Materials Science & Engincering © 111 (2020) 110796 ELSEVIER Journal homepage: www elsevier.com/locateimsec Contents lists available at ScienceDisect Materials Science & Engineering C Review The recent progress of tissue adhesives in design strategies, adhesive mechanism and applications a i Zixian Bao’, Minghong Gao’, Yue Sun, Rui Nian*, Mo Xian" (AS key Labora of Bae Mari Qngao isi of nmerg and Bore Teco Chinese Academy of Sines, No. 189 Sanging Roa Qigas Thoue adhesives have emerged as an effective method for wound corure and hemonasisin recent decades, due to their ability to bond tissues together, preventing separation from ene tsue to another. However, existing adhesives by improving pon existing adherives through diferent strategies Therefore, highlighting and sna Iying these design strategies are essential fr developing the next generation of advanced adhesives. To this en, wwe reviewed the availabe strategies for modifying traditional adhesives including cyanoacrylate glues, bein lant and bininepted adhesives) focusing on their sroctares, ahesive mechanisms, advantages, Himiatons, and ‘orrent applications, The bisinspted adhesives have nomerous advantages over tradional adhesives, which Wil bea wise dreton for achieving ussue adhesives with superar properties. 1. Introduction ‘A bioadhesive is a material that can bond tissues together when pplied on their surface, preventing separation by transfering the ap plied loads from one tissue to the other [1]. Its an attractive method ‘with potential to replace other surgical techniques such as suture oF staples. Various medical bioadhesives have been developed over the past decades, which can be divide into three categories ) hemortats that form blood clots via different mechanisms; i) glues that reattach Tacerated and traumatized tissues; andi) sealants that ereate a barrier to prevent the leakage of gases or liquids (2) Tissue adhesives are promising biomaterials that can be used for hemostasis, wound closure, Ussue repair and fixation of implants Compared with sutures, tistue adhesives have several advantages, sich ‘a being less traumatic, faster co use, easy to apply and versatile [3] Tissue adhesives can be classified into two categories: #) natural polymer-based tissue adhesives, including fibrin, albumin, and gelatin; li) synthetic tissue adhesives, including adhesives based on cyano: caylate, poly(ethylene glycol) (PEG), catechol and methacrylic anhy- “ride [4,5]. The ideal adhesive should meet all following ciceria: ‘easy to apply and polymerize in stu: i) sufficient mechanical flexibility ‘to accommodate complex wound contours and sizes; i) biocompatible; |v) sultable mechanieal and physical properties, such as burs, tensile ‘Conesponding authors and shear strengths; and v) high bonding strength with moist tissues oF organs (1,6-8], However, existing tissue adhesives are far from ideal, presenting with poor bonding strength in wet conditions, cytotoxicity And sequela. Ths, great efforts have been invested in evolving existing adhesives and developing novel adhesives to alleviate these concerns. Herein, the adhesive mechanisms, structures and design strategies of traditional tissue adhesives (including eyanoserylate glues, fibrin scalants and BioGlue) and emerging ones (including gelatin sealants ‘methacrylated sealants and bioinspired adhesives) are presented. The advantages, limitations and applications of each tissue adhesive are also discussed. We expect that this review will provide insights forthe de velopment of next-generation tissue adhesives, 2. Gyanoacrylate glues 2.1, Biochemical characteristics Cyanoacrylate (CA) glues are chemical synthetic and hybrid issue sealants, which possess strong, rapidly acting adhesive properties and are used prevalenly in medicine, industry and household actives [4 CCyanoacrylates can adhere and bind tothe target surface within 5-6 sof contact with basie substances (such as water, blood, body tissues or ‘moisture [2], and finally undergo exothermic polymerization to form a mall adéveses:rianralgeibedt ae.en (R Nan, sianmo@glve aces (ML Xap. there suthors contributed equally to thir work hip //do.rg/10.1018/} meee-2020.110795 Received & May 2018; Received in revised frm 18 April 2019; Acepted 29 February 2020 ‘Avallable online 05 March 2020 0926-4951/ © 2020 tleevier 3. Al rights reserved.Cyanoacrylate molecule CaN CEN H,C=C, => Nu-HC—C— H,C=C" \coor coor \coor J can ca Nu-HC—C—-H,C—C! coor \coor Fig. 1 Polymerization ofeyanouerylete glues. Nu: ncleophil strong film within 60 s [4] (Fg. 1). The strong cyanoacrylate film formed at the tissue surface degrades into cyanoacetate compounds and formaldehyde with time [10], which cannot be metabolized and liminated rapidly. This causes them to accumulate in tissue, which in tur leads to inflammation. The biodegradation speed is decreased with the length of alkyl chains inereasing [11]. Cyanoacrylate glues have a single component and do not contain any solvent. Moreover, these aahesives have high thermal resistance, with hemostatic and ant bacterial properties [12]. After reacting with tissues, cyanoacrylate monomers are vaporized as smoke, which may iritate sensitive mem- Danes of the eyes, nose and throat, However, the tone effects ar lost, instantaneously when cyanoacrylate monomers polymerize. Given the potential risks associsted with the use of eyanoaerylate glues, pre pparaton and arrangement of equipment and glue components before therapy are important to ensure its safety (13]. Thus, when using cy anoacryate glues, aeration should be very good in order to minimize these risks 2.2. Molecular design “The basie structure of cyanoacrylate is shown in Fig. 1, The carbon side chains and the alkyl determine the features of the adhesive. De ‘pending on the alkyl group (R group), the cyanoacrylate family ean be divided into five main groups, including methyl-2-cyanoacrylate (2 (MCA), ethyl-2- 100 