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Scaffolding biomaterials are gaining great importance due to their beneficial properties for medical purposes. Targeted biomaterial engineering strategies through the synergy of different material types can be applied to design hybrid scaffolding biomaterials with advantageous properties for biomedical applications. In our research, a novel combination of the bioactive agent Manuka honey (MHo) with 2-hydroxyethyl methacrylate/gelatin (HG) hydrogel scaffolds was created as an efficient bioactive platform for biomedical applications. The effects of Manuka honey content on structural characteristics, porosity, swelling performance, in vitro degradation, and in vitro biocompatibility (fibroblast and keratinocyte cell lines) of hybrid hydrogel scaffolds were studied using Fourier transform infrared spectroscopy, the gravimetric method, and in vitro MTT biocompatibility assays. The engineered hybrid hydrogel scaffolds show advantageous properties, including porosity in the range of 71.25% to 90.09%, specific pH- and temperature-dependent swelling performance, and convenient absorption capacity. In vitro degradation studies showed scaffold degradability ranging from 6.27% to 27.18% for four weeks. In vitro biocompatibility assays on healthy human fibroblast (MRC5 cells) and keratinocyte (HaCaT cells) cell lines by MTT tests showed that cell viability depends on the Manuka honey content loaded in the HG hydrogel scaffolds. A sample containing the highest Manuka honey content (30%) exhibited the best biocompatible properties. The obtained results reveal that the synergy of the bioactive agent, Manuka honey, with 2-hydroxyethyl methacrylate/gelatin as hybrid hydrogel scaffolds has potential for biomedical purposes. By tuning the Manuka honey content in HG hydrogel scaffolds advantageous properties of hybrid scaffolds can be achieved for biomedical applications.

New composite 3D scaffolds were developed as a combination of synthetic polymer, poly(2-hydroxyethyl methacrylate) (PHEMA), and a natural polymer, gelatin, with a ceramic component, nanohydroxyapatite (ID nHAp) dopped with metal ions. The combination of a synthetic polymer, to be able to tune the structure and the physicochemical and mechanical properties, and a natural polymer, to ensure the specific biological functions of the scaffold, with inorganic filler was applied. The goal was to make a new material with superior properties for applications in the biomedical field which mimics as closely as possible the native bone extracellular matrix (ECM). Biodegradable PHEMA hydrogel was obtained by crosslinking HEMA by poly(β-amino esters) (PBAE). The scaffold’s physicochemical and mechanical properties, in vitro degradation, and biological activity were assessed so to study the effects of the incorporation of nHAp in the (PHEMA/PBAE/gelatin) hydrogel, as well as the effect of the different pore-forming methods. Cryogels had higher elasticity, swelling, porosity, and percent of mass loss during degradation than the samples obtained by porogenation. The composite scaffolds had a higher mechanical strength, 10.14 MPa for the porogenated samples and 5.87 MPa for the cryogels, but a slightly lower degree of swelling, percent of mass loss, and porosity than the hybrid ones. All the scaffolds were nontoxic and had a high cell adhesion rate, which was 15–20% higher in the composite samples. Cell metabolic activity after 2 and 7 days of culture was higher in the composites, although not statistically different. After 28 days, cell metabolic activity was similar in all scaffolds and the TCP control. No effect of integrating nHAp into the scaffolds on osteogenic cell differentiation could be observed. Synergetic effects occurred which influenced the mechanical behavior, structure, physicochemical properties, and interactions with biological species.

Hydrogel scaffolding biomaterials are one of the most attractive polymeric biomaterials for regenerative engineering and can be engineered into tissue mimetic scaffolds to support cell growth due to their similarity to the native extracellular matrix. The novel, versatile hydrogel scaffolds based on alginate, gelatin, 2-hydroxyethyl methacrylate, and inorganic agent hydroxyapatite were prepared by modified cryogelation. The chemical composition, morphology, porosity, mechanical properties, effects on cell viability, in vitro degradation, in vitro and in vivo biocompatibility were tested to correlate the material’s composition with the corresponding properties. Scaffolds showed an interconnected porous microstructure, satisfactory mechanical strength, favorable hydrophilicity, degradation, and suitable in vitro and in vivo biocompatible behavior. Materials showed good biocompatibility with healthy human fibroblast in cell culture, as well as in vivo with zebrafish assay, suggesting newly synthesized hydrogel scaffolds as a potential new generation of hydrogel scaffolding biomaterials with tunable properties for versatile biomedical applications and tissue regeneration.

