Melanin Materials for Tissue Repair

Abstract

Aspects disclosed herein include a method for treating a subject, the method comprising the steps of: topically administering (thereby administering) a melanin formulation having an artificial melanin material to damaged skin (or to a site of damaged skin of the subject) of the subject; the administered artificial melanin material to the damaged skin (or to the site of damaged skin) comprising extracellular artificial melanin material; and promoting skin healing within the wound via at least the extracellular artificial melanin material; the promoting skin healing comprising at least a portion of the extracellular artificial melanin material exerting therapeutic extracellular activity.

Description

[Background technology]

[0001]

[0003] Melanin is a widespread biomaterial found widely in different organisms. In humans, melanin is produced by melanosome organelles found in melanocytes. Uniquely, melanocytes are the only known cells capable of excreting organelles extracellularly. Melanin is known among other things as a dark brown or black pigment in the skin and functions as a broadband radiation absorber. Melanosome production increases upon increasing UV exposure, aiding in UV radiation protection. The properties of melanin are not limited to photoprotection; it has a myriad of other functions uncharacteristic of the function of biopigments, including structural coloration, metal chelation, small molecule absorption, and thermoregulation, which may explain its ubiquitous presence in nature.

[0002]

[0004] These diverse functions can be attributed to the chemical properties and morphology of melanin. Melanin can exhibit many intermolecular interactions such as hydrogen bonding, π-π stacking, and covalent interactions. The abundance of different intermolecular interactions is due to the various functional groups of melanin. Due to the different oxidation states of its functional groups, melanin can accept and donate electrons, allowing for redox activity. In addition, it has antioxidant activity due to its electron-donating ability. Melanin can quench radical oxygen species (ROS). The ability to prevent cell damage through the ROS pathway may be a pathway by which melanin protects cells from radiation to prevent or mitigate cell damage.

[0003]

[0005] However, there has been limited exploration of the therapeutic uses of melanin beyond its intracellular protective function, particularly with regard to artificial melanin materials. Summary of the Invention

[0004]

[0006] Included herein are methods for promoting tissue healing, particularly skin healing, in a living subject, such as for the treatment or correction of damaged skin, such as in the case of wound closure in a living subject, using melanin formulations having melanin material. Unexpectedly, for example, tissue healing can be promoted by administered melanin material that is present extracellularly in damaged skin.

[0005]

[0007] Aspects disclosed herein include a method for treating a subject, the method comprising the steps of: topically administering (thereby administering artificial melanin material) a melanin formulation having an artificial melanin material to damaged skin (or to a site of damaged skin of the subject); the administered artificial melanin material to the damaged skin (or to the site of damaged skin) comprises extracellular artificial melanin material; and promoting skin healing of (or within) the damaged skin via at least the extracellular artificial melanin material; the promoting skin healing comprises at least a portion of the extracellular artificial melanin material exerting therapeutic extracellular activity.

[0006]

[0008] Optionally, the artificial melanin material comprises a porous artificial melanin material, an artificial melanin particle, and / or a porous artificial melanin particle. Optionally, at least a portion of each of the artificial melanin particles and / or the porous artificial melanin particles comprises a composition according to an embodiment disclosed throughout this specification. Optionally, the wound comprises inflammation, and the promoting step comprises reducing inflammation as a result of the extracellular artificial melanin material quenching extracellular free radical species.

[0007]

[0009] Aspects disclosed herein include a method for treating a subject, comprising the steps of administering a melanin formulation to a wound of the subject, the wound comprising damaged tissue and extracellular free radical species; the melanin formulation comprising an artificial melanin material; the administering step comprising providing an artificial melanin material extracellularly of the wound; promoting tissue healing in the wound via the administered extracellular artificial melanin material; at least a portion of the artificial melanin particles being extracellularly of the wound during the promoting tissue healing step; the promoting tissue healing step comprising quenching at least the extracellular free radical species with the extracellular artificial melanin material. Optionally, the artificial melanin material comprises a porous artificial melanin material, artificial melanin particles, and / or porous artificial melanin particles. Optionally, at least a portion of each of the artificial melanin particles and / or porous artificial melanin particles comprises a composition according to the embodiments disclosed throughout this specification. Optionally, the wound comprises inflammation, and the promoting step comprises reducing inflammation as a result of the extracellular artificial melanin material quenching extracellular free radical species. Optionally, the melanin formulation is administered topically.

[0008]

[0010] Aspects disclosed herein include a method for treating a subject, the method comprising the steps of administering a melanin formulation to an area of ​​the subject, the area comprising damaged tissue and inflammation; the melanin formulation comprising melanin particles; and promoting tissue healing within the area as a result of the presence of the administered melanin particles.

[0009]

[0011] Aspects disclosed herein include a method for the treatment of a subject, comprising administering a melanin formulation to an area of ​​the subject, the area including damaged tissue; the melanin formulation including melanin particles; and promoting tissue healing in the area as a result of the presence of the melanin particles; including melanin particles that quench reactive oxygen species in the area. Optionally, the extracellular melanin particles of the administered formulation quench extracellular reactive oxygen species in the area. Optionally, the administration is topical and the tissue healing includes healing skin tissue.

[0010]

[0012] Aspects disclosed herein include a method for treating a subject, comprising administering a melanin formulation to a wound of the subject, the melanin formulation comprising melanin particles; and promoting tissue healing within the wound as a result of the presence of the melanin particles comprising melanin particles that quench reactive oxygen species within the wound. Optionally, the extracellular melanin particles of the administered formulation quench extracellular reactive oxygen species within the wound. Optionally, the administration is topical and the tissue healing comprises healing skin tissue.

[0011]

[0013] While not wishing to be bound by any particular theory, there may be discussion herein of underlying beliefs or understandings regarding the devices and methods disclosed herein, and it is recognized that regardless of the ultimate correctness of any mechanistic explanation or hypothesis, certain embodiments of the invention may nevertheless be effective and useful. [Brief description of the drawings]

[0012] [Figure 1A] 1A-1D show characterization of high and low surface area synthetic melanin particles corresponding to embodiments of artificial melanin materials herein, TEM and SEM micrographs of HSA-SMP, respectively. Scale bar 1 micron. [Figure 1B]1A-1D show characterization of high and low surface area synthetic melanin particles corresponding to embodiments of artificial melanin materials herein, TEM and SEM micrographs of HSA-SMP, respectively. Scale bar 1 micron. [Figure 1C] 1A-1D show characterization of high and low surface area synthetic melanin particles corresponding to embodiments of artificial melanin materials herein, TEM and SEM micrographs of LSA-SMP, respectively. Scale bar 1 micron. [Figure 1D] 1A-1D show characterization of high and low surface area synthetic melanin particles corresponding to embodiments of artificial melanin materials herein, TEM and SEM micrographs of LSA-SMP, respectively. Scale bar 1 micron. [Figure 1E] 1 shows characterization of high and low surface area synthetic melanin particles corresponding to embodiments of artificial melanin materials herein. H&E stained images of mouse skin sections containing solid and porous PDA, respectively, shown to be present on the surface of the skin. Scale bar 100 nm. [Figure 1F] 1 shows characterization of high and low surface area synthetic melanin particles corresponding to embodiments of artificial melanin materials herein. H&E stained images of mouse skin sections containing solid and porous PDA, respectively, shown to be present on the surface of the skin. Scale bar 100 nm. [Figure 1G] 1 shows the characterization of high and low surface area synthetic melanin particles corresponding to embodiments of artificial melanin materials herein.FIG. 2 shows the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity of antioxidants. [Figure 2A] 1 shows that SMP treatment improves skin healing following nitrogen mustard (NM) injury, an exemplary injured skin according to embodiments herein. Representative images of wounds on days 1-5. [Figure 2B]FIG. 1 shows that SMP treatment improves skin healing after nitrogen mustard (NM) injury, an exemplary damaged skin according to embodiments herein. Wound area reduction. n=11-18 mice per group; *p<0.05; ***p<0.001. [Figure 2C] FIG. 1 shows that SMP treatment improves skin healing after nitrogen mustard (NM) injury, an exemplary damaged skin according to embodiments herein. Bi-fold skin thickness measurements for vehicle (circles), LSA-SMP (squares), and HSA-SMP (triangles). n=9-10 mice per group; *p<0.03, ***p<0.0003, ****p<0.0001. [Figure 2D] FIG. 1 shows that SMP treatment improves skin healing following nitrogen mustard (NM) injury, an exemplary damaged skin according to embodiments herein. FIG. 1 shows time to scab detachment for vehicle (circles), LSA-SMP (squares), and HSA-SMP (triangles). n=9-10 mice per group; *p<0.05, ***p<0.001. [Figure 3A] FIG. 1 shows that PDA nanoparticle treatment corresponding to embodiments herein of artificial melanin material increases SOD activity following NM injury according to embodiments herein. 24 hours, n=. [Figure 3B] FIG. 1 shows that PDA nanoparticle treatment corresponding to embodiments herein of artificial melanin material increases SOD activity following NM injury according to embodiments herein. 48 hours, n=. [Figure 3C] FIG. 13 shows that PDA nanoparticle treatment corresponding to embodiments herein of artificial melanin material increases SOD activity following NM injury according to embodiments herein. 72 hours, n=. *p<0.05; **p<0.01:***p<0.001. [Figure 4A]Figure 1 shows TaqMan mouse immunoarray results. Significantly down-regulated genes in the HSA-SMP treatment group are shown (all p<0.05). The vehicle-only group was used as a reference corresponding to the absence of artificial melanin material. See also Tables 1 and 2. Gzmb values ​​in the untreated group were below the detection level. [Figure 4B] Figure 1 shows that SMP treatment downregulates pro-inflammatory signaling following NM-induced injury.Figure 2 shows Western blotting analysis of ERK1 / 2 phosphorylation 24 hours after injury (n=3). [Figure 4C] Figure 1 shows that SMP treatment downregulates pro-inflammatory signaling following NM-induced injury.Figure 2 shows densitometric quantification of the data shown in panel A. [Figure 4D] Figure 4: SMP treatment downregulates pro-inflammatory signaling after NM-induced injury. Expression of Mmp-9 after 48 (Figure 4D, n=) and 72 (Figure 4E, n=5) hours. *p<0.05, **p<0.01. [Figure 4E] Figure 4: SMP treatment downregulates pro-inflammatory signaling after NM-induced injury. Expression of Mmp-9 after 48 (Figure 4D, n=) and 72 (Figure 4E, n=5) hours. *p<0.05, **p<0.01. [Figure 4F] FIG. 4F shows that SMP treatment downregulates pro-apoptotic signaling following NM-induced injury. (FIG. 4F) TUNEL stained images. [Figure 4G] FIG. 4F shows that SMP treatment downregulates pro-apoptotic signaling following NM-induced injury. (FIG. 4F) TUNEL stained images. (FIG. 4F) Mean fluorescence intensity of TUNEL staining. [Diagram 5]Figure 1 shows that inhibition of Cu / Zn SOD abrogates the effect of SMPs on skin healing after NM injury. (A) Representative images of wounds on different days. (B) Double-sided skin thickness measurement, n=; (C) Wound area reduction, n= mice per group. (D) TUNEL staining. (E) SOD activity: inhibition of Cu / Zn SOD prevents PDA NPs from rescuing SOD activity. [Figure 6A] FIG. 6A shows staining images including low and high magnification images of damaged skin with nitrogen mustard (NM)-induced injury after treatment with vehicle / control (i.e., absence of melanin formulation with artificial melanin material), low surface area synthetic melanin particles (LSA-SMP), and high surface area synthetic melanin particles (HSA-SMP) (porous artificial melanin particles), showing that PDA nanoparticle treatment alleviates (promotes healing of) NM-induced damage in human skin explants. [Figure 6B] FIG. 6A shows staining images including low and high magnification images of damaged skin with nitrogen mustard (NM)-induced injury after treatment with vehicle / control (i.e., absence of melanin formulation with artificial melanin material), low surface area synthetic melanin particles (LSA-SMP), and high surface area synthetic melanin particles (HSA-SMP) (porous artificial melanin particles), showing that PDA nanoparticle treatment alleviates (promotes healing) NM-induced injury in human skin explants. Densitometric quantification of data for two key inflammatory factors from human skin explant data, CCL20 in FIG. 6B and CXCL8 in FIG. 6C. FIG. 6B and FIG. 6C confirm that the artificial melanin material disclosed herein downregulates these inflammatory factors. [Figure 6C]FIG. 6A shows staining images including low and high magnification images of damaged skin with nitrogen mustard (NM)-induced injury after treatment with vehicle / control (i.e., absence of melanin formulation with artificial melanin material), low surface area synthetic melanin particles (LSA-SMP), and high surface area synthetic melanin particles (HSA-SMP) (porous artificial melanin particles), showing that PDA nanoparticle treatment alleviates (promotes healing) NM-induced injury in human skin explants. Densitometric quantification of data for two key inflammatory factors from human skin explant data, CCL20 in FIG. 6B and CXCL8 in FIG. 6C. FIG. 6B and FIG. 6C confirm that the artificial melanin material disclosed herein downregulates these inflammatory factors. [Figure 7A] 1 shows high surface area synthetic melanin particles (HSA-SMP) (light grey) and low surface area synthetic melanin particles (LSA-SMP) (dark grey / black) characterization according to embodiments herein, N2 adsorption (black markers) and desorption (white markers) and pore size distribution determined using density functional theory (DFT). [Figure 7B] Figure 1 shows high surface area synthetic melanin particles (HSA-SMP) (light grey) and low surface area synthetic melanin particles (LSA-SMP) (dark grey / black) characterization according to embodiments herein. Figure 2 shows N2 adsorption (black markers) and desorption (white markers) and pore size distribution determined using density functional theory (DFT). Figure 3 shows pore size distribution of HSA-LSA determined using density functional theory (DFT). [Figure 7C] 1 shows high surface area synthetic melanin particles (HSA-SMP) (light grey) and low surface area synthetic melanin particles (LSA-SMP) (dark grey / black) characterization according to embodiments herein; [Figure 7D] 1 shows high surface area synthetic melanin particles (HSA-SMP) (light grey) and low surface area synthetic melanin particles (LSA-SMP) (dark grey / black) characterization according to embodiments herein. FIG. 2 shows UV-Vis spectroscopy. [Figure 8A] FIG. 1 shows the DPPH radical scavenging activity of antioxidants for high surface area synthetic melanin particles (HSA-SMP) (black markers) and low surface area synthetic melanin particles (LSA-SMP) (white markers) according to embodiments herein. [Figure 8B] FIG. 1 shows the DPPH radical scavenging activity of antioxidants of high surface area synthetic melanin particles (HSA-SMP) (black marker) and low surface area synthetic melanin particles (LSA-SMP) (white marker) according to embodiments herein. FIG. 2 shows the scavenging activity cycle. DPPH assay was performed on the particles (cycle 1) and later washed with water. The particles were left in water for one week and the DPPH assay was performed again (cycle 2). [Figure 9A] FIG. 1 shows that synthetic melanin particle treatment improves skin healing after ultraviolet (UV) injury. UV wound injury images of mouse skin on days 1-5 for vehicle, LSA SMP, and HSA SMP. [Figure 9B] Synthetic melanin particle treatment improves skin healing after ultraviolet (UV) injury. Wound area reduction. n=4-5 mice per group; *p<0.05; ***p<0.005; ***p<0.0005. [Figure 9C] Synthetic melanin particle treatment improves skin healing after ultraviolet (UV) injury. Shown are % skin thickness for UV vs. vehicle (circles), LSA SMP (squares), and HSA SMP (triangles). n=4-5 mice per group; *p<0.05; ***p<0.005; ***p<0.0005. [Figure 10A] Figure 1 shows, in an embodiment, that SMP treatment does not regulate catalase and thioredoxin activity following nitrogen mustard (NM)-induced injury.Figure 2 shows thioredoxin reductase activity. [Figure 10B] Figure 1 shows that in an embodiment, SMP treatment does not regulate catalase and thioredoxin activity following nitrogen mustard (NM)-induced injury. Figure 2 shows catalase activity. n=4-10 mice per group. [Figure 11-1] TaqMan mouse immune array results. *p<0.05 [Figure 11-2] TaqMan mouse immune array results. *p<0.05 [Figure 11-3] TaqMan mouse immune array results. *p<0.05 DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] [Description of chemical compounds and nomenclature]

[0025] Generally, the terms and phrases used herein have their art-recognized meanings, which can be found by reference to standard textbooks, journal references, and contexts known to those of ordinary skill in the art. The following definitions are provided to clarify their specific use in the context of the present invention.

[0014]

[0026] The term "damaged skin" refers to an area of ​​skin of a living subject, the area including damaged skin tissue. The damaged skin may optionally include free radical species, including extracellular free radical species. The damaged skin may optionally include inflammation. The damaged skin may optionally be a closed wound. The damaged skin may optionally include a stratum corneum. The damaged skin may optionally include one or more visible blisters, microscopic vesicles, and separation of the epidermis from the dermis. The damaged skin may optionally include thermally induced damage, chemically induced damage, UV induced damage, mechanical friction damage, infected cellulitis induced damage, and / or radiation induced damage.

[0015]

[0027] The term "closed wound" is intended to be consistent with the terminology of the technical field, particularly the field of biomedical science, and generally refers to a wound to which a remnant of surface skin is attached. Generally, a closed wound may, but does not necessarily, optionally include one or more small openings and / or compromised lesion areas while having a remnant of surface skin attached. For example, a lesion formed by excision biopsy of skin generally can be characterized as an open wound rather than a closed wound. For example, an open ulcer bed can be characterized as an open wound rather than a closed wound.

[0016]

[0028] The term "therapeutic extracellular activity" refers to a therapeutic activity or function that occurs outside the cell and / or involves at least one extracellular species that directly exerts or is directly involved in the activity. The term "therapeutic extracellular activity" is intended to be understood by those skilled in the art of biomedical science. For example, therapeutic extracellular activity may refer to the extracellular melanin material exerting or participating in a therapeutic activity. For example, therapeutic extracellular activity may refer to an extracellular species affecting a therapeutic effect. For example, therapeutic extracellular activity may refer to the extracellular melanin material exerting or participating in a therapeutic activity on or with extracellular species such as, but not limited to, extracellular free radical species, extracellular inflammatory factor(s), and / or extracellular enzymatic factor(s). A therapeutic activity or function is an activity or function that has a therapeutic or pharmacological effect or benefit, such as for the treatment or amelioration of an injury, wound, tissue damage, disease, pathology, or condition. The therapeutic activity or function may include one or more chemical and / or physical processes such as one or more chemical reactions or transformations, one or more physical transformations, covalent or non-covalent associations or interactions between species, adsorption, etc., and the therapeutic activity may include, but is not limited to, processes such as quenching or trapping, adsorption, regulation such as downregulation of gene expression, inhibition of activity or function of one or more species, such as, but not limited to, proteins, enzymes, or gene expression factors, and any combination thereof. The term "therapeutic intracellular activity" refers to a therapeutic activity or function that occurs within a cell and / or involves at least one intracellular species that directly exerts or is directly involved in the activity. The therapeutic activity or function may, for example, involve both extracellular and intracellular species, or if they do, may optionally be both therapeutic extracellular activity and therapeutic intracellular activity.

[0017]

[0029] The term "inflammatory factors" refers to factors associated with inflammation, as the term is recognized in the art, particularly in biomedical sciences. Inflammatory factors may include, but are not limited to, proteins, genes, enzymes, and / or other factors associated with inflammation. The term "enzymatic factors" refers to factors associated with enzymatic activity, optionally including enzymes associated with inflammation, as the term is recognized in the art, particularly in biomedical sciences. Inflammatory and / or enzymatic factors may include, but are not limited to, TNFα, iNOS, MMP9, ERK1 / 2, p38, JNK, one or more factors associated with downregulation of pro-inflammatory signaling, one or more factors controlling the expression of one or more genes associated with inflammation, one or more factors controlling the expression of one or more genes associated with apoptosis, one or more factors controlling the expression of MMP9, one or more proteins associated with the MAPK / ERK pathway, one or more enzymes associated with the MAPK / ERK pathway, or any combination thereof. The term "apoptotic factor" refers to a factor associated with cellular apoptosis, as the term is recognized in the art, particularly in the biomedical sciences.

[0018]

[0030] The term "wound" refers to an area of ​​a living subject having damaged tissue. The wound may optionally include free radical species, including extracellular free radical species. The wound may optionally include inflammation. The wound is optionally a wound of skin tissue or optionally includes damaged skin tissue. The wound may optionally include a stratum corneum. The wound may optionally include one or more blisters. The wound or damaged tissue thereof may optionally include thermally induced damage, chemically induced damage, UV induced damage, mechanical friction damage, infected cellulitis induced damage, and / or radiation induced damage.

[0019]

[0031] The term "free radical species" is intended to be consistent with the term as recognized by those skilled in the art of chemistry or biochemistry. Free radical species are generally molecular species capable of independent existence and containing one or more unpaired electrons. Free radical species may include those that are mutagenic, carcinogenic, cause the production of DNA strand breaks, and / or create DNA-protein crosslinks. Exemplary free radical species include, but are not limited to, reactive oxygen species such as reactive oxygen species (ROS).

[0020]

[0032] The terms "quench" and "scavenging" are used interchangeably herein and refer to the process of quenching or scavenging a free radical species consistent with the technical fields of chemistry or biochemistry. In general, quenching refers to a process or reaction with or involving a free radical species that results in the conversion / transformation of the free radical species into one or more products that are not the free radical species as a result of the reaction, or otherwise cessation of the existence of the free radical species.

[0021]

[0033] The term "non-melanin therapeutic agent" refers to a therapeutic agent that is not a melanin material and does not itself contain melanin material. A therapeutic agent may be, for example, a species such as a compound, molecule, or moiety that is therapeutically or pharma- ceutical active when exposed to a living subject, or that can treat or address a condition, such as a disease, in a living subject. For example, a therapeutic agent may be or include a small molecule drug, polymer, peptide, amino acid, DNA, or RNA. Optionally, for example, a therapeutic agent is one or more therapeutic agents (such as one or more compounds, molecules, or moieties) that can promote skin healing.

[0022]

[0034] The term "extracellular" when describing a species or process is intended to be consistent with the technical fields of pharmacology or biochemistry and refers to the described species or process being found or occurring outside of a cell (i.e., not within a cell).

[0023]

[0035] The term "subject" or "patient" refers to a living organism suffering from or having a wound, disease, or condition that can be at least partially treated or remedied by administration of a formulation or melanin material as described herein. Non-limiting examples include humans, other mammals, cows, rats, mice, dogs, monkeys, goats, sheep, cattle, deer, and other non-mammalian animals. In some embodiments, such as some of aspects 1-61, the subject is a human. In some embodiments, such as some of aspects 1-61, the subject is a mammal. In some embodiments, such as some of aspects 1-61, the subject is a mouse. In some embodiments, such as some of aspects 1-61, the subject is a laboratory animal. In some embodiments, such as some of aspects 1-61, the subject is a rat. In some embodiments, such as some of aspects 1-61, the subject is a test animal.

[0024]

[0036] The term "melanin" generally refers to one or more compounds or materials that function as pigments, such as when internalized or incorporated into a living cell. It should also be noted that melanin is not necessarily incorporated into a cell. Melanin can be incorporated into or on the cell wall of a fungus, such as to provide rigidity, defense mechanisms, and more. In another illustrative example, melanin is used by birds, such as when melanin is organized in a matrix of keratin or similar types of biomaterial, where it can be organized into monolayers or multilayers to provide structural color, warmth, and more. A melanin compound or material can be, for example, but is not limited to, melanin monomers, melanin oligomers, melanin polymers, melanin nanoparticles, melanin layers (e.g., melanin lamellae or coatings), or other melanin materials. For example, melanin nanoparticles internalized into a living cell function as pigments within the cell.

