Polymerizable rotaxane of cucurbituril protecting dopamine based adhesive hydrogels.

The catechol moiety found within mussel proteins plays a pivotal role in enhancing their adhesive properties. Nonetheless, catechol compounds, such as dopamine (DOP) derivatives, are susceptible to oxidation, leading to the formation of quinone. This oxidation process poses a significant challenge in the development of DOP-based hydrogels, hampering their adhesion capabilities and hindering polymerization. To protect DOP moieties from oxidation, DOP and N-(3-aminopropyl)methacrylamide (AMA) moieties were grafted onto the side groups of biocompatible poly(glutamic acid) (PGA). Subsequently, the DOP unit, serving as a second guest, would be captured by a polymerizable rotaxane of cucurbituril (CB[n]), in which the host molecule CB[8] complexed with the first guest, polymerizable methyl viologen (MV), forming a protective function and dynamic cross-linking. Upon exposure to light curing, a composite network emerged through the synergy of covalent cross-linking and supramolecular host-guest complexation of DOP with CB[8]. The generated complexation between DOP and CB[8] could protect the DOP moieties, resulting in photocured hydrogels with exceptional adhesive strength and remarkable tensile capabilities. Moreover, 3D printing technology was used to create various models with these DOP-based hydrogels, demonstrating their promising applications in future.

Marriage of High-Throughput Gradient Surface Generation With Statistical Learning for the Rational Design of Functionalized Biomaterials.

Functional biomaterial is already an important aspect in modern therapeutics; yet, the design of novel multi-functional biomaterial is still a challenging task nowadays. When several biofunctional components are present, the complexity that arises from their combinations and interactions will lead to tedious trial-and-error screening. In this work, a novel strategy of biomaterial rational design through the marriage of gradient surface generation with statistical learning is presented. Not only can parameter combinations be screened in a high-throughput fashion, but also the optimal conditions beyond the experimentally tested range can be extrapolated from the models. The power of the strategy is demonstrated in rationally designing an unprecedented ternary functionalized surface for orthopedic implant, with optimal osteogenic, angiogenic, and neurogenic activities, and its optimality and the best osteointegration promotion are confirmed in vitro and in vivo, respectively. The presented strategy is expected to open up new possibilities in the rational design of biomaterials.

Lipase-catalyzed ring-opening polymerization of natural compound-based cyclic monomers.

The need for sustainable and environment-friendly materials has led to growing interest in the development of biodegradable polymers based on natural compounds. However, metal-based catalysts used in the polymerization process may cause concerns about the toxicity of the resultant polymers. Therefore, polymers derived from natural compounds and synthesized through the use of green catalysts are highly desirable. Lipase-catalyzed ring-opening polymerization (ROP) of biocompound-based cyclic monomers has emerged as a promising and green strategy for the design and synthesis of such polymers. In this review, we summarize reports on the use of ROP catalyzed by lipase for cyclic monomers derived from natural compounds, including bile acid- and porphyrin-based macrocycles, carbonate-based macrocycles, lactones, and cyclic anhydrides, with an emphasis on ring-closure reactions for the synthesis of cyclic monomers, the types of lipases for the ROP and the choice of reaction conditions (temperature, solvent, reaction time, etc.). Moreover, the current challenges and perspectives for the choice and reusability of lipases, ring-closure versus ring-opening reactions, monomer design, and potential applications are discussed.

Main-Chain Cationic Bile Acid Polymers Mimicking Facially Amphiphilic Antimicrobial Peptides.

