Showing papers on "Self-healing hydrogels published in 1999"

A reversibly antigen-responsive hydrogel

Abstract: Stimuli-responsive hydrogels that undergo abrupt changes in volume in response to external stimuli such as pH, temperature and solvent composition have potential applications in biomedicine and the creation of 'intelligent' materials systems, for example as media for drug delivery, separation processes and protein immobilization. Hydrogels have been reported that respond to pH, temperature, electric fields and saccharides. For some biomedical applications it would be very useful to have a material whose swelling response was dictated by a specific protein. Here we report such a material, which swells reversibly in a buffer solution in response to a specific antigen. The hydrogel was prepared by grafting the antigen and corresponding antibody to the polymer network, so that binding between the two introduces crosslinks in the network. Competitive binding of the free antigen triggers a change in gel volume owing to breaking of these non-covalent crosslinks. In addition, we show that the hydrogel displays shape-memory behaviour, and that stepwise changes in antigen concentration can induce pulsatile permeation of a protein through the network.

New strategy for chemical modification of hyaluronic acid: preparation of functionalized derivatives and their use in the formation of novel biocompatible hydrogels.

Abstract: Biodegradable materials for spatially and temporally controlled delivery of bioactive agents such as drugs, growth factors, or cytokines are key to facilitating tissue repair. We have developed a versatile method for chemical crosslinking high-molecular-weight hyaluronic acid under physiological conditions yielding biocompatible and biodegradable hydrogels. The method is based on the introduction of functional groups onto hyaluronic acid by formation of an active ester at the carboxylate of the glucuronic acid moiety and subsequent substitution with a side chain containing a nucleophilic group on one end and a (protected) functional group on the other. We have formed hyaluronic acid with amino or aldehyde functionality, and subsequently hydrogels with these hyaluronic acid derivatives and bifunctional crosslinkers or mixtures of the hyaluronic acid derivatives carrying different functionalities using active ester- or aldehyde-mediated reactions. Size analysis of the hyaluronic acid derivatives showed that the chemical modification did not lead to fragmentation of the polysaccharide. Hydrogels formed with hyaluronic acid derivatized to a varying degree and crosslinked with low- or high-molecular-weight crosslinkers were evaluated for biodegradability by digestion with hyaluronidase and for biocompatibility and ectopic bone formation by subcutaneous implantation in rats. Several hydrogel formulations showed excellent cell infiltration and chondro-osseous differentiation when loaded with bone morphogenetic protein-2 (BMP-2). Synergistic action of insulin-like growth factor-1 with BMP-2 promoted cartilage formation in this model, while addition of transforming growth factor-beta and BMP-2 led to rapid replacement of the matrix by bone.

Hybrid hydrogels assembled from synthetic polymers and coiled-coil protein domains

Abstract: Stimuli-sensitive polymer hydrogels, which swell or shrink in response to changes in the environmental conditions, have been extensively investigated and used as 'smart' biomaterials and drug-delivery systems Most of these responsive hydrogels are prepared from a limited number of synthetic polymers and their derivatives, such as copolymers of (meth)acrylic acid, acrylamide and N-isopropyl acrylamide Water-soluble synthetic polymers have also been crosslinked with molecules of biological origin, such as oligopeptides and oligodeoxyribonucleotides, or with intact native proteins Very often there are several factors influencing the relationship between structure and properties in these systems, making it difficult to engineer hydrogels with specified responses to particular stimuli Here we report a hybrid hydrogel system assembled from water-soluble synthetic polymers and a well-defined protein-folding motif, the coiled coil These hydrogels undergo temperature-induced collapse owing to the cooperative conformational transition of the coiled-coil protein domain This system shows that well-characterized water-soluble synthetic polymers can be combined with well-defined folding motifs of proteins in hydrogels with engineered volume-change properties

Synthesis of superporous hydrogels: Hydrogels with fast swelling and superabsorbent properties

