Evaluation of hyaluronic acid-polymacrolactone hydrogels with 3D printing capacity.

The implementation of personalized patches, tailored to individual genetic profiles and containing specific amounts of bioactive substances, has the potential to produce a transformative impact within the medical sector. There are several methods of designing scaffolds in the context of personalized medicine, with three-dimensional (3D) printing emerging as a pivotal technique. This innovative approach can be used to construct a wide variety of pharmaceutical dosage forms, characterized by variations in shape, release profile, and drug combinations, allowing precise dose individualization and the incorporation of multiple therapeutic agents. To expand the potential and applicability of personalized medicine, particularly with regards to indomethacin (IND), a drug necessitating individualized dosing, this study proposes the development of new transdermal delivery systems for IND based on hyaluronic acid and a polylactone synthesized within our research group, namely poly(ethylene brasilate-co-squaric acid) (PEBSA). The obtained systems were characterized in terms of their swelling capacity, rheological behavior, and morphological characteristics that highlighted the formation of stable three-dimensional networks. To impart specific shape and geometry to the structures, multi-component systems based on PEBSA, HA, and methacrylate gelatin were obtained. The scaffolds were loaded with IND and subsequently 3D printed. The release capacity of IND and its dependence on the relative ratios of the components comprising the scaffold composition were highlighted. The cytocompatibility studies revealed the successful development of biocompatible and noncytotoxic systems.

Morphological Evaluation of Supramolecular Soft Materials Obtained through Co-Assembly Processes.

Low-molecular-weight gelators (LMWGs) are compounds with an intrinsic tendency to self-assemble forming various supramolecular architectures via non-covalent interactions. Considering that the development of supramolecular assemblies through the synergy of molecules is not entirely understood at the molecular level, this study introduced a Fmoc-short peptide and four Fmoc-amino acids as building blocks for the self-assembly/co-assembly process. Hence, we investigated the formation of supramolecular gels starting from the molecular aggregation following two triggering approaches: solvent/co-solvent method and pH switch. The complex morphological analysis (POM, AFM, and STEM) offered an insight into the spontaneous formation of well-ordered nanoaggregates. Briefly, POM and AFM images demonstrated that self-assembled gels present various morphologies like dendrimer, spherulite, and vesicle, whereas all co-assembled supramolecular systems exhibit fibrillar morphologies as a result of the interaction between co-partners of each system. STEM study has confirmed that the molecules interact and join together, finally forming a fibrous network, an aspect seen in both self-assembled and co-assembled gels. XRD allowed the determination of the molecular arrangement. The study emphasized that the Fmoc motif protected the amino groups and facilitated gelation through additional π-π interactions.

New Physical Hydrogels Based on Co-Assembling of FMOC-Amino Acids.

In the last years, physical hydrogels have been widely studied due to the characteristics of these structures, respectively the non-covalent interactions and the absence of other necessary components for the cross-linking processes. Low molecular weight gelators are a class of small molecules which form higher ordered structures through hydrogen bonding and π-π interactions. In this context it is known that the formation of hydrogels based on FMOC-amino acids is determined by the primary structures of amino acids and the secondary structure arrangement (alpha-helix or beta-sheet motifs). The present study aimed to obtain supramolecular gels through co-assembly phenomenon using FMOC-amino acids as low molecular weight gelators. The stability of the new structures was evaluated by the vial inversion test, while FTIR spectra put into evidence the interaction between the compounds. The gel-like structure is evidenced by viscoelastic parameters in oscillatory shear conditions. SEM microscopy was used to obtain the visual insight into the morphology of the physical hydrogel network while DLS measurements highlighted the sol-gel transition. The molecular arrangement of gels was determined by circular dichroism, fluorescence and UV-Vis spectroscopy.

Polymeric Carriers Designed for Encapsulation of Essential Oils with Biological Activity.

