Interfacial Fluid Transport Is a Key to Hydrogel Bioadhesion
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Interfacial fluid transport is a key to hydrogel bioadhesion Raphaël Michela,b,1, Léna Poiriera, Quentin van Poelvoordea, Josette Legagneuxc, Mathieu Manasserod,e, and Laurent Cortéa,b,1 aEcole Supérieure de Physique et Chimie Industrielle de la Ville de Paris (ESPCI Paris), Paris Sciences et Lettres Research University, Laboratoire Matière Molle et Chimie, CNRS UMR 7167, 75005 Paris, France; bMINES ParisTech, Paris Sciences et Lettres Research University, Centre des Matériaux, CNRS UMR 7633, 91003 Evry, France; cEcole de Chirurgie, Agence Générale des Équipements et Produits de Santé, Assistance Publique-Hôpitaux de Paris, 75005 Paris, France; dService de Chirurgie, Ecole Nationale Vétérinaire d’Alfort, 94700 Maisons-Alfort, France; and eLaboratoire de Bioingénierie et Bioimagerie Ostéo- Articulaire, CNRS UMR 7052, 75010 Paris, France Edited by David A. Weitz, Harvard University, Cambridge, MA, and approved December 3, 2018 (received for review August 3, 2018) Attaching hydrogels to soft internal tissues is a key to the devel- hydrogel−tissue adhesion remains to be elucidated, and its appli- opment of a number of biomedical devices. Nevertheless, the wet cability for the design of bioadhesive systems has been very little nature of hydrogels and tissues renders this adhesion most difficult exploited hitherto. Here, we address this question, using adhesion to achieve and control. Here, we show that the transport of fluids experiments of model hydrogels on animal tissues. across hydrogel−tissue interfaces plays a central role in adhesion. Our study concentrates on adhesion to the outside and inside tis- Using ex vivo peeling experiments on porcine liver, we character- sues of the liver, which is commonly used to assess the performance of ized the adhesion between model hydrogel membranes and the bioadhesives (7–9, 17–19). The outer part of the liver, the Glisson’s liver capsule and parenchyma. By varying the contact time, the tis- capsule, hereafter referred to as “capsule,” is delimited by a membrane sue hydration, and the swelling ratio of the hydrogel membrane, a constituted of superimposed thin tissue layers (20). Its outermost transition between two peeling regimes is found: a lubricated regime surface is composed of a monolayer of mesothelial cells attached where a liquid layer wets the interface, yielding low adhesion ener- to a 100-nm-thick basal membrane. These cells produce a liquid gies (0.1 J/m2 to 1 J/m2), and an adhesive regime with a solid binding coating, the glycocalyx, composed of an aqueous solution of 2 hyaluronan that has both a lubricant and a protective role (20). between hydrogel and tissues and higher adhesion energies (1 J/m “ ” to 10 J/m2). We show that this transition corresponds to a draining of The inner part of the liver, hereafter referred to as parenchyma, is the interface inducing a local dehydration of the tissues, which be- a soft porous structure irrigated by a dense network of vessels (21). come intrinsically adhesive. A simple model taking into account the It is divided into lobules having a characteristic diameter varying from 1 mm to 2.5 mm where the blood is filtered and bile is pro- microanatomy of tissues captures the transition for both the liver duced (22). Herein, we use porcine liver, which has an anatomy and capsule and parenchyma. In vivo experiments demonstrate that this hemodynamics that differ little from those of human liver (23). effect still holds on actively hydrated tissues like the liver capsule and Model hydrogel membranes were fabricated from poly(ethyl- show that adhesion can be strongly enhanced when using superab- ene glycol) (PEG) films. Similar PEG hydrogels are used in sorbent hydrogel meshes. These results shed light on the design of modern surgery as sealant (2). They are known to adhere to predictive bioadhesion tests as well as on the development of im- biological tissues due to hydrogen bonding between ether oxy- proved bioadhesive strategies exploiting interfacial fluid transport. gens and the protons of amino and hydroxy groups contained in biomolecules (24, 25) as well as short-range hydrophobic bioadhesion | hydrogel | interface | transport | liver Significance ydrogels are essential components of implants and surgical Hdevices, used as protective layers (1), sealants (2), platforms Bioadhesive hydrogels capable of sticking to living tissues are for drug or cell delivery (3), or substrates for biosensors (4). of utmost interest for better-integrated implants and less in- These applications require that hydrogels be secured on the soft vasive surgical techniques. Nevertheless, adhesion is most dif- and wet tissues of internal organs. Fixation by mechanical fas- ficult to achieve and control on the wet surface of internal teners like sutures is most often not satisfactory, as it damages tissues. This work demonstrates that fluid transport across the