Thermo‐responsive injectable hydrogel system based on poly(N‐isopropylacrylamide‐co‐vinylphosphonic acid). I. Biomineralization and protein delivery

To achieve the injectable hydrogel system in order to improve bone regeneration by locally delivering a protein drug including bone morphogenetic proteins, thermo‐responsive injectable hydrogels composed of N‐isopropylacrylamide (NIPAAm) and vinyl phosphonic acid (VPAc) were prepared. The P(NIPAAm‐co‐VPAc) hydrogels were also biomineralized by urea‐mediation method to create functional polymer hydrogels that deliver the protein drug and mimic the bone extracellular matrix. The loosely cross‐linked P(NIPAAm‐co‐VPAc) hydrogels were pliable and fluid‐like at room temperature and could be injected through a small‐diameter aperture. The lower critical solution temperature (LCST) of P(NIPAAm‐co‐VPAc) hydrogel was influenced by the monomer ratio of NIPAAm/VPAc and the hydrogel with a 96/4 molar ratio of NIPAAm/VPAc exhibited an LCST of ～34.5°C. Water content was influenced by temperature, NIPAAm/VPAc monomer ratio, and biomineralization; however, all hydrogels maintained more than about 77% of the water content even at 37°C. In a cytotoxicity study, the P(NIPAAm‐co‐VPAc) and biomineralized P(NIPAAm‐co‐VPAc) hydrogels did not significantly affect cell viability. The loading content of bovine serum albumin in hydrogel, which was used as a model drug, gradually increased with the amount of VPAc in the hydrogel owing to the ionic interaction between VPAc groups and BSA molecules. In addition, the release behavior of BSA from the P(NIPAAm‐co‐VPAc) hydrogels was mainly influenced by the drug loading content, water content, and biomineralization of the hydrogels. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

Effect of Morphological Characteristics and Biomineralization of 3D-Printed Gelatin/Hyaluronic Acid/Hydroxyapatite Composite Scaffolds on Bone Tissue Regeneration

The use of porous three-dimensional (3D) composite scaffolds has attracted great attention in bone tissue engineering applications because they closely simulate the major features of the natural extracellular matrix (ECM) of bone. This study aimed to prepare biomimetic composite scaffolds via a simple 3D printing of gelatin/hyaluronic acid (HA)/hydroxyapatite (HAp) and subsequent biomineralization for improved bone tissue regeneration. The resulting scaffolds exhibited uniform structure and homogeneous pore distribution. In addition, the microstructures of the composite scaffolds showed an ECM-mimetic structure with a wrinkled internal surface and a porous hierarchical architecture. The results of bioactivity assays proved that the morphological characteristics and biomineralization of the composite scaffolds influenced cell proliferation and osteogenic differentiation. In particular, the biomineralized gelatin/HA/HAp composite scaffolds with double-layer staggered orthogonal (GEHA20-ZZS) and double-layer alternative structure (GEHA20-45S) showed higher bioactivity than other scaffolds. According to these results, biomineralization has a great influence on the biological activity of cells. Hence, the biomineralized composite scaffolds can be used as new bone scaffolds in bone regeneration.     

类氨基酸基载药水凝胶敷料的制备与性能

为制备一种具有良好生物相容性、可控缓释的物理交联的水凝胶敷料,选用类氨基酸单体N-丙烯酰基甘氨酰胺（NAGA）与生物发酵产物衣康酸（IA）为单体,在紫外光条件下,通过自由基聚合,在不需要外加任何交联剂条件下即可形成水凝胶聚（N-丙烯酰基甘氨酰胺-衣康酸）（P(NAGA-IA)）。所得水凝胶具有溶胶-凝胶转变温度（UCST）、较高的水溶胀率（40倍）及力学性能（压缩模量最高540 kPa）、较优的药物负载性和缓释性,这是因为NAGA单元提供分子间多重氢键作用,进而赋予了水凝胶较优的综合性能;而IA单元赋予了聚合物的pH刺激响应性,从而可诱导药物的释放。因此,所得P (NAGA-IA)水凝胶可作敷料用于创伤治疗。     