The article reviews the possibilities of encapsulating essential oils EOs, due to their multiple benefits, controlled release, and in order to protect them from environmental conditions. Thus, we present the natural polymers and the synthetic macromolecular chains that are commonly used as networks for embedding EOs, owing to their biodegradability and biocompatibility, interdependent encapsulation methods, and potential applicability of bioactive blend structures. The possibilities of using artificial intelligence to evaluate the bioactivity of EOs-in direct correlation with their chemical constitutions and structures, in order to avoid complex laboratory analyses, to save money and time, and to enhance the final consistency of the products-are also presented.

Advancement in the Biomedical Applications of the (Nano)gel Structures Based on Particular Polysaccharides.

(Nano)gels from macromolecular compounds-natural, synthetic, or a combination thereof, suitable crosslinkers-and conferred characteristics-such as degradability, size, charge, amphiphilicity, responsiveness, and softness-are capable of responding to the challenges imposed by bioengineering applications. Polysaccharide-based gels have received particular attention in this field. This review addresses recent advancement in the use of (nano)gel structures prepared only from compounds based on gellan gum, heparin, chondroitin sulfate, carrageenan, guar gum, galactose, or agarose, which represent an important part of the special class of natural polymers, the polysaccharides. Also, future trends are taken into discussion regarding the (nano)gels' use in biomedical applications such as biomimetics, biosensors, artificial muscles, and chemical separations in relation with their ability to be used as a vehicle for various biomolecules due to their physicochemical properties, biocompatibility, and biodegradability.

The influence of excipients on physical and pharmaceutical properties of oral lyophilisates containing a pregabalin-acetaminophen combination.

OBJECTIVES: The purpose of the study was to investigate and characterize the oral lyophilisates containing the pregabalin-acetaminophen drug combination and as xcipients mannitol with microcrystalline cellulose or hydroxypropyl methylcellulose, in order to conclude upon drug-excipient interactions and their stability implications, impact of excipients on drug release and on the physicochemical and mechanical properties of the pharmaceutical formulations. METHODS: The oral tablets were made by using a Christ freeze-dryer alpha 2-4-LSC lyophilizer, and evaluated for stability, drug-excipient compatibility and homogeneity of the prepared pharmaceutical formulations. The formulations were evaluated for in vivo absorption in rabbits by histopathological exams. RESULTS: FTIR and thermogravimetric analyses, DLS technique, SEM and NIR-CI studies confirmed the compatibility between compounds. From the determined physical and biochemical parameters of the formulations it was established that they are stable, homogeneous, and meet the conditions for orally disintegrating tablets. CONCLUSION: In the case of the investigated pharmaceutical formulations the study evidenced the assembling through physical bonds between the excipients and the 'codrug' complex, which do not affect the release of the bioactive compounds.

Patterning poly(maleic anhydride-co-3,9-divinyl-2,4,8,10-tetraoxaspiro (5.5) undecane) copolymer bioconjugates for controlled release of drugs.

Owing to the special characteristics and abilities polymeric networks have received special interest for a range of biomedical applications especially for drug delivery systems. This study was devoted to preparation of new polymeric compounds based on maleic anhydride and 3,9-divinyl-2,4,8,10-tetraoxaspiro (5.5) undecane copolymer (poly maleic anhydride-co-3,9-divinyl-2,4,8,10-tetraoxaspiro (5.5) undecane) (PMAU) patterned as a network for bioconjugation and tested as drug carrier systems. The PMAU copolymer was improved in its functionality by opening the maleic anhydride ring with different amounts of erythritol, which is free of side effects in regular use and a multifunctional compound, and also confers antioxidant character for the new compounds. The new polymeric matrices were loaded with acetaminophen, codeine and their fixed dose combinations. The investigation demonstrated the capability of the new structures to be used as polymer networks for linking bioactive compounds and to perform controlled delivery. The physico-chemical investigations--Fourier transform infrared spectroscopy (FTIR) spectra, contact angle, zeta potential (ZP - z, PMAU and its derivatives samples loaded with medicines present decreased values of zeta potential attesting the bioconjugate formation and as well their stability), and hydrodynamic radius, near infrared chemical imaging evaluation (new specific bands being registered for bio-conjugate with acetaminophen around of 1150-1200 nm and 1700 nm, and also between 1150 and 1200 nm in case of the codeine bio-conjugate), scanning electron microscopy (SEM) studies, X-ray diffraction analysis--evidenced the formation of the bioconjugates in relation to the chemical composition of the polymer matrices, while in vitro release study and in vivo tests confirm the capacity for drug delivery of the prepared bioactive systems.

