WO2021041991A1

WO2021041991A1 - Hydrophilic biopolymer medicament delivery mechanism

Info

Publication number: WO2021041991A1
Application number: PCT/US2020/048637
Authority: WO
Inventors: Eric Mathur; Paul Wolff; Jason Phillips
Original assignee: Diomics Corporation
Priority date: 2019-08-29
Filing date: 2020-08-28
Publication date: 2021-03-04

Abstract

The instant technology generally relates to a composition including soluble, hydrophilic polycaprolactone substrate and medicament such as a plurality of stem cells or biomaterials such as growth factors or exosomes. The stem cells and/or biomaterials may be contained within, attached to, adhered to, growing on, or distributed on or in the soluble, hydrophilic polycaprolactone substrate. The soluble, hydrophilic polycaprolactone substrate may be used to differentiate, deliver, modify, or maintain the stem cells. The soluble, hydrophilic polycaprolactone substrate may be used to deliver the biomaterials. The soluble, hydrophilic polycaprolactone can be adjusted to dissolve at various rates, for example by adjusting the composition, density, thickness, etc. of the substrate.

Description

HYDROPHILIC BIOPOLYMER MEDICAMENT DELIVERY

MECHANISM

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No.

62/893,769 titled “HYDROPHILIC BIOPOLYMER STEM CELL DELIVERY MECHANISM” which was filed on August 29, 2019 and is incorporated by reference in its entirety.

BACKGROUND

[0002] Stem cell therapies hold potential for repairing diseased, dysfunctional, or injured tissue. Generally, stem cells are administered by injection (e.g., intravenous, intramuscular, intra- articular, or intrathecal injection). However, such administration allows the stem cells to diffuse from the site of injection. For many indications, it is preferable to maintain the stem cells at a desired location for a period of time. It would be advantageous to have a stem cell carrier for topical or implantation delivery of stem cells to a particular location.

[0003] 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.

[0004] 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

[0001] The instant technology generally relates to a composition including soluble, hydrophilic polycaprolactone substrate and medicament such as a plurality of stem cells or biomaterials such as growth factors or exosomes. The stem cells and/or biomaterials may be contained within, attached to, adhered to, growing on, or distributed on or in the soluble, hydrophilic polycaprolactone substrate. The soluble, hydrophilic polycaprolactone substrate may be used to differentiate, deliver, modify, or maintain the stem cells. The soluble, hydrophilic polycaprolactone substrate may be used to deliver the biomaterials. The soluble, hydrophilic polycaprolactone can be adjusted to dissolve at various rates, for example by adjusting the composition, density, thickness, etc. of the substrate.

[0002] In one aspect a composition including a soluble, hydrophilic polycaprolactone

(shPCL) substrate and stem cells is provided. In one aspect a composition including a soluble, hydrophilic polycaprolactone (shPCL) substrate and biomaterials is provided. In one aspect a composition including a soluble, hydrophilic polycaprolactone (shPCL) substrate, stem cells, and biomaterials is provided.

[0003] In embodiments, the polycaprolactone is/was exposed to basic, aqueous conditions with a pH value greater than 8.0. In embodiments, the polycaprolactone is/was exposed to the basic, aqueous conditions and a neutralizing agent to form a soluble, hydrophilic polycaprolactone. In embodiments, the soluble, hydrophilic polycaprolactone has a dissolution rate between about 5 minutes to about 2 years.

[0004] In embodiments, the substrate is a microbead, capsule, film, sheet, bandage, adhesive, mesh, netting, anatomical mimic, geometrical shape, dissolving microneedle (DMN), or computer-aided designed three-dimensional shape. In embodiments, the substrate is multi- layered. In embodiments, the soluble, hydrophilic polycaprolactone substrate has a textured surface, for example and without limitation a smooth, rough, punctured, dimpled, porous, semi- permeable, and/or channeled surface. In embodiments, the substrate has a size/thickness/diameter of about lOnm to about 0.6 mm. In embodiments, the substrate has a dissolution rate between 5 minutes up to 2 years in vivo. In embodiments, each layer in the multilayered substrate has a different dissolution rate.

[0005] In embodiments, the stem cells are embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), or adult stem cells (ASCs). In embodiments, the stem cells are present in an amount sufficient to support a desired level of differentiation, homeostasis, apoptosis, and/or pluripotency. In embodiments, stem cells and soluble, hydrophilic polycaprolactone substrate comprise a stem cell carrier where the stem cells are at a density of about 1.5 x 105 to about 1.0 x 107 per cm3 in suspension culture, and in the range of about 0.5 x 104 to about 1.0 x 105 per cm2 in adherent culture.

[0006] In embodiments, the stem cell biomaterials include a biomaterial derived from stem cells. In embodiments, the stem cell biomaterials include stem cell-conditioned media. In embodiments, the stem cell biomaterials include exosomes, microvesicles, or other vesicles derived from stem cells. In embodiments, the stem cell biomaterials include growth factors derived from stem cells. In embodiments, the stem cell biomaterials include other factors (e.g., proteins, lipids, etc.) derived from stem cells.

[0007] In embodiments, the soluble, hydrophilic polycaprolactone substrate includes one or more co-polymers in addition to PCL. In embodiments, the co-polymer includes polylactic acid, polylactide, L-polylactic acid, L-polylactide, poly(D,L)-lactic acid, poly(D,L)-lactide, polyglycolide, polydioxane, acrylamide, poly N-isopolyacrylamide, chitosan, polyethylene glycol, poly vinyl alcohol, and/or polyurethane. In embodiments, the co-polymer includes a polymer derived from extracellular matrix, decellularized extracellular matrix, decellularized tissue, fibrin, fibrinogen, alginate, fucoidan, chitin, silk, polypeptides, polynucleotides, oligosaccharides, starch, keratin, hyaluronic acid, and/or Wharton’s jelly. In embodiments, a copolymer forms a hydrogel. In embodiments, the co polymer has a dissolution rate that is faster or slower than the soluble, hydrophilic polycaprolactone substrate alone.

