Photopolymerization of alicyclic methacrylate hydrogels for controlled release

Alicyclic hydroxy methacrylate monomer, o‐hydroxycyclohexyl methacrylate (HCMA), was synthesized and characterized by Fourier transformed infrared spectroscopy (FT‐IR) and proton nuclear magnetic resonance spectroscopy (¹H‐NMR). Photopolymerization kinetics of HCMA was investigated via real‐time infrared spectroscopy (RT‐IR). Polymeric network hydrogels based on hydroxyethyl methacrylate (HEMA) and HCMA were prepared by using the photopolymerization technique. Mechanical strength, swelling characteristic, and controlled release behavior of hydrogels with various feed compositions were studied. Poly(HEMA‐co‐HCMA) hydrogel had higher storage modulus than that of poly(HEMA) hydrogel as investigated by dynamic mechanical analysis (DMA). Acid orange 8 was used as a model drug for the investigation of drug release behavior of copolymeric hydrogels. Results indicated that increase in HCMA ratio in hydrogel composition could reduce the swelling rate and prolong the release time. Scanning electron microscopy (SEM) was also utilized to study the surface morphology of hydrogels, and the results indicated that HCMA content influenced pore diameter on the hydrogel surface. Copyright © 2008 John Wiley & Sons, Ltd.     

Swelling and thermodynamic studies of temperature responsive 2-hydroxyethyl methacrylate/itaconic acid copolymeric hydrogels prepared via gamma radiation

The copolymeric hydrogels based on 2-hydroxyethyl methacrylate (HEMA) and itaconic acid (IA) were synthesized by gamma radiation induced radical polymerization. Swelling and thermodynamic properties of PHEMA and copolymeric P(HEMA/IA) hydrogels with different IA contents (2, 3.5 and 5 mol%) were studied in a wide pH and temperature range. Initial studies of so-prepared hydrogels show interesting pH and temperature sensitivity in swelling and drug release behavior. Special attention was devoted to temperature investigations around physiological temperature (37 °C), where small changes in temperature significantly influence swelling and drug release of these hydrogels. Due to maximum swelling of hydrogels around 40 °C, the P(HEMA/IA) hydrogel containing 5 mol% of IA without and with drug-antibiotic (gentamicin) were investigated at pH 7.40 and in the temperature range 25–42 °C, in order to evaluate their potential for medical applications.     

A new class of biodegradable hydrogels stereocomplexed by enantiomeric oligo(lactide) side chains of poly(HEMA‐g‐OLA)s

Two enantiomeric amphiphilic graft copolymers consisting of water soluble poly(2‐hydroxyethyl methacrylate) (HEMA) and biodegradable oligo(L ‐lactide) (OLLA) or oligo(D ‐lactide) (ODLA) were synthesized by free radical copolymerization. HEMA‐OL(D)LA macromonomers were synthesized by ring opening polymerization of L ‐ or D ‐lactide. Both HEMA‐OLA macromonomers and graft copolymers were characterized by NMR spectroscopy and gel permeation chromatography. Graft copolymers and their stereocomplexes were analyzed by wide angle X‐ray diffraction and differential scanning calorimetry (DSC). Due to the formation of stereocomplex crosslinks between poly(HEMA) main chains, amphiphilic, biodegradable hydrogels prepared by blending of two enantiomeric poly(HEMA‐g‐OLLA) and poly(HEMA‐g‐ODLA) degraded more slowly in phosphate buffered saline than individual optically pure poly‐(HEMA‐g‐OL(D)LA).     

