L-Arginine based polyester amide/hyaluronic acid hybrid hydrogel with dual anti-inflammation and antioxidant functions for accelerated wound healing

Nowadays, there are still many challenges to skin regeneration. As a new type of skin substitute, hydrogel has emerging gradually with its excellent properties. However, it is still a challenge to combine with biological active agents to facilitate skin regeneration. Under the circumstance, we synthesized argininebased poly(ester amide)(Arg-PEA) and hyaluronic acid(HA-MA), and combined them into new hybrid hydrogels via photo-crosslinking. We found that the internal structure and physicochemical...     

Preparation of rapidly curable hydrogels from gelatin and poly (carboxylic acid) and their adhesion to skin

Papidly curable hydrogels were prepared through chemical crosslinking of gelatin with poly(carboxylic acid)s including poly (L-glutamic acid) (PLGA), hyaluronic acid (HA), and poly (acrylic acid) (PAA) by use of water-soluble carbodiimide (WSC). The effects of the nature of added poly (carboxylic acid)s on gelation of mixed gelatinpoly (carboxylic acid) aqueous solutions and adhesion of the resulting hydrogels to the mouse skin were evaluated. The addition of poly (carboxylic acid) s reduced the gelation time of gelatin aqueous solutions except for HA. Mixed gelatin-PLGA solutions were cured more rapidly than other mixed solutions and the gelation time was shortened with the increasing PLGA molecular weight. The resulting gelatin-PLGA hydrogels exhibited stronger adhesion to the mouse skin than gelatin-HA and gelatin-PAA hydrogels. The bonding strength increased with the increase in PLGA molecular weight up to 83,000 and thereafter decreased. The longer gelation time and lower adhesion of the gelatin-PAA hydrogels than the gelatin-PLGA hydrogels seem to be due to poorer compatibility of gelatin with PAA than with PLGA. The mixed gelatin-PLGA solution underwent phase separation when the concentration and molecular weight of PLGA became higher than a threshold. The insignificant or suppressive effect of HA addition might be ascribed to the HA-WSC reaction which was the least effective in hydrogel formation.     

Development of injectable high molecular weight hyaluronic acid hydrogels for cartilage regeneration

The study focuses on developing hyaluronic acid (1200 kilo Dalton) hydrogels for cartilage regeneration. In spite of being highly biocompatible; a large amount of water absorption and easily degrading nature restricts the use of hyaluronic acid in the field of tissue regeneration. This can be rectified by crosslinking hyaluronic acid with a crosslinking agent such as divinyl sulfone; which results in a biocompatible hydrogel with superior rheological properties. Different amounts of divinyl sulfone have been used for crosslinking hyaluronic acid to get three types of hydrogels with differing properties. Swelling studies, rheology analysis, enzymatic degradation and scanning electron microscopic analysis were conducted on all the different types of hydrogels prepared. Viscoelastic properties of the hydrogel were analyzed so that a hydrogel with better elastic property and stability is obtained. Scanning electron microscopy was used to study the morphology of the HA hydrogels. The cytotoxicity testing was conducted to prove the non-toxic nature of the hydrogels and cell culture studies using adipose mesenchymal stem cells showed better adhesion and proliferation properties in all the three hydrogels. Thus hyaluronic acid hydrogel makes a promising material for cartilage regeneration.     

Analysis by high-performance gel permeation chromatography of hyaluronic acid in animal skins and rabbit synovial fluid

The simultaneous analysis of the molecular weight and concentration of hyaluronic acid in biological samples using high-performance liquid chromatography with two gel permeation columns is described. The elution volumes of various molecular weights of hyaluronic acids were linearily related to the logarithms of their molecular weights up to 600,000. The concentration of hyaluronic acid could be determined in the range from 20 to 100 micrograms/ml, i.e., from 4 to 20 micrograms per 200 microliter injected. The method was applied to the analysis of several animal skin extracts and rabbit synovial fluid. Skin extracts from mouse, rat, guinea-pig and rabbit could be chromatographed without prior isolation and purification. Hyaluronic acids in skin were separated clearly from chondroitin sulphates and their concentrations were determined. The molecular weights were estimated simultaneously to be more than 10(6). Rabbit synovial fluids from intact joints and saline- and carrageenin-treated joints could be chromatographed directly. The chromatograms showed that the concentration of hyaluronic acid in carrageenin-treated synovial fluid is lower than that in saline-treated fluid and the molecular weight distribution is broader. This technique enabled the rapid analysis of hyaluronic acid present at low levels in biological samples.     

