Article pubs.acs.org/Biomac
Photodegradable Iron(III) Cross-Linked Alginate Gels Remya P. Narayanan, Galina Melman, Nicolas J. Letourneau, Nicole L. Mendelson, and Artem Melman* Department of Chemistry and Biomolecular Science, Clarkson University, Potsdam New York 13699-5810, United States S Supporting Information *
ABSTRACT: Biocompatible photoresponsive materials are of interest for targeted drug delivery, tissue engineering, 2D and 3D protein patterning, and other biomedical applications. We prepared light degradable hydrogels using a natural alginate polysaccharide cross-linked with iron(III) cations. The “hard” iron(III) cations used to cross-link the alginate hydrogel were found to undergo facile photoreduction to “soft” iron(II) cations in the presence of millimolar concentrations of sodium lactate. The “soft” iron(II) cations have a decreased ability to cross-link the alginate which results in dissolution of the hydrogel and the formation of a homogeneous solution. The photodegradation is done using long wave UV or visible light at neutral pH. The very mild conditions required for the photodegradation and the high rate at which it occurs suggest applications for iron(III) cross-linked alginate hydrogels as lightcontrolled biocompatible scaffolds.
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INTRODUCTION Materials capable of responding to electrochemically applied potentials,1 magnetic fields,2 light,3 mechanical signals,4 temperature changes,5 ultrasound,6 and chemical/biochemical inputs7 are currently being designed and optimized for their potential biomedical applications in vitro8 and in vivo.9 Among the different types of exogenous stimuli, light is a particularly attractive tool for influencing shape and properties of biomaterials due to the high selectivity of irradiation and precision of 2D and 3D spatial control using photolithography techniques.10 Hydrogels are one of most common biomaterials that are extensively used for cell culturing, drug delivery, prosthetics, contact lenses, and tissue engineering. Photoresponsive hydrogels11 are of interest for several promising applications including drug delivery activated by exogenous stimuli,12 protein patterning,13 cell sorting and patterning,14,15 directed cell migration,16 and tissue engineering.17 Several approaches toward photoresponsive hydrogels and other biomaterials have been reported using photooxidation induced by a sensitizer,18 photoisomerization of azobenzenes,19 stilbenes,20 and spyropyrans,21 photodegradation of 2-nitrobenzyl compounds, selective heating of nanoparticles by surface plasmon resonance,22 and other methods.23 The main challenge in this approach is compatibility of conditions required for photodegradation of the cellular support with viability of the supported cells. The majority of known photodegradable polymers and gels are either toxic to living cells or require intensive UV irradiation for photodegradation.24 Despite recent achievements in the field,25−27 there are currently no materials for biocompatible photodegradation that conform to the whole complex of these requirements. Alginic acid, a natural biopolymer, has attracted researchers owing to its availability, compatibility with hydrophobic as well © 2012 American Chemical Society
as hydrophilic molecules, lack of toxicity, and tunable adhesive and mechanical properties. It is a copolymer composed from 1,4-linked β-D-mannuronic acid (M) and of epimeric α-Lguluronic acid residues (G) that are covalently bound in a linear fashion.28 Depending on the source and the production process, the molecular weight of alginic acid ranges from 10 to 600 kDa. Sodium or potassium salts of alginic acid form viscous homogeneous aqueous solutions that are converted into ionotropic hydrogels through cross-linking with metal cations such as Ca2+, Sr2+, or Ba2+.29,30 Cross-linking of alginate is caused by chelation of metal cations by carboxylate groups of βD-mannurate (M) and particularly of α-L-guluronate (G) residues of alginate. The arrangement of polymeric alginate chains around metal cations has been determined for Ca2+ cross-linked hydrogel where domains of four G subunits are bound by one Ca2+ in an “egg-box” 2:1 helical structure (Figure 1).31 These hydrogels, particularly Ca-alginate, have been proven to be biocompatible and nonimmunogenic so that molecules of drugs, biopolymers, and whole living cells can be entrapped inside without compromising their stability. The alginate backbone can be modified with cell-interactive peptides binding integrin receptors such as RGD32−34 or other cellular receptors (e.g., VEGF)35 to increase cell adhesion. Calciumalginate based hydrogels are commonly used in a variety of biomedical applications including wound dressing,36 slow drug release systems,37 scaffolding for cell cultures,38 and tissue engineering.39 Iron(III) cations also form stable alginate hydrogels.40 These hydrogels have been successfully used for cell culturing due to Received: May 7, 2012 Revised: July 7, 2012 Published: July 9, 2012 2465
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Figure 1. Structure of alginic acid and schematic representation of cross-linking of alginate by Mn+ metal cations.
