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The development of bioadhesives with strong adhesion and on-demand adhesion-detachment behavior is still critically important and challenging for facilitating painless and damage-free removal in clinical applications. In this work, for the first time, we report the easy fabrication of novel polyurethane-urea (PUU)-based bioadhesives with thermoresponsive on-demand adhesion and detachment behavior. The PUU copolymer was synthesized by a simple copolymerization of low-molecular-weight, hydrophilic, and biocompatible poly(ethylene glycol), glyceryl monolaurate (GML, a special chain extender with a long side hydrophobic alkyl group), and isophorone diisocyanate (IPDI). Here, GML was expected to not only adjust the temperature-dependent adhesion behavior but also act as an internal plasticizer. By simple adjustment of the water content, the adhesion strength of the 15 wt % water-containing PUU film toward porcine skin is as high as 55 kPa with an adhesion energy of 128 J/m 2 at 37 °C. The adhesion strength dramatically decreases to only 3 kPa at 10 °C, exhibiting switching efficiency as high as 0.95. Furthermore, the present PUU-based adhesive also shows good on-demand underwater adhesion and detachment with a cell viability close to 100%. We propose that biomaterial research fields, especially novel PUU/polyurethane (PU)-based functional materials and bioadhesives, could benefit from such a novel thermoresponsive copolymer with outstanding mechanical and functional performances and an easy synthesis and scaled-up process as described in this article.

Designing adhesive hydrogel wound dressings with inherent antibacterial and antioxidant properties is desirable to treat cutaneous full-thickness injuries in clinical care. Herein, a series of photo-induced Schiff base crosslinking-based adhesive hydrogels with promising traits are designed and prepared through Diels-Alder (DA) reactions between functional groups-grafted carboxymethyl chitosan (CMCS) and a photo-responsive polyethylene glycol (PEG) crosslinker. The quaternary ammonium and phenol groups in modified CMCS endows hydrogels excellent antibacterial and antioxidant properties. Upon UV (365 nm) irradiation, the generated o-nitrosobenzaldehyde from the photo-isomerization of o-nitrobenzyl in PEG derivative can subsequently crosslink with amino groups on tissue interfaces via Schiff base, endowing the hydrogel with well adhesiveness. Additionally, the hydrogel exhibits good BSA adsorption capacity, cytocompatibility and hemostatic property. The in vivo full-thickness skin defect study on mice indicates that the multi-functional hydrogel with considerable collagen deposition and vascularization capacities can be an effective and promising adhesive dressing for improving wound healing., (Copyright © 2021. Published by Elsevier Ltd.)

Hard or soft tissue adhesives have been presented as a promising candidate to replace traditional wound closure methods. However, there are mechanical strength problems in biological adhesives and biocompatibility problems in synthetic-based adhesives. At this point, we aimed to remove all these disadvantages and produce a single adhesive that contains all the necessary features and acrylate functionalized UV-curable polyurethane formulations were produced with high crosslink density, high adhesion strength, biocompatibility and injectable property for easy application as potential biomedical adhesives. Aliphatic isophorone diisocyanate (IPDI) was used as the isocyanate source and β-cyclodextrin was used for host-guest relationship with gentamicin by crosslinking. Proteins (gelatin (GEL), collagen (COL)) and PEGs of various molecular weight ranges (P200, P400, P600) were selected as the polyol backbone for polyurethane synthesis due to their multiple biological activities such as biocompatibility, biodegradability, biomimetic property. Several techniques have been used to characterize the structural, thermal, morphological, and various other physicochemical properties of the adhesive formulations. Besides, the possibility of its use as a hard tissue adhesive was investigated by evaluating the tissue adhesion strength in vitro and ex vivo via a universal testing analyzer in tensile mode. Corresponding adhesive formulations were evaluated by in vitro and in vivo techniques for biocompatibility. The best adhesion strength results were obtained as 3821.0 ± 214.9, and 3722.2 ± 486.8 kPa, for IPDI-COL-P200 and IPDI-GEL-P200, respectively. Good antibacterial activity capability toward Escherichia coli Pseudomonas aeruginosa, and Staphylococcus aureus were confirmed using disc diffusion method. Moreover, cell viability assay demonstrated that the formulations have no significant cytotoxicity on the L929 fibroblast cells. Most importantly, we finally performed the in vivo biodegradability and in vivo biocompatibility evaluations of the adhesive formulations on rat model. Considering their excellent cell/tissue viability, fast curable, strong adhesion, high antibacterial character, and injectability, these adhesive formulations have significant potential for tissue engineering applications., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Emergent and long-term hemorrhage control is requisite and beneficial for reducing global mortality and postoperative complications (e.g., second bleeding and adverse tissue adhesion). Despite recent advance in injectable hydrogels for hemostasis, achieving rapid gelation, strong tissue-adhesive property and stable mechanical strength under fluid physiological environment is still challenging. Herein, we developed a novel chitosan hydrogel (CCS@gel) via dynamic Schiff base reaction and mussel-inspired catechol chemistry. The hydrogel possessed high gelation rate (<10 s), strong wet adhesiveness, excellent self-healing performance and biocompatibility. More importantly, the CCS@gel exhibited saline-induced contractile performance and mechanical enhancement, promoting its mechanical property in moist internal conditions. In vivo studies demonstrated its superior hemostatic efficacy for diverse anticoagulated visceral and carotid bleeding scenarios, compared to commercialized fibrin glue. The hydrogel-treated rats survived for 8 weeks with minimal inflammation and postoperative adhesion. These results revealed that the promising CCS@gel would be a facile, efficient and safe sealant for clinical hemorrhage control., (Copyright © 2021. Published by Elsevier Ltd.)

In recent years, multifunctional hydrogels have garnered great interest. Usually, there is a contradiction between the toughness and interface adhesion of traditional hydrogels. In engineering and medical applications, hydrogels need to have good adhesive properties and toughness. The design of functional hydrogels with strong adhesion and high toughness is key to their application. In this review, the research progress of adhesive and tough hydrogels in recent years is outlined. Specifically, the structural design (such as integrated, layered, and gradient structures) and applications (such as cartilage repair, drug delivery, strain sensors, tissue adhesives, soft actuators, and supercapacitors) of adhesive and tough hydrogels are classified and discussed, providing new insights on their design and development.