Abstract: We have been interested in the synthesis of hydrogels with fast swelling kinetics and superabsorbent properties To increase the water absorption rate, interconnected pores were introduced to the hydrogels Since the pore size in the dried hydrogels is in the order of hundreds of micrometers, these hydrogels are called "superporous" hydrogels Superporous hydrogels were synthesized by crosslinking polymerization of various vinyl monomers in the presence of gas bubbles formed by the chemical reaction of acid and NaHCO3 The polymerization process was optimized to capture the gas bubbles inside the synthesized hydrogels The use of the NaHCO3/acid system allowed easy control of timing for gelation and foam formation We found that PF127 was the best foam stabilizer for most of the monomer systems used in our study Scanning electron microscope (SEM) pictures showed interconnected pores forming capillary channels The capillary channels, which were critical for fast swelling, were preserved during drying by dehydrating water-swollen hydrogels with ethanol before drying The ethanol-dehydrated superporous hydrogels reached equilibrium swelling within minutes The equilibrium swelling time could be reduced to less than a minute with the use of a wetting agent In our study, water moisture was used as a wetting agent since the amount of moisture content in the dried hydrogels easily could be controlled Preparation of superporous hydrogels using the right blowing system, foam stabilizer, drying method, and wetting agent makes it possible to reduce the swelling time to less than a minute regardless of the size of the dried gels The superporous hydrogels can be used where fast swelling and superabsorbent properties are critical

Hydrogels and their medical applications

Abstract: Biomaterials play a key role in most approaches for engineering tissues as substitutes for functional replacement, for components of devices related to therapy and diagnosis, for drug delivery systems and supportive scaffolds for guided tissue growth. Modern biomaterials could be composed of various components, e.g. metals, ceramics, natural tissues, polymers. In this last group, the hydrogels, hydrophilic polymeric gels with requested biocompatibility and designed interaction with living surrounding seem to be one of the most promising group of biomaterials. Especially, if they are formed by means of ionizing radiation. In early 1950s, the pioneers of the radiation chemistry of polymers began some experiments with radiation crosslinking of hydrophilic polymers. However, hydrogels were analyzed mainly from the point of view of the phenomenon associated with radiation synthesis, with topology of network and relation between radiation parameters of the processes. Fundamental monographs on radiation polymer physics and chemistry written by A. Charlesby (Atomic Radition and polymers, Pergamon Press, Oxford, 1960) and A. Chapiro (Radiation Chemistry of Polymeric Systems, Interscience, New York, 1962) proceed from this time. The noticeable interest in the application of radiation techniques to obtain hydrogels for biomedical purposes began in the late sixties as a result of the papers and patents invented by Japanese and American scientists, headed by Kaetsu in Japan and Hoffman in USA. Immobilization of biologically active species in hydrogel matrices, their use as drug delivery systems and enzyme traps as well as the modification of material surfaces to improve biocompatibility and their ability to bond antigens and antibodies had been the main subjects of these investigations. In this article a brief summary of investigations on mechanism and kinetics of radiation formation of hydrogels as well as some examples of commercialized hydrogel biomaterials have been presented.

A fluorescence-based glucose biosensor using concanavalin A and dextran encapsulated in a poly(ethylene glycol) hydrogel.

Abstract: A fluorescence biosensor is described that is based on a photopolymerized poly(ethylene glycol) (PEG) hydrogel incorporating fluorescein isothiocyanate dextran (FITC-dextran) and tetramethylrhodamine isothiocyanate concanavalin A (TRITC-Con A) chemically conjugated into the hydrogel network using an alpha-acryloyl, omega-N-hydroxysuccinimidyl ester of PEG-propionic acid. In the absence of glucose, TRITC-Con A binds with FITC-dextran, and the FITC fluorescence is quenched through fluorescence resonance energy transfer. Competitive glucose binding to TRITC-Con A liberates FITC-dextran, resulting in increased FITC fluorescence proportional to the glucose concentration. In vitro experiments of hydrogel spheres in a solution of 0.1 M phosphate-buffered saline (pH 7.2) and glucose were conducted for multiple TRITC-Con A/FITC-dextran ratios. Hydrogels were characterized on the basis of the percent change in fluorescence intensity when FITC-dextran was liberated by increasing glucose concentrations. The optimum fluorescent change between 0 and 800 mg/dL was obtained with a TRITC-Con A/FITC-dextran mass ratio of 500:5 micrograms/mL PEG. Fluorescent response was linear up to 600 mg/dL. At higher concentrations, the response saturated due to the displacement of the majority of the FITC-dextran and to concentration quenching by free FITC-dextran. Dynamic fluorescent change upon glucose addition was approximately 10 min for a glucose concentration step change from 0 to 200 mg/dL.

