From Supramolecular Hydrogels to Multifunctional Carriers for Biologically Active Substances

Supramolecular hydrogels are 3D, elastic, water-swelled materials that are held together by reversible, non-covalent interactions, such as hydrogen bonds, hydrophobic, ionic, host–guest interactions, and metal–ligand coordination. These interactions determine the hydrogels’ unique properties: mechanical strength; stretchability; injectability; ability to self-heal; shear-thinning; and sensitivity to stimuli, e.g., pH, temperature, the presence of ions, and other chemical substances. For this reason, supramolecular hydrogels have attracted considerable attention as carriers for active substance delivery systems. In this paper, we focused on the various types of non-covalent interactions. The hydrogen bonds, hydrophobic, ionic, coordination, and host–guest interactions between hydrogel components have been described. We also provided an overview of the recent studies on supramolecular hydrogel applications, such as cancer therapy, anti-inflammatory gels, antimicrobial activity, controlled gene drug delivery, and tissue engineering.     

Recent Progress in Biopolymer-Based Hydrogel Materials for Biomedical Applications

Hydrogels from biopolymers are readily synthesized, can possess various characteristics for different applications, and have been widely used in biomedicine to help with patient treatments and outcomes. Polysaccharides, polypeptides, and nucleic acids can be produced into hydrogels, each for unique purposes depending on their qualities. Examples of polypeptide hydrogels include collagen, gelatin, and elastin, and polysaccharide hydrogels include alginate, cellulose, and glycosaminoglycan. Many different theories have been formulated to research hydrogels, which include Flory-Rehner theory, Rubber Elasticity Theory, and the calculation of porosity and pore size. All these theories take into consideration enthalpy, entropy, and other thermodynamic variables so that the structure and pore sizes of hydrogels can be formulated. Hydrogels can be fabricated in a straightforward process using a homogeneous mixture of different chemicals, depending on the intended purpose of the gel. Different types of hydrogels exist which include pH-sensitive gels, thermogels, electro-sensitive gels, and light-sensitive gels and each has its unique biomedical applications including structural capabilities, regenerative repair, or drug delivery. Major biopolymer-based hydrogels used for cell delivery include encapsulated skeletal muscle cells, osteochondral muscle cells, and stem cells being delivered to desired locations for tissue regeneration. Some examples of hydrogels used for drug and biomolecule delivery include insulin encapsulated hydrogels and hydrogels that encompass cancer drugs for desired controlled release. This review summarizes these newly developed biopolymer-based hydrogel materials that have been mainly made since 2015 and have shown to work and present more avenues for advanced medical applications.     

Synthesis and Self-Assembly Properties of Bola-Amphiphilic Glycosylated Lipopeptide-Type Supramolecular Hydrogels Showing Colour Changes Along with Gel–Sol Transition

Supramolecular hydrogels formed by self-assembly of low-molecular-weight amphiphiles (hydrogelators) have attracted significant attention, as smart and soft materials. However, most of the observed stimuli-responsive behaviour of these supramolecular hydrogels are limited to gel–sol transitions. In this study, we present bola-amphiphilic glycosylated lipopeptide-type supramolecular hydrogelators that exhibit reversible thermochromism along with a gel–sol transition. The bola-amphiphiles have mono-, di-, tri- or tetra-phenylalanine (F) as a short peptide moiety. We investigate and discuss the effects of the number of F residues on the gelation ability and the morphology of the self-assembled nanostructures.     

Printable Hydrogels Based on Alginate and Halloysite Nanotubes

The design of hydrogels for the controlled release of active species is an attractive challenge. In this work, we prepared hybrid hydrogels composed of halloysite nanotubes as the inorganic component, and alginate as the organic counterpart. The reported procedure allowed us to provide the resulting materials with a peculiar wire-like shape. Both optical and scanning electron microscopy were used to characterize the morphological properties of the hydrogel wires, whose diameters were ca. 0.19 and 0.47 mm, respectively. The possibility to be exploited as drug delivery systems was carried out by loading the nanoclay with salicylic acid and by studying the release profiles. Thermogravimetric experiments showed that the amount of encapsulated drug was 4.35 wt%, and the salicylic acid was thermally stabilized after the loading into the nanotubes, as observed by the shift of the degradation peak in the differential thermograms from 193 to 267 °C. The kinetics investigation was conducted using UV–Vis spectrophotometry, and it exhibited the profound effects of both the morphology and dimensions on the release of the drugs. In particular, the release of 50% of the payload occurred in 6 and 10 h for the filiform hydrogels, and it was slower compared to the bare drug-loaded halloysite, which occurred in 2 h. Finally, an induction period of 2 h was observed in the release profile from the thicker sample.     