Upon synthesis of a polymeric matrix with pH and temperature responsiveness and antioxidant bioactivity based on poly(maleic anhydride-co-3,9-divinyl-2,4,8,10-tetraoxaspiro [5.5] undecane) derivatives.

Poly(maleic anhydride-co-3,9-divinyl-2,4,8,10-tetraoxaspiro [5.5] undecane), acquired through radical polymerization, was synthesized with the aim to prepare an alternant copolymer with precise placement of functional groups along the polymer backbones. The new structure owing to the suitable and specific functionalities is anticipated to be used as reactive polymer to link bioactive compounds via maleic anhydride moiety. The copolymer was improved in its functionality by maleic anhydride ring opening with different amounts of erythritol in order to confer antioxidant characteristics to the polymeric structure. The chemical structure of the new prepared polymers was confirmed by FTIR and (1)H NMR spectra, and the polymers were also characterized from the viewpoint of their thermal stability. The dual sensitivity of the polymeric structure, at temperature and pH, was evaluated by determining the hydrodynamic radius and zeta potential in interdependence with the environment conditions. The polymer morphology was investigated by SEM. The antioxidant character was evaluated measuring the scavenger properties of the functionalized copolymer with erythritol against the 2,2-diphenyl-1-picrylhydrazyl radicals. The acute toxicity investigation, realized in vivo for the copolymer and the derivatives, allows the inclusion of the compounds into the group of moderately toxic accordingly to Hodge and Sterner toxicity scale owing to the lethal dose 50 determined values.

Possibilities of quercetin insertion into poly(N,N-dimethylacrylamide-co-3, 9-divinyl-2, 4, 8, 10-tetraoxaspiro (5.5) undecane) network.

The study presents the possibility of coupling quercetin into poly(N,N-dimethylacrylamide-co-3, 9-divinyl-2, 4, 8, 10-tetraoxaspiro (5.5) undecane) (PDMA-co-U) gel network through a semi-imprinted procedure in order to obtain a responsive antioxidant composite. A continuous magnetic field was used during quercetin insertion for prearranging the compounds - macromolecular matrix and quercetin - and improving the coupling efficiency of the flavonoid structure into the polymeric network. The new supramolecular systems were characterized by FTIR, SEM and thermogravimetric analyses. The dependence of the swelling degree equilibrium and particle size distribution of the studied chemical structures were also evaluated related to the experimental conditions of preparation.

Semi-imprinting quercetin into poly[N,N-dimethylacrylamide-co-3, 9-divinyl-2, 4, 8, 10-tetraoxaspiro (5.5) undecane] network: evaluation of the antioxidant character.

A responsive antioxidant system constituted from quercetin inserted into poly[N,N-dimethylacrylamide-co-3, 9-divinyl-2, 4, 8, 10-tetraoxaspiro (5.5) undecane] through a semi-imprinted procedure was evaluated. A continuous magnetic field (MF) was used during supramolecular structure preparation. The strength of coupling quercetin was evaluated based on the template release from the polymeric matrices, as well as to what extent quercetin reloaded into the polymer matrix in prescribed conditions--with or without the MF presence--shows antioxidant properties. The antioxidant activity of the complex was investigated by radical inhibitor activity method using 2, 2-diphenyl-l-picrylhydrazyl. The evaluation of the homogeneity distribution of the quercetin inside the polymeric network was made by near-infrared chemical imaging and correspondingly statistical analysis. For in vivo biocompatibility investigation, granuloma test in rats was performed correlated with the activity of enzymes involved in oxidative stress as well as immunologic effects of tested supramolecular complexes that include quercetin as therapeutic agent.

Effect of pH and temperature upon self-assembling process between poly(aspartic acid) and Pluronic F127.