Regimes of microstructural evolution as observed from rheology and surface morphology of crosslinked poly(vinyl alcohol) and hyaluronic acid blends during gelation

Hyaluronic acid (HA)‐based materials are being investigated because of their role in biological fluids and tissues. Poly(vinyl alcohol) (PVA) when blended with HA at different compositions leads to superior mechanical properties compared to pure HA. The PVAHA blend hydrogels are potential candidates for pharmaceutical, biomedical, and cosmetic applications. It is essential to understand the structure, gelation time, and morphological properties of these hydrogels. In this work, a blend system of PVA crosslinked with glutaraldehyde in the presence of HA is studied. Semidilute solutions of PVA and HA are blended, followed by gelation due to crosslinking. The crosslinked gels as well as the gel cast membranes were examined. The effect of HA on the gelation process is investigated using rheological characterization. It is shown that kinetics of gelation is influenced by HA content, though storage modulus of the gels is influenced marginally. The structural features of PVAHA gels were also probed with scanning electron microscopy and dynamic light scattering. It is argued that there is a complex interplay between intra‐ and intermolecular crosslinking of PVA and PVA–HA interactions during the gel formation. Based on the insights obtained from various probing techniques for PVAHA gels with different HA content, three broad structural features were identified. It is shown that the hydrogel is semi‐interpenetrating network at lower HA content (<10% HA), cocontinuous morphology at moderate HA content and with domains at high HA content (>20% HA). © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 41081.     

Preparation of CaCO3‐based biomineralized polyvinylpyrrolidone–carboxymethylcellulose hydrogels and their viscoelastic behavior

In the blend of natural and synthetic polymer‐based biomaterial of polyvinylpyrrolidone (PVP) and carboxymethylcellulose (CMC), fabrication of CaCO₃ was successfully accomplished using simple liquid diffusion technique. The present study emphasizes the biomimetic mineralization in PVP–CMC hydrogel, and furthermore, several properties of this regenerated and functionalized hydrogel membranes were investigated. The physical properties were studied and confirmed the presence of CaCO₃ mineral in hydrogel by Fourier transform infrared spectroscopy and Scanning electron microscopy. Moreover, the absorptivity of water and mineral by PVP–CMC hydrogel was studied to determine its absorption capacity. Further, the viscoelastic properties (storage modulus, loss modulus, and complex viscosity) of mineralized and swelled samples (time: 5–150 min) were measured against angular frequency. It is interesting to know the increase of elastic nature of mineralized hydrogel filled with CaCO₃ maintaining the correlation between elastic property and viscous one of pure hydrogel. All these properties of biomineralized hydrogel suggest its application in biomedical field, like bone treatment, bone tissue regeneration, dental plaque and tissue replacement, etc. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40237.     

Microbial biomineralization of hydroxyapatite nanocrystals using Bacillus tequilensis

In this research, biomimetic deposition of “bone-like” apatite by novel Gram-positive bacterium Bacillus tequilensis was investigated. Hydroxyapatite (HA) was produced by Bacillus tequilensis using defined biomineralization media and dried. Calcination was carried out at different temperatures (100 °C–900 °C) and HA nanopowder was analysed for its structural phase composition, crystallinity, crystallite size and functional groups. X-ray diffractometry (XRD) indicated that increasing temperatures increased the crystallinity of HA nanocrystals. The presence of carbonate groups was evidenced by Fourier transform infrared (FTIR) spectrum and the purity of synthesized apatite nanocrystals was validated by absence of secondary peaks in XRD studies. Scanning electron microscopy (SEM) images depicted those uniform spherical agglomerates of HA comprised of nanosized crystallites. Transmission electron microscope (TEM) results identified needle-like crystal morphologies with average dimensions of 30–60 nm length and 3–10 nm width. Rich trace ion deposition was illustrated by energy dispersive x-ray spectroscopy (EDS) and quantified using inductively coupled plasma optical emission spectrometer (ICP-OES). Overall, microbial biomineralization by Bacillus tequilensis produced nanocrystals of HA that mimicked “bone-like apatite” as evidenced by pure phase, B-type carbonated form, poor crystallinity and trace amounts of vital elements (Mg, Na, K, Zn, Sr, Cl). Moreover, in vitro cytotoxicity studies revealed more than 80% cell viability highlighting the biocompatible nature of synthesized nano HA. Thereby, Bacillus tequilensis biomineralized nano HA reflects as a suitable candidate for applications in biomedicine addressing bone injuries and aiding regeneration.     