The sol-gel approach towards thermo-responsive poly(N-isopropyl acrylamide) hydrogels with improved mechanical properties

A new type of thermo-responsive hydrogels based on the polymer poly(N-isopropyl acrylamide) (PNIPAA) has been synthesized with the sol-gel technology. For the preparation of this type of nano-structured hydrogels, the inorganic silica phase was synthesized by the sol-gel process in the presence of an aqueous solution of high molecular weight PNIPAA. This combination of the organic and inorganic phases forms hybrid hydrogels with a semi-IPN morphology. The unique structure of these hydrogels improves the mechanical stability to a great extent as compared to conventional PNIPAA-hydrogels. This was shown by stress-strain experiments and the capability to absorb and desorb large amounts of water. The silica only slightly influences the transition temperature of the hydrogels but allows us to vary the thermo-responsive properties of the materials to a great extent.     

组织工程用水凝胶材料

综述了目前用于组织工程支架材料的水凝胶,包括胶原和明胶、透明质酸盐、海藻酸盐,琼脂糖和壳聚糖等天然水凝胶,聚丙烯酸及其衍生物、聚氧化乙烯及其衍生共聚物、聚乙烯醇、聚磷腈和合成多肽等合成水凝胶,并介绍了可注射性组织工程水凝胶。     

透明质酸的改性及在生物医用材料领域的应用研究

透明质酸(HA)是人体内最为常见的一种粘多糖,具有优良的生物相容性和可降解性,可广泛应用于药物输送、皮肤填充材料、组织工程、药物载体和3D仿生学等方面,是当前生物医用材料领域的研究热点之一。HA具有独特的结构使其显示出特定的物理化学性质,可通过物理或化学方法修饰,赋予其新功能和新应用。本文从HA的分子结构出发,重点综述了HA的官能团羧基、羟基和乙酰胺基的化学改性和物理改性,主要包括羧基的酰胺化反应和酯化反应,羟基与环氧化物的开环反应、与有机硫化物的反应、酯化反应、与卤化物的反应和氧化反应,以及HA脱乙酰基反应;介绍了HA在生物医用材料领域的应用,并对其前景进行展望。     

Polyelectrolyte complexes of soluble poly-2-[(methacryloyloxy)ethyl]trimethylammonium chloride and its hydrogels with poly(acrylic acid)

The complex formation of poly-2-[(methacryloyloxy)-ethyl]trimethylammonium chloride (PMADQUAT) with poly(acrylic acid) (PAA) of different molecular weights has been studied in aqueous solutions by potentiometric, viscometric, turbidimetric and FTIR spectroscopic methods. The formation of insoluble non-stoichiometric polyelectrolyte complexes has been shown. The stability of polyelectrolyte complexes in solutions of different pH and ionic strength has been evaluated. The formation of polyelectrolyte complexes between hydrogels of PMADQUAT and linear PAA of different molecular weights has been studied. It was shown that the molecular weight of PAA considerably affects the kinetics of interaction as well as the final state of gel-polymer complex.     

Enhanced Transdermal Absorption of Hyaluronic Acid via Fusion with Pep-1 and a Hyaluronic Acid Binding Peptide

It is always big challenges for hyaluronic acid (HA) in transmembrane absorbing and efficient delivering to the skin. Pep-1, as one of the cell-penetrating peptides, has been documented to permeate various substances across cellular membranes without covalent binding. Here, a novel hyaluronic acid binding peptide (named HaBP) is designed, and then combined with Pep-1 to enhance the cell-penetrating efficiency of HA. The results of ELISA and immunofluorescence assay show that HaBP could bind with HA very well, and a combination of Pep-1 and HaBP could efficiently improve the transmembrane ability of HA. Furthermore, HA gradually enters the dermis from the surface of the skin in mice when it is administrated with both HaBP and Pep-1, while there are no obvious allergies or other adverse reactions during this process. This study finds a new method to promote the efficient transmembrane and transdermal absorption of HA, and throws some light on further research on the development of hyaluronic acid and its related cosmetics or drugs.     

