Bioadhesive Material Research Articles

Mussel‐inspired stretchable, anti‐fatigue, self‐healing and biocompatible hydrogel adhesives

AbstractHydrogels can form physically or chemically interactions with tissues and are widely used in the design of bioadhesive material. Polydopamine (PDA)/polyacrylamide (PAM)‐based adhesion hydrogels have emerged as one of the hydrogel adhesive materials with great potential for development. However, this type of hydrogel has low mechanical and adhesion properties, which has certain limitations in practical applications. Herein, inspired by the mussel adhesion mechanism, we introduced PDA into PAM/3‐aminophenylboronic acid grafted sodium alginate (SA‐PBA) double network system prepared a series of adhesive hydrogels, PDA was crosslinked by dynamic boronic ester bonds with SA‐PBA. The experimental results established that the hydrogels have favorable adhesive, anti‐fatigue, stretchable, and self‐healing properties. Cytocompatibility assay and in vitro hemolysis assay also indicated that the multifunctional hydrogel has excellent cytocompatibility and hemocompatibility.

Three-Dimensional-Printed Oral Films Based on LCD: Influence Factors of the Film Printability and Received Qualities.

As an oral mucosal drug delivery system, oral films have been of wide concern in recent years because of their advantages such as rapid absorption, being easy to swallow and avoiding the first-pass effect common for mucoadhesive oral films. However, the currently utilized manufacturing approaches including solvent casting have many limitations, such as solvent residue and difficulties in drying, and are not suitable for personalized customization. To solve these problems, the present study utilizes liquid crystal display (LCD), a photopolymerization-based 3D printing technique, to fabricate mucoadhesive films for oral mucosal drug delivery. The designed printing formulation includes PEGDA as the printing resin, TPO as the photoinitiator, tartrazine as the photoabsorber, PEG 300 as the additive and HPMC as the bioadhesive material. The influence of printing formulation and printing parameters on the printing formability of the oral films were elucidated in depth, and the results suggested that PEG 300 in the formulation not only provided the necessary flexibility of the printed oral films, but also improved drug release rate due to its role as pore former in the produced films. The presence of HPMC could greatly improve the adhesiveness of the 3D-printed oral films, but excessive HPMC increased the viscosity of the printing resin solution, which could strongly hinder the photo-crosslinking reaction and reduce printability. Based on the optimized printing formulation and printing parameters, the bilayer oral films containing a backing layer and an adhesive layer were successfully printed with stable dimensions, adequate mechanical properties, strong adhesion ability, desirable drug release and efficient in vivo therapeutic efficacy. All these results indicated that an LCD-based 3D printing technique is a promising alternative to precisely fabricate oral films for personalized medicine.

Chondroitin sulfate and L-Cysteine conjugate modified cationic nanostructured lipid carriers: Pre-corneal retention, permeability, and related studies for dry eye treatment

In this study, a novel bioadhesive material, a conjugate of chondroitin sulfate and L-cysteine (CS-Cys), was synthesized and modified on the surface of the cationic nanostructured lipid carriers loaded dexamethasone to prepare a novel nano-lipid ocular delivery system (Dex-CS-Cys-cNLC). Through the permeation and retention studies of isolated cornea, it was demonstrated that Dex-CS-Cys-cNLC has better corneal permeation and retention ability and can better overcome the barrier effect of the ocular surface. In addition, the fluorescent probe (RhB) was used to replace the drug, and fluorescence imaging was used to investigate the ocular surface retention ability of the formulation, and the results showed that CS-Cys-cNLC has stronger retention ability and can effectively prolong the time of drug action in the ocular surface. Dex-CS-Cys-cNLC was not irritating to rabbit eye tissues and was a safe delivery system. The results of rabbit dry eye pharmacodynamic experiments also showed that Dex-CS-Cys-cNLC could effectively alleviate dry eye symptoms in rabbits, effectively repair corneal damage, and improve the stability of tear film. All these experimental results suggest that Dex-CS-Cys-cNLC is a promising drug delivery carrier for the treatment of anterior segment of the eye disease.

3D Printability Assessment of Poly(octamethylene maleate (anhydride) citrate) and Poly(ethylene glycol) Diacrylate Copolymers for Biomedical Applications.

