**6. References**

24 Biomedicine

Lifelong requirement of immunosuppressive drugs has deleterious effects on β-cell function and on host's ability to fight disease. To protect islets from immune-mediated destruction, camouflaging the islet surfaces is necessary for immunoisolation and immunoprotection. Current islet modification strategies are challenging for transplantation due to interference with islet functioning, limited nutrient transport, and/or cytotoxicity. Thus, current strategies mostly involve either imbedding islets within thick hydrogels that have limited nutrient transport and require large injection volumes or covalent conjugation to islet

The ultra-thin coating approach possesses several advantages. Islets modified with such coatings can be easily implanted into liver through the portal vein, the preferable site for islet implantation. Islet necrosis can be avoided because of the rapid diffusion of nutrients and oxygen through the coating. Moreover, due to a minimal volume of the enclosed islets, an adequate release of insulin can be achieved in response to blood glucose changes. Though, despite the advantages, chemical modification of the cell membrane using covalent conjugation of molecules to the cell membrane proteins can result in cell physiology disturbance. In this respect, non-covalent modification method based on LbL can afford for cytocompatible coatings if non-toxic components are used. The ultrathin LbL coating allows for faster response to stimulation and the possibility to bind factors or protective molecules to the protective ultrathin shell with the later slow triggered release of these molecules. By selecting specific polyelectrolytes, a defined cutoff of the coating is possible, as is inhibitor binding to prevent graft rejection, microphage attacks, or antibody recognition. Another important point is that the mechanical properties of the LbL-based films can be adjusted through an introduction of appropriate components or the chemical modification of the constituents. This issue is particularly important as β-cell in mature islets can still grow (Dor et al., 2004) causing the islet size increase. Unlike hydrogel-based ultrathin coatings, LbL coatings have the ability to withstand islet size increase and effectively enclose the islets for long periods of time. Another crucial issue is the preservation of the islet integrity because functionality losses were observed when islets disintegrated or fused in suspension culture. In this respect, the LbL technique provides a conformal and stable coating of individual

However, despite the significant promise of the LbL strategy for islet modification, the main drawback of the approach is cytotoxicity of the used compounds. Moreover, ultra-thin encapsulating films may not work as reliable barriers against free-radicals. Indeed, thick agarose microbeads or alginate microcapsules can provide a more effective shield capable of inactivating free radicals. This issue is particularly crucial since most inflammatory processes are associated with oxidative stress initiated by production of reactive oxygen

Considering the previous studies, it is important to develop new strategies for design of new multifunctional coatings with immunomodulatory capabilities which can permit the reestablishment of ECM support and maintain the physiological needs of the islets. In this respect, the LbL approach offers opportunities for integration of the inherent advantages of both islet microencapsulation and surface modification approaches. For example, multifunctional LbL materials designed from non-toxic biologically-active polymers can provide novel immunoprotective and anti-inflammatory coatings crucial for prolonged islet

species which can function as signaling molecules in many cell types.

surfaces, which can interfere with cell function.

islets.

viability and functions.


Encapsulation and Surface Engineering of Pancreatic Islets: Advances and Challenges 27

De Koker, S., De Geest, B.G., Cuvelier, C., Ferdinande, L., Deckers, W., Hennink, W.E., De

De Vos, P., De Haan, B., & Van Schilfgaarde, R. (1997). Effect of the alginate composition on

De Vos, P., Smedema, I., van Goor, H., Moes, H., van Zanten, J., Netters, S., de Leij, L.F.M.,

De Vos, P., Van Hoogmoed, C.G., Van Zanten, J., Netter, S., Strubbe, J.H., & Busscher, H.J.

Dor, Y., Brown, J., Martinez, O.I., & Melton, D.A. (2004). Adult pancreatic beta-cells are

Doxastakis, M., Sum, A.K., & de Pablo, J.J. (2005). Modulating Membrane Properties: The

Drucker, D. (2001). Development of glucagon-like peptide-1-based pharmaceuticals as

Drucker, D. (2002). Biological actions and therapeutic potential of the glucagon-like peptides. *Gastroenterology*, Vol.122, No.2, pp.531-544, ISSN 0016-5085 Esmon, C.T. (2004) Crosstalk between inflammation and thrombosis. *Maturitas*, Vol.47, No.4,

Esmon, N., Owen, W., & Esmon, C.T. (1982). Isolation of a membrane-bound cofactor for

Gimi, B., Kwon, J., Kuznetsov, A., Vachha, B., Magin, R.L., Philipson, L.H., & Lee, J.B. (2009).

