WO2024092091A1

WO2024092091A1 - Biodegradable pocket for drug delivery and associated methods

Info

Publication number: WO2024092091A1
Application number: PCT/US2023/077854
Authority: WO
Inventors: Selin ISGUVEN; Noreen J. Hickok; Flemming Forsberg
Original assignee: Thomas Jefferson University
Priority date: 2022-10-26
Filing date: 2023-10-26
Publication date: 2024-05-02

Abstract

A drug delivery device having; a pocket with first and second outer surface portions surrounding a closed interior volume; the first outer surface portion having a thickness greater than the second outer surface portion; and a quantity of cavitation nuclei positioned in the closed interior volume configured to rupture when exposed to acoustic pressure, breaking the second outer surface portion and releasing a quantity of a drug from the closed interior volume.

Description

TITLE

BIODEGRADABLE POCKET FOR DRUG DELIVERY AND ASSOCIATED METHODS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63/419,526, filed on October 26, 2022, incorporated herein by reference in its entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0002] This invention was made with government support under Grant No. R01AR069119 awarded by the National Institutes of Health. The government has certain rights in the invention.

BACKGROUND OF THE INVENTION

[0003] Innovation is needed regarding drug delivery devices that deliver therapeutic molecules at a certain target site (e.g. a tumor), leaving healthy tissue unharmed (Geerset al., Journal of Controlled Release vol. 164,3 (2012): 248-55). The general goal of drug delivery is to improve the efficacy of drug action in the region of the disease while reducing undesired side effects (Hernot et al., Advanced Drug Delivery Reviews vol. 60,10 (2008): 1153-66).

[0004] Systemic drug delivery overwhelmingly suffers from off-target side effects and not delivering sufficient drug to the area of interest. Existing methods of local drug delivery are usually passive, such as adding Vancomycin powder during closing of the surgical site in many orthopaedic surgeries or mixing antibiotics into bone cement. Controlled and targeted local drug delivery aims to eliminate both of these problems. [0005] To design an on-demand drug delivery system, a concept that was first described in the beginning of the 20th century, one needs to develop a drug carrier that responds to a stimulus applied by an external force or produced by the target tissue itself. Different external stimuli such as electromagnetic waves (IR, UV of visible light) or magnetic and electrochemical forces can be used to achieve such a trigger. Another type of local stimulus can be generated through mechanical pressure waves transmitted by an ultrasound transducer (Geerset al., Journal of Controlled Release vol. 164,3 (2012): 248-55).

[0006] Ultrasound waves are used in medical imaging (e g. echocardiography). An ultrasound image is formed by ultrasound waves becoming reflected by tissues with a density different from the surrounding medium. To enhance the contrast of the vasculature or other blood containing tissues that do not reflect ultrasound well, ultrasound contrast agents (UCAs) can be intravenously injected. UCAs are micron sized (1-10 pm) gas bubbles (microbubbles) with a shell composed out of phospholipids, polymers or proteins. These microbubbles are suitable contrast agents because of their compressibility (Geerset al., Journal of Controlled Release vol. 164,3 (2012): 248-55).

[0007] A microbubble will start to oscillate in response to the exerted cycles of negative and positive pressure associated with insonation. Increased pressure will compress the microbubbles, while negative pressure will induce rarefaction of the bubbles. This process has been investigated in detail by Bouakaz, Versluis and de Jong using high speed light microscopy (Geerset al., Journal of Controlled Release vol. 164,3 (2012): 248-55). At higher acoustical pressures this process transitions into so-called cavitation, which induces progressively more violent microbubble oscillations, eventually resulting in extensive microbubble destruction (termed ‘inertial cavitation’). Inertial cavitation is particularly useful in drug delivery as it can trigger (a) release of drugs from the microbubbles and (b) uptake of the released drugs into the cells whose membranes become temporarily permeabilized due to the localized mechanical effects related to microbubble implosion. Since ultrasound is only applied at a specific location, time- and space- controlled drug delivery may become feasible (Geerset al., Journal of Controlled Release vol. 164,3 (2012): 248-55). [0008] Due to adverse side effects of drugs and lowered efficacy from non-targeted drug delivery, there is the need in the art for a spatio-temporal drug delivery system with an ultrasound-triggered drug release for local drug delivery.

SUMMARY OF THE INVENTION

[0009] In some aspects, a drug delivery device having: a pocket with first and second outer surface portions surrounding a closed interior volume; the first outer surface portion having a thickness greater than the second outer surface portion; and a quantity of cavitation nuclei positioned in the closed interior volume configured to rupture when exposed to acoustic pressure, breaking the second outer surface portion and releasing a quantity of a drug from the closed interior volume.

[0010] In some aspects, a drug delivery device having a pocket comprising first and second outer surface portions surrounding a closed interior volume; the first outer surface portion having a thickness greater than the second outer surface portion; and a quantity of cavitation nuclei positioned in the closed interior volume configured to rupture when exposed to acoustic pressure, breaking the second outer surface portion and releasing a quantity of a drug from the closed interior volume.

[0011] In some embodiments, the pocket has a biodegradable polymer. In some embodiments, the pocket has a mixture of biodegradable polymers. In some embodiments, the pocket has a polylactic polymer film. In some embodiments, the pocket has a polycitrate polymer film. In some embodiments, the pocket has a polycaprolactone polymer film. In some embodiments, the pocket has a mixture of the said material and an insoluble salt. In some embodiments, the insoluble salt is vancomycin HCL.

[0012] In some embodiments, the pocket is sealed with a sealing agent. In some embodiments, the sealing agent is cyanoacrylate glue. In some embodiments, the closed interior volume contains antibiotics. In some embodiments, the cavitation nuclei are microbubbles. In some embodiments, the pocket is configured to be inserted into a surgical site after a procedure. [0013] In some aspects, a method of making a biodegradable film pocket, having the steps of forming a first outer surface portion having a first thickness from a sheet of a biodegradable film; forming a second outer surface portion having a second thickness less than the first thickness; combining the first and second outer surfaces into a pocket; inserting a quantity of cavitation nuclei and a quantity of drugs into the pocket; and sealing the first and second outer surfaces together with an adhesive thereby closing the pocket.

[0014] In some embodiments, the biodegradable film comprises polylactic acid (PLA). In some embodiments, the biodegradable film comprises polycitrate. In some embodiments, the biodegradable film comprises polycaprolactone (PCL). In some embodiments, the adhesive is cyanoacrylate. In some embodiments, the method has the step of inserting a quantity of a drug into the pocket. In some embodiments, the drug is an antibiotic. In some embodiments, the cavitation nuclei are microbubbles.

[0015] In some aspects, a method of releasing a quantity of a drug into a subject, having the steps of providing a pocket comprising first and second outer surface portions surrounding an interior volume and a plurality of cavitation nuclei positioned in the closed interior volume, the first outer surface portion having a thickness greater than the second outer surface portion; loading a quantity of a drug into the interior volume; sealing the interior volume; implanting the pocket into a subject; and rupturing the cavitation nuclei by exposing the pocket to ultrasound, thereby rupturing the second outer surface portion and releasing at least a portion of the quantity of the drug into the subject.

BRIEF DESCRIPTION OF THE DRAWINGS

[0016] The foregoing purposes and features, as well as other purposes and features, will become apparent with reference to the description and accompanying figures below, which are included to provide an understanding of the invention and constitute a part of the specification, in which like numerals represent like elements, and in which:

Fig. 1 A depicts a bottom view of an exemplary polymer film pocket drug delivery device according to an aspect of the present invention. Fig. IB depicts a bottom view of an exemplary polymer film pocket drug delivery device with methylene blue (MeB)-loaded (empty) pocket. Fig. 1C depicts a bottom view of an exemplary polymer film pocket drug delivery device with MeB-loaded (full) pocket.

Fig. 2A depicts a top view of an exemplary polymer film pocket drug delivery device according to an aspect of the present invention. Fig. 2B depicts a top view of an exemplary polymer film pocket drug delivery device with MeB-loaded (empty) pocket. Fig. 2C depicts a top view of an exemplary polymer film pocket drug delivery device with MeB-loaded (full) pocket. Fig. 2D depicts a top view of an exemplary polymer film pocket drug delivery device according to an aspect of the present invention.

Fig. 3A depicts a perspective/side view of an exemplary polymer film pocket drug delivery device according to an aspect of the present invention. Fig. 3B depicts side views of an exemplary polymer film pocket drug delivery device with MeB-loaded (empty) pocket. Fig. 3C depicts a perspective/side view of an exemplary polymer film pocket drug delivery device with MeB-loaded (full) pocket.

Figs. 4A - 4D depict various views of an exemplary polymer film pocket drug delivery device according to an aspect of the present invention. Fig. 4A depicts a perspective view, Fig. 4B depicts a side view, Fig. 4C depicts a perspective view, and Fig. 4D depicts various side views.

Fig. 5 depicts additional shapes for exemplary polymer film pocket drug delivery devices according to aspects of the present invention.

Fig. 6A depicts an exemplary base layer of a polymer film pocket drug delivery device according to an aspect of the present invention. Fig. 6B depicts an exemplary rupturable layer of a polymer film pocket drug delivery device according to an aspect of the present invention.

Fig. 7 depicts a top down view (left) and side view (right) of an exemplary rupturable layer for a polymer film pocket drug delivery device according to aspects of the present invention.