Supramolecular Bioconjugates for Protein and Small Drug Delivery

Supramolecular conjugation techniques have been developed to produce novel nanosized systems by assembling materials with diverse physicochemical and biological features. These techniques have been adapted to obtain innovative bioconjugates to deliver drugs with poor biopharmaceutical properties and nano-devices with potential “theranostic” activity. Supramolecular drug delivery systems include polymer therapeutics such as drug–polymer bioconjugates, and colloidal carriers such as micelles, liposomes, polyplexes, and organic and inorganic nanoparticles. By virtue of their wide array of chemical composition and properties, polymers represent key elements for the construction of novel supramoelcular formulations. Polymer bioconjugation is a fledged technique for fabrication of protein–polymer conjugates. PEGylation, in particular, produces derivatives with enhanced pharmacokinetic, immunological, and stability properties as compared to the parent protein. Over the years, new methods have been set up to obtain site-directed polymer conjugation. In this review we report few grafting to and growing from PEGylation examples for the preparation of therapeutically effective protein bioconjugates. Supramolecular formulations with unique properties can be also obtained by assembling functional polymers, targeting agents, physicochemical modifiers, and biomodulators. These systems may be designed for disease tissue disposition and cell recognition/penetration. Cyclodextrins, for example, have been functionalized with polyethylene glycol and folic acid to produce tumor-targeted drug carriers. Interesting results have been obtained with this novel class of drug delivery systems. In addition, responsive polymers have been conjugated to gold nanoparticles to endow a new colloidal platform with triggerable cell disposition properties, which can be exploited either in biomedicine or diagnosis.     

Development and Characterization of Highly Stable Silver NanoParticles as Novel Potential Antimicrobial Agents for Wound Healing Hydrogels

Recurrent microbial infections are a major cause of surgical failure and morbidity. Wound healing strategies based on hydrogels have been proposed to provide at once a barrier against pathogen microbial colonization, as well as a favorable environment for tissue repair. Nevertheless, most biocompatible hydrogel materials are more bacteriostatic than antimicrobial materials, and lack specific action against pathogens. Silver-loaded polymeric nanocomposites have efficient and selective activity against pathogenic organisms exploitable for wound healing. However, the loading of metallic nanostructures into hydrogels represents a major challenge due to the low stability of metal colloids in aqueous environments. In this context, the aim of the present study was the development of highly stable silver nanoparticles (AgNPs) as novel potential antimicrobial agents for hyaluronic acids hydrogels. Two candidate stabilizing agents obtained from natural and renewable sources, namely cellulose nanocrystals and ulvan polysaccharide, were exploited to ensure high stability of the silver colloid. Both stabilizing agents possess inherent bioactivity and biocompatibility, as well as the ability to stabilize metal nanostructures thanks to their supramolecular structures. Silver nitrate reduction through sodium borohydride in presence of the selected stabilizing agents was adopted as a model strategy to achieve AgNPs with narrow size distribution. Optimized AgNPs stabilized with the two investigated polysaccharides demonstrated high stability in phosphate buffer saline solution and strong antimicrobial activity. Loading of the developed AgNPs into photocrosslinked methacrylated hyaluronic acid hydrogels was also investigated for the first time as an effective strategy to develop novel antimicrobial wound dressing materials.     