Chitosan-based hydrogels have been widely used for various biomedical applications due to their versatile properties such as biocompatibility, biodegradability, muco-adhesiveness, hemostatic effect and so on. However, the inherent rigidity and brittleness of pure chitosan hydrogels are still unmanageable, which has limited their potential use in biomaterial research. In this study, we developed in situ forming chitosan/PEG hydrogels with improved mechanical properties, using the enzymatic crosslinking reaction of horseradish peroxidase (HRP). The effect of PEG on physico-chemical properties of hybrid hydrogels was thoroughly elucidated by varying the content (0-100 %), molecular weight (4, 10 and 20 kDa) and geometry (linear, 4-arm) of the PEG derivatives. The resulting hydrogels demonstrated excellent hemostatic ability and are highly biocompatible in vivo, comparable to commercially available fibrin glue. We suggest these chitosan/PEG hybrid hydrogels with tunable physicochemical and tissue adhesive properties have great potential for a wide range of biomedical applications in the near future., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Hemorrhage remains one of the direct causes of high mortality. The development of ideal hemostatic materials with sound ability to deal with severe wound is urgent needed. Although starch-based hemostatic powder has been widely used, hydrous physiological environments severely hamper its binding to the target tissue, thereby limiting the effectiveness in hemostasis. Herein, inspired by mussel adhesive protein, a novel injectable tissue-adhesive hydrogel (St-Dopa hydrogel) composed of starch, succinic anhydride and dopamine was developed in situ by enzymatic crosslinking. The results show that St-Dopa hydrogels were intimately integrated with biological tissue and formed robust barriers to reduce blood loss. St-Dopa hydrogels exhibited superior capacity for in vitro and in vivo hemostasis as compared with chitin hydrogels. In addition to the ease of operation, St-Dopa hydrogels exhibited rapid sol-gel transition, porous microscopic morphology, good swelling ratio and biodegradability, tissue-like elastomeric mechanical properties and excellent cyto/hemo-compatibility. These results suggest that this newly developed St-Dopa hydrogel is a promising biological adhesive and hemostatic material.

Tissue adhesives have emerged as an effective method for wound closure and hemostasis in recent decades, due to their ability to bond tissues together, preventing separation from one tissue to another. However, existing tissue adhesives still have several limitations. Tremendous efforts have been invested into developing new tissue adhesives by improving upon existing adhesives through different strategies. Therefore, highlighting and analyzing these design strategies are essential for developing the next generation of advanced adhesives. To this end, we reviewed the available strategies for modifying traditional adhesives (including cyanoacrylate glues, fibrin sealants and BioGlue), as well as design of emerging adhesives (including gelatin sealants, methacrylated sealants and bioinspired adhesives), focusing on their structures, adhesive mechanisms, advantages, limitations, and current applications. The bioinspired adhesives have numerous advantages over traditional adhesives, which will be a wise direction for achieving tissue adhesives with superior properties., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Schiff base reaction crosslinking hydrogels are advantageous by rapid formation and absence of external crosslinkers. However, poor mechanical hindered their broader applications. Here, a mechanically strengthened tissue adhesive was constructed through incorporation of chitin nano-whiskers (CtNWs) with a Schiff base crosslinking hydrogel of carboxymethyl chitosan (CMCS) and dextran dialdehyde (DDA). The optimal formulation of complexed hydrogel exhibited 1.87 folds higher compressive stress than non-complexed and 1.51 time higher adhesive strength on porcine skin. The complexed hydrogel exhibited negligible cytotoxicity, anti-swelling performance in PBS, optimum antibacterial and hemostatic capacities. In vivo implantation studies confirmed the complexed hydrogel was degradable without long-term inflammatory responses. Desirable efficacy of injectable complexed hydrogel as hemostat was demonstrated in rat liver injury model, which could avoid severe postoperative adhesion and necrosis as observed in the treatment with commercial 3 M™ vetbond™ tissue adhesive. The results highlighted that the complexed hydrogel potentiated rapid hemostasis and wound repair applications., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Tuning the configuration of lanthanide-doped upconversion nanoparticles (UCNPs) has been proven to be an effective approach to enhance upconversion (UC) efficiency, especially for neodymium (Nd 3+ )-sensitized UCNPs. Rational configuration design can spatially separate activators and sensitizers, achieving the evolution from single core to multilayer structures. However, optimizing multiphoton UC emission via configuration modulation, especially in the ultraviolet range, is yet to be fully investigated. In this work, thickness tuning of the sensitizing layer containing Nd 3+ ions and the inert layer containing gadolinium ions at a fixed combined thickness of 5 nm in tetralayer UCNPs to exclude the size effect is reported for the first time. The optimal thickness of sensitizing and inert layers was determined to be 3 and 2 nm respectively, showing a new strategy of balancing sensitization and surface passivation to enhance 4-photon (360 nm) emission. Although 3-photon emission (475 nm) is mainly influenced by the overall size, its emission intensity remains similar in all the tetralayer UCNPs. Additionally, an 808 nm cross-linked hydrogel has been demonstrated as a potential near-infrared activated tissue sealant. Our results have uncovered the structural parameters for optimal ultraviolet UC emissions and elucidated the strategic importance of nano-configuration design to minimize the energy loss in the high-photon UC process.

Wound dressing materials are widely used to protect wounds from the external environment and to promote wound healing. However, conventional wound dressings lack tissue adhesive properties and anti-inflammatory functions, which lead to fibrosis and stricture, in cases such as gastrointestinal wounds after endoscopic surgery. In the current study, we report tissue-adhesive and anti-inflammatory properties of a wound dressing composed of corticosteroid-modified gelatin particles. Hydrocortisone (HC), which is a class of anti-inflammatory corticosteroid, was used to modify Alaska-pollock gelatin (ApGltn) to synthesize HC-modified ApGltn (HC-ApGltn). Microparticles (MPs) of HC-ApGltn were fabricated by adding ethanol in HC-ApGltn aqueous solution and performing thermal crosslinking (TC) without the use of toxic surfactants and crosslinking reagents. Modification of ApGltn with hydrophobic HC containing cholesterol backbone structure improved its adhesion strength to gastric submucosal tissues under wet conditions owing to hydrophobic interactions. This retention of adhesive property under wet conditions allows for stable protection of wounds from the external environment. We found that HC-ApGltn MPs were taken up by macrophages and they effectively suppressed morphological changes of LPS-activated macrophages and the expression level of the inflammatory cytokine. Robust tissue adhesive and anti-inflammatory MPs may serve as an advanced wound dressing that can protect wounds and suppress inflammatory responses for promoting wound healing., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interest., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Mussels are well-known for their extraordinary capacity to adhere onto different surfaces in various hydrophillic conditions. Their unique adhesion ability under water or in wet conditions has generated considerable interest towards developing mussel inspired polymeric systems that can mimic the chemical mechanisms used by mussels for their adhesive properties. Catechols like 3,4-dihydroxy phenylalanine (DOPA) and their biochemical interactions have been largely implicated in mussels' strong adhesion to various substrates and have been the centerpoint of research and development efforts towards creating superior tissue adhesives for surgical and tissue engineering applications. In this article, we review bioadhesion and adhesives from an engineering standpoint, specifically the requirements of a good tissue glue, the relevance that DOPA and other catechols have in tissue adhesion, current trends in mussel-inspired bioadhesives, strategies to develop mussel-inspired tissue glues, and perspectives for future development of these materials.

Bio-inspired wet adhesives attract considerable attention in the biomedical field. However, achieving reversible and controllable wet adhesion still remains a challenging issue. In this study, we report a new thermo-responsive polysaccharide wet adhesive conjugate named Chitosan-Catechol-poly(N-isopropyl acrylamide) (Chitosan-Catechol-pNIPAM), where catechol, the wet adhesive moiety, and pNIPAM, the thermal responsive group, are chemically tethered to a chitosan backbone. The as-synthesized Chitosan-Catechol-pNIPAM presents a reversible sol-gel transition behavior when the temperature is cycled below and above the lower critical solution temperature (LCST, 35 °C), along with dynamic switching between lubrication and wet adhesion on various materials. Based on these excellent features, Chitosan-Catechol-pNIPAM can realize controllable attachment/detachment behavior over the skin through heating/cooling processes. Due to its good biocompatibility, the Chitosan-Catechol-pNIPAM coated syringe needles exhibit instant hemostasis after removing the needles from the punctured sites of mouse veins. Overall, the as-synthesized Chitosan-Catechol-pNIPAM is expected to be used as a new intelligent adhesive in various biomedical settings.