Enzymatic polymerization to artificial hyaluronic acid using a transition state analogue monomer

Artificial hyaluronic acid has been synthesized in vitro via enzymatic polymerization catalyzed by testicular hyaluronidases, which is the first successful example of the hyaluronic acid synthesis via non-biosynthetic pathways. The novel GlcAβ(1→3)GlcNAc oxazoline derivative was designed and synthesized as a transition state analogue monomer for the hyaluronidase catalysis. The oxazoline monomer was efficiently recognized by the enzymes at pH 7.1 to 9.0 and the polymerization reaction proceeded in a regio- and stereo-selective manner to give rise to artificial hyaluronic acid with molecular weight higher than 15000. These results strongly suggest that the transition state of these testicular hyaluronidases catalysis corresponds to a sugar oxazolinium ion.     

Specific high performance liquid chromatographic determination of the molecular weight and concentration of hyaluronic acid in complex mixtures by labelled hyaluronate binding proteins.

A simple High performance liquid chromatographic (HPLC) method for the specific determination of the molecular weight and concentration of hyaluronic acid (HA) in complex mixtures has been developed. Hyaluronate-binding proteins isolated from bovine cartilage labelled by 125I or fluoresceinisothiocyanate were used as specific markers. The specific binding affinities of the markers were compared and were found to have association constants of 1.6 x 10(7) M-1 and 1.2 x 10(7) M-1 respectively. The HA levels and molecular weight distributions can be easily determined in the range 10-500 ng/mL in complex mixtures by the use of markers, molecular sieving HPLC columns and appropriate detectors. It has been demonstrated clearly that the method is useful for the highly specific determination of the parameters in complex biological samples such as serum and synovial fluids and is recommended for clinical applications.     

Effect of C-terminal modification on the self-assembly and hydrogelation of fluorinated Fmoc-Phe derivatives

The development of hydrogels resulting from the self-assembly of low molecular weight (LMW) hydrogelators is a rapidly expanding area of study. Fluorenylmethoxycarbonyl (Fmoc) protected aromatic amino acids derived from phenylalanine (Phe) have been shown to be highly effective LMW hydrogelators. It has been found that side chain functionalization of Fmoc-Phe exerts a significant effect on the self-assembly and hydrogelation behavior of these molecules; fluorinated derivatives, including pentafluorophenylalanine (F(5)-Phe) and 3-F-phenylalanine (3-F-Phe), spontaneously self-assemble into fibrils that form a hydrogel network upon dissolution into water. In this study, Fmoc-F(5)-Phe-OH and Fmoc-3-F-Phe-OH were used to characterize the role of the C-terminal carboxylic acid on the self-assembly and hydrogelation of these derivatives. The C-terminal carboxylic acid moieties of Fmoc-F(5)-Phe-OH and Fmoc-3-F-Phe-OH were converted to C-terminal amide and methyl ester groups in order to perturb the hydrophobicity and hydrogen bond capacity of the C-terminus. Self-assembly and hydrogelation of these derivatives was investigated in comparison to the parent carboxylic acid compounds at neutral and acidic pH. It was found that hydrogelation of the C-terminal acids was highly sensitive to solvent pH, which influences the charge state of the terminal group. Rigid hydrogels form at pH 3.5, but at pH 7 hydrogel rigidity is dramatically weakened. C-terminal esters self-assembled into fibrils only slowly and failed to form hydrogels due to the higher hydrophobicity of these derivatives. C-terminal amide derivatives assembled much more rapidly than the parent carboxylic acids at both acidic and neutral pH, but the resultant hydrogels were unstable to shear stress as a function of the lower water solubility of the amide functionality. Co-assembly of acid and amide functionalized monomers was also explored in order to characterize the properties of hybrid hydrogels; these gels were rigid in unbuffered water but significantly weaker in phosphate buffered saline. These results highlight the complex nature of monomer/solvent interactions and their ultimate influence on self-assembly and hydrogelation, and provide insight that will facilitate the development of optimal amino acid LMW hydrogelators for gelation of complex buffered media.     