Godbey, W.T., Wu, K.K., & Mikos, A.G. (1999). Size matters: molecular weight affects the

Hallé, J.P., Leblond, F.A., Pariseau, J.F., Jutras, P., Brabant, M.J., & Lepage, Y. (1994). Studies

Haug, A., Larsen, B., & Smidsrød, O. (1974). Uronic acid sequence in alginate from different sources. *Carbohydrate Research*, Vol.32, No.2, pp.217–225, ISSN 0008-6215

*Diabetes Sci. Technol*., Vol.3, No.2, pp.297-303, ISSN 1932-2968

pp.3754-3763, ISSN 1616-301X

No.3, pp.273-278, ISSN 0142-9612

No.6987, pp41-46, ISSN 0028-0836

pp.305–314, ISSN 0378-5122

pp.365-372, ISSN 0963-6897

864, ISSN 0021-9258

Vol.109, No.50, pp.24173–24181, ISSN 1520-6106

Vol.7, No.14, pp.1399-1412, ISSN 1381-6128

Vol.45, No.3, pp.286-275, ISSN 0021-9304

ISSN 0012-186X

1797

Smedt, S., Mertens, N. (2007). In vivo cellular uptake, degradation, and biocompatibility of polyelectrolyte microcapsules. *Adv. Funct. Mater*., Vol.17, No.18,

the biocompatibility of alginate-polylysine microcapsules. *Biomaterials*, Vol.18,

de Haan, A., & de Haan, B.J. (2003). Association between macrophage activation and function of micro-encapsulated rat islets. *Diabetologia*, Vol.46, No.5, pp.666-673,

Long-term biocompatibility, chemistry, and function of microencapsulated pancreatic islets. (2003). *Biomaterials,* Vol. 24, No.2, pp.305–312, ISSN 0142-9612 De Vos, P., Van Straaten, J.F.M., Nieuwenhuizen, A.G., De Groot, M., Ploeg, R.J., De Haan,

B.J., & Van Schilfgaarde, R. (1999). Why do microencapsulated islet grafts fail in the absence of fibrotic overgrowth? *Diabetes,* Vol.48, No.7, pp.1381-1388, ISSN 0012-

formed by self-duplication rather than stem-cell differentiation. *Nature*, Vol.429,

Effect of Trehalose and Cholesterol on a Phospholipid Bilayer. *J. Phys. Chem. B*,

therapeutic agents for the treatment of diabetes. *Current Pharmaceutical Design*,

thrombin-catalyzed activation of protein C. *J. Biol. Chem*., Vol.257, No.2, pp.859–

A nanoporous, transparent microcontainer for encapsulated islet therapy. *J.* 

efficiency of poly(ethylenimine) as a gene delivery vehicle. *J. Biomed. Mater. Res*.,

on small (< 300 microns) microcapsules: II. Parameters governing the production of alginate beads by high voltage electrostatic pulses. *Cell Transplant*, Vol.3, No.5,


Cabric, S., Sanchez, J., Lundgren, T., Foss, A., Felldin, M., Källen, R., Salmela, K., Tibell, A.,

Chandy, T., Mooradian, D.L., & Rao, G.H.R. (1999). Evaluation of modified alginate-

Chen, J.P., Chu, I.M., Shiao, M.Y., Hsu, B.R.S., & Fu, S.H. (1998). Microencapsulation of islets

Chen, H., Teramura, Y., Iwata, H. (2011). Co-immobilization of urokinase and

phospholipid. *J. Control. Release.* Vol.150, No.2, pp.229-234, ISSN 0168-3659 Chluba, J., Voegel, J.C., Decher, G., Erbacher, P., Schaaf, P., & Ogier, J. (2001). Peptide

Chow, L.W., Wang, L.J., Kaufman, D.B., & Stupp, S.I. (2010). Self-assembling nanostructures

Contreras, J. L., Smyth, C.A., Bilbao, G., Young, C.J., Thompson, J.A., & Eckhoff, D.E. (2002).

functionality. *Transplantation*, Vol.74, No.9, pp.1252–1259, ISSN 0041-1337 Cui, W., Barr, G., Faucher, K.M., Sun, X.-L., Safley, S.A., Weber, C.J., & Chaikof, E.L. (2004).