[0008] In embodiments, the composition includes a stem cell support additive. In embodiments, the stem cell support additive may include (for example and without limitation) non-stem cells, buffer reagents, vitamins, antibiotics, antifungal agents, therapeutic agents, growth factors, oxygenating factors, hormones, developmental factors, immunological agents, integration factors, angiogenic factors, dissolution factors, wound healing factors, hair-growth factors, cytokines, chemokines, hydroxyapatite, calcium phosphate cement, stromal cell-derived factor- 1 alpha (SDF-Ia), ibuprofen, triptolide- micelles, dexamethasone, silver nanoparticles, teratoma inhibitors, adefovir dipiroxil (ADV), interleukin- 1 receptor inhibitory peptide (IL- 1RIP) FEWTPGWYQPY-NH2, TNF-a antibody, interleukin- 10 (IL-10), miRNAs, MMP inhibitors, prostaglandin E2 (PGE2), resolvins, protectins, lipoxins, maresins, pentoxifylline, aspirin, anti-viral treatments, and/or cosmetic factors.

[0009] In one aspect, a method of delivering in vivo to a subject a composition including a soluble, hydrophilic polycaprolactone substrate and stem cells or biomaterials such as growth factors is provided. In embodiments, the method includes delivering a composition including a soluble, hydrophilic polycaprolactone substrate and a plurality of stem cells or biomaterials such as growth factors to a site of interest. In embodiments, the site of delivery includes, for example and without limitation, a site in a human, a site in a non-human mammal, a site in an organ, and/or a site in an organoid. In embodiments, the site is internal to a subject. In embodiments, the site is topical. In embodiments, the composition is delivered by injection, microinjection, nonsurgical implantation, and/or surgical implantation. In embodiments, the composition is for cosmetic, medical, or dental use.

[0010] In one aspect a method of making a composition including a soluble, hydrophilic polycaprolactone substrate and stem cells or biomaterials such as growth factors is provided. In embodiments, the PCL substrate is contacted with a plurality of stem cells such that the PCL substrate is impregnated with, coated with, and/or carries the plurality of stem cells, thereby forming a PCL-stem cell carrier. In embodiments, the PCL substrate is contacted with the stem cell biomaterials such that the PCL substrate is impregnated with, coated with, and/or carries the stem cell biomaterials, thereby forming a PCL-biomaterial carrier. In embodiments, the PCL substrate is contacted with stem cells and the stem cell biomaterials such that the PCL substrate is impregnated with, coated with, and/or carries the stem cells and stem cell biomaterials, thereby forming a PCL-stem cell carrier. In embodiments, the PCL- stem cell carrier or PCL-biomaterial carrier is contacted with a device for implantation such that the PCL-stem cell carrier or PCL- biomaterial carrier is associated with the device.

[0011] A general aspect is a composition. The composition includes a soluble, hydrophilic polycaprolactone (PCL) substrate and stem cell materials that are in contact with the PCL substrate where the PCL substrate has been treated with a base having a pH greater than 8 for increasing hydrophilicity. The contact of the stem cell materials with the PCL substrate may be at least one of impregnation within the PCL substrate, coating the outside of the PCL substrate with the stem cell materials, or being held by the PCL substrate. The PCL substrate may be hydrophilic, as measured by having a contact angle of less than 75 degrees with a droplet of an aqueous solution. The aqueous solution may include at least one of a buffering agent, a salt, a surfactant, a detergent, cell culture media, or a plasma. The stem cell materials may include stem cell biomaterials that are derived from a plurality of stem cells. The stem cell materials may include at least one of stem cell growth factor, stem cell differentiation factor, stem cell support media, or stem cell support matrix. The stem cell materials may include at least one of embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), or adult stem cells (ASCs). The stem cell materials may include a biomedical implant. The biomedical implant may be an organoid. The stem cell materials may include a number of stem cells sufficient to support at least one of differentiation, homeostasis, apoptosis, or pluripotency of the stem cells. The stem cell materials may have a density of about 1.5 x 10⁵ to 1.0 x 10⁷ per cm³ in suspension culture, and in the range of about 0.5 x 10⁴to 1.0 x 10⁵ per cm² in adherent culture. The composition may further include a stem cell support additive. The stem cell support additive may include at least one of non-stem cells, buffer reagents, vitamins, antibiotics, antifungals, therapeutic reagents, growth factors, oxygenating factors, hormones, developmental factors, immunological reagents, integration factors, angiogenic factors, dissolution factors, wound-healing factors, hair-growth factors, antibodies, active agents, cytokines, chemokines, hydroxyapatite, calcium phosphate cement, teratoma inhibitors, or cosmetic factors. The PCL substrate may be configured to dissolve over time after application to a subject. The base treatment may result in the addition of a carboxyl group to the PCL substrate. The stem cell materials may be bound through a covalent bond to the PCL substrate at the carboxyl group. The covalent bond may be an amide bond. The covalent bond may form a peptide bond. The stem cell materials may be bound to the PCL substrate through electrostatic forces. The PCL substrate may be in the form of a microbead, capsule, film, sheet, bandage, adhesive, mesh, netting, anatomical mimic, geometrical shape, dissolving microneedle (DMN), or a computer-aided designed three-dimensional shape. The PCL substrate may be in the form of a microhead with a thickness of between about 0.01 micron and 1.0 mm. The PCL substrate may be multi layered. The PCL substrate may be configured to dissolve at a rate between about 30 minutes to about 2 years in an aqueous environment. The aqueous environment may include the bloodstream, nasal mucosa, oral and peritoneal cavities, dermis, intradermis and subdermal tissues of a human or animal subject. The PCL substrate may be configured to be delivered by at least one of a needle, a microneedle, or an implant. 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 with the co-polymer may have a rate of dissolution that is higher than a rate of dissolution of PCL without the co-polymer.

[0012] Another general aspect is a composition. The composition includes a soluble, hydrophilic polycaprolactone (PCL) substrate and an active agent that is in contact with the PCL substrate where the PCL substrate has been treated with a base having a pH greater than 8 for increasing hydrophilicity. The contact of the active agent with the PCL substrate may include at least one of impregnation within the PCL substrate, coating the outside of the PCL substrate, or being held by the PCL substrate. The PCL substrate may be hydrophilic, as measured by having a contact angle of less than 75 degrees with a droplet of an aqueous solution. The aqueous solution may include at least one of a buffering agent, a salt, a surfactant, a detergent, cell culture media, or a plasma. The base treatment may result in the addition of a carboxyl group to the PCL substrate. The active agent may be bound through a covalent bond to the PCL substrate at the carboxyl group. The covalent bond may be an amide bond. The active agent may be an amino acid. The active agent may be bound to the PCL substrate through at least one of electrostatic forces, hydrogen bonding, or Van der Waals forces. The PCL substrate may be in the form of at least one of a microbead, a capsule, a film, a sheet, a bandage, an adhesive, a mesh, a netting, an anatomical mimic, a geometrical shape, a dissolving microneedle (DMN), or a computer-aided designed three-dimensional shape. The PCL substrate may be configured to dissolve over time after application to a subject. The PCL substrate may be in the form of a microbead with a thickness of between about 10 nm and 0.6 mm. The PCL substrate may be configured to dissolve at a rate between about 5 minutes to about 2 years in an aqueous environment. The aqueous environment may include the bloodstream of a subject. The PCL substrate may be configured to be delivered by at least one of a needle, a microneedle, or an implant. 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 with the co polymer may have a rate of dissolution that is higher than a rate of dissolution of PCL without the co-polymer.

