Drug‐Loaded Elastin‐Like Polypeptide–Collagen Hydrogels with High Modulus for Bone Tissue Engineering

Emphasizing the role of hydrogel stiffness and cellular differentiation, this study develops collagen and elastin‐like polypeptide (ELP)–based bone regenerative hydrogels loaded with recombinant human bone morphogenetic protein‐2 (rhBMP‐2) and doxycycline with mechanical properties suitable for osteogenesis. The drug‐incorporated collagen–ELP hydrogels has significantly higher modulus of 35 ± 5 kPa compared to collagen‐only hydrogels. Doxycycline shows a bi‐phasic release with an initial burst release followed by a gradual release, while rhBMP‐2 exhibits a nearly linear release profile for all hydrogels. The released doxycycline shows anti‐microbial activity against Pseudomonas aeruginosa, Streptococcus sanguinis, and Escherichia coli. Microscopic observation of the hydrogels reveals their interconnected, macroporous, 3D open architecture with pore diameters between 160 and 400 µm. This architecture supports human adipose–derived stem cell attachment and proliferation from initial days of cell seeding, forming a thick cellular sheath by day 21. Interestingly, in collagen and collagen–ELP hydrogels, cell morphology is elongated with stretched slender lamellipodial formation, while cells assemble as spheroidal aggregates in crosslinked as well as drug‐loaded hydrogels. Osteogenic markers, alkaline phosphatase and osteocalcin, are expressed maximally for drug‐loaded hydrogels compared to those without drugs. The drug‐loaded collagen–ELP hydrogels are thus promising for combating bacterial infection and promoting guided bone regeneration.     

A polarizable dipole–dipole interaction model for evaluation of the interaction energies for NH···OC and CH···OC hydrogen‐bonded complexes

In this article, a polarizable dipole–dipole interaction model is established to estimate the equilibrium hydrogen bond distances and the interaction energies for hydrogen‐bonded complexes containing peptide amides and nucleic acid bases. We regard the chemical bonds N? H, C?O, and C? H as bond dipoles. The magnitude of the bond dipole moment varies according to its environment. We apply this polarizable dipole–dipole interaction model to a series of hydrogen‐bonded complexes containing the N? H···O?C and C? H···O?C hydrogen bonds, such as simple amide‐amide dimers, base‐base dimers, peptide‐base dimers, and β‐sheet models. We find that a simple two‐term function, only containing the permanent dipole–dipole interactions and the van der Waals interactions, can produce the equilibrium hydrogen bond distances compared favorably with those produced by the MP2/6‐31G(d) method, whereas the high‐quality counterpoise‐corrected (CP‐corrected) MP2/aug‐cc‐pVTZ interaction energies for the hydrogen‐bonded complexes can be well‐reproduced by a four‐term function which involves the permanent dipole–dipole interactions, the van der Waals interactions, the polarization contributions, and a corrected term. Based on the calculation results obtained from this polarizable dipole–dipole interaction model, the natures of the hydrogen bonding interactions in these hydrogen‐bonded complexes are further discussed. © 2013 Wiley Periodicals, Inc.     

Synthesis and characterization of novel thermoresponsive‐co‐biodegradable hydrogels composed of N‐isopropylacrylamide,poly(L‐lactic acid), and dextran

A series of novel multifunctional hydrogels that combined the merits of both thermoresponsive and biodegradable polymeric materials were designed, synthesized, and characterized. The hydrogels were copolymeric networks composed of N‐isopropylacrylamide (NIPAAM) as a thermoresponsive component, poly(L‐lactic acid) (PLLA) as a hydrolytically degradable and hydrophobic component, and dextran as an enzymatically degradable and hydrophilic component. The chemical structures of the hydrogels were characterized by an attenuated total reflection–Fourier transform infrared spectroscopy (ATR–FTIR) technique. The hydrogels were thermoresponsive, showing a lower critical solution temperature (LCST) at approximately 32 °C, and their swelling properties strongly depended on temperature changes, the balance of the hydrophilic/hydrophobic components, and the degradation of the PLLA component. The degradation of the hydrogels caused by hydrolytic cleavage of ester bonds in the PLLA component was faster at 25 °C below the LCST than at 37 °C above the LCST, determined by the ATR–FTIR technique. Due to their multifunctional properties, the designed hydrogels show great potential for biomedical applications, including drug delivery and tissue engineering. © 2004 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 42: 5054–5066, 2004     

