自组装肽基纳米材料运载药物和基因的研究进展

肽基分子自组装以其丰富的自组装驱动力、新颖的自组装体纳米结构、自组装体的特殊功能及良好的生物相容性等,在纳米生物材料、护肤和化妆产品、药物传输释放、组织工程支架材料等方面有着广泛的应用前景。由天然氨基酸组成的自组装短肽具有良好的低细胞毒性,可控的降解性能,高的运载效率及细胞摄取率,同时还具有降低药物的毒副作用等优点。因此,它在作为药物和基因的纳米载药材料方面有着巨大的发展前景。使用自组装肽基材料形成的纳米载体对疏水性抗癌药物、蛋白质药物及基因等进行传递释放已成为生物医药学领域的研究重点,因此,对近年来自组装肽基纳米材料作为药物和基因载体在生物医药学上的研究进展做了综述。     

Thiol–norbornene photoclick hydrogels for tissue engineering applications

Thiol–norbornene (thiol–ene) photoclick hydrogels have emerged as a diverse material system for tissue engineering applications. These hydrogels are crosslinked through light‐mediated orthogonal reactions between multifunctional norbornene‐modified macromers [e.g., poly(ethylene glycol) (PEG), hyaluronic acid, gelatin] and sulfhydryl‐containing linkers (e.g., dithiothreitol, PEG–dithiol, biscysteine peptides) with a low concentration of photoinitiator. The gelation of thiol–norbornene hydrogels can be initiated by long‐wave UV light or visible light without an additional coinitiator or comonomer. The crosslinking and degradation behaviors of thiol–norbornene hydrogels are controlled through material selections, whereas the biophysical and biochemical properties of the gels are easily and independently tuned because of the orthogonal reactivity between norbornene and the thiol moieties. Uniquely, the crosslinking of step‐growth thiol–norbornene hydrogels is not oxygen‐inhibited; therefore, gelation is much faster and highly cytocompatible compared with chain‐growth polymerized hydrogels with similar gelation conditions. These hydrogels have been prepared as tunable substrates for two‐dimensional cell cultures as microgels and bulk gels for affinity‐based or protease‐sensitive drug delivery, and as scaffolds for three‐dimensional cell encapsulation. Reports from different laboratories have demonstrated the broad utility of thiol–norbornene hydrogels in tissue engineering and regenerative medicine applications, including valvular and vascular tissue engineering, liver and pancreas‐related tissue engineering, neural regeneration, musculoskeletal (bone and cartilage) tissue regeneration, stem cell culture and differentiation, and cancer cell biology. This article provides an up‐to‐date overview on thiol–norbornene hydrogel crosslinking and degradation mechanisms, tunable material properties, and the use of thiol–norbornene hydrogels in drug‐delivery and tissue engineering applications. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 41563.     

Biodegradable polymers exhibiting temperature-responsive sol–gel transition as injectable biomedical materials

Injectable biodegradable copolymer hydrogels, which exhibit temperature-responsive sol-to-gel transition, have recently drawn much attention as promising biomedical materials such as drug delivery, cell implantation, and tissue engineering. These injectable hydrogels can be implanted in the human body with minimal surgical invasion. Temperature-responsive gelling copolymers usually possess block- and/or branched architectures and amphiphilicity with a delicate hydrophobic/hydrophilic balance. Poly(ethylene glycol) (PEG) has typically been used as hydrophilic segments due to its biocompatibility and temperature-dependent dehydration nature. Aliphatic polyesters such as polylactide, poly(lactide-co-glycolide), poly(ε-caprolactone), and their modified copolymers have been used as hydrophobic segments based on their biodegradability and biocompatibility. Copolymers of PEG with other hydrophobic polymers such as polypeptides, polydepsipeptides have also been recently reported as injectable hydrogels. In this review, brief history and recent advances in injectable biodegradable polymer hydrogels are summarized especially focusing on the relationship between polymer architecture and their gelation properties. Moreover, the applications of these injectable polymer gels for biomedical use such as drug delivery and tissue engineering are also described.     

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.     