Fig. 8 depicts an exemplary method of loading one or more drugs into a polymer film pocket drug delivery device according to aspects of the present invention. Fig. 9 shows an exemplary polymer film pocket drug delivery device submerged in a water bath before insonation with High-Intensity Focused Ultrasound (HIFU). The shown device is a Methlyn Blue (MeB)-loaded, sealed PLA pocket with the rupturable side facing up.

Fig. 10 shows the water bath of Fig. 9 after insonation of the polymer drug delivery device with High-Intensity Focused Ultrasound (HIFU) for 20 minutes. Shown is that the rupture of the device has occurred, the device has been retrieved, and the change in color of the water bath reflects the released MeB.

DETAILED DESCRIPTION

[0017] It is to be understood that the figures and descriptions of the present invention have been simplified to illustrate elements that are relevant for a clear understanding of the present invention, while eliminating, for the purpose of clarity, many other elements found in related systems and methods. Those of ordinary skill in the art may recognize that other elements and/or steps are desirable and/or required in implementing the present invention. However, because such elements and steps are well known in the art, and because they do not facilitate a better understanding of the present invention, a discussion of such elements and steps is not provided herein. The disclosure herein is directed to all such variations and modifications to such elements and methods known to those skilled in the art.

[0018] Unless defined otherwise, 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 invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, exemplary methods and materials are described.

[0019] As used herein, each of the following terms has the meaning associated with it in this section. [0020] The articles “a” and “an” are used herein to refer to one or to more than one (z.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0021] “About” as used herein when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ±20%, ±10%, ±5%, ±1%, and ±0.1% from the specified value, as such variations are appropriate.

[0022] Throughout this disclosure, various aspects of the invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, 6 and any whole and partial increments therebetween. This applies regardless of the breadth of the range.

Drug Delivery Device and Method

[0023] In one example, the present invention relates to a polymer film pocket device designed for ultrasound-triggered local drug delivery. In some embodiments, a drug solution containing the drug of interest and cavitation nuclei is encapsulated within a drug depot volume in the interior of the polymer film pocket. In some examples, the polymer can be a biodegradable polymer, such as polycitrate or PLA. In other examples, the polymer can be polycaprolactone. In some aspects, the invention relates to the use of a biocompatible and biodegradable polymer. The biodegradation of the polymer is advantageous as there should not be the need for additional surgery to retrieve the (empty) drug delivery device or the increased risk of infection due to foreign material presence in the body. According to the present invention, the polymer film should be thin enough to allow rupturing of the drug depot, while being stable enough to contain the drug solution until the time the device is triggered by ultrasound. In one example, at the time of triggering, the ultrasound, enhanced by cavitation nuclei (in some cases microbubbles), cause the polymer film to rupture as a result of applying acoustic pressure and cause the drug depot to burst and deliver the drug.

[0024] In some aspects, the present invention relates to an ultrasound-triggered drug delivery device with spatio-temporal control. Now referring to Figure 1A and Figure 4D, shown is polymer drug delivery device 100 comprising pocket 102, first outer surface 103, second outer surface 105 with interior volume drug depot 104 and drug loading opening 106.

[0025] In some embodiments, device 100 comprises at least one pocket 102 comprising a thin film polymer encapsulating at least one interior volume that forms drug depot 104. In some embodiments, device 100 comprises at least one pocket 102 with first outer surface 103 forming a thick base and second outer surface 105 forming a thin rupturable film of varying thickness. It should be noted that in other embodiments, device 100 may comprise 1, 2, 3, 4, 5 or more films that form the outer surfaces. Additionally, device 100 may comprise 1, 2, 3, 4, 5 or more pockets creating interior volumes for the loading of drug and/or other materials. In some embodiments, drug depot 104 comprises an interior volume sealed from the exterior of device 100. In some embodiments, device 100 comprises drug loading opening 106 wherein drug may be loaded into drug depot 104. In other embodiments, device 100 comprises more than one drug loading opening 106, in some cases at least one of the openings allows for the escape of air while loading drug. In some embodiments, drug loading opening 106 fluidly communicates drug depot 104 with the exterior of device 100. In some embodiments, drug loading opening 106 is later sealed and/or closed after drug depot 104 is filled with drug. Now referring to Fig. 6A, in some embodiments, attachment tag 107 is present along the edges of the device to help with attachment of the device to implants and/or local tissue parts, to secure the location and orientation of the device in the body. Attachment tag 107 may comprise 1, 2, 3, 4, 5, or more pieces. In some embodiments, the tags may be perforated with a sharp device, such as a needle, and threaded with suture line or other biocompatible material.

[0026] In some aspects, the present disclosure relates to the shape of polymer drug delivery device 100. Now referring to Fig. 5, depicted are various embodiments of device 100 showing different shapes possible for the device. In some embodiments, device 100 comprises a cylindrical shape. In some embodiments, device 100 comprises a conical shape. In some embodiments, device 100 comprises a spherical shape. In some embodiments, device 100 is toroidal in shape. In some embodiments, device 100 is in the shape of an envelope. In some embodiments, device 100 is in the shape of a pouch. The primary difference between the cone and the pouch shape is that in the cone, the base layer is created by folding a flat fdm. For the pouch, the thick film may be shaped with a mold or solvent casting and bending while semi-dry, therefore not requiring a folding step. Although examples of mold or solvent casting is provided, device 100 may comprise films and/or layers produced via methods known to those having ordinary level of skill in the art, including, but not limited to, 3D printing and Fused Filament Fabrication (FFF). In some embodiments, device 100 is in the shape of a triangle. A triangular reservoir may be achieved by working with semi-wet thin film and folding it over itself or onto a thick triangular film. Although examples of shapes for device 100 are provided, the device may comprise any shape wherein an interior volume may be created with a combination of thin/rupturable and thick/base films, as would be known by someone of ordinary skill in the art.

[0027] Aspects of the present invention relate to creating a drug delivery volume shape for the intended surgical site. For example, a device 100 intended to be used along a spine is going to be elongated and several inches in length, whereas a device 100 intended to be used next to a fracture will be circular and smaller.

[0028] In some aspects, the present invention relates to device 100 comprising at least one pocket 102 with at least one outer surface 103 and at least one second outer surface 105. In some embodiments, device 100 comprises first outer surface 103 making a thick base and folded to create a conical shape and joined with second outer surface 105 as a thin film to form an interior volume comprising drug depot 104. In some embodiments, device 100 comprises outer surface 103 and second outer surface 105 adjoined together and then folded and sealed to create an interior volume comprising drug depot 104. In some embodiments, outer surface 103 and second outer surface 105 of device 100 are different shapes or sizes. In some embodiments, device 100 comprises outer surface 103 and second outer surface 105 that are circular in shape with outer surface 103 having a larger radius than second outer surface 105. In some embodiments, outer surface 103 is folded into a conical shape, and second outer surface 105 is used to seal the base of the conical shape. In some embodiments, the outer surface 103 and second outer surface 105 may have varying thickness, such that outer surface 103 is folded and sealed into a conical shape and forms an open cavity comprising drug depot 104 with second outer surface 105 having lesser thickness and used to seal the open side of the cone cavity at the base, but leaving an aperture comprising drug loading opening 106. In some embodiments, drug loading opening 106 is later sealed and/or closed after the loading of drug and/or material to create a closed interior volume comprising drug depot 104.

[0029] In some embodiments, device 100 comprises at least one polymer film. For example, two layers of polymer film may be layered to form pocket 102 of device 100. In some embodiments, device 100 may comprise at least one polymer film, wherein each film may vary by: thickness, density, shape, pattern, porosity, presence of lyoprotectant, lyoprotectant concentration and/or presence of cytoprotectant, and cytoprotectant concentration.

[0030] In some embodiments, one polymer film layer may be more porous than the other polymer film layer. In some embodiments, outer layer 103 and/or second outer layer 105 may comprise perforations. In some embodiments, device 100 may comprise one layer of film that is of higher concentration of polymer than the other layer of film. In some embodiments, device 100 may comprise an inner layer of film with low concentration of polymer, and an outer layer of film with a higher concentration of polymer. In some embodiments, device 100 may comprise a lattice shaped film. For example, an inner layer of film may comprise a low concentration of polymer with a thin film layer, surrounded by a polymer film lattice that comprises a thicker layer with a higher concentration of polymer. In some embodiments, device 100 may comprise a checkerboard pattern. In some embodiments, pocket 102 may provide a structure to device 100 to prevent drug depot 104 from bursting prematurely from interior or exterior pressures and/or forces. In some embodiments, device 100 may comprise embossed or debossed features in device 100, pocket 102, first outer layer 103 and/or second outer layer 105 that enable various drug delivery characteristics upon rupturing of the device and release of drug.

[0031] In some aspects, the present invention relates to the dimensions of polymer drug delivery device 100. For example, aspects of the present invention relate to the length, width, height and interior volume of the device. Now referring to Fig. 3C and Fig. 3D, shown are the dimensions for an embodiment of device 100 according to an aspect of the present invention. In Fig. 4, the dimensions shown are length 110, height 112 and width 114. [0032] In some embodiments, length 110 of device 100 is, but not limited to, about 5 mm, 10 mm, 15 mm, 20 mm, 25 mm, 30 mm, 35mm, 40 mm, 45 mm, 50 mm, 55 mm, 60 mm, 65 mm, 70 mm, 75 mm, 80 mm, 85 mm, 90 mm, 95 mm, or about 100 mm. In some embodiments, the length is less than 100 mm. In some embodiments, the length is greater than 5 mm. In some embodiments, the length may range from 10 mm to 90 mm. In some embodiments, the length may range from 25 mm to 75 mm. In some embodiments, the length may range from 30 mm to 60 mm. In some embodiments, the length may range from 40 mm to 50 mm.