Antibiotic-resistant bacterial infections have led to an increased demand for antibacterial agents that do not contribute to antimicrobial resistance. Antimicrobial peptides (AMPs) with the facially amphiphilic structures have demonstrated remarkable effectiveness, including the ability to suppress antibiotic resistance during bacterial treatment. Herein, inspired by the facially amphiphilic structure of AMPs, the facially amphiphilic skeletons of bile acids (BAs) are utilized as building blocks to create a main-chain cationic bile acid polymer (MCBAP) with macromolecular facial amphiphilicity via polycondensation and a subsequent quaternization. The optimal MCBAP displays an effective activity against Gram-positive methicillin-resistant Staphylococcus aureus (MRSA) and Gram-negative Escherichia coli, fast killing efficacy, superior bactericidal stability in vitro, and potent anti-infectious performance in vivo using the MRSA-infected wound model. MCBAP shows the low possibility to develop drug-resistant bacteria after repeated exposure, which may ascribe to the macromolecular facial amphiphilicity promoting bacterial membrane disruption and the generation of reactive oxygen species. The easy synthesis and low cost of MCBAP, the superior antimicrobial performance, and the therapeutic potential in treating MRSA infection altogether demonstrate that BAs are a promising group of building blocks to mimic the facially amphiphilic structure of AMPs in treating MRSA infection and alleviating antibiotic resistance.

A self-monitoring microneedle patch for light-controlled synergistic treatment of melanoma.

Melanoma is the most aggressive and malignant form of skin cancer. Current melanoma treatment methods generally suffer from frequent drug administration as well as difficulty in direct monitoring of drug release. Here, a self-monitoring microneedle (MN)-based drug delivery system, which integrates a dissolving MN patch with aggregation-induced emission (AIE)-active PATC microparticles, is designed to achieve light-controlled pulsatile chemo-photothermal synergistic therapy of melanoma. The PATC polymeric particles, termed D/I@PATC, encapsulate both of chemotherapeutic drug doxorubicin (DOX) and the photothermal agent indocyanine green (ICG). Upon light illumination, PATC gradually dissociates into smaller particles, causing the release of encapsulated DOX and subsequent fluorescence intensity change of PATC particles, thereby not only enabling direct observation of the drug release process under light stimuli, but also facilitating verification of drug release by fluorescence recovery after light trigger. Moreover, encapsulation of ICG in PATC particles displays significant improvement of its photothermal stability both in vitro and in vivo. In a tumor-bearing mouse, the application of one D/I@PATC MN patch combining with two cycles of light irradiation showed excellent controllable chemo-photothermal efficacy and exhibited ∼97% melanoma inhibition rate without inducing any evident systemic toxicity, suggesting a great potential for skin cancer treatment in clinics.

Inhalable GSH-Triggered Nanoparticles to Treat Commensal Bacterial Infection in In Situ Lung Tumors.

Bacterial infection has been considered one of the primary reasons for low survival rate of lung cancer patients. Herein, we demonstrated that a kind of mesoporous silica nanoparticles loaded with anticancer drug doxorubicin (DOX) and antimicrobial peptide HHC36 (AMP) (MSN@DOX-AMP) can kill both commensal bacteria and tumor cells under GSH-triggering, modulating the immunosuppressive tumor microenvironment, significantly treating commensal bacterial infection, and eliminating in situ lung tumors in a commensal model. Meanwhile, MSN@DOX-AMP encapsulated DOX and AMP highly efficiently via a combined strategy of physical adsorption and click chemistry and exhibited excellent hemocompatibility and biocompatibility. Importantly, MSN@DOX-AMP could be inhaled and accumulate in lung by a needle-free nebulization, achieving a better therapeutic effect. This system is expected to serve as a straightforward platform to treat commensal bacterial infections in tumors and promote the translation of such inhaled GSH-triggered MSN@DOX-AMP to clinical treatments of lung cancer.

Polymerizable rotaxane hydrogels for three-dimensional printing fabrication of wearable sensors.

While hydrogels enable a variety of applications in wearable sensors and electronic skins, they are susceptible to fatigue fracture during cyclic deformations owing to their inefficient fatigue resistance. Herein, acrylated ß-cyclodextrin with bile acid is self-assembled into a polymerizable pseudorotaxane via precise host-guest recognition, which is photopolymerized with acrylamide to obtain conductive polymerizable rotaxane hydrogels (PR-Gel). The topological networks of PR-Gel enable all desirable properties in this system due to the large conformational freedom of the mobile junctions, including the excellent stretchability along with superior fatigue resistance. PR-Gel based strain sensor can sensitively detect and distinguish large body motions and subtle muscle movements. The three-dimensional printing fabricated sensors of PR-Gel exhibit high resolution and altitude complexity, and real-time human electrocardiogram signals are detected with high repeating stability. PR-Gel can self-heal in air, and has highly repeatable adhesion to human skin, demonstrating its great potential in wearable sensors.

