Addressing Unmet Clinical Needs with UV Bioadhesives

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Review

Addressing unmet clinical needs with UV bioadhesives Richard D. O'Rorke, Oleksandr Pokholenko, Feng Gao, Ting Cheng, Ankur Shah, Vishal Mogal, and Terry W.J. Steele Biomacromolecules, Just Accepted Manuscript • DOI: 10.1021/acs.biomac.6b01743 • Publication Date (Web): 26 Jan 2017 Downloaded from http://pubs.acs.org on January 30, 2017

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Addressing unmet clinical needs with UV bioadhesives. Richard D. O'Rorke1, Oleksandr Pokholenko2, Feng Gao2, Ting Cheng2, Ankur Shah2, Vishal Mogal2,3 and Terry W.J. Steele2* 1

Singapore University of Technology and Design, 8 Somapah Road, Singapore, 487372

2

School of Materials Science and Engineering, Nanyang Technological University, Block N4.1, Nanyang

Avenue, Singapore, 639798. 3

Faculty of Dentistry, National University of Singapore, 11 Lower Kent Ridge Road, Singapore 119083.

* [email protected]

Keywords Adhesive; bioadhesive; UV activation; photo activation; wound closure.

Abstract The invasive practice of suturing for wound closure has persisted for millennia – with the rate of medical development it is staggering that there are few viable alternatives to invasive mechanical fasteners. Biocompatible and biodegradable polymers are attractive candidates for versatile bioadhesives and could revolutionise surgical procedures. Bioadhesives can be broadly placed into two groups, activated and instant. Almost all commercially available bioadhesives are instant, which crosslink by mixing two components or on contact with moisture. Activated bioadhesives, on the other hand, allow control of when and where a bioadhesive crosslinks and, in some cases, the extent of crosslinking. Despite significant progress there has been little translation of activated bioadhesives to clinical use. This review discusses recent developments in UV-activated bioadhesives towards addressing unmet clinical needs.

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Introduction Tissue bonding has forever been a problem for humankind, from closing wounds on the battlefield to sealing incisions after surgery. To this end, mechanical fasteners have been used in various forms throughout history; ancient civilisations used bone needles and sutures made from cat-gut1-3, South American cultures stapled wounds with the pincer-like jaws of ants3-4, and the Romans closed blood vessels with gut ligatures after amputations. The European medical renaissance saw the introduction of cauterising open wounds with heat and the rediscovery of ligating blood vessels. Despite the advent of modern medicine, mechanical fastening remains the primary method of closing wounds and surgical incisions1, 5, and the most notable innovations are biodegradable sutures and drug eluting dressings6-7. Apart from causing local trauma and patient discomfort, suturing can be prohibitively difficult, such as anastomosis of capillaries during hand surgery, and unfeasible in the case of sealing the pleural membrane after lung biopsy (8—64% patients suffer pneumothorax as the biopsy needle is removed8). On the other hand, for a skilled hand suturing is fast and effective, offers tactile feedback, and is augmented by robotics for more precise application. The global market for surgical sealants and adhesives is dominated by three products: TISSEEL (Baxter; fibrin); BioGlue (CryoLife; bovine serum albumin and glutaraldehyde); and DERMABOND (Ethicon; cyanoacrylate)9. These products represent a USD$673 million global market as of 2013, which is expected to reach USD$845 million by 2018 – a tiny fraction of the USD$8.6 billion market for advanced wound therapies9. Bioadhesives have tremendous potential for advanced healthcare, from reducing surgery time and cost to delivering therapeutic agents and facilitating new minimally invasive procedures. Two major milestones in the development of bioadhesives are haemostatic sealants and cyanoacrylate (CA) topical skin adhesives. Haemostatic sealants consist of fibrin and thrombin, proteins involved in the natural blood clotting process10-11, and initiate the blood coagulation cascade. Despite being effective at stopping blood loss, haemostatic sealants suffer inferior mechanical properties and their human or bovine origin raises sensitive ethical concerns10-12. CA rapidly polymerises on contact with water, forming a physical barrier against blood flow11-13, and were used for emergency wound closure during the Vietnam War. The exothermic polymerisation prevented widespread use, until 2-octyl cyanoacrylate (which has a lengthened alkyl chain that slows the polymerisation) was approved by the Food and Drug Administration (FDA) for topical wound closure in 199811. Nonetheless, toxic and inflammatory side effects remain a concern and limit CA to topical wound closure and emergency use13. More recently, biocompatible polymers such as poly(urethane) (PU)14 and poly(ethylene glycol) (PEG)15-19 have been used as backbones in two-part bioadhesive formulations that crosslink upon mixing for use in vivo. Similar twopart bioadhesives employ bovine serum albumin and aldehyde groups as a vascular sealant, however


