, a pin, an anchor, a disc, or any combination thereof; or (c) both (a) and (b).

[0041] These and other aspects, objects, features, and advantages of the exemplary embodiments will become apparent to those skilled in the art upon consideration of the following detailed description of the exemplary embodiments.

[0042] A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments in which the principles of the invention may be utilized and the accompanying drawings of which: [Brief explanation of the drawings]

[0043] [Figure 1] This shows an image of a gel loaded with 33% vancomycin (by weight) after 14 days. Body fluids were replicated with phosphate-buffered saline (PBS) at 37°C, and the gel and PBS were combined in a well of a tissue culture plate.

[0044] [Figure 2] A table of ELISA results from antibiotic elution tests from collagen-alginate gels is shown, and these results are presented graphically in Figure 3.

[0045] [Figure 3] Graph showing the ELISA results described in Figure 2. The x-axis is vancomycin concentration and the y-axis is normal gel and cross-linked gel.

[0046] [Figure 4] This table shows the results of an in vitro evaluation of the degradation kinetics of collagen-alginate gels over 28 days. Gels of two different concentrations, with and without UV cross-linking, were prepared and tested. Samples loaded with either vancomycin or penicillin were placed in simulated body fluid with and without collagenase to mimic the in vivo environment. After 7, 14, 28, and 42 days, the samples were dried and weighed, and the degradation rates were calculated.

[0047] [Figure 5] Images of the dried gel are shown at days 7 and 14. "C" indicates that the gel in the container is crosslinked.

[0048] [Figure 6] 1 illustrates an exemplary application of the gel, specifically placement of the gel in the shoulder joint during an orthopedic surgical procedure.

[0049] [Figure 7] Images A-B show zone of inhibition tests of various elution gels against MRSA, which exhibits significantly higher resistance to various antibiotics. The center disc of each plate is the vancomycin 30 mcg control, and the top disc (at the 12 o'clock position) is the vancomycin 5 mcg control. Clockwise from the vancomycin 5 mcg control are days 3, 7, 14, 21, and 28. A shows collagen, and B shows peroxide.

[0050] [Figure 8] 1 shows a graph illustrating the effect of gel oxidation on vancomycin release from the gel.

[0051] [Figure 9]9A-9B show exemplary embodiments of collagen-alginate gels described herein. In some embodiments, the gel is homogeneous (FIG. 9A). In some embodiments, the gel may contain two or more distinct layers of collagen-alginate-antibiotic, and may optionally include one or more impermeable and / or biodegradable layers (FIG. 9B).

[0052] [Figure 10] Selectively oxidized collagen-alginate hydrogels can be shown to continuously release therapeutic concentrations of antibiotics. The leftmost panel is a graph of ELISA results for vancomycin released in simulated body fluid versus time. These data demonstrate that drug release characteristics can be controlled by manipulating the oxidation state of the hydrogel. As can be seen from the graph, therapeutic levels of antibiotic are still present after 14 days. Inset: Photograph of the ABED gel.

[0053] The figures herein are for illustrative purposes only and are not necessarily drawn to scale. DETAILED DESCRIPTION OF THE INVENTION

[0054] Before describing the present disclosure in detail, it is to be understood that this disclosure is not limited to particular embodiments described, as these may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0055] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, the preferred methods and materials are now described.

[0056] All publications and patents cited herein are cited to disclose and describe the methods and / or materials in connection with which they are cited. All such publications and patents are incorporated herein by reference to the same extent as if each individual publication or patent were specifically and individually indicated to be incorporated by reference. Such incorporation by reference is expressly limited to the methods and / or materials in the cited publications and patents, and does not extend to definitions of terms provided by the cited publications and patents. Any definitions of terms in the cited publications and patents that are not expressly repeated in this application should not be taken as definitions themselves or read as defining terms recited in the appended claims. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present disclosure is not entitled to antedate such publication by prior art. Further, the publication dates provided may be different from the actual publication dates, which may need to be independently confirmed.

[0057] As will be apparent to those skilled in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has distinct elements and features that can be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the disclosure. Any recited method can be carried out in the order of events recited or in any other order that is logically possible.

[0058] When a range is expressed, a further embodiment includes from one particular value and / or to the other particular value. When a range of values ​​is described, it is understood that every intervening value between the upper and lower limit of that range, to every tenth of the unit of the lower limit unless expressly stated otherwise, and any other specified or intervening value within that stated range, is also encompassed within the disclosure. The upper and lower limits of these smaller ranges can each independently be included in the smaller range and are also encompassed within the disclosure, provided that any specifically excluded limit in the stated range is subject to such exclusion. When a stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included within the disclosure. For example, when a stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included within the disclosure; for example, a phrase "from x to y" includes not only a range from "x" to "y," but also a range greater than "x" and less than "y." The range may also be expressed as an upper limit, for example, "about x, y, z, or less," which should be interpreted to include the specific ranges of "about x," "about y," and "about z," as well as the ranges "less than x," "less than y," and "less than z." Similarly, the phrase "about x, y, z, or more" should be interpreted to include the specific ranges of "about x," "about y," and "about z," as well as the ranges "greater than x," "greater than y," and "greater than z." Additionally, the phrase "about 'x' to 'y'" (where 'x' and 'y' are numbers) includes "about 'x' to about 'y'."

[0059] It should be noted that ratios, concentrations, amounts, and other numerical data may be expressed herein in a range format. It is further understood that the endpoints of a range are meaningful both in relation to the other endpoint, and independently of the other endpoint. While several values ​​are disclosed herein, it is understood that each value is also disclosed herein as "about" that particular value in addition to the value itself. For example, if a value of "10" is disclosed, "about 10" is also disclosed. Ranges can be expressed herein as from "about" one particular value and / or to "about" another particular value. Similarly, when values ​​are expressed as approximations, the use of the antecedent "about" will understand that the particular value forms a further aspect. For example, if a value of "about 10" is disclosed, "10" is also disclosed.

[0060] It should be understood that such range formats are used for convenience and brevity and, therefore, should be interpreted flexibly to include not only the numerical values ​​explicitly recited as the limits of the range, but also all individual numerical values ​​or subranges subsumed within that range, as if each numerical value and subrange were explicitly recited. As an example, a numerical range of "about 0.1% to 5%" should be interpreted to include not only the explicitly recited values ​​of about 0.1% to about 5%, but also individual values ​​(e.g., about 1%, about 2%, about 3%, and about 4%) and subranges (e.g., about 0.5% to about 1.1%, about 5% to about 2.4%, about 0.5% to about 3.2%, and about 0.5% to about 4.4%, as well as other possible subranges) within the stated range.

[0061] general definition Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Definitions of common terms and techniques in molecular biology can be found in Molecular Cloning: A Laboratory Manual, 2004. ndedition(1989)(Sambrook,Fritsch,and Maniatis);Molecular Cloning:A Laboratory Manual,4 th edition(2012)(Green and Sambrook);Current Protocols in Molecular Biology(1987)(F.M.Ausubel et al.eds.);the series Methods in Enzymology(Academic Press,Inc.):PCR 2:A Practical Approach(1995)(M.J.MacPherson,B.D.Hames,and G.R.Taylor eds.):Antibodies,A Laboratory Manual(1988)(Harlow and Lane,eds.):Antibodies A Laboratory Manual,2 ndedition 2013(EAGreenfield ed.);Animal Cell Culture(1987)(RIFreshney,ed.);Benjamin Lewin,Genes IX,published by Jones and Bartlett,2008(ISBN 0763752223);Kendrew et al.(eds.),The Encyclopedia of Molecular Biology,published by Blackwell Science Ltd.,1994(ISBN 0632021829); Robert A. Meyers(ed.), Molecular Biology and Biotechnology: a Comprehensive Desk Reference, published by VCH Publishers, Inc., 1995(ISBN 9780471185710); Singleton et al., Dictionary of Microbiology and Molecular Biology 2nd ed., J. Wiley & Sons(New York, NY1994), March, Advanced Organic Chemistry Reactions, Mechanisms and Structure 4th ed., John Wiley & Sons (New York, NY1992); and Marten H. Hofker and Jan van Deursen, Transgenic Mouse Methods and Protocols, 2 nd edition (2011).

[0062] As used herein, the singular forms "a," "an," and "the" include both the singular and plural referents unless the context clearly indicates otherwise.

[0063] As used herein, the terms "about," "approximately," "substantially," and the like, when used in connection with a measurable variable, such as a parameter, amount, temporal duration, and the like, are intended to encompass variation from the specified value, including variation within experimental error (e.g., that may be determined for a given data set, by standards accepted by those of ordinary skill in the art, and / or by, for example, a given confidence interval (e.g., a 90%, 95% or greater confidence interval from the mean)), to the extent that such variation is appropriate for the practice of the disclosed invention, including variation of + / - 10% or less, + / - 5% or less, + / - 1% or less, and + / - 0.1% or less of the specified value. As used herein, the terms "about," "approximately," "nearly," and "substantially" can mean that the amount or value in question can be the exact value or a value that will produce an equivalent result or effect as recited in a claim or taught herein. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not, and need not be, exact, but can be approximate and / or can be increased or decreased, as desired, to reflect tolerances, conversion factors, rounding, measurement error, and other factors known to those of skill in the art, while achieving equivalent results or effects. In some situations, it may not be possible to reasonably determine a value that will achieve equivalent results or effects. Generally, amounts, sizes, formulations, parameters, or other quantities or characteristics are "about," "approximately," or "nearly," whether or not explicitly stated. When "about," "approximately," or "nearly" is used before a quantitative value, it is understood that the parameter also includes the specific quantitative value itself, unless otherwise specified.

[0064] The term "optional" or "optionally" means that the subsequently described event, circumstance, or substituent may or may not occur, and the description includes both instances when the event or circumstance occurs and instances when it does not occur.

[0065] The recitation of numerical ranges by endpoints includes not only the recited endpoints but also all numbers and fractions subsumed within the respective ranges.

[0066] As used herein, a "biological sample" can encompass whole cells and / or viable cells and / or cell debris. A biological sample can comprise (or be derived from) a "body fluid." The present invention encompasses embodiments in which the body fluid is selected from amniotic fluid, aqueous humor, vitreous humor, bile, serum, breast milk, cerebrospinal fluid, earwax (ear wax), chyle, chyme, endolymph, perilymph, exudate, feces, vaginal fluid, gastric acid, gastric juice, lymph, mucus (including nasal secretions and phlegm), pericardial fluid, peritoneal fluid, pleural effusion, pus, mucous-based secretions, saliva, sebum (skin oil), semen, sputum, synovial fluid, sweat, tears, urine, vaginal secretions, vomit, and mixtures of one or more of these. Biological samples include cell cultures, body fluids, and cell cultures derived from body fluids. Body fluids can be obtained from a mammal, for example, by paracentesis or other collection or sampling procedures.

[0067] The terms "subject," "individual," and "patient" are used interchangeably herein to refer to a vertebrate, preferably a mammal, more preferably a human. Mammals include, but are not limited to, murines, simians, humans, farm animals, sport animals, and pets. Tissues, cells, and progeny of biological entities obtained in vivo or cultured in vitro are also encompassed.

