ROS-responsive hydrogels: from design and additive manufacturing to biomedical applications.

Hydrogels with intricate 3D networks and high hydrophilicity have qualities resembling those of biological tissues, making them ideal candidates for use as smart biomedical materials. Reactive oxygen species (ROS) responsive hydrogels are an innovative class of smart hydrogels, and are cross-linked by ROS-responsive modules through covalent interactions, coordination interactions, or supramolecular interactions. Due to the introduction of ROS response modules, this class of hydrogels exhibits a sensitive response to the oxidative stress microenvironment existing in organisms. Simultaneously, due to the modularity of the ROS-responsive structure, ROS-responsive hydrogels can be manufactured on a large scale through additive manufacturing. This review will delve into the design, fabrication, and applications of ROS-responsive hydrogels. The main goal is to clarify the chemical principles that govern the response mechanism of these hydrogels, further providing new perspectives and methods for designing responsive hydrogel materials.

Polyphenols-based intelligent oral barrier membranes for periodontal bone defect reconstruction.

Periodontitis-induced periodontal bone defects significantly impact patients' daily lives. The guided tissue regeneration and guided bone regeneration techniques, which are based on barrier membranes, have brought hope for the regeneration of periodontal bone defects. However, traditional barrier membranes lack antimicrobial properties and cannot effectively regulate the complex oxidative stress microenvironment in periodontal bone defect areas, leading to unsatisfactory outcomes in promoting periodontal bone regeneration. To address these issues, our study selected the collagen barrier membrane as the substrate material and synthesized a novel barrier membrane (PO/4-BPBA/Mino@COL, PBMC) with an intelligent antimicrobial coating through a simple layer-by-layer assembly method, incorporating reactive oxygen species (ROS)-scavenging components, commercial dual-functional linkers and antimicrobial building blocks. Experimental results indicated that PBMC exhibited good degradability, hydrophilicity and ROS-responsiveness, allowing for the slow and controlled release of antimicrobial drugs. The outstanding antibacterial, antioxidant and biocompatibility properties of PBMC contributed to resistance to periodontal pathogen infection and regulation of the oxidative balance, while enhancing the migration and osteogenic differentiation of human periodontal ligament stem cells. Finally, using a rat periodontal bone defect model, the therapeutic effect of PBMC in promoting periodontal bone regeneration under infection conditions was confirmed. In summary, the novel barrier membranes designed in this study have significant potential for clinical application and provide a reference for the design of future periodontal regenerative functional materials.

Supramolecular assembly of isomeric SN-38 prodrugs regulated by conjugation sites.

Supramolecular polymers (SPs) are an emerging class of drug transporters employed to improve drug therapy. Through the rational design of self-assembling monomers, one can optimize the properties of the resulting supramolecular nanostructures, such as size, shape, surface chemistry, release, and, therefore, biological fates. This study highlights the design of isomeric SN38 prodrugs through the conjugation of hydrophilic oligo(ethylene glycol) (OEG) with hydroxyls at positions 10 and 20 on hydrophobic SN-38. Self-assembling prodrug (SAPD) isomers 10-OEG-SN38 and 20-OEG-SN38 can self-assemble into giant nanotubes and filamentous assemblies, respectively, via aromatic associations that dominate self-assembly. Our study reveales the influence of modification sites on the assembly behavior and ability of the SN38 SAPDs, as well as drug release and subsequent in vitro and in vivo antitumor effects. The SAPD modified at position 20 exhibits stronger π-π interactions among SN38 units, leading to more compact packing and enhanced assembly capability, whereas OEG at position 10 poses steric hindrance for aromatic associations. Importantly, owing to its higher chemical and supramolecular stability, 20-OEG-SN38 outperforms 10-OEG-SN38 and irinotecan, a clinically used prodrug of SN38, in a CT26 tumor model, demonstrating enhanced tumor growth inhibition and prolonged animal survival. This study presents a new strategy of using interactions among drug molecules as dominating features to create supramolecular assemblies. It also brings some insights into creating effective supramolecular drug assemblies via the engineering of self-assembling building blocks, which could contribute to the optimization of design principles for supramolecular drug delivery systems.

Sonochemical Synthesis of Natural Polyphenolic Nanoparticles for Modulating Oxidative Stress.