Chitosan‐based hydrogels: recent design concepts to tailor properties and functions

Chitosan (CS) has received much attention as a functional biopolymer for designing various hydrogels for biomedical applications. This review provides an overview of the different types of CS‐based hydrogels, the approaches that can be used to fabricate hydrogel matrices with specific features and their applications in controlled drug delivery and tissue engineering. Emphasis is laid on the recent design concepts of hybrid hydrogels based on mixtures of CS and natural or synthetic polymers, interpenetrating polymer networks as well as composite hydrogels prepared by embedding nanoparticles into CS matrices. © 2017 Society of Chemical Industry     

Functionalized silver doped hydroxyapatite scaffolds for controlled simultaneous silver ion and drug delivery

Bacterial infections are a major problem in bone tissue regeneration, thus it is essential to incorporate antibacterial properties within the bone scaffolds. Silver compounds are frequently used as antibacterial agents to prevent bacterial infections and numerous studies have shown that silver ions can be incorporated within the biocompatible and osteoconductive biomaterial hydroxyapatite (HAp) structure, but, so far, no study has thoroughly evaluated silver ion release rates in long term. Therefore, we have established a novel carrier system for local drug delivery based on functionalized silver doped hydroxyapatite with determined long term silver ion release rates. Silver ions from prepared scaffolds were released with a rate of 0.001±0.0005 wt%/h taking into account the incorporated silver amount. Moreover, lidocaine hydrochloride was incorporated in the prepared scaffolds, to provide local anesthetic effect. These scaffolds were functionalized with sodium alginate and chitosan and in vitro drug release rate in simulated body fluid was evaluated. The results suggested that the developed novel composite scaffolds possess the antibacterial activity up to one year as well as controlled anesthetic drug delivery up to two weeks.     

Biodegradable Inorganic–Organic POSS–PEG Hybrid Hydrogels as Scaffolds for Tissue Engineering

Biodegradable hydrogels have attracted much attention in tissue engineering due to their good biocompatibility and elastomeric behavior. In this work, a series of inorganic–organic polyhedral oligomeric silsequioxanes–poly(ethylene glycol) (POSS–PEG) hybrid hydrogels are prepared by covalently grafting POSS into PEG and further cross‐linked by matrix metalloproteinase (MMP) degradable peptide via Michael‐type addition polymerization. All the POSS–PEG hybrid hydrogels have a porous structure and high hydrophilic ability, and the grafted hydrophobic POSS macromers result in a higher mechanical properties and lower equilibrium swelling ratio. Additionally, the hydrogels can be biodegraded by MMP‐2 solution and the POSS loading level can influence the degradation rate. It is worth mentioning that POSS‐containing hybrid hydrogels can be prepared in water and be used for 3D cell culture. In vitro cell viability study on human umbilical vein endothelial cells for 3D cell culture indicates POSS–PEG hydrogels have good compatibility. All of these results suggest that these POSS–PEG hybrid hydrogels exhibit the potential for tissue engineering scaffolds.     

In situ incorporation of monodisperse drug nanoparticles into hydrogel scaffolds for hydrophobic drug release

The effective and locally sustained delivery of hydrophobic drug with hydrogels as carriers is still a challenge owing to the inherent incompatibility of hydrophilic hydrogel network and hydrophobic drug. One promising approach is to use porous hydrogels to encapsulate and deliver hydrophobic drug in the form of nanoparticles to the disease sites. However, this approach is currently limited by the inability to load concentrated hydrophobic drug nanoparticles into the hydrogels because of the severe nanoparticle aggregation during the loading process. In this article, we firstly designed and fabricated efficient drug nanoparticles embedded hydrogels for hydrophobic drug delivery by incorporating monodisperse silybin (hydrophobic drug for liver protection) nanoparticles into acrylated hyaluronic acid (HA‐AC) based hydrogels through in situ cross‐linking. The silybin nanoparticles embedded hydrogel scaffolds proved to be a good sustained release system with a long period of 36 h. The drug release from this hybrid hydrogels could be modulated by tuning HA‐AC concentration, cross‐linking ratio, chain length of cross‐linker and drug loading amount. The different kinetic models were applied, and it was observed that the release profile of silybin best followed the Hixson‐Crowell model for the release of drug from the hydrogels embedding silybin nanoparticles. It could be envisioned that this process would significantly advance the potential applications of hydrogel scaffolds mediated hydrophobic drug delivery in clinical therapies. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 43111.     

