One-step construction of multiplexed enzymatic biosensors using light-addressable electrochemistry on a single silicon photoelectrode.

The multiplexed detection of metabolites in parallel within a single biosensor plate is sufficiently valuable but also challenging. Herein, we combine the inherent light addressability of silicon with the high selectivity of enzymes, for the construction of multiplexed photoelectrochemical enzymatic biosensors. To conduct a stable electrochemistry and reagentless biosensing on silicon, a new strategy involving the immobilization of both redox mediators and enzymes using an amide bond-based hydrogel membrane was proposed. The membrane characterization results demonstrated a covalent coupling of ferrocene mediator to hydrogel, in which the mediator acted as not only a signal generator but also a renewable sacrifice agent. By adding corresponding enzymes on different spots of hydrogel membrane modified silicon and recording local photocurrents with a moveable light pointer, this biosensor setup was used successfully to detect multiple metabolites, such as lactate, glucose, and sarcosine, with good analytical performances. The limits of detection of glucose, sarcosine and lactate were found to be 179 µM, 16 µM, and 780 µM with the linear ranges of 0.5-2.5 mM, 0.3-1.5 mM, and 1.0-3.0 mM, respectively. We believe this proof-of-concept study provides a simple and rapid one-step immobilization approach for the fabrication of reagentless enzymatic assays with silicon-based light-addressable electrochemistry.

Engineering self-healing adhesive hydrogels with antioxidant properties for intrauterine adhesion prevention.

Intrauterine adhesion (IUA) is the fibrosis within the uterine cavity. It is the second most common cause of female infertility, significantly affecting women's physical and mental health. Current treatment strategies fail to provide a satisfactory therapeutic outcome for IUA patients, leaving an enormous challenge for reproductive science. A self-healing adhesive hydrogel with antioxidant properties will be highly helpful in IUA prevention. In this work, we prepare a series of self-healing hydrogels (P10G15, P10G20, and P10G25) with antioxidant and adhesive properties. Those hydrogels exhibit good self-healing properties and can adapt themselves to different structures. They possess good injectability and fit the shape of the human uterus. Moreover, the hydrogels exhibit good tissue adhesiveness, which is desirable for stable retention and therapeutic efficacy. The in vitro experiments using P10G20 show that the adhesive effectively scavenges ABTS+, DPPH, and hydroxyl radicals, rescuing cells from oxidative stress. In addition, P10G20 offers good hemocompatibility and in vitro and in vivo biocompatibility. Furthermore, P10G20 lowers down the in vivo oxidative stress and prevents IUA with less fibrotic tissue and better endometrial regeneration in the animal model. It can effectively downregulate fibrosis-related transforming growth factor beta 1 (TGF-ß1) and vascular endothelial growth factor (VEGF). Altogether, these adhesives may be a good alternative for the clinical treatment of intrauterine adhesion.

Adhesive hydrogels in osteoarthritis: from design to application.

Osteoarthritis (OA) is the most common type of degenerative joint disease which affects 7% of the global population and more than 500 million people worldwide. One research frontier is the development of hydrogels for OA treatment, which operate either as functional scaffolds of tissue engineering or as delivery vehicles of functional additives. Both approaches address the big challenge: establishing stable integration of such delivery systems or implants. Adhesive hydrogels provide possible solutions to this challenge. However, few studies have described the current advances in using adhesive hydrogel for OA treatment. This review summarizes the commonly used hydrogels with their adhesion mechanisms and components. Additionally, recognizing that OA is a complex disease involving different biological mechanisms, the bioactive therapeutic strategies are also presented. By presenting the adhesive hydrogels in an interdisciplinary way, including both the fields of chemistry and biology, this review will attempt to provide a comprehensive insight for designing novel bioadhesive systems for OA therapy.

Succinic Ester-Based Shape Memory Gelatin Sponge for Noncompressible Hemorrhage without Hindering Tissue Regeneration.

