Drug eluting shape memory foam

Abstract

Tumor resection is often performed to prevent progression of cancer. However, there are post-surgical concerns, including the formation of voids that can allow cancer cells to escape at the site of surgery, which increases the risk of metastasis. To combat this challenge, embodiments include a polyurethane-based shape memory foam as a tissue void filling device that can also release an anti-cancer drug. Such a foam can activate at body temperature and become malleable. Such properties can enable the foam to be shaped to precisely seal a tissue void and then serve as a drug eluting device. Based on the drug composition with polyvinyl alcohol (PVA), the characteristics of drug release from the foam can be varied depending on the application.

Description

[0001] Cross-references to related applications

[0002] 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. Technical Field

[0003] The embodiments of the present invention belong to the field of medical devices. Background Technology

[0004] Cancer is the second leading cause of death, and is estimated to have caused approximately 600,000 deaths in the United States alone in 2019. For solid tumors, one of the main medical interventions involves surgery, in which the tumor is removed along with a portion of the surrounding tissue to ensure no cancer cells remain. However, salvaging normal tissue is crucial in vital organs such as the lungs, and there is currently no accurate method to predict the boundaries of cancer cells. This can potentially lead to the retention of cancer cells, which can subsequently cause cancer recurrence. Furthermore, research has linked the increased likelihood of metastasis to either a) the presence of tissue gaps after resection (through which cancer cells can escape) or b) postoperative stress. Typically, tissue gaps are closed after surgery using either biodegradable or non-biodegradable sutures. Several challenges exist associated with suturing methods, including complications related to ineffective wound healing and the removal of sutures from non-soluble sutures. In the case of soluble sutures, the degradation rate can be accelerated depending on the patient's physiological condition. For example, if a patient has a high fever, the sutures are more likely to degrade faster than predicted, potentially leading to inadequate wound healing. Attached Figure Description

[0005] The features and advantages of embodiments of the invention will become apparent from the appended claims, the following detailed description of one or more exemplary embodiments, and the corresponding drawings. Reference numerals in the drawings are repeated where appropriate to indicate corresponding or similar elements.

[0006] Figure 1 This includes a non-cumulative release curve from one embodiment of the present invention.

[0007] Figure 2 This includes a non-cumulative release curve from one embodiment of the present invention.

[0008] Figure 3 This includes a non-cumulative release curve from one embodiment of the present invention.

[0009] Figure 1-3 The Y-axis depicts the mass of the reagent eluted from the foam.

[0010] Figure 4 The cross-section of a shape memory polymer foam support, including one embodiment of the present invention.

[0011] Detailed description

[0012] Referring now to the accompanying drawings, similar structures may be provided with similar suffix reference numerals. To illustrate the structures of the various embodiments more clearly, the drawings included herein are illustrative representations of the structures. Therefore, the actual appearance of a manufactured structure may differ, for example, in a photograph, yet still be consistent with the claimed structure of the illustrated embodiment (e.g., in an actual manufactured device, the walls may not be exactly orthogonal to each other). Furthermore, the drawings may only show structures useful for understanding the illustrated embodiments. Other structures known in the art may not be included to maintain clarity of the drawings. For example, not every layer of the device may be shown. Terms such as “one embodiment,” “various embodiments,” etc., indicate that the described embodiment may include specific features, structures, or characteristics, but not every embodiment must include specific features, structures, or characteristics. Some embodiments may have some, all, or none of the features described for other embodiments. Terms such as “first,” “second,” “third,” etc., describe common objects and indicate different instances of similar objects mentioned. Such adjectives do not imply that the described objects must be in a given order in time, space, sequence, or any other manner. "Connection" can indicate that elements are in direct physical or electrical contact with each other, while "coupling" can indicate that elements cooperate or interact with each other, but they may or may not be in direct physical or electrical contact. Phrases such as "containing at least one of A or B" include cases with A, B, or A and B.

[0013] To address the aforementioned issues, biodegradable sutures have been widely used for wound closure postoperatively. Efforts have also been made to utilize sutures as drug delivery systems. However, due to numerous challenges, including suboptimal mechanical strength of the sutures and the inability to achieve sustained drug release, the applicant has determined that very few drug-eluting sutures are clinically transferable. The applicant further determined that poor control over drug release from the suture (or even the ability to load drug onto the suture) further impairs therapeutic efficacy. Sutures are frequently immersed in the drug solution, resulting in an immediate and uncontrolled release of the drug. Consequently, the residence time of the drug in the body to achieve the desired therapeutic effect is much shorter. The applicant has identified another major problem associated with absorbable sutures: increased inflammation. In the context of tumor resection, sutures often fail to facilitate precise wound closure. Therefore, wound areas not in contact with the sutures may pave the way for the escape of residual cancer cells.

[0014] Postoperative biodegradable implants, such as hydrogels, are alternatives to sutures. A key characteristic of hydrogels is their ability to release drugs. Hydrogels can be engineered to further release the load in response to various stimuli, including temperature and pH. For example, the tumor microenvironment tends to have a lower pH compared to physiological pH. Hydrogels can be chemically engineered to be sensitive to low pH environments, resulting in preferential load delivery within the tumor microenvironment. While this is a theoretically effective alternative to drug-eluting sutures for controlled drug delivery, the applicant determined that hydrogels do not possess sufficient tensile strength to allow for precise control over the timing of drug release or wound sealing. The increased water content in hydrogels creates a non-rigid and liquid structure, rendering them ineffective for precisely sealing tissue voids. This mechanical property also causes premature dissolution of the device, leading to uncontrolled release of the load.

[0015] In light of the above, the applicant determined that a platform is needed to more precisely seal tissue gaps while simultaneously preventing the development of metastasis in treatment.

[0016] To this end, the implementation scheme includes an SMP foam, which can be used to match pores based on the SMP properties of the foam. The foam is loaded with small therapeutic molecules to promote the killing of residual cancer cells near the excised surface. Therefore, such an implementation scheme offers advantages over conventional techniques because such foams are biocompatible and can be loaded with drugs having tunable release properties to prevent or slow the recurrence of malignant diseases.

[0017] Small molecule drugs can be loaded onto or into foams by co-cultivating foams with drugs in a polyvinyl alcohol (PVA) solution. Activation of the foam at body temperature then allows for the release of the drug (or a portion thereof) from the foam. The release time can be adjusted using different percentages of PVA, enabling a modulated drug elution device. Drug release characteristics can be adjusted by changing the chemical composition of the foam, the amount of PVA included in the foam, the pore size in the foam, the network structure of the foam pores, or combinations thereof.

