Hydrogel-based biological delivery vehicle

Abstract

A hydrogel-based biodelivery vehicle is provided that is used to effectively deliver drugs and biomaterials to tissue or organ sites. [Solution] A hydrogel-based biodelivery vehicle may include a hydrogel binding matrix comprising a biopolymer backbone containing carboxyl groups. Tyramine may replace at least a portion of the carboxyl groups, such that upon addition of hydrogen peroxide, covalent bonds are formed between the tyramine molecules, crosslinking the hydrogel binding matrix and allowing it to transition from a liquid state to a gel state. In its liquid form, the hydrogel binding matrix encapsulates drug reservoirs and produces a homogeneous liquid containing particles containing drugs or target molecules uniformly dispersed therein. As the hydrogel binding matrix solidifies into a gel state, the newly formed crosslinks do not destroy or react with the drugs or target molecules contained within the drug reservoirs.

Description

Technical Field

[0001] (Cross - Reference to Related Applications) This application claims the benefit of U.S. Provisional Application No. 62 / 335,457, filed May 12, 2016, entitled "HYDROGEL - BASED BIOLOGICAL DELIVERY VEHICLE".

[0002] The present disclosure relates to a delivery system hydrogel - binding matrix used to effectively deliver formulations of drugs and biomaterials. More specifically, the present disclosure relates to a hydrogel matrix that forms cross - links when transitioning from a liquid state to a gel state. The hydrogel matrix, in its liquid form, can encapsulate a drug container and produce a homogeneous liquid in which a drug container containing one or more drugs or target molecules is uniformly dispersed. As the binding matrix (i.e., the hydrogel in which the drug containers are uniformly dispersed) solidifies into a gel state, cross - links are formed, and these cross - links do not destroy or react with one or more target drugs or molecules contained within the drug container. This hydrogel - based biological delivery vehicle can be used for various pharmaceutical applications.

Background Art

[0003] Hydrogels have become popular in pharmaceutical applications for several reasons. To form a hydrogel, it is often necessary to cross - link the hydrogel using a compound that generates free radicals or other radiation. However, this results in residual substances that need to be removed due to potentially dangerous effects on the recipient subject. Additionally, drugs or pharmaceuticals are typically added to the hydrogel either by passive diffusion or by using heat treatment or irradiation. These are not the ideal ways to add to a hydrogel, as passive diffusion results in low concentrations of drugs or pharmaceuticals, and heat treatment or irradiation often causes the drug to react with the hydrogel or become damaged or inactivate biological agents.

[0004] Liposomal formulations are mostly diluents and have a relatively low viscosity close to that of water. When used as a drug delivery vehicle, liposomal formulations can be easily extruded out from the injection site or discharged from the target tissue through the interstitial cavity, and the drug or target molecule may be transported away from the target site. Some liposomes have unpredictable stability. For example, when liposomes fuse and are rapidly destroyed, they may release the target molecule too quickly, or when liposomes are sufficiently diluted, they may remain stable and prevent the target molecule from being delivered to the target tissue in a timely manner. There are also alternative drug delivery vehicles or other forms of drug containers, such as high-density hydrogel particles or porous particles. However, the particles tend to move and aggregate at one location even after injection or placement.

[0005] Therefore, there is a need for a solution that can crosslink the hydrogel without generating residual substances, promote the filling of high levels of drug / medicine concentration, does not react with or inactivate the drugs / medicines added to the hydrogel, enables a drug delivery vehicle (also called a drug container), makes it more stable, and releases it at a predictable rate at the desired location. Summary of the Invention Means for Solving the Problems

[0006] The disclosed hydrogel-based biodelivery vehicle is composed of a drug container encapsulating a drug or a target molecule and a hydrogel matrix, and is a delivery system called a binding matrix when used to hold the drug container at a predetermined location. The binding matrix disclosed herein acts as a support for holding the drug container in a uniformly dispersed state throughout the delivery system when implanted in the body or on the surface of a subject. The binding matrix does not significantly interfere with the diffusion and elution of the active target molecule from the drug container. According to one embodiment, the desired hydrogel formulation can be adjusted to diffuse the target molecule and increase or decrease the elution rate.

[0007] More specifically, the delivery systems disclosed herein address the issues associated with the stability and release of liposomal formulations by encapsulating the liposomal formulation into a liquid formulation of the binding matrix before crosslinking occurs. This results in the production of a homogeneous liquid in which the liposomes are well mixed throughout. Upon mixing, the relatively mild reaction conditions that generate crosslinks within the hydrogel matrix do not disrupt the liposomes or react with the components of the liposomes or the drugs or target molecules contained within the liposomes.

[0008] The delivery systems disclosed herein also address the issues associated with the release of incorporated particulate formulations by suspending the particles throughout the binding matrix, distributing them uniformly, and holding them in predetermined positions relative to one another. This enables a uniform and predictable elution of the drug from the particles after the delivery system has been injected or placed at a specific delivery site. On the other hand, the elution of liposomes depends on physically separating the target molecules from around their lipid bilayer, and the particles elute the target molecules depending on diffusion from the particles. Diffusion varies depending on the affinity of the target molecule for the particle material, the tortuosity of the path, changes in isotonicity within and at the boundaries of the particles, the chemical potential, and the resulting chemical substance gradient. If the target molecule first dissolves in the surrounding fluid, the phase change may be the rate-limiting step.

[0009] Mixtures of multiple types of hydrogel consistencies can be used to create various drug delivery rates and thus various delivery times for different target molecules. The hydrogel matrix can be formulated in a range from a thick liquid consistency to hard solid gelatin particles. The consistency of the hydrogel matrix affects the degree of degradation of the hydrogel matrix and thus the release rate from the delivery system and the delivery of the drug or target molecule to the target tissue. In the case of particulate formulations, the degradation of the hydrogel allows the particles to come into direct contact with the tissue, and after the drug has been distributed, the particles can be adsorbed into the body. The particles may be composed of a protein scaffold that promotes healing and regrowth.

[0010] In some embodiments, due to the thick nature of the hydrogel matrix composition, the delivery vehicle (i.e., the drug container) coats the tissue so that the target site is ensured at the obtained drug delivery position and can remain at a predetermined position within those tissues. If the hydrogel matrix formulation is sufficiently concentrated and highly cross-linked, it will affect the elution and absorption rates. BRIEF DESCRIPTION OF THE DRAWINGS

[0011]

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[0012] The present disclosure relates to a biologic delivery vehicle used to effectively deliver drugs and target molecules to specific tissue sites. With reference to the drawings, various embodiments of the biologic delivery vehicle are described in detail, and like reference numerals represent like parts and assemblies throughout several of the drawings. References to various embodiments are not intended to limit the scope of the biologic delivery vehicle disclosed herein. Further, any examples shown herein are not intended to be limiting, but merely describe some of the many possible embodiments of the biologic delivery vehicle. Various omissions and substitutions of equivalents are envisioned, whether suggesting or rendering convenient, which are intended to embrace applications or embodiments without departing from the spirit or scope of the present disclosure. It should also be understood that the phrases and terms used herein are for the purpose of explanation and should not be considered limiting.

[0013] The disclosed hydrogel-based biologic delivery vehicle is a delivery system 100 called a binding matrix 102, which is composed of a drug container 104 that encapsulates a drug or target molecule 106 and a hydrogel matrix, and is used to hold the drug container 104 in a predetermined location.

[0014] Generally, the biodelivery vehicle disclosed in the present application is a delivery system 100, which consists of a drug container 104 that encapsulates a drug or target molecule 106 and is suspended in a hydrogel matrix, and is called a binding matrix 102 when used to hold the drug container at a predetermined position. The drug container 104 can be, for example, a high-density hydrogel particle, a porous particle, a liposome, a cellulose particle, the drug itself, or a protein fragment in a crystalline or solid phase that dissolves when eluted from the delivery system 100, or it can be a cellulose or liposome drug container 104 instead of a tyramine-substituted high-density hydrogel particle for association with tyrosine. The process of creating the delivery system 100 generally involves associating the drug container 104 with the drug or target molecule 106, mixing this combination into a pre-crosslinked liquid hydrogel matrix (e.g., tyramine-substituted sodium hyaluronate, where a predetermined proportion of carboxyl groups in sodium hyaluronate are substituted with tyramine), and then crosslinking (e.g., by adding hydrogen peroxide to create covalent bonds with the tyramine molecules) to generate the final binding matrix 102. This crosslinking occurs in the presence of the drug or target molecule 106 and preferably does not result in harsh reaction conditions or cause a reaction with the drug or target molecule 106. The delivery system 100 can then be injected or placed on the surface of the desired delivery site 108a or at that site, and the drug elutes at a predetermined rate depending on the density of the binding matrix 102 and the specific drug container 104 used.

[0015] Liposomes are an example of a drug container 104. Liposomes are spherical vesicles with at least one lipid bilayer encapsulating an internal aqueous solution. Liposomes are mainly used as vehicles for delivering a drug or other target molecule 106 to a target site 108a in a biological system. There are various different types of liposomes, which vary in size from small to large and in the number of layers from a single bilayer to multiple lamellar vesicles (i.e., liposomes containing multiple lipid bilayers). Liposomes are typically prepared by mixing aliphatic amphiphilic molecules with a polar solvent and a target molecule, and then subjecting the mixture to sonication, extrusion, or shear conditions.

[0016] The present disclosure relates to a biological delivery vehicle (i.e., delivery system 100) created by incorporating a useful drug container 104 into a binding matrix 102 to stabilize and control the drug delivery rate. In some embodiments, liposomes are a preferred delivery vehicle 104 because they can protect highly reactive drugs or target molecules 106 (e.g., toxins, antibodies, macromolecules, etc.) from reacting with the hydrogel matrix. However, these drugs or target molecules 106 may aggregate within the liposomes. Accordingly, other drug containers 104 are considered and disclosed.

[0017] Generally, a drug container 104 containing a drug, protein, biomolecule, and / or target substance / molecule 106 is encapsulated within a hydrogel matrix, which crosslinks to form a binding matrix 102 containing the drug container 104. The binding matrix 102 allows the drug container 104 to be encapsulated within a liquid formulation prior to crosslinking, and no purification step is required after crosslinking. The gentle crosslinking reaction does not damage or react with the drug container 104 or the target molecule 106 contained therein.

[0018] While the delivery system 100 is placed on the target biological tissue 108a, as shown in FIG. 1, the drug containers 104 in the binding matrix 102 are stabilized and held in place relative to each other by the surrounding cross-linked hydrogel material. After a predetermined time has elapsed, as shown in FIG. 1, the binding matrix 102 is disrupted and absorbed by the surrounding tissue, and the drug containers 104 and the target molecules 106 within the drug containers 104 are released into the surrounding tissue 108a by passive diffusion. This enables more predictable and reproducible delivery of the drug containers 104 and the molecules 106 stacked thereon to the target biological tissue 108a.

[0019] In addition to passive diffusion, the drugs and target molecules 106 elute from the drug containers 104 through the binding matrix 102 into the surrounding tissue 108a, and two-dimensional or three-dimensional diffusion may occur. More specifically, after the delivery system 100 is placed on, in, or near the surface of the tissue site 108a, the binding matrix 102 has a higher osmotic pressure than the surrounding tissue 108a, absorbs water from the surrounding tissue 108a (slowing the elution rate), is broken down into small particles, and its surface area will increase. Then, as the surface area increases, the ratio of surface area to volume increases, and the elution rate increases. Thus, over time, the elution rate will increase.

[0020] In some embodiments, multiple layers of different hydrogel densities may be used to create the binding matrix 102, as shown in FIG. 2. Hydrogels with lower densities enable faster elution rates, and by using multiple layers of different hydrogel densities, the elution rate can be further controlled. In one example, the binding matrix 102 may have the highest density material in the center, and each successive layer may have a lower density than the previous layer. In another example, the binding matrix 102 may have the lowest density material in the center, and each successive layer may have a higher density than the previous layer.