[0013] An exemplary embodiment is a method for manufacturing a PCL medicament carrier. The method includes providing a soluble, hydrophilic polycaprolactone (PCL) substrate that has been treated with a base having a pH greater than 8 for increasing hydrophilicity where the PCL substrate is in contact with a medicament for treating a subject. The medicament may include stem cell materials. The stem cell materials may include at least one of embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), or adult stem cells (ASCs). The stem cell materials may include a biomedical implant. The biomedical implant may include an organoid. The stem cell materials may include a number of stem cells sufficient to support at least one of differentiation, homeostasis, apoptosis, or pluripotency of the stem cells. The stem cell materials may have a density of about 1.5 x 10⁵ to 1.0 x 10⁷ per cm³ in suspension culture, and in the range of about 0.5 x 10⁴ to 1.0 x 10⁵ per cm² in adherent culture. The medicament may further include a stem cell support additive. The stem cell support additive may include at least one of non-stem cells, buffer reagents, vitamins, antibiotics, antifungals, therapeutic reagents, growth factors, oxygenating factors, hormones, developmental factors, immunological reagents, integration factors, angiogenic factors, dissolution factors, wound-healing factors, hair-growth factors, antibodies, active agents, cytokines, chemokines, hydroxyapatite, calcium phosphate cement, teratoma inhibitors, or cosmetic factors. The stem cell materials may include stem cell biomaterials that are derived from a plurality of stem cells. The medicament may include an active agent. The PCL substrate may be configured to dissolve over time after application to a subject. The contact of the medicament with the PCL substrate may include at least one of impregnation within the PCL substrate, coating the outside of the PCL substrate, or being held by the PCL substrate. The PCL substrate may be hydrophilic, as measured by having a contact angle of less than 75 degrees with a droplet of an aqueous solution. The aqueous solution may include at least one of a buffering agent, a salt, a surfactant, a detergent, cell culture media, or a plasma. The base treatment may result in the addition of a carboxyl group to the PCL substrate. The medicament may be bound through a covalent bond to the PCL substrate at the carboxyl group. The covalent bond may be an amide bond. The medicament may include an amino acid. The medicament may be bound to the PCL substrate through at least one of electrostatic forces, hydrogen bonding, or Van der Waals forces. The PCL substrate may be configured to dissolve at a rate between about 5 minutes to about 2 years in an aqueous environment. The PCL substrate may be in the form of a microbead with a thickness of between about 10 nm and 0.6 mm. 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 with the co-polymer may have a rate of dissolution that is higher than a rate of dissolution of PCL without the co-polymer.

BRIEF DESCRIPTION OF THE DRAWINGS

[0014] FIG. 1 is an illustration of a magnification of a hydrophilic PCL microbead.

[0015] FIG. 2 is a microscopic image showing a multitude of untreated PCL microheads suspended in a solution.

[0016] FIG. 3 is a microscopic image showing a multitude of PCL microbeads, suspended in a solution of 50% (w/w) NaOH.

[0017] FIG. 4 is a magnified photograph of a hydrophobicity test of a water droplet on a polycaprolactone wafer.

[0018] FIG. 5 is an electron microscopy image showing the microporous structure of base-treated hydrophilic PCL foam.

[0019] FIG. 6 is a reaction diagram of base-catalyzed hydrolysis of the ester linkages present in the backbone of polycaprolactone.

[0020] 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.

[0021] 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.

[0022] 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. [0023] FIG. 10 is an illustration of an embodiment of a PCL dissolving microneedle.

[0024] FIG. 11 is a series of microscopic images that show the surface of a PCL microbead as it is treated by a basic solution.

[0025] FIG. 12 is an illustration of an application of hydrophilic PCL microbeads that are coated with a medicament, to skin of a subject.

DETAILED DESCRIPTION

[0026] 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.

[0027] 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.

[0028] 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.

[0029] 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

[0030] 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:

[0031] 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.

[0032] “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.

[0033] 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%.

[0034] “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.

[0035] By the phrases “modified polycaprolactone” or “modified PCL” is meant to be any polycaprolactone (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, punctured, protrusions, porous, semipermeable, and other irregularities. Any suitable treatment methods, including chemical or physical treatments, for modifying surface features of PCL can be used.

[0036] 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. Lor 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 NaHC03 and NaOH.

[0037] 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 co polymer. 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. Lor 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/SL), and/or polyurethane. Additional co- polymers are described herein.

[0038] 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). Lor 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-s-caprolactone.

[0039] As used herein, the term “microbead” refers to a shape that is less than 1 mm in diameter in the widest dimension, can be solid or hollow, can be filled with cells/hydrogel/support additives, and can be filled with stem cell support additives/have stem cells attached to exterior. The microbead can be comprised of a barrier that has a controlled pore size to limit the inflow of surrounding particles and/or cells based on size (e.g. antibodies), while letting smaller molecules (e.g. peptides, nucleotides, saccharides, salts, small proteins, etc.) in/out of the interior. The barrier can be comprised of soluble, hydrophilic polycaprolactone, and/or a co-polymer comprised of one or more polymers and polycaprolactone (can be cross- linked and/or entangled), and/or can be further functionalized by attaching stem cell support additives.

[0040] As used herein, the term “capsule” refers to a small case or container that encloses a body, which is greater than 1 mm in the largest dimension. The capsule can be comprised of a barrier that has a controlled pore size to limit the inflow of surrounding particles and/or cells based on size (e.g. antibodies), while letting smaller molecules (e.g. peptides, nucleotides, saccharides, salts, small proteins, etc.) in/out of the interior. The barrier can be comprised of soluble, hydrophilic polycaprolactone, and/or a co-polymer comprised of one or more polymers and polycaprolactone (can be cross-linked and/or entangled), and/or can be further functionalized by attaching stem cell support additives.

[0041] 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, lpm, 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.

[0042] 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.

[0043] 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.