Dai, Z., Wilson, J.T., & Chaikof, E.L. (2007). Construction of pegylated multilayer

Daoud, J., Petropavlovskaia, M., Rosenberg, L., & Tabrizian, M. (2010). The effect of

Dawson, R.M., Broughton, R.L., Stevenson, W.T., & Sefton, M.V. (1987). Microencapsulation

Decher, G., & Schlenoff, J.B. (Eds.). (2002). *Multilayer Thin Films: Sequential Assembly of Nanocomposite Materials*, Wiley-VCH, ISBN 3-527-30440-1, Weinheim. Dembczynski, R., Jankowski, T. (2001). Determination of pore diameter and molecular

*Biomater. Sci. Polym. Ed*., Vol.12, No.9, pp.1051-1058, ISSN 0920-5063

vitro. *Biomaterials*, Vol.31, No.7, pp.1676-1682, ISSN 0142-9612

*Biomaterials*, Vol.8, No.5, pp.360-366, ISSN 0142-9612

transplantation. *Diabetes*, Vol.56, No.8, pp.2008-2015, ISSN 0012-1797 Calafiore, R., Basta, G., Luca, G., Boselli, C., Bufalari, A., Giustozzi, G.M., Moggi, L.,

Vol.831, pp.313-322, ISSN 0077-8923

ISSN 0922-338X

800-805, ISSN 1525-7797

pp.6154-6161, ISSN 0142-9612

pp.1206-1208, ISSN 0041-1345

*C*, Vol.27, No.3, pp.402-408, ISSN 0928-4931

*Organs,*Vol.23, No.10, pp.894–903, ISSN 0160-564X

Tufveson, G., Larsson, R., Korsgren, O., & Nilsson, B. (2007). Islet surface heparinization prevents the instant blood-mediated inflammatory reaction in islet

Brunetti, P. (2006). Alginate/polyaminoacidic coherent microcapsules for pancreatic islet graft immunoisolation in diabetic recipients. *Ann N.Y. Academy Sci*.,

chitosan-poly(ethylene glycol) microcapsules for cell encapsulation. *Artif.* 

in PEG-amine modified alginate-poly(L-lysine)-alginate microcapsules for constructing bioartificial pancreas. *J. Ferment. Bioeng*., Vol.86, No.2, pp.185-190,

thrombomodulin on islet surfaces by poly(ethylene glycol)-conjugated

hormone covalently bound to polyelectrolytes and embedded into multilayer architectures concerving full biological activity. *Biomacromolecules*, Vol.2, No.3, pp.

to deliver angiogenic factors to pancreatic islets. *Biomaterials*, Vol.31, No.24,

17, beta-estradiol protects isolated human pancreatic islets against proinflammatory cytokine-induced cell death: Molecular mechanisms and islet

A Membrane-mimetic barrier for islet encapsulation. *Transplant. Proc*., Vol.36, No.4,

architectures via (strept)avidin/biotin interactions. *Materials science and engineering* 

extracellular matrix components on the preservation of human islet function in

of CHO cells in a hydroxyethyl methacrylate-methyl methacrylate copolymer.

weight cut-off of hydrogel-membrane liquid-core capsules for immunoisolation. *J.* 


Encapsulation and Surface Engineering of Pancreatic Islets: Advances and Challenges 29

King, A., Andersson, A., & Sandler, S. (2000). Cytokine-induced functional suppression of

King, A., Sandler, S., Andersson, A. (2001). The effect of host factors and capsule

Kizilel, S., Scavone, A., Liu, X., Nothias, J.M., Ostrega, D., Witkowski, P., & Millis, M. (2010).

Koster, K.L., Lei, Y.P., Anderson, M., Martin, S., & Bryant, G. (2000). Effects of vitrified and

Kozlovskaya, V., & Sukhishvili, S.A. (2006). pH-Controlled permeability of layered

Krishnamurthy, V.R., Wilson, J.T., Cui, W., Song, X., Lasanajak, Y., Cummings, R.D., &

Krol, S., Guerra, S., Grupillo, M., Diasporo, A., Gliozzi, A., & Marchetti, P. (2006). Multilayer

Lacy, P., & Kostianovsky, M. (1967) Method for the isolation of intact islets of Langerhans from the rat pancreas. *Diabetes*, Vol.16, No.1, pp.35-39, ISSN 0012-1797 Lee, D.Y., Nam, J.H., & Byun, Y. (2004). Effect of polyethylene glycol grafted onto islet