Natural polyphenolic compounds play a vital role in nature and are widely utilized as building blocks in the fabrication of emerging functional nanomaterials. Although diverse fabrication methodologies are developed in recent years, the challenges of purification, uncontrollable reaction processes and additional additives persist. Herein, a modular and facile methodology is reported toward the fabrication of natural polyphenolic nanoparticles. By utilizing low frequency ultrasound (40 kHz), the assembly of various natural polyphenolic building blocks is successfully induced, allowing for precise control over the particle formation process. The resulting natural polyphenolic nanoparticles possessed excellent in vitro antioxidative abilities and in vivo therapeutic effects in typical oxidative stress models including wound healing and acute kidney injury. This study opens new avenues for the fabrication of functional materials from naturally occurring building blocks, offering promising prospects for future advancements in this field.

Quaternary Ammonium Assisted Synthesis of Melanin-like Poly(l-DOPA) Nanoparticles with a Boosted Photothermal Effect.

Poly(levodopa) nanoparticles (P(l-DOPA) NPs) are another kind of melanin mimetic besides well-established polydopamine nanoparticles (PDA NPs). Due to the presence of carboxyl groups, the oxidative polymerization of l-DOPA to obtain particles was not as efficient as that of dopamine. Several established methods toward P(l-DOPA) NP fabrication do not combine convenience, morphological regularity, size controllability, low cost, and adaptability to metal-free application scenarios. In this work, P(l-DOPA) NPs were successfully prepared in hot water with the assistant of organic quaternary ammonium, due to the extra physical cross-linking mediated by cations. The employed physical interactions could also be affected by quaternary ammonium structure (i.e., number of cation heads, length of alkyl chain) to achieve different polymerization acceleration effects. The obtained P(l-DOPA) NPs retained superior photothermal properties and outperformed PDA-based melanin materials. Furthermore, P(l-DOPA) NPs were used in photothermal tumor therapy and showed better efficacy. This study offers new insights into the synthesis of melanin-like materials, as well as new understanding of the interaction between quaternary ammonium and bioinspired polyphenolic materials.

Eumelanin-like Poly(levodopa) Nanoscavengers for Inflammation Disease Therapy.

In the current years, polydopamine nanoparticles (PDA NPs) have been extensively investigated as an eumelanin mimic. However, unlike natural eumelanin, PDA NPs contain no 5,6-dihydroxyindole-2-carboxylic acid (DHICA)-derived units and may be limited in certain intrinsic properties; superior eumelanin-like nanomaterials are still actively being sought. Levodopa (l-DOPA) is a natural eumelanin precursor and expected to convert into DHICA and further remain within the final product through covalent or physical interactions. Herein, poly(levodopa) nanoparticles [P(l-DOPA) NPs] were synthesized with the assistance of zinc oxide as a supplement to synthetic eumelanin. This study found that P(l-DOPA) NPs had ∼90% DHICA-derived subunits on their surface and exhibited superior antioxidant activity compared to PDA NPs due to their looser polymeric microstructure. Benefitting from a stronger ROS scavenging ability, P(l-DOPA) NPs outperformed PDA NPs in treating cellular oxidative stress and acute inflammation. This research opens up new possibilities for the development and application of novel melanin-like materials.

Functional Polyphenol-Based Nanoparticles Boosted the Neuroprotective Effect of Riluzole for Acute Spinal Cord Injury.

Riluzole is commonly used as a neuroprotective agent for treating traumatic spinal cord injury (SCI), which works by blocking the influx of sodium and calcium ions and reducing glutamate activity. However, its clinical application is limited because of its poor solubility, short half-life, potential organ toxicity, and insufficient bioabilities toward upregulated inflammation and oxidative stress levels. To address this issue, epigallocatechin gallate (EGCG), a natural polyphenol, was employed to fabricate nanoparticles (NPs) with riluzole to enhance the neuroprotective effects. The resulting NPs demonstrated good biocompatibility, excellent antioxidative properties, and promising regulation effects from the M1 to M2 macrophages. Furthermore, an in vivo SCI model was successfully established, and NPs could be obviously aggregated at the SCI site. More interestingly, excellent neuroprotective properties of NPs through regulating the levels of oxidative stress, inflammation, and ion channels could be fully demonstrated in vivo by RNA sequencing and sophisticated biochemistry evaluations. Together, the work provided new opportunities toward the design and fabrication of robust and multifunctional NPs for oxidative stress and inflammation-related diseases via biological integration of natural polyphenols and small-molecule drugs.

UV absorption enhanced polydopamine coating.