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glutaraldehyde can cause adverse local inflammatory reactions20. Examples such as these highlight the progress of bioadhesive development. Nonetheless, two-part instant adhesives have limited application time after mixing, adhere to any surface they wet and have pre-determined mechanical properties. Despite these limitations, the majority of commercially available bioadhesives are of the instant variety, as illustrated in Figure 1. Activated bioadhesives, on the other hand, allow the user to control the onset of crosslinking, thus giving better control of the application site, and can allow tuning of the mechanical and adhesive properties to match the surrounding tissue21. This has the advantage of avoiding interfacial stress concentration, which is often the cause of bond failure. Research on activated bioadhesives is dominated by UV-sensitive crosslinking chemistries; bioadhesives activated by IR light22-27, RF radiation28-29, heat30-31 and atmospheric plasma32-33 have been reported but these represent a small subset of the field and will not be discussed further. There have been several informative reviews of instant bioadhesives34 and commercially available bioadhesives/sealants11,

35

in recent years. The purpose of this review is to

highlight recent developments in UV-activated bioadhesives that may have a disruptive impact on healthcare by allowing end-user control over the onset of adhesion and mechanical properties of the adhesive.


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Figure 1. Schematic of commercially available bioadhesives approved by the US Food and Drug Administration (FDA) since 2000; Adherus AutoSpray Dural Sealant15; Progel Pleural Air Leak Sealant36; TissuGlu Surgical Adhesive14; ReSure® Sealant16; ArterX Surgical Sealant37; Ethicon™OMNEX™ Surgical Sealant38; DuraSeal Spine Sealant System17; Histoacryl39; Matrix VSG™ System18; CoSeal™ Surgical Sealant19; Indermil™ Tissue Adhesive40; CryoLife BioGlue Surgical Adhesive41 and; FocalSealSynthetic Absorbable Sealant42.

UV-Activated Bioadhesives The popularity of UV-crosslinking chemistries reflects the ease with which free-radical polymerisation can be triggered with biocompatible photoinitiators43-45. In most cases natural or synthetic polymers chosen from the FDA Compendium of Biomaterials46 are chemically modified with acrylic groups (acrylated) and mixed with a photo-initiator. Many of these polymers can form stable hydrogels through hydrogen or ionic bonding, but long gel times and poor mechanical properties limit their usefulness as bioadhesives. Acrylation allows rapid crosslinking by free-radical polymerisation of acrylic groups. Whilst this approach can be applied to a wide range of polymers, toxic effects may arise from unreacted 4 ACS Paragon Plus Environment

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pendent acrylic groups and photoinitiators leaching into surrounding tissue during degradation. Alternatives to acrylation have begun to emerge, which we will discuss in the following section.