their increased cell adhesion in comparison to Ca2+ cross-linked alginate hydrogels.41,42 While iron(II) cations are also capable of cross-linking of alginate,43 it is a “soft” metal cation that tends to bind neutral ligands containing nitrogen and sulfur atoms. In contrast, the iron(III) cation is a typical example of a “hard” metal cation that preferentially binds oxygen atoms in negatively charged ligands such as carboxylate, phenolate, or hydroxamate groups.44 The dramatic difference in binding of carboxylate groups by iron(II) and iron(III) is evident from stability constants of their citrate complexes which have pK1 values 3.2 and 11.85, correspondingly. The opposite order of stability can be observed in complexes with ″soft″ nitrogen ligands such as histamine with pK1 values of 9.60 for iron(II) and 3.72 for iron(III).45 The difference in coordination chemistry of iron(III) and iron(II) cations has been previously utilized for the preparation of molecular switches.46 We have very recently shown that cross-linking of alginate by iron cations strongly depends on their oxidation state so electrochemical oxidation of homogeneous solution of iron(II) cations in alginate results in formation of insoluble iron(III) crosslinked hydrogel, which can be dissolved back through electrochemical reduction.47 These results are expanded further in this paper as we demonstrate that reduction of iron(III) cations in iron(III) cross-linked hydrogel can be efficiently induced by UV or visible light thus resulting in photoinduced dissolution of the hydrogel under biocompatible conditions.
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comparison to that of after 1 min of irradiation. After linear regression fitting (Supporting Information) averaged relative rates of photoreduction were calculated and normalized to the rate of photoreduction by butyric acid (Figure 3). Photoinduced Dissolution of Iron(III) Cross-Linked Alginate Beads Containing Gold Nanoparticles. A suspension of iron(III) cross-linked alginate beads (N = 50) containing entrapped colloidal gold48 in 100 mL of solution containing 20 mM of MOPS and 20 mM of sodium lactate with pH adjusted to pH 7.0 was irradiated with a fluorescent 365 nm UVA lamp having a light intensity of 10 mW/cm2. Every 2 min, 2.5 mL aliquots were taken. Concentration of partially aggregated colloidal gold particles released in the process of dissolution of alginate beads was detected spectrophotometrically using light absorption at 540 nm maximum. Preparation of Iron(III) Cross-Linked Alginate Gel by Air Oxidation of Iron(II) Alginate Solution. To a solution of sodium alginate (100 mg) in distilled water (9.5 mL) was added very slowly dropwise under vigorous stirring a solution of iron(II) chloride in distilled water (0.4 mL of 500 mM solution) in 20 min. Homogeneous solutions from these component can be obtained with up to 0.6 mL of iron(II) chloride solution which correspond to 30 mM concentration in the final mixture. Further addition of iron(II) chloride solution results in formation of gel clumps. The resultant transparent pale yellow solution solidified within 6 h of exposure to air. A solution of iron(II) alginate prepared as above was transferred into 4 mm path quartz cell. The kinetics of air oxidation was monitored every 60 min by UV−vis spectroscopy in the range 350−600 nm for 48 h. To minimize the influence of relatively slow diffusion of oxygen on the spectra the measurement was conducted in a round 2 mm spot positioned 3 mm below the surface of the solution. The process of gelation was found to be sensitive to composition of sodium alginate. Preparations of iron(III) cross-linked gel with different samples of sodium alginate are described in Supporting Information. Photodegradation of Iron(III) Cross-Linked Alginate Gel Containing Sodium Lactate by UV Light. To a solution of sodium alginate (100 mg) in distilled water (9.1 mL) was added a solution of sodium lactate with pH adjusted to 7.0 (0.4 mL of 500 mM solution) and then dropwise under vigorous stirring solution of iron(II) chloride in degassed distilled water (0.5 mL of 500 mM solution in 20 min). The resultant homogeneous solution was transferred to scintillation vials to form