Medical devices for local bioactive delivery

Medical devices for local bioactive delivery are described. A medical device includes a first biodegradable layer, a second biodegradable layer, and a bioactive disposed between the first and second biodegradable layers. The first and second biodegradable layers are positioned such that a surface of the first biodegradable layer faces a surface of the second biodegradable layer and such that a peripheral portion of one biodegradable layer is folded over a peripheral portion of the other biodegradable layer. Methods of making medical devices and methods of using medical devices are also described.

FIELD

The disclosure relates generally to the field of medical devices. More particularly, the disclosure relates to the field of medical devices suitable for use in delivery of a bioactive agent to a point of treatment in or on the body of an animal, such as a human being, and methods of making such medical devices.

BACKGROUND

Cancer is a leading cause of death worldwide. Current treatments for many cancers include systemic administration of bioactive agents that have negative side effects and that can have significant impact on a patient's quality of life. Local delivery of bioactive agents directly to a point of treatment may provide a route of administration that avoids the side effects and quality of life implications associated with systemic delivery of cancer treatment agents and other bioactive agents. The art does not provide, however, suitable medical devices for achieving suitable local dosages while avoiding systemic spread of the bioactive agent.

A need exists, therefore, for improved medical devices for delivering a bioactive to a point of treatment, and for methods of making and using such medical devices.

BRIEF SUMMARY OF SELECTED EXAMPLES

Several medical devices are described and illustrated herein. An example medical device comprises a first biodegradable layer having a first peripheral edge, first and second opposing surfaces, and a first peripheral portion including portions of the first and second opposing surfaces and a portion of the first peripheral edge, the first layer having a first area; a second biodegradable layer having a second peripheral edge, third and fourth opposing surfaces, and a second peripheral portion including portions of the third and fourth opposing surfaces and a portion of the second peripheral edge, the second layer having a second area that is less than the first area; the first and second biodegradable layers positioned such that the second surface faces the third surface; the first peripheral portion folded over the second peripheral portion such that a portion of the second surface contacts a portion of the fourth surface; and a bioactive disposed between the first and second biodegradable layers.

Another example medical device comprises a first biodegradable layer having a first peripheral edge, first and second opposing surfaces, and a first peripheral portion including portions of the first and second opposing surfaces and the entire first peripheral edge, the first layer having a first area; a second biodegradable layer having a second peripheral edge, third and fourth opposing surfaces, and a second peripheral portion including portions of the third and fourth opposing surfaces and the entire second peripheral edge, the second layer having a second area that is less than the first area; the first and second biodegradable layers positioned such that the second surface faces the third surface; the first peripheral portion folded over the second peripheral portion such that a portion of the second surface contacts a portion of the fourth surface; and a bioactive disposed between the first and second layers.

Another example medical device comprises a first biodegradable layer having a first peripheral edge, first and second opposing surfaces, and a first peripheral portion including portions of the first and second opposing surfaces and the entire first peripheral edge, the first layer having a first area; a second biodegradable layer having a second peripheral edge, third and fourth opposing surfaces, and a second peripheral portion including portions of the third and fourth opposing surfaces and the entire second peripheral edge, the second layer having a second area that is less than the first area; the first and second biodegradable layers positioned such that the second surface contacts the third surface; the first peripheral portion folded over the second peripheral portion such that a portion of the second surface contacts a portion of the fourth surface; and a bioactive disposed between the first and second layers, the bioactive comprising a powder.

Several methods of making a medical device are described and illustrated herein. An example method comprises disposing a bioactive onto a first biodegradable layer; disposing a second biodegradable layer onto the bioactive and first biodegradable layer; and securing the first and second biodegradable layers to each other. One optional step comprises forming a triple laminate structure on the periphery of the first and second biodegradable layers.

Additional understanding of the claimed medical devices and methods can be obtained by reviewing the description of selected examples, below, with reference to the appended drawings.