Preparation and characterization of composite hydrogels based on crosslinked hyaluronic acid and sodium alginate

In this study, a novel composite hydrogel with improved cellular structure and mechanical properties was prepared by the crosslinking of hyaluronic acid (HA) and sodium alginate (SAL). The amide linkages (covalent bonds) in the hydrogel that we expected to form were confirmed by Fourier transform infrared spectroscopy. The hydrogels had a pore size larger than 100 μm and were observed by scanning electron microscopy. Texture profile analysis indicated that the hardness of the hydrogels was enhanced by an increase in the polymer's concentration, but it declined with an increase in the HA/SAL molar ratio. The swelling capacity was reduced with increases in the polymer's concentration and the 1‐ethyl‐3‐(3‐dimethyl aminopropyl)‐1‐carbodiimide hydrochloride (EDC)/HA molar ratio, and it was enhanced by an increase in the HA/SAL molar ratio. The resistance against hyaluronidase was negatively correlated with the proportion of HA in the hydrogels and positively correlated with the EDC/HA molar ratio. Given the improved physicochemical properties that we produced, these novel hydrogels may have the potential to be applied in tissue engineering scaffolding. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 41898.     

Thiol–norbornene photoclick hydrogels for tissue engineering applications

Thiol–norbornene (thiol–ene) photoclick hydrogels have emerged as a diverse material system for tissue engineering applications. These hydrogels are crosslinked through light‐mediated orthogonal reactions between multifunctional norbornene‐modified macromers [e.g., poly(ethylene glycol) (PEG), hyaluronic acid, gelatin] and sulfhydryl‐containing linkers (e.g., dithiothreitol, PEG–dithiol, biscysteine peptides) with a low concentration of photoinitiator. The gelation of thiol–norbornene hydrogels can be initiated by long‐wave UV light or visible light without an additional coinitiator or comonomer. The crosslinking and degradation behaviors of thiol–norbornene hydrogels are controlled through material selections, whereas the biophysical and biochemical properties of the gels are easily and independently tuned because of the orthogonal reactivity between norbornene and the thiol moieties. Uniquely, the crosslinking of step‐growth thiol–norbornene hydrogels is not oxygen‐inhibited; therefore, gelation is much faster and highly cytocompatible compared with chain‐growth polymerized hydrogels with similar gelation conditions. These hydrogels have been prepared as tunable substrates for two‐dimensional cell cultures as microgels and bulk gels for affinity‐based or protease‐sensitive drug delivery, and as scaffolds for three‐dimensional cell encapsulation. Reports from different laboratories have demonstrated the broad utility of thiol–norbornene hydrogels in tissue engineering and regenerative medicine applications, including valvular and vascular tissue engineering, liver and pancreas‐related tissue engineering, neural regeneration, musculoskeletal (bone and cartilage) tissue regeneration, stem cell culture and differentiation, and cancer cell biology. This article provides an up‐to‐date overview on thiol–norbornene hydrogel crosslinking and degradation mechanisms, tunable material properties, and the use of thiol–norbornene hydrogels in drug‐delivery and tissue engineering applications. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 41563.     