[0033] In some embodiments, width 114 of device 100 is, but not limited to, about 5 mm, 10 mm, 15 mm, 20 mm, 25 mm, 30 mm, 35 mm, 40 mm, 45 mm, 50 mm, 55 mm, 60 mm, 65 mm, 70 mm, 75 mm, 80 mm, 85 mm, 90 mm, 95 mm, or about 100 mm. In some embodiments, the width is less than 10 0mm. In some embodiments, the width is greater than 5 mm. In some embodiments, the width may range from 10 mm to 90 mm. In some embodiments, the width may range from 25 mm to 75 mm. In some embodiments, the width may range from 30 mm to 60 mm. In some embodiments, the length may range from 40 mm to 50 mm.

[0034] In some embodiments, height 112 of device 100 is, but not limited to, about 5 mm, 10 mm, 15 mm, 20 mm, 25 mm, 30 mm, 35 mm, 40 mm, 45 mm, 50 mm, 55 mm, 60 mm, 65 mm, 70 mm, 75 mm, 80 mm, 85 mm, 90 mm, 95 mm, or about 100 mm. In some embodiments, the height is less than 100 mm. In some embodiments, the height is greater than 5 mm. In some embodiments, the height may range from 10 mm to 90 mm. In some embodiments, the height may range from 25 mm to 75 mm. In some embodiments, the height may range from 30 mm to 60 mm. In some embodiments, the height may range from 40 mm to 50 mm.

[0035] In some embodiments, the interior volume of drug depot 104 of device 100 is, but not limited to, about 10 mm², 15 mm², 20 mm², 25 mm², 30 mm², 35 mm², 40 mm², 45 mm², 50 mm², 55 mm², 60 mm², 65 mm², 70 mm², 75 mm², 80 mm², 85 mm², 90 mm², 95 mm², 100 mm², 105 mm², 110 mm², 115 mm², 120 mm², 125 mm², 130 mm², 135 mm², 140 mm², 145 mm², 150 mm², 155 mm², 160 mm², 165 mm², 170 mm², 175 mm², 180 mm², 185 mm², 190 mm², 195 mm², 200 mm², 205 mm², 210 mm², 215 mm², 220 mm², 225 mm², 230 mm², 235 mm², 240 mm², 245 mm², or about 250 mm². In some embodiments, the interior volume is less than 250 mm². In some embodiments, the interior volume is greater than 10 mm². In some embodiments, the interior volume is in a range of 25 mm² to 225 mm². In some embodiments, the interior volume is in a range of about 50 mm² to 200 mm². In some embodiments, the interior volume is in a range of about 75 mm² to 175 mm². In some embodiments, the interior volume is in a range of about 100 mm² to 150 mm². In some embodiments, the interior volume is in a range of about 115 mm² to 135 mm².

[0036] In some aspects, the present invention relates to the materials of polymer drug delivery device 100. In some embodiments, device 100 comprises polylactic acid. In some embodiments, device 100 comprises polycitrate. In some embodiments, device 100 comprises a biopolymer. In some embodiments, device 100 comprises polycaprolactone. In some embodiments, device 100 comprises other polymers, biodegradable polymers, or materials as would be known by someone of ordinary level of skill in the art. In some embodiments, device 100 may comprise hyaluronic acid (HA), either as a polymer or as a compound to blend with a polymer backbone.

[0037] In some embodiments, device 100 comprises materials such as, but not limited to, hydrogels including cross-linked polymers, poly(alkyl methacrylates), poly((meth)acrylic acid), poly(vinyl alcohol), poly(N-vinyl-2-pyrrolidone), poly(ethylene oxide) and polyethylene gycol), Cellulose derivatives, alginates, soy derivatives, collagen and gelatin (animal derived), alginate derivatives, agarose, polysulphone, PEG-DA, PVA, polymer comprises alginic acid- polyethylene glycol copolymer, poly(ethylene glycol), poly(2-methyl-2-oxazoline), poly(ethylene oxide), poly(vinyl alcohol), poly(acrylamide), poly(n-butyl acrylate), poly-(a- esters), poly(glycolic acid), poly(lactic-co-glycolic acid), poly(L-lactic acid), poly(N- isopropylacrylamide), butyryl -tri hexyl -citrate, di(2-ethylhexyl)phthalate, di-iso-nonyl-1,2- cyclohexanedicarboxylate, expanded polytetrafluoroethylene, ethylene vinyl alcohol copolymer, poly(hexamethylene diisocyanate), highly crosslinked poly(ethylene), poly (isophorone diisocyanate), poly(amide), poly(acrylonitrile), poly(carbonate), poly(caprolactone diol), poly(D- lactic acid), poly(dimethylsiloxane), poly(dioxanone), poly(ethylene), polyether ether ketone, polyester polymer alloy, polyether sulfone, polyethylene terephthalate), poly(hydroxyethyl methacrylate), poly(methyl methacrylate), poly(methylpentene), poly(propylene), polysulfone, poly(vinyl chloride), poly(vinylidene fluoride), poly(vinylpyrrolidone), poly(styrene-b- isobutylene-b-styrene), or any combination thereof. [0038] In some embodiments, device 100 comprises other polymers, including, but not limited to synthetic polymers and/or copolymers. Examples of suitable polymers are synthetic polymers or copolymers which are prepared from monomers selected from the group consisting of acrylic acid, methacrylic acid, ethyleneimine, crotonic acid, acrylamide, ethyl acrylate, methyl methacrylate, 2-hydroxyethyl methacrylate, lactic acid, glycolic acid, s-caprolactone, acrolein, cyanoacrylate, cyanomethacrylate, bisphenol A, epichlorhydrin, hydroxyalkylacrylates, siloxane, dimethylsiloxane, ethylene oxide, ethylene glycol, hydroxyalkylmethacrylates, N-substituted acrylamides, N-substituted methacrylamides, N-vinyl-2- pyrrolidone, 2,4-pentadiene-l-ol, vinyl acetate, acrylonitrile, styrene, p-amino- styrene, p-aminobenzylstyrene, sodium styrene sulfonate, sodium 2- sulfoxyethyl-methacrylate, vinyl pyridine, aminoethyl methacrylates, lactides, and 2- methacryloyloxytrimethyl-ammonium chloride. Examples of synthetic (copolymers are, for instance, polyacrylic acid, polyethyleneimine, polymethacrylic acid, polymethylmethacrylate, polycyanomethacrylate, polyamidoamine dendrimers, organophosphorus dendrimers, polysiloxane, polydimethylsiloxane, polylactic acid, polyCs-caprolactone), epoxy resin, polyamide, poly vinylidene- polyacrylonitrile, polyvinylidene-polyacrylonitrile- polymethylmethacrylate, polylactide coglycolide polymers (such as poly-d-L-lactide coglycolide polymers), nylon and polystyrene-polyacrylonitrile as well as polyfunctional crosslinking monomers such as N,N' -methylenebisacrylamide, ethylene glycol dimethacrylates, 2,2'- (p-phenylenedioxy)-diethyl dimethacrylate, divinylbenzene, triallylamine and methylenebis-(4- phenyl-isocyanate), including combinations thereof, as well as polyvinyls (such as, for example, polyvinyl alcohol (PVA), polyvinylchloride and polyvinylpyrrolidone), polystyrene, polylactic acids, fluorinated hydrocarbons, fluorinated carbons (such as, for example, polytetrafluoroethylene), and polymethylmethacrylate, and derivatives thereof. Also included are amphiphilic compounds composed of cationic polymers covalently modified with hydrophobic (e.g. lipid moieties as palmitoyl) and/or hydrophilic (polyethylene glycol) groups. The polymers may optionally be cross-linked, if desired, to enhance, for example, the stability of the nanoparticles. This could be achieved by cross linking cysteine-bearing polymers by oxidative polycondensation.

[0039] In some embodiments, device 100 may comprise biodegradable water-insoluble lipids, for instance, solid water insoluble mono-, di- or tri-glycerides, fatty acids, fatty acid esters, sterols such as cholesterol, waxes and mixtures thereof. Mono-, di- and tri- glycerides include mainly the mono-, di- and tri-laurin compounds as well as the corresponding -myristin, -palmitin, -stearin, -arachidin and -behenin derivatives. Mono-, di- and tri- myristin, -palmitin -stearin and mixed triglycerides such as dipalmitoylmonooleyl glyceride are particularly useful; tripalmitin and tristearin are advantageous. Fatty acids include solid (at room temperature, about 18-250C) fatty acids (in some embodiments, saturated fatty acids) having 12 carbon atoms or more, including, for instance, lauric, arachidic, behenic, palmitic, stearic, sebacic, myristic, cerotinic, melissic and erucic acids and the fatty acid esters thereof. It is advantageous if the fatty acids and their esters are used in admixture with other glycerides. The sterols are typically used in admixture with the other glycerides and or fatty acids and are selected from cholesterol, phytosterol, lanosterol, ergosterol, etc. and esters of the sterols with the above mentioned fatty acids; however, cholesterol is advantageous.