[0025]

[0037] The terms "artificial melanin" and "synthetic melanin" are used interchangeably herein and refer to one or more melanin compounds, molecules, or materials, such as melanin monomers, melanin oligomers, or melanin nanoparticles, that are synthetic and are not derived or extracted, at least in part, or preferably in whole, from a natural source, such as a biological source, a living organism, or a once living organism. The terms "synthetic" and "artificial" are used interchangeably herein when referring to melanin or materials that include melanin. The terms "synthetic melanin nanoparticles" and "artificial melanin nanoparticles" are used interchangeably herein and are intended to have the same meaning throughout this disclosure and refer to nanoparticles formed of artificial melanin, such as artificial melanin monomers and / or artificial melanin oligomers. The terms "synthetic melanin film" and "artificial melanin film" are used interchangeably herein and are intended to have the same meaning throughout this disclosure and refer to a film formed of artificial melanin, such as artificial melanin monomers and / or artificial melanin oligomers. The terms "synthetic melanin layer" and "artificial melanin layer" are used interchangeably herein and are intended to have the same meaning throughout this disclosure and refer to a layer formed of artificial melanin, such as artificial melanin monomer and / or artificial melanin oligomer. The artificial melanin nanoparticles, artificial melanin thin film, artificial melanin layer, and any compound, material, or preparation comprising any of these, comprise artificial melanin monomer, artificial melanin oligomer, and / or artificial melanin polymer. Optionally, the artificial melanin nanoparticles, artificial melanin thin film, artificial melanin layer, and any compound, material, or preparation comprising any of these, comprise artificial melanin monomer, artificial melanin oligomer, and / or artificial melanin polymer, or consist essentially of artificial melanin, such as artificial melanin monomer, artificial melanin oligomer, and / or artificial melanin polymer. Optionally, the artificial melanin nanoparticles, artificial melanin thin film, artificial melanin layer, and any compound, material, or preparation comprising any of these, comprise artificial melanin free (or substantially free) of artificial melanin monomer, and comprise artificial melanin oligomer and / or artificial melanin polymer.Preferably, each artificial melanin monomer, artificial melanin oligomer, and artificial melanin polymer of the artificial melanin nanoparticles, artificial melanin thin film, artificial melanin layer, and any compound, material, or formulation containing any of them, is not bound to, conjugated to, attached to, coated by, enclosed by, or otherwise chemically associated with natural or biological proteinaceous lipids. Natural or biological proteinaceous lipids refer to lipids that are naturally derived or biologically derived or extracted from natural or biological sources, such as from a once living organism, and the lipids contain one or more proteins, such as the lipid (plasma) membrane of melanocytes or melanosomes. Optionally, each artificial melanin monomer, artificial melanin oligomer, and artificial melanin polymer of the artificial melanin nanoparticles, artificial melanin film, artificial melanin layer, and any compound, material, or formulation comprising any of these, is not bound to, conjugated to, attached to, coated by, encapsulated by, or otherwise chemically associated with natural or biological lipids (e.g., lipid bilayers, lipid membranes, or phospholipid compounds). Natural or biological lipids refer to lipids derived from natural or biological sources, such as lipids derived from nature or from biologically derived organisms or lipids extracted from natural or biological sources, such as once living organisms. Optionally, each artificial melanin monomer, artificial melanin oligomer, and artificial melanin polymer of the artificial melanin nanoparticles, artificial melanin film, artificial melanin layer, and any compound, material, or formulation comprising any of these, is bound to, conjugated to, attached to, coated by, encapsulated by, and / or otherwise associated with synthetic or artificial lipids or synthetic or artificial phospholipids. Synthetic or artificial lipids refer to lipids that are synthesized and not derived or extracted from natural or biological sources, such as former living organisms.

[0026]

[0038] The term "artificial melanin precursor" refers to a compound or material that can form an artificial melanin material after chemical reaction, such as after chemical reaction with an oxidizing agent. An artificial melanin precursor can be, but is not necessarily, a melanin itself. For example, an artificial melanin precursor can be, but is not necessarily, a melanin monomer. For example, contacting an artificial melanin precursor, such as a melanin monomer, with an oxidizing agent can result in oxidative oligomerization (or polymerization) between the artificial melanin precursors, thereby forming an artificial melanin material(s).

[0027]

[0039] The term "selenomelanin" refers to melanin that includes selenium. For example, a selenomelanin material includes selenium. Preferably, the chemical formula of the selenomelanin material includes selenium (e.g., at least one selenium atom).

[0028]

[0040] In certain embodiments, the term "pheomelanin" refers to melanins whose chemical formula includes at least one substituted or unsubstituted benzothiazine, at least one substituted or unsubstituted benzothiazole, at least one substituted or unsubstituted benzoselenazole, at least one substituted or unsubstituted benzoselenazine, at least one derivative of any of these, or any combination thereof. In certain embodiments, the term pheomelanin refers to melanins made from L-DOPA and cysteine ​​whose chemical formula includes at least one substituted or unsubstituted benzothiazine, at least one substituted or unsubstituted benzothiazole, at least one substituted or unsubstituted benzoselenazole, at least one substituted or unsubstituted benzoselenazine, at least one derivative of any of these, or any combination thereof. In certain embodiments, selenium pheomelanin refers to melanins whose chemical formula includes at least one substituted or unsubstituted benzoselenazole, at least one substituted or unsubstituted benzoselenazine, at least one derivative of any of these, or any combination thereof.

[0029]

[0041] In certain embodiments, the term eumelanin refers to a melanin whose chemical formula includes at least one dihydroxyindole (DHI) (e.g., 5,6-dihydroxyindole), at least one dihydroxyindole-2-carboxylic acid (DHICA) (e.g., 5,6-dihydroxyindole-2-carboxylic acid), or a combination thereof.

[0030]

[0042] As used herein, the term "nanoparticle" refers to a physical particle having at least one size characteristic or physical dimension less than 1 μm. Preferably, as used herein, the term "nanoparticle" refers to a physical particle having a longest size characteristic or physical dimension less than 1 μm.

[0031]

[0043] The term "size characteristic" refers to a property or set of properties of a particle that is directly or indirectly related to a size attribute. According to some embodiments, the size characteristic corresponds to an empirically derived size characteristic of the particle(s) detected, such as a size characteristic based on, determined by, or corresponding to data from any technique or device that can be used to determine particle size, such as electron microscopy (e.g., SEM and TEM) or light scattering (e.g., DLS). For example, the size characteristic may correspond to a spherical particle that exhibits similar or substantially the same properties, such as aerodynamic, hydrodynamic, optical, and / or electrical properties, when the particle(s) is detected. According to some embodiments, the size characteristic corresponds to a physical dimension, such as a cross-sectional size (e.g., length, width, thickness, or diameter).

[0032]

[0044] The term "particle" refers to small solid objects that can be dispersed and / or suspended in a fluid (e.g., a liquid). For example, slurries, dispersions, and suspensions each contain particles in a fluid. The terms "particle" and "particulate" are sometimes used interchangeably. An exemplary particle is an artificial melanin nanoparticle. Multiple particles may associate with each other to form particle agglomerates. In general, the term "particle", such as "nanoparticle" or "melanin nanoparticle", refers to individual particles rather than agglomerates of such individual particles.

[0033]

[0045] The term "dispersed" refers to species such as particles in a fluid that form a dispersion. As used herein, the term "dispersion" refers broadly to a mixture of one or more chemical species such as particles in a fluid, as in the art-recognized meanings of solution, dispersion, and / or suspension. Chemical species such as particles dispersed in a dispersion may be referred to as dispersed species. Preferably, a dispersion is a mixture of particles such as artificial melanin particles in a liquid such as a solvent. Preferably, but not necessarily, a dispersion is a homogeneous mixture. In the context of a dispersion, the term "homogeneous" refers to a liquid mixture that appears uniform to the naked eye. In contrast, a heterogeneous liquid mixture includes particles that have precipitated from or are suspended in the liquid mixture and are large enough to be clearly visible in the liquid mixture by the naked eye. A heterogeneous liquid mixture includes, for example, particles that have settled and / or are settling. Preferably, but not necessarily, the term "dispersion" is intended broadly to include dispersions such as solutions and colloids that are not heterogeneous liquid mixtures. Preferably, but not necessarily, a dispersion is a microscopically homogeneous or uniform mixture of particles in a liquid, such as a solvent. Preferably, but not necessarily, a dispersion is thermodynamically favored to remain stably dispersed or to separate by settling, but settling is kinetically slowed or prevented. Particles of a dispersion characterized as stably dispersed remain dispersed in the dispersion and do not settle or precipitate from the liquid of the dispersion under ambient temperature and pressure (NTP) and air exposure for at least 5 hours, preferably at least 12 hours, preferably at least 24 hours, more preferably at least 1 week. In an embodiment, particles that are not dispersed or cannot be dispersed in a fluid refer to particles that form a sediment or precipitate when mixed in the fluid.

[0034]

[0046] When referring to a material, such as a polymer, that is aqueous, the term "aqueous" refers to said material being dispersed, dissolved, or otherwise solvated by water. An "aqueous solution" refers to a solution that includes water as a solvent and one or more solute species that are dispersed, dissolved, or otherwise solvated by water. An aqueous process, such as polymerization, is a process that occurs in an aqueous solution. Optionally, but not necessarily, an aqueous solution or aqueous solvent includes no more than 20 vol.%, optionally no more than 15 vol.%, optionally no more than 10 vol.%, and preferably no more than 5 vol.% of non-aqueous or organic species. Optionally, but not necessarily, an aqueous solution or aqueous solvent includes no more than 20 vol.%, optionally no more than 15 vol.%, optionally no more than 10 vol.%, and preferably no more than 5 vol.% of non-aqueous liquids.

[0035]

[0047] The term "peak size" refers to the statistical mode, or peak frequency, of a particle size distribution, or the particle size most commonly found in the particle size distribution. Particle size distributions can be measured, for example, using dynamic light scattering.

[0036]

[0048] The term "sphere" as used herein refers in its usual and customary sense to a round or substantially round geometric object in three-dimensional space, which is essentially the surface of a perfectly round ball, similar to a circular object in two dimensions. A sphere can be mathematically defined as a set of points in three-dimensional space that are all or substantially all at the same distance r from a given point, where r is the radius of the mathematical ball, and the given point is the center or substantially the center of the mathematical ball. In an embodiment, the longest straight line through the ball that connects two points of the sphere passes through the center, and therefore its length is twice the radius; it is the diameter of the ball. A nanosphere is a nanoparticle with a radius of less than 1 μm.

[0037]

[0049] The terms "reactive oxygen species" and "ROS" are used interchangeably herein in their ordinary and customary sense to refer to transient species typically formed during exposure to radiation (e.g., UV irradiation) that are capable of inducing oxidative degradation.

[0038]

[0050] The terms "cell" and "biological cell" are used interchangeably and refer to a cell that performs metabolic or other functions sufficient to preserve or replicate its genomic DNA. A cell can be identified by methods well known in the art, including, for example, the presence of an intact membrane, staining with a particular dye, and the ability to produce progeny or, in the case of gametes, to combine with a second gamete to produce viable progeny. Cells may include prokaryotic and eukaryotic cells. Prokaryotic cells include, but are not limited to, bacteria. Eukaryotic cells include, but are not limited to, yeast cells and cells derived from plants and animals, such as mammalian, insect (e.g., Spodoptera) and human cells. A "living cell" is a living biological cell.

[0039]

[0051] The term "substantially" refers to a property, condition, or value that is within 20%, 10%, 5%, 1%, optionally within 0.1%, or equivalent to a reference property, condition, or value. The terms "substantially equal," "substantially equivalent," or "substantially unchanged," when used in conjunction with a reference value describing a property or condition, refer to a value that is within 20%, 10%, optionally within 5%, optionally within 1%, optionally within 0.1%, or optionally equivalent to the described reference value. For example, a diameter is substantially equal to 100 nm (or "is substantially 100 nm") if the diameter value is within 20%, optionally within 10%, optionally within 5%, optionally within 1%, 0.1%, or optionally equal to 100 nm. The term "substantially greater than," when used in conjunction with a reference value describing a property or condition, refers to a value that is at least 1%, optionally at least 5%, optionally at least 10%, or optionally at least 20% greater than the reference value described. The term "substantially less than," when used in conjunction with a reference value describing a property or condition, refers to a value that is at least 1%, optionally at least 5%, optionally at least 10%, or optionally at least 20% less than the reference value described.

[0040]

[0052] As used herein, the term "about" refers to a range of values ​​that includes the specified value that a person skilled in the art would consider to be fairly close to the specified value. In an embodiment, about refers to within a standard deviation using measurements generally accepted in the art. In an embodiment, about refers to a range that extends to + / - 10% of the specified value. In an embodiment, about refers to the specified value.

[0041]

[0053] The term "treat" or "treatment" as used herein refers to any evidence of success in treating or ameliorating an injury, disease, condition, or disease, including any objective or subjective parameter, such as remission; sedation; attenuation of symptoms or making the injury, condition, or state more tolerable to the patient; slowing the rate of degeneration or decline; making the end point of degeneration less debilitating; improving the physical or mental health of the patient. The treatment or amelioration of symptoms can be based on objective or subjective parameters, including the results of a physical exam, neuropsychiatric exam, and / or psychiatric evaluation. The term "treat" and its conjugations include prevention of injury, condition, or disease.

[0042]

[0054] The term "effective amount" as used herein refers to an amount sufficient to achieve a stated purpose (e.g., to obtain the effect for which it is administered, to treat a disease, to alleviate one or more symptoms of a disease or condition, etc.). An example of an "effective amount" is an amount sufficient to contribute to the treatment, prevention, or alleviation of one or more symptoms of a disease, which may also be referred to as a "therapeutically effective amount". "Alleviation" of one or more symptoms (and grammatical equivalents of this phrase) means a reduction in the severity or frequency of the symptom(s), or the elimination of the symptom(s). A "prophylactically effective amount" of a drug is an amount of a drug that, when administered to a subject, will have a desired prophylactic effect, such as preventing or delaying the onset (or recurrence) of an injury, disease, pathology, or condition, or reducing the likelihood of the onset (or recurrence) of an injury, disease, pathology, or condition, or a symptom thereof. A complete prophylactic effect does not necessarily occur by administration of a single dose, but may occur only after administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. The exact amount will depend on the purpose of the treatment and will be ascertainable by one of skill in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (Vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th ed., 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0043]

[0055] The term "administering" as used herein refers to oral administration, administration as an inhaled aerosol or inhaled dry powder, suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal or subcutaneous administration to a subject, or implantation of a sustained release device, such as a mini-osmotic pump. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarteriolar, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, and the like. By "co-administering" it is meant that the compositions described herein are administered simultaneously with, immediately before, or immediately after the administration of one or more additional therapies, such as cancer therapies, such as chemotherapy, hormonal therapy, radiation therapy, or immunotherapy. The compounds of the present invention can be administered alone or co-administered to a patient. Co-administration is intended to include simultaneous or sequential administration of compounds (more than one compound or agent) individually or in combination. The compositions of the present invention can be delivered by topical routes, transdermally, and can be formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, liniments, powders, and aerosols. Oral preparations include tablets, pills, powders, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, and the like, suitable for ingestion by the patient. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. Liquid form preparations include solutions, suspensions, and emulsions, e.g., water or water / propylene glycol solutions. The compositions of the present invention may additionally include components to provide sustained release and / or comfort. Such components include high molecular weight anionic mucomimetic polymers, gelling polysaccharides, and finely divided drug carrier substrates. These components are discussed in more detail in U.S. Patent Nos. 4,911,920, 5,403,841, 5,212,162, and 4,861,760, the entire contents of which are incorporated herein by reference in their entirety for all purposes.The compositions of the invention can also be delivered as microspheres for sustained release in the body. For example, microspheres can be administered via intradermal injection of drug-containing microspheres for slow subcutaneous release (see Rao, J Biomater Sci. Polym. Ed. 7:623-645, 1995), as biodegradable, injectable gel formulations (see, e.g., Gao Pharm. Res. 12:857-863, 1995), or as microspheres for oral administration (see, e.g., Eyles, J Pharm. Pharmacol. 49:669-674, 1997). In another embodiment, formulations of the compositions of the invention can be delivered by the use of liposomes that fuse with cell membranes or are endocytosed, i.e., by using receptor ligands attached to the liposomes that bind to surface membrane protein receptors of the cells, resulting in endocytosis. Liposomes can be used to deliver in vivo, particularly if the liposome surface bears receptor ligands specific to target cells or is otherwise preferentially directed to a particular organ. Delivery of the compositions of the invention into target cells in vivo can be focused (see, e.g., Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Qstio, Am. J Hasp. Pharm. 46:1576-1587, 1989).

[0044]

[0056] The term "contacting" may include reacting, interacting, or physically contacting two species, where the two species may be, for example, a pharmaceutical composition as described herein and a cell. In embodiments, contacting includes, for example, interacting a pharmaceutical composition as described herein with a cell or a patient.

[0045]

[0057] The terms "analog" and "analogue" are used interchangeably and according to their obvious ordinary meaning within chemistry and biology to refer to a chemical compound that is structurally similar to another compound (i.e., a so-called "reference" compound) but differs in composition, e.g., the replacement of certain atoms by atoms of different elements, or the presence of certain functional groups, or the replacement of certain functional groups by other functional groups, or the absolute stereochemistry of one or more chiral centers of the reference compound, including isomers thereof. Thus, an analogue is a compound that is similar or equivalent in function and appearance to the reference compound, but not similar or equivalent in structure or origin.

[0046]

[0058] Unless otherwise specified, the term "molecular weight" refers to average molecular weight. Unless otherwise specified, the term "average molecular weight" refers to number average molecular weight. Number average molecular weight is defined as the total weight of the sample volume divided by the number of molecules in the sample. As is customary and well known in the art, peak average molecular weight and weight average molecular weight may be used to characterize the molecular weight of a distribution of polymers within a sample.

[0047]

[0059] The term "weight average molecular weight" (M w ) is the molecular weight of each polymer molecule (M i ) with its weight fraction (w i ) multiplied by M w =Σw i M i As is customary and well known in the art, peak average molecular weight and number average molecular weight may be used to characterize the molecular weight of a distribution of polymers within a sample.

[0048]

[0060] The term "wt.%" or "wt%" refers to weight percent or mass fraction expressed as mass percentage. The term "at.%" or "at%" refers to atomic percentage or atomic ratio expressed as the percentage of one type of atom relative to the total atoms in a given substance such as a molecule, compound, material, nanoparticle, polymer, dispersion, etc.

[0049]

[0061] The term "oligomerization" refers to a chemical process that converts a monomer or a mixture of monomers into an oligomer. The term "oxidative oligomerization" refers to a chemical process of oligomerization that involves the chemical oxidation of one or more monomers to form an oligomer. Oligomerization is a polymerization process in which oligomers are formed as a result of polymerization.

[0050]

[0062] As used herein, the term "polymer" refers to a molecule composed of repeating structural units connected by covalent chemical bonds, often characterized by several repeating units (e.g., two or more base units) also called base units. As used herein, the term "polymer" includes "oligomer" (i.e., an oligomer is a polymer; i.e., a polymer is optionally an oligomer). "Oligomer" refers to a molecule composed of repeating structural units, also called base units, connected by covalent chemical bonds, often characterized by fewer repeating units, such that an oligomer is a low molecular weight polymer. Preferably, but not necessarily, for example, an oligomer has 100 or fewer repeating units. Preferably, but not necessarily, for example, an oligomer has a lower molecular weight of 10,000 Da or less. An oligomer may be the polymerization product of one or more monomer precursors. The polymerization of one or more monomers or monomer precursors resulting in the formation of an oligomer may be referred to as oligomerization. An oligomer optionally comprises 100 or less, 50 or less, 15 or less, 12 or less, 10 or less, or 5 or less repeat units (or "basic units"). An oligomer may be characterized as having a molecular weight of 10,000 Da or less, 5,000 Da or less, 1,000 Da or less, 500 Da or less, or 200 Da or less. A dimer, trimer, tetramer, or pentamer is an oligomer having 2, 3, 4, or 5 repeat units or basic units, respectively. A polymer may have, for example, more than 100 repeat units. A polymer may have a high molecular weight, for example, more than 10,000 Da, in some embodiments 50,000 Da or more, or 100,000 Da or more. The term polymer includes homopolymers, or polymers consisting essentially of a single repeating monomer subunit. The term polymer also includes copolymers, which are formed when two or more different types of monomers are linked within the same polymer. Copolymers may contain two or more types of monomer subunits, including random, block, brush, brush block, alternating, segmented, grafted, tapered and other structures.Useful polymers include organic or inorganic polymers that may be in an amorphous, semi-amorphous, crystalline or semi-crystalline state. Polymer side chains capable of crosslinking (e.g., physically crosslinking) the polymer may be useful for some applications.

[0051]

[0063] "Oligomer" refers to a molecule composed of repeating structural units, also called base units, connected by covalent chemical bonds, often characterized by fewer repeat units than those of a polymer (e.g., 100 or fewer repeat units) and a lower molecular weight than a polymer (e.g., 10,000 Da or less). An oligomer may be the polymerization product of one or more monomer precursors. The polymerization of one or more monomers or monomer precursors resulting in the formation of an oligomer may be referred to as oligomerization. An oligomer optionally contains 100 or fewer, 50 or fewer, 15 or fewer, 12 or fewer, 10 or fewer, or 5 or fewer repeat units (or "base units"). An oligomer may be characterized as having a molecular weight of 10,000 Da or less, 5,000 Da or less, 1,000 Da or less, 500 Da or less, or 200 Da or less. A dimer, trimer, tetramer, or pentamer is an oligomer having two, three, four, or five repeating units, or base units, respectively.

[0052]

[0064] As used herein, the term "group" may refer to a functional group of a chemical compound. A group of the compound refers to an atom or a collection of atoms that is part of the compound. The groups of the present invention may be attached to other atoms of the compound through one or more covalent bonds. Groups may also be characterized in terms of their valence state. The present invention includes groups that are characterized as monovalent, divalent, trivalent, etc.

[0053]

[0065] The term "moiety" refers to a group, such as a functional group, of a chemical compound or molecule. A moiety is a collection of atoms that is part of a chemical compound or molecule. The present invention includes moieties that are characterized as being monovalent, divalent, trivalent, etc., in terms of their valence state. Generally, but not necessarily, a moiety contains more than one functional group.

[0054]

[0066] As used herein, the term "substituted" refers to a compound in which one or more hydrogens have been replaced with another functional group, provided that the normal valence of the designated atom is not exceeded. Exemplary substituents include, but are not limited to, halogen or halide, alkyl, cycloalkyl, aryl, heteroaryl, acyl, alkoxy, alkenyl, alkynyl, alkylaryl, arylene, heteroarylene, alkenylene, cycloalkenylene, alkynylene, hydroxyl (-OH), carbonyl (RCOR'), sulfide (e.g., RSR'), phosphate (ROP(=O)(OH)2), azo (RNNR'), cyanate (ROCN), amine (e.g., primary, secondary, or tertiary), imine (RC(=NH)R'), nitrile (RCN), pyridinyl (or pyridyl), diamine, triamine, azide, diimine, triimine, amide, diimide, or ether (ROR') (wherein each of R and R' is independently hydrogen or a substituted or unsubstituted alkyl group, aryl group, alkenyl group, or combination thereof). Optionally substituted functional groups are similarly described below. In some embodiments, such as some of aspects 1-61, the term substituted refers to a compound in which each of more than one hydrogen is replaced by another functional group, such as a halogen group. For example, when a substituent is oxo (i.e., =O), two hydrogens on the atom are replaced. The substituent can be any of the substituents described herein. For example, the substituent can include one or more of hydroxyl, amino (e.g., primary, secondary, or tertiary), aldehyde, carboxylic acid, ester, amide, ketone, nitro, urea, guanidine, cyano, fluoroalkyl (e.g., trifluoromethane), halo (e.g., fluoro), aryl (e.g., phenyl), heterocyclyl or heterocyclic groups (i.e., cyclic groups, e.g., aromatic (e.g., heteroaryl) or non-aromatic, with one or more heteroatoms), oxo, or combinations thereof. Combinations of substituents and / or variables are permissible provided that the substitutions do not significantly adversely affect the synthesis or use of the compound.

[0055]

[0067] As used herein, the term "derivative" refers to any of the following: hydrogen, halogen or halide, alkyl, cycloalkyl, aryl, heteroaryl, acyl, alkoxy, alkenyl, alkynyl, alkylaryl, arylene, heteroarylene, alkenylene, cycloalkenylene, alkynylene, hydroxyl (-OH), carbonyl (RCOR'), sulfide (e.g., RSR'), phosphate (ROP(=O)(OH)2), azo (RNNR'), cyanate (ROCN), amine (e.g., primary, secondary, or tertiary), imine (RC(=NH)R'), nitrile (RCN), pyridinyl (or pyridyl), diamine, triamine, azide, diimine, triimine, amide, diimide, or ether (ROR') (wherein each of R and R' is independently hydrogen or a substituted or unsubstituted alkyl group, aryl group, alkenyl group, or combination thereof). Optionally, the substituted functional group is also described below. Preferably, the term "derivative" refers to a compound in which one or two atoms or functional groups are independently replaced by another atom or functional group. Optionally, the term derivative does not refer to or include the replacement of a chalcogen atom (S, Se) that is a member of a heterocyclic group. Optionally, unless otherwise stated, the term derivative does not refer to or include replacement of a chalcogen atom (S, Se) or N (nitrogen) when the chalcogen atom and N are members of the same heterocyclic group. Optionally, but not necessarily, the term derivative does not include breaking of the ring structure, replacement of a ring member, or removal of a ring member.