[0044] 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. [0045] As used herein, the term “dissolvable microneedle” refers to a shape resembling a needle, that can be hollow, solid, coated, can be stand-alone, and/or can be attached to a reservoir in any configuration. The microneedle can dissolve at different rates.

[0046] As used herein, a "stem cell" is a cell characterized by the ability of self renewal 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.

[0047] 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.

[0048] 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, exosomes, micro vesicles, 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.

[0049] The term “stem cell materials” may include both stem cells themselves and stem cell biomaterials, which may be derived from the stem cells.

[0050] 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.

[0051] 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, non stem 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 co administered after the implant, or dosed after the implant for a range of time.

[0052] 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.

[0053] 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- lbeta (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 colony- stimulating 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.

[0054] 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.

[0055] 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).

[0056] 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.

[0057] 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.

[0058] 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.

[0059] 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.

[0060] 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)

[0061] 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, polyglycolide 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 polyvinylidene. 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 polyvinylidene 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.

[0062] 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.

[0063] Soluble, hydrophilic PCL for use in the stem cell carrier described herein may be in any form. The PCL-containing stem cell carrier can incorporate/absorb the stem cells and/or stem cell biomaterials of interest and optionally include the appropriate stem cell growth factors, stem cell differentiation factors, stem cell support media, and/or stem cell support matrices. In embodiments, the PCL-containing stem cell carrier releases the stem cells and/or stem cell biomaterials over time after administration of the stem cell carrier to a subject. In embodiments, the PCL-containing stem cell carrier dissolves or breaks down over time to release the stem cells and/or stem cell biomaterials and optional supporting reagents over time after administration of the stem cell carrier to a subject. In embodiments, the dissolution/release rate of the active agent is dependent on the properties of the PCL. For example, a thicker PCL layer is expected to take a longer time to release the stem cells and/or stem cell biomaterials (e.g., slower dissolution rate, and/or longer lifespan of the stem cell carrier) than a thinner PCL layer. In embodiments, the PCL is combined with one or more additional polymers to form a co-polymer to adjust the dissolution rate of the stem cell carrier. For example, a co-polymer that dissolves more quickly than PCL alone after administration of the stem cell carrier to a subject can be used.

[0064] Alternatively, a co-polymer that dissolves more slowly than PCL alone after administration of the stem cell carrier to a subject can be used. In embodiments, multiple PCL (or co-polymer) layers are used, each layer having a defined stem cell and/or stem cell biomaterials dissociation rate (or defined PCL or co-polymer dissolution rate).

[0065] 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.

[0066] 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 agent- containing 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.

[0067] 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.

[0068] 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. Further, the PCL or co-polymer may be formed, cut, or molded into any shape. For example, the PCL or co-polymer may be shaped as a microbead, capsule, film, sheet, bandage, adhesive, mesh, netting, anatomical mimic, geometrical shape, dissolving microneedle (DMN), and/or computer-aided designed three-dimensional shape.

[0069] Stem cell carriers may be applied topically, for example to the skin of a subject. Further, stem cell carriers as described herein may be applied internally to a subject, e.g., subdermal, within a body cavity, surgically implanted at a site of interest, partially replace or fully replace an internal structure, partially or fully replace an external structure.

[0070] Stem cell carriers may be applied in combination with a device, including, but not limited to, an existing medical, cosmetic, elective, or non-elective device, implant, or prosthetic. For example, to partially or fully replace a knee in a subject, the stem cell carrier can be attached to any component of an artificial knee. Further, stem cell carriers as described herein may be applied externally, internally, or within a body cavity of a subject in combination with any other medical device.

[0071] A stem cell carrier as described herein may contain one or more layers of soluble, hydrophilic PCL or co-polymer thereof. The stem cell carrier may also contain one or more layers of an additional polymer. In embodiments, one or more layers of PCL and/or additional polymer contains more than one stem cell type. In embodiments, different layers contain different stem cells and/or stem cell biomaterials, stem cell growth factors, stem cell differentiation factors, stem cell support media, and/or stem cell support matrices. In embodiments, different layers contain the same stem cells and/or stem cell biomaterials, stem cell growth factors, stem cell differentiation factors, stem cell support media, and/or stem cell support matrices. In embodiments, stem cell growth factors, stem cell differentiation factors, stem cell support media can be applied immediately before implantation of the stem cell carrier composition.

[0072] The hydrophilicity of the PCL, modified PCL, and PCL co-polymers can be determined by any method known in the art. In embodiments, hydrophilicity is determined by measuring the contact angle between a drop of water applied to the surface of the PCL polymer of interest. In embodiments, hydrophilicity is determined by measuring the static contact angle, sliding angle, advancing angle, and/or the receding angle between the drop of water and the surface. In embodiments, the contact angle is measured by calculating the contact angle hysteresis of the advancing and receding angles. In embodiments, hydrophilicity is determined by measuring the attractive forces between water and a surface by measuring the wettability of the surface. In embodiments, the wettability of the surface is measured using, but not limited to, a goniometer, atomic force microscopy, or a microbalance. In embodiments, water adsorption by the dry PCL, modified PCL, PCL co- polymer, or conjugated PCL is measured by simple mass measurement after exposure to water or aqueous media for any length of time. For this measurement, the dry composition is initially weighed, as defined by Wd; the hydrated composition is removed and again weighed, as defined by Ws; the water adsorption by the composition is calculated using the equation:

Water absorption (%) = ([Ws - Wd]/Wd) x 100

It is expected that hydrophilic compositions with have a value greater than zero for the calculated water adsorption % value.

[0073] PCL dissolution is measured by the dissolution, partial dissolution, degradation, partial degradation, disappearance, or partial disappearance of a PCL layer over time. The PCL layer may have a different rate of dissolution depending on the surrounding environment. The stem cell carrier may contain layers with the same dissolution rates and/or different dissolution rates. Soluble, hydrophilic PCL may have the same or different rate of dissolution as a co- polymer composition. Soluble, hydrophilic PCL may have the same or different dissolution rate as a conjugated composition. Soluble, hydrophilic PCL may have the same or different dissolution rate in contact with a device. The rate of dissolution can be calculated by the Noyes- Whitney equation or the Nernst and Brunner equation of the form:

where m is the mass of dissolved material, t is time, A is the surface area of the interface between the dissolving substance and the solvent, D is the diffusion coefficient, d = thickness of the boundary layer of the solvent at the surface of the dissolving substance, C_s is the mass concentration of the substance on the surface, and C_b is the mass concentration of the substance in the bulk solvent. Any appropriate analytical technique can be used to measure the change in dissolved mass of polymers, including change in refractive index, particle light scattering, size-exclusion chromatography, or analytical ultracentrifugation of the bulk solvent. The rate of dissolution can be measured by an apparatus and technique described in Section 711 of the United States Pharmacopeia (USP). The rate of dissolution in vivo may be measured by microscopic techniques and/or by implantation site inspection over time.

