WO2022072597A1 - Transdermal medicament delivery device - Google Patents

Abstract

A medical device for transdermal implantation is disclosed. The medical device includes a soluble, hydrophilic polycaprolactone (PCL) substrate and a medicament in contact with the PCL substrate where the PCL substrate has been treated with a base having a pH greater than 8. The medicament includes one or more stem cell materials.

Description

TRANSDERMAL MEDICAMENT DELIVERY DEVICE

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63/086,045 titled “TRANSDERMAL MEDICAMENT DELIVERY DEVICE MECHANISM” which was filed on September 30, 2020 and is incorporated by reference in its entirety.

BACKGROUND

[0002] Biodegradable polymeric materials have the promise to revolutionize delivery of drugs and therapeutic compounds which can improve the quality of life for millions of patients. Typically, natural biodegradable materials are preferred over synthetic polymers. While both biologically derived and synthetic polymers have been extensively investigated for biocompatibility, natural polymers have many advantages including biodegradability, cytocompatibility, and unique physical, chemical, and mechanical properties. Biological polymers also offer cell recognition sites necessary for cell adhesion and proliferation. However, most of these natural polymers exhibit poor stability, process variability and can be subject to contamination or immunogenic responses.

[0003] Synthetic polymers have excellent design flexibility because their composition and structure can be tailored to specific applications. Poly (e-caprolactone) has drawn a great deal of attention in the past several years and has been successfully incorporated as an implantable biomaterial for medical applications, including sutures and wound dressing, cardiovascular tissue engineering, nerve regeneration, and bone tissue engineering. The use of PCL as a vehicle for controlled delivery of therapeutic molecules (e.g., drug, protein, gene), has also been extensively explored. PCL is a linear aliphatic polyester. It is a hydrophobic, semi crystalline (50%), biocompatible, and relatively slow-degrading polymer, which has been widely used in the biomedical field for the last few decades. It is a thermoplastic polymer with several desirable features, including good stability under ambient conditions, ease of processability (thermal & solution), and has already been approved for use in products by the U.S. Food and Drug Administration. While PCL has a combination of desirable properties including biodegradability, biocompatibility and high permeability, practical therapeutic applications are still hampered by the hydrophobic nature of the polymer. The water-repelling character of PCL results in slow in vivo dissolution rates and the polymer lacks reactive surface charges to promote coupling to proteins and small molecules. The hydrophobic surface also prevents stem cell adhesion, which is critical for cell replacement therapies. As such PCL biomaterials for use as a vehicle for drug delivery has not translated more widely into clinical use. Although PCL exhibits several desirable characteristics for the long-term delivery of therapeutic molecules, including biodegradability, biocompatibility, and high permeability, practical application is still hampered by issues such as low encapsulation efficiency, burst release, and low bioactivity toward tissue, due to its hydrophobicity.

SUMMARY OF THE INVENTION

[0004] A device for transdermal delivery of medicament is disclosed. A general aspect is a medical device. The medical device includes a soluble, hydrophilic polycaprolactone (PCL) substrate and medicament in contact with the PCL substrate where the PCL substrate having been treated with a base having a pH greater than 8. The medicament may comprise stem cells. The stem cells may be configured to produce one or more hormones. The one or more hormones may include insulin. The one or more hormones may include glucagon. The medical device may further include factors that promote cell survival of the stem cells in contact with the stem cells. The medical device may further include factors that promote cell function of the stem cells in contact with the stem cells. The factors may be substances selected from a list consisting of oxygen generating particles or cytokines. The medical device may further include a continuous glucose monitor. The continuous glucose monitor may be configured to measure insulin secretion by the stem cells. The continuous glucose monitor may be configured to measure a duration of insulin secretion by the stem cells. The continuous glucose monitor may be configured to signal when an additional infusion is needed. The PCL substrate may further include a co-polymer. The co-polymer may include at least one of polylactic acid (PLA), polylactide, L-PLA, L-polylactide, poly(D,L)-lactic acid, poly(D,L)-lactide, polyglycolide (PGA), polydioxane, acrylamide, poly N-isopolyacrylamide, chitosan, polyethylene glycol, poly vinyl alcohol, hydroxyapatite/silk fibrion (HAP/SF), or polyurethane. The PCL substrate may be configured to dissolve between about 2 hours to about 2 years under aqueous conditions. The medical device may be configured to be implanted under the skin of a subject. The medical device may be further configured to be implanted in a sub cutaneous space.

[0005] Another general aspect is a medical device. The medical device includes a soluble, hydrophilic polycaprolactone (PCL) substrate and a medicament in contact with the soluble, hydrophilic PCL substrate where the soluble, hydrophilic PCL substrate has been treated with a base having a pH greater than 8. The medicament includes one or more stem cell materials. The soluble, hydrophilic PCL substrate may include two or more layers that are in contact with at least one of the one or more stem cell materials. The two or more layers may include a first layer and a second layer. The second layer may be positioned to at least partially protect a first layer from a foreign body response in an individual. The one or more stem cell materials may include products that regulate an inflammation response. Each of the one or more stem cell materials may be in contact with a separate layer of the two or more layers. The products that regulate an inflammation response may be in contact with the second layer. The soluble, hydrophilic PCL substrate may be implantable into a subcutaneous space. The first layer may be positioned with at least one face exposed to blood vessels in the subcutaneous space. The second layer may be positioned away from the blood vessels relative to the first layer. The first layer may be in contact with stem cell materials that regulate insulin production.

[0006] An exemplary embodiment is a method for manufacturing a medical device. The method includes differentiating one or more stem cell materials to perform a specific bodily function and growing the one or more stem cell materials on a soluble, hydrophilic polycaprolactone (PCL) substrate that is implantable into a subcutaneous space. The soluble, hydrophilic PCL substrate may be implantable into a human individual. The soluble, hydrophilic PCL substrate may include two or more layers that are in contact with at least one of the one or more stem cell materials. The two or more layers may include a first layer and a second layer. The method may further include positioning the second layer to at least partially protect the first layer from a foreign body response in the human individual. The one or more stem cell materials may include products that regulate an inflammation response. Each of the one or more stem cell materials may be in contact with a separate layer of the two or more layers. The products that regulate an inflammation response may be in contact with the second layer. The first layer may be positioned with at least one face exposed to blood vessels in the subcutaneous space. The second layer may be positioned away from the blood vessels relative to the first layer. The first layer may be in contact with stem cell materials that regulate insulin production. The method may further include determining a dissolution of the soluble, hydrophilic PCL substrate based on detection by a continuous glucose monitor.

[0007] Another general aspect is a medical device. The medical device includes a multi-layered soluble, hydrophilic polycaprolactone (PCL) substrate and two or more stem cell materials in contact with the multi-layered soluble, hydrophilic PCL substrate. The one or more stem cell materials may include substances that regulate an inflammation response. A first layer of the multi-layered soluble, hydrophilic PCL substrate may be in contact with the substances that regulate an inflammation response. The first layer may be positioned to at least partially protect a second layer from a foreign body response in an individual.

BRIEF DESCRIPTION OF THE DRAWINGS

[0008] Fig. 1 is an illustration of a magnification of a hydrophilic PCL microbead.

[0009] Fig. 2 is a microscopic image showing a multitude of untreated PCL microbeads suspended in a solution.

[0010] fig. 3 is a microscopic image showing a multitude of PCL microbeads, suspended in a solution of 50% (w/w) NaOH.

[0011] fig. 4 is a magnified photograph of a hydrophobicity test of a water droplet on a polycaprolactone wafer.

[0012] fig. 5 is an electron microscopy image showing the microporous structure of base-treated hydrophilic PCL foam.

