Smart Hydrogels for Advanced Drug Delivery Systems

Since the last few decades, the development of smart hydrogels, which can respond to stimuli and adapt their responses based on external cues from their environments, has become a thriving research frontier in the biomedical engineering field. Nowadays, drug delivery systems have received great attention and smart hydrogels can be potentially used in these systems due to their high stability, physicochemical properties, and biocompatibility. Smart hydrogels can change their hydrophilicity, swelling ability, physical properties, and molecules permeability, influenced by external stimuli such as pH, temperature, electrical and magnetic fields, light, and the biomolecules’ concentration, thus resulting in the controlled release of the loaded drugs. Herein, this review encompasses the latest investigations in the field of stimuli-responsive drug-loaded hydrogels and our contribution to this matter.     

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.     

Radiation Synthesis of pH-Sensitive Hydrogels From Carboxymethyl Cellulose/Poly(ethylene Oxide) Blends as Drug Delivery Systems

Gamma irradiation was used to prepare hydrogels from carboxymethyl cellulose (CMC) and poly(ethylene oxide) (PEO) blends in the form of films. The hydrogels were characterized by IR spectroscopy, differential scanning calorimetry, thermogravimetric analysis, mechanical testing, and scanning electron microscopy. The swelling in different buffers of different pH values was also studied. The results indicated the formation of network structure and that the swelling of hydrogels is thermo- and pH-sensitive. The CMC/PEO hydrogels were evaluated for the possible use in drug delivery field, in which the release profile of ketoprofen, as a drug model was investigated.     

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.     

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.     

Synthesis of Grafted Hydrogels as Mono-Divalent Cation Exchange for Drug Delivery

pH-sensitive acrylic acid grafted polyvinylalcohol (AAc-g-PVA) hydrogels has been prepared by gamma irradiation. The maximum grafting yield was at monomer concentration 50% and dose 50 kGy. The swelling, network parameters, thermogravimetric analysis, activation energy and scanning electron microscope of the grafted hydrogels were evaluated. Hydrogel demonstrate high swelling at pH 6.8. The deswelling of the swollen gel in Ni²⁺ and Cu²⁺ cations solution was explained on the basis of mono-divalent cation exchange. The release of antihistaminic chlorphenamine maleate hydrochloride (CPM) was faster in gastric fluid (SGF) of pH 1.1 than in intestinal fluid (SIF) of pH 6.8.     

Succinyl Chitosan-Colistin Conjugates as Promising Drug Delivery Systems

The growth of microbial multidrug resistance is a problem in modern clinical medicine. Chemical modification of active pharmaceutical ingredients is an attractive strategy to improve their biopharmaceutical properties by increasing bioavailability and reducing drug toxicity. Conjugation of antimicrobial drugs with natural polysaccharides provides high efficiency of these systems due to targeted delivery, controlled drug release and reduced toxicity. This paper reports a two-step synthesis of colistin conjugates (CT) with succinyl chitosan (SucCS); first, we modified chitosan with succinyl anhydride to introduce a carboxyl function into the polymer molecule, which was then used for chemical grafting with amino groups of the peptide antibiotic CT using carbodiimide chemistry. The resulting polymeric delivery systems had a degree of substitution (DS) by CT of 3–8%, with conjugation efficiencies ranging from 54 to 100% and CT contents ranging from 130–318 μg/mg. The size of the obtained particles was 100–200 nm, and the ζ-potential varied from −22 to −28 mV. In vitro release studies at pH 7.4 demonstrated ultra-slow hydrolysis of amide bonds, with a CT release of 0.1–0.5% after 12 h; at pH 5.2, the hydrolysis rate slightly increased; however, it remained extremely low (1.5% of CT was released after 12 h). The antimicrobial activity of the conjugates depended on the DS. At DS 8%, the minimum inhibitory concentration (MIC) of the conjugate was equal to the MIC of native CT (1 µg/mL); at DS of 3 and 5%, the MIC increased 8-fold. In addition, the developed systems reduced CT nephrotoxicity by 20–60%; they also demonstrated the ability to reduce bacterial lipopolysaccharide-induced inflammation in vitro. Thus, these promising CT-SucCS conjugates are prospective for developing safe and effective nanoantibiotics.     