[0040] In some embodiments, the present invention relates to sealing agents for assembly, sealing and/or closing device 100. In some embodiments, an adhesive agent is used to seal polymer fdm to create an interior volume in device 100. For example, cyanoacrylate glue may be used to seal one or more polymer fdms. In another example, cyanoacrylate glue is used to seal polylactic acid and/or polycitrate. Although an example of cyanoacrylate glue is provided, any sealing agent appropriate for biocompatible applications may be used to seal the polymer film as would be known by someone of ordinary level of skill in the art. For example, biocompatible adhesives used in surgical applications may be used as a sealing agent in device 100. In another embodiment, a liquid agent such as chloroform is used to activate the polymer to make a portion of the film sticky. In another embodiment, a solvent casting method is used in the preparation of the films, allowing the device to be sealed without a sealing agent as the polymer is sticky while drying.

[0041] In some aspects, the present invention relates to the loading of drug into device 100 for the targeted delivery to an area in the body. In some embodiments, a drug is loaded inside device 100 in drug depot volume 104. In some embodiments, a drug is loaded in the polymer film comprising outer surface 103 and outer surface 105. For example, the polymer film of device 100 may comprise antibiotics (e.g. Vancomycin powder) and/or insoluble salts. These antibiotic or salt particles may be included in the solvent mixture that is later cast to form the film, or added to the fdm after it has been cast, either during the drying process or after it has dried, by pressing the particles onto the fdm.

[0042] In some embodiments, drugs may be loaded into an interior volume inside device 100 that may include, but are not limited to, b-lactam antibiotics, penicillins (such as natural penicillins, aminopenicillins, penicillinase-resistant penicillins, carboxy penicillins, ureido penicillins), cephalosporins (all generation cephalosporins), other b-lactams (such as imipenem, monobactams), b-lactamase inhibitors, peptide antibiotics such as vancomycin, aminoglycosides and spectinomycin, tetracycline family, chloramphenicol, the macrolide family including erythromycin, lincomycin, clindamycin, rifampin, metronidazole, polymyxins, sulfonamides and trimethoprim, or quinolines, daptomycin, silver nanoparticles. Other anti-bacterials may be without limitation Acedapsone; Acetosulfone Sodium; Alamecin; Alexidine; Amdinocillin; Amdinocillin Pivoxil; Amicycline; Amifloxacin; Amifloxacin Mesylate; Amikacin; Amikacin Sulfate; Aminosalicylic acid; Aminosalicylate sodium; Amoxicillin; Amphomycin; Ampicillin; Ampicillin Sodium; Apalcillin Sodium; Apramycin; Aspartocin; Astromicin Sulfate; Avilamycin; Avoparcin; Azithromycin; Azlocillin; Azlocillin Sodium; Bacampicillin Hydrochloride; Bacitracin; Bacitracin Methylene Disalicylate; Bacitracin Zinc; Bambermycins; Benzoylpas Calcium; Berythromycin; Betamicin Sulfate; Biapenem; Biniramycin; Biphenamine Hydrochloride; Bispyrithione Magsulfex; Butikacin; Butirosin Sulfate; Capreomycin Sulfate; Carbadox; Carbenicillin Disodium; Carbenicillin Indanyl Sodium; Carbenicillin Phenyl Sodium; Carbenicillin Potassium; Carumonam Sodium; Cefaclor; Cefadroxil; Cefamandole; Cefamandole Nafate; Cefamandole Sodium; Cefaparole; Cefatrizine; Cefazaflur Sodium; Cefazolin; Cefazolin Sodium; Cefbuperazone; Cefdinir; Cefepime; Cefepime Hydrochloride; Cefetecol; Cefixime; Cefmenoxime Hydrochloride; Cefmetazole; Cefmetazole Sodium; Cefonicid Monosodium; Cefonicid Sodium; Cefoperazone Sodium; Ceforanide; Cefotaxime Sodium; Cefotetan;

Cefotetan Disodium; Cefotiam Hydrochloride; Cefoxitin; Cefoxitin Sodium; Cefpimizole; Cefpimizole Sodium; Cefpiramide; Cefpiramide Sodium; Cefpirome Sulfate; Cefpodoxime Proxetil; Cefprozil; Cefroxadine; Cefsulodin Sodium; Ceftazidime; Ceftibuten; Ceftizoxime Sodium; Ceftriaxone Sodium; Cefuroxime; Cefuroxime Axetil; Cefuroxime Pivoxetil; Cefuroxime Sodium; Cephacetrile Sodium; Cephalexin; Cephalexin Hydrochloride; Cephaloglycin; Cephaloridine; Cephalothin Sodium; Cephapirin Sodium; Cephradine; Cetocycline Hydrochloride; Cetophenicol; Chloramphenicol; Chloramphenicol Palmitate; Chloramphenicol Pantothenate Complex; Chloramphenicol Sodium Succinate; Chlorhexidine Phosphanilate; Chloroxylenol; Chlortetracycline Bisulfate; Chlortetracycline Hydrochloride; Cinoxacin; Ciprofloxacin; Ciprofloxacin Hydrochloride; Cirolemycin; Clarithromycin; Clinafloxacin Hydrochloride; Clindamycin; Clindamycin Hydrochloride; Clindamycin Palmitate Hydrochloride; Clindamycin Phosphate; Clofazimine; Cloxacillin Benzathine; Cioxacillin Sodium; Cloxyquin; Colistimethate Sodium; Colistin Sulfate; Coumermycin; Coumermycin Sodium; Cyclacillin; Cycloserine; Dalfopristin; Dapsone; Daptomycin; Demeclocycline; Demeclocycline Hydrochloride; Demecycline; Denofungin; Diaveridine; Dicloxacillin;

Dicloxacillin Sodium; Dihydrostreptomycin Sulfate; Dipyrithione; Dirithromycin; Doxycycline; Doxycycline Calcium; Doxy cy cline Fosfatex; Doxycycline Hy elate; Droxacin Sodium; Enoxacin; Epicillin; Epitetracycline Hydrochloride; Erythromycin; Erythromycin Acistrate; Erythromycin Estolate; Erythromycin Ethyl succinate; Erythromycin Gluceptate; Erythromycin Lactobionate; Erythromycin Propionate; Erythromycin Stearate; Ethambutol Hydrochloride; Ethionamide; Fleroxacin; Floxacillin; Fludalanine; Flumequine; Fosfomycin; Fosfomycin Tromethamine; Fumoxicillin; Furazolium Chloride; Furazolium Tartrate; Fusidate Sodium; Fusidic Acid; Gentamicin Sulfate; Gloximonam; Gramicidin; Haloprogin; Hetacillin; Hetacillin Potassium; Hexedine; Ibafloxacin; Imipenem; Isoconazole; Isepamicin; Isoniazid; Josamycin;

Kanamycin Sulfate; Kitasamycin; Levofuraltadone; Levopropylcillin Potassium; Lexithromycin; Lincomycin; Lincomycin Hydrochloride; Lomefloxacin; Lomefloxacin Hydrochloride;

Lomefloxacin Mesylate; Loracarbef; Mafenide; Meclocycline; Meclocycline Sulfosalicylate; Megalomicin Potassium Phosphate; Mequidox; Meropenem; Methacycline; Methacycline Hydrochloride; Methenamine; Methenamine Hippurate; Methenamine Mandelate; Methicillin Sodium; Metioprim; Metronidazole Hydrochloride; Metronidazole Phosphate; Mezlocillin; Mezlocillin Sodium; Minocycline; Minocycline Hydrochloride; Mirincamycin Hydrochloride; Monensin; Monensin Sodium; Nafcillin Sodium; Nalidixate Sodium; Nalidixic Acid;

Natamycin; Nebramycin; Neomycin Palmitate; Neomycin Sulfate; Neomycin Undecylenate; Netilmicin Sulfate; Neutramycin; Nifuradene; Nifuraldezone; Nifuratel; Nifuratrone; Nifurdazil; Nifurimide; Nifurpirinol; Nifurquinazol; Nifurthiazole; Nitrocycline; Nitrofurantoin; Nitromide; Norfloxacin; Novobiocin Sodium; Ofloxacin; Ormetoprim; Oxacillin Sodium; Oximonam;

Oximonam Sodium; Oxolinic Acid; Oxytetracycline; Oxytetracycline Calcium; Oxytetracycline Hydrochloride; Paldimycin; Parachlorophenol; Paulomycin; Pefloxacin; Pefloxacin Mesylate; Penamecillin; Penicillin G Benzathine; Penicillin G Potassium; Penicillin G Procaine; Penicillin G Sodium; Penicillin V; Penicillin V Benzathine; Penicillin V Hydrabamine; Penicillin V Potassium; Pentizidone Sodium; Phenyl Aminosalicylate; Piperacillin Sodium; Pirbenicillin Sodium; Piridicillin Sodium; Pirlimycin Hydrochloride; Pivampicillin Hydrochloride; Pivampicillin Pamoate; Pivampicillin Probenate; Polymyxin B Sulfate; Porfiromycin;

Propikacin; Pyrazinamide; Pyrithione Zinc; Quindecamine Acetate; Quinupristin; Racephenicol; Ramoplanin; Ranimycin; Relomycin; Repromicin; Rifabutin; Rifametane; Rifamexil; Rifamide; Rifampin; Rifapentine; Rifaximin; Rolitetracycline; Rolitetracycline Nitrate; Rosaramicin; Rosaramicin Butyrate; Rosaramicin Propionate; Rosaramicin Sodium Phosphate; Rosaramicin Stearate; Rosoxacin; Roxarsone; Roxithromycin; Sancycline; Sanfetrinem Sodium; Sarmoxicillin; Sarpicillin; Scopafungin; Sisomicin; Sisomicin Sulfate; Sparfloxacin; Spectinomycin Hydrochloride; Spiramycin; Stallimycin Hydrochloride; Steffimycin;