[0013] fig. 6 is a reaction diagram of base-catalyzed hydrolysis of the ester linkages present in the backbone of polycaprolactone.

[0014] fig. 7 is a reaction diagram of a coupling of surface-exposed carbonyl groups to amino groups on a polypeptide to create a peptide bond.

[0015] fig. 8 is an illustration of an embodiment of a surface of a hydrophilic PCL microbead as the hydrophilic PCL microbead binds to stem cells.

[0016] fig. 9 is a series 900 of microscopic images that illustrate a rate of dissolution of PCL microbeads in 5% (w/w) NaOH vs. 50% (w/w) NaOH.

[0017] fig. 10 is an illustration of an embodiment of a PCL dissolving microneedle.

[0018] fig. 11 is a series of microscopic images that show the surface of a PCL microbead as it is treated by a basic solution. [0019] fig. 12 is an illustration of an application of hydrophilic PCL microbeads that are coated with a medicament, to skin of a subject.

[0020] FIG. 13 is an illustration of a hydrophilic PCL structure that is implanted into a subcutaneous space of a forearm of a subject.

[0021] FIG. 14 is an illustration of a layered hydrophilic PCL structure that is implanted under the skin of a subject.

[0022] FIG. 15 is an illustration of a continuous glucose monitor that can detect when the hydrophilic PCL structure has substantially dissolved.

DETAILED DESCRIPTION

[0023] After reading this description it will become apparent to one skilled in the art how to implement the invention in various alternative embodiments and alternative applications. However, all the various embodiments of the present invention will not be described herein. It will be understood that the embodiments presented here are presented by way of an example only, and not limitation. As such, this detailed description of various alternative embodiments should not be construed to limit the scope or breadth of the present invention as set forth below.

[0024] Before the present invention is disclosed and described, it is to be understood that the aspects described below are not limited to specific compositions, methods of preparing such compositions, or uses thereof as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting.

[0025] The detailed description of the invention is divided into various sections only for the reader’ s convenience and disclosure found in any section may be combined with that in another section. Titles or subtitles may be used in the specification for the convenience of a reader, which are not intended to influence the scope of the present invention.

[0026] The disclosed subject matter is a hydrophilic, biocompatible polymer designed for delivery of immunoproteins, stem-cell biologies and small molecules for therapeutic and diagnostic applications. The base material is polycaprolactone (PCL), a biodegradable polymer approved for in human use by the United States Food and Drug Administration (FDA) with applications in tissue engineering, rhinoplasty and other surgeries because of its non-immunogenic, biocompatible properties. A preparation method involves controlled cleavage of the PCL polymer resulting in exposure of charged carboxyl and hydroxyl groups on the polymer surfaces. The charged moieties increase hydrophilicity and impart a weak cationic exchange character to the polymer, which enables facile binding and coupling of proteins and small molecules. The preparation accelerates the rate of in vivo dissolution of PCL which occurs naturally in the human body. The polymer can be form fashioned into foams, ultra-thin films, microbeads and nanoparticles using electrospray, 3D printing and other sophisticated material processing methods.

Definitions

[0027] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In this specification and in the claims that follow, reference will be made to a number of terms that shall be defined to have the following meanings:

[0028] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0029] “Optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0030] The term “about” when used before a numerical designation, e.g., temperature, time, amount, concentration, and such other, including a range, indicates approximations which may vary by ( + ) or ( - ) 10%, 5%, 1%, or any subrange or subvalue there between. Preferably, the term “about” when used with regard to a dose amount means that the dose may vary by +/- 10%.

[0031] “Comprising” or “comprises” is intended to mean that the compositions and methods include the recited elements, but not excluding others. “Consisting essentially of’ when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination for the stated purpose. Thus, a composition consisting essentially of the elements as defined herein would not exclude other materials or steps that do not materially affect the basic and novel characteristic(s) of the claimed invention. “Consisting of’ shall mean excluding more than trace elements of other ingredients and substantial method steps. Embodiments defined by each of these transition terms are within the scope of this invention.

[0032] By the phrases “modified polycaprolactone” or “modified PCL” is meant any PCL that has been treated or modified such that the hydrophilicity of the PCL is increased and/or such that one or more surface features of the PCL have been modified (e.g., chemical and/or physical modifications). Examples of surface features include texture (e.g., roughness, smoothness), holes, dimples, channels, protrusions and other irregularities. Any suitable treatment methods, including chemical or physical treatments, for increasing hydrophilicity and/or modifying surface features of PCL can be used. For example, PCL can be subjected to (treated with) a base (e.g. having a pH above 8). Non-limiting examples of bases include NaHCQ3 and NaOH.

[0033] As used herein, the phrase “soluble, hydrophilic polycaprolactone”, “soluble, hydrophilic PCL”, or “hydrophilic PCL” means polycaprolactone (PCL) that has been treated in some manner to make it absorb water and to increase its solubility (i.e., increase dissolution rate) when used in a composition, a stem cell carrier, or an implant. Any suitable treatment methods, including chemical or physical treatments, for increasing hydrophilicity and solubility of PCL can be used. For example, PCL can be subjected to (treated with) a base (e.g. having a pH above 8) as described in WO 2016/025021 Al, which is incorporated herein by reference in its entirety for all purposes, including for all methods of making, modifying, and using PCL and modified PCL. Non-limiting examples of bases include NaHCO3 and NaOH.

[0034] As used herein, “polycaprolactone co-polymer” refers to any combination of the polymer made by a ring-opening polymerization of epsilon caprolactone (PCL) and a copolymer. Co-polymers can include polylactide, polyglycolide or polydioxanone. PCL may be copolymerized with other esters such as polylactide to alter properties. In addition to polylactide, PCL may be copolymerized with other lactone-containing polymers such as poly-glycolide, poly (3 tolO-membered) lactone ring-containing compounds, etc. Generally, high molecular weight (MW) biodegradable lactone co-polymers are used, but poly ethylene glycol and poly vinyl styrene can also be used. In a typical embodiment, a molecular weight range of PCL is 5,000 to 300,000. For example, an 80,000 MW PCL polymer can be used. In addition, a co-polymer can include, but not be limited to, any polypeptide, polynucleotide, polylactic acid (PLA), polylactide, L-PLA, L-polylactide, poly(D,L)-lactic acid, poly(D,L)- lactide, polyglycolide (PGA), polydioxane, acrylamide, poly N-isopolyacrylamide, chitosan, polyethylene glycol, poly vinyl alcohol, hydroxyapatite/silk fibrion (HAP/SF), and/or polyurethane. Additional co- polymers are described herein.

[0035] As used herein, the term “copolymerized” refers to using two or more monomeric units to form a polymer with inclusion of both in some random (e.g., AABABBBAABAAABBBBA) or defined order (such as, e.g., AAABAAABAAAB or ABABABAB or ABAABAABAABAABAABA). For example, when referring to PCL that is copolymerized with at least one agent such as, e.g., L-lactic acid, the copolymer formed is a polycaprolactide called poly-L-lactic-co-e-caprolactone.

[0036] As used herein, the term “film” refers to a thin, membranous covering or coating. A film may be in the range of thickness in the range of about 10 nm„ lOOnm, 1pm, 0.01 mm, 0.02 mm, 0.03 mm, 0.04 m, 0.05 mm, 0.06 mm, 0.07 mm, 0.08 mm, 0.09 mm, 0.1 mm, 0.2 mm, 0.3 mm, 0.4 mm, 0.5 mm, to about 0.6 mm.

[0037] As used herein, the term “anatomical mimic” refers to any shape that recapitulates an existing structure found in natural anatomy. An anatomical shape includes a partial or full- representation of a shape found in a patient’s own anatomy or that exists.