[0056]

[0068] As is customary and well known in the art, hydrogen atoms in formulae are not always explicitly shown, e.g., hydrogen atoms bonded to carbon atoms of aromatic, heteroaromatic, and alicyclic rings are not always explicitly shown. The structures depicted herein, e.g., in the context of the formulae and the illustrations and structures in the figures, are intended to convey to those of skill in the art the chemical composition of the compounds of the methods and compositions of the invention, and as would be understood by one of skill in the art, the depicted structures do not depict the specific positions and / or orientations of the atoms and corresponding bond angles between the atoms of these compounds.

[0057]

[0069] As used herein, the terms "alkylene" and "alkylene group" are used interchangeably and refer to a divalent group derived from an alkyl group as defined herein. The present invention includes compounds having one or more alkylene groups. The alkylene groups of some compounds function as linking and / or spacer groups. The compounds of the present invention may have one or more linking groups (e.g., L 1 ~L 6 ) may be, for example, substituted and / or unsubstituted C1-C 20 Alkylene, C1-C 10 It may contain alkylene and C1 to C5 alkylene groups.

[0058]

[0070] As used herein, the terms "cycloalkylene" and "cycloalkylene group" are used interchangeably and refer to a divalent radical derived from a cycloalkyl group, as defined herein. The present invention includes compounds having one or more cycloalkylene groups. The cycloalkyl groups of some compounds function as linking and / or spacer groups. The compounds of the present invention may have one or more linking groups (e.g., L 1 ~L 6 ) may be, for example, substituted and / or unsubstituted C 20 Cycloalkylene, C3-C 10 It may have a cycloalkylene and a C3 to C5 cycloalkylene group.

[0059]

[0071] As used herein, the terms "arylene" and "arylene group" are used interchangeably and refer to a divalent radical derived from an aryl group as defined herein. The present invention includes compounds having one or more arylene groups. In some embodiments, such as some of aspects 1-61, an arylene is a divalent radical derived from an aryl group by removal of hydrogen atoms from two endocyclic carbon atoms of the aromatic ring of the aryl group. The arylene groups of some compounds function as linking and / or spacer groups. The arylene groups of some compounds function as chromophores, fluorophores, aromatic antennae, dyes and / or imaging groups. The compounds of the present invention include compounds having one or more linking groups (e.g., L 1 ~L 6 ) may be, for example, substituted and / or unsubstituted C 30 Arylene, C3~C 20 Arylene, C3~C 10 Includes arylene and C1-C5 arylene groups.

[0060]

[0072] As used herein, the terms "heteroarylene" and "heteroarylene group" are used interchangeably and refer to a divalent group derived from a heteroaryl group as defined herein. The present invention includes compounds having one or more heteroarylene groups. In certain embodiments, a heteroarylene is a divalent group derived from a heteroaryl group by removal of hydrogen atoms from two endocyclic carbon or nitrogen atoms of the heteroaromatic or aromatic ring of the heteroaryl group. The heteroarylene groups of some compounds function as linking and / or spacer groups. The heteroarylene groups of some compounds function as chromophores, aromatic antennae, fluorophores, dyes and / or imaging groups. The compounds of the present invention include compounds having one or more linking groups (e.g., L 1 ~L 6 ) may be, for example, substituted and / or unsubstituted C 30 Heteroarylene, C3-C 20 Heteroarylene, C1-C 10 Includes heteroarylene and C3-C5 heteroarylene groups.

[0061]

[0073] As used herein, the terms "alkenylene" and "alkenylene group" are used interchangeably and refer to a divalent radical derived from an alkenyl group as defined herein. The present invention includes compounds having one or more alkenylene groups. The alkenylene groups of some compounds function as linking and / or spacer groups. The compounds of the present invention may have one or more linking groups (e.g., L 1 ~L 6 ) may be, for example, substituted and / or unsubstituted C2-C 20 Alkenylene, C2-C 10 Includes alkenylene and C2-C5 alkenylene groups.

[0062]

[0074] As used herein, the terms "cycloalkenylene" and "cycloalkenylene group" are used interchangeably and refer to a divalent radical derived from a cycloalkenyl group as defined herein. The present invention includes compounds having one or more cycloalkenylene groups. The cycloalkenylene groups of some compounds function as linking and / or spacer groups. The compounds of the present invention may also include one or more linking groups (e.g., L 1 ~L 6 ) may be, for example, substituted and / or unsubstituted C 20 Cycloalkenylene, C3-C 10 Includes sylcoalkenylene and C3-C5 sylcoalkenylene groups.

[0063]

[0075] As used herein, the terms "alkynylene" and "alkynylene group" are used interchangeably and refer to a divalent radical derived from an alkynyl group as defined herein. The present invention includes compounds having one or more alkynylene groups. The alkynylene groups of some compounds function as linking and / or spacer groups. The compounds of the present invention may have one or more linking groups (e.g., L 1 ~L 6 ) may be, for example, substituted and / or unsubstituted C2-C 20 Alkynylene, C2-C 10 Includes alkynylene and C2-C5 alkynylene groups.

[0064]

[0076] As used herein, the term "halo" refers to a halogen group such as fluoro (-F), chloro (-Cl), bromo (-Br), iodo (-I) or astat (-At).

[0065]

[0077] The term "heterocyclic" refers to a ring structure that contains at least one other type of atom in addition to carbon in the ring. Examples of such heteroatoms include nitrogen, oxygen, and sulfur. Heterocyclic rings include heteroalicyclic rings and heteroaromatic rings. Examples of heterocyclic rings include, but are not limited to, pyrrolidinyl, piperidyl, imidazolidinyl, tetrahydrofuryl, tetrahydrothienyl, furyl, thienyl, pyridyl, quinolyl, isoquinolyl, pyridazinyl, pyrazinyl, indolyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, pyridinyl, benzoxadiazolyl, benzothiadiazolyl, triazolyl, and tetrazolyl groups. Atoms of the heterocyclic ring can be bonded to a wide range of other atoms and functional groups, for example, other atoms and functional groups provided as substituents.

[0066]

[0078] The term "carbocyclic" refers to a ring structure that contains only carbon atoms in the ring. The carbon atoms of a carbocyclic ring can be bonded to a wide range of other atoms and functional groups, including other atoms and functional groups provided as substituents.

[0067]

[0079] The term "alicyclic ring" refers to a ring or multiple fused rings that is not aromatic. Alicyclic rings include both carbocyclic and heterocyclic rings.

[0068]

[0080] The term "aromatic ring" refers to a ring or multiple fused rings that contain at least one aromatic ring group. The term aromatic ring includes aromatic rings that contain carbon, hydrogen, and heteroatoms. Aromatic rings include carbocyclic and heterocyclic aromatic rings. Aromatic rings are components of aryl groups.

[0069]

[0081] The term "fused ring" or "fused ring structure" refers to multiple alicyclic and / or aromatic rings provided in a fused ring configuration, such as fused rings that share at least two ring carbon atoms and / or heteroatoms.

[0070]

[0082] As used herein, the term "alkoxyalkyl" refers to a substituent of formula alkyl-O-alkyl.

[0071]

[0083] As used herein, the term "polyhydroxyalkyl" refers to a substituent having 2 to 12 carbon atoms and 2 to 5 hydroxyl groups, such as 2,3-dihydroxypropyl, 2,3,4-trihydroxybutyl, or 2,3,4,5-tetrahydroxypentyl residues.

[0072]

[0084] As used herein, the term "polyalkoxyalkyl" refers to a group of the formula alkyl-(alkoxy) n -alkoxy, where n is an integer from 1 to 10, preferably 1 to 4, and more preferably 1 to 3 for some embodiments.

[0073]

[0085] Amino acids include glycine, alanine, valine, leucine, isoleucine, methionine, proline, phenylalanine, tryptophan, asparagine, glutamine, glycine, serine, threonine, serine, threonine, asparagine, glutamine, tyrosine, cysteine, lysine, arginine, histidine, aspartic acid and glutamic acid. As used herein, reference to "side chain residues of natural α-amino acids" specifically includes the side chains of the amino acids referred to above. Peptides and peptide moieties, as used and described herein, include two or more amino acid groups connected via peptide bonds.

[0074]

[0086] Amino acids and amino acid groups refer to naturally occurring amino acids, non-naturally occurring (non-naturally occurring) amino acids, and / or combinations thereof. Naturally occurring amino acids are those encoded by the genetic code, as well as those that are later modified, such as hydroxyproline, γ-carboxyglutamate, and O-phosphorylated serine. Naturally occurring α-amino acids include, but are not limited to, alanine (Ala), cysteine ​​(Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (Ile), arginine (Arg), lysine (Lys), leucine (Leu), methionine (Met), asparagine (Asn), proline (Pro), glutamine (Gln), serine (Ser), threonine (Thr), valine (Val), tryptophan (Trp), tyrosine (Tyr), and combinations thereof. Naturally occurring stereoisomers of α-amino acids include, without limitation, D-alanine (D-Ala), D-cysteine ​​(D-Cys), D-aspartic acid (D-Asp), D-glutamic acid (D-Glu), D-phenylalanine (D-Phe), D-histidine (D-His), D-isoleucine (D-Ile), D-arginine (D-Arg), D-lysine (D-Lys), D-leucine (D-Leu), D-methionine (D-Met), D-asparagine (D-Asn), D-proline (D-Pro), D-glutamine (D-Gln), D-serine (D-Ser), D-threonine (D-Thr), D-valine (D-Val), D-tryptophan (D-Trp), D-tyrosine (D-Tyr), and combinations thereof.

[0075]

[0087] Non-natural (non-naturally occurring) amino acids include, without limitation, amino acid analogs in either the L- or D-configuration, amino acid mimetics, synthetic amino acids, N-substituted glycines, and N-methyl amino acids that function in a manner similar to naturally occurring amino acids. For example, an "amino acid analog" can be a non-natural amino acid that has the same basic chemical structure as a naturally occurring amino acid (i.e., a hydrogen, a carboxyl group, and a carbon attached to an amino group) but has a modified side group or a modified peptide backbone, such as homoserine, norleucine, methionine sulfoxide, or methionine methylsulfonium. An "amino acid mimetic" refers to a chemical compound that has a structure that differs from the general chemical structure of an amino acid, but functions in a manner similar to a naturally occurring amino acid. Amino acids may be referred to herein by either the commonly known three letter symbols or the one letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission.

[0076]

[0088] The terms "monomer unit", "repeating monomer unit", "repeat unit", and "polymerized monomer" may be used interchangeably and may refer to the monomeric portion of the polymer described herein that is derived from or is the product of polymerization of one individual "monomer" or "polymerizable monomer". Each individual monomer unit of a polymer is derived from or is the product of polymerization of one polymerizable monomer. Each individual "monomer unit" or "repeat unit" of a polymer comprises one (polymerized) polymer backbone group. For example, in a polymer comprising monomer units X and Y arranged as XYXYXYXY (where each X is identical to each other and each Y is identical to each other), each X and each Y may be independently referred to as a repeat unit or monomer unit.

[0077]

[0089] Alkyl groups include straight chain, branched and cyclic alkyl groups. Alkyl groups include those having 1-30 carbon atoms. Alkyl groups include small alkyl groups having 1-3 carbon atoms. Alkyl groups include medium length alkyl groups having 4-10 carbon atoms. Alkyl groups include long alkyl groups having more than 10 carbon atoms, especially those having 10-30 carbon atoms. The term cycloalkyl specifically refers to alkyl groups having ring structures such as those having 3-30 carbon atoms, optionally 3-20 carbon atoms, and optionally 2-10 carbon atoms, including alkyl groups having one or more rings. Cycloalkyl groups include those having 3, 4, 5, 6, 7, 8, 9 or 10 carbon membered ring(s), especially those having 3, 4, 5, 6, 7, or 8 ring(s). The carbocyclic rings within the cycloalkyl group can also carry alkyl groups. Cycloalkyl groups can include bicyclic and tricyclic alkyl groups. The alkyl groups are optionally substituted. Substituted alkyl groups include, among others, those substituted with aryl groups, which in turn can be optionally substituted. Particular alkyl groups include methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, n-butyl, s-butyl, t-butyl, cyclobutyl, n-pentyl, branched pentyl, cyclopentyl, n-hexyl, branched hexyl, and cyclohexyl groups, all of which are optionally substituted. Substituted alkyl groups include fully halogenated or semi-halogenated alkyl groups, such as alkyl groups in which one or more hydrogens are replaced with one or more fluorine, chlorine, bromine, and / or iodine atoms. Substituted alkyl groups include fully fluorinated or semi-fluorinated alkyl groups, such as alkyl groups in which one or more hydrogens are replaced with one or more fluorine atoms. Alkoxy groups are alkyl groups modified by linkage with oxygen, which can be represented by the formula RO, and are sometimes referred to as alkyl ether groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, and heptoxy. Alkoxy groups include substituted alkoxy groups in which the alkyl portion of the group is substituted as described herein in connection with the description of alkyl groups.As used herein, MeO- refers to CHO-. The compositions of some embodiments of the present invention include alkyl groups as end groups, such as polymer backbone end groups and / or polymer side chain end groups. Substituted alkyl groups may include substitutions incorporating one or more silyl groups, for example, substitutions in which one or more carbons are replaced by Si.

[0078]

[0090] Alkenyl groups include linear, branched and cyclic alkenyl groups. Alkenyl groups include those having one, two or more double bonds, with at least two of the double bonds being conjugated double bonds. Alkenyl groups include those having 2 to 20 carbon atoms. Alkenyl groups include small alkenyl groups having 2 to 3 carbon atoms. Alkenyl groups include medium length alkenyl groups having 4 to 10 carbon atoms. Alkenyl groups include long alkenyl groups having more than 10 carbon atoms, especially those having 10 to 20 carbon atoms. Cycloalkenyl groups include those in which the double bond is within the ring or within an alkenyl group attached to the ring. The term cycloalkenyl specifically refers to alkenyl groups having ring structures, including alkenyl groups having (one or more) 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-membered carbon ring(s), especially those having (one or more) 3-, 4-, 5-, 6- or 7-membered ring(s). The carbocycles within the cycloalkenyl group can also carry alkyl groups. Cycloalkenyl groups can include bicyclic and tricyclic alkenyl groups. Alkenyl groups are optionally substituted. Substituted alkenyl groups include, among others, those substituted with alkyl or aryl groups, which in turn can be optionally substituted. Particular alkenyl groups include ethenyl, prop-1-enyl, prop-2-enyl, cycloprop-1-enyl, but-1-enyl, but-2-enyl, cyclobut-1-enyl, cyclobut-2-enyl, pent-1-enyl, pent-2-enyl, branched pentenyl, cyclopent-1-enyl, hex-1-enyl, branched hexenyl, cyclohexenyl, all of which are optionally substituted. Substituted alkenyl groups include fully halogenated or semi-halogenated alkenyl groups, such as alkenyl groups in which one or more hydrogens are replaced with one or more fluorine, chlorine, bromine and / or iodine atoms. Substituted alkenyl groups include fully fluorinated or semi-fluorinated alkenyl groups, such as alkenyl groups in which one or more hydrogen atoms are replaced with one or more fluorine atoms. The compositions of some embodiments of the present invention include alkenyl groups as end groups, such as polymer backbone end groups and / or polymer side chain end groups.

[0079]

[0091] Aryl groups include groups having one or more 5-, 6-, 7-, or 8-membered aromatic rings, including heteroaromatic rings. The term heteroaryl specifically refers to aryl groups having at least one 5-, 6-, 7-, or 8-membered heteroaromatic ring. Aryl groups can include one or more fused aromatic rings, including one or more fused heteroaromatic rings, and / or combinations of one or more aromatic rings and one or more non-aromatic rings that can be fused or linked via covalent bonds. Heteroaromatic rings can include one or more N, O, or S atoms in the ring. Heteroaromatic rings can include those with one, two, or three N atoms, those with one or two O atoms, and those with one or two S atoms, or combinations of one, two, or three N, O, or S atoms. Aryl groups are optionally substituted. Substituted aryl groups include, inter alia, those substituted with alkyl or alkenyl groups, which in turn can be optionally substituted. Particular aryl groups include phenyl, biphenyl groups, pyrrolidinyl, imidazolidinyl, tetrahydrofuryl, tetrahydrothienyl, furyl, thienyl, pyridyl, quinolyl, isoquinolyl, pyridazinyl, pyrazinyl, indolyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, pyridinyl, benzoxadiazolyl, benzothiadiazolyl, and naphthyl groups, all of which are optionally substituted. Substituted aryl groups include fully halogenated or semi-halogenated aryl groups, such as aryl groups in which one or more hydrogens are replaced with one or more fluorine, chlorine, bromine, and / or iodine atoms. Substituted aryl groups include fully fluorinated or semi-fluorinated aryl groups, such as aryl groups in which one or more hydrogens are replaced with one or more fluorine atoms.Aryl groups include, but are not limited to, aromatic or heteroaromatic groups corresponding to any one of the following: benzene, naphthalene, naphthoquinone, diphenylmethane, fluorene, anthracene, anthraquinone, phenanthrene, tetracene, tetracenedione, pyridine, quinoline, isoquinoline, indoles, isoindole, pyrrole, imidazole, oxazole, thiazole, pyrazole, pyrazine, pyrimidine, purine, benzimidazole, furans, benzofuran, dibenzofuran, carbazole, acridine, acridone, phenanthridine, thiophene, benzothiophene, dibenzothiophene, xanthene, xanthone, flavone, coumarin, azulene, or anthracycline. As used herein, groups corresponding to the groups listed above expressly include aromatic or heteroaromatic groups, including monovalent, divalent and polyvalent groups of the aromatic and heteroaromatic groups listed herein, provided in a covalent configuration in the compounds of the invention at any suitable attachment point. In embodiments, the aryl group contains between 5 and 30 carbon atoms. In embodiments, the aryl group contains one aromatic or heteroaromatic 6-membered ring and one or more additional 5- or 6-membered aromatic or heteroaromatic rings. In embodiments, the aryl group contains between 5 and 18 carbon atoms in the ring. The aryl group optionally has one or more aromatic or heteroaromatic rings with one or more electron donating groups, electron withdrawing groups and / or targeting ligands as substituents. The compositions of some embodiments of the invention include aryl groups as end groups, such as polymer backbone end groups and / or polymer side chain end groups.

[0080]

[0092] An arylalkyl group is an alkyl group substituted with one or more aryl groups, where the alkyl group optionally has additional substituents and the aryl group is optionally substituted. A particular alkylaryl group is a phenyl-substituted alkyl group, for example, a phenylmethyl group. An alkylaryl group is alternatively described as an aryl group substituted with one or more alkyl groups, where the alkyl group optionally has additional substituents and the aryl group is optionally substituted. A particular alkylaryl group is an alkyl-substituted phenyl group, such as methylphenyl. Substituted arylalkyl groups include fully halogenated or semi-halogenated arylalkyl groups, such as arylalkyl groups having one or more alkyl and / or aryl groups in which one or more hydrogens are replaced with one or more fluorine, chlorine, bromine and / or iodine atoms. The composition of some embodiments of the present invention includes arylalkyl groups as end groups, such as polymer backbone end groups and / or polymer side chain end groups.

[0081]

[0093] With respect to any of the groups described herein that contain one or more substituents, it is understood that such groups do not include any substitutions or substitution patterns that are sterically impractical and / or synthetically not feasible. In addition, the compounds of the present invention include all stereochemical isomers resulting from the substitution of these compounds. Optional substitution of an alkyl group includes substitution with one or more alkenyl groups, aryl groups, or both, where the alkenyl group or aryl group is optionally substituted. Optional substitution of an alkenyl group includes substitution with one or more alkyl groups, aryl groups, or both, where the alkyl group or aryl group is optionally substituted. Optional substitution of an aryl group includes substitution of an aryl ring with one or more alkyl groups, alkenyl groups, or both, where the alkyl group or alkenyl group is optionally substituted.

[0082]

[0094] Optional substituents on any of the alkyl, alkenyl and aryl groups include, inter alia, substitution with one or more of the following substituents: Halogens, including fluorine, chlorine, bromine or iodine; -CN-containing pseudohalides; -COOR, where R is hydrogen or an alkyl or aryl group, more particularly where R is a methyl, ethyl, propyl, butyl, or phenyl group, all of which groups are optionally substituted; -COR (wherein R is hydrogen or an alkyl or aryl group, more particularly where R is a methyl, ethyl, propyl, butyl, or phenyl group, all of which groups are optionally substituted); -CON(R)2, where each R, independently of the other R, is hydrogen or an alkyl or aryl group, more particularly where R is a methyl, ethyl, propyl, butyl, or phenyl group, all of which groups are optionally substituted; where R and R can form a ring which can contain one or more double bonds and can contain one or more additional carbon atoms; -OCON(R)2, where each R, independently of the other R, is hydrogen or an alkyl or aryl group, more particularly where R is a methyl, ethyl, propyl, butyl, or phenyl group, all of which groups are optionally substituted; where R and R can form a ring which can contain one or more double bonds and can contain one or more additional carbon atoms; -N(R)2, where each R, independently of the other R, is hydrogen, or an alkyl group, or an acyl group, or an aryl group, more particularly, where R is a methyl, ethyl, propyl, butyl, phenyl or acetyl group, all of which are optionally substituted; where R and R can form a ring which can contain one or more double bonds and can contain one or more additional carbon atoms; -SR, where R is hydrogen or an alkyl or aryl group, more particularly, where R is hydrogen, methyl, ethyl, propyl, butyl, or phenyl group, each of which is optionally substituted; -SO2R, or -SOR (wherein R is an alkyl group or an aryl group, more particularly, where R is a methyl, ethyl, propyl, butyl, or phenyl group, all of which are optionally substituted); -OCOOR (wherein R is an alkyl or aryl group); -SO2N(R)2, where each R, independently of the other R, is hydrogen, or an alkyl group, or an aryl group, all of which are optionally substituted, and where R and R can form a ring which can contain one or more double bonds and which can contain one or more additional carbon atoms; and

[0095] -OR, where R is H, an alkyl group, an aryl group, or an acyl group, all of which are optionally substituted. In certain instances, R can be acyl, resulting in -OCOR'', where R is hydrogen or an alkyl group or an aryl group, more particularly, where R is a methyl, ethyl, propyl, butyl, or phenyl group, all of which are optionally substituted.

[0083]

[0096] Particular substituted alkyl groups include haloalkyl groups, especially trihalomethyl groups, particularly trifluoromethyl groups. Particular substituted aryl groups include mono-, di-, tri-, tetra- and pentahalo-substituted phenyl groups; mono-, di-, tri-, tetra-, penta-, hexa- and hepta-halo-substituted naphthalene groups; 3- or 4-halo-substituted phenyl groups, 3- or 4-alkyl-substituted phenyl groups, 3- or 4-alkoxy-substituted phenyl groups, 3- or 4-RCO-substituted phenyl, 5- or 6-halo-substituted naphthalene groups. More particularly, substituted aryl groups include acetylphenyl groups, especially 4-acetylphenyl groups; fluorophenyl groups, especially 3-fluorophenyl and 4-fluorophenyl groups; chlorophenyl groups, especially 3-chlorophenyl and 4-chlorophenyl groups; methylphenyl groups, especially 4-methylphenyl groups; and methoxyphenyl groups, especially 4-methoxyphenyl groups.

[0084]

[0097] With respect to any of the above groups containing one or more substituents, it is understood that such groups do not contain any substitutions or substitution patterns that are sterically impractical and / or synthetically not feasible.

[0085]

[0098] Many of the molecules disclosed herein contain one or more ionizable groups. Ionizable groups include groups that can remove (e.g., -COOH) or add (e.g., amine) protons and groups that can be quaternized (e.g., amine). All possible ionic forms of such molecules and their salts are intended to be included individually in the disclosure of this specification. With respect to salts of the compounds of this specification, those skilled in the art can select from a wide variety of available counterions that are suitable for preparing the salt of the present invention for a given application. In a particular application, the selection of a given anion or cation for preparing a salt may result in the improvement or decrease of the solubility of the salt.

[0086]

[0099] The compounds of the present invention may contain one or more chiral centers. Thus, the present invention is intended to include racemic mixtures, diastereomers, enantiomers, tautomers, and mixtures enriched in one or more stereoisomers. The scope of the present invention as described and claimed includes the racemic forms of the compounds as well as the individual enantiomers and non-racemic mixtures thereof.

[0087]

[0100] As used herein, the term "isomers" refers to compounds that have the same number and kinds of atoms, and therefore the same molecular weight, but differ with respect to the structural arrangement or configuration of the atoms.

