Drug-eluting shape memory foam

Abstract

Tumor resection is commonly performed to prevent cancer progression. However, post-surgery concerns include the formation of voids at the surgical site that allow cancer cells to escape, increasing the risk of metastasis. To address this issue, one embodiment includes a polyurethane-based shape-memory foam as a tissue void-filling device that can also release anti-cancer drugs. The foam is activated by body temperature and becomes malleable. This property allows the foam to be molded to precisely seal tissue voids and then function as a drug-eluting device. Based on the drug composition with polyvinyl alcohol (PVA), the drug release profile from the foam can be tailored to suit the application.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 62 / 916,515 (filed October 17, 2019, entitled "Drug-Eluting Shape Memory Foam"), the contents of which are incorporated herein by reference.

[0002] Technical Field

[0002] Embodiments of the present invention relate to the field of medical devices. [Background technology]

[0003] Cancer is the second leading cause of death, estimated to kill approximately 600,000 people in the United States alone in 2019. For solid tumors, one of the primary medical interventions involves surgical removal of the tumor along with some of the surrounding tissue to ensure no cancer cells remain. However, in vital organs such as the lungs, preserving normal tissue is essential, and there is currently no accurate detection method to predict the boundaries of cancer cells. This can lead to the retention of cancer cells, which can later cause cancer recurrence. Furthermore, several studies have suggested that a) cancer cells may detach by utilizing the gaps in the tissue after resection, or b) postoperative stress may increase metastasis. Traditionally, gaps in tissue after surgery are closed using biodegradable or nondegradable sutures. This suturing method presents certain challenges, such as complications due to poor wound prognosis and the need to remove nondegradable sutures. In the case of dissolving sutures, the degradation rate can be accelerated depending on the patient's physiological condition. For example, if a patient presents with a high fever, the sutures are likely to deteriorate faster than expected, leading to a poor wound outcome.

[0004]

[0004] Features and advantages of embodiments of the present invention will be apparent from the appended claims, the following detailed description of one or more embodiments, and the corresponding drawings, in which, where appropriate, reference numerals are repeated to indicate corresponding or analogous elements. [Brief explanation of the drawings]

[0005] [Figure 1] 5 is a graph containing non-cumulative release curves for embodiments of the present invention. [Figure 2]

[0006] 1 is a graph containing non-cumulative release curves for embodiments of the present invention. [Figure 3]

[0007] 1 is a graph containing non-cumulative release curves for embodiments of the present invention.

[0008] The Y-axis in Figures 1 to 3 indicates the mass of drug dissolved from the foam. [Figure 4]

[0009] FIG. 1 is a cross-sectional view of a shape memory polymer foam strut in one embodiment of the present invention. Summary of the Invention [Problem to be solved by the invention]

[0006]

[0010] Reference is now made to the drawings, in which like structures may be referred to with like suffix reference designations. To more clearly illustrate the structures of various embodiments, the drawings included herein are schematic representations of the structures. Thus, the actual appearance of a manufactured structure, e.g., a photograph, may appear different while still incorporating the claimed structure of the illustrated embodiment (e.g., walls may not be exactly perpendicular to one another in an actual manufactured device). Furthermore, the drawings may only show structures useful for understanding the illustrated embodiment. Additional structures known in the art may not be included to maintain clarity of the drawings. For example, not all layers of a device are necessarily shown. "An embodiment," "various embodiments," etc. refer to possible multiple embodiments described as such, but not all embodiments necessarily include a particular feature, structure, or characteristic. An embodiment may have some, all, or all of the characteristics described for other embodiments. "First," "second," "third," etc. describe a common object and indicate that different instances of the same object are being referenced. Such adjectives do not imply that the objects so described must be in a predetermined order, whether in time, space, ranking, or in any other way. "Connected" may indicate that elements are in direct physical or electrical contact with each other, and "coupled" may indicate that elements cooperate or interact with each other, but they may or may not be in direct physical or electrical contact. A statement such as "comprises at least one of A or B" includes situations where A, B, or A and B.

[0007]

[0011] To address the above issues, biodegradable sutures have been widely used to close wounds after surgery. Attempts have also been made to use these sutures as drug delivery systems. However, the inventors have found that few drug-eluting sutures are clinically applicable due to numerous issues, including suboptimal mechanical strength and the inability to achieve sustained drug release. Furthermore, the inventors have found that poor control of drug release from sutures (or even the ability to load drugs into sutures) further impairs therapeutic efficacy. Sutures are often immersed in a drug solution, resulting in the inability to immediately control drug release. The drug's internal residence time is too short to achieve the desired therapeutic effect. The inventors have cited increased inflammation as another major concern regarding absorbable sutures. During tumor resection, sutures may not be able to accurately seal the wound. Therefore, residual cancer cells may detach from areas of the wound not in contact with the suture.

[0008]

[0012] Alternatives to sutures include postoperative biodegradable implants, such as hydrogels. The drug-release capabilities of hydrogels have been extensively characterized. Hydrogels can be engineered to respond to various stimuli, including temperature and pH, to release their payload. For example, the pH of the tumor microenvironment tends to be lower compared to physiological pH. By chemically engineering hydrogels to be sensitive to low pH environments, it is possible to selectively deliver payloads in the tumor microenvironment. While this is theoretically an effective drug delivery alternative to drug-eluting sutures, the inventors have determined that hydrogels lack sufficient tensile strength to precisely control the timing of drug release and wound sealing. As the water content in hydrogels increases, they form a non-rigid, liquid-like structure, making them less effective solutions for precisely sealing tissue gaps. This mechanical property also leads to premature dissolution of the device and uncontrolled release of the payload.

[0009]

[0013] Therefore, the inventors have determined that there is a need for a platform foam that more precisely seals the tissue void while therapeutically inhibiting the development of metastases. [Means for solving the problem]

[0010]

[0014] To that end, one embodiment includes an SMP foam that can be used to conform to the void based on the foam's SMP properties. The foam carries small therapeutic molecules that promote the killing of resident cancer cells near the resection surface. Thus, this embodiment provides advantages over the prior art in that the foam is biocompatible and can be loaded with drugs with release profiles that can be tailored to prevent or delay the recurrence of malignant disease. DETAILED DESCRIPTION OF THE INVENTION

[0011]

[0015] Small molecule drugs can be loaded onto or into foams by incubating the foam with the drug in a polyvinyl alcohol solution. The foam can then be activated by body temperature to release the drug (or a portion of it) from the foam. The release time can also be adjusted by using different ratios of PVA, allowing for the tailoring of the drug-eluting device. The drug release profile can be tailored by varying the chemical composition of the foam, the amount of PVA in the foam, the size of the cells in the foam, the degree of reticulation of the cells in the foam, or a combination thereof.

[0012]

[0016] One embodiment includes tissue void-filling and drug-eluting shape memory polymer (SMP) foams. SMP foams include hexamethylene diisocyanate (HDI)-based foams. However, other embodiments include foams that are the reaction product of hydroxypropylethylenediamine (HPED), triethanolamine (TEA), and 2,2,4-trimethylhexamethylene diisocyanate (TMHDI). TMHDI foams can have smaller pore sizes compared to HDI foams, and therefore have different drug delivery profiles.