transparent gel with 1−6 mm thickness after air oxidation at 100% humidity either for 16 h or for 48 h. Photoinduced dissolution of the resultant gel was conducted by irradiation of the bottom of scintillation vials by UVA fluorescent lamp with a light intensity of 10 mW/cm2 until all the content of the vial was fully converted into a homogeneous solution. Spatially Selective Photodegradation of Iron(III) CrossLinked Alginate Gel Containing Sodium Lactate by Visible Light. To a solution of sodium alginate (100 mg) in distilled water (9.1 mL) was added a solution of sodium lactate with pH adjusted to 7.0 (0.4 mL of 500 mM solution) and then dropwise under vigorous stirring a solution of iron(II) chloride in degassed distilled water (0.5 mL of 500 mM solution in 20 min). The resultant homogeneous solution (2 mL) was transferred to a Petri dish (40 mm in diameter) forming 1.2 mm layer that was oxidized by air for 16 h at 100% humidity. The resultant gel was irradiated for 60, 90, and 120 s through an aluminum mask with a 5 mm hole in the center of Petri
EXPERIMENTAL SECTION
Materials and Instruments. Alginic acid sodium salt from brown algae was purchased from Sigma (M.W. 100−200 kD, catalog number 71238). Iron(II) chloride, iron(III) chloride, phenanthroline, 3-(Nmorpholino)propanesulfonic acid (MOPS), and carboxylic acids were purchased from Fisher Scientific and used without additional purification. Near UV irradiation was conducted by three Cosmolux 10005 15W fluorescent lamps that provided irradiation in the 350− 370 nm range. Visible irradiation was done by 300 mW 405 nm laser. Light intensities were measured by Hioki 3664 optical power meter. Light intensity of ultraviolet irradiation was measured by UV512AB UV light meter. Optical measurements were performed in a 1 mL quartz cuvette with an optical path length of 4 mm using Cary 100 and Agilent 8453 UV−vis spectrometers at 25 ± 0.5 °C. Photoreduction of Iron(III) Chloride in the Presence of Butyric, Methoxyacetic, Formic, Malic, or Lactic Acid. To a 10 mM solution of iron(III) chloride (100 mL) was added a carboxylic acid from the list (1 mmol). The resultant homogeneous solution was irradiated by the fluorescent UVA lamp with an intensity of 10 mW/ cm2. After 1, 2, 3, and 4 min, 2 mL aliquots of the solution were taken (four samples per carboxylic acid tested). To each aliquot were added a solution of phenanthroline in ethanol (0.5 mL of 100 mM solution) and water (1 mL) followed by measurement of UV−vis absorption of the resultant complex in the range 350−650 nm. Relative rates of photoreduction for different carboxylic acids were calculated for 1−5 min irradiation time as the increase of absorption at 508 nm in 2466
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dish by light of 405 nm laser on distance 50 cm focused to give 3 cm spot having a light intensity of 44 mW/m2 in the center. The exposed zone was dissolved by treatment with 0.9% saline (3 mL) using orbital shaker (10 min, 50 rpm).
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RESULTS AND DISCUSSION Photochemical Reduction of Iron(III) Cations by Substituted Carboxylic Acids in Solution Phase. In addition to commonly used chemical reactions or electrochemical reduction, iron(III) cations can be converted into iron(II) through photoinduced processes that involve cooxidation of a coordinated organic ligand.49 Excitation of iron(III) cation complexes with carboxylic acids has been reported to result in oxidative decarboxylation of these acids with concomitant reduction of iron(III).50,51 To evaluate the most suitable photoreducing agent we did an experimental comparison of the relative abilities of various carboxylic acids for the photoreduction of iron(III) cations. These experiments were performed through irradiation of aqueous solutions containing 50 mM iron(III) chloride in the presence of 100 mM of butyric, methoxyacetic, formic, lactic, and malic acids by 365 nm UV lamp. The progress of the photoreduction (Figure 2) was monitored by measuring concentrations of iron(II)
Figure 3. Comparison of relative rates of photoreduction of selected carboxylic acids calculated from relative amounts of iron(II) after 3 min of long wave UV irradiation.