The discovery of novel biodegradable biomaterials able to support and control cellular activity as well as development of an enhanced and efficient method for their fabrication, are of paramount importance in the field of tissue engineering. This study highlights the design of novel degradable hydrogels based on gelatin and hydroxyethyl (meth)acrylates using the innovative combined two-step sequential microwave-assisted and UV photo-polymerization technique. Chemical composition, morphology, swelling capacity and degradation rate of the synthesized hydrogels were evaluated by Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), swelling and weight loss measurements. As an initial step for evaluation of performance of the hydrogels in the biological environment, the in vitro biocompatibility of these hydrogels, was evaluated using L929 mouse fibroblasts. Obtained results demonstrated that the hydrogels possess a porous morphology with interconnected pores, 50% in vitro degradation after 7 months, and satisfied biocompatibility on L929 fibroblast cells. These unique performances of the hydrogels make them promising candidates for in vivo evaluation in clinical studies aiming at tissue regeneration.

In this study, three series of semi-interpenetrating networks were synthesized based on 2-hydroxyethyl methacrylate (HEMA), 2-hydroxyethyl acrylate (HEA), itaconic acid (IA), and poly(vinyl pyrrolidone) (PVP) as interpenetrating polymer. Syntheses were performed by free radical cross-linking/polymerization reaction. The first series represented hydrogels based on 2-hydroxyethyl methacrylate, poly(vinyl pyrrolidone), and itaconic acid, varying of poly(vinyl pyrrolidone) content. The second series of samples were hydrogels based on 2-hydroxyethyl acrylate, poly(vinyl pyrrolidone), and itaconic acid, varying of itaconic acid content. The third series of synthesized samples were based on 2-hydroxyethyl acrylate, poly(vinyl pyrrolidone), and itaconic acid, varying of poly(vinyl pyrrolidone) content. The content of component was varied in order to examine the influence on the structure, pH- and temperature-sensitive swelling-“intelligent” behavior, mechanical properties of hydrogels, as well as antimicrobial and biocompatible potential of hydrogels. Poly(vinyl pyrrolidone) is a linear polymer, which shows satisfactory biocompatibility and hydrophilicity. Itaconic acid gives pH-sensitive-“intelligent” behavior and better hydrophilicity. Hydrogels based on HEMA and HEA show excellent biocompatibility and satisfactory hydrophilicity. All three series of samples showed satisfactory cytocompatibility, as well as the antimicrobial potential tested against most common microbes. The results obtained and presented in this research can contribute to the development of new efficient polymeric biomaterials for biomedical applications.

The strategy of combining polymers of natural and synthetic origin with inorganic components to use their unique synergistic effect for the development of the novel, sophisticated, and efficient 3D polymeric biomaterials, whose structure and properties mimic the extracellular matrix and simultaneously represent the suitable hydrogel platform for controlled drug release, is presented. The novel versatile 2-hydroxyethyl methacrylate/gelatin/alginate/iron(III) oxide based hydrogels are prepared by a simple but effective method-modified porogenation. Chemical composition, morphology, swelling capacity, porosity, mechanical properties, effects on cell viability, and in vitro degradation are tested to correlate the material's composition with the corresponding properties. The hydrogels show an interconnected porous microstructure, satisfactory mechanical strength, pH-sensitivity, and favorable curcumin release performances. The materials show good compatibility with healthy human fibroblast in cell culture judged by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, suggesting newly synthesized hydrogels as potentially a new generation of 3D biomaterials with tunable properties for versatile biomedical and pharmaceutical applications.