[0038] As used herein, the term “geometrical shape” refers to any shape found in geometry or any combination of shapes found in geometry. A geometrical shape can be comprised of any solid, film, sheet, netting, and/or mesh.

[0039] As used herein, the term “computer-aided designed shape” refers to any shape generated with the aid of computation; which can be a shape found in nature or a novel shape.

[0040] As used herein, a "stem cell" is a cell characterized by the ability of selfrenewal through mitotic cell division and the potential to differentiate into a tissue or an organ. Among mammalian stem cells, embryonic stem cells (ES cells), somatic stem cells (e.g., HSC), and induced pluripotent stem cells (iPSC) can be distinguished. Embryonic stem cells reside in the blastocyst and give rise to embryonic tissues. Somatic stem cells reside in adult tissues for the purpose of tissue regeneration and repair. Induced-pluripotent stem cells are adult cells genetically reprogramed to an embryonic stem cell-like state.

[0041] As used herein, “potency” refers to the differentiation potential of a stem cell. Potency can further refer to five specific subclasses of potency. Totipotent, or omnipotent, stem cells can differentiate into an embryonic state. Pluripotent stem cells can differentiate into almost all cells, including the three germ layers of embryonic development. Multipotent stem cells can differentiate into a number of cell types that are related, for example, a multipotent blood stem cell can differentiate into multiple types of blood cells, including the three main types of white blood cells: monocytes, lymphocytes, and neutrophils. Oligopotent stem cells can differentiate into a smaller number of types, for example, a vascular stem cell can differentiate into a smooth muscle cell or an endothelial cell. Unipotent stem cells are cells that only differentiate one way, for example, a hepatoblast differentiates into a hepatocyte.

[0042] As used herein, the term “stem cell biomaterials” refers to any biomaterials derived from stem cells. Stem cell biomaterials include, without limitation, stem cell- conditioned media, cytokines, exosomes, microvesicles, or other vesicles derived from stem cells, growth factors derived from stem cells, and/or other factors (e.g., proteins, lipids, cellular fragments, etc.) derived from stem cells.

[0043] The term “stem cell materials” may include both stem cells themselves and stem cell biomaterials, which may be derived from the stem cells.

[0044] As used herein, “stem cell additive” refers to any compound/composition that aids in growth, proliferation, differentiation, survival, modulation, etc. of the stem cells. For example, the stem cell additive may be any or all combinations of stem cell growth factor, stem cell support media, stem cell support matrix, and/or other active ingredients used to promote, protect, differentiate, modulate, or otherwise influence the stem cells within the stem cell carrier. Further, a stem cell additive can refer to any additive that facilitates the integration of the stem cell carrier with the site of implantation or administration, and surrounding tissues.

[0045] As used herein, “active agent” refers to any anti-inflammatory, pro- inflammatory, pro-wound healing, angiogenic, proliferation, or differentiation factor. The active agent may be, for example, conjugated to the soluble, hydrophilic PCL. Individual active agents or mixtures thereof, if desired, can be employed. An active agent can include, but is not limited to, antibiotics, antifungals, anti-inflammatory drugs, hypoimmunogenic factors, hypoproliferative factors, anti-inflammatory cytokines, anti-proliferative cytokines, any FDA-approved molecule for the treatment of disease, any therapeutic reagent, dermal filler, any molecule used for support of the receiving area of stem cell carrier implant, nonstem cells, growth factors, oxygenating factors, reducing factors, hormones, immunological reagents, implantation-site integration factors, angiogenic factors, anti-angiogenic factors, dissolution factors, wound-healing specific factors, general cytokines, general chemokines, and teratoma inhibitors. An active ingredient can be added integrated with the implant or coadministered after the implant, or dosed after the implant for a range of time.

[0046] As used herein, the term “medicament” refers to any substance that can be used for the medical treatment of a subject. Medicaments may include active agents, stem cells, derivatives of stem cells such as stem cell biomaterials, and the like.

[0047] As used herein, “stem cell growth factor” refers to any small molecule, biomolecule, protein, antibody, peptide, nucleotide, polymer, cross-linked polymer, matrix, scaffold, oligonucleotide, oligosaccharide, biopolymer, cross-linked biopolymer, inorganic, or organic molecule, or any combination thereof, used to promote the growth of stem cells. Further, stem cell growth factors described herein include, but are not limited to, human interleukin- Ibeta (IL-lbeta), human interleukin-2 (IL-2), human interleukin-3 (IL-3), human interleukin-4 (IL-4), human interleukin-6 (IL-6), human interleukin-7 (IL-7), human interleukin-9 (IL-9), human interleukin- 10 (IL-10), human interleukin- 11 (IL-11), human interleukin- 12 (IL- 12), human interleukin - 13 (IL- 13), human interleukin- 15 (IL- 15), human interleukin- 16 (IL-16), human interleukin-27 (IL-27), human interleukin-32 (IL-32), human interleukin-33 (IL-33), human interleukin-34 (IL-34), human angiopoietin- 1 (ANGPT1), human stem cell factor (SCF), human granulocyte-macrophage colonystimulating factor (GM-CSF), human leukemia inhibitory factor (LIF), human erythropoietin (EPO), human Flt-3 ligand, human thyroperoxidase (TPO), human macrophage colony stimulating factor (M-CSF), human fibroblast growth factor- 1 (FGF-1, aFGF), human fibroblast growth factor-2 (FGF-2, bFGF), human fibroblast growth factor-4 (FGF-4), human fibroblast growth factor-5 (FGF-5), human fibroblast growth factor-6 (FGF-6), human fibroblast growth factor-7 (FGF-7), human fibroblast growth factor- 8 (FGF-8), human fibroblast growth factor-9 (FGF-9), human fibroblast growth factor- 10 (FGF-10), human fibroblast growth factor-12 (FGF-12), human fibroblast growth factor-16 (FGF-16), human fibroblast growth factor-17 (FGF-17), human fibroblast growth factor-18 (FGF-18), human fibroblast growth factor-19 (FGF-19), human fibroblast growth factor-20 (FGF-20), human fibroblast growth factor-21 (FGF-21), human fibroblast growth factor-22 (FGF-22), human fibroblast growth factor-23 (FGF-23), human insulin growth factor 1 (IGF-1), human insulin growth factor 2 (IGF-2), human Wnt-1 (Wingless Int-1), human Wnt-2, human Wnt- 7a, human transforming growth factor beta (TGF-beta), human vascular epithelial growth factor (VEGF), human epidermal growth factor (EGF), human bone morphogenetic protein 2 (BMP-2), human bone morphogenetic protein 3 (BMP-3), human bone morphogenetic protein 7 (BMP-7), human thrombopoeitin (TPO), human platelet-derived growth factor BB (PDGF-BB), human activin-A, human activin-B, human inhibin, human CD3 antibody, human CD 28 antibody, or human CD2 antibody.

[0048] As used herein, “stem cell differentiation factor” refers to any small molecule, biomolecule, protein, antibody, peptide, nucleotide, polymer, cross-linked polymer, matrix, scaffold, oligonucleotide, oligosaccharide, biopolymer, cross-linked biopolymer, inorganic, or organic molecule, or any combination thereof, used to promote the differentiation of stem cells. Any factor known to promote differentiation of stem cells to a particular (desired) cell type may be used. Stem cell differentiation factors can vary depending on the type of stem cells and/or the desired cell type, and are well known in the art.

[0049] As used herein, “stem cell support media” refers to any small molecule, biomolecule, protein, antibody, peptide, nucleotide, polymer, cross-linked polymer, biopolymer, cross-linked biopolymer, matrix, scaffold, oligonucleotide, buffer, commercial media, media, inorganic, or organic molecule, or any combination thereof, used to promote the physical support, growth, or differentiation of stem cells. In particular, stem cell support media comprise cell culture media, with or without supplementation (e.g., by serum, BSA, or other proteins).

