Effect of pH on the Poly(acrylic acid)/Poly(vinyl alcohol)/Lysozyme Complexes Formation.

The interactions between poly(acrylic acid) (PAA), poly(vinyl alcohol) (PVA), and lysozyme (Lys) in an aqueous environment at pHs of 2, 4, and 7.4 were discussed considering the experimental data obtained by turbidimetry, electrokinetic and rheological measurements, and FTIR analysis. It was found that the increase in PAA amount reduces the coacervation zone by shifting the critical pHcr1to higher values while the critical pHcr2 remains unchanged. The coacervation zone extended from 3.1-4.2 to 2.9-4.7 increasing the Lys concentration from 0.2% to 0.5%. The zeta potential measurements showed that the PAA-PVA-Lys mixture in water is the most stable in the pH range of 4.5-8. Zero shear viscosity exhibited deviations from additivity at both investigated pHs, and a maximum value corresponding to a maximum hydrodynamic volume was revealed at PAA weight fractions of 0.4 and 0.5 for pHs of 4 and 7.4, respectively. The binding affinity to Lys of PAA, established by molecular dynamics simulation, was slightly higher than that of PVA. The more stable complex was PAA-Lys formed in a very acidic environment; for that, a binding affinity of -7.1 kcal/mol was determined.

Chitosan Derivatives in Macromolecular Co-assembly Nanogels with Potential for Biomedical Applications.

Maleoyl-chitosan/poly(aspartic acid) nanogels were developed and characterized in order to assess its suitability for biomedical applications. Thus, the physicochemical properties were investigated and correlated with the composition of the new structures. Dynamic light scattering measurements, correlated with transmission electron microscopy images, demonstrated that nanogels size distribution was narrow with average diameter between 186 and 246 nm, and presented positive zeta potential values. The sensitivity of nanogels at pH and temperature was also evaluated. Nanogels loaded with amoxicillin showed a controlled release profile dependent on nanogel content. The formulations loaded with amoxicillin had antibacterial properties, and the cytotoxicity tests indicated good in vivo biocompatibility. In conclusion, the new synthesized polyelectrolyte nanogels, which can provide a stable environment for the encapsulated drugs, can be used as a multifunctional platform for administration of antimicrobial agents from the spectrum of antibiotics that have a very poor biodistribution.

Design and applications of polymer-like peptides in biomedical nanogels.

INTRODUCTION: Polymer nanogels are among the most promising nanoplatforms for use in biomedical applications. The substantial interest for these drug carriers is to enhance the transportation of bioactive substances, reduce the side effects, and achieve optimal action on the curative sites by targeting delivery and triggering the release of the drugs in a controlled and continuous mode. AREA COVERED: The review discusses the opportunities, applications, and challenges of synthetic polypeptide nanogels in biomedicine, with an emphasis on the recent progress in cancer therapy. It is evidenced by the development of polypeptide nanogels for better controlled drug delivery and release, in complex in vivo microenvironments in biomedical applications. EXPERT OPINION: Polypeptide nanogels can be developed by choosing the amino acids from the peptide structure that are suitable for the type of application. Using a stimulus - sensitive peptide nanogel, it is possible to obtain the appropriate transport and release of the drug, as well as to achieve desirable therapeutic effects, including safety, specificity, and efficiency. The final system represents an innovative way for local and sustained drug delivery at a specific site of the body.

Study on cellulose nanofibrils/copolymacrolactone based nano-composites with hydrophobic behaviour, self-healing ability and antioxidant activity.

The multiple uses of cellulose nanofibrils (CNFs) originate from their availability from renewable resources, and are due to their physico-chemical properties, biodegradability and biocompatibility. At the same time, reducing sensitivity to humidity, increasing interfacial adhesion and hydrophobic modification of the CNF surface to diversify applications and improve operation, are current targets pursued. This study focuses on the preparation of a novel gel structure using cellulose nanofibrils (CNFs) and poly(ethylene brassylate-co-squaric acid) (PEBSA50/50), a bio-based copolymacrolactone. The primary goal is to achieve the gel with reduced sensitivity to humidity and enhanced hydrophobic behaviour. The new system was characterized in comparison to its constituent components using various techniques, such as Fourier transform infrared spectroscopy, thermal analysis, X-ray diffraction, and NIR - chemical imaging. Rheological tests demonstrated the formation of the CNF_PEBSA50/50 gel as a result of physical interactions between the two polymeric partners and revealed self-healing abilities for the prepared gels. Determination of the contact angle, surface free energy, as well as dynamic measurements of the vapour sorption of the CNF_PEBSA50/50 system, confirmed the achievement of the study's aim. Furthermore, the CNF_PEBSA50/50 network was utilized to encapsulate citric acid, resulting in the creation of a new bioactive composite with both antioxidant and antimicrobial activity.