P. PCL Substrate

[0074] The PCL substrate has a surface texture that is smooth, rough, punctured, dimpled, porous, semi-permeable, and/or channeled.

[0075] The PCL substrate may be shaped as a microbead, capsule, film, sheet, bandage, adhesive, mesh, netting, anatomical mimic, geometrical shape, dissolving microneedle (DMN), and/or computer-aided designed three-dimensional shape. In embodiments, the PCL substrate is multi-layered.

[0076] The PCL substrate may be attached to a device that is an existing medical, cosmetic, elective, or non-elective device, implant, or prosthetic.

PI. Stem Cells

[0077] The stem cell carrier includes stem cells such as embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), or adult stem cells (ASCs).

[0078] In embodiments, the stem cells are ESCs. Embryonic stem cells may be derived from embryos, and are pluripotent and immortal. In embodiments, the stem cells are iPSCs. iPSCs are derived from somatic cells and have been reprogrammed to a pluripotent state. In embodiments, the cells are ASCs. ASCs are derived from adult tissues.

[0079] In embodiments, the stem cells are further differentiated into mesenchymal stem cells (MSCs). In embodiments, the stem cells are adipose stem cells. In embodiments, the stem cells are hematopoietic stem cells. In embodiments, the stem cells are endodermal stem cells. In embodiments, the stem cells are ectodermal stem cells. In embodiments, the stem cells are mesodermal. In embodiments, the stem cells are derived from placenta. In embodiments, the stem cells are derived from umbilical cord (e.g., umbilical cord blood). In embodiments, the stem cells are derived from amniotic fluid. In embodiments, the stem cells are derived from bone marrow. In embodiments, the stem cells are derived from adipose tissue. In embodiments, the stem cells are muse cells. In embodiments, the stem cells are dental pulp cells.

[0080] In embodiments, the stem cells are progenitor cells (precursor cells).

Progenitor cells are more differentiated than stem cells, but have the capability of differentiating into multiple cell types. In embodiments, the stem cells are retinal progenitor cells. In embodiments, the stem cells are satellite cells. In embodiments, the stem cells are neural progenitor cells. In embodiments, the cells are radial glial cells. In embodiments, the stem cells are pancreatic progenitor cells. In embodiments, the stem cells are angioblasts. In embodiments, the stem cells are boundary cap cells. In embodiments, the stem cells are blast cells. In embodiments, the stem cells are radial glial cells. In embodiments, the stem cells are bone marrow cells. In embodiments, the stem cells are periosteum in origin.

[0081] In embodiments, any of the listed types of stem cells may be specifically, independently excluded. Cells may be non-human, e.g. rabbit, guinea pig, rat, mouse or other rodent (including cells from any animal in the order Rodentia), cat, dog, pig, sheep, goat, cattle, horse, non-human primate or other non-human vertebrate organism; and/or non human mammalian cell. In embodiments, the cells are human cells.

[0082] In embodiments, the stem cells are modified stem cells. Modified stem cells include, without limitation, stem cells that have been genetically modified to express one or more molecules of interest, to correct a genetic mutation that was present in stem cells prior to modification, to reduce or eliminate expression of one or more molecules, to express a marker protein, and the like. Modified stem cells also include stem cells that have been modified to differentiate or begin differentiating into a cell type of interest. The cell type may be any cell type that may treat or augment treatment of a disease or condition in a subject. In embodiments, the stem cells have been modified by gene therapy, including by gene editing, gene addition, and gene knockout. In embodiments, stem cells have been modified by RNA-based therapeutics, including RNA interference, siRNA, shRNA, miRNA, RNA aptamers, and ribozymes. In embodiments, stem cells have been modified by tissue- specific cytokines, chemokines, growth factors, hormones, metabolites, extracellular pH, reactive-oxygen species (ROS), inorganic compounds, and organic compounds. In embodiments, the stem cells have been modified by antibody-based transdifferentiation. In embodiments, the stem cells have been modified by conditionally reprogrammed cells (CRC), including by a Rho-kinase inhibitor, and CD47 inhibition. In embodiments, the stem cells are modified by their out membrane glycoprotein profile, including O-GlcNAc- and O- LacNAc-dependent tuning of the Notch signaling pathway. In embodiments, the stem cells are exposed to leukemia inhibiting factor (LIF). In embodiments, the Nanog transcription factor is downregulated and/or upregulated in the stem cells. In embodiments, Oct4 (octamer-binding transcription factor) is downregulated and/or upregulated in the stem cells. In embodiments, Wnt signaling is downregulated and/or upregulated in the stem cells. In embodiments, the miRNA molecules miR-9, miR-124, mirR-125, miR-302, and/or Let-7 are downregulated and/or upregulated in the stem cells. In embodiments, the PI3K/AKT signaling pathway is downregulated and/or upregulated in the stem cells. In embodiments, the methylation of CpG DNA bases is regulated in the stem cells. In embodiments, stem cell histones are modified to change gene expression profiles toward modification. In embodiments, retinoic acid is used to control stem cell modification. In embodiments, stem cell differentiation and modification is controlled by the surrounding metabolite composition, including controlling relative lactic acid concentration, and other oxidative phosphorylation pathway promoting metabolite concentrations. In embodiments, the stem cells are modified before contacting them with the PCL substrate. In embodiments, the stem cells are modified after contacting them with the PCL substrate.

[0083] In embodiments, the stem cells are differentiated or partially differentiated prior to administration of the PCL substrate-stem cell composition to a subject. In embodiments, the stem cells are differentiated before contacting them with the PCL substrate. In embodiments, the stem cells are differentiated after contacting them with the PCL substrate.

IV. Stem Cell Biomaterials

[0084] Stem cell biomaterials include, without limitation, stem cell-conditioned media, exosomes, micro vesicles, other vesicles or particles derived from stem cells, growth factors derived from stem cells, and/or other factors (e.g., proteins, lipids, etc.) derived from stem cells. In embodiments, the factors derived from stem cells are factors that are secreted by stem cells. In embodiments, the factors derived from stem cells include microRNAs. In embodiments, stem cell biomaterials do not include living stem cells. In embodiments, stem cell biomaterials include dead cells. In embodiments, stem cell biomaterials are free of cells.

