ABSTRACT
Injectable, covalently in situ forming hydrogels based on poly(N-isopropylacrylamide) have been designed on the basis of mixing hydrazide-functionalized nucleophilic precursor polymers with electrophilic precursor polymers functionalized with a combination of ketone (slow reacting) and aldehyde (fast reacting) functional groups. By tuning the ratio of aldehyde:ketone functional groups as well as the total number of ketone groups in the electrophilic precursor polymer, largely independent control over hydrogel properties including gelation time (from seconds to hours), degradation kinetics (from hours to months), optical transmission (from 1 to 85%), and mechanics (over nearly 1 order of magnitude) can be achieved. In addition, ketone-functionalized precursor polymers exhibit improved cytocompatibility at even extremely high concentrations relative to polymers functionalized with aldehyde groups, even at 4-fold higher functional group densities. Overall, increasing the ketone content of the precursor copolymers can result in in situ-gellable hydrogels with improved transparency and biocompatibility and equivalent mechanics and stimuli-responsiveness while only modestly sacrificing the speed of gel formation.
Subject(s)
Acrylic Resins/chemistry , Aldehydes/chemistry , Hydrogels/chemistry , Ketones/chemistry , Biocompatible Materials/chemistry , Kinetics , Temperature , Tissue EngineeringABSTRACT
Hydrogels that can form spontaneously via covalent bond formation upon injection in vivo have recently attracted significant attention for their potential to address a variety of biomedical challenges. This review discusses the design rules for the effective engineering of such materials, and the major chemistries used to form injectable, in situ gelling hydrogels in the context of these design guidelines are outlined (with examples). Directions for future research in the area are addressed, noting the outstanding challenges associated with the use of this class of hydrogels in vivo.
Subject(s)
Biomedical Engineering/instrumentation , Hydrogels/chemistry , Polymers/chemistry , Biomedical Research , Humans , Hydrogels/chemical synthesis , Polymers/chemical synthesisABSTRACT
Injectable, in situ-gelling magnetic composite materials have been fabricated by using aldehyde-functionalized dextran to cross-link superparamagnetic nanoparticles surface-functionalized with hydrazide-functionalized poly(N-isopropylacrylamide) (pNIPAM). The resulting composites exhibit high water contents (82-88 wt.%) while also displaying significantly higher elasticities (G' >60 kPa) than other injectable hydrogels previously reported. The composites hydrolytically degrade via slow hydrolysis of the hydrazone cross-link at physiological temperature and pH into degradation products that show no significant cytotoxicity. Subcutaneous injections indicate only minor chronic inflammation associated with material degradation, with no fibrous capsule formation evident. Drug release experiments indicate the potential of these materials to facilitate pulsatile, "on-demand" changes in drug release upon the application of an external oscillating magnetic field. The injectable but high-strength and externally triggerable nature of these materials, coupled with their biological degradability and inertness, suggest potential biological applications in tissue engineering and drug delivery.
Subject(s)
Acrylamides/chemistry , Ferric Compounds/chemistry , Magnetite Nanoparticles/chemistry , Polymers/chemistry , Acrylic Resins , Animals , Biocompatible Materials/chemistry , Capsules , Elasticity , Gels/chemistry , Hydrogels/chemistry , Hydrogen-Ion Concentration , Injections , Mice , Mice, Inbred BALB C , Temperature , Tissue Engineering/methodsABSTRACT
A series of synthetic oligomers (based on the thermosensitive polymer poly(N-isopropylacrylamide) and carbohydrate polymers (including hyaluronic acid, carboxymethyl cellulose, dextran, and methylcellulose) were functionalized with hydrazide or aldehyde functional groups and mixed using a double-barreled syringe to create in situ gelling, hydrazone-cross-linked hydrogels. By mixing different numbers and ratios of different reactive oligomer or polymer precursors, covalently cross-linked hydrogel networks comprised of different polymeric components are produced by simple mixing of reactive components, without the need for any intermediate chemistries (e.g., grafting). In this way, hydrogels with defined swelling, degradation, phase transition, drug binding, and mechanical properties can be produced with properties intermediate to those of the mixture of reactive precursor polymers selected. When this modular mixing approach is used, one property can (in many cases) be selectively modified while keeping other properties constant, providing a highly adaptable method of engineering injectable, rapidly gelling hydrogels for potential in vivo applications.
