This study was supported by National Research Foundation of South Korea: Mid-career scientist grant (2014002855), and Ministry of Industry, Trade, and Natural Resources: World Premier Material Development Program. This work is also supported by in part by Center for Nature-inspired Technology (CNiT) in KAIST Institute for NanoCentury (KINC).

All animal care and experiments are performed in accordance with the ethical protocol provided by the KAIST (Korea Advanced Institute of Science and Technology) IRB (Institutional Review Board).
1. TAPE Formation
<ol>
	<li>For preparing a TA solution, place a 4 ml-sized glass vial on a magnetic stirrer, and add 1 ml of distilled water with a stirring bar. Add 1 g of tannic acid to the vial, and dissolve it in the water by gentle stirring at 200 rpm for more than 1 hr. When the TA is completely dissolved, the mix...

<ol>
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H., Lee, Y., Kong, W. H., Kim, T. G., Park, T. G., Lee, H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Catechol-functionalized+chitosan/pluronic+hydrogels+for+tissue+adhesives+and+hemostatic+materials.">Catechol-functionalized chitosan/pluronic hydrogels for tissue adhesives and hemostatic materials.</a> Biomacromolecules. 12 (7), 2653-2660 (2011).</li><li>Mahdavi, A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+biodegradable+and+biocompatible+gecko-inspired+tissue+adhesive.">A biodegradable and biocompatible gecko-inspired tissue adhesive.</a> Proc Natl Acad Sci USA. 105 (7), 2307-2310 (2008).</li><li>Lee, H., Lee, B. P., Messersmith, P. 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D., Burks, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Hemostats,+sealants,+and+adhesives:+components+of+the+surgical+toolbox.">Hemostats, sealants, and adhesives: components of the surgical toolbox.</a> Transfusion (Paris). 48 (7), 1502-1516 (2008).</li><li>Erel, I., Schlaad, H., Demirel, A. L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Effect+of+structural+isomerism+and+polymer+end+group+on+the+pH-stability+of+hydrogen-bonded+multilayers.">Effect of structural isomerism and polymer end group on the pH-stability of hydrogen-bonded multilayers.</a> J Colloid Interface Sci. 361 (2), 477-482 (2011).</li><li>Shutava, T. G., Prouty, M. D., Agabekov, V. E., Lvov, Y. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Antioxidant+Properties+of+Layer-by-Layer+films+on+the+Basis+of+Tannic+Acid.">Antioxidant Properties of Layer-by-Layer films on the Basis of Tannic Acid.</a> Chem Lett. 35 (10), 1144-1145 (2006).</li><li>Schmidt, D. J., Hammond, P. T. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Electrochemically+erasable+hydrogen-bonded+thin+films.">Electrochemically erasable hydrogen-bonded thin films.</a> Chem Commun. 46 (39), 7358-7360 (2010).</li><li>Shutava, T., Prouty, M., Kommireddy, D., Lvov, Y. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=pH+Responsive+Decomposable+Layer-by-Layer+Nanofilms+and+Capsules+on+the+Basis+of+Tannic+Acid.">pH Responsive Decomposable Layer-by-Layer Nanofilms and Capsules on the Basis of Tannic Acid.</a> Macromolecules. 38 (7), 2850-2858 (2005).</li><li>Erel, I., Zhu, Z., Zhuk, A., Sukhishvili, S. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Hydrogen-bonded+layer-by-layer+films+of+block+copolymer+micelles+with+pH-responsive+cores.">Hydrogen-bonded layer-by-layer films of block copolymer micelles with pH-responsive cores.</a> J Colloid Interface Sci. 355 (1), 61-69 (2011).</li><li>Kim, B. -. S., Lee, H. -. I., Min, Y., Poon, Z., Hammond, P. T. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Hydrogen-bonded+multilayer+of+pH-responsive+polymeric+micelles+with+tannic+acid+for+surface+drug+delivery.">Hydrogen-bonded multilayer of pH-responsive polymeric micelles with tannic acid for surface drug delivery.</a> Chem Commun. 45 (28), 4194-4196 (2009).</li><li>Murakami, Y., Yokoyama, M., Nishida, H., Tomizawa, Y., Kurosawa, H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+simple+hemostasis+model+for+the+quantitative+evaluation+of+hydrogel-based+local+hemostatic+biomaterials+on+tissue+surface.">A simple hemostasis model for the quantitative evaluation of hydrogel-based local hemostatic biomaterials on tissue surface.</a> Colloids Surf B Biointerfaces. 65 (2), 186-189 (2008).</li><li>Kim, K., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=TAPE:+A+Medical+Adhesive+Inspired+by+a+Ubiquitous+Compound+in+Plants.">TAPE: A Medical Adhesive Inspired by a Ubiquitous Compound in Plants.</a> Adv Funct Mater. 25 (16), 2402-2410 (2015).</li><li>Suzuki, S., Ikada, Y. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Adhesion+of+cells+and+tissues+to+bioabsorbable+polymeric+materials:+scaffolds,+surgical+tissue+adhesives+and+anti-adhesive+materials.">Adhesion of cells and tissues to bioabsorbable polymeric materials: scaffolds, surgical tissue adhesives and anti-adhesive materials.</a> J Adhes. Sci. Technol. 24 (13), 2059-2077 (2010).</li><li>Lomova, M. V., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Multilayer+Capsules+of+Bovine+Serum+Albumin+and+Tannic+Acid+for+Controlled+Release+by+Enzymatic+Degradation.">Multilayer Capsules of Bovine Serum Albumin and Tannic Acid for Controlled Release by Enzymatic Degradation.</a> ACS Appl Mater Interfaces. 7 (22), 11732-11740 (2015).</li><li>Shin, M., Ryu, J. H., Park, J. P., Kim, K., Yang, J. 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The authors have nothing to disclose.