Inspired by the mussel foot protein and chitosan-based macromolecular adhesives, a series of chitosan-graft-polypeptides were synthesized by ring-opening polymerization of three N-carboxyanhydrides (NCAs) - 3,4-dihydroxyphenylalanine-N-carboxyanhydride (DOPA-NCA), cysteine-NCA (Cys-NCA) and arginine-NCA (Arg-NCA) - using partial-NH 2 -protected chitosan as an initiator. These copolymers demonstrated good biodegradability and low cytotoxicity. The results of lap-shear adhesion test showed that the maximum lap-shear adhesion strength on the porcine skin and aluminum sheet were 195.97 ± 21.1 kPa and 3080 ± 320 kPa, respectively, and the maximum tensile adhesion strength on bone was 642.70 ± 61.1 kPa. The rat experiment in vivo showed that these copolymers exhibited good hemostatic performance and can promote the healing of skin wound and bone fracture. It is expected that thesecopolymeric adhesives will have broad applications in hemostasis and soft tissue adhesions., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Bioadhesives such as tissue adhesives, hemostatic agents, and tissue sealants have gained increasing popularity in different areas of clinical operations during the last three decades. Bioadhesives can be categorized into internal and external ones according to their application conditions. External bioadhesives are generally applied in topical medications such as wound closure and epidermal grafting. Internal bioadhesives are mainly used in intracorporal conditions with direct contact to internal environment including tissues, organs and body fluids, such as chronic organ leak repair and bleeding complication reduction. This review focuses on internal bioadhesives that, in contrast with external bioadhesives, emphasize much more on biocompatibility and adhesive ability to wet surfaces rather than on gluing time and intensity. The crosslinking mechanisms of present internal bioadhesives can be generally classified as follows: 1) chemical conjugation between reactive groups; 2) free radical polymerization by light or redox initiation; 3) biological or biochemical coupling with specificity; and 4) biomimetic adhesion inspired from natural phenomena. In this review, bioadhesive products of each class are summarized and discussed by comparing their designs, features, and applications as well as their prospects for future development., Statement of Significance: Despite the emergence of numerous novel bioadhesive formulations in recent years, thus far, the classification of internal and external bioadhesives has not been well defined and universally acknowledged. Many of the formulations have been proposed for treatment of several diseases even though they are not applicable for such conditions. This is because of the lack of a systematic standard or evaluation protocol during the development of a new adhesive product. In this review, the definition of internal and external bioadhesives is given for the first time, and with a focus on internal bioadhesives, the criteria of an ideal internal bioadhesive are adequately discussed; this is followed by the review of recently developed internal bioadhesives based on different gluing mechanisms., (Copyright © 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Cyanoacrylate adhesives and their homologues have elicited interest over the past few decades owing to their applications in the biomedical sector, extending from tissue adhesives to scaffolds to implants to dental material and adhesives, because of their inherent biocompatibility and ability to polymerize solely with moisture, thanks to which they adhere to any substrate containing moisture such as the skin. The ability to tailor formulations of alkyl cyanoacrylate to form derivative compounds to meet application requirements along with their biodegradability in conjunction with their inherent biocompatibility make them highly sought after candidates in the biomedical sector. There has been extensive exploration of cyanoacrylate adhesives and their homologue systems in biomedical applications, but no consolidated literature of the vast data is available. The ability of cyanoacrylate adhesives to cure at low temperatures and without the need for any hardener, which is attributed to the high-strength bonding interaction between two non-amalgamating substrates, with their ease of dispersion and self-curing, avoids the curtailing of the effective utilization of such adhesives in biomedical engineering applications as bio glues for amalgamating tissues, implants, scaffolds etc. This article consolidates copious work on cyanoacrylate adhesives and their derived systems which are functional in versatile biomedical engineering applications such as bio glues, dental material and adhesives and other potential applications.

Tissue adhesives play an important role in surgery to close wounds, seal tissues, and stop bleeding, but existing adhesives are costly, cytotoxic, or bond weakly to tissue. Inspired by the water-resistant adhesion of plant-derived tannins, we herein report a new family of bioadhesives derived from a facile, one-step Michael addition of tannic acid and gelatin under oxidizing conditions and crosslinked by silver nitrate. The oxidized polyphenol groups of tannic acid enable wet tissue adhesion through catecholamine-like chemistry, while both tannic acid and silver nanoparticles reduced from silver nitrate provide antimicrobial sources inherent within the polymeric network. These tannin-inspired gelatin bioadhesives are low-cost and readily scalable and eliminate the concerns of potential neurological effect brought by mussel-inspired strategy due to the inclusion of dopamine; variations in gelatin source (fish, bovine, or porcine) and tannic acid feeding ratios resulted in tunable gelation times (36 s-8 min), controllable degradation (up to 100% degradation within a month), considerable wet tissue adhesion strengths (up to 3.7 times to that of fibrin glue), excellent cytocompatibility, as well as antibacterial and antifungal properties. The innate properties of tannic acid as a natural phenolic crosslinker, molecular glue, and antimicrobial agent warrant a unique and significant approach to bioadhesive design., Statement of Significance: This manuscript describes the development of a new family of tannin-inspired antimicrobial bioadhesives derived from a facile, one-step Michael addition of tannic acid and gelatin under oxidizing conditions and crosslinked by silver nitrate. Our strategy is new and can be easily extended to other polymer systems, low-cost and readily scalable, and eliminate the concerns of potential neurological effect brought by mussel-inspired strategy due to the inclusion of dopamine. The tannin-inspired gelatin bioadhesives hold great promise for a number of applications in wound closure, tissue sealant, hemostasis, antimicrobial and cell/drug delivery, and would be interested to the readers from biomaterials, tissue engineering, and drug delivery area., (Copyright © 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