Injectable Networks Based on a Hybrid Synthetic/Natural Polymer Gel and Self-Assembling Peptides Functioning as Reinforcing Fillers.

Double network (DN) hydrogels composed of self-assembling low-molecular-weight gelators and a hybrid polymer network are of particular interest for many emerging biomedical applications, such as tissue regeneration and drug delivery. The major benefits of these structures are their distinct mechanical properties as well as their ability to mimic the hierarchical features of the extracellular matrix. Herein, we describe a hybrid synthetic/natural polymer gel that acts as the initial network based on sodium alginate and a copolymer, namely poly(itaconic anhydride-co-3,9-divinyl-2,4,8,10-tetraoxaspiro (5,5) undecane). The addition of amino acids and peptide-derived hydrogelators, such as Fmoc-Lys-Fmoc-OH and Fmoc-Gly-Gly-Gly-OH, to the already-made network gives rise to DNs crosslinked via non-covalent interactions. Fourier transform infrared spectroscopy (FTIR) and thermal analysis confirmed the formation of the DN and highlighted the interactions between the two component networks. Swelling studies revealed that the materials have an excellent water absorption capacity and can be classified as superabsorbent gels. The rheological properties were systematically investigated in response to different variables and showed that the prepared materials present injectability and a self-healing ability. SEM analysis revealed a morphology consisting of a highly porous and interconnected fibrous network. Finally, the biocompatibility was evaluated using the MTT assay on dermal fibroblasts, and the results indicated that the new structures are non-toxic and potentially useful for biomedical applications.

Enzymatically-Crosslinked Gelatin Hydrogels with Nanostructured Architecture and Self-Healing Performance for Potential Use as Wound Dressings.

Development of natural protein-based hydrogels with self-healing performance and tunable physical properties has attracted increased attention owing to their wide potential not only in the pharmaceutical field, but also in wounds management. This work reports the development of a versatile hydrogel based on enzymatically-crosslinked gelatin and nanogels loaded with amoxicillin (Amox), an antibiotic used in wound infections. The transglutaminase (TGase)-crosslinked hydrogels and encapsulating nanogels were formed rapidly through enzymatic crosslinking and self-assembly interactions in mild conditions. The nanogels formed through the self-assemble of maleoyl-chitosan (MAC5) and polyaspartic acid (PAS) may have positive influence on the self-healing capacity and drug distribution within the hydrogel network through the interactions established between gelatin and gel-like nanocarriers. The physicochemical properties of the enzymatically-crosslinked hydrogels, such as internal structure, swelling and degradation behavior, were studied. In addition, the Amox release studies indicated a rapid release when the pH of the medium decreased, which represents a favorable characteristic for use in the healing of infected wounds. It was further observed through the in vitro and in vivo biocompatibility assays that the optimized scaffolds have great potential to be used as wound dressings.

New Hydrogels Based on Agarose/Phytagel and Peptides.

Short aromatic peptide derivatives, i.e., peptides or amino acids modified with aromatic groups, such as 9-fluorenylmethoxycarbonyl (Fmoc), can self-assemble into extracellular matrix-like hydrogels due to their nanofibrillar architecture. Among different types of amino acids, lysine (Lys) and glycine (Gly) are involved in multiple physiological processes, being key factors in the proper growth of cells, carnitine production, and collagen formation. The authors have previously successfully presented the possibility of obtaining supramolecular gels based on Fmoc-Lys-Fmoc and short peptides such as Fmoc-Gly-Gly-Gly in order to use them as a substrate for cell cultures. This paper investigates how the introduction of a gelling polymer can influence the properties of the network as well as the compatibility of the resulting materials with different cell types. A series of hydrogel compositions consisting of combinations of Fmoc-Lys-Fmoc and Fmoc-Gly-Gly-Gly with Agarose and Phytagel are thus obtained. All compositions form structured gels as shown by rheological studies and scanning electron microscopy. Fourier transform infrared spectroscopy analysis evidences the formation of H-bonds between the polysaccharides and amino acids or short peptides. Moreover, all gels exhibit good cell viability on fibroblasts as demonstrated by a live-dead staining test and good in vivo biocompatibility, which highlights the great potential of these biomaterials for biomedical applications.