[0085] Stem cell biomaterials and methods of preparing them from many different types of stem cells are known in the art. See, e.g., U.S. Pub. Nos. 2015/0190430; 2015/0079046; 2016/0002597; and 20180066307; each of which is incorporated herein in its entirety, including all methods, compositions, reagents, etc. taught therein.

V. Methods of Making

[0086] In embodiments, the stem cell carrier is constructed by impregnating, attaching, confining, encapsulating, or layering stem cells and/or stem cell biomaterials within or attached to the PCL substrate.

[0087] In embodiments, the stem cells are cultured in the presence of the PCL substrate, such that at least a portion of the cultured stem cells adhere to the PCL substrate.

[0088] 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. In embodiments, the PCL substrate is sterilized. Sterilization may be by any means, such as autoclave, chemical sterilization, gas sterilization, and the like. In embodiments, the PCL substrate is contacted with the plurality of stem cells and/or stem cell biomaterials. In embodiments, the PCL substrate is contacted (e.g., coated on at least one side) with a material that aids in the interaction between stem cells and/or stem cell biomaterials and the PCL substrate (e.g., an ECM molecule) prior to contacting with the stem cells and/or stem cell biomaterials. In embodiments, multiple layers are added by contacting the stem cells and/or stem cell biomaterials or PCL substrate with a next layer. In embodiments, a coating is added that covers at least one side of the PCL substrate and/or stem cells and/or stem cell biomaterials. In embodiments, the PCL substrate-stem cell carrier is encased in the coating.

[0089] In embodiments, the PCL substrate is contacted with the stem cells and/or stem cell biomaterials by enclosing a stem cell suspension or the biomaterials, or by direct stem cell adherence to the PCL surface. Stem cells are administered, seeded, or applied to the stem cell carrier. Stem cells can be adherent and/or in suspension. The stem cells can be seeded by exposure to the stem cell carrier layers in the range of about 1.5 x 105 to about 1.0 x 107 per cm3 in suspension cultures. The stem cells can be seeded by exposure to the stem cell carrier in the range of about 0.5 x 104 to about 1.0 x 105 per cm2 in adherent cultures. Suspension cultures include stem cells that are suspended in stem cell support media, hydrogel, or in any three dimensional configuration that does not include anchoring to form a surface. Adherent culture refers to stem cells that are anchored to any surface in a partial monolayer, monolayer, or multilayer configuration.

[0090] In embodiments, the PCL substrate can have pores of diameter size range of about 70 to 100 microns, to promote partial diffusion of nutrients, stem cell biomaterials, stem cell growth factors, stem cell differentiation factors, and support factors from the environment of implantation, without permitting large antibodies/proteins greater than 150,000 Da, or host cells from passing through the substrate.

[0091] In embodiments, the PCL substrate can have pores of the size range of about

0.05 - 6.0 pm in diameter. The pore sizes can be about 0.05 um, 0.5 pm, 0.6 pm, 0.7 pm,

0.8 pm, 0.9 pm, 1.0 pm, 1.5 pm, 2.0 pm, 2.5 pm, 3.0 pm, 3.5 pm, 4.0 pm, 4.5 pm, 5.0 pm, 5.5 pm, to about 6.0 pm.

[0092] In embodiments, the stem cells and/or stem cell biomaterials are micro- encapsulated. In embodiments, stem cells are encapsulated as suspended free cells, adherent cells, suspended cellular aggregates, cells embedded in a hydrogel, cells embedded in a matrix, and/or cells embedded in a micro stem cell carrier, including, but not limited to, a microbead. In embodiments, the stem cells and/or stem cell biomaterials are micro- encapsulated by a process analogous to using co-axial air-flow droplet generator, for example by mixing the PCL substrate with stem cells, then extruding the PCL - stem cell mixture through a needle (e.g., a 400 pm needle). In embodiments, extrusion is performed using a pump and a co-axial air-flow. In embodiments, droplets are formed and further polymerized in a chemical and/or biomolecular bath, e.g. a gelation bath including HEPES and CaC12 buffer.

[0093] In embodiments, the stem cells and/or stem cell biomaterials are macro- encapsulated. For example, implants that are thicker than 200 pm may contain a 3D interior growth chamber to provide a microenvironment that is specific to the needs of the implanted cell population. The interior growth chamber can include stem cell support factors and/or co polymers. In embodiments, the microenvironment layer is enclosed in a biocompatible, immunoprotective growth chamber. In embodiments, the biocompatible, immunoprotective growth chamber comprises soluble, hydrophilic PCL. Macro-encapsulation can take place in a three-dimensional shape including, but not limited to, a capsule, anatomical mimic, geometrical shape, dissolving microneedle (DMN), and/or computer-aided designed three- dimensional shape. The three dimensional shape can be comprised of one or more layers.

VI. Methods of Using

[0094] The hydrophilic PCL substrate has diverse applications serving as delivery vehicles for in-human therapeutic applications. Applications currently under development include microbeads bound to SARS CoV2 neutralizing antibodies for temporary protection against the virus and viral load / shedding reduction with infected patients. In this case, the hydrophilic, charged surfaces created on the microbeads will facilitate adherence to the mucosal cells and accelerate absorption into the tissues, thus preventing cilia from rapidly clearing the microbeads from the nasal passages into the trachea. Hydrophilic PCL microbeads have also been coupled to the receptor binding domain (RBD) from SARS CoV2 and may be implanted ~2mm beneath the surface of the skin for detection of circulating antibodies against the virus. In this case, RBD polypeptides will be linked to the microbeads via amide bonds. The implanted microbeads dissolve over time and serve to sequester the antigen and present the epitopes for recruitment of localized immune response, which can be detected simply by visual observation. Other manifestations of the product include use of hydrophilic PCL microbeads and nanoparticles as vehicles for nasal, intradermal, subdermal, intra-peritoneal and intravenous vaccinations, imbibing stem cells and their biologic components for use in skin creams, they can be used transdermal, intradermal and even sublingual.

[0095] Uses of the stem cell carrier include delivery of stem cells and/or stem cell biomaterials in a time-dependent fashion to an area of interest in the subject.