[0088]

[0101] The term "tautomer" as used herein refers to one of two or more structural isomers that exist in equilibrium and are easily converted from one isomeric form to another. It will be apparent to one skilled in the art that certain compounds of the present invention may exist in tautomeric forms, and all such tautomeric forms of the compounds are within the scope of the present invention.

[0089]

[0102] Unless otherwise stated, structures depicted herein are also intended to include all stereochemical forms of the structure; i.e., the R and S configurations at each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention.

[0090]

[0103] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen by deuterium or tritium, or 13 C- or 14 Compounds having this structure except for the replacement of a carbon with a C-enriched carbon are within the scope of this invention.

[0091]

[0104] The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain, for example, tritium ( 3 H), iodine-125( 125 I), or carbon-14 ( 14

[0033] All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0105] symbol" [ka] " represents the point of attachment of a chemical moiety, functional group, atom, ion, unpaired electron, or other chemical species to the depicted molecule, compound, or chemical formula. For example, [ka] In the formula, "X" represents a molecule or compound, and the symbol " [ka] " represents the point of attachment of a chemical moiety, functional group, atom, ion, unpaired electron, or other chemical species to X (where X corresponds to the depicted molecule, compound, or chemical formula) via a covalent bond. As used herein, the various depicted functional groups will be understood to have a point of attachment at the functional group having a hyphen or dash (-) or a dash used in combination with an asterisk (*). In other words, in the case of -CH2CH2CH3 or -CH2CH2CH3, the point of attachment will be understood to be the leftmost CH2 group. When a group is written without the asterisk or dash, the point of attachment is indicated by the clear and ordinary meaning of the described group.

[0092]

[0106] Where substituents are designated by their conventional chemical formula written from left to right, they equally encompass those chemically identical substituents that would result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-.

[0093]

[0107] The term "±" refers to an inclusive range of values ​​such that "X±Y," where each of X and Y is independently a number, refers to an inclusive range of values ​​selected from the range of XY to X+Y. In the case of "X±Y," where Y is a percentage (e.g., 1.0±20%), the inclusive range of values ​​is selected from the range of XZ to X+Z, where Z is equal to X·(Y / 100). For example, 1.0±20% refers to an inclusive range of values ​​selected from the range of 0.8 to 1.2.

[0094]

[0108] The term "and / or" is used in the specification, description and claims to refer to only a single element or any combination of elements from the term and / or list in which it appears. In other words, a list of two or more elements with the term "and / or" is intended to cover embodiments having either of the individual elements only or any combination of the listed elements. For example, the phrase "element A and / or element B" is intended to cover embodiments having only element A, only element B, or both elements A and B together. For example, the phrase "element A, element B, and / or element C" is intended to cover embodiments having only element A, only element B, only element C, elements A and B together, elements A and C together, elements B and C together, or elements A, B, and C together.

[0095]

[0109] In some embodiments, compositions or compounds of the invention, such as alloys or alloy precursors, are isolated or substantially purified. In some embodiments, isolated or purified compounds are at least partially isolated or substantially purified as would be understood in the art. In some embodiments, substantially purified compositions, compounds or formulations of the invention have a chemical purity of 95% purity, optionally 99% for some applications, optionally 99.9% for some applications, optionally 99.99% for some applications, and optionally 99.999% for some applications. EXAMPLES

[0096] Detailed Description of the Invention

[0110] In the following description, numerous specific details of the devices, device components and methods of the present invention are set forth in order to fully explain the precise nature of the invention. However, it will be apparent to one skilled in the art that the present invention may be practiced without these specific details.

[0097]

[0111] Various embodiments are contemplated herein, some of which are described in the following paragraphs. It is expressly contemplated that any embodiment or portion thereof may be combined to form an embodiment. Furthermore, for example, the term "any one of the preceding embodiments" means to refer to any embodiment that appears before the embodiment containing such phrase (e.g., the clause "embodiment 10: a method according to any one of the preceding embodiments" means to refer to any embodiment before embodiment 10, including embodiments 1-9). In addition, any reference to embodiment X (where X is an integer corresponding to one of the following embodiments (e.g., embodiment 11)) is expressly contemplated to include a reference to embodiment AXa, AXb, and / or AXc (if present), etc. (e.g., embodiment 11a, embodiment 11b, embodiment 11c, and / or embodiment 11d).

[0098]

[0112] Aspect 1: A method for treating a subject, comprising: locally administering (to the site of the damaged skin of the subject) a melanin formulation having an artificial melanin material (thereby administering an artificial melanin material); the administered artificial melanin material comprises an extracellular artificial melanin material to the damaged skin (or to the site of the damaged skin); and promoting skin healing of (or within) the damaged skin via at least the extracellular artificial melanin material; the promoting skin healing comprises at least a portion of the extracellular artificial melanin material exerting a therapeutic extracellular activity. The term "on damaged skin" generally refers to an area including the site of the damaged skin or at least a portion of the damaged skin, optionally, but not necessarily, also including some areas / areas directly surrounding or adjacent to the damaged skin. The term "on damaged skin" generally includes "on at least a portion of the damaged skin". Promoting skin healing generally, but not exclusively, refers to or includes accelerating or hastening skin healing compared to the healing of the same or comparable damaged skin without or in the absence of treatment of the damaged skin with a melanin preparation, optionally in the absence of any treatment. Optionally in this embodiment, at least 50% of the administered artificial melanin material is extracellular artificial melanin material. Optionally in this embodiment, the extracellular artificial melanin material remains extracellular (e.g., until removed) for as long as (or the entire time) it is present in the damaged skin. Optionally in this embodiment, the method includes at least a portion of the administered artificial melanin adsorbing, inactivating / deactivating, or otherwise converting one or more inflammatory factors, one or more enzymatic factors, and / or one or more apoptotic factors into different species.

[0099]

[0113] Aspect 2a: The method of aspect 1, wherein the damaged skin is a closed wound.Aspect 2b: The method of aspect 1, wherein the damaged skin is a closed wound having remnants of the superficial skin attached.

[0100]

[0114] Aspect 3a: The method of any one of the preceding aspects, wherein the damaged skin is associated with thermally induced damage, chemically induced damage, and / or radiation induced damage.Aspect 3b: The method of any one of the preceding aspects, wherein the damaged skin is associated with thermally induced damage, chemically induced damage, radiation induced damage (such as UV induced damage), mechanical friction damage, and / or infected cellulitis induced damage.

[0101]

[0115] Aspect 4a: The method of any one of the preceding aspects, wherein the damaged skin comprises one or more blisters.Aspect 4b: The method of any one of the preceding aspects, wherein the damaged skin comprises one or more visible blisters, one or more microscopic blister, separation of the epidermis from the dermis, or any combination thereof.

[0102]

[0116] Embodiment 5: A method according to any one of the preceding embodiments, wherein at least a portion of the extracellular melanin material is within the stratum corneum of the damaged skin.

[0103]

[0117] Aspect 6: The method of any one of the preceding aspects, wherein the damaged skin comprises extracellular free radical species; and the therapeutic extracellular activity comprises at least a portion of the extracellular artificial melanin material quenching at least the extracellular free radical species (or at least a portion of the extracellular free radical species).

[0104]

[0118] Embodiment 7: The method of embodiment 6, wherein the extracellular free radical species comprises a reactive oxygen species.

[0105]

[0119] Aspect 8: The method of aspect 6 or 7, wherein at least a portion of the quenched extracellular free radical species is within the stratum corneum.

[0106]

[0120] Aspect 9: The method of any one of the preceding aspects, wherein the damaged skin comprises inflammation; and the step of promoting skin healing comprises at least a portion of the administered artificial melanin material directly and / or indirectly reducing the inflammation.

[0107]

[0121] Aspect 10: The method of aspect 9, wherein the therapeutic extracellular activity comprises at least a portion of the extracellular artificial melanin material directly and / or indirectly reducing inflammation.

[0108]

[0122] Aspect 11a: The method according to aspect 9 or 10, wherein the directly and / or indirectly reducing inflammation comprises at least a portion of the administered artificial melanin adsorbing one or more inflammatory factors and / or one or more enzymatic factors. Aspect 11b: The method according to aspect 9 or 10, wherein the directly and / or indirectly reducing inflammation comprises at least a portion of the administered artificial melanin adsorbing, inactivating / deactivating, or otherwise converting one or more inflammatory factors, one or more enzymatic factors, and / or one or more apoptotic factors into different species. Aspect 11c: The method according to aspect 9 or 10, wherein the directly and / or indirectly reducing inflammation comprises at least a portion of the administered artificial melanin directly and / or indirectly downregulating the expression of one or more genes associated with inflammation. Aspect 11d: The method according to aspect 9 or 10, wherein directly and / or indirectly reducing inflammation comprises that at least a portion of the administered artificial melanin adsorbs, inactivates / deactivates, or otherwise converts one or more inflammatory factors, one or more enzymatic factors, and / or one or more apoptotic factors into different species.Aspect 11e: The method according to aspect 9 or 10, wherein directly and / or indirectly reducing inflammation comprises that at least a portion of the administered artificial melanin directly and / or indirectly downregulates the expression of Fas, Gzmb, Bcl2l1, Bcl2, Bax, or a combination thereof.

[0109]

[0123] Aspect 12a: The method according to any one of aspects 9 to 11, wherein the directly and / or indirectly reducing inflammation comprises at least a portion of the extracellular artificial melanin adsorbing one or more extracellular inflammatory factors and / or one or more extracellular enzymatic factors. Aspect 12b: The method according to any one of aspects 9 to 11, wherein the directly and / or indirectly reducing inflammation comprises at least a portion of the extracellular artificial melanin adsorbing one or more inflammatory factors, one or more enzymatic factors, and / or one or more apoptotic factors. Aspect 12c: The method according to any one of aspects 9 to 11, wherein the directly and / or indirectly reducing inflammation comprises at least a portion of the extracellular artificial melanin adsorbing, inactivating / deactivating or otherwise converting one or more inflammatory factors, one or more enzymatic factors, and / or one or more apoptotic factors into a different species.

[0110]

[0124] Embodiment 13a: The method according to embodiment 11 or 12, wherein the one or more inflammatory factors and / or one or more enzymatic factors comprise TNFα, iNOS, MMP9, one or more proteins associated with the MAPK / ERK pathway, and / or one or more enzymes associated with the MAPK / ERK pathway.

[0111]

[0125] Aspect 14: The method of any one of aspects 11 to 13, wherein at least a portion of the adsorbed inflammatory factor and / or the adsorbed extracellular enzymatic factor is within the stratum corneum.

[0112]

[0126] Aspect 15a: The method of any one of the preceding aspects, wherein the promoting step comprises at least a portion of the administered artificial melanin directly and / or indirectly downregulating inflammation-related genes and / or apoptosis-related genes compared to when the artificial melanin material is not present. Aspect 15b: The method of any one of the preceding aspects, wherein the promoting step comprises at least a portion of the extracellular artificial melanin directly and / or indirectly downregulating inflammation-related genes and / or apoptosis-related genes compared to when the artificial melanin material is not present. Aspect 15c: The method of any one of the preceding aspects, wherein the promoting step comprises at least a portion of the extracellular artificial melanin directly and / or indirectly downregulating Fas, Gzmb, Bcl2l1, Bcl2, Bax, Cxcr3, Stat1, Stat3, Ccr2, Ece1, MMP9, or a combination thereof. Generally, "in the absence of artificial melanin material" refers to or corresponds to a comparative case in which no melanin formulation is administered, or an equivalent melanin formulation that does not contain melanin is administered (e.g., to the same or equivalent skin lesion serving as a control), such as the control or vehicle case discussed in Examples 1A-1B.

[0113]

[0127] Aspect 16: A method as described in any one of the preceding aspects, wherein the promoting step includes at least a portion of the administered artificial melanin directly and / or indirectly inhibiting apoptosis compared to when the artificial melanin material is not present.

[0114]

[0128] Aspect 17: The method of any one of the preceding aspects, wherein the step of promoting skin healing further comprises at least a portion of the administered artificial melanin material exerting therapeutic intracellular activity.

[0115]

[0129] Aspect 18: The therapeutic intracellular activity is quenching intracellular free radical species; and / or Adsorbing one or more intracellular inflammatory factors and / or one or more intracellular enzymatic factors. 20. The method of embodiment 17, comprising:

[0116]

[0130] Aspect 19: Skin healing is Reduction in the wound area containing damaged tissue; Reduces inflammation of damaged skin; Increased superoxide dismutase activity in damaged skin; Reduction in bifold skin thickness of lesional skin; Reduced skin edema in damaged skin; Decreased time to scabbing of injured skin; A reduction in the depth of injury to damaged skin; and / or Stabilizing the epithelial layer of damaged skin 5. The method of any one of the preceding aspects, comprising:

[0117]

[0131] Aspect 20: Skin healing exhibits the following healing properties that are less than the same one or more healing properties in the absence of the artificial melanin material during skin healing: The total time (e.g., average total time) required to reduce the amount or concentration of damaged tissue by 50% immediately prior to administration of the melanin preparation; the total time (e.g., average total time) to reduce inflammation in the lesional skin by 50% immediately prior to administration of the melanin preparation; The total time (e.g., average total time) for the lesion to reduce to 50% of its two-fold skinfold thickness immediately prior to administration of the melanin preparation; the total time (e.g., average total time) required for the skin edema of the lesion to decrease by 50% immediately prior to administration of the melanin preparation; the total time (e.g., the average total time) to reduce the depth of injury of the damaged skin by 50% of that immediately prior to administration of the melanin preparation; and / or The method of any one of the preceding aspects, characterized by one or more of: total time (e.g., average total time) to desquamation in the area. Generally, "in the absence of artificial melanin material" refers to or corresponds to a comparative case in which no melanin formulation is administered, or an equivalent melanin formulation that does not contain melanin is administered (e.g., to the same or equivalent skin lesion serving as a control).

[0118]

[0132] Aspect 21: Skin healing exhibits the following healing properties that are greater than the same one or more healing properties in the absence of the artificial melanin material during skin healing: The rate (e.g., average rate) of reduction of the wound area including the damaged skin; the rate at which inflammation in the injured skin decreases (e.g., the average rate); the rate of reduction in bifold skin thickness of the injured skin (e.g., average rate); the rate of reduction of skin edema in the injured skin (e.g., average rate); the rate of decrease in the depth of injury of the damaged skin (e.g., average rate); The rate (e.g., average rate) of stabilization of the epithelial layer of damaged skin; and / or Superoxide dismutase activity (e.g., average activity) in damaged skin The method of any one of the preceding aspects, characterized by one or more of:

[0119]

[0133] Example 22: The method of any one of the preceding examples, wherein the artificial melanin material comprises a porous artificial melanin material.

[0120]

[0134] Embodiment 23: The method of any one of the preceding embodiments, wherein the artificial melanin material comprises artificial melanin particles.

[0121]

[0135] Embodiment 24: The method of any one of the preceding embodiments, wherein the artificial melanin material comprises porous artificial melanin particles.

[0122]

[0136] Aspect 25: The method of any one of the preceding aspects, wherein at least a portion of the artificial melanin material is characterized as eumelanin, pheomelanin, allomelanin, or a combination thereof.

[0123]

[0137] Aspect 26: The method of any one of the preceding aspects, wherein the artificial melanin material comprises an amorphous artificial melanin material.

[0124]

[0138] Aspect 27: The method of any one of the preceding aspects, wherein the artificial melanin material comprises a plurality of melanin oligomers and / or polymers; each melanin oligomer and / or polymer comprises a plurality of covalently linked melanin building blocks.

[0125]

[0139] Aspect 28: The method of aspect 27, wherein the melanin building blocks are one or more substituted or unsubstituted catechol-based monomeric units, substituted or unsubstituted polyol-based monomeric units, substituted or unsubstituted phenol-based monomeric units, substituted or unsubstituted indole-based monomeric units, substituted or unsubstituted benzothiazine-based monomeric units, substituted or unsubstituted benzothiazole-based monomeric units, substituted or unsubstituted dopamine-based monomeric units, or any combination thereof.

[0126]

[0140] Aspect 29: The method of aspect 27 or 28, wherein at least a portion of each of the artificial melanin materials comprises allomelanin.

[0127]

[0141] Aspect 30: The method of any one of aspects 27 to 29, wherein at least a portion of the melanin building blocks each independently comprise a substituted or unsubstituted naphthalene.

[0128]

[0142] Aspect 31: The method of any one of aspects 27 to 30, wherein at least a portion of the melanin building blocks each independently comprise a dihydroxynaphthalene.

[0129]

[0143] Aspect 32: A method according to any one of aspects 27 to 31, wherein at least a portion of the artificial melanin material comprises nitrogen-free melanin oligomers.

[0130]

[0144] Aspect 33: A method according to any one of aspects 27 to 28, wherein at least a portion of the artificial melanin material comprises polydopamine.

[0131]

[0145] Aspect 34: The method of any one of aspects 27, 28, or 33, wherein at least a portion of the melanin building blocks independently comprise substituted or unsubstituted dopamine monomers.

[0132]

[0146] Aspect 35: The method of any one of aspects 27, 28, or 33-34, wherein at least a portion of the melanin building blocks are each independently selected from the group consisting of substituted or unsubstituted dihydroxydopamine monomer units, substituted or unsubstituted dioxydopamine monomer units, substituted or unsubstituted dihydroxynaphthalene monomer units, substituted or unsubstituted dihydroxyphenylalanine monomer units, substituted or unsubstituted dioxydopamine monomer units, substituted or unsubstituted tyrosine monomer units, substituted or unsubstituted tyramine monomer units, any derivatives thereof, and any combinations thereof.

[0133]

[0147] Aspect 36: The method of any one of aspects 27, 28, or 33-35, wherein at least a portion of the melanin building blocks are each independently selected from the group consisting of 3,4-dihydroxydopamine monomer units, 3,4-dioxydopamine monomer units, 3,4-dihydroxynaphthalene monomer units, 1,8-dihydroxynapthalene, 1-3,4-dihydroxyphenylalanine monomer units, and any combination thereof.

[0134]

[0148] Aspect 37: The method of any one of aspects 27 to 36, wherein at least 50% of the plurality of melanin oligomers are selected from the group consisting of monomer units, dimers, trimers, tetramers, pentamers, and any combination thereof.

[0135]

[0149] Aspect 38: The method of any one of aspects 27 to 37, wherein each melanin oligomer is non-covalently associated with at least one other melanin oligomer or melanin monomer via at least one of hydrogen bonds and π-π stacking of naphthalene rings; and the melanin monomer comprises a melanin base unit.

[0136]

[0150] Aspect 39: The artificial melanin material comprises a porous artificial melanin material (e.g., porous artificial melanin (nano)particles); the melanin oligomers and / or polymers of the porous artificial melanin material are arranged to form an internal structure having a plurality of pores; the porous artificial melanin material is 0.1 cm 3 39. The method of any one of aspects 27-38, wherein the pores are characterized by a pore volume per mass of material of at least 100 / g or more, and at least a portion of the pores have at least one size dimension of 0.5 nm or more.

[0137]

[0151] Aspect 40: The method of any one of aspects 27 to 39, wherein the artificial melanin material comprises artificial melanin particles; at least a portion of the artificial melanin particles are solid particles, hollow particles, lacy particles, or any combination thereof.

[0138]

[0152] Aspect 41: The method of any one of the preceding aspects, wherein at least a portion of the artificial melanin material comprises one or more selenomelanin polymers; the one or more selenomelanin polymers comprise a plurality of covalently bonded selenomelanin building blocks; and the chemical formula of each of the one or more selenomelanin building blocks comprises at least one selenium atom.

[0139]

[0153] Example 42: The method of example 41, wherein each selenomelanine polymer is a pheomelanin.

[0140]

[0154] Embodiment 43: The method of embodiment 41 or 42, wherein the chemical formula of each of the one or more selenomelanin building blocks comprises at least one covalent bond with each of the at least one selenium atom.

[0141]

[0155] Aspect 44: The method of any one of aspects 41 to 43, wherein the chemical formula of each of the one or more selenomelanine building blocks comprises substituted or unsubstituted benzoselenazine or a derivative thereof, substituted or unsubstituted benzoselenazole or a derivative thereof, substituted or unsubstituted 7,10-dihydro-2H-[1,4]selenazino[3,2-h]isoquinolin-3(4H)-one or a derivative thereof, substituted or unsubstituted benzoselenazinone or a derivative thereof, or any combination thereof.

[0142]

[0156] Aspect 45a: The method of any one of the preceding aspects, wherein the artificial melanin material comprises artificial melanin particles having a size (or characteristic size, such as diameter) selected from the range of 10 nm to 1000 nm (wherein any intermediate range is expressly contemplated), optionally greater than 10 nm to less than 1000 nm, optionally 10 nm to 50 nm, optionally 20 nm to 1000 nm, optionally 100 nm to 1000 nm, optionally 150 nm to 1000 nm, optionally 200 nm to 1000 nm, optionally 220 nm to 1000 nm, optionally 240 nm to 1000 nm, optionally 250 nm to 1000 nm, optionally 275 nm to 1000 nm, optionally 300 nm to 1000 nm, optionally 240 nm to 900 nm. Embodiment 45b: The artificial melanin material has a thickness of 10 nm to 1000 nm (wherein any intermediate range is expressly contemplated), optionally greater than 10 nm to less than 1000 nm, optionally 10 nm to 50 nm, optionally 20 nm to 1000 nm, optionally 100 nm to 1000 nm, optionally 150 nm to 1000 nm, optionally 200 nm to 1000 nm, optionally 220 nm to 1000 nm, optionally 240 nm to 1000 nm, optionally 250 The method of any one of the preceding aspects, comprising artificial melanin particles having an average size (or an average characteristic size, such as an average diameter) selected from the ranges of from 275 nm to 1000 nm, optionally from 300 nm to 1000 nm, optionally from 240 nm to 900 nm, optionally from 300 nm to 900 nm, optionally from 250 nm to 800 nm, optionally from 250 nm to 800 nm, optionally from 275 nm to 800 nm.Aspect 45c: The artificial melanin material has a thickness of from 10 nm to 1000 nm (wherein any intermediate range is expressly contemplated), optionally from greater than 10 nm to less than 1000 nm, optionally from 10 nm to 50 nm, optionally from 20 nm to 1000 nm, optionally from 100 nm to 1000 nm, optionally from 150 nm to 1000 nm, optionally from 200 nm to 1000 nm, optionally from 220 nm to 1000 nm, optionally from 240 nm to 1000 nm, optionally from 250 nm to 10 100 nm, optionally 275 nm to 1000 nm, optionally 300 nm to 1000 nm, optionally 240 nm to 900 nm, optionally 300 nm to 900 nm, optionally 250 nm to 800 nm, optionally 250 nm to 800 nm, optionally 275 nm to 800 nm.

[0143]

[0157] Aspect 46a: The concentration of the artificial melanin material in the melanin formulation is from 0.5 mg / mL to 100 mg / mL, optionally from 1 mg / mL to 100 mg / mL, optionally from 2 mg / mL to 100 mg / mL, optionally from 5 mg / mL to 100 mg / mL, optionally from 10 mg / mL to 100 mg / mL, optionally from 15 mg / mL to 100 mg / mL, optionally from 20 mg / mL to 100 mg / mL, optionally from 50 mg / mL to 100 mg / mL, Aspect 46b: The method of any one of the preceding aspects, wherein the concentration of the artificial melanin material in the melanin formulation is selected from the range of 0.1 mg / mL to 1000 mg / mL (wherein any intermediate range is expressly contemplated).

[0144]

[0158] Aspect 47a: the melanin formulation is from 0.5 mg / mL to 100 mg / mL, optionally from 1 mg / mL to 100 mg / mL, optionally from 2 mg / mL to 100 mg / mL, optionally from 5 mg / mL to 100 mg / mL, optionally from 10 mg / mL to 100 mg / mL, optionally from 15 mg / mL to 100 mg / mL, optionally from 20 mg / mL to 100 mg / mL, optionally from 50 mg / mL to 100 mg / mL, optionally from 0.5 mg / mL to 50 Aspect 47b: The method of any one of the preceding aspects, wherein the melanin formulation comprises artificial melanin particles having a concentration selected from the range of 0.1 mg / mL to 1000 mg / mL (wherein any intermediate range is expressly contemplated).

[0145]

[0159] Aspect 48: A method according to any one of the preceding aspects, wherein the melanin formulation is such that the administering step comprises forming a layer of artificial melanin material on at least a portion of the damaged skin.

[0146]

[0160] Aspect 49: A method according to any one of the preceding aspects, wherein the melanin formulation is hydrophilic and / or the artificial melanin material is hydrophilic.