Figure 2. Dependence on concentration of iron(II) produced during irradiation of 50 mM FeCl3 in the presence of 100 mM of selected carboxylic acids calculated from absorbance of phenanthroline − iron(II) complex at 508 nm.
comparable to previously reported photoreductions of iron(III) cation chelate complexes with compounds containing an αhydroxy carboxylic function.50,52 Owing to the efficient photoreduction of iron(III) cations and its biocompatibility, lactic acid was selected for use in further experiments as a sacrificial photoreductant for preparation of photodegradable iron(III) cross-linked alginate gels. Photodegradation of Iron(III) Cross-Linked Alginate Beads. After preliminary studies demonstrated easy dissolution of iron(III) cross-linked alginate beads in the presence of ascorbic acid or glutathione (see Supporting Information), we conducted photoinduced dissolution of these beads. To study this process, we prepared iron(III) cross-linked alginate beads containing entrapped gold nanoparticles.53 The large size of the gold nanoparticles completely prevented their diffusion through the gel so absorption of gold nanoparticles in the solution phase allowed for quantitative monitoring of bead dissolution. Iron(III) cross-linked alginate beads containing entrapped gold nanoparticles were suspended in 20 mM sodium lactate solution at pH 7.0 and irradiated by 365 nm fluorescent lamps. The irradiation resulted in dissolution of the alginate beads accompanied by release of colloidal gold that was detected by visible absorbance with maximum at 540 nm (Figure 4). The process of photoreduction and release of colloidal gold
cations in aliquots of the reaction mixture. The detection was done by addition of 1,10-phenanthroline in 10-fold excess, immediately followed by measurement of optical density of the resultant iron(II)-phenanthroline complex at the maximum absorbance at 508 nm. Concentrations of iron(II) cations produced during photoreduction show close to linear dependence on irradiation time (Figure 2). The amount of iron(II) cations produced was proved to depend on the structures of carboxylic acids (Figure 3). Conventional carboxylic acids such as butyric acid were found to be rather poor photoreductants while α-methoxyacetic and formic acid were substantially better ones. The most pronounced increase in photoreduction rates were observed with α-hydroxy carboxylic acids such as lactic and malic acids. Both of these acids showed much higher rates of photoreduction than other carboxylic acids, most likely due to their efficient bidentate binding of iron cations. These results are
Figure 4. Dependence of 540 nm absorption of colloidal gold particles released from iron(III) cross-linked alginate beads suspended in 20 mM pH 7.0 sodium lactate solution on irradiation time. 2467
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Figure 5. Air oxidation of a solution of 1% sodium alginate and 20 mM FeCl2 (4 mm layer) monitored by UV−vis spectroscopy with 60 min intervals.
monitored by UV−vis spectroscopy using the absorption of iron(III) cations between 360 and 450 nm. Figure 5 shows UV−vis spectra of the reaction mixture containing 20 mM of iron cations taken in the 360−600 nm range with 1 h intervals. As can be seen from this data, the process of oxidation is slow and its completion takes at least 24 h. However, the formation of gel does not require complete oxidation and initial gelation of the mixture in a parallel experiment was already detected by the inverted vial test after 6 h of exposure to air. However, sodium alginate obtained from different sources showed considerable variations in the rate of gelation and required concentration of iron(II) cations (these experiments are summarized in Supporting Information). As expected, obtained iron(III) cross-linked hydrogels were transparent and clear because the process of gelation started from homogeneous solutions which cannot be obtained using previously known methods. The prepared hydrogels were stable at room temperature for at least two weeks under conditions that prevented their drying. Similar processes of gelation were observed in all solutions containing 1% w/v alginate, 20 mM sodium lactate, and 20−30 mM of iron(II) chloride. Solutions containing 15 mM and less of iron(II) chloride remained fluid and did not form hydrogels even after prolonged air exposure. The minimal concentration of iron (20 mM) observed is approximately three times lower than the combined concentration of carboxylate groups of mannuronate and guluronate residues in 1% w/v alginate solutions. It is likely that the initial gel is cross-linked by both iron(III) and iron(II) cations because the initial gelation was achieved after 6 h when conversion of iron(II) to iron(III) was not complete, according to UV−vis data. While air oxidation of iron(II) alginate provide highly homogeneous gel for 2D cell cultures the prolonged time necessary for gel formation (6−48 h) introduces certain limitations for its use for cell encapsulation and tissue engineering applications. In these cases, formation of alginate beads described above can be a more suitable solution. In both above-mentioned methods of gel formation, additional studies of cytocompatibility and biocompatibility of the process of gel formation will be needed to determine response of growing cell to the presence of millimolar concentrations of iron cations.