Cryogel System Based on Poly(vinyl alcohol)/Poly(ethylene brassylate-co-squaric acid) Platform with Dual Bioactive Activity.

The inability to meet and ensure as many requirements as possible is fully justified by the continuous interest in obtaining new multifunctional materials. A new cryogel system based on poly(vinyl alcohol) (PVA) and poly(ethylene brassylate-co-squaric acid) (PEBSA) obtained by repeated freeze-thaw processes was previously reported and used for the incorporation of an antibacterial essential oil-namely, thymol (Thy). Furthermore, the present study aims to confer antioxidant properties to the PVA/PEBSA_Thy system by encapsulating α-tocopherol (α-Tcp), targeting a double therapeutic effect due to the presence of both bioactive compounds. The amphiphilic nature of the PEBSA copolymer allowed for the encapsulation of both Thy and α-Tcp, via an in situ entrapment method. The new PVA/PEBSA_Thy_α-Tcp systems were characterized in terms of their influence on the composition, network morphology and release profiles, as well as their antimicrobial and antioxidant properties. The study underlined the cumulative antioxidant efficiency of Thy and α-Tcp, which in combination with the PEBSA copolymer have a synergistic effect (97.1%). We believe that the convenient and simple strategy offered in this study increases applicability for these new PVA/PEBSA_Thy_α-Tcp cryogel systems.

Thermosensitive Polyurethane-Based Hydrogels as Potential Vehicles for Meloxicam Delivery.

Meloxicam (MX) is a nonsteroidal anti-inflammatory drug (NSAID) used mainly to reduce pain, inflammation, and fever. In the present study, thermosensitive polyurethane (PU)-based hydrogels with various excipients (PEG, PVP, HPC, and essential oil) were prepared and loaded with MX. Rheological investigations were carried out on the PU-based formulations in various shear regimes, and their viscoelastic characteristics were determined. The average size of the PU micelles was 35.8 nm at 37 °C and slightly increased at 37 nm in the presence of MX. The zeta potential values of the hydrogels were between -10 mV and -11.5 mV. At pH = 6 and temperature of 37 °C, the formulated PU-based hydrogels loaded with MX could deliver significant amounts of the active substance, between 60% and 80% over 24-48 h and more than 90% within 2 weeks. It was found that anomalous transport phenomena dominated MX's release mechanism from the PU-based networks. The results are encouraging for further studies aiming to design alternative carriers to commercial dosage forms of nonsteroidal anti-inflammatory drugs.

Bioactive Composite Cryogels Based on Poly (Vinyl Alcohol) and a Polymacrolactone as Tissue Engineering Scaffolds: In Vitro and In Vivo Studies.

In light of the increasing resistance of pathogenic microorganisms to the action of antibiotics, essential oils extracted from plants with therapeutic activity provide a significant alternative to obtaining dressings for the treatment of skin wounds. The encapsulation of essential oils in an amphiphilic gel network allows better dispersion and preservation of hydrophobic bioactive substances while promoting their prolonged release. In this study, we focused on the development of a poly (vinyl alcohol) (PVA)/poly (ethylene brassylate-co-squaric acid) (PEBSA) platform embedded with thymol (Thy), and α-tocopherol (α-Tcp) as a co-drug structure with prospective use for the treatment and healing of skin wounds. The new complex bioactive system was prepared through repeated freeze-thaw processes. The influence of the composition on surface topography, hydrophilic/hydrophobic character, and in vitro interaction with simulated body fluids was evidenced. BALB/3T3 fibroblast cell culture demonstrated the cryogel scaffolds' cytocompatibility. Tests on Wistar rats confirmed their biocompatibility, integration with host tissue, and the absence of inflammatory processes. The bioactive compound significantly enhanced the healing process of full-thickness excision wounds in a rat model. Further investigations on in vivo infection models would assess the potential of the PVA/PEBSA platform with dual bioactive activity for clinical antimicrobial and wound healing therapy.