Synthesis and characterization of injectable poly(N-isopropylacrylamide)-based hydrogels that support tissue formation in vitro

Abstract: Hydrogels that support tissue formation in vitro were developed using poly(N-isopropylacrylamide) [P(NIPAAm)]. Loosely cross-linked P(NIPAAm) and poly(NIPAAm-co-acrylic acid) [P(NIPAAm-co-AAc)] hydrogels were synthesized with N,N‘-methylenebis(acrylamide) cross-linker. At room temperature (RT), the hydrogels were transparent and extremely pliable, while at 37 °C, the matrices became opaque and were significantly more rigid. The P(NIPAAm-co-AAc) hydrogel demonstrated significantly less volume change between RT and 37 °C, contained significantly more water at 37 °C, and had a lower critical solution temperature which was significantly higher, as compared to that of the P(NIPAAm) hydrogel. The hydrogels supported bovine articular chondrocyte viability for at least 28 days of in vitro culture, and cartilage-like tissue was formed in the matrices. These hydrogels can be injected through a small-diameter aperture and offer the benefit of in situ stabilization without the possible deleterious effects of in situ ...

Synthesis and characteristics of interpenetrating polymer network hydrogel composed of chitosan and poly(acrylic acid)

Abstract: Interpenetrating polymer network (IPN) hydrogels composed of chitosan and poly(acrylic acid) (PAAc) were synthesized by UV irradiation method, and their structure, crystallinity, swelling behavior, thermal property, and mechanical property were investigated. Chitosan/PAAc IPNs exhibited relatively high equilibrium water content and also showed reasonable sensitivity to pH. From the swelling behaviors at various pH's, Fourier transform infrared spectra at high temperature and thermal analysis confirmed the formation of polyelectrolyte complex due to the reaction between amino groups in chitosan and carboxyl groups in PAAc. For this reason, even at a swollen state, the present chitosan/PAAc IPNs possess good mechanical properties. Particularly, the CA-2 sample (with a weight ratio of chitosan/PAAc = 50/50, molar ratio [NH2]/[COOH] = 25/75) showed the lowest equilibrium water content and free water content, attributed to the more compact structure of the polyelectrolyte than CA-1 or CA-3 due to the high amount of interchain bond within the IPN. © 1999 John Wiley & Sons, Inc. J Appl Polym Sci 73: 113–120, 1999

Molecular design and in vitro studies of novel pH-sensitive hydrogels for the oral delivery of calcitonin

Abstract: pH-sensitive hydrogels are suitable candidates for oral drug delivery of peptides due to their ability to respond to their environment. We have developed new hydrogels composed of poly(methacrylic acid) (PMAA) grafted with poly(ethylene glycol) (PEG) (P(MAA-g-EG)) which can be used as drug delivery carriers for salmon calcitonin. P(MAA-g-EG) hydrogels were prepared by free radical solution polymerization. The monomer mixture was diluted using a 50% w/w solution of ethanol and water. The percentage of monomer in solution was varied from 84% to 45% v/v. Swelling studies were conducted to investigate the effects of solvent content used during polymer preparation in the swelling behavior. The effects of dilution on the swelling behavior were not observed until the monomer mixture was diluted to approximately 50%. Salmon calcitonin was successfully incorporated and released in vitro from the system. Solutions of approximately 0.1 mg/mL of salmon calcitonin were used to load the protein into the gels at pH = 7 ...

Biodegradation of Hydrogel Carrier Incorporating Fibroblast Growth Factor

Abstract: In vivo release of basic fibroblast growth factor (bFGF) from a biodegradable gelatin hydrogel carrier was compared with the in vivo degradation of hydrogel. When gelatin hydrogels incorporating 125I-labeled bFGF were implanted into the back subcutis of mice, the bFGF radioactivity remaining decreased with time and the retention period was prolonged with a decrease in the water content of the hydrogels. The lower the water content of 125I-labeled gelatin hydrogels, the faster both the weight of the hydrogels and the gelatin radioactivity remaining decreased with time. The decrement profile of bFGF remaining in hydrogels was correlated with that of hydrogel weight and gelatin radioactivity, irrespective of the water content. Subcutaneous implantation of bFGF-incorporating gelatin hydrogels into the mice induced significant neovascularization. The retention period of neovascularization became longer as the water content of the hydrogels decreased. To study the decrease of activity of bFGF when implanted, bFGF-incorporating hydrogels were placed in diffusion chamber and implanted in the mouse subcutis for certain periods of time. When hydrogels explanted from the mice were again implanted, significant neovascularization was still observed, indicating that most of the biological activity of bFGF was retained in the hydrogels. It was concluded that, in our hydrogel system, biologically active bFGF was released as a result of in vivo degradation of the hydrogel. The release profile was controllable by changing the water content of hydrogels.