Subject(s)
Acrylamides/chemical synthesis , Biocompatible Materials/chemical synthesis , Hyaluronic Acid/chemistry , Hydrogels/chemical synthesis , Polymers/chemical synthesis , Tissue Engineering/methods , Acrylic Resins , Aldehydes/chemistry , Biocompatible Materials/analysis , Bupivacaine/metabolism , Carboxymethylcellulose Sodium/chemistry , Dextrans/chemistry , Drug Compounding , Elasticity , Injections , Kinetics , Methylcellulose/chemistry , Phase Transition , Solutions , TemperatureABSTRACT
Cell adhesion to biomaterials can be mediated in part by mechanisms aside from the traditionally recognized opsinization and integrin binding mechanisms. In this study, we investigated the role of scavenger receptor A (SR-A) in leukocyte binding to a series of well-controlled polyanionic and uncharged hydrogels based on a poly(N-isopropylacrylamide) backbone. The hydrogels were injected in the peritoneal cavity of SR-A knockout (KO) and wild-type mice using a minimally invasive procedure and allowed to set in situ. After 24 h, the hydrogels were recovered and analyzed, the peritoneal cavity was lavaged, and cytokine concentrations were assessed by ELISA. The polyanionic hydrogels retrieved from the KO animals were found to be completely devoid of adherent leukocytes, which were present in other materials regardless of the mouse strain in which they were injected. Results from a subsequent in vitro cellular adhesion study with a RAW264.7 cell line failed to yield a similarly definitive role for SR-A in the cellular binding of a polyanionic hydrogel. Taken together, the results of this study show that SR-A mediates leukocyte adhesion to a polyanionic hydrogel in the peritoneal cavity, but other adhesion mechanisms contribute to cellular binding in vitro.
Subject(s)
Hydrogels/pharmacology , Leukocytes/metabolism , Polymers/pharmacology , Scavenger Receptors, Class A/metabolism , Acrylic Resins/pharmacology , Animals , Carboxymethylcellulose Sodium/chemistry , Cell Adhesion/drug effects , Cross-Linking Reagents/chemistry , Cytokines/metabolism , Dextrans/chemistry , Elastic Modulus/drug effects , Mice , Mice, Inbred C57BL , Mice, Knockout , Molecular Weight , Peritoneal Lavage , Polyelectrolytes , RAW 264.7 Cells , Rheology/drug effectsABSTRACT
Injectable PEG-analogue hydrogels based on poly(oligoethylene glycol methacrylate) have been developed based on complementary hydrazide and aldehyde reactive linear polymer precursors. These hydrogels display the desired biological properties of PEG, form covalent networks in situ following injection, and are easily modulated for improved control over their functionality and physiochemical properties.
Subject(s)
Hydrogels/chemistry , Methacrylates/chemistry , Polyethylene Glycols/chemistry , 3T3 Cells , Adsorption , Animals , Cell Adhesion/drug effects , Cell Survival/drug effects , Fibrinogen/chemistry , Hydrazones/chemistry , Hydrogels/administration & dosage , Hydrogels/pharmacology , Injections, Subcutaneous , Methacrylates/administration & dosage , Methacrylates/pharmacology , Mice , Mice, Inbred BALB C , Polyethylene Glycols/administration & dosage , Polyethylene Glycols/pharmacology , Polymethacrylic Acids , Serum Albumin, Bovine/chemistryABSTRACT
The potential of poly(oligoethylene glycol methacrylate) (POEGMA) hydrogels with varying thermosensitivities as soft materials for biomedical applications is demonstrated. Hydrogels are prepared from hydrazide and aldehyde functionalized POEGMA precursors, yielding POEGMA hydrogels with a volume phase transition temperature (VPTT) below (PO0), close to (PO10) and well above (PO100) physiological temperature. Hydrogels with VPTTs close to and above physiological temperature exhibit biological properties similar to those typically observed for poly(ethylene glycol) hydrogels (i.e. low protein adsorption, low cell adhesion and minimal inflammatory responses in vivo) while hydrogels with VPTTs lower than physiological temperature exhibit biological properties more analogous to poly(N-isopropylacrylamide) above its phase transition temperature (temperature-switchable cell adhesion, higher protein adsorption and somewhat more acute inflammation in vivo). As such, the use of POEGMA precursors with varying chain lengths of ethylene oxide grafts offers a versatile platform for the design of hydrogels with tunable physiological properties via simple copolymerization.
Subject(s)
Hydrogels , Materials Testing , Methacrylates , Polyethylene Glycols , Animals , Hydrogels/chemical synthesis , Hydrogels/chemistry , Hydrogels/pharmacology , Methacrylates/chemical synthesis , Methacrylates/chemistry , Methacrylates/pharmacology , Mice , Mice, Inbred BALB C , NIH 3T3 Cells , Polyethylene Glycols/chemical synthesis , Polyethylene Glycols/chemistry , Polyethylene Glycols/pharmacology , Polymethacrylic AcidsABSTRACT
Degradable, covalently in situ gelling analogues of thermoresponsive poly(N-isopropylacrylamide) (PNIPAM) hydrogels have been designed by mixing aldehyde and hydrazide-functionalized PNIPAM oligomers with molecular weights below the renal cutoff. Co-extrusion of the reactive polymer solutions through a double-barreled syringe facilitates rapid gel formation within seconds. The resulting hydrazone cross-links hydrolytically degrade over several weeks into low molecular weight oligomers. The characteristic reversible thermoresponsive swelling-deswelling phase transition of PNIPAM hydrogels is demonstrated. Furthermore, both in vitro and in vivo toxicity assays indicated that the hydrogel as well as the precursor polymers/degradation products were nontoxic at biomedically relevant concentrations. This chemistry may thus represent a general approach for preparing covalently cross-linked, synthetic polymer hydrogels that are both injectable and degradable.