Cloud point suppression in dilute solutions of model gradient copolymers with prespecified composition profiles

Gradient copolymers of 2‐hydroxyethyl methacrylate (HEMA) and 2‐(dimethylamino)ethyl methacrylate (DMAEMA) having prescribed linear, parabolic, and hyperbolic composition profiles were synthesized with the guidance of a numerical model that determines the instantaneous comonomer feed rate. These materials exhibit low polydispersity indices (<1.1); the evolution of the overall DMAEMA content and the absolute molecular weight of the copolymers are all in good agreement with the quantities predicted by our model. Compared to random copolymers of HEMA and DMAEMA, the cloud points of dilute buffered aqueous solutions of gradient copolymers decrease with increasing gradient strength; where the gradient strength is defined as the largest difference in the instantaneous composition along the copolymer. The temperature range over which the solutions transition from transparent to turbid also broadens significantly with increasing gradient strength. Both observations suggest the onset of transition to be dictated by the least soluble ends of the polymer chains. These correlations point to the importance of monomer sequence distribution in determining the macroscopic physical properties of copolymers. © 2011 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys, 2011     

Hydrogels based on physiologically clotted fibrin–gelatin composites

Fibrin–gelatin composite (PFG) films were prepared and crosslinked with glutaraldehyde as reported by us previously. These composites were graft‐copolymerized with poly(2‐hydroxyethyl methacrylate) (PHEMA) and poly(2‐hydroxypropyl methacrylate) (PHPMA) with a potassium persulfate and sodium metabisulfite redox initiation system. The graft copolymers (PFG‐HEMA and PFG‐HPMA) were characterized for their percentage of grafting, percentage of equilibrium water content, and percentages of free water and bound water. The chemical composition and thermal, mechanical, morphological, and surface characteristics were also evaluated. The optimum conditions for obtaining a maximum percentage of grafting were standardized. PFG and its graft copolymers exhibited higher equilibrium water contents ranging from 60 to 77% when compared with those of HEMA and HPMA homopolymers. DSC studies revealed increased freezing water contents and decreased bound‐water contents for the graft copolymers when compared with those of PFG alone. These properties improved the efficacy of hydrogels. PFG demonstrated better mechanical properties as compared with its graft copolymers. This may be attributed to the alkaline reaction conditions wherein protein hydrolysis of PFG would have occurred thereby reducing the overall strength of the graft copolymers. IR and scanning electron microscopic studies confirmed the grafting of PHEMA and PHPMA onto PFG. Contact‐angle studies revealed increased polarity for graft copolymers, which is a symbol for increased hydrophilicity. © 2004 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 42: 2241–2252, 2004     

Synthesis and characterization of polycholesteryl methacrylate–polyhydroxyethyl methyacrylate block copolymers

We report the synthesis and characterization of a series of novel diblock copolymers, poly(cholesteryl methacrylate‐b‐2‐hydroxyethyl methacrylate) (PCMA‐b‐PHEMA). Monomers, cholesteryl methacrylate (CMA) and 2‐(trimethylsiloxy)ethyl methacrylate (HEMA‐TMS), were prepared from methyacryloyl chloride and 2‐hydroxyethyl methacrylate, respectively. Homopolymers of CMA, PCMA, with well‐defined molecular weights and polydispersity indices (PDI), were prepared by reversible addition fragmentation and chain transfer (RAFT) method. Precursor diblock copolymers, PCMA‐b‐P(HEMA‐TMS), were synthesized using PCMA as macromolecular chain transfer agent and monomer, HEMA‐TMS. Product diblock copolymers, PCMA‐b‐PHEMA, were prepared by deprotecting trimethylsilyl units in the precursor diblock copolymers using acid catalysts. Detailed molecular characterization of the precursor diblock copolymers, PCMA‐b‐P(HEMA‐TMS), and the product diblock copolymers, PCMA‐b‐PHEMA, confirmed the composition and structure of these polymers. This versatile synthetic strategy can be used to prepare new amphiphilic block copolymers with cholesterol in one block and hydrogen‐bonding moieties in the second block. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 6801–6809, 2008     

Simultaneous reversible addition fragmentation chain transfer and ring‐opening polymerization