Mussel-inspired polydopamine (PDA) coatings have gained significant attention in various fields, including biomedicine, energy, detection, and UV protection, owing to their versatile and promising properties. Among these properties, UV shielding stands out as a key feature of PDA coatings. Nevertheless, the current methods for tuning the UV-shielding properties of PDA coatings are quite limited, and only rely on thickness adjustment, which might involve additional issues like color and visible light transmittance to the coating layer. In this study, we propose a facile and modular approach to enhance the UV absorption of PDA coatings by incorporating thiol-heterocycle (TH) derivatives. Both pre- and post-modification strategies can effectively impede the formation of conjugated structures within PDA, leading to enhanced UV absorption within the PDA layers. More importantly, these strategies can improve the UV absorption of PDA coatings while reducing the visible light absorption. Furthermore, this method enabled efficient regulation of the UV absorption of PDA coatings by altering the ring type (benzene ring or pyridine ring) and substituent on the ring (methoxyl group or hydrogen atom). These PDA coatings with enhanced UV absorption demonstrate great promise for applications in UV protection, antibacterial activity, wound healing and dye degradation.

Polyphenolic Platform Ameliorated Sanshool for Skin Photoprotection.

Natural evolution has nurtured a series of active molecules that play vital roles in physiological systems, but their further applications have been severely limited by rapid deactivation, short cycle time, and potential toxicity after isolation. For instance, the instability of structures and properties has greatly descended when sanshool is derived from Zanthoxylum xanthoxylum. Herein, natural polyphenols are employed to boost the key properties of sanshool by fabricating a series of nanoparticles (NPs). The intracellular evaluation and in vivo animal model are conducted to demonstrate the decreased photodamage score and skin-fold thickness of prepared NPs, which can be attributed to the better biocompatibility, improved free radical scavenging, down-regulated apoptosis ratios, and reduced DNA double-strand breaks compared to naked sanshool. This work proposes a novel strategy to boost the key properties of naturally occurring active molecules with the assistance of natural polyphenol-based platforms.

Natural polyphenolic antibacterial bio-adhesives for infected wound healing.

Bio-adhesives used clinically, commonly have the ability to fill surgical voids and support wound healing, but which are devoid of antibacterial activity, and thus, could not meet the particular needs of the infected wound site. Herein, a series of natural polyphenolic antibacterial bio-adhesives were prepared via simple mixing and heating of polyphenols and acid anhydrides without any solvent or catalyst. Upon the acid anhydride ring opening and acylation reactions, various natural polyphenolic bio-adhesives could adhere to various substrates (i.e., tissue, wood, glass, rubber, paper, plastic, and metal) based on multi-interactions. Moreover, these bio-adhesives showed excellent antibacterial and anti-infection activity, rapid hemostatic performance and appropriate biodegradability, which could be widely used in promoting bacterial infection wound healing and hot burn infection wound repair. This work could provide a new strategy for strong adhesives using naturally occurring molecules, and provide a method for the preparation of novel multifunctional wound dressings for infected wound healing.

Robust and Multifunctional Therapeutic Nanoparticles against Peritonitis-Induced Sepsis.

Apart from bacterial growth and endotoxin generation, the excessive production of reactive radicals linked with sepsis also has a substantial impact on triggering an inflammatory response and further treatment failure. Hence, the rational design and fabrication of robust and multifunctional nanoparticles (NPs) present a viable means of overcoming this dilemma. In this study, we used antibiotic polymyxin B (PMB) and antioxidant natural polyphenolic protocatechualdehyde (PCA) to construct robust and multifunctional NPs for sepsis treatment, leveraging the rich chemistries of PCA. The PMB release profile from the NPs demonstrated pH-responsive behavior, which allowed the NPs to exhibit effective bacterial killing and radical scavenging properties. Data from in vitro cells stimulated with H2O2 and lipopolysaccharide (LPS) showed the multifunctionalities of NPs, including intracellular reactive oxygen species (ROS) scavenging, elimination of the bacterial toxin LPS, inhibiting macrophage M1 polarization, and anti-inflammation capabilities. Additionally, in vivo studies further demonstrated that NPs could increase the effectiveness of sepsis treatment by lowering the bacterial survival ratio, the expression of the oxidative marker malondialdehyde (MDA), and the expression of inflammatory cytokine TNF-α. Overall, this work provides ideas of using those robust and multifunctional therapeutic NPs toward enhanced sepsis therapy efficiency.

Metal-polyphenol networks-modified tantalum plate for craniomaxillofacial reconstruction.

