Hyaluronic Acid Hydrogels Formed in Situ by Transglutaminase-Catalyzed Reaction (original) (raw)
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Crosslinked hyaluronic acid hydrogels: a strategy to functionalize and pattern
Biomaterials, 2005
The physiological activity of hyaluronic acid (HA) polymers and oligomers makes it a promising material for a variety of applications. The development of HA-hydrogel scaffolds with improved mechanical stability against degradation and biochemical functionality may enhance their application to tissue engineering. In this report, a crosslinking strategy targeting the alcohol groups via a poly(ethylene glycol) diepoxide crosslinker was investigated for the generation of degradable HA hydrogels. To provide support for cell adhesion in vitro, collagen was incorporated into the HA solution prior to the crosslinking process. The hydrogels have a continuous exterior and a porous interior, with pore diameters ranging from 6 to 9 mm. HA and HA-collagen hydrogels degrade in the presence of hyaluronidase and collagenase enzymes, indicating that the chemical modification does not prevent biodegradation. Complete degradation of the hydrogels occurred within 14 days in hyaluronidase (100 U/ml) and 3 days in collagenase (66 U/ml). Pattern transfer was employed to introduce a surface topography onto the hydrogel, which was able to orient cell growth. Furthermore, the hydrogels could be functionalized with the biomolecule neutravidin by incorporation of biotin along the HA backbone. This biotinylation approach may allow attachment of bioactive molecules that are conjugated to avidin.
Biomaterials, 2007
The nanometer-scale mesh size of many synthetic crosslinked hydrogel networks restricts encapsulated cells to a rounded morphology that can inhibit cellular processes such as proliferation and migration that are essential for the early stages of remodeling and tissue formation. The objective of these studies was to investigate an approach for accelerating cellular remodeling based on the creation of semi-interpenetrating networks (IPNs) composed of hydrolytically degradable poly(ethylene glycol) (PEG) diacrylate macromers and native, enzymatically degradable extracellular matrix (ECM) components (collagen, gelatin and hyaluronic acid (HA)). Among the three ECM components investigated, addition of HA at concentrations of 0.12% w/v and greater supported fibroblast spreading throughout the three-dimensional network and significantly increased proliferation relative to control hydrogels without HA. Incorporation of HA resulted in relatively small changes in hydrogel physical/chemical properties such as swelling, degradation rate, and elastic modulus. Fibroblast spreading was eliminated by the addition of hyaluronidase inhibitors, demonstrating that cell-mediated enzymatic degradation of HA is a necessary mechanism responsible for the observed increases in fibroblast activity. By accelerating early cellular remodeling and growth, these semi-IPNs may be useful vehicles for cell transplantation in a variety of tissue engineering applications.
Hyaluronic acid-based hydrogels: from a natural polysaccharide to complex networks
Soft Matter, 2012
Hyaluronic acid (HA) is one of nature's most versatile and fascinating macromolecules. Being an essential component of the natural extracellular matrix (ECM), HA plays an important role in a variety of biological processes. Inherently biocompatible, biodegradable and non-immunogenic, HA is an attractive starting material for the construction of hydrogels with desired morphology, stiffness and bioactivity. While the interconnected network extends to the macroscopic level in HA bulk gels, HA hydrogel particles (HGPs, microgels or nanogels) confine the network to microscopic dimensions. Taking advantage of various scaffold fabrication techniques, HA hydrogels with complex architecture, unique anisotropy, tunable viscoelasticity and desired biologic outcomes have been synthesized and characterized. Physical entrapment and covalent integration of hydrogel particles in a secondary HA network give rise to hybrid networks that are hierarchically structured and mechanically robust, capable of mediating cellular activities through the spatial and temporal presentation of biological cues. This review highlights recent efforts in converting a naturally occurring polysaccharide to drug releasing hydrogel particles, and finally, complex and instructive macroscopic networks. HA-based hydrogels are promising materials for tissue repair and regeneration. body by hyaluronidase and reactive oxygen species, with tissue half-lives ranging from minutes in the blood to hours or days in skin and joints. 6 HA is an attractive building block for the fabrication of artificial matrices for tissue engineering because it is biocompatible, biodegradable, bioactive, non-immunogenic and non-thrombogenic. 