Materials with programmable properties controlled by light

Abstract

Disclosed are methods, compositions, reagents, systems, and kits to prepare materials with viscoelastic properties that respond to irradiation with light. Various embodiments show that bio-inspired histidine:transition metal ion complexes allow precise and tunable control over the viscoelastic properties of polymer networks containing these types of crosslinks pre and post-irradiation. These materials have the potential to aid biomedical materials scientists in the development of materials with specific stress-relaxing or energy-dissipating properties.

Claims

1. A method for altering the properties of a polymer network comprising exposing the polymer network to ultraviolet (UV) light in the presence of a photoinitiator; wherein the photoinitiator is an organic small molecule; wherein the polymer network is comprised of polymers non-covalently crosslinked by coordination of the polymers to metals; and wherein the metals undergo oxidation and/or reduction reactions upon exposure to ultraviolet (UV) light in the presence of the photoinitiator.

2. The method of claim 1, wherein the resulting polymer network upon exposure to ultraviolet (UV) light forms a hydrogel.

3. The method of claim 1, wherein the altered properties are selected from the group consisting of stiffness, toughness, viscosity, elasticity, energy dissipation, dynamic modulus, complex modulus, storage modulus, loss modulus, plateau modulus, and relaxation time.

4. The method of claim 1, wherein the polymers are multi-arm polymers.

5. The method of claim 4, wherein the polymers are four-arm polymers.

6. The method of claim 1, wherein the polymers are of the formula: ##STR00005## wherein: X is carbon, silicon, nitrogen, oxygen, sulfur, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxy, or a combination thereof; each L.sub.1 and L.sub.2 are independently optionally substituted, cyclic or acyclic, branched or unbranched aliphatic; optionally substituted, cyclic or acyclic, branched or unbranched heteroaliphatic; optionally substituted aryl; optionally substituted heteroaryl, or a combination thereof; each P is independently a linear or branched, homopolymer or copolymer, or a combination thereof, having a number average molecular weight of about 100 Da to 60000 Da; each L.sub.A is independently a ligand moiety that coordinates to a metal; and n is an integer between 2 and 4, inclusive.

7. The method of claim 6, wherein X is a carbon.

8. The method of claim 6, wherein L.sub.1 is unsubstituted, acyclic, unbranched heteroaliphatic.

9. The method of claim 6, wherein L.sub.2 is unsubstituted, acyclic, unbranched heteroaliphatic.

10. The method of claim 6, wherein P is a linear homopolymer or linear copolymer.

11. The method of claim 6, wherein n is 4.

12. The method of claim 6, wherein each L.sub.A is independently selected from the group consisting of proteins, polysaccharides, nucleic acids, amino acids, organic diacids, polypeptides, amines, thiols, ethers, alcohols, polyacids, polyamines, heterocycles, and heteroaryls.

13. The method of claim 6, wherein each L.sub.A is histidine.

14. The method of claim 1, wherein the polymers are of the formula: ##STR00006## wherein each n is independently between 1 and 100, inclusive.

15. The method of claim 1, wherein the metals are selected from the group consisting of copper, nickel, cobalt, and combinations thereof.

16. The method of claim 1, wherein the wavelength of the ultraviolet (UV) light is between approximately 100 nm and approximately 400 nm, inclusive.

17. The method of claim 1, wherein the photoinitiator is selected from the group consisting of benzoin ethers, benzyl ketals, α-dialkoxyacetophenones, α-hydroxyalkylphenones, α-amino alkylphenonones, acylphophine oxides, acylphosphinates, azobisisobutyronitrile, 1,1′-azobis(cyclohexanecarbonitrile), di-tert-butyl peroxide, benzoyl peroxide, methyl ethyl ketone peroxide, and acetone peroxide.

18. The method of claim 1, wherein the photoinitiator undergoes photo-dissociation to generate free radicals upon exposure to ultraviolet (UV) light.

19. The method of claim 18, wherein the free radicals effect oxidation or reduction of the metals.

20. The method of claim 1, wherein the metals are a combination of nickel and copper, a combination of nickel and cobalt, or a combination of cobalt and copper.

21. The method of claim 1, wherein the wavelength of the ultraviolet (UV) light is between approximately 300 nm and approximately 400 nm, inclusive.

22. The method of claim 1, wherein the photoinitiator is an acylphosphinate.

23. The method of claim 1, wherein the photoinitiator is lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP).

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) The accompanying drawings, which constitute a part of this specification, illustrate several embodiments of the invention and together with the description, serve to explain the principles of the invention.

(2) FIG. 1 shows the four-arm polyethylene glycol of which the hydrogels are composed, where the end of each arm is functionalized with an N-terminal histidine residue (4PEG-His). The histidines form complexes with transition metal ions M.sup.2+ (M=Ni, Cu, Co), which crosslink the 4PEG-His polymers resulting in a viscoelastic hydrogel. A water-soluble radical photo-initiator, lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP), was used to create hydrogels with viscoelastic properties that are responsive to longwave (˜365 nm) irradiation. The radicals generated by the photo-dissociation of LAP react with the His:M.sup.2+ crosslinks in different ways depending on the metal ion, resulting in a variety of viscoelastic properties which can be triggered by low-intensity UV irradiation, as shown in the bottom figure: Cu.sup.2+-based hydrogels lose all rigidity, while Co.sup.2+-based hydrogels become several orders of magnitude stiffer. In contrast, Ni.sup.2+-based hydrogels are not strongly affected by UV-generated radicals.

(3) FIGS. 2A-2C show the viscoelastic moduli across an expanded frequency regime both pre- and post-UV treatment and highlights the extreme differences in response. Ni.sup.2+-containing hydrogels are relatively unaffected, with a slight decrease in both plateau modulus G.sub.P (defined as G′(ω.fwdarw.∞)) and relaxation time τ(ω(G′=G″).sup.−1) (FIG. 2A). In contrast, Cu.sup.2+-based hydrogels become viscous fluids, with G′ and G″ decreasing by several orders of magnitude (FIG. 2B). Co.sup.2+-based gels stiffen substantially post-UV, and gain a low-frequency modulus which explains their solid-like behavior (FIG. 2C). A high-frequency resonant dissipation mode remains, although at lower frequencies (longer timescales) than the pre-UV hydrogels.

(4) FIG. 3 shows that 4PEG-His:Co:LAP hydrogels stiffen dramatically under UV irradiation by gaining a low-frequency relaxation mode associated with His:Co.sup.3+ crosslinks. However, the hydrogels maintain their resonant energy dissipation at higher frequencies, similar to the timescale associated with the His:Co.sup.2+ crosslinks. This high-frequency energy dissipation decreases in magnitude with increasing LAP concentration, while low-frequency energy dissipation increases in magnitude as shown at right. Error bars show standard deviations of 3 measurements.