Herein, we present the first example of 3D printing with poly(octamethylene maleate (anhydride) citrate) (POMaC), a bio-adhesive material which has shown particular promise for implantable biomedical devices. The current methods to fabricate such devices made from POMaC are hindered by the imposed constraints of designing complex molds. We demonstrate the feasibility of exploiting additive manufacturing to 3D print structural functional materials consisting of POMaC. We present 3D printing of biomaterial copolymers consisting of mixtures of poly(ethylene glycol) diacrylate (PEGDA) and POMaC at different ratios. The required parameters were optimized, and characterization of the printing fidelity and physical properties was performed. We have also demonstrated that a range of mechanical properties can be achieved by tuning the POMaC/PEGDA ratio. The biocompatibility of the copolymers was ascertained via a cell viability assay. Such tunable 3D printed biomaterials consisting of POMaC and PEGDA will have significant potential application in the development of functional biomaterial tissue scaffolds and biomedical devices for the future of personalized medicine.

Soluplus® polymeric nanomicelles improve solubility of BCS-class II drugs

The issue of poor aqueous solubility is often a great hitch in the development of liquid dosage forms for those drugs that the Biopharmaceutics Classification System (BCS) includes in classes II and IV. Among the possible technological solutions, inclusion of the drug molecule within polymeric micelles, and particularly nanomicelles, has been proposed in the last years as a valid strategy. Our attention has been recently attracted by Soluplus®, an amphiphilic polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer able to form small and stable nanomicelles. The aim of this study was to characterize Soluplus® nanomicelles to enhance the apparent solubility of three model APIs, categorized in BCS class II: ibuprofen (IBU), idebenone (IDE), and miconazole (MIC). Drug-loaded Soluplus® micelles with a mean size around 60–70 nm were prepared by two methods (direct dissolution or film hydration method). The prepared nanosystems were characterized in terms of mean particle size and Zeta potential, physical stability, drug solubility, and in vitro drug release. The solubility of the tested APIs was shown to increase linearly with the concentration of graft copolymer. Soluplus® can be easily submitted to membrane filtration (0.2 µm PES or PTFE membranes), showing the potential to be sterilized by this method. Freeze-drying enabled to obtain powder materials that, upon reconstitution with water, maintained the initial micelle size. Finally, viscosity studies indicated that these nanomicelles have potential applications where a bioadhesive material is advantageous, such as in topical ocular administration.Graphical abstract

Crosslink bio-adhesives for bronchoscopic lung volume reduction: current status and future direction.

Several bronchoscopic lung volume reduction (BLVR) treatments have been developed to reduce hyperinflation in emphysema patients. Lung bio-adhesives are among the most promising new BLVR treatment options, as they potentially provide a permanent solution for emphysematous patients after only a single application. To date, bio-adhesives have mainly been used as haemostats and tissue sealants, while their application in permanently contracting and sealing hyperinflated lung tissue has recently been identified as a novel and enticing opportunity. However, a major drawback of the current adhesive technology is the induction of severe inflammatory responses and adverse events upon administration. In our review, we distinguish between and discuss various natural, semi-synthetic and synthetic tissue haemostats and sealants that have been used for pulmonary applications such as sealing air/fluid leaks. Furthermore, we present an overview of the different materials including AeriSeal and autologous blood that have been used to achieve lung volume reduction and discuss their respective advantages and drawbacks. In conclusion, we describe the key biological (therapeutic benefit and biocompatibility) and biomechanical (degradability, adhesive strength, stiffness, viscoelasticity, tunability and self-healing capacity) characteristics that are essential for an ideal lung bio-adhesive material with the potential to overcome the concerns related to current adhesives.

Microbial Transglutaminase Improves ex vivo Adhesion of Gelatin Methacryloyl Hydrogels to Human Cartilage.