[0068] As used herein, "administering" refers to any suitable administration to the agent(s) to be delivered and / or the subject to whom the agent(s) are administered, and may be oral, topical, intravenous, subcutaneous, transdermal, transdermal absorption, intramuscular, intraarticular, parenteral, intraarterial, intradermal, intravenous, intraosseous, intraocular, intracranial, intraperitoneal, intralesional, intranasal, intracardiac, intraarticular, intracavity, intrathecal, intravitreal, intracerebral and intraventricular, intratympanic, intracochlear, rectal, vaginal, inhalation, catheter, stent, or other device that administers the composition to implanted reservoirs or perivascular spaces and adventitia either actively or passively (e.g., by diffusion). For example, a medical device such as a stent can contain a composition or formulation disposed on its surface, which can dissolve or otherwise distribute to surrounding tissues and cells. The term "parenteral" can include subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Examples of administration routes include auricular (ear), buccal, conjunctival, skin, teeth, electroosmosis, intracervical, intrasinus, intratracheal, enteral, epidural, extraamniotic, extracorporeal, hemodialysis, infiltration, intrainterstitial, intraperitoneal, intraamniotic, intra-arterial, intra-articular, intra-bile duct, intra-bronchial, intra-vesical, intracardiac, intracartilage, intra-sacral, intra-cavity, intra-cavity, intra-brain, intra-cistern, intra-cornea, intra-dental crown (tooth), intra-coronary artery, intracavernous, intradermal, intra-vertebral disc, intra-duct, intra-duodenal, intra-dural, intra-epidermal, intra-esophageal, intra-gastric, intra-gingival, intra-ileum, intra-lesional, intra-luminal, intra-lymphatic, intramedullary, intrameningeal, intramuscular, intraocular, intra-ovarian, intra-pericardial, intra-peritoneal, intra-pleural, intra-prostatic, intra-pulmonary, intra-cavity, intra-spinal cord, intra-synovial, intra-tendon, intra-testicular, intra-thecal, intra-thoracic, and intra-canalicular. , intratumoral, intratympanic, intrauterine, intravascular, intravenous, intravenous bolus, intravenous drip, intravenous, intravenous, intravenous, intravenous, intravenous, intravitreal, iontophoresis, perfusion, laryngeal, nasal, nasogastric, occlusive dressing, ophthalmic, oral, oropharyngeal, other, parenteral, transdermal, periarticular, peridural, perineural, periodontal, rectal, respiratory (inhalation), retrobulbar, soft tissue, subarachnoid, subconjunctival, subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transplacental, transtracheal, transtympanic, ureteral, urethral, ​​and / or vaginal administration, and / or any combination of the above routes of administration, typically depending on the disease being treated, the subject being treated, and / or the agent(s) being administered.

[0069] As used herein, "agent" refers to any substance, compound, molecule, etc. that can be administered to a subject. An agent can be inert. An agent can be an active agent. An agent can be a primary active agent, or in other words, a component(s) of a composition to which all or part of the composition's effect is due. An agent can be a secondary active agent, or in other words, a component(s) of a composition to which additional portions of the composition and / or other effects are due.

[0070] As used herein, the term "biodegradable" generally refers to a material that breaks down or erodes under physiological conditions into smaller units or chemical species that can be metabolized, eliminated, or excreted by the subject. Degradation time varies depending on composition and morphology. Degradation time can be hours, days, weeks, or months.

[0071] As used herein, "chemotherapeutic agent" or "chemotherapeutic" refers to a therapeutic agent used in the prevention or treatment of cancer.

[0072] As used herein, "dose," "unit dose," or "dosage" may refer to physically discrete units suitable for use in a subject, each unit containing a predetermined amount of an implantable device described herein calculated to produce a desired response or responses associated with its administration.

[0073] As used herein, "hydrogel" refers to a gelled colloid or aggregate of finely dispersed polymer molecules in a semi-solid state, where the polymer molecules are in the external or dispersed phase and water (or an aqueous solution) forms the internal or dispersed phase. Generally, hydrogels are at least 90% by weight of an aqueous solution, but may vary as described elsewhere herein.

[0074] As used herein, "immunomodulatory agent" refers to an agent, such as a drug, that can modulate or regulate one or more immune functions or responses.

[0075] As used herein, "infection" refers to the presence of an infectious agent, such as a pathogen, e.g., a microorganism, in or on a subject, the presence or growth of which, if inhibited, can be beneficial to the subject. Thus, the term refers to a condition resulting from the establishment, or more specifically, invasion and proliferation, of an infectious agent, such as a pathogen, e.g., a microorganism, in or on a suitable host. Infection can result in tissue damage and progress to overt disease through a variety of cellular and virulence mechanisms.

[0076] The term "molecular weight" as used herein generally refers to the mass or average mass of a substance. In the case of polymers or oligomers, molecular weight may refer to the relative average chain length or relative chain mass of the bulk polymer. In practice, the molecular weight of polymers and oligomers can be estimated or characterized in a variety of ways, including gel permeation chromatography (GPC) or capillary viscosimetry. GPC molecular weight is the number average molecular weight (M n ), as opposed to the weight average molecular weight (M w Capillary viscosities provide an estimate of molecular weight as the intrinsic viscosity determined from a dilute polymer solution using a specific set of concentration, temperature, and solvent conditions.

[0077] As used herein, "prophylactic" and "prevention" refer to preventing or halting a disease or condition before it occurs, even if undiagnosed, or while the disease or condition is still in an asymptomatic stage.

[0078] As used herein, the term "radiosensitizer" refers to an agent that can selectively enhance cell killing by radiation in a desired cell population, such as tumor cells, while not being toxic to tumor or normal cells as a single agent.

[0079] As used herein, "substantially" and "substantially" refer to an amount of 95% to 100% (inclusive), 96% to 100% (inclusive), 97% to 100% (inclusive), 98% to 100% (inclusive), or 99% to 100% (inclusive).

[0080] As used interchangeably herein, the terms "sufficient" and "effective" can refer to an amount (e.g., mass, volume, dosage, concentration, and / or duration) necessary to achieve one or more desired result(s). For example, a therapeutically effective amount refers to an amount necessary to achieve one or more therapeutic or prophylactic effects or other desired effects. In the context of hydrogels herein, an effective amount (or ratio) of collagen and / or alginate refers to the amount of each (or ratio of both) when considered in relation to the remainder of the hydrogel components, effective to provide a moldable hydrogel that can have a desired release profile, such as releasing a therapeutically effective and / or prophylactic amount of a therapeutic or prophylactic agent contained in the hydrogel layer over a desired period of time, such as 1 to 42 days, or a period described elsewhere herein. In relation to a therapeutic and / or prophylactic amount of a therapeutic or prophylactic agent, that amount can be a minimum effective amount (or concentration). A minimum effective amount (or concentration) is the minimum effective amount / concentration necessary to achieve a therapeutic and / or prophylactic effect. Those skilled in the art will recognize the desired therapeutic and / or prophylactic effect based on the therapeutic and / or prophylactic agents contained in the implantable device. For example, if an antibiotic is included, an effective amount is the amount or minimum amount necessary to kill and / or inhibit the growth and / or proliferation of one or more bacteria.

[0081] Various embodiments are described below. Note that specific embodiments are not intended to be exhaustive or limiting of the broader aspects discussed herein. An aspect described in connection with a particular embodiment is not necessarily limited to that embodiment and may be implemented in any other embodiment(s). References throughout this specification to "one embodiment," "an embodiment," or "an exemplary embodiment" mean that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, the appearances of the phrases "in one embodiment," "in an embodiment," or "an exemplary embodiment" in various places throughout this specification do not necessarily all refer to the same embodiment, although they may. Furthermore, particular features, structures, or characteristics in one or more embodiments can be combined in any suitable manner, as would be apparent to one of ordinary skill in the art from this disclosure. Furthermore, some embodiments described herein include some features included in other embodiments, but not other features, and combinations of features from different embodiments are also contemplated within the scope of the present invention. For example, in the appended claims, any of the claimed embodiments can be used in any combination.

[0082] All publications, published patent documents, and patent applications cited in this specification are herein incorporated by reference to the same extent as if each individual publication, published patent document, or patent application was specifically and individually indicated to be incorporated by reference.

[0083] overview Surgical site infections remain a significant concern following orthopedic and cosmetic procedures, particularly following surgeries such as joint replacements and other orthopedic or cosmetic implant placement, during the treatment of chronic and other wounds, and during the treatment of burns. There are few commercially available devices, prophylaxis, and / or treatments for sustained antibiotic delivery in orthopedic, surgical, and other applications where internal long-term and / or recurrent infections are a problem.

[0084] Nevertheless, some exemplary embodiments disclosed herein provide an implantable device containing one or more layers of a moldable gel, each of which contains a therapeutic and / or prophylactic compound and which can release the therapeutic and / or prophylactic compound(s) into the environment surrounding the implantable device over a period of time, particularly over an extended period (e.g., weeks to months or longer). The implantable device can be included in a kit along with a delivery device, a storage container, and / or a delivery and / or storage solution, etc. Some exemplary embodiments described herein provide a method of implanting an implantable device described herein into a subject's wound, such as a surgical site or surgical wound, or other wound caused by trauma or secondary to another condition (e.g., ulcer, necrosis, etc.). In some embodiments, the method can provide treatment or prevention of surgical site infections, foreign body implant site infections, skin or other soft tissue graft infections, and / or wound infections (including, but not limited to, chronic wounds and / or wounds that involve large areas of the body or other difficult-to-heal wounds). In some cases, the wound requires a skin or other soft tissue graft. The implantable devices described herein can be effective in treating and / or preventing microbial growth and / or biofilm formation.

[0085] Other compositions, compounds, methods, features, and advantages of the present disclosure will be or become apparent to one of ordinary skill in the art upon examination of the following figures, detailed description, and examples, and all such additional compositions, compounds, methods, features, and advantages are intended to be included in this description and within the scope of the present disclosure.

[0086] Implantable drug-eluting devices Some exemplary embodiments described herein provide an implantable device containing or consisting entirely of one or more layers of moldable gel, each of which contains or consists entirely of an amount of collagen, an amount of alginate (wherein the collagen and alginate form the implantable moldable gel), and one or more therapeutic and / or prophylactic compounds dispersed throughout the moldable gel, the moldable gel being configured to release the one or more therapeutic and / or prophylactic compounds over a period of time. The moldable gel may be a hydrogel in which the matrix portion is formed from collagen and alginate.

[0087] In some embodiments, the total weight of the implantable device, e.g., when weighed in a fully hydrated or substantially undegraded state, is from about 1 to / or about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 80, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, or 1000 μg, mg, or g, or any number in any of these ranges.In some embodiments, the total volume of the implantable device, e.g., in a fully hydrated or substantially undegraded state, is from about 1 to / or about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490 , 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, 1000 nL, μL, or mL (or cc), or any number in any of these ranges.

[0088] In some embodiments, the total weight of each moldable gel layer present in the implantable device, e.g., when weighed in a fully hydrated or substantially undegraded state, can be independently from about 1 to / or from about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, , 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 7 80, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, 1000 ng, μg, mg, or g, or any number in any of these ranges.In some embodiments, the total volume of each moldable gel layer present in the implantable device, e.g., in a fully hydrated or substantially undegraded state, can be independently from about 1 to / or from about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940 , 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, 1000 μL or mL (or cc), or any number in any of these ranges.