Preparation a novel pH‐sensitive blend hydrogel based on polyaspartic acid and ethylcellulose for controlled release of naproxen sodium

Hydrogels based on pH‐sensitive polymers are of great interest as potential biomaterials for the controlled delivery of drug molecules. In this study, a novel, pH‐sensitive hydrogel was synthesized by poly(aspartic acid) (PASP) crosslinked with 1,6‐hexanediamine and reinforced with ethylcellulose (EC). The loading and release characteristics of naproxen sodium (NS) were studied. The PASP–EC blend hydrogels had pH‐sensitive characteristics and were strongly dependent on the pH value. The release kinetics for NS from the PASP–EC blend hydrogels and PASP hydrogel were evaluated in simulated gastric fluid (pH = 1.05) and simulated intestinal fluid (pH = 6.8) at 37°C. The results showed that the drug‐loaded hydrogels were resistant to simulated gastric fluid, and hence, they could be useful for oral drug delivery. Compared with the PASP hydrogel, the PASP–EC blend hydrogels showed a lower release rate of NS in the same pH conditions. It was evident that the presence of hydrophobic groups (EC) retarded the release of NS and led to sustained release. The kinetics of NS release from the drug‐loaded hydrogels conformed to the Korsmeyer–Peppas model. The release exponent of the model was 0.7291, which indicated multiple drug release. The PASP–EC blend hydrogels were biodegradable and pH sensitive; there would be a wide range of applications for them in controlled drug‐delivery systems. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

Modeling of network degradation in mixed step-chain growth polymerizations

The ability to form degradable hydrogels having controlled network structure is important for applications related to both drug delivery and tissue engineering. Although significant advances have occurred, these applications cannot reach full potential without the availability of materials with tunable degradation behavior. Here, we present novel thiol-acrylate degradable networks, which provide a simple method for forming degradable networks having specific degradation profiles. Degradable thiol-acrylate networks are formed from copolymerizing a thiol monomer with PLA-b-PEG-b-PLA based diacrylate macromers. A theoretical model has been developed to describe the kinetic chain length distribution, the bulk degradation behavior, and the reverse gelation point of these thiol-acrylate hydrogels. Varying the thiol functionality, as well as the relative stoichiometries of the thiol and acrylate functional groups, provides a facile means to control the kinetic chain length distribution and the concomitant degradation behavior of these systems. The extent of percentage mass loss of the network at the reverse gelation point is controlled from as low as 30% to as high as 95%, thereby giving the unique ability to dictate the material properties of the hydrogel before the network becomes completely soluble.     

Chemical synthesis of biomimetic hydrogels for tissue engineering

Owing to their high water content, porous structure, biocompatibility and tissue‐like viscoelasticity, hydrogels have become attractive and promising biomaterials for use in drug delivery, three‐dimensional cell culture and tissue engineering applications. Various chemical approaches have been developed for hydrogel synthesis using monomers or polymers carrying reactive functional groups. For in vivo tissue repair and in vitro cell culture purposes, it is desirable that the crosslinking reactions occur under mild conditions, do not interfere with biological processes and proceed at high yield with exceptional selectivity. Additionally, the crosslinking reaction should allow straightforward incorporation of bioactive motifs or signaling molecules, at the same time providing tunability of the hydrogel microstructure, mechanical properties and degradation rates. In this review, we discuss various chemical approaches applied to the synthesis of complex hydrogel networks, highlighting recent developments from our group. The discovery of new chemistries and novel materials fabrication methods will lead to the development of the next generation of biomimetic hydrogels with complex structures and diverse functionalities. These materials will likely facilitate the construction of engineered tissue models that may bridge the gap between two‐dimensional experiments and animal studies, providing preliminary insight prior to in vivo assessments. © 2017 Society of Chemical Industry     

Recent advances in shear-thinning and self-healing hydrogels for biomedical applications

Shear-thinning and self-healing hydrogels are being investigated in various biomedical applications including drug delivery, tissue engineering, and 3D bioprinting. Such hydrogels are formed through dynamic and reversible interactions between polymers or polypeptides that allow these shear-thinning and self-healing properties, including physical associations (e.g., hydrogen bonds, guest–host interactions, biorecognition motifs, hydrophobicity, electrostatics, and metal–ligand coordination) and dynamic covalent chemistry (e.g., Schiff base, oxime chemistry, disulfide bonds, and reversible Diels–Alder). Their shear-thinning properties allow for injectability, as the hydrogel exhibits viscous flow under shear, and their self-healing nature allows for stabilization when shear is removed. Hydrogels can be formulated as uniform polymer and polypeptide assemblies, as hydrogel nanocomposites, or in granular hydrogel form. This review focuses on recent advances in shear-thinning and self-healing hydrogels that are promising for biomedical applications. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2020 , 137, 48668.     