In the present study, MG-g-poly(NVP) was synthesized using microwave-assisted graft co-polymerization reaction. Synthesis of graft co-polymer was optimized using response surface methodology. The influence of concentration of Moringa gum, N-vinyl-2-pyrrolidone and ammonium persulfate on grafting efficiency of graft copolymer was studied using 3-factor, 3-level central composite experimental design. The optimal calculated parameters were found to be concentration of Moringa gum-1% (w/v), N-vinyl-2-pyrrolidone-2% (w/v), and ammonium persulfate-10 mMol/L, which yielded a graft co-polymer of% grafting efficiency (24.23%). The graft co-polymer were further characterized by Fourier-transform infrared spectroscopy, X-ray diffraction and scanning electron microscopy studies. The results of characterization revealed that grafting of N-vinyl-2-pyrrolidone on Moringa gum decreases its crystallinity and makes its surface smoother. Graft copolymer was further evaluated for pharmaceutical application by formulating clotrimazole-loaded buccal discs. A comparative evaluation of buccal discs of graft co-polymer with native gum revealed higher ex-vivo bioadhesion time and greater sustained release effect of the graft copolymer than of native gum., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: The development and application of medical glue has been continuously expanding and advancing. However, there are few glues that combine low-cost with excellent biocompatibility., Methods: We have prepared a medical tissue glue using a gelatin (Gel), sericin (SS) and carboxymethyl chitosan (CMCS) blend solution, cross-linked with 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC). The combination's characteristics and microstructure morphology were observed by Fourier transform infrared spectroscopy (FT-IR) and scanning electron microscope (SEM). Bond strength tests were used to measure the bond strength of the glue. To assay blood compatibility, a hemolytic test, dynamic coagulation test and platelet adherence test were also investigated. Further, the cellular behavior of L-929 and a systemic acute toxicity test on the Gel/SS/CMCS tissue glue were also investigated by MTT and H&E staining., Results: Characterization analysis showed that there was stable binding between raw materials, forming an amide bond with homogeneous holes. The bond strength of the tissue glue reached 2.50 ± 0.04 N in 10 minutes, slightly higher than the alpha-cyanoacrylate biological glue (2.25 ± 0.05 N). Blood compatibility tests revealed that the glue had outstanding blood compatibility. Further, cytotoxicity test and systemic acute toxicity test both showed that the glue was without cytotoxicity and not toxic to the body., Conclusions: The Gel/SS/CMCS tissue glue we prepared at low cost had excellent biocompatibility and structural characteristics. It could be a better candidate for tissue engineering in biomedical applications applied in clinical practice to promote skin wound healing and to further reduce the formation of skin wound scars.

Tissue adhesives based on polyamidoamine (PAMAM) dendrimer, grafted with UV-sensitive aryldiazirine (PAMAM-g-diazirine) are promising new candidates for light active adhesion on soft tissues. Diazirine carbene precursors form interfacial and intermolecular covalent crosslinks with tissues after UV light activation that requires no premixing or inclusion of free radical initiators. However, primary amines on the PAMAM dendrimer surface present a potential risk due to their cytotoxic and immunological effects. PAMAM-g-diazirine formulations with cationic pendant amines converted into neutral amide groups were evaluated. In vitro toxicity is reduced by an order of magnitude upon amine capping while retaining bioadhesive properties. The in vivo immunological response to PAMAM-g-diazirine formulations was found to be optimal in comparison to standard poly(lactic- co -glycolic acid) (PLGA) thin films., Competing Interests: The authors declare no conflict of interest.

Purpose: To assess long-term efficacy and safety of self-made cryopreservative fibrin glue (SMC) applied in pterygium surgery., Methods: Prospective, comparative, interventional case series. Forty eyes of 40 patients with nasal primary pterygium, 24 male and 16 female, were enrolled. The patients were assigned to two groups and each contained 12 male and eight female based on the pterygium area encroaching onto the cornea. In one group, the conjunctival autograft was attached to the sclera with SMC stored for 2 months, and in the other group, commercial fibrin glue kit (CK) was applied after the pterygium was removed. All the patients were followed up postoperatively on days 1, 3, 7 and 14 then at months 1, 3, 6, 12. The main outcome measures included operating time, postoperative discomfort, recurrence rate and complications., Results: There were no significant differences in surgery time (p = 0.713) and postoperative discomfort (day 1, 3, 7; p = 0.747, p = 0.766, p = 0.983, respectively) between the two groups. By the end of 1-year follow-up, the recurrence rate was 0% in the SMC group and 5% in the CK group (p = 1.000). There were no infections and severe visual acuity (VA) threatening complications in either group., Conclusion: Self-made cryopreservative fibrin glue (SMC) is as effective as standard CK for autograft fixation in pterygium surgery and it also has good safety after long-term follow-up. For its convenience and low cost, this new methods should be popularized, especially in underdeveloped area., (© 2017 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

In this work, an in situ gelling system composed of glycol chitosan (GC) was fabricated and evaluated regarding its tissue-adhesive, anti-bacterial and hemostatic properties. GC conjugated with 3-(4-hydroxyphenyl) propionic acid gelled immediately after illumination with blue light in the presence of ruthenium complex. The phenolic GC hydrogel was investigated regarding its mechanical property, hydration, degradation rate, cytotoxicity, tissue adhesiveness, and hemostatic ability. The hydrogel was shown to glue two pieces of tissues tightly in an egg-membrane model. The antibiotic-incorporated hydrogel killed bacteria effectively. When the hydrogel was applied to a wound in a mouse liver model, bleeding was reduced quickly and greatly. All the promising results show that the photo-chemically crosslinkable GC hydrogel could be used as a tissue adhesive, controlled drug release, and a hemostat., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Development of bioadhesives with tunable mechanical strength, high adhesiveness, biocompatibility, and injectability is greatly desirable in all surgeries to replace or complement the sutures and staples. Herein, the dual catalytic activity of horseradish peroxidase is exploited to in situ form the hydroxyphenyl propionic acid-gelatin/thiolated gelatin (GH/GS) adhesive hydrogels including two alternative crosslinks (phenol-phenol and disulfide bonds) with fast gelation (few seconds - several minutes) and improved physicochemical properties. Their elastic moduli increase from 6.7 to 10.3 kPa by adding GS polymer that leads to the better stability of GH/GS hydrogels than GH ones. GH/GS adhesive strength is respectively 6.5-fold and 15.8-fold higher than GH-only and fibrin glue that is due to additional disulfide linkages between hydrogels and tissues. Moreover, in vitro cell study with human dermal fibroblast showed the cell-compatibility of GH/GS hydrogels. Taken together, GH/GS hydrogels can be considered as promising potential adhesive materials for various biomedical applications., (© 2017 Wiley Periodicals, Inc.)

Tissue adhesives have emerged as an alternative to sutures and staples for wound closure and reconnection of injured tissues after surgery or trauma. Owing to their convenience and effectiveness, these adhesives have received growing attention particularly in minimally invasive procedures. For safe and accurate applications, tissue adhesives should be detectable via clinical imaging modalities and be highly biocompatible for intracorporeal procedures. However, few adhesives meet all these requirements. Herein, we show that biocompatible tantalum oxide/silica core/shell nanoparticles (TSNs) exhibit not only high contrast effects for real-time imaging but also strong adhesive properties. Furthermore, the biocompatible TSNs cause much less cellular toxicity and less inflammation than a clinically used, imageable tissue adhesive (that is, a mixture of cyanoacrylate and Lipiodol). Because of their multifunctional imaging and adhesive property, the TSNs are successfully applied as a hemostatic adhesive for minimally invasive procedures and as an immobilized marker for image-guided procedures.