Lee, D. Y., Nam, J.H., Byun, Y. (2007). Functional and histological evaluation of transplanted

Lee, D.Y., Park, S.J., Nam, J.H., & Byun, Y. (2006). A new strategy toward improving

Lee, D.Y., Yang, K., Lee, S., Chae, S.Y., Kim, K.W., Lee, M.K., Han, D.J., & Byun, Y. (2002).

capsules. *J. Biomed. Mater. Res*., Vol.62, No.3, pp.372–377, ISSN 0021-9304 Lee, S.-H., Lee, S., Youn, Y.S., Na, D.H., Chae, S.Y., Byun, Y., & Lee, K.C. (2005). Synthesis,

Peptide-1. *Bioconjug. Chem*., Vol.16, No.2, pp.377-382, ISSN 1043-1802 Lim, F., & Sun, A.M. (1980). Microencapsulated islets as bioartificial endocrine pancreas.

*Science,* vol.210, No.4472, pp.908-910, ISSN 0036-8075

*Mater. Res*., Vol.57, No.3, pp.374-383, ISSN 0021-9304

*J.*, Vol.78, No.4, pp.1932-1946, ISSN 0006-3495

islets. *Nano Lett*., Vol.6, pp.1933-1939, ISSN 1530-6984

*Biomaterials*, Vol.28, No.11, pp.1957–1966, ISSN 0142-9612

*Ed*. Vol.15, No.6, pp.753–766, ISSN 0920-5063

Vol.110, No.2, pp.290–295, ISSN 0168-3659

pp.380-383, ISSN 0041-1337

ISSN 1937-3341

ISSN 0024-9297

0743-7463

microencapsulated rat pancreatic islets in vitro. *Transplantation*, Vol.70, No.2,

composition on the cellular overgrowth on implanted alginate capsules. *J. Biomed.* 

Encapsulation of pancreatic islets within nano-thin functional polyethylene glycol coatings for enhanced insulin secretion. *Tissue Eng. A*, Vol.16, No.7, pp.2217-2228,

nonvitrified sugars on phosphatidylcholine fluid-to-gel phase transitions. *Biophys.* 

hydrogen-bonded polymer capsules. *Macromolecules*, Vol.39, No.16, pp.5569-5572,

Chaikof, E.L. (2010). Chemoselective Immobilization of Peptides on Abiotic and Cell Surfaces at Controlled Densities. *Langmuir*, Vol.26, No.11, pp.7675-7678, ISSN

nanoencapsulation. New approach for immune protection of human pancreatic

capsules on prevention of splenocytes and cytokine attacks. *J. Biomater. Sci. Polym.* 

pancreatic islets immunoprotected by PEGylation and cyclosporine for 1 year.

immunoprotection in cell therapy for diabetes mellitus: long-functioning PEGylated islets in vivo. *Tissue Eng.,*Vol.12,No.3, pp.615–623, ISSN 1076-3279 Lee, D.Y., Park, S.J., Nam, J.H., & Byun, Y. (2006). A combination therapy of PEGylation and

immunosuppressive agent for successful islet transplantation*. J. Control. Release*,

Optimization of monomethoxy-polyethylene glycol grafting on the pancreatic islet

Characterization, and Pharmacokinetic Studies of PEGylated Glucagon-like


Herring, B.J., Kandaswamy, R., Harmon, J.V., Ansite, J.D., Clemmings, S.M., Sakai, T.,

Hortin, G.L., Lok, H.T., & Huang, S.T. (1997). Progress toward preparation of universal

Hsu, B.R., Chen, H.C., Fu, S.H., Huang, Y.Y., & Huang, H.S. (1994). The use of field effects to

Hume, P.S., Bowman, C.N., & Anseth, K.S. (2011). Functionalized PEG hydrogels through

Ichii, H., Sakuma, Y., Pileggi, A., Fraker, C., Alvarez, A., Montelongo, J., Szust, J., Khan, A.,

Inui, O., Teramura, Y., & Iwata, H. (2010). Retention dynamics of amphiphilic polymers

Iwata, H., Takagi, T., Amemiya, H., Shimizu, H., Yamashita, K., Kobayashi, K., & Akutsu, T.

Jeong, J.-H., Hong, S.W., Hong, S., Yook, S., Jung, Y., Park, J.-B., Khue, C.D., Im, B.-H., Seo,

Johansson, U., Elgue, G., Nilsson, B., & Korsgren, O. (2005). Composite islet-endothelial cell

Kharlampieva, E., & Sukhishvili, S.A. (2006). Hydrogen-bonded layer-by-layer films.