Using three-dimensional (3D) printing technology to make the porous tantalum plate and modify its surface. The physicochemical properties, cytocompatibility, antioxidant capacity, and histocompatibility of the modified materials were evaluated to prepare for the repair of craniomaxillofacial bone defects. The porous tantalum plates were 3D printed by selective laser melting technology. Tantalum plates were surface modified with a metal polyphenol network. The surface-modified plates were analyzed for cytocompatibility using thiazolyl blue tetrazolium bromide and live/dead cell staining. The antioxidant capacity of the surface-modified plates was assessed by measuring the levels of intracellular reactive oxygen species, reduced glutathione, superoxide dismutase, and malondialdehyde. The histocompatibility of the plates was evaluated by animal experiments. The results obtained that the tantalum plates with uniform small pores exhibited a high mechanical strength. The surface-modified plates had much better hydrophilicity. In vitro cell experiments showed that the surface-modified plates had higher cytocompatibility and antioxidant capacity than blank tantalum plates. Through subcutaneous implantation in rabbits, the surface-modified plates demonstrated good histocompatibility. Hence, surface-modified tantalum plates had the potential to be used as an implant material for the treatment of craniomaxillofacial bone defects.

Natural Polyphenolic Nanodots for Alzheimer's Disease Treatment.

The abnormal amyloid-ß accumulation is essential and obbligato in Alzheimer's disease pathogenesis and natural polyphenols exhibit great potential as amyloid aggregation inhibitors. However, the poor metabolic stability, low bioavailability, and weak blood-brain barrier crossing ability of natural polyphenol molecules fail to meet clinical needs. Here, a universal protocol to prepare natural polyphenolic nanodots is developed by heating in aqueous solution without unacceptable additives. The nanodots are able to not only inhibit amyloid-ß fibrillization and trigger the fibril disaggregation, but mitigate the amyloid-ß-plaque-induced cascade impairments including normalizing oxidative microenvironment, altering microglial polarization, and rescuing neuronal death and synaptic loss, which results in significant improvements in recognition and cognition deficits in transgenic mice. More importantly, natural polyphenolic nanodots possess stronger antiamyloidogenic performance compared with small molecule, as well as penetrate the blood-brain barrier. The excellent biocompatibility further guarantees the potential of natural polyphenolic nanodots for clinical applications. It is expected that natural polyphenolic nanodots provide an attractive paradigm to support the development of the therapeutics for Alzheimer's disease.

Biomimetic Polyphenolic Scaffolds with Antioxidative Abilities for Improved Bone Regeneration.

Bone defects have a severe impact on the health and lives of patients due to their long-lasting and difficult-to-treat features. Recent studies have shown that there are complex microenvironments, including excessive production of reactive oxygen species. Herein, a surface functionalization strategy using metal-polyphenolic networks was used, which was found to be beneficial in restoring oxidative balance and enhancing osseointegration. The surface properties, biocompatibility, intracellular ROS scavenging, and osseointegration capacity were evaluated, and the therapeutic effects were confirmed using a skull defect model. This approach has great potential to improve complex microenvironments and enhance the efficiency of bone tissue regeneration.

Robust and Multifunctional Nanoparticles Assembled from Natural Polyphenols and Metformin for Efficient Spinal Cord Regeneration.

The treatment of spinal cord injury (SCI) remains unsatisfactory owing to the complex pathophysiological microenvironments at the injury site and the limited regenerative potential of the central nervous system. Metformin has been proven in clinical and animal experiments to repair damaged structures and functions by promoting endogenous neurogenesis. However, in the early stage of acute SCI, the adverse pathophysiological microenvironment of the injury sites, such as reactive oxygen species and inflammatory factor storm, can prevent the activation of endogenous neural stem cells (NSCs) and the differentiation of NSCs into neurons, decreasing the whole repair effect. To address those issues, a series of robust and multifunctional natural polyphenol-metformin nanoparticles (polyphenol-Met NPs) were fabricated with pH-responsiveness and excellent antioxidative capacities. The resulting NPs possessed several favorable advantages: First, the NPs were composed of active ingredients with different biological properties, without the need for carriers; second, the pH-responsiveness feature could allow targeted drug delivery at the injured site; more importantly, NPs enabled drugs with different performances to exhibit strong synergistic effects. The results demonstrated that the improved microenvironment by natural polyphenols boosted the differentiation of activated NSCs into neurons and oligodendrocytes, which could efficiently repair the injured nerve structures and enhance the functional recovery of the SCI rats. This work highlighted the design and fabrication of robust and multifunctional NPs for SCI treatment via efficient microenvironmental regulation and targeted NSCs activation.

Plant cell wall composition modulates the gut microbiota and metabolites in in-vitro fermentation.