(5) FIG. 4 shows that because the ligand exchange kinetics control the energy dissipation timescale, and the exchange kinetics vary by orders of magnitude depending on the metal ion, using combinations of metal ions results in hydrogels with multiple characteristic energy dissipation timescales. Here, hydrogels made with the three metal ion pairs are highlighted: Ni.sup.2+:Cu.sup.2+, Ni.sup.2+:Co.sup.2+, and Co.sup.2+:Cu.sup.2+. Because the ligand exchange kinetics for Ni.sup.2+ complexes are ˜100× slower than Co.sup.2+ and Cu.sup.2+, using Ni.sup.2+ to crosslink 4PEG-His results in a relatively slow dissipation timescale, while Co.sup.2+ or Cu.sup.2+ result in hydrogels with much shorter, and similar, relaxation times. Hybrid hydrogels made with Ni.sup.2+ and either Co.sup.2+ or Cu.sup.2+ show both slow and fast energy dissipation timescales. All hydrogels shown use a constant His:M.sup.2+ ratio of 2:1.

(6) FIG. 5 shows that because His:Cu bonds are effectively removed with LAP+UV, Ni:Cu hydrogels with a small amount of Cu exhibit a fast relaxation mode that can be deleted with UV irradiation, leaving the slow Ni.sup.2+-controlled mode to dominate the post-UV viscoelastic properties. In hydrogels with lower concentrations of Ni.sup.2+, there is little evidence of a slow, Ni.sup.2+-associated energy dissipation mode before UV irradiation. However, a new relaxation mode emerges in these hydrogels after UV irradiation which was associated with new His:Ni.sup.2+ crosslinks forming when His ligands switch from coordinating Cu to coordinating Ni. Arrows indicate the approximate terminal relaxation time of the material as a guide to the eye. All hydrogels shown here use a constant His:M.sup.2+:LAP ratio of 2:1:2.

(7) FIG. 6 shows that because UV irradiation can cause His ligands to switch from coordinating Cu to coordinating Ni, at intermediate Ni:Cu ratios, UV irradiation causes the terminal viscosity |η.sub.0*| of the hydrogel to increase (|η.sub.0*|.sub.post-UV/|η.sub.0*|.sub.pre-UV>1). At higher amounts of Cu, there are not enough His:Ni crosslinks to contribute mechanically to the network and removing His:Cu crosslinks via UV irradiation causes the viscosity to decrease.

(8) FIG. 7 shows that while 4PEG-His:Ni:Co hydrogels in the pre-UV state exhibit both a fast energy dissipation mode (ω˜50 rad/s) and slow energy dissipation mode (ω˜1 rad/s) similarly to 4PEG-His:Ni:Cu hydrogels, their viscoelastic material functions respond very differently to UV irradiation because His:Co crosslinks strengthen in response to oxidation, while His:Cu crosslinks weaken.

(9) FIG. 8 shows that because Co and Cu have relatively similar pre-UV viscoelastic properties, mixtures of the two metals do not result in large shifts in moduli. However, they react very differently to photo-generated LAP radicals, as shown at right. Therefore, a wide array of post-UV viscoelastic property pairs can be achieved.

(10) FIGS. 9A-9C show characterization of LAP photoinitiator. FIG. 9A shows UV-vis absorption of a 2.5 wt % solution of LAP shows the strong absorbance band at ca. 350-400 nm, and FIG. 9B shows that its characteristic absorbance is linearly proportional to its concentration. In FIG. 9C, the functionality of LAP was confirmed by using it to photopolymerize a 10 wt %, 10 kDa four-arm PEG-acrylate hydrogel (structure above figure). The gel point occurs within ˜2-3 minutes after initiating UV irradiation, and full cure of the gel on the apparatus occurs in approximately 5-10 minutes as measured by G′(1 rad/s).

(11) FIG. 10 shows mechanical properties of hydrogels with increased LAP loading. While using additional LAP further decreases the moduli and relaxation time of 4PEG-His:Ni hydrogels, the effect pales in comparison to the effects observed in Cu-crosslinked or Co-crosslinked hydrogels.

(12) FIG. 11 shows LAP-concentration dependence of |G.sup.*|=√{square root over (G′.sup.2+G″.sup.2)} at ω=10 rad/s for 4PEG-His:Cu hydrogels. Even at the highest LAP loading measured here, the modulus of 4PEG-His:Cu hydrogels is still higher than the 4PEG-His solution itself, suggesting that His:Cu crosslinks still exist after UV irradiation. An estimate of the modulus of H.sub.2O is provided for reference (assuming η.sub.H2O≈mPa.Math.s).

(13) FIG. 12 shows evidence for Co.sup.3+ oxidation. (left) UV irradiation distinctly changes the color of 4PEG-His:Co:LAP hydrogels. The lower figure zooms in on how the color changes over the course of UV irradiation. (right) Ascorbic acid reduces Co.sup.3+, dissolving hydrogels significantly faster than EDTA. After 24 h, the hydrogel treated with ascorbic acid (a reducing agent) has lost its orange color, and after 48 h it is fully dissolved. In contrast, hydrogels treated with H.sub.2O or ethylenediaminetetraacetic acid (EDTA, a strong, broad-spectrum metal chelator) do not dissolve after 48 h.

(14) FIG. 13 shows the UV-rheology apparatus. The light source used is the “HQRP Longwave 12 LED UV Flashlight 365 nm” modified to be powered by a DC power source and to fit onto the rheometer.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

(15) Before the disclosed systems, compositions, methods, reagents, and kits are described in more detail, it is to be understood that the aspects described herein are not limited to specific embodiments, methods, apparati, or configurations, and as such can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and, unless specifically defined herein, is not intended to be limiting.

(16) Provided herein are polymer networks capable of undergoing changes to static and dynamic properties due to oxidation and/or reduction reactions. In certain embodiments, the present disclosure describes methods of switching between material properties of polymer networks of the general form: polymer-ligand:metal, by exposure to light. Also included within the present disclosure are descriptions for the uses of these polymer networks (e.g., hydrogels), kits comprising these polymer networks, and materials and reagents to synthesize, prepare, modify, and manipulate these polymer networks.

(17) In one embodiment, the present disclosure describes methods for altering the properties of a polymer network comprising exposing the polymer network to light in the presence of a photoinitiator; wherein the polymer network is comprised of polymers non-covalently crosslinked by coordination of the polymers to metals; and wherein the metals undergo oxidation and/or reduction reactions upon exposure to light in the presence of the photoinitiator. In certain embodiment, the resulting polymer network forms a hydrogel. In some embodiments, the metal ions form complexes with ligand moieties, which act as transient crosslinks to control the properties of a polymer network, and different metal ion complexes respond in dramatically different fashions when exposed to light-generated radicals from the photoinitator. By selecting the metal ion mixtures which form the transient crosslinks, it is possible to create materials with specific energy-dissipation properties and therefore “designer” viscoelastic material functions. With the understanding of how each metal ion complex responds to radicals generated from photo-dissociation of a photoinitiator, the energy-dissipation modes can be programmed to adopt a new set of strengths and characteristic timescales, creating materials with viscoelastic material functions that are programmable with light irradiation. These types of strategies could be applied to the design of soft adhesives or in the creation of biomaterials optimized for specific dynamic loading contexts.

(18) Components of Polymer Network

(19) Polymers

(20) One aspect of the present disclosure relates to polymers. In certain embodiments, the polymers are multi-arm polymers. In certain embodiments, the end of each polymer arm is covalently bound to a ligand moiety. In certain embodiments, the arms of the multi-arm polymers are attached to a central atom, an optionally substituted alkyl group, an optionally substituted heteroalkyl group, optionally substituted alkoxy group, or a combination thereof.