years [118]. Since 1970, fibrin sealant has been standardized with the following components: concentrated i brinogen eryoprecpitate, factor XM and thrombin (starter solution) 119]. The thrombin component typically contains calcium and an antifibrinolytic agent (eg aprotinin) to prevent rapid ‘brinolysis [120]. The component solutions are reconstituted in two separate sy inges before use. Upon being mixed, these agents can form a clot by simulating the lst stages ofthe natural coagulation cascade, initially prodicing fibrin monomers which subsequently assemble into a cros linked polymer {15}. Thrombin cleaves fibrinopeptide A and B located fon the fibrinogen, forming afbrin monomer. Thea, thrombin activates factor XII inthe presence of calcium, promoting the conversion of the fibrin monomer inco a fibrin elot [121,122] (Wig. 2. The speed of elot formation varies with the concentration of anlfibrinolyics. Different from eyanoacryletes, fibrin glue ean be completely absorbed by mac rophages and angio-ibroblasts within two weeks after application due to its natural origin [123]. Moreover, the degradation rate could be tuned by controlling the precursor concentration and ionic strength 124). 3.2, Moleclar design Fibein glue consists of concentrated fibrinogen exyoprecipitate, factor XIII and thrombin, Therefore, the evolution of fibrin sealant ie ‘mainly based on changing the origin of the fibrinogen eryopreciptate and thrombin, Fibrinogen and thrombin are generally derived from human blood and bovine thrombin, Several manufacturers produce fibrin glues for medical use, such as Tisseel (Baxter), Vitagel (Orthovita), Artiss Gaxter), Fvieel (Ethicon/JE) and Tachosil (Baxter). Tisseel, Vitagel and Evicel are approved by FDA for use in hemostasis during surgical procedures (125). Artis, which has a low concentration of thrombin (45 TU), is FDA approved for use in facelits, providing che surgeon with up to 60 s for operation [125,125]. Tackosll is approved for he rmostasis during cardiac surgery only [125] In adeition, the use of fibrinogen derived from the patients auto Jogous plasma in the form of platelet rich or poor plasma should be ‘mentioned, although it was not specifically approved by the FDA for producing fibrin sealants. Advantages of this method include the re duced cost and reduced risk of disease transmission. However, this method also has several limitations when compared to commercial f brin sealants, including the time, consent and lower fibrinogen con- centration [126] In 1978, the FDA suspended the commercialization of fibrin glue due tothe possible transmission of infectious diseases (127,128]. Thus Jn the 1990s, che Center for the Scudy of Venoms an Venomous Ani mals at Sio Paulo State University proposed a new heterologous bio product composed of a thrombinlike enzyme obtained from Crotalus dhurissusterfieus venom and fibrinogen-rich eryoprecipitate extracted fom bulfalo Bubalus bubals (119,129-11]. The serine protease (gy roxin) purified from shake venom isa thrombin-like en2yme. Due to its enzymatic activity, the serine protease acts on human and animal f brinogen and cleaves the a-chain proximal to the Neterminal. The re sultant fibrin monomers are then polymerized in an intense stable network unlike that eaditionally produced by thrombin (119). Cryo: precipitate is cold precipitate of frozen fresh plasma. In 1998,Maral Since & gern C111 2020) 210796, 2 be eat foro woe ais opps me YoY & weve lesan) (ores tua) wetore lorvel seeeny 6 eons ws orang squons prams pur ous) aed oven oo pg 930 eGo snore preg une ope aoneayeae Hap Wa oerFibrinogen Thrombin —_—Factor Xl {[—1W#@1__ cat eoluble fan Factor Xilla monomers | Aprotinin Ff 4 Unstable fibrin polymer cit” Ofosslinked fibrin polymer ig. 2, Seer ofrinogen and thrombin interaction to yield a mate rin fhe ct ‘brinogen extracted from bulfaloes was for the frst time proposed to replace fibrinogen from human [132]. The authors evaluated the ‘eryoprecipitate level of diverse animals (including bovine, equine, ‘ovine and buffalo), and compared them with that extracted from hu mans. Due tothe high fibrinogen concentration in their eryoprecpitate, buffalos were selected at the ideal donors (122). Cryoprecipitate con. tains fibrinogen, factor Vill, Willebrand factor, factor XIIl and ft Dronectin [119,193,134]. It must be stored at ~20 °C and has a shelf life of one year. After > 20 years of efforts, this product is now under clinical tials (135-138) In conclision, the evolution of fibrin sealants is mainly focused on the optimization of fibrinogen and thrombin. To avoid the transmission ‘of infectious diseases, autologous fibsinogen, recombinant thrombin ‘and heterologous fibrin sealants are being explored successively. Taking all into account, the heterologous fibrin sealant (especially from snake 1m) represents a promising alternative for future applications 136}, 3.3. Applications 3.3.1, Hemostasis and anastomoset ‘The adhesive and hemostatic properties of fibrin glue have been demonstrated in multiple studies. The value of fibrin as a hemostatic ‘agent was frst discussed in 1909 (139). Fibrin sealant has been used for ‘hemostasis in various procedures, such as variceal bleeding, nonsutur able intraoperative bleeding, endoscopic sinus surgery, liver trans. plantation hemostasis and total knee arthroplssty (11,65~7). The he rmostatie properties of fibrin adhesive make it useful in resections of the liver, spleen and pancreas, because these often present with bleeding ‘across large areas, which is difficult to contol with conventional ‘methods [58]. The fibrin adhesive has also been used in traumatic abdominal injury. In addition, Ribrin adhesive has been reported ef fective in fistula closure, especially for anal fotua, enterocutaneous fistula, gastrocutaneous fistula and esophageal perforations (59-74] 33.2, Onthopelc sugery ‘The rte of fibrin polymerization can be decreased by decreasing