Series of novel dual-sensitive poly(2-hydroxypropyl acrylate/itaconic acid) hydrogels were designed as multifunctional drug delivery system which can provide several advantages including drug protection, self-regulated oscillatory release and targeted delivery to a single entity. The hydrogels were synthesized by the free-radical crosslinking copolymerization and evaluated as carriers for hydrophobic drug, Oxaprozin, with specific controlled release properties. Structural, morphological, thermal, surface charge, swelling and antimicrobial properties of the hydrogels were investigated for unloaded and Oxaprozin-loaded samples. Swelling studies demonstrated pH- and temperature-sensitivity of drug-free and drug-loaded P(HPA/IA) hydrogels. The results of swelling and oscillatory swelling, and swelling behavior of drug-free, and drug-loaded hydrogels in simulated gastrointestinal conditions, and in vitro Oxaprozin release studies confirmed these hydrogels as a highly effective colon-specific drug delivery system with excellent performance of long-term controlled release. These unique properties make the P(HPA/IA) hydrogels highly attractive materials for developing multifunctional drug delivery systems.

Gelatin hydrogels have great potential in regenerative medicine but their weak mechanical properties are a major drawback for the load-bearing applications, such as scaffolds for tissue engineering. To overcome this deficiency, novel biodegradable hydrogels with improved mechanical properties were prepared by combining gelatine with 2-hydroxyethyl methacrylate (HEMA), using a double network synthetic procedure. The first, superporous and mechanically strong network, was obtained by free radical polymerization of HEMA at cryogenic temperature, in the presence of gelatin. Degradable poly (beta-amino ester) (PBAE) macromers of different chemical composition or molecular weight were used as crosslinkers to introduce hydrolytically labile bonds in PHEMA. The second gelatin network was formed by crosslinking gelatin with glutaraldehyde. For comparison, a set of biodegradable PHEMA networks was obtained by polymerization of HEMA at cryogenic temperature. All samples were characterized revealing that mechanical strength, swelling behavior and degradation rate as well as high biocompatibility of new IPNs are in accordance with values required for scaffolds in tissue engineering applications and that tuning of these properties is accomplished by simply using different PBAE macromers. This is peer-reviewed version of the article: Filipović, V., Nedeljkovic, B. D. B., Vukomanovic, M.,& Tomić, S. Lj. (2018). Biocompatible and degradable scaffolds based on 2-hydroxyethyl methacrylate, gelatin and poly(beta amino ester) crosslinkers. Polymer TestingElsevier Sci Ltd, Oxford., 68, 270-278. [https://doi.org/10.1016/j.polymertesting.2018.04.024] The published version: [https://cer.ihtm.bg.ac.rs/handle/123456789/2440]

In this study we prepared hydrogels based on 2-hydroxyethyl methacrylate (HEMA): PHEMA homopolymer and two terpolymers of HEMA, itaconic acid (IA) and two poly(alkylene glycol) (meth) acrylates (PAGM): poly(ethylene glycol)(6) acrylate (P(HEMA/IA/PAGM1)) and poly(propylene glycol)(5) methacrylate (P(HEMA/IA/PAGM2)). Hydrogels were synthesized by gamma-irradiated radical polymerization and subjected to swelling measurements and genotoxicity evaluation. Swelling studies confirmed that these hydrogels deserve consideration as biomaterials due to their ability to swell in phosphate buffer but maintaining physical integrity for a prolonged contact time after equilibrium state has been reached. Comet assay showed certain genotoxic effect following cell exposure to extracts of hydrogels, which was dependent on the concentration of extracts, chemical composition of hydrogels and the degree of crosslinking. The influence of concentration on genotoxicity was the most pronounced. The synthesis of these novel HEMA-based hydrogels should be optimized so as to reduce their toxicity and enable the use in clinical practice.

This work describes radiolytic synthesis of silver nanoparticles (Ag NPs) within the poly(N-vinyl-2-pyrrolidone) (PVP) hydrogel. The hydrogel matrix was obtained by gamma irradiation-induced cross-linking, while the in situ reduction of Ag(+) ions was performed using strong reducing species formed under water radiolysis. Absorption spectrum of the Ag/PVP nanocomposite confirmed the formation of Ag NPs, showing the surface plasmon band maxima at 405 nm. Ag/PVP nanocomposites were characterized by XRD and TEM analysis, accompanied with investigations of swelling and diffusion properties in the simulated body fluid at 37 degrees C, and mechanical properties in bioreactor conditions. It was shown that Ag/PVP nanocomposite exhibited higher values of equilibrium swelling degree, Youngs modulus, and molar mass between crosslinks, while lower values of the diffusion coefficient and effective crosslink density were obtained, as compared to the pure PVP. (C) 2011 Elsevier Ltd. All rights reserved.