[0089] The amount of collagen present in each moldable gel layer of the implantable device may each independently be from about 0.1 to / or from about 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, 99.9 w / w%, w / v%, or v / v%, or any value or range of values ​​therein.

[0090] In some embodiments, the amount of collagen in each moldable gel layer in the implantable device is independently from about 1 to / or about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, , 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, 1000 ng, μg, mg, or g.

[0091] The amount of alginate present in each moldable gel layer of the implantable device may each independently be from about 0.1 to / or about 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, 99.9 w / w%, w / v%, or v / v%, or any value or range of values ​​therein.

[0092] In some embodiments, the amount of alginate in each moldable gel layer in the implantable device is independently from about 1 to / or about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980 , 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, 1000 ng, μg, mg, or g.

[0093] In some embodiments, the alginate and collagen together comprise about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 11 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8 to / or about 99.9 w / w%, w / v%, or v / v%, or any value or range of values ​​therein.

[0094] Collagen and alginate can be present in the moldable gel layer of the implantable device in a relative ratio to one another. In some embodiments, the collagen to alginate ratio is 0.1-10:1, 1:0.1-10, or 0.1-10:0.1-10. In some embodiments, the collagen to alginate ratio is 1:3, 1:2.75; 1:2.5; 1:2.25; 1:2; 1:1.75; 1:1.5; 1:1.25; 1:1; 1.25:1; 1.5:1; 1.75:1; 2:1; 2.25:1; 2.5:1; 2.75:1, or 3:1.

[0095] In some embodiments, the amount of collagen and / or the amount of alginate is an effective amount. In some embodiments, the ratio of collagen to alginate is an effective ratio.

[0096] In some embodiments, the alginate, collagen, or both are modified. In some embodiments, the modification is oxidation. In some embodiments, the modification is acidification. In some embodiments, the modification is heating. In some embodiments, the alginate is at least partially oxidized. In some embodiments, the collagen is acidified. In some embodiments, the collagen is acidified to a pH between 1 and 6, or 2 and 5, or 3 and 4. In some embodiments, the collagen is acidified to a pH of 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4.0. In some embodiments, the collagen is heated for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours.

[0097] In some embodiments, the alginate is about 1-50% oxidized, hi some embodiments, the alginate is about 1% to / or about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50% oxidized. In some embodiments, the alginate is about 3-50%, about 5-50%, about 7-50%, about 10-50%, about 12-50%, about 15-50%, about 20-50%, about 25-50%, about 30-50%, about 35-50%, about 40-50%, about 45-50%, about 30-45%, about 30-40%, about 30-35%, about 25-40%, about 45-50%, about 40-45 ... The alginate may be 5%, about 25-40%, about 25-35%, about 20-45%, about 20-40%, about 20-35%, about 15-45%, about 15-40%, about 15-35%, about 10-45%, about 10-40%, about 10-35%, about 5-45%, about 5-40%, about 1-35%, about 1-45%, about 1-40%, or about 1-35% oxidized. In some embodiments, the alginate is 1-30% oxidized. In some embodiments, the alginate is about 3-30%, about 5-30%, about 7-30%, about 10-30%, about 12-30%, about 15-30%, about 20-30%, about 25-30%, about 1-25%, about 3-25%, about 5-25%, about 7-25%, about 10-25%, about 12-25%, about 15-25%, about 20-25%, about 1-20%, about 3-20%, about 5-20%, about 7-20%, about 10 ~20%, about 12-20%, about 15-20%, about 1-15%, about 3-15%, about 5-15%, about 7-15%, about 10-15%, about 12-15%, about 1-12%, about 1-12%, about 5-12%, about 7-12%, about 10-12%, about 1-10%, 1-3%, about 5-10%, about 7-10%, about 1-7%, about 3-7%, about 5-7%, about 1-5%, about 3-5%, or about 1-3% oxidized.

[0098] The collagen can be any suitable collagen. In some embodiments, the collagen is type I, type II, type III, type IV collagen, or any combination thereof. In some embodiments, the collagen is type I collagen. In some embodiments, the collagen is type III collagen.

[0099] Each layer may contain additional components such as salt (which may be in the form of saline or other buffered salt solutions).

[0100] The pH of each of the shapable gel layers can be independently acidic, neutral, or basic. In some embodiments, the pH of each of the shapable gel layers is independently about 7 to about 7.4, e.g., about 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, or 8.0. In some embodiments, the pH of each of the shapable gel layers is approximately the same. In some embodiments, the pH of at least two of the shapable gel layers is different. In some embodiments, the pH of at least two of the shapable gel layers is the same. In some embodiments, the pH of each of the shapable gel layers is different.

[0101] As discussed elsewhere herein, current eluting gels are unable to provide extended drug elution periods. In some embodiments, the implantable device can provide extended drug elution periods, such as 14 days or more (e.g., 14-28 days, 36 days, 42 days, or 48 days or more). In some embodiments, the period is at least 1-42 days or more, about 7-42 days, about 14-42 days, about 21-42 days, about 28-42 days, about 1-28 days, about 7-28 days, about 14-28 days, about 21-28 days, about 1-21 days, about 7-21 days, about 14-21 days, about 1-14 days, about 7-14 days, or In some embodiments, the implantable device releases the therapeutic and / or prophylactic compound for about 1 day and / or about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48 days or more.

[0102] In some embodiments, one or more layers of the moldable gel are substantially homogeneous.

[0103] In some embodiments, one or more layers of the moldable gel are heterogeneous. In this context, "heterogeneous" refers to the difference in at least one characteristic throughout the gel, such as the composition of the hydrogel (e.g., amount of alginate and / or collagen, amount of therapeutic and / or prophylactic compound(s), etc.), pH, and / or other characteristics. For example, the layers can be formed so that a concentration gradient or different concentrations of therapeutic and / or prophylactic agent are present in the layer. This can allow for fine tuning of the release profile. For example, in embodiments where pockets or strips of therapeutic and / or prophylactic compound are present, a bolus or pulsed release from the layer can be provided as the gel degrades.

[0104] In some embodiments where the implantable device includes multiple layers, two or more layers are the same. In some embodiments where the implantable device includes multiple layers, all of the layers can be the same. In some embodiments where the implantable device includes multiple layers, two or more layers differ in at least one characteristic. In some embodiments where the implantable device includes multiple layers, all of the layers differ from each other in at least one characteristic. In some embodiments, the difference is the type of therapeutic and / or prophylactic compound(s) included in the layer, the amount of collagen and / or alginate, the percent oxidation of the alginate, or any combination thereof.

[0105] In some embodiments, the implantable device contains one or more impermeable but degradable layers, hi some embodiments, each of the one or more impermeable but degradable layers is sandwiched between two layers of moldable gel and / or forms an outer layer surrounding one or more moldable gel layers and / or one or more other degradable layers.

[0106] In some embodiments, one or more of the one or more impermeable but degradable layers are biodegradable and / or degradable in response to an external stimulus. Exemplary external stimuli include, but are not limited to, pH, light energy, electromagnetic energy, magnetic energy, and acoustic energy. In this manner, release can be controlled externally, such as by applying a light source (e.g., a cold laser) to the subject's skin above the location of the implant to stimulate release of the therapeutic and / or prophylactic agent within the layer.

[0107] In some embodiments, the implantable device has multiple moldable gel layers and, optionally, one or more impermeable but degradable layers, the device is configured as a core, with stratified layers surrounding the core, such that if the device is cut in half, each half has the same shape from the core outward. The implantable device can have any three-dimensional regular or irregular shape. The implantable device can have any width, length, or thickness. In some embodiments, the largest dimension (width, length, height, diameter, etc.) is 0.001 to 1 nm, micrometers, or centimeters.

[0108] Each layer may contain one or more (e.g., 1, 2, 3, 4, 5, or more) therapeutic and / or prophylactic compounds (also referred to herein as agents). In some embodiments, the one or more therapeutic and / or prophylactic compounds are present in one or more of the one or more layers of the moldable gel, respectively, in 1-70% by weight of the moldable gel layer. In some embodiments, the one or more therapeutic and / or prophylactic compounds are present in one or more of the one or more layers of the moldable gel, respectively, in 1-65% of the moldable gel layer, 1-60% of the moldable gel layer, 1-55% of the moldable gel layer, 1-50% of the moldable gel layer, 1-45% by weight of the moldable gel layer, 1-40% by weight of the moldable gel layer, 1-35% by weight of the moldable gel layer, 1-30% by weight of the moldable gel layer, 1-25% by weight of the moldable gel layer, In some embodiments, the one or more therapeutic and / or prophylactic compounds are present in one or more of the one or more layers of the moldable gel at 1 to 20% by weight of the moldable gel layer, 1 to 15% by weight of the moldable gel layer, 1 to 10% by weight of the moldable gel layer, or 1 to 5% by weight of the moldable gel layer. ... , 61, 62, 63, 64, 65, 66, 67, 68, 69, 70% by weight.

[0109] In some embodiments, each layer independently has from about 1 to / or about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, 1000, 10 90, 910, 920, 930, 940, 950, 960, 970, 980, 990, 1000 pg, ng, μg, mg, or g of each of one or more therapeutic and / or prophylactic compounds.

[0110] In some embodiments, each layer independently has a molecular weight of from about 1 to / or 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, 1000, 0, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, 1000 pM, nM, μM, mM, or M of each of one or more therapeutic and / or prophylactic compounds.

[0111] In some embodiments, each layer independently has a molecular weight of from about 1 to / or 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520 , 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, 1000 IU of each of one or more therapeutic and / or prophylactic compounds.

[0112] In some embodiments, the one or more therapeutic and / or prophylactic compounds are selected from the group consisting of anti-infective agents, chemotherapeutic agents, immunomodulatory agents, antipyretics, analgesics, antispasmodics, anti-inflammatory agents, antihistamines, radiosensitizers, chemotherapysensitizers, anti-infective sensitizers, biological agents, bisphosphonates, or combinations thereof.

[0113] Suitable immunomodulatory agents include, but are not limited to, prednisone, azathioprine, 6-MP, cyclosporine, tacrolimus, methotrexate, interleukins (e.g., IL-2, IL-7, and IL-12), cytokines (e.g., interferons (e.g., IFN-α, IFN-β, IFN-ε, IFN-K, IFN-ω, and IFN-γ), granulocyte colony-stimulating factor, and imiquimod), chemokines (e.g., CCL3, CCL26, and CXCL7), cytosine phosphate-guanosine, oligodeoxynucleotides, glucans, antibodies, and aptamers).

[0114] Suitable antipyretic agents include, but are not limited to, nonsteroidal anti-inflammatory drugs (e.g., ibuprofen, naproxen, ketoprofen, and nimesulide), aspirin and related salicylates (e.g., choline salicylate, magnesium salicylate, and sodium salicylate), paracetamol / acetaminophen, metamizole, nabumetone, phenazone, and quinine.