the ‘concentration of thrombin. With low concentrations of thrombin, fibrin _glve can be percutancously injected as liquid state, and molded into a desired form after polymerization {10}. In addition, fibrin adhesive has been shown to promote a variety of cellular response, including increased cell migration, proliferation and even therapeutic effect 141,142]. Thus fibrin glue is suitable for use in orthopedie surgery. It hhas been shown that fibrin glue seeded with chondrocytes could pro duce high-quality neocartilages [75]. However, the concentration of fibrin glue, cartilage source and chondrocyte concentration did not have a significant effect on neocartilage formation [76]. Moreover, f- brin adhesive plays a significant role in cartilage repair. A tissue Maral Since & gern C111 2020) 210796, engineered cartilage substitute fabricated with mesenchymal stem cells and fibrin glues was proposed [77]. Their results demoastrated that mesenchymal stem celle are valid and superior alternatives to chon- Arocytes for articular cartilage repair. Total hip arthroplasty is considered a major orthopedic surgery to treat end-age osteonecrose of the femoral head, degenerative arthritis and traumatic conditions such as displaced femoral neck fractures [78] Fibrin glue has been used in tozal hip arthroplasty for reducing perio erative blood los, as described in previous literature. A meta-analysis was performed to analyze the efficacy and safety of fibrin glu for total hip arthroplasty [78]. The data showed that fibrin sealant might reduce {otal blood loss and postoperative hemoglobin decline. However, ta ‘peramic acid has been reported to perform beter than fibrin sealant in reducing. postoperative transfusions [79,80]. Therefore, fibrin ad hesives may now be largely out of favor 3.3.3. Seroma prevention ‘Seroma formation isthe most common complication following face lift or breast cancer surgery, which may delay adjuvant therapy and prolong hospital stays [81]. The first report associating the use of fibrin slue with hematoma prevention dates back to 1994 [82]. Recently, a meta-analysis was performed to evaluate the effacy of fibrin sealants fn preventing seroma formation [83]. Thirteen studies involving 2343 patients (from 1994 to 2015) were retrieved, and the data were ano lyzed. The results showed a statistically signifieant deerease in pos operative hematoma and wound drainage with the administration of fibrin sealants. However, recent studies have reported that the admin ‘stration of fibrin sealants does not reduce the amount of Hid Tost ater breast surgery, only reducing hospital stays and costs [81,54] 3.3.4. Nervous system treatment Lesions to the nervous system often produce hemorthage and tissue Toss that are difielt to repair. Scar formation, inflammation and ee vitation can worsen the impairment and the condition of the patient. Using commercial fibrin sealants can effectively avoid the need for suturing, while reducing surgical time and improving postoperative recovery. The most common us of fibrin sealants inthe central nervous system (brain and spinal cord) isthe teatment and prevention of eer cbraspinal fluid leaks, Several studies have reported that the applica tion of fibrin sealants can effectively reduce the incidence of post ‘operative cerebrospinal uid leaks (85-87), The combination of fibrin sealant with therapeutic agents (suchas cells and collagen) can enhance the sealing and tissue regeneration properties [88,89]. In addition, f brin glue has been explored as a hemostatic agent following the total or partial extraction of brain tumors, and for coaptation of nerves and brain vessels [90-92] Fibrin glue has been used clinically in peripheral nerve repair for cover forty years [93]. Fibrin sealant can decrease operative time, in prove gross surgical results [94], maintain the fascicular orientation [95], and reduce fibrosis an inflammation during newral scarring [95] tis also used experimentally a a filer and drug-delivery matrix for stabilizing nerve repair and delivering neurotrophic factors [97,95] Despite these benefits, there is still hesitancy in using fibrin glue for peripheral nerve repair, because it encourages sear Ussue inflation that impedes functional nerve regeneration [9] 3.4, Advantages and limitations cyanoacrylate and fibrin glues are the most extensively used tissue adhesives. Compared with cyanoacrylate, fibrin glues have several ‘advantages [143]: 1) supporting cell growth; ii) nontoxie and bio ‘compatible; i fllyresorbable; iv) their eloting and degradation time can be controlled (Table 2) Although fibrin sealants have excelent properties, their limitations are sill unignorable [144,145]: anaphylaxis; iD) antibody formation against fibrinogen and chrombin leading to coagulopathy ané bleedingli infectious disease transmission; iv) systemic embolization; v) poor ‘mechanical strength, 4, BioGlue sealant 4.1. Biochemical characteristics ‘BioGlue sealant is composed of 45% bovine albumin and 103% glu taraldenyde. Compared with other currently available products (such as fibrin sealants), BioGlue sealant has superior bonding and sealing ‘capabilities. BioGlue was approved by the FDA in December 2001 for use in the US as an adjunet to achieving hemostasis in adult patients ‘undergoing open surgical repair of large vessels [146]. The two com ponent solutions are loaded in two separate cartridges before se. After Alispensing, the glutaraldehyde molecules covalently crosslink with ‘amino groups of bovine albumin through a Schiff base formation [147] Upon exposure to glutaraldehyde, the lysine molecules (amino groups) ‘on the bovine albumin, extracellular matrix and cell surface bind to ‘each other through CN bonds, creating a flexible mechaneal seal at the repair site, The transformation of ligid glue into hydrogel is quick (within 2 min) BioGlue degrades via proteolysis and is resorbed slowly. ‘Therefore, ie