Self-assembly in magnetic supramolecular hydrogels

Most recent advances in the synthesis of supramolecular hydrogels based on low molecular weight gelators (LMWGs) have focused on the development of novel hybrid hydrogels, combining LMWGs and different additives. The dynamic nature of the noncovalent interactions of supramolecular hydrogels, together with the specific properties of the additives included in the formulation, allow these novel hybrid hydrogels to present interesting features, such as stimuli-responsiveness, gel-sol reversibility, self-healing and thixotropy, which make them very appealing for multiple biomedical and biotechnological applications. In particular, the inclusion of magnetic nanoparticles in the hydrogel matrix results in magnetic hydrogels, a particular type of stimuli-responsive materials that respond to applied magnetic fields. This review focuses on the recent advances in the development of magnetic supramolecular hydrogels, with special emphasis in the role of the magnetic nanoparticles in the self-assembly process, as well as in the exciting applications of these materials.     

Multilayer assembly of hyaluronic acid/poly(allylamine): control of the buildup for the production of hollow capsules

The objective of this work was to investigate the formation of hollow microcapsules composed of hyaluronic acid (HA) and poly(allylamine) (PAH) by layer-by-layer adsorption on CaCO 3 microparticles and subsequent core removal by addition of chelating agents for calcium ions. We found that the molecular weight of HA as well as the HA solution concentration used during deposition are crucial parameters influencing the multilayer structure. Whereas the effect of molecular weight of HA was mainly attributed to the porous structure of the template which allows penetration of polyelectrolytes when their size is below the maximum pore size of the template ( approximately 60 nm), that of the concentration of the HA solution was related to the intrinsic properties of the polysaccharide. Indeed, as shown by quartz crystal microbalance with dissipation monitoring as well as electron microscopy techniques, the latter leads to dense structures for concentrations from five to ten times the critical overlap concentration during adsorption. Such conditions were found to be favorable for the formation of hollow shells. Regarding conditions for core dissolution, we demonstrated the possibility to use either ethylenediaminetetraacetic acid (EDTA) or citric acid as chelating agents. However, in some cases, it was necessary to chemically cross-link the shell to maintain its integrity.     

Synthesis of cationic water‐soluble copolymers and hydrogels based on [2‐(methacryloyloxy)ethyl]trimethylammonium chloride and 2‐hydroxyethylacrylate and their complex formation with poly(acrylic acid)

Water‐soluble cationic copolymers and hydrogels were synthesized by radical copolymerization of [2‐(methacryloyloxy)ethyl]trimethylammonium chloride (MADQUAT) and 2‐hydroxyethylacrylate (HEA). The kinetics of copolymerization has been studied and the reactivity ratios were determined. It was found that MADQUAT exhibits higher reactivity in copolymerization. The complexation between linear MADQUAT‐HEA and linear poly(acrylic acid) (PAA) has been studied in aqueous solutions at different pH. It results in the formation of insoluble polyelectrolyte complexes, whose composition and stability to aggregate depends on MADQUAT content in copolymers and pH. The hydrogels were synthesized by three‐dimensional radical copolymerization of MADQUAT and HEA in the presence of a crosslinker. The effects of the feed mixture composition on yield and swelling properties of the hydrogels were studied. The interactions of these hydrogels with linear PAA result in formation of gel–polyelectrolyte complexes and contraction of the samples. It was found that the contraction depends on copolymer composition, PAA molecular weight, and solution pH. © 2006 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 44:845–853, 2006     

Injectable Hyaluronic Acid/Poly(γ-glutamic acid) Hydrogel with Step-by-step Tunable Properties for Soft Tissue Engineering

Injectable hydrogels as an important class of biomaterials have gained much attention in tissue engineering. However, their crosslinking degree is difficult to be controlled after being injected into body. As we all know, the crosslinking degree strongly influences the physicochemical properties of hydrogels. Therefore, developing an injectable hydrogel with tunable crosslinking degree in vivo is important for tissue engineering. Herein, we present a dual crosslinking strategy to prepare injectable hydrogels with step-by-step tunable crosslinking degree using Schiff base reaction and photopolymerization. The developed hyaluronic acid/poly(γ-glutamic acid)(HA/γ-PGA) hydrogels exhibit step-bystep tunable swelling behavior, enzymatic degradation behavior and mechanical properties. Mechanical performance tests show that the storage moduli of HA/γ-PGA hydrogels are all less than 2000 Pa and the compressive moduli are in kilopascal, which have a good match with soft tissue. In addition, NIH 3 T3 cells encapsulated in HA/γ-PGA hydrogel exhibit a high cell viability, indicating a good cytocompatibility of HA/γ-PGA hydrogel.Therefore, the developed HA/γ-PGA hydrogel as an injectable biomaterial has a good potential in soft tissue engineering.     