[0018] The embodiments include tissue pore fillers and drug-eluting shape memory polymer (SMP) foams. SMP foams include hexamethylene diisocyanate (HDI)-based foams. However, another embodiment includes foams comprising the reaction products of hydroxypropyl ethylenediamine (HPED), triethanolamine (TEA), and 2,2,4-trimethylhexamethylene diisocyanate (TMHDI). Compared to HDI foams, TMHDI foams can have smaller pore sizes and therefore different drug delivery properties.

[0019] In this embodiment, acridine yellow (a fluorescent small molecule) is used as a loading agent to illustrate the release characteristics of the therapeutic agent from the foam. In this embodiment, PVA is used to improve reagent uptake onto or within the foam. Different drug uptake and release characteristics can be achieved using mesh-based, partially mesh-based, and non-mesh-based TMHDI-based foams or other SMP foams.

[0020] Shape memory materials possess the useful ability to be formed into a primary shape, reformed into a stable secondary shape, and then controlled to recover their primary shape. Both metallic alloys and polymeric materials can exhibit shape memory. In the case of metals, shape memory arises from a thermally induced solid-state transformation, in which the lattice structure of atoms changes, leading to macroscopic changes in modulus and size. In the case of polymeric materials, the primary shape is acquired after processing and fixed through physical structure or chemical cross-linking. The secondary shape is obtained by deforming the material while it is in an elastic state, and this shape is fixed in one of several ways, including cooling the polymer below its crystallization, liquid crystal, or glass transition temperature; or by inducing further covalent or ionic cross-linking, etc.

[0021] In the secondary shape, some or all of the polymer chains are perturbed from their equilibrium random walk conformation, exhibiting a degree of bulk orientation. The oriented chains possess a certain potential energy due to their reduced entropy, which provides the driving force for shape recovery. However, they cannot recover spontaneously due to kinetic effects (if below their lower Tg) or physical constraints (physical or chemical crosslinking). Actuation occurs to restore the primary shape by removing this constraint (e.g., heating the polymer above its glass transition temperature or melting temperature, removing ionic or covalent crosslinks, etc.). Other types of polymers that undergo shape memory behavior due to photon-induced conformational changes, conformational changes due to variations in the chemical environment (pH, ionic strength, etc.) (e.g., rod-coil transition), or structural changes due to applied fields (e.g., electric fields, magnetic fields, etc.) can also be used.

[0022] Therefore, SMPs are smart polymer materials that possess the ability to recover from a deformed state (temporary shape) to their original (permanent) shape inducible by external stimuli (triggers) such as temperature changes. SMPs can maintain two or more shapes, and the transitions between these shapes are temperature-induced. Besides temperature changes, shape changes in SMPs can also be triggered by electric or magnetic fields, light, or solvent plasticization. In addition to typical polymers, SMPs encompass a wide range of properties, from stable to biodegradable, from soft to hard, and from elastic to rigid, depending on the structural units that constitute the SMP. SMPs include thermoplastic and thermosetting (covalently cross-linked) polymer materials.

[0023] The implementation scheme offers several advantages over other technologies, such as hydrogel-based technologies. The implementation scheme utilizes a carrier polymer incorporated into the SMP foam. The applicant has determined that many SMP foams (without such a carrier polymer) may not be able to load significant amounts of drug (e.g., small molecules). Water is a small molecule, but the applicant has previously determined that after exposing the SMP foam to different humidity levels for different durations, the foam exhibits a maximum water uptake of 8.0% (by mass) after 96 hours of exposure to 100% relative humidity. Water is polar, but small, and many HDI and TMHDI-based SMP foams are relatively hydrophilic. Therefore, the applicant has determined that a carrier polymer can be incorporated into the foam to deliver or retain more drug. However, the applicant has further determined that the thickness and total mass of the carrier polymer incorporated into the foam will limit the foam's curling and / or shape recovery (which will limit the ability to deliver the foam via a tortuous path, such as using a catheter to deliver the foam through a small and tortuous vascular system). However, the applicant has determined that PVA offers advantages over conventional technologies, such as hydrogels, in that its shape recovery rate and diameter are not as limited compared to those conventional technologies. Furthermore, PVA is more tunable relative to the total mass of the deposit than many hydrogels, thus it can also help reduce curling limitations caused by increased mass. SMP foam can expand in a controlled manner while maintaining precise placement. SMP foam expands to its permanent shape within a short period of time (e.g., a few seconds) after actuation, which is much faster than conventional hydrogel-based devices.

[0024] The applicant identified key aspects of some applications, such as the potential need for timed release into local tissues for certain cancers. This may be due to the difficulty in identifying cancer margins and the inability to be certain that all cancers are surgically removed along with the tumor. Chemotherapy and radiation are secondary methods for eliminating residual margins and / or metastatic cells circulating in the bloodstream. However, release rates from PVA and SMP, and dual release, are beneficial for the local and sustained delivery of anticancer molecules targeted to tumor sites. “Dual release” addresses the release of therapeutic agents from both PVA (where PVA can be in the form of a shell outside the foam) and SMP foam (where the agent can be within the pores of the foam, with or without PVA also present in the pores).

[0025] The implementation includes a method for generating drug-eluting SMP foam. The method involves incubating foam in a 0.017 mg / mL acridine yellow solution (e.g., a 1 mg / mL acridine yellow solution in dimethyl sulfoxide (DMSO)) mixed with different PVA solutions of 0%, 1%, 2%, 3%, and 10% (w / v), and incubating overnight on a vortex mixer at room temperature (n=3). Different PVA concentrations can be used to increase drug viscosity and drug uptake onto or within the foam. In other implementations, the PVA concentration remains constant, and the acridine yellow concentration is varied (this alters the PVA viscosity). The foam can then be removed from its respective drug / PVA solution and dried in a vacuum chamber for 5 days. The foam is then incubated in 0.4 mL phosphate-buffered saline (PBS) at 37°C. The supernatant can be removed at various time points, and fluorescence at 416 / 514 nm (Ex / Em) can be measured.

[0026] Acridinium yellow concentration (mg / mL) PVA concentration (weight / volume) (%) 0.017 0 0.017 1 0.017 2 0.017 3 0.017 10

[0027] The table above shows the chemical composition of several implementation schemes.

[0028] Increasing the PVA concentration relative to the drug solution will proportionally increase the viscosity. This increased viscosity can increase the retention of the drug within the foam. Other viscosities-modifying compounds (such as carboxymethyl cellulose) can also be used (instead of PVA or other compounds) to achieve similar drug uptake and release.