Synthesis and Antimicrobial Activity of Some Novel Cross-Linked Chitosan Hydrogels

Four novel hydrogels based on chitosan were synthesized via a cross-linking reaction of chitosan with different concentrations of oxalyl bis 4-(2,5-dioxo-2H-pyrrol- 1(5H)-yl)benzamide. Their structures were confirmed by fourier transform infrared X-ray (FTIR), scanning electron microscopy (SEM) and X-ray diffraction. The antimicrobial activities of the hydrogels against two crop-threatening pathogenic fungi namely: Aspergillus fumigatus (A. fumigatus, RCMBA 06002), and Aspergillus niger (A. niger, RCMBA 06106), and five bacterial species namely: Bacillis subtilis (B. subtilis, RCMBA 6005), Staphylococcus aureus (S. aureus, RCMBA 2004), Streptococcus pneumoniae (S. pneumonia, RCMB 000101) as Gram positive bacteria, and Salmonella typhimurium (S. typhimurium, RCMB 000104), and Escherichia coli (E. coli, RCMBA 5003) as Gram negative bacteria have been investigated. The prepared hydrogels showed much higher antimicrobial activities than that of the parent chitosan. The hydrogels were more potent in case of Gram-positive bacteria than Gram-negative bacteria. Increasing the degree of cross-linking in the hydrogels resulted in a weaker antimicrobial activity.     

Poly(chitosan-ester-ether-urethane) Hydrogels as Highly Controlled Genistein Release Systems

Polymeric hydrogels play an increasingly important role in medicine, pharmacy and cosmetology. They appear to be one of the most promising groups of biomaterials due to their favorable physicochemical properties and biocompatibility. The objective of the presented study was to synthesize new poly(chitosan-ester-ether-urethane) hydrogels and to study the kinetic release of genistein (GEN) from these biomaterials. In view of the above, six non-toxic hydrogels were synthesized via the Ring-Opening Polymerization (ROP) and polyaddition processes. The poly(ester-ether) components of the hydrogels have been produced in the presence of the enzyme as a biocatalyst. In some cases, the in vitro release rate of GEN from the obtained hydrogels was characterized by near-zero-order kinetics, without “burst release” and with non-Fickian transport. It is important to note that developed hydrogels have been shown to possess the desired safety profile due to lack of cytotoxicity to skin cells (keratinocytes and fibroblasts). Taking into account the non-toxicity of hydrogels and the relatively highly controlled release profile of GEN, these results may provide fresh insight into polymeric hydrogels as an effective dermatological and/or cosmetological tool.     

Advanced Hydrogels as Exosome Delivery Systems for Osteogenic Differentiation of MSCs: Application in Bone Regeneration

Hydrogels are known as water-swollen networks formed from naturally derived or synthetic polymers. They have a high potential for medical applications and play a crucial role in tissue repair and remodeling. MSC-derived exosomes are considered to be new entities for cell-free treatment in different human diseases. Recent progress in cell-free bone tissue engineering via combining exosomes obtained from human mesenchymal stem cells (MSCs) with hydrogel scaffolds has resulted in improvement of the methodologies in bone tissue engineering. Our research has been actively focused on application of biotechnological methods for improving osteogenesis and bone healing. The following text presents a concise review of the methodologies of fabrication and preparation of hydrogels that includes the exosome loading properties of hydrogels for bone regenerative applications.     

Human‐Iris‐Like Aperture and Sphincter Muscle Comprising Hyperelastic Composite Hydrogels Containing Graphene Oxide

Soft hydrogels are extensively studied for developing human‐body‐mimicking actuators because of their stimuli‐responsive volume change and elasticity. Mimicking a human eye with hydrogels is very challenging because both the large variation in the volume and the high modulus of the gels should be concurrently achieved. In the human eye, adjusting the iris for controlling the focal point and light transmittance is achieved by the contraction of the sphincter muscle. In this work, a hyperelastic poly(N‐isopropylacrylamide) containing graphene oxide (PNIPAm/GO) composite hydrogels, which exhibits a thermo‐responsive volume phase transition is developed. The fact that the inner hole size for center‐cut hydrogels can increase or decrease during heating depending on the geometry of the hydrogels is revealed. Based on these findings, human‐iris‐like actuators capable of controlling the shape of a polydimethylsiloxane (PDMS) lens for adjusting magnification of an object is developed. When heated, the hyperelastic hydrogels act like the sphincter muscle in the eye, inducing the curvature change of the attached PDMS lens. Thus, hyperelastic hydrogels of large variation can provide an efficient platform to fabricate various soft actuation systems.     