The simultaneous ring‐opening polymerization (ROP) of ε‐caprolactone (ε‐CL) and 2‐hydroxyethyl methacrylate (HEMA) polymerization via reversible addition fragmentation chain transfer (RAFT) chemistry and the possible access to graft copolymers with degradable and nondegradable segments is investigated. HEMA and ε‐CL are reacted in the presence of cyanoisopropyl dithiobenzoate (CPDB) and tin(II) 2‐ethylhexanoate (Sn(Oct)₂) under typical ROP conditions (T > 100 °C) using toluene as the solvent in order to lead to the graft copolymer PHEMA‐g‐PCL. Graft copolymer formation is evidenced by a combination of size‐exclusion chromatography (SEC) and NMR analyses as well as confirmed by the hydrolysis of the PCL segments of the copolymer. With targeted copolymers containing at least 10% weight of PHEMA and relatively small PHEMA backbones (ca. 5,000–10,000 g mol^?1) the copolymer grafting density is higher than 90%. The ratio of free HEMA‐PCL homopolymer produced during the “one‐step” process was found to depend on the HEMA concentration, as well as the half‐life time of the radical initiator used. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 3058–3067, 2008     

Hydrogels for encapsulation of mammalian cells

In our attempt to prepare new hydrogels for cell encapsulation, we decided to use synthetic copolymers presuming that chemical bonds should bring better mechanical stability of capsules than electrostatic forces between polyanions and polycations in the so far predominantly used materials based on polyelectrolyte complexes. Two series of copolymers of 2‐hydroxyethyl methacrylate (HEMA) with alkyl acrylates (methacrylates) or N‐alkylacrylamides (methacrylamides) were prepared. The copolymers, prepared by solution copolymerization in ethanol, were characterized by swelling in water and PBS solution, viscometric molecular weight, and NMR analysis, and their encapsulation processability was tested. Their characteristics and the first biological tests are the subject of this paper.     

Nitroxide‐Mediated Polymerization of 2‐Hydroxyethyl Methacrylate (HEMA) Controlled with Low Concentrations of Acrylonitrile and Styrene

Nitroxide‐mediated controlled radical polymerization of 2‐hydroxyethyl methacrylate (HEMA) is achieved using the copolymerization method with a small initial concentration of acrylonitrile (AN, 5–16 mol%)) or styrene (S, 5–10 mol%). The polymerization is mediated by N‐tert‐butyl‐N‐(1‐diethyl phosphono‐2,2‐dimethyl propyl) nitroxide (SG1)‐based BlocBuilder unimolecular alkoxyamine initiator modified with an N‐succinimidyl ester group (N‐hydroxysuccinimide‐BlocBuilder). As little as 5% molar feed of acrylonitrile results in a controlled polymerization, as evidenced by a linear increase in number average molecular weight M _n with conversion and dispersities (? ) as low as 1.30 at 80% conversion in N ,N‐dimethylformamide (DMF) at 85 °C. With S as the controlling comonomer, higher initial S composition (≈10 mol%) is required to maintain the controlled copolymerization. Poly(HEMA‐ran‐AN)s with M _n ranging from 5 to 20 kg mol^?1 are efficiently chain extended using n‐butyl methacrylate/styrene mixtures at 90.0 °C in DMF, thereby showing a route to HEMA‐based amphiphilic block copolymers via nitroxide‐mediated polymerization.

     

A pH‐sensitive water‐soluble N‐carboxyethyl chitosan/poly(hydroxyethyl methacrylate) hydrogel as a potential drug sustained release matrix prepared by photopolymerization technique

Biocompatible pH‐sensitive semi‐interpenetration polymeric network hydrogels (semi‐IPN) based on water‐soluble N‐carboxyethyl chitosan (CECS) and 2‐hydroxyethyl methacrylate (HEMA) were synthesized by the photopolymerization technique. pH‐sensitivity, cytotoxicity, morphology, mechanical property, and water state of hydrogel were investigated by a swelling test, methylthiazolydiphenyl‐tetrazolium bromide (MTT) assay, scanning electron microscopy (SEM), universal testing machine, and differential scanning calorimetry (DSC), respectively. The drug release studies were carried out using 5‐Flurouracil as the model drug. The results indicated that the hydrogels were sensitive to pH of the medium and its wet state had good mechanical properties. The results of cytotoxicity and prolonged drug release characteristics revealed the suitability of the hydrogels as drug delivery matrices. The release kinetics was evaluated by fitting the experimental data to standard release equations, and the best fit was obtained with the Higuchi model of the hydrogel. Copyright © 2008 John Wiley & Sons, Ltd.     