This research investigated the effect of different types of plant cell wall fibres, including cereal (i.e., barley, sorghum, and rice), legume (i.e., pea, faba bean, and mung bean), and tuber (potato, sweet potato, and yam) cell wall fibres on in vitro faecal fermentation profiles and gut microbiota composition. The cell wall composition, specifically the content of lignin and pectin, was found to have a significant influence on the gut microbiota and fermentation outcomes. Compared with type I cell walls (legume and tuber) which have high pectin content, the type II cell walls (cereal) which are high in lignin but low in pectin had a lower fermentation rates and less short-chain fatty acid production. The redundancy analysis showed samples with similar fibre composition and fermentation profiles clustered together, and the principal coordinate analysis revealed separation among different types of cell walls and closer proximity among the same cell wall types. These findings emphasize the importance of cell wall composition in shaping the microbial community during fermentation and contribute to a better understanding of the relationship between plant cell walls and gut health. This research has practical implications for the development of functional foods and dietary interventions.

dECM based dusal-responsive vascular graft with enzyme-controlled adenine release for long-term patency.

Rapid occlusion is the culprit leading to implantation failure of biological blood vessels. Although adenosine is a clinical-proven drug to overcome the problem, its short half-life and turbulent burst-release limit its direct application. Thus, a pH/temperature dual-responsive blood vessel possessed controllable long-term adenosine secretion was constructed based on acellular matrix via compact crosslinking by oxidized chondroitin sulfate (OCSA) and functionalized with apyrase and acid phosphatase. These enzymes, as adenosine micro-generators, controlled the adenosine release amount by "real-time-responding" to acidity and temperature of vascular inflammation sites. Additionally, the macrophage phenotype was switched from M1 to M2, and related factors expression proved that adenosine release was effectively regulated with the severity of inflammation. What's more, the ultra-structure for degradation resisting and endothelialization accelerating was also preserved by their "double-crosslinking". Therefore, this work suggested a new feasible strategy providing a bright future of long-term patency for transplanted blood vessels.

An injectable all-small-molecule dynamic metallogel for suppressing sepsis.

All-small-molecule dynamic hydrogels have shown great promise in cell culture, tissue engineering, and controlled drug release. The further development of more kinds of all-small-molecule dynamic hydrogels is severely hindered by the lack of enough commensurate building blocks from nature and on the market. Inspired by the widely developed metal-organic framework structures, herein we report a facile fabrication of metallogels by direct gelation of small molecular compounds including aminoglycosides (AGs), 2,2'-bipyridine-4,4'-dicarboxaldehyde (BIPY), and metal ions via coordination interactions and Schiff base reactions. These prepared metallogels exhibited good biodegradability and biosafety, excellent conductivity, tunable mechanical properties and potent antibacterial activities both in vitro and in vivo. This study provides a new strategy for expanding the scope of all-small-molecule dynamic metallogels for various biomedical applications.

Polyphenolic-modified cellulose acetate membrane for bone regeneration through immunomodulation.

To enhance the bioactivity of cellulosic derivatives has become an important strategy to promote their value for clinical applications. Herein, protocatechualdehyde (PCA), a polyphenolic molecule, was used to modify a cellulose acetate (CA) membrane by combining with metal ions to confer an immunomodulatory activity. The PCA-modified CA membrane has shown a significant radical scavenging activity, thereby suppressed the inflammatory response and created a favorable immune microenvironment for osteogenesis and mineralization. Moreover, addition of metal ions could further stimulate the osteogenic differentiation of stem cells and accelerate bone regeneration both in vitro and in vivo. This study may provide a strategy to promote the immunomodulatory activity of cellulose-based biomaterials for bone regeneration.

Natural polyphenol-based nanoparticles for the treatment of iron-overload disease.

Iron-overload diseases are characterized by a variety of symptoms resulting from excessive iron stores, oxidative stress and consequent end-organ damage. Deferoxamine (DFO) is an iron-chelator that can protect tissues from iron-induced damage. However, its application is limited due to its low stability and weak free radical scavenging ability. Herein, natural polyphenols have been employed to enhance the protective efficacy of DFO through the construction of supramolecular dynamic amphiphiles, which self-assemble into spherical nanoparticles with excellent scavenging capacity against both iron (III) and reactive oxygen species (ROS). This class of natural polyphenols-assisted nanoparticles was found to exhibit enhanced protective efficacy both in vitro in an iron-overload cell model and in vivo in an intracerebral hemorrhage model. This strategy of constructing natural polyphenols- assisted nanoparticles could benefit the treatment of iron-overload related diseases with excessive accumulation of toxic or harmful substances.