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Self-sealing hyaluronic acid (HA)-coated self-sealing 30-gauge needles exhibiting instant leakage prevention of intravitreal humor and injected drug were developed in this study. Ninety New Zealand rabbits were used in this study. We assessed dye regurgitation in intravitreal ICG dye injections using HA-coated needles (HA needle group) and conventional needles (control group). Vitreous humor levels of anti-vascular endothelial growth factor (VEGF) were compared between groups one, three, and seven days after intravitreal bevacizumab (0.016 mL) injections. Expression levels of inflammatory cytokines in the aqueous humor and vitreous humor, including prostaglandin E2 (PGE2), interferon-γ, tumor necrosis factor-α, interleukin (IL)-1β, IL-4, IL-6, IL-17, and IL-8, were compared between HA needle, control, and normal (in which intravitreal injection was not performed) groups following 12 intravitreal injections over a period of one week. In the HA needle group, HA remained at the injection site and blocked the hole after intravitreal injection. Dye regurgitation occurred significantly less frequently in the HA needle group (16.7%) than the control group (55.6%) after intravitreal ICG dye injection. Meanwhile, vitreous anti-VEGF levels were markedly higher in the HA needle group than the control group one and three days after intravitreal bevacizumab injections. After 12 intravitreal injections, expression levels of aqueous and vitreous IL-8 significantly increased in the control group compared to the HA needle and normal groups. Conversely, there were no significant differences in the expression of the other seven cytokines among the three groups. Intravitreal injections using HA-coated self-sealing 30-gauge needles can block the outflow of vitreous humor and drugs through the needle passage.

Marine mussels secrete adhesive proteins to attach to solid surfaces. These proteins contain phenolic and basic amino acids exhibiting wet adhesion properties. This study used a mussel-inspired hemostatic polymer, chitosan-catechol, to treat gastrointestinal bleeding caused by endoscopic mucosal resection in a heparinized porcine model. We aimed to evaluate the hemostatic efficacy and short-term safety of this wet adhesive chitosan-catechol. We used 15 heparinized pigs. Four iatrogenic bleeding ulcers classified as Forrest Ib were created in each pig using an endoscopic mucosal resection method. One ulcer in each pig was untreated as a negative control (no-treatment group). The other three ulcers were treated with gauze (gauze group), argon plasma coagulation (APC group), and chitosan-catechol hemostatic agent (CHI-C group) each. The pigs were sacrificed on Days 1, 5, and 10, and histological examination was performed (n = 5 per day). Rapid hemostasis observed at 2 min after bleeding was 93.3% (14/15) in the CHI-C group, 6.7% (1/15) in the no-treatment group, 13.3% (2/15) in the gauze group, and 86.7% (13/15) in the APC group. No re-bleeding was observed in the CHI-C group during the entire study period. However, a few re-bleeding cases were observed on Day 1 in the no-treatment, gauze, and APC groups and on Day 5 in the gauze and APC groups. On histological analysis, the CHI-C group showed the best tissue healing among the four test groups. Considering the results, chitosan-catechol is an effective hemostatic material with reduced re-bleeding and improved healing.

Mussel-inspired adhesion chemistry provides a useful alternative to the use of fibrin glues., Since the first report of underwater adhesive proteins of marine mussels in 1981, numerous studies have reported mussel-inspired synthetic adhesive polymers. However, none of them have developed up to human-level translational studies. Here, we report a sticky polysaccharide that effectively promotes hemostasis from animal bleeding models to first-in-human hepatectomy. We found that the hemostatic material instantly generates a barrier layer that seals hemorrhaging sites. The barrier is created within a few seconds by in situ interactions with abundant plasma proteins. Therefore, as long as patient blood contains proper levels of plasma proteins, hemostasis should always occur even in coagulopathic conditions. To date, insufficient tools have been developed to arrest coagulopathic bleedings originated from genetic disorders, chronic diseases, or surgical settings such as organ transplantations. Mussel-inspired adhesion chemistry described here provides a useful alternative to the use of fibrin glues up to a human-level biomedical application.