Acrylic formulations Natural polymers, such as dextran43-45,

47-48

and sodium alginate49-52 have been widely used in

bioadhesives. Dextran has been conjugated with 2-isocyantoethyl methacrylate (IEMA) to give Dextranurethane-methacrylate (Dex-U)43-45, 47, and also with acryloyl chloride to give Dextran-acrylate (Dex-A)48. Similarly, sodium alginate has been conjugated either with 2-aminoethyl methacrylate (AEMA)50, styrylpyridine51, or methacrylic anhydride52. Using Irgacure 2959 as a photo-initiator, these formulations crosslink within 10 minutes upon exposure to 320—400 nm light (UVA) with doses from 3—30 J cm-2. A range of co-polymers have been reported, including acrylate epoxidised soybean oil (AESO)48, gelatine52, and PEG-DOPA47. DOPA residue is found on the adhesive protein secreted by marine mussels for underwater adhesion and has been used as an instant mucoadhesive53. Similarly, synthetic polymers such as poly(glycerol sebacate) (PGS)54, poly(vinyl acetate) (PVA)55-56, PEG57-58 and poly(ε-caprolactone) (PCL)59-61 have been acrylated for subsequent UV activation using either Irgacure 2959 or Darocur 2959 as a photoinitiator. A pre-polymer of PGS, acrylated with acryloyl chloride (poly(glycerol sebacate acrylate); PGSA) was crosslinked using 320—390 nm light (UVA) with a dose of 1.9 J cm-2 in 5 seconds54. The mechanical properties of PGSA are comparable to human softtissue62-64 and the adhesive was found to entangle with native collagen fibres54. UV-PVA (PVA modified with acryloyl chloride) has been reported as a co-polymer with acrylated DOPA, although the activation time was 15 minutes55-56. PEG diacrylate (PEG-DA) has been reported as a skin adhesive that crosslinks upon exposure to 350—500 nm light (UVA) with a dose of 86.8 J cm-2 in 7 seconds57. PEG has also been 5 ACS Paragon Plus Environment

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modified with acryloyl chloride and crosslinked with 320—480 nm light (UVA) however, a dose of 9 J cm-2 resulted in a cure time of 15 minutes58. PCL, modified with IEMA crosslinked in 1 minute, however the authors did not specify the wavelength or intensity of light used59. L-lactic acid has been modified with isocyanate-functional unsaturated acrylic ester (LAROMER® LR 9000) and crosslinked by irradiation at 254—354 nm (UVA—UVC) for 120 seconds60, and also modified with methacrylic anhydride and crosslinked in the same manner61, but the UV intensity was not mentioned. Photo-active azide pendant groups An interesting alternative to acrylic formulations are photo-active azides. Chitosan, a haemostatic polyaminosaccharide, has been modified via free amine groups with lacto bionic acid (allowing solubility in aqueous, non-acidic medium) and with p-azido benzoic acid to allow crosslinking by 300—380 nm light (UVA—UVB) in one minute via nitrene formation, although the intensity was not specified65-66. The activated chitosan formed a hydrogel that proved more effective than sutures and fibrin glue (TachoComb) in a rat liver injury model65, and was comparable to fibrin glue for ex-vivo nerve anastomosis66. The addition of PEG has been shown to improve the adhesive strength of the hydrogel, by reaction of one –OH end of PEG with reactive species from photoactivated azide, which resulted in entanglement of pendant PEG chains and the formation of a semi-interpenetrating network67. A benefit over acrylic formulations, they required no photoinitiators for activation. Nitrogen was a side product, which created a gas-filled, sponge-like matrix. This may be seen as an advantage, since it expands upon activation (acrylate and epoxy-based adhesives shrink upon propagation) or a disadvantage, in that mechanical properties will be limited to moduli in the kPa range.

Another downside that limits

exploration of azido groups, is their explosive nature and nucleophilic character that is speculated to give them a limited shelf-life. Metal-ion complexes as photo-oxidisers In contrast to using photoinitiators to generate free radicals, ruthenium photochemistry has been used to crosslink gelatine using a halogen lamp (300—1200 nm; UVB-VIS), although the dose was not specified68. Gelatine was mixed with sodium persulphate and the ruthenium metal-ion complex [RuII(bpy3)]2+, as illustrated in Figure 2. Tensile adhesive strength to bovine amnion was five-times higher than fibrin controls, and a sheep lung injury model was successfully sealed68. The adhesion mechanism is fast, requiring only seconds of irradiation, but is ultimately limited to protein environments that are rich in tyrosine—this makes it ideal as a tissue sealant but does not allow expansion into adhesion of synthetic biomaterials.


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Figure 2. Gelatine crosslinking via ruthenium photo-chemistry.

Photo-acid generators for de-protecting DOPA functional groups Interestingly, researchers have developed a method of caging a functional group similar to the catechol group of DOPA, which is de-protected upon exposure to visible light (UV-filtered mercury xenon lamp), resulting in polyDOPA mediated crosslinking69. This process is illustrated in Figure 3. A unique advantage of this mechanism allows reversible bonding. The inclusion of a photo-acid generator allows reversible adhesion owing to locally reduced pH on exposure to visible light, disrupting the catechol-Fe3+ complex70-71. Whilst the sensitivity to visible light inherently limits the application as a bioadhesive, the use of de-protecting groups is an innovative approach to photoactivation. However, the deprotection kinetics will need to be optimized for clinical application, as the reported formulation required 30 min of irradiation to complete deprotection. 7 ACS Paragon Plus Environment

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Figure 3. Light activation of caged mussel adhesive protein mimetic polymer. Reprinted with permission from ref 69. Copyright 2013 American Chemical Society.