Development and Characterization of Gentamicin-Loaded Arabinoxylan-Sodium Alginate Films as Antibacterial Wound Dressing

Biopolymer-based antibacterial films are attractive materials for wound dressing application because they possess chemical, mechanical, exudate absorption, drug delivery, antibacterial, and biocompatible properties required to support wound healing. Herein, we fabricated and characterized films composed of arabinoxylan (AX) and sodium alginate (SA) loaded with gentamicin sulfate (GS) for application as a wound dressing. The FTIR, XRD, and thermal analyses show that AX, SA, and GS interacted through hydrogen bonding and were thermally stable. The AXSA film displays desirable wound dressing characteristics: transparency, uniform thickness, smooth surface morphology, tensile strength similar to human skin, mild water/exudate uptake capacity, water transmission rate suitable for wound dressing, and excellent cytocompatibility. In Franz diffusion release studies, >80% GS was released from AXSA films in two phases in 24 h following the Fickian diffusion mechanism. In disk diffusion assay, the AXSA films demonstrated excellent antibacterial effect against E.coli, S. aureus, and P. aeruginosa. Overall, the findings suggest that GS-loaded AXSA films hold potential for further development as antibacterial wound dressing material.     

Graphene Oxide Hybrid Supramolecular Hydrogels with Self‐Healable,Bioadhesive and Stimuli‐Responsive Properties and Drug Delivery Application

Self‐healable hydrogels are promising soft materials with great potential in biomedical applications due to their autonomous self‐repairing capability. Although many attempts are made to develop new hydrogels with good self‐healing performance, to integrate this characteristic along with other responsive multifunctions into one hydrogel still remains difficult. Here, a self‐healable hybrid supramolecular hydrogel (HSH) with tunable bioadhesive and stimuli‐responsive properties is reported. The strategy is imparting graphene oxide (GO) nanosheets and quadruple hydrogen bonding ureido‐pyrimidinone (UPy) moieties into a thermoresponsive poly(N‐isopropylacrylamide) (PNIPAM) polymer matrix. The obtained GO–HSH hydrogel shows rapid self‐healing behavior and good adhesion to various surfaces from synthetic materials to biological tissue. In addition, doxorubicin hydrochloride (DOX) release profiles reveal the dual thermo‐ and pH‐responsiveness of the GO–HSH hydrogel. The DOX‐loaded hydrogel can further directly adhere to titanium substrate, and the released DOX from this thin hydrogel coating remains biologically active and has high capability to kill tumor cells.     

Enzyme-Responsive Hydrogels as Potential Drug Delivery Systems—State of Knowledge and Future Prospects

Fast advances in polymer science have provided new hydrogels for applications in drug delivery. Among modern drug formulations, polymeric type stimuli-responsive hydrogels (SRHs), also called smart hydrogels, deserve special attention as they revealed to be a promising tool useful for a variety of pharmaceutical and biomedical applications. In fact, the basic feature of these systems is the ability to change their mechanical properties, swelling ability, hydrophilicity, or bioactive molecules permeability, which are influenced by various stimuli, particularly enzymes. Indeed, among a great number of SHRs, enzyme-responsive hydrogels (ERHs) gain much interest as they possess several potential biomedical applications (e.g., in controlled release, drug delivery, etc.). Such a new type of SHRs directly respond to many different enzymes even under mild conditions. Therefore, they show either reversible or irreversible enzyme-induced changes both in chemical and physical properties. This article reviews the state-of-the art in ERHs designed for controlled drug delivery systems (DDSs). Principal enzymes used for biomedical hydrogel preparation were presented and different ERHs were further characterized focusing mainly on glucose oxidase-, β-galactosidase- and metalloproteinases-based catalyzed reactions. Additionally, strategies employed to produce ERHs were described. The current state of knowledge and the discussion were made on successful applications and prospects for further development of effective methods used to obtain ERH as DDSs.     

Bioactive Carboxymethyl Starch-Based Hydrogels Decorated with CuO Nanoparticles: Antioxidant and Antimicrobial Properties and Accelerated Wound Healing In Vivo