Kim, S.C., Han, D.J., Kim, I.H., Woo, K.O., We, Y.M., Kang, S.Y., Back, J.H., Kim, Y.H., Kim,

culture in the rat. *Transplant. Proc*., Vol.37, pp.3472-3475, ISSN 0041-1345 Kim, T.G., & Park, T.G. (2006). Biomimicking extracellular matrix: Cell Adhesive RGD

*Formos. Med. Assoc*., Vol.93, No.3, pp.240-245, ISSN 0929-6646

CD3 antibody. *Am. J. Transplant*. Vol.4, No.3, 390-401, ISSN 1600-6135 Holz, G.G., & Chepurny, O.G. (2003). Glucagon-like peptide-1 synthetic analogs: new

Vol.10, No.22, pp.2471-2483, ISSN 0929-8673

Vol.32, No.26, pp.6204-6212, ISSN 0142-9612

No.5, pp.1514-1520, ISSN 1944-8244

No.31. pp.7961-7970, ISSN 0142-9612

pp.967-977, ISSN 0021-9304

*Transplant*., Vol.7, No.4, pp.1010-1020, ISSN 1600-6135

*J. Transplant*., Vol.5, No.11, pp.2632-2639, ISSN 1600-6135

*Polymer Reviews*, Vol.46, No.4, pp.377-395, ISSN 1558-3724

*Tissue Eng*., Vol.12, No.2, pp.221-233, ISSN 1076-3279

491, ISSN 1073-1199

Paraskevas, S., Eckman, P.M., Sageshima. J., Nakano, M., Sawada, T., Matsumoto, I., Zhang, H.J., Sutherland, D.E., & Bluestone, J.A. (2004). Transplantation of cultured islets from two-layer preserved pancreases in type I diabetes with anti-

therapeutic agents for use in the treatment of diabetes mellitus. *Curr. Med. Chem*.,

donor red cells. Artif. Cells Blood Subs. *Immobil. Biotechnol*., Vol.25, No.5, pp.487-

generate calcium alginate microspheres and its application in cell transplantation. *J.* 

reactive dip-coating for the formation of immunoactive barriers. *Biomaterials*,

Inverardi, L., Naziruddin, B., Levy, M.F., Klintmalm, G.B., Goss, J.A., Alejandro, R., & Ricordi, C. (2007). Shipment of human islets for transplantation. *Am. J.* 

PEG-lipids and PVA-Alkyl on the cell surface. *ACS Appl. Mater. Interfaces*, Vol.2,

(1992). Agarose for a bioartificial pancreas. J. Biomed. Mater. Res., Vol.26, No.7,

J., Lee, H., Ahn, C.-H., Lee, D.Y., & Byun, Y. (2011). Surface camouflage of pancreatic islets using 6-arm-PEG-catechol in combined therapy with tacrolimus and anti-CD154 monoclonal antibody for xenotransplantation. *Biomaterials*, Vol.32,

grafts: a novel approach to counteract innate immunity in islet transplantation. *Am.* 

J.H., & Lim, D.G. (2005). Comparative study on biologic and immunologic characteristics of the pancreas islet cell between 24 degrees C and 37 degrees C

Peptide modified electrospun poly(D,L-lactic-co-glycolic acid) nanofiber mesh.


Encapsulation and Surface Engineering of Pancreatic Islets: Advances and Challenges 31

Paulick, M.G., Forstner, M.B., Groves, J.T., & Bertozzi, C.R. (2007). A chemical approach to

Pratt, J.R., Hibbs ,M.J., Laver, A.J., Smith, R.A., & Sacks, S.H. (1996). Effects of complement

Qi, Z., Shen, Y., Yanai, G., Yang, K., Shirouzu, Y., Hiura, A., & Sumi, S. (2010). The in vivo

Rabuka, D., Forstner, M.B., Groves, J.T., & Bertozzi, C.R. (2008). Noncovalent cell surface

Riachy, R., Vandewalle, B., Conte, J.K., Moerman, E., Sacchetti, P., Lukowiak, B., Gmyr,V.,

Ricordi, C., Lacy, P.E., Sterbenz, K., & Davie, J.M. (1987). Low-temperature culture of human