Influence of gel composition on the solubility parameter of poly(2‐hydroxyethyl methacrylate‐itaconic acid) hydrogels

The solubility parameters of pure poly(2‐hydroxyethyl methacrylate) (PHEMA) and poly(2‐hydroxyethyl methacrylate/itaconic acid) [P(HEMA/IA)] hydrogels were determined by 20 solvents with various solubility parameters in swelling experiments. The solubility parameter of pure PHEMA was 26.93 ± 0.46 (MPa)^1/2. The effect of mole percentages of itaconic acid (IA) in P(HEMA/IA) hydrogels on the solubility parameter was investigated. The measured values were compared to literature and solubility values theoretically determined by group contribution values of van Krevelen and Hoy. The incorporation of IA into the hydrogel system slightly increased the solubility parameter. © 2002 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 40: 1995–2003, 2002     

Synthesis of poly(2‐hydroxyethyl methacrylate) in protic media through atom transfer radical polymerization using activators generated by electron transfer

Atom transfer radical polymerization (ATRP) using activators generated by electron transfer (AGET) was investigated for the controlled polymerization of 2‐hydroxyethyl methacrylate (HEMA) in a protic solvent, a 3/2 (v/v) mixture of methyl ethyl ketone and methanol. The AGET process enabled ATRP to be started with an air‐stable Cu(II) complex that was reduced in situ by tin(II) 2‐ethylhexanoate. The reaction temperature, Cu catalysts with different ligands, and variation of the initial concentration ratio of HEMA to the initiator were examined for the synthesis of well‐controlled poly(2‐hydroxyethyl methacrylate) and a poly(methyl methacrylate)‐b‐poly(2‐hydroxyethyl methacrylate) block copolymer. The level of control in AGET ATRP was similar to that in normal ATRP in protic solvents, and this resulted in a linear increase in the molecular weight with the conversion and a narrow molecular weight distribution (weight‐average molecular weight/number‐average molecular weight < 1.3). © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 3787–3796, 2006     

Poly(l‐glutamic acid)‐based micellar hydrogel with improved mechanical performance and proteins loading

Soft tissues, such as fat and skin, present high flexibility and are capable of withstanding large deformation in various functions. Hydrogels that can resemble the mechanical performance of soft tissue are unique and widely demanded. In this study, micellar hydrogels based on biocompatible poly(l ‐glutamic acid) (PLGA) were designed with the enhanced capacity to bear large deformation. Amphipathic triblock copolymer poly(ethylene glycol) acrylate‐co‐poly(ε‐caprolactone)‐co‐poly (ethylene glycol) acrylate (APEG‐PCL‐APEG) with two terminal double bonds was synthesized and self‐assembled into micelles. At the same time, graft copolymers, poly(l ‐glutamic acid)‐g‐hydroxyethyl methacrylate (PLGA‐g‐HEMA) with double bonds were synthesized. APEG‐PCL‐APEG micelles and PLGA‐g‐HEMA were mixed to construct micellar hydrogel via radical polymerization. The crystalline structure and hydrophobic aggregation of copolymers (APEG‐PCL‐APEG) were found to associate with PCL molecular weight. Due to the hydrophobic stress dissipation and crystalline structure of the micelles, the softness and toughness of hydrogels were promoted, exhibiting a 25% increase in ultimate strain. Moreover, the micellar hydrogels were able to load proteins with long‐term retention. In addition, under dynamic mechanical stimulation, the release of proteins could be accelerated. Besides, the micellar hydrogels also supported rabbit adipose‐derived stem cells (rASCs) growth, thus exhibiting the potential toward soft tissue engineering. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2019 , 57, 1115–1125     

Preparation of amphiphilic statistical copolymers of 2‐hydroxyethyl methacrylate with 2‐diethylaminoethyl methacrylate,precursors of water‐soluble copolymers