[0029] In the implementation scheme, acridine yellow is used as a loading in the form of a free drug (which helps illustrate the release characteristics of drug solutions with different PVA concentrations). Implementation schemes with increased PVA concentrations will result in increased drug uptake onto or within the foam (see, for example, Figure 1 , 23). This is likely at least in part due to the increased drug viscosity when combined with PVA, which allows the drug to be trapped within or on the pores present in the foam. Embodiments involving immersing the foam in a drug solution without PVA (0% PVA) have less drug uptake compared to solutions with increased PVA concentrations. Embodiments may include depositing multiple foams onto the surgical site, where these foams have varying PVA contents and therefore varying release characteristics (this allows for drug elution over programmed time periods). Release characteristics also vary relative to the PVA content within the drug solution. Drug solutions with 0% PVA enable delayed, abrupt release, while solutions with higher PVA concentrations enable immediate release from the foam. Therefore, this drug formulation mixed with PVA can have its drug uptake and release characteristics modulated by adjusting the PVA concentration. Notably, although the anti-inflammatory drug acridine yellow is used in the embodiments, other drug molecules (e.g., doxorubicin) can be loaded onto or into the foam. Many therapeutic agents are small, hydrophobic molecules and can therefore be expected to have similar loading and release characteristics to acridine yellow. In other implementations, such a therapeutic agent may replace acridine yellow or be added to acridine yellow.

[0030] Similarly, as mentioned above, drug release characteristics can be tuned according to the desired therapeutic effect. For example, drug-encapsulated nanoparticles can be used instead of unencapsulated "free drug" to alter release characteristics. Once the particles are released from the foam, the drug-encapsulated medium (including micro and nanoparticles and hydrogels) can achieve delayed, sustained release. Therefore, depending on the load and type of PVA used, drug-eluting SMP foams can facilitate both short-term and long-term drug delivery. Drug release can also be optimized based on the drug's stock concentration.

[0031] For information on the in vitro release of acridine yellow from HDI-based SMP foam, see [link to relevant documentation]. Figure 1 .exist Figure 1 In the non-cumulative release curves, the release of acridine yellow from SMP foam increases (or at least varies) with increasing PVA concentration. This is likely due to the increased loading of acridine yellow due to PVA (and PVA's affinity for foam). Figure 2 In the study, the non-cumulative release curves showed that as the PVA concentration increased, the amount of acridine yellow released from the mesh HH80 SMP foam increased (or at least varied).

[0032] Different implementations may include different drug release characteristics, such as longer release time, no peak release, double-peak release, etc. This may be performed as explained in the claims section below.

[0033] exist Figure 3The release of acridine yellow from non-reticulated TMHDI 60 foam in vitro is discussed. Figure 3 In the non-cumulative release curves, it is shown that the amount of acridine yellow released from TH60 SMP foam increases (or at least varies) with increasing PVA concentration.

[0034] The implementation scheme includes an SMP foam loaded with doxorubicin with an increased PVA concentration, wherein the foam is rolled to a diameter of 0.8 mm. This size limitation allows for better injection of the foam into the intraperitoneal region of mice using an 18G needle.

[0035] Although SMP foams that include reagents along with PVA are sometimes compared to combinations of SMP foams and hydrogels, in some embodiments, the foam may be coupled to both the PVA / reagent portion and the reagents included in the hydrogel.

[0036] The following examples relate to further implementation schemes.

[0037] Example 1. An apparatus comprising: a shape memory polymer (SMP) foam including an open-cell structure, the SMP foam having a first state and a second state; and a material composition comprising within the open-cell structure, the material composition comprising: (a) at least one therapeutic agent, and (b) at least one of polyvinyl alcohol (PVA), carboxymethyl cellulose, or combinations thereof; wherein the at least one therapeutic agent comprises at least one of a drug, peptide, protein, antigen, nucleic acid, anesthetic, antihistamine, antifungal agent, vasodilator, anti-inflammatory agent, immunosuppressant, growth factor, cytokine, interleukin, or combinations thereof.

[0038] In some embodiments, the foam is a thermosetting polyurethane foam. In some embodiments, PVA is not chemically bonded to the foam. In some embodiments, the therapeutic agent is not chemically bonded to the foam. In some embodiments, both PVA and the therapeutic agent are not chemically bonded to the foam. In some embodiments, PVA is not chemically bonded to the therapeutic agent.

[0039] Example 1.1 An apparatus comprising: a shape memory polymer (SMP) foam including an open-cell structure, the SMP foam having a first state and a second state; and a material composition comprising within the open-cell structure, the material composition comprising: (a) at least one therapeutic agent, and (b) at least one of polyvinyl alcohol (PVA), carboxymethyl cellulose, hydrogel, or combinations thereof; wherein the at least one therapeutic agent comprises at least one of a drug, peptide, protein, antigen, nucleic acid, anesthetic, antihistamine, antifungal agent, vasodilator, anti-inflammatory agent, immunosuppressant, growth factor, cytokine, interleukin, or combinations thereof.

[0040] Example 2. The apparatus described in Example 1, wherein the SMP foam is configured to reduce the glass transition temperature (Tglass transition temperature) of the SMP foam when plasticized at 37°C. g When the temperature drops below 25°C, it expands from the first state to the second state.

[0041] For example, "plasticizing SMP foam at 37°C" includes plasticizing across a range of temperatures. Plasticizing can occur within a certain temperature range, such as 33°C to 40°C, including 37°C, but also occurs at 35°C and 39°C. Furthermore, "lowering the glass transition temperature (Tg) of SMP foam to below 25°C" includes lowering Tg to, for example, 24°C, 23°C, 22°C, 21°C, 20°C, 19°C, 18°C, 17°C, 16°C, 15°C, 14°C, 13°C, 12°C, 11°C, 10°C, 9°C, 8°C, 7°C, 6°C, 5°C, 4°C, 3°C, 2°C, 1°C, 0°C, etc.

[0042] In one embodiment, when plasticized in water at 37°C, the glass transition temperature (Tg) decreases to approximately 12°C. This allows for actuation when exposed to fluids at body temperature. In another embodiment, the SMP foam is formed into a mesh to create an open-cell structure. The pore size is adjustable between 200-1500 µm. In yet another embodiment, the SMP foam is hydrophilic. Various embodiments have tuned the hydrophilicity of the SMP, thus enabling the device to actuate at different rates.

[0043] As used herein, “body temperature” is intended to convey the range of normal body temperature. Normal body temperature varies with person, age, activity level, and time of day. The average normal body temperature is generally accepted as 98.6℉ (37°C); however, “normal” can have a wide range, from 97℉ (36.1°C) to 99℉ (37.2°C). Temperatures exceeding 100.4℉ (38°C) may indicate a fever, but are still within the range of the implementation described herein.

[0044] Example 2.1. The device described in Example 2, wherein: the SMP foam comprises at least one of hexamethylene diisocyanate (HDI), trimethylhexamethylene diisocyanate (TMHDI), or combinations thereof; the SMP foam comprises at least one of triethanolamine (TEA), hydroxypropyl ethylenediamine (HPED), or combinations thereof.