Chemical synthesis of biomimetic hydrogels for tissue engineering

Owing to their high water content, porous structure, biocompatibility and tissue‐like viscoelasticity, hydrogels have become attractive and promising biomaterials for use in drug delivery, three‐dimensional cell culture and tissue engineering applications. Various chemical approaches have been developed for hydrogel synthesis using monomers or polymers carrying reactive functional groups. For in vivo tissue repair and in vitro cell culture purposes, it is desirable that the crosslinking reactions occur under mild conditions, do not interfere with biological processes and proceed at high yield with exceptional selectivity. Additionally, the crosslinking reaction should allow straightforward incorporation of bioactive motifs or signaling molecules, at the same time providing tunability of the hydrogel microstructure, mechanical properties and degradation rates. In this review, we discuss various chemical approaches applied to the synthesis of complex hydrogel networks, highlighting recent developments from our group. The discovery of new chemistries and novel materials fabrication methods will lead to the development of the next generation of biomimetic hydrogels with complex structures and diverse functionalities. These materials will likely facilitate the construction of engineered tissue models that may bridge the gap between two‐dimensional experiments and animal studies, providing preliminary insight prior to in vivo assessments. © 2017 Society of Chemical Industry     

Bioactive factor delivery strategies from engineered polymer hydrogels for therapeutic medicine

Polymer hydrogels have been widely explored as therapeutic delivery matrices because of their ability to present sustained, localized and controlled release of bioactive factors. Bioactive factor delivery from injectable biopolymer hydrogels provides a versatile approach to treat a wide variety of diseases, to direct cell function and to enhance tissue regeneration. The innovative development and modification of both natural- (e.g., alginate (ALG), chitosan, hyaluronic acid (HA), gelatin, heparin (HEP), etc.) and synthetic- (e.g., polyesters, polyethyleneimine (PEI), etc.) based polymers has resulted in a variety of approaches to design drug delivery hydrogel systems from which loaded therapeutics are released. This review presents the state-of-the-art in a wide range of hydrogels that are formed though self-assembly of polymers and peptides, chemical crosslinking, ionic crosslinking and biomolecule recognition. Hydrogel design for bioactive factor delivery is the focus of the first section. The second section then thoroughly discusses release strategies of payloads from hydrogels for therapeutic medicine, such as physical incorporation, covalent tethering, affinity interactions, on demand release and/or use of hybrid polymer scaffolds, with an emphasis on the last 5 years.     

Characterization of PVA/glycerin hydrogels made by <Emphasis Type="Italic">γ</Emphasis>-irradiation for advanced wound dressings

The aim of this study was to investigate the enhanced absorption property of PVA/Glycerin (PVA/Gly) hydrogel for advanced wound dressing. A simple crosslinking method was introduced to prepare the PVA/Gly hydrogels with the use of γ-irradiation. An absorption ratio and thermal properties of the PVA/Gly hydrogels can be controlled by varying the irradiation dose and weight ratio of the PVA/Gly. When the PVA/Gly content was 20/5 wt% and the irradiation dose at 25 kGy, the PVA/Gly hydrogels showed excellent absorption properties (>350%). These results imply that the PVA/Gly hydrogel is highly absorbent and converts wound exudates to the hydrogel matrices that create a moist and clean environment in the wound healing process. Therefore, the PVA/Gly hydrogel prepared by this method can be used as an advanced wound dressing.     

Preparation of microgel composite hydrogels by heating natural drying microgel composite polymers

Acrylamide‐co‐2‐acrylamido‐2‐methylpropane sulfonic acid‐based microgel composite (MC) hydrogels were prepared by heating natural drying MC polymers. It can reduce the influence of water content on the hydrogel properties. The natural drying MC polymer was swelling when the microgel content exceeded 0.5. It was soluble when the microgel content was 0.25, which was used to investigate the heating conditions. Under 50°C, MC hydrogels was obtained and hydrogen bonding was the reason for their formation. The tensile strength increased and the tensile elongation decreased as the heating time increased. When the heating time was 3 h, the tensile elongation decreased, as the heating temperature increased from 50°C to 80°C. However, the tensile strength increased first and then decreased. Under 60°C, the MC hydrogel had a high tensile strength of 155.3 kPa and a high tensile elongation of 313.3%. The more crosslinking density and the formation of covalent crosslinking bonds between the microgel particles and hydrogel matrix led to an increase in the tensile strength. However, the excess crosslinking of the polymer chains under high temperature could reduce the tensile strength. The tensile strength increased as the microgel content increased to 0.75 and then decreased as microgel content further increased. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40841.     