Rigidity of Two-Component Hydrogels Prepared from Alginate and Poly(ethylene glycol)−Diamines

Abstract: Alginate hydrogels have been attractive for a variety of biomedical applications, but they possess limited mechanical properties when ionically cross-linked with divalent cations. Therefore, covalent cross-linking of alginate with poly(ethylene glycol)−diamines of various molecular weights was investigated as a means to generate hydrogels with a range of mechanical properties. Hydrogels with a range of elastic moduli could be generated by controlling either the chain length of the cross-linking molecule or the cross-linking density. The elastic modulus increased gradually with an increase in cross-linking density or weight fraction of PEG in the hydrogel up to ∼27% (w/w) of PEG. The change of mechanical properties was interpreted in terms of molecular weight between cross-links (Mc) according to the rubber-elasticity model, and the results of this analysis were generally consistent with the measured PEG−diamine incorporation efficiencies in this range. However, as the weight fraction of PEG in the hydroge...

Methods for forming regional tissue adherent barriers and drug delivery systems

Abstract: Methods are provided for forming hydrogel barriers in situ that adhere to tissue and prevent the formation of post-surgical adhesions or deliver drugs or other therapeutic agents to a body cavity. The hydrogels are cross-linked, resorb or degrade over a period of time, and may be formed by free radical polymerization initiated by a redox system or thermal initiation, or electrophilic-neutrophilic mechanism, wherein two components of an initiating sytem are simultaneously or sequentially poured into a body cavity to obtain widespread dispersal and coating of all or most visceral organs within that cavity prior to gelation and polymerization of the regional barrier. The hydrogel materials are selected to have a low stress at break in tension or torsion, and so as to have a close to equilibrium hydration level when formed.

A Laminin and Nerve Growth Factor-Laden Three-Dimensional Scaffold for Enhanced Neurite Extension

Abstract: Agarose hydrogel scaffolds were engineered to stimulate and guide neuronal process extension in three dimensions in vitro. The extracellular matrix (ECM) protein laminin (LN) was covalently coupled to agarose hydrogel using the bifunctional cross-linking reagent 1,19- carbonyldiimidazole (CDI). Compared to unmodified agarose gels, LN-modified agarose gels significantly enhanced neurite extension from three-dimensionally (3D) cultured embryonic day 9 (E9) chick dorsal root ganglia (DRGs), and PC 12 cells. After incubation of DRGs or PC 12 cells with YIGSR peptide or integrin beta1 antibody respectively, the neurite outgrowth promoting effects in LN-modified agarose gels were significantly decreased or abolished. These results indicate that DRG/PC 12 cell neurite outgrowth promoting effect of LN-modified agarose gels involves receptors for YIGSR/integrin beta1 subunits respectively. 1,2-bis(10, 12-tricosadiynoyl)-sn-glycero-3-phosphocholine (DC(8,9)PC)-based lipid microcylinders were loaded with nerve growth factor (NGF), and embedded into agarose hydrogels. The resulting trophic factor gradients stimulated directional neurite extension from DRGs in agarose hydrogels. A PC 12 cell-based bioassay demonstrated that NGF-loaded lipid microcylinders can release physiologically relevant amounts of NGF for at least 7 days in vitro. Agarose hydrogel scaffolds may find application as biosynthetic 3D bridges that promote regeneration across severed nerve gaps.

BIODEGRADABLE pH/THERMOSENSITIVE HYDROGELS FOR SUSTAINED DELIVERY OF BIOLOGICALLY ACTIVE AGENTS

Abstract: The present invention relates generally to the development of pharmaceutical compositions which provide for sustained release of biologically active polypeptides. More specifically, the invention relates to the use of pH/thermosensitive, biodegradable hydrogels, consisting of a A-B di block or A-B-A tri block copolymer of poly(d,l- or 1-lactic acid) (PLA) or poly(lactide-co-glycolide) (PLGA) (block A) and polyethylene glycol (PEG) (block B), with ionizable functional groups on one or both ends of the polymer chains, for the sustained delivery of biologically active agents.

Composite hydrogel drug delivery systems

Abstract: Compositions and methods are provided to control the release of relatively low molecular weight therapeutic species through hydrogels by first dispersing or dissolving such therapeutic species within relatively hydrophobic rate modifying agents to form a mixture. The mixture is formed into microparticles that are dispersed within bioabsorbable hydrogels, so as to release the water soluble therapeutic agents in a controlled fashion. Methods of using the compositions of the present invention in therapeutic systems are also provided.

Designing biomaterials to direct biological responses.