Statistical copolymers of 2‐hydroxyethyl methacrylate (HEMA) and 2‐diethylaminoethyl methacrylate (DEA) were synthesized at 50 °C by free‐radical copolymerization in bulk and in a 3 mol L^?1 N,N′‐dimethylformamide solution with 2,2′‐azobisisobutyronitrile as an initiator. The solvent effect on the apparent monomer reactivity ratios was attributed to the different aggregation states of HEMA monomer in the different solvents. The copolymers obtained were water‐insoluble at a neutral pH but soluble in an acidic medium when the molar fraction of the DEA content was higher than 0.5. The quaternization of DEA residues increased the hydrophilic character of the copolymers, and they became water‐soluble at a neutral pH when the HEMA content was lower than 0.25. © 2002 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 40: 2427–2434, 2002     

Preparation of Feather Keratin Hydrolyzate‐Gelatin Composites and Their Graft Copolymers

With the aim of utilizing the Keratinous waste material, poultry feather, which is up till now discarded as a waste, was hydrolyzed to form keratin hydrolyzate (FH). As FH does not form a film, it was mixed with gelatin (G) and FH‐G composite was prepared in film form. FH‐G was further graft co‐polymerized with 2‐hydroxyethyl methacrylate (HEMA) to achieve better physico‐chemical properties for the resultant hydrogels. Percentage grafting studies and IR studies confirmed the grafting of PHEMA onto FH‐G. FH‐G‐PHEMA exhibited better mechanical properties compared to FH‐G and FH‐PHEMA. TG studies clearly indicated the grafting of HEMA onto FH and FH‐G. SEM (Scanning Electron Microscopy) pictures of FH‐G and FH‐PHEMA films exhibited brittle nature on their surface, whereas continuity and A smooth surface was observed on for the FH‐G‐PHEMA films.     

Click functionalization of methacrylate‐based hydrogels and their cellular response

Methacrylate‐based hydrogels, such as homo‐ and copolymers of 2‐hydroxyethyl methacrylate (HEMA), have demonstrated significant potential for use in biomedical applications. However, many of these hydrogels tend to resist cell attachment and growth at their surfaces, which can be detrimental for certain applications. In this article, glycidyl methacrylate (GMA) was copolymerized with HEMA to generate gels functionalized with epoxide groups. The epoxides were then functionalized by two sequential click reactions, namely, nucleophilic ring opening of epoxides with sodium azide and then coupling of small molecules and peptides via Huisgen's copper catalyzed 1,3‐dipolar cycloaddition of azides with alkynes. Using this strategy it was possible to control the degree of functionalization by controlling the feed ratio of monomers during polymerization. In vitro cell culture of human retinal pigment epithelial cell line (ARPE‐19) with the hydrogels showed improved cell adhesion, growth and proliferation for hydrogels that were functionalized with a peptide containing the RGD sequence. In addition, the cell attachment progressively decreased with increasing densities of the RGD containing peptide. In summary, a facile methodology has been presented that gives rise to hydrogels with controlled degrees of functionality, such that the cell response is directly related to the levels and nature of that functionality. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 1781–1789     

Biocompatible amphiphilic conetwork based on crosslinked star copolymers: A potential drug carrier

A series of amphiphilic conetworks (APCNs) is synthesized through crosslinking of well‐defined tri‐arm star diblock copolymers via atom transfer radical polymerization. A new three‐arm initiator is synthesized to initiate the polymerization of 2‐hydroxyethyl methacrylate (HEMA) via “core‐first” method. The resulting star HEMA homopolymers with well‐defined molecular weight and narrow polydispersity are used as macroinitiator to incorporate allyl methacrylate to get the star diblock copolymers. Then, the precursors with allyl pendant groups are fully crosslinked with polyhydrosiloxanes through hydrosilylation. The so‐prepared APCNs exhibit unique properties of microphase separation of hydrophilic (HI) and hydrophobic (HO) phases with small channel size, a variable swelling capacity, excellent biocompatibility, and outstanding mechanical strength (2 ± 0.5 MPa). The properties of APCNs depend on the ratio of HI to HO, which can be regulated via precise synthesis of the star diblock copolymers. The APCNs show well‐controlled drug release to choline theophyllinate, suggesting a promising intelligent drug carrier for controlled release. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015 , 53, 2537–2545     