Ricordi, C., & Strom, T.B. (2004) Clinical islet transplantation: advances and immunological challenges. *Nat. Rev. Immunol.,* Vol. 4, No.4, pp.259-268, ISSN 1474-1733 Ris, F., Hammar, E., Bosco, D., Pilloud, C., Maedler, K., Donath, M.Y., Oberholzer, J.,

Robertson, R.P. (2000) Successful islet transplantation for patients with diabetes – Fact or

Robertson, R.P., & Harmon, J.S. (2007). Pancreatic islet beta-cell and oxidative stress: the

Sakai, S., Mu, C., Kawabata, K., Hashimoto, I., & Kawakami, K. (2006). Biocompatibility of

fantasy? *N. Engl. J. Med*., Vol.343, No.4, pp.289-290, ISSN 0028-4793

in vitro. *Diabetologia,* Vol.45, pp.841-850, ISSN 0012-186X

*Res. A*, Vol.78, No.2, pp.394-398, ISSN 1549-3296

*Natl. Acad. Sci. U. S. A*., Vol.104, No.51, pp.20332–20337, ISSN 0027-8424 Pi, J., Bai, Y., Zhang, Q., Wong, V., Floering, L.M., Daniel, K., Reece, J.M., Deeney, J.T.,

ISSN 0012-1797

1199

pp.2055-2066, ISSN 0002-9440

pp.4809–4819, ISSN 0013-7227

pp.8080-8084, ISSN 0027-8424

ISSN 0014-5793

No.14, pp.4026-4031, ISSN 0142-9612

unraveling the biological function of the glycosylphosphatidylinositol anchor. *Proc.* 

Andersen, M.E., Corkey, B.E., & Collins, S. (2007). Reactive oxygen species as a signal in glucose-stimulated insulin secretion. *Diabetes*, Vol.56, No.7, pp.1783-1791,

inhibition with soluble complement receptor -1 on vascular injury and inflammation duringrenal allograft rejection in the rat. *Am. J. Pathol*., Vol.149, No.6,

performance of polyvinyl alcohol macro-encapsulated islets. *Biomaterials*, Vol.31,

engineering: incorporation of bioactive synthetic glycopolymers into cellular membranes. *J. Am. Chem. Soc.*, Vol.130, No.18, pp.5947–5953, ISSN 0002-7863 Raymond, M.-C., Neufeld, R.J., Poncelet, D., (2004). Encapsulation of brewers yeast in

chitosan coated carrageenan microspheres by emulsification/thermal gelation. *Artif. Cells, Blood Substit. Immobil. Biotechnol*., Vol.32, No.2, pp.275-291, ISSN 1073-

Bouckenooghe, T., Dubois, M., & Pattou, F. (2002). 1,25-dihydroxyvitamin D3 protects RINm5F and human islet cells against cytokine-induced apoptosis: Implication of the antiapoptotic protein A20. *Endocrinology,* Vol.143, No.12,

islets or in vivo treatment with L3T4 antibody produces a marked prolongation of islet human-to mouse xenograft survival. *Proc. Natl. Acad. Sci. USA*, Vol.84, No.22,

Zeender, E., Morel, P., Rouiller, D., & Halban, P.A. (2002). Impact of integrin-matrix matching and inhibition of apoptosis on the survival of purified human beta-cells

importance of glutathione peroxidase. *FEBS Lett*., Vol.581, No.19, pp.3743-3748,

subsieve-size capsules versus conventional-size microcapsules. *J. Biomed. Mater.* 


Lin, C.-C., & Anseth, K.S. (2009). Glucagon-like peptide-1 functionalized PEG hydrogels

Lin, C.-C., Metters, A.T., & Anseth, K.S. (2009). Functional PEG-peptide hydrogels to

Liu, X.Y., Nothias, J.M., Scavone, A., Garfinkel, M., & Millis, J.M. (2010). Biocompatibility

Luan, N.M., Teramura, Y., & Iwata, H. (2011). Layer-by-layer co-immobilization of soluble

Lv, N., Song, M.Y., Kim, E.K., Park, J.W., Kwon, K.B., & Park, B.H. (2008). Guggulsterone, a

Meloche, R.M. (2007).Transplantation for the treatment of Type I diabetes. *World J.* 

Menger, F.M., Seredyuk, V.A., Kitaeva, M.V., Yaroslavov, A.A., & Melik-Nubarov, N.S.