both tissues and hydrogels (5). Much more appropriate fixation tissue−hydrogel interface governs the creation of adhesion. methods are sutureless approaches producing an intimate and Through ex vivo experiments and a simple model, we capture adhesive contact at the interface between hydrogels and tissues how the onset of adhesion depends on a competition between (6). In recent years, major progress has been made to create draining and wetting of the interface. This coupling between bioadhesive hydrogel surfaces by introducing binding interac- adhesion and interfacial transport provides a potent key to tions between hydrogel networks and biological tissues through – improve the accuracy of adhesion tests and to enhance the surface functionalization (7 9), mechanical interlocking (10), or bioadhesive performance of hydrogels. We illustrate this po- coating with nanoparticles (11). Nevertheless, the design of such tential in vivo by using superabsorbent hydrogel membranes bioadhesive hydrogels is greatly challenged by the wet conditions to make strong liver adhesives. of the interface (12). Tissue surfaces are continuously perfused by vascular flows and hydrated by surrounding biological fluids, Author contributions: R.M. and L.C. designed research; R.M., L.P., Q.v.P., J.L., M.M., and which hinders the contact between hydrogels and tissues and L.C. performed research; R.M., L.P., Q.v.P., M.M., and L.C. analyzed data; and R.M., M.M., compromises the establishment of adhesive binding. Most in- and L.C. wrote the paper. terestingly, hydrogel formulations are often not swollen to equi- The authors declare no conflict of interest. librium at the moment of contact with biological tissues. Therefore, This article is a PNAS Direct Submission. water ought to be transported from the tissue into the hydrogel. Published under the PNAS license. Seminal studies on adhesion to mucus membranes have shown that 1To whom correspondence may be addressed. Email: [email protected] or laurent. the tissue dehydration resulting from this transport could be a [email protected]. driving mechanism for bioadhesion (13, 14). Adhesion experi- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. ments between model hydrogels have confirmed this effect (15, 1073/pnas.1813208116/-/DCSupplemental. 16). However, the contribution of such interfacial transport to Published online January 2, 2019. 738–743 | PNAS | January 15, 2019 | vol. 116 | no. 3 www.pnas.org/cgi/doi/10.1073/pnas.1813208116 Downloaded by guest on September 27, 2021 interactions with tissue proteins (26), as illustrated in Fig. 1A.In the hydrogel surface, indicating a cohesive rupture in the tissue (SI this study, smooth 1-mm-thick films having a roughness of less Appendix,Fig.S4). than 1 μm(SI Appendix, Fig. S1) were produced from diacrylate The interfacial adhesion energy, G, can be calculated from those telechelic PEG chains (Mn = 700 kg/mol) chemically cross-linked peeling curves using Kendall’s (27) theory of elastic peeling. For 90° with multifunctional thiols (SI Appendix, SI Materials and Meth- peeling, the adhesion energy is simply given by G = F/w,whereF/w is ods). In water, these films reach equilibrium swelling in 2.5 h (SI the mean steady-state value of the peeling force, F, normalized by the Appendix, Fig. S2). In the following, hydrogel swelling is char- ribbon width, w. Adhesion energy for a 5-min contact time with dry acterized by the swelling ratio, Q, defined as the mass of the PEG ribbons was measured on several liver samples from different swollen film over the mass of the dry film. At equilibrium in animals (n = 6) (Fig. 1F). For the capsule, all peelings were in 2 water, the swelling ratio of the studied PEG films is Qeq = 2.00 ± the adhesive regime with an adhesion energy of 2.3 ± 0.5 J/m , 0.05, which corresponds to a water content of 50 wt%. while, for the parenchyma, peeling was either in a lubricated or adhesive regime depending on the liver. In the latter case, the Results and Discussion difference in adhesion energy between lubricated (open sym- 2 Ex Vivo Adhesion Measurements. The adhesion between PEG bols, G = 0.9 ± 0.3 J/m ) and adhesive regimes (full symbols, hydrogels and porcine liver tissues was measured ex vivo using a G = 3.1 ± 0.3 J/m2)isstatisticallysignificant(P < 0.0001). 90° peeling experiment as depicted in Fig. 1B.Ineachexperiment, The hydrogel−liver adhesion depends on the swelling state of a 1-cm-thick, 3-cm-wide and 12-cm-long rectangular section of the deposited hydrogels. To show this dependence, PEG ribbons liver was cut and glued onto a flat holder. A 1-cm-wide ribbon of were swollen to different swelling ratios from dry state (Q = 1) to PEG hydrogel was deposited on the liver surface over an 8-cm equilibrium swelling (Qeq = 2). The corresponding adhesion en- length (step i). A pressure of 50 kPa to 60 kPa was applied with a ergies are given in Fig. 1G for a 5-min contact time on the same finger over the contact area for 1 min to reproduce a surgical liver.