[0050] Further, stem cell support media described herein includes, but is not limited to, Dulbecco’s modified eagle’s medium (DMEM), modified eagle’s medium (MEM), eagle’s basal medium (BME), Roosevelt Park Memorial Institute medium (RPMI), F12 medium, phosphate buffered saline (PBS), L-glutamine, L-alanyl-Lglutamate, non-essential amino acids (NEAA), fetal bovine serum (FBS), bovine calf serum (BCS), horse serum (HS), bovine serum albumin (BSA), human serum albumin (HSA), sodium bicarbonate, sodium carbonate, sodium pyruvate, lipoic acid, ascorbic acid, vitamin B12, nucleosides, cholesterol, oxygenating factors (perfluorocarbons (PFCs), sodium percarbonate, calcium peroxide, magnesium peroxide, hydrogen peroxide), apo- transferrin, insulin, reducing factors (glutathione), Wharton’s jelly, and transferrin.

[0051] As used herein, “stem cell support matrix” refers to any small molecule, biomolecule, protein, antibody, peptide, nucleotide, polymer, cross-linked polymer, biopolymer, cross-linked biopolymer, matrix, scaffold, oligonucleotide, inorganic, or organic molecule, or any combination thereof, used to hold, protect, separate, maintain, modify, and/or adhere stem cells. Further, stem cell support matrices described herein includes, but are not limited to, agar, methylcellulose, collagen, extracellular matrix, vitronectin, fibronectin, gelatin, elastin, fibrinogen, collagen, tropoelastin, hyaluronic acid polymers, heparin sulfate, matrigel, thioreactive crosslinking reagents, and laminin.

[0052] As used herein, “biomedical implant” refers to any permanent or removable implant for the treatment of a disease, for surgical reconstruction, for a cosmetic application, or for a dental application, for any of these cases either electively implanted or medically required. The biomedical implant can be comprised of any approved substance by FDA (ceramic, metal alloy, pure metal, plastic). The biomedical implant can be comprised of human or animal tissue or components of tissue approved for implantation.

[0053] As used herein, “organoid” refers to a plurality of cells that represents the micro- anatomy of an organ. An organoid displays three factors: a plurality of different cell types that are found in the original organ of interest, performs at least a partial function of the original organ of interest, and the cells comprising the organoid are organized in three- dimensional space.

[0054] As used herein, “hydrophilicity” refers to the physical property of a compound that has an affinity for or is attracted to water. The attractive interaction between water and a surface is further known as wetting. Further, in the field of surface science, hydrophilicity refers to a contact angle of less than about 90 degrees between a droplet of water and the surface it contacts. In various embodiments, a hydrophilicity refers to a contact angle of less than about 75 degrees The contact angle usually refers to the static contact angle. Hydrophilicity can also be measured using a sliding angle, an advancing angle, and a receding angle of the water droplet contacting the surface of interest, and additional derivations using one or more angle measurements. Further the wetting and adhesion interactions between water and a surface can be measured by calculating the attractive force between the water and surface using a microbalance, goniometer, or atomic force microscopy.

I. Soluble, Hydrophilic Polycaprolactone (PCL)

[0055] The substrate as provided herein contains soluble, hydrophilic polycaprolactone (PCL). PCL is a monopolymer made by a ring-opening polymerization of epsilon caprolactone. Similar polymers are polylactide, polyglycolide or polydioxanone. PCL may be copolymerized with other esters such as polylactide, poly glycolide polydioxanone, or poly (3 tolO-membered) lactone ring-containing compounds to alter properties. Polymers of acrylamide may also be used, such as poly N-isopropylacrylamide. In some embodiments, the PCL is copolymerized with a polystyrene or a poly vinylidene. Any suitable polystyrene can be used. Any suitable polyvinylidene can be used. Examples of polystyrenes that can be used include polystyrene, polystyrene sulfonate, carboxylated polystyrene, carboxylate modified polystyrene, iodinated polystyrene, brominated polystyrene, chlorinated polystyrene, fluorinated polystyrene, lithium polystyryl modified iodinated polystyrene, iodinated polystyrene derivatives, polystyrene ionomers, polystyrene ion exchange resin, sodium polystyrene sulfonate, polystyrene sulfonate, chlorinated polystyrene derivatives, brominated polystyrene derivatives and derivatives thereof. Examples of poly vinylidene include polyvinylidine fluoride, polyvinylidine chloride, polyvinylidine bromide, polyvinylidine iodide, polyvinylidine acetate, polyvinylidine alcohol and derivatives thereof. Further examples of suitable agents for copolymerizing with PCL include polyvinylpyrrolidone, polyvinylpyrrolidone iodine, polyvinylpyrrolidone bromide, polyvinylpyrrolidone chloride, polyvinylpyrrolidone fluoride, polyethylene, iodinated polyethylene, brominated polyethylene, chlorinated polyethylene, fluorinated polyethylene, polyethylene terephthalate, polypropylene, iodinated polypropylene, brominated polypropylene, chlorinated polypropylene, fluorinated polypropylene and derivatives thereof.

[0056] Soluble, hydrophilic polycaprolactone as described herein can be made, for example, using the methods described in U.S. Patent No. 9,359,600, which is incorporated herein by reference in its entirety. In embodiments, the soluble, hydrophilic polycaprolactone is DIO MAT®. DIOMAT® has been described, for example, in U.S. Patent Nos. 9,708,600; 9,359,600; 8,759,075; 9,662,096; and 8,685,747; and U.S. Pub. Nos. 2016/0025603 and 2016/0047720, each of which is incorporated herein by reference in its entirety.

[0057] In embodiments, a PCL substrate includes any form of PCL, soluble, hydrophilic PCL, PCL and co-polymer composition, conjugated PCL, conjugated PCL and co-polymer composition, in any size, shape, or configuration. The PCL substrate can dissolve in three ranges, short-term, medium-term, and long-term. The short-term range is about 5 minutes up to 24 hours, 30 minutes, 60 minutes, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 18 hours, and 24 hours. The medium-term range is about 24 hours up to 1 month, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, and 4 weeks. The long-term range is about 1 month to 2 years, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 12 months, 18 months, 2 years.

[0058] In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 5 minutes to about 24 hours. Each soluble, hydrophilic PCL substrate can have a different dissolution rate than any other soluble, hydrophilic containing substrate in the stem cell carrier. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 5 minutes to about 30 minutes. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 5 minutes to about 1 hour. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 5 minutes to about 24 hours. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 5 minutes to about 18 hours. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 5 minutes to about 12 hours. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 5 minutes to about 6 hours. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 5 minutes to about 5 hours, 4 hours, 3 hours, 2 hours, and 1 hour. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 5 minutes to about 24 hours. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 30 minutes to about 24 hours. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 30 minutes to about 18 hours. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 30 minutes to about 12 hours. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 30 minutes to about 6 hours. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 30 minutes to about 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, or 1 hour. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 1 hour to about 24 hours. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 1 hour to about 18 hours. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 1 hour to about 12 hours. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 1 hour to about 6 hours. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 1 hour to about 6 hours, 5 hours, 4 hours, 3 hours, or 2 hours. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 2 hours to about 24 hours. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 2 hours to about 24 hours. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 2 hours to about 18 hours. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 2 hours to about 12 hours. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 2 hours to about 6 hours. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about hours to about 5 hours, 4 hours, or 3 hours. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 3 hours to about 24 hours. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 3 hours to about 24 hours. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 3 hours to about 18 hours. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 3 hours to about 12 hours. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 3 hours to about 6 hours. In embodiments, the active agent- containing substrate dissolves in about 3 hours to about 5 hours, or 4 hours. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 4 hours to about 24 hours. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 4 hours to about 24 hours. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 4 hours to about 18 hours. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 4 hours to about 12 hours. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 4 hours to about 6 hours. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 4 hours to about 5 hours. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 5 hours to about 24 hours. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 5 hours to about 24 hours. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 5 hours to about 18 hours. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 5 hours to about 12 hours. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 5 hours to about 6 hours. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 6 hours to about 24 hours. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 6 hours to about 18 hours. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 6 hours to about 12 hours. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 12 hours to about 18 hours. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 12 hours to about 24 hours. In embodiments, the active agentcontaining substrate dissolves in about 4 weeks to about 4 weeks. The dissolution time may be any value or subrange within the recited ranges, including endpoints. For example, the active agent-containing substrate may dissolve in about 5 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 18 hours, 24 hours, etc.