[0147]

[0161] Embodiment 50: The method of any one of the preceding embodiments, wherein the melanin preparation comprises one or more additives.

[0148]

[0162] Embodiment 51: The method according to any one of the preceding embodiments, characterized in that the melanin preparation is a cream or ointment.

[0149]

[0163] Embodiment 52: The method of any one of the preceding embodiments, wherein the melanin formulation comprises a hydrogel.

[0150]

[0164] Aspect 53: The method of any one of the preceding aspects, wherein the melanin formulation does not comprise artificial melanin material to which a non-melanin therapeutic agent has been attached or functionalized with a non-melanin therapeutic agent.

[0151]

[0165] Aspect 54: The method of any one of the preceding aspects, wherein the melanin formulation does not comprise hollow and / or semi-hollow melanin particles carrying a non-melanin therapeutic agent.

[0152]

[0166] Embodiment 55: The method of any one of the preceding embodiments, wherein the melanin formulation does not include a non-melanin therapeutic agent.

[0153]

[0167] Embodiment 56: A method according to any one of the preceding embodiments, wherein the administering step occurs after a skin damage event has occurred in the area of ​​the subject.

[0154]

[0168] Embodiment 57: The method of embodiment 56, comprising a step of damaging the skin prior to the administering step to form damaged skin.

[0155]

[0169] Embodiment 58: The method of any one of the preceding embodiments, comprising repeating the administering step.

[0156]

[0170] Embodiment 59: A method according to any one of the preceding embodiments, wherein the subject is a mammal and / or the skin to be healed is mammalian skin.

[0157]

[0171] Aspect 60: A method according to any one of the preceding aspects, wherein at least 50% (optionally at least 60%, optionally at least 70%, optionally at least 80%, optionally at least 90%) of the administered artificial melanin material is extracellular artificial melanin material (present outside the cells of the damaged skin during the step of promoting skin healing).

[0158]

[0172] Aspect 61: A method according to any one of the preceding aspects, wherein the extracellular artificial melanin material remains extracellular for as long (or the entire time) as it is present in the damaged skin (e.g., until it is removed).

[0159]

[0173] Various potentially useful explanations, background information, applications / uses of the embodiments herein, terminology (to the extent not inconsistent with the terms as defined herein), mechanisms, compositions, methods, definitions, and / or other embodiments are incorporated herein by reference, each to the extent not inconsistent with the present specification, including, but not limited to, International Patent Application No. PCT / US2017 / 041596 (published as International Patent Publication No. WO2018013609A2); ... No. PCT / US2020 / 039769 (published as International Patent Publication No. WO2021021350A3), International Patent Application No. PCT / US2020 / 057902 (published as International Patent Publication No. WO2021087076A1), and International Patent Application No. PCT / US2020 / 057939 (published as International Patent Publication No. WO2021096692A1).

[0160]

[0174] In some embodiments, such as some of aspects 1-61, optionally, the artificial melanin material comprises synthetic melanin particles, also referred to herein as artificial melanin particles, also referred to herein interchangeably as artificial melanin-like particles or synthetic melanin-like particles, prepared by natural oxidation of melanin monomers in aqueous solution under alkaline conditions to produce biocompatible synthetic analogs of naturally occurring melanosomes.

[0161]

[0175] Optionally, in some embodiments, such as some of aspects 1-61, the artificial melanin material includes synthetic melanin particles including non-natural particles composed of (e.g., comprising, consisting of, or consisting essentially of) melanin that is not bound to, conjugated to, attached to, coated by, encapsulated by, or otherwise associated with lipids (i.e., lipids that include one or more proteins, such as the lipid (plasma) membrane of a melanocyte or melanosome). Optionally, in some embodiments, such as some of aspects 1-61, the artificial melanin material includes synthetic melanin particles including non-natural particles composed of (e.g., consisting of, consisting essentially of) melanin that is not bound to, conjugated to, attached to, coated by, encapsulated by, or otherwise associated with proteinaceous lipids (i.e., lipids that include one or more proteins, such as the lipid (plasma) membrane of a melanocyte or melanosome).

[0162]

[0176] Optionally, in some embodiments, such as some of aspects 1-61, the artificial melanin material includes synthetic melanin particles that include a melanin polymer that is a fused ring melanin polymer that includes (e.g., consists of, or consists essentially of) monomers of fused ring heteroaryl monomers and / or fused ring heterocycloalkyl monomers. Optionally, in some embodiments, such as some of aspects 1-61, the artificial melanin material includes synthetic melanin particles that include a melanin polymer that is a fused ring metal-bound melanin polymer that includes a melanin polymer bound to a plurality of transition metals, including but not limited to iron. Optionally, in some embodiments, such as some of aspects 1-61, the artificial melanin material includes synthetic melanin particles that include a fused ring melanin polymer that is a dopamine monomer, including but not limited to dihydroxydopamine, 3,4-dihydroxydopamine, dioxidopoamine, and / or 3,4-dioxydopamine. In some embodiments, such as some of aspects 1-61, each of the fused ring heteroaryl monomers and / or fused ring heterocycloalkyl monomers may be optionally substituted with one or more substituents selected from hydroxyl, carboxyl, and / or oxy. In some embodiments, such as some of aspects 1-61, each of the fused ring heteroaryl monomers is optionally a 6,6-fused ring heteroaryl monomer, a 5,6-fused ring heteroaryl monomer, or a 6,5-fused ring heteroaryl monomer, and each of the fused ring heterocycloalkyl moieties is optionally a 6,6-fused ring heterocycloalkyl monomer, a 5,6-fused ring heterocycloalkyl monomer, or a 6,5-fused ring heterocycloalkyl monomer. In some embodiments, such as some of aspects 1-61, the fused ring heteroaryl monomer and / or the fused ring heterocycloalkyl monomer (in monovalent or divalent form) are optionally selected from indoles (such as dihydroxyindole, 5,6-dihydroxyindole (DHI), 5,6-dihydroxyindole-2-carboxylic acid, dioxindole, 5,6-dioxindole, 5,6-hydroxyindole-2-carboxylic acid), benzothiazines, and benzothiazoles.In some embodiments, such as some of the aspects 1-61, the fused ring monomer units of the fused ring melanin polymer are optionally dihydroxy fused ring units (e.g., dihydroxy fused ring heteroaryl monomers and / or dihydroxy fused ring heterocycloalkyl monomers) in which hydroxy substituents are attached to adjacent carbons of a six-membered ring (e.g., a six-membered carbocyclic ring) of the fused ring monomer (also referred to herein as a "catechol fused ring monomer"). In some embodiments, such as some of the aspects 1-61, the fused ring melanin polymer can also optionally include oxidized versions of the dihydroxy fused ring units in which one or both of the hydroxyl substituents are oxy substituents. Optionally in some embodiments, such as some of aspects 1-61, the synthetic melanin particles can be in the form of spheres, hollow spheres, nanorods, worm-like structures, cylindrical structures, and the like, preferably having a high aspect ratio, with at least one axis thereof being about 1 nm to about 1000 nm, about 1 nm to about 1000 nm, about 50 nm to about 500 nm, or about 100 nm to about 300 nm. Optionally in some embodiments, such as some of aspects 1-61, the synthetic melanin particles are in the form of spheres with an average diameter of about 50 nm to about 500 nm, about 100 nm to about 300 nm, about 150 nm to about 250 nm, or about 250 nm. Optionally in some embodiments, such as some of aspects 1-61, the synthetic melanin particles are in the form of hollow spheres, optionally hollow spheres filled with silica. Optionally in some embodiments, such as some of aspects 1-61, the synthetic melanin particles can function as a pigment. In some embodiments, such as some of aspects 1-61, the synthetic melanin particles are optionally synthetic melanin nanoparticles.

[0163]

[0177] In some embodiments, such as some of the aspects 1-61, optionally, the artificial melanin material disclosed herein comprises artificial melanin nanoparticles, wherein each melanin nanoparticle of the plurality of artificial melanin nanoparticles comprises a plurality of melanin oligomers; each melanin oligomer comprises a plurality of covalently bonded melanin building blocks; and each melanin building block comprises a substituted or unsubstituted naphthalene.

[0164]

[0178] Optionally, in some embodiments, such as some of aspects 1-61, the artificial melanin material disclosed herein comprises artificial melanin nanoparticles, each melanin nanoparticle of the plurality of artificial melanin nanoparticles comprises a plurality of melanin oligomers, each melanin oligomer comprises a plurality of covalently bonded melanin building blocks, the plurality of artificial melanin nanoparticles are characterized by a peak size selected from the range of 100 nm to 300 nm and a polydispersity index selected to 0.10 or less, and optionally for some embodiments a polydispersity index selected to 0.3 or less, and optionally for some embodiments a polydispersity index selected to 0.2 or less. Optionally, the plurality of artificial melanin nanoparticles are characterized by a peak size selected from the range of 100 nm to 200 nm and a polydispersity index selected to 0.10 or less.

[0165]

[0179] Optionally, in some embodiments, such as some of aspects 1-61, the artificial melanin material disclosed herein comprises artificial melanin nanoparticles, where each melanin nanoparticle of the plurality of artificial melanin nanoparticles comprises a plurality of melanin oligomers; each melanin oligomer comprises a plurality of covalently bonded melanin building blocks; and the plurality of artificial melanin nanoparticles exhibit structural color. Optionally, the plurality of artificial melanin nanoparticles exhibit structural color when the plurality of artificial melanin nanoparticles are in the form of a layer or film, such as a monolayer or thicker, or in the form of pellets, such as free-standing pellets. Optionally, the plurality of artificial melanin nanoparticles exhibit structural color when the plurality of artificial melanin nanoparticles are in the form of a packed and / or ordered structure. Optionally, the plurality of artificial melanin nanoparticles exhibit structural color when the plurality of artificial melanin nanoparticles are dried or otherwise deposited on a substrate.

[0166]

[0180] Optionally, in some embodiments, such as some of aspects 1-61, the artificial melanin material disclosed herein comprises artificial melanin nanoparticles, wherein each melanin nanoparticle of the plurality of artificial melanin nanoparticles comprises a plurality of melanin oligomers; each melanin oligomer comprises a plurality of covalently bonded melanin building blocks; and at least 50% of the plurality of melanin oligomers are selected from the group consisting of monomers, dimers, trimers, tetramers, pentamers, and any combination thereof. The monomers, dimers, trimers, tetramers, and pentamers have 1, 2, 3, 4, and 5 melanin building blocks, respectively. Optionally, at least 30%, optionally at least 40%, optionally at least 50%, optionally at least 60%, and optionally at least 80% of the plurality of melanin oligomers are selected from the group consisting of dimers, trimers, tetramers, pentamers, and any combination thereof, and the artificial melanin nanoparticles further comprise monomers. Optionally, at least 50% of the plurality of melanin oligomers are selected from the group consisting of dimers, trimers, tetramers, pentamers, and any combination thereof, and the artificial melanin nanoparticles further comprise a monomer. Optionally, at least 30%, optionally at least 40%, optionally at least 50%, optionally at least 60%, and optionally at least 80% of the plurality of melanin oligomers are selected from the group consisting of dimers, trimers, tetramers, and any combination thereof, and the artificial melanin nanoparticles further comprise a monomer. Optionally, at least 50% of the plurality of melanin oligomers are selected from the group consisting of dimers, trimers, tetramers, and any combination thereof, and the artificial melanin nanoparticles further comprise a monomer. Optionally, at least 30% by weight, optionally at least 40% by weight, optionally at least 50% by weight, optionally at least 60% by weight, optionally at least 80% by weight of each of the plurality of artificial melanin nanoparticles are melanin oligomers selected from the group consisting of monomers (each monomer having only one melanin base unit) and / or dimers, trimers, tetramers, pentamers, and any combination thereof.Optionally, at least 30% by weight, optionally at least 40% by weight, optionally at least 50% by weight, optionally at least 60% by weight, optionally at least 80% by weight of each of the plurality of artificial melanin nanoparticles is a melanin oligomer selected from the group consisting of monomers (each monomer having only one melanin base unit) and dimers, trimers, tetramers, pentamers, and any combination thereof. Optionally, at least 30% by weight, optionally at least 40% by weight, optionally at least 50% by weight, optionally at least 60% by weight, optionally at least 80% by weight of each of the plurality of artificial melanin nanoparticles is a melanin oligomer selected from the group consisting of monomers (each monomer having only one melanin base unit) and / or dimers, trimers, tetramers, and any combination thereof. Optionally, at least 30% by weight, optionally at least 40% by weight, optionally at least 50% by weight, optionally at least 60% by weight, optionally at least 80% by weight of each of the plurality of artificial melanin nanoparticles is a melanin oligomer selected from the group consisting of monomers (each monomer having only one melanin base unit) and dimers, trimers, tetramers, and any combination thereof.

[0167]

[0181] Optionally, in some embodiments, such as some of Aspects 1-61, the artificial melanin material disclosed herein comprises artificial melanin nanoparticles, wherein each melanin nanoparticle of the plurality of artificial melanin nanoparticles comprises a plurality of melanin oligomers; each melanin oligomer comprises a plurality of covalently linked melanin building blocks; and each nanoparticle has a sphericity of less than 0.90 and a shape characterized as at least one of a walnut-like, a collapsed sphere or collapsed ellipsoid, and a sphere or ellipsoid with multiple dimples.

[0168]

[0182] Optionally, in some embodiments, such as some of aspects 1-61, the artificial melanin material disclosed herein comprises artificial melanin nanoparticles, wherein each melanin nanoparticle of the plurality of artificial melanin nanoparticles comprises a plurality of melanin oligomers, each melanin oligomer comprises a plurality of covalently bonded melanin building blocks, and wherein the plurality of artificial melanin nanoparticles are characterized by a radical scavenging activity that is greater than the radical scavenging activity of a polydopamine nanoparticle having the same diameter as the plurality of artificial melanin nanoparticles under otherwise identical conditions. Optionally, the plurality of artificial melanin nanoparticles are characterized by a radical scavenging activity that is at least 5%, optionally at least 10%, optionally at least 15%, and optionally at least 20% greater than the radical scavenging activity of a polydopamine nanoparticle having the same diameter as the plurality of artificial melanin nanoparticles under otherwise identical conditions.

[0169]

[0183] Optionally in some embodiments, such as some of aspects 1-61, the artificial melanin material disclosed herein comprises an artificial melanin nanoparticle, where each melanin building block comprises a substituted or unsubstituted naphthalene. Optionally in some embodiments, such as some of aspects 1-61, the artificial melanin material disclosed herein comprises an artificial melanin nanoparticle, where each melanin building block comprises a dihydroxynaphthalene. Optionally in some embodiments, such as some of aspects 1-61, the artificial melanin material disclosed herein comprises an artificial melanin nanoparticle, where each melanin building block comprises a 1,8-dihydroxynaphthalene. According to certain embodiments, each melanin building block comprises a compound represented by the formula FX1: [ka] The structure includes:

[0170]

[0184] Optionally in some embodiments, such as some of aspects 1-61, the artificial melanin material disclosed herein comprises artificial melanin nanoparticles, where each melanin oligomer does not contain nitrogen. According to certain embodiments, at least 20%, optionally at least 40%, optionally at least 50%, optionally at least 80% of the plurality of melanin oligomers are dimers having two covalently bonded melanin building blocks. Optionally in some embodiments, such as some of aspects 1-61, the artificial melanin material disclosed herein comprises artificial melanin nanoparticles, where 20%-80% of the plurality of melanin oligomers are dimers having two covalently bonded melanin building blocks. In some embodiments, such as some of aspects 1-61, the artificial melanin material disclosed herein optionally comprises an artificial melanin nanoparticle, wherein at least 50% of the plurality of melanin oligomers are selected from the group consisting of monomers, dimers, trimers, tetramers, pentamers, and any combination thereof. The monomers, dimers, trimers, tetramers, and pentamers have 1, 2, 3, 4, and 5 melanin base units, respectively. Optionally, at least 30%, optionally at least 40%, optionally at least 50%, optionally at least 60%, and optionally at least 80% of the plurality of melanin oligomers are selected from the group consisting of dimers, trimers, tetramers, pentamers, and any combination thereof, and the artificial melanin nanoparticle further comprises a monomer. In some embodiments, such as some of Aspects 1-61, optionally, the artificial melanin material disclosed herein comprises artificial melanin nanoparticles, wherein at least 40% of the plurality of melanin oligomers are selected from the group consisting of monomers, dimers, trimers, tetramers, pentamers, and any combination thereof.Optionally, in some embodiments, such as some of aspects 1-61, the artificial melanin material disclosed herein comprises artificial melanin nanoparticles, where at least 20%, optionally at least 40%, optionally at least 80% of the melanin oligomers are selected from the group consisting of monomers, dimers, and trimers, and any combination thereof. Optionally, in some embodiments, such as some of aspects 1-61, the artificial melanin material disclosed herein comprises artificial melanin nanoparticles, where at least 50% of the melanin oligomers are selected from the group consisting of monomers, dimers, and trimers, and any combination thereof. In some embodiments, such as some of aspects 1-61, optionally, the artificial melanin material disclosed herein comprises artificial melanin nanoparticles, where at least 30%, optionally at least 40%, optionally at least 50%, optionally at least 60%, optionally at least 80% by weight of each of the plurality of artificial melanin nanoparticles, or at least 80% of each of the plurality of artificial melanin nanoparticles, are melanin oligomers selected from the group consisting of monomers (each monomer having only one melanin base unit) and / or dimers, trimers, tetramers, pentamers, and any combination thereof. In some embodiments, such as some of aspects 1-61, optionally, the artificial melanin material disclosed herein comprises artificial melanin nanoparticles, where at least 30%, optionally at least 40%, optionally at least 50%, optionally at least 60%, optionally at least 80% by weight of each of the plurality of artificial melanin nanoparticles, or at least 80% of each of the plurality of artificial melanin nanoparticles, are melanin oligomers selected from the group consisting of monomers (each monomer having only one melanin base unit) and dimers, trimers, tetramers, pentamers, and any combination thereof.In some embodiments, such as some of aspects 1-61, optionally, the artificial melanin material disclosed herein comprises artificial melanin nanoparticles, where at least 30%, optionally at least 40%, optionally at least 50%, optionally at least 60%, optionally at least 80% by weight of each of the plurality of artificial melanin nanoparticles, or at least 80% of each, are melanin oligomers selected from the group consisting of monomers (each monomer having only one melanin base unit) and / or dimers, trimers, tetramers, and any combination thereof. In some embodiments, such as some of the aspects 1-61, the artificial melanin material disclosed herein optionally comprises artificial melanin nanoparticles, where at least 30%, optionally at least 40%, optionally at least 50%, optionally at least 60%, optionally at least 80% by weight of each of the plurality of artificial melanin nanoparticles are melanin oligomers selected from the group consisting of monomers (each monomer having only one melanin base unit) and dimers, trimers, tetramers, and any combination thereof. In some embodiments, such as some of the aspects 1-61, the artificial melanin material disclosed herein optionally comprises artificial melanin nanoparticles, where each melanin oligomer is non-covalently associated with at least one other melanin oligomer via at least one of hydrogen bonds and π-π stacking of naphthalene rings. In some embodiments, such as some of Aspects 1-61, optionally, the artificial melanin material disclosed herein comprises artificial melanin nanoparticles, where each melanin oligomer is non-covalently associated with at least one other melanin oligomer or melanin monomer via at least one of hydrogen bonding and π-π stacking of naphthalene rings.In some embodiments, such as some of aspects 1-61, optionally, the artificial melanin material disclosed herein comprises artificial melanin nanoparticles, where the melanin monomer comprises a melanin building block.

[0171]

[0185] Optionally, in some embodiments, such as some of aspects 1-61, the artificial melanin material disclosed herein comprises artificial melanin nanoparticles, where at least 50%, optionally at least 75%, optionally at least 90%, optionally at least 95% of the nanoparticles are characterized by a sphericity of greater than 0.90. Optionally, in some embodiments, such as some of aspects 1-61, the artificial melanin material disclosed herein comprises artificial melanin nanoparticles, where the nanoparticles are characterized by a polydispersity index of 0.10 or less. Optionally, in some embodiments, such as some of aspects 1-61, the artificial melanin material disclosed herein comprises artificial melanin nanoparticles, where each nanoparticle has a size characteristic, such as a diameter, selected from the range of 10 nm to 1000 nm or less, optionally 100±50 nm to 300±50 nm. Optionally, in some embodiments, such as some of the aspects 1-61, the artificial melanin material disclosed herein comprises artificial melanin nanoparticles, where the average size characteristic, such as the average diameter of the artificial melanin nanoparticles, is selected from the range of 10 nm to 1000 nm or less, optionally 20 nm to 500 nm, optionally 100 nm to 900 nm, optionally 200 nm to 900 nm, optionally 100 nm to 800 nm, optionally more than 250 nm and less than 1000 nm. Optionally, in some embodiments, such as some of the aspects 1-61, the artificial melanin material disclosed herein comprises artificial melanin nanoparticles, where at least 55% (optionally at least 75%, optionally at least 80%, optionally at least 85%) of the nanoparticles each have a size characteristic, such as a diameter, selected from the range of more than 200 nm, optionally more than 250 nm to less than 1000 nm.Optionally, in some embodiments, such as some of the aspects 1-61, the artificial melanin material disclosed herein comprises artificial melanin nanoparticles, each nanoparticle having a size characteristic, such as a diameter selected from the range of 10 nm to 1000 nm or less, optionally 100 nm to 300 nm. Optionally, in some embodiments, such as some of the aspects 1-61, the artificial melanin material disclosed herein comprises artificial melanin nanoparticles, each nanoparticle having a size characteristic, such as a diameter selected from the range of 20 nm to 300±50 nm. Optionally, in some embodiments, such as some of the aspects 1-61, the artificial melanin material disclosed herein comprises artificial melanin nanoparticles, each nanoparticle having a size characteristic, such as a diameter selected from the range of 10 nm to 1000 nm or less, optionally 100 nm to 300 nm. Optionally, in some embodiments, such as some of aspects 1-61, the artificial melanin material disclosed herein comprises artificial melanin nanoparticles, wherein the plurality of artificial melanin nanoparticles are characterized by a peak size selected from the range of 10 nm to 1000 nm or less, optionally 100 nm to 200 nm. Optionally, in some embodiments, such as some of aspects 1-61, the artificial melanin material disclosed herein comprises artificial melanin nanoparticles, wherein the plurality of artificial melanin nanoparticles are characterized by a peak size selected from the range of 50 nm to 300 nm, optionally 50 nm to 200 nm.

[0172]

[0186] Optionally, in some embodiments, such as some of aspects 1-61, the artificial melanin material in the melanin formulation disclosed herein comprises artificial melanin nanoparticles, where the melanin formulation comprises a solvent or solvent mixture that is at least 50% water, optionally at least 75% water, optionally at least 90% water, optionally at least 95% by volume. According to certain embodiments, the solvent or solvent mixture comprises an organic solvent. According to certain embodiments, the solvent or solvent mixture comprises a buffer. According to certain embodiments, the organic solvent comprises methanol, ethanol, acetonitrile, acetone dichloromethane, dimethylformamide, ethyl acetate, acetone, or any combination thereof. In some embodiments, such as some of aspects 1-61, the artificial melanin nanoparticles are further aged or further oxidized after synthesis. In some embodiments, such as some of aspects 1-61, aging or further oxidation of the nanoparticles affects their solubility or dispersibility (in the melanin formulation) to increase their stability in the presence of organic solvents. According to certain embodiments, the nanoparticles in the melanin formulation are characterized by a zeta potential or average zeta potential selected from the range of -50 mV to -10 mV, optionally -40 to -20 mV, in a solvent or solvent solution that is optionally at least 95% water by volume. According to certain embodiments, the nanoparticles in the melanin formulation are stably dispersed without forming precipitates after at least 5 hours at a concentration selected from the range of 0.01 mg / mL to 5 mg / mL, optionally 0.01 mg / mL to 1 mg / mL, optionally within 20% of 0.1 mg / mL. According to certain embodiments, the nanoparticles in the melanin formulation are stably dispersed without forming precipitates after at least 12 hours at a concentration selected from the range of 0.01 mg / mL to 5 mg / mL, optionally 0.01 mg / mL to 1 mg / mL, optionally within 20% of 0.1 mg / mL.

[0173]

[0187] Optionally in some embodiments, such as some of aspects 1-61, the artificial melanin material disclosed herein includes melanin monomers, each of which has a substituted or unsubstituted naphthalene. Optionally in some embodiments, such as some of aspects 1-61, the artificial melanin material disclosed herein includes melanin monomers, each of which has a dihydroxynaphthalene. Optionally in some embodiments, such as some of aspects 1-61, the artificial melanin material disclosed herein includes melanin monomers, each of which has a 1,8-dihydroxynaphthalene. Optionally in some embodiments, such as some of aspects 1-61, the artificial melanin material disclosed herein includes melanin monomers, each of which does not contain nitrogen. According to certain embodiments, the artificial melanin material is not derived or extracted from a biological source or living organism.