Shape memory sponges are very promising in stopping the bleeding from noncompressible and narrow entrance wounds. However, few shape memory sponges have fast degradable properties in order to not hinder tissue healing. In this work, based on cryopolymerization, a succinic ester-based sponge (Ssponge) is fabricated using gelatin and bi-polyethylene glycol-succinimidyl succinate (Bi-PEG-SS). Compared with the commercially available gelatin sponge (Csponge), Ssponge possesses better water/blood absorption ability and higher mechanical pressure over the surrounding tissues. Moreover, in the models of massive liver hemorrhage after transection and noncompressive liver wounds by penetration, Ssponge exhibits a better hemostasis performance than Csponge. Furthermore, in a liver regeneration model, Ssponge-treated livers shows higher regeneration speed compared with Csponge, including a lower injury score, more cavity-like tissues, less fibrosis and enhanced tissue regeneration. Overall, it is shown that Ssponge, with a fast degradation behavior, is not only highly efficient in stopping bleeding but also not detrimental for tissue healing, possessing promising clinical translational potential.

Hydrogel-based delivery system applied in the local anti-osteoporotic bone defects.

Osteoporosis is an age-related systemic skeletal disease leading to bone mass loss and microarchitectural deterioration. It affects a large number of patients, thereby economically burdening healthcare systems worldwide. The low bioavailability and complications, associated with systemic drug consumption, limit the efficacy of anti-osteoporosis drugs currently available. Thus, a combination of therapies, including local treatment and systemic intervention, may be more beneficial over a singular pharmacological treatment. Hydrogels are attractive materials as fillers for bone injuries with irregular shapes and as carriers for local therapeutic treatments. They exhibit low cytotoxicity, excellent biocompatibility, and biodegradability, and some with excellent mechanical and swelling properties, and a controlled degradation rate. This review reports the advantages of hydrogels for adjuvants loading, including nature-based, synthetic, and composite hydrogels. In addition, we discuss functional adjuvants loaded with hydrogels, primarily focusing on drugs and cells that inhibit osteoclast and promote osteoblast. Selecting appropriate hydrogels and adjuvants is the key to successful treatment. We hope this review serves as a reference for subsequent research and clinical application of hydrogel-based delivery systems in osteoporosis therapy.

Cohesion Design-Led Tough Sealants with Controllably Dissolvable Properties.

Leakage is a common complication of surgeries and injuries, causing pain and increasing the economic burden on patients. Although there are commercially available sealants for leakage prevention, few of them are entirely satisfactory due to disease transmission, high cost, and poor biocompatibility. In addition, none of them can be controllably removed for further healthcare. In this paper, by using cohesion design, a sealant based on amino-modified gelatin (AG) and bi-polyethylene glycol N-hydroxysuccinimide active ester (Bi-PEG-SS) was fabricated. To increase the bursting pressure, the cohesion strength was enhanced by increasing the cross-linking density of the sealant. To endow the sealant with controllably dissolvable properties, the smart succinic ester units were introduced into the cohesion network. Both the in vitro and in vivo experiments showed that this sealant processed high bursting pressure with efficient hemorrhage control. Moreover, no side effects were observed after 7 days of in vivo sealing, including little inflammation and fibrogenesis. These results, together with the easy availability of the raw materials, revealed that this sealant might be a promising alternative for leakage sealing.

Cohesion mechanisms for bioadhesives.

Due to the nature of non-invasive wound closure, the ability to close different forms of leaks, and the potential to immobilize various devices, bioadhesives are altering clinical practices. As one of the vital factors, bioadhesives' strength is determined by adhesion and cohesion mechanisms. As well as being essential for adhesion strength, the cohesion mechanism also influences their bulk functions and the way the adhesives can be applied. Although there are many published reports on various adhesion mechanisms, cohesion mechanisms have rarely been addressed. In this review, we have summarized the most used cohesion mechanisms. Furthermore, the relationship of cohesion strategies and adhesion strategies has been discussed, including employing the same functional groups harnessed for adhesion, using combinational approaches, and exploiting different strategies for cohesion mechanism. By providing a comprehensive insight into cohesion strategies, the paper has been integrated to offer a roadmap to facilitate the commercialization of bioadhesives.

Rapidly Self-Deactivating and Injectable Succinyl Ester-Based Bioadhesives for Postoperative Antiadhesion.