(21) In certain embodiments, the polymers are of formula:

(22) ##STR00003##
wherein: X is carbon, silicon, nitrogen, oxygen, sulfur, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxy, or a combination thereof, each L.sub.1 and L.sub.2 are independently substituted or unsubstituted, cyclic or acyclic, branched or unbranched aliphatic; substituted or unsubstituted, cyclic or acyclic, branched or unbranched heteroaliphatic; substituted or unsubstituted aryl; or substituted or unsubstituted heteroaryl, or a combination thereof, each P is independently a linear or branched, homopolymer or copolymer, or a combination thereof, having a number average molecular weight of about 10) Da to 60000 Da; each L.sub.A is independently a ligand moiety that coordinates to a metal (For an example of a histidine moiety coordinating to a metal, see FIG. 1); and n is an integer between 2 and 4, inclusive.

(23) In certain embodiments, the polymers are multi-arm polymers consisting of covalently bound ligand moieties at the end of each polymer arm. In certain embodiments, the polymers are selected from a group consisting of one-arm polymers, two-arm polymers, three-arm polymers, four-arm polymers, five-arm polymers, six-arm polymers, seven-arm polymers, and eight-arm polymers. In certain embodiments, X is carbon and the polymers are four-arm polymers. In certain embodiments, X is silicon and the polymers are four-arm polymers. In certain embodiments, X is nitrogen and the polymers are three-arm polymers. In certain, embodiments, X is oxygen and the polymers are two-arm polymers. In certain, embodiments, X is sulfur and the polymers are two-arm polymers.

(24) In certain embodiment, each arm of the polymer comprises repeating units covalently bound together. In certain embodiments, the repeating units are monomers selected from the group consisting of ethylene oxide, DL-lactide, glycolide, ε-caprolactone, ethylene, and propylene glycol. In certain embodiments, each arm of the polymer comprises 1 to 100 repeating units, inclusive. In certain embodiments, each arm of the polymer comprises 2 to 100 repeating units, inclusive. In certain embodiments, each arm of the polymer comprises 2 to 75 repeating units, inclusive. In certain embodiments, each arm of the polymer comprises 2 to 50 repeating units, inclusive. In certain embodiments, each arm of the polymer comprises 2 to 25 repeating units, inclusive. The polymers of the polymer arms may be of any molecular weight. In certain embodiments, the polymers of the polymer arms each independently have a number average molecular weight ranging from about 100 to about 60000 Da, about 500 to about 60000 Da, about 1000 to about 60000 Da, about 2000 to about 60000 Da, about 5000 to about 60000 Da, about 10000 to about 60000 Da, about 20000 to about 60000 Da, about 10000 to about 50000 Da, about 20000 to about 50000 Da, about 30000 to about 50000 Da, or about 30000 to about 60000 Da; each range being inclusive.

(25) In certain embodiment, each arm of the polymer comprises a polymer selected from the group consisting of linear homopolymer, branched homopolymer, random copolymer, block copolymer, alternating copolymer, segmented copolymer, linear copolymer, branched copolymer, grafted copolymer, and tapered copolymers. In certain embodiment, each polymer arm contains a polymer selected from the group consisting of polyethylene glycol, poly(D,L-lactide), polyglycolide, poly(ε-caprolactone), polyethylene, and polyethylene glycol (PEG).

(26) In certain embodiments, the ligand moiety covalently bound to the end of the polymer arms are selected from the group consisting of proteins, polysaccharides, nucleic acids, amino acids, organic diacids, polypeptides, amines, thiols, ethers, alcohols, polyacids, polyamines, heterocycles, and heteroaryls. In certain embodiments, the end of each arm of the polymer is covalently bound to the same ligand moiety. In certain embodiments, the end of each arm of the polymer is covalently bound to the different ligand moieties. In certain embodiments, the ligand moiety is terpyridine. In certain embodiments, the ligand moiety is catechol. In certain embodiments, the ligand moiety is histidine.

(27) In certain embodiments, the polymers are multi-arm polymers, wherein each arm of the polymer comprises polyethylene glycol (PEG). In certain embodiments, the polymers are multi-arm polymers, wherein each arm of the polymer comprises polyethylene glycol (PEG) substituted with a histidine moiety. In certain embodiments, the polymers are four-arm polymers, wherein each arm of the polymer comprises polyethylene glycol (PEG) substituted with a histidine moiety. In one embodiment, each arm of the polymer comprises a histidine moiety. In certain embodiment, the polymer is of the formula:

(28) ##STR00004##
wherein n is between 1 and 100, inclusive.
Metals

(29) In certain embodiments, one or more metals are selected from the group consisting of scandium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, copper, zinc, yttrium, zirconium, niobium, molybdenum, technetium, ruthenium, rhodium, palladium, silver, cadmium, hafnium, tantalum, tungsten, rhenium, osmium, iridium, platinum, gold, mercury, rutherfordium, dubnium, seaborgium, bohrium, hassium, and meitnerium. In certain embodiments, the metal is one metal. In certain embodiments, the metal is cobalt. In certain embodiments, the metal is nickel. In certain embodiments, the metal is copper. In certain embodiments, the metal is zinc. In certain embodiments, the metal is a combination of two to five different metals, inclusive. In certain embodiments, the metal is a combination of two to four different metals, inclusive. In certain embodiments, the metal is a combination of two to three different metals, inclusive. In certain embodiments, the metal is a combination of five metals. In certain embodiments, the metal is a combination of four metals. In certain embodiments, the metal is a combination of three metals. In certain embodiments, the metal is a combination of two metals. In certain embodiment, the metal is a combination of nickel and copper. In certain embodiment, the metal is a combination of nickel and cobalt. In certain embodiment, the metal is a combination of cobalt and copper. The molar ratio of the metal ions of the double-metal polymer networks can range between 1:99 to 99:1. In certain embodiments, the molar ratio of the metal ions of the double-metal polymer networks can range between 1:99 and 10:90, 10:90 and 20:80, 20:80 and 30:70, 30:70 and 40:60, 40:60 and 50:50, 50:50 and 60:40, 60:40 and 70:30, 70:30 and 80:20, 80:20 and 90:10, or 90:10 and 99:1.

(30) The oxidation number of the metal can range from 0 to 8, inclusive. In certain embodiment, the oxidation number of the metal is 1. In certain embodiment, the oxidation number of the metal is 2. In certain embodiment, the oxidation number of the metal is 3. In certain embodiment, the oxidation number of the metal is 4. In certain embodiment, the oxidation number of the metal is 5. In certain embodiment, the oxidation number of the metal is 6. In certain embodiment, the oxidation number of the metal is 7. In certain embodiment, the oxidation number of the metal is 8. In certain embodiments, the oxidation number of nickel is between 0 and 4, inclusive. In certain embodiments, the oxidation number of nickel is 2. In certain embodiments, the oxidation number of cobalt is between 0 and 5, inclusive. In certain embodiments, the oxidation number of cobalt is 2. In certain embodiments, the oxidation number of cobalt is 3. In certain embodiments, the oxidation number of copper is between 0 and 4, inclusive. In certain embodiments, the oxidation number of copper is 2. In certain embodiments, the oxidation number of copper is 1. In certain embodiments, the oxidation number of nickel is the same throughout the polymer network. In certain embodiments, the oxidation number of nickel differs within the polymer network. In certain embodiments, the oxidation number of cobalt is the same throughout the polymer network. In certain embodiments, the oxidation number of cobalt differs within the polymer network. In certain embodiments, the oxidation number of copper is the same throughout the polymer network. In certain embodiments, the oxidation number of copper differs within the polymer network.