Synthesis and properties of water‐soluble azlactone copolymers

Preparation and study of a series of copolymers incorporating 2‐vinyl‐4,4‐dimethylazlactone (VDMA) is reported. The reactivity ratios for photo‐initiated free radical copolymerization of VDMA with methacrylic acid (MAA), acrylic acid (AA), acrylamide (AAm), dimethylacrylamide (DMAA), hydroxyethyl methacrylate (HEMA), methoxy poly(ethylene glycol) methacrylate (MPEG₃₀₀MA), and 2‐methacryloyloxyethyl phosphorylcholine (MPC), were determined by fitting comonomer conversion data obtained by in situ ¹H NMR to a terminal copolymerization equation. Semi‐batch photo‐copolymerizations were then used to synthesize the corresponding VDMA copolymers with constant composition. Their solubility and dissolution behavior, as well as their hydrolysis half‐lives under physiological conditions, were determined. P(VDMA‐co‐MAA) copolymers with 52 to 93 mol % VDMA showed decreasing initial solubility and increasing hydrolysis half‐lives with increasing VDMA content. VDMA copolymers with nonionic monomers AAm and DMAA were water soluble only at VDMA contents of 41 and 22 mol % or less, respectively, and showed longer hydrolysis half‐lives than comparable MAA copolymers. VDMA copolymers with HEMA and MPEG₃₀₀MA were found to crosslink during storage, so their hydrolysis half‐lives were not determined. VDMA copolymers with 18% zwitterionic MPC showed a much longer half‐life and superior initial solubility compared to analogous p(VDMA‐co‐MAA), identifying this copolymer as a promising candidate for macromolecular crosslinkers in, for example, aqueous layer‐by‐layer co‐depositions with polyamines. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

Synthesis of gradient copolymers with simultaneously tailor‐made chain composition distribution and glass transition temperature by semibatch ATRP: From modeling to application

Recent studies have demonstrated that gradient copolymers exhibit unique thermal properties. Although these properties can be determined by copolymer composition, other factors such as chain and sequence lengths and their distributions can also influence them. Accordingly, the synthesis of gradient copolymers requires simultaneously tailor‐made chain structure and thermal properties. In this work, we carried out a systematic study on the preparation of poly(methyl methacrylate‐grad‐2‐hydroxyethyl methacrylate) [poly(MMA‐grad‐HEMA)] with synchronously tailor‐made chain composition distribution and glass transition temperature (T_g) through semibatch atom transfer radical polymerization. First, a comprehensive model for simultaneously predicting gradient copolymer microstructure and T_g was presented using the concept of pseudo‐kinetic rate coefficients and Johnston equation. The model was validated by comparing simulation results with the classical reference data. Furthermore, the model was used to guide the experimental synthesis of the poly(MMA‐grad‐HEMA) gradient copolymers potentially as excellent damping material. The thermal properties of these gradient copolymer samples were evaluated. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

The Effect of Copolymer Composition on Surface Free‐Energy of Poly(2‐Hydroxyethyl Methacrylate–Crotonic Acid) Copolymers

Abstract

Poly(2‐hydroxyethyl methacrylate–crotonic acid) P(HEMA/CrA) copolymers with varying compositions were prepared from ternary mixtures of 2‐hydroxyethyl methacrylate (HEMA)/crotonic acid (CrA)/water by using ⁶⁰Co γ‐rays. The wetting forces were determined according to the Wilhelmy Plate Technique. Di‐iodomethane, ethylene glycol, and formamide were used as probe liquids. Lifshitz–van der Waals surface energy components, Lewis acid–base surface components, and total surface energies were calculated using van Oss et al. methodology. It was determined that Lifshitz–van der Waals component (γ_S ^LW) of the copolymers did not differ much from the copolymer composition. However, the electron‐donor surface free energy components (γ_S ^?) of the copolymers were decreased considerably with the increase of the CrA content of the copolymers, the surfaces of these copolymers were still found to have a basic character.