Facially Amphiphilic Skeleton-Derived Antibacterial Cationic Dendrimers.

It is urgent to develop biocompatible and high-efficiency antimicrobial agents since microbial infections have always posed serious challenges to human health. Herein, through the marriage of facially amphiphilic skeletons and cationic dendrimers, high-density positively charged dendrimers D-CA6-N+ (G2) and D-CA2-N+ (G1) were designed and synthesized using the "branch" of facially amphiphilic bile acids, followed by their modification with quaternary ammonium charges. Both dendrimers could self-assemble into nanostructured micelles in aqueous solution. D-CA6-N+ displays potent antibacterial activity against Staphylococcus aureus and Escherichia coli, with minimum inhibitory concentrations (MICs) as low as 7.50 and 7.79 µM, respectively, and has an evidently stronger antibacterial activity than D-CA2-N+. Moreover, D-CA6-N+ can kill S. aureus faster than E. coli. The facial amphiphilicity of the bile acid skeleton facilitates the selective destruction of bacterial membranes and endows dendrimers with negligible hemolysis and cytotoxicity even under a high concentration of 16× MIC. In vivo studies show that D-CA6-N+ is much more effective and safer than penicillin G in treating S. aureus infection and promoting wound healing, which suggests facially amphiphilic skeleton-derived cationic dendrimers can be a promising approach to effectively enhance antibacterial activity and biocompatibility of antibacterial agent, simultaneously.

Upper Critical Solution Temperature Polyvalent Scaffolds Aggregate and Exterminate Bacteria.

Specific recognition and strong affinities of bacteria receptors with the host cell glycoconjugates pave the way to control the bacteria aggregation and kill bacteria. Herein, using aggregation-induced emission (AIE) molecules decorated upper critical solution temperature (UCST) polyvalent scaffold (PATC-GlcN), an approach toward visualizing bacteria aggregation and controlling bacteria-polyvalent scaffolds affinities under temperature stimulus is described. Polyvalent scaffolds with diblocks, one UCST block PATC of polyacrylamides showing a sharp UCST transition and typical AIE behavior, the second bacteria recognition block GlcN of hydrophilic glucosamine modified polyacrylamide, are prepared through a reversible addition and fragmentation chain transfer polymerization. Aggregated chain conformation of polyvalent scaffolds at temperature below UCST induces the aggregation of E. coli ATCC8739, because of the high density of glucosamine moieties, whereas beyond UCST, the hydrophilic state of the scaffolds dissociates the bacteria aggregation. The sweet-talking of bacteria toward the polyvalent scaffolds can be visualized by the fluorescent imaging technique, simultaneously. Due to the specific recognition of polyvalent scaffolds with bacteria, the photothermal agent IR780 loaded PATC-GlcN shows the targeted killing ability toward E. coli ATCC8739 in vitro and in vivo under NIR radiation.

Macroporous Adhesive Nano-Enabled Hydrogels Generated from Air-in-Water Emulsions.

Developing nanocomposite hydrogel with multi-functions including adjustable mechanical property, tissue-adhesion, and blood coagulation property to accelerate wound healing is highly desirable in surgical application. Here a macroporous adhesive nano-enabled hydrogel constructed from gelatin methacryloyl stabilized air-in-water emulsions incorporated with dopamine-grafted-gelatin (GelDA) and Laponite nanoclay is reported. The hydrogel exhibits interconnected macroporous structure. The physical/chemical cross-linked network formed among the various components contributes to the good mechanical strength of hydrogel, which could be further regulated by adjusting the concentration of Laponite nanoclay. Furthermore, the nanocomposite macroporous hydrogel is endowed with self-healing properties and tissue adhesion by the intermolecular hydrogen bonds, ionic interactions among Laponite nanoclay and polymers, as well as the catechol functional groups. The in vitro studies demonstrate that the macroporous hydrogel has good biocompatibility and could significantly reduce blood clotting time, which is expected to be applied for the rapid sealing and hemostasis of bleeding wounds.