In this study, nanocomposite hydrogels composed of sodium carboxymethylated starch (CMS)-containing CuO nanoparticles (CMS@CuO) were synthesized and used as experimental wound healing materials. The hydrogels were fabricated by a solution-casting technique using citric acid as a crosslinking agent. They were characterized by Fourier-transform infrared spectroscopy (FTIR), energy-dispersive X-ray spectroscopy (EDS), X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM), and thermogravimetric analysis (TGA) to evaluate their physicochemical properties. In addition, swelling, antibacterial activities, antioxidant activities, cytotoxicity, and in vivo wound healing were investigated to evaluate the wound healing potential of the CMS@CuO nanocomposite hydrogels. Growth inhibition of the Gram-positive and Gram-negative pathogens, antioxidant activity, and swelling were observed in the CMS@CuO nanocomposite hydrogels containing 2 wt.% and 4 wt.% CuO nanoparticles. The hydrogel containing 2 wt.% CuO nanoparticles displayed low toxicity to human fibroblasts and exhibited good biocompatibility. Wounds created in rats and treated with the CMS@2%CuO nanocomposite hydrogel healed within 13 days, whereas wounds were still present when treated for the same time-period with CMS only. The impact of antibacterial and antioxidant activities on accelerating wound healing could be ascribed to the antibacterial and antioxidant activities of the nanocomposite hydrogel. Incorporation of CuO nanoparticles in the hydrogel improved its antibacterial properties, antioxidant activity, and degree of swelling. The present nanocomposite hydrogel has the potential to be used clinically as a novel wound healing material.     

Hydrogels Based on 2-Hydroxyethylmethacrylate and Chitosan: Preparation,Swelling Behavior,and Drug Delivery

The authors report preparation of chitosan by deacetylation of chitin extracted from shrimp shells. The quality of chitosan depended on the chemical extraction process, the concentration of chemicals used, soaking time, sequence of deproteination, decalcification, and deacetylation. Hydrogels composed of hydroxyethylmethacrylate and chitosan were subsequently prepared and their swelling and ibuprofen delivery kinetics at various chitosan concentrations were studied. The swelling properties of the network varied with the chitosan concentration. Furthermore, the swelling process followed second-order kinetics, while ibuprofen diffusion into the hydrogel showed Fickian behavior.     

The Potential of Polyelectrolyte Multilayer Films as Drug Delivery Materials

Polyelectrolyte multilayers (PEMs) represent a group of polyelectrolyte complex (PEC)–based materials widely investigated in the biomedical and pharmaceutical sciences. Despite the unflagging popularity of the aforementioned systems in tissue engineering, only a few updated scientific reports concerning PEM potential in drug administration can be found. In fact, PEM coatings are currently recognized as important tools for functionalizing implantable scaffolds; however, only a small amount of attention has been given to PEMs as drug delivery materials. Scientific reports on PEMs reveal two dominant reasons for the limited usability of multilayers in pharmaceutical technology: complex and expensive preparation techniques as well as high sensitivity of interacting polyelectrolytes to the varieties of internal and external factors. The aim of this work was to analyze the latest approaches, concerning the potential of PEMs in pharmacy, chemical technology, and (primarily) tissue engineering, with special attention given to possible polymer combinations, technological parameters, and physicochemical characteristics, such as hydrophilicity, adhesive and swelling properties, and internal/external structures of the systems formed. Careful recognition of the above factors is crucial in the development of PEM-based drug delivery materials.     

Chitosan hydrogel loaded with Aloe vera gel and tetrasodium ethylenediaminetetraacetic acid (EDTA) as the wound healing material: in vitro and in vivo study

The main aim of the current study was to develop a chitosan hydrogel containing Aloe vera gel and Ethylenediaminetetraacetic acid (EDTA) as the wound healing materials. Chitosan with the concentration of (2% w/v) was prepared in AA (0.5%, v/v) and Tetrasodium EDTA (0.01% w/w) and AV (0.5% v/v) were added to the prepared polymer solution. As prepared solution was cross-linked by β-GP with the weight ratio of 1/6 w/w (1 chitosan and 6 β-GP). The characterization of the hydrogels showed that the hydrogels have porous structures and interconnected pores with the pores size range from 41.5 ± 14 to 48.3 ± 11 μm. The swelling and weight loss measurements of the hydrogels showed that the hydrogels could swell up to 240% of their initial weight during 8 h and loss 79.7 ± 3.5% of the initial weight during 14 days. The antibacterial studies depicted that the prepared Cs/tEDTA/AV hydrogel inhibited the growth of Staphylococcus aureus (the minimum inhibition concentration, MIC of 73 ± 4.8) and Pseudomonas aeruginosa (the MIC of 40 ± 7.9). Moreover, the prepared hydrogels were hemocompatible (Cs/tEDTA/AV: OD of 0.24 ± 0.30) and biocompatible (Cs/tEDTA/AV: OD of 0.38 ± 0.01). At the final stage, the wound healing assessments in the animal model revealed that the application of the prepared hydrogels effectively enhanced the wound healing process. In conclusion, the results confirmed the efficacy of the prepared hydrogels as the wound healing materials.     