[0115] Suitable analgesics include, but are not limited to, paracetamol / acetaminophen, nonsteroidal anti-inflammatory drugs (e.g., ibuprofen, naproxen, ketoprofen, and nimesulide), COX-2 inhibitors (e.g., rofecoxib, celecoxib, and etoricoxib), opioids (e.g., morphine, codeine, oxycodone, hydrocodone, dihydromorphine, pethidine, buprenorphine), tramadol, norepinephrine, flupiretin, nefopam, orphenadrine, pregabalin, gabapentin, cyclobenzaprine, scopolamine, methadone, ketobemidone, piritramide, and aspirin and related salicylates (e.g., choline salicylate, magnesium salicylate, and sodium salicylate).

[0116] Suitable antispasmodic agents include, but are not limited to, mebeverine, papuverine, cyclobenzaprine, carisoprodol, orphenadrine, tizanidine, metaxalone, methocarbamol, chlorzoxazone, baclofen, dantrolene, baclofen, tizanidine, and dantrolene. Suitable anti-inflammatory agents include, but are not limited to, prednisone, nonsteroidal anti-inflammatory agents (e.g., ibuprofen, naproxen, ketoprofen, and nimesulide), COX-2 inhibitors (e.g., rofecoxib, celecoxib, and etoricoxib), and immunoselective anti-inflammatory derivatives (e.g., submandibular peptide-T and its derivatives).

[0117] Suitable antihistamines include H1 receptor antagonists (e.g., acrivastine, azelastine, bilastine, bromphenylamine, buclizine, bromodiphenhydramine, carbinoxamine, cetirizine, chlorpromazine, cyclizine, chlorpheniramine, clemastine, cyproheptadine, desloratadine, dexbrompheniramine, dexchlorpheniramine, dimenhydrinate, dimethindene, diphenhydramine, doxylamine, evasin, embramine, fexofenadine, hydroxydiphenhydramine, Antihypertensives include, but are not limited to, benzodiazepines, levocetirizine, loratadine, meclozine, mirtazapine, olopatadine, orphenadrine, phenindamine, pheniramine, phenyltoloxamine, promethazine, pyrilamine, quetiapine, rupatadine, tripelennamine, and triprolidine), H2 receptor antagonists (e.g., cimetidine, famotidine, lafutidine, nizatidine, lafitidine, and roxatidine), tritoqualine, catechin, cromoglycate, nedocromil, and p2-adrenergic agonists.

[0118] Suitable anti-infective agents include anti-amebic agents (e.g., nitazoxanide, paromomycin, metronidazole, tinidazole, chloroquine, miltefosine, amphotericin b, and iodoquinol), aminoglycosides (e.g., paromomycin, tobramycin, gentamicin, amikacin, kanamycin, and neomycin), anthelmintics (e.g., pyrantel, mebendazole, ivermectin, praziquantel, abendazole, thiabendazole, oxamniquine), antifungals (e.g., azole antifungals (e.g., itraconazole, fluconazole), antimalarials (e.g., pyrimethamine / sulfadoxine, artemether / lumefantrine, atovaquone / procanil, quinine, hydroxychloroquine, mefloquine, chloroquine, doxycycline, pyrimethamine, and haloperidol), echinocandins (e.g., caspofungin, anidulafungin, and micafungin), griseofulvin, terbinafine, flucytosine, and polyenes (e.g., nystatin and amphotericin B), antimalarials (e.g., pyrimethamine / sulfadoxine, artemether / lumefantrine, atovaquone / procanil, quinine, hydroxychloroquine, mefloquine, chloroquine, doxycycline, pyrimethamine, and haloperidol), antivirals (e.g., benzodiazepine, benzocaine ... Fantrine), antituberculous agents (e.g., aminosalicylates (e.g., aminosalicylic acid), isoniazid / rifampicin, isoniazid / pyrazinamide / rifampicin, bedaquiline, isoniazid, ethambutol, rifampicin, rifabutin, rifapentine, capreomycin, and cycloserine), antiviral agents (e.g., amantadine, rimantadine, abacavir / lamivudine, emtricitabine / tenofovir, cobicistat / elvitegravir / emtricitabine / tenofovir, efavirenz / emtricitabine / tenofovir, Abacavir / lamivudine / zidovudine, lamivudine / zidovudine, emtricitabine / tenofovir, emtricitabine / opinavir / ritonavir / tenofovir, interferon alfa-2v / ribavirin, peginterferon alfa-2b, maraviroc, raltegravir, dolutegravir, enfuvirtide, foscarnet, fomivirsen, oseltamivir, zanamivir, nevirapine, efavirenz, etravirine, rilpivirine, delaviridine, nevirapine, entecavir, lamivudine, adefovir, sofosbuvir, didanosine, tenofovir,avasivudine, zidovudine, stavudine, emtricitabine, xalcitabine, telbivudine, simeprevir, boceprevir, telaprevir, lopinavir / ritonavir, fosamprevir, dolanavir, ritonavir, tipranavir, atazanavir, nelfinavir, amprenavir, indinavir, sauvignon vigor, ribavirin, valciclovir, acyclovir, famciclovir, ganciclovir, and valganciclovir), carbapenems (e.g., doripenem, meropenem, ertapenem, and cilastatin / imipenem), cephalosporins (e.g., Antibiotics (e.g., cefadroxil, cephradine, cefazolin, cephalexin, cefepime, cefuralorine, loracarbef, cefotetan, cefuroxime, cefprozil, loracarbef, cefoxitin, cefaclor, ceftibuten, ceftriaxone, cefotaxime, cefpodoxime, cefdinir, cefixime, cefditoren, cefizoxime, and ceftazidime), glycopeptide antibiotics (e.g., vancomycin, dalbavancin, oritavancin, and telvancin), glycylcyclines (e.g., tigecycline), antileprosy agents (e.g., clotrimazole, thiazolinone ... azithromycin and thalidomide), lincomycin and its derivatives (e.g., clindamycin and lincomycin), macrolides and their derivatives (e.g., telithromycin, fidaxomicin, erythromycin, azithromycin, clarithromycin, dirithromycin, and troleandomycin), linezolid, sulfamethoxazole / trimethoprim, rifaximin, chloramphenicol, fosfomycin, metronidazole, aztreonam, bacitracin, penicillins (amoxicillin, ampicillin, bacampicillin, carbamazepine ... cyclosporin, piperacillin, ticarcillin, amoxicillin / clavulanic acid, ampicillin / sulbactam, piperacillin / tazobactam, clavulanic acid / ticarcillin, penicillin, procaine penicillin, oxacillin, dicloxacillin, and nafcillin), quinolones (e.g., lomefloxacin, norfloxacin, ofloxacin, moxifloxacin, ciprofloxacin, levofloxacin, gemifloxacin, moxifloxacin, cinoxacin, nalidixic acid, enoxacin, grepafloxacin, gatifloxacin, trovafloxacin,and sparfloxacin), sulfonamides (e.g., sulfamethoxazole / trimethoprim, sulfasalazine, and sulfasoxazole), tetracyclines (e.g., doxycycline, demeclocycline, minocycline, doxycycline / salicylic acid, doxycycline / omega-3 polyunsaturated fatty acids, and tetracycline), and anti-urinary tract infection agents (e.g., nitrofurantoin, methenamine, fosfomycin, cinoxacin, nalidixic acid, trimethoprim, and methylene blue).

[0119] Suitable chemotherapeutic agents include paclitaxel, brentuximab vedotin, doxorubicin, 5-FU (fluorouracil), everolimus, pemetrexed, melphalan, pamidronate, anastrozole, exemestane, nelarabine, ofatumumab, bevacizumab, belinostat, tositumomab, carmustine, bleomycin, bosutinib, busulfan, alemtuzumab, and irinotecan. , vandetanib, bicalutamide, lomustine, daunorubicin, clofarabine, cabozantinib, dactinomycin, ramucirumab, cytarabine, cytoxan, cyclophosphamide, decitabine, dexamethasone, docetaxel, hydroxyurea, dacarbazine, leuprolide, epirubicin, oxaliplatin, asparaginase, estramustine, cetuximab, vismodegib, ErwiniaChrysanthemi-derived asparaginase, amifostine, etoposide, flutamide, toremifene, fulvestrant, letrozole, degarelix, pralatrexate, methotrexate, floxuridine, obinutuzumab, gemcitabine, afatinib, imatinib mesylate, carmustine, eribulin, trastuzumab, altretamine, topotecan, ponatinib, idarubicin, ifosfamide, ibrutinib, axitinib, interferon alfa-2a, gefitinib, romidine diuretic Depsin, ixabepilone, ruxolitinib, cabazitaxel, ado-trastuzumab emtansine, carfilzomib, chlorambucil, sargramostim, cladribine, mitotane, vincristine, procarbazine, megestrol, trametinib, mesna, strontium-89 chloride, mechlorethamine, mitomycin, busulfan, gemtuzumab ozogamicin, vinorelbine, filgrastim, pegfilgrastim, sorafenib, nilutamide, pentostatin, tamoxifen, mitoxin Santrone, pegaspargase, denileukin diftitox, alitretinoin, carboplatin, pertuzumab, cisplatin, pomalidomide, prednisone, aldesleukin, mercaptopurine, zoledronic acid, lenalidomide, rituximab, ocretide, dasatinib, regorafenib, histrelin, sunitinib, siltuximab, omacetaxine, thioguanine (thioguanine), dabrafenib, erlotinib, bexarotene, temozolomide, thiotepa, thalidomide, BCG, temsirolimus , bendamustine hydrochloride, triptorelin, arsenic trioxide, lapatinib, valrubicin, panitumumab, vinblastine, bortezomib, tretinoin, azacitidine, pazopanib, teniposide, leucovorin, crizotinib, capecitabine, enzalutamide, ipilimumab, goserelin, vorinostat, idelalisib, ceritinib, abiraterone, epothilones, tafluposide, azathioprine, doxifluridine, vindesine, and all-trans retinoic acid.

[0120] Suitable radiosensitizers include, but are not limited to, 5-fluorouracil, platinum analogs (e.g., cisplatin, carboplatin, and oxaliplatin), gemcitabine, DNA topoisomerase I-targeted drugs (e.g., camptothecin derivatives (e.g., topotecan and irinotecan)), epidermal growth factor receptor blockers (e.g., cetuximab, gefitinib), farnesyltransferase inhibitors (e.g., L-778-123), COX-2 inhibitors (e.g., rofecoxib, celecoxib, and etoricoxib), bFGF and VEGF-targeted agents (e.g., bevazucimab and thalidomide), NBTXR3, Nimoral, trans-sodium crocetinate, NVX-108, and combinations thereof. See also, for example, Kvols, LK., JNuclMed 2005;46:187S-190S.

[0121] Suitable bioactive factors include those that promote the growth, remodeling, regeneration, and / or healing of soft tissue and / or bone, including, but not limited to, growth factors (e.g., TGF-beta, fibroblast growth factors (FGFs) (e.g., basic FGF), and insulin-like growth factors (IGFs) (e.g., IGF-I), vascular endothelial growth factors (VEGFs), and platelet-derived growth factors (PDGFs)), hormones, fatty acids, bone morphogenetic proteins (BMPs) (e.g., BMP2, BMP3, BMP4, BMP6, and BMP7), and any combination thereof.