In this study a novel series of hydrogels, based on 2-hydroxyethyl methacrylate (HEMA), itaconic acid (IA) and poly(ethylene glycol) dimethacrylates (PEGDMA) (of varying molecular weight and concentration) were prepared by free radical cross-linking copolymerization. Preliminary hemocompatibility characterization of hydrogels obtained by hemolytic activity assay indicated good compatibility with blood. Preliminary biocompatibility characterization of P(HEMA/IA/PEGDMA) hydrogels, done by the cytotoxicity assays using the HeLa cell line revealed that the cell viability of all samples was in the range of 97-100%, with no significant decrease in cell viability with the change of PEGDMA molecular weight and concentration. Swelling studies were conducted for all P(HEMA/IA/PEGDMA) samples in a physiological pH and temperature range and network parameters were determined. Swelling studies showed pH sensitive behaviour, typical for anionic hydrogels, and temperature dependent swelling. The effects of concentration of PEGDMA component on hydrogel swelling properties depend on the PEGDMA molecular weight. The samples with 550PEGDMA show different swelling capacities when 550PEGDMA content is changed, whereas for P(HEMA/IA/875PEGDMA) samples there was practically no difference in equilibrium degree of swelling, qe, with varying 875PEGDMA content, which trend is the same as in the case of qe versus pH dependences. It was concluded that P(HEMA/IA/PEGDMA) hydrogels show good potential to be used as biomedical materials. U radu je izvedena sinteza dva nova tipa kopolimernih hidrogelova na bazi 2- -hidroksietil (met)akrilata, itakonske kiseline i poli(etilen glikol) dimetakrilata, s ciljem primene ovih polimernih sistema u biomedicinske svrhe. Testirana je biokompatibilnost preko probe hemokompatibilnosti. Hemolitička aktivnost svih hidrogelova je bila u dozvoljenim granicama, prihvatljivim za biomedicinsku primenu. Studije bubrenja hidrogelova, izvedene u opsegu fizioloških pH i temperaturnih vrednosti, pokazale su da bubrenje zavisi od pH i temperature. Sintetisani hidrogelovi su pokazali sličan trend zavisnosti stepena bubrenja od pH i temperature. Sadržaj 550PEGDMA u hidrogelu utiče na stepen bubrenja, dok koncentracija 875PEGDMA komponente vrlo malo utiče na stepen bubrenja. Hidrogel sa 15 mol% 550PEGDMA manje bubri od uzoraka sa manjim sadržajem ove komponente (5 i 10 mol%), što ukazuje da pri toj koncentraciji preovladava umrežavajuće dejstvo ove komponente. Duži PEG lanci u 875PEGDMA su fleksibilniji, pa je efekat umrežavanja uravnotežen sa efektom fleksibilnosti lanca, što ima za posledicu slično bubrenje za sve uzorke u opsegu koncentracija koje su korišćene u ovom radu.

For nanoscience to become true nanotechnology, there is a need for breakthroughs in the engineering science of processing and manufacturing at the nanoscale. The radiation technology may offer a novel approaches to solving the problems of placement, high throughput, as well as integration across multiple length scales. Furthermore, there are critical needs for advanced materials in the area of biomaterial engineering, primarily in generating biomaterials of enhanced specific functionalities, which can be achieved by introduction of proper functionalities at the nanoscale dimensions. The radiation techniques are uniquely suited for such task, due to their favorable characteristics and in most cases not possible by other methods of synthesis. Therefore, we are systematically developing novel synthetic strategies for incorporation of noble metal nanoparticles in hydrogel networks by gamma irradiation, for possible biomedical application, using liquid filled cavities in hydrogels as nanoreactors (template synthesis). The radiation process has various advantages, such as easy process control, the possibility of joining synthesis and sterilization in one technological step. The radiation technique does not require any extra substances, and does not need any further purification. On the other hand, in recent years nanoscale antibacterial materials, such as nanocrystalline silver, as novel antimicrobial species have been seen as promising candidates for application owing to their high surface to volume ratio and their novel physical and chemical properties on the nanoscale level. Silver can be safely used even for patients who have diseases like Diabetes Mellitus that interfere with wound healing. The recent emergence of nanotechnology has provided a new therapeutic modality in silver nanoparticles for healing wounds.