Purpose InnoSEAL Plus is an adhesive, coagulant-free hemostatic material that mimics the adhesion mechanism of marine mussels. This study reports on the safety and efficacy of InnoSEAL Plus for patients with hemorrhage after hepatectomy despite first-line hemostasis treatments. Methods This is a multicenter, prospective, single-blinded, randomized clinical trial involving 96 hepatectomy patients. TachoSil was used as a comparator group. Three-minute and 10-minute hemostatic success rates were monitored. Rebleeding rates were also observed. Safety was assessed by recording all novel undesirable symptoms. Results InnoSEAL Plus showed a 3-minute hemostasis rate of 100%, while TachoSil had a rate of 98.0% (48 of 49 patients), demonstrating that the 2 had similar hemostatic efficacies. The difference in efficacy between the test and comparator group was 2.04%, and the lower limit of the one-sided 97.5% confidence interval was −1.92%; as this is greater than the noninferiority limit of −23.9%, the 2 treatments were equivalent. Meanwhile, the 10-minute hemostatic success rate was the same in both groups (100%). No rebleeding occurred in either group. In the safety evaluation, 89 patients experienced adverse events (45 in the test group and 44 in the comparator group). The difference between the 2 groups was not significant. No death occurred after application of the test or comparator group product. Conclusion Given that InnoSEAL Plus is a coagulation factor-free product, the hemostasis results are encouraging, especially considering that TachoSil contains a coagulation factor. InnoSEAL Plus was found to be a safe and effective hemostatic material for control of bleeding in hepatectomy patients.

Mussel-inspired adhesive coatings on biomedical devices have attracted significant interest due to their unique properties such as substrate independency and high efficiency. The key molecules for mussel-inspired adhesive coatings are catechol and amine groups. Along with the understanding of catechol chemistry, chitosan-catechol has also been developed as a representative mussel-inpired adhesive polymer that contains catechol and amine groups for adhesiveness. Herein, we demonstrated the direct writability of chitosan-catechol as a bioink for 3D printing, one of the additive techniques. The use of chitosan-catechol bioink results in the formation of 3D constructs in normal culture media via rapid complexation of this bioink with serum proteins; in addition, the metal/catechol combination containing tiny amounts of vanadyl ions, in which the ratio of metal to catechol is 0.0005, dramatically enhances the mechanical strength and printability of the cell-encapsulated inks, showing a cell viability of approximately 90%. These findings for mussel-inspired bioinks will be a promising way to design a biocompatible 3D bioink cross-linked without any external stimuli.

Joseph P. Park, Mi-Young Koh, Pil Soo Sung, Keumyeon Kim, Min Sun Kim, Moon Sue Lee, Eui-Cheol Shin*, Ki Hong Kim*, and Haeshin Lee* 1Graduate School of Nanoscience and Technology, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Korea 2Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Korea 3R & D Center, InnoTherapy Inc., Daejeon 305-732, Korea 4Department of Aquatic Life Medicine, Pukyoug National University, Busan 608-737, Korea

Adhesives play an important role in industrial fields such as electronics, architectures, energy plantation, and others. However, adhesives used for medical purpose are rather under-developed compared with those used in industry and consumer products. One key property required for medical adhesives is to maintain their adhesiveness in the presence of body fluid. Here, an entirely new class of medical adhesives called TAPE is reported; this is produced by intermolecular hydrogen bonding between a well-known polyphenol compound, tannic acid, and poly(ethylene glycol). The preparation method of TAPE is extremely easy, forming a few liters at once by just the simple mixing of the two compounds without any further chemical synthetic procedures. TAPE shows a 250% increase in adhesion strength compared with fibrin glue, and the adhesion is well maintained in aqueous environments. It is demonstrated that TAPE is an effective hemostatic material and a biodegradable patch for detecting gastroesophageal reflux disease in vivo. Widespread use of TAPE is anticipated in various medical and pharmaceutical applications such as muco-adhesives, drug depots, and others, because of its scalability, adhesion, and facile preparation.