We developed an entirely new class of hemostatic adhesive named TAPE inspired by the water-resistant molecular interaction of a plant-derived polyphenolic compound, TA. TA is a representative hydrolysable tannin that has significantly attracted attention due to its anti-oxidant, anti-bacterial, anti-mutagenic, and anti-carcinogenic properties.
The process of making TAPE is extremely simple, scalable, and environmentally friendly, as it is just the one-step mixing of two aqueous solutions follo...

In a past decade, efforts have been made to replace current surgical sutures and staples to close wounds with biodegradable/bioabsorbable adhesives due to their convenience in usage and low tissue invasiveness during surgical treatments. Commercially available tissue-adhesives are classified into four types: (1) cyanoacrylate derivatives1, (2) fibrin glues formed by enzymatic conversion from fibrinogen to fibrin polymers by thrombin2,3, (3) protein-based materials such as chemically or physically cross-linked albumin and/or gelatin4,5, and (4) synthetic polymer-based ones6. Although they have been used in many clinical applications, all adhesives have their own intrinsic disadvantages and drawbacks that can be obstacles to their widespread usage. Cyanoacrylate-based glues show high adhesion strength to tissues, but their toxic by-products such as cyanoacetate and formaldehyde formed during degradation, often cause significant degrees of inflammatory responses7. Fibrin glues and albumin or gelatin-based materials have safety issues regarding the transmission of infectious components, such as viruses from animal sources: human blood plasma for fibrin glues and animals including cattle, chicken, pigs, and fish for gelatin-based glues8. Although a few synthetic polymer-based adhesives have been approved by the Federal Drug Administration (FDA), most adhesives made of synthetic polymers continue to have difficulties in minimizing the manufacturing process steps and achieving biocompatibility9. Most importantly, all glues suffer from poor mechanical and adhesion strength to wet tissues10. Recently, biomimetic tissue adhesives inspired by marine mussels11-13, geckos14, gecko with mussel15, and endoparasitic worms16 have been emerging as promising alternatives to current medical glues due to their tunable mechanical and adhesive properties with biocompatibility. However, to this day, there are still issues to be addressed before they become commercial products17.
Here, we report an entirely new type of medical glue called TAPE that is prepared by the intermolecular hydrogen bonding between a plant-derived adhesive molecule, Tannic acid (TA), and a bio-inert polymer Poly(ethylene glycol) (PEG), as its name indicates. TA is a representative hydrolysable tannin ubiquitously found during the secondary metabolism of plants. It has attracted much attention due to its anti-oxidant, anti-mutagenic, and anti-carcinogenic properties and has been shown to participate in supramolecular interactions with many polymers, such as poly(N-isopropylacrylamide) (PNIPAM) and poly(N-vinylpyrrolidone) (PVPON), to form layer-by-layer (LbL) films18-20 and drug-releasing microcapsules21-23. In this study, we discover that TA can act as an efficient water-resistant adhesive functional moiety to form a medical adhesive, TAPE. By simple mixing with TA, a non-fouling polymer PEG becomes a supramolecular glue with 2.5-fold increased adhesion strength compared with commercial fibrin glue, and this adhesion was maintained throughout up to 20 cycles of attachment and detachment, even in the presence of water. Its hemostatic ability was tested on a liver bleeding model in vivo and showed good hemostatic ability to stop bleeding within a few seconds. TAPE has its significant meaning in a related field as the first plant-derived adhesive that can reveal new insight into solving the drawbacks of current problems with bio-inspired approaches. We also expect the widespread use of TAPE in a variety of medical and pharmaceutical applications such as muco-adhesives, drug-releasing patches, wound-care dressings, and others due to its simple preparation method, scalability, tunable biodegradation rate, as well as highly wet-resistant adhesion properties.