[0013]

[0017] In one embodiment, acriflavine, a fluorescent small molecule, is used as a payload to demonstrate therapeutic agent release profiles from foams. In one embodiment, PVA is used to improve drug incorporation onto or into the foam. Different drug incorporation and release profiles may be achieved using reticulated, partially reticulated, and non-reticulated TMHDI-based foams or other SMP foams.

[0014]

[0018] Shape memory materials have the useful ability to be molded into a primary shape, reformed into a stable secondary shape, and then controllably actuated to recover that primary shape. Both metal alloys and polymeric materials can possess shape memory. In metals, the shape memory effect arises from a thermally induced solid-state phase transformation that alters the atomic lattice structure, resulting in macroscopic changes in elastic modulus and dimensions. In polymeric materials, the primary shape is achieved after processing and is fixed by physical structure or chemical crosslinks. The secondary shape is achieved by deforming the material while it is in an elastomeric state, and the shape is fixed in one of several ways, including cooling the polymer below its crystalline, liquid crystal, or glass transition temperature; inducing additional covalent or ionic crosslinks; etc.

[0015]

[0019] While in the secondary shape, some or all of the polymer chains are perturbed from their equilibrium random-walk conformation and acquire a degree of bulk orientation. The oriented chains, due to their reduced entropy, acquire a certain potential energy, which provides the driving force for shape recovery. However, they do not spontaneously recover due to either kinetic effects (below the low Tg) or physical constraints (physical or chemical crosslinks). Removal of the constraints (e.g., heating the polymer above its glass transition or melting temperature, removing ionic or covalent crosslinks, etc.) triggers recovery to the primary shape. Other polymers that exhibit shape memory behavior due to photon-induced conformational transformations, conformational changes (e.g., rod-coil transitions) caused by changes in the chemical environment (e.g., pH, ionic strength), or structural changes caused by the application of an electric field (e.g., electric, magnetic, etc.) may also be used.

[0016]

[0020] Thus, SMPs are polymeric smart materials that have the ability to recover from a deformed state (temporary shape) to its original (permanent) shape when triggered by an external stimulus such as a temperature change. SMPs can maintain two or more shapes, and the transition between them is temperature-induced. In addition to temperature changes, SMP shape changes can be triggered by electric fields, magnetic fields, light, or solvent plasticization. Like general polymers, SMPs can cover a wide range of properties, from stable to biodegradable, soft to hard, and elastic to rigid, depending on the structural units that make up the SMP. SMPs include thermoplastic and thermosetting (covalently crosslinked) polymeric materials.

[0017]

[0021] Embodiments offer certain advantages over other technologies, such as hydrogel-based technologies. One embodiment utilizes a carrier polymer added to an SMP foam. The inventors have found that many SMP foams (without the carrier polymer) cannot be loaded with significant amounts of drug (e.g., small molecules). Although water is a small molecule, the inventors have previously exposed SMP foams to different humidity levels for various periods of time and found that after 96 hours at 100% relative humidity, the foams exhibited 8.0% (by mass) water absorption. Water is polar, but it is small, and many HDI- and TMHDI-based SMP foams are relatively hydrophilic. Therefore, the inventors have found that adding a carrier polymer to the foam can deliver or retain more drug. However, the inventors have also found that the thickness and total mass of the carrier polymer added to the foam can limit the foam's compression and / or shape recovery (which can limit the ability to deliver the foam through tortuous pathways, such as through a small, winding vasculature using a catheter). However, the inventors have found that PVA offers advantages over prior art (e.g., hydrogels) in that shape recovery rates and diameters are less limited compared to such prior art. Furthermore, because PVA allows for more control over the total mass deposited than many hydrogels, it is believed that PVA also helps reduce the crimping restrictions caused by adding mass. SMP foams can be controllably expanded while retaining their precise positioning. After actuation, SMP foams expand to their permanent shape within a short time (e.g., a few seconds), which is much more rapid than conventional hydrogel-based devices.

[0018]

[0022] The inventors have found that, important for some applications, certain cancers may require timed release to local tissues. This may be due to the difficulty in identifying cancer margins and the inability to be certain that all of the cancer has been surgically removed along with the tumor. Chemotherapy and radiation therapy are secondary methods for eliminating residual resection sites and metastatic cells circulating in the bloodstream. However, the release rate and dual release from PVA and SMP foams are beneficial for localized and sustained delivery of anti-cancer molecules to tumor sites. "Dual release" allows for the release of therapeutic agents from both the PVA (which may be in the form of the outer shell of the foam) and the SMP foam (which may have the agent present within the cells of the foam, with or without PVA present within the cells).

[0019]

[0023] One embodiment includes a method for making drug-eluting SMP foams. The method involves incubating foams (n=3) overnight on a rotator at room temperature in a 0.017 mg / mL acriflavine solution (e.g., 1 mg / mL acriflavine solution in dimethyl sulfoxide (DMSO)) mixed with various PVA solutions at 0%, 1%, 2%, 3%, and 10% (wt. / vol). Varying PVA concentrations can be used to increase drug viscosity and drug incorporation onto or within the foam. In other embodiments, the PVA is kept constant and the acriflavine concentration is varied (varying PVA viscosity). Foams can then be removed from each drug / PVA solution and dried in a vacuum chamber for 5 days. Foams can then be incubated in 0.4 mL of phosphate-buffered saline (PBS) at 37°C. At various time points, the supernatant can be removed and fluorescence at 416 / 514 nm (Ex / Em) can be measured.

[0020] [Table 1]

[0024] The table above shows the chemical composition for several embodiments.

[0021]

[0025] Increasing the concentration of PVA in the drug solution can proportionally increase the viscosity. This increase in viscosity can enhance the retention of the drug within the foam. Other viscosity-altering compounds, such as carboxymethylcellulose, can also be used (in place of or in addition to PVA) to achieve similar drug uptake and release.

[0022]

[0026] In one embodiment, acriflavine is used as the free drug payload (which serves to illustrate the release profiles of drug solutions with different PVA concentrations). Increasing PVA concentrations increase drug uptake onto or in the foam (see, e.g., Figures 1, 2, and 3). This may be due, at least in part, to the increased viscosity of the drug when used in conjunction with PVA, allowing the drug to be trapped in or on the pores present in the foam. In an embodiment involving immersion of a foam in a drug solution without PVA (0% PVA), drug uptake is lower compared to solutions with increasing PVA concentrations. One embodiment may involve depositing multiple foams at a surgical site, with the foams comprising varying PVA contents and therefore varying release profiles (which allows drug elution to be distributed over a programmed period). The release profile also varies relative to the PVA content in the drug solution. A delayed burst release is achieved with a drug solution with 0% PVA, while solutions with higher PVA concentrations allow for immediate release from the foam. Therefore, this PVA-infused drug formulation allows for the adjustment of drug uptake and drug release profiles by adjusting the PVA concentration. It is noteworthy that although the anti-inflammatory drug acriflavine is used in the embodiment, other drug molecules (e.g., doxorubicin) can be loaded onto or into the foam. Many therapeutic agents are hydrophobic small molecules and are therefore expected to have similar loading and release profiles to acriflavine. In other embodiments, such therapeutic agents may be used in place of acriflavine or may be added together with acriflavine.