remains in sia much longer than other sealants, which ‘auses a prolonged inflammatory response [18]. BioGlue sealant ean be stored and used at room temperature, which offers the advantage of, Immediate availability. However, ths adhesive has very low viscosity, ‘making it dtfcae to flly control during application, particularly i iis rapidly released (101,149) 42. Molecular design Glutaraldehyde isthe key component that imparts BioGlue an a¢- hesive property. The glutaraldehyde released. from polymerized BloGlue sealant is capable of inducing cytotoxic effets, A 25% glu taraldehyde solution can cause contac injury with the phrenic nerve, resulting in diaphragmatic paralysis, postoperative respiratory feilure and even death [150]. Therefore, the concentration of glutaraldehyde ‘must be controlled in a sae range (< 10%). However, large amounts of BioGlue used as hemostatic tissue sealant for lung damage might stil lead to fibrotic changes [151]. Although BioGlue sealant has been used Clinically for decades, its components have not been modified to im prove elfeacy and minimize complications 43. Applications BioGlue requires a bloodless field to adhere, so i i not useful for controlling active bleeding, All clotted and fresh blood must be re ‘moved from the target areas before application. Therefore, BioGlue is generally used to seal pulmonary air leaks, and repair injury in splenic, ‘urological, abdominal and cardiothoracic surgery, especially for aortic ‘anastomosis in acute aortic dissection [100-104]. The kidneys are highly vascular organs, and bleeding may be encountered during li paroscopic partial nephrectomy. Due to the hemostatic property of [BioGlue sealant, i can be an alternative hemostatic agent for nephron sparing surgery. Moreover, It significantly reduces the blood loss and shorten ischemia time in cardiac surgery. laparoscopic renal cryoabla tion and nephron-sparing surgery (101,105,106) Although BioGlue has been extensively used in the clinic, the se ‘curity ofthis sealant is stil uncertain. BioGlue reinforcement impaired vascular growth and caused stricture when used on cardiovascular ‘anastomoses in pediatric patents [152]. Subsequendy, the same au thors evaluated the tonicity of BioGlue for nerves and cardiae conduc Lon Ustues. The results demonstrated that BioGlue could cause acute nerve injury and myocardial necrosis, which further led to sinoatria node damage [145]. Another pitfall to conser is embolization. Ad- hesive embolization can cause catastrophic complications, such as myocardial infarction, limb ischemia and pulmonary emboliem Maral Since & gern C111 2020) 210796, [153-156]. In addition, the use of BioGlue is generally accompanied by reported complications caused by sealant leakage, including diaphray matic paralysis, false aneurysm, aseptic mediastinal est and recurrent Jate wound healing problems [148]. Therefore, several technical prac tices have been adopted to prevent the glie from leaking, including proper training and the use of moist gauze sponges or water soluble gel {o protect adjacent structures [103]. Given the above-mentioned risks, BioGlue sealant ie not recommended for routine use, 44, Advantages and limitations BioGlue sealant has several advantages (Fable 23, making it well suited for cardiovascular and plmonazy repair: excellent tensile and. shear stength; i) rapid availability; il) fast polymerization, Although the wse of BioGlue may provide certain benefits, chs sealant also has several limitations: i) risk of catastrophic complics tions; 1) low viseosity ii) difficult to operate, requiring. proper raining. 5. Gelatin tissue sealants 5.1, Traditional gelatin tissue sealants Gelatin i a thermal degeneration product of collagen. Its nontoxic, and contains Inherent peptide sequences that induce cell adhesion 1157], facilitating its use in issue sealants Gelatin-esoreinol-formaldehyde (GRF) glues were fist proposed in 11966 [158], and then popularized by French cardiothoracic surgeons in the late 1970s for the treatment of acute type A aortic dissections [107,108]. However, the use of GRF glues led to high rates of in competence and reoperation, and the formaldehyde caused severe histopathological changes within the treated tissues [159], which af fected its application. Thus, a new gelatin glue consisting of gelatin and slutaraldehyde was developed, which exhibited higher bonding ‘rength and lower eytotoxicty than fibrin glue [109,110] Another commercialized sealant is the gelatin matrix hemostatic sealant (Floseal, Surgifo). Tais adhesive is the combination of gelatin matrix (bovine) and reconstituted thrombin human) component (Table 2). The gelatin component swells up to produce mechanical compression, serving as a platform for clot formation, whereas hrombin activates futor XU Co stabilize the clot. This hemostatic sealant was fist approved in 1999 by the FDA in the USA [112]. It has significant hemostatic properties and has been applied in various pro cedures, such as total thyroidectomy, neurosurgery, postecio epistaxis, pelvic surgery and tubal pregnancy [111-117] 5.2, Emerging gelatin tissue sealants There are several emerging gelatin sealants stil under laboratory research (Table 3). Depending on the gelation mechanism, these gelatin sealants can be divided into two groupe, namely, chemical eroslinking sealants and photo-crosslinking sealants, The penetration of a tissue adhesive into soft tissues facilitates the formation of covalent bonds. Consequently, diferent adhesives com prising hydrophobically modified gelatin and disuccinimidyl tartrate ‘were prepared for tissue penetration, including hexanoyl, palmitoyl, stearoyl and oleoyl group graft [162]. The results demonstrated thatthe 1Ostearoyl-deuccinimidyl tartrate adhesive possessed excellent bio compatibility, a8 well as high bonding/peeling strength. Based on this background, a tissue adhesive composed of cholesteryl group-modified