Biomimetic cartilage-lubricating polymers regenerate cartilage in rats with early osteoarthritis.

The early stages of progressive degeneration of cartilage in articular joints are a hallmark of osteoarthritis. Healthy cartilage is lubricated by brush-like cartilage-binding nanofibres with a hyaluronan backbone and two key side chains (lubricin and lipid). Here, we show that hyaluronan backbones grafted with lubricin-like sulfonate-rich polymers or with lipid-like phosphocholine-rich polymers together enhance cartilage regeneration in a rat model of early osteoarthritis. These biomimetic brush-like nanofibres show a high affinity for cartilage proteins, form a lubrication layer on the cartilage surface and efficiently lubricate damaged human cartilage, lowering its friction coefficient to the low levels typical of native cartilage. Intra-articular injection of the two types of nanofibre into rats with surgically induced osteoarthritic joints led to cartilage regeneration and to the abrogation of osteoarthritis within 8 weeks. Biocompatible injectable lubricants that facilitate cartilage regeneration may offer a translational strategy for the treatment of early osteoarthritis.

Polypseudorotaxanes Derived from Tetraphenylethylene: Preparation and Tandem-Activated Aggregation-Induced Emission.

Tuning the fluorescence of aggregation-induced emission (AIE)-based materials in a reversible way is essential and a requisite for their applications. The multiple host-guest interactions of polypseudorotaxanes (PPRs) could alter the aggregation state of hydrophobic AIE-based polymeric materials and consequently switch the fluorescence. Herein, tetraphenylethylene (TPE) as a typical AIE molecule has been incorporated into the main chains of the guest polyurethane via a step condensation between poly(ethylene glycol) (PEG)-based dicarbonate and TPE-diamine along with the cleavable disulfide bonds. γ-Cyclodextrins (γ-CDs) can selectively recognize the TPE units at the polyurethane chains to afford a PPR. Hydrophilic PEG segments and γ-CD molecules in the PPR could promote the disaggregation of TPE units, suppressing the fluorescence emission of TPE. To restore the aggregated state and fluorescence of TPE units, tris(2-carboxyethyl)phosphine (TCEP) and α-amylase are sequentially introduced to cleave the disulfide bonds and cut α-1,4 glycosidic bonds of γ-CD, reactivating the AIE behavior of PPR tandemly and accomplishing the reversible cycle of tuning the fluorescence of TPE. The present study provides a tandem way to switch the AIE behavior of polymeric materials reversibly.

Recent Progress in Bile Acid-Based Antimicrobials.

With the emergence of drug-resistant bacteria and the formation of biofilms by bacteria and fungi, microbial infections gradually threaten global health. Natural antimicrobial peptides (AMPs) have low susceptibility for developing resistance due to the membrane targeted mechanism, but instability and high manufacturing cost limit their applications in clinic. Bile acids, a group of steroids in the human body, with high stability, biocompatibility, and inherent facial amphiphilic structure similar to the characteristics of AMPs, have been applied to the biological field, such as drug delivery systems, self-healing hydrogels, antimicrobials, and so on. In this review, we mainly focus on the different classes of bile acid-based antimicrobials in recent years. Various designs and methods for the preparation of unimolecular antimicrobials with bile acid skeletons are first introduced, including coupling of primary amine, quaternary ammonium, and amino acid units with bile acid skeletons. Some representative oligomeric antimicrobials, including dimers of bile acids, are summarized. Finally, macromolecular antimicrobials bearing some positive charges at the main chain or side chain and interaction mechanisms of these bile acid-based antimicrobials are discussed.

Fusion peptide engineered "statically-versatile" titanium implant simultaneously enhancing anti-infection, vascularization and osseointegration.