[0021] In one embodiment, at least a portion of the drug containers 104 used in combination with the binding matrix 102 are high-density hydrogel particles, and the high-density hydrogel particles are first prepared by dissolving a drug or a target molecule 106 in a pre-crosslinked liquid hydrogel matrix. In some embodiments, the pre-crosslinked liquid hydrogel matrix may contain a predetermined proportion of tyramine-substituted sodium hyaluronate (hereinafter "THA") in combination with an enzyme (e.g., horseradish peroxidase). After adding the drug or target molecule 106 to the mixture of THA and the enzyme, a crosslinking agent (e.g., hydrogen peroxide) may be added to the hydrogel matrix to promote crosslinking and solidification of the formulation, thereby promoting the binding of the drug or target molecule 106 and including high-density hydrogel particles formed at a predetermined position. The result of this procedure is the production of high-density hydrogel particles, which may be ground and sized to have a uniform particle diameter.

[0022] The advantage of sizing the high-density hydrogel particles is to create particles with a desired surface area to volume ratio, which can be used to control a constant dissolution rate. For example, by completing the procedure described above, a mixture of high-density hydrogel particles with various densities and surface area to volume ratios for various volumes is made multiple times, and in the final formulation, as shown in FIG. 3A, various particles may be mixed together. As shown in FIG. 3B, the individual dissolution rates may vary, but the overall dissolution rate can be made constant at a controlled dissolution rate for a desired period, thereby obtaining a flat dissolution curve as shown in FIG. 3C.

[0023] Accordingly, as shown in FIGS. 1 and 3A, after creating high-density hydrogel particles having one or more diameters, these particles are mixed within a hydrogel-based binding matrix 102. The hydrogel matrix may be similar to the high-density hydrogel particle formulation in the preparation, but is less dense and thus can be rapidly dissolved when placed in or near the surface of the target tissue 108a. To further control the total elution and dosage, the high-density hydrogel particles can be mixed into the binding matrix 102 at a desired matrix volume ratio to the particle volume. If desired, the density of the binding matrix 102 can be varied to affect the elution rate from the total delivery volume.

[0024] Using porous particles as the drug container 104, to place the desired drug or target molecule 106 in the target living tissue 108a, the porous particles may be polymers and have porous properties. First, the desired drug or target molecule 106 is added, and then it is directly added to the hydrogel matrix as it is, or mixed with porous materials of various porosities and surface areas and then added. In a preferred embodiment, the desired drug or target molecule 106 is in the pores of the porous particles, and the surrounding target tissue 108a can absorb the porous particles. In addition to liposomes, high-density hydrogel particles and porous particles, other hydrogels or water-soluble polymers, such as cellulose particles, can be used to create the drug container 104 before binding in the hydrogel matrix. Alternatively, the crystalline or solid-phase form of the drug or target molecule 106 may be directly added to the binding matrix 102, and the drug container 104 may not be used.

[0025] The binding matrix 102 may be further modified to be thicker or thinner for the purpose of use and to remain in a predetermined position in the target biological tissue 108a. More specifically, the degree of crosslinking and the composition can be designed such that the binding matrix 102 separates at a desired rate, optimizing the delivery of the target molecules from the drug container 106 to the biological tissue 108a. For example, a binding matrix 102 having a high degree of crosslinking takes a long time to decompose, and the delivery system 100 (when injected), and thus the drug or medicine 106 in the drug container 104, will take a long time to enter and remain in the target tissue region 108a.

[0026] In some embodiments, the disclosed delivery system 100 enables the placement of high concentrations of target drugs and molecules 106 at a desired tissue site 108a and can elute them from the placed mass at a desired rate. For example, an analgesic substance added to the delivery system 100 using the method described above can be placed at a relatively high concentration at the surgical site and eluted at a desired rate to treat postoperative pain. The delivery system 100 can be designed to elute the analgesic drug over several days, which may prevent the occurrence of pain syndromes, allow the patient to recover more quickly, and be sent home immediately.

[0027] Another example is the use of a compound with systemic toxicity (i.e., bupivacaine (cardiotoxicity)) that can be released into the tissue 108a over a desired treatment time. Administering a high concentration of a compound with systemic toxicity systemically over the same period at an effective concentration sufficient to treat the condition using other delivery methods may cause systemic effects.

[0028] Similarly, a chemical toxicant can be supplied from a relatively high-concentration mass locally, affecting nearby rapidly growing cells (i.e., tumors), but not affecting the entire biological system in the same way. This results in fewer symptoms of chemotherapy for the patient, yet a locally high concentration of the chemical toxicant is produced, making it more effective.

[0029] In another example, adding endotoxin / pyrogen or cytokine to the drug container 104 can locally induce a large immune response, activate the patient's immune system, recognize cancer near the implanted delivery system 100 as foreign cells, and attack the tumor cells. Interleukin-2 or other similar immune system activators can be used to induce a similar response.

[0030] Overview of Hydrogel Compositions and Use Cases Hydrogel Composition: Overview In some embodiments, the hydrogel matrix is composed of a biopolymer backbone having carboxyl chemical functional groups. Examples of biopolymer backbones include sodium hyaluronate and proteins. The carboxyl groups can be reacted with tyramine to create a substitution of 0.5% to 5.0% of the carboxyl groups with tyramine molecules. Theoretically, even less (e.g., 0.1%) substitution and even more (e.g., 7.0%) substitution can be made. The substitution ratio indicates the ratio of tyramine substitution made in relation to the number of carboxyl groups available for substitution. In addition to the desired substitution rate, a preferred embodiment of the hydrogel matrix has a desired THA concentration. More specifically, a preferred embodiment of the binding matrix 102 is composed of a THA concentration of 1.0 to 5.0% (i.e., 1.0 to 5.0% THA in water) and a tyramine substitution of 1.5% or less. A preferred embodiment of the high-density hydrogel particles has a concentration (i.e., the ratio of THA in water) higher than 5% (i.e., 15 to 20%).

[0031] More specifically, in some embodiments, the THA is placed in a solution containing the drug container mixture 104 in the solvent phase. In the examples used in this disclosure, a solution containing up to 20% THA is a preferred concentration. If the liposomes are replaced with a mixture of high-density hydrogel particles or particles having various consistencies, or if the mixture contains both liposomes and high-density particles to control the delivery rate of the target molecule, the high-density particles may have a tyramine substitution of about 5.5%, but usually have a biopolymer (such as sodium hyaluronate) backbone of up to 20%, and in some embodiments, have a biopolymer backbone of more than 20%.

[0032] The following simple examples and descriptions further illustrate the basic concept of how the disclosed delivery system 100 can be used to effectively deliver drugs and target molecules 106, as described below, in various additional medical applications.

[0033] Use Case: Overview of Plasma Protein Binder Complement To enhance the pharmacological response to nearby tissues, acetaminophen, ibuprofen, and other small molecules may be incorporated into the drug container 104 in combination with a potent analgesic. Acetaminophen preferentially binds to plasma proteins and becomes a potent analgesic that confers an invasive stimulus response at low concentrations. The use of high-density hydrogel particles or porous particles in the binding matrix 102, in contrast to liposomes, causes the main drug to last longer and be effective at low concentrations.

[0034] Use Case: Overview of Immunostimulation in Cancer Treatment The drug container 104 disclosed herein may be added, for example, but not limited to, with immune system stimulants such as interleukin-2 and other cytokines. A localized strong immune response can be created against the tumor tissue located near the implanted delivery system 100 and function as an effective treatment against the tumor or other target tissue 108a.

[0035] Usage Example: Overview of Cancer / Abnormal Tissue Growth Treatment due to Chemical Toxicity The chemical toxicant may be encapsulated within the drug container 104 and then used to create the delivery system 100, which may be delivered to the target tissue to stop unwanted benign or non-cancerous growth or to target cancerous tissue. The local placement of the chemical toxicant not only significantly reduces systemic effects and reduces symptoms from exposure to the chemical toxicant, but also maintains a medically effective dose of the chemical toxicant close to the target tissue or tumor 108a. This application can be used for the treatment of solid tumors, fibromas, prostate, keratin growth, etc. Continuous exposure to the chemical toxicant that elutes near the target tissue site 108a makes it impossible to ensure that the cells themselves can repair and survive the treatment. One reason this is beneficial is that because the chemical toxicant is used multiple times during treatment, its systemic effects become a limiting factor in treating difficult tumors. Minimizing systemic exposure while maximizing exposure to the target tissue is a new concept demonstrated by the disclosed delivery system 100.

[0036] Usage Example: Overview of Radiation, Radio Wave, Microwave Treatment of Target Tissue and Tumors In some embodiments, for the follow-up of radiation, radio wave, proton or antibody therapy, a target molecule can be locally delivered to a target cell or tumor 108a. Metal particles or ions may be concentrated in the drug container 104 and then added to the hydrogel matrix to create the delivery system 100. The delivery system 100 containing the metal particles or ions can then be injected into or near the target tumor 108a. Once irradiated, secondary radiation scattering can promote the treatment. Artificial gamma radiation has lower energy than galactic cosmic rays, but can increase the energy by creating secondary scattering due to metals such as tantalum that can be placed in the target tissue 108a. However, while the target tumor 108a is affected by this treatment, the metal present in the delivery system 100 behind the tumor can shield the tissue behind the delivery system 100 during proton beam therapy. Finally, the metal material present in the delivery system 100 can be excited by radio wave irradiation to create local hot spots capable of thermally killing the target tissue or tumor 108a.

[0037] The delivery system 100 and use cases described above are simple examples of the disclosed technology. The hydrogel binding matrix 102, drug container 104, available drugs and target molecules 106 and various beneficial uses of the final delivery system 100 are described in more detail below.

[0038] Tyramine-crosslinked biopolymer: Chemistry As described above, a portion of the hydrogel matrix formulation may include a tyramine-crosslinked biopolymer. These biopolymers may be glycosaminoglycans, tyramine-crosslinked polyamino acids, usually tyramine-substituted crosslinked molecules having carboxyl functional groups, having a specific ratio of tyramine substitution for the carboxyl group, a specific crosslinking mechanism, a specific chemical composition including a crosslinked biopolymer at a specific concentration in water, and / or may include copolymers. Two main forms of biopolymers are envisioned, a tyramine-substituted sodium hyaluronate (HA)-based binding matrix 102a and a protein-based binding matrix 102b, both forms being based on a binding matrix 102 having a tyramine-based crosslinking mechanism.

[0039] More specifically, the composition of the hydrogel matrix may include glycosaminoglycans such as, but not limited to, sodium hyaluronate (i.e., tyramine-crosslinked sodium hyaluronate), heparin / heparin sulfate, chondroitin sulfate / dermatan sulfate or keratan sulfate. The composition may also include tyramine-crosslinked polyamino acids, which may mimic proteins and would be ideal for drug delivery. Polyamino acids can be used in the hydrogel matrix to create molecules such as, but not limited to, collagen, elastin or synthetic polypeptides. In some embodiments, the composition may include a tyramine-crosslinked molecule having a carboxyl functional group, which molecule is a biopolymer or a biocompatible polymer. The biopolymer used to create the hydrogel may have a tyramine substitution rate of 0.1% to 7.0%, although certain formulations may use a lower or higher substitution rate. Preferably, a substitution rate of 1.0 to 5.0% is typical for this use.

[0040] There are various mechanisms for cross-linking that can be performed to create the binding matrix 102. However, in a preferred embodiment, an enzyme, such as horseradish peroxidase (HRP), is used in combination with a cross-linking agent to cross-link a liquid hydrogel matrix. For example, in one embodiment, hydrogen peroxide (H2O2) combined with HRP may be used to induce cross-linking. In another example, various chemicals or light waves may be used to create free radicals in the hydrogel matrix, and then HRP may be used to cross-link tyramine molecules. For example, ultraviolet light (UV) itself or in combination with HRP may be used to induce cross-linking. In a further embodiment, titanium dioxide (TiO2) may be added to UV and HRP and used as a catalyst to induce cross-linking. In yet another embodiment, gamma radiation may be used with TiO2 and HRP to induce cross-linking to create the binding matrix 102. In yet another embodiment, ionizing radiation using HRP will likely induce cross-linking.