Photo-active diazirine Diazirine is an emerging candidate for UV-activated adhesives, as it decays to carbene (a known polymerisation catalyst72) upon irradiation with 365 nm (UVA) light. We have functionalised poly(lactide-co-glycolide) (PLGA) thin films with diazirine that crosslink to tissue upon irradiation with 365 nm light at a dose of 300 mJ cm-2 in 10 minutes73. We have also functionalised poly(amido amine) (PAMAM) dendrimers with diazirine, as shown in Figure 4, for activation either by low-voltage electrical stimulation74 or UV light21. Unlike free radical mediated acrylate polymerization, carbene mediated crosslinking allows control over both initiation and propagation—thus adhesion, viscoelasticity, and modulus can be tuned via the UV dose. Diazirine (among other carbene precursors) is similar to the the azido-functional groups in that it requires no free radical initiators for activation and the only leachant is benign diatomic nitrogen, N2. The gas byproduct produces a foamed matrix, expanding under activation which is the opposite of most adhesives that contract and shrink. One important advantage diazirine has over azido groups, is its higher activation wavelength and does not have the explosive sensitivity that azido groups are known for. However, like the chitosan-azido bioadhesive discussed above, effective moduli will be limited to the kPa range due to N2 generation.


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Figure 4. Structure of PAMAM-diazirine

Discussion

Adhesion to wet tissue Physical adhesion is the quintessential adhesion mechanism, where a liquid adhesive flows between adherent surfaces and locks in place upon hardening. The result is exquisite contact between adhesive and substrate, and subsequently strong adhesion from weak interactions such as hydrogen bonding, exemplified in biomimetic dry adhesives75. Such intimate contact is shown in histology micrographs21, 27, 68

in Figure 5. Physical adhesion can be enhanced via entanglement of polymer chains and collagen

fibres54, which can occur in such close proximity. Chemical adhesion is distinguished by covalent bonding between adhesive and substrate, resulting in a stronger bond than physical adhesion alone. In the context of bioadhesion, chemical bonding is facilitated by proteins on the surface of soft-tissue. In the case of acrylic groups, chemical bonds can be formed with nearby thiols on cysteine residues and amino groups on lysine residues76-77 of membrane proteins. Individual lysine residues, however, are usually protonated at physiological pH and therefore inactive towards acrylic groups. Free radical polymerisation in general offers a route for chemical bonding by radical propagation to the tissue surface, which can initiate chain transfer to (and subsequent polymer chain growth from) the tissue surface. Polymerisation from the tissue surface can also be facilitated by surface activation using, for example, atmospheric plasma to generate surface free-radicals33, 73. In contrast, carbene and nitrene radicals can insert into most carbon-hydrogen bonds, potentially allowing a higher density of chemical bonds to tissue 9 ACS Paragon Plus Environment

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than acrylic adhesives. Both physical and chemical bonding are complicated by the presence of water on the tissue surface, which can prevent direct contact between the adhesive and tissue. This is especially problematic for acrylic formulations that react with water, as crosslinking may occur to the water molecules instead of tissue. Design of adhesive formulations to displace the water layer, for example by swelling/expansion of hydrogel adhesives or physical exclusion by hydrophobic formulations, would make chemical bonding more likely. Mechanical properties and adhesive/cohesive failure Tuning the mechanical properties of a bioadhesive to those of surrounding tissue is crucial to avoid interfacial stress concentrations, which are the leading cause of bond failure. Most UV activated bioadhesive formulations allow control over the final material properties by the relative concentrations of constituent parts, but this is typically set by the manufacturer with the end-user having little to no control. Tuning mechanical properties during application, for example by controlling UV intensity or activation time21, makes for a versatile bioadhesive that can be applied to a range of tissue surfaces and synthetic biomaterials. Viscoelastic adhesives can mitigate stress concentration via stress relaxation across the interface. Interpenetrating networks are attracting much attention for biomedical applications as they employ both chemically crosslinked and hydrogen-bonded polymer networks to give a tough, viscoelastic material. 78-79

67,

. The drawback of using IPNs for bioadhesives is that they may be limited to certain adhesive

chemistries (acrylates have shown the best results to date) and the hydrogen bonded network increases the viscosity of the adhesive prior to activation, causing a trade-off between initial tissue wetting and final adhesive toughness.