The present investigation was made in order to evaluate the capability of self-assembling of the two water soluble polymers, respectively, poly(aspartic acid) and Pluronic F127 into well interpenetrated mixture, and to evidence the connection effects intervened during polymer complex formation to exhibit good stability once formed, as well to understand and correlate the binding strength and the interval between better association domains. The effect of pH and temperature on the interpolymeric complex formation between poly(aspartic acid) and Pluronic F127 was studied by combining rheology with light scattering technique. The solution mixtures between poly(aspartic acid) and Pluronic F127 are Newtonian fluids for all ratios among them. Depending on the polymeric mixture composition and experimental temperature, positive or negative deviations of the experimental values from the additive dependence appear. An interesting behavior was registered around 1/1 wt. ratio between the two polymers, when the hydrodynamic diameter of the interpenetrated polymeric particles decreased suddenly. This allows us to conclude the formation of core-shell micelle structure with poly(aspartic acid) core and Pluronic F127 as shell, performed through strong interactions between polymers. This behavior was sustained by the increase of absolute value of zeta potential owing to the decrease of functional groups number at the surface of micelles.

Upon some multi-membrane hydrogels based on poly(N,N-dimethyl-acrylamide-co-3,9-divinyl-2,4,8,10-tetraoxaspiro (5.5) undecane): preparation, characterization and in vivo tests.

The study presents the possibility of preparation of multi-membrane gel systems with different morphologies and properties, based on poly(N,N-dimethyl-acrylamide-co-3,9-divinyl-2,4,8,10-tetraoxaspiro (5.5) undecane) copolymer and crosslinked with N,N'-methylene-bis-acrylamide. The basic copolymer has dual thermo- and pH sensitive character. After the core hydrogel is realized, the preformed gel is immersed in the aqueous solutions of ammonia, sodium chloride and sodium citrate for further edge constructing of the supramolecular assemblies. Then, the new layers by adding new sets of gelifying components are realized. The new multi-membrane gel systems are intended to be used as matrix for bioactive substances embedding. In this context the systems were loaded with norfloxacin as drug model. The in vivo tests show good biocompatibility for the implants based on multi-membrane gel structures loaded with drug.

Multilayered structure based on poly(N,N-dimethyl-acrylamide-co-3,9-divinyl-2,4,8,10-tetraoxaspiro (5.5) undecane) prepared in a multiphase gelation process.

The study is devoted to the preparation of a multi-membrane gel system based on poly(N,N-dimethyl-acrylamide-co-3,9-divinyl-2,4,8,10-tetraoxaspiro (5.5) undecane) copolymer. The complex supra-structure was realized by layer by layer deposition technique, from the gel-core to the periphery by crosslinking poly(N,N-dimethyl-acrylamide-co-3,9-divinyl-2,4,8,10-tetraoxaspiro (5.5) undecane) (P(DMA-co-U)) with N,N'-methylene-bis-acrylamide and using as well ß-cyclodextrin with double purpose as compound for constructing further the edge of the interfacial supramolecular assemblies and to improve the host-guest complexation of further bioactive compounds. Basic copolymer has dual thermo- and pH sensitive character. The multi-membrane 'onion-like' gel system was tested as matrix for embedding Norfloxacin. Hematologic, biochemical, immunologic studies used to determine the biocompatibility of multi-membrane gel structures loaded with drug that directly contact living tissue provided a reasonable assessment of safety as implants. Histopathologic exams did not reveal any disturbances of the normal liver architecture in animals with multi-membrane gel system containing Norfloxacin compared to control group with sterile cotton pellets implant. Good biocompatibility for the implants based on multi-membrane gel structures loaded with drug were achieved from the in vivo tests these suggesting that biomaterials may be suitable for in vivo use as a local drug delivery system.

Characterization of the semi-interpenetrated network based on collagen and poly(N-isopropyl acrylamide-co-diethylene glycol diacrylate).