Mørch, Y.A., Donati, I., Strand, B.L., & Skjåk-Braek, G. (2006). Effect of Ca2+, Ba2+, and Sr2+

Murdoch, T.B., Ghee-Wilson, D., Shapiro, A.M., & Lakey, J.R. (2004). Methods of human

Nafea E.H., Marson, A., Poole-Warren, L.A., & Martens, P.J. (2011). Immunoisolating semi-

Narang, A.S., & Mahato, R.I. (2006). Biological and biomaterial approaches for improved islet transplantation. *Pharmacol. Rev*. Vol.58, No.2, pp.194–243, ISSN 0031-6997 Nielsen, J.H. (1982). Effect of growth hormone, prolactin, and placental lactogen on insulin

Opara, E.C., Mirmalek-Sani, S.-H., Khanna, O., Moya, M.L., & Brey, E.M. (2010). Design of a

Panza, J.L., Wagner, W.R., Rilo, H.L., Rao, R.H., Beckman, E.J., & Russell, A.J. (2000).

islets. *Endocrinology*, Vol.110, No.2, pp.600-606, ISSN 0013-7227

*Gastroenterol*., Vol.13, No.47, pp.6347-6355, ISSN 1007-9327

*Release*, Vol.154, No.2, pp.110-122, ISSN 0168-3659

No.10, pp.2846-2847, ISSN 0002-7863

*Biomacromolecules*, Vol.10, No.9, pp.2460-2467, ISSN 1525-7797

alpha. *Biomaterials*, Vol.30, No.28, pp.4907-4914, ISSN 0142-9612

encapsulation. *ASAIO J*., Vol.56, No.3, pp.241-245, ISSN 1058-2916

6492, ISSN 1878-5905

0897-4756

7797

8267

pp.1155–1164, ISSN 0142-9612

0963-6897

promote survival and function of encapsulated pancreatic beta-cells.

modulate local inflammation induced by the pro-inflammatory cytokine TNF-

investigation of polyethylene glycol and alginate-poly-L-lysine for islet

complement receptor 1 and heparin on islets. *Biomaterials*, Vol.32, No.27, pp.6487-

plant sterol, inhibits NF-kappa B activation and protects pancreatic beta cells from cytokine toxicity. *Mol. Cell Endocrinol*., Vol.289, No.1–2, pp.49–59, ISSN 0303-7207 Martens, P., Blundo, J. Nilasaroya, A., Odell, R.A., Cooper-White, J., & Poole-Warren, L.A.

(2007). Effect of poly(vinyl alcohol) macromer chemistry and chain interactions on hydrogel mechanical properties. *Chem. Mater*, Vol.19, No.10, pp.2641-2648, ISSN

(2003). Migration of poly-L-lysine through a lipid bilayer. *J. Am. Chem. Soc*., Vol.125,

on alginate microbeads. *Biomacromolecules*, Vol.7, No.5, pp.1471-1480, ISSN 1525-

islet culture for transplantation. *Cell Transplant*., Vol.13, No.6, pp.605-617, ISSN

permeable membranes for cell encapsulation: Focus on hydrogels. *J. Controlled* 

content and release, and deoxyribonucleic acid synthesis in cultured pancreatic

bioartificial pancreas. *J. Investigative Medicine*, Vol.58, No.7, pp.831-837, ISSN 1708-

Treatment of rat pancreatic islets with reactive PEG. *Biomaterials,* Vol.21, No.11,


Encapsulation and Surface Engineering of Pancreatic Islets: Advances and Challenges 33

Thu, B., Bruheim, P., Espevik, T., Smidsrød, O., Soon-Shiong, P., & Skjåk-Braek, G. (1996).

Tierney, L. M., McPhee, S.J., & Papadakis, M.A. (2002). *Current medical diagnosis & treatment*.

Wang, R.N., & Rosenberg, L. (1999). Maintenance of beta-cell function and survival

Weber, L.M., & Anseth, K.S. (2008). Hydrogel encapsulation environments functionalized

Weber, L.M., Cheung, C.Y., & Anseth, K.S. (2007). Multifunctional pancreatic islet

Weber, L.M., Hayda, K.N., Haskins, K., & Anseth, K.S. (2007). The effects of cell-matrix

Weber, L.M., He, J., Bradley, B., Haskins, K., & Anseth, K.S. (2006). PEG-based hydrogels as

microenvironments. *Acta Biomaterialia*, Vol.2, No.1, pp.1-8, ISSN 1742-7061 Weber, L.M., Lopez, C.G., & Anseth, K.S. (2008). Effects of PEG hydrogel crosslinking