Stimuli‐Responsive Dipeptide–Protein Hydrogels through Schiff Base Coassembly

Different from the conventional irreversible covalent conjugations, a simple and efficient dynamic Schiff base covalent assembly is developed to construct the stable and smart dipeptide–protein hydrogels under mild conditions. Diphenylalanine–hemoglobin hydrogel is chosen to investigate the gelation formation process and mechanism. It is found that such assembled dipeptide–protein hydrogels are sensitive to pH variation, and simultaneously the proteins can be released without changing the native secondary structures from the gels. Furthermore, these adaptive hydrogels can encapsulate a series of small molecules, multicomponent proteins, and functional nanoparticles. These versatile hydrogels may find a great potential in bioapplications.     

The Mechanical and Biological Performance of Photopolymerized Gelatin-Based Hydrogels as a Function of the Reaction Media

From the first experiments with biomaterials to mimic tissue properties, the mechanical and biochemical characterization has evolved extensively. Several properties can be described, however, what should be essential is to conduct a proper and physiologically relevant characterization. Herein, the influence of the reaction media (RM) and swelling media (SM)–phosphate buffered saline (PBS) and Dulbecco's modified Eagle's medium (DMEM) with two different glucose concentrations–is described in gelatin methacrylamide (GelMA) hydrogel mechanics and in the biological behavior of two tumoral cell lines (Caco-2 and HCT-116). All scaffolds are UV-photocrosslinked under identical conditions and evaluated for mass swelling ratio and stiffness. The results indicate that stiffness is highly susceptible to the RM, but not to the SM. Additionally, PBS-prepared hydrogels exhibited a higher photopolymerization degree according to high resolution magic-angle spinning (HR-MAS) NMR. These findings correlate with the biological response of Caco-2 and HCT-116 cells seeded on the substrates, which demonstrated flatter morphologies on stiffer hydrogels. Overall, cell viability and proliferation are excellent for both cell lines, and Caco-2 cells displayed a characteristic apical-basal polarization based on F-actin/Nuclei fluorescence images. These characterization experiments highlight the importance of conducting mechanical testing of biomaterials in the same medium as cell culture.     

Poly(ethylene glycol)–poly(L‐lactide) star block copolymer hydrogels crosslinked by metal–ligand coordination

The aqueous solution behavior and thermoreversible gelation properties of pyridine‐end‐functionalized poly(ethylene glycol)–poly(L ‐lactide) (PEG–(PLLA)₈–py) star block copolymers in the presence of coordinating transition metal ions were studied. In aqueous solutions, the macromonomers self‐assembled into micelles and micellar aggregates at low concentrations and formed physically crosslinked, thermoreversible hydrogels above a critical gel concentration (CGC) of 8% w/v. In the presence of transition metal ions like Cu(II), Co(II), or Mn(II), the aggregate dimensions increased. Above the CGC, the gel–sol transition shifted to higher temperatures due to the formation of additional crosslinks from intermolecular coordination complexes between metal ions and pyridine ligands. Furthermore, as an example, PEG–(PLLA)₈–py hydrogels stabilized by Mn(II)–pyridine coordination complexes were more resistant against degradation/dissolution when placed in phosphate buffered saline at 37 °C when compared with hydrogels prepared in water. Importantly, the stabilizing effect of metal–ligand coordination was noticeable at very low Cu(II) concentrations, which have been reported to be noncytotoxic for fibroblasts in vitro. These novel PEG–(PLLA)₈–py metallo‐hydrogels, which are the first systems to combine metal–ligand coordination with the advantageous properties of PEG–PLLA copolymer hydrogels, are appealing materials that may find use in biomedical as well as environmental applications like the removal of heavy metal ions from waste streams. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