Synthesis and Comparative Studies of Glucose Oxidase Immobilized on Fe3O4 Magnetic Nanoparticles Using Different Coupling Agents.

Squaric acid (SA) is a compound with potential to crosslink biomacromolecules. Although SA has become over the last years a well-known crosslinking agent as a result of its good biocompatibility, glutaraldehyde (GA), a compound with proven cytotoxicity is still one of the most used crosslinkers to develop nanomaterials. In this regard, the novelty of the present study consists in determining whether it may be possible to substitute GA with a new bifunctional and biocompatible compound, such as SA, in the process of enzyme immobilization on the surface of magnetic nanoparticles (MNPs). Thus, a direct comparison between SA- and GA-functionalized magnetic nanoparticles was realized in terms of physico-chemical properties and ability to immobilize catalytic enzymes. The optimal conditions of the synthesis of the two types of GOx-immobilized MNPs were described, thus emphasizing the difference between the two reagents. Scanning Electron Microscopy and Dynamic Light Scattering were used for size, shape and colloidal stability characterization of the pristine MNPs and of those coupled with GOx. Binding of GOx to MNPs by using GA or SA was confirmed by FT-IR spectroscopy. The stability of the immobilized and free enzyme was investigated by measuring the enzymatic activity. The study confirmed that the resulting activity of the immobilized enzyme and the optimization of enzyme immobilization depended on the type of reagent used and duration of the process. The catalytic performance of immobilized enzyme was tested, revealing that the long-term colloidal stability of SA-functionalized MNPs was superior to those prepared with GA. In conclusion, the SA-functionalized bioconjugates have a better potential as compared to the GA-modified nanosystems to be regarded as catalytic nanodevices for biomedical purposes such as biosensors.

New Fmoc-Amino Acids/Peptides-Based Supramolecular Gels Obtained through Co-Assembly Process: Preparation and Characterization.

One of the methods of obtaining supramolecular gels consists of the possibility of self-assembly of low molecular weight gelators (LMWGs). However, LMWG-based gels are often difficult to handle, easy to destroy and have poor rheological performance. In order to improve the gels' properties, the LMWGs molecules are co-assembled, which induces more cross-links with more stable structures. Starting from these aspects, the present study refers to the preparation of a bionic hydrogel stabilized with a physiologically occurring, bifunctional biomolecule, L-lysine, co-assembled with other amino acids or peptides (such as a modified amino acid (Fmoc-serine or Fmoc-glutamic acid) or a tripeptide (Fmoc-Gly-Gly-Gly)) with the potential to support the repair of injuries or the age-related impaired structures or functions of living tissues. The introduction of a copartner aims to improve hydrogel characteristics from a morphological, rheological and structural point of view. On the other hand, the process will allow the understanding of the phenomenon of specific self-association and molecular recognition. Various characterization techniques were used to assess the ability to co-assemble: DLS, FT-IR, SEM and fluorescence microscopy, rheology and thermal analysis. Studies have confirmed that the supramolecular structure occurs through the formation of inter- and intramolecular physical bonds that ensure the formation of fibrils organized into 3D networks. The rheological data, namely the G' > G″ and tan δ approximately 0.1−0.2 gel-like behavior observed for all studied samples, demonstrate and sustain the appearance of the co-assembly processes and the ability of the samples to act as LMWG. From the studied systems, the Fmoc−Lys−Fmoc_ Fmoc−Glu sample presented the best rheological characteristics that are consistent with the observations that resulted from the dichroism, fluorescence and SEM investigations.

New Cryogels Based on Poly(vinyl alcohol) and a Copolymacrolactone System: I-Synthesis and Characterization.