Figure 5. (A) Histology of anastomosed sheep intestine (I) using SurgiLux (S); scale bar 100µm. 10 ACS Paragon Plus Environment

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Reproduced with permission from ref 27. Copyright 2010 American Chemical Society. (B) Crosssectional SEM of PAMAM-diazirine attached to excised porcine aorta. Reproduced with permission from ref 21. Copyright 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. (C-D) Histology of gelatine adhered to amnion before (C) and after (D) bond failure during tensile testing; arrow indicates cohesive failure of amnion. Reproduced from ref 68, Copyright (2010), with permission from Elsevier.

Challenges for in-situ photoactivation The delivery of UV light to the treatment site of a bioadhesive poses a significant engineering challenge and potential barrier to clinical use. For example, closure of surgical incisions requires penetration of UV light throughout the depth of the incision, and closure of arterial defects requires laparoscopic delivery of UV light via a fibre optic catheter. There are numerous commercially available fibre optic light guides with a range of light output configurations for visible and infra-red light (for use in photodynamic therapy, for example) however, there has been little progress in the delivery of UV light. Despite this, there are several promising developments for in situ light delivery. Biodegradable polymers have been used as planar waveguides to scatter IR light throughout an incision, becoming part of the bioadhesive themselves, as shown in Figure 680. Also, in situ UV generation has been reported for controlled drug release from polymer matrices81 using metamaterials (lanthanide-doped LiYF4 nanoparticles) to upconvert incident IR light to locally-emitted UV light82.

Figure 6. (a) Transparent and flexible poly (L-lactic acid) biopolymer film obtained by melt-pressing technique. Inset: biopolymers in their initial powder form before film formation. (b) A twisted bio-film before laser cutting. (c) Laser cutting allows for a simple fabrication of films with well-controlled meshes. (d) A fibre-coupled waveguide array with an unstructured top region uniformly coupling the light to the array of thin waveguides. Left, off state; right, light on. Only the lower part of the devices is to be embedded into tissue, the top structure including the pigtail fibre is cut off and removed after use. (e) Red light coupled to a waveguide array. (f) A polyethylene glycol hydrogel waveguide array carrying green 11 ACS Paragon Plus Environment

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laser light. Scale bars, 10 mm. Reproduced with permission from ref 80 under a Creative Commons Attribution 4 International License (https://creativecommons.org/licenses/by/4.0/), Nature Publishing Group.

Beyond the challenges of light delivery, UV irradiation may damage nearby healthy tissue. The harmful effects of UV light are wavelength and dose dependent; safe exposure limits for UV radiation are shown in Figure 7 for UVA (315—400nm), UVB (238—315nm) and UVC (100—280nm) wavelengths83. These safe exposure limits were determined for highly sensitive skin (i.e. melano-compromised), and provide a context in which to evaluate the safety of UV bioadhesives. The majority of the articles reviewed here employed UVA wavelengths at doses from several J cm-2 to several tens of J cm-2, putting them at the limit of safe exposure for sensitive skin. Moreover, some reports don’t state the wavelength59, 62, 70, 84 or the intensity59, 65, 67-71, 84, making evaluation of UV safety difficult, whilst others use harmful UVB and UVC wavelengths60, 65-66.

Figure 7. Plot of UV dose (mJ cm-2) as a function of intensity and time. Safe exposure limits are indicated for 280nm (3.4 mJ cm-2), 315 nm (500 mJ cm-2) and 400nm (105 mJ cm-2) for melano-compromised skin83.