continued for 38 min after which all alginate beads were dissolved and absorption at 540 nm stabilized at an optical density of 0.58. In a control experiment, the alginate beads were incubated in a 20 mM sodium lactate solution at pH 7 in the absence of light. Under these conditions no traces of released gold nanoparticles were detected. These experiments demonstrated the possibility of photoinduced reduction of iron(III) cross-linked alginate gel in sodium lactate solutions. This approach was subsequently used for light controlled photodegradation of homogeneous iron(III) cross-linked gel containing sodium lactate. Formation of Iron(III) Cross-Linked Alginate Gel through Air Oxidation of Iron(II) Alginate in the Presence of Sodium Lactate. Existing methods for the preparation of iron(III) cross-linked alginate gels are restricted to formation of gel beads through dropwise addition of alginate solution to iron(III) salts39 and to the reaction of dried alginate films with iron(III) solution.41,42 Neither of these methods produces clear homogeneous hydrogels. In contrast to known methods for the preparation of bulk homogeneous Ca2+ crosslinked alginate gels,54 formation of a homogeneous gel by the slow release of metal cations from a suspension of weakly soluble salts is not possible for iron(III) cation as its salts undergo rapid hydrolysis forming insoluble iron(III) hydroxide. Our approach involved preparation of a homogeneous alginate solution containing iron(II) cations followed by slow generation of iron(III) cations by air oxidation. Such approach allowed us to introduce sodium lactate, serving as the photoreducing reagent, in the stage of gel preparation. Furthermore, addition of sodium lactate was found to diminish previously observed gelation of sodium alginate40 by iron(II) so that homogeneous solutions were formed with up to 30 mM concentration of iron(II) chloride. Further increase in concentration of iron(II) chloride resulted in formation of heterogeneous mixtures containing gel clumps. The prepared solutions containing 1% w/v of sodium alginate, 20 mM of sodium lactate, and 10−30 mM of iron(II) chloride were exposed to air at 100% humidity to prevent evaporation of water. To determine the rate of oxidation the reaction was 2468
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Photodegradation of Homogeneous Iron(III) CrossLinked Alginate Gel Obtained by Air Oxidation of Iron(II) Alginate. Homogeneous iron(III) cross-linked alginate hydrogels for photodegradation experiments were prepared from an aqueous solution containing 1% w/v sodium alginate, 20 mM iron(II) chloride, and 20 mM sodium lactate. The pale yellow homogeneous solution obtained was oxidized by air at 25 °C for 48 h. In analogy to formation of iron(III) cations described previously, the process of photoreduction of iron(III) cations in the obtained gel was monitored by UV−vis spectroscopy. Iron(III) cross-linked gel prepared in a 4 mm path quartz cuvette was irradiated with 365 nm UV lamp. Every 30 s, the irradiation stopped and UV−vis spectra in the range 380−550 nm was recorded (Figure 7, left). The irradiation
above were irradiated at 365 nm from the bottom of vials with a light intensity of 10 mW/cm2. The irradiation resulted in gradual degradation of the gel and eventual formation of a homogeneous yellow solution. The time required for this transformation (Figure 6) was proportional to the thickness of the gel layer proceeding with approximately 3 min per 1 mm of gel thickness rate for the gel prepared by 48 h air oxidation. Photodegradation of the gel prepared by 16 h air oxidation produced similar results with close to linear dependence between the complete dissolution time and the thickness of the gel layer. As expected, in this case, photodegradation was substantially faster with a complete dissolution rate near 1 min per 1 mm of gel layer. Substantially shorter photodegradation times in the latter case can be attributed to incomplete oxidation of iron(II) cations to iron(III) after 16 h of air exposure that required only partial photoreduction of iron(III) for the complete dissolution of the gel. Iron(III) cross-linked alginate gel has been previously reported as a versatile support for cell growth.51 The outcome of the described above photodegradation experiments suggests that the iron(III)−lactate−alginate system can be a perspective scaffold for 2D and 3D cell growth that can be spatially controlled by light.25 The use of biocompatible 405 nm light for photoreduction of iron(III) cations in the presence of sodium lactate could therefore be highly beneficial for these applications. To prove feasibility of gel surface patterning, we attempted to perform spatially selective degradation of iron(III) cross-linked alginate gel under 405 nm irradiation (Figure 8). A
Figure 6. Dependence of complete dissolution time of iron(III) crosslinked alginate gel layer containing 20 mM sodium lactate on its thickness.