[0023]

[0027] Again, as noted above, the drug release profile can be tailored depending on the desired therapeutic effect. For example, instead of using unencapsulated "free drug," drug-encapsulated nanoparticles can be used to modify the release profile. Drug-encapsulated vehicles (including microparticles, nanoparticles, and hydrogels) allow for delayed, sustained release as the particles are released from the foam. Thus, drug-eluting SMP foams can facilitate short-term and long-term drug delivery, depending on the payload and PVA used. Drug release can also be optimized based on the drug stock concentration.

[0024]

[0028] For in vitro release of acriflavine from HDI-based SMP foams, see Figure 1. The non-cumulative release curves in Figure 1 show that acriflavine release from SMP foams increases (or at least differs) with increasing PVA concentration. This is likely due to increased acriflavine loading by PVA (and its affinity for the foam). In Figure 2, the non-cumulative release curves show that acriflavine release from reticulated HH80 SMP foams increases (or at least differs) with increasing PVA concentration.

[0025]

[0029] Different embodiments may include different drug release profiles, for example, longer release times, no spike release, dual spike release, etc. This may be implemented as described below in the claims section.

[0026]

[0030] The in vitro release of acriflavine from non-reticulated TMHDI 60 foams is shown in Figure 3. In Figure 3, the non-cumulative release curves show that acriflavine release from TH60 SMP foams increases (or at least differs) with increasing PVA concentration.

[0027]

[0031] An embodiment includes doxorubicin-loaded SMP foams with increasing PVA concentrations, where the foams are crimped to a diameter of 0.8 mm. This size restriction allows for better injection of the foam into the intraperitoneal region of mice using an 18G needle.

[0028]

[0032] SMP foams containing a drug in PVA may be compared to a combination of SMP foam and hydrogel, although in some embodiments the foam may be bonded to the PVA / drug moiety in a manner similar to a drug in a hydrogel.

[0033] The following examples relate to further embodiments.

[0029]

[0034] Example 1. A device comprising a shape memory polymer (SMP) foam comprising open cells, the SMP foam having a first and a second state, and a material composition contained in the open cells, wherein the material composition comprises (a) at least one therapeutic agent and (b) at least one of polyvinyl alcohol (PVA), carboxymethyl cellulose, or a combination thereof, and the at least one therapeutic agent comprises at least one of a drug, a peptide, a protein, an antigen, a nucleic acid, an anesthetic, an antihistamine, an antifungal, a vasodilator, an anti-inflammatory agent, an immunosuppressant, a growth factor, a cytokine, an interleukin, or a combination thereof.

[0030]

[0035] In one embodiment, the foam is a polyurethane thermoset foam. In some embodiments, the PVA is not chemically bonded to the foam. In some embodiments, the therapeutic agent is not chemically bonded to the foam. In some embodiments, the PVA is not chemically bonded to the foam and the therapeutic agent is not chemically bonded to the foam. In one embodiment, the PVA is not chemically bonded to the therapeutic agent.

[0031]

[0036] Example 1.1. A device comprising a shape memory polymer (SMP) foam comprising open cells, the SMP foam having a first and a second state; and a material composition contained in the open cells, wherein the material composition comprises (a) at least one therapeutic agent and (b) at least one of polyvinyl alcohol (PVA), carboxymethyl cellulose, hydrogel, or combinations thereof, and the at least one therapeutic agent comprises at least one of a drug, peptide, protein, antigen, nucleic acid, anesthetic, antihistamine, antifungal, vasodilator, anti-inflammatory agent, immunosuppressant, growth factor, cytokine, interleukin, or combinations thereof.

[0032]

[0037] Example 2. The apparatus of Example 1, wherein the SMP foam is configured to expand from a first state to a second state when the SMP foam is plasticized at 37°C and a glass transition temperature (Tg) of the SMP foam drops below 25°C.

[0033]

[0038] For example, "the SMP foam is plasticized at 37°C" includes plasticization across a spectrum of temperatures. For example, plasticization can occur over a temperature range of, e.g., 33°C to 40°C, including 37°C, but plasticization can occur at 35°C and 39°C. Furthermore, "the glass transition temperature (Tg) of the SMP foam is reduced to below 25°C" includes reducing the Tg to, e.g., 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0°C, etc.

[0034]

[0039] In one embodiment, when plasticized in 37°C water, the glass transition temperature (Tg) drops to ~12°C, allowing actuation when exposed to body temperature fluids. In one embodiment, the SMP foam is reticulated to form an open pore structure. The pore size can be tuned between 200 and 1500 μm. In one embodiment, the SMP foam is hydrophilic. Various embodiments adjust the hydrophilicity of the SMP to allow the device to actuate at different speeds.

[0035]

[0040] As used herein, "body temperature" is meant to convey a normal temperature range. Normal body temperature varies by person, age, activity, and time of day. Average normal body temperature is generally accepted to be 98.6°F (37°C), but "normal" body temperature spans a wide range, from 97°F (36.1°C) to 99°F (37.2°C). A temperature above 100.4°F (38°C) may indicate a fever, but would still be within the scope of the embodiments described herein.

[0036]

[0041] Example 2.1. The apparatus of Example 2, wherein the SMP foam comprises at least one of hexamethylene diisocyanate (HDI), trimethylhexamethylene diisocyanate (TMHDI), or a combination thereof, and the SMP foam comprises at least one of triethanolamine (TEA), hydroxypropylethylenediamine (HPED), or a combination thereof.

[0042] In one embodiment, the foam is biodegradable.

[0037]

[0043] Example 3. The device of Example 2, wherein the SMP foam comprises a reaction product of at least a first component and a second component, wherein the first component comprises at least one of hexamethylene diisocyanate (HDI), trimethylhexamethylene diisocyanate (TMHDI), or a combination thereof, and the second component comprises at least one of triethanolamine (TEA), hydroxypropylethylenediamine (HPED), or a combination thereof.

[0038]

[0044] Example 4. The apparatus of Example 2, wherein the SMP foam comprises at least one of hexamethylene diisocyanate (HDI), trimethylhexamethylene diisocyanate (TMHDI), or a combination thereof, and the SMP foam comprises at least one of glycerol, 1,2,6-hexanetriol (HT), 3-methyl-1,5-pentanediol (MPD), 2-butyl-2-ethylpropanediol (BEP), or a combination thereof.

[0039]

[0045] Example 5. The apparatus of Example 2, wherein the SMP foam comprises a reaction product of at least a first component and a second component, wherein the first component comprises at least one of hexamethylene diisocyanate (HDI), trimethylhexamethylene diisocyanate (TMHDI), or a combination thereof, and the second component comprises at least one of glycerol, 1,2,6-hexanetriol (HT), 3-methyl-1,5-pentanediol (MPD), 2-butyl-2-ethylpropanediol (BEP), or a combination thereof.

[0040]

[0046] Example 6. The apparatus of Example 2, wherein the SMP foam comprises at least one of hexamethylene diisocyanate (HDI), trimethylhexamethylene diisocyanate (TMHDI), or a combination thereof; the SMP foam comprises at least one of glycerol, 1,2,6-hexanetriol (HT), 3-methyl-1,5-pentanediol (MPD), 2-butyl-2-ethylpropanediol (BEP), or a combination thereof; and the SMP foam comprises at least one of 5-amino-2,4,6-triiodoisophthalic acid (ATIPA), iohexol, triiodophenol, or a combination thereof.