DETAILED DESCRIPTION OF SELECTED EXAMPLES

The following detailed description and appended drawings describe and illustrate various examples of the invention. The description and drawings serve to enable one skilled in the art to make and use the inventive medical devices and methods; they are not intended to limit the scope of the invention or the protection sought in any manner. The invention is capable of being practiced or carried out in various ways; the examples described herein are exemplary in nature and are not exhaustive. As such, the language used in the description of examples is to be given the broadest possible scope and meaning.

Relevant background information is available in U.S. Pat. No. 8,658,196 to Janis on Feb. 25, 2014 for “GRAFT MATERIALS AND METHODS FOR STAGED DELIVERY OF BIOACTIVE COMPONENTS” and United States Published Application No. 2014/0180398 to Milner et al. for “BIOABSORBABLE MEDICAL DEVICES AND METHODS OF USE THEREOF”, the contents of which are expressly incorporated into this disclosure in their entirety.

The following definitions are used throughout the disclosure: the term ‘bioactive’ and grammatically related terms refer to a substance that has a biological effect in an animal.

FIGS. 1 through 3illustrate a first example medical device100. The medical device100comprises first110and second112layers and a bioactive114. The bioactive114is disposed between the first110and second112layers, effectively creating a sandwich structure. As described in detail below, the bioactive114can comprise a layer disposed between the first110and second112layers, or can comprise a solution or other form that is initially disposed between the first110and second112layers and that diffuses into the material of one or both of the layers110,112.

As described in detail below, the medical device100can be used as a temporary bioactive delivery device that degrades after a period of time. Accordingly, each of the first110and second112layers is formed of a biodegradable material. The layers110,112can be formed of the same or different materials.

Any suitable biodegradable material can be used for the layers, and a skilled artisan will be able to select one or more suitable biodegradable materials for use in a particular medical device based on various considerations, including any desired size and/or configuration of the medical device, any desired directional release of the bioactive in the medical device, and any desired degradation timeline for the medical device. Example of suitable biodegradable materials for use in the first and second layers of medical devices according to embodiments include, but are not limited to, polyglycolic acid, polylactide, poly(dioxanone), poly(trimethylene carbonate) copolymers, and poly (ϵ-caprolactone) homopolymers and copolymers, polyanhydrides, polyorthoesters, polyphosphazenes, and other biodegradable polymers. Cellulose materials are also considered suitable.

The inventors have determined that carboxymethyl cellulose (CMC) is particularly well-suited for use in one or both layers of a medical device according to an embodiment at least because of its well-characterized nature. Hydroxylpropyl methyl cellulose (HMC) is also considered particularly well-suited for use in the inventive medical devices at least because of its well-characterized nature.

For medical devices in which the first and second layers are formed of different biodegradable materials, a skilled artisan will be able to select two suitable biodegradable materials for use in a particular medical device based on various considerations. For example, if a desired directional release of the bioactive in the medical device is desired, a first biodegradable material that degrades relatively quickly in vivo can be used as the first layer in the medical device and a second biodegradable material that degrades relatively slowly in vivo can be used as the second layer in the medical device. In a medical device having such a pair of layers, the first layer will degrade relatively quickly, resulting in release of the bioactive to the surrounding tissue at the point of treatment, while the second layer will degrade relatively slowly, effectively providing a barrier to release of the bioactive and conferring directionality onto the medical device.

The medical devices can have any suitable size, shape and configuration. Likewise, each of the layers in a particular medical device can have any suitable size, shape and configuration. A skilled artisan will be able to select an overall size, shape and configuration for a medical device according to a particular embodiment based on various considerations, including spatial properties of the point of treatment at which the medical device is intended to be used. Similarly, a skilled artisan will be able to select an overall size, shape and configuration for each of the layers in a medical device according to a particular embodiment based on various considerations, including the desired overall size, shape and configuration of the medical device and the size, shape and configuration of the other layer in the medical device.