In this study, superporous hydrogels were synthesized by free radical polymerization of 2-hydroxyethyl methacrylate without and in the presence of gelatin. Highly porous hydrogel structures were obtained by two different techniques: using a gas blowing agent, sodium bicarbonate, and a cryogenic treatment followed by freeze-drying. After the gel synthesis, gelatin molecules were covalently immobilised onto PHEMA via glytaraldehyde activation. All samples were characterized for morphological, mechanical, swelling and antibacterial properties. The results obtained show that samples with gelatin show better properties in comparison with PHEMA samples, which make these materials highly attractive for developing hydrogel scaffolds for tissue regeneration.

A series of dual-sensitive poly(2-hydroxypropyl acrylate/itaconic acid) (P(HPA/IA)) hydrogels were synthesized and evaluated as potential highly effective antiproliferative drug delivery system. Investigated hydrophobic antiproliferative agent, Ni(II) complex with Oxaprozin, was successfully synthesized and efficiently loaded into the’”intelligent” P(HPA/IA) hydrogels. Swelling studies showed that loaded agent did not annul pH- and temperature-sensitivity of the investigated hydrogels. In vitro antiproliferative activity of investigated complex against human cervical (HeLa) and melanoma cancer (FemX) cell lines was tested. The results of in vitro release study at different pH values confirmed synthesized hydrogels loaded with investigated complex as a highly effective pH-triggered drug delivery system for the advanced anticancer therapy as well as for the targeted treatment of intestine/colon cancers.

A series of poly(2-hydroxyethyl acrylate-co-itaconic acid), P(HEA/IA), hydrogels with different HEA/IA ratio, were synthesized using free radical crosslinking/copolymerization and investigated as sorbents for Pb2+ ions from aqueous solutions. Hydrogels were characterized using DMA, FTIR, DSC, SEM and AFM. The adsorption was found to be highly dependent on hydrogel composition, solution pH, sorbent weight, ionic strength and contact time. Five isotherm models, Langmuir, Freundlich, Redlich-Peterson, Temkin and Dubinin-Radushkevich, were applied to the sorption data. The best fit was obtained with Redlich-Peterson isotherm. The separation factor, RL, value indicated favorable sorption for Pb2+ ions. The maximum sorption capacities were 392.2 and 409.8 mg/g for P(HEA/2IA) and P(HEA/10IA), respectively. Kinetic data showed best fit with pseudo-second-order model. Thermodynamic studies revealed that the reaction was exothermic and proceeds with a decrease in entropy. Moreover, P(HEA/IA) hydrogel showed the most pronounced sorption toward Pb2+ ions from environment containing Cu2+, Zn2+, Cd2+, Ni2+ and Co2+ ions. Sorption/desorption experiments, showed that the P(HEA/IA) hydrogels could be reused without significant loss of the initial properties even after three adsorption-desorption cycles. [Projekat Ministarstva nauke Republike Srbije, br. 172015 i br. 172062]

In order to evaluate biological response and potential toxicity prior to clinical use as wound dressing materials, three series of hydrogels, based on 2-hydroxyethyl acrylate (HEA) and itaconic acid (IA), unloaded, with incorporated copper(II) ions and reduced copper, were subjected to cytotoxicity testing on L929 cell line (mouse fibroblasts). MTT test revealed proper fibroblast growth in the presence of tested hydrogels, with an absence of any acute toxic effects. Mechanical properties of all three hydrogel series were studied by dynamic mechanical analysis (DMA) and obtained results indicated dominant elastic over viscous behaviour, which supports their application in wound management. The temperature sensitive behaviour of the hydrogels was detected in swelling study conducted in wide range of temperature values 25–50 °C, in buffer pH 7.40. The hydrogels exhibited excellent microbial barrier characteristics against Pseudomonas aeruginosa, reducing the risk of bacterial infection in wound bed.