<table>
	<tbody>
		<tr>
			<td>Tannic acid</td>
			<td>Sigma-aldrich</td>
			<td>403040</td>
			<td></td>
		</tr>
		<tr>
			<td>Poly(ethylene oxide), 4-arm, hydroxy terminated</td>
			<td>Aldrich</td>
			<td>565709</td>
			<td>Averge Mn ~10,000</td>
		</tr>
		<tr>
			<td>Poly(ethylene glycol)</td>
			<td>Aldrich</td>
			<td>373001</td>
			<td>Average Mn 4,600</td>
		</tr>
		<tr>
			<td>Biopsy punch</td>
			<td>Miltex</td>
			<td>33-36</td>
			<td>Diameter = 6 mm</td>
		</tr>
		<tr>
			<td>Aron Alpha&#174;</td>
			<td>Toagosei Co., Ltd.</td>
			<td></td>
			<td>Instant glue</td>
		</tr>
		<tr>
			<td>Universal testing machine (UTM)</td>
			<td>Instron</td>
			<td>5583</td>
			<td></td>
		</tr>
		<tr>
			<td>Microcentrifuge tubes</td>
			<td>SPL life science</td>
			<td>60015</td>
			<td>1.5 mL</td>
		</tr>
		<tr>
			<td>Petri dish</td>
			<td>SPL life science</td>
			<td>10090</td>
			<td>90 x 15 mm</td>
		</tr>
		<tr>
			<td>Sodium phosphate monobasic</td>
			<td>Sigma</td>
			<td>S5011</td>
			<td>1x PBS ingredient</td>
		</tr>
		<tr>
			<td>Sodium phosphate dibasic</td>
			<td>Sigma</td>
			<td>S5136</td>
			<td>1x PBS ingredient</td>
		</tr>
		<tr>
			<td>Sodium chloride</td>
			<td>Duchefa biochemie</td>
			<td>S0520.5000</td>
			<td>1x PBS ingredient</td>
		</tr>
		<tr>
			<td>Incubating shaker</td>
			<td>Lab companion</td>
			<td>SIF6000R</td>
			<td></td>
		</tr>
		<tr>
			<td>ICR mice</td>
			<td>Orient bio</td>
			<td>Normal ICR mouse</td>
			<td>6 weeks, 30-35 g, male</td>
		</tr>
		<tr>
			<td>Tiletamine-zolazepam (Zoletil 50)</td>
			<td>Virbac</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Zylazine (Rompun)</td>
			<td>Bayer</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>PrecisionGlideTM needle (18 G)</td>
			<td>BD</td>
			<td>302032</td>
			<td>18 G</td>
		</tr>
		<tr>
			<td>Filter paper</td>
			<td>Whatman</td>
			<td>1001 125</td>
			<td>Diameter = 125 mm</td>
		</tr>
		<tr>
			<td>Parafilm</td>
			<td>Bemis Flexible Pakaging</td>
			<td>PM996</td>
			<td></td>
		</tr>
	</tbody>
</table>

tape: a biodegradable hemostatic glue inspired by a ubiquitous compound in plants for surgical application