selatin coupled with disuccinimidyl tartrace (DST) was developed [60,161]. Research results showed that this novel tissue adhesive is ‘seful for sortie dissection treatment, However, these tissue adhesives are prepared with porcine-derived gelatin. The porcine-derived gelatin {sa gel at room temperature because of the high content imino acid content [220], s0 the tissue adhesives require heat treatment beforeMaral Since & gern C111 2020) 210796, 2 be eat tore lose see Uses peegnongna peu pe sy _preanpin sy pie ape Br, oear guna oid GPE aS capearonan res ponpersianpapied pa Ses Po appends seut asype pds sons pomtomar neu suoutean aor ruey _soneaie) 3 yBsonn ae akingpe a sarqun eras meoglrpc—_pRREDSnap it sages Purp HereGEeDAt rama: pee en9 Sd ery ‘rend Bape ee eo Sipe oa RP sae,2 be weak og tel Tamms rl c12-ApGitn a > Maral Since & gern C111 2020) 210796, SA Tissue Fig. 2, The syathesi fa eee sealant composed of ApGtn with 4-PE6. ‘being used in surgery. In onder to eliminate the need for preheating, the same authors developed a new tissue adhesive composed of Alaska Pollock-derived gelatin (ApGKzn) and pentaerythritol poly(ethylene aslycol) ether tecrasuccinimidylglotaate (48-PEG) [6,163] Pig. 3). The ‘amino group residues of ApGitn were also modified with a dodecy! ‘group (hydrophobic group) to enhance the adhesive ability of the sealant. Subsequently, study results showed that this glue had an ef fective sealing effet on moist tissues and good biocompatibility Alginate is a natural polymer, which has the ability to form hy: rogels.A composite hydrogel bioadhesive composed of gelatin (cold water fish) and alginate was proposed [2]. The gelatin and alginate ‘were crosslinked with carbodiimide to combine high mechanical strength with biocompatibility. Keolin and montmorillonite (MMT) were loaded as hemostatic agents. The incorporation of Kaolin and [MMT in composite sealants effectively improved the bonding strength Uhrough their reinforcing effets and increased viscosity. Based on va. lidation results, this composite bioadhesive is a promising. surgical sealant for use in hemorrhagic environments, In order to achieve rapid sol-gel transformation, the photo-induced Lissue adhesion technologies are proposed. The sol-gel transformation is ‘riven by photochemical reactions [153,155]. Photocurable gelatins were prepared by coupling gelatin witha xanthene dye (eg. fluorescein sodium salt, eosin ¥ and rose hengal) [106]. High-pressure mercury lamps or extremely high-energy excimer lasess must be used for the polymerization of photocurable gelatins, which may cause potenti health hazards [157]. Therefore, Nakayama and Matsuda designed 9 novel visible lightcurable hemostatic coating system based on photo curable gelatins and poly(ethylene glycol) dizeryate [167] Lastly, a highly elastic sue sealant was developed based on photo polymerized gelatin (164). Gelatin was mixed with ruthenium (Rull (py)s*"] and sodium persulfate, and irradiated at room temperature with quartz tungsten halogen lamp (300-1200 nem, 300 W) for polymerization. The ability ofthis adhesive to seal sutured incisions in the gastrointestinal (GI) tract was evaluated, The results shovved that the photo-polymerized gelatin sealant facilitated wound healing with ‘no inflammation and was a superior choice for Gt surgical procedures 168}, (6, Methacrylated tissue sealants ‘Methacrylic anhydride (MA) is an organic matter, capable of covalent cross-linking by lightactivation. The anhydride imparts the ‘methacrylic anhydride an active group which can react with other ac Live groups, such as amino and hydroxyl groups. Therefore, several tissue adhesives have been developed based on modification to me ‘thacrylie anhydride (Table 2), 6.1, Methacrylated polysaccharide tissue sealants [A new approach was proposed to functionalize chonéroitin sulfate (CS) with two distinct organic moieties (methacrylate and aldehyde groups) for cartilage repair [171]. Methacrylate groups were con jugated to C8 to form methacrylated C8, Then adjacent hydroxyls onthe (SS backbone were oxidized with sodium periodate to form aldehyde sr0ups. The aldehydes form a covalent bond with the native cartilage Aissue, and the methacrylate groups participate in the polymerization reaction of the outer biomaterials. The function ofthis adhesive is mila to the primers used by dentists to bond restorative materials to teeth, In addition, this tissue adhesive did not damage the cells deliv ered by the outer biomaterial or the native cartilage. The efficiency of {his Ussue adhesive was subsequently evaluated in two different in v0 experiments using rabbits and goats. Utimately, the tissue adhesive led to significant tissue repair in cartilage defects. Similarly, a tssue sealant based on alginate functionalized with methacrylate and aldehyde groups was proposed in 2016 [159]. The rmethacrylated alginate (AMA) was als oxidized with sodium periodate to form AMA dialdehyde (AMA-DA) (Fig. 4a). Methacrylation of alg nate rendered the polysaccharide capable of photo-crossinking by ex posure to visible green light when mixed with a Y-based photoinitiator. AMA is non-adhesive, However, oxidation of the alginate backbone elicited functional aldehyde groups, which can form covalent bonds with extracellular matrix proteins. The resulting AMA-DA is an in jectable tissue adhesive, which is curable in sta. Burst pressure prop ceties and adhesion characteristics were then correlated with the de agrees of methacrylation and oxidation. in the next year, the same authors developed AMA.DA hydeogel into an anticancer therapeutle Uissue sealant Jor lung repair [170]. Doxorubicinencapsulated sub microspheres were blended with AMA-DA precursor solution, injected {nto molds and Iyophilized to form sealant patches. The patches were hydrated and crosslinked by exposure to visible green light (525 nm) when ready to use. The addition of AMA could improve the