Although antimicrobial titanium implants can prevent biomaterial-associated infection (BAI) in orthopedics, they display cytotoxicity and delayed osseointegration. Therefore, versatile implants are desirable for simultaneously inhibiting BAI and promoting osseointegration, especially "statically-versatile" ones with nonessential external stimulations for facilitating applications. Herein, we develop a "statically-versatile" titanium implant by immobilizing an innovative fusion peptide (FP) containing HHC36 antimicrobial sequence and QK angiogenic sequence via sodium borohydride reduction promoted Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC-SB), which shows higher immobilization efficiency than traditional CuAAC with sodium ascorbate reduction (CuAAC-SA). The FP-engineered implant exhibits over 96.8% antimicrobial activity against four types of clinical bacteria (S. aureus, E. coli, P. aeruginosa and methicillin-resistant S. aureus), being stronger than that modified with mixed peptides. This can be mechanistically attributed to the larger bacterial accessible surface area of HHC36 sequence. Notably, the implant can simultaneously enhance cellular proliferation, up-regulate expressions of angiogenesis-related genes/proteins (VEGF and VEGFR-2) of HUVECs and osteogenesis-related genes/proteins (ALP, COL-1, RUNX-2, OPN and OCN) of hBMSCs. In vivo assay with infection and non-infection bone-defect model reveals that the FP-engineered implant can kill 99.63% of S. aureus, and simultaneously promote vascularization and osseointegration. It is believed that this study presents an excellent strategy for developing "statically-versatile" orthopedic implants.

An activity-based fluorescent probe and its application for differentiating alkaline phosphatase activity in different cell lines.

Herein, a new fluorescent probe, AE-Phos, is reported for detecting the ALP activity with the combined advantages of aggregation-induced emission (AIE) and excited state intramolecular proton transfer (ESIPT). Further detailed fluorescence experiments demonstrated that AE-Phos exhibited excellent selectivity and sensitivity, a large Stokes shift, and a fast response towards ALP. Furthermore, AE-Phos was applied to imaging the ALP activity in different cell lines quantitatively.

Conductive and antimicrobial macroporous nanocomposite hydrogels generated from air-in-water Pickering emulsions for neural stem cell differentiation and skin wound healing.

Electro-active conducting hydrogels have shown promising applications in promoting soft tissue regeneration. However, achieving good conductive performance while simultaneously imparting macroporous structures to these hydrogels still remains challenging. In this study, we report the development of multifunctional conductive macroporous nanocomposite hydrogels (MNHs) prepared by an air-in-water emulsion template that is stabilized by colloidal hybrids of carbon nanotubes (CNTs) and gelatin methacryloyl. The MNH hydrogels demonstrated tunable pore size, electrical conductivity and mechanical properties with various CNT concentrations in the crosslinking matrices. An in vitro cell assay showed that the MNH hydrogels could promote the spreading and differentiation of NE-4C neural stem cells. Furthermore, sustainable release of antimicrobial peptides (AMPs) from the MNH hydrogel can be achieved and the released AMPs maintained high S. aureus killing activity. An in vivo evaluation of the MNH hydrogel using a murine dorsal skin model further showed that the conductive MNH hydrogel loaded with AMPs demonstrated appealing antimicrobial and wound healing performance in two weeks.

Polypeptide-based self-healing hydrogels: Design and biomedical applications.

Self-healing hydrogels can heal themselves on the damaged sites, which opens up a fascinating way for enhancing lifetimes of materials. Polypeptide/poly(amino acid) is a class of polymers in which natural amino acid monomers or derivatives are linked by amide bonds with a stable and similar secondary structure as natural proteins (α-helix or ß-fold). They have the advantages of nontoxicity, biodegradability, and low immunogenicity as well as easy modification. All these properties make polypeptides extremely suitable for the preparation of self-healing hydrogels for biomedical applications. In this review, we mainly focus on the progress in the fabrication strategies of polypeptide-based self-healing hydrogels and their biomedical applications in the recent 5 years. Various crosslinking methods for the preparation of polypeptide-based self-healing hydrogels are first introduced, including host-guest interactions, hydrogen bonding, electrostatic interactions, supramolecular self-assembly of ß-sheets, and reversible covalent bonds of imine and hydrazone as well as molecular multi-interactions. Some representative biomedical applications of these self-healing hydrogels such as delivery system, tissue engineering, 3D-bioprinting, antibacterial and wound healing as well as bioadhesion and hemostasis are also summarized. Current challenges and perspectives in future for these "smart" hydrogels are proposed at the end . STATEMENT OF SIGNIFICANCE: Polypeptides with the advantages of nontoxicity, biodegradability, hydrophilicity and low immunogenicity, are extremely suitable for the preparation of self-healing hydrogels in biomedical applications. Recently, the researches of polypeptide-based self-healing hydrogel have drawn the great attentions for scientists and engineers. A review to summarize the recent progress in design and biomedical applications of these polypeptide-based self-healing hydrogels is highly needed. In this review, we mainly focus on the progress in fabrication strategies of polypeptide-based self-healing hydrogels and biomedical applications in recent five years and aim to draw the increased attention to the importance of these "smart" hydrogels, facilitating the advances in biomedical applications. We believe this work would draw interest from readers of Acta Biomaterialia.