Introduction of pH‐sensitivity into mechanically strong nanoclay composite hydrogels based on N‐isopropylacrylamide

pH‐sensitive nanoclay composite hydrogels based on N‐isopropylacrylamide (NIPA) were synthesized by copolymerization with cationic and anionic comonomers. Laponite nanoclay particles served as multifunctional crosslinkers, producing hydrogels with exceptionally high mechanical strengths, as measured by elongation at break. Cationic copolymer gels based on NIPA and dimethylaminoethylmethacrylate were prepared by aqueous free radical polymerization, adopting a procedure reported by Haraguchi (Adv Mater 2002, 14, 1120–1124). Without modification, this technique failed to produce anionic copolymer gels of NIPA and methacrylic acid (MAA), due to flocculation of clay particles. Three methods were conceived to incorporate acidic MAA into nanoclay hydrogels. First, NIPA was copolymerized with sodium methacrylate under dilute conditions, producing hydrogels with good pH‐sensitivity but weak mechanical characteristics. Second, NIPA was copolymerized with methyl methacrylate, which was then hydrolyzed to generate acid sidegroups, yielding hydrogels that were much stronger but less pH sensitive. Third, NIPA was copolymerized with MAA following modification of the nanoclay surface with pyrophosphate ions. The resulting hydrogels exhibited both strong pH‐sensitivities at 37 °C and excellent tensile properties. Optical transparency changed during polymerization, depending on hydrophobicity of the components. This work increases the diversity and functionality of nanoclay hydrogels, which display certain mechanical advantages over conventionally crosslinked hydrogels. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 6630–6640, 2008     

Disulfide bond as a cleavable linker for molecular self-assembly and hydrogelation

Here we reported on the first example of using the disulfide bond as a cleavable linker to control molecular self-assembly and the formation of small molecular (SM) hydrogels.     

Self‐assembled graphene oxide–gelatin nanocomposite hydrogels: Characterization,formation mechanisms,and pH‐sensitive drug release behavior

Novel physically crosslinked graphene oxide (GO)‐gelatin nanocomposite hydrogels were obtained by self‐assembly. The hydrogels with various ratios of GO to gelatin were prepared, and characterized by X‐ray diffraction, Fourier transform infrared spectroscopy, Raman spectroscopy, and scanning electron microscopy. The static and dynamic rheological properties of the hydrogels were investigated, along with the underlying hydrogel formation mechanisms. The storage modulus of the hydrogels (containing 98–98.5 wt % water) reached 114.5 kPa, owing to the relatively strong physical bonding (i.e., hydrogen bonding and electrostatic forces) between GO and gelatin. Drug release tests showed that the drug release from the hydrogel was pH‐dependent, with 96% of the model drug released in a neutral environment, compared to 28% released in an acidic medium. These hydrogels could have potential in pH‐sensitive drug delivery. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2015 , 53, 356–367     

Electron transport through carbon nanotube intramolecular heterojunctions with peptide linkages

We present a systematic analysis of electron transport characteristics of carbon nanotube (CNT) intramolecular heterojunctions with peptide linkages, MM, SS, SM1, and SM2 where M and S stand for metallic and semiconducting CNT electrodes, respectively. Our theoretical investigations show that the incorporation of peptide linkages and their associated dipole moments play an important role in determining the electron transport characteristics and lead to materials with unique properties, such as Schottky-like behavior. Furthermore, we show that the Schottky-like behavior is observed in our SM1 junction but not in the SM2 junction because of the different effects that arise from both the direction and strength of their dipole moments. We believe that our results will pave the way towards the design and implementation of various electronic logic functions based on carbon nanotubes for applications in the field of nanoelectronics.     