Future Perspectives The major breakthroughs in tissue fixation in the past century have been resorbable sutures, fibrin sealants and cyanoacrylate glue. Sutures are invasive, fibrin glue is a poor adhesive, and cyanoacrylate is cytotoxic and restricted to topical and emergency use only. Although research efforts have focused on developing novel bioadhesives, there has been little translation to clinical use. The few commercially available bioadhesives are of the instant crosslinking variety, which are limited in their usefulness, offering little control over final mechanical properties and adhering to every surface they touch. Activated bioadhesives 12 ACS Paragon Plus Environment

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offer several advantages over instant, e.g. control over when, where and for how long an adhesive is crosslinked. Almost exclusively, UV irradiation has been the preferred activation method, owing, we assume, to the convenience of crosslinking acrylic groups via UV photoinitiators. This has led to a wealth of literature on acrylic-based bioadhesives, where the novelty is in the choice, and acrylation of, the polymer backbone. Whilst Irgacure 2959 and Darocur 2959 are biocompatible, unreacted acrylic monomers (or pendant groups cleaved during degradation) could penetrate nearby tissue and cause local toxicity – a major drawback for any implantable material. Breaking the reliance on the acrylation/photoinitiator combination will be a significant step forward for UV bioadhesives, and this has already begun. UVactivated de-protecting groups69-71, photo-active azides65-66, and carbene radical crosslinking21,

74

offer

innovative alternatives to acrylation, and provide an exciting prospect for next generation bioadhesives. Unmet clinical applications Equally exciting are the potential applications of these bioadhesives. With closer interaction between researchers and clinicians comes awareness of unmet clinical needs, to which bioadhesives development can be tailored. Instead of replacing sutures for wound closure, UV bioadhesives have the potential to enable new procedures for which no tissue fixation method currently exists. The potential applications of UV bioadhesives go beyond the suggestions below, but they serve as high impact areas where the ondemand adhesive activation may be most relevant in terms of current and reported fixation methods. Sports lacerations In contact sports such as hockey and boxing, the most common injury is skin lacerations that occur on unprotected areas, such as facial and ocular protrusions. An ideal tissue adhesive for skin lacerations requires a water resistant covering, anisotropic elastic modulus, infection preventative, minimal followup and cosmetic acceptance. Dermabond, activated by moisture, has been employed towards sports lacerations with some success, however the octyl-cyanoacrylate formulation requires a minimum of 150 seconds for maximum bonding strength85. Unrestrained polymer propagation does not allow tuning the cured matrix mechanical properties, giving moduli 1000 times greater than soft tissues it is bonding to. Paired with handheld UV emitting LEDs, UV activated adhesives may overcome these drawbacks, where curing can be done in less than 60 seconds (time between boxing rounds) and in a more controlled manner, allowing matching tissue moduli and less interfacial stress. Laparoscopic & Keyhole surgeries


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Minimally invasive surgeries employ robotics and other thin instruments through small incisions, often far from the tissue of interest. The laparoscope incorporates a fibre optic cable system for illumination and digital viewing devices. As illumination components are already present, it serves as a gateway to activate UV activatable bioadhesives towards sealants and tissue fixation, which would offer more flexibility than the two-part adhesives and sealants. For example, lung biopsies are a routine out-patient procedure, but commonly results in lung collapse (pneumothorax) owing to inadequate sealing of the plural membrane8. Gelatin sponges and fibrin sealants have had little treatment success necessitating more advanced designs that allow expansion and wet tissue adhesion86-87. Another example is laparoscopic prenatal surgery88-92, where common complications include leakage of amniotic fluid or the separation of placental and embryonic membranes which can result in premature birth or miscarriage93. This leaves open surgery in a procedure similar to a caesarean section the preferred option94. Injectable bioadhesive sealants may facilitate translation to low-risk, minimally invasive prenatal surgery95-96. A rabbit midgestational model has served to compare two-part tissue adhesives of mussel mimetic adhesive with fibrin sealants97-98. Anastomoses Arterial and intestinal anastomosis is a procedure used in various surgeries, such as vascular bypass, organ transplant, and excision of colorectal cancers. End-to-end and side-to-end surgical anastomoses are usually created using sutures, which is technically complicated and time consuming

99

. This approach

inflicts additional tissue damage, requires long application times and could elicit immunological response. A possible alternative route is the application of UV activatable bioadhesives that either reinforce (through water tight seals) or replace suturing in clinical procedures. Many different bioadhesive formulations have been reviewed, yet few have become part of clinical procedures

100-101

. Towards

colorectal anastomosis, fibrin sealants tend to have more positive results than Dermabond which is likely due to the fibrin sealants having a modulus closer to intestinal tissue (kPa) than Dermabond (MPa). A rat-colitis model has recently been described for testing various tissue adhesives towards anastomotic sealing and this will serve to accelerate clinical development within this area102.