This video describes the simplest protocol for preparing biodegradable surgical glue that has an effective hemostatic ability and greater water-resistant adhesion strength than commercial tissue adhesives. Medical adhesives have attracted great attention as potential alternative tools to sutures and staples due to their convenience in usage with minimal invasiveness. Although there are several protocols for developing tissue adhesives including those commercially available such as fibrin glues and cyanoacrylate-based materials, mostly they require a series of chemical syntheses of organic molecules, or complicated protein-purification methods, in the case of bio-driven materials (i.e., fibrin glue). Also, the development of surgical glues exhibiting high adhesive properties while maintaining biodegradability is still a challenge due to difficulties in achieving good performance in the wet environment of the body. We illustrate a new method to prepare a medical glue, known as TAPE, by the weight-based separation of a water-immiscible supramolecular aggregate formed after a physical mixing of a plant-derived, wet-resistant adhesive molecule,&#160;Tannic Acid (TA), and a well-known biopolymer, Poly(Ethylene) glycol (PEG). With our approach, TAPE shows high adhesion strength, which is 2.5-fold more than commercial fibrin glue in the presence of water. Furthermore, TAPE is biodegradable in physiological conditions and can be used as a potent hemostatic glue against tissue bleeding. We expect the widespread use of TAPE in a variety of medical settings and drug delivery applications, such as polymers for muco-adhesion, drug depots, and others.

TAPE is a supramolecular aggregate that settles down after centrifuging the mixture of two aqueous solutions containing TA (1 g/ml in distilled water) and PEG (1 g/ml in distilled water) with 2:1 volume ratio (Figure 1A). The mixing ratio is the key factor in achieving high adhesion strength; when TAPE is formed by a 2:1 mixing ratio, 20 units of the hydroxyl group (-OH) in 25 units of TA interact with each ether group (-O-) in PEG, resulting in the highest intermolecular...

Watch this Scientific Journal Video about TAPE: A Biodegradable Hemostatic Glue Inspired by a Ubiquitous Compound in Plants for Surgical Application at JoVE.com

TAPE: A Biodegradable Hemostatic Glue Inspired by a Ubiquitous Compound in Plants for Surgical Application

We describe the simplest protocol to prepare biodegradable medical glue that has an effective hemostatic ability. TAPE is a water-immiscible supramolecular aggregate prepared by mixing of tannic acid, a ubiquitous compound found in plants, and poly(ethylene) glycol, yielding a 2.5 times greater water-resistant adhesion compared with commercial fibrin glue.

This video describes the simplest protocol for preparing biodegradable surgical glue that has an effective hemostatic ability and greater water-resistant ...