Nonconformal interaction models and thermodynamics of polar fluids

In this work, we develop a simple potential model for polar molecules which represents effectively and accurately the thermodynamics of dilute gases. This potential models dipolar interactions whose nonpolar part is either spherical, as in Stockmayer (SM) molecules, or diatomic, as for 2-center Lennard-Jones molecules (2CLJ). Predictions of the second virial coefficient for SM and polar 2CLJ fluids for various dipole moments and elongations agree very well with results of recent numerical calculations by C. Vega and co-workers (Phys. Chem. Chem Phys. 2002, 4, 3000). The model is used to predict the critical temperature of Stockmayer fluids for variable dipole moment and is applied to HCl as an example of a real polar molecule.     

Glycerol‐lactic acid star‐shaped oligomers as efficient biobased surface modifiers for improving superabsorbent polymer hydrogels

The glycerol‐lactic acid‐based star‐shaped modifier (SM) were synthesized and employed for surface modification of hygienic superabsorbent polymer (SAP) hydrogels for the first time. Surface crosslinking was carried out to increase the saline‐absorbency under load (AUL) and the swollen gel strength. The surface treatment process was analyzed employing free absorbency and AUL tests, salt sensitivity, attenuated total reflectance‐Fourier‐transform infrared spectroscopy (ATR‐FTIR), oscillatory rheometry, as well as scanning electron microscopy analysis. The effect of the branched architecture and the contents of SM on the properties of the modified SAPs were studied. The implementation of surface treatment leads to increase up to a 28% in the AUL of the modified SAP. Moreover, the loss modulus was surprisingly increased, while the storage modulus was enhanced (possibly due to the star architecture of oligomers). M_c and crosslink density values have been estimated based on modified rubber elasticity theory. Salt sensitivity factor (f) was calculated; the modified samples showed lower salt sensitivity in NaCl (f = 0.7) and CaCl₂ (f = 0.93–0.95) compared with the intact SAP (f = 0.84 for NaCl, and f = 0.95–0.97 for CaCl₂).     

High water content clay–nanocomposite hydrogels incorporating guanidinium‐pendant methacrylamide: Tuning of mechanical and swelling properties by supramolecular approach

Novel clay–polymer composite hydrogels with high water content (up to 98 wt %) are developed, in which mechanical properties are reinforced by the formation of multiple ion‐pairs between the polymer chains and clay nanosheets (CNS). When a small amount of guanidinium‐pendant methacrylamide (0.1–0.2 wt %) is copolymerized with a neutral monomer (0.5–2.0 wt %) in an aqueous dispersion of CNS (1.0–3.0 wt %), a self‐standing hydrogel with satisfactory mechanical toughness and elasticity results, despite its high water content (95–98 wt %). The mechanical properties and swelling behaviors of the hydrogels can be tuned by the amount of the guanidinium‐pendant acrylamide. A systematic study indicates that the ion pairs, formed between the guanidinium groups in the polymer chains and the oxyanions on the surfaces of the CNS, serve as crosslinking points in the three‐dimensional network developed in these hydrogels. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 839–847     

Chiral,pH responsive hydrogels constructed by N‐Acryloyl‐alanine and PEGDA/α‐CD inclusion complex: preparation and chiral release ability