Figure 8. Sample of iron(III) cross-linked alginate gel containing 20 mM sodium lactate after a 2 min exposure of the central zone to 405 nm light and dissolution of the exposed gel with water.
beam of 405 nm laser, diffused to a 3 cm spot with an intensity of 44 mW/cm2, was passed through a 5 mm round hole in an aluminum foil mask to irradiate a thin layer of the gel. After the irradiation for 120 s, the 5 mm exposed zone of the gel was converted to a viscous liquid. Rinsing the gel surface with 0.9% solution of sodium chloride resulted in complete dissolution of the exposed zone leaving the remaining gel intact. The intensity of light required for the photodegradation is analogous to the one required in reported photoresponsive hydrogels55 (∼40 mW/cm2 vs 25 mW/cm2) while providing short treatment time. Assuming complete absorption of light by gel layer (1.2 mm), the absorbed dose in the treatment is not more than 4 J/ g of hydrogel, which can cause less than 1 °C increase of hydrogel temperature making the overall process potentially cyto- and biocompatible. These results demonstrate the efficiency for photodegradation of thinly layered iron(III) cross-linked alginate gels containing lactate, which indicate this gel as a potential biocompatible positive photoresist that can be dissolved by visible light under very mild conditions. However, cytocompatibility of the overall sequence that involves gel
Figure 7. Photoreduction of iron(III) cross-linked alginate gel containing 20 mM sodium lactate by UVA irradiation (left) with intensity 12 mW/cm2 and 405 nm (right) irradiation with intensity 41 mW/cm2. Changes in UV−vis spectra in the 380−550 nm range feature progressive decrease of absorption of iron(III) cations.
resulted in gradual decrease of iron(III) cation absorption demonstrating an efficient photoreduction. An identical experiment was further conducted with another sample of gel by diffused beam of 405 nm laser (Figure 7, right). Comparison of rates of photoreduction in both experiments showed comparable efficiencies of UV and visible light induced photoreduction: within the first 30 s, 0.16 decrease of optical density at 400 nm with a 12 mW/cm2 intensity of UV light and 0.55 decrease for a 41 mW/cm2 intensity of 405 nm light. To study the process of photodegradation samples of iron(III) cross-linked alginate gel with 1−6 mm thickness in 20 mL scintillation vials prepared by the procedure described 2469
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preparation, cell culturing, and photodegradation needs further comprehensive biological studies on a variety of cell lines.
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CONCLUSIONS Cross-linking of alginate by iron cations strongly depends on their oxidation state. We have demonstrated that oxidation of alginate solutions containing iron(II) cations by air produces homogeneous and transparent iron(III) cross-linked alginate hydrogels. Chemical reduction of iron(III) cations in iron(III) cross-linked alginate beads by ascorbate results in their disintegration and subsequent dissolution. Photochemical reduction of iron(III) cations to iron(II) can be done in the presence of carboxylic acids of which α-hydroxy carboxylic acids, such as lactic acid, produce the best result. Exposure of iron(III) cross-linked alginate gel containing small amounts of sodium lactate to visible light results in rapid photodegradation of the gel making it soluble in 0.9% saline. Biocompatibility of iron(III) cross-linked alginate gels and the very mild conditions of its photodegradation suggest its potential applications in biomedical fields that are currently under investigation in our laboratory.
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ASSOCIATED CONTENT
* Supporting Information S
Information on synthesis of iron(III) cross-linked alginate beads, size, weight, and images of beads; chemical degradation of beads in the presence ascorbic acid and glutathione; comparison of preparation of iron(III) cross-linked gel by air oxidation of iron(II) alginate solution using different sources of sodium alginate. This material is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This research was supported by NSF Grant 1150768. The authors thank Dr. Dan V. Goya for providing water solution of gold nanoparticles.
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REFERENCES
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