[0122] In some embodiments, the one or more therapeutic and / or prophylactic compounds include at least an anti-infective. In some embodiments, the one or more therapeutic and / or prophylactic compounds include at least an antibiotic. In some embodiments, the one or more therapeutic and / or prophylactic compounds include at least an aminoglycoside or derivative thereof (e.g., paromomycin, tobramycin, gentamicin, amikacin, kanamycin, and neomycin), a carbapenem or derivative thereof (e.g., doripenem, meropenem, ertapenem, and cilastatin / imipenem), a cephalosporin or derivative thereof (e.g., cefadroxil, cephradine, cefazolin, cephalexin, cefepime, cefraroline, loraca), or a cephalosporin or derivative thereof (e.g., cephalosporin ... cefotaxime, cefprozil, loracarbef, cefoxitin, cefaclor, ceftibuten, ceftriaxone, cefotaxime, cefpodoxime, cefdinir, cefixime, cefditoren, cefizoxime, and ceftazidime), glycopeptides or derivatives thereof (e.g., vancomycin, dalbavancin, oritavancin, and telvancin), glycylcyclines (e.g., tigecycline), lincomycin or derivatives thereof (e.g., clindamycin and rifamycin), comcomycin), macrolides or their derivatives (e.g., telithromycin, fidaxomicin, erythromycin, azithromycin, clarithromycin, dirithromycin, and troleandomycin), linezolid, sulfamethoxazole / trimethoprim, rifaximin, chloramphenicol, fosfomycin, metronidazole, aztreonam, bacitracin), penicillins (e.g., amoxicillin, ampicillin, bacampicillin, carbenicillin, piperacillin, thiamin mononitrate ... lucillin, amoxicillin / clavulanic acid, ampicillin / sulbactam, piperacillin / tazobactam, clavulanic acid / ticarcillin, penicillin, procaine penicillin, oxacillin, dicloxacillin, and nafcillin), quinolones (e.g., lomefloxacin, norfloxacin, ofloxacin, moxifloxacin, ciprofloxacin, levofloxacin, gemifloxacin, moxifloxacin, cinoxacin, nalidixic acid, enoxacin, grepafloxacin, gatifloxacin,trovafloxacin, and sparfloxacin), sulfonamides (e.g., sulfamethoxazole / trimethoprim, sulfasalazine, and sulfasoxazole), tetracyclines (e.g., doxycycline, demeclocycline, minocycline, doxycycline / salicylic acid, doxycycline / omega-3 polyunsaturated fatty acids, and tetracycline), or combinations thereof.

[0123] In some embodiments, the therapeutic and / or prophylactic compounds are effective against bacteria of the species Staphylococcus, Streptococcus, Pseudomonas, Enterococcus, Escherichia, Acinetobacter, or any combination thereof. In some embodiments, the therapeutic and / or prophylactic compounds are effective against Staphylococcus aureus. In some embodiments, the therapeutic and / or prophylactic compounds are effective against methicillin-resistant Staphylococcus aureus (MRSA).

[0124] In some embodiments, the implantable device and / or its therapeutic compound is effective in treating and / or preventing biofilm formation, microbial growth, or both. In some embodiments, biofilm formation, microbial growth, or both is present at a surgical site, suture, or wound (e.g., any wound created in one or more parts of the body during a surgical procedure), near a foreign body implanted in a subject, in a non-surgical wound (e.g., one created by trauma or other conditions (e.g., ulcers, necrosis, such as those resulting from diabetes or other circulatory conditions)), at or near a graft, such as a skin graft or other soft tissue transplant (including allografts, xenografts, autografts), or any combination thereof. In some embodiments, the surgical or non-surgical wound is a skin wound. Exemplary implantable foreign bodies include, but are not limited to, implantable devices such as catheters, stents, fixation devices (e.g., screws, pins, rods, plates, cages, anchors, discs, balls, sutures, wires, etc.), replacement joints or components thereof, other cosmetic implants, other orthopedic implants, and / or the like. In some embodiments, the foreign body implant is a penile implant, breast implant, buttocks implant, cheek implant, lip implant, or other cosmetic or orthopedic implant.

[0125] Exemplary methods for making hydrogels are described in the Examples herein and will be known to those of skill in the art in light of the description provided herein. Methods for oxidizing alginate are described, for example, in the Examples herein.

[0126] kit Any or a combination of the compounds, compositions, formulations, and / or devices described herein may be presented as a combination kit. As used herein, a "combination kit" or "kit of parts" refers to any additional components used to package, sell, market, deliver, and / or administer a combination of components, such as a compound, composition, formulation, and / or device, and an active ingredient contained in the kit, or a single component. Such additional components include, but are not limited to, packaging, syringes, blister packs, bottles, and the like. Separate kit components may be contained in a single package or in separate packages within the kit.

[0127] In some embodiments, the combination kit also includes instructions printed on or otherwise contained in a tangible medium. The instructions may provide information regarding the contents of the compounds, compositions, formulations, and / or devices described herein or combinations thereof included in the kit, safety information regarding the contents of the compounds, compositions, formulations, and / or devices (e.g., implantable devices), information regarding dosages, indications for use, and / or recommended treatment regimen(s) for the compounds, compositions, formulations, and / or devices included in the kit. In some embodiments, the instructions may provide directions for administering the compounds, compositions, formulations, and / or devices described herein or combinations thereof to a subject in need thereof. In some embodiments, the instructions and / or label provide directions for administering or otherwise delivering an embodiment of an implantable device described herein to a surgical site and / or wound of a subject in need thereof. In some embodiments, the instructions and / or label may specify a primary surgical site and / or a re-surgical site. In some embodiments, the instructions and / or label specify that the subject has or is at risk for developing a surgical site infection or wound infection. In some embodiments, the instructions and / or label specify that the subject has or is at risk for developing a chronic and / or resistant bacterial infection. In some embodiments, the instructions and label specify that the implantable device is effective for treating and / or preventing a surgical site infection, such as a chronic and / or resistant infection. In some embodiments, the instructions and label specify that the implantable device is effective for treating and / or preventing a surgical site infection caused by bacteria. In some embodiments, the instructions and label specify that the implantable device is effective for treating and / or preventing a surgical site infection caused by bacteria of the species Staphylococcus, Streptococcus, Pseudomonas, Enterococcus, Escherichia, Acinetobacter, or any combination thereof.In some embodiments, the instructions and label specify that the implantable device is effective for treating and / or preventing surgical site infections caused by bacteria of the species Staphylococcus aureus. In some embodiments, the instructions and label specify that the implantable device is effective for treating and / or preventing surgical site infections caused by methicillin-resistant Staphylococcus aureus (MRSA). In some embodiments, the instructions and label specify that the implantable device is effective for treating and / or preventing biofilm formation, microbial growth, or both.

[0128] In some embodiments, the kit further comprises one or more implantable foreign bodies, soft tissue grafts, bone grafts, or any combination thereof.

[0129] How to use an implantable device The implantable device can be delivered to a subject, for example, to a surgical site or wound during a surgical procedure. One or more layers of the device can degrade over time and / or in response to external stimuli, releasing one or more therapeutic and / or prophylactic compounds into the device's surrounding environment. As discussed elsewhere herein, in some embodiments, the implantable device can provide sustained release over a long period of time, thereby treating and / or preventing infections, particularly resistant bacterial populations. It is understood that in many chronic and / or resistant infections, small bacterial populations remain after the initial administration of antibiotics, which can reemerge and persist the infection or become resistant to the initially used anti-infective agent. This type of infection is a major cause of surgical site infections, especially chronic cases. Current delivery devices and strategies are unable to control and / or prevent these infections because they are unable to deliver a therapeutic dose for a sufficient period of time. Typically, these devices can deliver a therapeutic dose for only a few days at most. This is why these devices are not widely used and why systemic antibiotics are often delivered prophylactically for long periods after surgical procedures. In some cases, such as treatment of joints and the back or other areas with poor circulation, extensive wounds (such as burns), or subjects with poor circulation in one or more areas, systemic administration of antibiotics may have limited effectiveness in controlling infection in these areas and / or may cause undesirable side effects due to the very high doses required to achieve a therapeutic dose at these sites. Furthermore, in many areas, the physical space for any implant is so limited that current devices simply cannot load enough active agent to deliver a therapeutic dose.

[0130] Exemplary embodiments herein describe methods of treating and / or preventing surgical site infections, infections at or near the site of an implanted foreign body, or wound infections in a subject in need thereof, comprising implanting an implantable device as described elsewhere herein into a surgical site or other non-surgical wound in a subject in need thereof. In some embodiments, the surgical site or wound is within or near a joint of the subject, at or near the site of a foreign body implanted in the subject, or at or near the site of a skin or other soft tissue graft.

[0131] In some embodiments, the subject has or is at risk of developing a microbial infection at or near the site of surgery, a foreign body implanted in the subject, or a skin or other soft tissue graft. In some embodiments, the subject has or is at risk of developing a microbial infection, optionally a bacterial infection or a yeast infection. In some embodiments, the bacterial infection is a chronic bacterial infection, a resistant bacterial infection, or both. In some embodiments, the bacterial infection comprises a biofilm. In some embodiments, the bacterial infection is caused by bacteria of the species Staphylococcus, Streptococcus, Pseudomonas, Enterococcus, Escherichia, Acinetobacter, or any combination thereof. In some embodiments, the bacterial infection is caused by Staphylococcus aureus. In some embodiments, the bacterial infection is caused by methicillin-resistant Staphylococcus aureus (MRSA).

[0132] In some embodiments, the implantation occurs during an initial surgical procedure performed on the subject. In some embodiments, the implantation occurs during a follow-up surgical procedure performed on the subject. In some embodiments, the implantation occurs within 0.5 to 72 hours of a non-surgical wound that results in trauma to the subject. Exemplary trauma includes, but is not limited to, burns, blunt trauma, trauma caused by impact with a foreign body or device, and / or the like. In some embodiments, the trauma is secondary to a disease or condition, such as, for example, diabetes or any disease that causes poor circulation to one or more areas, resulting in a wound (e.g., an ulcer, etc.). In some embodiments, the wound is a burn or other trauma that requires a skin or other soft tissue graft.

[0133] In some embodiments, the implanted foreign object is a penile implant, a soft tissue implant (e.g., a breast implant, a calf implant, a buttocks implant, a cheek implant, and / or the like), a replacement joint or portion thereof, a fixation implant (e.g., a screw, a plate, and / or the like), or any combination thereof.

[0134] In some embodiments, the method includes degrading one or more moldable gel layers in the implant and releasing one or more therapeutic and / or prophylactic agents present in the one or more moldable gel layers. The degradation can be biodegradation over time caused by the implant's response to the subject's body. In some embodiments, the degradation can be induced by exposing the gel to an external stimulus, as described above.

[0135] The amount of implantable device will vary depending on the particular site to which the device is delivered, in some embodiments, the amount of gel delivered is 0.1-100 ug, mg, g, μL, or μg.

[0136] Further embodiments are illustrated in the following examples, which are provided for illustrative purposes only and are not intended to limit the scope of the invention. [Example]

[0137] Having generally described embodiments of the present disclosure, some additional embodiments of the present disclosure will now be described in the following examples. While embodiments of the present disclosure will be described in conjunction with the following examples and corresponding text and figures, it is not intended that the embodiments of the present disclosure be limited to these descriptions. On the contrary, the intent is to cover all alternatives, modifications, and equivalents that fall within the spirit and scope of the embodiments of the present disclosure. The following examples are presented to provide those of ordinary skill in the art with a complete disclosure and description of how to practice the methods and use the probes disclosed and claimed herein. While efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperatures, etc.), some error and variation should be accounted for. Unless otherwise indicated, parts are parts by weight, temperatures are in degrees Celsius, and pressures are at or near atmospheric. Standard temperature and pressure are defined as 20°C and 1 atmosphere.