A surgical adhesive that can be used in different surgical situations with or without sutures is a surgeons' dream and yet none has been able to fulfill many such demanding requirements. It was therefore a major challenge to develop an adhesive biomaterial that stops bleeding and bond tissues well, which at the same time is non-toxic, biocompatible and yet biodegradable, economically viable and appealing to the surgeon in terms of the simplicity of application in complex surgical situations. With this aim, we developed an in situ setting adhesive based on biopolymers such as chitosan and dextran. Dextran was oxidized using periodate to generate aldehyde functions on the biopolymer and then reacted with chitosan hydrochloride. Gelation occurred instantaneously upon mixing these components and the resulting gel showed good tissue adhesive properties with negligible cytotoxicity and minimal swelling in phosphate buffered saline (PBS). Rheology analysis confirmed the gelation process by demonstrating storage modulus having value higher than loss modulus. Adhesive strength was in the range 200-400gf/cm 2 which is about 4-5 times more than that of fibrin glue at comparable setting times. The adhesive showed burst strength in the range of 400-410mm of Hg which should make the same suitable as a sealant for controlling bleeding in many surgical situations even at high blood pressure. Efficacy of the adhesive as a hemostat was demonstrated in a rabbit liver injury model. Histological features after two weeks were comparable to that of commercially available BioGlue®. The adhesive also demonstrated its efficacy as a drug delivery vehicle. The present adhesive could function without the many toxicity and biocompatibility issues associated with such products., Statement of Significance: Though there are many tissue adhesives available in market, none are free of shortcomings. The newly developed surgical adhesive is a 2-component adhesive system based on time-tested, naturally occurring polysaccharides such as chitosan and dextran which are both biocompatible and biodegradable. Simple polymer modification has been carried out on both polysaccharides so that when aqueous solutions of both are mixed, the solutions gel in less than 10s and forms an adhesive that seals a variety of incisions. The strength of the adhesive is over 5-times the strength of commercially available Fibrin glue and is more tissue compliant than BioGlue®. This adhesive biomaterial showed excellent tissue bonding, was hemostatic, biocompatible and biodegradable. The significance of this work lies on the features of the developed tissue adhesive that it stops bleeding, bond the tissues well, can act as a drug delivery vehicle and would appeal to the surgeon in terms of the simplicity of application in complex surgical situations. There is no need for special delivery systems for application of this adhesive. The two-component adhesive can be applied one over the other using syringes. There is also no need for light curing with UV or visible light and the gelation between the two components spontaneously takes place on application leading to excellent tissue bonding., (Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Marine mussels tightly adhering to various underwater surfaces inspires human to design adhesives for wet tissue adhesion in surgeries. Characterization of mussel adhesive plaques describes a matrix of proteins containing 3,4-dihydroxyphenylalanine (DOPA), which provides strong adhesion in aquatic conditions. Several synthetic polymer systems have been developed based on this DOPA chemistry. Herein, a citrate-based tissue adhesives (POEC-d) was prepared by a facile one-pot melt polycondensation of two diols including 1,8-octanediol and poly(ethylene oxide) (PEO), citric acid (CA) and dopamine, and the effects of hydrophilic and soft PEO on the properties of adhesives were studied. It was found that the obtained adhesives exhibited water-soluble when the mole ratio of PEO to 1,8-octanediol was 70%, and the equilibrium swelling percentage of cured adhesive was about 144%, and degradation rate was in the range of 1-2 weeks. The cured adhesives demonstrated soft rubber-like behavior. The lap shear adhesion strength measured by bonding wet pig skin was in the range of 21.7-33.7 kPa, which was higher than that of commercial fibrin glue (9-15 kPa). The cytotoxicity tests showed the POEC-d adhesives had a low cytotoxicity. Our results supports that POEC-d adhesives, which combined strong wet adhesion with good biodegradability, acceptable swelling ratio, good elasticity and low cytotoxicity, have potentials in surgeries where surgical tissue adhesives, sealants, and hemostatic agents are used.

Silk fibroin from the domesticated silkworm Bombyx mori is a naturally occurring biopolymer with charged hydrophilic terminal regions that end-cap a hydrophobic core consisting of repeating sequences of glycine, alanine, and serine residues. Taking inspiration from mussels that produce proteins rich in L-3,4-dihydroxyphenylalanine (DOPA) to adhere to a variety of organic and inorganic surfaces, the silk fibroin was functionalized with catechol groups. Silk fibroin was selected for its high molecular weight, tunable mechanical and degradation properties, aqueous processability, and wide availability. The synthesis of catechol-functionalized silk fibroin polymers containing varying amounts of hydrophilic polyethylene glycol (PEG, 5000 g/mol) side chains was carried out to balance silk hydrophobicity with PEG hydrophilicity. The efficiency of the catechol functionalization reaction did not vary with PEG conjugation over the range studied, although tuning the amount of PEG conjugated was essential for aqueous solubility. Adhesive bonding and cell compatibility of the resulting materials were investigated, where it was found that incorporating as little as 6 wt % PEG prior to catechol functionalization resulted in complete aqueous solubility of the catechol conjugates and increased adhesive strength compared with silk lacking catechol functionalization. Furthermore, PEG-silk fibroin conjugates maintained their ability to form β-sheet secondary structures, which can be exploited to reduce swelling. Human mesenchymal stem cells (hMSCs) proliferated on the silks, regardless of PEG and catechol conjugation. These materials represent a protein-based approach to catechol-based adhesives, which we envision may find applicability as biodegradable adhesives and sealants.

Many surgeries are complicated by the need to anastomose, or reconnect, micrometre-scale vessels. Although suturing remains the gold standard for anastomosing vessels, it is difficult to place sutures correctly through collapsed lumen, making the procedure prone to failure. Here, we report a multiphase transitioning peptide hydrogel that can be injected into the lumen of vessels to facilitate suturing. The peptide, which contains a photocaged glutamic acid, forms a solid-like gel in a syringe and can be shear-thin delivered to the lumen of collapsed vessels (where it distends the vessel) and the space between two vessels (where it is used to approximate the vessel ends). Suturing is performed directly through the gel. Light is used to initiate the final gel-sol phase transition that disrupts the hydrogel network, allowing the gel to be removed and blood flow to resume. This gel adds a new tool to the armamentarium for micro- and supermicrosurgical procedures.

A novel surgical sealant was developed by partially modifying the amino groups of Alaska pollock-derived gelatin derivative with cholesteryl groups (Chol-apGltn), which was combined with the crosslinker, pentaerythritol poly(ethylene glycol) ether tetrasuccinimidyl glutarate (4S-PEG). The burst strength of the resultant sealant was tested using fresh porcine aorta as an adherend. The Chol-apGltn/4S-PEG sealant cured within 25.4 ± 2.0 s. Burst strength increased with increasing degree of Chol modification up to a maximum value of 8.3 mol% (8.3Chol-apGltn). The highest burst strength of the 8.3Chol-apGltn/4S-PEG sealant was 341.3 ± 77.5 mmHg, which was 3.5- and 11.6-fold higher than that of the original apGltn/4S-PEG and commercial fibrin sealants, respectively. The 8.3Chol-apGltn/4S-PEG sealant swelled only slightly in solution (1.1-fold as compared to commercially prepared sealant). Furthermore, tissue migration into the 8.3Chol-apGltn/4S-PEG sealant and subsequent biodegradation was observed following implantation for 4-8 weeks. These results suggest that the 8.3Chol-apGltn/4S-PEG sealant has biomedical applications, including use in cardiovascular and thoracic surgery.