[0045] In the implementation plan, the foam is biodegradable.

[0046] Example 3. The device described in Example 2, wherein: the SMP foam comprises at least a first component and a second component reaction product: 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 the SMP foam comprising triethanolamine (TEA), hydroxypropyl ethylenediamine (HPED), or a combination thereof.

[0047] Example 4. The device described in 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.

[0048] Example 5. The device described in Example 2, wherein: the SMP foam comprises at least a first component and a second component reaction product: 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.

[0049] Example 6. The device described in Example 2, wherein: the SMP foam comprises at least one of hexamethylene diisocyanate (HDI), trimethylhexamethylene diisocyanate (TMHDI), or combinations 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 combinations thereof; the SMP foam comprises at least one of 5-amino-2,4,6-triiodophthalic acid (ATIPA), iohexol, triiodophenol, or combinations thereof.

[0050] Example 7. The device described in Example 2, wherein: the SMP foam comprises at least a first component, a second component, and a third component of the reaction product: 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-triiodophthalic acid (ATIPA), iohexol, triiodophenol, or a combination thereof.

[0051] Example 8. The system described in Example 2, wherein at least one therapeutic agent includes at least one selected from doxorubicin, cisplatin, paclitaxel, amoxicillin, doxycycline, and cephalexin.

[0052] Example 9. A system comprising the device according to any one of Examples 1-8, the system comprising a conduit including an SMP foam having a material composition included within an opening.

[0053] "Included in the opening" reagents, with or without PVA, include, for example, reagents with or without PVA-filled, partially filled, or coated openings.

[0054] In one embodiment, PVA / reagent is found throughout the SMP foam or in various portions of the SMP foam. PVA / reagent is deposited in small portions on the supports of the SMP foam and / or forms a thin film on the supports. PVA / reagent may also fill the entire volume (or nearly the entire volume) of the foam. In another embodiment, small pieces of the SMP / PVA / reagent complex (e.g., beads) are injected into the wound, provided that these pieces are large enough to avoid entering and connecting within the patient's vascular system. In yet another embodiment, the SMP / PVA / reagent combination device is attached to a bandage for placement in a wound (e.g., during skin cancer excision), and then the wound is compressed based on the bandage's pressure on the patient.

[0055] Example 10. The system described in Example 9, wherein the catheter includes a further embodiment of the device according to any one of Examples 1-8.

[0056] For example, multiple foams may be included in a needle, sheath, or catheter. The foams may be substantially the same or may be different. For example, some foams may include reagents without PVA, while other foams may include reagents within PVA. This can allow for longer release characteristics. Furthermore, the reagents may be the same as or different from each other. For example, a system may be provided to elute a first drug during a first time period (based on its coupling to or absence of PVA) and to elute a second drug (with a chemical composition different from the first drug) during a second time period (which may overlap with the first time period for a period and then not overlap with the first time period for another period), anticipating changes in the physiological characteristics of the surgical site and / or cavities and / or wound.

[0057] In this implementation, the kit can be enclosed in a container. The kit may include moderately curled SMP foam within a sheath that holds the foam in a curled state. The foam may have a therapeutic agent coupled to it via PVA or carboxymethyl cellulose or any viscosity modifier. The foam can be inserted into the surgical site manually or via a catheter, sheath, or cannula.

[0058] However, other implementation methods do not require any catheters. For example, a healthcare provider can simply add foam into the gap using his or her fingers or tweezers.

[0059] The kit may include multiple foams with different drug release characteristics, and healthcare providers can select a combination of foams to apply to patients based on the ability of the selected foams to modulate the release characteristics.

[0060] In this implementation, the catheter is coupled to a syringe, or may be coupled to a syringe. The saline solution in the syringe can be used to deploy foam into the patient.

[0061] Example 10.1 The system described in Example 9, wherein: the SMP foam is in a first state and the maximum outer diameter is no more than 1.2 mm; the SMP foam is compressed in the first state and configured to expand to a second state.

[0062] However, other implementations may use larger implementations, wherein the SMP foam is in the first state and the maximum outer diameter is at least 1.2, 1.5, 1.8, 2.0 mm or greater.

[0063] In implementations, the curled / compressed shape is typically planar, cylindrical, spherical, etc. These various forms may have the same or different permanent shapes (e.g., rectangular, oval, spherical, etc.).

[0064] Example 11. The system of any one of Examples 9-10.1, wherein the catheter comprises an 18-gauge or smaller needle.

[0065] This size can be critical for some applications (e.g., pediatrics, animals). For example, incorporating hydrogel into a foam can limit the curl to 1.33 mm, which may not fit within an 18G needle. However, implementations using PVA to couple reagents to a foam can be included within an 18G needle. In some countries, any needle exceeding the 18G limit is not considered an “injection” and is therefore potentially an invasive procedure, which may increase the risks and costs of treatment. Furthermore, such a small outer diameter of the curl (at least partially made possible by the use of PVA) can better facilitate deployment via endovascular devices that, for example, must traverse tortuous vascular systems and / or other deployment paths that benefit from small shape factors.

[0066] Example 12. The system according to any one of Examples 1-11, wherein the material composition is in direct contact with one of the pores of the SMP foam.

[0067] Example 13. The system described in Example 12, wherein the material composition is in direct contact with the inner wall of one of the pores of the SMP foam.

[0068] In other words, the material composition is not merely contained within the shell of PVA surrounding the foam. Rather, the material composition is actually included within some pores.

[0069] In one embodiment, the reagent comprises small molecules no larger than about ~900 Daltons. This may be necessary for inclusion within a foam with small pores, which can be compressed to a desired outer diameter to suit injection via needles, catheters, sheaths, etc. In other embodiments, the reagent may comprise small molecules, which are molecules smaller than 1000, 800, 700, or 600 Daltons.

[0070] Given that small molecules (as used herein) are no larger than approximately ~900 Daltons, the applicant determined that drug loading of small molecules is difficult for foams with pores / cells having a maximum diameter of micrometers or larger. Chemotherapy agents typically use small molecules, and such molecules can often escape from such foams (with pores having a maximum diameter of micrometers or larger) immediately after implantation. Therefore, immersing such foams in a solution of small molecule drugs may not result in increased drug uptake into the foam or controlled drug release. However, embodiments have improved drug loading in implantable SMP foams by incorporating PVA. PVA is an aqueous solution and a viscosity modifier. The use of PVA allows small molecules no larger than approximately ~900 Daltons to remain in SMP foam openings with a diameter greater than ~900 Daltons. The use of PVA allows small molecules no larger than approximately ~900 Daltons to remain in SMP foam openings with a diameter greater than 1 micrometer.