Bioactive factor delivery strategies from engineered polymer hydrogels for therapeutic medicine

Polymer hydrogels have been widely explored as therapeutic delivery matrices because of their ability to present sustained, localized and controlled release of bioactive factors. Bioactive factor delivery from injectable biopolymer hydrogels provides a versatile approach to treat a wide variety of diseases, to direct cell function and to enhance tissue regeneration. The innovative development and modification of both natural- (e.g., alginate (ALG), chitosan, hyaluronic acid (HA), gelatin, heparin (HEP), etc.) and synthetic- (e.g., polyesters, polyethyleneimine (PEI), etc.) based polymers has resulted in a variety of approaches to design drug delivery hydrogel systems from which loaded therapeutics are released. This review presents the state-of-the-art in a wide range of hydrogels that are formed though self-assembly of polymers and peptides, chemical crosslinking, ionic crosslinking and biomolecule recognition. Hydrogel design for bioactive factor delivery is the focus of the first section. The second section then thoroughly discusses release strategies of payloads from hydrogels for therapeutic medicine, such as physical incorporation, covalent tethering, affinity interactions, on demand release and/or use of hybrid polymer scaffolds, with an emphasis on the last 5 years.     

Alginate: properties and biomedical applications

Alginate is a biomaterial that has found numerous applications in biomedical science and engineering due to its favorable properties, including biocompatibility and ease of gelation. Alginate hydrogels have been particularly attractive in wound healing, drug delivery, and tissue engineering applications to date, as these gels retain structural similarity to the extracellular matrices in tissues and can be manipulated to play several critical roles. This review will provide a comprehensive overview of general properties of alginate and its hydrogels, their biomedical applications, and suggest new perspectives for future studies with these polymers.     

Thermo- and pH-responsive HPC-g-AA/AA hydrogels for controlled drug delivery applications

This paper describes smart hydrogels composed of pH-sensitive poly(acrylic acid) (PAA) and biodegradable temperature-sensitive hydroxypropylcellulose-g-acrylic acid (HPC-g-AA) for controlled drug delivery applications. In a pH-responsive manner, the hydrogels with the higher HPC-g-AA content resulted in the lower equilibrium swelling. Although temperature had little influence on the swelling of the hydrogels, optical transmittance of the hydrogels was changed as a function of temperature, which reflecting that the HPC parts of hydrogel became hydrophobic at temperature above the lower critical solution temperature (LCST). Scanning electron microscopic analysis revealed that the pore size and the morphology of the hydrogels could be controlled by changing the composition of AA and the crosslinking density. Using BSA as a model drug, in vitro drug release experiment was carried out in artificial gastric juice (pH = 1.2) for the first 2 h and then in artificial intestinal liquid (pH = 6.8) for the subsequent 6 h. The release profiles indicated that both HPC-g-AA and AA contents played important roles in the drug release behaviors. The temperature- and pH-responsive HPC-g-AA/AA hydrogels might be exploited for wide applications in controlled drug delivery.     

Preparation of a novel pH-sensitive hydrogel based on acrylic acid and polyhedral oligomeric silsesquioxane for controlled drug release of theophylline

Hydrogels based on pH-sensitive polymers are of great interest as potential biomaterials for the controlled delivery of drug molecules. In this study, a novel pH-sensitive copolymer hydrogel based on acrylic acid (AA) monomer by free-radical solution polymerization were synthesized with organic–inorganic cross-linking agent of octavinyl polyhedral oligomeric silsesquioxane (OVPOSS). And its properties were compared with conventional hydrogels using N,N′-methylenebisacrylamide (MBA) as cross-linking agent. The copolymers were characterized by Fourier transform infrared spectra and differential scanning calorimetry. The morphology after swelling was presented by scanning electron microscopy. Swelling behaviors in different pH and potential applications in controlled drug delivery of the hydrogels were also examined. The results showed that both hydrogels were pH sensitive. However, as the addition of OVPOSS limited the movement of the molecular chain segment, the swelling ratio and the drug-release rate of theophylline in SGF decreased obviously when using OVPOSS as cross-linking agent, comparing with P(MBA-co-AA) hydrogels. The results in this study suggested that P(OVPOSS-co-AA) could serve as potential candidate for theophylline drug delivery.     