Layer-by-Layer Engineered Superparamagnetic Polyelectrolyte Hybrid Hollow Microspheres With High Magnetic Content as Drug Delivery System

Polyelectrolyte hybrid hollow microspheres with sandwich structure of about 450 nm have been accomplished by layer-by-layer self-assembling of two modified ferroferric oxide nanoparticles, lysine modified ferroferric oxide nanoparticles (Fe₃O₄-LYs) and citrate modified ferroferric oxide nanoparticles (Fe₃O₄-CA), as the main assembling materials via electrostatic interaction for the first time. They are superparamagnetic with saturation magnetization of 45.69 emu/g, revealing their high magnetic content of 70%. As drug delivery system, they also exhibited pH-stimuli responsive controlled release of an anticancer drug doxorubicin, following the Fickian diffusion model. Their unique structure and high magnetic content make them good candidate for targeted delivery.     

Aptamer-Functionalized Hybrid Nanostructures for Sensing,Drug Delivery,Catalysis and Mechanical Applications

Sequence-specific nucleic acids exhibiting selective recognition properties towards low-molecular-weight substrates and macromolecules (aptamers) find growing interest as functional biopolymers for analysis, medical applications such as imaging, drug delivery and even therapeutic agents, nanotechnology, material science and more. The present perspective article introduces a glossary of examples for diverse applications of aptamers mainly originated from our laboratory. These include the introduction of aptamer-functionalized nanomaterials such as graphene oxide, Ag nanoclusters and semiconductor quantum dots as functional hybrid nanomaterials for optical sensing of target analytes. The use of aptamer-functionalized DNA tetrahedra nanostructures for multiplex analysis and aptamer-loaded metal-organic framework nanoparticles acting as sense-and-treat are introduced. Aptamer-functionalized nano and microcarriers are presented as stimuli-responsive hybrid drug carriers for controlled and targeted drug release, including aptamer-functionalized SiO₂ nanoparticles, carbon dots, metal-organic frameworks and microcapsules. A further application of aptamers involves the conjugation of aptamers to catalytic units as a means to mimic enzyme functions “nucleoapzymes”. In addition, the formation and dissociation of aptamer-ligand complexes are applied to develop mechanical molecular devices and to switch nanostructures such as origami scaffolds. Finally, the article discusses future challenges in applying aptamers in material science, nanotechnology and catalysis.     

Tunable Engineering of Heparinized Injectable Hydrogels for Affinity‐Based Sustained Delivery of Bioactive Factors

Here, the design of an in situ‐forming injectable hydrogel is reported based on pH‐ and temperature‐responsive copolymers finely engineered with heparin for the sustained delivery of bioactive factors. In order to develop such heparinized injectable hydrogels, pH‐ and temperature‐responsive copolymers based on poly(ethylene glycol) and poly(urethane sulfamethazine) (PEG‐PUSSM) are synthesized and acrylated, and subsequently coupled with thiolated heparin through Michael‐addition reaction. The content of heparin in the bioconjugates (Hep‐PUSSM) is finely tuned to control the release of heparin‐binding bioactive factors. The free‐flowing bioconjugate sols at room temperature transform to stable viscoelastic gel in physiological conditions, indicating that heparin modification does not affect the sol–gel transition. The subcutaneous administration of bioconjugate sols to the dorsal‐region of Sprague‐Dawley rats forms a hydrogel depot and shows controlled degradation. The bioconjugates effectively bind with bioactive factors (VEGF) through simple mixing, and the release is controlled over a period of 4 weeks without an initial burst. As a result, the implantation of VEGF‐loaded bioconjugate gel induces angiogenesis throughout the hydrogel network. The tunable engineering of the injectable hydrogel by heparinization with independent controllable physical properties sustains the release of bioactive factors, indicating that it may be a promising platform for the delivery of bioactive factors.     