[0059] In embodiments, the soluble, hydrophilic PCL substrate dissolves in about one day to about one month. Each soluble, hydrophilic PCL layer can have a different dissolution rate than any other soluble, hydrophilic PCL layer in the stem cell carrier. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 24 hours to about 72 hours. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 30 hours to about 72 hours. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 24 hours to about 4 weeks. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 24 hours to about 3 weeks. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 24 hours to about 2 weeks. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 24 hours to about 1 week. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 24 hours to about 6 days, 5 days, 4 days, 3 days, or 2 days. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 30 hours to about 1 month. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 30 hours to about 4 weeks. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 30 hours to about 3 weeks. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 30 hours to about 2 weeks. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 30 hours to about 1 week. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 30 hours to about 6 days, 5 days, 4 days, 3 days, or 2 days. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 30 hours to about 1 month. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 48 hours to about 4 weeks. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 48 hours to about 3 weeks. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 48 hours to about 2 weeks. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 48 hours to about 1 week. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 48 hours to about 6 days, 5 days, 4 days, or 3 days. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 3 days to about 1 month. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 3 days to about 4 weeks. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 3 days to about 3 weeks. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 3 days to about 2 weeks. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 3 days to about 1 week. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 3 days to about 6 days, 5 days, or 4 days. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 4 days to about 1 month. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 4 days to about 4 weeks. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 4 days to about 3 weeks. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 4 days to about 2 weeks. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 4 days to about 1 week. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 4 days to about 6 days, or 5 days. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 5 days to about 1 month. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 5 days to about 4 weeks. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 5 days to about 3 weeks. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 5 days to about 2 weeks. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 5 days to about 1 week. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 5 days to about 6 days. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 6 days to about 1 month. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 6 days to about 4 weeks. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 6 days to about 3 weeks. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 6 days to about 2 weeks. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 6 days to about 1 week. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 1 week to about 1 month. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 1 week to about 4 weeks. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 1 week to about 3 weeks. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 1 week to about 2 weeks. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 2 weeks to about 1 month. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 2 weeks to about 4 weeks. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 2 weeks to about 3 weeks. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 3 weeks to about 1 month. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 4 weeks to about 4 weeks. The dissolution time may be any value or subrange within the recited ranges, including endpoints. For example, the soluble, hydrophilic PCL substrate may dissolve in about 24 hours, 30 hours, 48 hours, 3 days, 4 days, 5 days, 6 days, 7, 8, 9, 10, 11, 12, 13 days, 2 weeks, 3 weeks, 4 weeks, one month, etc.In embodiments, the soluble, hydrophilic PCL substrate dissolves in about one month to about 2 years. Each soluble, hydrophilic PCL layer can have a different dissolution rate than any other soluble, hydrophilic PCL layer in the stem cell carrier. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 1 month to about 3 months. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 2 months to about 3 months. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 1 month to about 2 years. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 1 month to about 18 months. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 1 month to about 12 months. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 1 month to about 6 months. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 1 month to about 6 months, 5 months, 4 months, 3 months, or 2 months. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 2 months to about 2 years. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 2 months to about 18 months. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 2 months to about 12 months. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 2 months to about 6 months. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 2 months to about 6 months, 5 months, 4 months, or 3 months. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 3 months to about 2 years. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 3 months to about 18 months. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 3 months to about 12 months. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 3 months to about 6 months. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 3 months to about 6 months, 5 months, or 4 months. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 4 months to about 2 years. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 4 months to about 18 months. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 4 months to about 12 months. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 4 months to about 6 months. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 4 months to about 5 months. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 5 months to about 2 years. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 5 months to about 18 months. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 5 months to about 12 months. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 5 months to about 6 months. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 6 months to 2 years. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 6 months to about 18 months. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 6 months to about 12 months. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 12 months to about 18 months. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 12 months to about 2 years. In embodiments, the soluble, hydrophilic PCL substrate dissolves in about 18 months to about 2 years. The dissolution time may be any value or subrange within the recited ranges, including endpoints. For example, the soluble, hydrophilic PCL substrate may dissolve in about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 12 months, 18 months, 2 years, etc.

[0060] The PCL or co-polymer may be shaped or molded to adjust the size, shape, stem cell and/or stem cell biomaterials dissociation rate, and/or dissolution rate of the stem cell carrier

II. Methods of Making

[0061] In embodiments, the PCL substrate is formed as described in any one of WO 2016/025021 Al, WO 2015/168374 Al, WO 2016/014455 Al, WO 2010/019920 A2, and US 9,708,600, each of which is incorporated herein by reference in its entirety.

[0062] In various embodiments, medicament may be attached, confined, layered, or otherwise bound to hydrophilic PCL. In one example, medicaments may be contacted to a hydrophilic PCL material to bind the medicament to the hydrophilic PCL material.

[0063] Referring to Fig. 1, Fig. 1 is an illustration 100 of a magnification 105 of a PCL microbead 110. The illustration 100 shows the potential change in the surface chemistry of a PCL microbead 110 after treatment with 5% (w/w) NaOH. As shown in Fig. 1, the PCL may be in the form of a PCL microbead 110. In various embodiments, the PCL microbead may be in a variety of sizes. For example, the PCL microbead may have a diameter from about 0.03 pm to about 6.0 pm. In another example, the PCL microbead may have a diameter from about 10 nm to about 0.6 mm.

[0064] The PCL microbead 110 may have a spherical shape, as shown in Fig. 1, or other 3 dimensional shape. Further the PCL microbead 110 may contain pores, which are not shown in Fig. 1, through which various substances may enter. The pores may have various diameters that are smaller than the diameter of the PCL microbead 110. The pores effectively increase the total surface area of the PCL microbead 110 and may result in increased reactivity and/or dissolution rate.

[0065] An illustration of the untreated surface 115 is shown on the left side of the magnification 105. The untreated surface 115 of the PCL microbead 110 may contain a carbonyl group for units of the polymer chain that comprise an ester. Upon treatment with a base such as 5% (w/w) NaOH 125 a portion of the carbonyl groups may be hydrolyzed. Thus, the treated surface 120 may contain hydroxyl groups in place of a portion of the carbonyl groups. The hydrolysis reaction may increase the hydrophilicity of the PCL substrate. Additionally, the hydrolysis may modify the surface of the PCL substrate. A hydrolyzed surface may be rougher and contain more pores and pores of greater size. Reactivity of the hydroxyl groups may result in binding of the PCL substrate to various medicaments. For example, an active agent may form covalent bonds with the treated surface 120. In another example, stem cells may be bound through electrostatic, hydrogen bonding, and/or Van der Waals forces to the treated surface 120.