Acknowledgements Authors acknowledge support from the following research grants: Ministry of Education Tier 2 Grant: Tailored soft-tissue bioadhesives for site-specific therapy (MOE2012-T2-2-046); Ministry of Education Tier 2 Grant: Reversible, electrocuring adhesives (MOE2014-T2-2-100); NTU-Northwestern Institute for


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Nanomedicine Grant: 3D-Printing of Electro-Curing Nanocomposite Living Electrodes for Cardiac Tissue Regeneration.

References

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89. Adzick, N. S. In Fetal surgery for spina bifida: past, present, future, Seminars in pediatric surgery, Elsevier: 2013; pp 10-17. 90. Adzick, N. S.; Harrison, M. R.; Flake, A. W.; Howell, L. J.; Golbus, M. S.; Filly, R. A., Fetal surgery for cystic adenomatoid malformation of the lung. Journal of pediatric surgery 1993, 28 (6), 806-812. 91. Harrison, M. R.; Golbus, M. S.; Filly, R. A.; Callen, P. W.; Katz, M.; de Lorimier, A. A.; Rosen, M.; Jonsen, A. R., Fetal surgery for congenital hydronephrosis. New England Journal of Medicine 1982, 306 (10), 591-593. 92. Gupta, R.; Kilby, M.; Cooper, G., Fetal surgery and anaesthetic implications. Continuing Education in Anaesthesia, Critical Care & Pain 2008, 8 (2), 71-75. 93. Peranteau, W. H.; Adzick, N. S., Prenatal surgery for myelomeningocele. current opinion in obstetrics and gynecology 2016, 28 (2), 111-118. 94. Beck, V.; Lewi, P.; Gucciardo, L.; Devlieger, R., Preterm prelabor rupture of membranes and fetal survival after minimally invasive fetal surgery: a systematic review of the literature. Fetal diagnosis and therapy 2012, 31 (1), 1-9. 95. Bilic, G.; Brubaker, C.; Messersmith, P. B.; Mallik, A. S.; Quinn, T. M.; Haller, C.; Done, E.; Gucciardo, L.; Zeisberger, S. M.; Zimmermann, R.; Deprest, J.; Zisch, A. H., Injectable candidate sealants for fetal membrane repair: bonding and toxicity in vitro. American Journal of Obstetrics and Gynecology 2010, 202 (1), 85.e1-85.e9. 96. Devlieger, R.; Millar, L. K.; Bryant-Greenwood, G.; Lewi, L.; Deprest, J. A., Fetal membrane healing after spontaneous and iatrogenic membrane rupture: A review of current evidence. American Journal of Obstetrics and Gynecology 2006, 195 (6), 1512-1520. 97. Kivelio, A.; Dekoninck, P.; Perrini, M.; Brubaker, C. E.; Messersmith, P. B.; Mazza, E.; Deprest, J.; Zimmermann, R.; Ehrbar, M.; Ochsenbein-Koelble, N., Mussel mimetic tissue adhesive for fetal membrane repair: initial in vivo investigation in rabbits. European Journal of Obstetrics & Gynecology and Reproductive Biology 2013, 171 (2), 240-245. 98. Haller, C. M.; Buerzle, W.; Brubaker, C. E.; Messersmith, P. B.; Mazza, E.; Ochsenbein-Koelble, N.; Zimmermann, R.; Ehrbar, M., Mussel-mimetic tissue adhesive for fetal membrane repair: a standardized ex vivo evaluation using elastomeric membranes. Prenatal Diag 2011, 31 (7), 654-660. 99. Jaquiss, R. D. B., Coarctation of the Aorta: End-to-End Anastomosis. Operative Techniques in Thoracic and Cardiovascular Surgery 2002, 7 (1), 2-10. 100. Vakalopoulos, K. A.; Daams, F.; Wu, Z.; Timmermans, L.; Jeekel, J. J.; Kleinrensink, G. J.; van der Ham, A.; Lange, J. F., Tissue adhesives in gastrointestinal anastomosis: a systematic review. J Surg Res 2013, 180 (2), 290-300. 101. Bouten, P. J. M.; Zonjee, M.; Bender, J.; Yauw, S. T. K.; van Goor, H.; van Hest, J. C. M.; Hoogenboom, R., The chemistry of tissue adhesive materials. Progress in Polymer Science 2014, 39 (7), 1375-1405. 102. Wu, Z. Q.; Boersema, G. S. A.; Kroese, L. F.; Taha, D.; Vennix, S.; Bastiaansen-Jenniskens, Y. M.; Lam, K. H.; Kleinrensink, G. J.; Jeekel, J.; Peppelenbosch, M.; Lange, J. F., Reducing Colorectal Anastomotic Leakage with Tissue Adhesive in Experimental Inflammatory Bowel Disease. Inflamm Bowel Dis 2015, 21 (5), 1038-1046.