[0041] The composition of the binding matrix 102 may contain certain molecules in a certain concentration range. For example, the concentration of THA in water may range from 0.0% to 20.0%, and H2O2 may be diluted, and its concentration depends on the concentrations of HRP and THA. In some embodiments, water is a preferred buffer to create high isotonicity in the binding matrix 102 (although other buffers such as saline or phosphate are also considered), and then the binding matrix 102 absorbs fluid from the surrounding tissue. By absorbing additional fluid (i.e., water) from the surrounding tissue, the drug elution process from the binding matrix 102 is slowed down.

[0042] Tyramine-crosslinked biopolymer: Sterilization / Disinfection In some embodiments, certain sterilization and disinfection measurements may be made to ensure that the delivery system 100 does not cause further problems when injected into or used by a patient. For example, the delivery system 100 may use aseptic preparation such as sterile filtration. Another method of sterilization may include ethylene oxide sterilization (ETO), and the delivery system 100 can be chemically sterilized. Further methods that can be used are gamma radiation and / or plasma sterilization with hydrogen peroxide. Various preservatives may be used to maintain the sterilized state.

[0043] Tyramine-crosslinked biopolymer: Physical form The binding matrix 102 composed of tyramine-crosslinked biopolymer may be in various physical forms. One such form may be a hydrogel, and the hydrogel may produce a spectrum of consistencies depending on how long the drug container 104 needs to remain intact in the binding matrix 102. For example, a lower density, more liquid binding matrix 102 containing a low concentration of tyramine-crosslinked biopolymer will dissolve quickly, resulting in a faster delivery rate of the drug or target molecule, while a higher density, harder, tyramine-crosslinked biopolymer particle will dissolve slowly, resulting in a slower delivery rate of the drug or target molecule.

[0044] In some embodiments, the physical form of the delivery system 100 may have a two-way tensile strength and / or may be available for use in response to multiple components. In some embodiments, the physical form may be a coating, as shown in FIGS. 10 - 12, and / or may have tensegrity (e.g., nested geometries), as shown in FIGS. 8 - 9. Tensegrity is useful in situations where signal transduction or growth-promoting molecules need to be delivered. Other physical forms that the delivery system 100 may take include, but are not limited to, a sheet, cord, woven or non-woven mesh (e.g., woven tube), dry powder (e.g., mixed powder) or particles. The particles may be of various sizes (e.g., from less than a micron to large particles) and may have a reproducible particle size distribution. The particles may have different densities. For example, high-density particles may act as drug containers 104, and particles with a coarser density may act as binders for nanoparticles.

[0045] Coating Coatings are important for many medical device applications. For example, coatings can be created using the delivery system 100, by using techniques such as covalent bonding to polymer surfaces or simply relying on mechanical adhesion to the device surface. Further, once adhered to the medical device surface, the coating can be enhanced by adding substances and then cross-linking a new layer to the base layer that contacts the medical device. Coatings may also be performed on non-medical devices (e.g., gauze) and can also prevent new tissue 108b from binding to the gauze.

[0046] Layers with different compositions, and if desired, but not limited to, a base layer of the THA-based binding matrix 102a can also be created, which is covered by a layer of the collagen or protein-based binding matrix 102b. Similarly, the THA-based binding matrix 102a may be coated with an anticoagulant (e.g., warfarin or modified warfarin), and this may be cross-linked to the THA-based binding matrix 102a.

[0047] An example of a particular use case is the coating of the THA-based binding matrix 102a on a biosensor. For example, the THA-based binding matrix 102a may be coated on a blood glucose sensor via a covalent bond, as shown in FIG. 11. This coating can prevent fouling of the surface of the blood glucose sensor, which would otherwise change the diffusion rate of the substance being measured and thus result in incorrect readings. By preventing the formation of connective tissue (i.e., scar tissue) on the surface of the biosensor, the THA-based binding matrix 102a can provide substance transport properties similar to those of the surrounding tissue so that the measurement does not change reliably.

[0048] Tensegrity In some embodiments, the disclosed delivery system 100 acts as a synthetic equivalent to a naturally occurring collagen structure and can thus construct biological tensegrity, and the surrounding tissue 108a can move through the base material and begin to generate new tissue 108b based on the shape of the tissue cells, the size and space of the surrounding tissue 108a. As a result, the base material (i.e., the delivery system 100) will, as it did before, assist in the regrowth of the tissue. For example, the disclosed technology can create a structure derived from artificial collagen or protein that mimics a natural organ or tissue and allows stem cells and migrating endothelial cells to recreate a new organ or tissue 108b.

[0049] More specifically, one way to recreate a new organ or tissue is to create voids by creating particles of a mixed composition, as shown in FIG. 8. One set of particles may be a protein or collagen-based binding matrix 102b, while the voids, or a second set of particles, can be created from a THA-based binding matrix 102a. Using hyaluronidase after creating a stable cross-linked protein structure can form voids of a preferred shape and size within a new tissue structure 108b of the protein-hydrogel. Cells (e.g., general stem cells or cells from surrounding tissue) placed within structure 108b may then be promoted to form a new tissue 108c such that they are directed by the size and shape of the voids within the protein structure 108b (i.e., the cells differentiate into the appropriate tissue type). This process occurs naturally when a scab acts as a scaffold. However, it is not an ideal solution as scar tissue is produced. The use of a THA-based binding matrix 102a prevents the production of binding (i.e., scar) tissue.

[0050] Another option for recreating a new organ or tissue is to print a plurality of shapes (e.g., oval, sphere, cube, etc.) and create a desired cell scaffold. Alternatively, a collagen scaffold derived from living tissue may be used and coated with a protein-based binding matrix 102b to promote cell differentiation and thus tissue growth 108b.

[0051] As shown in FIG. 9, a nested geometry may be added to the tensgrity to create a second, higher level structure, which may mimic blood vessels, tendons, connective tissue, etc. Structural elements created by or coated with the THA-based binding matrix 102a may be added to hold the structures together during the growth of the new tissue 108b. This can create microscopic / cellular level geometries and large voids or separations between large geometries or tissue layers (e.g., when the THA-based binding matrix 102a coats each layer). More specifically, blood vessels may naturally connect to the surrounding generated blood vessels and supply nutrients and oxygen to the growing tissue 108b. Depending on the complexity of the new organ or tissue 108b being created, further higher level organization may be induced.

[0052] Sheet Generally, the hydrogel matrix may have a low tensile strength. However, in some embodiments, the binding matrix 102 may be a high-concentration protein-based binding matrix 102b having a useful tensile strength. This type of binding matrix 102 may be in the form of a sheet that can be applied to the tissue surface 108a, as shown in FIGS. 5-7. This hydrogel sheet delivery system 100 protects the tissue surface 108a from drying or damage in some embodiments. In other embodiments, it can prevent the tissue surface 108a from generating scar tissue or connective tissue after surgery.

[0053] Some already known causes may include hydrogel sheets, but their viscous nature and difficulty of use have hindered their widespread use. In the case of this disclosure, a resorbable material is used as the base material and can be easily deployed in the body. Another advantage of using one embodiment of the disclosed delivery system 100 is that it can retain the advantages of the hyaluronan-based binding matrix 102a. More specifically, due to its hygroscopicity, it can prevent the formation and drying of connective tissue.

[0054] To be used as a base for the growth of the new tissue 108b, the hydrogel sheet delivery system 100 can also be created. For example, FIG. 7 shows the case of skin replacement, where a non-resorbable polymer sheet 112 (which may be a woven sheet or a non-woven sheet) is coated with a THA-based binding matrix 102a and a protein-based binding matrix 102b, which can be impregnated into the basal tissue of the skin and applied to the traumatic injury surface 108a. The binding matrices 102a, 102b can help relieve pain, promote healing, or also contain drugs or pharmaceuticals 106 that are growth-promoting biofactors. The protein-based binding matrix 102b can promote the movement of cells to the wound site 108a and the creation of new skin 108b, while the THA-based binding matrix 102a is sandwiched between the polymer sheet 112 and the protein-based binding matrix 102b and can prevent the newly created tissue 108b from directly binding to the polymer sheet 112. The polymer sheet 112 can protect the wound, seal it, prevent water loss from the binding matrices 102a, 102b, and provide mechanical support. Or, if necessary, a porous or membrane material can be used to allow the inflow of oxygen to the healing wound surface 108a. In another embodiment, the binding matrices 102a, 102b do not include the polymer layer 112 and may be applied to the surface.

[0055] Code As disclosed above, another physical form that the disclosed delivery system 100 can take is in the form of a code, which may be made as either a single fiber or a cord, or may be woven from several basic fibers. The woven rope of the material may have a hollow core or a filled core. In a preferred embodiment of the delivery system 100 in the form of a code, the code can provide the tensile strength necessary to hold stable surfaces together. More specifically, the delivery system 100 can be used to coat into a code or rope of a biopolymer to fill the gaps.

[0056] There may perhaps be uses that require the base of the cord or rope to remain in the body for a long time (for example, stainless or titanium meshes in bone repair, arthroplasty, tendon repair, etc.), but in almost all uses, it is desirable to construct the cord support using a resorbable material. Resorbable materials include, but are not limited to, polyglycolic acid, polydioxanone, and polycaprolactone. Preferred polymers for use may include glycolide, caprolactone, trimethylene carbonate, l-lactide, and p-dioxanone. However, silk, proteins, and other natural biopolymers may also function well. Xenograft and autograft tissues may also be acceptable for use in some of these applications.

[0057] Mesh The mesh is a further physical form that the disclosed delivery system 100 can take. When the tensile strength of the hydrogel is required to stably hold the edges of the tissue together (i.e., when closing gaps, holes, or voids in the tissue), a mesh base can be used to support the relatively brittle binding matrix 102. The mesh base can also function as a mechanical support when a large volume of hydrogel is required to hold it in place after placement.

[0058] In some embodiments, the mesh base may be in the form of a sheet, and the mesh or cloth sheet may be in a woven form and a non-woven form. There may perhaps be uses that require the mesh base to remain in the body for a long time (for example, stainless or titanium meshes in bone repair, arthroplasty, etc.), but in almost all uses, it is desirable to construct the mesh or fabric support using a resorbable material and it may be composed of the materials described above.

[0059] Mesh: Woven One form of the mesh sheet is a woven sheet. In some embodiments, long threads, fibers, and / or strings may be made from the woven fabric and the base material of the sheet, woven, and formed into a sheet of usable size. The woven material may have various tensile strengths depending on the construction material and the relative direction of the fibers. The warp threads are the combined threads that hold the weft threads in place. The properties of the fabric will vary depending on the material properties of the warp and weft threads, and the packing density and the size of the threads.

[0060] An example of a woven sheet of hydrogel is a woven tube. The woven tube can be incorporated into the wall of the tube structure to give the material mechanical strength. In some cases, the woven support material may be layered so that the material or tissue is included in the sheet.

[0061] Mesh: Non-woven fabric A second form of the mesh sheet is a non-woven sheet. In some embodiments, a mixture of threads of various lengths is used to create a non-woven fabric, and these threads of various lengths are bonded together using heat, mechanical entanglement, or chemical bonding. In some embodiments, if additional tensile strength is required for the material, the non-woven fabric may be laminated to a woven fabric.