Physical cryogels were obtained using the successive freeze-thaw technique of poly(vinyl alcohol) (PVA)/poly(ethylene brassylate-co-squaric acid) (PEBSA) solutions. The cryogel systems were prepared by using two different molecular weights of PVA and PEBSA with three different ratios between the ethylene brassylate (EB) and squaric acid (SA) comonomers. The presence of interactions, the thermal properties and the morphology were investigated using Fourier Transform Infrared Spectroscopy (FT-IR), thermogravimetry (TGA and DTG) and scanning electron microscopy (SEM), respectively. The influence of the composition on the degree of swelling in a physiological environment was demonstrated. The study highlighted improvements in terms of new network flexibility due to the intermolecular chains interactions brought by the introduction of PEBSA in the cryogel structure. We also concluded that the presence of PEBSA in the PVA/PEBSA cryogel network improved the loading capacity of the new system with specific hydrophobic agents, for example essential oils, which (due to their antimicrobial character) can lead to the use of new systems obtained for various applications.

Structural Characterization of a New Collagen Biomimetic Octapeptide with Nanoscale Self-Assembly Potential: Experimental and Theoretical Approaches.

Bioinspired peptides are attractive biomolecules which can improve our understanding of self-assembly processes for rational design of new peptide-based materials. Herein, a new amidated peptide FRSAPFIE (FRS), based on a sequence present in human collagen, was synthesized, characterized by mass spectrometry and subjected to self-assembling investigations. The optimal conditions for self-assembly were disclosed by dynamic light scattering at 32 °C and a peptide concentration of 0.51 %. In addition, AFM studies revealed ellipsoidal FRS shapes with an area between 0.8 and 3.1 µm2 . The ability of self-assembly was also proved using FAD dye as extrinsic fluorescence reporter. According to the theoretical analysis, the FRS peptide tends to form a bundle-type association, with a type of fibrillary tangles particle. Altogether, our findings address new challenges regarding the FRS peptide which can be used in further self-assembly studies to design biocompatible drug-delivery platforms.

Development of a new polymer network system carrier of essential oils.

The study presents the development of a new copolymacrolactone structure based on ethylene brassylate (EB) and squaric acid (SA) with different ratios between comonomers. The new system was tested as a network for essential oils encapsulation. The structure of the copolymers was confirmed by spectroscopic investigations and correlated in interdependence with the comonomers content. The interfacial characteristics of the poly(ethylene brassylate-co-squaric acid) copolymers were determined, and the transition from a moderate hydrophilic surface towards a hydrophobic region by increasing the molar content of SA comonomer was highlighted. The affinity for hydrophobic substances of the synthesised macromolecular compounds was used in a process of encapsulation of thymol (Thy) and carvacrol (CC). The newly prepared bioactive compounds were characterised by in vivo biocompatibility tests, and antimicrobial activity, Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC).

Preparation of an Antioxidant Assembly Based on a Copolymacrolactone Structure and Erythritol following an Eco-Friendly Strategy.

The study presents the achievement of a new assembly with antioxidant behaviour based on a copolymacrolactone structure that encapsulates erythritol (Eryt). Poly(ethylene brassylate-co-squaric acid) (PEBSA) was synthesised in environmentally friendly conditions, respectively, through a process in suspension in water by opening the cycle of ethylene brassylate macrolactone, followed by condensation with squaric acid. The compound synthesised in suspension was characterised by comparison with the polymer obtained by polymerisation in solution. The investigations revealed that, with the exception of the molecular masses, the compounds generated by the two synthetic procedures present similar properties, including good thermal stability, with a Tpeak of 456 °C, and the capacity for network formation. In addition, the investigation by dynamic light scattering techniques evidenced a mean diameter for PEBSA particles of around 596 nm and a zeta potential of -25 mV, which attests to their stability. The bio-based copolymacrolactone was used as a matrix for erythritol encapsulation. The new PEBSA-Eryt compound presented an increased sorption/desorption process, compared with the PEBSA matrix, and a crystalline morphology confirmed by X-ray diffraction analysis. The bioactive compound was also characterised in terms of its biocompatibility and antioxidant behaviour.

One-Step Preparation of Carboxymethyl Cellulose-Phytic Acid Hydrogels with Potential for Biomedical Applications.