In nature, a variety of functional water-insoluble organic materials are biologically synthesized in aqueous conditions without chemical additives and organic solvents. Insect cuticle, crustacean shells, and many others are representative examples. The insoluble materials are prepared by enzyme reactions and programmed self-assembly in water from water-soluble precursors. If the water-basis could be adapted, environment-friendly strategy developed in nature, many problems caused by the vast consumption of petroleum-based olefin materials could be solved or significantly attenuated. Here, the spontaneous formation of water-insoluble, biocompatible films from a water-soluble polymer is demonstrated without using any chemical additives and organic solvents. It is found that a water-soluble chitosan–catechol polymeric precursor is spontaneously self-converted to flexible water-insoluble thin film by simple dehydration. The preparation of mechanically robust, water-insoluble, flexible, transparent chitosan–catechol film is a completely unexpected result because most water-soluble polymers exist as powders when dehydrated. The film can be used as a bag similar to polyvinyl one and is multifunctional and biocompatible for drug delivery depots and tissue engineering applications.

Organically modified silicates incorporated with calcium salts produce novel, bioactive materials, which bond directly to living bone, because after exposure to a physical environment, calcium silicates have a high hydroxyapatite-deposit potential. In this study, transparent, monolithic, bi-structured hybrids were prepared using a sol–gel process for the CaO–SiO2-PTMO system. To establish the bi-structure, two types of sols were prepared: a polymer-rich sol that had a starting composition of PTMO/TEOS in an 80/20 mass ratio and a ceramic-rich sol that had a starting composition of TEOS/Ca(NO3)2 in a 1/0.3 molar ratio. The bi-structured hybrid was synthesized using a gelation process, where the ceramic-rich sol was placed on the polymer-rich wet gel. An interfacial structure with tight binding was established between the two gels that had the potential to form calcium phosphate within a period of 6 h on the bi-structured hybrid. This process led to the successful synthesis of a bi-structured hybrid with a high potential for bone-bonding property, which was also flexible.

The formation of hydroxyapatite is important for artificial materials to show high biological affinities for bone tissue. The present study focused on the synthesis of hydrogels capable of showing apatite formation, through modification of polyglutamic acid (PGA) with 3-aminopropyltriethoxysilane (APTES), followed by treatment with calcium chloride solution. A transparent bulk hydrogel was obtained at a molar ratio of PGA/APTES of 0.5. Prior soaking of the PGA hydrogel in calcium chloride solution accelerated the formation of bone-like apatite in a simulated body fluid. The modified PGA hydrogel is a candidate material for a biodegradable scaffold for bone regeneration.

The osteoconduction potential of artificial materials is usually evaluated in vitro by apatite formation in a simulated body fluid (SBF) proposed by Kokubo and his colleagues. This paper reports the compositional dependence of apatite formation on organic-inorganic hybrids in the CaO-SiO(2)-PO(5/2)-poly(tetramethylene oxide) system, initiated from tetraethoxysilane (TEOS), triethyl phosphate (OP(OEt)(3)), calcium chloride (CaCl(2)) and poly(tetramethylene oxide)(PTMO) modified with alkoxysilane. Formation of an apatite layer was observed on the surface of the organic-inorganic hybrids with molar ratios of TEOS/OP(OEt)(3) ranging from 100/0 to 20/80. The rate of apatite formation remarkably decreased when the hybrids were synthesized with TEOS/OP(OEt)(3) ratios of 40/60 or less. Hybrids without TEOS showed no apatite formation in SBF for up to 14 days. Addition of small amounts of OP(OEt)(3) to TEOS in the hybrids led to the high dissolution of calcium and silicate, while addition of large amounts of OP(OEt)(3) decreased the dissolution of calcium and silicate ions and resulted in reduced apatite formation regardless of the dissolution of phosphate ions from the hybrids.