(31) Methods for Preparing and Altering Properties of Polymer Networks

(32) In certain embodiments, the present disclosure provides methods for altering the properties of a polymer network (e.g., metal-crosslinked hydrogels) comprising exposing the polymer network to light in the presence of a photoinitiator; wherein the polymer network is comprised of polymers non-covalently crosslinked by coordination of the polymers to metals (e.g., copper, nickel, cobalt); and wherein the metals undergo oxidation and/or reduction upon exposure to light in the presence of the photoinitiator.

(33) In certain embodiments, the polymer network was formed by mixing in order: (1) a solution of polymer in solvent, (2) a buffer solution, (3) solvent, (4) a solution of photoinitiator, and (5) and a solution of metal salts. Upon adding the solution of metal salts, gelation (polymer network formation) was observed nearly instantaneously at the site of injection. Samples were thoroughly homogenized by vortex mixing, centrifuged to remove air bubbles, and stored at room temperature in the dark. This protocol allows for the formation of the polymer network in the presence of the photoinitiator, but avoids uncontrolled photo-dissociation of the photoinitiator. In certain embodiment, the solution of polymer in solvent is 200 mg/mL solution of 4PEG-His in MilliQ H.sub.2O. In certain embodiment, the buffer solution is 1.0 M solution of 3-(N-morpholino)propanesulfonic acid (MOPS) buffer at pH 7.4. In certain embodiment, the solvent is MilliQ H.sub.2O. In certain embodiment, the solution of photoinitiator an aqueous solution of LAP. In certain embodiments, the solution of metal salts is an aqueous solution of NiCl.sub.2.6H.sub.2O, CuCl.sub.2.2H.sub.2O, or CoCl.sub.2.6H.sub.2O. In certain embodiments, the solution of metal salts consists of one type of metal ion. In certain embodiments, the solution of metal salts consists of two types of metal ions. In certain embodiments, the solution of metal salts consists of more than two types of metal ions. In certain embodiments, the final buffer concentration was 0.2 M in polymer network. In certain embodiment, the samples were centrifuged for 5 minutes.

(34) In certain embodiments, polymer networks containing a photoinitiator is irradiated with light. In certain embodiment, the light irradiation causes photo-dissociation of the photoinitiator to generate free radicals. In certain embodiment, the free radicals can effect oxidation and/or reduction of the metals. In certain embodiment, the oxidation and/or reduction of the metals alters properties of the resulting polymer network.

(35) In certain embodiments, a polymer network prepared by a process comprising the steps of: providing a substrate polymer network comprised of polymers non-covalently crosslinked by coordination of the polymers to metals; contacting the polymer network with a photoinitiator to form a mixture; irradiating the mixture with light; whereby the irradiation results in a change in the oxidation state of the metal. In certain embodiments, the mixture further comprises a solvent. Solvents can be polar or non-polar, protic or aprotic. Common organic solvents useful in the methods described herein include acetone, acetonitrile, benzene, benzonitrile, 1-butanol, 2-butanone, butyl acetate, tert-butyl methyl ether, carbon disulfide carbon tetrachloride, chlorobenzene, 1-chlorobutane, chloroform, cyclohexane, cyclopentane, 1,2-dichlorobenzene, 1,2-dichloroethane, dichloromethane (DCM), N,N-dimethylacetamide N,N-dimethylformamide (DMF), 1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone (DMPU), 1,4-dioxane, 1,3-dioxane, diethylether, 2-ethoxyethyl ether, ethyl acetate, ethyl alcohol, ethylene glycol, dimethyl ether, heptane, n-hexane, hexanes, hexamethylphosphoramide (HMPA), 2-methoxyethanol, 2-methoxyethyl acetate, methyl alcohol, 2-methylbutane, 4-methyl-2-pentanone, 2-methyl-1-propanol, 2-methyl-2-propanol, 1-methyl-2-pyrrolidinone, dimethylsulfoxide (DMSO), nitromethane, 1-octanol, pentane, 3-pentanone, 1-propanol, 2-propanol, pyridine, tetrachloroethylene, tetrahyrdofuran (THF), 2-methyltetrahydrofuran, toluene, trichlorobenzene, 1,1,2-trichlorotrifluoroethane, 2,2,4-trimethylpentane, trimethylamine, triethylamine, N,N-diisopropylethylamine, diisopropylamine, water, o-xylene, p-xylene. In certain embodiments, the solvent is water. In certain embodiments, the mixture does not include a solvent.

(36) In certain embodiments, the photoinitiator is selected from a group consisting of benzoin ethers, benzyl ketals, α-dialkoxyacetophenones, α-hydroxyalkylphenones, α-amino alkylphenonones, acylphophine oxides, peroxides, acylphosphinates, azobisisobutyronitrile, 1,1′-azobis(cyclohexanecarbonitrile), di-tert-butyl peroxide, benzoyl peroxide, methyl ethyl ketone peroxide, and acetone peroxide. In certain embodiments, the photoinitiator is an acylphosphinate. In certain embodiment, the photoinitiator is lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP). In certain embodiments, the photoinitiator is is soluble in one or more solvents. In certain embodiments, the photoinitiator is soluble in one or more organic solvents and one or more non-organic solvents. In certain embodiments, the photoinitiator is soluble in one or more organic solvents. In certain embodiments, the photoinitiator is soluble in one or more non-organic solvents. In certain embodiment, the photoinitiator is soluble in water.

(37) In certain embodiments, the photoinitiator undergoes photo-dissociation to generate free radicals upon exposure to light irradiation. In certain embodiments, the photo-dissociation of lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP) generates free radicals upon UV irradiation. The free radicals are capable of effecting oxidation and/or reduction of metals within the polymer network. In certain embodiments, the free radicals effect multi-electron reduction and/or multi-electron oxidation of metals within the polymer network. In certain embodiments, the free radicals effect single-electron reduction and/or single-electron oxidation of metals within the polymer network. In certain embodiments, the percentage of metal ions of any type that undergo reduction by the free radicals is in the range between 0% to 10%, 10% to 20%, 20% to 30%, 30% to 40%, 40% to 50%, 50% to 60%, 60% to 70%, 70% to 80%, 80% to 90%, or 90% to 100%. In certain embodiments, the percentage of metal ions of any type that undergo oxidation by the free radicals is in the range between 0% to 10%, 10% to 20%, 20% to 30%, 30% to 40%, 40% to 50%, 50% to 60%, 60% to 70%, 70% to 80%, 80% to 90%, or 90% to 100%.