[0174]

[0188] Optionally, in some embodiments, such as some of aspects 1-61, the artificial melanin material or the plurality of artificial melanin nanoparticles disclosed herein is characterized by a radical scavenging activity that is higher than the radical scavenging activity of a polydopamine nanoparticle having the same diameter as the plurality of artificial melanin nanoparticles under otherwise identical conditions. Optionally, in some embodiments, such as some of aspects 1-61, the artificial melanin material or the plurality of artificial melanin nanoparticles disclosed herein is characterized by a radical scavenging activity that is at least 10%, optionally at least 15%, optionally at least 50% higher than the radical scavenging activity of a polydopamine nanoparticle having the same diameter as the plurality of artificial melanin nanoparticles under otherwise identical conditions. Optionally, in some embodiments, such as some of aspects 1-61, the artificial melanin material or the plurality of artificial melanin nanoparticles disclosed herein is characterized by a radical scavenging activity of at least 0.012 mol / g using the 2,2-diphenyl-1-(2,4,6-trinitrophenyl)hydrazyl (DPPH) assay.

[0175]

[0189] In some embodiments, such as some of aspects 1-61, the artificial melanin materials disclosed herein optionally include one or more porous artificial melanin materials. In some embodiments, such as some of aspects 1-61, the artificial melanin materials disclosed herein optionally include (i) a porous artificial melanin material comprising one or more melanin oligomers, polymers, or combinations thereof, wherein the one or more melanin oligomers and / or polymers comprise a plurality of covalently bonded melanin building blocks; the melanin oligomers and / or polymers are arranged to form an internal structure having a plurality of pores. In some embodiments, such as some of Aspects 1-61, optionally, the artificial melanin material disclosed herein includes: (i) a porous artificial melanin material comprising one or more melanin oligomers, polymers, or combinations thereof, wherein the one or more melanin oligomers and / or polymers comprise a plurality of covalently bonded melanin building blocks; the melanin oligomers and / or polymers are arranged to form an internal structure having a plurality of pores; and the porous artificial melanin material has a diameter of less than 0.1 cm. 3 / g or more, optional 0.3cm 3 Optionally, in some embodiments, such as some of aspects 1-61, the artificial melanin materials disclosed herein are characterized by a pore volume per mass of material of 0.1 cm 2 / g or more, with at least some of the pores having at least one size dimension, such as a cross-sectional or longitudinal dimension, of 0.5 nm or more. 3 / g~0.6cm 3 / g, and optionally 0.1~1cm 3 / g, and optionally 0.3 cm 3 / g~0.6cm 3Optionally, in some embodiments, such as some of the aspects 1-61, the artificial melanin material disclosed herein includes a porous artificial melanin material that is a microporous material or a mesoporous material. Optionally, in some embodiments, such as some of the aspects 1-61, the artificial melanin material disclosed herein includes a porous artificial melanin material in which the pores of the porous artificial melanin material include micropores having at least one average size dimension, such as a cross-sectional dimension and / or a longitudinal dimension, respectively, selected from the range of 0.5 nm to 2.5 nm, and optionally 0.5 nm to 1.3 nm. Optionally, in some embodiments, such as some of the aspects 1-61, the artificial melanin material disclosed herein includes a porous artificial melanin material in which the pores of the porous artificial melanin material include mesopores having at least one average size dimension, such as a cross-sectional dimension and / or a longitudinal dimension, respectively, selected from the range of 2 nm to 50 nm, and optionally 2 nm to 25 nm. Optionally in some embodiments, such as some of aspects 1-61, the artificial melanin material disclosed herein includes a porous artificial melanin material, in which the pores are characterized by a distribution of pore sizes ranging from 0.5 nm to 50 nm. Optionally in some embodiments, such as some of aspects 1-61, the artificial melanin material disclosed herein includes a porous artificial melanin material, in which the pores of the internal structure are formed by organization of melanin oligomers and / or polymers of the porous artificial melanin material. Optionally in some embodiments, such as some of aspects 1-61, the artificial melanin material disclosed herein includes a porous artificial melanin material, in which the pores of the internal structure are formed by close-packing and / or self-assembly of melanin oligomers and / or polymers of the porous artificial melanin material. Optionally in some embodiments, such as some of aspects 1-61, the artificial melanin material disclosed herein includes a porous artificial melanin material, in which the pores of the internal structure are formed by templating of melanin oligomers and / or polymers of the porous artificial melanin material.Optionally in some embodiments, such as some of aspects 1-61, the artificial melanin materials disclosed herein include porous artificial melanin materials in which the pores are not uniformly distributed throughout the porous melanin material, for example because the material is non-crystalline and / or amorphous. Optionally in some embodiments, such as some of aspects 1-61, the artificial melanin materials disclosed herein include porous artificial melanin materials that are at least partially non-crystalline and / or amorphous materials. Optionally in some embodiments, such as some of aspects 1-61, the artificial melanin materials disclosed herein include porous artificial melanin materials in which the pores of the internal structure are randomly distributed. Optionally in some embodiments, such as some of aspects 1-61, the artificial melanin materials disclosed herein include porous artificial melanin materials in which the pores of the internal structure are arranged in a repeating structure, and the amorphous porous artificial melanin materials are arranged in an at least partially non-crystalline or amorphous state. In some embodiments, such as some of Aspects 1-61, optionally, the artificial melanin material disclosed herein comprises a porous artificial melanin material, wherein the pores of the porous artificial melanin material comprise one or more pore types selected from the group of cylindrical pores, channel-like pores, slit-shaped pores, ink bottle pores, and any combination thereof.

[0176]

[0190] Optionally in some embodiments, such as some of aspects 1-61, the artificial melanin material disclosed herein includes a porous artificial melanin material having porous melanin particles, such as nanoparticles. Optionally in some embodiments, such as some of aspects 1-61, the artificial melanin material disclosed herein includes a porous artificial melanin material having porous melanin particles characterized by an average size selected from the range of 20 nm to 500 nm in diameter. Optionally in some embodiments, such as some of aspects 1-61, the artificial melanin material disclosed herein includes a porous artificial melanin material having porous melanin particles that are one or more of solid particles, hollow particles, lacy particles, and any combination thereof. Optionally in some embodiments, such as some of aspects 1-61, the artificial melanin material disclosed herein includes a porous artificial melanin material having solid porous artificial melanin particles, e.g., having pores distributed, e.g., uniformly or randomly distributed, throughout the particle, and not having a hollow configuration. Optionally in some embodiments, such as some of aspects 1-61, the artificial melanin materials disclosed herein include porous artificial melanin materials having lacy porous artificial melanin particles, e.g., lacy porous artificial melanin particles having pores distributed throughout the particle, e.g., uniformly or randomly distributed, and no hollow configuration. Optionally in some embodiments, such as some of aspects 1-61, the artificial melanin materials disclosed herein include porous artificial melanin materials having hollow porous artificial melanin particles.

[0177]

[0191] In some embodiments, such as some of Aspects 1-61, optionally, the artificial melanin material disclosed herein comprises a porous artificial melanin material having purified or isolated porous melanin particles.

[0178]

[0192] In some embodiments, such as some of Aspects 1-61, optionally, the artificial melanin material disclosed herein comprises a porous artificial melanin material having melanin building blocks that are one or more substituted or unsubstituted catechol-based monomers, substituted or unsubstituted polyol-based monomers, substituted or unsubstituted phenol-based monomers, substituted or unsubstituted indole-based monomers, substituted or unsubstituted benzothiazine-based monomers, substituted or unsubstituted benzothiazole-based monomers, substituted or unsubstituted dopamine-based monomers, or any combination thereof.

[0179]

[0193] In some embodiments, such as some of the aspects 1-61, the artificial melanin material disclosed herein optionally comprises a porous artificial melanin material having or being an allomelanin. In some embodiments, such as some of the aspects 1-61, for example, at least some, and optionally all, of the melanin building blocks each independently comprise a substituted or unsubstituted naphthalene. In some embodiments, such as some of the aspects 1-61, for example, at least some, and optionally all, of the melanin building blocks each independently comprise a dihydroxynaphthalene. In some embodiments, such as some of the aspects 1-61, for example, at least some, and optionally all, of the melanin building blocks each independently comprise a 1,8-dihydroxynaphthalene. In some embodiments, such as some of the aspects 1-61, for example, at least some, and optionally all, of the melanin building blocks each independently comprise a 1,8-dihydroxynaphthalene. In some embodiments, such as some of the aspects 1-61, for example, at least some, and optionally all, of the melanin building blocks each independently comprise a compound represented by the formula FX1: [ka] In some embodiments, such as some of aspects 1-61, for example, each melanin oligomer does not include nitrogen.

[0180]

[0194] In some embodiments, such as some of aspects 1-61, the artificial melanin material disclosed herein optionally comprises a porous artificial melanin material having polydopamine. In some embodiments, such as some of aspects 1-61, for example, at least a portion, and optionally all, of the melanin building blocks each independently comprise a substituted or unsubstituted dopamine monomer. In some embodiments, such as some of aspects 1-61, for example, at least a portion, and optionally all, of the melanin building blocks each independently comprise a substituted or unsubstituted dihydroxydopamine monomer, a substituted or unsubstituted dioxydopamine monomer, a substituted or unsubstituted dihydroxynaphthalene monomer, a substituted or unsubstituted dioxydopamine monomer, and any combination thereof. In some embodiments, such as some of aspects 1-61, for example, at least a portion, and optionally all, of the melanin building blocks each independently comprise a 3,4-dihydroxydopamine monomer, a 3,4-dioxydopamine monomer, a 3,4-dihydroxynaphthalene monomer, and any combination thereof.

[0181]

[0195] In some embodiments, such as some of aspects 1-61, the artificial melanin material disclosed herein optionally comprises a porous artificial melanin material having allomelanin.

[0182]

[0196] Optionally in some embodiments, such as some of aspects 1-61, the artificial melanin material disclosed herein comprises a substituted or unsubstituted catechol-based or polyol-based compound. Optionally in some embodiments, such as some of aspects 1-61, the artificial melanin material disclosed herein comprises a substituted or unsubstituted dopamine monomer. Optionally in some embodiments, such as some of aspects 1-61, the artificial melanin material disclosed herein comprises a substituted or unsubstituted: dopamine monomer, 1,8-dihydroxynaphthalene or a derivative thereof, tyrosine monomer, tyramine monomer, amino acid, phenolamine, catecholamine, or any combination thereof. Optionally in some embodiments, such as some of aspects 1-61, the artificial melanin material disclosed herein comprises a substituted or unsubstituted: dopamine monomer, tyrosine monomer, tyramine monomer, or any combination thereof. Optionally in some embodiments, such as some of aspects 1-61, the artificial melanin material disclosed herein comprises a substituted or unsubstituted: dopamine monomer, tyrosine monomer, tyramine monomer, or any combination thereof. Optionally, in some embodiments, such as some of aspects 1-61, the artificial melanin material disclosed herein does not include phenol derivatives, resorcinol, and / or paraphenylenediamine. Optionally, the dopamine monomer is selected from the group consisting of substituted or unsubstituted: dihydroxydopamine monomer, dihydroxydopamine dimer, dihydroxydopamine oligomer, dioxydopamine monomer, dioxydopamine dimer, dioxydopamine oligomer, dihydroxynaphthalene monomer, dihydroxynaphthalene dimer, dihydroxynaphthalene oligomer, dioxydopamine monomer, dioxydopamine dimer, dioxydopamine oligomer, and any combination thereof. Optionally, the dopamine monomer is selected from the group consisting of tyrosine and derivatives, phenol and derivatives, resorcinol and derivatives, and any combination thereof. Optionally, the dopamine monomer is selected from the group consisting of phenol, resorcinol, L-DOPA, tyrosine, and any combination thereof. Optionally, the dopamine monomer is selected from the group consisting of a cysteine ​​derivative, a chalcogenide derivative, selenocysteine, and any combination thereof.In some embodiments, such as some of aspects 1-61, the artificial melanin material disclosed herein optionally comprises: [ka] , any combination thereof, and any derivative thereof. Optionally, in some embodiments, such as some of aspects 1-61, the artificial melanin material disclosed herein comprises one or more monomers selected from the group consisting of: [ka] (In the formula, R 1 ~R 7 one or more (optionally one, optionally two) of R 1 ~R 7 and each of the others is a functional group. 1 ~R 7 The remaining ones are hydrogen, C1 to C 10 Alkyl, C3-C 10 Cycloalkyl, C5-C 10 Aryl, C5-C 10 Heteroaryl, C1-C 10 Acyl, C1-C 10 Hydroxyl, C1-C 10 Alkoxy, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C5-C 10 Alkylaryl, -COR 30 , -CONR 31 R 32 , -COR 33 , -NR 39 R 40 , -NR 41 COR 42 , C1~C 10 is selected from the group consisting of alkyl halide, acrylate, or catechol; 30 ~R 42 Each of is independently hydrogen, C1 to C10 Alkyl or C5-C 10 Optionally, for any method disclosed herein, the artificial melanin precursor is of formula (FX3): [ka] (In the formula, R 1 ~R 8 one or more (optionally one, optionally two) of R 1 ~R 8 and each of the others is a functional group. 1 ~R 7 The remaining ones are hydrogen, C1 to C 10 Alkyl, C3-C 10 Cycloalkyl, C5-C 10 Aryl, C5-C 10 Heteroaryl, C1-C 10 Acyl, C1-C 10 Hydroxyl, C1-C 10 Alkoxy, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C5-C 10 Alkylaryl, -COR 30 , -CONR 31 R 32 , -COR 33 , -NR 39 R 40 , -NR 41 COR 42 , C1~C 10 is selected from the group consisting of alkyl halide, acrylate, or catechol; 30 ~R 42 Each of is independently hydrogen, C1 to C 10 Alkyl or C5-C 10aryl. In some embodiments, such as some of aspects 1-61, the artificial melanin materials disclosed herein optionally include one or more thiol-reactive moieties. Optionally, the thiol-reactive moieties are one or more groups selected from the group consisting of thiols, maleimides, pyridyl disulfide-based compounds, alkenes, alkyl halides, and any combination thereof. In some embodiments, such as some of aspects 1-61, the artificial melanin materials disclosed herein optionally include one or more monomers having the formula (FX2) or (FX3), where R 1 ~R 8 One or more of are thiol-reactive moieties, such as thiols, maleimides, pyridyl disulfide-based compounds, alkenes, alkyl halides, and any combination thereof.

[0183]

[0197] Optionally, in some embodiments, such as some of aspects 1-61, the artificial melanin materials disclosed herein include one or more artificial selenomelanin materials having one or more selenomelanin polymers, the one or more selenomelanin polymers comprising a plurality of covalently bonded selenomelanin building blocks; and the chemical formula of each of the one or more selenomelanin building blocks comprises at least one selenium atom. Optionally, each selenomelanin polymer is a pheomelanin. Optionally, each of the selenomelanin monomers is an amino acid. Optionally, the chemical formula of each of the one or more selenomelanin building blocks comprises at least one covalent bond with each of the at least one selenium atom. Optionally, each of the one or more selenomelanine polymers is not bound to, conjugated to, attached to, coated by, encapsulated by, or otherwise chemically associated with a natural or biological proteinaceous matrix, component, or lipid. Optionally, each of the plurality of selenomelanine building blocks is not bound to, conjugated to, attached to, coated by, encapsulated by, or otherwise chemically associated with a natural or biological proteinaceous matrix, component, or lipid. Optionally, the chemical formula of each of the one or more selenomelanine building blocks includes one selenium atom and two covalent bonds to the selenium atom. Optionally, the chemical formula of each of the one or more selenomelanine building blocks includes substituted or unsubstituted benzoselenazine or a derivative thereof, substituted or unsubstituted benzoselenazole or a derivative thereof, substituted or unsubstituted 7,10-dihydro-2H-[1,4]selenazino[3,2-h]isoquinolin-3(4H)-one or a derivative thereof, substituted or unsubstituted benzoselenazinone or a derivative thereof, or any combination thereof.Optionally, each of the one or more selenomelanin building blocks comprises a moiety characterized by the formula FX11, FX12, FX13A, FX13B, FX14, any combination thereof, or a derivative of any of these: [ka] Optionally, each of the one or more selenomlanine building blocks comprises a moiety characterized by the formula FX11, FX12, FX13A, FX13B, FX14, or any combination thereof. Optionally, each of the one or more selenomlanine building blocks comprises a moiety characterized by the formula FX11, FX12, FX13A, FX13B, FX14, or any combination thereof. Optionally, each of the one or more selenomlanine building blocks comprises a moiety characterized by the formula FX11, FX12, FX13A, FX13B, or FX14. Optionally, each of the one or more selenomlanine building blocks comprises a moiety characterized by the formula FX11. Optionally, the artificial selenomlanine material is one or more of an artificial selenomlanine nanoparticle, an artificial selenomlanine layer, or an artificial selenomlanine thin film. Optionally, the artificial selenomlanine material is one or more of artificial selenomlanine nanoparticles. Optionally, each of the one or more selenomlanine building blocks includes a heterocyclic moiety that includes Se as a member of its ring structure. Optionally, each of the one or more selenomlanine building blocks includes a heterocyclic moiety that includes Se and N as members of its ring structure. Optionally, each of the one or more selenomlanine building blocks includes a moiety characterized by the formula FX23, FX24, FX25, FX26, FX27, a derivative of any one of these, or any combination thereof: [ka] Optionally, each of the one or more selenomelanine building blocks comprises a moiety characterized by the formula FX23, FX24, FX25, FX26, FX27, or any combination thereof. Optionally, each of the one or more selenomelanine building blocks comprises a moiety characterized by the formula FX23, FX24, FX25, FX26, or FX27. Optionally, each of the selenomelanine monomers is characterized by the formula FX15, FX16, FX17, FX18, FX19, FX20, or FX21: [ka] .

[0184]

[0198] In some embodiments, such as some of Aspects 1-61, optionally, the artificial melanin materials disclosed herein include one or more artificial selenomelanin materials, wherein each of the one or more selenomelanin polymers is not bound to, conjugated to, attached to, coated by, encapsulated by, or otherwise chemically associated with a natural or biological proteinaceous matrix, component, or lipid.

[0185]

[0199] Optionally in some embodiments, such as some of Aspects 1-61, the artificial melanin material disclosed herein comprises one or more artificial seleno-melanin materials, wherein the chemical formula of each of the one or more seleno-melanin building blocks comprises benzoselenazine, and the material comprises a concentration of benzoselenazine selected from the range of 10 wt.% to 100 wt.%. Optionally in some embodiments, such as some of Aspects 1-61, the artificial melanin material disclosed herein comprises one or more artificial seleno-melanin materials having a concentration of benzoselenazine selected from the range of 50 wt.% to 60 wt.%. For example, the chemical formula of each of the one or more seleno-melanin building blocks comprises benzoselenazine, and the material comprises a concentration of benzoselenazine of 55 wt.%. In some embodiments, such as some of aspects 1-61, the artificial melanin material disclosed herein optionally includes one or more artificial seleno-melanin materials characterized by a concentration of selenium selected from the range of 2 wt.% to 23 wt.%. For example, the artificial seleno-melanin material can be characterized by a concentration of 12 wt.% selenium.

[0186]

[0200] In some embodiments, such as some of the aspects 1-61, optionally the artificial melanin material in the melanin formulation disclosed herein comprises one or more artificial seleno-melanin materials, wherein the solvent or solvent mixture is at least 50% water. In some embodiments, such as some of the aspects 1-61, optionally the artificial melanin material in the melanin formulation disclosed herein comprises one or more artificial seleno-melanin materials having artificial seleno-melanin nanoparticles characterized by an absolute value of zeta potential selected from the range of 15mV to 50mV, preferably 20mV to 50mV, optionally 15mV to 40mV, optionally 20mV to 40mV, optionally 15mV to 30mV, optionally 20mV to 30mV, optionally 17mV to 34mV. (The absolute value, or modulus, of a real number is a real, non-negative value, regardless of its sign.) Optionally, the sign of the zeta potential corresponding to the artificial seleno-melanine nanoparticles in the artificial seleno-melanine nanoparticle dispersion is negative. Optionally, in some embodiments, such as some of aspects 1-61, the artificial melanin material in the melanin formulations disclosed herein has a zeta potential of 0.1 mg / mL to 10 mg / mL, relative to the average size of the nanoparticles at a concentration of 0.1 mg / mL. -4In some embodiments, such as some of the aspects 1-61, the artificial melanin material in the melanin formulation disclosed herein optionally comprises one or more artificial seleno-melanin materials having artificial seleno-melanin nanoparticles that are size stable at a nanoparticle concentration selected from the range of mg / mL. In some embodiments, such as some of the aspects 1-61, the artificial melanin material in the melanin formulation disclosed herein optionally comprises one or more artificial seleno-melanin materials having artificial seleno-melanin nanoparticles that are size stable when exposed to a concentration of NaCl in the dispersion selected from the range of 50 mM to 250 mM, preferably a concentration of NaCl that is 250 mM, relative to the average size of the nanoparticles in the equivalent dispersion without NaCl. In some embodiments, such as some of the aspects 1-61, optionally the artificial melanin material in the melanin formulations disclosed herein comprises one or more artificial selenomelanin materials having artificial seleno-melanin nanoparticles that are stably dispersed in the dispersion under ambient conditions for at least 7 days, preferably at least 14 days, preferably at least 60 days.

[0187]

[0201] In some embodiments, such as some of aspects 1-61, optionally the artificial melanin material in the melanin formulations disclosed herein comprises one or more artificial seleno-melanin materials having artificial seleno-melanin nanoparticles characterized by a melanin purity of at least 20%, optionally at least 25%, optionally at least 30%, preferably at least 50%, more preferably at least 70%, even more preferably at least 80%, yet even more preferably at least 90%, more preferably for some applications at least 95%, even more preferably for some applications at least 99%, and yet even more preferably for some applications at least 99.9%. In some embodiments, such as some of aspects 1-61, optionally the artificial melanin material in the melanin formulation disclosed herein comprises one or more artificial seleno-melanin materials having artificial seleno-melanin nanoparticles, wherein at least 50%, optionally at least 75%, preferably at least 90%, more preferably at least 95%, even more preferably at least 99%, of the plurality of artificial melanin nanoparticles each comprise a seleno-melanin polymer having a seleno-melanin building block comprising a moiety characterized by the formula FX11, FX12, FX13A, FX13B, FX14, or any combination thereof: [ka] In some embodiments, such as some of aspects 1-61, optionally the artificial melanin material in the melanin formulation disclosed herein comprises one or more artificial seleno-melanin materials having artificial seleno-melanin nanoparticles, wherein at least 50%, optionally at least 75%, preferably at least 90%, more preferably at least 95%, even more preferably at least 99% of the plurality of artificial melanin nanoparticles each comprise a seleno-melanin polymer having a seleno-melanin building block that includes a heterocyclic moiety that includes Se as a member of its ring structure. In some embodiments, such as some of the aspects 1-61, optionally the artificial melanin material in the melanin formulation disclosed herein comprises one or more artificial seleno-melanin materials having artificial seleno-melanin nanoparticles, wherein at least 50%, optionally at least 75%, preferably at least 90%, more preferably at least 95%, even more preferably at least 99%, of the plurality of artificial melanin nanoparticles each comprise a seleno-melanin polymer having a seleno-melanin building block that includes a heterocyclic moiety that includes Se and N as members of its ring structure. In some embodiments, such as some of aspects 1-61, optionally the artificial melanin material in the melanin formulation disclosed herein comprises one or more artificial seleno-melanin materials having artificial seleno-melanin nanoparticles, wherein at least 50%, optionally at least 75%, preferably at least 90%, more preferably at least 95%, even more preferably at least 99% of the plurality of artificial melanin nanoparticles each comprise a seleno-melanin polymer having a seleno-melanin building block comprising a moiety characterized by the formula FX23, FX24, FX25, FX26, FX27, a derivative of any one of these, or any combination thereof.In some embodiments, such as some of aspects 1-61, optionally the artificial melanin material in the melanin formulation disclosed herein comprises one or more artificial selenomelanin materials having artificial seleno-melanin nanoparticles, wherein at least 50%, optionally at least 75%, preferably at least 90%, more preferably at least 95%, even more preferably at least 99% of the plurality of artificial melanin nanoparticles each comprise a seleno-melanin polymer having a seleno-melanin building block comprising a moiety characterized by the formula FX23, FX24, FX25, FX26, FX27, or any combination thereof. In some embodiments, such as some of aspects 1-61, optionally the artificial melanin material in the melanin formulation disclosed herein comprises one or more artificial selenomelanin materials having artificial seleno-melanin nanoparticles, wherein at least 50%, optionally at least 75%, preferably at least 90%, more preferably at least 95%, even more preferably at least 99% of the plurality of artificial melanin nanoparticles each comprise a seleno-melanin polymer having a seleno-melanin building block comprising a moiety characterized by the formula FX23, FX24, FX25, FX26, or FX27. Optionally in some embodiments, such as some of Aspects 1-61, the artificial melanin material in the melanin formulations disclosed herein comprises one or more artificial selenomelanin materials having artificial seleno-melanin nanoparticles, each of which is not bound to, conjugated to, attached to, coated by, encapsulated by, or otherwise chemically associated with a natural or biological proteinaceous matrix, component, or lipid.Optionally in some embodiments, such as some of Aspects 1-61, the artificial melanin material in the melanin formulation disclosed herein comprises one or more artificial seleno-melanin materials having artificial seleno-melanin nanoparticles, each of which is free of artificial melanin monomers, at least 50%, optionally at least 75%, preferably at least 80%, preferably at least 90%, more preferably at least 95%, even more preferably at least 99% of the artificial seleno-melanin nanoparticles. Optionally in some embodiments, such as some of Aspects 1-61, the artificial melanin material in the melanin formulation disclosed herein comprises one or more artificial seleno-melanin materials having artificial seleno-melanin nanoparticles, each of which is free of artificial melanin monomers. For example, the artificial selenomlanin material, such as nanoparticles, may be washed extensively with HCl solution (e.g., once) and pure water (e.g., three times), such that the artificial selenomlanin material, or a dispersion or formulation thereof, is free of artificial selenomlanin monomers, as characterized by solid-state NMR, UV-Vis spectroscopy, or the like. Optionally, the melanin formulations disclosed herein include a concentration of melanin monomers that is lower than the IC50 of each monomer. Optionally, in some embodiments, such as some of aspects 1-61, the artificial melanin material in the melanin formulations disclosed herein includes one or more artificial selenomlanin materials having artificial selenomlanin nanoparticles, each of which is outside (extracellular) of a biological cell.