[0062] For example, FIG. 6 shows the use of a hernia patch, where a high-tensile biopolymer 110 is covered on both sides by a protein-based binding matrix 102b, which attracts macrophages and endothelial cells for the growth of new tissue 108b and is itself surrounded by a THA-based binding matrix 102a. The macrophages break down the material of the protein-based binding matrix 102b, enabling the surrounding cells to participate in and perform wound healing. In another embodiment, a highly resorbable fabric base may be covered on both sides by non-woven fabric, which has a large contact area to which the hydrogel 102 can mechanically bind. The advantage of this type of configuration is that the base material can provide sufficient tensile strength to keep the holes closed. Furthermore, the THA-based binding matrix 102a can prevent the formation of body scar tissue between the patch and the surrounding original tissue 108a, allowing the body to be resorbed and new tissue 108b to be created around the underlying fabric, thereby creating new tissue 108b in the void while having directional selectivity.

[0063] Tyramine-crosslinked biopolymer: Delivery method Syringe The delivery system 100 may be delivered using various methods. In one embodiment, a syringe may be used. For example, the syringe may be used in combination with a needle, coater, nozzle, catheter, or oral medication.

[0064] In embodiments using a coater, the coater can create a 1- to 2-inch-wide thin sheet of the delivery system 100 by discharging the delivery system 100 through a syringe in a plastic or metal applicator and discharging the delivery system 100 through the die face in sheet form. This is useful when attempting to apply the delivery system 100 to a large tissue surface 108a to protect the target tissue 108a or to create a high surface area for eluting a drug, biologic, or target molecule 106 into the tissue 108a. Nozzles having various shapes and geometries can also be used to discharge a large volume of the delivery system 100 into, or within, a void or target tissue 108a.

[0065] In the case of a catheter, the delivery system 100 can be adjusted so that it can be extruded from a small diagnostic catheter in a liquid structure. Alternatively, the individual components (the binding matrix 102, the drug container 104 containing the drug or target molecule 106, the enzyme and cross-linking agent) can be mixed immediately before inserting the catheter so that the cross-linking reaction occurs in the body. This would be desirable as it facilitates delivery when it is necessary to discharge a large volume of material from the catheter. Importantly, the reaction rate can be varied in many ways (i.e., enzyme concentration) so that the delivery system 100 can be made into the desired form after delivery and a short operating set-up time. Situations related to plugs, sphincter formation, mitral valves, and dermal fillers would benefit from a delay in the set-up time. Catheter-based applications may specifically include a plug or filler for a plugging wire.

[0066] Auxiliary Device In some embodiments, it may be necessary to apply a concentrated solution of the delivery system 100 to the surface of, or to, the target tissue 108a. In these situations, valve auxiliary devices such as a ratchet screw, screw, or trigger device may be used.

[0067] In a preferred embodiment, the ratchet screw has threads on the plunger and is a high-pressure syringe and plunger configuration that delivers a series of set volumes, and the amount delivered is known due to the click noise created when a tab on the plunger collides with a second tab on the syringe body. The screw-like configuration allows for the delivery of materials under high pressures not achievable with standard syringes. One variation could be a device where the pre-crosslinked binding matrix 102 can be placed in a first barrel and a crosslinking agent (e.g., hydrogen peroxide) can be placed in a second barrel through a catheter or lumen for delivery by an auxiliary device with a ratchet screw.

[0068] The screw-assisted device is similar to the ratchet-screw-assisted device. However, the screw-assisted device does not have an audible notification of the volume delivered. Thus, it is best used when the large volumes required under high pressure do not require exact precision.

[0069] The trigger device may assist in the application of the concentrated solution of the delivery system 100. The trigger device is much like a caulking gun and can move the plunger and release the concentrated substance from the syringe in response to a linear motion of pulling the trigger. This would be convenient for even more precise control of the flow rate.

[0070] Visualization In addition to the various delivery methods, some embodiments of the delivery system 100 include the ability to visualize the delivery system 100 after it has been administered to a patient. These methods include, but are not limited to, contrast agents and solid pigments, such as radiopaque coloring pigments. The visualization and location of the compounds and implants, and also importantly, the activity for proper function and use of the medical device and delivery of the pharmacologically active ingredient, may vary. The delivery system 100 disclosed herein provides an opportunity to visualize the location of the medical device by fluoroscopy, direct visualization, ultrasound, fluorescence, any combination or variation of the above.

[0071] Although the binding matrix 102 and its contents cannot be directly observed by a syringe, catheter, or other remote device, a contrast agent may be used in applications where it can be visualized by fluoroscopy by incorporating an iodine-based contrast agent into the delivery system 100. The contrast agent may be directly dissolved in the binding matrix 102, may be contained within high-density hydrogel particles carried within the binding matrix 102, or may be contained within another drug container 104 that holds the contrast for the duration of the procedure. Since the contrast will ultimately elute from the binding matrix 102 and the particles or other container 104, this method is ideally used for applications where contrast is only needed for short-term visualization. After a short period of time, the contrast agent can no longer be seen by fluoroscopy.

[0072] Solid pigments or particles, such as radiopaque ones (pigments and solid substances opaque to X-rays) and colored ones, may be added to the binding matrix 102 for certain labeling purposes. In contrast to the contrast agent, the solid pigment does not elute from the delivery system 100 and essentially permanently visualizes the delivery system 100 unless its body absorbs the binding matrix 102, the drug container 104, and the drug or target molecule 106. In some embodiments, the binding matrix 102 may be a fixation site for a living organism, such as a xenograft or a manipulated unicellular organism. These living organisms can be designed to add or process metabolic compounds or to produce compounds that induce a desired effect on the surrounding tissue 108a.

[0073] Examples of radiopaque materials include, but are not limited to, tantalum peroxide (TaOx), titanium dioxide (TiO2), Pt / Ir, iron-based materials, zirconium, I-based, halogenated polymers, and crystallized polymers. Further descriptions of some of these are included below.

[0074] Tantalum peroxide may be used as a radiopaque label for labels for plugs and coatings for medical devices. The medical device can be visualized by fluoroscopy. This is because the substance is radiopaque. This material is biocompatible and dissolves only negligibly in water. Tantalum particles may be added to the precursor of the binding matrix 102 and cross-linked at a predetermined position when suspended in the formulation. By retaining the radiopaque particles, the delivery system 100 can be visualized as long as the binding matrix 102 is present.

[0075] Titanium dioxide particles can also be used in a similar manner by suspending them in a liquid or hydrogel formulation and cross-linking them at a predetermined position. A property inherent to TiO2 is the ability to generate ozone in the presence of water and ultraviolet light. The inherent manner of generating the binding matrix 102 is to irradiate the binding matrix 102 containing TiO2 with UV radiation. Peroxidase utilizes ozone to generate tyramine-tyramine cross-links. The bright white color of TiO2 is also a way to directly visualize the delivery system 100.

[0076] Pt-Ir is commonly used as a marker band for catheters and medical devices to visualize the advancing surface. Pt-Ir is biocompatible and insoluble in water. Similar to the methods already described, particles of Pt-Ir may be suspended in the liquid binding matrix 102 and then cross-linked at a predetermined position. The delivery system 100 is then visualized by fluoroscopy.

[0077] In addition to the iron-based material, the delivery system 100 can be made radiopaque and visualized by fluoroscopy. A low concentration of FE / magnetic particles can be suspended in the binding matrix 102 and used to move the drug container 104, which can be moved throughout the body until it reaches the desired tissue location. This may be of particular interest in tissues such as the eye. Here, the operation of the delivery system 100 would help to flatten and reposition the detached retinal tissue surface against the back of the eye. Once the repair has been made, the delivery system 100 may be removed by a similar method of movement.

[0078] Zirconia is a radiopaque material commonly used in dental implants. Zirconia has a color similar to tooth enamel, is biocompatible, and dissolves only negligibly in water. Zirconia particles can be suspended as described above and used to indicate the position of the delivery system 100 by fluoroscopy.

[0079] Instead of radiopaque pigments and solid materials, some embodiments of the delivery system 100 may use solid coloring pigments or materials to visualize the delivery. Dyes having various colors may be added to the binding matrix 102 to help directly visualize the delivery system 100. The dyes would be used in applications where they elute from the hydrogel binding matrix 102 and have a short visualization time. Examples of dyes include UV-fluorescent, visible light, and dyes with a reactive color change.

[0080] Dithiolamine crosslinks fluoresce under ultraviolet light. During the placement of the delivery system 100 or before closing surgically, a UV source can be shone on the site to determine whether the delivery system 100 is correctly positioned. This would be particularly useful in determining whether the delivery system 100 completely coats the tissue 108a or completely fills a void or interstitial cavity.

[0081] Thiolamine-crosslinked biopolymer: drug delivery As disclosed herein, there are multiple modes by which a drug, target molecule, or other biological agent 106 in a drug container 104 can be delivered from a delivery vehicle 100 to a targeted tissue or organ site 108a. Some examples include, but are not limited to, elution and binding matrix / retention. The drug, target molecule, or other biological agent 106 to be delivered can include, but is not limited to, macromolecules or small molecules.

[0082] Macromolecule Examples of macromolecules include, but are not limited to, monoclonal antibodies, which are generally very useful either alone or in combination for the treatment of autoimmune diseases, ophthalmic and other specific applications. However, monoclonal antibodies are typically present at low concentrations in formulations. This is because in solution, monoclonal antibodies bind to each other and either crystallize or precipitate and settle out of the solution. Thus, to increase the concentration of monoclonal antibodies present in a formulation (binding matrix 102), the monoclonal antibodies can be cross-linked at a given location without being damaged, and due to their solid nature, there is less liquid volume compared to a liquid solution, and thus the movement of the monoclonal antibodies can be reduced. By diffusing the monoclonal antibodies through a high-density drug container 104 to bring them into contact with each other, the delivery system 100 reduces the likelihood of the monoclonal antibodies contacting each other and effectively prevents their aggregation, thereby allowing for a higher concentration to be present in the formulation.

[0083] In particular, when the antibody targets a signaling molecule or cascade intermediate, there are many applications, including the elution of monoclonal antibodies from the delivery system 100, that assist in the long-term treatment of conditions and diseases such as age-related macular degeneration.

[0084] Small molecule Examples of low-molecular-weight substances include, but are not limited to, non-steroidal anti-inflammatory drugs (NSAIDs), steroids, anti-seizure drugs, antibiotics, antifungal agents, biologic agents, antipsychotics, platelet-rich plasma (PRP), albumin, gout medications, teriparatide (e.g., FORTEO®), denosumab (e.g., Prolia®), albumin, erythropoietin, and tumor therapeutics.

[0085] Low molecular weight: NSAID Available NSAIDs include naproxen, ibuprofen, celecoxib, acetaminophen, aspirin, dexibuprofen, diflunisal, salsalate, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen, indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac, aceclofenac, piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, phenylbutazone, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, clonixin, and licofelone.

[0086] Generally, NSAIDs are delivered by low-molecular-weight drug elution. The drug container 104 may have a higher concentration of THA. For example, depending on the requirements of the drug container concentration, the drug container 104 may have a concentration greater than at least 10%, preferably 10 - 20%. The NSAID may be combined with a carrier molecule. Otherwise, the NSAID would be hindered by the influx of water and the influx of serum from the surrounding tissue 108a. In one embodiment, ibuprofen may be mixed with acetaminophen and included within the binding matrix 102 for direct placement within the tissue 108a, for application as a topical gel, or for mechanical adhesion to an application film (e.g., a patch). In this example, acetaminophen may bind to plasma proteins, thereby making the ibuprofen more effective.

[0087] Using many of the NSAIDs disclosed herein, it is possible to treat migraine, osteoarthritis, kidney stones, rheumatoid arthritis, psoriatic arthritis, gout, ankylosing spondylitis, menstrual pain, tendinitis, macular edema and bursitis. These may be applied directly near the treatment tissue or organ site 108a (i.e., by injection or gel application during surgery), or may be applied as a topical patch near the tissue or organ site 108a. These may be used in combination with antibiotics, antifungals, selective steroids (when localized), anticoagulants (e.g., to prevent thrombosis), monoclonal antibodies, opioids and other compounds. In some embodiments, acetaminophen may be a complement to the NSAID and can make the NSAID more effective by binding to plasma proteins. However, in the drug delivery system 100 that elutes the drug, the dosage may reach 8 to 10 times the typical dosage of the NSAID due to the slow elution of the drug from the delivery system 100. This is convenient for individuals who have to receive the drug directly from a medical professional frequently. The drug container 104 may be used with up to 7% tyramine substitution and up to 20% THA concentration. The preferred concentration is 1.5% substitution at a concentration of 15 - 20%. The binding matrix 102 holds the drug container 104 in place and may use up to 1.5% substitution, and the concentration is adjusted to suit the consistency of the desired application (i.e., a liquid-like form has a low concentration while a jelly-like form has a high concentration).