Chitosan—A versatile semi-synthetic polymer in biomedical applications

This review outlines the new developments on chitosan-based bioapplications. Over the last decade, functional biomaterials research has developed new drug delivery systems and improved scaffolds for regenerative medicine that is currently one of the most rapidly growing fields in the life sciences. The aim is to restore or replace damaged body parts or lost organs by transplanting supportive scaffolds with appropriate cells that in combination with biomolecules generate new tissue. This is a highly interdisciplinary field that encompasses polymer synthesis and modification, cell culturing, gene therapy, stem cell research, therapeutic cloning and tissue engineering. In this regard, chitosan, as a biopolymer derived macromolecular compound, has a major involvement. Chitosan is a polyelectrolyte with reactive functional groups, gel-forming capability, high adsorption capacity and biodegradability. In addition, it is innately biocompatible and non-toxic to living tissues as well as having antibacterial, antifungal and antitumor activity. These features highlight the suitability and extensive applications that chitosan has in medicine. Micro/nanoparticles and hydrogels are widely used in the design of chitosan-based therapeuticsystems. The chemical structure and relevant biological properties of chitosan for regenerative medicine have been summarized as well as the methods for the preparation of controlled drug release devices and their applications.     

Poly-3-hydroxybutyrate-based constructs with novel characteristics for drug delivery and tissue engineering applications—A review

Herein, we reviewed polymeric constructs of polyhydroxyalkanoates (PHAs) at large and poly-3-hydroxybutyrate (P3HB), in particular, for drug delivery and tissue engineering applications. Polymeric constructs that can efficiently respond to numerous variations in their surroundings have gained notable attention from different industrial sectors such as biomedical, clinical, pharmaceutical, and cosmeceutical. Among them, considerable importance is given to their drug delivery and tissue engineering applications. PHAs with peculiar reference to P3HB are gaining prominence attention as candidate materials with such requisite potentialities. The unique structural and functional characteristics of PHAs and P3HB are of supreme interest and being used to engineer novel constructs for efficient drug delivery and tissue regeneration purposes. So far, an array of methodological approaches, such as in vitro, in vivo, and ex vivo techniques have been exploited though using different materials with different geometries for a said purpose. However, a low-level production majorly limits their proper exploitation. Various physiochemical characteristics and production strategies have been introduced in this review. The data have been summarized on PHAs production by several microorganisms aiming to cover the scope of the last 10 years. The present review highlights the recent applications of PHAs and P3HB-based constructs, such as micro/nanoparticles, biocomposite, nanofibers, and hydrogels as novel drug carries for regenerative medicine and tissue engineering. In summary, drug delivery and tissue engineering potentialities of PHAs and P3HB-based constructs are discussed with suitable examples and envisioned directions of future developments.     

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.     

Synthesis and degradation of agar‐carbomer based hydrogels for tissue engineering applications

Hydrogels studied in this investigation, synthesized starting from agarose and Carbomer 974P, were chosen for their potential use in tissue engineering. The strong ability of hydrogels to mimic living tissues should be complemented with optimized degradation time profiles: a critical property for biomaterials but essential for the integration with target tissue. In this study, chosen hydrogels were characterized both from a rheological and a structural point of view before studying the chemistry of their degradation, which was performed by several analysis: infrared bond response [Fourier transform infrared (FT‐IR)], calorimetry [differential scanning Calorimetry (DSC)], and % mass loss. Degradation behaviors of Agar‐Carbomer hydrogels with different degrees of crosslinkers were evaluated monitoring peak shifts and thermal property changes. It was found that the amount of crosslinks heavily affect the time and the magnitude related to the process. The results indicate that the degradation rates of Agar‐Carbomer hydrogels can be controlled and tuned to adapt the hydrogel degradation kinetics for different cell housing and drug delivery applications. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2011