Streptomycin Sulfate; Streptonicozid; Sulfabenz; Sulfabenzamide; Sulfacetamide; Sulfacetamide Sodium; Sulfacytine; Sulfadiazine; Sulfadiazine Sodium; Sulfadoxine; Sulfalene; Sulfamerazine; Sulfameter; Sulfamethazine; Sulfamethizole; Sulfamethoxazole; Sulfamonomethoxine; Sulfamoxole; Sulfanilate Zinc; Sulfanitran; Sulfas alazine; Sulfasomizole; Sulfathiazole; Sulfazamet; Sulfisoxazole; Sulfisoxazole Acetyl; Sulfisoxazole Diolamine; Sulfomyxin; Sulopenem; Sultamicillin; Suncillin Sodium; Talampicillin Hydrochloride; Teicoplanin;

Temafloxacin Hydrochloride; Temocillin; Tetracycline; Tetracycline Hydrochloride; Tetracycline Phosphate Complex; Tetroxoprim; Thiamphenicol; Thiphencillin Potassium; Ticarcillin Cresyl Sodium; Ticarcillin Disodium; Ticarcillin Monosodium; Ticlatone; Tiodonium Chloride; Tobramycin; Tobramycin Sulfate; Tosufloxacin; Trimethoprim; Trimethoprim Sulfate; Trisulfapyrimidines; Troleandomycin; Trospectomycin Sulfate; Tyrothricin; Vancomycin; Vancomycin Hydrochloride; Virginiamycin; or Zorbamycin. Anti- mycobacterial agents may be without limitation Myambutol (Ethambutol Hydrochloride), Dapsone (4,4'- diaminodiphenylsulfone), Paser Granules (aminosalicylic acid granules), Priftin (rifapentine), Pyrazinamide, Isoniazid, Rifadin (Rifampin), Rifadin IV, Rifamate (Rifampin and Isoniazid), Rifater (Rifampin, Isoniazid, and Pyrazinamide), Streptomycin Sulfate or Trecator- SC (Ethionamide).

[0043] In some embodiments, other forms of drugs may be loaded into an interior volume of device 100, such as, but not limited to including, for instance, antineoplastic agents such as vincristine, vinblastine, vindesine, busulfan, chlorambucil, spiroplatin, cisplatin, carboplatin, methotrexate, adriamycin, mitomycin, bleomycin, cytosine arabinoside, arabinosyl adenine, mercaptopurine, mitotane, procarbazine, dactinomycin (antinomycin D), daunorubicin, doxorubicin hydrochloride, taxol, plicamycin, aminoglutethimide, estramustine, flutamide, leuprolide, megestrol acetate, tamoxifen, testolactone, trilostane, amsacrine (m-AMSA), asparaginase (Lasparaginase), etoposide, interferon a-2a and 2b, blood products such as hematoporphyrins or derivatives of the foregoing; biological response modifiers such as muramylpeptides; antifungal agents such as ketoconazole, nystatin, griseofulvin, flucytosine, miconazole or amphotericin B; hormones or hormone analogues such as growth hormone, melanocyte stimulating hormone, estradiol, beclomethasone dipropionate, betamethasone, cortisone acetate, dexamethasone, flunisolide, hydrocortisone, methylprednisolone, paramethasone acetate, prednisolone, prednisone, triamcinolone or fludrocortisone acetate; vitamins such as cyanocobalamin or retinoids; enzymes such as alkaline phosphatase or manganese superoxide dismutase; antiallergic agents such as amelexanox; anticoagulation agents such as warfarin, phenprocoumon or heparin; antithrombotic agents; circulatory drugs such as propranolol; metabolic potentiators such as glutathione; antituberculars such as p-aminosalicylic acid, isoniazid, capreomycin sulfate, cyclosexine, ethambutol, ethionamide, pyrazinamide, rifampin or streptomycin sulphate; antivirals such as acyclovir, amantadine, azidothymidine, ribavirin or vidarabine; blood vessel dilating agents such as diltiazem, nifedipine, verapamil, erythritol tetranitrate, isosorbide dinitrate, nitroglycerin or pentaerythritol tetranitrate; antibiotics such as dapsone, chloramphenicol, neomycin, cefaclor, cefadroxil, cephalexin, cephradine, erythromycin, clindamycin, lincomycin, amoxicillin, ampicillin, bacampicillin, carbenicillin, dicloxacillin, cyclacillin, picloxacillin, hetacillin, methicillin, nafcillin, penicillin or tetracycline; antiinflammatories such as diflunisal, ibuprofen, indomethacin, medefenamate, mefenamic acid, naproxen, phenylbutazone, piroxicam, tolmetin, aspirin or salicylates; antiprotozoans such as chloroquine, metronidazole, quinine or meglumine antimonate; antirheumatics such as penicillamine; narcotics such as paregoric; opiates such as codeine, morphine or opium; cardiac glycosides such as deslaneside, digitoxin, digoxin, digitalin or digitalis; neuromuscular blockers such as atracurium mesylate, gallamine triethiodide, hexafluorenium bromide, metocurine iodide, pancuronium bromide, succinylcholine chloride, tubocurarine chloride or vecuronium bromide; sedatives such as amobarbital, amobarbital sodium, apropbarbital, butabarbital sodium, chloral hydrate, ethchlorvynol, ethinamate, flurazepam hydrochloride, glutethimide, methotrimeprazine hydrochloride, methyprylon, midazolam hydrochloride, paraldehyde, pentobarbital, secobarbital sodium, talbutal, temazepam or triazolam; local anaesthetics such as bupivacaine, chloroprocaine, etidocaine, lidocaine, mepivacaine, procaine or tetracaine; general anaesthetics such as droperidol, etomidate, fentanyl citrate with droperidol, ketamine hydrochloride, methohexital sodium or thiopental and pharmaceutically acceptable salts (e.g. acid addition salts such as the hydrochloride or hydrobromide or base salts such as sodium, calcium or magnesium salts) or derivatives (e.g. acetates) thereof; and radiochemicals, e.g. comprising alpha-, beta-, or gamma-emitters such as, for instance 177Lu, 90Y or 1311.

[0044] In some aspects, the present invention may relate to the loading of drugs within device 100. In some embodiments device 100 is loaded with a single drug solution. In some embodiments, device 100 is loaded with one or more drug-containing solutions. In some embodiments, device 100 may be loaded with a bolus of antibiotic drug. In some aspects, the present invention may comprise encapsulating the drug in microspheres prior to loading into device 100. In some embodiments, device 100 is loaded with drug-filled microspheres and/or microbubbles. In some embodiments, device 100 is loaded with a suspension fluid and additional polymer pockets loaded with drug. In some embodiments, the drug contained in device 100 may be encapsulated in PLGA-PEG Microspheres, liposomes, PEGylated liposomes, copolymers, micelles, nanoparticles and/or carbon nanotubes (CNT). In some embodiments, the microspheres may comprise targeting ligands intended to direct the drug-loaded microspheres to specific targeted areas or features in the body. In some embodiments, the polymers used in device 100 may comprise surfactants to modify the drug encapsulation characteristics, rupturing characteristics and/or surface tension of the film pocket, rupturable film, microspheres, etc.

[0045] In some aspects, the present invention relates to cavitation nuclei loaded inside device 100 such that when exposed to ultrasound the cavitation nuclei may react to rupture the thin-film pocket and trigger the delivery of drug. In some embodiments, the ultrasonic exposure of device 100 may cause the microbubbles to cavitate and then collapse, causing a force as a result of acoustic pressure on polymer film 102, that ruptures polymer film 102, causing drug depot 104 to evacuate the loaded drug to the exterior of device 100 to an area of interest. In some embodiments, the cavitation nuclei comprise microbubbles of gas that are loaded into drug depot 104 of device 100. Tn other embodiments, the cavitation nuclei are nanodroplets. In some embodiments, the cavitation nuclei are pre-mixed with the drug to be loaded in device 100.

[0046] In some aspects, the present invention relates to the method of use for an ultrasound- mediated drug delivery device. In some examples, the invention comprises device 100 used with the following methods for spatio-temporal drug delivery applications. In some embodiments, the method comprises the steps of: forming the drug delivery pocket from at least one polymer film, filling the drug depot of the pocket with a drug and cavitation nuclei, sealing and/or closing the pouch, implanting and/or placing the formed device to a location of choice, and exposing the device to ultrasound.

[0047] In some aspects, the present invention relates to placing device 100 inside a human body for the intended use of spatio-temporal delivery of drug. In some embodiments, device 100 is intended for placement inside a surgical cavity prior to the closure of the surgical cavity. In some embodiments, device 100 is placed in a tumor resection cavity. In some embodiments, device 100 is intended for use in parenteral implantation applications. In some embodiments, device 100 is intended to be inserted subcutaneously via surgical means. In some embodiments, device 100 is placed at the desired location using a laparoscope. In some embodiments, device 100 is placed at the desired location in the alimentary canal using an endoscope. In some embodiments, device 100 is placed in the desired location in the GI tract using an endoscope.