7 In physiological solutions, HA assumes an expanded random coil structure that occupies a very large domain that facilitates solute diffusion. Although high molecular weight HA at high concentrations in solution (e.g. 5 MDa at >0.1 mg/mL) can form entangled molecular networks that are viscoelastic, solutions of HA do not have long lasting mechanical integrity. To afford HA-based hydrogels with tailored mechanical properties and degradation rates, while at the same time maintaining their native biological functions, controlled chemical modification and covalent crosslinking are often necessary. By varying the molecular weight of HA, the degree of modification and the concentration of the reactive HA precursors, hydrogels with varying stiffness, pore size and degradation rate can be readily produced. Additional biological functionality can be incorporated into HA gels via the coupling of different biological moieties, cytokines and therapeutic drugs. Efficient, biocompatible and chemo-selective crosslinking chemistries have enabled the encapsulation of cells during gelation, giving rise to three dimensional (3D) cell/gel constructs with intimate cell-matrix interactions. 10
Enzymatically cross-linked alginic–hyaluronic acid composite hydrogels as cell delivery vehicles
International Journal of Biological Macromolecules, 2013
An injectable composite gel was developed from alginic and hyaluronic acid. The ezymatically cross-linked injectable gels were prepared via the oxidative coupling of tyramine modified sodium algiante and sodium hyaluronate in the presence of horse radish peroxidase (HRP) and hydrogen peroxide (H 2 O 2). The composite gels were prepared by mixing equal parts of the two tryaminated polymer solutions in 10U HRP and treating with 1.0% H 2 O 2. The properties of the alginate gels were significanly affected by the addition of hyaluronic acid. The percentage water absorption and storage modulus of the composite gels were found to be lower than the alginate gels. The alginate and composite gels showed lower protein release compared to hyaluronate gels in the absence of hyaluronidase. Even hyaluronate gels showed only approximately 10% protein release after 14 days incubation in phosphate buffer solution. ATDC-5 cells encapsulated in the injectable gels showed high cell viability. The composite gels showed the presence of enlarged spherical cells with significantly higher metabolic activity compared to cells in hyaluronic and alginic acid gels. The results suggest the potential of the composite approach to develop covalently cross-linked hydrogels with tuneable physical, mechanical, and biological properties.
Recent advances in hyaluronic acid hydrogels for biomedical applications
Hyaluronic acid (HA) is widely used in the design of engineered hydrogels, due to its biofunctionality, as well as numerous sites for modification with reactive groups. There are now widespread examples of modified HA macromers that form either covalent or physical hydrogels through crosslinking reactions such as with click chemistry or supramolecular assemblies of guest-host pairs. HA hydrogels range from relatively static matrices to those that exhibit spatiotemporally dynamic properties through external triggers like light. Such hydrogels are being explored for the culture of cells in vitro, as carriers for cells in vivo, or to deliver therapeutics, including in an environmentally responsive manner. The future will bring new examples of HA hydrogels due to the synthetic diversity of HA.
Bioactive modification of poly(ethylene glycol) hydrogels for tissue engineering
In this review, we explore different approaches for introducing bioactivity into poly(ethylene glycol) (PEG) hydrogels. Hydrogels are excellent scaffolding materials for repairing and regenerating a variety of tissues because they can provide a highly swollen three-dimensional (3D) environment similar to soft tissues. Synthetic hydrogels like PEG-based hydrogels have advantages over natural hydrogels, such as the ability for photopolymerization, adjustable mechanical properties, and easy control of scaffold architecture and chemical compositions. However, PEG hydrogels alone cannot provide an ideal environment to support cell adhesion and tissue formation due to their bio-inert nature. The natural extracellular matrix (ECM) has been an attractive model for the design and fabrication of bioactive scaffolds for tissue engineering. ECM-mimetic modification of PEG hydrogels has emerged as an important strategy to modulate specific cellular responses. To tether ECM-derived bioactive molecules (BMs) to PEG hydrogels, various strategies have been developed for the incorporation of key ECM biofunctions, such as specific cell adhesion, proteolytic degradation, and signal molecule-binding. A number of cell types have been immobilized on bioactive PEG hydrogels to provide fundamental knowledge of cell/scaffold interactions. This review addresses the recent progress in material designs and fabrication approaches leading to the development of bioactive hydrogels as tissue engineering scaffolds.