High performances of dual network PVA hydrogel modified by PVP using borax as the structure-forming accelerator

A dual network hydrogel made up of polyvinylalcohol (PVA) crosslinked by borax and polyvinylpyrrolidone (PVP) was prepared by means of freezing-thawing circles. Here PVP was incorporated by linking with PVA to form a network structure, while the introduction of borax played the role of crosslinking PVA chains to accelerate the formation of a dual network structure in PVA/PVP composite hydrogel, thus endowing the hydrogel with high mechanical properties. The effects of both PVP and borax on the hydrogels were evaluated by comparing the two systems of PVA/PVP/borax and PVA/borax hydrogels. In the former system, adding 4.0% PVP not only increased the water content and the storage modulus but also enhanced the mechanical strength of the final hydrogel. But an overdose of PVP just as more than 4.0% tended to undermine the structure of hydrogels, and thus deteriorated hydrogels’ properties because of the weakened secondary interaction between PVP and PVA. Likewise, increasing borax could promote the gel crosslinking degree, thus making gels show a decrease in water content and swelling ratio, meanwhile shrinking the pores inside the hydrogels and finally enhancing the mechanical strength of hydrogels prominently. The developed hydrogel with high performances holds great potential for applications in biomedical and industrial fields.     

Synthesis,Characterization, and drug release study of acrylamide‐co‐itaconic acid based smart hydrogel

A new kind of pH and temperature responsive poly(acrylamide‐co‐itaconic acid) hydrogel was prepared by free radical polymerization using ammonium persulfate as initiator and different comonomer ratios. The hydrogels were characterized in terms of chemical composition, swelling‐deswelling behavior, morphology, crystallographic behavior, and drug release properties. All the hydrogels showed high swelling ability in aqueous solutions, the maximum being at pH 7. Swelling decreased on either side of pH 7 (i.e., both in acidic and alkaline region) and increased with increase in temperature. The hydrogel with 10 mol% itaconic acid (IA) absorbed maximum water among the copolymer gels. The cellular structures of the hydrogels were clearly revealed by microscopic analysis and SEM pictures. Swelling of the gels in water followed non‐Fickian type of diffusion principle. The hydrogel was proved to be a controlled release vehicle, for example in drug delivery by using its smart properties. The hydrogel with 10 mol% IA also absorbed maximum amount of drug (ascorbic acid) under study. Incorporation of drug in hydrogel matrix was established from XRD peak analysis. POLYM. ENG. SCI., 55:113–122, 2015. © 2014 Society of Plastics Engineers     

Synthesis of highly swellable hydrogels of water‐soluble carboxymethyl chitosan and poly(ethylene glycol)

Highly swellable hydrogels were produced by crosslinking of high molecular weight carboxymethylated chitosan (CmCHT) with poly(ethylene glycol) (PEG) oligomers. The hydrogel swelling capacity could be controlled via the crosslinking density and ranged from 900% to 5600%. The hydrogels showed good homogeneity with a high interconnected porosity in the swollen state and with nanodomains rich in CmCHT and others rich in PEG diglycidyl ether. Oscillatory frequency sweep analysis showed a storage modulus of 27 kPa for the hydrogel with the highest crosslinking density, which together with the exhibited enzyme degradability with lysozyme at 59 days indicate that these hydrogels have potential use in delivery systems or soft tissue regeneration. © 2017 Society of Chemical Industry     