[0048] In some aspects, the present invention relates to ultrasound, insonation and exposure of a device to ultrasound, insonation and ultrasound emitting devices. In some embodiments, ultrasound is used to create acoustic pressure within device 100 to rupture pocket 102 and cause the bulk release of drug to a local area. In some embodiments, an ultrasound emitting device is placed near device 100 filled with drug and microbubbles, thereby exposing device 100 to ultrasound waves and causing pocket 102 to rupture due to acoustic pressure and microbubble cavitation. This rupturing of pocket 102 causes the release of drug to a local area and/or target region within the body. In some embodiments, ultrasound is produced using a commercial-off- the-shelf ultrasound device as would be used in healthcare applications. In some embodiments, various ultrasound probes may be used to emit the necessary ultrasonic radiation including, but not limited to, linear probes, standard convex probes, micro convex probes, phased array probes. Although examples of commercially available ultrasound devices are provided, any ultrasound emitting device as would be known to someone of ordinary level of skill in the art may be used with device 100, causing ultrasonic waves to be applied to device 100.

[0049] In some aspects, the present invention relates to ultrasound regimes beyond those approved for diagnostic imaging. In some embodiments, device 100 is exposed to High-Intensity Focused Ultrasound (HIFU). In some embodiments, device 100 is exposed to Micro-Focused Ultrasound (MFU). Although these examples of ultrasound are provided, any form of ultrasound may be used as would be known by one of ordinary level of skill in the art.

[0050] In some aspects, the present invention relates to the ultrasound-triggered rupturing characteristics of device 100. In some embodiments, device 100 comprises a polymer film designed to rupture completely upon exposure with ultrasound. For example, device 100 may comprise a thin peripheral region of polymer film intended to primarily rupture upon ultrasound exposure. In some embodiments, device 100 comprises a polymer film designed to partially rupture upon ultrasound exposure. For example, device 100 may comprise thin windowed areas of polymer film that are intended to primarily rupture upon ultrasound exposure, leaving areas of the polymer film intact, and potentially causing a suppressed release of drug from the interior volume to the targeted region. In some embodiments, the polymer film may comprise small perforations intended to cleave upon ultrasound exposure, causing a slow release of drug through the said perforations. For example, holes or other features may be debossed in the polymer film such that the polymer film cleaves at these locations upon ultrasound exposure.

[0051] In some embodiments, the ultrasound-triggered drug delivery device is configured to provide an immediate and complete release of drug upon activation. In some embodiments, the ultrasound-triggered drug delivery device is configured to provide zero-order release drug delivery kinetics.

[0052] In some embodiments, the ultrasound-triggered drug delivery device is configured to provide a sustained drug delivery release kinetic for a duration of time. The duration of time may or may not be the same as the duration of the insonation period. For example, the duration of time, upon US triggering of the device, may have a duration of, but not limited to, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days or about 14 days. In some embodiments, the duration is less than 14 days. In some embodiments, the duration is greater than 1 hour. In some embodiments, the duration ranges from 2 hours to 13 days. In some embodiments, the duration ranges from 12 hours to 12 days. In some embodiments, the duration ranges from 24 hours to 10 days. In some embodiments, the duration ranges from 2 days to 8 days. In some embodiments, the duration ranges from 3 days to 7 days. In some embodiments, the duration ranges from 4 days to 6 days.

[0053] In some aspects, the present invention relates to the insonation period for triggering the ultrasound-triggered drug delivery device. The insonation period is the amount of time device 100 is exposed to ultrasound. In some embodiments, the insonation period is about 1 min, 2 min, 3 min, 4 min, 5 min, 6 min, 7 min, 8 min, 9 min, 10 min, 11 min, 12 min, 13 min, 14 min, 15 min, 16 min, 17 min, 18 min, 19 min, 20 min, 21 min, 22 min, 23 min, 24 min, 25 min, 26 min, 27 min, 28 min, 29 min, 30 min, 31 min, 32 min, 33 min, 34 min, 35 min, 36 min, 37 min, 38 min, 39 min or about 40 min. Although example insonation periods are given, the period of time required to rupture device 100 may be correlated to the size of the device, the amount of drug loaded in the device, the thickness of the polymer films and/or other drug delivery features of device 100.

[0054] In some embodiments, the ultrasound-triggered drug delivery device is configured to provide a first-order drug release kinetic with a primary release of drug followed by an extended taper for a period of time.

[0055] Aspects of the present invention relate to a drug delivery device comprising a film formed into a shape and sealed with a sealing agent. For example, the device may comprise a polylactic acid (PLA) thin film, formed into a conical shape, and sealed using a cyanoacrylate glue.

[0056] In some embodiments, the thin film is a PLA film made by solvent casting; dissolving PLA pellets in chloroform, dichloromethane, acetonitrile, or other solvent(s), including a mixture of solvents. In some embodiments, the terms solvent casting and casting solution may be used interchangeably. In some embodiments, the thin film is made by 3D printing, Fused Filament Fabrication (FFF), and the like. In some embodiments, the thin film is produced by any method as would be known to one of ordinary skill in the art. In some embodiments, the PLA may or may not be medical grade, but it is advantageous that natural PLA without any dyes, additives, preservatives is used, e.g. natural, colorless PLA for 3D printing. It is to be noted that if the PLA is not in the shape of pellets, such as with a 3D-printing fdament, it is important to cut the PLA into smaller pieces for easier dissolution in the chloroform. In some embodiments, the chloroform is placed in a glass beaker with a stir bar and placed on the stir plate. The stir can be gentle, a setting of 2-3, only enough to create a vortex in the liquid. In some embodiments, following the creation of a vortex, the PLA pellets can be added. The pellets dissolve within a few minutes. It is important to not add a large amount of pellets at once (the definition of large changes depending on the volume of the beaker and volume of chloroform added), because the PLA pellets can form a ball of PLA that becomes harder to dissolve. As the PLA dissolves, the solution becomes a little thicker. In some embodiments, while the PLA is dissolving, the beaker should be covered with aluminum foil to minimize chloroform evaporation. Once all the PLA is dissolved, the beaker is removed from the stir plate and the stir bar is held on one side with a magnetic wand. Next, the PLA solution is poured onto a surface.

[0057] The PLA solution on the surface will form a fdm due to the evaporation of chloroform. This surface can be many things, but a good option is a nonstick pan. This will make sure the PLA film is easy to peel after drying and also contain the solution while it is liquid. The film starts drying right away, but for complete dryness, it is best to leave the film in the fume hood for a few hours or overnight; even a few days, sometimes removing the film from the pan to expose both sides of the film to air.

[0058] Once dry, the film can be easily removed from the pan with a spatula, a pair of tweezers, or by hand. Next step involves turning a piece of film, or a few pieces of film, into a ‘pocket’. The film, while not completely dry, can be folded onto itself or combined with other PLA/polymer films, as it will have an inherent “stickiness” and will self-seal. If the film is dry, cyanoacrylate, or ‘super glue’, can be used to bring the film pieces together. Cyanoacrylate has been used in animals and humans, with caution, due to dose-dependent concerns of toxicity. Other glues may be used; cyanoacrylate is a good option because it dries quickly, does not need a catalyst such as UV light or heat, and can be applied in varying amounts and methods. The glue is best applied with a brush. There are multiple ways of putting together this pocket, including different shapes and sizes. The PLA film can also be made for different thicknesses by changing the amount of PLA in solution (a starting point is 1.5 g PLA in 30 mL chloroform). Described below is one way of putting together the pocket:

[0059] Aspects of the present invention relate to the formulation and casting of thin films with varying thicknesses. In some examples, a combination of PLA and chloroform is used to formulate thin PLA films used to create the pocket of the drug delivery device. In some embodiments, PLA films are created having two different thicknesses using varying amounts of PLA in chloroform, e.g. 5 g PLA in 70 mL chloroform and 1.2 g PLA in 30 mL chloroform. The PLA chloroform ratio may vary; however, it should be noted that if too much PLA is added to too little chloroform (e.g. 5 g in 30 mL) the solution may become too viscous, which affects the casting step of the film. As a result of the mixtures, the 5 g and 1.2 g films when cast are of different thickness. For the thin film, it is important to have a thicker edge that can be used for maintaining integrity of the seal. For example, if glue is used for part of the construction, a thick “donut” shaped film may be adhered to the thin film while the thin film is drying. Likewise, the thin film may be cut and folded along the edges onto itself, to create the thick edge. In some embodiments, the device comprises circular shapes of varying thicknesses formed into a pocket.