[0088] Naproxen is an example of an NSAID. The typical dosage of naproxen may range from 125 mg to 750 mg for a single dose. However, in the disclosed delivery system 100, the dosage may reach up to 8 times this amount due to its slow elution.

[0089] Ibuprofen is another example of an NSAID. The typical dosage of ibuprofen may be in the range of 200 mg to 800 mg for a single dose. However, in the disclosed delivery system 100, the dosage may reach 8 to 10 times this amount due to its slow elution.

[0090] Celecoxib is yet another example of an NSAID. The typical dosage of celecoxib may be in the range of 100 mg to 400 mg for a single dose. However, in the disclosed delivery system 100, the dosage may reach 8 to 10 times this amount due to its slow elution.

[0091] Acetaminophen is another example of an NSAID. The typical dosage of acetaminophen may be in the range of 500 mg to 1000 mg for a single dose. However, in the disclosed delivery system 100, the dosage may reach 8 to 10 times this amount due to its slow elution.

[0092] Aspirin is a further example of an NSAID. The typical dosage of aspirin may be in the range of 81 mg to 1 g for a single dose. However, in the disclosed delivery system 100, the dosage may reach 8 to 10 times this amount due to its slow elution.

[0093] Dexibuprofen is a further example of an NSAID. The typical dosage of dexibuprofen may be in the range of 500 mg to 1000 mg for a single dose. However, in the disclosed delivery system 100, the dosage may reach 8 to 10 times this amount due to its slow elution.

[0094] Other examples of NSAIDs for which the disclosed delivery system 100 can increase the dosage 8 to 10 times compared to typical dosing include diflunisal, salsalate, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen, indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac, aceclofenac, piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, phenylbutazone, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, clonixin, and licofelone.

[0095] Low molecular weight: Steroid Steroids that can be used are progestogens (e.g., progesterone), corticosteroids, androgens (e.g., testosterone), estrogens, dexamethasone, moxifloxacin, interferon β-1b, and glatiramer acetate.

[0096] Progesterone is an example of a steroid and can be administered as a single bolus injection, or topically as a gel or in patch form. Progesterone can be used for amenorrhea, uterine bleeding, hyperplasia, progesterone deficiency, preterm labor, seizures, and premenopausal symptoms.

[0097] Among the various corticosteroids that can be used are alclometasone dipropionate, amcinonide, beclomethasone dipropionate, budesonide, betamethasone, betamethasone dipropionate, betamethasone valerate, clobetasol propionate, clobetasone butyrate, desonide, desoxymethasone, dexamethasone, diflorasone diacetate, fluocinonide, fluocinolone acetonide, fludrocortisone, fluticasone furoate, fluticasone propionate, mometasone furoate, ciclesonide, cortisone acetate, halcinonide, halobetasol propionate, halometasone, hydrocortisone aceponate, hydrocortisone acetate, hydrocortisone buteprate, hydrocortisone butyrate, hydrocortisone valerate, hydrocortisone, methylprednisolone, prednisone, prednicarbate, tixocortol pivalate, triamcinolone, and triamcinolone acetonide.

[0098] Alclometasone dipropionate is a corticosteroid that can be applied as a topical gel, as a patch, or in another delivery form. However, in a preferred embodiment, topical application in gel form or liquid form is desirable. The concentration may vary depending on the steroid strength. For example, if the administration of delivery system 100 is via a patch or single delivery, alclometasone dipropionate may be administered up to 10 times the typical dosage, depending on the application site, the physical form of delivery system 100, and the container drug concentration. A typical binding matrix 102 containing alclometasone dipropionate would be composed of up to 7% tyramine substitution at THA concentrations up to 20%. In a preferred embodiment, the binding matrix 102 may have less than 1.5% tyramine substitution and less than 5% THA concentration.

[0099] Several other corticosteroids, such as, but not limited to, amcinonide, beclomethasone dipropionate, betamethasone dipropionate, clobetasol propionate, clobetasone butyrate, desonide, desoxymethasone, diflorasone diacetate, fluocinonide, fluocinolone acetonide, mometasone furoate, halcinonide, halobetasol propionate, halometasone, hydrocortisone aceponate, hydrocortisone acetate, hydrocortisone buteprate, hydrocortisone butyrate, hydrocortisone valerate, hydrocortisone, prednicarbate, tixocortol pivalate, and triamcinolone can also be applied as a topical gel, as a patch, or in another delivery form. However, in a preferred embodiment, topical application of these drugs in a gel or liquid form is desirable. The concentration may vary depending on the steroid strength. For example, if the administration of delivery system 100 is via a patch or a single delivery, the drugs listed above may be administered up to 10 times the typical dosage, depending on the application site, the physical form of delivery system 100, and the container drug concentration. A typical binding matrix 102 containing the drugs listed above will be composed of up to 7% tyramine substitution at a THA concentration of up to 20%. The binding matrix 102 may have less than 1.5% tyramine substitution and less than 5% THA concentration in a preferred embodiment.

[0100] Budesonide is a corticosteroid that can be used as an inhalant. In sustained release, the inhaled form of the disclosed technology would be superior because it is less frequent than what is required as a dosage of the inhalant. The drug container particles 104 are thought to be very small (less than 1 micron) such that they have an appropriate size and ability to release the steroid upon contact with lung tissue 108a. For reliable and complete absorption by the body, the tyramine substitution may be less than 1%, and since the drug container 104 is presumably in solid form, it can be carried by a propellant. Budesonide can also be used to treat rhinitis and nasal polyps. For treating these, the physical form may be a thin liquid. For example, it may be a THA-based binding matrix 102a, and the binding matrix 102a has a tyramine substitution of less than 1% and a THA concentration of less than 1%. The drug container 104 may have a tyramine substitution of 1.5% or less and a THA concentration up to 20%. To treat inflammatory bowel disease, Crohn's disease, and ulcerative colitis using budesonide, the delivery system 100 may be applied as a suppository. The drug container 104 may consist of a tyramine substitution of 5.5% - 7% and a THA concentration up to 20%, while the binding matrix 102 may have a tyramine substitution of 1.5% and a THA concentration up to 10%. The suppository may be a high-density gel or may have a solid gelatinous consistency.

[0101] Betamethasone is a corticosteroid that may be injected or applied as a cream and can be used to treat skin disorders, allergic conditions such as asthma, early labor for neonatal lung development, Crohn's disease, inflammatory bowel disease ("IBD"), and adrenal insufficiency. One limitation of using betamethasone in delivery system 100 is that in injection form, it needs to be injectable using a needle of reasonable size. In some embodiments, the drug container 104 may be high-density hydrogel particles consisting of up to 1.5% thiamine substitution and up to 20% THA concentration, while the binding matrix 102 may have up to 1.5% thiamine substitution and up to 1% THA concentration. The binding matrix 102 may consist of up to 7% thiamine substitution and up to 20% THA concentration, but a preferred embodiment for betamethasone may have up to 1.5% thiamine substitution and less than 5% THA concentration.

[0102] Betamethasone valerate is a corticosteroid that may be applied as a topical gel, as a patch, or in another delivery form and can be used to treat a number of diseases and conditions including, but not limited to, rheumatoid arthritis, systemic lupus, dermatitis, psoriasis, asthma, lung development in early labor, Crohn's disease, IBD, and some types of blood cancer. The concentration may vary depending on the steroid strength. For example, if the administration of delivery system 100 is via a patch or single delivery, betamethasone valerate may be administered up to 10 times the typical dosage, depending on the application site, the physical form of delivery system 100, and the container drug concentration. A typical binding matrix 102 containing betamethasone valerate will likely be composed of up to 7% thiamine substitution at up to 20% THA concentration. The binding matrix 102 may, in a preferred embodiment, have less than 1.5% thiamine substitution and less than 5% THA concentration.

[0103] Dexamethasone is a corticosteroid with anti-inflammatory and immunosuppressive properties that can be administered by injection or applied as a cream, and can be used to treat a number of diseases and conditions including, but not limited to, rheumatoid arthritis, systemic lupus, dermatitis, psoriasis, asthma, lung development in preterm labor, Crohn's disease, IBD, and several types of blood cancer. Dexamethasone can also be used as a complement to analgesics in viscosupplementation applications. One limitation to the use of dexamethasone in delivery system 100 is that in injection form, it needs to be injectable using a reasonably sized needle. In some embodiments, drug container 104 may be high-density hydrogel particles consisting of up to 1.5% tyramine substitution and up to 20% THA concentration, while binding matrix 102 may have up to 1.5% tyramine substitution and up to 1% THA concentration. Binding matrix 102 may consist of up to 7% tyramine substitution and up to 20% THA concentration, but preferred embodiments for betamethasone may have up to 1.5% tyramine substitution and less than 5% THA concentration.

[0104] Fluocortolone is a corticosteroid that can be applied as a gel or suppository and can be used to treat hemorrhoids. In some embodiments, drug container 104 may consist of 5.5% - 7% tyramine substitution and up to 20% THA concentration, while binding matrix 102 may have 1.5% tyramine substitution and up to 10% THA concentration. The suppository may be a high-density gel or may have a solid gelatinous consistency.

[0105] Fluticasone furoate, fluticasone propionate, ciclesonide and triamcinolone acetonide are corticosteroids applicable as nasal gels, but in preferred embodiments are applied as a mist to the mucosa for treating rhinitis, nasal polyps and asthma. Ideally, the drug container 104 is very fine and appears to be suspended in a liquid carrier solution so that the propellant can carry this solid particle form. In some embodiments, an inhaler may be used, but the drug container particles 104 are thought to be very small (less than 1 micron) such that they contact the lung tissue 108a and have an appropriate size and ability to release the steroid. In some embodiments, the drug container 104 will have a tyramine substitution of up to 1.5% (1% in the case of ciclesonide and triamcinolone acetonide) and a THA concentration of 10 - 20% for reliable and complete absorption by the body. The osmotic pressure of the drug container 104 is preferably normal, but may be varied to control the elution rate of fluticasone furoate and / or fluticasone propionate.

[0106] Cortisone acetate is a corticosteroid that can be used to treat inflammation and pain and swelling resulting from trauma to joints, tendons or bursae. Further, cortisone acetate is an ideal candidate for combination with NSAIDs, cortisone and viscosupplementation components. For example, acetaminophen and cortisone acetate may be combined with ibuprofen in a viscosupplement hydrogel. In some embodiments, the drug container 104 may be high density hydrogel particles consisting of up to 1.5% tyramine substitution and up to 20% THA concentration, while the binding matrix 102 may have a tyramine substitution of 1.5% - 7% and a THA concentration of up to 1%. The binding matrix 102 may consist of up to 7% tyramine substitution and up to 20% THA concentration, but the preferred embodiment for cortisone acetate may be up to 1.5% tyramine substitution and less than 5% THA concentration.

[0107] Methylprednisolone is a corticosteroid that may be injected or applied as a cream, and prednisone is a corticosteroid with immunosuppressive properties that may be administered orally or by injection. These can be used to treat skin disorders, allergic conditions, Crohn's disease, IBD, and adrenal insufficiency. One limitation of the use of methylprednisolone and prednisone in delivery system 100 is that, in injection form, it is necessary to be able to inject using a needle of reasonable size. In some embodiments, the drug container 104 may be high-density hydrogel particles consisting of up to 1.5% tyramine substitution and up to 20% THA concentration, while the binding matrix 102 may have up to 1.5% tyramine substitution and up to 1% THA concentration. Preferred embodiments for methylprednisolone and prednisone will be up to 1.5% tyramine substitution and less than 5% THA concentration.