[0071] Example 14. The system described in Example 13, wherein: one of the pores of the SMP foam is included within the interior portion of the SMP foam and is substantially surrounded by other pores; the other pores are included in planes orthogonal to each other.

[0072] Therefore, the internal pores located in the middle inner part of the foam can still contain reagents within those pores (and the reagents are not only within the PVA shell surrounding the foam). Having reagents at different depths within the foam allows for longer delivery characteristics.

[0073] In the implementation, the small molecule reagent (e.g., acridine yellow) may be located within the PVA and the foam, but not necessarily within the PVA. As a result, the reagent can be released at different times. For example, a reagent not included in the PVA but still within the foam may be released after a reagent included in the PVA but not necessarily within the foam. Such PVA-packaged reagents can be on the outer surface of the foam and held in place by coupling the reagent to the PVA of the foam. Therefore, even though the SMP foam may not necessarily be able to absorb as much reagent as in the case without PVA, a combination of foams having portions with PVA-packaged reagents and portions without PVA-packaged reagents can be advantageous.

[0074] The implementation scheme includes an SMP coated with PVA having bimodal or trimodal release kinetics, such that there are immediate release agents from the PVA and delayed pellets of the same or different therapeutic agents directly loaded in the SMP polymer network.

[0075] The implementation may include a first reagent and a second reagent, the first reagent being contained within a PVA shell surrounding the foam, and the second reagent being contained within the PVA and within the pores of the foam. The first and second reagents may have the same or different chemical compositions. In this arrangement, the first reagent can be eluted first, followed by the second reagent.

[0076] The implementation scheme may include a first reagent, a second reagent, and a third reagent. The first reagent is contained within a PVA shell surrounding the foam; the second reagent is contained within (or not contained within) the PVA and within the outer pores of the foam; and the third reagent is contained within (or not contained within) the PVA and within the inner pores of the foam. The first, second, and third reagents may have the same or different chemical compositions. In this arrangement, the first reagent may be eluted first, followed by the second reagent, and then the third reagent.

[0077] Example 15. A system according to any one of Examples 1-11, wherein the therapeutic agent is encapsulated with at least one of a polymer, liposomes, micelle particles, or a combination thereof.

[0078] Implementation schemes may include a three-stage delayed release of the drug, for example via a triggered mechanism (e.g., ultrasonically fragmented microbeads with an additional drug load) or an automated mechanism (e.g., a moderately bound drug released with degradation). For example, in some implementations, a portion of the reagent may be included in a foam in an unencapsulated state, while another portion of the foam may be included in an encapsulated state. The initial release of the reagent may originate from the unencapsulated reagent, followed by release from the encapsulated reagent once the encapsulated reagent has been subjected to sufficient energy (e.g., ultrasound). The unencapsulated and encapsulated reagents may be different reagents or the same reagent.

[0079] Such implementations with drugs loaded onto hydrogels can offer advantages over systems using foams and hydrogels. The foam readily dissolves the hydrogel upon contact with the physiological environment. In such cases, drug release can be better controlled by loading free drugs or drugs encapsulated within polymers, liposomes, or micelle-like particles.

[0080] Drug release characteristics can be tuned to suit the desired therapeutic effect. For example, using drug-encapsulated nanoparticles instead of free drug can alter delivery characteristics. Once the particles are released from the foam, the drug-encapsulated medium (including microparticles, nanoparticles, and hydrogels) can achieve delayed, sustained release. Therefore, depending on the load and type of PVA used, drug-eluting SMP foams can facilitate both short-term and long-term drug delivery. The amount of drug released can also be optimized based on the drug's stock concentration.

[0081] Example 16. The system described in Example 15, wherein: the encapsulated therapeutic agent comprises at least one of polyvinyl alcohol (PVA), carboxymethyl cellulose, or a combination thereof; at least one of polyvinyl alcohol (PVA), carboxymethyl cellulose, or a combination thereof is located between the pore walls of the SMP foam and the encapsulated therapeutic agent, such that the encapsulated therapeutic agent does not directly contact the walls.

[0082] Example 17. A method comprising: forming a cavity in a patient's tissue; positioning a device according to any one of Examples 1-10.1 or 12-16 within the cavity.

[0083] Example 18. A method comprising: forming a cavity in a patient's tissue; positioning the distal tip of a catheter according to any one of Examples 9-11 within the cavity, wherein the catheter includes a device according to any one of Examples 1-16; and moving the device from the catheter into the cavity.

[0084] Example 19. A method comprising: 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 combinations thereof; applying the composition to a shape memory polymer (SMP) foam comprising an open-cell structure 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 have a primary shape, and then molding the SMP foam to form a stable secondary shape, wherein the SMP foam is configured to be controlled actuated to restore the primary shape; wherein the SMP foam in the secondary shape comprises the SMP foam, at least one therapeutic agent, DMSO, and at least one of PVA and carboxymethyl cellulose, or combinations thereof; wherein 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.

[0085] However, in other embodiments, alternatives to DMSO, such as ethanol, salt-based solvents, and water-based solvents, can be used instead of DMSO. In other embodiments, DMSO or its alternatives can be removed during the manufacturing process so that DMSO or its alternatives are no longer included in the SMP foam in its secondary shape. Such solvents (e.g., DMSO) can be included within the therapeutic agent (anticancer drug) itself.

[0086] In some implementations, the reagent and PVA can be combined and added to the foam simultaneously, while in other implementations, they can be added to the foam separately.

[0087] In one embodiment, the reagent is loaded into the foam by swelling with DMSO solvent. The reagent-containing foam is then loaded into a PVA hydrogel surrounding the foam to form a hydrogel-foam composite.

[0088] One method includes: (1) heating the SMP foam / PVA / reagent device above its Tg and maintaining it in a desired geometry for packaging; (2) cooling the device below its Tg to program the shape of the packaging into the device; (3) sterilizing the device under EtO sterilization and packaging and storing it at a temperature below 30°C; (4) removing the foam from the packaging and inserting it into any part of the patient’s body in order to apply the foam; (5) plasticizing the foam at body temperature to expand and fill some or all of the voids; and (6) allowing drug elution to occur over time.

[0089] Example 20. Porous, biodegradable / bioresorbable shape memory polymer (SMP) foam used to fill voids in tissue left by surgery or other procedures associated with the removal of cancerous, precancerous, or other tissues from a patient, preventing metastasis.

[0090] Example 21. SMP foam as described in Example 20, loaded with and eluted with an anticancer therapeutic agent (a single therapeutic agent in combination).

[0091] Example 22. Drug-loaded spherical foams can also be injected into the blood vessels fed into the tumor, potentially increasing the drug concentration at the tumor site and minimizing side effects that damage normal tissue.