[0060] In one example, two circles are cut out of these films, the circle on the thin film has a radius of 4 cm and the radius on the thick film has a radius of 6 cm. Now referring to Figure 7, in this example, the thicker circle will become the “bottom” or “base” part of this pocket, and can be formed into a cone shape. Slits can be cut in the base layer about 0.5 cm in from the edge to help flatten the disc. The cone shape is created by folding the film onto itself at an angle of approximately 30°-45°. This creates enough depth/space to load the drug solution. In this example, the thin film stays flat. The glue can be brushed along the edges of the thick film cone, approximately 0.5 cm wide. Alternatively, the thick edge of the thin film circle can be brushed with glue, except for a 1.0 cm gap where the drug solution will be added. The thick cone is placed on top of the thin film after centering the two pieces. The edges of the two film circles are pressed together firmly and held for 30 seconds. The glue is left to dry for 10 minutes. Then, the seal is tested by adding some drug solution first. If no leakage is detected, then the rest of the drug solution and the microbubbles are added. [0061 ] Now referring to Figure 8, the drug solution (e g., antibiotics like vancomycin) + microbubbles (e.g. Sonazoid; GE Healthcare, Oslo, Norway, reconstituted) may be loaded into the pocket during the assembly phase or after assembly is complete. Once assembled, the drug + bubbles can be injected into the pocket from the base or pocket side, and the hole sealed with glue and a piece of thick film. In some embodiments, the thick film is about 0.3 cm x 0.3 cm and is used to patch the hole at the drug loading opening 106. The pocket is sealed when most the drug is loaded, by brushing glue in the open edge of the circle and pressing the films together. Then, the pocket is laid against an upright surface. There will be an air bubble at the top. With a syringe needle, inject some more drug into the pocket, entering on the thick side of the film at the top, aiming at the bubble. Once the pocket is full, remove the syringe, apply glue and seal the hole by patching a small piece of thick film. Alternatively, the entire pocket may be assembled first and the entire drug and microbubble solution may be added by injection, and then the injection site sealed; as described.

[0062] In another example, the seal on the film is formed through pressing the thin film pieces together while the film is still sticky or tacky. Finally, the thin film can be used to fit a pocket that is either molded or fused filament fabricated to a specific geometry suitable for a surgical site. Final sealing after drug addition can be through application of solvent or through use of glue.

[0063] To test the patency of the sealing process, the loaded PLA film pocket can be submerged in a plastic tray containing water. The pocket can be visualized by ultrasound imaging, either in B-mode or a contrast-specific imaging mode.

EXPERIMENTAL EXAMPLES

[0064] The invention is further described in detail by reference to the following experimental examples. These examples are provided for purposes of illustration only, and are not intended to be limiting unless otherwise specified. Thus, the invention should in no way be construed as being limited to the following examples, but rather, should be construed to encompass any and all variations which become evident as a result of the teaching provided herein. [0065] Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the system and method of the present invention. The following working examples therefore, specifically point out the exemplary embodiments of the present invention, and are not to be construed as limiting in any way the remainder of the disclosure.

Example 1 : In Vitro US-Triggered Drug Release from Polymer Film Pocket

[0066] Infection after spinal fusion surgery occurs in up to 16% of cases, prolonging hospital stays and increasing healthcare costs. We have designed an antibacterial drug reservoir to remain stable 3-5 days after surgery with subsequent US-triggered drug delivery (UTDD). We tested rupture capabilities as a function of cavitational nuclei, material properties, and acoustics.

[0067] Polylactic acid (PLA) pockets with one rupturable film (0.5-1.2 g PLA) and one foundational film (3 g PLA) encompassing a ~3 mL internal reservoir were assembled. Pockets were loaded with cavitational nuclei, either 1-1.5 mL of Sonazoid microbubbles or 2-2.8 mL of nanodroplets derived from Definity microbubbles (Lantheus, N Billerica, MA) and MeB solution as the surrogate drug.

[0068] Pockets were submerged in a water bath (Fig. 9) with either clinical US or High Intensity Focused Ultrasound (HIFU). Clinical US used a S50 scanner (SonoScape, Shenzhen, China) with a curvilinear Cl -6 probe for 20 min of Power Doppler imaging (2.2 MHz, highest line density, 100% power) followed by 10 min of flash replenishment imaging (3.0 MHz harmonic imaging at 100% power every 4 seconds). HIFU involved 20 min of insonation (2.0 MHz at 4V with 50% duty cycle) using an SU-101 probe (Sonic Concepts, Bothell, Washington) run by a 8116A pulse generator (Hewlett Packard, Palo Alto, CA) with 50 dB amplification.

[0069] Three groups were compared using Fisher’s exact test (Stata 15; StataCorp, College Station, TX): film thickness (0.5 g PLA for rupturable film vs >0.5 g), type of US (clinical vs HIFU), and cavitational agent (microbubbles vs nanodroplets).

[0070] In all, 24 pockets were created. The thickness of the PLA films were 23 ± 5 pm (0.5 g films) and 61 ± 10 pm (1.0 g films). Six out of 24 sealed and insonated pockets were ruptured successfully (Fig. 10). 8 pockets contained nanodroplets and 16 contained Sonazoid bubbles, out of which 3 in each group ruptured (p > 0.35). 8 pockets were insonated with HIFU and 16 with clinical US; again, 3 ruptured in each group (p > 0.35). The thickness of the rupturable film did not make a difference as 4 of 16 thin and 2 of 8 thick films were successfully ruptured.

[0071] The feasibility of assembling a drug-loaded pocket using a biodegradable polymer film and achieving UTDD with internal cavitation nuclei was established. Using nanodroplets and applying HIFU were more successful for UTDD, even though the results did not reach statistical significance in this small sample size.

[0072] There is a need for better infection control in spinal implant surgery. A tunable, flexible UTDD system for targeted, noninvasive local drug delivery that would be applicable to many kinds of implant surgeries for post-surgical infection prophylaxis was designed and tested.

Example 2: In vivo experiments with PLA film pockets

[0073] A pilot animal study was conducted to test feasibility and efficacy of ultrasound (US) controlled drug delivery from PLA film pockets. Five (5) rabbits were used for the in vivo pocket experiments. Rabbits 1, 2 and 5 used neat PLA, while rabbits 3 & 4 used PLA-Van for the thin layer. Rabbit 1 : 4 pockets; Rabbit 2: 4 pockets; Rabbit 3: 4 pockets; Rabbit 4: 3 pockets; Rabbit 5: 2 pockets.

[0074] For each animal, up to 4 methylene blue-loaded, PLA pockets were placed subcutaneously in the back; 2 per side. The dimensions of the pockets used were no more than a diameter of 4 cm and a height of 2 cm. All animals received analgesia for 3 days after surgery, and thereafter as needed. The animals were allowed to ambulate in their cages post implantation. The rabbits were split into two groups (a control group and an active group). After 3 days of recovery, animals in the active group were placed under anesthesia and each of their PLA pockets were insonified with ultrasound for 30 minutes using an S50 clinical, ultrasound scanner (Sonoscape, Shenzhen, China). At the end of the study (after 6 days), animals were euthanized and pockets removed. The sites were monitored from implantation through removal for methylene blue leak or release. 1 Table 1: Control Experiments

[0075] Six out of ten (6/10) control pockets demonstrated early leak (within 1 hour of insertion) and all (10/10) pockets showed leakage by Day 4. Three (3) of the late-leak pockets were still intact as of Day 3 (2 of these pockets were neat PLA), one (1) of the late-leak pockets leaked sometimes between the early hours and Day 3.

[0076] Four out of six (4/6) Neat PLA and 2/4 PLA-Van control pockets demonstrated early leak.

Table 2: Active (US) Experiments

[0077] All the active pockets achieved US-triggered MeB release, and none of the pockets had MeB leak prior to insonation. Photoacoustic imaging was also conducted.

[0078] The rabbit in vivo studies showed that the current design had varying degrees of stability, since 6/10 pockets started to release the enclosed dye before the 3 day waiting period. There was not a noticeable difference between neat PLA and PLA-Van pockets (4/6 and 2/4 demonstrated leakage, respectively). The active US experiments, on the other hand, all (5/5) achieved US- controlled drug release. While the control arm indicated limited stability, all 5 of the pockets that underwent insonation survived that 3 day period. Overall, the limited release could be used for limited prophylaxis followed by a burst release with insonation.

Example 3: In Vitro Ultrasound-Triggered Drug Release from a Polydactic acid) Film Pocket with Embedded Vancomycin Powder

[0079] Infection after spinal fusion surgery occurs in up to 16% of cases, prolonging hospital stays and increasing healthcare costs. Antibiotic prophylaxis, both systemic and local, is an important way to fight infections before they can establish. Biofilm formation is a particularly intractable problem for implants, emphasizing the need for prophylaxis. Many surgeons place 1- 2 g of Vancomycin (VAN) after spinal surgery with implants, yet infections still occur. This may be due to the VAN being depleted over the course of a few days. There is an urgent need for a more effective local prophylaxis method. Proposed is a novel drug reservoir, a poly(lactic acid) (PLA) film pocket, which would be stable until it underwent ultrasound-triggered drug delivery (UTDD) after a period of time (e.g., 3-5 days) after surgery. Such a reservoir could be combined with VAN powder during spinal surgery to prolong prophylaxis duration, or be used elsewhere in the body where delayed, spatially and temporally controlled drug delivery may be beneficial. It was previously shown that the UTDD capacity of this pocket did not change as a function of cavitational nuclei, material properties (i.e., thickness of film), and acoustics. Disclosed herein, the UTDD capacity of the disclosed pocket design is further investigated according to the presence of salt (i.e., VAN powder) in the rupturable film.

[0080] PLA films were cast by dissolving PLA pellets in chloroform and casting and drying on a non-stick surface. Pockets with one rupturable film (0.5-1.2 g PLA) and one foundational film (3-5 g PLA) encompassing a ~3 mL internal reservoir were assembled. To increase the likelihood of rupture, 20-50 mg VAN powder (Athenex, Buffalo, NY) was added to the PLA- chloroform mixture before the rupturable film was cast. Pockets with and without VAN were loaded with methylene blue (MeB, as the surrogate drug; Sigma Aldrich, St. Louis, MO) solution in water or phosphate buffered saline (PBS) and cavitational nuclei, 1-1.5 mL of Sonazoid microbubbles (GE Healthcare, Oslo, Norway) or 2-3 mL of nanodroplets derived from Definity microbubbles (Lantheus, N Billerica, MA).