(38) The wavelength of light irradiation to the photoinitiator corresponds to at least enough energy to effect photo-dissociation of the photoinitiator. In the present disclosure, the wavelength of light irradiation to the photoinitiator can range from 10 nm to 1000 nm. In certain embodiments, the wavelength of light irradiation is between approximately 10 nm and approximately 100 nm, inclusive. In certain embodiments, the wavelength of light irradiation is between approximately 100 nm and approximately 200 nm, inclusive. In certain embodiments, the wavelength of light irradiation is between approximately 200 nm and approximately 300 nm, inclusive. In certain embodiments, the wavelength of light irradiation is between approximately 300 nm and approximately 400 nm, inclusive. In certain embodiments, the wavelength of light irradiation is between approximately 400 nm and approximately 500 nm, inclusive. In certain embodiments, the wavelength of light irradiation is between approximately 500 nm and approximately 600 nm, inclusive. In certain embodiments, the wavelength of light irradiation is between approximately 600 nm and approximately 700 nm, inclusive. In certain embodiments, the wavelength of light irradiation is between approximately 700 nm and approximately 800 nm, inclusive. In certain embodiments, the wavelength of light irradiation is between approximately 800 nm and approximately 900 nm, inclusive. In certain embodiments, the wavelength of light irradiation is between approximately 900 nm and approximately 1000 nm, inclusive. In certain embodiments, the wavelength of light irradiation is within the ultraviolet range of the electromagnetic spectrum. The wavelength of ultraviolet irradiation is between approximately 10 nm and approximately 400 nm, inclusive. In certain embodiments, the ultraviolet light irradiation is between approximately 10 nm and approximately 100 nm, inclusive. In certain embodiments, the wavelength of the ultraviolet light is approximately 365 nm.

(39) In certain embodiments, the altered properties are viscoelastic properties. In certain embodiments, the altered properties are mechanical properties. In certain embodiments, the altered properties are stress-relaxing properties. In certain embodiments, the altered properties are energy-dissipating properties. In certain embodiment, the altered properties are selected from the group consisting of stiffness, toughness, viscosity, elasticity, energy dissipation, dynamic modulus, complex modulus, storage modulus, loss modulus, plateau modulus, and relaxation time. In certain embodiments, the altered properties are measured by a rheometer.

(40) Kits

(41) In yet another aspect, the present disclosure describes kits. In certain embodiments, the kits are comprised of a polymer network comprised of multi-arm polymers covalently bound to ligand moieties which are coordinated to one or more metals; a photoinitiator; and optionally, instructions for use. In certain embodiments, the kits further comprise of one or more metals. In certain embodiments, the kits further comprise a light source, wherein the light has a wavelength in the range of about 10 nm to about 1000 nm.

(42) In certain embodiments, the kits are comprised of multi-arm polymers covalently bound to a terminal group selected from the group consisting of halogen, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted hydroxyl, optionally substituted amino, and optionally substituted thio; one or more reagents; one or more reactants; a photoinitiator; and optionally, instructions for use. In certain embodiments, the kits further comprise of one or more metals. In certain embodiments, the kits further comprise a light source, wherein the light has a wavelength in the range of about 10 nm to about 1000 nm.

(43) Uses

(44) The polymer networks described herein may be useful in a variety of applications. For example, the ability to control the stress-relaxing or energy-dissipating properties of polymer networks with light irradiation can provide useful materials such as adhesives, biomaterials, and coatings. In certain embodiments, the adhesives, biomaterials, and coatings are self-healing.

(45) Additional uses will be self evident to one of ordinary skill in the art.

EXAMPLES

(46) In order that the invention described herein may be more fully understood, the following examples are set forth. The synthetic examples described in this application are offered to illustrate the compounds and methods provided herein and are not to be construed in any way as limiting their scope.

(47) Materials and Methods

(48) All chemicals were purchased from Sigma-Aldrich unless otherwise noted.

(49) Synthesis of 4PEG-His

(50) 4PEG-His was synthesized using appropriate modifications of the procedure by Fullenkamp et al., Macromolecules, 2013, 46, 1167-1174. Briefly: 1-5 g of four-arm PEG-NH.sub.2.HCl (0.25 equivalents PEG, 1.0 equivalent —NH.sub.2 groups) (JenKem USA) was mixed with N-α-Boc-N-tau-trityl-L-histidine (Boc-His(Trt)-OH) (1.5 equivalents) and (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) reagent (1.5 equivalents) and dissolved in 15 mL dichloromethane. N,N-Diisopropylethylamine (DIPEA) (535 equivalents) was added and the reaction was allowed to proceed for 2 hours under nitrogen gas (N.sub.2). The product was purified by precipitation one time in diethyl ether, three times in methanol at −20° C., one time in diethyl ether, and then vacuum dried. Protecting groups were removed by a cleavage solution of 95 mL trifluoroacetic acid, 2.5 mL triisopropylsilane, and 2.5 mL H.sub.2O for 2 hours. The solvent was removed under reduced pressure and the product purified by re-dissolving in methanol, precipitation three times in diethyl ether, and vacuum drying.

(51) Synthesis of LAP Photoinitiator

(52) Lithium phenyl-2,4,6-trimethylbenzoylphosphinate (also called lithium acylphosphinate. LAP) was synthesized according to literature procedures (see, e.g., Fairbanks et al., Biomaterials, 2009, 30, 6702-6707, Majima et al., Die Makromolekulare Chemie, 1991, 192, 2307-2315). To an N.sub.2-purged round bottom schlenk flask, 0.952 mL (1.02 g, 6.0 mmol, 1.0 equivalent) dimethyl phenylphosphonite (from Alfa Aesar) was added. Under continuous stirring, 1.0 mL (1.10 g, 6.0 mmol, 1.0 equivalent) of 2,4,6-trimethyl benzoyl chloride (from Alfa Aesar) was added dropwise. The mixture was stirred for 18 h, when 2.08 g (24.0 mmol, 4.0 equivalents) LiBr (from Alfa Aesar) was dissolved in approximately 30 mL of 2-butanone (from Alfa Aesar), added to the reaction mixture, and the mixture was vented. The mixture was then heated to 50° C. via an oil bath, and after 10 minutes the solution became cloudy. The heat was removed, and after 3.5 hours, the solution had a paste-like consistency due to the precipitation of the product. Excess 2-butanone was added to ease handling of the mixture, and the precipitate was centrifuged and decanted with excess 2-butanone three times to remove unreacted precursors. The product was vacuum dried overnight. Final yield: 1.58 g, 5.37 mmol, 89.5% yield based on moles of precursors.

(53) Solutions of the product in MilliQ H.sub.2O show a strong absorbance peak at approximately 370 nm, corresponding to the established spectra of LAP (FIGS. 9A-9C). The activity of LAP was confirmed by using it to photocure a four-arm PEG-acrylate hydrogel. 10 kDa four-arm PEG-acrylate was purchased from JenKem USA and used as received. A 100 mg/mL four-arm PEG-acrylate solution in MilliQ H.sub.2O with a 1:1 ratio of acrylate groups: LAP was loaded onto the rheometer, and the storage and loss moduli were measured at an angular frequency of 1 rad/s. After 5 minutes, the UV lamp was turned on, and the hydrogel reached full cure in the approximate time range of 5 to 10 minutes (FIGS. 9A-9C).