The development of adhesive materials, such as cyanoacrylate derivatives, fibrin glues, and gelatin-based adhesives, has been an emerging topic in biomaterial science because of the many uses of these materials, including in wound healing patches, tissue sealants, and hemostatic materials. However, most bio-adhesives exhibit poor adhesion to tissue and related surfaces due to the presence of body fluid. For a decade, studies have aimed at addressing this issue by developing wet-resistant adhesives. Mussels demonstrate robust wet-resistant adhesion despite the ceaseless waves at seashores, and mussel adhesive proteins play a key role in this adhesion. Adhesive proteins located at the distal end (i.e., those that directly contact surfaces) are composed of nearly 60% of amino acids called 3,4-dihydroxy-l-phenylalanine (DOPA), lysine, and histidine, which contain side chains of catechol, primary amines, and secondary amines, respectively. Inspired by the abundant catecholamine in mussel adhesive proteins, researchers have developed various types of polymeric mimics, such as polyethylenimine-catechol, chitosan-catechol, and other related catecholic polymers. Among them, chitosan-catechol is a promising adhesive polymer for biomedical applications. The conjugation of catechol onto chitosan dramatically increases its solubility from zero to nearly 60mg/mL (i.e., 6% w/v) in pH 7 aqueous solutions. The enhanced solubility maximizes the ability of catecholamine to behave similar to mussel adhesive proteins. Chitosan-catechol is biocompatible and exhibits excellent hemostatic ability and tissue adhesion, and thus, chitosan-catechol will be widely used in a variety of medical settings in the future. This review focuses on the various aspects of chitosan-catechol, including its (1) preparation methods, (2) physicochemical properties, and (3) current applications., (Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

As poly L-lactic acid (PLLA) is a polymer with good biocompatibility and biodegradability, we created a new tissue adhesive (TA), pre-polymerized allyl 2-cyanoacrylate (PACA) mixed with PLLA in an effort to improve biocompatibility and mechanical properties in healing dermal wound tissue. We determined optimal mixing ratios of PACA and PLLA based on their bond strengths and chemical structures analyzed by the thermal gravimetric analysis (TGA) and Fourier transform infrared (FT-IR) spectroscopy. In vitro biocompatibility of the PACA/PLLA was evaluated using direct- and indirect-contact methods according to the ISO-10993 cytotoxicity test for medical devices. The PACA/PLLA have similar or even better biocompatibility than those of commercially available cyanoacrylate (CA)-based TAs such as Dermabond® and Histoacryl®. The PACA/PLLA were not different from those exposed to Dermabond® and Histoacryl® in Raman spectra when biochemical changes of protein and DNA/RNA underlying during cell death were compared utilizing Raman spectroscopy. Histological analysis revealed that incised dermal tissues of rats treated with PACA/PLLA showed less inflammatory signs and enhanced collagen formation compared to those treated with Dermabond® or Histoacryl®. Of note, tissues treated with PACA/PLLA were stronger in the tensile strength compared to those treated with the commercially available TAs. Therefore, taking all the results into consideration, the PACA/PLLA we created might be a clinically useful TA for treating dermal wounds., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Polysaccharide hyaluronic acid (HA) was chemically modified with cysteine ethyl ester (CYS). By immobilization of the thiol-bearing ligand on the polymeric backbone the thiolated bioconjugate HA-CYS was obtained. METHODOLOGY & RESULTS: Mucoadhesion, permeation enhancement effect and stability was tested. Furthermore mechanical, physicochemical properties as well as mucoadhesive strength, swelling index and residence time on the mucosa were investigated. The developed thiolated bioconjugate displayed 1.5-fold improved mucoadhesiveness on buccal mucosa as well as an enhanced permeation behavior and 2.5-fold higher polymer stability. The near neutral pH and 2.49±0.49% cytotoxicity over 12-h studies indicated their non-irritability and biocompatible nature with biological tissues. Further, the model drug sulforhodamine 101 was incorporated to determine its drug release profiles, which revealed a 2.8-fold controlled release of HA-CYS in comparison to unmodified HA., Conclusion: Thus, the promising results encourage further investigations and exploitation of this versatile polysaccharide.

Background: Anastomotic needle hole bleeding is a frequently encountered problem in cardiovascular surgeries., Objective: To examine the feasibility of crosslinked gelatin glue as an anastomotic needle hole sealant in comparison with fibrin glue., Methods: The in vitro burst water pressures were measured for gelatin and fibrin glue sealed needle holes of expanded polytetrafluoroethylene (ePTFE) or collagen coated woven polyester grafts. For in vivo investigations, abdominal aorta-ePTFE graft anastomoses of heparinized beagle dogs were sealed by gelatin or fibrin glue and hemostatic efficacy was judged. The implanted sites were re-examined 4 weeks postoperatively., Results: The in vitro burst water pressures of gelatin glue sealed needle holes of both grafts were higher than those sealed by fibrin glue. For in vivo canine studies, hemostasis was successful for all gelatin glue applied suture lines, but not two out of three fibrin glue treated sites when 3-0 polypropylene suture was employed. Although adhesions of surrounding tissues were intense for all sites 4 weeks postoperatively, inflammation was more severe for the fibrin glue group compared to those of gelatin glue., Conclusions: Gelatin glue was found to be an effective and safe sealant for accomplishing hemostasis of anastomotic needle holes of vascular grafts.

Alkyl cyanoacrylates are interesting products for use in industry because of their properties enabling them to stick together a wide range of substrates. n-Butyl cyanoacrylate is one of the most successfully used tissue adhesives in the field of medicine because it exhibits bacteriostatic and haemostatic characteristics, in addition to its adhesive properties. At present, its synthesis is performed with good yields via Knoevenagel condensation using conventional sources of heating, but this requires a long processing time. The aim of this work was to look for a new way of synthesising n-butyl cyanoacrylate using microwave irradiation as the source of heating. This non-conventional source of heating most likely reduces the process time of the synthesis. In comparison with a conventional heating source, such as an oil bath, the results showed the advantages of this method whereby the n-butyl cyanoacrylate gave the same yield and quality with a reduction in the reaction time by a factor of 3-5-fold.

In this study, a hybrid photopolymeric bioadhesive system consisting of urethane methacrylated dextran (Dex-U) and 3, 4-Dihydroxyphenyl-l-alanine (DOPA) modified three-arm poly (ethylene glycol) s (PEG-DOPAs) was designed. The process of photopolymerization was detected by Photo-Differential Scanning Calorimetry (Photo-DSC). The adhesion strength was evaluated by the lap shear tests. The surface tension of the solutions, burst pressures and the cytotoxicity assays were also investigated. The addition of PEG-DOPAs significantly improved the properties of Dex-U especially in the field of adhesion strength and burst pressure. And materials variation could be tailored to match the demands for tissue repair. Compared to the Dex-U systems, the maximum adhesion strength of the copolymeric system increased from 2.7±0.1 MPa to 4.0±0.6 MPa. Owing to its strong adhesion strength, rapid curing rate and good biocompatibility, such photocrosslinkable hydrogelsa could be applied to the areas of bioadhesive., (Crown Copyright © 2013. Published by Elsevier B.V. All rights reserved.)