Current surgical techniques to treat articular cartilage defects fail to produce a satisfactory long-term repair of the tissue. Regenerative approaches show promise in their ability to generate hyaline cartilage using biomaterials in combination with stem cells. However, the difficulty of seamlessly integrating the newly generated cartilage with the surrounding tissue remains a likely cause of long-term failure. To begin to address this integration issue, our strategy exploits a biological enzyme (microbial transglutaminase) to effect bioadhesion of a gelatin methacryloyl implant to host tissue. Mechanical characterization of the bioadhesive material shows that enzymatic crosslinking is compatible with photocrosslinking, allowing for a dual-crosslinked system with improved mechanical properties, and a slower degradation rate. Biocompatibility is illustrated with a 3D study of the metabolic activity of encapsulated human adipose derived stem cells. Furthermore, enzymatic crosslinking induced by transglutaminase is not prevented by the presence of cells, as measured by the bulk modulus of the material. Adhesion to human cartilage is demonstrated ex vivo with a significant increase in adhesive strength (5.82 ± 1.4 kPa as compared to 2.87 ± 0.9 kPa, p < 0.01) due to the addition of transglutaminase. For the first time, we have characterized a bioadhesive material composed of microbial transglutaminase and GelMA that can encapsulate cells, be photo crosslinked, and bond to host cartilage, taking a step toward the integration of regenerative implants.

Switchable Photonic Bio-Adhesive Materials.

A soft photonic bio-adhesive material is designed with real-time colorimetrical monitoring of switchable adhesion by integrating a responsive bio-photonic matrix with mobile hydrogen-binding networking. Synergetic materials sequencing creates a unique iridescent appearance directly coupled with both adhesive ability and shearing strength, in a highly reversible manner. The responsive photonic materials, having a physically hydrogen-bonded chiral nematic organization, vary their adhesion strength due to a transition in cohesive and interfacial failure mechanism in humid surroundings. The bright color appearance shifts from blue to red to transparent and back due to a change in pitch length of the chiral helicoidal organization that also triggers coupled changes in both mechanical strength and interfacial adhesion. Such reversible strength-adhesion-iridescence triple-coupling phenomenon is further explored for design of super-strong switchable bio-adhesives for synthetic/biological surfaces with quick remotely triggered sticky-to-nonsticky transitions, removable conformal soft stickers, and wound dressings with visual monitoring of the healing process, to colorimetric stickers for contaminated respiratory masks.

Comparative assessment between bio-adhesive material and silk suture in regard to healing, clinical attachment level and width of keratinized gingiva in gingival recession defects cases.

The objective of this study was to compare the silk suture with a cyanoacrylate adhesive to stabilize the free gingival graft in conjunction with Er: YAG laser-assisted recipient site preparation to augment the keratinized tissue in gingival recession cases. This randomized trial comprised of 300 recession defects patients. All the included patients were diagnosed using Miller class I and II gingival recession defects classification. Group I sites were treated with a free gingival graft (FGG) harvested using an Er: YAG laser and further sutured with silk. Group II sites were stabilized with isoamyl 2 cyanoacrylate bio-adhesive material. Clinical parameters, such as gingival recession depth, clinical attachment level, gain in gingival tissue thickness, and width of keratinized gingiva were recorded at baseline, and at third month, sixth month, and 12th month postoperatively. The mean changes in gingival recession from months 3 to 6 and months and 6 to 12 were significant (p < 0.05) in both groups. However, the improvement in recession depth was better in group II than in group I. The mean change in clinical attachment level did not differ significantly between the groups at the different time intervals. However, values tended to be higher in group II than in group I. The width of the keratinized gingiva tended to be higher from baseline to 3 months, baseline to 6 months, baseline to 12 months, 3 to 6 months, and from 6 to 12 months in group II as compared with group I (p > 0.05). Cyanoacrylate could be used as a substitute to silk sutures to stabilize FGGs. Cyanoacrylate was easy to apply, consumed less operating time, and was considered equally efficacious for stabilizing FGGs.

Synthesis of peptide derivative as bio adhesive

Bio adhesive material is a protein adhesive, which has recently been highlighted as an attractive biologically based and highly functional adhesive as a new chemo enzymatic synthesis of co polypeptide. The bio adhesive polymer was prepared by modification of pepsin structure with vinyl monomer such as maleic anhydride using ceric ammonium nitrate as an initiator, then the grafted copolymer was substituted with amino drugs. This design carries controlled delivery over an extended period of time due to its digesting nature. The new drug copolymer was investigated using common spectroscopy methods, such as FTIR, 1H-NMR and UV Spectroscopy. The physical properties for the prepared polymers were tested. Our results show that deprotonated is required for drug copolymers when analyzed in different pH values at 37 °C in vitro study and controlled drug release was compared at zero time and after three days. The rate of hydrolysis in basic medium was higher than acidic medium. It was concluded There are several advantages of sustain release by modified drug with slow release and in vivo performance was noted to be promising using for applications of polymer used different mice and rabbits infected with bacteria and wounds.

