Synthesis,Properties and Applications of Biodegradable Polymers Derived from Diols and Dicarboxylic Acids: From Polyesters to Poly(ester amide)s

Poly(alkylene dicarboxylate)s constitute a family of biodegradable polymers with increasing interest for both commodity and speciality applications. Most of these polymers can be prepared from biobased diols and dicarboxylic acids such as 1,4-butanediol, succinic acid and carbohydrates. This review provides a current status report concerning synthesis, biodegradation and applications of a series of polymers that cover a wide range of properties, namely, materials from elastomeric to rigid characteristics that are suitable for applications such as hydrogels, soft tissue engineering, drug delivery systems and liquid crystals. Finally, the incorporation of aromatic units and α-amino acids is considered since stiffness of molecular chains and intermolecular interactions can be drastically changed. In fact, poly(ester amide)s derived from naturally occurring amino acids offer great possibilities as biodegradable materials for biomedical applications which are also extensively discussed.     

Injectable Thixotropic β–Cyclodextrin–Functionalized Hydrogels Based on Guanosine Quartet Assembly

Facile method for the preparation of β–cyclodextrin–functionalized hydrogels based on guanosine quartet assembly was described. A series of seven hydrogels were prepared by linking β–cyclodextrin molecules with guanosine moieties in different ratios through benzene–1,4–diboronic acid linker in the presence of potassium hydroxide. The potassium ions acted as a reticulation agent by forming guanosine quartets, leading to the formation of self–sustained transparent hydrogels. The ratios of the β–cyclodextrin and guanosine components have a significant effect on the internal structuration of the components and, correspondingly, on the mechanical properties of the final gels, offering a tunablity of the system by varying the components ratio. The insights into the hydrogels’ structuration were achieved by circular dichroism, scanning electron microscopy, atomic force microscopy, and X–ray diffraction. Rheological measurements revealed self–healing and thixotropic properties of all the investigated samples, which, in combination with available cyclodextrin cavities for active components loading, make them remarkable candidates for specific applications in biomedical and pharmaceutical fields. Moreover, all the prepared samples displayed selective antimicrobial properties against S. aureus in planktonic and biofilm phase, the activity also depending on the guanosine and cyclodextrin ratio within the hydrogel structure.     

Supramolecular Gels Incorporating Cordyline terminalis Leaf Extract as a Polyphenol Release Scaffold for Biomedical Applications

Cordyline terminalis leaf extract (aqCT) possesses abundant polyphenols and other bioactive compounds, which are encapsulated in gelatin–polyethylene glycol–tyramine (GPT)/alpha-cyclodextrin (α-CD) gels to form the additional functional materials for biomedical applications. In this study, the gel compositions are optimized, and the GPT/α-CD ratios equal to or less than one half for solidification are found. The gelation time varies from 40.7 min to 5.0 h depending on the increase in GPT/α-CD ratios and aqCT amount. The aqCT extract disturbs the hydrogen bonding and host–guest inclusion of GPT/α-CD gel networks, postponing the gelation. Scanning electron microscope observation shows that all gels with or without aqCT possess a microarchitecture and porosity. GPT/α-CD/aqCT gels could release polyphenols from 110 to 350 nmol/mL at the first hour and sustainably from 5.5 to 20.2 nmol/mL for the following hours, which is controlled by feeding the aqCT amount and gel properties. GPT/α-CD/aqCT gels achieved significant antioxidant activity through a 100% scavenging DPPH radical. In addition, all gels are non-cytotoxic with a cell viability more than 85%. Especially, the GPT3.75α-CD10.5aqCT gels with aqCT amount of 3.1–12.5 mg/mL immensely enhanced the cell proliferation of GPT3.75α-CD10.5 gel without extract. These results suggest that the inherent bioactivities of aqCT endowed the resulting GPT/α-CD/aqCT gels with effective antioxidant and high biocompatibility, and natural polyphenols sustainably release a unique platform for a drug delivery system or other biomedical applications.     