Each of the layers in a medical device according to a particular embodiment can have any suitable thickness extending between the first and second surfaces, such as surfaces110aand110bfor the first layer in the medical device110illustrated inFIGS. 1 through 3. Furthermore, in a particular medical device, the layers can have the same or different thicknesses. A skilled artisan will be able to select suitable thicknesses for each of the layers in a medical device according to a particular embodiment based on various considerations, including the bioactive or bioactives in the medical device, the nature of the material of which the layer is made, any desired release profile and/or dynamics for the bioactive or bioactives, and the spatial configuration of the point of treatment at which the medical device is intended to be used. Indeed, each layer in a medical device according to a particular embodiment can comprise a sheet, a film, or a thin film.

Each of the layers110,112is advantageously flexible and capable of being physically manipulated, e.g., bent, curved, folded, twisted, etc., by hand. Having both layers110,112have these properties allows a user to physically manipulate the medical device100at the time of treatment to accommodate any physical constraints or features of a particular point of treatment to achieve the desired localized delivery of the bioactive114.

In the medical device100illustrated inFIGS. 1 through 3, the first layer110has a first surface110aand a second surface110b. Similarly, the second layer112has a first surface112aand a second surface112b. The first layer110is rectangular in shape. The second layer112has a rectangular main portion116and first118and second120tabs extending from the main portion116. The first tab118has a first lateral edge122that is continuous with an adjacent lateral edge124of the rectangular portion116and a second lateral edge126that is not continuous with an adjacent lateral edge128of the rectangular portion116. Similarly, the second tab120has a first lateral edge130that is continuous with an adjacent lateral edge132of the main portion116and a second lateral edge134that is not continuous with an adjacent lateral edge (not visible in the Figures) of the main portion116. In the illustrated embodiment, each of the second lateral edge126of the first tab118and the second lateral edge134of the second tab120extends at a non-orthogonal angle to the respective adjacent edge of the main portion116. This allows the second lateral edges126,134to be disposed adjacent and in continuous contact with each other when the tabs118,120are folded onto the first layer110, as best illustrated inFIG. 1and described in detail below.

As best illustrated inFIG. 3, the first surface112aof the second layer112is larger than the second surface110bof the first layer110. This configuration allows the first layer110to be placed substantially onto the main portion116of the second layer112, represented by arrow A inFIG. 3, leaving the tabs118,120substantially free of the first layer until the tabs118,120are folded over peripheral portions of the first layer110, as indicated by the arrows B and C inFIG. 3. This manipulation of the layers110,112and tabs118,120produces the final device structure illustrated inFIGS. 1 and 2. In the final structure, the tabs118,120are folded over the first layer110such that portions of the first surface112aof the first layer112, the portions on the tabs118,120, are disposed adjacent and in contact with portions of the first surface110aof the first layer110.

As best illustrated inFIG. 1, this structural configuration provides a triple laminate structure150for two continuous edges152,154of the medical device110. This structure is considered advantageous at least because it can provide lateral directionality to the release of the bioactive114, particularly when the second layer112is formed of a material that degrades relatively more slowly than the material of the first layer110. Furthermore, the triple laminate structure150provides a visual and tactile indicator that conveys information to a user of the medical device about any lateral directionality of the release profile of the medical device100. Also, as the medical device is well-suited for gross physical manipulation at a point of treatment, such as hand manipulation to conform to a tissue, cavity or space, the triple laminate structure confers a physical feature onto the medical device110that can facilitate handling and manipulation. This can be particularly advantageous for handling and manipulation of the medical device100because the user of the device is expected to be donning examination and/or surgical gloves at the time of use.

The bioactive used in a particular method can comprise a single bioactive, two bioactives, or a plurality of bioactives. When more than one bioactive is used, the bioactives can be mixed prior to being disposed on another component of the medical device according to an embodiment, or can be separately disposed on components of a medical device according to an embodiment. For example, a layer or a solution containing a first bioactive can be applied to the first layer110of a medical device100, and a layer or solution containing a second bioactive can be applied to the second layer112of the medical device100. The layers110,112can then be brought together such that the two bioactives are both disposed between the layers110,112in the final medical device100assembly.