[0092] Examples of therapeutic agents that can be loaded into SMP foam include small molecules used as anticancer agents, including but not limited to doxorubicin, cisplatin, and paclitaxel, antigens, and peptides. Other examples of therapeutic agents include antibiotics, including but not limited to amoxicillin, doxycycline, and cephalexin, used to treat infectious diseases, which can also be loaded onto the foam. Other therapeutic agents include antigens, proteins, and nucleic acids, which can also be loaded onto the foam.

[0093] The loads applied to foam can also include local anesthetics, antihistamines, antifungals, vasodilators, anti-inflammatory agents, and immunosuppressants.

[0094] Examples of carrier materials for loading drugs and coating them onto and within SMP foams include PVA, CMC, hydrogels, and other polymer-based nanoparticles to achieve different release properties.

[0095] Example 1a. An apparatus comprising: a shape memory polymer (SMP) foam including openings and additional openings, the SMP foam having a first state and a second state; and a material composition comprising within the openings, said material composition comprising: (a) a therapeutic agent, and (b) at least one of polyvinyl alcohol (PVA), carboxymethyl cellulose, or combinations thereof; wherein the therapeutic agent comprises at least one of a drug, peptide, protein, antigen, nucleic acid, anesthetic, antihistamine, antifungal agent, vasodilator, anti-inflammatory agent, immunosuppressant, growth factor, cytokine, interleukin, or combinations thereof.

[0096] While this embodiment lists at least one of PVA, carboxymethyl cellulose, or combinations thereof, other embodiments may include viscosity increasers such as (depending on the application of the embodiment) gum arabic, agar, alamic acid, aluminum monostearate, palygorskite, bentonite, carbomer, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, carrageenan, cellulose, dextrin, gelatin, gellan gum, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, magnesium aluminum silicate, maltodextrin, methyl cellulose, microcrystalline cellulose, pectin, polyethylene oxide, povidone, propylene glycol alginate, silica, sodium alginate, starch (corn, potato, cassava, wheat), tragacanth gum, xanthan gum, or combinations thereof.

[0097] In the implementation scheme, the material composition will fluoresce to help healthcare providers monitor the release of reagents over time (via imaging).

[0098] Another version of Example 1a. A device comprising: a shape memory polymer (SMP) foam including openings and additional openings, the SMP foam having a first state and a second state; and a fluorescent material composition comprising within the openings, said material composition comprising: (a) a therapeutic agent, and (b) at least one of polyvinyl alcohol (PVA), carboxymethyl cellulose, or combinations thereof; wherein the therapeutic agent comprises at least one of a drug, peptide, protein, antigen, nucleic acid, anesthetic, antihistamine, antifungal agent, vasodilator, anti-inflammatory agent, immunosuppressant, growth factor, cytokine, interleukin, or combinations thereof.

[0099] Another version of Example 1a. An apparatus comprising: a shape memory polymer (SMP) foam including openings and additional openings, the SMP foam having a first state and a second state; and a material composition included in the openings, the material composition comprising: (a) a therapeutic agent, and (b) at least one of polyvinyl alcohol (PVA), carboxymethyl cellulose, or combinations thereof; wherein the 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; wherein the SMP foam is configured to expand into irregularly shaped tissue voids when the SMP foam expands from the first state to the second state, thereby physically directly pressing the SMP foam against the edges of the irregularly shaped tissue voids.

[0100] Another version of Example 1a. An apparatus comprising: a shape memory polymer (SMP) foam including openings and additional openings, the SMP foam having a first state and a second state; and a material composition included in the openings, the material composition comprising: (a) a therapeutic agent, and (b) at least one of polyvinyl alcohol (PVA), carboxymethyl cellulose, or combinations thereof; wherein the 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; wherein the SMP foam is configured to expand into irregularly shaped tissue voids when the SMP foam expands from the first state to the second state, thereby conforming the SMP foam to the irregularly shaped edges of the irregularly shaped tissue voids.

[0101] The implementation schemes discussed in this article provide for: (1) precise closure of postoperative tissue gaps, and / or (2) highly loaded and controlled release of chemotherapeutic agents to prevent cancer recurrence and metastasis. The implementation schemes demonstrate that: (1) drug loading increases by approximately 80% with increasing PVA concentration, and / or (2) delayed burst release and sustained release of the drug are achieved based on the PVA concentration used.

[0102] The result is an implementation scheme that incorporates drug-loaded SMP foam, which enables increased uptake of chemotherapy drugs while effectively sealing tissue voids. This provides a comprehensive solution to combat the occurrence of metastasis after tumor resection.

[0103] Another version of Example 1a. A device comprising: a shape memory polymer (SMP) foam including openings and additional openings, the SMP foam having a first state and a second state; and a material composition comprising within the openings, said material composition comprising: (a) a therapeutic agent, and (b) at least one viscosity-inducing agent; wherein the therapeutic agent comprises at least one of a drug, peptide, protein, antigen, nucleic acid, anesthetic, antihistamine, antifungal agent, vasodilator, anti-inflammatory agent, immunosuppressant, growth factor, cytokine, interleukin, or a combination thereof.

[0104] Example 2a. The apparatus described in Example 1a, wherein the SMP foam is configured to reduce the glass transition temperature (Tglass transition temperature) of the SMP foam when plasticized at 37°C. g When the temperature drops below 25°C, it expands from the first state to the second state.

[0105] Example 3a. The device described in Example 2a, wherein: the SMP foam comprises at least a first component and a second component reaction product: 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 triethanolamine (TEA), hydroxypropyl ethylenediamine (HPED), or a combination thereof.

[0106] Example 4a. The device described in Example 2a, wherein: the SMP foam comprises at least a first component and a second component reaction product: 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.

[0107] Example 5a. The device described in Example 2a, wherein: the SMP foam comprises at least a first component, a second component, and a third component of the reaction product: 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-triiodophthalic acid (ATIPA), iohexol, triiodophenol, or a combination thereof.

[0108] Example 6a. The device according to any one of Examples 1a to 5a, wherein the therapeutic agent comprises at least one of doxorubicin, cisplatin, paclitaxel, amoxicillin, doxycycline, cephalexin, or combinations thereof.

[0109] Example 7a. The device according to any one of Examples 1a to 6a, the device includes a conduit comprising SMP foam.

[0110] Example 8a. An additional case of the device described in Example 7a, wherein the conduit comprises SMP foam.