Synthesis of pH and Glucose Responsive Silk Fibroin Hydrogels

Silk fibroin (SF) has attracted much attention due to its high, tunable mechanical strength and excellent biocompatibility. Imparting the ability to respond to external stimuli can further enhance its scope of application. In order to imbue stimuli-responsive behavior in silk fibroin, we propose a new conjugated material, namely cationic SF (CSF) obtained by chemical modification of silk fibroin with ε-Poly-(L-lysine) (ε-PLL). This pH-responsive CSF hydrogel was prepared by enzymatic crosslinking using horseradish peroxidase and H₂O₂. Zeta potential measurements and SDS-PAGE gel electrophoresis show successful synthesis, with an increase in isoelectric point from 4.1 to 8.6. Fourier transform infrared (FTIR) and X-ray diffraction (XRD) results show that the modification does not affect the crystalline structure of SF. Most importantly, the synthesized CSF hydrogel has an excellent pH response. At 10 wt.% ε-PLL, a significant change in swelling with pH is observed. We further demonstrate that the hydrogel can be glucose-responsive by the addition of glucose oxidase (GOx). At high glucose concentration (400 mg/dL), the swelling of CSF/GOx hydrogel is as high as 345 ± 16%, while swelling in 200 mg/dL, 100 mg/dL and 0 mg/dL glucose solutions is 237 ± 12%, 163 ± 12% and 98 ± 15%, respectively. This shows the responsive swelling of CSF/GOx hydrogels to glucose, thus providing sufficient conditions for rapid drug release. Together with the versatility and biological properties of fibroin, such stimuli-responsive silk hydrogels have great potential in intelligent drug delivery, as soft matter substrates for enzymatic reactions and in other biomedical applications.     

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.     

手性α-氨基酸的不对称合成

按合成方法综述了手性α-氨基酸的研究进展。简要介绍了手性拆分、L-氨基酸的高同系化、不对称烷基化、亚胺的不对称烷基化、脱氢氨基酸的不对称氢化等各种合成方法。对手性α-氨基酸合成的今后发展方向做了讨论。     

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.     

Influence of Unmodified and β-Glycerophosphate Cross-Linked Chitosan on Anti-Candida Activity of Clotrimazole in Semi-Solid Delivery Systems

The combination of an antifungal agent and drug carrier with adjunctive antimicrobial properties represents novel strategy of complex therapy in pharmaceutical technology. The goal of this study was to investigate the unmodified and ion cross-linked chitosan’s influence on anti-Candida activity of clotrimazole used as a model drug in hydrogels. It was particularly crucial to explore whether the chitosans’ structure modification by β-glycerophosphate altered its antifungal properties. Antifungal studies (performed by plate diffusion method according to CLSI reference protocol) revealed that hydrogels obtained with chitosan/β-glycerophosphate displayed lower anti-Candida effect, probably as a result of weakened polycationic properties of chitosan in the presence of ion cross-linker. Designed chitosan hydrogels with clotrimazole were found to be more efficient against tested Candida strains and showed more favorable drug release profile compared to commercially available product. These observations indicate that novel chitosan formulations may be considered as promising semi-solid delivery system of clotrimazole.     

La3+ modified poly(γ-glutamic acid) hydrogels with high strength and anti-swelling property for cartilage regeneration

The applications of synthetic hydrogels in cartilage regeneration are usually limited by their weak mechanical properties, uncontrolled swelling/degradation, and insufficient osteogenic activity. Developing tough hydrogels have been attracting great attention in biomedical engineering. In this study, a high strength and tough poly(γ-glutamic acid) (γ-PGA) hydrogels with excellent anti-swelling property were developed by immersing as-prepared γ-PGA hydrogels in LaCl₃ aqueous solution. Results revealed that the concentration of LaCl₃ aqueous solution has great influence on the mechanical properties of γ-PGA hydrogels. The tensile strength of γ-PGA hydrogels improved from 0.12 ± 0.02 MPa to 14.65 ± 0.48 MPa when LaCl₃ concentration was 0.15 M. Moreover, the swelling ratio decreased from 1035.75 ± 33.16% to 18.21 ± 3.08%. The morphology and microstructure of La³⁺ reinforced γ-PGA hydrogels were characterized by SEM/EDS, FT-IR and XPS. Furthermore, in vitro cytocompatibility of La³⁺ reinforced γ-PGA hydrogels was evaluated via MC3T3-E1 cells. Finally, this study provides a facile and effective strategy for modifying the mechanical and swelling properties of γ-PGA-based hydrogels, which offers great potential applications in cartilage repair and regeneration.     

Synthesis and Evaluation of AlgNa-g-Poly(QCL-co-HEMA) Hydrogels as Platform for Chondrocyte Proliferation and Controlled Release of Betamethasone

Hydrogels obtained from combining different polymers are an interesting strategy for developing controlled release system platforms and tissue engineering scaffolds. In this study, the applicability of sodium alginate-g-(QCL-co-HEMA) hydrogels for these biomedical applications was evaluated. Hydrogels were synthesized by free-radical polymerization using a different concentration of the components. The hydrogels were characterized by Fourier transform-infrared spectroscopy, scanning electron microscopy, and a swelling degree. Betamethasone release as well as the in vitro cytocompatibility with chondrocytes and fibroblast cells were also evaluated. Scanning electron microscopy confirmed the porous surface morphology of the hydrogels in all cases. The swelling percent was determined at a different pH and was observed to be pH-sensitive. The controlled release behavior of betamethasone from the matrices was investigated in PBS media (pH = 7.4) and the drug was released in a controlled manner for up to 8 h. Human chondrocytes and fibroblasts were cultured on the hydrogels. The MTS assay showed that almost all hydrogels are cytocompatibles and an increase of proliferation in both cell types after one week of incubation was observed by the Live/Dead^® assay. These results demonstrate that these hydrogels are attractive materials for pharmaceutical and biomedical applications due to their characteristics, their release kinetics, and biocompatibility.     