[0081] Pockets were submerged in a water bath and insonated with either clinical ultrasound or high intensity focused ultrasound (HIFU). The former used an S50 scanner (SonoScape, Shenzhen, China) with a curvilinear Cl -6 probe for 20 min of Power Doppler imaging (2.2 MHz, highest line density, 100% power) followed by 10 min of flash replenishment imaging (3.0 MHz harmonic imaging at 100% power every 4 seconds). HIFU involved 20 min of insonation (2.0 MHz at 4 V with 50% duty cycle) using an SU-101 probe (Sonic Concepts, Bothell, WA) run by a 8116A pulse generator (Hewlett Packard, Palo Alto, CA) with 50 dB amplification. Pocket rupture was noted and compared based on whether the PLA film included embedded VAN or not. Additionally, mechanical analysis was performed for films made from 0.5 g PLA, with or without embedded VAN powder, using ElectroForce 3200 Series III (TA Instruments, New Castle, DE). Results were compared with Fisher’s exact and Mann-Whitney U tests using Prism 9 (GraphPad Software, San Diego, CA; a<0.05).

[0082] In total, 39 pockets were created and tested for UTDD. Four (4) out of the 5 pockets (80%) that contained a rupturable film with embedded VAN were ruptured successfully as indicated by marked MeB visualization in the water bath. Out of the 34 pockets that were made with a rupturable film without the VAN, 6 (18 %) achieved ultrasound-triggered rupture, which was significantly lower than for the VAN pockets (p = 0.011).

[0083] Eight (8) pieces of film made from 0.5 g PLA underwent mechanical analysis; 3 films made of PLA only and 5 made with VAN powder in the PLA solution. For all samples, gauge length and the width of sample were both 0.5 cm. The thickness of the films was 21.3 ± 6.7 pm for PLA-only samples and 66.0 ± 32.5 pm for PLA-VAN samples; VAN does not dissolve in chloroform and remains as a salt while embedded in the film, which explains the large variation in the thickness of PLA-VAN films. Stress versus strain curves were plotted for each sample, and toughness was calculated via the area under the curve. For PLA-only films the toughness was 2.57 ± 0.63 J/mm3, while for PLA-VAN films the toughness was 0.65 ± 0.20 J/mm3 (p = 0.036). [0084] A tunable, flexible UTDD system for targeted, noninvasive drug delivery was designed and tested as a function of VAN presence in the polymer-solvent solution. VAN addition causes flakes in the PLA film, which it was speculated results in porosity or weak points in the thin polymer film; these heterogeneities facilitate ultrasound-triggered rupture. Indeed, the increase in VAN film rupture (80% vs 18%; p = 0.011) supports this hypothesis. Toughness from the stressstrain curves demonstrate the amount of energy required before a material fails. It was hypothesized that the lower toughness may be easier to rupture, and this is indeed the case in the current study, where the toughness for PLA-VAN films is lower than PLA-only films, and the films are otherwise identical (p = 0.036). These results match the pocket rupture results. Finally, VAN’s presence in the film surface might confer some antimicrobial effects, although the primary benefit of the VAN would be for facilitating UTDD.

[0085] The feasibility of engineering a drug- and cavitation nuclei-loaded polymer pocket for UTDD has been demonstrated. Including VAN powder in the PLA films appears to improve film rupture and UTDD success.

Example 4: Polyflactic acid) film pocket for ultrasound-controlled prophylaxis against spinal infections: in vitro evaluations

[0086] Infection after spinal implant surgery occurs in up to 21% of the cases; a devastating complication given the need for continuous spinal stability. There is a need for more effective antibiotic prophylaxis. A poly(lactic acid) (PLA) film pocket has been designed for delayed local delivery of prophylactic antibiotics and was evaluated in vitro.

[0087] PLA pockets with one rupturable film (0.5-1.2 g PLA) and one foundational film (3-5 g PLA) encompassing a ~3mL internal reservoir were assembled. To increase the likelihood of rupture, 10-50 mg of Vancomycin (VAN) powder (Athenex) was incorporated into the PLA films. Pockets were loaded with methylene blue (MeB; Sigma Aldrich) solution and cavitational nuclei, 0.6-1.5 mL of Sonazoid microbubbles (GE Healthcare) or 2-3 mL of nanodroplets derived from Definity microbubbles (Lantheus). Pockets were submerged in a water bath and insonated with either clinical ultrasound using an S50 scanner (SonoScape) with a curvilinear Cl -6 probe or high intensity focused ultrasound (HIFU) using an SU-101 probe (Sonic Concepts). Pocket rupture was compared for PLA films with embedded VAN vs no VAN. [0088] 53 pockets were tested for ultrasound-triggered rupture. Eleven out of the 13 pockets (85%) containing a film with VAN ruptured successfully as indicated by marked MeB release. Of the 40 pockets made with a film without VAN, 9 (23%) achieved rupture, which was significantly lower than for the VAN pockets (p=0.0001).

[0089] Results demonstrate the ability to use a pocket made of VAN-embedded PLA film for ultrasound-triggered drug delivery.

[0090] The following publications are hereby incorporated by reference in their entireties:

[0091] S. Isguven, L. J. Delaney, H. Falatah, R. Tomlinson, N. J. Hickok, F. Forsberg. In vitro ultrasound-triggered drug release from a poly(lactic acid) film pocket with embedded Vancomycin powder. J Ultrasound Med, vol 42(Suppl 1), pp. S17 - S18, 2023.

[0092] Isguven S, Delaney LJ, Falatah H, Tomlinson RE, Hickok NJ, Forsberg F. In Vitro Ultrasound-Triggered Drug Release from a Poly(lactic acid) Film Pocket with Embedded Vancomycin Powder. AIUM, Orlando, FL, 2023

[0093] F. Forsberg, S. Isguven, L. J. Delaney, H. Falatah, N. J. Hickok. Poly(lactic acid) film pocket for ultrasound-controlled prophylaxis against spinal infections: in vitro evaluations. Proc Euroson, pp. 209, 2023.

[0094] The disclosures of each and every patent, patent application, and publication cited herein are hereby incorporated herein by reference in their entirety. While this invention has been disclosed with reference to specific embodiments, it is apparent that other embodiments and variations of this invention may be devised by others skilled in the art without departing from the true spirit and scope of the invention. The appended claims are intended to be construed to include all such embodiments and equivalent variations.

Claims

CLAIMS What is claimed is:

1. A drug delivery device comprising: a pocket comprising first and second outer surface portions surrounding a closed interior volume; the first outer surface portion having a thickness greater than the second outer surface portion; and a quantity of cavitation nuclei positioned in the closed interior volume configured to rupture when exposed to acoustic pressure, breaking the second outer surface portion and releasing a quantity of a drug from the closed interior volume.

2. The device of claim 1, the pocket comprising a biodegradable polymer.

3. The device of claim 1, the pocket comprising a mixture of biodegradable polymers.

4. The device of claim 1, the pocket comprising a polylactic polymer film.

5. The device of claim 1 , the pocket comprising a polycitrate polymer film.

6. The device of claim 1, the pocket comprising a poly caprolactone film.

7. The device of any preceding claim, wherein the pocket comprises a mixture of the said material and an insoluble salt.

8. The device of claim 7, wherein the insoluble salt is vancomycin HCL.

9. The device of any preceding claim, wherein the pocket is sealed with a sealing agent.

10. The device of claim 9, wherein the sealing agent is cyanoacrylate glue.

11 . The device of any preceding claim, wherein the closed interior volume contains antibiotics.

12. The device of any preceding claim, wherein the cavitation nuclei are microbubbles.

13. The device of any preceding claim, wherein the pocket is configured to be inserted into a surgical site after a procedure.

14. A method of making a biodegradable film pocket, comprising the steps of forming a first outer surface portion having a first thickness from a sheet of a biodegradable film; forming a second outer surface portion having a second thickness less than the first thickness; combining the first and second outer surfaces into a pocket; inserting a quantity of cavitation nuclei and a quantity of drugs into the pocket; and sealing the first and second outer surfaces together with an adhesive thereby closing the pocket.

15. The method of claim 14, wherein the biodegradable film comprises polylactic acid.

16. The method of claim 14, wherein the biodegradable film comprises polycitrate.

17. The method of claim 14, wherein the biodegradable film comprises polycaprolactone.

18. The method of claim 14, wherein the adhesive is cyanoacrylate.

19. The method of claim 14, further comprising the step of inserting a quantity of a drug into the pocket.

20. The method of claim 19, wherein the drug is an antibiotic.

21 . The method of claim 14, wherein the cavitation nuclei are microbubbles.

22. A method of releasing a quantity of a drug into a subject, comprising the steps of: providing a pocket comprising first and second outer surface portions surrounding an interior volume and a plurality of cavitation nuclei positioned in the closed interior volume, the first outer surface portion having a thickness greater than the second outer surface portion; loading a quantity of a drug into the interior volume; sealing the interior volume; implanting the pocket into a subject; and rupturing the cavitation nuclei by exposing the pocket to ultrasound, thereby rupturing the second outer surface portion and releasing at least a portion of the quantity of the drug into the subject.