[0188]

[0202] The present invention can be further understood from the following non-limiting examples.

[0189]

[0203] Example 1A: Synthetic melanin promotes tissue repair

[0204] While not wishing to be limited by any particular theory, the examples include some illustrative, but non-limiting, methods, materials, processes, techniques, compositions, formulations, and the like that are useful in the practice of the invention, as well as illustrative, but non-limiting data, arguments, and hypotheses. It will be recognized that regardless of the ultimate correctness of any mechanistic explanation or hypothesis, certain embodiments of the invention may nevertheless be valid and useful.

[0190]

[0205] Melanin is a widespread biopolymer that is widely distributed across different organisms. 1 In humans, melanin is produced by melanosome organelles found in melanocytes, which are uniquely the only known cells capable of excreting the organelles extracellularly, primarily to keratinocytes within the skin. 2 Melanin, known inter alia as the dark brown or black pigment in the skin, acts as a broadband radiation absorber. 3、4 Melanosome production increases with increasing UV exposure, aiding in UV radiation protection. The properties of melanin are not limited to photoprotection; it provides structural coloration, 5 Metal chelation, 6 Small molecule absorption, 7~9 and thermoregulation 10 Melanin has numerous other functions not characteristic of biological pigments, which may explain its ubiquitous presence in nature, including: 8 The richness of intermolecular interactions is due to the various functional groups of melanin, including catechol, carboxyl, and amine. Due to the different oxidation states of its catechol groups, melanin can accept and donate electrons, allowing for redox activity. 11 Additionally, it has antioxidant activity due to its electron donating ability. Melanin has been shown to quench radical oxygen species (ROS) and other reactive oxygen species that are mutagenic, carcinogenic, cause the production of DNA strand breaks, and create DNA-protein crosslinks. 1、4、12The ability to prevent cell damage via the ROS pathway may be the primary way in which melanin protects against radiation. The use of antioxidants for wound healing has been investigated, and it is contemplated that they may accelerate wound healing through mediation of oxidative stress. 13、14 These properties suggest that the role of melanin in the organism, and in our own skin, may be more complex than we know.

[0191]

[0206] In this example, we synthesize well-defined nanoscale synthetic melanin particles (SMPs). SMPs are synthesized through the oxidative polymerization of dopamine. Synthetic melanin mimics have applications in bioimaging due to their biocompatibility and myriad functionalities. 15 , Drug Delivery 16 , and theranostics 17 Melanin has been used extensively in biomedical applications, including in the treatment of cancer. Of interest is the ability of melanin to scavenge radical oxygen species for wound healing purposes. As a result of thermal, chemical, or puncture wounds, different pathways can be signaled to release excess ROS that have deleterious wound healing effects. 18、19 In this example, we use low and high surface area synthetic melanin particles synthesized based on previous methods. 20 To investigate the importance of melanin availability to skin after chemical and thermal wound models, low and high surface area particles are applied. Upon application of SMP, inflammation and wound area are reduced. The advantage of high surface area SMP over low surface area SMP in tissue repair is observed. The mechanism behind these wound healing properties is addressed and an increase in superoxide dismutase activity is found.

[0192]

[0207] Example results:

[0208] PDA Nanoparticles: Synthesis and Characterization:

[0209] Porous and solid melanin mimics were synthesized through oxidative polymerization of dopamine based on a previously reported method (Figure 1A-G). 20The surface area and morphology of the particles were characterized using N adsorption, dynamic light scattering, and ultraviolet-visible (UV-vis) spectroscopy (Figures 7A-7D). As previously reported, high surface area synthetic melanin particles (HSA-SMPs) were synthesized with a 190 μm 2 / g and pores of approximately 14 and 30 Å, whereas the low surface area synthetic melanin particles (LSA-SMP) had a BET area of ​​20 m 2 The porous structure was non-porous with a BET area of ​​100 nm / g (FIGS. 7A to 7B). 20 By DLS, HSA-SMP had a hydrodynamic diameter of 220±50 nm, and LSA-SMP had a hydrodynamic diameter of 320±10 nm (FIG. 7C). In addition, LSA and HSA-SMP appeared identical by UV-vis spectroscopy (FIG. 7D). Both particles had an absorption maximum around 200 nm with a shoulder and broad absorption tail at 300 nm. Except for porosity, the two particles had similar properties. Neither HSA nor LSA-SMP was able to penetrate the stratum corneum of the skin (FIGS. 1E-F).

[0193]

[0210] The entrapment activity of HSA-SMP and LSA-SMP was also assessed using the DPPH assay (Figure 1G). HSA-SMP achieved higher entrapment activity at lower particle concentrations than LSA-SMP. The entrapment activity of both particles plateaued around 100ug, with HSA-SMP achieving approximately 90% entrapment activity and LSA-SMP achieving approximately 80%. The entrapment activity was consistent between different batches of particles (Figure 8A). The entrapment activity decreased to approximately 40% for both SM particles when used again (Figure 8B).

[0194]

[0211] PDA nanoparticle treatment improves skin healing after NM-induced injury:

[0212] To test the hypothesis that treatment with topical SMP improves wound healing, we utilized a NM-induced chemical injury mouse model. Topical NM was applied to the shaved skin of each mouse. Two hours later, topical SMP was applied to the wound site. Topical SMP application was repeated at 24 and 48 hours. Animals were monitored for up to 16 days. Double-fold skin thickness, a surrogate for skin edema, was measured until tough scab formation prevented accurate measurement, usually for several days. Photographs of the injury site were taken daily to track wound closure (Figure 2A).

[0195]

[0213] Treatment with either type of SMP improved wound healing as evidenced by a faster rate of wound area reduction (FIG. 2B) and time to eschar detachment (FIG. 2D) compared to the vehicle group. HSA-SMP-treated animals healed faster than both the vehicle and LSA-SMP groups, with 50% of HSA mice exhibiting eschar detachment 11 days after injury compared to 30% and 0% of the LSA and vehicle groups, respectively (FIG. 2D). Furthermore, only HSA-SMP-treated animals experienced a significant reduction in skin edema compared to vehicle-treated mice (FIG. 2C).

[0196]

[0214] Despite our consideration of this effect by implementing a 2-hour time interval, the same experiment was repeated using a UV radiation-induced injury model to confirm that physical adsorption of NM in SMP-treated mice did not affect the severity of the initial injury. We again found that SMP treatment resulted in reduced skin edema and a faster rate of wound closure.

[0197]

[0215] PDA nanoparticle treatment increases SOD activity after NM injury:

[0216] Skin injury leads to excessive release of ROS. Antioxidant enzymes play a major role in protecting against the harmful effects of ROS. One of the most important antioxidant enzymes is SOD. Known to be affected by skin injury, we evaluated how SOD activity was affected by SMP treatment. We assessed SOD activity from skin samples collected 24, 48, and 72 hours after NM injury using a commercially available colorimetric kit that measures the dismutation of superoxide radicals. We found that NM-treated mice had significantly lower SOD activity (p<0.01) than controls 24 hours after injury. Treatment with either type of SMP significantly improved SOD activity compared to the vehicle group (p<0.05 for both) (Figure 3A). At 48 and 72 hours after injury, the SMP-treated groups continued to show improved SOD activity compared to vehicle, but only HSA-SMP treatment achieved statistical significance.

[0198]

[0217] To investigate whether other antioxidant enzymes were affected by SMP treatment, we measured the activities of thioredoxin reductase, e and catalase, but found no statistically significant differences between the experimental groups under the specific conditions of the embodiment.

[0199]

[0218] Porous PDA nanoparticles downregulate inflammatory and apoptotic pathways:

[0219] Next, we used Taqman mouse immunoarray to confirm the possible mechanism of SMP activity. Because each array card can only accommodate four samples, we pooled the genetic information from three mice per condition to create a single representative sample for each group. We repeated the assay three times, using different pooled samples from each group, except for the untreated group, which was used to bridge the data obtained for analysis. In the analysis, the NM+vehicle group was used as a reference.

[0200]

[0220] Following NM-induced injury, treatment with HSA SMP significantly downregulated 29 genes compared to vehicle-treated animals (Figures 4A-G and S11). In the LSA-SMP-treated group, only two genes (Bcl2 and Ece1) were statistically significantly downregulated due to the large variability between individual arrays, but the trend was toward downregulation of inflammation-related genes (Figure S11). Analysis of this gene expression data using the PANTHER Classification System identified "inflammation mediated by chemokine and cytokine signaling" and "apoptotic signaling" as two of the major enriched pathways in SMP-treated mice, each containing seven differentially expressed genes compared to the vehicle group (Figure 4A). See Table 1 for TaqMan Mouse Immune Array results corresponding to gene downregulation by HSA-SMP compared to the vehicle group corresponding to the category "apoptotic signaling" and Table 2 for TaqMan Mouse Immune Array results corresponding to gene downregulation by HSA-SMP compared to the vehicle group corresponding to the category "inflammation mediated by chemokine and cytokine signaling."

[0201] [Table 1]

[0202] [Table 2]

[0203]

[0221] In addition to inducing oxidative stress, vesicants such as NM also induce pro-inflammatory signaling through the mitogen-activated protein kinase (MAPK) pathway [Kumar, 2015]. We performed western blotting analysis to determine the effect of SMP treatment on MAPK pathway (ERK1 / 2, p38, JNK) signaling. We found that treatment with either type of SMP significantly inhibited phosphorylation of ERK1 / 2 at 24 hours post-injury (Figure 5A-B), while p38 phosphorylation was unaffected. Since MAPK pathway signaling controls a myriad of inflammatory mediators at the translational and transcriptional levels [citation], we sought to determine whether changes in SMP treatment-associated signaling would translate into altered expression of known NM injury-associated pro-inflammatory mediators. Expression of MMP9 was significantly reduced by HSA-SMP at both 48 and 72 hours post-injury and by LSA-SMP at 72 hours.

[0204]

[0222] To confirm that SMP treatment inhibited apoptosis, we performed terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining of skin samples collected from each experimental group. As expected, only NM injury resulted in strong TUNEL positive staining (Figures 4A-G). TUNEL staining was significantly reduced in mice treated with either SMP compared to the vehicle-only group in mean fluorescence intensity (p<0.05 for both), indicating reduced apoptosis (Figures 4A-G).

[0205]

[0223] Inhibition of Cu / Zn SOD partially reverses the effect of SMP on cutaneous wound healing

[0224] The sample preparation method we used to measure SOD activity aids in the isolation of cytosolic SOD1, which contains Cu and Zn. Therefore, to determine whether the beneficial effects of SMP on wound repair depend on SOD1 activation, we repeated the animal experiments in the presence of ATN-224, a small molecule copper chelator and a well-known inhibitor of SOD1. Based on literature data, the lack of SOD1 was expected to have a negative effect on wound healing, and we attempted to provide a treatment regimen (i.e., inhibitor dose and duration of treatment) that would produce a relatively mild effect on wound healing, comparable to animals not exposed to the inhibitor.

[0206]

[0225] Images of the wounds are shown in FIG. 2A. The development of NM-induced edema was slightly more pronounced in all groups treated with ATN-224 compared to the PBS (vehicle for ATN-224) control group. We then confirmed that treatment with ATN-224 inhibited the upregulation of SOD activity in mouse skin. After confirming that treatment with ATN-224 inhibited the upregulation of SOD activity in our mice, we found that ATN-224 treatment further prevented any reduction in edema, blunted the improvement in wound healing rate, and limited the inhibition of apoptosis previously observed in ATN-224- / SMP+ mice. However, both ATN-224+ / SMP+ groups still healed faster than the ATN-224+ / SMP- group, but there was no statistically significant difference between the SMP groups. Thus, inhibition of Cu / Zn SOD at least partially reversed the beneficial effects of PDA NPs on skin wound healing.

[0207]

[0226] Synthetic melanin particle treatment mitigates NM-induced damage in human skin explants:

[0227] We evaluated the effect of SMP treatment on injured human skin using ex vivo skin explants obtained from healthy donors undergoing laparoscopic surgery. NM-induced injury resulted in characteristic histopathological features including disruption of the epidermal-dermal junction, epithelial separation (bleb formation), and nuclear pyknosis of keratinocytes.

[0208]

[0228] It was also found that exposure of healthy human skin to therapeutic doses of NM (0.016% w / w mechlorethamine gel) resulted in the upregulation of a signature set of pro-inflammatory genes. Suppression of these genes by vitamin D3 treatment suggested their specific role in healing. It was considered whether the expression of this set of genes would be altered by SMP treatment of human skin explants.

[0209]

[0229] Non-limiting discussion: Novel particles, topical application:

[0230] Topical application of synthetic melanin particles (SMPs) improved skin healing after chemical and thermal injury. Melanin is a natural polymeric biomaterial that plays a role in skin protection from radiation. Due to its electron-rich functional groups, melanin has a complex redox potential that allows it to scavenge radical oxygen species and adsorb other harmful molecules generated in the skin during UV radiation exposure. This antioxidant activity of melanin is particularly interesting because it has previously been shown to aid in wound healing. The massive accumulation of reactive oxygen species generated by wound injury can prolong or block the transition from the inflammatory to the proliferative phase. Thus, biocompatible radical scavenging materials are attractive for tissue repair after chemical or thermal wounding.

[0210]

[0231] Non-toxic, biocompatible synthetic melanin particles (SMPs) have been synthesized to mimic natural melanin in skin. Previous studies have been performed on melanin nanoparticles similar to low surface area particles (LSA-SMPs) in 2D cell cultures of human adult keratinocyte cells (HEKa), which showed no significant changes in toxicity or cell viability. 21To further elucidate the role of melanin in wound healing, high surface area particles (HSA-SMP) with increased catechol concentration and possible trapping sites were synthesized compared to low surface area particles (LSA-SMP). Although 2D keratinocyte cells can take up SMP, neither LSA nor HSA-SMP penetrate the stratum corneum of skin when applied topically, yet they still exhibit wound healing capabilities, including reducing wound area size and skin thickness. Overall, both LSA and HSA-SMP showed wound healing effects, with HSA-SMP outperforming LSA-SMP in certain cases. As seen in the radical scavenging DPPH assay, HSA-SMP has higher radical scavenging activity at lower concentrations and may be more efficient than LSA-SMP in quenching radicals, contributing to its superior performance.

[0211]

[0232] ROS; (skin) ROS in wounds:

[0233] ROS are highly reactive molecules formed when O2 is reduced with an additional electron. The most studied molecules within this family include superoxide anion, peroxide, hydrogen peroxide, hydroxyl radical, and hydroxyl ion. During homeostasis, basal levels of ROS are tightly regulated and are responsible for keeping normal cells functioning, while changes in ROS levels can induce proapoptotic signaling or cell cycle arrest.

[0212]

[0234] Role of SOD and SOD1:

[0235] The SOD family has three isoforms: Cu / Zn SOD1, which is found predominantly in the cytoplasm, Mn / Zn SOD2, which is in the mitochondrial matrix, and Cu / Zn SOD3, which is located extracellularly.

[0213]

[0236] Inflammatory pathways, apoptosis:

[0237] Stimulation of the MAPK pathway leads to the activation of several different cellular events, including inflammatory responses, apoptosis, migration, proliferation, etc. Exposure of mouse skin to vesicants such as sulfur mustard, NM, and SEES was shown to result in MAPK phosphorylation, supporting the idea that MAPK plays a role in the inflammatory responses triggered by these agents. Thus, Kumar et al. showed that after NM injury in mouse skin, there was a significant increase in the phosphorylation of ERK1 / 2, p38, and JNK1 / 2, as well as in the levels of pro-inflammatory molecules such as TNFα, iNOS, and MMP9. Meanwhile, ROS were involved in the activation of MAPK. Data indicate that reduction of ROS load by SMP reduced pro-inflammatory signaling, reduced ERK1 / 2 phosphorylation, and inhibited apoptosis in injured mouse skin.

[0214]

[0238] Example 1B: Exemplary, non-limiting materials and methods correspond to Example 1A.

[0239] Materials: Tetraethyl orthosilicate (TEOS) and 25 wt% poly(acrylic acid) solution (PAA) were purchased from Acros Organics. Hexadecyltrimethylammonium bromide (CTAB) was ordered from Tokyo Chemical Industry Co., Ltd. (TCI). Dopamine hydrochloride was obtained from Alfa Aesar. Ammonium hydroxide was purchased from Fisher Scientific. Hydrofluoric acid (HF), ethanol, and Trizma@Base (Tris) were obtained from Sigma Aldrich. All materials were used as received without further purification.

[0215]

[0240] Preparation of mesoporous silica templates: Mesoporous silica nanoparticles (MS) used as templates were synthesized based on previous literature methods. 220.55g of CTAB and 3.00g of PAA were dissolved in 25mL of ultrapure water and the vigorously stirred solution was clear. 2.0g of ammonium hydroxide was added to the stirred solution. After 20 minutes, 2.08g of TEOS was added and stirred for another 15 minutes. The solution was then placed in an oven at 120°C for 48 hours. The mixture was then centrifuged and dried, after which the particles were calcined at 550°C for 6 hours to remove the remaining organic template.

[0216]

[0241] Preparation of PDA porous: PDA porous was prepared based on the reported literature method. 20 250 mg of MS was sonicated in ultrapure water for 1 h. To 225 mL of ultrapure water and 25 mL of ethanol (9:1 H2O:EtOH by volume), 250 mg of MS and 225 mg of dopamine were added and stirred at room temperature for 1 h. Tris (10 mM, pH 8.5) was then added to the reaction and stirred for an additional 4 h. After the allotted time, the reaction was centrifuged and washed five times with ultrapure water. The template was removed through an overnight hydrofluoric acid (10 wt%) etch, then centrifuged and washed five times with ultrapure water.

[0217]

[0242] Preparation of PDA solid: PDA solid was synthesized through oxidative polymerization of dopamine. Briefly, 900 mg of dopamine was dissolved in 300 mL of ultrapure water, and 4 mL of 1 M NaOH was added to the solution at room temperature and stirred for 18 h. The solution was then centrifuged and washed five times with ultrapure water.

[0218]

[0243] DPPH assay for radical scavenging activity: The DPPH radical scavenging activity of PDA porous and solid was determined according to the reported literature method. 23100 μL of PDA nanoparticles dispersed in water were added to a 1.8 mL solution of DPPH (0.2 mM in 95% ethanol). The total amount of PDA particles was varied from 5 to 200 μg. The solutions were left in the dark for 20 minutes. Afterwards, the scavenging activity was monitored by taking the absorbance of the solution at 516 nm. The following calculation (Equation 1) was used to determine the DPPH radical scavenging activity:

[0219]

number

[0220] I is the DPPH radical scavenging activity, A i is the absorbance of the sample containing DPPH, and A j is the absorbance of the sample without DPPH, and A c is the absorbance of the DPPH without PDA sample.

[0221]

[0244] Characterization: All PDA particles were initially characterized by transmission electron microscopy (TEM, Hitachi Ltd. HT-7700, 120KV, or STEM, Hitachi Ltd. HD-2300A, 200KV). Dynamic light scattering (DLS, Malvern Instruments Ltd, Nano ZS), zeta potential (Malvern Instruments Ltd, Nano ZS), and ultraviolet-visible spectroscopy (UV-Vis, Agilent Technologies Cary 100 UV-Vis) were used to investigate the hydrodynamic diameter.

[0222]

[0245] Sample activation: Samples were thermally activated under vacuum at 100°C for mesoporous silica and 75°C for pre-etched PDA porous using a Micromeritics Smart VacPrep.

[0223]

[0246] PDA samples were activated using a tousimis SAMDRI-PVT-3D Advanced Manual Critical Point Dryer. Prior to activation, samples were exchanged into ethanol overnight. Using the supercritical dryer, samples were added to the sample chamber, cooled to 0-10°C, and pressurized to 800 psi. Ethanol was exchanged with liquid CO2 for 10 hours, purging the system for 5 minutes every 2 hours. After the fifth purge, the temperature was raised to 40°C and the system was pressurized to 1200-1400 psi. Pressure was slowly released overnight at a rate of 0.5 cc / min. Samples were immediately transferred onto a Micromeritics Smart VacPrep and placed under vacuum at 25°C for 2 hours before adsorption measurements.

[0224]

[0247] Nitrogen isotherms: For the silica and pre-etched PDA porous samples, N2 isotherms were collected on a Micromeritics TriStar physisorption instrument at 77K.

[0225]

[0248] For the PDA samples, nitrogen physisorption measurements were collected using a Micromeritics ASAP 2020 instrument at 77 K. Pore size distributions were obtained using density functional theory (DFT) calculations with carbon slit geometry and the N2DFT model.

[0226]

[0249] Animals: All animal studies were approved by the Northwestern University IACUC. Six to eight week old C57BL / 6J female mice were purchased from Jackson Laboratories.

[0227]

[0250] Nitrogen mustard skin injury model: The dorsal flank of mice was shaved and chemically depilated 48 hours prior to skin injury induction. Mice were anesthetized and placed on a heat pad under a chemical fume hood. A 0.5% solution of mechloroethamine hydrochloride (nitrogen mustard, NM) (Sigma, 122564) in 1.5% DMSO-PBS was prepared immediately prior to application. A total of 40 μl of NM solution was applied to a circular (12 mm diameter) area in two consecutive applications. After application, mice were placed in a temporary housing space under a chemical fume hood for 2 hours.

[0228]

[0251] UV radiation skin injury model: Mice were exposed to UV radiation as previously described [X]. Briefly, a 12 mm diameter circular area of ​​depilated dorsal skin was exposed to UVB radiation from six FS-40 fluorescent lamps filtered through Kodacel (Eastman Kodak Co., Rochester, NY). UVB emission was measured with an IL-443 phototherapy radiometer (International Light, Newburyport, MA) equipped with an IL SED 240 detector. To induce skin inflammation, mice were exposed to a single UVB dose of 100 mJ / cm2.

[0229]

[0252] Treatment with polydopamine nanoparticles (PDA NPs): PDA NPs were diluted in milli-Q water at a concentration of 50 μg / μl. A total amount of 1 mg of particles was applied to the injured skin area 2 hours after injury induction, then 24 and 48 hours later. Milli-Q water was used as a vehicle for the control group. During the treatment, mice were anesthetized using isoflurane.

[0230]

[0253] Monitoring of skin injury and measurement of wound healing: After induction of skin injury, mice were non-invasively followed up. Monitoring was performed daily starting from the day of skin injury. Photographs of the injury area were taken, and the double-fold skin thickness of the injury area was measured using a digital caliper (Mitutoyo Corporation, PK0505CPX) and weight was measured. The area of ​​inflammation / wound was measured using Image J and QuPath software.