[0041]

[0047] Example 7. The device of Example 2, wherein the SMP foam comprises a reaction product of at least a first component, a second component, and a third component, wherein the first component comprises at least one of hexamethylene diisocyanate (HDI), trimethylhexamethylene diisocyanate (TMHDI), or a combination thereof; the second component comprises at least one of glycerol, 1,2,6-hexanetriol (HT), 3-methyl-1,5-pentanediol (MPD), 2-butyl-2-ethylpropanediol (BEP), or a combination thereof; and the third component comprises at least one of 5-amino-2,4,6-triiodoisophthalic acid (ATIPA), iohexol, triiodophenol, or a combination thereof.

[0042]

[0048] Example 8. The system of Example 2, wherein the at least one therapeutic agent comprises at least one of doxorubicin, cisplatin, paclitaxel, amoxicillin, doxycycline, cephalexin, or a combination thereof.

[0043]

[0049] Example 9. A system comprising the device of any of Examples 1-8, the system comprising a conduit comprising an SMP foam with a material composition contained within the open cells.

[0044]

[0050] The term "contained within open cells" refers to, for example, when the drug, with or without PVA, completely fills the cells, partially fills the cells, or coats the struts of the cells.

[0045]

[0051] In one embodiment, the PVA / drug is present throughout the SMP foam or in various portions of the SMP foam. The PVA / drug is deposited in small portions on the struts of the SMP foam and / or forms a thin film on the struts. The PVA / drug may also fill the entire volume (or nearly the entire volume) of the foam. In one embodiment, small pieces (e.g., beads) of the SMP / PVA / drug complex are injected into the wound, provided that the pieces are large enough to avoid entry into and transmission within the patient's vascular system. In another embodiment, the SMP / PVA / drug combination device is placed on a wound (e.g., a skin cancer excision) and attached to a bandage, which then presses the device against the wound with the bandage exerting pressure on the patient.

[0046]

[0052] Example 10. The system of Example 9, wherein the conduit includes a further instance of the device of any of Examples 1-8.

[0047]

[0053] For example, multiple foams can be included in a needle, sheath, or catheter. The foams can be essentially the same or different. For example, one foam can contain a drug without PVA, while another foam can contain a drug in PVA. This can result in a longer release profile. Furthermore, the drugs can be the same or different from one another. For example, the system can be provided such that a first drug elutes during a first period of time (based on binding, or lack thereof, with PVA), and a second drug (not identical in chemical composition to the first drug) elutes during a second period of time (some periods overlapping with the first period and other periods not overlapping with the first period) in anticipation of changing physiological characteristics of the surgical site and / or void and / or wound.

[0048]

[0054] In one embodiment, the kit can be packaged in a container. The kit can include a suitably compressed SMP foam within a sheath that holds the foam in the compressed state. The foam can have a therapeutic agent bound to it via PVA, carboxymethylcellulose, or any viscosity modifier. The foam can be inserted into the surgical site manually or via a catheter, sheath, or cannula.

[0049]

[0055] However, in other embodiments, no conduit is necessary at all - for example, a healthcare provider can simply use their fingers or forceps to add foam to the void.

[0050]

[0056] The kit may include multiple foams, each with a different drug release profile, and a healthcare provider may select a foam combination to apply to a patient with the foam combination having the ability to tailor the release profile based on the foam selected.

[0051]

[0057] In one embodiment, the conduit is connected or capable of being connected to a syringe, in which saline can be used to deploy the foam within the patient.

[0052]

[0058] Example 10.1. The system of Example 9, wherein the SMP foam has a maximum outer diameter of 1.2 mm or less in a first state and is configured to be compressed in the first state and expanded to a second state.

[0053]

[0059] However, in other embodiments, larger embodiments of the SMP foam may be used, having a maximum outer diameter in the first state of 1.2, 1.5, 1.8, 2.0 mm or more.

[0060] In one embodiment, the crimped / compressed shape is generally planar, cylindrical, spherical, etc. Such various shapes may be the same or different permanent shapes (e.g., rectangular, oval, spherical, etc.).

[0054]

[0061] Example 11. The system of any of Examples 9-10.1, wherein the conduit comprises an 18 gauge or smaller needle.

[0055]

[0062] This size may be important for some applications (e.g., pediatrics, veterinary). For example, adding hydrogel to the foam may limit the crimp to 1.33 mm, which may not fit within an 18 G needle. However, embodiments in which PVA is used to bind the drug to the foam may be included in an 18 G needle. Injection needles exceeding the 18 G limit may not be considered "injections" in some countries and therefore may be invasive procedures, increasing the risks and costs of treatment. Furthermore, the smaller crimp outer diameter (enabled, at least in part, by the use of PVA) may better facilitate deployment via, for example, intravascular means that must traverse tortuous vasculature and / or other deployment routes that benefit from a small form factor.

[0056]

[0063] Example 12. The system of any of Examples 1-11, wherein the material composition directly contacts one of the cells of the SMP foam.

[0057]

[0064] Example 13. The system of Example 12, wherein the material composition directly contacts the interior wall of one of the cells of the SMP foam.

[0065] In other words, the material composition is not simply in a PVA shell surrounding the foam, instead, the material composition is actually contained within some of the cells.

[0058]

[0066] In embodiments, the agent comprises a small molecule of up to about 900 daltons or less. This may be necessary for inclusion within a small cell foam that can be compressed to a desired outer diameter suitable for injection through a needle, catheter, sheath, etc. In other embodiments, the agent can comprise a small molecule, that is a molecule of less than 1000, 800, 700, or 600 daltons.

[0059]

[0067] The inventors have found that loading small molecule drugs into foams with cells / pores with maximum diameters of microns or larger is difficult, given that small molecules (as the term is used herein) are approximately 900 daltons or smaller. Chemotherapeutic agents typically use small molecules, but these molecules may desorb from foams (whose cells have, on average, maximum diameters of microns or larger) immediately after implantation. Therefore, immersing the foam in a small molecule drug solution may result in poor drug uptake or lack of controlled drug release. However, in one embodiment, the incorporation of PVA improves drug loading in implantable SMP foams. PVA is a water-based solution that acts as a viscosity modifier. Using PVA, small molecules with diameters of approximately 900 daltons or smaller could be retained within the open cells of SMP foams with diameters greater than approximately 900 daltons. Using PVA, small molecules with diameters of approximately 900 daltons or smaller could be retained within the open cells of SMP foams with diameters greater than 1 micron.

[0060]

[0068] Example 14. The system of Example 13, wherein one of the cells of the SMP foam is contained within an interior portion of the SMP foam and is substantially surrounded by additional cells, the additional cells being contained in mutually orthogonal planes.

[0061]

[0069] Thus, interior cells located within the interior portion of the foam can still contain drug within the cells (and the drug is not simply within a PVA shell surrounding the foam). Providing drug in foams of different depths can result in a longer delivery profile.

[0062]

[0070] In one embodiment, a small molecule drug (e.g., acriflavine) may be located within the PVA and within the foam, but not necessarily within the PVA. This allows the drugs to be released at different times. For example, a drug not contained in the PVA but present in the foam may be released after a drug contained in the PVA but not necessarily within the foam. Such PVA-encapsulated drugs may be on the outer surface of the foam and held in place by the PVA, which binds the drug to the foam. Thus, while the SMP foam without PVA may not necessarily be able to incorporate as much drug as one with PVA, a foam that combines a portion of drug encapsulated in PVA with a portion of drug not encapsulated in PVA may still be beneficial.