burst ressure performance and decrease delamination of the AMA-DA sea nt. The tissue adhesive was effective in decreasing human lung cancer cell viability when losded with doxorubicin-encapsulated submiero: spheres. However, the performance of this adhesive has not bees tested ‘on animal models 6.2, Methacrylated protein tissue sealants Another kind of methacrylaed tue adhesive is based on gelatin and proteins. Photopolymerization of gelatin methacrylate (GelMA) is an inexpensive and technically simple approach to fabricate hydrogels for biomedical applications (172). GeIMA hydrogel has been proven to be a suitable biomaterial for various tissue engineering applicationsa Sodium Alginate (Ale) Methacrylated Alginate (ama) Sodium periodate Methacrylated Alginate Dialdehyde (AMAA) Maral Since & gern C111 2020) 210796, b . ee Gelatin Te rome | = Methucyed cent Mp C_- ‘oma 4 Iegacure 2959 \~ eradation x ee GelMA zw aye e “t Fig. 4. The syathess of methacrylate alginate and dildehyde (a), and synthesis of mechacrylate gelatin and its UV-curing (). because of its desired cytocompatibilty [221,222]. However, GelMA, hydrogel cannot adhere to wet surfaces, which limite its usage as @ flexible and highly adhesive sealant “The physical properties and adhesion of GelMA sealant were opti mized by tuning the degree of gelatin modification, prepolymer con ‘eniration, photoinitiator concentration and crosslinking conditions 172] (Fig. 4). GelMA sealant was proven to effectively seal large lung Teakages without using sutures or staples in two different lung leskage ‘models using rats and pigs. In addition, GelMA sealant allowed for ‘adequate wound healing, and exhibited low inflammatory host re sponse and fast degradation in vv, which demonstrates that GeIMA sealant is a promising commercial sealant for stopping air leakages and supporting tissue regeneration In the same year a superior sealant (Mero) based on methacryloy ‘and human tropoelastin was developed by the same authors [3]. Tais sealant is highly elastic, biocompatible and slowly biodegradable, The Metro sealant is formed through photo-crosslinking with an UV light (69 mW/em?, 360 to 480 nm). The MeTro sealant offers superior ad- Iesive strength and Durst pressure resistance when compared (0 com: ‘mercially available clinical sealants (Evicel, Coseal and Progel). The Metro sealant can provide Nexibilty without compromising adhesion to prevent fluid leakages under different surgical conditions. In vivo ‘experiments in rats and porcine models demonstrated complete sealing, ‘of leaking lung tissue, with no clinical or sonographic signs of pnew mothorax. Thus, the MeTro sealant has high potential for clinial ap plications because ofits superior adhesion and mechanical properties. 6.3. Methacrylated organic polymer tissue sealants Several photo-croslinking tissue sealants have also been developed based on organic polymer, such as poly(lactic acid) (PLA), poly ‘eaprolactone (PCL), PEG and other polymerie blends {175} PLA is a widely used polymer approved by the FDA for quite a ime ss biodegradable sutures, isu engineering scaffolds and drug delivery systems, Recently, PLA is found to be a desirable adhesive material. 4 ‘arm star-shaped PLA was functionalized with methacrylic anhydride oF Risocyanatoethyl methacrylate to introduce terminal hydrogen: bonding, resulting in PLA bioadhesives with better performance in terms of tensile strength and Young's modulus [174]. However, these prepolymers exhibit as glassy solid at room temperature due to their high molecular weights (> 2000 g mol"). Therefore, chloroform is initially used asa solvent to dissolve these solid substances, resulting in ‘an unsuitable formulation for human use, More recently, anew strategy to produce photocrosslinkable bioadhesives from lactic acid without audition of catalysts or organie solvents has been reported. The UV: curable bioadhesive was produced by modifying the hydroxy! termi- nated Iclactic acié with isoeyanate-functional unsaturated acrylic ester (LAROMER LR 9000), ssocyanatoethyl methacrylate or methacrylic anhydride, which was biocompatible and effective in sustaining wound closure and repair [175-178 PCL consists of semi-crystalline linear biodegradable aliphatic polyester, which is being epplied in the fields of drug detivery, re Sothable sutures and tissue regeneration. PCL could be modified with 2 feocyanatoethyimethacrylate to form a UV-curable bioadhesive using Ingacure 2956 as a photoinitiator [179,180], which exhibited desirable swelling capacity, adhesive capacity, mechanical thermal capacity and hemocompatibility. This demonstrated that the prepared macromer could be used as an effective medical adhesive, In order to further Improve the mechanical properties, star shaped PCL was functionalized with methacrylate, which was used as the erosslinker to connect N*- dimethylaminoethy! methacrylate chains. The prepared hydrogel ex hibited 0.3 MPa of Young modulus. The swelling and mechanical properties could be tailored by tuning the amount of the eroslinker 182}. Photocurable PEG-based formulations have been considered as promising raw materials for tissue adhesives production, de to their biocompatibility and hydrolysable properties under wet conditions Diacrylated or riaerylated PEG combined with polyvinylpyrrolidane or 3,4-dihydroxyphenyl-L-alanine have been developed as UV-curable bioadhesives [181,183]. However, PEG-based adhesives may con- siderably swell up after tr vivo application, leading to the significant reduction oftheir mechanical strength and adhesion (184,185) Other synthetic polymers such as poly(vinyl acetate) (PVA) [185,188] and poly(glycerol sebacate) (PGS) [187] have also been ac rylated for subsequent UV activation and developed as tissue adhesives, 7. Bioinspired adhesives Adhesion to wet and dynamic biological tissues is important, but challenging. Consequenty, researchers have designed diferent bioin spired adhesives in an attempt to bypass this problem. 