Postoperative adhesion not only causes severe complications for patients but also increases their economic burden. Injectable bioadhesives with adhesiveness to tissues can cover irregular wounds and stay stable in situ, which is a promising barrier for antiadhesion. However, the potential tissue adhesion caused by bioadhesives' indiscriminate adhesiveness between normal and wounded tissue is still a problem. Herein, by using poly(ethylene glycol) succinimidyl succinate (PEG-SS) and gelatin, a succinyl ester-based bioadhesive (SEgel) was fabricated with self-deactivating properties for postoperative antiadhesion. Because N-hydroxysuccinimide esters (NHS-esters) were used as the adhesive group, the bioadhesives' side in contact with the tissue built covalent anchors quickly to maintain the stability, but the superficial layer facing outward withstood fast hydrolysis and then lost its adhesion within minutes, avoiding the indiscriminate adhesiveness. In addition, because of the specific degradation behavior of succinyl ester, the SEgel with proper in vivo retention was achieved without the worry of causing foreign body reactions and unexpected tissue adhesion. Both the cecum-sidewall adhesion and hepatic adhesion models showed that the SEgel markedly reduced the severity of tissue adhesion. These results, together with the ease of the preparation process and well-proven biocompatibility of raw materials, revealed that the SEgel might be a promising solution for postoperative antiadhesion.

Applications of Bioadhesives: A Mini Review.

Bioadhesives have demonstrated their superiority in clinical applications as tissue adhesives, hemostats, and tissue sealants. Because of the intrinsic stickiness, the applications have been expanded to various areas, such as functional wound dressing, factor delivery vehicles, and even medical device fixation. While many literature works discussed the mechanism of bioadhesives, few of them specifically summarized the applications of bioadhesives. To fill in the blanks, this review covers recent research articles and focuses precisely on the applications of bioadhesives which can be generally classified as follows: 1) wound closure, 2) sealing leakage, and 3) immobilization, including those already in the clinic and those showing great potential in the clinic. It is expected that this article will provide a whole picture on bioadhesives' applications and lead to innovations in the application of bioadhesives in new fields.

Design of tunable gelatin-dopamine based bioadhesives.

Bioadhesives have a potential to modulate the wound closure process with significant biological outcomes. However, none of the currently commercialized adhesives are satisfactory in their performance. It is a challenging task to develop an adhesive system that can work on wet surface and enhances tissue repair and closure. In this study, we have fabricated a series of gelatin-dopamine (Gel-dop) conjugates and studied their adhesive properties after being chemically crosslinked using sodium periodate. The designed material was assessed for its adhesive properties including tensile, lap shear and peeling study by varying the degree of dopamine substitution. It was observed that the adhesive property has a direct correlation with increase in dopamine content until reaching a maximum and then a subsequent decrease. We tested the adhesive strength of the different formulations by varying the degree of substitution and compared against fibrin glue, which is considered as the gold standard of adhesives. The formulation with a moderate substitution degree demonstrated the optimal adhesive property than those formulations with lower and larger substitution degree. Further, the in vitro cytotoxicity study showed that this tunable Gel-dop adhesives are to non-cytotoxic, indicating a potential use in clinic applications. This study illustrates that adhesiveness can be regulated by changing the degree of dopamine substitution.

Lithium Loaded Octa-Poly(Ethylene Glycol) Based Adhesive Facilitates Axon Regeneration and Reconnection of Transected Peripheral Nerves.

At present, reconnecting the transected nerve in clinic is still mainly reliant on surgery suture. This is a procedure that requires thorough training and is also time consuming. Here, an octa-poly(ethylene glycol) (PEG)-based adhesive for fast reconnecting of the transected peripheral nerve is reported. To enhance the therapeutic efficacy, a succinyl unit is applied to endow the controllably dissolvable property of the adhesive, and lithium is loaded in the adhesive to improve the axonal regeneration. Present data reveal that this adhesive possesses good cytocompatibility and can significantly shorten the reconnecting time of the transected nerve ends compared to that required for suture surgery. Histology, electrophysiological, and behavior assessments indicate that the adhesive reconnected nerves exhibit a low grade of fibrosis, inflammation response, and myoatrophy as well as robust axonal regeneration and functional recovery. Together, these results indicate that this octa-PEG adhesive can act as an alternative to traditional nerve suture in peripheral nerve injury.

An Injectable and Instant Self-Healing Medical Adhesive for Wound Sealing.