[0063]

[0071] One embodiment may be a PVA-coated SMP with bimodal or trimodal release kinetics, resulting in an immediate release of PVA and one or more delayed boluses of drugs that may be the same or different drugs loaded directly into the SMP polymer network.

[0064]

[0072] In some embodiments, the cells of the foam can contain a first drug contained in a PVA shell surrounding the foam, and a second drug contained in and contained within the PVA. The chemical compositions of the first drug and the second drug can be the same or different. In this arrangement, the first drug can elute first, followed by the second drug.

[0065]

[0073] In some embodiments, the cells of the foam can contain a first drug contained in a PVA shell surrounding the foam, a second drug in the outer cells of the foam that may or may not be contained in PVA, and a third drug in the inner cells of the foam that may or may not be contained in PVA. The chemical compositions of the first drug, second drug, and third drug can be the same or different. In this arrangement, the first drug can elute first, followed by the second drug, and then the third drug.

[0066]

[0074] Example 15. The system of any of Examples 1-11, wherein the therapeutic agent is encapsulated by at least one of a polymer, a liposome, a micellar particle, or a combination thereof.

[0067]

[0075] Some embodiments include, for example, tertiary delayed release of drug via a triggered mechanism (e.g., ultrasonically disrupted microbeads loaded with additional drug) or an automatic mechanism (e.g., a suitably bound drug that is released upon degradation). For example, in some embodiments, a portion of the drug can be contained within a foam in an unencapsulated state, while another portion of the foam can be contained within a foam in an encapsulated state. The drug released first can be the unencapsulated drug, and then, when the encapsulated drug is exposed to sufficient energy (e.g., ultrasound), the encapsulated drug can be released. The unencapsulated drug and the encapsulated drug can be different drugs or the same drug.

[0068]

[0076] Such embodiments may have advantages over systems using foams and drug-loaded hydrogels, where the foams tend to dissolve the hydrogel quickly upon contact with the physiological environment, and drug release can then be better controlled by loading either free drug or drug encapsulated within polymers, liposomes, or micelle-like particles.

[0069]

[0077] The drug release profile can be tailored depending on the desired therapeutic effect. For example, the delivery profile can be altered by using drug-encapsulated nanoparticles instead of free drug. Drug-encapsulating vehicles (including microparticles, nanoparticles, and hydrogels) can provide delayed, sustained release when the particles are released from the foam. Thus, drug-eluting SMP foams can promote short-term and long-term drug delivery, depending on the type of payload and PVA used. The amount of drug released can also be optimized based on the drug stock concentration.

[0070]

[0078] Example 16. The encapsulated therapeutic agent is contained in at least one of polyvinyl alcohol (PVA), carboxymethyl cellulose, or a combination thereof; The system of Example 15, wherein the at least one of the PVA, carboxymethyl cellulose, or combination thereof is between the walls of the SMP foam cells and the encapsulated therapeutic agent such that the encapsulated therapeutic agent does not directly contact the walls.

[0071]

[0079] Example 17. A method comprising forming a void in tissue of a patient and placing a device according to any of Examples 1-10.1 or 12-16 within said void.

[0072]

[0080] Example 18. A method comprising: forming a void in tissue of a patient; positioning a distal end of a conduit according to any of Examples 9-11 within the void, wherein the conduit includes a device of any of Examples 1-16; and moving the device from within the conduit into the void.

[0073]

[0081] Example 19. Forming a composition comprising (a) at least one therapeutic agent, (b) dimethyl sulfoxide (DMSO), and (c) at least one of polyvinyl alcohol (PVA), carboxymethyl cellulose, or a combination thereof; applying the composition to an open-cell shape memory polymer (SMP) foam to form a combination of the SMP foam and the composition; drying the combination at a pressure less than 1,013.25 mbar; programming the SMP foam to a primary shape; and forming the SMP foam into a stable secondary shape. wherein the SMP foam is configured to be controllably actuated to resume the primary shape, and the SMP foam in the secondary shape comprises the SMP foam, the at least one therapeutic agent, the DMSO, and at least one of the PVA, the carboxymethylcellulose, or a combination thereof, wherein the at least one therapeutic agent comprises at least one of a drug, a peptide, a protein, an antigen, a nucleic acid, an anesthetic, an antihistamine, an antifungal, a vasodilator, an anti-inflammatory, an immunosuppressant, a growth factor, a cytokine, an interleukin, or a combination thereof.

[0074]

[0082] However, in other embodiments, substitutes for DMSO, such as ethanol, salt-based solvents, and water-based solvents, can be used instead of or in addition to DMSO. In other embodiments, DMSO or its substitutes can be removed during the manufacturing process so that DMSO or its substitutes are no longer present in the SMP foam in its secondary form. The solvent (e.g., DMSO) can be present in the therapeutic agent (anticancer agent) itself.

[0075]

[0083] In some embodiments, the drug and PVA may be added to the foam at the same time, while in other embodiments, they may be added to the foam separately.

[0076]

[0084] In one embodiment, the drug is loaded into the foam by solvent swelling with DMSO, and the drug-containing foam is then loaded into a PVA hydrogel surrounding the foam, forming a composite of the hydrogel and foam.

[0077]

[0085] A method comprising: (1) heating an SMP foam / PVA / drug device above its Tg and holding it in a desired shape for packaging; (2) cooling the device below its Tg and programming the packaged shape into the device; (3) EtO sterilizing the device and packaging and storing it at a temperature below 30°C; (4) removing the foam from the package and inserting it somewhere within a patient to apply it; (5) plasticizing the foam at body temperature, expanding and filling some or all of the voids; and (6) allowing drug elution over time.

[0078]

[0086] Example 20. A porous, biodegradable / bioabsorbable shape memory polymer (SMP) foam used to fill voids within tissue remaining from surgery or other procedures associated with removing cancerous, precancerous, or other tissue from a patient to prevent metastasis.

[0079]

[0087] Example 21. The SMP foam of Example 20 loaded with and eluted with one or more anti-cancer therapeutic agents (single therapeutic agents of a combination).

[0080]

[0088] Example 22. Drug-loaded spherical foams can also be injected into blood vessels supplying tumors, potentially increasing drug concentrations at the site of the tumor and minimizing side effects due to damaging normal tissue.

[0081]

[0089] Examples of therapeutic agents that can be loaded into SMP foams include, but are not limited to, small molecules, antigens, and peptides used as anti-cancer drugs, such as doxorubicin, cisplatin, and paclitaxel. Other examples of therapeutic agents include, but are not limited to, antibiotics used to treat infectious diseases, such as amoxicillin, doxycycline, and cephalexin. Other therapeutic agents that can be loaded into foams include antigens, proteins, and nucleic acids.

[0082]

[0090] Payloads loaded into the foam also include local anesthetics, antihistamines, antifungals, vasodilators, anti-inflammatory agents, and immunosuppressants.

[0083]

[0091] Examples of carrier materials that can be loaded with drugs and coated onto and into SMP foams include PVA, CMC, hydrogels, and other polymeric nanoparticles that can alter the release profile.