[0108] Testosterone is an androgen steroid that can be used for testosterone deficiency and can be applied as a topical gel, as a patch, or in another delivery form (e.g., by injection for long-term elution, which is superior to elution through the skin via a patch or gel). However, in preferred embodiments, for these drugs, topical application of delivery system 100 in gel form or liquid form is desirable. The concentration may vary depending on the steroid strength. For example, if the administration of delivery system 100 is via a patch or single delivery, testosterone may be administered up to 10 times the typical dosage, depending on the application site, the physical form of delivery system 100, and the container drug concentration. A typical binding matrix 102 containing testosterone will likely be composed of up to 7% tyramine substitution at up to 20% THA concentration. The binding matrix 102 may preferably have less than 1.5% tyramine substitution and less than 5% THA concentration.

[0109] Testosterone can be administered to transgender patients and can also be used in oncology to treat prostate cancer. High doses of testosterone appear to cause prostate cancer to be fatal, and when administered as a bolus injection near the cancer, high doses can be delivered locally over a long period of time (compared to the situation of systemic administration), ensuring that cancer cells are exposed to high doses of testosterone. One potential risk is that low to medium levels of testosterone may promote the growth of prostate cancer. Therefore, if the testosterone dose is not high enough, it may not be useful and may be harmful. When using corticosteroids, one limitation of testosterone use in delivery system 100 is that in the injection form, it is necessary to be able to inject using a needle of reasonable size. In some embodiments, the drug container 104 may be high-density hydrogel particles consisting of up to 1.5% tyramine substitution and up to 20% THA concentration, while the binding matrix 102 may have up to 1.5% tyramine substitution and up to 1% THA concentration. A typical binding matrix 102 containing testosterone would be composed of up to 7% tyramine substitution at up to 20% THA concentration. The binding matrix 102 may preferably have less than 1.5% tyramine substitution and less than 5% THA concentration in a preferred embodiment.

[0110] Estrogen is a steroid and may be injected or applied as a topical gel, as a patch, or in another delivery form, and can be used to treat estrogen deficiency in postmenopausal women or transgender patients. One limitation of estrogen use in delivery system 100 is that in the injectable form, it needs to be injectable using a needle of reasonable size. In some embodiments, the drug container 104 may be high-density hydrogel particles consisting of up to 1.5% tyramine substitution and up to 20% THA concentration, while the binding matrix 102 may have up to 1.5% tyramine substitution and up to 1% THA concentration. A typical binding matrix 102 containing testosterone would be composed of up to 7% tyramine substitution at up to 20% THA concentration. The binding matrix 102 may preferably have less than 1.5% tyramine substitution and less than 5% THA concentration.

[0111] In the topical or patch form of delivery system 100, the concentration may vary depending on the steroid strength. For example, if the administration of delivery system 100 is via a patch or single delivery, estrogen may be administered up to 10 times the typical dosage, depending on the application site, the physical form of delivery system 100, and the container drug concentration. A typical binding matrix 102 containing estrogen would be composed of up to 7% tyramine substitution at up to 20% THA concentration. The binding matrix 102 may preferably have less than 1.5% tyramine substitution and less than 5% THA concentration.

[0112] Low molecular weight: Antibiotics The various antibiotics that can be used in the disclosed delivery system 100 are avalox (e.g., moxifloxacin), β-lactams (e.g., penicillin derivatives and cephalosporins), macrolides, fluoroquinolones, tetracyclines, chlortetracycline, oxytetracycline, demeclocycline, lymecycline, meclocycline, methacycline, minocycline, rolitetracycline, doxycycline, tigecycline, and aminoglycosides.

[0113] Small molecule: Biologics In some embodiments, biologics such as, but not limited to, Copaxone (immunomodulator) and Betaseron (immunosuppressant) may be administered by injection (e.g., subcutaneously) and can be used to treat multiple sclerosis. By delivering the biologics using the disclosed delivery system 100, higher concentrations can be used and the frequency of injections can be reduced. One limitation of using biologics in the delivery system 100 is that in injection form, it is necessary to be able to inject using a needle of reasonable size. In some embodiments, the drug container 104 may be high-density hydrogel particles consisting of up to 1.5% tyramine substitution and up to 20% THA concentration, while the binding matrix 102 may have up to 1.5% tyramine substitution and up to 1% THA concentration.

[0114] Small molecule: Others Other small molecules that can be included in the disclosed delivery system 100 can treat conditions and diseases such as seizures, psychosis, autoimmune diseases such as rheumatoid arthritis and multiple sclerosis, gout, liver failure, anemia, and cancer. NSAIDs and gold can be used to aid in rheumatoid arthritis. Teriparatide, denosumab, and albumin can be used for liver failure. Erythropoietin (EPO) can be used for anemia and cancer.

[0115] In addition to injection, as briefly described above, the delivery system 100 can be delivered and used for a variety of other applications such as, but not limited to, anti-adhesion, coagulation, tissue patches, tissue reinforcement, drug delivery, orthopedics, coating, plugs, and tissue engineering.

[0116] Tyramine-crosslinked biopolymer: Anti-adhesion Many invasive medical procedures and surgeries damage the internal tissue 108a during activities such as manipulation, cutting, suturing, and drying that can occur during the procedure. After surgery, the delivery system 100 may be applied as a sheet, or the affected tissue surface 108a may be coated and injected as a sticking mass, thereby preventing adhesion. Hyaluronic acid is a natural barrier in the body and protects the tissue 108a from scarring. One advantage of the disclosed delivery system 100 is that it can keep the damaged tissue site 108a coated in hyaluronic acid long enough to heal the unintended trauma without generating a scar portion of the connective tissue between the damaged tissue site 108a and the surrounding tissue surface 108a.

[0117] In some embodiments, the delivery system 100 including the THA-based binding matrix 102a is thick enough to coat and adhere to the tissue surface 108a, but thin enough to be applied by a syringe, application tube or bottle, or a special sheet applicator. Similar to other medical applications, other drugs or molecules 106 can be added to aid in healing and protect the affected tissue 108a. Various examples include, but are not limited to, the following. (a) NSAIDs can be added to reduce swelling and treat pain, (b) antibiotics and antifungal drugs can be added to protect the wound site 108a from infection, (c) strong analgesics can be added and eluted from the hydrogel binding matrix 102 over time to treat local pain, (d) growth factors and promoters can be added and eluted over a period of more than one week to promote rapid healing.

[0118] Tyramine-crosslinked biopolymer: Coagulation Bleeding from traumatic wounds, extensive abrasions or lacerations and contusions in patients who have ingested anticoagulants, if not stopped, can immediately become life-threatening. In some embodiments, the disclosed delivery system 100 provides several options for promoting coagulation at the wound site 108a, such as, for example, but not limited to, dehydration, use of fibrin, use of specific osmotic pressures, use of vasoconstrictors, or any combination of the above.

[0119] Coagulation: Dehydration Adsorbing and dehydrating the plasma components of blood promotes coagulation at the wound or trauma site 108a. Thus, in one embodiment, the user can apply a delivery system 100 comprising a coarse powdered THA-based binding matrix 102a containing a drug container 104 to the bleeding and / or weeping diseased tissue 108a to absorb the plasma. In another embodiment, as shown in FIG. 4, the user can apply the powder as a lyophilized gel powder from a dry powder aerosol delivery system containing a propellant, extrude the cannister of the lyophilized gel powder, and apply it as a dry powder to the wound surface. FIG. 4 shows various tissues (e.g., epidermis, skin basal layer, adipose tissue, muscle layer) that are exposed due to trauma and thus benefit from the disclosed delivery system 100. The powder quickly adheres to the bleeding or weeping blood or tissue surface 108a, is quickly absorbed, and coagulated. In some embodiments, the binding matrix 102 in powder form may be pre-crosslinked when applied. In another embodiment, when the leakage is absorbed, a solution or mist of H2O2 may be applied to the THA-based binding matrix 102a to crosslink the THA-based binding matrix 102a. The delivery system 100 may act as a physical barrier and also as a tamponade.

[0120] Coagulation: Fibrin In some embodiments, a coagulation promoter (e.g., fibrin) may be added to the binding matrix 102 and cross-linked at a predetermined location so that the fibrin remains active. The delivery system 100 containing the fibrin-crosslinked binding matrix 100 may then be dispensed onto the wound surface 108a as a sheet or a series of sheets. In some embodiments, it can be injected into the center of the bruise to promote coagulation in the bleeding tissue.

[0121] Coagulation: Osmotic pressure Another way in which the delivery system 100 can promote coagulation is by creating a high osmotic pressure binding matrix 102 by using low-substituted THA at a high concentration. The binding matrix 102 itself has a high enough osmotic pressure to absorb water from the surrounding tissue and collapse bleeding capillaries and small-diameter blood vessels. However, adding a large amount of salt can further increase the osmotic pressure. Using this application, it is also possible to collapse spider veins (arteries) in cosmetic applications.

[0122] Coagulation: Vasoconstrictor In some embodiments, a vasoconstrictor such as epinephrine and a strong stimulant may be added to the binding matrix 102 and cross-linked at a predetermined location, and the final product may be applied to the wound site 108a or injected into the bruise. When used in combination with the binding matrix 102, the vasoconstrictor promotes slowing of blood vessel flow and can escape from the vascular system, while the binding matrix 102 can promote dehydration and blood coagulation.

[0123] Coagulation: Combined device Any combination of the above-described methods for promoting coagulation may be used. Vasoconstriction can be caused in the capillaries and small blood vessels near the bleeding site, while the binding matrix 102 and the coagulation promoter can coagulate the blood and seal the wound surface 108a. Without limitation, various auxiliary components 106 such as antibiotics, antifungal agents, analgesics, etc. may be added to protect the site until further medical treatment can be carried out. In some embodiments, the delivery system 100 can form a physical protective barrier once it covers the wound surface 108a and can function like a natural scab.

[0124] Tyramine-crosslinked biopolymer: tissue patch In addition to preventing adhesion and stimulating coagulation, as shown in FIG. 6 and as described above, the disclosed delivery system 100 may be used as a tissue patch to treat various disease states. Polymer tissue patches, nets and hammocks made of Teflon®, polypropylene and polyethylene may form scar tissue in the body around the implant, which may cause pain, may corrode the surrounding tissue, thereby causing tissue gaps or holes to become mixed or worsen. In one embodiment of the disclosed delivery system 100, the delivery system 100 may function as a tissue patch that supports the surrounding tissue 108a, may close holes and gaps, and / or may be long enough to heal the tissue and maintain the closure. It is then absorbed into the body, thereby eliminating the need for removal. The binding matrix 102 can also add growth promoters, analgesics, collagen particles directly or indirectly (i.e., using a drug container), or can be partially formulated from the collagen backbone so that supporting connective tissue can be generated over the gap or hole.

[0125] Delivery system 100 may be used in its tissue patch form to heal wounds, provide mechanical support, or be used for packing. Delivery system 100 may be formulated to contain collagen particles or may be made directly using low molecular weight collagen. Delivery system 100 may be combined with other strong tension materials or other hydrogels to create a protective sheet. As with other applications, drugs such as antibiotics, antifungal agents, analgesics, steroids, NSAIDs or target molecules 106 may be added to binding matrix 102 to treat the symptoms of wounds due to injury or trauma.