[0066] Referring to Fig. 2, Fig. 2 is a microscopic image 200 showing a multitude of untreated PCL microbeads suspended in a solution. The solution contains a concentration of 30 pM of the PCL microbeads. The scale bar for the image 200 is 200 pm. PCL microbeads may be prepared by stirring polycaprolactone in a solvent at a high rate such as 6000 rpm for about 2 minutes. The microbeads, thus formed, may be isolated by centrifugation. PCL microbeads may be washed and dried. For the preparation of PCL nanospheres of smaller diameter, the above procedure may be modified by increasing the stir rate and time. For example, a stirring speed of 12000 rpm for 5 minutes may result in much smaller microbeads, which may be referred to as nanospheres.

[0067] The PCL microbeads may be treated with a base to prepare a hydrophilic PCL substrate. The strength of the base and the length of base treatment are directly proportional to the hydrophilicity of the resulting PCL substrate. Further, a size of microbead may be indirectly proportional to the dissolution rate of the resulting PCL substrate as the higher surface area to volume of smaller PCL microbeads may result in increased interaction with the basic solution.

[0068] Referring to Fig. 3, Fig. 3 is a microscopic image 300 showing a multitude of PCL microbeads 305, suspended in a solution of 50% (w/w) NaOH. The scale bar for the image 300 is 200 pm. The PCL microbeads 305 have been treated in the NaOH solution for 1 hour. In various embodiments, the PCL microbeads 305 may be treated for various amounts of time and in solutions of various concentrations of base. In an exemplary embodiment, additional treatment with the NaOH base results in increased hydrophilicity.

[0069] As shown in the image 300, the surface 310 of the PCL microbeads 305, that have been treated, has noticeably changed from the surface 210 of the untreated PCL microbeads 205. The treated PCL microbeads 305 have a more textured surface 310 than the surface 210 of the untreated PCL microbeads 205. In various embodiments, the treatment by the NaOH base cleaves the PCL polymer chain, creating a carboxyl group on one side of the cleaved chain, and a hydroxyl group on the other side of the cleaved chain.

[0070] The surface 310 of the treated PCL microbeads 305 may facilitate layering a medicament on the surface 310. For example, stem cells, may be bound to the surface 310. In various embodiments, IgG antibodies may be attached to the treated PCL microbeads 305. The PCL microbeads with IgG antibodies may have a variety of uses; one of which may be to offer protection from pathogens. PCL microbeads with IgG antibodies may be coated on a surface of a subject, whereby the surface may receive increase protection from one or more pathogens.

[0071] Referring to Fig. 4, Fig. 4 is a magnified photograph 400 of a hydrophobicity test of a water droplet 405 on a polycaprolactone wafer 410. The hydrophilicity of polycaprolactone may be determined by observing the interaction of a flat polycaprolactone wafer 410 with a droplet of a polar liquid such as water. The contact angle, which is the angle that the sides of the water droplet 405 make with the plane of the polycaprolactone wafer 410, is indicative of the hydrophobicity of the surface of the polycaprolactone wafer 410.

[0072] A low angle (<90°) indicates that the material is hydrophilic while a higher angle (>90°) indicates that the material is hydrophobic. In various embodiments, a lower angle (<75 °) indicates that the material is hydrophilic. A hydrophobicity test was conducted on multiple polycaprolactone samples that were treated in various ways to control and modify the hydrophobicity of the samples. The contact angle, as indicated by the angle of the tangent lines 415, that are drawn on either side of the droplet, with the plane of the wafer, is approximately 72°, thus indicating that the wafer is hydrophilic.

[0073] Referring to Fig. 5, Fig. 5A is an electron microscopy image 500 showing the microporous structure of base-treated hydrophilic PCL foam. The structural components of the solid phase of polycaprolactone matrix, namely the porosity of the may appear to have a somewhat non-laminar configuration as though some were cut from a single sheet, it will be understood that this appearance may in part be attributed to the difficulties of representing complex three-dimensional structures in a two dimensional figure.

[0074] The PCL foam may comprise hydrophilic polycaprolactone. The size and number of holes 505 in the PCL foam may correspond to a porosity of the PCL foam. Porosity may be inversely proportional to the dissolution rate of the PCL foam. The porosity has been found to be proportional to the molecular weight and weight per volume of the PCL foam. Thus, to increase the dissolution rate, a polycaprolactone with a lower molecular weight and/or lower weight per volume may be used to produce the PCL foam.

[0075] Referring to Fig. 5B, is an electron microscopy image 550 showing the microporous structure of PCL microbeads. Like the PCL foam, the PCL microbeads may comprise hydrophilic polycaprolactone. And like the PCL foam, the size and number of holes 555 in the PCL microbeads may correspond to a porosity of the PCL microbeads. The microbeads may be coupled with a medicament. The medicament may be delivered to a subject as the PCL microbeads dissolve. In an exemplary embodiment, the medicament may be an active agent that is covalently bonded to the PCL microbeads.

[0076] Referring to Fig. 6, Fig. 6 is a reaction diagram 600 of base-catalyzed hydrolysis of the ester linkages present in the backbone of polycaprolactone. The preparation of the hydrophilic PCL material is shown in Figs. 6 and 7. The hydrophilic PCL material may be prepared by a base-catalyzed hydrolysis of the ester linkages present in the backbone of polycaprolactone. The time of treatment with the base may be correlated to the dissolution rate of the hydrophilic PCL material.

[0077] Untreated PCL is a hydrophobic polymer which undergoes dissolution and bioabsorption into human tissues and mineralizes into break down products which are safe for in human use. The base catalyzed ester hydrolysis process generates carboxylic acid and hydroxyl groups resulting from controlled hydrolytic cleavage of the polyester strands in the PCL polymer. The hydrolysis converts PCL from an extremely hydrophobic polymer to a hydrophilic matrix which increases the dissolution rate and imparts a charged characteristic to the microbeads under physiological conditions. The process essentially accelerates the in vivo dissolution of PCL, which occurs naturally in the human body.

[0078] The exposed carboxylic acid and hydroxy groups convert the hydrophobic surface chemistry of the PCL substrate into a weak cation exchanger. The charged surfaces on the PCL substrate will facilitate binding and adsorption of proteins via electrostatic interactions between the negatively charged surface carboxylate groups and positive charged primary amines present on the surface of the protein. Alternatively, carboxylic acids moieties on the PCL substrate can be chemically activated to promote formation of covalent amide bonds between the protein’s primary amines and the carboxylic moieties on the PCL substrate. [0079] Referring to Fig. 7, Fig. 7 is a reaction diagram 700 is a reaction diagram of a coupling of surface-exposed carbonyl groups to amino groups on a polypeptide to create a peptide bond. Carbonyl groups may be exposed through the base-catalyzed hydrolysis reaction shown in Fig. 6. In an exemplary embodiment, a peptide bond may be created through the reaction of hydrophilic PCL with a polypeptide and l-Ethyl-3-(3- dimethylaminopropyl) carbodiimide (“EDC”). The reaction may produce a peptide bond between a PCL substrate and an amino acid chain, which results in an amide. A urea byproduct may be produced as part of the reaction.

[0080] The R-group in Fig. 7 may be various functional groups, amino acid chains, or the like. In various embodiments, the R-group is an amino acid chain that forms a protein. The resulting reaction that forms an amide may be the protein bound to a PCL chain. In various embodiments, the R-group is an amino acid chain in a cell membrane. Also, in various embodiments, the R-group may be an antigen.