[0231]

[0254] Statistical analysis: GraphPad Prism V.8.3.0 software was used to generate visual graphics and calculate statistical significance. One-way ANOVA and t-tests were used to calculate p-values.

[0232]

[0255] References corresponding to Examples 1A and 1B: 1. D'Alba, L.; Shawkey, MD,Melanosomes: Biogenesis, Properties, and Evolution of an Ancient Organelle.Physiol. Rev. 2019, 99 (1), 1-19. 2. Simon, JD; Peels, DN, The Red and the Black. Acc. Chem. Res. 2010, 43 (11), 1452-1460. 3. Solano, F., Melanins: Skin Pigments andMuch More-Types, Structural Models, Biological Functions, and Formation Routes.New Sci. J. 2014, 2014, 1-28. 4. Jakubiak, P.; Lack, F.; Thun, J.; Urtti, A.; Alvarez-Sanchez, R., Influence of MelaninCharacteristics on Drug Binding Properties. Mol Pharm 2019, 16 (6), 2549-2556. 5. Razanowska, M.; Sarna, T.; Land, E. J.; Truscott, T. G., Free radical scavenging properties of melanin:Interaction of eu- and pheo-melanin models with reducing and oxidisingradicals. Free Radic Biol Med 1999, 26 (6), 518-525. 6. Kim, K.; Tsay, O. G.; Atwood, D. A.; Churchill, D. G., Destruction and Detection of Chemical WarfareAgents. Chem. Rev. 2011, 111 (9), 5345-403. 7. Smart, J. K., Medical Aspects of Chemicaland Biological Warfare. Office of the Surgeon General: Washington, DC, 1997. 8. Tu, A. T., Natural and SelectedSynthetic Toxins. Tu, A. T.; Gaffield, W., Eds. American Chemical Society:Washington DC, 2000; Vol. 745. 9. Makarovsky, I.; Markel, G.; Hoffman, A.; Schein, O.; Finkelstien, A.; Brosh-Nissimov,T.; Tashma, Z.; Dushnitsky, T.; Eisenkraft, A., Osmium Tetroxide: ANew Kind of Weapon. Isr. Med. Assoc. J. 2007, 9 (10), 750-752. 10. Saladi, R. N.; Smith, E.;Persaud, A. N., Mustard: a potential agent of chemical warfare and terrorism.Clin Exp Dermatol 2006, 31 (1), 1-5. 11. Ryu, J. H.; Messersmith, P. B.;Lee, H., Polydopamine Surface Chemistry: A Decade of Discovery. ACS Appl.Mater. Interfaces 2018, 10 (9), 7523-7540. 12. Siwicka, Z. E.; Son, F.A.; Battistella, C.; Moore, M. H.; Korpanty, J.; McCallum, N. C.; Wang, Z.; Johnson, B. J.; Farha, O. K.;Gianneschi, N. C., Synthetic Porous Melanin. Journal of the American ChemicalSociety 2021, 143 (8), 3094-3103. 13. Huang, L.; Liu, M.; Huang,H.; Wen, Y.; Zhang, X.; Wei, Y., Recent Advances and Progress onMelanin-like Materials and Their Biomedical Applications. Biomacromolecules2018, 19 (6), 1858-1868. 14. Wang, Z.; Carniato, F.; Xie, Y.; Huang, Y.; Li, Y.; He, S.; Zang, N.; Rinehart, JD; Botta, M.; Gianneschi, NC, High RelaxivityGadolinium-Polydopamine Nanoparticles. Small 2017, 13 (43). 15. Zhang, R.; Fan, Q.; Yang,M.; Cheng, K.; Lu, X.; Zhang, L.; Huang, W.; Cheng, Z.,Engineering Melanin Nanoparticles as an Efficient Drug-Delivery System forImaging-Guided Chemotherapy. Advanced Materials 2015, 27 (34), 5063-5069. 16. Cheng, W.; Nie, J.; Gao,N.; Liu, G.; Tao, W.; Xiao, X.; Jiang, L.; Liu,Z.; Zeng, X.; Mei, L., A Multifunctional Nanoplatform against MultidrugResistant Cancer: Merging the Best of Targeted Chemo / Gene / Photothermal Therapy.Advanced Functional Materials 2017, 27 (45), 1704135. 17. Wang, J.-G.; Zhou, H.-J.; Sun, P.-C.; Ding, D.-T.; Chen, T.-H., Hollow Carved Single-CrystalMesoporous Silica Templated by Mesomorphous Polyelectrolyte-SurfactantComplexes. Chem. Matter. 2010, 22 (13), 3829-3831. 18. Ju, K.-Y.; Lee, Y.; Lee, S.; Park, S. B.; Lee, J.-K., Bioinspired Polymerization of Dopamine to Generate Melanin-Like Nanoparticles Having an Excellent Free-Radical-Scavenging Property. Biomacromolecules 2011, 12 (3), 625-632.

[0233]

[0256] Additional references: 1. D'Alba, L.; Shawkey, M. D., Melanosomes: Biogenesis, Properties, and Evolution of an Ancient Organelle. Physiol. Rev. 2019, 99 (1), 1-19. 2. Van Den Bossche, K.; Naeyaert, J.-M.; Lambert, J., The Quest for the Mechanism of Melanin Transfer. Traffic 2006, 7 (7), 769-778. 3. Simon, J. D.; Peels, D. N., The Red and the Black. Acc. Chem. Res. 2010, 43 (11), 1452-1460. 4. Solano, F., Melanins: Skin Pigments and Much More - Types, Structural Models, Biological Functions, and Formation Routes. New Sci. J. 2014, 2014, 1-28. 5. D'Alba, L.; Van Hemert, C.; Spencer, K. A.; Heidinger, B. J.; Gill, L.; Evans, N.P.; Monaghan, P.; Handel, C. M.; Shawkey, M. D., Melanin-basedcolor of plumage: role of condition and of feathers' microstructure. IntegrComp Biol 2014, 54 (4), 633-44. 6. Goiran, C.; Bustamante, P.;Shine, R., Industrial Melanism in the Seasnake Emydocephalus Annulatus. Curr.Biol. 2017, 27 (16), 2510-2513. 7. Schroeder, R. L.; Gerber, J. P.,Chloroquine and Hydroxychloroquine Binding to Melanin: Some PossibleConsequences for Pathologies. Toxicol. Rep. 2014, 1, 963-968. 8. Jakubiak, P.; Lack, F.; Thun, J.; Urtti, A.; Alvarez-Sanchez, R., Influence of MelaninCharacteristics on Drug Binding Properties. Mol Pharm 2019, 16 (6), 2549-2556. 9. Price, R. J.; Lee, J. S., ParalyticShellfish Poison and Melanin Distribution in Fractions of Toxic Butter Clam(Saxidomus giganteus) Siphon. Can. J. Fish. Aquat. Sci. 1972, 29 (11),1657-1658. 10. Margalida, A.; Negro, J. J.;Galvan, I., Melanin-based color variation in the Bearded Vulture suggests athermoregulatory function. Comp Biochem Physiol A Mol Integr Physiol 2008, 149(1), 87-91. 11. Razanowska, M.; Sarna, T.; Land, E. J.; Truscott, T. G., Free radical scavenging properties of melanin:Interaction of eu- and pheo-melanin models with reducing and oxidisingradicals. Free Radic Biol Med 1999, 26 (6), 518-525. 12. Burgoyne, T.; O'Connor, M.N.; Seabra, M. C.; Cutler, D. F.; Futter, C. E., Regulation ofmelanosome number, shape and movement in the zebrafish retinal pigmentepithelium by OA1 and PMEL. Journal of Cell Science 2015, 128 (7), 1400-1407. 13. Puertas-Bartolome, M.; Benito-Garzon, L.; Fung, S.; Kohn, J.; Vazquez-Lasa, B.; SanRoman, J., Bioadhesive functional hydrogels: Controlled release of catecholspecies with antioxidant and antiinflammatory behavior. Materials Science andEngineering: C 2019, 105, 110040. 14. Bagheri, M.; Validi, M.; Gholipour, A.; Makwandi, P.; Sharifi, E., Chitosan nanofiberbiocomposites for potential wound healing applications: Antioxidant activitywith synergic antibacterial effect. Bioengineering & Translational Medicine2022, 7 (1). 15. Wang, Z.; Carniato, F.; Xie, Y.; Huang, Y.; Li, Y.; He, S.; Zang, N.; Rinehart, JD; Botta, M.; Gianneschi, NC, High RelaxivityGadolinium-Polydopamine Nanoparticles. Small 2017, 13 (43). 16. Zhang, R.; Fan, Q.; Yang,M.; Cheng, K.; Lu, X.; Zhang, L.; Huang, W.; Cheng, Z.,Engineering Melanin Nanoparticles as an Efficient Drug-Delivery System forImaging-Guided Chemotherapy. Advanced Materials 2015, 27 (34), 5063-5069. 17. Cheng, W.; Nie, J.; Gao,N.; Liu, G.; Tao, W.; Xiao, X.; Jiang, L.; Liu,Z.; Zeng, X.; Mei, L., A Multifunctional Nanoplatform against MultidrugResistant Cancer: Merging the Best of Targeted Chemo / Gene / Photothermal Therapy.Advanced Functional Materials 2017, 27 (45), 1704135. 18. Bryan, N.; Ahswin, H.; Smart, N.; Bayon, Y.; Wohlert, S.; Hunt, J., Reactive oxygenspecies (ROS)-a family of fate deciding molecules pivotal in constructiveinflammation and wound healing. European Cells and Materials 2012, 24, 249-265. 19. Dunnill, C.; Patton, T.; Brennan, J.; Barrett, J.; Dryden, M.; Cooke, J.; Leaper, D.; Georgopoulos, N. T., Reactive oxygen species (ROS) and woundhealing: the functional role of ROS and emerging ROS-modulating technologiesfor augmentation of the healing process. International Wound Journal 2017, 14(1), 89-96. 20. Siwicka, Z. E.; Son, F.A.; Battistella, C.; Moore, M. H.; Korpanty, J.; McCallum, N. C.; Wang, Z.; Johnson, B. J.; Farha, O. K.;Gianneschi, N. C., Synthetic Porous Melanin. Journal of the American ChemicalSociety 2021, 143 (8), 3094-3103. 21. Huang, Y.; Li, Y.; Hu,Z.; Yue, X.; Proetto, MT; Jones, Y.; Gianneschi, NC,Mimicking Melanosomes: Polydopamine Nanoparticles as Artificial Microparasols.ACS Cent. Sci. 2017, 3 (6), 564-569. 22. Wang, J.-G.; Zhou, H.-J.; Sun, P.-C.; Ding, D.-T.; Chen, T.-H., Hollow Carved Single-CrystalMesoporous Silica Templated by Mesomorphous Polyelectrolyte-SurfactantComplexes. Chem. Mater. 2010, 22 (13), 3829-3831. 23. Ju, K.-Y.; Lee, Y.; Lee,S.; Park, SB; Lee, J.-K., Bioinspired Polymerization of Dopamine toGenerate Melanin-Like Nanoparticles Having an Excellent Free-Radical-ScavengingProperty. Biomacromolecules 2011, 12 (3), 625-632.

[0234] INCORPORATION BY REFERENCE AND VARIATION STATEMENT

[0258] All references throughout this application, e.g., issued or granted patents or equivalents; patent application publications; and patent documents, including non-patent literature or other source materials, are hereby incorporated by reference in their entirety, to the extent that each reference is not at least partially inconsistent with the disclosure of this application, as if each were individually incorporated by reference (e.g., a reference that is partially inconsistent is incorporated by reference except for the partially inconsistent portion of the reference).

[0235]

[0259] The terms and expressions used in this specification are used as terms of description and not as terms of limitation, and there is no intention in the use of such terms and expressions to exclude any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention as claimed. Thus, although the present invention has been disclosed in detail by preferred embodiments, exemplary embodiments, and optional features, it should be understood that modifications and variations of the concepts disclosed herein may be used by those skilled in the art, and such modifications and variations are considered to be within the scope of the invention as defined by the appended claims. The specific embodiments described herein are examples of useful embodiments of the invention, and it will be apparent to those skilled in the art that the invention may be carried out using many variations of the devices, device components, and method steps described in this description. As will be apparent to those skilled in the art, the methods and devices useful for the methods can include many optional configurations and processing elements and steps.

[0236]

[0260] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to "a cell" includes a plurality of such cells and equivalents thereof known to those of skill in the art. Furthermore, the terms "a" (or "an"), "one or more," and "at least one" may be used interchangeably herein. It should also be noted that the terms "comprising," "including," and "having" may be used interchangeably. The phrase "of any of claims XX-YY" (where XX and YY refer to claim number) is intended to set forth multiple dependent claims in the alternative and, in some embodiments, is interchangeable with the phrase "as in any one of claims XX-YY."

[0237]

[0261] When a group of substituents is disclosed herein, it is understood that all individual members of the group and all subgroups, including any isomers, enantiomers, and diastereomers of the group members, are disclosed separately. When Markush groups or other groupings are used herein, it is intended that all individual members of the group and all possible combinations and subcombinations of the group are individually included in the disclosure. When a compound is described herein such that a specific isomer, enantiomer, or diastereomer of the compound is not specified, for example in the formula or chemical name, the description is intended to include each isomer and enantiomer of the compound described, individually or in any combination. In addition, unless otherwise specified, all isotopic variants of the compounds disclosed herein are intended to be encompassed by the disclosure. For example, it will be understood that any one or more hydrogens in the disclosed molecules can be replaced with deuterium or tritium. Isotopic variants of molecules are generally useful as standards in assays for the molecule and in chemical and biological studies related to the molecule or its use. Methods for preparing such isotopic variations are known in the art. The specific names of the compounds are intended to be exemplary, as it is known that one of ordinary skill in the art may name the same compound differently.

[0238]

[0262] Certain molecules disclosed herein may contain one or more ionizable groups [groups that can remove (e.g., -COOH) or add (e.g., amine) a proton, or can be quaternized (e.g., amine)]. All possible ionic forms of such molecules and their salts are intended to be included individually in the disclosure of this specification. With respect to salts of the compounds of this specification, those skilled in the art can select from a wide variety of available counterions that are appropriate for preparing the salt of the present invention for a given application. In a particular application, the selection of a given anion or cation for preparing a salt may result in the improvement or decrease of the solubility of the salt.

[0239]

[0263] Unless otherwise indicated, any materials, formulations, combinations of materials, and methods described or exemplified herein can be used to practice the present invention.

[0240]

[0264] Whenever a range, e.g., a temperature range, a time range, or a composition or concentration range, is given herein, it is intended that all intermediate ranges and subranges, as well as all individual values ​​contained within the given range, are included in the disclosure. It will be understood that any subrange or individual value within a range or subrange included in the description herein may be excluded from the claims herein.

[0241]

[0265] All patents and publications mentioned in this specification are indicative of the level of skill of those skilled in the art to which this invention pertains. References cited in this specification are incorporated herein by reference in their entirety to indicate the state of the art as of their publication or filing date, and it is intended that this information may be used herein to exclude, if necessary, certain embodiments that exist in the prior art. For example, when a composition of matter is claimed, it should be understood that compounds that are known and available in the art prior to the applicant's invention, including compounds whose enabling disclosures are described in the references cited herein, are not intended to be included in the composition of matter claimed herein.

[0242]

[0266] As used herein, "comprising" is synonymous with "including," "containing," or "characterized by," and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. As used herein, "consisting of" excludes any element, step, or ingredient not specified in the claim element. As used herein, "consisting essentially of" does not exclude materials or steps that do not materially affect the basic and novel characteristics of the claim. In each instance herein, any of the terms "comprising," "consisting essentially of," and "consisting of" may be replaced with any of the other two terms. The invention illustratively described herein can suitably be practiced in the absence of any element or elements, or limitation or limitations not specifically disclosed herein.

[0243]

[0267] Those skilled in the art will understand that starting materials, biological materials, reagents, synthesis methods, purification methods, analytical methods, assay methods, and biological methods other than those specifically exemplified may be used in the practice of the present invention without resorting to undue experimentation. All art-known functional equivalents of any such materials and methods are intended to be included in the present invention. The terms and expressions used are used as terms of description and not as terms of limitation, and there is no intention in the use of such terms and expressions to exclude any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention as claimed. Thus, although the present invention has been disclosed in detail by preferred embodiments and optional features, it should be understood that modifications and variations of the concepts disclosed herein may be used by those skilled in the art, and that such modifications and variations are considered to be within the scope of the present invention as defined by the appended claims.

[0244] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 181,055, filed April 28, 2021, the entirety of which is incorporated herein by reference.

[0245] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0002] This invention was made with Government support under Grant Nos. AR071168 and AR079795 awarded by the National Institutes of Health and Grant No. FA9550-18-1-0142 awarded by the Air Force Office of Scientific Research. The Government has certain rights in this invention.

Claims

1. 1. A composition for treating damaged skin in a subject, comprising: The composition comprises an artificial melanin material, for topical administration to damaged skin of the subject; the administered artificial melanin material comprises extracellular artificial melanin material at the damaged skin; for promoting skin healing of said damaged skin via at least said extracellular artificial melanin material; The composition, wherein the promotion of skin healing comprises at least a portion of the extracellular artificial melanin material exerting a therapeutic extracellular activity.

2. The damaged skin is closed, the damaged skin is associated with thermally induced damage, chemically induced damage, radiation induced damage, mechanical friction damage, and / or infected cellulitis induced damage; or The composition of claim 1 , wherein the damaged skin comprises one or more blisters.

3. The composition of claim 1 , wherein at least a portion of the extracellular melanin material is within the stratum corneum of the damaged skin.

4. the damaged skin comprises extracellular free radical species; the therapeutic extracellular activity comprises the at least a portion of the extracellular artificial melanin material quenching at least the extracellular free radical species; Optionally, said extracellular free radical species comprises reactive oxygen species; Optionally, at least a portion of the quenched extracellular free radical species is within the stratum corneum.

5. 2. The composition of claim 1, wherein the damaged skin comprises inflammation; and the promotion of skin healing comprises at least a portion of the administered artificial melanin material directly and / or indirectly reducing the inflammation.

6. Directly and / or indirectly reducing the inflammation comprises at least a portion of the artificial melanin material adsorbing one or more inflammatory factors and / or one or more protein factors; The composition of claim 5, wherein the one or more inflammatory factors and / or one or more protein factors comprise TNFα, iNOS, MMP9, one or more proteins associated with the MAPK / ERK pathway, and / or one or more enzymes associated with the MAPK / ERK pathway.

7. (i) The artificial melanin material comprises a porous artificial melanin material, (ii) the artificial melanin material comprises artificial melanin particles; (iii) the artificial melanin material comprises porous artificial melanin particles; or (iv) any combination of (i) to (iii); The composition according to any one of claims 1 to 6.

8. The composition of any one of claims 1 to 6, wherein at least a portion of the artificial melanin material is characterized as eumelanin, pheomelanin, allomelanin, or combinations thereof.

9. The composition of any one of claims 1 to 6, wherein the artificial melanin material comprises an amorphous artificial melanin material.

10. The composition of any one of claims 1 to 6, wherein the artificial melanin material comprises a plurality of melanin oligomers and / or polymers; each melanin oligomer and / or polymer comprises a plurality of covalently linked melanin building blocks.

11. 11. The composition of claim 10, wherein the melanin building blocks are one or more substituted or unsubstituted catechol-based monomeric units, substituted or unsubstituted polyol-based monomeric units, substituted or unsubstituted phenol-based monomeric units, substituted or unsubstituted indole-based monomeric units, substituted or unsubstituted benzothiazine-based monomeric units, substituted or unsubstituted benzothiazole-based monomeric units, substituted or unsubstituted dopamine-based monomeric units, or any combination thereof.

12. The composition of claim 10 , wherein at least a portion of said artificial melanin materials each comprise an allomelanin. (i) at least a portion of the melanin building blocks independently comprise substituted or unsubstituted naphthalene; or (ii) at least a portion of the melanin building blocks each independently contain a dihydroxynaphthalene; (iii) at least a portion of the melanin building blocks independently comprise substituted or unsubstituted dopamine monomers; or (iv) any combination of (i) to (iii); The composition of claim 10.

14. (i) at least a portion of the artificial melanin material comprises a nitrogen-free melanin oligomer, (ii) at least a portion of the artificial melanin material comprises polydopamine; or (iii) a combination of (i) and (ii); The composition of claim 10.

15. 11. The composition of claim 10, wherein at least a portion of the melanin building blocks are each independently selected from the group consisting of substituted or unsubstituted dihydroxydopamine monomer units, substituted or unsubstituted dioxydopamine monomer units, substituted or unsubstituted dihydroxynaphthalene monomer units, substituted or unsubstituted dihydroxyphenylalanine monomer units, substituted or unsubstituted dioxydopamine monomer units, substituted or unsubstituted tyrosine monomer units, substituted or unsubstituted tyramine monomer units, any derivatives thereof, and any combinations thereof.

16. 11. The composition of claim 10, wherein at least a portion of the melanin building blocks are each independently selected from the group consisting of 3,4-dihydroxydopamine monomer units, 3,4-dioxydopamine monomer units, 3,4-dihydroxynaphthalene monomer units, 1,8-dihydroxynaphthalene, 1-3,4-dihydroxyphenylalanine monomer units, and any combination thereof.

17. (i) at least 50% of the plurality of melanin oligomers are selected from the group consisting of monomeric units, dimers, trimers, tetramers, pentamers, and any combination thereof; or (ii) each melanin oligomer is non-covalently associated with at least one other melanin oligomer or melanin monomer through at least one of hydrogen bonding and π-π stacking of naphthalene rings; said melanin monomer comprises said melanin building block; or (iii) a combination of (i) and (ii); The composition of claim 10.

18. (i) the artificial melanin material comprises a porous artificial melanin material; the melanin oligomers and / or polymers of the porous artificial melanin material are arranged to form an internal structure having a plurality of pores; the porous artificial melanin material has a thickness of 0.1 cm ３ / g or more of pore volume per mass of material, at least a portion of the pores having at least one size dimension of 0.5 nm or more; (ii) the artificial melanin material comprises artificial melanin particles; at least a portion of the artificial melanin particles are solid particles, hollow particles, lacy particles, or any combination thereof; or (iii) a combination of (i) and (ii); The composition of claim 10.

19. at least a portion of the artificial melanin material comprises one or more selenomelanin polymers; the one or more selenomelanin polymers comprise a plurality of covalently bonded selenomelanin building blocks; the chemical formula of each of the one or more selenomelanin building blocks comprises at least one selenium atom; Optionally, each selenomelanine polymer is a pheomelanine; Optionally, said formula of each of said one or more selenomelanine building blocks comprises at least one covalent bond to each of said at least one selenium atom; Optionally, the chemical formula of each of the one or more selenomelanine building blocks comprises substituted or unsubstituted benzoselenazine or a derivative thereof, substituted or unsubstituted benzoselenazole or a derivative thereof, substituted or unsubstituted 7,10-dihydro-2H-[1,4]selenazino[3,2-h]isoquinolin-3(4H)-one or a derivative thereof, substituted or unsubstituted benzoselenazinone or a derivative thereof, or any combination thereof; The composition according to any one of claims 1 to 6.

20. The composition according to any one of claims 1 to 6, wherein the artificial melanin material comprises artificial melanin particles having a size selected from the range of 10 nm to 1000 nm.

21. The composition according to any one of claims 1 to 6, wherein the concentration of the artificial melanin material in the composition is selected from the range of 0.5 mg / mL to 100 mg / mL.

22. The composition according to any one of claims 1 to 6, wherein the composition comprises artificial melanin particles having a concentration selected from the range of 0.5 mg / mL to 100 mg / mL.

23. The composition of any one of claims 1 to 6, wherein said administration forms a layer of said artificial melanin material on at least a portion of said damaged skin.

24. (i) the composition is hydrophilic and / or the artificial melanin material is hydrophilic; (ii) the composition comprises one or more additives; (iii) the composition is a cream or an ointment; (iv) the composition comprises a hydrogel; or (v) any combination of (i) to (iv); The composition according to any one of claims 1 to 6.

25. The composition, (i) does not contain artificial melanin materials to which non-melanin therapeutic agents have been added or which have been functionalized with non-melanin therapeutic agents; (ii) does not contain hollow and / or semi-hollow melanin particles carrying non-melanin therapeutic agents; (iii) does not contain a non-melanin therapeutic agent; or (iv) any combination of (i) to (iii); The composition according to any one of claims 1 to 6.

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