Novel Chitosan-Silica Hybrid Hydrogels for Cell Encapsulation and Drug Delivery

Hydrogels constructed from naturally derived polymers provide an aqueous environment that encourages cell growth, however, mechanical properties are poor and degradation can be difficult to predict. Whilst, synthetic hydrogels exhibit some improved mechanical properties, these materials lack biochemical cues for cells growing and have limited biodegradation. To produce hydrogels that support 3D cell cultures to form tissue mimics, materials must exhibit appropriate biological and mechanical properties. In this study, novel organic-inorganic hybrid hydrogels based on chitosan and silica were prepared using the sol-gel technique. The chemical, physical and biological properties of the hydrogels were assessed. Statistical analysis was performed using One-Way ANOVAs and independent-sample t-tests. Fourier transform infrared spectroscopy showed characteristic absorption bands including amide II, Si-O and Si-O-Si confirming formation of hybrid networks. Oscillatory rheometry was used to characterise the sol to gel transition and viscoelastic behaviour of hydrogels. Furthermore, in vitro degradation revealed both chitosan and silica were released over 21 days. The hydrogels exhibited high loading efficiency as total protein loading was released in a week. There were significant differences between TC₂G and C₂G at all-time points (p < 0.05). The viability of osteoblasts seeded on, and encapsulated within, the hydrogels was >70% over 168 h culture and antimicrobial activity was demonstrated against Pseudomonas aeruginosa and Enterococcus faecalis. The hydrogels developed here offer alternatives for biopolymer hydrogels for biomedical use, including for application in drug/cell delivery and for bone tissue engineering.     

Silk Fibroin as an Efficient Biomaterial for Drug Delivery,Gene Therapy,and Wound Healing

Silk fibroin (SF), an organic material obtained from the cocoons of a silkworm Bombyx mori, is used in several applications and has a proven track record in biomedicine owing to its superior compatibility with the human body, superb mechanical characteristics, and its controllable propensity to decay. Due to its robust biocompatibility, less immunogenic, non-toxic, non-carcinogenic, and biodegradable properties, it has been widely used in biological and biomedical fields, including wound healing. The key strategies for building diverse SF-based drug delivery systems are discussed in this review, as well as the most recent ways for developing functionalized SF for controlled or redirected medicines, gene therapy, and wound healing. Understanding the features of SF and the various ways to manipulate its physicochemical and mechanical properties enables the development of more effective drug delivery devices. Drugs are encapsulated in SF-based drug delivery systems to extend their shelf life and control their release, allowing them to travel further across the bloodstream and thus extend their range of operation. Furthermore, due to their tunable properties, SF-based drug delivery systems open up new possibilities for drug delivery, gene therapy, and wound healing.     

Synthesis and Characterization of pH Sensitive Poly (Hydroxy Ethyl Methacrylate-co-acrylamidoglycolic Acid) Based Hydrogels for Controlled Release Studies of 5-Fluorouracil

Hydrogels were prepared from 2-hydroxy ethyl methacrylate and acrylamidoglycolic acid using N,N’-methylene bis acrylamide as a crosslinking agent in presence of potassium persulfate initiator. The average molecular mass between crosslinks (M _c) and polymer-solvent interaction parameter of hydrogels were determined from equilibrium swelling values. Fourier transform infrared spectroscopy of hydrogels shows the confirmation of the formation of co-polymeric hydrogels. Scanning electron microscopy of hydrogels shows the porous network structure. Differential scanning calorimetry and X-ray diffraction were performed to understand the crystalline nature of hydrogel and drug after encapsulation in to hydrogels. In vitro release studies indicated the release of 5-Fluorouracil for more than 12 h.     