Chiral, pH‐responsive hydrogels are constructed by poly(ethylene glycol) diacrylate/α‐cyclodextrin (PEGDA/α‐CD) inclusion complex and L‐N‐acryloyl‐alanine or D‐N‐acryloyl‐alanine (L‐NAA or D‐NAA) by an effective free radical polymerization approach. PEGDA containing two C=C end groups was used simultaneously to introduce α‐CD units in the resulting hydrogels and to serve as a cross‐linking agent, by which forming the designed hydrogels in quantitative yield. Hydrophilic α‐CD moieties acted as pore‐forming agent, while the L(D)‐NAA‐based polymer chains bearing –COOH groups enabled the hydrogels to display remarkable swelling–deswelling behavior in response to pH variation. The chiral NAA monomer‐derived polymer chains rendered the hydrogels with intriguing optical activity, according to circular dichroism spectra. Scanning electron microscopy revealed the uniformly porous microstructures of hydrogels. More remarkably, the L‐NAA‐based hydrogels preferentially adsorbed trans‐4‐hydroxy‐d ‐proline and preferentially released trans‐4‐hydroxy‐l ‐proline, while D‐NAA‐based hydrogels provided opposite results. The hydrogels also demonstrated remarkable enantioselective release ability towards chiral drug ibuprofen. Copyright © 2015 John Wiley & Sons, Ltd.     

Thermoresponsive properties of porous poly(N‐isopropylacrylamide) hydrogels prepared in the presence of nanosized silica particles and subsequent acid treatment

Porous poly(N‐isopropylacrylamide) hydrogels were prepared by the free‐radical polymerization of its monomer and a suitable crosslinker in the presence of spherical silica particles of different sizes (74 and 1600 nm) and by the subsequent acid extraction of silica. The yields were 81–83%, and the yields were not affected by the silica content. Scanning electron microscopy observations revealed the porous structure of the hydrogels. Porous and nonporous hydrogels showed volume phase transitions from swelling states to deswelling states at approximately 30 °C, as analyzed by the ratio of the diameter of cylinder‐shaped hydrogels to that of the glass tube used for the hydrogel preparation at the corresponding temperature. Deswelling, which was analyzed by rapid changes in the temperature of the aqueous media from 20 to 40 °C, was facilitated by decreased silica particle size and increased silica content. The deswelling rate constant of the hydrogel prepared with 74‐nm silica at 10 v/v % (silica/solvent) was more than 1500 times greater than that of conventional hydrogels. Swelling was similarly analyzed through changes in the temperature from 40 to 20 °C and was independent of the pore structure. The deswelling–swelling cycle was repeatable with reasonable reproducibility. Moreover, the mechanical strength of the porous hydrogels was significantly maintained compared with that of conventional nonporous hydrogels. This method produced thermoresponsive hydrogels of suitable mechanical strength and remarkable deswelling properties. © 2002 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 40: 4228–4235, 2002     

pH‐responsive ionic poly(N,N‐diethylaminoethyl methacrylate‐co‐N‐vinyl‐2‐pyrrolidone) hydrogels: Synthesis and swelling properties

A series of an ionic hydrogels composed of N,N‐diethylaminoethyl methacrylamide (DEAEMA), N‐vinyl‐2‐pyrrolidone (VP), and itaconic acid were synthesized by free‐radical cross‐linking copolymerization in water–ethanol mixture by using N,N‐methylenebis(acrylamide) as the cross‐linker, ammonium persulfate as the initiator, and N,N,N′,N′‐tetramethylenediamine as the activator. The swelling behaviors of these hydrogels were analyzed in buffer solutions at various pH. It was observed that the swelling behavior of cross‐linked ionic poly(N,N‐diethylaminoethyl methacrylamide‐co‐N‐vinyl‐2‐pyrrolidone) [P(DEAEMA/VP)] hydrogels at different pH agreed with the modified Flory–Rehner equation based on the affine network model and the ideal Donnan theory. The swelling process in buffer solutions at various pH was found to be Fickian‐type diffusion. The pH‐reversibility and on–off switching properties of the P(DEAEMA/VP) hydrogels may be considered as good candidate to design novel drug‐delivery system. © 2005 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 43: 2819–2828, 2005     

Preparation and characterization of macroporous poly(N‐isopropylacrylamide) hydrogels for the controlled release of proteins