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TOC Grapic 133x55mm (96 x 96 DPI)

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Figure 1. Schematic of commercially available bioadhesives approved by the US Food and Drug Administration (FDA) since 2000; Adherus AutoSpray Dural Sealant15; Progel Pleural Air Leak Sealant36; TissuGlu Surgical Adhesive14; ReSure® Sealant16; ArterX Surgical Sealant37; Ethicon™OMNEX™ Surgical Sealant38; DuraSeal Spine Sealant System17; Histoacryl39; Matrix VSG™ System18; CoSeal™ Surgical Sealant19; Indermil™ Tissue Adhesive40; CryoLife BioGlue Surgical Adhesive41 and; FocalSeal-Synthetic Absorbable Sealant42. 175x239mm (300 x 300 DPI)


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Figure 2. Gelatine crosslinking via ruthenium photo-chemistry 97x210mm (150 x 150 DPI)


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Figure 3. Light activation of caged mussel adhesive protein mimetic polymer. Reprinted with permission from ref 69. Copyright 2013 American Chemical Society. 176x85mm (150 x 150 DPI)


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Figure 4. Structure of PAMAM-diazirine 157x192mm (150 x 150 DPI)


Biomacromolecules

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Figure 5. (A) Histology of anastomosed sheep intestine (I) using SurgiLux (S); scale bar 100µm. Reproduced with permission from ref 27. Copyright 2010 American Chemical Society. (B) Cross-sectional SEM of PAMAM-diazirine attached to excised porcine aorta. Reproduced with permission from ref 21. Copyright 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. (C-D) Histology of gelatine adhered to amnion before (C) and after (D) bond failure during tensile testing; arrow indicates cohesive failure of amnion. Reproduced from ref 68, Copyright (2010), with permission from Elsevier. 199x171mm (150 x 150 DPI)


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Biomacromolecules

Figure 6. (a) Transparent and flexible poly (L-lactic acid) biopolymer film obtained by melt-pressing technique. Inset: biopolymers in their initial powder form before film formation. (b) A twisted bio-film before laser cutting. (c) Laser cutting allows for a simple fabrication of films with well-controlled meshes. (d) A fibre-coupled waveguide array with an unstructured top region uniformly coupling the light to the array of thin waveguides. Left, off state; right, light on. Only the lower part of the devices is to be embedded into tissue, the top structure including the pigtail fibre is cut off and removed after use. (e) Red light coupled to a waveguide array. (f) A polyethylene glycol hydrogel waveguide array carrying green laser light. Scale bars, 10 mm. Reproduced from ref 80 under a Creative Commons Attribution 4 International License (https://creativecommons.org/licenses/by/4.0/), Nature Publishing Group 78x132mm (150 x 150 DPI)


Biomacromolecules

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Figure 7. Plot of UV dose (mJ cm-2) as a function of intensity and time. Safe exposure limits are indicated for 280nm (3.4 mJ cm-2), 315 nm (500 mJ cm-2) and 400nm (105 mJ cm-2) for melano-compromised skin83. 148x111mm (96 x 96 DPI)


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Addressing Unmet Clinical Needs with UV Bioadhesives

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