The study is devoted to the characterization of the semi-interpenetrating polymeric network (semi-IPN) structures, prepared as dual sensitive networks, based on poly(N-isopropyl acrylamide-co-diethylene glycol diacrylate) inserted into a collagen porous membrane with potential biomedical-applications. The pharmaceutical applications are related to the possibility of using the semi-synthetic networks for inclusion, retention, transportation and release of drug molecules. The insertion and the homogeneity distribution of the drug into the polymeric network were evaluated by near infrared-chemical imaging (NIR-CI) technique. The drug release was investigated from the kinetically viewpoint in simulated biological environment by using UV-vis spectrophotometric technique. The zeta potential measurement results showed meaningful change of the electric potential of the network surface at the interfacial double layer with the environment in the interdependence with the network composition and environment characteristics. The biodegradable character of the semi-synthetic network, also presented, undergoes with tissue engineering request for achievement of tissue substituents. Texture analysis of the semi-IPN was realized in order to evidence the potential applications of the prepared compounds in tissue engineering. The adhesion properties reveal the possibility to control the surface adhesion by: network composition, the ratio between the polymer types, and the crosslinking degree of polymeric networks. The evaluation of the semi-IPN characteristics in medical terms, concerned the surface electrical charge, the loading, retention and release properties of an active compound, the adhesion properties and the effect of collagenase enzyme over the collagen fibres as component in semi-IPN, and from the pharmaceutical terms emphasizes the potential applications of the new polymeric semi-IPN networks.

Synergistic behavior of poly(aspartic acid) and Pluronic F127 in aqueous solution as studied by viscometry and dynamic light scattering.

Pluronic F127/poly(aspartic acid) mixtures were investigated in dilute solutions by viscometry and dynamic light scattering. The two polymers were chosen due to well known applications in biomedical field, taking into account the final purpose (the use of the complex structure as drug delivery systems). The central item was to identify the possibility of complexation between the poly(carboxylic acid) and a non-ionic polymer and to investigate the conditions of the interpolymer complex formation. The ability of Pluronic F127 to form micelle is well known. Poly(aspartic acid), as a polycarboxylic acid with resemblance with polyacrylic acid, can act as dispersant, antiscalant, superabsorber, being also able to form micelles. Due to its functional groups, -COOH and -NH(2), poly(aspartic acid) can make physical and/or chemical bonds with other macromolecular compounds. The intrinsic viscosity and the dynamic light scattering data obtained for PLU/PAS mixtures at 25 °C have shown that interpolymer complex formation occurs around 1/1 wt. ratio between the two polymers.

Indomethacin-loaded polymer nanocarriers based on poly(2-hydroxyethyl methacrylate-co-3,9-divinyl-2,4,8,10-tetraoxaspiro (5.5) undecane): preparation, in vitro and in vivo evaluation.

The study is focused on the development of copolymers based on poly(2-hydroxyethyl methacrylate-co-3,9-divinyl-2,4,8,10-tetraoxaspiro [5.5]-undecane). The macromolecular compounds were synthesized by dispersion polymerization in the presence of the radical initiator 4,4'-azobis(cyanopentanoic acid) and using sodium lauryl sulfate as tensioactive compound and poly(aspartic acid) (PAS) as protective colloid. PAS presents biocompatibility and biodegradability, and assures the increase of the absorbent character for the new synthesized network, and also, can supplement the hydrogen bonds contributing to the stability of the achieved complexes. The prepared polymeric networks were characterized by FTIR, SEM, and thermogravimetric analyses. The dependence on the pH of the swelling degree equilibrium was also evaluated correlated also with different temperature values. The poly(2-hydroxyethyl methacrylate-co-3,9-divinyl-2,4,8,10-tetraoxaspiro [5.5]-undecane) copolymers were evaluated as matrix for indomethacin (INN) as model drug loaded onto these polymeric networks. The evaluation of the homogeneity distribution of the INN drug in polymeric network was made by near infrared chemical imaging (NIR-CI) and correspondingly statistical analysis. The pharmacokinetic profile was achieved performing the in vitro release of the INN drug from the polymeric network. The data resulted from the in vivo experimental studies, respectively the biocompatibility tests, somatic nociceptive experimental model (Tail flick test) and visceral nociceptive experimental model (Writhing test)-are also reported in the study.