Design of an Antibacterial Bio-adhesive Material with Silver Nanoparticles

This paper proposes a possible antibacterial bio-adhesive. In the paper, a new bio-adhesive has been designed by combining nano-silver gel, which has a high antibacterial effect, with human fibrin adhesive to get a bio-adhesive material with antibacterial ability. Although the mechanical properties of the new adhesive need to be further measured, if the mechanical properties are as good as the currently used fibrin adhesives, it is worthwhile to continue development and research. By designing a new type of adhesive, this paper presents the potential for more widespread medical use of adhesives that can reduce the risk of bacterial infection at the incision site.

Preparation and characterization of gelatin-gallic acid/ZnO nanocomposite with antibacterial properties as a promising multi-functional bioadhesive for wound dressing applications

It has been a great challenge to develop suitable tissue adhesives that can be efficient on wet internal tissues with acceptable adhesion strength and biocompatibility. It has been demonstrated that certain mussel adhesive proteins, such as the catechol group of dihydroxyphenylalanine (l- DOPA) and its analogs, along with the surface roughness of some nanoparticles, can improve the adhesiveness characteristics to any substrate. To this end, we have devised the functionalization of gelatin with gallic acid (GA, l-DOPA analogue) and in turn, the formation of a cross-linked network with an organosilane (GPTMS) to obtain an efficient bioadhesive material. To provide a bacterium–free environment that improves the healing process, zinc oxide nanoparticles (ZnO NP) were incorporated into the Gelatin-catechol matrix at 1 and 3 wt%. The obtained nanocomposite materials were characterized by attenuated total reflection infrared spectroscopy (ATR-FTIR), scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Their mechanical and adhesive properties, swelling, hydrolytic degradation, antimicrobial activity and cytotoxicity were evaluated. According to the obtained results, the nanocomposite material mechanical and biological properties are significantly affected by the addition of ZnO nanoparticles. These nanocomposites show excellent antimicrobial properties particularly at 3 wt% of ZnO NPs while the adhesive properties are increased when adding 1 wt% of these ZnO NPs. Thus, the novelty of this research is focused in the production of a Gelatin-Gallic acid/ZnO nanocomposite material with a notorious adhesion performance combined with enhanced antimicrobial properties, which offer significant promise as materials for wounds and burns dressing applications.

Development of formaldehyde-free bio-board produced from mushroom mycelium and substrate waste

Synthetic adhesives in the plywood industry are usually volatile compounds such as formaldehyde-based chemical which are costly and hazardous to health and the environment. This phenomenon promotes an interest in developing bio-boards without synthetic adhesives. This study proposed a novel application of natural mycelium produced during mushroom cultivation as natural bio-adhesive material that convert spent mushroom substrate (SMS) into high-performance bio-board material. Different types of spent mushroom substrates were compressed with specific designed mould with optimal temperature at 160 °C and 10 mPa for 20 min. The bio-board made from Ganoderma lucidum SMS had the highest internal bonding strength up to 2.51 mPa. This is far above the 0.4−0.8 range of China and US national standards. In addition, the material had high water and fire resistance, high bonding and densified structures despite free of any adhesive chemicals. These properties and the low cost one step procedure show the potential as a zero-waste economy chain for sustainable agricultural practice for waste and remediation.

The chemistry and engineering of mussel-inspired glue matrix for tissue adhesive and hemostatic

The present study aimed to develop a bio-adhesive material with excellent hemostatic and rapid wound healing properties using a catechol moiety (2chloro-3′,4′-dihydroxyacetophenone) conjugated to poly(dimethyl amino ethyl methacrylate-co-t-butyl methacrylate) [poly(DMA-co-t-BMA)-2-chloro-3′,4′-dihydroxyacetophenone (CA), C-PDB]. The desired glue matrix was formed by crosslinking between C-PDB and chitosan via the Michael addition reaction. During glue matrix formation, chitosan plays a vital role as a cross-linker because the amine group of chitosan can easily react with the quinone from CA, based on catechol chemistry under mild alkaline conditions. Lap shear strength tests showed that the formulated glue matrix had a significant adhesive force at around 1.288MPa and it formed quickly in vitro. In addition, when applied on a bleeding site on a rat aorta in vivo, the prepared glue matrix displayed strong hemostatic behavior. Hematoxylin and eosin (H&E), Masson’s trichrome, and reticulin staining of wounds (hepatic tissue) treated with the prepared glue matrix displayed rapid wound healing. Therefore, the prepared glue matrix is a potential candidate as a hemostatic and wound-healing agent for clinical applications.