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 degrees C), where small changes in temperature significantly influence swelling and drug release of these hydrogels. Due to maximum swelling of hydrogels around 40 degrees C, the P(HEMA/IA) hydrogel containing 5mol% of IA without and with drug-antibiotic (gentamicin) were investigated at pH 7.40 and in the temperature range 25-42 degrees C, in order to evaluate their potential for medical applications. (c) 2007 Elsevier Ltd. All rights reserved. 11th Tihany Symposium on Radiation Chemistry, Aug 26-31, 2006, Eger, Hungary

The effects of gamma irradiation on the structure and properties of hydroxyapatite/poly L-lactide (HAp/PLLA) biomaterial have been investigated. Effects of radiation on microstructure, degradation of polymer part and thermal stability of composite were determined by scanning electronic microscopy (SEM), gel permeation chromatography (GPC) and thermogravimetric analysis (TGA), respectively. Mechanical properties were obtained through mechanical strength and elasticity modulus. Presented results show that properties of HAp/PLLA decay with irradiation dose, but for doses required for sterilization, changes and damaging effects are acceptable. (C) 2006 Elsevier Ltd. All rights reserved.

In this study, a series of novel stimuli-sensitive hydrogels based on 2-hydroxyethyl acrylate and itaconic acid monomers were designed for the controlled release of hydrophobic drug, Oxaprozin. All samples were synthesized by the free-radical crosslinking copolymerization and characterized for structural, morphological, thermal, surface charge, swelling and antibacterial properties. In order to investigate the influence of the drug on hydrogel properties the same characterization was conducted for all Oxaprozin-loaded samples. The chemical composition of hydrogels was studied using Fourier transform infrared spectroscopy, while their morphology and thermal properties were examined by scanning electron microscopy and differential scanning calorimetry. Swelling studies, conducted in the physiological pH range from 2.20 to 8.00 and in the temperature range from 25 to 50 degrees C, showed that the loaded drug does not modify the pH and temperature sensitivity of the hydrogels, but reduces their swelling capacity. The in vitro drug release study conducted at pH 2.20 and 7.40 showed that all hydrogels can be tailored as colon specific drug delivery systems, and the drug release rate can be effectively controlled by IA content. In addition, the antibacterial activity of the hydrogels was determined against Escherichia coli and Staphylococcus aureus, by the zone of inhibition test. Results of our study indicate that these "smart" hydrogels, with specific morphology, surface charge, swelling capacity, drug loading efficiency and release behavior, could be designed to obtain an enhanced and site-specific controlled drug release system by simply adjusting their composition.

Series of novel hydrogels based on 2-hydroxyethyl acrylate (HEA) and itaconic acid (IA), P(HEA/IA) copolymers, were prepared by free radical cross-linking copolymerization and investigated as potential adsorbents for Cd2+ removal from aqueous solution. The hydrogels before and after Cd2+ adsorption were characterized using FTIR, temperature sensitive. In order to evaluate adsorption behavior of samples various factors affecting the Cd2+ uptake behavior, such as: contact time, temperature, pH, ionic strength, adsorbent weight, competitive ions and initial concentration of the metal ions were investigated. Five adsorption isotherms and two kinetic models were studied. The adsorption behavior can be very well described by the pseudo-second order kinetic model and Langmuir isotherm. Multicomponent adsorption studies revealed that adsorption of cadmium depends on the type of metal ions present in the system. Desorption studies showed that hydrogel can be reused three times with only 15% loss of adsorption capacity. All results indicate that the sample with the highest IA content is the most promising adsorbent for Cd2+ removal. This is the peer-reviewed version of the article: [https://doi.org/10.1016/j.apsusc.2015.02.133] [http://cer.ihtm.bg.ac.rs/handle/123456789/1764]