[0084]

[0092] Example 1a. A device comprising: a shape memory polymer (SMP) foam comprising open cells and additional open cells, the SMP foam having a first and second state; and a material composition contained in the open cells, wherein the material composition comprises (a) a therapeutic agent and (b) at least one of polyvinyl alcohol (PVA), carboxymethyl cellulose, or a combination thereof, and the therapeutic agent comprises at least one of a drug, a peptide, a protein, an antigen, a nucleic acid, an anesthetic, an antihistamine, an antifungal, a vasodilator, an anti-inflammatory agent, an immunosuppressant, a growth factor, a cytokine, an interleukin, or a combination thereof.

[0085]

[0093] Examples of such additives include at least one of PVA, carboxymethylcellulose, or combinations thereof, while other embodiments may include viscosity-increasing agents such as acacia, agar, alamic acid, aluminum monostearate, attapulgite, bentonite, carbomer, calcium carboxymethylcellulose, sodium carboxymethylcellulose, carrageenan, cellulose, dextrin, gelatin, gellan gum, guar gum, hydroxyethylcellulose, hydroxypropylcellulose, hypromellose, magnesium aluminum silicate, maltodextrin, methylcellulose, microcrystalline cellulose, pectin, polyethylene oxide, povidone, propylene glycol alginate, silicon dioxide, sodium alginate, starch (corn, potato, tapioca, wheat), tragacanth, xanthum gum, or combinations thereof (depending on the application of the embodiment).

[0086]

[0094] In one embodiment, the material composition can cause the drug to fluoresce to aid healthcare providers in monitoring drug release (via imaging) over time.

[0087]

[0095] A variation of Example 1a: A device comprising: a shape memory polymer (SMP) foam comprising open cells and further open cells, the SMP foam having a first and a second state; and a fluorescent material composition contained in the open cells, wherein the fluorescent material composition comprises (a) a therapeutic agent and (b) at least one of polyvinyl alcohol (PVA), carboxymethyl cellulose, or a combination thereof, and the therapeutic agent comprises at least one of a drug, a peptide, a protein, an antigen, a nucleic acid, an anesthetic, an antihistamine, an antifungal, a vasodilator, an anti-inflammatory agent, an immunosuppressant, a growth factor, a cytokine, an interleukin, or a combination thereof.

[0088]

[0096] A variation of Example 1a: A device comprising: a shape memory polymer (SMP) foam comprising open cells and additional open cells, the SMP foam having a first and second state; and a material composition contained within the open cells, wherein the material composition comprises (a) a therapeutic agent and (b) at least one of polyvinyl alcohol (PVA), carboxymethyl cellulose, or combinations thereof, and the therapeutic agent comprises at least one of a drug, a peptide, a protein, an antigen, a nucleic acid, an anesthetic, an antihistamine, an antifungal, a vasodilator, an anti-inflammatory agent, an immunosuppressant, a growth factor, a cytokine, an interleukin, or combinations thereof; wherein the SMP foam is configured to expand into an irregularly shaped tissue void when expanded from the first state to the second state, thereby physically compressing the SMP foam directly against the margins of the irregularly shaped tissue void.

[0089]

[0097] A variation of Example 1a: A device comprising: a shape memory polymer (SMP) foam comprising open cells and additional open cells, the SMP foam having a first and second state; and a material composition contained within the open cells, wherein the material composition comprises (a) a therapeutic agent and (b) at least one of polyvinyl alcohol (PVA), carboxymethyl cellulose, or combinations thereof, and the therapeutic agent comprises at least one of a drug, a peptide, a protein, an antigen, a nucleic acid, an anesthetic, an antihistamine, an antifungal, a vasodilator, an anti-inflammatory agent, an immunosuppressant, a growth factor, a cytokine, an interleukin, or combinations thereof, wherein the SMP foam is configured to expand into an irregularly shaped tissue void when expanded from the first state to the second state, thereby conforming to the irregularly shaped margins of the irregularly shaped tissue void.

[0090]

[0098] The embodiments featured herein provide (1) precise plugging of tissue gaps after surgery, and / or (2) high loading and controlled release of chemotherapeutic agents to prevent cancer recurrence and metastasis. In embodiments, (1) increasing the PVA concentration has been shown to improve drug loading by ∼80% and / or (2) delayed burst and sustained release of drug was achieved based on the PVA concentration used.

[0091]

[0099] As a result, certain embodiments include drug-loaded SMP foams that can effectively seal tissue voids while enhancing the uptake of chemotherapy drugs, thereby providing a viable solution to metastasis following tumor resection.

[0092]

[0100] A variation of Example 1a: A device comprising: a shape memory polymer (SMP) foam comprising open cells and further open cells, the SMP foam having a first and a second state; and a material composition contained in the open cells, wherein the therapeutic agent comprises at least one of a drug, a peptide, a protein, an antigen, a nucleic acid, an anesthetic, an antihistamine, an antifungal, a vasodilator, an anti-inflammatory, an immunosuppressant, a growth factor, a cytokine, an interleukin, or a combination thereof.

[0093]

[0101] Example 2a. The apparatus of Example 1a, wherein the SMP foam is configured to expand from a first state to a second state when the SMP foam is plasticized at 37°C and a glass transition temperature (Tg) of the SMP foam drops below 25°C.

[0094]

[0102] Example 3a. The device of Example 2a, wherein the SMP foam comprises a reaction product of at least a first component and a second component, wherein the first component comprises at least one of hexamethylene diisocyanate (HDI), trimethylhexamethylene diisocyanate (TMHDI), or a combination thereof, and the second component comprises at least one of triethanolamine (TEA), hydroxypropylethylenediamine (HPED), or a combination thereof.

[0095]

[0103] Example 4a. The device of Example 2a, wherein the SMP foam comprises a reaction product of at least a first component and a second component, wherein the first component comprises at least one of hexamethylene diisocyanate (HDI), trimethylhexamethylene diisocyanate (TMHDI), or a combination thereof, and the second component comprises at least one of glycerol, 1,2,6-hexanetriol (HT), 3-methyl-1,5-pentanediol (MPD), 2-butyl-2-ethylpropanediol (BEP), or a combination thereof.

[0096]

[0104] Example 5a. The device of Example 2a, wherein the SMP foam comprises a reaction product of at least a first component, a second component, and a third component, wherein the first component comprises at least one of hexamethylene diisocyanate (HDI), trimethylhexamethylene diisocyanate (TMHDI), or a combination thereof; the second component comprises at least one of glycerol, 1,2,6-hexanetriol (HT), 3-methyl-1,5-pentanediol (MPD), 2-butyl-2-ethylpropanediol (BEP), or a combination thereof; and the third component comprises at least one of 5-amino-2,4,6-triiodoisophthalic acid (ATIPA), iohexol, triiodophenol, or a combination thereof.

[0097]

[0105] Example 6a. The device of any of Examples 1a-5a, wherein the therapeutic agent comprises at least one of doxorubicin, cisplatin, paclitaxel, amoxicillin, doxycycline, cephalexin, or a combination thereof.

[0106] Example 7a. The apparatus of any of Examples 1a-6a, comprising a conduit, said conduit comprising SMP foam.