改性聚天冬氨酸复合水凝胶的制备及性能

以聚琥珀酰亚胺（PSI）、丙烯酸（AA）和丙烯酰胺（AM）为原料,KH550和KH570为联合交联剂,采用水溶液聚合法合成了聚天冬氨酸/聚（丙烯酸-丙烯酰胺）复合水凝胶［KPAsp/P（AA-AM）］;探讨了交联剂用量、原料配比对KPAsp/P（AA-AM）复合水凝胶溶胀性能的影响;采用FTIR和TG对水凝胶进行了表征。结果表明当v（KH550）∶v（KH570）=1∶1和n（PSI）∶n（AA）∶n（AM）=1∶3∶1时,所合成的复合水凝胶溶胀性能最佳,溶胀度达到395。通过吸水动力学研究表明,共聚链的引入改变了水凝胶的吸水行为。研究了复合水凝胶对阿莫西林的控释性能,结果表明,复合水凝胶的载药量可达29.98mg/g;在37℃、pH=1.8的NaCl溶液中,负载了阿莫西林的复合水凝胶在2h对药物的释放率达到57%,24h左右达到85%。     

Gelatin based pH‐sensitive hydrogels for colon‐specific oral drug delivery: Synthesis,characterization, and in vitro release study

Based on gelatin (Gltn) and acrylic acid (AAc), biodegradable pH‐sensitive hydrogel was prepared using gamma radiation as super clean source for polymerization and crosslinking. Incorporation of PAAc in the prepared hydrogel was confirmed by Fourier transform infrared spectroscopy (FTIR). The effect of PAAc content on the morphological structure of the prepared hydrogel swollen at pH 1, 5, and 7 was examined using scanning electron microscopy (SEM). The results showed the dependence of the porous structure of the prepared hydrogels on AAc content and the pH of the swelling medium. Swelling properties of gelatin/acrylic acid copolymer hydrogels with different AAc contents were investigated at different pH values. Swelling data showed that the prepared hydrogels possessed pronounced pH sensitivity. In vitro release studies were performed to evaluate the hydrogel potential as drug carrier using ketoprofen as a model drug. Experimental data showed that the release profile depends on both hydrogel composition and pH of the releasing medium. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

Photopolymerized hydrogel composites from poly(ethylene glycol) and hydroxyapatite for controlled protein delivery in vitro

The incorporation of hard particles into soft hydrogels can improve the mechanical properties and provide necessary bioactivity to the hydrogels for desired biomedical applications. Hydrogel composites containing hydroxyapatite (HA) are promising materials for orthopedic applications. In this study, injectable poly(ethylene glycol) (PEG) hydrogel precursor solutions containing HA particles and model protein bovine serum albumin (BSA) were synthesized in situ by photopolymerization. In vitro BSA release properties from the hydrogel composites containing various amounts of HA were investigated and discussed. Fourier transform infrared spectroscopy and scanning electron microscopy were employed to investigate the interaction between HA and the hydrogel network and the morphology of the hydrogel composites. It is found that PEG hydrogel composites containing HA sustained the release of BSA for at least 5 days and the presence of HA slowed down BSA release. Photopolymerized hydrogel composites containing HA may find potential use as a drug delivery matrix for orthopedic tissue engineering. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013     

β‐cyclodextrin‐conjugated hyaluronan hydrogel as a potential drug sustained delivery carrier for wound healing

In order to develop a potential drug sustained delivery carrier suitable for wound healing, a series of β‐cyclodextrin conjugated hyaluronan hydrogels (β‐CD‐HA) with adjustable crosslink densities were synthesized and characterized, meanwhile the delivery kinetics and mechanism of diclofenac as a model anti‐inflammatory drug from these hydrogels were investigated. By controlling the feeding molar ratio of β‐CD/HA, a β‐CD substitution degree of 4.65% was obtained by ¹H‐NMR analysis. The incorporation of β‐CD modification had little effect on the internal porous structure, water swelling ratio, and rheological property of HA hydrogel, which however were influenced by the crosslink density. Although the crosslink density had an influence on the drug loading and release profile by altering the water swelling property, the interaction between β‐CD and drug was the primary factor for the high loading capacity and long‐term sustained delivery of diclofenac. The semiempirical equation fit showed that the release of diclofenac from HA‐based hydrogels followed a pseudo‐Fickian diffusion mechanism. By the aid of β‐CD and controlled crosslink density, a β‐CD‐HA hydrogel with a diclofenac sustained delivery period of over 28 days and desirable physicochemical properties was achieved, which will be a promising drug sustained delivery carrier for wound healing. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 43072.