Evaluation of the controlled release ability from the poly(2-hydroxyethyl methacrylate-co-3,9-divinyl-2,4,8,10-tetraoxaspiro[5.5]-undecane) polymer network synthesized in the presence of ß-cyclodextrin.

The study presents the possibility to use the 2-hydroxyethyl methacrylate--HEMA copolymer with a comonomer with spiroacetal moiety, 3,9-divinyl-2,4,8,10-tetraoxaspiro[5.5]-undecane)-U, as polymer network for loading the indomethacin--INN as drug model, and also, the controlled release evaluation of the prepared bioactive system. The macromolecular compounds were prepared by radical dispersion polymerization in the presence of a pair of surfactants. The use of cyclodextrin as surfactant allowed the building of the host-guest complexes by inclusion of hydrophobic molecules. Also, the cyclodextrin supplemented the hydrogen bonds and the hydrophobic interactions responsible for the stability of the achieved complexes. The copolymers composition and the INN inclusion onto the polymeric matrix were confirmed by FTIR analysis. The porous structure of the lyophilized P(HEMA-U) samples was illustrated by SEM images. The swelling studies evidenced the interdependence between P(HEMA-U) network properties and the spiroacetal moiety amount. Thus, the copolymers presented the increase of the equilibrium swelling degree with pH and temperature. Also, the polymeric matrices manifested dual sensitivity with pH and temperature. The in vitro release of the INN drug from the polymeric network as well as the in vivo experimental studies evidenced the benefit consequence of the spiroacetal compound presence. The clinical observation of the experimental groups does not show any behavioral modifications to suggest a possible toxic effect of these polymeric formulations with and without INN.

Indomethacin uptake into poly(2-hydroxyethyl methacrylate-co-3,9-divinyl-2,4,8,10-tetraoxaspiro [5.5]-undecane) network: In vitro and in vivo controlled release study.

Networks based on poly(2-hydroxyethyl methacrylate-co-3,9-divinyl-2,4,8,10-tetraoxaspiro [5.5]-undecane), synthesized through radical dispersion polymerization, were used as template for indomethacin (INN) as model drug. The copolymers were characterized by swelling studies at three pH values (2.4, 5.5 and 7.4) and two temperatures (room temperature 24 °C and physiological temperature 37 °C). Fourier transform infrared (FTIR) spectroscopic analysis was used to sustain the copolymer structures. Scanning electron microscopy (SEM) and thermogravimetric (TG) investigations were used to examine microstructure and appreciate the thermal stability of the polymer samples. The studies of the INN drug release from the copolymer networks were in vitro performed. The in vivo study results (biocompatibility tests, somatic nociceptive experimental model (tail flick test) and visceral nociceptive experimental model (writhing test)) are also reported in this paper.

Effect of emulsion polymerization and magnetic field on the adsorption of albumin on poly(methyl methacrylate)-based biomaterial surfaces.

The adsorption of bovine serum albumin (BSA) onto the surfaces of poly(methyl methacrylate) (PMMA) and of methyl methacrylate copolymer with 2,3-epoxypropyl methacrylate, it was investigated. The polymeric matrices were obtained through radical emulsion polymerization with and without the presence of a continuous external magnetic field (MF) of 1,500 Gs intensity. Two types of surfactant agents were used for polymers' synthesis: a classic one sodium lauryl sulphate (SLS) and beta-cyclodextrin (CD). The protein adsorption was conducted in the presence as well as in the absence of MF, by varying the coupling conditions, respectively, the temperature, pH and albumin/polymer ratio. The study underlines the assistance of MF during the adsorption process, materialized into growth of the BSA adsorbed quantity. Thus, MF presence during adsorption determines the doubling of the BSA adsorbed quantity onto the surface of polymers prepared in the MF. The adsorption process was also related to the tensioactive used for the synthesis of polymeric matrices. The higher content of the adsorbed BSA corresponds to the polymers with CD instead of SLS. The fact was attributed to the catalytic activity of the MF, which determines the molecules distortions, the growth of distance interactions and the modifications of the angles between bonds, with benefit effect upon adsorption.