[0107] Example 8a. The apparatus of Example 7a, wherein the conduit comprises additional instances of the SMP foam.

[0108] Variation of Example 8a: The device of Example 7a, wherein the conduit comprises another open-celled SMP foam, the other SMP foam having first and second states, and the other open-celled material composition comprises (a) another therapeutic agent and (b) at least one of PVA, carboxymethylcellulose, or a combination thereof, wherein the other therapeutic agent comprises at least one of a drug, a peptide, a protein, an antigen, a nucleic acid, an anesthetic, an antihistamine, an antifungal, a vasodilator, an anti-inflammatory agent, an immunosuppressant, a growth factor, a cytokine, an interleukin, or a combination thereof, and the material composition comprises a first amount of at least one of PVA, carboxymethylcellulose, or a combination thereof, and the other material composition comprises a second amount of at least one of PVA, carboxymethylcellulose, or a combination thereof; and the first amount is not equal to the second amount.

[0098]

[0109] Variation of Example 8a: The device of Example 7a, wherein the conduit comprises another open-cell SMP foam, the other SMP foam having first and second states, the other material composition comprising at least one of (a) another therapeutic agent and (b) another PVA, carboxymethylcellulose, or a combination thereof, wherein the other therapeutic agent comprises at least one of a drug, a peptide, a protein, an antigen, a nucleic acid, an anesthetic, an antihistamine, an antifungal, a vasodilator, an anti-inflammatory agent, an immunosuppressant, a growth factor, a cytokine, an interleukin, or a combination thereof, the material composition comprising a first amount of the therapeutic agent and the other material composition comprising a second amount of the other therapeutic agent, the first amount not equal to the second amount.

[0099]

[0110] Example 9a. The SMP foam has a maximum outer diameter of 1.2 mm or less in a first state; The device of Example 7a, configured to be compressed in the first state and expand to a second state.

[0100]

[0111] For example, if a hydrogel were used instead of PVA, it would be extremely difficult to crimp such a small diameter.

[0101]

[0112] Example 10a. The device of Example 9a, wherein the conduit comprises an 18 gauge or smaller needle.

[0102]

[0113] However, in other embodiments, a needle or conduit may not be necessary: ​​for example, a healthcare provider may wish to simply pick up an SMP foam described herein and apply it directly to tissue using their hand (e.g., tumor resection).

[0103]

[0114] Example 11a. The device of Example 9a, wherein the open cells have a maximum diameter of at least 50 microns and the therapeutic agent has a size of 900 daltons or less.

[0115] In other embodiments, the maximum diameter of the open cells is between 50 microns and 2 mm, hi other embodiments, the maximum diameter of the open cells is less than 2 mm but greater than 50, 75, 100, 125, 150, 175, or 200 microns.

[0104]

[0116] Example 12a. The open cells include at least one of a strut and an interior wall; The device of Example 9a, wherein the material composition directly contacts at least one of the struts and the interior wall.

[0105]

[0117] Example 13a. The device of Example 12a, wherein the open cells are contained within the SMP foam, are substantially surrounded by further open cells, and do not directly contact the exterior surface of the SMP foam.

[0106]

[0118] Example 14a. The device of any of Examples 1a-13a, wherein the therapeutic agent is encapsulated by at least one of a polymer, a liposome, a micelle particle, or a combination thereof.

[0107]

[0119] Example 15a. The device of Example 14a, wherein the encapsulated therapeutic agent is contained in at least one of PVA, carboxymethylcellulose, or a combination thereof, and the at least one of PVA, carboxymethylcellulose, or a combination thereof is between the walls of the SMP foam cells and the encapsulated therapeutic agent such that the encapsulated therapeutic agent does not directly contact the walls.

[0108]

[0120] Example 16a. The device of Example 1a, comprising a coating, wherein the open cells comprise struts, the coating is on the struts, and the coating comprises a material composition.

[0109]

[0121] Example 17a. The device of Example 16a, wherein an interior portion of the strut includes at least one of the therapeutic agent, an additional therapeutic agent, or a combination thereof.

[0110]

[0122] See, for example, Figure 4. Agents (e.g., drugs) may be incorporated into the struts via a solvent (e.g., DMSO). Based on the foam chemistry in certain embodiments (e.g., Examples 3a-5a), the PVA coating cannot by itself carry the agent into the SMP strut. Without the solvent, the agent would remain within the carrier coating. Therefore, the use of a solvent can contribute to the incorporation of the agent into the strut (rather than just on the strut).

[0111]

[0123] As a method, strut above The struts (or SMP foam cell walls or general base) are loaded with the drug in a separate process. Inside For example, drug A is first loaded onto the SMP strut using a solvent. Inside Next, drug B (or additional drug A) is loaded onto the strut surface using a carrier coating.

[0112]

[0124] Variation of Example 17a: The device of Example 16a, wherein (a) when the SMP foam is in a first state, an interior portion of the strut comprises at least one of a therapeutic agent, an additional therapeutic agent, or a combination thereof, and (b) when the SMP foam is in a second state, an interior portion of the strut comprises at least one of a therapeutic agent, an additional therapeutic agent, or a combination thereof.

[0113]

[0125] Example 18a: The device of Example 16a, wherein the therapeutic agent of the coating is configured to elute from the SMP foam into the patient's tissue during a first period of time, and wherein an interior portion of the strut comprises at least one of the therapeutic agent, an additional therapeutic agent, or a combination thereof, and is configured to elute from the SMP foam into the patient's tissue during a second period of time, the second period of time occurring at least one day after the first period of time.

[0114]

[0126] For example, drug A in the coating may elute into the surgical margin tissue over a first time frame (e.g., 1-48 hours), while drug B (or drug A or drugs A and B) within the strut may elute into the tissue more slowly (e.g., after 48 hours or 1 week). This may occur because the drug within the strut elutes from the intact strut. However, it may also occur because the strut is biodegradable and degrades over time. As the strut degrades, any drug within it elutes into the surrounding tissue.

[0115]

[0127] The above scenarios are examples of "dual release" mechanisms in which a drug (drug A) is released from the coating (first pathway of dual release) and drugs (drugs A, B, or A and B) are released from within the strut or cell platform components (second pathway of dual release).

[0116]

[0128] In one embodiment, the drug (in the coating or strut) may be hydrophilic. This is noteworthy because hydrophilic drugs may not dissolve in organic solvents. Doxorubicin and acriflavine are soluble in DMSO and water. The presence of DMSO (even in trace amounts) in the foam contributes to the expansion of the foam (resulting in more drug penetrating into the foam core). Hydrophilic drugs can be loaded into the struts or cell walls of Examples 3a-5a using solvents such as organic solvents. Examples of such solvents include DMSO, methanol, ethanol, propanol, dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), and glycerol. Some of these solvents may be unsuitable for certain applications due to their interaction with tissue if they remain in the SMP foam.

[0117]

[0129] Example 19a. The device of any of Examples 17a-18a, wherein an interior portion of the strut comprises an additional therapeutic agent.

[0118]

[0130] Example 20a. The device of any of Examples 17a-19a, wherein the interior portion of the strut does not include at least one of PVA, carboxymethyl cellulose, or a combination thereof.

[0119]

[0131] Variation of Example 20a: The device of any of Examples 17-19, wherein the interior portion of the strut does not include at least one of PVA, carboxymethyl cellulose, or a combination thereof, and the material composition is not crosslinked around the periphery of the strut.