Bioactive organic-inorganic hybrids can be used as biomaterials for bone substitution because they exhibit osteoconduction and other functions due to their organic components, such as flexibility and bioabsorbability. In this study, we synthesized uniform organic-inorganic hybrids from triethoxysilane-functionalized poly (tetramethylene oxide) (Si-PTMO), tetraethoxysilane (TEOS) and calcium chloride (CaCl 2 ) via the sol-gel process. The starting composition of Si-PTMO/TEOS molar had a weight ratio ranging from 20/80 to 90/10. The CaCl 2 concentration was kept constant at a CaCl 2 /TEOS molar ratio of 0.15. Uniform and transparent hybrids were obtained with a Si-PTMO/TEOS compositional range from 20/80 to 90/10. The potential bioactivity was evaluated by determining the formation of a bone-like apatite layer in simulated body fluid (SBF). Formation of a bone-like apatite layer was observed on the surface of the organic-inorganic hybrids when they were prepared from starting compositions of Si-PTMO/TEOS with weight ratios ranging from 20/80 to 50/50. An appreciable quantity of the calcium silicate is required to produce bioactive organic-inorganic hybrids.

Synthetic model of a large transparent crack-free monolithic ceramic-polymer hybrid, which was synthesized using triethoxysilane end-capped poly(tetramethylene oxide) (Si-PTMO) and tetraethoxysilane (TEOS), was examined in the CaO-SiO2-PTMO sol-gel system. Bulk precursor with nominal mass ratio of PTMO: TEOS = 80: 20 and surface precursor with nominal molar ratio of TEOS: Ca(NO3)2 = 1: 0.3 were subjected to hybridization through hydrolysis and condensation process, producing a bi-structured hybrid in which polymeric bulk was molecular hybridized with bioactive silicate surface. Spectroscopic and microscopic characterizations revealed that the surface of hybrid was typical bioactive silicate. In vitro study using a simulated body fluid (SBF) revealed that the hybrid formed an apatite on its surface within 6 hours in SBF, suggesting bioactive materials with high capability of tissue integration as well as polymeric physical properties.

Synthetic model of a ceramic–polymer composite, in which thin layer of bioactive silicate ceramic is molecular-hybridized onto surface of polydimethylsiloxane (PDMS) bulk, has been examined in the tetraethoxysilane (TEOS)–PDMS sol–gel system. A TEOS precursor solution of silica was subjected to hydrolysis and condensation on TEOS–PDMS precursor solution forming silica–PDMS hybrid bulk through co-polymerization, producing single large transparent crack-free monolithic hybrid bulk. Spectroscopic characterizations complemented with microscope observation showed that the surface of this hybrid was bioactive silicate, and that the surface silicate was successfully hybridized with the bulk silica–PDMS hybrid without revealing a distinct interface. These suggest a synthetic process of bioactive composites which have bioactive functionally graded ceramic surfaces on polymers, and thereby function with various polymeric physical properties as well as with ceramic bioactivity.

A ceramic-polymer nano-hybrid, in which the bioactive silicate surface is nano-hybridized with flexible silicone bulk, was synthesized in the tetraethoxysilane (TEOS)-polydimethylsiloxane (PDMS) sol-gel system. Different solutions for surface silicate and bulk silicone, whose component ratio of SiO2: PDMS were respectively 100: 0 and 50: 50, were subjected to lamination and delayed polymerization and condensation process, producing a large transparent crack-free monolithic bulk. Characterizations at near-surface cross-section of the hybrid bulk revealed typical bioactive silicate structure with no distinct interface with the interior, indicating possibility of a novel bioactive nano-composite with enhanced physical and biological functions.

Hydrogels able to form a bone-like hydroxyapatite (HAp) layer in the body environment are attractive materials as scaffolds for tissue engineering because they show osteoconductivity, i.e. bone-bonding property. In the present study, we synthesized hydrogels from sodium carboxymethylcellulose (sCMC), a water soluble polymer, through modification with a cross-linking agent, either ethylenediamine (EDA) or 3-aminopropyltriethoxysilane (APTES), followed by treatment with an aqueous solution containing calcium chloride aqueous solution. Formation of the bone-like HAp on the hydrogels was evaluated after immersion in a simulated body fluid (SBF). Hydrogels modified with the cross-linking agents EDA or APTES, and treated with 0.1 mol/dm3 of calcium chloride aqueous solution, formed a bone-like HAp layer on their surfaces after immersion in SBF for 3 days. Modification of organic polymers rich in carboxyl groups with APTES and CaCl2 offers a new method to produce biomaterials with greater potential for forming HAp, which provides high affinity to living bone because the incorporation of silanol groups confers the high ability to induce HAp formation.