[0111] Another version of Example 8a. The device of Example 7a, wherein: the catheter includes additional SMP foam, the additional SMP foam includes additional openings, the additional SMP foam having a first state and a second state; and an additional material composition is included in the additional openings, the additional material composition comprising: (a) an additional therapeutic agent, and (b) at least one of additional PVA, carboxymethyl cellulose, or combinations thereof; wherein the additional therapeutic agent comprises at least one of a drug, peptide, protein, antigen, nucleic acid, anesthetic, antihistamine, antifungal agent, vasodilator, anti-inflammatory agent, immunosuppressant, growth factor, cytokine, interleukin, or combinations thereof; wherein the material composition comprises at least one of a first amount of PVA, carboxymethyl cellulose, or combinations thereof; wherein the additional material composition comprises at least one of a second amount of additional PVA, carboxymethyl cellulose, or combinations thereof; wherein the first amount is not equal to the second amount.

[0112] Another version of Example 8a. The device of Example 7a, wherein: the catheter includes additional SMP foam, the additional SMP foam includes additional openings, the additional SMP foam having a first state and a second state; and an additional material composition is included in the additional openings, the additional material composition comprising: (a) an additional therapeutic agent, and (b) at least one of additional PVA, carboxymethyl cellulose, or combinations thereof; wherein the additional therapeutic agent comprises at least one of a drug, peptide, protein, antigen, nucleic acid, anesthetic, antihistamine, antifungal agent, vasodilator, anti-inflammatory agent, immunosuppressant, growth factor, cytokine, interleukin, or combinations thereof; wherein the material composition comprises a first amount of the therapeutic agent; wherein the additional material composition comprises a second amount of the additional therapeutic agent; wherein the first amount is not equal to the second amount.

[0113] Example 9a. The device described in Example 7a, wherein: the SMP foam is in a first state and the maximum outer diameter is no greater than 1.2 mm; the SMP foam is compressed in the first state and configured to expand to a second state.

[0114] For example, if hydrogels were used instead of PVA, the ability to roll them into such small diameters would be extremely difficult.

[0115] Example 10a. The device described in Example 9a, wherein the catheter includes an 18-gauge or smaller needle.

[0116] However, other implementation methods may not require needles or catheters. For example, a healthcare provider may wish to simply remove the SMP foam described herein and apply it directly to tissue using his or her hand (e.g., tumor resection).

[0117] Example 11a. The device described in Example 9a, wherein: the opening has a maximum diameter of at least 50 micrometers; the therapeutic agent has a maximum of 900 Daltons.

[0118] In other embodiments, the maximum diameter of the opening is between 50 micrometers and 2 mm. In other embodiments, the maximum diameter of the opening is less than 2 mm, but greater than 50, 75, 100, 125, 150, 175, or 200 micrometers.

[0119] Example 12a. The device described in Example 9a, wherein: the opening includes at least one of a support column and an inner wall; and the material composition is in direct contact with at least one of the support column and the inner wall.

[0120] Example 13a. The device described in Example 12a, wherein the opening: is included within the internal portion of the SMP foam; is substantially surrounded by other openings; and does not directly contact the outer surface of the SMP foam.

[0121] Example 14a. The device according to any one of Examples 1a to 13a, wherein the therapeutic agent is encapsulated by at least one of a polymer, liposomes, micelle particles, or a combination thereof.

[0122] Example 15a. The device of Example 14a, wherein: the encapsulated therapeutic agent comprises at least one of PVA, carboxymethyl cellulose, or a combination thereof; at least one of PVA, carboxymethyl cellulose, or a combination thereof is located between the pore walls of the SMP foam and the encapsulated therapeutic agent, such that the encapsulated therapeutic agent does not directly contact the walls.

[0123] Example 16a. The device of Example 1a, the device comprising a coating, wherein: the opening comprises a support; the coating is on the support; and the coating comprises a material composition.

[0124] Example 17a. The device described in Example 16a, wherein the internal portion of the support includes at least one of a therapeutic agent, another therapeutic agent, or a combination thereof.

[0125] For example, see Figure 4 Reagents (e.g., pharmaceuticals) can be incorporated into the interior of the pillar via a solvent (e.g., DMSO). Due to the chemical properties of the foam in some embodiments (e.g., Examples 3a to 5a), the PVA coating cannot carry the reagent into the SMP pillar itself. Without any solvent, the reagent remains in the carrier coating. Therefore, using a solvent can facilitate the incorporation of the reagent into the pillar (rather than just on the pillar).

[0126] One method involves loading a reagent into a pillar (or the wall of an SMP foam pore or a general substrate) in a step different from the step of loading the reagent onto the pillar. For example, drug A is first loaded into the SMP pillar using a solvent. Second, drug B (or more of drug A) is loaded onto the pillar surface using a carrier coating.

[0127] Another version of Example 17a. The device of Example 16a, wherein: (a) when the SMP foam is in a first state, the internal portion of the pillar includes at least one of a therapeutic agent, another therapeutic agent, or a combination thereof, and (b) when the SMP foam is in a second state, the internal portion of the pillar includes at least one of a therapeutic agent, another therapeutic agent, or a combination thereof.

[0128] Example 18a. The device of Example 16a, wherein: the therapeutic agent of the coating is configured to elute from the SMP foam and enter the patient tissue during a first time period; the internal portion of the pillar includes at least one of the therapeutic agent, additional therapeutic agents, or combinations thereof, configured to elute from the SMP foam and enter the patient tissue during a second time period; the second time period occurs at least one day after the first time period.

[0129] For example, drug A in the coating may elute into the tissue at the excision margin within an initial time window (e.g., 1–48 hours), while drug B (or drug A or both) inside the strut may elute into the tissue later (e.g., after 48 hours or 1 week). This could occur because the drug inside the strut elutes from the intact strut. However, it could also occur because the strut is biodegradable and degrades over time. As the strut degrades, any drug inside it will elute into the surrounding tissue.

[0130] The above scenario discusses an example of a "dual release" mechanism, in which a drug (drug A) is released from the coating (the first pathway of dual release) and a drug (drugs A, B, or A and B) is released from within the support or hole foundation structural component (the second pathway of dual release).

[0131] In the implementation, the drug (whether in the coating or in the strut) can be hydrophilic. This is noteworthy because hydrophilic drugs may be insoluble in organic solvents. Doxorubicin and acridine yellow are soluble in both DMSO and water. The presence of DMSO (even in trace amounts) in the foam contributes to the expansion of the foam (leading to more drug penetration into the foam core). The hydrophilic agent can be loaded into the interior of the strut or pore walls having the chemical properties of Examples 3a to 5a using solvents (e.g., organic solvents). Such solvents include, for example, DMSO, methanol, ethanol, propanol, dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), and glycerol. If the solvent remains in the SMP foam, some of these solvents may be unsuitable for certain applications due to their interaction with tissue.

[0132] Example 19a. The device according to any one of Examples 17a-18a, wherein the internal portion of the support includes an additional therapeutic agent.

[0133] Example 20a. The device according to any one of Examples 17a-19a, wherein the internal portion of the support does not include at least one of PVA, carboxymethyl cellulose, or combinations thereof.