[0126] In some embodiments, prior to placement and crosslinking, binding matrix 102 may be seeded with red blood cells or white blood cells. In other embodiments, after crosslinking and after placement of delivery system 100, binding matrix 102 may be seeded with red blood cells or white blood cells by directly injecting the red blood cells or white blood cells into binding matrix 102. In addition to red blood cells or white blood cells, binding matrix 102 may be seeded with plasma components (e.g., PRP) before or after placement or crosslinking. Once placed in a given location, macrophages can attract fibroblasts, stem cells and migrating tissue cells to delivery system 100. Depending on the type and location of the wound, delivery system 100 will likely provide the best results when applied in a thin layer at regular intervals. Severe deep penetrating wounds may respond best when binding matrix 102 (e.g., protein-based binding matrix 102a) is applied as a single large bolus as shown in FIG. 5.

[0127] More specifically, deep penetrating wounds similarly require the growth of new tissue 108b, and the disclosed binding matrix 102 is specifically formulated to address this. For example, as shown in FIG. 5, the protein-based binding matrix 102b may be applied over or at the wound site to the damaged tissue 102a, and the THA-based binding matrix 102a may be applied over the tissue 108a as a protective coat. Over time, the protein-based binding matrix 102b attracts macrophages and endothelial tissue for the growth of new tissue 108b. The macrophages break down the protein-based binding matrix 102b material and attract endothelial cells or other surrounding cells to the binding matrix 102, enabling the generation of new tissue 108b. The THA-based binding matrix 102a serves to protect the wound site and prevent the formation of scar tissue.

[0128] In addition to wound healing, the disclosed delivery system 100 may provide mechanical support, may be in the form of a hernia patch, and may be used to aid in the repair of skin and muscle, may be used to aid in the repair or creation of new blood vessels, or may be used for packing.

[0129] Tyramine-crosslinked biopolymer: tissue reinforcement Another use of the disclosed delivery system 100 is for tissue reinforcement. For example, for urological purposes (e.g., urinary and fecal incontinence), as a vitreous replacement, for myocardial tissue (e.g., mitral or aortic valve), for esophageal tissue, for gastrointestinal purposes (e.g., gastric bypass), for the treatment of vocal cord folds, for fascia, as a space filler (e.g., as an organ replacement), or as a healing pad (e.g., for diabetes), the delivery system 100 may be used as a skin filler.

[0130] Regarding use as a dermal filler, the delivery system 100 can be made dense enough to have sufficient durability to act as a dermal filler. The sodium hyaluronate form can act as a filler to swell and expand dermal tissue so as to stretch the surface and remove folds and deep wrinkles. Additional components can be added to the hydrogel formulation to increase the duration of the filler (e.g., but not limited to, collagen powder and / or fibers) in dermal tissue. These additional components can promote the generation of new tissue 108b by facilitating the movement of macrophages into the binding matrix 102, attracting endothelial cells to the binding matrix 102, and creating new dermal tissue 108b.

[0131] Tyramine-crosslinked biopolymer: Drug delivery In some embodiments, as described above, the delivery system may be used as a drug delivery vehicle. For example, it may contain a drug or target molecule 106 and thus may assist in wound healing, pain, oncology, and ophthalmology. It may contain low molecular weight drugs and may act as a metabolic container, steroid container, or skin patch. The binding matrix 102 may be optically transparent, may have an optimal density for various operations, may be absorbed, and it may not be necessary to remove the delivery system 100 after treatment.

[0132] Tyramine-crosslinked biopolymer: Plastic surgery In some embodiments, delivery system 100 may be used as an orthopedic tool. For example, it can assist with viscosupplementation, artificial cartilage, bone paste or cement, growth plate repair, tendon repair, and myofasciitis. From the perspective of use in viscosupplementation, binding matrix 102 can be used to help replenish synovial fluid, which naturally contains 3 - 4 mg / mL of hyaluronan and is the natural lubricant found in bursae and tendon sheaths. Older joints and tissues cannot produce sufficient synovial fluid, so in cartilage and severely damaged joints, the bone contacts adjacent surfaces, causing pain. Thus, binding matrix 102 can heal the joint enough to replenish synovial fluid and minimize pain. Since hyaluronan is typically recycled fairly rapidly in bone, some embodiments of the disclosed invention may use an artificial hyaluronan solution containing cross-linked hyaluronan that is resistant to enzymatic degradation. In other embodiments of delivery system 100, highly substituted, cross-linked hydrogel formulations can be used, which are superior to existing formulations because they do not require purification after cross-linking. As described above, auxiliary components 106, such as, but not limited to, steroids, NSAIDs, analgesics, growth factors, and auxiliary lubricating materials, may be added to binding matrix 102.

[0133] Tyramine-crosslinked biopolymer: coating A further use of the delivery system 100 described above is as a coating. As shown in FIG. 10, before using the delivery system 100 in a catheter, as shown in FIG. 12, in a surgical device and in an organ requiring preservation, as shown in FIG. 11, in a transplantable sensor, and before using in an artificial heart and an artificial blood vessel, hyaluronic acid is incorporated into the binding matrix 102. Cross-linking at a given position on the surface may reduce the generation of microparticles during manufacture, so it is important to incorporate hyaluronic acid before placing it on the device surface. Hyaluronic acid is present in the extracellular matrix, synovial fluid and the vitreous humor of the eye. Hyaluronic acid is extremely hygroscopic, so it attracts water and gives tissues a swollen feel. Hyaluronic acid is extremely lubricious and plays an important role in lubricating tissue surfaces (e.g., joints, tendons and tendon sheaths, and eyes). Hyaluronic acid is one of the main components of the vitreous humor of the eye because it is optically transparent. Finally, hyaluronic acid functions as a barrier against tissue cells, thereby, in some cases, preventing the formation of scar tissue. For example, hyaluronic acid prevents tissue cells from entering the space occupied by a mass of high concentration of hyaluronic acid, and by preventing tissue cells from entering the space, prevents the formation of scar tissue. Certain microorganisms (e.g., streptococcus) are covered by themselves within a thick hyaluronic acid coat, and the immune system cannot reach the cell wall, and in an infection, initially, the attack of infectious microorganisms begins. Similarly, a hyaluronic acid coating can be used to protect, lubricate and make the surface to be coated stain-resistant.

[0134] In addition to various formulations of hydrophilic and lubricious coatings that already coat catheters and wires, these can also be coated by an embodiment of the disclosed binding matrix 102 that includes hyaluronic acid, as shown in FIG. 10. This coating of the THA-based binding matrix 102a can have a pharmaceutical and bioactive material (e.g., stem cells, biomaterials for preventing spasms) 106 added prior to crosslinking and coating. Once coated (e.g., using covalent bonds to the catheter surface), the THA-based binding matrix 102a can be crosslinked and can provide an elution space into the bloodstream. A further layer of the THA-based binding matrix 102a can be added on top of the initial layer of the THA-based binding matrix 102a. The drug and bioactive material 106 can be eluted during the procedure for various advantages (e.g., to create a vascular response). In some embodiments, the entire catheter can be coated, which helps prevent the artery from responding and being damaged. In other embodiments, the coating can be limited to specific parts of the catheter, such as the working length. The catheter can be designed to include removable parts that are intentionally left in the vasculature and surrounding tissue. Thus, a protective coating of the THA-based binding matrix 102a on a part of the catheter remains in the vasculature or tissue, which would be beneficial to the patient.

[0135] Surgical devices used to manipulate tissue can be coated with the THA-based binding matrix 102a after sterilization to create a protective and lubricious surface, thereby preventing the tissue from being abraded and adhering by the device during use. Clamps, retractors, ports, etc. are examples of devices that can be coated with the THA-based binding matrix 102a to protect tissue during surgery.

[0136] In some embodiments, the disclosed THA-based binding matrix 102a may be used in a delivery system 100 for use in an organ. More specifically, organs removed for transplantation often have a limited amount of time available for transplantation and pre-transplant testing. This is because the removed tissue begins to dry on the outer surface and may then no longer have good O2 exchange. To combat these problems, the organ may be coated with a delivery system 100 containing the THA-based binding matrix 102a to protect the outer surface from drying and improve O2 movement into the tissue. As previously disclosed, components 106 that enhance tissue health and viability may be added to the binding matrix 102. The thick nature of the delivery system 100 containing the cross-linked binding matrix 102 allows it to be held in place on the tissue surface.

[0137] The THA-based binding matrix 102a can also be used in a delivery system 100 for use on an organ during a procedure, as shown in FIG. 12, to prevent the formation of connective tissue. More specifically, during a particular procedure or surgery, a surgeon may grasp and move surrounding tissue or organs to access the necessary area within the body. This movement may promote the formation of scar tissue on the surface of these corresponding tissues or organs 108a and, in the case of the intestine, may cause pain or intestinal obstruction.

[0138] The disclosed delivery system 100 may be assisted by an implanted sensor. As shown in FIG. 11, many sensors quickly become fouled after implantation, thereby changing the diffusion rate for the variables being measured and preventing accurate readings of the variables for which the sensor was implanted for monitoring. The delivery system 100 containing the THA-based binding matrix 102a not only protects the sensor surface from fouling but also prevents the formation of scar tissue around the sensor, and the mass transfer and diffusion characteristics of the tissue are the same. Thus, proteins, hormones, or small molecules monitored by the sensor can move across the THA-based binding matrix 102a coating without being hidden, and the sensor can make accurate measurements.

[0139] Artificial hearts are difficult devices because the flow characteristics can cause blood vessel cells to be destroyed and blood clots to form. To reduce the shear force near the wall surface, a delivery system 100 containing a THA-based binding matrix 102a can be used as a coating for the artificial heart. Further, the binding matrix 102 may be impregnated with collagen, which promotes the migration of endothelial cells to the delivery system 100 and generates a coating such as that of the blood vessel wall. The delivery system 100 containing the THA-based binding matrix 102a can also prevent surface fouling and the occurrence of thrombosis.

[0140] As described above, in some embodiments, the disclosed delivery system 100 can be used in artificial blood vessels; in two-component fibers or cords derived from the outer ring of a collagen / protein-based system containing a sodium hyaluronate code impregnated in endothelial tissue or stem cell tissue; on the skin; in combination with antibiotics, antifungal agents, growth factors, nutrients, and living tissue, in addition to or impregnated in the binding matrix 102; for example, as a plug to fill a circular space such as a blood vessel or fistula (e.g., arteriovenous fistula, hemorrhoidal fistula, and obstetric fistula), or as a plug to fill a diverticulum. It may also be used as a filling agent behind the left atrial appendage, in solid tumors, or in uterine fibroids, in arteriovenous malformations, aneurysms, in the spaces of the brain, or in the aorta.

[0141] In the case of solid tumors, the delivery system 100 may be inserted into the main nutrient artery to occlude the tumor. In some embodiments, the delivery system 100 may contain a blood clot promoter. It can also incorporate chemical toxic compounds, monoclonal antibody-targeted tumor-specific, apoptosis signals (e.g., fas receptor, caspase, and Bcl-2 inhibitors), osmotic disrupting agents, radio frequency absorbing particles, free radical generating agents (e.g., TiO2 with ionizing radiation), and immunogenic compounds / promoters.

[0142] A further use of the delivery system 100 is a gel for embolization that includes components that promote blood clotting. For example, the binding matrix 102 that includes components of high osmotic pressure can cause the surrounding blood vessels to spasm and contract tightly. Maintaining the contracted state over a long period (e.g., for several minutes) can block the blood flow to the solid tumor and cause the downstream tissue to die. A chemotoxic drug may be added to the binding matrix 102 and / or the drug container 104, and this can be eluted into the surrounding tissue 108a to provide a locally high concentration of chemotoxic compounds. This can similarly increase the possibility of causing the nearby cancerous tissue to die while preventing the systemic effects from a systemic high dose of chemotoxic drug or compound.

[0143] Another example of a component that promotes blood clotting is a blood coagulation promoter component. The blood coagulation promoter component may be added to the delivery system 100 (e.g., to the binding matrix 102 of high osmotic pressure or to the standard binding matrix 102) and eluted from the embolization delivery system 100 to generate a blood clot.