Pain perception following epithelialized gingival graft harvesting: a randomized clinical trial.

The aim of this study was to compare the effects of a hemostatic collagen sponge and a collagen sponge sealed with a bio-adhesive material on the palatal donor sites with the purpose of minimizing postoperative pain after epithelialized gingival graft (EGG) harvesting. The present study consisted of 44 EGGs harvested in 44 patients. In the control group, a hemostatic collagen sponge was applied over the palatal wound, while the test group was treated with additional cyanoacrylate. Patients were observed for 14days, evaluating the pain level by using the visual analogic scale. The consumption of analgesic during the postoperative period, the willingness for retreatment and the characteristic of the graft were also analyzed. Statistically significant differences in pain perception were found between test and control groups in each of the studied days (p < 0.01). Analgesic consumption was lower in the test group (p < 0.01). Graft width < 14mm was found to be associated with lower discomfort (p < 0.01). Adding an additional layer of cyanoacrylate over a hemostatic collagen sponge on the palatal wound following EGG harvesting was found to be successful in minimizing the postoperative discomfort and the need for analgesics. Postoperative pain after palatal tissue harvesting can be successfully minimized if the donor site open wound is protected with an external layer of cyanoacrylate over a collagen sponge.

Development of highly electrocatalytic and electroconducting imprinted film using Ni nanomer for ultra-trace detection of thiamine

The present work describes a new molecularly imprinted polymer-based electrochemical sensor for thiamine (vitamin B1), which has been fabricated exploiting both surface imprinting and nanotechnology. Of two monomers used in this work, N-methacryloylglutamic acid served as a biocompatible and bio-adhesive material, whereas the assistant monomer, acryloylated nickel nanoparticles-functionalized multiwalled carbon nanotubes (Ni nanomer) induced large electro-catalytic and conducting activities to the molecularly imprinted polymer film. The polymer synthesis was carried out, following the ‘surface grafting from’ protocol, with the free radical polymerization directly on the surface of Ni nanomer modified pencil graphite electrode. The presence of functionalized-MWCNTs in the polymer film was inevitable to render stability to the coating via aromatic π−π interactions at the film-nanomer modified electrode interface. Thiamine, being electrochemically inactive, was estimated indirectly by a probe, hexamine ruthenium (II) chloride, with signal transduction via differential pulse anodic stripping voltammetric technique. The limits of detection were in the range 0.17–0.2ngmL−1 (S/N=3) in aqueous, multi-vitamin tablet, urine, and human blood serum, without any cross-reactivity and false- positives. The proposed sensor assures a reliable estimation of thiamine in the patients suffering from its acute deficiency.

Preparation and evaluation of gastric adhesive-floating pellets for Bolo leaf phenols

Gastric adhesive-floating pellets for Bolo leaf phenols (BLP) were prepared by extrusion-spheronization method, with chitosan as skeleton bioadhesive material, and stearyl alcohol as help-bleaching agent to evaluate its in vitro adhesivity, floatability and in vivo retention situation, and investigate its in vitro release characteristics. The in vitro adhesivity and floatability were evaluated respectively by in vitro tissue retention method and visual observation method. The retention of pellets in rats was investigated by in vivo tissue retention method and in vivo imaging of small animals. In addition, the in vitro release of p-coumaric acid and caffeic acid as the index components in pellets were evaluated. Results showed that the in vitro adhesivity of the prepared gastric adhesive-floating pellets reached (73.2±3.4)%, and the pellets could float immediately in simulated gastric fluid for more than 12 h; the retention rate of adhesive-floating pellets in rats reached more than 40% after 6 h, while the retention rate of common reference pellets was decreased by 15% as compared with the gastric adhesive-floating pellets, with significant difference (P<0.01); the drug in vitro release time can reach more than 6 h, and the drug release behaviors were lined with Higuchi equation. In vivo and in vitro studies showed that, the gastrointestinal bioadhesive and floating pellets prepared in this study have good bioadhesivity, floatability and good sustained release characteristics.