Preparation of collagen/cellulose nanocrystals composite films and their potential applications in corneal repair.

As the main component of the natural cornea, collagen (COL) has been widely applied to the construction of corneal repair materials. However, the applications of collagen are limited due to its poor mechanical properties. Cellulose nanocrystals (CNCs) possess excellent mechanical properties, optical transparency and good biocompatibility. Therefore, in this study, we attempted to introduce cellulose nanocrystals into collagen-based films to obtain corneal repair materials with a high strength. CNCs were incorporated at 1, 3, 5, 7 and 10 wt%. The physical properties of these composite films were characterized, and in vitro cell-based analyses were also performed. The COL/CNC films possessed better mechanic properties, and the introduction of CNCs did not affect the water content and light transmittance. The COL/CNC films demonstrated good biocompatibility toward rabbit corneal epithelial cells and keratocytes in vitro. Moreover, the collagen films with appropriate ration of CNCs effectively induced the migration of corneal epithelial cells and inhibited the myofibroblast differentiation of keratocytes. A collagen film with 7 wt% CNCs displayed the best combination of physical properties and biological performance in vitro among all the films. This study describes a nonchemical cross-linking method to enhance the mechanical properties of collagen for use in corneal repair materials and highlights potential application in corneal tissue engineering.

AND logic gate based fluorescence probe for simultaneous detection of peroxynitrite and hypochlorous acid.

Hypochlorous acid (HOCl) and peroxynitrite (ONOO-) are two of the most important reactive species and associated with various diseases in various physiological and pathological processes. Nonetheless, many of their roles are still vague due to the shortage of methods for simultaneously detecting HOCl and ONOO-. Herein, three simple yet useful fluorogenic probes, LG-1, LG-2 and LG-3, have been fabricated with facile synthesis route and used to monitor the coexistence of HOCl and ONOO- as AND-based logic gate fluorescent probe firstly. LG-1 and LG-2, which consists of 1,3-oxathiolane group and boronate group respectively, were designed to verify the capacity of monitoring HOCl and ONOO- without interference from each other. The result showed that these two groups are perfect reaction sites of detecting HOCl and ONOO- respectively via specific analyte-induced reactions. Hence, LG-3, which is attached by these two groups to suppress the fluorophore core, can response to HOCl and ONOO- simultaneously without mutual interference and generate the significant time-dependent fluorescence enhancement. By investigating the absorption and fluorescence properties of LG-3 towards HOCl and ONOO- individually and collectively, the result confirmed clearly that LG-3 has the capacity of monitoring the coexistence of HOCl and ONOO-, which could act as a two-input AND-based logic gate fluorescent probe.

Engineering topography: Effects on corneal cell behavior and integration into corneal tissue engineering.

Cell-material interactions are important to tissue engineering. Inspired by the natural topographic structures on the extracellular matrix, a growing number of studies have integrated engineering topography into investigations of cell behavior on biomaterials. Engineering topography has a significant influence on cell behaviors. These cell-topography interactions play an important role in regenerative medicine and tissue engineering. Similarly, cell-topography interactions are important to corneal reconstruction and regeneration. In this review, we primarily summarized the effects of topographic cues on the behaviors of corneal cells, including cell morphology, adhesion, migration, and proliferation. Furthermore, the integration of engineering surface topography into corneal tissue engineering was also discussed.