[0144] The delivery system 100 can also be used as a mass for embolization to occlude uterine fibroids. When used for solid tumors, the binding matrix 102 or the drug container 104 may contain a blood clot promoter and / or a chemotoxic drug for refractory or diffuse fibromas if direct occlusion is insufficient for fibrous disruption.

[0145] Another use for the delivery system 100 as an occluding substance is for fistulas and diverticula. The peptide-based binding matrix 102 can promote the migration of macrophages and sclerosing tissue formation. In some embodiments, the binding matrix 102 or the drug container 104 may or may not contain stem cells and may contain endothelial cells for tissue formation and occlusion.

[0146] Tyramine-crosslinked biopolymer: Tissue engineering In addition to the above uses, the disclosed delivery system 100 may be used in in-vivo or in-vitro tissue engineering. Examples of in-vitro tissue engineering include 3D autologous grafts, 3D allogeneic grafts, 3D stem cells, 3D combinations of autologous and allogeneic tissues (e.g., allogeneic islet cells combined with collagen and autologous stem cells to promote angiogenesis around the allogeneic transplanted cells), 2D bladders, 2D skin, 2D cannulas, neural tubes, collagen nest geometries, freeze-dried and pulverized inner walls of the stomach and bladder.

[0147] Examples of 3D autologous grafts that include the disclosed delivery system 100 include collected islet cells. More specifically, after collecting host pancreatic tissue or pancreatic and mesenchymal stem cells from adipose tissue, the collected cells were added to a collagen shell of a cadaver or porcine pancreas or a 3D printed scaffold. The stem cells were manipulated with the host tissue to create new islet cells within a scaffold that included a nest geometry that mimicked the space, void size, and density of the pancreatic cell scaffold. To protect the scaffold and the new islet cells, the binding matrix 102 of the delivery system 100 may be used as a THA coating.

[0148] In some embodiments, the delivery system 100 can also be used as a cellulose shell in the cylinder for mechanical protection, or can be injected as granules or particle fragments with a diameter of less than 1.5 mm. More specifically, one way to protect the xenograft is to embed the xenograft in a cellulose shell composed of a thin wall, cellulose, and straw-shaped tubes so as to prevent the host tissue from being attacked, where the shell has high mechanical strength. One limitation of the cellulose shell is that the diffusion of nutrients and oxygen to the graft is restricted, and the diffusion of waste from the graft is restricted. To address this limitation of diffusion, some embodiments of the disclosed techniques incorporate the delivery system 100 into the cellulose shell. Hydrogel particles paired with a hydrogel could be made small and would not require a high-strength shell. Furthermore, the diffusion of substances in and out of the graft is considerably easier using the delivery system 100. One drawback of the delivery system 100 is that its components may be absorbed in the body, and thus, if absorbed, the xenograft cells cannot be retained at the desired location over a long period of time. Therefore, a combination of the cellulose shell and the delivery system 100 can be used to protect against attack by the host tissue and achieve durability at the desired location.

[0149] Similar to the 3D autograft, the disclosed delivery system 100 may be assisted with a 3D allograft. The THA-based binding matrix 102a can protect cells (e.g., islet cells) from the host immune system, sourced from pigs, human donors, or human cadavers. In some embodiments, the binding matrix 102 can be combined with hepatic stellate cells to obtain long-term viability. The cells are then concentrated, and a solid rod with a maximum diameter of 1.5 mm (e.g., a cellulose shell) may be surrounded by the cells encapsulated within the THA-based binding matrix 102a. The cellulose shell can provide a delivery method and mechanical protection for the delivery system 100. The composition may be modified by using a degradable shell (i.e., cat intestine), and the THA-based binding matrix 102a can protect the allograft from the host immune system. In moderately vascularized tissue, a diffusion distance of up to 1.5 mm would be possible (e.g., for O2, nutrient, waste removal, etc.). Some embodiments can modify the composition to exist without the cellulose shell (i.e., high-density gel particles) when used for injection. In one embodiment, there is viability for at least 30 days. In a preferred embodiment, there is viability for at least 12 months. In one embodiment, an alternative would be to use an embodiment of the delivery system 100 that includes a high-density THA-based binding matrix 102a surrounding the cells. The delivery system 100 including the high-density THA-based binding matrix 102a can be injected through a small-diameter needle while flowing the substance to the site and into the interstitial cavity.

[0150] In addition to islet cells, thyroid cells from cadaver donors can be used for xenografts after collection and sorting in the host tissue. In the case of thyroid cancer, excessive nodules or traumatic neck injuries, viable thyroid cells can be collected from cadavers or donors, and the xenografts can be encapsulated as described above for islet cells. Viable tissue can produce hormones and the hormone levels found in the tissue can be monitored. This is beneficial because the living system is much better at controlling dosage and dosing timing compared to artificial systems.

[0151] Similar to the methods disclosed for islet cells and thyroid cells, pituitary cells derived from living tissue can be collected or donated and transplanted if there is insufficient growth hormone or luteinizing hormone due to injury, genetic deficiency or other causes. The advantages would be to prevent syndromes, abnormal growth rates and to complete the transplantation in a well-controlled manner. In the case of dwarfism, growth hormone can be supplied directly from the tissue. In the case of gigantism, the pituitary gland can be inactivated by radiation or surgical means and then viable tissue can be delivered using delivery system 100 to administer growth hormone at an acceptable rate.

[0152] To create 3D stem cells, a three-dimensional tissue scaffold can be created by layering a thin layer of the delivery system 100 downward against the following top, and each layer includes a specific geometry that mimics the type of target tissue in microscopic and macroscopic geometries. Different substances can also be used in different regions of the layer to induce the desired response from the surrounding tissue. An example of the desired response is to promote the movement of stem cells or macrophages to the nucleation site, where new stem cells can enter and initiate the wound healing process, and the final result is a functional and fully differentiated desired tissue type. In another embodiment, the method includes creating voids and macroscopic geometries using a substance that easily dissolves, such as paraffin or a low molecular weight polymer, filling the interstitial cavity with the binding matrix 102, and crosslinking at a predetermined position. When the polymer or filling material is removed by dissolution, the hydrogel scaffold remains as a negative space with the original desired geometry. This enables nested geometries (such as circular blood vessels, high-density and not-so-high-density regions, etc.) as shown in FIG. 9. Although large structures could be created using both methods, different approaches may be optimal compared to other methods.

[0153] In some embodiments, these delivery systems 100 can be used to create a simple bladder tissue by using the binding matrix 102 as a basal layer and constructing it with bladder endothelial cells. The surface geometry can be set to promote tissue growth, nutrients and growth promoters can be supplied to the binding matrix 102, and the tissue can be grown faster than what is currently growing in the laboratory. Similar to the process described above for 3D cells, microscopic and macroscopic geometries can be created to promote the growth of a complex and mature bladder wall.

[0154] In some embodiments, the delivery system 100 can be used to create neural tubes, e.g., but not limited to, olfactory ensheathing cells or nanotubes. For example, various concentrations of olfactory ensheathing cells can be suspended in the binding matrix 102 and injected into the spinal column or nerve bundle portion.

[0155] Another form of in-vitro tissue engineering using the delivery system 100 is for the collagen-nest geometry. In some embodiments, the collagen of the binding matrix 102 can be applied to a 3D printer in continuous layers to create a collagen network structure similar to the extracellular matrix found in the target organ. When stem cells are seeded onto this binding matrix 102, the undifferentiated cells take on the shape of the collagen matrix and, due to its mechanical form, begin to transform into differentiated cells of this target organ.

[0156] The freeze-dried or freely dried inner walls of the stomach, bladder, or subcutaneous tissue are a further form of in-vitro tissue engineering that can be accomplished using the disclosed delivery system 100. Historically, freeze-dried powders of the bladder have, in certain situations, been applied to the surface of open wounds to advance healing cells anteriorly. Theoretically, the tissues found in the inner wall of the stomach, the inner wall of the bladder, and the skin basal layer contain growth factors that promote high-speed tissue growth. This is because these are tissues that must quickly be lost and then continue to grow to replace the lost / abraded surface. These growth factors, when combined with the collagen scaffold made by the rehydrated powder, cause the surrounding tissue to move from the wound to the scaffold and begin to grow, starting to grow outward to fill the wound. The surrounding tissue 108a also has control factors that differentiate new cells and create the appropriate tissue type in the correct location. This can create the same situation as how a lizard can regrow its tail and how an amphibian can regrow its leg. In this application, the powdered tissue can be incorporated into the binding matrix 102 in a dense, tight formulation that can protect the wound from infection. This formulation can seal the edges and create a strong matrix in which new cells can move and new tissue growth 108b can begin. In one embodiment, the delivery system 100 can be applied as a small sheet to build cells from the tissue basal layer 108a and create new tissue 108b in the correct location. Without tensegrity and / or cell signal dentags from the surrounding tissue, large limb growth or replacement would have to occur within a small, thin sheet applied daily until the limb was fully regrown. Similarly, this method can be used to heal large wounds where a mass of tissue has been lost and there is a large gap or opening in the body or a large tunnel-shaped wound has been created.

[0157] The various embodiments described above are given by way of example only and should not be construed as limiting the scope of the claims appended hereto. Those skilled in the art will readily recognize various modifications and changes that may be made without departing from the true spirit and scope of the following claims and without following the example embodiments and applications shown and described herein.

Claims

1. A hydrogel-based biodelivery vehicle for delivering drugs to a living body, comprising: a plurality of drug containers and a binding matrix, wherein at least one of the plurality of drug containers contains the drug, the binding matrix is a cross-linked hydrogel matrix having covalent bonds between tyramine molecules, the cross-linked hydrogel matrix is a cross-linked and solidified liquid hydrogel matrix, the plurality of drug containers are dispersed in the liquid hydrogel matrix and uniformly present in the binding matrix, the liquid hydrogel matrix contains water, horseradish peroxidase, hydrogen peroxide, and sodium hyaluronate substituted with tyramine, the sodium hyaluronate substituted with tyramine is one in which 0.5% to 1.5% of the carboxyl groups of sodium hyaluronate are substituted with tyramine molecules, where the tyramine molecules form covalent bonds between the tyramine molecules of the cross-linked hydrogel matrix, the cross-linking of the liquid hydrogel matrix is carried out with horseradish peroxidase and hydrogen peroxide, and does not destroy or react with the plurality of drug containers or the drug, the plurality of drug containers are selected from the group consisting of high-density hydrogel particles, porous particles, liposomes, and cellulose particles, A hydrogel-based biodelivery vehicle, characterized by the above.

2. The hydrogel-based biodelivery vehicle according to claim 1, wherein the plurality of drug containers further contain high-density hydrogel particles formed by cross-linking a liquid hydrogel matrix for high-density hydrogel particles, where the liquid hydrogel matrix for high-density hydrogel particles contains sodium hyaluronate substituted with tyramine for high-density hydrogel particles, the sodium hyaluronate substituted with tyramine for high-density hydrogel particles is one in which 1.5% of the carboxyl groups of sodium hyaluronate are substituted with tyramine molecules, A hydrogel-based biodelivery vehicle, characterized by the above.

3. The hydrogel-based biodelivery vehicle according to claim 1, wherein the plurality of drug containers are liposomes. A hydrogel-based biodelivery vehicle, characterized by the above.

4. The hydrogel-based biodelivery vehicle according to claim 2 or 3, wherein the drug is an analgesic, the hydrogel-based biodelivery vehicle.

5. The hydrogel-based biodelivery vehicle according to claim 4, wherein the analgesic is bupivacaine, the hydrogel-based biodelivery vehicle.

6. The hydrogel-based biodelivery vehicle according to claim 1, wherein the hydrogel-based biodelivery vehicle is disposed on, in or near the surface of the living tissue of the living body to deliver the drug, and the binding matrix has a higher osmotic pressure than the living tissue, the hydrogel-based biodelivery vehicle.

7. The hydrogel-based biodelivery vehicle according to claim 6, wherein the binding matrix absorbs liquid from the living tissue, the hydrogel-based biodelivery vehicle.

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