Self-healable polyacrylic acid-polyacrylamide-ferric ion dual-crosslinked hydrogel with good biotribological performance as a load-bearing surface

Although having been widely investigated, polymer hydrogels still have many defects like poor tribological properties and insufficient durability, hindering their further applications in biomedical fields. In this study, we present a simple method to synthesize polyacrylic acid-polyacrylamide-ferric ion (PAA-PAAm-Fe³⁺) dual-crosslinked hydrogels with self-healing abilities and “soft-hard” hydrogel-polyetheretherketone (PEEK) combined load-bearing surfaces with low friction coefficients. After analytical characterizations, the results demonstrated that the hydrogels could repair themselves without any external stimuli. Because of the excellent biphasic and aqueous lubrication provided by the hydrogel layer and the load-bearing capacity provided by the PEEK substrate, the friction coefficient of a load-bearing surface was as low as 0.048 in water, much lower than a pristine PEEK block or a hydrogel block sample. This work fabricated self-healable PAA-PAAm-Fe³⁺ hydrogels and low friction bearing surfaces, successfully improving the tribology properties of hydrogels, hopefully promoting their applications as biomedical materials such as articular cartilage. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2020 , 137, 48499.     

The synthesis,mechanisms, and additives for bio-compatible polyvinyl alcohol hydrogels: A review on current advances,trends, and future outlook

Vinyl polymers are widely used in biological, textile and industrial applications and are currently attracting research attention for specialized bio-based applications. Polyvinyl alcohol (PVA) hydrogels show great advantages as a material with high biocompatibility, permeability, hydrophilicity, and low-friction coefficient, allowing applications as smart materials, wound dressings, and flexible sensors. However, the poor mechanical properties of PVA hydrogels and biocompatibility less than natural polymers make them unsuitable in practical applications. Additives are often added to PVA hydrogels to enhance mechanical properties, endow more compatibility, functionality and expand their application range. Among them, bio-additives such as nanocellulose, natural polysaccharides and proteins are biodegradable, biocompatible, and inexpensive, broadening their applications in the biomedical and tissue engineering fields. This work reviews the synthesis of PVA hydrogels, methods to enhance their mechanical properties, types of bio-additives incorporated for biocompatibility, their mechanism of interaction with PVA and future prospects of PVA composite bio-hydrogels for application in various fields. Representative cases are carefully selected and discussed with regard to their composition and pros and cons are discussed. Finally, future requirements, as well as the opportunities and challenges of these bio-additives for improving the multifunctionality of PVA hydrogels are also presented.     

Dipeptides of S-Substituted Dehydrocysteine as Artzyme Building Blocks: Synthesis,Complexing Abilities and Antiproliferative Properties

Background: Dehydropeptides are analogs of peptides containing at least one conjugate double bond between α,β-carbon atoms. Its presence provides unique structural properties and reaction centre for chemical modification. In this study, the series of new class of dipeptides containing S-substituted dehydrocysteine with variety of heterocyclic moieties was prepared. The compounds were designed as the building blocks for the construction of artificial metalloenzymes (artzymes). Therefore, the complexing properties of representative compounds were also evaluated. Furthermore, the acknowledged biological activity of natural dehydropeptides was the reason to extend the study for antiproliferative action of against several cancer cell lines. Methods: The synthetic strategy involves glycyl and phenylalanyl-(Z)-β-bromodehydroalanine as a substrate in one pot addition/elimination reaction of thiols. After deprotection of N-terminal amino group the compounds with triazole ring were tested as complexones for copper(II) ions using potentiometric titration and spectroscopic techniques (UV-Vis, CD, EPR). Finally, the antiproliferative activity was evaluated by sulforhodamine B assay. Results and Conclusions: A simple and efficient procedure for preparation of dipeptides containing S-substituded dehydrocysteine was provided. The peptides containing triazole appeared to be strong complexones of copper(II) ions. Some of the peptides exhibited promising antiproliferative activities against number of cancer cell lines, including cell lines resistant to widely used anticancer agent.     

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.     