[0081] Referring to Fig. 8, Fig. 8 is an illustration 800 of an embodiment of a surface 805 of a hydrophilic PCL microbead as the hydrophilic PCL microbead binds to stem cells 810. As shown in Fig. 8, the medicament that is bound to the hydrophilic PCL microbead may be stem cells 810. In an exemplary embodiment, the medicament may be bound to the surface 805 of a hydrophilic PCL microbead through electrostatic forces. Also, in various embodiments, the medicament may be bound to the hydrophilic PCL microbead through covalent bonding, hydrogen bonding, Van Der Waals forces, entrapment within the lattice of the hydrophilic PCL microbead, or the like. The hydrophilic PCL substrate may comprise a form other than the microbead, such as a foam, PCL rods, a PCL wire, a PCL gauze, or the like.

[0082] In various embodiments, the stem cells 810 may produce stem cell biomaterials when the hydrophilic PCL microbead is administered to a subject. The hydrophilic PCL surface may comprise a structure that is implanted in vivo in a subject. The structure may dissolve in vivo as the stem cell biomaterials are produced. In various embodiments, a PCL and stem cell device may be configured into an organoid. Also, in various embodiments, the PCL and stem cell device may be configured into a biomedical implant. The hydrophilic PCL substrate may comprise the structure of the biomedical implant. Stem cells may coat the surface of the hydrophilic PCL substrate.

[0083] Referring to Fig. 9, Fig. 9 is a series 900 of microscopic images that illustrate a rate of dissolution of PCL microbeads in 5% (w/w) NaOH vs. 50% (w/w) NaOH. When treated by an aqueous solution, the PCL material may break down over a period of time. A basic aqueous solution may dramatically increase the rate by which the PCL material breaks down. Fig. 9 shows a comparison of the rate of dissolution of PCL microbeads for two different concentrations of basic NaOH solution

[0084] As shown in Fig. 9, a 50% (w/w) NaOH solution dissolves PCL microbeads at a dramatically higher rate than a 5% (w/w) NaOH solution. At the 0-hour images, the PCL microbeads 905 in the 5% (w/w) NaOH solution and the PCL microbeads 915 in the 50% (w/w) NaOH solution have not had time to dissolve. At one hour, the PCL microbeads have completely dissolved into the 50% (w/w) NaOH solution 920. On the other hand, the PCL microbeads 910 in the 5% (w/w) NaOH solution are still undissolved after 24-hours.

[0085] Referring to Fig. 10, Fig. 10 is an illustration 1000 of an embodiment of a PCL dissolving microneedle. The PCL material may dissolve in an aqueous solution. The PCL dissolving microneedle is configured to penetrate the skin or other surface of a subject. The dissolving microneedle may thus be subjected to the bodily fluids of the subject. Over time, the bodily fluids of the subject may dissolve the dissolving microneedle.

[0086] The dissolving microneedle may be configured to dissolve in varying lengths of time. The dissolving microneedle, which may comprise hydrophilic PCL substrate, may be treated with a base to break down the PCL substrate. The dissolution rate of the PCL substrate may be directly proportional to the strength of the base and the time a base treatment. Further treatment that increases the surface area of the PCL substrate may increase the dissolution rate. Lyophilization may increase the porosity of the PCL substrate, which may increase the dissolution rate.

[0087] Referring to Fig. 11, Fig. 11 is a series 1100 of microscopic images that show the surface of a PCL microbead as it is treated by a basic solution. The scale bar of the image is 10 pm. The series 1100 shows a PCL microbead 1105 that is untreated, a PCL microbead 1110 that had a 1-hour treatment, and a PCL microbead 1115 that had a 2-hour treatment. The series 1100 demonstrates how the surface of a PCL substrate may change as it is treated by a base.

[0088] As shown in the leftmost image, the PCL microbead 1105 that is untreated, has a relatively smooth surface. The PCL microbead 1110 that has been treated for 1-hour has a noticeably rougher surface than the untreated PCL microbead 1105. The PCL microbead 1115 that has been treated for 2-hours has a surface that is falling apart. Further treatment eventually dissolves the PCL microbead.

[0089] In various embodiments, the dissolution rate of the PCL substrate may be modified by the length of base treatment. For example, a PCL material that is configured to dissolve slowly over a period of a few months to a year, may have a short base treatment. Alternatively, a PCL material that is configured to dissolve over a period of a few hours to a day, may have a longer base treatment.

[0090] Referring to Fig. 12, Fig. 12 is an illustration 1200 of an application of hydrophilic PCL microbeads 1205 that are coated with a medicament, to skin of a subject. As shown in Fig. 12, PCL microbeads 1205 may be applied to skin 1215 that is wrinkled or damaged. For comparison, good skin 1210 is illustrated on the left. In various embodiments, PCL microbeads 1205 may be manufactured into a cream such that it may be easily applied to the skin of a subject.

[0091] As the PCL microbeads 1205 are applied to the skin of the subject, they may be exposed to the bodily fluids of the subject. The exposure to bodily fluids may degrade the PCL microbeads over a period a time such that they eventually disappear. As shown in Fig. 12, the PCL microbeads 1205 are applied externally to the skin 1215 of a subject. In various embodiments, the PCL microbeads may be applied to other locations on a subject. For example, the PCL microbeads may be inserted under the skin instead of externally. In another example, the PCL microbeads may be placed in a reservoir with an implantable device.

Transdermal Delivery of Medicament

[0092] In yet another embodiment, a delivery device for medicament is disclosed herein. The delivery device is an implantable structure that comprises hydrophilic PCL, heretofore referred to as a hydrophilic PCL structure. Medicaments such as active agents or stem cells may be bound to the hydrophilic PCL structure. The hydrophilic PCL structure may be implanted in a subject whereby it may gradually deliver medicament over a period of time to the subject.

[0093] In an exemplary embodiment, the hydrophilic PCL structure may be implanted subcutaneously in an individual. The subcutaneous implant would thereby effectuate transdermal delivery of medicament to the individual while, at the same time, be accessible for monitoring. In various embodiments where stem cells are bound to the hydrophilic PCL structure, factors that promote cell survival and function of stem cells may be additionally bound to the hydrophilic PCL structure. The factors may include but are not limited to: oxygen generating particles and cytokines to promote local immunosuppression and improved vascularization.

[0094] Referring to Fig. 13, Fig. 13 is an illustration of a hydrophilic PCL structure 1305 that is implanted into a subcutaneous space of a forearm 1310 of an individual.

Medicament may be bound to the various surfaces of the hydrophilic PCL structure 1305. In an exemplary embodiment, stem cells that are configured to perform a specialized function, are bound to the hydrophilic PCL structure 1305. A process to configure stem cells to perform a specific function is cell differentiation. In various embodiments, the stem cells comprise mesenchymal stem cells that are differentiated to secrete stem cell biomaterials that regulate an inflammatory response in the individual.

[0095] In various embodiments, the hydrophilic PCL structure 1305 may be implanted in a part of an individual’s body. A shape of the hydrophilic PCL structure 1305 may be adapted to be placed in a specific part of the individual’s body. The exemplary embodiment of the hydrophilic PCL structure 1305 has a substantially flat shape with one side that faces the layer of skin and another side that faces the blood vessels. As shown in the illustration 1300, the hydrophilic PCL structure 1305 is implanted in a subcutaneous space just below the surface of the skin such that the blood vessels 1315 are substantially on one side of the hydrophilic PCL structure 1305.

[0096] Accordingly, two medicaments may be bound to the opposite faces of the hydrophilic PCL structure 1305 based on advantageous positioning. For example, a first medicament may be bound to the side of the hydrophilic PCL structure 1305 that faces the blood vessels 1315 and a second medicament may be bound to the opposite side of the hydrophilic PCL structure 1305 that faces the skin surface and is not substantially in contact with the blood vessels 1315.