Hydrogels as smart biomaterials

Hydrogels were the first biomaterials rationally designed for human use. Beginning with the pioneering work of Wichterle and Lím on three‐dimensional polymers that swell in water, we review the design, synthesis, properties, and applications of hydrogels. The field of hydrogels has moved forward at a dramatic pace. The development of suitable synthetic methods encompassing traditional chemistry to molecular biology has been used in the design of hydrogels mimicking basic processes of living systems. Stimuli‐sensitive hydrogels, hydrogels with controlled degradability, genetically engineered poly(amino acid) polymers reversibly self‐assembling in precisely defined three‐dimensional structures, and hybrid polymers composed of two distinct classes of molecules are just some examples of these exciting novel biomaterials. The biocompatibility of hydrogels and their applications from implants to nanomaterials are also reviewed. Copyright © 2007 Society of Chemical Industry     

可生物降解药物控释系统的研究进展

可生物降解药物控释系统具有智能化、效率高和使用方便等特点,在药物控制释放研究领域越来越受到瞩目.基于国内外大量研究文献,对可生物降解药物控释系统进行了综述,着重介绍了温度和pH敏感型可生物降解智能化高分子给药系统的研究进展.     

Carboxymethyl-Dextran-Coated Superparamagnetic Iron Oxide Nanoparticles for Drug Delivery: Influence of the Coating Thickness on the Particle Properties

Carboxymethyl-dextran (CMD)-coated iron oxide nanoparticles (IONs) are of great interest in nanomedicine, especially for applications in drug delivery. To develop a magnetically controlled drug delivery system, many factors must be considered, including the composition, surface properties, size and agglomeration, magnetization, cytocompatibility, and drug activity. This study reveals how the CMD coating thickness can influence these particle properties. ION@CMD are synthesized by co-precipitation. A higher quantity of CMD leads to a thicker coating and a reduced superparamagnetic core size with decreasing magnetization. Above 12.5–25.0 g L⁻¹ of CMD, the particles are colloidally stable. All the particles show hydrodynamic diameters < 100 nm and a good cell viability in contact with smooth muscle cells, fulfilling two of the most critical characteristics of drug delivery systems. New insights into the significant impact of agglomeration on the magnetophoretic behavior are shown. Remarkable drug loadings (62%) with the antimicrobial peptide lasioglossin and an excellent efficiency (82.3%) were obtained by covalent coupling with the EDC/NHS (N-ethyl-N′-(3-(dimethylamino)propyl)carbodiimide/N-hydroxysuccinimide) method in comparison with the adsorption method (24% drug loading, 28% efficiency). The systems showed high antimicrobial activity with a minimal inhibitory concentration of 1.13 µM (adsorption) and 1.70 µM (covalent). This system successfully combines an antimicrobial peptide with a magnetically controllable drug carrier.     

壳聚糖-琼胶复合微球的制备及其药物释放性能

采用小分子离子交联法制备了pH值敏感的壳聚糖-琼胶复合微球,对壳聚糖-琼胶复合微球的粒径、形貌、pH值敏感性等进行了表征.以茶碱为模型药物研究了壳聚糖-琼胶复合微球的药物释放性能,结果发现一定量琼胶的引入有助于改善壳聚糖微球的药物缓释性能.     

还原氧化石墨烯水溶胶与气溶胶的制备及其应用

以氧化石墨(GO)为原料、铜纳米粒子为还原剂,制备得到三维还原氧化石墨烯水溶胶H;通过冷冻干燥,得到相应的还原氧化石墨烯气溶胶A。以得到的H催化还原对硝基苯酚(4-NP),结果表明,H对4-NP还原有良好的催化性能。     

Formulating Drug Delivery Systems by Spray Drying

The knowledge of the potential use of the spray-drying technology to prepare microparticulate drug delivery systems—microspheres and microcapsules—has been strongly improved over the last years. Various microparticulate spray drying systems used as vehicles for drug encapsulation and delivery that have been investigated for different purposes are presented here, including spray-dried powders formulated with hydrophilic polymers allowing controlled drug release, biodegradable microspheres prepared from aqueous systems, and spray-dried silica gel microspheres.