The overall goal of this protocol is to develop a biodegradable hemostatic glue for surgical application inspired by a ubiquitous compound in plants. This method can help us understand the water resistant adhesion mechanism of biometrics, such as tissue adhesives and sealant in biomedical application. The main advantage of this technique is that the process of making TAPE is extremely simple, scalable, and environmentally friendly.First, prepare a Tannic Acid solution in a four milliliter glass vial on a magnetic stirrer. Add one milliliter of distilled water and one gram of Tannic Acid with stirring at 200 rpm. After an hour, the Tannic Acid will be completely dissolved in a brown solution.Next, add one milliliter of distilled water to one gram of PEG powder and vortex them into a white slurry. Keep the slurry at 60 degrees for 10 minutes. It should become completely clear.Then, return it to room temperature. Next, in a microcentrifuge tube, mix 329 microliters of PEG solution with 671 microliters of the Tannic Acid solution. Take the aliquat slowly as the solutions are both quite viscous.Gently blend the solutions into a honey-like mixture with a narrow spatula. Spin the mixture at 12, 300 gs for three minutes in a fixed angle rotor. Then, carefully pipette off as much of the supernatant as possible, leaving the fully formed TAPE.Store the TAPE at four to eight degrees Celsius for several weeks. To measure the adhesive strength of the TAPE, prepare a test tissue from a porcine biopsy skin punch. Remove all the fat and then prepare two six millimeter diameter test tissues.Apply commercial cyanoacrylate glue to the outer side of each tissue and attach the rods or a similar object to be gripped by the test machine. Next, apply a drop of TAPE to one side of the tissue and spread it uniformly between the inner sides of the two tissues so they are attached. Then, attach and detach the tissues several times to make a homogeneous mix that fully covers the interface.Next, attach the rods to the testing apparatus. Begin with applying a force of 20 Newtons for one minute. Next, have the rods pull apart at a rate of one millimeter per minute until the tissues are completely detached.The data is given as a force-distance curve. To test adhesion strength in the presence of water, add 20 microliters of water to the detached area between the two tissues and immediately attach the wet surfaces with the TAPE. Repeat the test as before with no other changes.First, cut an eight millimeter diameter cap off a microcentrifuge tube and weigh it. Next, fill the cap with 150 milligrams of TAPE and measure the total weight. Do not fill the cap beyond the lip, which will be needed as a barrier.Add 50 milliliters of PBS buffer to the 75 square centimeter cell culture flask. Put the loaded cap into the flask and submerge the cap. Incubate the flask at 37 degrees Celsius on an orbital shaker set to 50 rpm, but not higher.At the desired time, remove the cap and dry it with nitrogen gas. Then, weigh the cap. Next, replace the PBS in the flask and continue the incubation with gentle shaking until the next time point.From the measurements, calculate the relative remaining weight. Begin with a fully anesthetized six-week old male mouse tested with a toe pinch. Be sure to apply vet ointment to the eyes prior to beginning surgery.Now, expose the liver using a midline abdominal incision, and place filter paper of known mass under the liver to immobilize it. Next, prick the liver with an 18-gauge needle to induce bleeding. While absorbing the blood with sterile gauze, immediately put 100 microliters of TAPE on the site of the incision.For positive controls, use cyanoacrylate or a similar glue and do nothing for negative controls. No further suturing is needed. After placing the adhesive, collect the blood from the damage site onto the paper.Replace the paper every 30 second for two minutes. Measure the mass of the absorbed blood on the four filter papers. The animal should be euthanized.Several ratios of TA and PEG were tested and the ideal combination to make TAPE was a two-to-one volume ratio. Such TAPE was applied between two porcine skins with a diameter of six millimeters then tested on a tensile machine as described. The force needed to detach two porcine skins was initially measured at 200 kilopascals and increased to 250 kilopascals with repeated cycles.When the skin samples were moistened after each cycle of attachment/detachment, the tensile strength of the bond dropped to 90 kilopascals initially and decreased to 50 kilopascals after 20 cycles. The durability of TAPE was tested in small volumes diluted in PBS with shaking at physiological light conditions. Mass was retained for 21 days using the two-to-one ratio formulation.A one-to-one ratio formulation of TAPE only lasted 13 days under these conditions. Next, a hemostatic test performed in vivo was conducted. The TAPE sealed liver was compared with commercial fibrin glue.The TAPE sealed liver bled significantly less than the fibrin glue sealed liver. Once mastered, the preparation of TAPE can be done in five minutes if it is performed properly. While attempting this procedure, it is important to remember to keep the optimized ratio between Tannic Acid and PEG because it can dramatically affect the adhesion force of TAPE.After its development, this technique paved the way for researchers in the field of biometrics to explore the nature inspired way to solve current problems in developing water resistant adhesive materials. Though this method can provide insight into hemostatic materials, it can also be applied to other systems such as tissue sealant for wound healing and implantable patch for drug delivery.

tape-biodegradable-hemostatic-glue-inspired-ubiquitous-compound

Research

JoVE Journal

Bioengineering

14.0K 조회수.  Korea Advanced Institute of Science and Technology (KAIST). The overall goal of this protocol is to develop a biodegradable hemostatic glue for surgical application inspired by a ubiquitous compound in plants. This method can help us understand the water resistant adhesion mechanism of biometrics, such as tissue adhesives and sealant in biomedical application. The main advantage of this technique is that the process of making TAPE is extremely simple, scalable, and environmentally friendly.First, prepare a Tannic Acid solution in a four millili...