Rheological behaviour of irradiated wound dressing poly(vinyl pyrrolidone) hydrogels

The use of hydrogels as biomaterials has increased lately. Poly(vinyl pyrrolidone) (PVP) is an example of polymer hydrogels applied for the synthesis of hydrogel to be used in different biomedical applications. This paper describes a study on rheological properties of PVP hydrogels obtained by gamma radiation techniques. PVP hydrogels were obtained by gamma radiation of PVP water solutions with different radiation doses. It was studied the influence of additives such as poly(ethylene glycol) (PEG), poly(ethylene oxide) (PEO) and glycerol on the rheological behaviour of the gel. The rheological behaviour of hydrogel samples was characterized by measuring the shear storage modulus (G′) under dynamic shear loading. Besides this, sterility and cytotoxicity tests were performed. The study on rheological behaviour of hydrogels showed that G′ of PVP gels change according to the additive used. Glycerol increases the fluidity of the gel. The influence of PEG depends on the amount and on its molecular mass. The increase on PEG amount and molecular mass cause a decrease of G′ and an increase in the crosslinking density of PVP hydrogel network. The use of high molecular weight PEO allows the increase of the elasticity of the PVP gels.     

咪唑盐类聚离子液体抗菌剂的制备及其在水凝胶敷料中的应用

皮肤伤口的感染严重威胁患者的生命安全,虽然传统的含有银离子或小分子抗生素的抗菌水凝胶伤口敷料具有广谱的杀菌功效,但这些抗菌水凝胶敷料中的抗菌剂存在一定的生物毒性和耐药性风险,无法满足临床长期使用的要求.咪唑盐类聚离子液体由于其含有较强的正电荷效应以及疏水链段,因此其作为新型的聚合物抗菌剂具有较强的抗菌效果.本研究首先通...     

Bioinspired dual dynamic network hydrogels promote cartilage regeneration through regulating BMSC chondrogenic differentiation

How to improve the therapeutic efficacy of cell delivery during mechanical injection has been a great challenge for tissue engineering. Here, we present a facile strategy based on dynamic chemistry to prepare injectable hydrogels for efficient stem cell delivery using hyaluronic acid (HA) and poly(γ-glutamic acid) (γ-PGA). The combination of the guest–host (GH) complexation and dynamic hydrazone bonds enable the HA/γ-PGA hydrogels with physical and chemical dual dynamic network and endow hydrogels a stable structure, rapid self-healing ability, and injectability. The mechanical properties, self-healing ability, and adaptability can be programmed by changing the ratio of GH network to hydrazine bond cross-linked network. Benefitting from the dynamic cross-linking networks, mild preparation process, and cytocompatibility of HA/γ-PGA hydrogels, bone marrow mesenchymal stem cells (BMSCs) show high cell viability in this system following mechanical injection. Moreover, HA/γ-PGA hydrogels can promote BMSC proliferation and upregulate the expression of cartilage-critical genes. Notably, in a rabbit auricular cartilage defect model, BMSC-laden HA/γ-PGA hydrogels can effectively promote cartilage regeneration. Together, we propose a general strategy to develop injectable self-healing HA/γ-PGA hydrogels for effective stem cell delivery in cartilage tissue engineering.     

(Bio)polymeric Hydrogels as Therapeutic Agents

Hydrogels derived from both natural and synthetic polymers have gained significant scientific attention in recent years for their potential use as biomedical materials to treat human diseases. While a great deal of research efforts have been directed towards investigating polymeric hydrogels as matrices for drug delivery systems, examples of such hydrogels exhibiting intrinsic therapeutic properties are relatively less common. Characteristics of synthetic and natural polymers such as high molecular weight, diverse molecular architecture, chemical compositions, and modulated molecular weight distribution are unique to polymers. These characteristics of polymers can be utilized to discover a new generation of drugs and medical devices. For example, polymeric hydrogels can be restricted to the gastrointestinal tract, where they can selectively recognize, bind, and remove the targeted disease-causing substances from the body without causing any systemic toxicity that are associated with traditional small molecule drugs. Similarly hydrogels can be implanted at specific locations (such as knee and abdomen) to impart localized therapeutic benefits. The present article provides an overview of certain recent developments in the design and synthesis of functional hydrogels that have led to several polymer derived drugs and biomedical devices. Some of these examples include FDA-approved marketed products.