Any suitable bioactive can be used in the methods and medical devices described herein. The specific bioactive, or bioactives, selected for any particular method or medical device will depend upon several considerations, including the desired effect and the type of treatment and/or procedure in which the medical device is intended to be used. Examples of suitable bioactives include anti-cancer agents, such as paclitaxel, tamoxifen citrate, and Taxol® or derivatives thereof; anthracyclines, such as doxorubicin; pyrimidine analogs, such as 5-fluorouracil; nucleoside analogs, such as gemcitabine; platinum-based antineoplastics, such as cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, triplatin, and lipoplatin; immunosuppressive agents, such as cyclosporine and sirolimus; and other anti-cancer chemotherapeutic agents. Monoclonal and polyclonal antibodies can also be used as a bioactive in the methods and medical devices described herein. For example, recombinant humanized angiogenesis inhibiting monoclonal antibodies, such as Bevacizumab, are suitable. Also, chimeric monoclonal antibodies that inhibit epidermal growth factor receptor (EGFR), such as Cetuximab, are suitable. Also, anti-idiotype tumor antigen epitope mirroring monoclonal antibodies, such as Abagovomab, are suitable. Other examples of bioactives that can be used in the methods and medical devices include, but are not limited to, heparin, covalent heparin or another thrombin inhibitor, hirudin, hirulog, argatroban, D-phenylalanyl-L-poly-L-arginyl chloromethyl ketone, or another antithrombogenic agent, or mixtures thereof; urokinase, streptokinase, a tissue plasminogen activator, or another thrombolytic agent, or mixtures thereof; a tyrosine-kinase inhibitor, such as Imatinib; a fibrinolytic agent; a vasospasm inhibitor; a calcium channel blocker, a nitrate, nitric oxide, a nitric oxide promoter or another vasodilator; an antimicrobial agent or antibiotic; aspirin, ticlopidine, a glycoprotein IIb/IIIa inhibitor or another inhibitor of surface glycoprotein receptors, or another antiplatelet agent; colchicine or another antimitotic, or another microtubule inhibitor, dimethylsulfoxide (DMSO), a retinoid or another antisecretory agent; cytochalasin or another actin inhibitor; or a remodeling inhibitor; deoxyribonucleic acid, an antisense nucleotide or another agent for molecular genetic intervention; methotrexate or another antimetabolite or antiproliferative agent; dexamethasone, dexamethasone sodium phosphate, dexamethasone acetate or another dexamethasone derivative, or another anti-inflammatory steroid or non-steroidal anti-inflammatory agent; tripodal (aPDGF antagonist), angiopeptin (a growth hormone antagonist), angiogenin or other growth factors, or an anti-growth factor antibody, or another growth factor antagonist; dopamine, bromocriptine mesylate, pergolide mesylate or another dopamine agonist; 60Co, 192Ir, 32P, 111In, 90Y, 99mTc or another radiotherapeutic agent; iodine-containing compounds, barium-containing compounds, gold, tantalum, platinum, tungsten or another heavy metal functioning as a radiopaque agent; a peptide, a protein, an enzyme, an extracellular matrix component, a cellular component or another biologic agent; captopril, enalapril or another angiotensin converting enzyme (ACE) inhibitor; ascorbic acid, alpha tocopherol, superoxide dismutase, deferoxamine, a 21-amino steroid (lasaroid) or another free radical scavenger, iron chelator or antioxidant; a 14C-, 3H-, 131I-, 32P- or 36S-radiolabelled form or other radiolabelled form of any of the foregoing; estrogen or another sex hormone; AZT or other antipolymerases; acyclovir, famciclovir, rimantadine hydrochloride, ganciclovir sodium or other antiviral agents; 5-aminolevulinic acid, meta-tetrahydroxyphenylchlorin, hexadecaflouoro zinc phthalocyanine, tetramethyl hematoporphyrin, rhodamine 123 or other photodynamic therapy agents; an IgG2 Kappa antibody againstPseudomonas aeruginosaexotoxin A and reactive with A431 epidermoid carcinoma cells, monoclonal antibody against the noradrenergic enzyme dopamine betahydroxylase conjugated to saporin or other antibody target therapy agents; enalapril or other prodrugs; any endothelium progenitor cell attracting, binding and/or differentiating agents, including suitable chemoattractive agents and suitable polyclonal and monoclonal antibodies; cell migration inhibiting agents, such as smooth muscle cell migration inhibitors, such as Bamimistat, prolylhydrolase inhibitors, Probacol, c-proteinase inhibitors, halofuginone, and other suitable migration inhibitors; and gene therapy agents, and a mixture of any of these.