Designing versatile functional medical adhesives with injectability, self-healing, and strong adhesion is of great significance to achieve desirable therapeutic effects for promoting wound sealing in healthcare. Herein, a self-healing injectable adhesive is fabricated by physical interaction of polyphenol compound tannic acid (TA) and eight-arm poly(ethylene glycol) end-capped with succinimide glutarate active ester (PEG-SG). The hydrogen bonding induced from the structural unit (-CH2-CH2-O-) of PEG and catechol hydroxyl (-OH) of TA, accompanied by ester exchange between N-hydroxysuccinimide (-NHS) and amino (-NH2) of proteins, contributes to self-healing ability and rapid strong adhesion. Notably, the PEG/TA adhesive can repeatedly adhere to rigid porcine tissues, close the coronary artery under a large incision tension, and bear a heavy load of 2 kg. By exhibiting shear-thinning and anti-swelling properties, the PEG/TA adhesive can be easily applied through single-syringe extrusion onto various wounds. The single-channel toothpaste-like feature of the adhesive ensures its storage hermetically for portable usage. Moreover, in vivo operation and histological H&E staining results indicate that the PEG/TA adhesive greatly accelerates wound healing and tissue regeneration in a rat model. With the specialty of injectability, instant self-healing, and long-lasting strong adhesion to facilitate excellent therapeutic effects, the multifunctional PEG/TA adhesive may provide a new alternative for self-rescue and surgical situations.

Tetra-PEG Based Hydrogel Sealants for In Vivo Visceral Hemostasis.

Medical sealant devices for in vivo hemostasis are far from satisfactory in the aged society. A major challenge is effective integration of quick hemorrhage control of the increased anticoagulated patients, high safety, and facile accessibility. Here, a well-defined ammonolysis-based Tetra-PEG hydrogel sealant is developed with rapid gelation speed, strong tissue adhesion, and high mechanical strength. Introduction of cyclized succinyl ester groups into a hydrogel matrix endows the sealant with fast degradable and controllably dissolvable properties. The hydrogel possesses outstanding hemostatic capabilities even under the anticoagulated conditions while displaying excellent biocompatibility and feasibility. These results reveal that the optimized hydrogel may be a facile, effective, and safe sealant for hemorrhage control in vivo.

Surface Modification of Aliphatic Polyester to Enhance Biocompatibility.

Aliphatic polyester is a kind of biodegradable implantable polymers, which shows promise as scaffolds in tissue engineering, drug carrier, medical device, and so on. To further improve its biocompatibility and cell affinity, many techniques have been used to modify the surface of the polyester. In the present paper, the key factors of influencing biocompatibility of aliphatic polyester were illuminated, and the different surface modification methods such as physical, chemical, and plasma processing methods were also demonstrated. The advantages and disadvantages of each method were also discussed with the hope that this review can serve as a resource for selection of surface modification of aliphatic products.

Microcapsule-embedded hydrogel patches for ultrasound responsive and enhanced transdermal delivery of diclofenac sodium.

Transdermal delivery of diclofenac sodium (DS) has drawn much attention for the advantages of avoiding first-pass metabolism, reduced systemic toxicity and better patient compliance, but the successful translation of reported transdermal drug delivery systems (TDDSs) is still limited by poor skin permeability and uncontrollable drug release. Herein, we designed and fabricated a novel ultrasound responsive TDDS by embedding DS-loaded polyester microcapsules into a hydrogel patch based on four-armed poly(ethylene glycol). The rational design endows the microcapsule-embedded hydrogel patch with good biocompatibility, excellent skin-adhesion properties and well-controlled ultrasound responsive release behavior. More importantly, by employing ultrasound as a simultaneous trigger of drug release and efficient penetration enhancer, the encapsulated drug could be released and pass through the skin barrier rapidly under ultrasound, while without the action of ultrasound, a negligible amount of drug was released and penetrated into the subcutaneous tissues in ex vivo and in vivo transdermal drug release experiments, indicating that improved and controllable transdermal delivery of DS was achieved. Our work demonstrated that the microcapsule-embedded hydrogel patch may be a promising candidate as an ultrasound responsive and enhanced TDDS of DS for treating diseases such as arthritis and topical soft tissue injuries.

Construction of Tough, in Situ Forming Double-Network Hydrogels with Good Biocompatibility.