7. Sluginspired tissue adhesives Slugs Arion subfuscus) can strongly adhere to wet surface, de to the defensive mucus secreted by slugs consisting of a matrix with intr penetrating positively charged proteins [223]. Inspired by the slugs, ough adhesives were designed consisting of two layers: an adhesive surface and a dissipative matrix [189] (Pig. 5). The adhesive surface contains an interpenetraling positively charged polymer, such as chit fosan and polyallylamine (PAA), which ean form covalent bonés with tissues and even penetrate into the target surface to form physical en tanglements, The dissipative matrix composed of alginate-poly acrylamide (Alg-PAAm) can dissipate energy effectively under2 be weak Maral Since & gern C111 2020) 210796, VA Bridging Dissipative polymer matrix Alginate Adhesve & surface Tissue Fig. 5. Tsue sealant consisting of dsipative matrix, made ofa hydrogel containing bth lonely (ealelum) eosliaked and coveleaty eeslnked polymer, and an adhesive surface that contains «bridging polymer with primary amines. deformation. These adhesives can adhere to diverse wet surfaces in ‘dependent of blood exposure and are compatible with in ve dynamic ‘movements. The adhesives exhibited remarkably high peeling energy (@naximum 1116) m~) against in vine diverse wet surfaces and strong adhesion (8.3 N em™*) against in vivo beating pig hearts [189] 7.2, MusseLinspied tissue adhesives ‘Mussels can firmly adhere to various wet surfaces and resist de. tachment in wavy conditions, mainly due to their secreted adhesive materials Studies have reported that eatechol containing L-DOPA isthe ‘major component in these secreted adhesive materials [22,225]. Inspired by the adhesion strategy of mussels, L-DOPA or catechol was functionalized with polymers or biopolymers such as PEG, block polymers, citric acd, chitosan, hyaluronic acid, alginate and gelatin to synthesize bioadhesves for tissue engineering. PEG isa biocompatible ‘and inert polymer with different architectures (inear and branched), which ean be grafted with catechol to improve the performance of ‘existing materials. With branched PEGs as the core, researchers mod iffed and grafted catechol in their endgroups, which was demonstrated to efficiently immobilize transplanted islet [190] and seal fetal mem ‘rane [181,192]. Block polymer (includes hexamethylene disocyanate, PEG and lysine-dopamine) was also incorporated to give the adhesives rapid curing ability controlled by pH and NalO, [162] Injectable e- trate-based tissue adhesive was prepared by polycondensation of PEG, citric acid and dopamine for suturelest wotind closure (1°4]. The wet ‘adhesion strength ofthis tissue adhesive was further improved by in twoducing click chemistry (195). Catechol functionalized chitosan was developed for hemostasis and wound closure [195,197]. The resulting hydrogel exhibited high adhesion strength of 73.56 kPa against wet skin [157], Similarly, other adhesives based on polysaccharides such es hhyalueonie acid and alginate have also been intcoduced with eatechol ‘0 improve biocompatibility and tissue adhesion [198,199]. Recent stu dies have shown that gelatin ean also be crosslinked with L-DOPA or catechol by Pe** ions to form hemostatic issue adhesives for seroma prevention and internal medieal use (200-202). The synthesized ma terials showed excellent biocompatibility, biodegradability and high wet adhesion, ‘Another interesting application was reported recently, in which a novel moldable nanocomposite hydrogel composed of a dopamine ‘modified PEG and a nancsilcate Laponite was developed as a fitto shape issue sealant [203] (Pig. 5). The key to this strategy lies in the interactions between polymer-bound dopamine and Laponite through ‘autoxidation and cross-linking of catechol moieties. The sealant can be remolded to different shapes under mild. physiological conditions ‘When the sealant is incubated for prolonged periods of time, it solidifies ‘to adopt the desired shape, sealing defects on the tissue, Therefore, this fitto-shape sealant is promising for sealing tissues with non-flat geo metres 1m addition to the strong adhesive strength, selthealing is a very, attractive property for adhesives which may significantly facilitate the closure of wounds, especially for remedy transit damage caused by rough tactlity. Therefore, several srategies have been suggested to xeate the selP- healing tissue adhesives based on catechol or dopamine “The selrepair ability was induced by the reversible chelation between catechol and metal ions (such as Fe'*, Ni?™ and V'") in alkaline condition [204-205], The resulting adhesives showed remarkable sto rage moduli of up to ~30 kPa [207]. Except for metal ions, boric ion (8!) can also form reversible B**-cacechol complexation [208,209] Similar to Fe", boric acid i able to form stable covalent conjugation with catechol groups at neutral and alkaline condition, The resulting complexations were triple-responsive and selchealable, and suitable to be used for tissue engineering and drug delivery (208,208]. In addition, ‘ mustelinspred adhesive with the ability of selthealing under acidic conditions has also been reported [210]. Tiethylsily-protecting ea techol was used to functionalize polyacrylate and polymethacrylate producing adhesive which could selt-heal at pH 3 under slight com pression [270] 7.3. Gecko and octopusinspiredtsse adhesives DMusseL-nspired tissue adhesives bated on chemical bonding can frrtare the skin and eause pain during their removal, which are more appropriately applied to permanent attachment and rarely used for repetitive and contaminationree adhesion against wet tissues. Animals such as gecko and octopus have strong attachment abilities to vertial and rough surfaces, which was attributed to the hierarchically struc tured attachment devices. Different from muscel-inspied