Two or more bioactives can be used when preparing a solution102for use in the method100. For example, FOLFIRI, folinic acid with fluorouracil and irinotecan, is suitable for use as the bioactive in the methods and medical devices described herein. Also, FOLFOX, folinic acid with fluorouracil and oxaliplatin, is suitable for use as the bioactive in the methods and medical devices described herein.

Furthermore, the solution can be prepared in any suitable manner. Accordingly, any suitable fluid or fluids can be used when preparing the solution. A skilled artisan will be able to select an appropriate fluid for a method according to a particular method based on various considerations, including the nature of the bioactive or bioactives being used in the method. Examples of suitable fluids include water, such as Sterile Water for Injection USP, and alcohols, including ethanol and other alcohols. Also, any suitable techniques, processes, or steps can be used when preparing the solution, including heating, stirring, cooling, mixing and other suitable techniques, processes and steps.

One or more excipients can be included in the solution if desired. If included, any suitable excipient can be included, including sugars and inorganic compounds.

The inventors have determined that a combination of paclitaxel and carboplatin that is disposed between the layers of a medical device according to an embodiment is suitable for use as the bioactive in the medical device. Furthermore, the inventors have determined that a solution of paclitaxel in ethanol is suitable for use as the bioactive in a medical device according to an embodiment.

No matter which bioactive or bioactives are used in a medical device according to a particular embodiment, the bioactive or bioactives can be associated with the medical device in any suitable manner. In the medical device100illustrated inFIGS. 1 through 3, the bioactive114has been disposed between the layers110,112in solution form, and the bioactive114has diffused into the material of the layers110,112(represented by the open circles in theFIGS. 1 through 3). A solution containing the bioactive114can be disposed between the layers in any suitable manner, including by application to one surface of one of the layers, e.g., surface112aof layer112, followed by placement of layer110onto surface112aof layer112. Alternatively, a solution containing the bioactive114can applied to surface110bof layer110, followed by placement of layer110onto surface112aof layer112. Also alternatively, a solution containing the bioactive114can be applied to surface110bof layer110and surface112aof layer112, followed by placement of layer110onto surface112aof layer112.

In the final assembled form, best illustrated inFIG. 1, layers110,112of medical device110are secured to each other. The layers110,112can be secured to each other in a variety of manners, such as by inclusion of an adhesive between the layers, crimping, inclusion of mechanical connectors, such as pins, clips, sutures or any other suitable mechanical connector, and any other suitable means for securing biodegradable layers to each other. If an additional component is included, such as a mechanical connector, it is considered advantageous that the additional component also be formed of a biodegradable material, such as a biodegradable suture. It is noted, too, that the physical properties of the layers in a medical device according to a particular embodiment may provide sufficient securement between the layers once the medical device is assembled into a final form such that additional elements and/or processing is not required.