[0120]

[0132] In one embodiment, the maximum diameter of the open cells is at least 50 microns and the therapeutic agent is 900 daltons or less. However, if the material composition surrounding the struts is not crosslinked, delayed or sustained release of the drug becomes more difficult. Therefore, the use of a viscosity-enhancing carrier polymer can help address the lack of crosslinking in the material composition to sustain drug release.

[0121]

[0133] In one embodiment, the material composition is not chemically bonded (e.g., covalently bonded) to the foam. Instead, the material composition is physically contained within the material composition, thereby avoiding damage to the agent in any way.

[0122]

[0134] The above description of embodiments of the present invention has been presented for purposes of illustration and description. It is not intended to be exhaustive or to limit the invention to the precise form disclosed. The present specification and claims include terms such as left, right, top, bottom, bottom, first, and second, but these terms are used for descriptive purposes only and should not be construed as limiting. For example, terms indicating relative vertical position refer to the situation where the side of a substrate is the "top" surface of that substrate. While the "top" surface of a substrate may be lower than the "bottom" surface in a standard ground reference frame, the substrate may actually be in any orientation within the meaning of the term "top." As used herein, the term "top" does not imply that a second layer is directly between and in direct contact with a first layer and a second layer above the first layer; a third layer or other structure may exist between the first layer and a second layer above the first layer. The embodiments of devices or articles described herein can be manufactured, used, or transported in numerous configurations and orientations. Those skilled in the art will appreciate that many modifications and variations are possible in light of the above teachings. Those skilled in the art will recognize various equivalent combinations and substitutions for the various components shown in the figures. Accordingly, it is intended that the scope of the invention be limited not by this detailed description, but rather by the claims appended hereto.

Claims

1. below: A shape memory polymer (SMP) foam comprising open cells and further open cells, the SMP foam having a first and a second state; a material composition contained in the open cells; and coating 1. An apparatus comprising: the material composition includes: (a) a therapeutic agent; and (b) at least one of polyvinyl alcohol (PVA), carboxymethyl cellulose, or a combination thereof; and the therapeutic agent comprises at least one of a drug, a peptide, a protein, an antigen, a nucleic acid, an anesthetic, an antihistamine, an antifungal, a vasodilator, an anti-inflammatory, an immunosuppressant, a growth factor, a cytokine, an interleukin, or a combination thereof; the open cell includes at least one strut; the coating is on the strut; and the coating comprises the material composition; the therapeutic agent of the coating is configured to elute from the SMP foam into the patient's tissue during a first period of time; an interior portion of the strut includes at least one of a therapeutic agent, an additional therapeutic agent, or a combination thereof, configured to elute from the SMP foam into the patient's tissue during a second period of time; the second period of time occurs at least one day after the first period of time; Device.

2. 10. The device of claim 1, wherein the SMP foam is configured to expand from a first state to a second state when the SMP foam is plasticized at 37°C and a glass transition temperature (Tg) of the SMP foam drops below 25°C.

3. The SMP foam comprises a reaction product of at least a first component and a second component, wherein: the first component comprises at least one of hexamethylene diisocyanate (HDI), trimethylhexamethylene diisocyanate (TMHDI), or a combination thereof; and the second component comprises at least one of triethanolamine (TEA), hydroxypropylethylenediamine (HPED), or a combination thereof; 3. The apparatus of claim 2.

4. The SMP foam comprises a reaction product of at least a first component and a second component, wherein: the first component comprises at least one of hexamethylene diisocyanate (HDI), trimethylhexamethylene diisocyanate (TMHDI), or a combination thereof; and the second component comprises at least one of glycerol, 1,2,6-hexanetriol (HT), 3-methyl-1,5-pentanediol (MPD), 2-butyl-2-ethylpropanediol (BEP), or a combination thereof; 3. The apparatus of claim 2.

5. The SMP foam comprises a reaction product of at least a first component, a second component, and a third component, wherein: the first component comprises at least one of hexamethylene diisocyanate (HDI), trimethylhexamethylene diisocyanate (TMHDI), or a combination thereof; the second component comprises at least one of glycerol, 1,2,6-hexanetriol (HT), 3-methyl-1,5-pentanediol (MPD), 2-butyl-2-ethylpropanediol (BEP), or a combination thereof; the third component comprises at least one of 5-amino-2,4,6-triiodoisophthalic acid (ATIPA), iohexol, triiodophenol, or a combination thereof; 3. The apparatus of claim 2.

6. The device of any one of claims 1 to 5, wherein the therapeutic agent comprises at least one of doxorubicin, cisplatin, paclitaxel, amoxicillin, doxycycline, cephalexin, or combinations thereof.

7. 6. The apparatus of any one of claims 1 to 5, comprising a conduit, said conduit comprising SMP foam.

8. the conduit includes another open-cell SMP foam, the other SMP foam having a first and a second state; another material composition contained in the other open cells, the other material composition comprising (a) another therapeutic agent, and (b) another at least one of PVA, carboxymethyl cellulose, or a combination thereof, wherein: the other therapeutic agent comprises at least one of a drug, a peptide, a protein, an antigen, a nucleic acid, an anesthetic, an antihistamine, an antifungal, a vasodilator, an anti-inflammatory, an immunosuppressant, a growth factor, a cytokine, an interleukin, or a combination thereof; the material composition comprises a first amount of at least one of PVA, carboxymethyl cellulose, or a combination thereof; the other material composition includes another second amount of at least one of PVA, carboxymethyl cellulose, or a combination thereof; the first amount is not equal to the second amount; 8. The apparatus of claim 7.

9. the SMP foam has a maximum outer diameter of 1.2 mm or less in a first state; configured to be compressed in the first state and expand to a second state; 8. The apparatus of claim 7.

10. 10. The device of claim 9, wherein the conduit comprises an 18 gauge or smaller needle.

11. 10. The device of claim 9, wherein the open cells have a maximum diameter of at least 50 microns and the therapeutic agent has a size of 900 Daltons or less.

12. the open cells further include an interior wall; the material composition directly contacts the inner wall; 10. The apparatus of claim 9.

13. The open cells are Contained within the SMP foam, surrounded by further open cells, and 13. The device of claim 12, wherein the device does not directly contact the exterior surface of the SMP foam.

14. The device of any one of claims 1 to 5, wherein the therapeutic agent is encapsulated by at least one of a polymer, a liposome, a micelle particle, or a combination thereof.

15. the encapsulated therapeutic agent is contained in at least one of PVA, carboxymethylcellulose, or a combination thereof; 15. The device of claim 14, wherein the at least one of the PVA, carboxymethyl cellulose, or combination thereof is between the walls of the SMP foam cells and the encapsulated therapeutic agent such that the encapsulated therapeutic agent does not directly contact the walls.

16. 10. The device of claim 1, wherein an interior portion of the strut includes at least one of the therapeutic agent, an additional therapeutic agent, or a combination thereof, and wherein the strut is biodegradable and the therapeutic agent is a hydrophilic therapeutic agent.

17. an interior portion of the strut does not include at least one of PVA, carboxymethyl cellulose, or a combination thereof; and the material composition is not crosslinked around the strut; 10. The apparatus of claim 1.

Images