Hydrogels are promising for a variety of medical applications due to their high water content and mechanical similarity to natural tissues. When made injectable, hydrogels can reduce the invasiveness of application, which in turn reduces surgical and recovery costs. Key schemes used to make hydrogels injectable include in situ formation due to physical and/or chemical cross-linking. Advances in polymer science have provided new injectable hydrogels for applications in drug delivery and tissue engineering. A number of these injectable hydrogel systems have reached the clinic and impact the health care of many patients. However, a significant remaining challenge is translating the ever-growing family of injectable hydrogels developed in laboratories around the world to the clinic. V C 2012 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 50: 2012
The goal of this work is to make an injectable physically and chemically cross-linking NIPAAmbased copolymer system for endovascular embolization. A copolymer with N-isopropylacrylamide (NIPAAm) and hydroxyethyl methacrylate (HEMA) was synthesized and converted to poly (NIPAAm-co-HEMA-acrylate) functionalized with olefins. When poly(NIPAAm-co-HEMAacrylate) was mixed with pentaerythritol tetrakis 3-mercaptopropionate (QT) stoichiometrically in 0.1 N PBS solution of pH 7.4, it formed a temperature-sensitive hydrogel with low swelling through the Michael-Type Addition reaction and showed improved elastic properties at low frequency compared to physical gelation. This material could be useful for applications requiring water-soluble injection but lower swelling and lower creep properties than available with other soluble in situgelling materials.
The objective of this work was to create an in situ physically and chemically cross-linking hydrogel for in vivo applications. N-Isopropylacrylamide (NIPAAm) was copolymerized with N-acryloxysuccinimide (NASI) via free radical polymerization. Poly(NIPAAm-co-NASI) was further modified to obtain poly(NIPAAm-co-cysteamine) through a nucleophilic attack on the carbonyl group of the NASI by the amine group of the cysteamine. Modification was verified by nuclear magnetic resonance. In addition to thermoresponsive physical gelling due to the presence of NIPAAm, this system also chemically gels via a Michael-type addition reaction when mixed with poly(ethylene glycol) diacrylate. The presence of both physical and chemical gelation resulted in material properties that are much improved compared to purely physical gels. The chemical gelation time of the copolymers was not significantly affected by the amount of thiol present due to the increased pKa of the copolymer containing more thiols. In addition, the swelling of the copolymers was highly dependent on the temperature and thiol content. Last, the rate of nucleophilic attack in the Michael-type addition reaction was shown to be highly dependent on pH and on the mole ratio of thiol to acrylate. Due to the improved mechanical properties, this material may be better suited for long-term functional replacement applications than other thermosensitive physical gels. With further development and biocompatibility testing, this material could potentially be applied as a temperature-responsive injectable biomaterial for functional embolization.
A novel process for the preparation of water-borne biomaterials for hard tissue repair from injectable precursors is described, where the precursors form crosslinked materials in situ under physiological conditions. The precursors react by means of a Michael-type addition reaction that makes use of addition donors such as pentaerythritol tetrakis 3'-mercaptopropionate (QT) and addition acceptors such as poly(ethylene glycol) diacrylate 570 MW (PEGDA), pentaerythritol triacrylate (TA), and poly(propylene glycol) diacrylate 900 MW (PPODA). These crosslinked materials (at 75 wt% solid), prepared from water dispersions or reverse emulsions, showed ultimate strengths in compression of 1.8 +/- 0.2 and 6.7 +/- 0.5 MPa and ultimate deformations of 35 +/- 2+/- and 37 +/- 2%, respectively. Scanning electron microscopy (SEM) shows that the morphology of the precursors templated the morphology of the final materials. The current study indicates that it is possible to obtain injectable high-modulus materials that have appropriate mechanical properties and gelation kinetics for tissue augmentation and stabilization applications such as mechanical stabilization of the intervertebral disc annulus.
The invasion of malignant glioblastoma (GBM) cells into healthy brain is a primary cause of tumor recurrence and associated morbidity. Here, we describe a high-throughput method for quantitative measurement of GBM proliferation and invasion in three-dimensional (3D) culture. Optically clear hydrogels composed of thiolated hyaluronic acid and gelatin were chemically crosslinked with thiol-reactive poly(ethylene glycol) polymers to form an artificial 3D tumor microenvironment. Characterization of the viscoelasticity and aqueous stability indicated the hydrogels were mechanically tunable with stiffness ranging from 18 Pa to 18.2 kPa and were resistant to hydrolysis for at least 30 days. The proliferation, dissemination and subsequent invasion of U118 and U87R GBM spheroids cultured on the hydrogels were tracked in situ with repeated fluorescence confocal microscopy. Using custom automated image processing, cells were identified and quantified through 500 µm of gel over 14 days. Proliferative and invasive behaviors were observed to be contingent on cell type, gel stiffness, and hepatocyte growth factor availability. These measurements highlight the utility of this platform for performing quantitative, fluorescence imaging analysis of the behavior of malignant cells within an artificial, 3D tumor microenvironment.
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