[0134] Another version of Example 20a. The device according to any one of Examples 17-19, wherein: the internal portion of the support does not include at least one of PVA, carboxymethyl cellulose, or combinations thereof; and the material composition is not crosslinked around the support.

[0135] In the implementation, the openings include a maximum diameter of at least 50 micrometers, and the therapeutic agent is no greater than 900 Daltons. However, in the absence of cross-linking of the material composition around the pillar, delayed or sustained release of the agent becomes more difficult. However, the use of a carrier polymer with increased viscosity can help combat the lack of cross-linking in the material composition to achieve sustained agent release.

[0136] In this embodiment, the material composition is not chemically bonded (e.g., covalently bonded) to the foam. Instead, the material composition is physically included within the material composition. This avoids any possibility of damaging the reagent in any way.

[0137] For illustrative and descriptive purposes, the above description of embodiments of the invention has been presented. It is not intended to be exhaustive, nor to limit the invention to the precise forms disclosed. This specification and the appended claims include terms such as left, right, top, bottom, above, below, above, below, first, second, etc., which are used for descriptive purposes only and should not be construed as limiting. For example, a term specifying a relatively vertical position refers to the case where one side of the substrate is the “top” surface of the substrate; the substrate can actually be in any orientation such that the “top” side of the substrate can be lower than the “bottom” side in a standard land reference frame, and still fall within the meaning of the term “top.” The term “above” as used herein (including in the claims) does not indicate that the first layer is directly on and in direct contact with the second layer, unless specifically stated otherwise; a third layer or other structure may exist between the first layer and the second layer on the first layer. Embodiments of the apparatus or article of manufacture described herein can be made, used, or transported in various locations and orientations. Those skilled in the art will understand that many modifications and variations are possible in accordance with the above teachings. Those skilled in the art will recognize various equivalent combinations and substitutions of the various components shown in the drawings. Therefore, the scope of the invention is not defined by this detailed description, but by the appended claims.

Claims

1. An apparatus for sealing a tissue void, comprising: A shape memory polymer foam, i.e. SMP foam, comprising open cells and further open cells, the SMP foam having a first state and a second state; and a material composition included in the aperture, the material composition including: (a) a therapeutic agent, and (b) at least one of polyvinyl alcohol (PVA), carboxymethyl cellulose, or a combination thereof; wherein the therapeutic agent includes at least one of a drug, a peptide, a protein, an antigen, a nucleic acid, an anesthetic agent, an antihistamine agent, an antifungal agent, a vasodilator, an anti-inflammatory agent, an immunosuppressant, a growth factor, a cytokine, an interleukin, or a combination thereof; wherein: the SMP foam includes a reaction product of at least a first component and a second component: the first component includes at least one of hexamethylene diisocyanate (HDI), trimethylhexamethylene diisocyanate (TMHDI), or a combination thereof; and the second component includes 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.

2. The apparatus of claim 1, wherein the SMP foam is configured to expand from the first state to the second state when the SMP foam is plasticized at 37 °C decreases the glass transition temperature T g of the SMP foam to below 25 °C.

3. The apparatus of claim 2, wherein: the SMP foam includes a reaction product of at least a first component, a second component, and a third component: the third component includes at least one of 5-amino-2,4,6-triiodobenzoic acid (ATIPA), iohexol, triiodophenol, or a combination thereof.

4. The apparatus of any one of claims 1-3, wherein the therapeutic agent includes at least one of doxorubicin, cisplatin, paclitaxel, amoxicillin, doxycycline, cephalexin, or a combination thereof.

5. The apparatus of claim 1, comprising a catheter including the SMP foam.

6. The apparatus of claim 5, wherein: the catheter includes a further SMP foam, the further SMP foam including a further aperture, the further SMP foam having a first state and a second state; and a further material composition included in the further aperture, the further material composition including: (a) a further therapeutic agent, and (b) at least one of a further PVA, carboxymethyl cellulose, or a combination thereof; wherein the further therapeutic agent includes at least one of a drug, a peptide, a protein, an antigen, a nucleic acid, an anesthetic agent, an antihistamine agent, an antifungal agent, a vasodilator, an anti-inflammatory agent, an immunosuppressant, a growth factor, a cytokine, an interleukin, or a combination thereof; wherein the material composition includes a first amount of the PVA, carboxymethyl cellulose, or at least one of a combination thereof; wherein the further material composition includes a second amount of the further PVA, carboxymethyl cellulose, or at least one of a combination thereof; wherein the first amount is not equal to the second amount.

7. The apparatus of claim 5, wherein: the SMP foam is in the first state and has a maximum outer diameter of no more than 1.2 mm; the SMP foam is compressed in the first state and is configured to expand to the second state.

8. The apparatus of claim 7, wherein the catheter includes an 18 gauge or smaller needle.

9. The apparatus of claim 7, wherein: the aperture includes a maximum diameter of at least 50 microns; the therapeutic agent is no more than 900 daltons.

10. The device of claim 7, wherein: the open cell comprises at least one of a strut and an inner wall; and the material composition directly contacts at least one of the strut and the inner wall.

11. The device of claim 7, wherein the open cell: is included within an interior portion of the SMP foam; is substantially surrounded by the additional open cell; and does not directly contact an outer surface of the SMP foam.

12. The device of claim 1, wherein the therapeutic agent is encapsulated by at least one of a polymer, a liposome, a micellar particle, or a combination thereof.

13. The device of claim 12, wherein: the encapsulated therapeutic agent is included in at least one of the PVA, carboxymethyl cellulose, or a combination thereof; the at least one of the PVA, carboxymethyl cellulose, or a combination thereof is between a cell wall of the SMP foam and the encapsulated therapeutic agent, such that the encapsulated therapeutic agent does not directly contact the wall.

14. The device of claim 1, comprising a coating, wherein: the open cell comprises a strut; the coating is on the strut; and the coating comprises the material composition.

15. The device of claim 14, wherein an interior portion of the strut comprises at least one of the therapeutic agent, an additional therapeutic agent, or a combination thereof.

16. The device of claim 14, wherein: the therapeutic agent of the coating is configured to elute from the SMP foam and into a patient tissue during a first time period; an interior portion of the strut comprises at least one of the therapeutic agent, an additional therapeutic agent, or a combination thereof, which is configured to elute from the SMP foam and into the patient tissue during a second time period; the second time period occurs at least one day after the first time period.

17. The device of any one of claims 15-16, wherein the interior portion of the strut comprises the additional therapeutic agent.

18. The device of any one of claims 15-16, wherein: the interior portion of the strut does not comprise at least one of the PVA, carboxymethyl cellulose, or a combination thereof; and the material composition is not crosslinked around the strut. ​

Images