Macroporous, temperature‐sensitive poly(N‐isopropylacrylamide) (PNIPAAm) hydrogels were synthesized with poly(ethylene glycol)s (PEGs; molecular weight = 2000–6000) as the pore‐forming agents. The influence of the molecular weight and PEG content on the responsive kinetics of these macroporous hydrogels was investigated. The PEG‐modified PNIPAAm hydrogels were characterized by the swelling ratio, deswelling–reswelling kinetics, Fourier transform infrared, and differential scanning calorimetry. The morphology of these hydrogels was analyzed with scanning electron microscopy. The prepared macroporous hydrogels exhibited some unique properties in comparison with the gels with low molecular weight PEGs (molecular weight < 2000) as the pore‐forming agents. In addition, a preliminary study on the controlled release of bovine serum albumin from these macroporous hydrogels was carried out. © 2002 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 41: 152–159, 2003     

Tough and self‐recoverable hydrogels crosslinked by triblock copolymer micelles and Fe3+ coordination

Tough hydrogels have great potentials in soft robotics, artificial muscles, tissue replacement, and so on. Here we introduce novel tough hydrogels crosslinked by triblock copolymer (F127DA) micelles and metal coordination. The gels showed outstanding tensile strength (∼1–11 MPa), toughness (∼4–32 MJ m⁻³), and excellent self‐recovery properties (∼56.8–87.2% toughness recovery in 9 min at room temperature). The mechanical and self‐recovery properties could be manipulated by varying contents of micelles and/or COO⁻ groups. Dynamic mechanical analysis of the hydrogels revealed apparent activation energy and relaxations for both physical interactions. In situ small‐angle X‐ray scattering measurements on hydrogels upon stretching revealed micelle deformations. XPS measurements on hydrogels before and after stretching revealed significant changes in the binding energy of Fe³⁺ ions in the gels, suggesting the rupture of coordination bonds. The experimental results strongly suggest a synergistic effect from the micelle‐crosslinking and Fe³⁺–COO⁻ coordination on the strength, toughness, and self‐recovery of the hydrogels. © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2018 , 56, 865–876     

Structural design of stimuli‐responsive bioconjugated hydrogels that respond to a target antigen

Stimuli‐responsive bioconjugated hydrogels that can respond to a target antigen (antigen‐responsive hydrogels) were prepared by introducing antigen‐antibody bindings as reversible crosslinks into the gel networks. The preparation conditions of the antigen‐responsive hydrogels and the mechanism of the antigen‐responsive behavior were investigated, focusing on bioconjugated hydrogel structures. This article also focuses on the effect of semi‐interpenetrating polymer network (semi‐IPN) structures on the antigen‐responsive swelling/shrinking behavior of bioconjugated hydrogels with antigen‐antibody bindings. The preparation conditions and the network structures of the bioconjugated hydrogels are discussed in relation to designing antigen‐responsive hydrogels. © 2009 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 47: 2144–2157, 2009     

Tunable Pentapeptide Self‐Assembled β‐Sheet Hydrogels

Oligopeptide‐based supramolecular hydrogels hold promise in a range of applications. The gelation of these systems is hard to control, with minor alterations in the peptide sequence significantly influencing the self‐assembly process. We explored three pentapeptide sequences with different charge distributions and discovered that they formed robust, pH‐responsive hydrogels. By altering the concentration and charge distribution of the peptide sequence, the stiffness of the hydrogels could be tuned across two orders of magnitude (2–200 kPa). Also, through reassembly of the β‐sheet interactions the hydrogels could self‐heal and they demonstrated shear‐thin behavior. Using spectroscopic and cryo‐imaging techniques, we investigated the relationship between peptide sequence and molecular structure, and how these influence the mechanical properties of the hydrogel. These pentapeptide hydrogels with tunable morphology and mechanical properties have promise in tissue engineering, injectable delivery vectors, and 3D printing applications.