FIG. 4illustrates a second example medical device200. The medical device200according to this embodiment is similar to the medical device100described above and illustrated inFIGS. 1 through 3, except as detailed below. Thus, medical device200comprises first210and second212layers and a bioactive214disposed between the layers210,212. The first layer210has a first surface210aand a second surface210b. Similarly, the second layer212has a first surface212aand a second surface212b. The first layer210is rectangular in shape. In this embodiment, the second layer212is also rectangular in shape. The second layer212is larger than the first layer210allowing a small portion270of the second layer212to be folded over a portion of the first layer210once the first layer210is disposed on the second layer212. This structural configuration provides a triple laminate structure250for only a single edge252of the medical device110.

The structure provided by a medical device having a triple laminate structure along only a single edge of the medical device may be advantageous for situations in which it is desirable to have a portion of the medical device that provides a structure that facilitates handling of the medical device and/or a structure that provides visual and tactile feedback of a directional release profile of the bioactive in the medical device, but also in which the point of treatment at which the medical is intended to be used has spatial concerns and/or limitations that prevent use of a bulkier structure, such as the medical device100illustrated inFIGS. 1 through 3.

In this embodiment, the bioactive214comprises a solid layer disposed between the layers210,212in a “sandwich” arrangement. A paste, powder, gel, film, solution-containing solid, or other suitable form of the bioactive or bioactives can be used to achieve this structural arrangement. Furthermore, the bioactive214can be disposed between the layers210,212in any suitable manner, including by application to one surface of one of the layers, e.g., surface212aof layer212, followed by placement of layer210onto surface212aof layer212. Alternatively, the bioactive214can applied to surface210bof layer210, followed by placement of layer210onto surface212aof layer212. Also alternatively, the bioactive214can be applied to surface210bof layer210and surface212aof layer212, followed by placement of layer210onto surface212aof layer212.

FIGS. 5 and 6illustrate a third example medical device300. The medical device300according to this embodiment is similar to the medical device100described above and illustrated inFIGS. 1 through 3, except as detailed below. Thus, medical device300comprises first310and second312layers and a bioactive314disposed between the layers310,312. In this embodiment, as best illustrated inFIG. 6, a solution containing the bioactive314has been disposed onto a surface312aof the second layer312and the bioactive314has diffused into the material of the layer312(represented by the open circles in theFIG. 6) prior to final assembly of the medical device300.

The first layer310has a first surface310aand a second surface310b. Similarly, the second layer312has a first surface312aand a second surface312b. The first layer310is rectangular in shape. In this embodiment, the second layer312has a rectangular central portion316and first380, second382, third384and fourth386peripheral tabs extending outwardly from the central portion316. The second layer312is larger than the first layer310allowing the peripheral tabs380,382,384,386of the second layer312to be folded over peripheral portions of the first layer310and into contact with the first surface310aof the first layer once the first layer310is disposed on the second layer312. This structural configuration provides a triple laminate structure350that extends continuously around the entire peripheral edge of the medical device300.

The structure provided by a medical device having a triple laminate structure that extends continuously around the entire peripheral edge of the medical device may be advantageous for a variety of situations. For example, the structure can be used to limit, and even prevent, if desired, lateral release of the bioactive from the peripheral edges of the medical device while permitting release of the bioactive from the exposed portion of the first layer. This provides a great deal of control over the direction in which the bioactive will be released at a point of treatment, allowing a user to focus the bioactive and its treatment effects on a particular location while having confidence that adjacent locations will have limited to no exposure to the bioactive.

FIG. 7illustrates a fourth example medical device400. The medical device400according to this embodiment is similar to the medical device300described above and illustrated inFIGS. 5 and 6, except as detailed below. Thus, medical device400comprises first410and second412layers and a bioactive414disposed between the layers410,412.

In this embodiment, a cavity490is disposed between the layers410,412and the bioactive414is disposed in the cavity490. In the illustrated embodiment, a powder containing the bioactive414occupies the entire space of the cavity490. It is noted, though, that the cavity490in a medical device according to a particular embodiment can be partially filled with a powder containing a bioactive or with another substance or solution containing the bioactive. Leaving some of the space of the cavity unfilled may be advantageous if it is desired to provide a medical device that can be physically manipulated to a greater degree, such as a medical device intended to be used at points of treatment that typically have greater degrees of physical variability between patients, for example.