Materials Today Bio
In the last decade, hyaluronic acid (HA) has attracted an ever-growing interest in the biomedical engineering field as a biocompatible, biodegradable, and chemically versatile molecule. In fact, HA is a major component of the extracellular matrix (ECM) and is essential for the maintenance of cellular homeostasis and crosstalk. Innovative experimental strategies in vitro and in vivo using three-dimensional (3D) HA systems have been increasingly reported in studies of diseases, replacement of tissue and organ damage, repairing wounds, and encapsulating stem cells for tissue regeneration. The present work aims to give an overview and comparison of recent work carried out on HA systems showing advantages, limitations, and their complementarity, for a comprehensive characterization of their use. A special attention is paid to the use of HA in three important areas: cancer, diseases of the central nervous system (CNS), and tissue regeneration, discussing the most innovative experimental strategies. Finally, perspectives within and beyond these research fields are discussed.
Soft Matter, 2010
We aimed to develop biomimetic hydrogel matrices that not only exhibit structural hierarchy and mechanical integrity, but also present biological cues in a controlled fashion. To this end, photocrosslinkable, hyaluronic acid (HA)-based hydrogel particles (HGPs) were synthesized via an inverse emulsion crosslinking process followed by chemical modification with glycidyl methacrylate (GMA). HA modified with GMA (HA-GMA) was employed as the soluble macromer. Macroscopic hydrogels containing covalently integrated hydrogel particles (HA-c-HGP) were prepared by radical polymerization of HA-GMA in the presence of crosslinkable HGPs. The covalent linkages between the hydrogel particles and the secondary HA matrix resulted in the formation of a diffuse, fibrilar interface around the particles. Compared to the traditional bulk gels synthesized by photocrosslinking of HA-GMA, these hydrogels exhibited a reduced sol fraction and a lower equilibrium swelling ratio. When tested under uniaxial compression, the HA-c-HGP gels were more pliable than the HA-p-HGP gels and fractured at higher strain than the HA-GMA gels. Primary bovine chondrocytes were photoencapsulated in the HA matrices with minimal cell damage. The 3D microenvironment created by HA-GMA and HA HGPs not only maintained the chondrocyte phenotype but also fostered the production of cartilage specific extracellular matrix. To further improve the biological activities of the HA-c-HGP gels, bone morphogenetic protein 2 (BMP-2) was loaded into the immobilized HGPs. BMP-2 was released from the HA-c-HGP gels in a controlled manner with reduced initial burst over prolonged periods of time. The HA-c-HGP gels are promising candidates for use as bioactive matrices for cartilage tissue engineering.
Hyaluronic Acid Hydrogel Particles Obtained Using Liposomes as Templates
Materials proceedings, 2021
Hydrogels (HG) are 3D networks of hydrophilic macromolecules linked by different "crosslinking points", which have as a main advantage their capacity for the adsorption of large amounts of water without any apparent dissolution. This allows hydrogels to undergo reversible swellingshrinking processes upon the modification of the environmental conditions (pH, ionic strength or temperature). This stimuli-responsiveness and their ability for entrapping in their interior different types of molecules makes hydrogels suitable platforms for drug delivery applications. Furthermore, HGs exhibit certain similarities to the extracellular tissue matrix and can be used as a support for cell proliferation and migration.
Strategies for Hyaluronic Acid-Based Hydrogel Design in Drug Delivery
Pharmaceutics, 2019
Hyaluronic acid (HA) is a natural, linear, endogenous polysaccharide that plays important physiological and biological roles in the human body. Nowadays, among biopolymers, HA is emerging as an appealing starting material for hydrogels design due to its biocompatibility, native biofunctionality, biodegradability, non-immunogenicity, and versatility. Since HA is not able to form gels alone, chemical modifications, covalent crosslinking, and gelling agents are always needed in order to obtain HA-based hydrogels. Therefore, in the last decade, different strategies for the design of physical and chemical HA hydrogels have been developed, such as click chemistry reactions, enzymatic and disulfide crosslinking, supramolecular assembly via inclusion complexation, and so on. HA-based hydrogels turn out to be versatile platforms, ranging from static to smart and stimuli-responsive systems, and for these reasons, they are widely investigated for biomedical applications like drug delivery, tis...