PLA Microspheres-Embedded PVA Hydrogels Prepared by Gamma-Irradiation and Freeze-Thaw Methods as Drug Release Carriers

A drug delivery system based on poly (vinyl alcohol) (PVA) hydrogels containing ibuprofen-loaded poly (lactic acid) (PLA) microspheres was developed to improve the release kinetics of this model drug. Gamma-irradiation and freeze-thawing were applied to prepare poly (vinyl alcohol) hydrogels. Properties and morphology of these composite hydrogels were investigated using FTIR, DSC, and SEM. In vitro release indicated that entrapment of the microspheres into the PVA hydrogels causes a reduction in both the release rate and the initial burst effect. PLA microspheres entrapped into the PVA hydrogels showed more suitable controlled release kinetics for drug delivery.     

Recent Advances in Food-Packing,Pharmaceutical and Biomedical Applications of Zein and Zein-Based Materials

Zein is a biodegradable and biocompatible material extracted from renewable resources; it comprises almost 80% of the whole protein content in corn. This review highlights and describes some zein and zein-based materials, focusing on biomedical applications. It was demonstrated in this review that the biodegradation and biocompatibility of zein are key parameters for its uses in the food-packing, biomedical and pharmaceutical fields. Furthermore, it was pointed out that the presence of hydrophilic-hydrophobic groups in zein chains is a very important aspect for obtaining material with different hydrophobicities by mixing with other moieties (polymeric or not), but also for obtaining derivatives with different properties. The physical and chemical characteristics and special structure (at the molecular, nano and micro scales) make zein molecules inherently superior to many other polymers from natural sources and synthetic ones. The film-forming property of zein and zein-based materials is important for several applications. The good electrospinnability of zein is important for producing zein and zein-based nanofibers for applications in tissue engineering and drug delivery. The use of zein’s hydrolysate peptides for reducing blood pressure is another important issue related to the application of derivatives of zein in the biomedical field. It is pointed out that the biodegradability and biocompatibility of zein and other inherent properties associated with zein’s structure allow a myriad of applications of such materials with great potential in the near future.     

Design,Synthesis, and Photophysical Properties of Pyrroloquinoline‐Based Compounds Showing Strong Blue Fluorescence as Potential Dyes for Biomedical Applications

A small library of 3‐ethylpyrrolo[3,2‐f]quinoline derivatives was synthesized to identify a novel class of dyes for use in biological studies. According to the spectroscopic analyses performed to evaluate the fluorimetric parameters of quantum yield and brightness, 7‐methyl‐ and 6,7‐dimethylpyrroloquinolin(9)one derivatives were found to be the best blue luminescent dyes for biological applications. To enhance the luminescence profiles and to obtain probes that could be conjugated to functional groups of supramolecular drug delivery systems, these compounds were further modified at position 3 to obtain 3‐heptanoic acid and 3‐aminohexylpyrroloquinolin(9)one methylated derivatives. The most brilliant 6,7‐dimethyl‐3‐aminohexylpyrroloquinolinone hydrochloride was conjugated to pullulan, a biocompatible polysaccharide used to produce colloidal systems for drug delivery. Comparative studies showed that this compound can be properly exploited as a blue fluorescent label in biological investigations, namely cell trafficking and pharmacokinetics/biodistribution studies. These molecules possess higher fluorescence efficiency than commercial dyes in biological media, making them suitable alternatives to commercially available products in current use.     

Design of Radiation Crosslinked Psyllium and Binary Monomers-Based Hydrogels for Use in Colon Drug Delivery

The present paper deals with the utilization of the cancer-lowering dietary fiber psyllium, for the development of double potential hydrogels meant for colon cancer drug delivery. The psyllium-acrylamide (AAm)-acrylic acid (AAc)-based hydrogels were synthesized by the radiation method and were characterized with FTIR, SEMs, and swelling behavior. Swelling and drug release mechanism were evaluated. The maximum water uptake (18.968 ± 0.880)g and (9.976 ± 0.364) g/g of gel were observed in solution of pH 7.4 buffer and solution of pH 2.2 buffer. respectively. The release of drug from the polymer matrix occurred through a Fickian-type diffusion mechanism.