adhesives, ‘ecko and octopus-inspiced tissue adhesives are usually used for hairy skin adhesion, biosignal monitoring and integrated bioelectronics [217,226,227] Millions of nano-structured setae on geckos’ sles impart them an ability to climb and strongly attach to vertical and inverted surfaces based on van der Waals interactions [215,228]. Inspired by geckos, several biomimetic adhesives were fabricated [213-215]. However, the relatively low adhesion on slightly rough and soft surfaces may be a hurdle to practical use, To address this problems, several composite microfibers were proposed for superior conformation and adhesion. The stem region was formed by rigid material (hard poly(dimethysloxane) PDMS) or PDMS with a higher amount of curing agend, and the top yer was integrated by a soft PDMS with a lower amount of curing agent or mushroom-shaped vinylsloxane tips [211,212]. The resulting adhesives exhibited excellent adhesion strength (~18 kPa) [212] ‘Octopus exhibits remarkable adhesion not only on dry surfaces but2 be eat ~ *\/7 PEG-DB * Dopamine Maral Since & gern C111 2020) 210796, Fig. 6. The synthesis of Steoshape ssw sealant ‘also on wet and rough surfaces due to their suction cups. The sucker ‘consists ofthe cup-like upper portion (infundibulum) and the dome-ike Tower portion (acetabulum), Inspired by the dome-like architecture of sucker, an artificial and reversible wet/dry adhesion system was fab cated based on ai-tep technique [216]. This bioinspired system ex Iibited strong, reversible and highly repeatable adhesion to silicon ‘wafers, glass and skin surfaces [216]. Other strategies were also pro posed £0 acquire octopus-inspired nanosuckers such as spin-coating (216] and partial wetting technique [2:7]. The maximum peeling en ‘ergy on a moist pig skin was up to 146 mJ (217) 7.4. Living gues based on engineered Bacillus subs biflms ‘The existing bioinspired adhesives formed based on slug, mussel and ‘other animals showed impressive performance characteristics. However, these artificial adhesives cannot exploit the full potential of ‘the natural adhesive systems, especialy lacking the abilities of selt-e ‘generation and environmental responsiveness, Therefore, a living glue made of Bacilus subtilis (B. subtils) biofilms was developed by lever: ‘aging tools from both genetic engineering and materials science [219]. Inspired by barnacle and mussel, an engineered amyloid protein (TasA) ‘was functionalized with a mussel foot protein (Mefp5) to inerease ad Inesion, and an engineered surface layer protein (BSIA) was functiona lized with Mip8sp protein to induce coacervation and improve aghe- sion. Fxopolysaccharides (HPSS), commonly negatively charged proteins, were reported to contebute to the strong underwater adhesion fof sandcastle worms (229]. Therefor, the biofilms of living glues was prepared by containing the TasA-MefpS, BsIA-Mfp3Sp and EPSs co achieve underwater adhesion. The adhesion performance could be tuned by inducible enzymatic modification and improved through metal ion-asisted curing. This smart cellular glue exhibited strong adhesive performance, regenerative capacity and environmental toler ance [219] 755. Advancages and limitations “These emerging tissve adhesives have several advantages compared to traditional tissue adhesives: D) superior adhesion, especially under ‘wet conditions; i) desired mechanical strength with high elastic mod ‘ulus; i) nontoxie and biocompatible; iv) burst pressure resistance; v) rapid cure reaction; vi) Bt-to-shape property However, emerging sealants are stil under experimental research “Thus, their adhesive performance and potential treatment sequela on ‘humans are still unknown. 8. Conclusions and perspectives Tissue bioadhesives bear superior properties over traditional wound management techniques, such as ease of operation, high efficiency for ‘wound closure and less trauma. Tissue adhesives have significant po tential in many fields, leading to more efforts on improving upon ex isting adhesives and developing new systems. Due tothe limitations of existing adhesives, fature design requirements for polymeric hydrogel bioadhesives are frst of all biocompatibility, as well as strong wet bonding strength, biodegradation, good mechanical strength, feasibility and low cost For traditional adhesives (Table 2), such as eyanoaerylate, fibrin and BioGlie, modifications can be introduced through enbanced graft {tegration and by optimizing the source of components. Based on the functioning mechanism, emerging adhesives developed with gelatin and methacrylated polymers aze designed with specific properties (Table 3). Besides, inspired by slags, mussels, geckor and octopus, versatile adhesives are being developed to exhibit satisfying properties ‘These adhesives have numerous advantages over traditional adhesives. “Therefore, these design strategies are particularly instructive for the future development of novel tssue adhesives. Based on the above ‘mentioned results, the development of biomimetic materials may be a wise direction for achieving tissue adhesives with superior properties. Acknowledgements ‘This work was supported by Shandong Provincial Natural Science Foundation, China (grant number 7R20188C027], Netionel Natural Science Foundation of China (grant numbers 21676286] and Primary Resesrch Development Plan of Shandong Province (grant number 20166SF121006], References In} M.Mesaiace, 2. Yang Desa sates ad applicants ieee, Compote hyo! onder and icon proper and bend haniom,AetaBmter 2017) 15-137. Behn GU atin Kang Gang AS We ‘iia ppcans, 36, Tas, Med 3 (410) OI?) eae their wage in urology, Turk J. Urology 43 (1) (2017) 14.24, Is} Seng 3A Taned hua Pace dl Corpo, esha reinforced Lyicopottaly-modied Ash pth gained seat Boma Se-UK WA Blowin Noval Rewrgoe EW Cost Xe! el osuomergent care, Mate lose #2) (2017) 232227 ‘hess for wand darren Chen. 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