Hydrogels are required to have high mechanical properties, biocompatibility, and an easy fabrication process for biomedical applications. Double-network hydrogels, although strong, are limited because of the complicated preparation steps and toxic materials involved. In this study, we report a simple method to prepare tough, in situ forming polyethylene glycol (PEG)-agarose double-network (PEG-agarose DN) hydrogels with good biocompatibility. The hydrogels display excellent mechanical strength. Because of the easily in situ forming method, the resulting hydrogels can be molded into any form as needed. In vitro and in vivo experiments illustrate that the hydrogels exhibit satisfactory biocompatibility, and cells can attach and spread on the hydrogels. Furthermore, the residual amino groups in the network can also be functionalized for various biomedical applications in tissue engineering and cell research.

Synthesis and Properties of Hemostatic and Bacteria-Responsive in Situ Hydrogels for Emergency Treatment in Critical Situations.

Immediate hemorrhage control and infection prevention are pivotal for saving lives in critical situations such as battlefields, natural disasters, traffic accidents, and so on. In situ hydrogels are promising candidates, but their mechanical strength is often not strong enough for use in critical situations. In this study, we constructed three hydrogels with different amounts of Schiff-base moieties from 4-arm-PEG-NH2, 4-arm-PEG-NHS, and 4-arm-PEG-CHO in which vancomycin was incorporated as an antimicrobial agent. The hydrogels possess porous structures, excellent mechanical strength, and high swelling ratio. The cytotoxicity studies indicated that the composite hydrogel systems possess good biocompatibility. The Schiff bases incorporated improve the adhesiveness and endow the hydrogels with bacteria-sensitivity. The in vivo hemostatic and antimicrobial experiments on rabbits and pigs demonstrated that the hydrogels are able to aid in rapid hemorrhage control and infection prevention. In summary, vancomycin-loaded hydrogels may be excellent candidates as hemostatic and antibacterial materials for first aid treatment of the wounded in critical situations.

Facile Construction of pH- and Redox-Responsive Micelles from a Biodegradable Poly(ß-hydroxyl amine) for Drug Delivery.

Here we demonstrate a type of pH and reduction dual-sensitive biodegradable micelles, which were self-assembled by a cationic polymer in an aqueous solution. Due to tumor cells or tissues showing low pH and high reduction concentration, these micelles possessed specific tumor targetability and maximal drug-release controllability inside tumor cells upon changes in physical and chemical environments, but presented good stability at physiological conditions. CCK-8 assay showed that the DOX-loaded micelles had a similar cytotoxicity for MCF-7 tumor cells as free DOX, and blank micelles had a very low cytotoxicity to the cells. Fluorescent microscopy observation revealed that the drug-loaded micelles could be quickly internalized by endosomes to inhibit cancer cell growth. These results indicated these biodegradable micelles, as a novel and effective pH- and redox-responsive nanocarrier, have a potential to improve drug delivery and enhance the antitumor efficacy.

Chain length effects in isoflavonoid daidzein alkoxy derivatives as antioxidants: a quantum mechanical approach.

Daidzein, an isoflavonoid with known prooxidative effects in heterogeneous lipid/water systems, changes to an antioxidant for 7-n-alkoxy derivatives of daidzein. For an alkyl length increasing from 4 to 8, 12, and 16 carbons, the oxidation potential decreases gradually from 1.09 V (vs NHE) for daidzein (D) to 0.94 V for D16 in tetrahydrofuran as determined by cyclic voltammetry at 25 °C. The prooxidative effects transform into antioxidative effects from D8 with a maximal effect for D12 for aqueous phase initiation of lipid oxidation in liposomes despite a gradual decrease in Trolox equivalent antioxidant capacity (TEAC) with increasing alkyl chain length. Quantum mechanical calculations using density functional theory (DFT) showed that the bond dissociation energy of the O-H bond of the 4'-phenol is constant along the homologue series in contrast to Δµ, the change in dipole moment upon hydrogen atom donation, which increases for increasing chain length. The frontier orbital energy gap goes through a maximum for D12. The change in the A-to-B dihedral angle upon hydrogen atom donation further shows a maximum for D12 of 6.45°. The importance of these microscopic properties for antioxidative activity was confirmed by a change in liposome fluorescence anisotropy using a fluorescent probe showing maximal penetration into the lipid bilayer for D12 along the homologue series.