[0096] The PCL substrate-stem cell carriers described herein may be used to treat any disease or condition treatable by administration of stem cells and/or stem cell biomaterials. Examples of such conditions include, without limitation, ocular diseases including macular degeneration (e.g., age-related macular degeneration, wet or dry), diabetic macular edema, idiopathic choroidal neovascularization, high myopia macular degeneration, advanced retinitis pigmentosa, corneal replacement, lens replacement; replacement of neurons damaged by spinal cord injury, stroke, Alzheimer’s disease, Parkinson’s disease, Lou Gehrig's disease, Huntington’s disease, multiple schlerosis, spina bifida, or other neurological problems; heart disease, such as treatment/replacement of heart muscle after heart attack; replacement of organs or organelles damaged by injury or disease, including transplant acceptance therapy; diabetes, including beta- cell replacement therapy; arthritis, including chondrocyte generation, rheumatoid arthritis, psoriatic arthritis, osteoarthritis; sickle cell anemia; skin (e.g., skin grafts); immune disorders, including Crohn’s disease, ulcerative colitis, celiac disease; metabolic disorders; cancer, such as leukemia, Down- syndrome-related leukemia, lymphoma, multiple myeloma, neuroblastoma, skin cancer, lung cancer, liver cancer; blood cell production; treatment for congenital heart defects; treatment for hemangioma; kidney disease, including diabetes-related kidney damage, polycystic kidney disease, and focal segmental glomerulosclerosis; chronic lung disease, including bronchopulmonary dysplasia, emphysema, bronchiolitis obliterans, chronic obstructive pulmonary disorder (COPD); liver disease, including hepatitis, liver regeneration; muscular disorders, including muscular dystrophy, autoimmune disease, including treatment for severe, combined immunodeficiency (SCID), male infertility; female infertility; hair-loss reversal; wound healing; bone-related disease, including new tooth generation, new bone generation, bone remodeling.

[0097] The type(s) of stem cells, number of cells, amount of stem cell biomaterials, amount and form of PCL substrate, etc. will vary depending on the disease and the subject to be treated.

[0098] In various embodiments, uses may include stem cell additives skin creams, anti inflammatory factors, cytokines, coupling IgG antibodies, and nasal aerosols.

[0099] 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.

[0100] 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.

[0101] 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.

[0102] 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 mM 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.

[0103] 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 microheads may result in increased interaction with the basic solution.

[0104] 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.

[0105] 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 microheads 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.

[0106] The surface 310 of the treated PCL microheads 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.

[0107] 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.

[0108] 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.

[0109] 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.

[0110] 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.

[0111] 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 microheads 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.

[0112] 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. [0113] 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.

[0114] 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.

[0115] 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 by product may be produced as part of the reaction.

[0116] 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.

[0117] 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 microhead 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 microhead 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.

[0118] In various embodiments, the stem cells 810 may produce stem cell biomaterials when the hydrophilic PCL microhead 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.

[0119] Referring to Fig. 9, Fig. 9 is a series 900 of microscopic images that illustrate a rate of dissolution of PCL microheads 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

[0120] 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 microheads 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 microheads 910 in the 5% (w/w) NaOH solution are still undissolved after 24-hours.

[0121] 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.

[0122] 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.

[0123] 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.

[0124] 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.

[0125] 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.

[0126] 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.

[0127] 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 microheads may be placed in a reservoir with an implantable device.

[0128] 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 composition, the composition comprising: a soluble, hydrophilic polycaprolactone (PCL) substrate; stem cell materials that are in contact with the PCL substrate; and the PCL substrate having been treated with a base having a pH greater than

8.

2. The composition of claim 1, wherein the contact of the stem cell materials with the PCL substrate comprises at least one of impregnation within the PCL substrate, coating the outside of the PCL substrate with the stem cell materials, or being held by the PCL substrate.

3. The composition of claim 1, wherein the PCL substrate is hydrophilic, as measured by having a contact angle of less than about 75 degrees with a droplet of an aqueous solution.

4. The composition of claim 3, wherein the aqueous solution comprises at least one of a buffering agent, a salt, a surfactant, a detergent, cell culture media, or a plasma.

5. The composition of claim 1, wherein the stem cell materials comprise stem cell biomaterials that are derived from a plurality of stem cells.

6. The composition of claim 1, wherein the stem cell materials comprise at least one of stem cell growth factor, stem cell differentiation factor, stem cell support media, or stem cell support matrix.

7. The composition of claim 1, wherein the stem cell materials comprise at least one of embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), or adult stem cells (ASCs).

8. The composition of claim 1, wherein the stem cell materials comprise a biomedical implant.

9. The composition of claim 8, wherein the biomedical implant comprises an organoid. , ₎

10. The composition of claim 1, wherein the stem cell materials comprise a number of stem cells sufficient to support at least one of differentiation, homeostasis, apoptosis, or pluripotency of the stem cells.

11. The composition of claim 1, wherein the stem cell materials have a density of about 1.5 x 10⁵ to 1.0 x 10⁷ per cm³ in suspension culture, and in the range of about 0.5 x 10⁴to 1.0 x 10⁵ per cm² in adherent culture.

12. The composition of claim 1, further comprising a stem cell support additive.

13. The composition of claim 12, wherein the stem cell support additive comprises at least one of non-stem cells, buffer reagents, vitamins, antibiotics, antifungals, therapeutic reagents, growth factors, oxygenating factors, hormones, developmental factors, immunological reagents, integration factors, angiogenic factors, dissolution factors, wound-healing factors, hair-growth factors, antibodies, active agents, cytokines, chemokines, hydroxyapatite, calcium phosphate cement, teratoma inhibitors, or cosmetic factors.

14. The composition of any one of claims 1-13, wherein the PCL substrate is configured to dissolve over time after application to a subject.

15. The composition of claim 14, wherein the base treatment results in addition of a carboxyl group to the PCL substrate.

16. The composition of claim 14, wherein the stem cell materials are bound through a covalent bond to the PCL substrate at the carboxyl group.

17. The composition of claim 16, wherein the covalent bond is an amide bond.

18. The composition of claim 16, wherein the covalent bond forms a peptide bond.

19. The composition of claim 14, wherein the stem cell materials are bound to the PCL substrate through electrostatic forces.

20. The composition of claim 14, wherein the PCL substrate is in a form of a microbead, capsule, film, sheet, bandage, adhesive, mesh, netting, anatomical mimic, geometrical shape, dissolving microneedle (DMN), or a computer-aided designed three-dimensional shape.

21. The composition of claim 20, wherein the PCL substrate is in the form of a microbead with a thickness of between about 10 nm and 0.6 mm.