In this embodiment, each of the first layer410and the second layer412is circular in shape. The second layer412is larger than the first layer410, allowing a peripheral portion488of the second layer412to be folded over a peripheral portion492of the first layer410once the bioactive414has been placed and the first layer410has been disposed over the second layer412and the bioactive414. The second layer414defines a circumferential shoulder494and a circumferential groove496that receives the peripheral edge498of the first layer. This structural configuration provides a triple laminate structure450that extends continuously around the peripheral edge of the medical device400. Also, the medical device400has an overall bowl-shaped configuration.

The structure provided by a medical device having a cavity disposed between the first and second layers may be advantageous for situations in which it is desirable to have a medical device that is adapted to fill a void or other space at a point of treatment, such as in an abdominal cavity or interstitial space of a human patient.

Methods

FIG. 8illustrates an example method500of making a medical device for delivering a bioactive. A step502comprises disposing a bioactive onto a first biodegradable layer. Another step504comprises disposing a second biodegradable layer onto the bioactive and first biodegradable layer. An optional step506comprises forming a triple laminate structure on the periphery of the first and second biodegradable layers. Another step508comprises securing the first and second biodegradable layers to each other.

The invention also includes the medical devices made by performance of the methods described herein. One example medical device comprises a medical device made by a method of making a medical device for delivering a bioactive, the method comprising disposing a bioactive onto a first biodegradable layer; disposing a second biodegradable layer onto the bioactive and first biodegradable layer; and securing the first and second biodegradable layers to each other. The method can optionally include forming a triple laminate structure on the periphery of the first and second biodegradable layers.

The invention also includes methods of using the medical devices described herein, such as by placing a medical device described herein into a body at a point of treatment, such as a point of treatment in a body cavity in contact with one or more margins of a resected tumor. Also, the invention includes methods of using the medical devices described herein in combination with another medical device, such as by placing a medical device described herein around a stent, such as an esophageal stent, and placing the medical devices together into a body at a point of treatment, such as a point of treatment in an esophagus of an animal. In this manner, the medical device is sandwiched between the tissue at the point of treatment and the stent.

It is noted that, in all methods, individual steps can be performed in any suitable order. For example, in a method that includes a step of massaging the substrate, the massaging step can be performed during the step of initiating flow of the solution toward the substrate, after completion of the step of initiating flow of the solution toward the substrate, or repeatedly and alternatively with several steps of initiating flow of the solution toward the substrate.

The methods described herein provide flexibility in the performance of treatment procedures. The methods can be performed in anticipation of performance of a treatment procedure on a patient that uses a medical device made by the method. For example, a pharmacy can perform a particular method to prepare a medical device for use in the treatment procedure hours, days or even weeks before the treatment procedure is to be performed. The medical device made by the method can be stored in suitable packaging and made available at the time of the treatment procedure. Also, the methods can be performed immediately prior to performance of a treatment procedure on a patient that uses a medical device made by the method. Indeed, the methods described herein can be performed bedside in a hospital, immediately before use of the resulting medical device on a particular patient. In cancer treatment procedures, for example, this allows a caregiver to select a desired chemotherapeutic bioactive or immunotherapeutic bioactive for local delivery for a particular patient and then perform a method of making a medical device, such as one of the methods described herein, or instruct another to perform a method of making a medical device, and then use the resulting medical device in the immediate treatment for the particular patient.

While various example medical devices and method are described with reference to specific features of particular drawings, it is understood that the various elements, steps and/or features described herein in connection with one particular example can be combined with those of another without departing from the scope of the invention. Furthermore, the medical devices and methods described and illustrated herein provide examples of the invention, and are not intended to limit the scope of the invention in any manner. Rather, they serve only to aid those skilled in the art to perform, make and use the invention.