[0138] Example 1 - Release kinetics of vancomycin-loaded gel This example demonstrates the release kinetics of antibiotics from CA (collagen-alginate) gels, evaluated at two different CA concentrations, with and without UV cross-linking, using ELISA. To be novel and effective, the gels must release therapeutic doses of antibiotics over a suitable period of 28 days.

[0139] CA gels were prepared at two different concentrations (5% and 30%) and loaded with either vancomycin or penicillin at 33% by weight. Furthermore, some gels were cross-linked, while others were not. Cross-linked gels were cross-linked using UV irradiation. Gels were placed in simulated body fluid and incubated at 37°C for up to 28 days. Antibiotic concentrations in time-course samples were tested by ELISA, and release kinetics was calculated and compared to the current standard of care.

[0140] We tested a 33 wt% vancomycin-loaded gel with and without UV crosslinking. Because the goal was to determine the effectiveness of the gel's retention ability to sustained-release vancomycin, we simplified the process by testing only one wt% vancomycin instead of two different wt%. Phosphate-buffered saline (PBS) at 37°C was used to simulate body fluid, and the gel and PBS were combined in a well (Figure 1). The PBS was replaced every Tuesday and Friday during the study period, and the solution was collected in 3 ml aliquots and stored at -70°C. An initial ELISA test was performed on the collected body fluid.

[0141] For the initial gels, adding collagen to the gel was difficult, resulting in early precipitation of vancomycin. Therefore, initial studies began with alginate alone. Initial studies included alginate gels containing vancomycin, both with and without cross-linking.

[0142] Finally, collagen was successfully combined with alginate to form CA gels, and the elution rate of vancomycin from collagen-alginate gels was determined using the same steps as above for alginate-only gels. ELISA tests were performed with the following eluents, listed and illustrated in Figures 2 and 10. The results are shown in Figures 1-3 and 10.

[0143] The ELISA test results in Figure 2 are shown graphically in Figure 3 (x-axis represents vancomycin concentration, y-axis represents normal and cross-linked gels). They reveal little difference in antibiotic elution from either the cross-linked or non-cross-linked gels. Furthermore, the antibiotic elution rate was high initially, followed by a relatively rapid decline. Without being bound by theory, it is likely that factors affecting elution are related to pH. The next step in our investigation was to modify the pH to slow the vancomycin elution rate. The antibiotic was retained for over a week, a very positive result, suggesting that this device represents an improvement over existing methods that directly insert vancomycin powder. A mathematical model of drug elution was developed and used to predict how the gel would elute in the closed shoulder capsule (Figure 6). Rather than being readily released, vancomycin was found to be retained within the gel, which was the opposite of what we expected. These test results demonstrate that controlled release of vancomycin is possible for at least 7 days. We then added collagenase to the gel to attempt to increase antibiotic release from the gel.

[0144] Next, we evaluated the degradation kinetics of CA gels over 28 days in vitro. Briefly, gels with two different concentrations, with and without UV cross-linking, were prepared and tested. Gels loaded with either vancomycin or penicillin were placed in simulated body fluid with or without collagenase to mimic the in vivo environment. After 7, 14, 28, and 42 days, the samples were dried and weighed, and the degradation rates were calculated.

[0145] Two sets of weights were measured for each gel: the wet weight immediately after removal from the PBS simulated body fluid and the weight after one week of complete drying (Figures 4-5). After 45 days, the gels were observed to have not completely degraded.

[0146] Example 2 - Antibiotic release from gels over time. This example shows the results of testing the efficacy of two concentrations of gels and two different antibiotics over time against cultures of methicillin-resistant Staphylococcus aureus (S. aureus), E. coli, and P. acnes. Similar to Example 1, two different concentrations of gels, with and without cross-linking, were loaded with either vancomycin or penicillin. These gels were eluted in vitro for 7, 14, 21, and 28 days (as part of the experimental process in Example 1). At predetermined time points, the gels were removed and placed in active bacterial culture for 24 hours. After 24 hours, the gels were removed and the bacterial exclusion zone was measured. These data can indicate the efficacy of the eluting gel over time.

[0147] Briefly, methicillin-resistant Staphylococcus aureus (MRSA) was cultured in brain heart infusion broth and diluted to a 0.5 McFarland turbidity standard. The resulting culture was tested by Gram staining to confirm the presence of MRSA. After confirming the presence of Gram-positive MRSA, the MRSA was carefully spread onto 150 mm agar plates and inoculated. Disks loaded with 5 mcg and 30 mcg vancomycin were placed on each agar plate as antibiotic controls. This experiment was performed on six plates: three plates contained aliquots using peroxide (eluate collected from the study in Objective 1 of Example 1) (Figure 7A), and the other three plates contained aliquots using collagenase and phosphate-buffered saline (Figure 7B).

[0148] Aliquots from days 3, 7, 14, 21, and 28 were used. 10 μL of each aliquot was pipetted onto filter paper and placed on an agar plate. The agar plates were incubated at 37°C for 24 hours, and the zones of inhibition were measured the following morning. The results of the experiment are shown in Table 1 below. [Table 1]

[0149] Aliquots of vancomycin were observed to inhibit the growth of MRSA, which is highly resistant to a variety of antibiotics, with a measurable zone of inhibition for at least 14 days (Figures 7A-7B).

[0150] Example 3 - Effect of oxidized gel on antibiotic release profile The effect of gel oxidation percentage on vancomycin release was investigated. The results are shown in Figure 8. Briefly, to test the effect of gel oxidation percentage, gels were placed in 6-well plates and photographs of the gels without dPBS were taken at the start of the study. 5 mL of sterile PBS was added to each well and placed in a CO2 incubator at 37°C. The dPBS was changed twice a week for 28 days. Photographs of the gels were taken at each harvest time. The harvests were frozen at -80°C (1.5 mL x 2 in sterile Eppendorf tubes). Prior to ELISA assay, the harvests were acidified with 50 μl of 17N HCl to resuspend any precipitates. The acidified harvest solution was then tested for vancomycin using a standard ELISA kit assay.

[0151] Example 4 - Exemplary configurations of antibiotic-eluting implantable devices 9A-9B show exemplary configurations of collagen-alginate gels described herein. In some embodiments, the gel is homogeneous (FIG. 9A). In some embodiments, the gel may contain two or more distinct layers of collagen-alginate-antibiotic, optionally including one or more impermeable and degradable layers, with each impermeable and degradable layer disposed between two layers and / or present as the outermost layer (FIG. 9B). In some examples, a first, inner gel matrix may contain a collagen-alginate-antibiotic of a different composition than the outer layer or layers and an impermeable and biodegradable layer. Each of the outer layers present may contain the same or different collagen-alginate-antibiotic composition. The antibiotic elutes first from the outermost layer. The impermeable and biodegradable layer(s) present may form a block to prevent elution from the layer before a suitable time and / or elution from the outer layer(s) occurs. This configuration may allow for tailoring of the elution profile and / or elution of different compounds at different times.

[0152] Example 5 - Oxidation of Alginate Alginate was oxidized at two different concentrations (5% and 30%).

[0153] 5% oxidized alginate For 5% oxidized alginate, approximately 1 gram of alginate was dissolved in approximately 100 mL of HO. Approximately 5 mL of sodium periodate solution (C=0.05M) was added, and the solution was stirred in the dark for approximately 24 hours to allow the oxidation reaction to occur. To terminate the oxidation reaction, approximately 0.02 mL of ethylene glycol was added. Approximately 2.9 g of NaCl was then added to the solution and completely dissolved. 200 mL of 70% ethanol was then mixed into the solution. The solution was then centrifuged at approximately 2000 rpm for approximately 10 minutes to precipitate the alginate. The pellet was then redissolved in approximately 100 mL of water, followed by approximately 200 mL of 70% ethanol. The solution was centrifuged again. The supernatant was removed, and the alginate pellet was lyophilized for approximately 24 hours or until completely dry.

[0154] 30% oxidized alginate For 30% oxidized alginate, approximately 1 gram of alginate was dissolved in approximately 100 mL of HO. Approximately 8 mL of sodium periodate solution (C=0.05M) was added, and the solution was stirred in the dark for approximately 24 hours to allow the oxidation reaction to occur. To terminate the oxidation reaction, approximately 0.11 mL of ethylene glycol was added. Approximately 2.9 g of NaCl was then added to the solution and completely dissolved. 200 mL of 70% ethanol was then mixed into the solution. The solution was then centrifuged at approximately 2000 rpm for approximately 10 minutes to precipitate the alginate. The pellet was then redissolved in approximately 100 mL of water, followed by approximately 200 mL of 70% ethanol. The solution was centrifuged again. The supernatant was removed, and the alginate pellet was lyophilized for approximately 24 hours or until completely dry.

[0155] Example 6 - Exemplary Method for Making Collagen Vancomycin Gel Day 1: A 4% alginate solution was prepared by mixing 2 grams of alginate powder (high molecular weight LF20 / 40) in 50 mL of 1x phosphate-buffered saline (PBS) with stirring until all the alginate was dissolved. This was then left overnight (approximately 8-16 hours) at 4°C in preparation for mixing with collagen. 200 mL of 0.3 M CaCl2 in diH20 was prepared. The collagen was prepared by thawing the collagen overnight (approximately 8-16 hours) at 4°C. The pans were weighed. Approximately 1 g of collagen was added to each pan. The collagen was kept on ice. The weight of the pan plus the weight of the wet collagen was calculated. The collagen was then baked in an oven for a minimum of approximately 6 hours or overnight (approximately 8-16 hours).

[0156] Day 2: Vancomycin was prepared by adding 2 ml of diH2O to a 1 g vial of vancomycin and dissolving with nutator mixing. This took approximately 2 hours. Collagen was prepared by weighing the dried collagen after baking. The protein percentage was calculated according to Table 2 below. [Table 2]

[0157] Vancomycin solution was added to collagen in an amount necessary to achieve a final weight of 100 mg vancomycin per gel according to Eq. 1, as shown in Table 3 below. The collagen was acidified to pH 3.5 using 12 N HCl. The solution was allowed to equilibrate for at least 1 hour. C1×V1=C2×V2(Eq.1) C1 = initial concentration of collagen calculated from dry weight V1 = amount of collagen required (unknown) C2 = known collagen concentration (1.5% in this example) V2 = Final required known amount of collagen (10 mL in this example) [Table 3]

[0158] The gel was assembled by adding the desired amount of alginate solution to the collagen solution and mixing thoroughly. One mL of the collagen-alginate-vancomycin solution was placed in a 25 mm x 20 mm x 5 mm cryomold. When adding the mixture to the cryomold, gently tap the mold to ensure the gel covered the bottom of the mold, ensuring the mixture evenly covered the mold. The filled mold was placed on a flat tray for easy handling. The filled mold was then covered with 0.3 M CaCl2 in H2O for a total volume of 1.5 mL. The gel solidified in approximately 15-30 minutes.