22. The composition of claim 20, wherein the PCL substrate is multi-layered.

23. The composition of claim 20, wherein the PCL substrate is configured to dissolve at a rate between about 5 minutes to about 2 years in an aqueous environment.

24. The composition of claim 23, wherein the aqueous environment comprises a bloodstream of a subject.

25. The composition of claim 20, wherein the PCL substrate is configured to be delivered by at least one of a needle, a microneedle, or an implant.

26. The composition of claim 20, wherein the PCL substrate further comprises a co-polymer.

27. The composition of claim 26, wherein the co-polymer comprises 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.

28. The composition of claim 26, wherein the PCL substrate with the co polymer has a rate of dissolution that is higher than a rate of dissolution of PCL without the co-polymer.

29. A composition, the composition comprising: a soluble, hydrophilic polycaprolactone (PCL) substrate; an active agent that is in contact with the PCL substrate; and the PCL substrate having been treated with a base having a pH greater than

8.

30. The composition of claim 29, wherein the contact of the active agent with the PCL substrate comprises at least one of impregnation within the PCL substrate, coating the outside of the PCL substrate, or being held by the PCL substrate.

31. The composition of claim 29, wherein the PCL substrate is hydrophilic, as measured by having a contact angle of less than about 75 degrees with a droplet of an aqueous solution.

32. The composition of claim 31, wherein the aqueous solution comprises at least one of a buffering agent, a salt, a surfactant, a detergent, cell culture media, or a plasma.

33. The composition of claim 29, wherein the base treatment results in addition of a carboxyl group to the PCL substrate.

34. The composition of claim 33, wherein the active agent is bound through a covalent bond to the PCL substrate at the carboxyl group.

35. The composition of claim 34, wherein the covalent bond is an amide bond.

36. The composition of claim 35, wherein the active agent is an amino acid.

37. The composition of claim 29, wherein the active agent is bound to the PCL substrate through at least one of electrostatic forces, hydrogen bonding, or Van der Waals forces.

38. The composition of claim 29, wherein the PCL substrate is in the form of at least one of a microbead, a capsule, a film, a sheet, a bandage, an adhesive, a mesh, a netting, an anatomical mimic, a geometrical shape, a dissolving microneedle (DMN), or a computer-aided designed three-dimensional shape.

39. The composition of any one of claims 29-38, wherein the PCL substrate is configured to dissolve over time after application to a subject.

40. The composition of claim 39, wherein the PCL substrate is in a form of a microbead with a thickness of between about 10 nm and about 0.6 mm.

41. The composition of claim 39, wherein the PCL substrate is configured to dissolve at a rate between about 5 minutes to about 2 years in an aqueous environment.

42. The composition of claim 41, wherein the aqueous environment comprises a bloodstream of a subject.

43. The composition of claim 39, wherein the PCL substrate is configured to be delivered by at least one of a needle, a microneedle, or an implant.

44. The composition of claim 39, wherein the PCL substrate further comprises a co-polymer.

45. The composition of claim 44, wherein the co-polymer comprises 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.

46. The composition of claim 44, wherein the PCL substrate with the co polymer has a rate of dissolution that is higher than a rate of dissolution of PCL without the co-polymer.

47. A method for manufacturing a PCL medicament carrier, the method comprising: providing a soluble, hydrophilic polycaprolactone (PCL) substrate that has been treated with a base having a pH greater than 8; and the PCL substrate is in contact with a medicament for treating a subject.

48. The method of claim 47, wherein the medicament comprises stem cell materials.

49. The method of claim 48, wherein the stem cell materials comprise at least one of embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), or adult stem cells (ASCs).

50. The method of claim 49, wherein the stem cell materials comprise a biomedical implant.

51. The method of claim 50, wherein the biomedical implant comprises an organoid.

52. The method of claim 48, wherein the stem cell materials comprise a number of stem cells sufficient to support at least one of differentiation, homeostasis, apoptosis, or pluripotency of the stem cells.

53. The method of claim 48, wherein the stem cell materials have a density of about 1.5 x 10⁵ to 1.0 x 10⁷ per cm³ in suspension culture, and in the range of about 0.5 x 10⁴to 1.0 x 10⁵ per cm² in adherent culture.

54. The method of claim 48, wherein the medicament further comprises a stem cell support additive.

55. The method of claim 54, wherein the stem cell support additive comprises at least one of non-stem cells, buffer reagents, vitamins, antibiotics, antifungals, therapeutic reagents, growth factors, oxygenating factors, hormones, developmental factors, immunological reagents, integration factors, angiogenic factors, dissolution factors, wound-healing factors, hair-growth factors, antibodies, active agents, cytokines, chemokines, hydroxyapatite, calcium phosphate cement, teratoma inhibitors, or cosmetic factors.

56. The method of claim 48, wherein the stem cell materials comprise stem cell biomaterials that are derived from a plurality of stem cells.

57. The method of claim 47, wherein the medicament comprises an active agent.

58. The method of any one of claims 47-57, wherein the PCL substrate is configured to dissolve over time after application to a subject.

59. The method of claim 58, wherein the contact of the medicament with the PCL substrate comprises at least one of impregnation within the PCL substrate, coating the outside of the PCL substrate, or being held by the PCL substrate.

60. The method of claim 58, wherein the PCL substrate is hydrophilic, as measured by having a contact angle of less than about 75 degrees with a droplet of an aqueous solution.

61. The method of claim 60. wherein the aqueous solution comprises at least one of a buffering agent, a salt, a surfactant, a detergent, cell culture media, or a plasma.

62. The method of claim 60, wherein the base treatment results in addition of a carboxyl group to the PCL substrate.

63. The method of claim 62, wherein the medicament is bound through a covalent bond to the PCL substrate at the carboxyl group.

64. The method of claim 63, wherein the covalent bond is an amide bond.

65. The method of claim 64, wherein the medicament comprises an amino acid.

66. The method of claim 58, wherein the medicament is bound to the PCL substrate through at least one of electrostatic forces, hydrogen bonding, or Van der Waals forces.

67. The method of claim 58, wherein the PCL substrate is configured to dissolve at a rate between about 5 minutes to about 2 years in an aqueous environment.

68. The method of claim 58, wherein the PCL substrate is in a form of a microbead with a thickness of between about 10 nm and about 0.6 mm.

69. The method of claim 58, wherein the PCL substrate further comprises a co polymer.

70. The method of claim 69, wherein the co-polymer comprises 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.

71. The method of claim 70, wherein the PCL substrate with the co-polymer has a rate of dissolution that is higher than a rate of dissolution of PCL without the co-polymer.