Thixotropic Hydrogels Composed of Self-Assembled Nanofibers of Double-Hydrophobic Elastin-Like Block Polypeptides

Physically crosslinked hydrogels with thixotropic properties attract considerable attention in the biomedical research field because their self-healing nature is useful in cell encapsulation, as injectable gels, and as bioinks for three-dimensional (3D) bioprinting. Here, we report the formation of thixotropic hydrogels containing nanofibers of double-hydrophobic elastin-like polypeptides (ELPs). The hydrogels are obtained with the double-hydrophobic ELPs at 0.5 wt%, the concentration of which is an order of magnitude lower than those for previously reported ELP hydrogels. Although the kinetics of hydrogel formation is slower for the double-hydrophobic ELP with a cell-binding sequence, the storage moduli G′ of mature hydrogels are similar regardless of the presence of a cell-binding sequence. Reversible gel–sol transitions are demonstrated in step-strain rheological measurements. The degree of recovery of the storage modulus G′ after the removal of high shear stress is improved by chemical crosslinking of nanofibers when intermolecular crosslinking is successful. This work would provide deeper insight into the structure–property relationships of the self-assembling polypeptides and a better design strategy for hydrogels with desired viscoelastic properties.     

Biodegradable poly(ester amide)s – A remarkable opportunity for the biomedical area: Review on the synthesis,characterization and applications

Poly(ester amide)s have emerged in the last years as an important family of biodegradable synthetic polymers. These polymers present both ester and amide linkages in their structure and they gather in the same entity the good degradability of polyesters with the good thermo-mechanical properties of polyamides. Particularly, poly(ester amide)s containing α-amino acids have risen as important materials in the biomedical field. The presence of the α-amino acid contributes to better cell–polymer interactions, allows the introduction of pendant reactive groups, and enhances the overall biodegradability of the polymers.     

Thermal Aging Rheological Behavior of Magnetorheological Elastomers Based on Silicone Rubber

Engineering rubber composites have been widely used as main components in many fields including vehicle engineering and biomedical applications. However, when a rubber composite surface area is exposed to heat or sunlight and over a long-term accelerated exposure and lifecycle of test, the rubber becomes hard, thus influencing the mechanical and rheological behavior of the materials. Therefore, in this study, the deterioration of rheological characteristics particularly the phase shift angle (δ) of silicone rubber (SR) based magnetorheological elastomer (MRE) is investigated under the effect of thermal aging. SR-MRE with 60 wt% of CIPs is fabricated and subjected to a continuous temperature of 100 °C for 72 h. The characterization of SR-MRE before and after thermal aging related to hardness, micrograph, and rheological properties are characterized using low vacuum scanning electron microscopy (LV-SEM) and a rheometer, respectively. The results demonstrated that the morphological analysis has a rough surface and more voids occurred after the thermal aging. The hardness and the weight of the SR-MRE before and after thermal aging were slightly different. Nonetheless, the thermo-rheological results showed that the stress–strain behavior have changed the phase-shift angle (δ) of SR-MRE particularly at a high strain. Moreover, the complex mechanism of SR-MRE before and after thermal aging can be observed through the changes of the ‘in-rubber structure’ under rheological properties. Finally, the relationship between the phase-shift angle (δ) and the in-rubber structure due to thermal aging are discussed thoroughly which led to a better understanding of the thermo-rheological behavior of SR-MRE.     

Novel semi-interpenetrated networks based on collagen-polyurethane-polysaccharides in hydrogel state for biomedical applications

The development of collagen hydrogels with tailored properties for improved applications in biomedicine represents an area of opportunity for materials science. The collagen can form semi-interpenetrated networks (semi-IPN) with various natural and/or synthetic polymers. This work aims the preparation of novel hydrogels generated from a collagen matrix cross-linked with polyurethane (PU), and the subsequent inclusion of polysaccharide chains to form semi-IPN systems with improved properties. The choice of polysaccharides for this purpose is related to their ability to modulate the biocompatibility and the antibacterial capacity in various biomedical strategies. The work contemplates to study the effect of the chemical structure of polysaccharide (hydroxyethylcellulose (HEC), hydroxypropylmethylcellulose (HPMC) or starch (Alm)) on the properties of these novel hydrogels. The results indicate that the semi-IPN hydrogels that include Alm exhibit the formation of stronger intermolecular interactions promoted by hydrogen bonds than HEC and HPMC, significantly improving the mechanical properties and their degradation rate in acidic, alkaline, and proteolytic media; also showing high capacity to inhibit the growth of E. colli. The semi-IPN hydrogels based on HEC and HPMC exhibit excellent improvement in both thermal and proteolytic degradation, compared with the collagen-PU matrix. On the other hand, this semi-IPN system does not present cytotoxic character for monocytes and fibroblasts growing for up to 48 h of culture. Therefore, these innovative 3D matrices will be excellent candidates with potential application in biomedical strategies such as wound healing dressings.