[0159] Harvesting protocol. Gels were placed in 6-well plates, and a photograph of the gel without dPBS was taken at the start of the test. 5 mL of sterile PBS was added to each well, and the plate was incubated in a CO2 incubator at 37°C. dPBS was changed twice a week for 4 weeks (28 days). A photograph of the gel was taken at each harvest. Harvesting was frozen at -80°C in appropriate collection tubes (e.g., 2 x 1.5 mL in sterile Eppendorf tubes). Before performing the ELISA assay, the harvest was acidified with 50 μl of 17 N HCl to resuspend any precipitates. ***

[0160] Various modifications and variations of the described methods, pharmaceutical compositions, and kits of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. While the invention has been described in connection with specific embodiments, it should be understood that the invention is capable of further modifications, and that the claimed invention should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention that are obvious to those skilled in the art are intended to be within the scope of the invention. This application is intended to cover any variations, uses, or applications of the invention that generally follow the principles of the invention, including such departures from the present disclosure as are within known customary practice in the art to which this invention pertains, and as may be applied to the essential features described herein.

[0161] Further attributes, features, and embodiments of the present invention can be understood by reference to the following numbered aspects of the disclosed invention. Reference to disclosure in any of the preceding aspects is also applicable to any preceding numbered aspect and any combination of any number of the preceding aspects, so long as appropriate prior disclosure in any combination of the preceding aspects that is operable is recognized. The following numbered aspects are provided: 1. An implantable device comprising one or more layers of moldable gel, the moldable gel of each of the one or more layers comprising an amount of collagen, an amount of alginate (wherein the collagen and the alginate form an implantable moldable gel), and one or more therapeutic and / or prophylactic compounds dispersed throughout the moldable gel, the moldable gel configured to release the one or more therapeutic and / or prophylactic compounds over a period of time. 2. The implantable device of aspect 1, wherein the amount of collagen and / or the amount of alginate is an effective amount. 3. The implantable device of any one of aspects 1-2, wherein the ratio of collagen to alginate is an effective ratio. 4. The implantable device of any one of aspects 1-3, wherein the alginate, the collagen, or both, are modified. 5. The implantable device of any one of aspects 1-4, wherein the alginate is at least partially oxidized. 6. The alginate is about 1 to 50%, about 3 to 30%, about 5 to 30%, about 7 to 30%, about 10 to 30%, about 12 to 30%, about 15 to 30%, about 20 to 30%, about 25 to 30%, about 1 to 25%, about 3 to 25%, about 5 to 25%, about 7 to 25%, about 10 to 25%, about 12 to 25%, about 15 to 25%, about 20 to 25%, about 1 to 20%, about 3 to 20%, about 5-20%, approximately 7-20%, approximately 10-20%, approximately 12-20%, approximately 15-20%, approximately 1-15%, approximately 3-15%, approximately 5-15%, approximately 7-15%, approximately 10-15%, approximately 12-15%, approximately 1-12%, approximately 1-12%, approximately 5-12%, approximately 7-12%, approximately 10-12%, approximately 1-10%, 1-3%, approximately 5-10%, approximately 7-10%, approximately 1-7%, approximately 3-7%, approximately 5-7%, about 1-5%, about 3-5%, about 1-3%, about 3-50%, about 5-50%, about 7-50%, about 10-50%, about 12-50%, about 15-50%, about 20-50%, about 25-50%, about 30-50%, about 35-50%, about 40-50%, about 45-50%, about 30-45%, about 30-40%, about 30-35%, about 25-45%, about 25-40%, about 2 6. The implantable device of any one of aspects 1-5, wherein the implantable device is 5-35%, about 20-45%, about 20-40%, about 20-35%, about 15-45%, about 15-40%, about 15-35%, about 10-45%, about 10-40%, about 10-35%, about 5-45%, about 5-40%, about 1-35%, about 1-45%, about 1-40%, or about 1-35% oxidized. 7. The implantable device of any one of aspects 1-6, wherein the period of time is at least 1 to 42 days, about 7 to 42 days, about 14 to 42 days, about 21 to 42 days, about 28 to 42 days, about 1 to 28 days, about 7 to 28 days, about 14 to 28 days, about 21 to 28 days, about 1 to 21 days, about 7 to 21 days, about 14 to 21 days, about 1 to 14 days, about 7 to 14 days, or about 1 to 7 days. 8. The implantable device of any one of aspects 1-7, wherein the one or more layers of moldable gel are substantially homogeneous. 9. The implantable device of any one of aspects 1-8, wherein one or more layers of said moldable gel are heterogeneous. 10. The implantable device of any one of aspects 1-9, wherein the implantable device further comprises one or more impermeable but degradable layers, each of which is sandwiched between two layers of the moldable gel and / or forms an outer layer surrounding the one or more moldable gel layers and / or one or more other degradable layers. 11. The implantable device of aspect 10, wherein one or more of the one or more impermeable but degradable layers is (a) biodegradable, (b) degradable in response to an external stimulus, or both (a) and (b). 12. The implantable device of any one of aspects 1-11, wherein the one or more therapeutic and / or prophylactic compounds are present in one or more of the one or more layers of the moldable gel, respectively, in between 1 and 70% by weight of the moldable gel layer, between 1 and 65% by weight of the moldable gel layer, between 1 and 60% by weight of the moldable gel layer, between 1 and 55% by weight of the moldable gel layer, between 1 and 50% by weight of the moldable gel layer, between 1 and 45% by weight of the moldable gel layer, between 1 and 40% by weight of the moldable gel layer, between 1 and 35% by weight of the moldable gel layer, between 1 and 30% by weight of the moldable gel layer, between 1 and 25% by weight of the moldable gel layer, between 1 and 20% by weight of the moldable gel layer, between 1 and 15% by weight of the moldable gel layer, between 1 and 10% by weight of the moldable gel layer, or between 1 and 5% by weight of the moldable gel layer. 13. The implantable device of any one of aspects 1-12, wherein the one or more therapeutic and / or prophylactic compounds are selected from the group consisting of anti-infective agents, chemotherapeutic agents, immunomodulatory agents, antipyretics, analgesics, antispasmodics, anti-inflammatory agents, antihistamines, radiosensitizers, chemotherapysensitizers, anti-infective sensitizers, biological agents, bisphosphonates, or any combination thereof. 14. The implantable device of any one of aspects 1-13, wherein the one or more therapeutic and / or prophylactic compounds comprises an anti-infective agent. 15. The implantable device of aspect 14, wherein the one or more therapeutic and / or prophylactic compounds comprise an antibiotic. 16. The implantable device of any one of aspects 1-15, wherein the one or more therapeutic and / or prophylactic compounds comprise an aminoglycoside or a derivative thereof. 17. The implantable device of aspect 16, wherein the aminoglycoside is selected from paromomycin, tobramycin, gentamicin, amikacin, kanamycin, neomycin, and any combination thereof. 18. The implantable device of any one of aspects 1-17, wherein the one or more therapeutic and / or prophylactic compounds are each independently selected from an aminoglycoside or derivative thereof, a carbapenem or derivative thereof, a cephalosporin or derivative thereof, a glycopeptide or derivative thereof, a glycylcycline or derivative thereof, a lincomycin or derivative thereof, a macrolide or derivative thereof, a penicillin or derivative thereof, a quinolone or derivative thereof, a sulfonamide or derivative thereof, a tetracycline or derivative thereof, or any combination thereof. 19. (a) Aminoglycosides include paromomycin, tobramycin, gentamicin, amikacin, kanamycin, and neomycin, or any combination thereof; (b) Carbapenems include doripenem, meropenem, ertapenem, and cilastatin / imipenem; (c) Cephalosporins include cefadroxil, cephradine, cefazolin, cephalexin, cefepime, ceflaroline, loracarbef, cefotetan, cefuroxime, cefprozil, loracarbef, cefoxitin, cefaclor, ceftibuten, and ceftriaxone. (d) the glycopeptide includes vancomycin, dalbavancin, oritavancin, telvancin, or any combination thereof; (e) the glycylcycline includes tigecycline; (f) the lincomycin includes clindamycin or lincomycin; (g) the macrolide includes telithromycin, fidaxomicin, erythromycin, azithromycin, orthocycline; (h) penicillin is amoxicillin, ampicillin, bacampicillin, carbenicillin, piperacillin, ticarcillin, amoxicillin / clavulanic acid, ampicillin / sulbactam, piperacillin / tazobactam, clavulanic acid / ticarcillin, penicillin, propranolol, rifaximin, chloramphenicol, fosfomycin, metronidazole, aztreonam, bacitracin, or any combination thereof; or (i) penicillin is amoxicillin, ampicillin, bacampicillin, carbenicillin, piperacillin, ticarcillin, amoxicillin / clavulanic acid, ampicillin / sulbactam, piperacillin / tazobactam, clavulanic acid / ticarcillin, penicillin, propranolol, rifaximin, chloramphenicol, fosfomycin, metronidazole, aztreonam, bacitracin, or any combination thereof; (i) the quinolone includes lomefloxacin, norfloxacin, ofloxacin, moxifloxacin, ciprofloxacin, levofloxacin, gemifloxacin, moxifloxacin, cinoxacin, nalidixic acid, enoxacin, grepafloxacin, gatifloxacin, trovafloxacin, sparfloxacin, or any combination thereof; (j) the sulfonamide includes sulfamethoxazole / trimethoprim,The implantable device of embodiment 18, comprising sulfasalazine, sulfasoxazole, or any combination thereof; (k) tetracycline comprising, for example, doxycycline, demeclocycline, minocycline, doxycycline / salicylic acid, doxycycline / omega-3 polyunsaturated fatty acid, and tetracycline; or (l) any combination of (a)-(k). 20. The implantable device of any one of aspects 1-19, wherein the implantable device is effective for treating and / or preventing microbial infection, microbial growth, biofilm formation, or any combination thereof. 21. A kit comprising the implantable device of any one of aspects 1-20. 22. A method of treating and / or preventing a surgical site infection, an infection at or near the site of an implanted foreign body, or a wound infection in a subject in need thereof, comprising implanting an implantable device of any one of aspects 1-20 into a surgical site or wound in said subject in need thereof. 23. The method of aspect 22, wherein the surgical site or wound is within or near a joint of the subject, at or near the site of a foreign body implanted in a subject, or at or near the site of a skin or other soft tissue graft. 24. The method of any one of aspects 22-23, wherein the subject has or is at risk of developing a surgical site infection, an implant foreign body site infection, or a wound site infection. 25. The method of any one of aspects 22-24, wherein the subject has or is at risk of developing a microbial infection. 26. The method of aspect 25, wherein the microbial infection comprises a bacterial infection, a yeast infection, or both. 27. The method of aspect 26, wherein the bacterial infection comprises a chronic bacterial infection, a resistant bacterial infection, or both. 28. The method of any one of aspects 26-27, wherein the bacterial infection comprises a biofilm. 29. The method of any one of aspects 26-28, wherein the bacterial infection is caused by bacteria of the species Staphylococcus, Streptococcus, Pseudomonas, Enterococcus, Escherichia, Acinetobacter, or any combination thereof. 30. The method of aspect 29, wherein the bacterial infection is caused by Staphylococcus aureus. 31. The method of any one of aspects 22-30, wherein implantation occurs during the first surgical procedure performed on the subject. 32. The method of any one of aspects 22-31, wherein the implantation is performed during a second surgical procedure performed on the subject. 33. The method of any one of aspects 22-32, wherein the implantation occurs within 0.5 to 72 hours of a traumatic non-surgical wound to the subject. 34. The method of any one of aspects 22-33, wherein the wound is a burn or other trauma requiring a skin graft. 35. The method of any one of aspects 22-34, wherein the implanted foreign object is a penile implant, a soft tissue implant, a replacement joint or part thereof, a fixation implant, or any combination thereof. 36. The method of embodiment 35, wherein (a) the soft tissue implant comprises a breast implant, a calf implant, a buttocks implant, or a cheek implant; (b) the fixation implant comprises a screw, a plate, a cage, a rod, a pin, an anchor, a disc, or any combination thereof; or (c) both (a) and (b).