(54) Polymer Network Formation

(55) The polymer network was formed by mixing appropriate volumes of, in order: (1) 200 mg/mL solution of 4PEG-His in MilliQ H.sub.2O, (2) 1.0 M solution of 3-(N-morpholino)propanesulfonic acid (MOPS) buffer at pH 7.4, (3) MilliQ H.sub.2O, (4) aqueous solution of LAP (briefly sonicated via bath sonicator to aid in dissolution), and (5) aqueous solution of NiCl.sub.2.6H.sub.2O, CuCl.sub.2.2H.sub.2O, or CoCl.sub.2.6H.sub.2O. The final buffer concentration was 0.2 M in polymer network. Upon adding the M.sup.2+ solution, gelation (polymer network formation) was observed nearly instantaneously at the site of injection. Samples were thoroughly homogenized by vortex mixing, centrifuged for 5 minutes to remove air bubbles, and stored at room temperature in the dark for at least 12 h prior to characterization. This protocol allows for the formation of the polymer network in the presence of the photoinitiator, but avoids uncontrolled photo-dissociation of the photoinitiator.

(56) Specifically, the resulting polymer network contain histidine ligand moieties groups that form relatively strong yet reversible bonds with certain metal ions (M.sup.2+=Ni.sup.2+, Co.sup.2+, or Cu.sup.2+), which transiently crosslink the polymers into a viscoelastic hydrogel. The ligand exchange kinetics between histidine and the metal ions primarily control the bulk network viscoelastic relaxation, and therefore the choice of metal drastically impacts the energy dissipative timescale(s) of the hydrogel (see e.g. Annable et al., Journal of Rheology, 1993, 37, 695; Grindy et al., Nature Materials, 2015, 14, 1210-1216; Loveless et al., Macromolecules, 2005, 38, 10171-10177; Yount et al., Journal of the American Chemical Society, 2005, 127, 14488-96; Fullenkamp et al., Macromolecules, 2013, 46, 1167-1174; Yount et al., Angewandte Chemie, 2005, 44, 2746-2748). Inspired by researchers using radical photoinitiators to reduce Cu.sup.2+.fwdarw.Cu.sup.1+ to catalyze the copper-catalyzed alkyne-azide (CuAAC) “click” reaction (see e.g. Adzima et al., Nature Chemistry, 2011, 3, 258-261; Gong et al., Chemical Communications, 2013, 49, 7950), to reduce Cu.sup.2+.fwdarw.Cu.sup.0 to form Cu nanoparticles (see e.g. Sakamoto et al., Chemistry of Materials, 2008, 20, 2060-2062), and using hydrogen peroxide to oxidize Co.sup.2+.fwdarw.Co.sup.3+ in 4PEG-His hydrogels (see e.g. Wegner et al., Macromolecules, 2016, 49, 4229-4235), the water-soluble photoinitiator lithium phenyl-2,4,6-trimethylbenzoylphosphinate (also called lithium acylphosphinate or LAP, FIG. 1) was introduced to the hydrogels to explore how changing the redox state of His:M.sup.2+ complexes can affect viscoelastic mechanical properties. As shown in FIGS. 9A-9C, LAP has a strong absorption band between 350-400 nm. Irradiating LAP-laden hydrogels with ca. 365 nm radiation causes the LAP to dissociate (Fairbanks et al., Biomaterials, 2009, 30, 6702-6707), producing free radicals which can oxidize or reduce the metal centers of the 4PEG-His:M.sup.2+ crosslinks. As discussed below, this change in oxidation state of the metal ion in the coordinate crosslinks can have significant effects on the bulk gel viscoelastic properties.

(57) UV-Rheology Apparatus and Procedure

(58) For rheological measurements, polymer networks containing LAP were loaded on to a custom-built apparatus to irradiate samples while simultaneously measuring rheological properties, schematically outlined in FIG. 13. The light source used was an inexpensive hand-held 365 nm LED flashlight (HQRP Longwave 12 LED UV Flashlight 365 nm) modified to fit in the testing apparatus and powered by either a Hewlett Packard E3612A DC power supply or a Hewlett Packard 6212A DC power supply set in current-limiting mode to 30 mA. The operating voltage was approximately 3.2 V. Measurements were conducted on an Anton Paar MCR 302 stress-controlled rheometer in a parallel-plate geometry with a 25 mm-diameter plate and a 0.2 mm gap, at room temperature. Samples were first pre-sheared at γ=0.1 s.sup.−1 for 5 minutes and rested for 5 minutes to erase memory of the loading history. A frequency sweep is then conducted at γ.sub.θ=5% strain amplitude to measure pre-irradiated rheological properties. The samples were then measured at a constant frequency ω=0.5 rad/s for M.sup.2+=Ni.sup.2+ samples or ω=1 rad/s for M.sup.2+=Cu.sup.2+, Co.sup.2+ and all mixed-metal samples, and a constant strain amplitude γ.sub.0=5% in the dark for 10 minutes, at which point the UV lamp was turned on for 1 hour. After 1 hour of irradiation, the UV lamp was turned off and mechanical properties were measured in the dark for 1 more hour. Finally, a second frequency sweep was conducted at γ.sub.0=5% strain to establish post-irradiated rheological properties.

(59) Results of Rheology Studies for Single-Metal Polymer Networks

(60) In FIG. 1, it is shown how 4PEG-His:M.sup.2+ hydrogel stiffness (as measured by the magnitude of the complex shear modulus |G*|) responds to LAP+UV irradiation for each of the three metal ion crosslinks studied here. The three systems respond in drastically different ways: 4PEG-His:Co.sup.2+ hydrogels stiffen by several orders of magnitude, 4PEG-His:Ni.sup.2+ hydrogels are largely unaffected, and 4PEG-His:Cu.sup.2+ hydrogels weaken significantly. In order to more completely understand the effects of the radicals generated from photo-dissociation of a photoinitiator on the hydrogels' viscoelastic mechanics, the entire material function is considered, the complex modulus G*(ω)=G′(ω)+iG″(ω) rather than just the value of the modulus at a single frequency. To do so, oscillatory rheology is used to measure the storage modulus (G′) and loss modulus (G″) at different angular frequencies and thereby characterize the relevant energy dissipation timescales in the materials. The frequency where G′=G″ is an estimation of the dominant metal-coordinate crosslink resonant energy dissipation timescale T of the material. In FIGS. 2A-2C, it can be observed that the relaxation times of 4PEG-His:M.sup.2+ hydrogels follow the pattern τ.sub.Ni>τ.sub.Co>τ.sub.Cu, corresponding with known trends of ligand dissociation rates (see, e.g., Helm et al., Chemical Reviews, 2005, 105, 1923-1960.).

(61) LAP has only small measurable effects on the rheological properties of 4PEG-His:Ni.sup.2+ hydrogels as shown in FIG. 2A: UV irradiation only slightly decreases both the plateau modulus and relaxation time. Even at higher LAP concentrations, the relaxation time only drops from approximately 4 seconds before UV exposure to approximately 1 second after UV exposure (FIG. 10), which pales in comparison to the effects to the viscoelastic properties of 4PEG-His:Co.sup.2+ or 4PEG-His:Cu.sup.2+ crosslinked hydrogels upon UV irradiation.