Hydrogels based on natural, biodegradable materials have gained considerable interest in the medical field due to their improved drug delivery profiles and tissue-mimicking architecture. In this regard, this study was devoted to the preparation and characterization of new physically crosslinked hydrogels based on carboxymethyl cellulose and an unconventional crosslinking agent, phytic acid. Phytic acid, in addition to its antioxidant and antibacterial effects, can improve the biological properties and stability of gels, without adding toxicity. Fourier transform infrared (FTIR) spectroscopy, rheological studies and thermal analysis confirmed the hydrogel formation. The influence of the ratio between the cellulose derivative and the crosslinker upon the morphological structure and water uptake was evidenced by scanning electron microscopy (SEM) and swelling measurements in simulated body fluids. Furthermore, procaine was entrapped within the hydrogels and used as a model drug for in vitro studies, which highlighted the dependence of the drug release on the phytic acid content of the matrix. The materials demonstrated antibacterial effects against Escherichia coli and Staphylococcus aureus bacteria. The biocompatibility was assessed on fibroblast cells, and according to our results, hydrogels can improve cell viability highlighting the potential of these systems as therapeutic scaffolds for skin tissue engineering.

Alginate enriched with phytic acid for hydrogels preparation.

Alginate hydrogels are extremely versatile and flexible biomaterials, with an enormous potential for bio-applications use. Their similarity with extracellular matrix is a key factor in their performance for cell and tissue regeneration. In this study superabsorbent high porous hydrogels based on sodium alginate physical crosslinked with a natural crosslinker compound namely phytic acid were prepared and evaluated from the viewpoint of their specific properties. The resulting hydrogels obtained with different ratios between alginate and phytic acid were characterized by Fourier transform infrared spectroscopy technique, scanning electron microscopy, XRD measurements, swelling tests in physiological environment, and thermal analysis by using a simultaneous TG/FT-IR/MS system. There are put into evidence the differences in physico-chemical properties of the hydrogels in relation with their composition, which endows them tunable properties and versatility.

New Hydrogel Network Based on Alginate and a Spiroacetal Copolymer.

This study reports a strategy for developing a biohybrid complex based on a natural/synthetic polymer conjugate as a gel-type structure. Coupling synthetic polymers with natural compounds represents an important approach to generating gels with superior properties and with potential for biomedical applications. The study presents the preparation of hybrid gels with tunable characteristics by using a spiroacetal polymer and alginate as co-partners in different ratios. The new network formation was tested, and the structure was confirmed by FTIR and SEM techniques. The physical properties of the new gels, namely their thermal stability and swelling behavior, were investigated. The study showed that the increase in alginate content caused a smooth increase in thermal stability due to the additional crosslinking bridges that appeared. Moreover, increasing the content of the synthetic polymer in the structure of the gel network ensures a slower release of carvacrol, the encapsulated bioactive compound.

Alginate enriched with phytic acid for hydrogels preparation. Therapeutic applications.

In the last decade, numerous innovative strategies have been used to obtain highly efficient synthetic or semi-synthetic biomaterials. Between these innovative biomaterials, hydrogels occupy a distinct place due to their superior biological and physico-chemical characteristics. Alginate is a natural linear polysaccharide with important physico-chemical and biological properties. Recently, we obtained a new hydrogel based on alginate and phytic acid with improved physico-chemical properties. In the present study, the hydrogels previously obtained were tested in terms of their biological properties and possibilities of use in the biomedical field. For this purpose, the hydrogels were loaded with norfloxacin (NRF), an antibacterial compound utilised in the treatment against Gram-negative and Gram-positive organisms. Unfortunately, NRF has low solubility and permeability. In order to provide protection against loss, but also for enhanced bioavailability, and controlled-release of norfloxacin, a drug inclusion complex with cyclodextrin was realized. The effect of complexation on the release profile was highlighted. The addition of NRF to the hydrogel matrices greatly improved the antibacterial activity of the tested compounds. The presence of CD did not affect the homogeneity of the drug distribution. Changes in the polymeric matrix structure were registered after the incorporation of the drug, which were attributed to the relaxation of the network subsequently to the penetration and diffusion of the drug solution simultaneously with the swelling process. The release of NRF from Alg_PA polymeric network has been successfully modulated by the use of CD as a host molecule.