[0097] The hydrophilic PCL structure 1305 will dissolve over a period of time as it is exposed to the bodily fluids of the individual in the subcutaneous space. A time of dissolution may be controlled based on pretreatment and based on the shape of the hydrophilic PCL structure 1305. For instance, a longer base treatment will result in a shorter time of dissolution. Likewise, a thinner structure will result in a shorter time of dissolution. [0098] In an exemplary embodiment, differentiated stem cells that are programmed to secrete hormones like insulin and glucagon are bound to the subcutaneous implant. The insulin delivering subcutaneous implant could replace more invasive treatments such as implanting cellular constructs (“islets”) of 1000-1500 cells in a tissue format that secrete hormones. The hydrophilic PCL structure could be smaller than the islets, thus less invasive and safer.

[0099] Referring to Fig. 14, Fig. 14 is an illustration 1400 of a layered hydrophilic PCL structure 1405 that is implanted under the skin 1410 of a subject. A hydrophilic PCL structure may be adapted into layers that each have a unique function. The geometric orientation of one or more layers may affect a response based on the medicaments that are bound to the layers. In Fig. 14, the hydrophilic PCL structure 1405 includes two flat layers that are oriented in parallel with a layer of skin 1410 in an individual.

[0100] In an exemplary embodiment, an outer layer 1415, which is relatively close to the outside layer of skin 1430, has medicament bound to it that regulates an inflammatory response. A type of inflammatory response is a foreign body response (FBR), which is a natural immune reaction to most implants. An example of a medicament that regulates an inflammatory response is differentiated stem cells that release stem cell products that regulate an inflammatory response.

[0101] Mesenchymal stem cells can be differentiated or programmed to secrete products that repel cellular constituents involved in immune destruction. The mesenchymal stem cells can be bound to an outer layer 1415 that protects an inner layer 1420 from an immune response. In various embodiments, the outer layer provides a shell-like coating that surrounds an inner layer. The inner layer 1420 of the hydrophilic PCL structure 1405 comprises a medicament that is protected by the outer layer. For instance, the inner layer 1420 of the hydrophilic PCL structure 1405 may be bound with mesenchymal stem cells that are differentiated to secrete insulin.

[0102] Because of the geometric positioning of the inner and outer layers, the inner layer 1420 of the hydrophilic PCL structure 1405 could be protected from FBR by the outer layer 1415 of the hydrophilic PCL structure 1405. The inner layer 1420, which faces blood vessels 1425, may secrete insulin directly into the blood stream while the outer layer 1415 secretes anti-inflammatory products that prevent FBR to the hydrophilic PCL structure 1405. The two-flat-layered embodiment shown in the illustration 1400 is just one example of a multitude of geometric positions of the two layers. An exemplary embodiment, which is not shown in the illustration 1400, is a capsule structure where the outer layer is bound to an anti-inflammatory medicament that protects another layer on the inside of the capsule structure.

[0103] The subcutaneous hydrophilic PCL implant may be monitored by various means. For example, a subcutaneous hydrophilic PCL implant that delivers insulin may be monitored using continuous glucose monitors to determine the function and duration of insulin secretion. The continuous glucose monitor may create a signal when an additional infusion is needed.

[0104] Referring to Fig. 15, Fig. 15 is an illustration 1500 of a monitoring device 1505 that can detect when the hydrophilic PCL structure 1510 has substantially dissolved. As disclosed above, the hydrophilic PCL structure 1510 may be configured to dissolve in varying periods of time, but the exact and precise time that the hydrophilic PCL structure 1510 dissolves to the point that the medicament is no longer functioning may be unknown. Thus, the monitoring device 1505 may detect when the hydrophilic PCL structure 1510 needs replacement. In various embodiments, the monitoring device 1505 may be configured to detect products that are secreted from the hydrophilic PCL structure 1510. In an exemplary embodiment, the monitoring device is adapted to detect a bodily response from the hydrophilic PCL structure 1510.

[0105] In one example where the hydrophilic PCL structure 1510 is adapted with mesenchymal stem cells that secrete insulin, the monitoring device 1505 may comprise a continuous glucose monitor. The continuous glucose monitor could detect when glucose levels are not properly regulated by the body and determine that the hydrophilic PCL structure 1510 is substantially dissolved because it is no longer producing insulin for the body. In various embodiments, the continuous glucose monitor could transmit a wireless signal to alert the individual that the hydrophilic PCL structure 1510 is in need of replacement.

[0106] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

Claims

WHAT IS CLAIMED IS:

1. A medical device, the medical device comprising: a soluble, hydrophilic polycaprolactone (PCL) substrate; medicament in contact with the soluble, hydrophilic PCL substrate; the soluble, hydrophilic PCL substrate having been treated with a base having a pH greater than 8; wherein the medicament comprises one or more stem cell materials.

2. The medical device of claim 1, wherein the soluble, hydrophilic PCL substrate comprises two or more layers that are in contact with at least one of the one or more stem cell materials.

3. The medical device of claim 2, wherein the two or more layers comprise a first layer and a second layer.

4. The medical device of claim 3, wherein the second layer is positioned to at least partially protect a first layer from a foreign body response in an individual.

5. The medical device of claim 4, wherein the one or more stem cell materials comprise products that regulate an inflammation response.

6. The medical device of claim 5, wherein each of the one or more stem cell materials are in contact with a separate layer of the two or more layers.

7. The medical device of claim 6, wherein the products that regulate an inflammation response are in contact with the second layer.

8. The medical device of claim 7, wherein the soluble, hydrophilic PCL substrate is implantable into a subcutaneous space.

9. The medical device of claim 8, wherein the first layer is positioned with at least one face exposed to blood vessels in the subcutaneous space.

10. The medical device of claim 9, wherein the second layer is positioned away from the blood vessels relative to the first layer.

11. The medical device of claim 10 wherein the first layer is in contact with stem cell materials that regulate insulin production.

12. A method for manufacturing a medical device, the method comprising: differentiating one or more stem cell materials to perform a specific bodily function; growing the one or more stem cell materials on a soluble, hydrophilic polycaprolactone (PCL) substrate that is implantable into a subcutaneous space; and wherein the soluble, hydrophilic PCL substrate is implantable into a human individual.

13. The method of claim 12, wherein the soluble, hydrophilic PCL substrate comprises two or more layers that are in contact with at least one of the one or more stem cell materials.

14. The method of claim 13, wherein the two or more layers comprise a first layer and a second layer.

15. The method of claim 14, further comprising positioning the second layer to at least partially protect the first layer from a foreign body response in the human individual.

16. The method of claim 15, wherein the one or more stem cell materials comprise products that regulate an inflammation response.

17. The method of claim 16, wherein each of the one or more stem cell materials are in contact with a separate layer of the two or more layers; and wherein the products that regulate an inflammation response are in contact with the second layer.

18. The method of claim 17, wherein the first layer is positioned with at least one face exposed to blood vessels in the subcutaneous space; wherein the second layer is positioned away from the blood vessels relative to the first layer; and wherein the first layer is in contact with stem cell materials that regulate insulin production.

19. The method of claim 18, further comprising determining a dissolution of the soluble, hydrophilic PCL substrate based on detection by a continuous glucose monitor.

20. A medical device, the medical device comprising: a multi-layered soluble, hydrophilic polycaprolactone (PCL) substrate; two or more stem cell materials in contact with the multi-layered soluble, hydrophilic PCL substrate; wherein the one or more stem cell materials comprise substances that regulate an inflammation response; wherein a first layer of the multi-layered soluble, hydrophilic PCL substrate is in contact with the substances that regulate an inflammation response; and wherein the first layer is positioned to at least partially protect a second layer from a foreign body response in an individual.