(62) As shown in FIG. 2B, the moduli of 4PEG-His:Cu.sup.2+ gels decrease by several orders of magnitude after UV treatment, and as the LAP concentration is increased, the modulus approaches that of the un-crosslinked polymer solution (FIG. 11). The drastic change in mechanical properties is most likely caused by reduction of the Cu.sup.2+ metal center to Cu.sup.+.

(63) In contrast to Cu.sup.2+, the reaction of LAP with His:Co.sup.2+ crosslinks causes a significant increase in gel moduli overall (G′(ω=100 rad/s) increases from ≈10.sup.3 Pa to ≈10.sup.4 Pa) and a dramatic viscoelastic fluid to solid transition evidenced by the flat storage modulus at low frequencies shown in FIG. 2C. As proposed by Wegner et al. (see e.g. Wegner et al., Macromolecules, 2016, 49, 4229-4235), this transition is likely caused by the oxidation of Co.sup.2+.fwdarw.Co.sup.3+ (FIG. 12) because the histidine ligand exchange kinetics are orders of magnitude slower for Co.sup.3+ than Co.sup.2+ complexes (see e.g. Helm et al., Chemical Reviews, 2005, 105, 1923-1960), and therefore His:Co.sup.3+ crosslinks are effectively permanent in the frequency regime. Despite the plateau of G′ at low frequencies, after UV irradiation the fast energy dissipation mode associated with His:Co.sup.2+ crosslinks remains, as shown by the local maximum at ω≈50 rad/s in FIGS. 2A-2C, which suggests UV irradiation incompletely converts Co.sup.2+ to Co.sup.3+.

(64) Further study of the rheological properties of 4PEG-His:Co hydrogels with different LAP concentrations support the conclusion that both His:Co.sup.2+ and His:Co.sup.3+ crosslinks are present after UV irradiation: the energy dissipation associated with His:Co.sup.2+ crosslinks at ≥approximately 50-100 rad/s after UV irradiation decreases in magnitude with increasing LAP concentration, and the low-frequency loss modulus increases with increasing LAP:Co ratio (FIG. 3). This inverse relationship between G″(ω˜10.sup.−2) and G″(ω˜10.sup.2) suggests that increasing the LAP concentration oxidizes a higher fraction of Co.sup.2+ to Co.sup.3+, which accordingly decreases the magnitude of energy dissipation at ω approximately 50-100 rad/s.

(65) Results of Rheology Studies for Double-Metal Polymer Networks

(66) It has been shown that 4PEG-His transient network hydrogels with combinations of different metal ions generally have multiple characteristic relaxation timescales, and it was demonstrated how the relative contribution of these different relaxation modes to the viscoelastic material function can be tuned by simply controlling the metal ion composition (see, e.g., Grindy et al., Nature Materials, 2015, 14, 1210-1216). This is demonstrated in FIG. 4 for a selected set of metal ion compositions. It was observed that hydrogels with both a “fast” crosslink (His:Cu.sup.2+, His:Co.sup.2+) and a “slow” crosslink (His:Ni.sup.2+) exhibit fast and slow relaxation modes that approximately correspond in timescale to that of the single-metal networks. On the other hand, hydrogels with two “fast” crosslinks (4PEG-His:Co.sup.2+:Cu.sup.2+) display viscoelastic properties that are difficult to distinguish from the pure single-metal networks due to the similarity in relaxation timescales of His:Cu.sup.2+ and His:Co.sup.21 crosslinks.

(67) Building on the demonstration that 4PEG-His:(Ni.sup.2+), 4PEG-His:(Cu.sup.2+), and 4PEG-His:(Co.sup.2+) each respond in a drastically different way to radicals generated from photo-dissociation of a photoinitiator, double-metal ion hydrogels with various combinations of His:(Ni.sup.2+, Cu.sup.2+, Co.sup.2+) were studied in the same manner. Below, it is shown how each pair of metal ions studied here can indeed be used in different proportions to program hydrogels with unique UV-switchable viscoelastic material functions.

(68) 4PEG-His:Ni:Cu

(69) As shown in FIG. 4 and FIG. 5, before UV irradiation 4PEG-His:Ni:Cu hydrogels exhibit two characteristic relaxation modes approximately corresponding to the relaxation timescales of 4PEG-His:Ni and 4PEG-His:Cu hydrogels, respectively. Of note is that, even at relatively small concentrations of Cu, the fast relaxation mode has a larger contribution to the modulus than its slow mode counterpart (viz. Ni:Cu=90:10 before UV irradiation, G″(50 rad/s)>G″ (0.5 rad/s)). This is attributed to the relative coordinating strengths of the complexes, as His:Cu bonds are much stronger than His:Ni bonds: K.sub.1.sup.Ni≈10.sup.6.64; K.sub.1.sup.CU≈10.sup.8.47, (see, e.g., Fullenkamp et al., Macromolecules, 2013, 46, 1167-1174) where K.sub.1.sup.M is the equilibrium constant for the reaction His+M.sup.2+.fwdarw.HisM.sup.2+. Accordingly, in hydrogels with higher amounts of Cu (≥50%), the slower Ni-relaxation mode cannot be observed in the pre-UV rheological properties (FIG. 5, top).

(70) Because 4PEG-His:Cu.sup.2+ hydrogels significantly weaken upon reacting with radicals generated from photo-dissociation of a photoinitiator, while 4PEG-His:Ni.sup.2+ hydrogels do not respond strongly to radicals, it should be expected that 4PEG-His:Ni:Cu hydrogels contain a fast relaxation mode that weakens significantly in response to UV irradiation. Indeed, this is what is observed in hydrogels with at least 90% Ni: the resonant energy dissipation peak at ω approximately 50 rad/s disappears (FIG. 5). However, the magnitude of the energy dissipation at the slow timescale associated with His:Ni crosslinks increases rather than remain constant as it does in 4PEG-His:Ni gels. A logical explanation for this observation is that as the radicals generated from photo-dissociation of a photoinitiator reduce Cu.sup.2+.fwdarw.Cu.sup.1+, His ligands switch from coordinating Cu to coordinating Ni. This increases the concentration of PEG chains crosslinked by a His:Ni.sup.2+ crosslink, increasing the energy dissipation associated with His:Ni.sup.2+ crosslinks. At lower Ni:Cu ratios (≤50% Ni), the terminal relaxation time after UV irradiation (identified approximately by the arrows in FIG. 5) is much slower than the relaxation time of the pre-UV hydrogels, again showing that UV irradiation increases the concentration of His:Ni.sup.2+ crosslinks by effectively removing Cu.sup.2+ crosslinks.

(71) Another way to examine this trend is to compare the change in terminal complex viscosity |η.sub.0*|≡lim.sub.ω.fwdarw.0(√{square root over (G′.sup.2+G″.sup.2/ω)}) of 4PEG-His:Ni:Cu hydrogels caused by UV irradiation. As shown in FIG. 6, at both high and low Ni:Cu ratios, |η.sub.0*| decreases after UV irradiation, while at intermediate ranges of Ni:Cu ratio, the hydrogel's viscosity increases after UV irradiation. At high Ni:Cu ratios, the mechanics of the hydrogel are dominated by His:Ni crosslinks in both the pre-UV and post-UV state, and therefore UV irradiation causes the viscosity to decrease as it does in 4PEG-His:Ni.sup.2+ hydrogels. At low Ni:Cu ratios, the viscosity decreases because the mechanics of the hydrogels are controlled by His:Cu bonds, which weaken significantly with UV irradiation and there are not enough His:Ni crosslinks to increase the viscosity. However, at intermediate Ni:Cu ratios. UV irradiation causes His ligands to switch from Cu to Ni, increasing the concentration of slow, His:Ni crosslinks and therefore increasing |η.sub.0*|.