In the past two decades tissue adhesives and sealants have revolutionized bleeding control and wound healing. This paper focuses on existing tissue adhesive design, their structure, functioning mechanism, and their pros and cons in wound management. It also includes the latest advances in the development of new tissue adhesives as well as the emerging applications in regenerative medicine. We expect that this paper will provide insightful discussion on tissue bioadhesive design and lead to innovations for the development of the next generation of tissue bioadhesives and their related biomedical applications., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Tissue adhesives can bind together damaged tissues and serve as tools to deliver and localize therapeutics to facilitate regeneration. One emerging therapeutic trend in orthopedics is the use of intraoperative biologics (IOB), such as bone marrow (BM) and platelet-rich plasma (PRP), to stimulate healing. Here, we introduce the application of the biomaterial chondroitin sulfate succinimidyl succinate (CS-NHS) to deliver IOB in a hydrogel adhesive. We demonstrate the biomaterial's ability to bind various tissue types and its cellular biocompatibility with encapsulated human mesenchymal stem cells (hMSCs). Further, we examine in detail the CS-NHS adhesive combined with BM aspirate for use in bone applications. hMSCs were encapsulated in CS-BM and cultured for 5 weeks in osteogenic medium. Quantitative RT-PCR demonstrated osteogenesis via upregulation of the osteogenic transcription factor Runx2 and bone markers alkaline phosphatase and osteocalcin. Significant deposition of calcium and osteocalcin was detected using biochemical, histological, and immunohistochemical techniques. Shear testing demonstrated that the CS-BM adhesive exhibited an adhesive strength approximately an order of magnitude stronger than fibrin glue and approaching that of a cyanoacrylate adhesive. These results indicate that CS-NHS is a promising delivery tool for IOB in orthopedic applications requiring a strong, degradable, and biocompatible adhesive that supports bone growth., (Copyright © 2012 Orthopaedic Research Society.)

The one-step synthesis and characterization of novel bioinspired bioadhesive polymers that contain Dopa, implicated in the extremely adhesive byssal fibers of certain gastropods, is reported. The novel polymers consist of combinations of either of two polyanhydride backbones and one of three amino acids, phenylalanine, tyrosine, or Dopa, grafted as side chains. Dopa-grafted hydrophobic backbone polymers exhibit as much as 2.5 × the fracture strength and 2.8 × the tensile work of bioadhesion of a commercially available poly(acrylic acid) derivative as tested on live, excised, rat intestinal tissue., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Multiparticulate floating drug delivery systems have proven potential as controlled-release gastroretentive drug delivery systems that avoid the "all or none" gastric emptying nature of single-unit floating dosage forms. An objective of the presence investigation was to develop calcium silicate (CaSi)/calcium alginate (Ca-Alg)/hydroxypropyl methylcellulose (HPMC) mucoadhesive-floating beads that provide time- and site-specific drug release of alfuzosin hydrochloride (Alf). Beads were prepared by simultaneous internal and external gelation method utilizing 3(2) factorial design as an experimental design; with two main factors evaluated for their influence on the prepared beads; the concentration of CaSi as floating aid (X (1)) and the percentage of HPMC as viscosity enhancer and mucoadhesive polymer (X (2)), each of them was tested in three levels. Developed formulations were evaluated for yield, entrapment efficiency, particle size, surface topography, and buoyancy. Differential scanning calorimetry, Fourier transform infrared spectroscopy, in vitro drug release, as well as in vitro mucoadhesion using rat stomach mucosal membrane were also conducted. Percentage yield and entrapment efficiency ranged from 57.03% to 78.51% and from 49.78% to 83.26%, respectively. Statistical analysis using ANOVA proved that increasing the concentration of either CaSi or HPMC significantly increased the beads yield. Both CaSi and HPMC concentrations were found to significantly affect Alf release from the beads. Additionally, higher CaSi concentration significantly increased the beads diameter while HPMC concentration showed significant positive effect on the beads mucoadhesive properties. CaSi/Ca-Alg/HPMC beads represent simple floating-mucoadhesive gastroretentive system that could be useful in chronopharmacotherapy of benign prostatic hyperplasia.

An ideal adhesive for anastomosis of severed peripheral nerves should tolerate strains imposed on rejoined nerves. We use blends of photocrosslinkable 4-azidobenzoic acid-modified chitosan (Az-C) and polyethylene glycol (PEG) as a new in-situ-forming bioadhesive for anastomosing and stabilizing the injured nerves. Cryo-scanning electron microscopy suggests that the polymer blends form a semi-interpenetrating network (semi-IPN), where PEG interpenetrates the Az-C network and reinforces it. Az-C/PEG semi-IPN gels have higher storage moduli than Az-C gel alone and fibrin glue. Nerves anastomosed with an Az-C/PEG gel tolerate a higher force than those with fibrin glue prior to failure. A series of ex vivo and in vitro cell experiments indicate the Az-C/PEG gels are compatible with nerve tissues and cells. In addition, Az-C/PEG gels release PEG over a prolonged period, providing sustained delivery of PEG, a potential aid for nerve cell preservation through membrane fusion. Az-C/PEG semi-IPN gels are promising bioadhesives for repairing severed peripheral nerves not only because of their improved mechanical properties but also because of their therapeutic potential and tissue compatibility., (Copyright © 2012 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Mussel-inspired adhesive hydrogels represent innovative candidate medical sealants or glues. In the present work, we describe an enzyme-degradable mussel-inspired adhesive hydrogel formulation, achieved by incorporating minimal elastase substrate peptide Ala-Ala into the branched poly(ethylene glycol) (PEG) macromonomer structure. The system takes advantage of neutrophil elastase expression upregulation and secretion from neutrophils upon recruitment to wounded or inflamed tissue. By integrating adhesive degradation behaviors that respond to cellular cues, we expand the functional range of our mussel-inspired adhesive hydrogel platforms. Rapid (<1 min) and simultaneous gelation and adhesion of the proteolytically active, catechol-terminated precursor macromonomer was achieved by addition of sodium periodate oxidant. Rheological analysis and equilibrium swelling studies demonstrated that the hydrogel is appropriate for soft tissue-contacting applications. Notably, hydrogel storage modulus (G') achieved values on the order of 10 kPa, and strain at failure exceeded 200% strain. Lap shear testing confirmed the material's adhesive behavior (shear strength: 30.4 ± 3.39 kPa). Although adhesive hydrogel degradation was not observed during short-term (27 h) in vitro treatment with neutrophil elastase, in vivo degradation proceeded over several months following dorsal subcutaneous implantation in mice. This work represents the first example of an enzymatically degradable mussel-inspired adhesive and expands the potential biomedical applications of this family of materials.

Cyanoacrylate glues are easily applied to wounds with good cosmetic results. However, they tend to be brittle and can induce local tissue toxicity. A series of cyanoacrylate monomers with a flexible ether linkage and varying side-chain lengths was synthesized and characterized for potential use as tissue adhesives. The effect of side-chain length on synthesis yield, physical and mechanical properties, formaldehyde generation, cytotoxicity in vitro and biocompatibility in vivo were examined. The incorporation of etheric oxygen allowed the production of flexible monomers with good adhesive strength. Monomers with longer side-chains were found to have less toxicity both in vitro and in vivo. Polymerized hexoxyethyl cyanoacrylate was more elastic than its commercially available and widely used alkyl analog 2-octyl cyanoacrylate, without compromising biocompatibility., (Published by Elsevier Ltd.)