Claims

1. 1. An implantable device comprising: one or more layers of moldable gel, the moldable gel in each of the one or more layers comprising: A certain amount of collagen an amount of alginate, wherein the collagen and the alginate form an implantable, moldable gel; and one or more therapeutic and / or prophylactic compounds dispersed throughout the moldable gel, wherein the moldable gel is configured to release the one or more therapeutic and / or prophylactic compounds over a period of time.

2. The implantable device of claim 1 , wherein the amount of collagen and / or the amount of alginate is an effective amount.

3. 10. The implantable device of claim 1, wherein the ratio of collagen to alginate is an effective ratio.

4. The implantable device of claim 1 , wherein the alginate, the collagen, or both are modified.

5. The implantable device of claim 1 , wherein the alginate is at least partially oxidized.

6. The alginate is about 1-50%, about 3-30%, about 5-30%, about 7-30%, about 10-30%, about 12-30%, about 15-30%, about 20-30%, about 25-30%, about 1-25%, about 3-25%, about 5-25%, about 7-25%, about 10-25%, about 12-25%, about 15-25%, about 20-25%, about 1-20%, about 3-20%, about 5-20%, about 7-20%, about 10-20%, about 12-20%, about 15-20%, about 1-15%, about 3-15%, about 5-15%, about 7-15%, about 10-15%, about 12-15%, about 1-12%, about 1-12%, about 5-12%, about 7-12%, about 10-12%, about 1-10%, 1-3%, about 5-10%, about 7-10%, about 1-7%, about 3-7% %, about 5-7%, about 1-5%, about 3-5%, about 1-3%, 3-50%, about 5-50%, about 7-50%, about 10-50%, about 12-50%, about 15-50%, about 20-50%, about 25-50%, about 30-50%, about 35-50%, about 40-50%, about 45-50%, about 30-45%, about 30-40%, about 30-35%, about 25-45%, about 25- 10. The implantable device of claim 1, which is oxidized to 40%, about 25-35%, about 20-45%, about 20-40%, about 20-35%, about 15-45%, about 15-40%, about 15-35%, about 10-45%, about 10-40%, about 10-35%, about 5-45%, about 5-40%, about 1-35%, about 1-45%, about 1-40%, or about 1-35%.

7. 2. The implantable device of claim 1, wherein the period of time is at least 1 to 42 days or more, about 7 to 42 days, about 14 to 42 days, about 21 to 42 days, about 28 to 42 days, about 1 to 28 days, about 7 to 28 days, about 14 to 28 days, about 21 to 28 days, about 1 to 21 days, about 7 to 21 days, about 14 to 21 days, about 1 to 14 days, about 7 to 14 days, or about 1 to 7 days.

8. 10. The implantable device of claim 1, wherein the one or more layers of moldable gel are substantially homogeneous.

9. 10. The implantable device of claim 1, wherein one or more layers of the moldable gel are heterogeneous.

10. 10. The implantable device of claim 1, wherein the implantable device further comprises one or more impermeable but degradable layers, each of which is sandwiched between two layers of the moldable gel and / or forms an outer layer surrounding the one or more moldable gel layers and / or one or more other degradable layers.

11. 11. The implantable device of claim 10, wherein one or more of the one or more impermeable but degradable layers is (a) biodegradable, (b) degradable in response to an external stimulus, or both (a) and (b).

12. 2. The implantable device of claim 1, wherein one or more therapeutic and / or prophylactic compounds are present in one or more of the one or more layers of the moldable gel, respectively, at 1-70% by weight of the moldable gel layer, 1-65% by weight of the moldable gel layer, 1-60% by weight of the moldable gel layer, 1-55% by weight of the moldable gel layer, 1-50% by weight of the moldable gel layer, 1-45% by weight of the moldable gel layer, 1-40% by weight of the moldable gel layer, 1-35% by weight of the moldable gel layer, 1-30% by weight of the moldable gel layer, 1-25% by weight of the moldable gel layer, 1-20% by weight of the moldable gel layer, 1-15% by weight of the moldable gel layer, 1-10% by weight of the moldable gel layer, or 1-5% by weight of the moldable gel layer.

13. 2. The implantable device of claim 1, wherein the one or more therapeutic and / or prophylactic compounds are selected from the group consisting of anti-infective agents, chemotherapeutic agents, immunomodulatory agents, antipyretics, analgesics, antispasmodics, anti-inflammatory agents, antihistamines, radiosensitizers, chemotherapy sensitizers, anti-infective sensitizers, biological factors, bisphosphonates, or any combination thereof.

14. The implantable device of claim 1 , wherein the one or more therapeutic and / or prophylactic compounds comprises an anti-infective agent.

15. 15. The implantable device of claim 14, wherein the one or more therapeutic and / or prophylactic compounds comprise an antibiotic.

16. The implantable device of claim 1 , wherein the one or more therapeutic and / or prophylactic compounds comprise an aminoglycoside or a derivative thereof.

17. 17. The implantable device of claim 16, wherein the aminoglycoside is selected from paromomycin, tobramycin, gentamicin, amikacin, kanamycin, neomycin, and any combination thereof.

18. The implantable device of claim 1, wherein the one or more therapeutic and / or prophylactic compounds are each independently selected from an aminoglycoside or derivative thereof, a carbapenem or derivative thereof, a cephalosporin or derivative thereof, a glycopeptide or derivative thereof, a glycylcycline or derivative thereof, a lincomycin or derivative thereof, a macrolide or derivative thereof, a penicillin or derivative thereof, a quinolone or derivative thereof, a sulfonamide or derivative thereof, a tetracycline or derivative thereof, or any combination thereof.

19. (a) the aminoglycoside comprises paromomycin, tobramycin, gentamicin, amikacin, kanamycin, and neomycin, or any combination thereof; (b) the carbapenems include doripenem, meropenem, ertapenem, and cilastatin / imipenem; (c) the cephalosporin comprises cefadroxil, cephradine, cefazolin, cephalexin, cefepime, cefuralorine, loracarbef, cefotetan, cefuroxime, cefprozil, loracarbef, cefoxitin, cefaclor, ceftibuten, ceftriaxone, cefotaxime, cefpodoxime, cefdinir, cefixime, cefditoren, cefizoxime, ceftazidime, or any combination thereof; (d) the glycopeptide comprises vancomycin, dalbavancin, oritavancin, telvancin, or any combination thereof; (e) the glycylcycline comprises tigecycline; (f) the lincomycin comprises clindamycin or lincomycin; (g) the macrolide comprises telithromycin, fidaxomicin, erythromycin, azithromycin, clarithromycin, dirithromycin, troleandomycin, linezolid, sulfamethoxazole / trimethoprim, rifaximin, chloramphenicol, fosfomycin, metronidazole, aztreonam, bacitracin, or any combination thereof; (h) the penicillin comprises amoxicillin, ampicillin, bacampicillin, carbenicillin, piperacillin, ticarcillin, amoxicillin / clavulanic acid, ampicillin / sulbactam, piperacillin / tazobactam, clavulanic acid / ticarcillin, penicillin, procaine penicillin, oxacillin, dicloxacillin, nafcillin, or any combination thereof; (i) the quinolone comprises lomefloxacin, norfloxacin, ofloxacin, moxifloxacin, ciprofloxacin, levofloxacin, gemifloxacin, moxifloxacin, cinoxacin, nalidixic acid, enoxacin, grepafloxacin, gatifloxacin, trovafloxacin, sparfloxacin, or any combination thereof; (j) the sulfonamide comprises sulfamethoxazole / trimethoprim, sulfasalazine, sulfasoxazole, or any combination thereof; (k) the tetracycline includes, for example, doxycycline, demeclocycline, minocycline, doxycycline / salicylic acid, doxycycline / omega-3 polyunsaturated fatty acid, and tetracycline; or (l) The implantable device of claim 18, comprising any combination of (a) through (k).

20. 10. The implantable device of claim 1, wherein the implantable device is effective in treating and / or preventing microbial infection, microbial growth, biofilm formation, or any combination thereof.

21. A kit comprising an implantable device according to any one of claims 1 to 20.

22. 1. A method of treating and / or preventing a surgical site infection, an infection at or near the site of an implanted foreign body, or a wound infection in a subject in need thereof, comprising: The method comprises implanting the implantable device of any one of claims 1 to 20 into a surgical site or wound in the subject in need thereof.

23. 23. The method of claim 22, wherein the surgical site or wound is within or near a joint of the subject, at or near the site of a foreign object implanted in a subject, or at or near the site of a skin or other soft tissue graft.

24. 23. The method of claim 22, wherein the subject has or is at risk of developing a surgical site infection, an implant foreign body site infection, or a wound site infection.

25. 23. The method of claim 22, wherein the subject has or is at risk of developing a microbial infection.

26. 26. The method of claim 25, wherein the microbial infection comprises a bacterial infection, a yeast infection, or both.

27. 27. The method of claim 26, wherein the bacterial infection comprises a chronic bacterial infection, a resistant bacterial infection, or both.

28. 27. The method of claim 26, wherein the bacterial infection comprises a biofilm.

29. 27. The method of claim 26, wherein the bacterial infection is caused by bacteria of the species Staphylococcus, Streptococcus, Pseudomonas, Enterococcus, Escherichia, Acinetobacter, or any combination thereof.

30. 30. The method of claim 29, wherein the bacterial infection is caused by Staphylococcus aureus.

31. 23. The method of claim 22, wherein implantation occurs during a first surgical procedure performed on the subject.

32. 23. The method of claim 22, wherein implantation occurs during a second surgical procedure performed on the subject.

33. 23. The method of claim 22, wherein implantation occurs within 0.5 to 72 hours of a traumatic non-surgical wound to the subject.

34. 23. The method of claim 22, wherein the wound is a burn or other trauma requiring a skin graft.

35. 23. The method of claim 22, wherein the implanted foreign object is a penile implant, a soft tissue implant, a replacement joint or part thereof, a fixation implant, or any combination thereof.

36. (a) the soft tissue implant comprises a breast implant, a calf implant, a buttocks implant, or a cheek implant; (b) the fixation implant comprises a screw, plate, cage, rod, pin, anchor, disc, or any combination thereof; or (c) The method of claim 35, comprising both (a) and (b).

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