The 12-3-12 cationic gemini surfactant as a novel gastrointestinal bioadhesive material for improving the oral bioavailability of coenzyme Q10 naked nanocrystals

To improve the oral bioavailability of nanocrystalline drug preparations, the cationic 12-3-12 quaternary ammonium surfactant gemini was introduced into nanocrystals as a novel gastrointestinal bioadhesive material. Coenzyme Q10 (CoQ10), a typical Biopharmaceutics Classification System (BCS) class II drug, was used as a model drug. The 12-3-12 gemini surfactant was added to the preparation at a low concentration and imbued the particles with abundant positive charges. In vitro and in vivo gastrointestinal adhesion tests confirmed that the gemini-modified nanocrystals were prone to adhere to the upper gastrointestinal tract (GIT), thereby prolonging retention time in the GIT and enhancing absorption. In the distribution study in rats, the use of nanocrystals modified with gemini led to greater drug distribution to the heart and the liver than that achieved with the naked nanocrystals. A pharmacokinetic study in beagle dogs showed that the gemini-modified CoQ10 nanocrystals improved the oral bioavailability of CoQ10 in a dose-dependent manner, and the smaller size produced a much better effect with the same gemini modification. These results demonstrate that the cationic surfactant gemini is a promising oral bioadhesive material with applications in nanoscale drug delivery systems.

Comparative evaluation of healing after periodontal flap surgery using isoamyl 2-cyanoacrylate (bioadhesive material) and silk sutures: A split-mouth clinical study.

Background:Many factors contribute to uneventful and healthy postoperative healing. Hence, closure of periodontal flap postsurgery for the attainment of primary union between flap margins is of utmost importance. Isoamyl 2-cyanoacrylate is a tissue adhesive, which can be used for the closure of elevated flaps to overcome the problems associated with conventional suture material like silk.Aim:This study aims to compare healing after periodontal flap surgery using isoamyl 2-cyanoacrylate (bioadhesive material) and silk sutures.Materials and Methods:The study was carried out on twenty patients who needed flap surgical procedure for pocket therapy.Statistical Analysis Used:Results were subjected to statistical analysis. Paired t-test was used for intragroup postprocedure improvement in each parameter, and independent sample t-test was used for intergroup comparison.Results:Early healing was seen with isoamyl 2-cyanoacrylate during the 1st week when compared with silk. However, no significant difference was seen in the 2nd week when both the materials were compared.Conclusions:It can be concluded that cyanoacrylate aids in early initial healing.

Bioadhesive floating microsponges of cinnarizine as novel gastroretentive delivery: Capmul GMO bioadhesive coating versus acconon MC 8-2 EP/NF with intrinsic bioadhesive property.

Introduction:The study was aimed at the development of low-density gastroretentive bioadhesive microsponges of cinnarizine by two-pronged approach (i) coating with bioadhesive material and (ii) exploration of acconon MC 8-2 EP/NF as bioadhesive raw material for fabrication.Materials and Methods:Microsponges were prepared by quasi-emulsion solvent diffusion method using 32 factorial design. Capmul GMO was employed for bioadhesive coating. In parallel, potential of acconon for the fabrication of bioadhesive floating microsponges (A8) was assessed.Results:Formulation with entrapment efficiency = 82.4 ± 3.4%, buoyancy = 82.3 ± 2.5%, and correlation of drug release (CDR8h) = 88.7% ± 2.9% was selected as optimized formulation (F8) and subjected to bioadhesive coating (BF8). The %CDR8h for A8 was similar to BF8 (87.2% ± 3.5%). Dynamic in vitro bioadhesion test revealed comparable bioadhesivity with BF8. The ex vivo permeation across gastric mucin displayed 63.16% for BF8 against 56.74% from A8; affirmed the bioadhesivity of both approaches.Conclusion:The study concluded with the development of novel bioadhesive floating microsponges of cinnarizine employing capmul GMO as bioadhesive coating material and confirmed the viability of acconon MC 8-2EP/NF as bioadhesive raw material for sustained targeted delivery of drug.