(72) 4PEG-His:Ni:Co

(73) In a similar vein to 4PEG-His:Ni:Cu hydrogels, the pre-UV state of 4PEG-His:Ni:Co hydrogels exhibit two distinct relaxation times that correspond to the relaxation times in the single-metal hydrogels (FIG. 4 and FIG. 7). However, in contrast to 4PEG-His:Ni:Cu hydrogels, the fast relaxation time in 4PEG-His:Ni:Co hydrogels should be expected to become several orders of magnitude slower upon UV irradiation due to the radical-induced oxidation of Co.sup.2+.fwdarw.Co.sup.3+. As observed in FIG. 7, UV irradiation indeed results in an increase in G′ at low frequencies, supporting the presence of a long-time relaxation mode associated with His:Co.sup.3+ crosslinks.

(74) Similar to 4PEG-His:Ni:Cu gels, in 4PEG-His:Ni:Co hydrogels the resonant energy dissipation mode corresponding to His:Ni crosslinks increases in magnitude post-UV, suggesting that His ligands may switch from coordinating Co to coordinating Ni. However, in contrast to 4PEG-His:Ni:Cu gels, in 4PEG-His:Ni:Co hydrogels the energy dissipation associated with His:Ni crosslinks increases as the concentration of Ni.sup.2+ ions in the network is decreased. This is counterintuitive: in all of the other metal ion combinations studied here, the energy dissipation associated with a certain His:M crosslink is proportional to the concentration of that particular metal ion. This particular paradox supports the general idea that the amount of energy dissipation from a certain relaxation mode depends on the spatio-temporal network context in which it operates (e.g., the presence of other relaxation timescales in the material).

(75) In further contrast with 4PEG-His:Ni:Cu where the fast energy dissipation mode is no longer present after UV irradiation, the energy dissipation mode at ω approximately 50 rad/s associated with His:Co.sup.2+ crosslinks is still present in 4PEG-His:Ni,Co hydrogels after UV, which suggests that complete conversion of Co.sup.2+.fwdarw.Co.sup.3+ is not obtained.

(76) 4PEG-His:Co:Cu

(77) Prior to UV irradiation, the relaxation times of 4PEG-His:Co and 4PEG-His:Cu hydrogels are relatively similar, with τ≈0.01 seconds. Therefore, unlike the previously discussed 4PEG-His:Ni:(Cu or Co) hydrogels, mixtures of Co.sup.2+ and Cu.sup.2+ do not result in two clearly identifiable viscoelastic energy dissipation timescales and hydrogels made with mixtures of Co:Cu crosslinks resemble the viscoelastic properties of hydrogels made entirely with Co.sup.2+ or Cu.sup.2+ (as shown in FIG. 4 and FIG. 8). However, because His:Co.sup.2+ and His:Cu.sup.2+ bonds react in opposite ways to the radicals generated from photo-dissociation of a photoinitiator, significantly different viscoelastic properties should be expected after UV irradiation: samples with His:Co crosslinks should grow a low-frequency modulus associated with His:Co.sup.3+ crosslinks, and this low-frequency modulus should be proportional to the Co concentration in the hydrogel. Samples with His:Cu crosslinks should have a high-frequency energy dissipation mode which disappears upon UV irradiation. This behavior is confirmed in FIG. 8: the low-frequency modulus associated with the His:Co.sup.3+ crosslink scales with Co:Cu ratio. As was the case for 4PEG-His:Ni:Cu hydrogels before UV irradiation, a small amount of Cu displays a disproportionate effect. Even in hydrogels with only 10% Cu, the low-frequency post-UV storage modulus is diminished by over an order of magnitude, and with Cu content as high as 25% the low-frequency relaxation is barely noticeable. The fact that a relatively small amount of Cu.sup.2+ in the network has a disproportionate effect on the viscoelastic properties may be caused by the large disparity in coordinating energies of His:Cu.sup.2+ and His:Co.sup.2+ complexes: K.sub.1(His:Cu.sup.2+)≈10.sup.8.47>>K.sub.1(His:Co.sup.2+)≈10.sup.4.99, (see, e.g., Fullenkamp et al., Macromolecules, 2013, 46, 1167-1174) so His ligands strongly prefer to coordinate Cu rather than Co. Regardless of the specific details, 4PEG-His:Co:Cu hydrogels represent a family of hydrogels with very similar pre-UV irradiation viscoelastic material functions (regardless of the Co:Cu ratio), yet vastly different post-UV irradiation viscoelastic material functions which strongly depends on the Co:Cu ratio.

(78) The results in FIGS. 5-8 explicitly show that judicious choice of the transition metal ions used to crosslink 4PEG-His networks can be used as a strategy to control energy dissipation timescales in both the pre-UV and post-UV state. Of the different chemistries discussed here, three distinct energy dissipation timescales can be controlled: ω<<10.sup.−2 rad/s, ω approximately 10.sup.−1 rad/s, and ω approximately 10.sup.2 rad/s. The mapping of which sets of metal ions and UV treatments correspond to which sets of energy dissipation timescales is outlined in Table 1.

(79) TABLE-US-00001 TABLE 1 Each pair of metal ions uniquely control the possible viscoelastic material functions, both before UV irradiation and after UV irradiation. Dissipation at ω << 10.sup.−2 ω~10.sup.−1 ω~10.sup.2 controlled by Ni:Cu Before UV — [Ni] [Cu] After UV — [Ni] — Ni:Co Before UV [Ni] [Co] After UV [Co] [Ni], [Co] [Co] Co:Cu Before UV — — [Co], [Cu] After UV [Co] — [Co]
Ascorbic Acid Treatment of Histidine Methyl Ester:Cu Complexes

(80) Histidine methyl ester (HisOMe):Cu solutions were prepared in 0.2 M MOPS buffer at pH 7.4, with final concentrations [HisOMe]=0.04 M, [CuCl.sub.2.2H.sub.2O]=0.02 M, with 0, 1, or 2 equivalents of ascorbic acid per Cu ion. The samples were mixed, sealed in centrifuge tubes, and left to react for 30 min, after which absorption spectra were taken.

(81) Dissolution of 4-PEG-His:Co Hydrogels

(82) A 4PEG-His:Co:LAP hydrogel, using a His:Co:LAP ratio of 2:1:2 (previously used for rhoeological testing) was split into three pieces using a razor blade and each piece was immersed in 0.5 mL (i) MilliQ H.sub.2O, (ii) 50 mM ethylenediaminetetraacetic acid (a broad-spectrum metal chelator), or (iii) 50 mM ascorbic acid (a reducing agent). The samples were stored at room temperature, and solutions were replaced after 10 h, 24 h, and 48 h (see FIG. 12).

EQUIVALENTS AND SCOPE

(83) In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

(84) Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein.

(85) It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

(86) This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

(87) Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.