Abstract: We have set forth a design strategy for creating biomimetic materials that direct the formation of tissue surrounding implants or regeneration within porous scaffolds. Our studies have established that heterogeneous mimetic peptide surfaces (MPS) containing both the -RGD- (cell-binding) and-FHRRIKA- (putative heparin-binding) peptides, unique to BSP, in the ratio of 75:25 (MPS II) or 50:50 (MPS III) proved to be more biologically relevant and specific for RCO cell function. The initial response of human osteoblast-like cells to these surfaces was mediated by the collagen (alpha 2 beta 1) and vitronectin receptors (alpha v beta 3), whereas the vitronectin receptor alone dominated longer-term events (> 30 min). MPS II and III surfaces enhanced cell spreading and long-term events such as mineralization of the extracellular matrix compared to homogenous peptide surfaces and controls. Furthermore, extensive mineralization of the ECM deposited by RCOs occurred when the peptide was coupled to an interfacial interpenetrating polymer network (IPN) that resisted protein deposition (i.e., non-specific adsorption) and fouling. Work on thermo-reversible P(NIPAAm-co-AAc) hydrogels demonstrated the ability to create materials that can be delivered to the body in a minimally invasive manner and support tissue regeneration. These hydrogels can be modified to incorporate biofunctional components such as the biomimetic peptides, theoretically enhancing their ability to foster tissue regeneration. These results suggest that biomaterials can be engineered to mimic ECM components of bone (e.g., various organs) by grafting peptides in the appropriate ratios of the cell and heparin-binding domains, and ultimately modulate the expression of the osteoblast cell phenotype. Approaches similar to the one presented in this work can be used to design materials for hybrid artificial organs and other tissues.

Transdermal photopolymerization of poly(ethylene oxide)-based injectable hydrogels for tissue-engineered cartilage.

Abstract: Transdermal photopolymerization, a minimally invasive method for implantation, was used to subcutaneously place a mixture of polymer and isolated chondrocytes to regenerate cartilage tissue in vivo. Semi-interpenetrating networks of varying proportions of poly(ethylene oxide)-dimethacrylate and poly(ethylene oxide) and primary bovine articular chondrocytes were implanted in athymic mice. Four mice (12 implants) were harvested at 2, 4, and 7 weeks. Chondrocytes survived implantation and photopolymerization and formed neocartilage containing 1.5 to 2.9% wet weight collagen and 4 to 7% glycosaminoglycan. Thirty-five percent of the total collagen was type II collagen. Histologic analysis exhibited tissue structure resembling neocartilage, and safranin O staining demonstrated glycosaminoglycan distribution throughout the hydrogels. This study demonstrates the potential use of transdermal photopolymerization for minimally invasive subcutaneous implantation of hydrogels and chondrocytes for in vivo cartilage regeneration.

An obstruction-scaling model for diffusion in homogeneous hydrogels

Abstract: A mathematical description of the restricted movement a solute experiences while diffusing in a homogeneous hydrogel is presented. The model is based on the premise that physical obstruction effects dominate the diffusive process, and a scaling law expression is incorporated to describe the distance between cross-links in the polymer network. The model was compared to experimental data taken from literature sources and found to provide good agreement to the effects of both polymer volume fraction and solute size on the diffusivity of a solute within the hydrogel.

Neural tissue formation within porous hydrogels implanted in brain and spinal cord lesions: ultrastructural, immunohistochemical, and diffusion studies.

Abstract: A biocompatible heterogeneous hydrogel of poly [N-(2-hydroxypropyl) methacrylamide] (PHPMA), was evaluated for its ability to promote tissue repair and enhance axonal regrowth across lesion cavities in the brain and spinal cord in adult and juvenile (P17 P21) rats. Incorporation of PHPMA hydrogels into surrounding host tissue was examined at the ultrastructural level and using immunohistochemical techniques. In addition, and in parallel to these studies, diffusion parameters (volume fraction and tortuosity of the gel network) of the PHPMA hydrogels were evaluated pre- to postimplantation using an in vivo real-time iontophoretic method. The polymer hydrogels were able to bridge tissue defects created in the brain or spinal cord, and supported cellular ingrowth, angiogenesis, and axonogenesis within the structure of the polymer network. As a result, a reparative tissue grew within the porous structure of the gel, composed of glial cells, blood vessels, axons and dendrites, and extracellular biological matrices, such as laminin and/or collagen. Consistent with matrix deposition and tissue formation within the porous structure of the PHPMA hydrogels, there were measurable changes in the diffusion characteristics of the polymers. Extracellular space volume decreased and tortuosity increased within implanted hydrogels, attaining values similar to that seen in developing neural tissue. PHPMA polymer hydrogel matrices thus show neuroinductive and neuroconductive properties. They have the potential to repair tissue defects in the central nervous system by replacing lost tissue and by promoting the formation of a histotypic tissue matrix that facilitates and supports regenerative axonal growth. () ()