Bioinspired from adhesion behaviors of mussels, injectable and thermosensitive chitosan/Pluronic composite hydrogels were synthesized for tissue adhesives and hemostatic materials. Chitosan conjugated with multiple catechol groups in the backbone was cross-linked with terminally thiolated Pluronic F-127 triblock copolymer to produce temperature-sensitive and adhesive sol-gel transition hydrogels. A blend mixture of the catechol-conjugated chitosan and the thiolated Pluronic F-127 was a viscous solution state at room temperature but became a cross-linked gel state with instantaneous solidification at the body temperature and physiological pH. The adhesive chitosan/Pluronic injectable hydrogels with remnant catechol groups showed strong adhesiveness to soft tissues and mucous layers and also demonstrated superior hemostatic properties. These chitosan/Pluronic hydrogels are expected to be usefully exploited for injectable drug delivery depots, tissue engineering hydrogels, tissue adhesives, and antibleeding materials.

In this study, we synthesized a new cell immobilization support having poly(glycidyl methacrylate) as a graft polymer chain and used this support for cell cultivation. Base polymer particle was synthesized by suspension polymerization and epoxy polymer chain was extended from particle surface on graft polymerization. Produced polymer particles had broad particle size distribution ranging from 20 to 1000 μm and the degree of polymerization of grafted polymer chain was ranged from 500 to 1000. The effects of various factors, such as grafted polymer chain length and its surface density, composition of base polymer network and graft polymer chain, on the cell growth of murine fibroblast cell line (MS-5 cell) on polymer particle were studied. This polymer particle could cultivate not only fibroblast cell line but also epidermal cell line (HeLa cell), osteoblast cell line (MC3T3E1 cell), and chondrocyte cell line (ch-8 cell) on its surface. Growth rate is almost the same as that of cells using poly(styrene) tissue culture dish. To apply this cell cultivation system for examination of cell co-culture, HeLa cell immobilized on 100 μm of polymer particle was successfully co-cultured with MS-5 cell immobilized on 300 μm of polymer particle for four weeks., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Current investigation aimed to develop a novel Amiloride loaded mucoadhesive nanoemulsion formulation for nose-to-brain delivery. Furthermore, nasal irritation study and histopathological examination of the nasal mucosa were also carried out to assess nonirritant nature of the nanoemulsion. The optimized formulation, surface epithelium lining and the granular cellular structure of the nasal mucosa were totally intact, whereas KCl caused major changes in the ultrastructure of mucosa. Amiloride loaded mucoadhesive nanoemulsion formulations are non toxic on nasal mucosa and can be administered by intranasal route for effective treatment of epilepsy.

The purpose of this study was to develop and evaluate the bioadhesivity, in vitro drug release, and permeation of an intravaginal bioadhesive polymeric device (IBPD) loaded with 3'-azido-3'-deoxythymidine (AZT) and polystyrene sulfonate (PSS). Modified polyamide 6,10, poly(lactic-coglycolic acid), polyacrylic acid, polyvinyl alcohol, and ethylcellulose were blended with model drugs AZT and PSS as well as radio-opaque barium sulfate (BaSO4) and then compressed into caplet devices on a tableting press. One set of devices was coated with 2% w/v pentaerythritol polyacrylic acid (APE-PAA) while another remained uncoated. Thermal analysis was performed on the constituent polymers as well the IBPD. The changes in micro-environmental pH within the simulated human vaginal fluid due to the presence of the IBPD were assessed over a period of 30 days. Textural profile analysis indicated that the bioadhesivity of the APE-PAA-coated devices (3.699 +/- 0.464 N; 0.0098 +/- 0.0004 J) was higher than that of the uncoated devices (1.198 +/- 0.150 N; 0.0019 +/- 0.0001 J). In addition, BaSO4-facilitated X-ray imaging revealed that the IBPD adhered to pig vaginal tissue over the experimental period of 30 days. Controlled drug release kinetics was obtained over 72 days. During a 24-h permeation study, an increase in drug flux for both AZT (0.84 mg cm(-2) h(-1)) and PSS (0.72 mg cm(-2) h(-1)) was realized up to 12 h and thereafter a steady-state was achieved. The diffusion and dissolution dynamics were mechanistically deduced based on a chemometric and molecular structure modeling approach. Overall, results suggested that the IBPD may be sufficiently bioadhesive with desirable physicochemical and physicomechanical stability for use as a prolonged intravaginal drug delivery device.

The great versatility of polymers makes them very useful in the biomedical and pharmaceutical fields. The combination of natural and synthetic polymers leads to new materials with tailored functional properties. The aim of this work consists in the preparation of new drug delivery system based on chitosan (natural polymer) and polybetaines (synthetic polymers), by a simple process, well known in the literature as complex coacervation methods. Also, the adsorption and release studies of two antibiotics as well as the preservation of their bactericidal capacities were performed.

Although gluing bone is in theory a very attractive alternative to classical fracture treatment, this method is not yet clinically established due to the lack of an adhesive which would meet all the necessary requirements. We therefore developed a novel two-component bioadhesive system with the potential to be used as a bone adhesive based on biocompatible and degradable biopolymers (chitosan, oxidised dextran or starch). After mixing in water, the two components covalently cross-link by forming a Schiff's base. By the same mechanism, the glue binds to any other exposed amino group such as for example those exposed in fractured bone, even in the presence of water. Modified chitosan was synthesised from commercially available chitosan by deacetylation and was then reduced in molecular weight by heating in acid. The amount of free amino groups was analysed by IR. The molecular weight was determined by viscosimetry. Starch or dextran were oxidised with periodic acid to generate aldehyde groups, which were quantified by titration. l-Dopa was conjugated to oxidised dextran or starch in analogy to the gluing mechanism of mussels. Biomechanical studies revealed that the new glue is superior to fibrin glue, but has less adhesive strength than cyanoacrylates. In vitro cell testing demonstrated excellent biocompatibility, rendering this glue a potential candidate for clinical use.

The mechanical properties of casted Eudragit E-100 films were tested for the combined effect of two cohesion promoters (succinic or citric acid) and triacetin as a plasticizer. The prepared films were elastic, self-adhesive, transparent and pale yellow in colour. Films containing either of the tested cohesion promoters showed a significant reduction in both tensile strength and Young's modulus on increasing triacetin and/or cohesion promoter concentration. Films containing 7% (w/w) succinic acid and 45% (w/w) triacetin gave the highest elongation of the tested films at any given stress with a maximum of 1050% elongation. Optimal bonding to human skin surface (tack) with the highest peel adhesion (588 cN/cm) was observed with these films denoting good self-adhesive properties. In vitro metronidazole (MN) release from the plasticized Eudragit E-100 films was monitored for the influence of incorporation of cohesion promoters, secondary polymer (Eudragit RL or RS) as well as drug loading. Both cohesion promoters were seen to improve MN release from the films with the maximum drug flux (0.334 mg cm(-2) h(-1)) observed with 1.75% (w/w) succinic acid. The tested secondary polymers were also found to improve MN release from the tested films. The highest MN release was observed with 20% (w/w) Eudragit RL which gave 0.77 mg cm(-2) released after 3 h compared with only 0.34 mg cm(-2) for plain films. MN release from the films was increased by increasing drug load. Calculating the release rate constant (K(r)) showed a linear increase with the increase in drug load.