Wilson, J.T., & Chaikof, E.L. (2008). Challenges and emerging technologies in the

Wilson, J.T., Cui, W., & Chaikof, E.L. (2008). Layer-by-layer assembly of a conformal

Wilson, J.T., Cui, W., Kozlovskaya, V., Kharlampieva, E., Pan, D., Qu, Z., Krishnamurthy,

Wilson, J.T., Krishnamurthy, V.R., Cui, W., Qu, Z., & Chaikof, E.L. (2009). Noncovalent cell

Wolters, G.H.J., Fritschy, W.M., Gerrits, D., & Vanschilfagaarde, R. (1992). A versatile

Wyman, J.L., Kizilel, S., Skarbek, R., Zhao, X., Connors, M., Dillmore, W.S., Murphy, W.L.,

Vol.17, No.11, pp.1069-1079, ISSN 0142-9612

Vol.27, No.8, pp.667-673, ISSN 0945-053X

Vol.16, No.10, pp.1049-1057, ISSN 0963-6897

*Endocrinol*., Vol.163, No.2, pp.181-190, ISSN 0022-0795

*Mater. Res. A*, Vol.90, No.3, pp.720-729, ISSN 1549-3296

*Soc*., Vol.133, No.18, pp.7054-7064, ISSN 0002-7863

*Appl. Biomat*., Vol.3, No.4, 281-286. ISSN: 1045-4861

No.51, pp.18228-18229, ISSN 0002-7863

New York.

ISSN 0142-9612

145, ISSN 0169-409X

ISSN 1613-6810

pp.1940-1948, ISSN 1530-6984

Alginate polycation microcapsules. II. Some functional properties. *Biomaterials*,

(International edition), Large Medical Books/McGraw-Hill, ISBN: 007-1376-88-7,

following islet isolation requires re-establishment of the islet-matrix relationship. *J.* 

with extracellular matrix interactions increase islet insulin secretion. *Matrix Biology*,

encapsulationbarriers achieved via multilayer PEG hydrogels. *Cell Transplant*.,

interactions on encapsulated beta-cell function within hydrogels functionalized with matrix-derived adhesive peptides. *Biomaterials*, Vol.28, No.19, pp.3004-3011,

an in vitro encapsulation platform for testing controlled beta-cell

density on protein diffusion and encapsulated islet survival and function. *J. Biomed.* 

immunoisolation of cells and tissues. *Adv. Drug Deliv. Rev*., Vol.60, No.2, pp.124-

nanothin PEG coating for intraportal islet transplantation. *Nano Lett*., Vol.8, No.7,

V.R., Mets, J., Kumar, V., Wen, J., Song, Y., Tsukruk, V.V., & Chaikof, E.L. (2011). Cell surface engineering with polyelectrolyte multilayer thin films. *J. Am. Chem.* 

surface engineering with cationic graft copolymers. *J. Am. Chem. Soc*., Vol.131,

alginate droplet generator applicable for microencapsulation of pancreatic islets. *J.* 

Mrksich, M., Nagel, S.R., & Garfinkel, M.R. (2007). Immunoisolating pancreatic islets by encapsulation with selective withdrawal. *Small*, Vol.3, No.4, pp.683-690,


Schneider, S., & Klein, H.H. (2011). Preserved insulin secretion capacity and graft function of

Scott, M.D., & Murad, K.L. (1998). Cellular camouflage: fooling the immune system with polymers. *Curr. Pharm. Des.*, Vol. 4, No.6, pp.423–438, ISSN 1381-6128 Stabler, C.L., Sun, X.L., Cui, W., Wilson, J.T., Haller, C.A., & Chaikof, E.L. (2007). Surface re-

Stabler, C., Wilks, K., Sambanis, A., & Constantinidis, I. (2001). The effects of alginate

Stein, E., Mullen, Y., Benhamou, P.Y., Watt, P.C., Hober, C., Watanabe, Y., Nomura, Y., &

Stosic-Grujicic, S., Maksimovic, D., Badovinac, V., Samardzic, T., Trajkovic, V., Lukic, M., &

Strand, B.K., Ryan, L., Veld, P.I., Kulseng, B., Pokstad, A.M., Skjak-Braek, G., & Espevik, T.

cytokines. *Cell Transplant*., Vol.10, No.3, pp.263-277, ISSN 0963-6897 Su, J., Hu, B.H., Lowe, W.L.Jr., Kaufman, D.B., & Messersmith. P.B. (2010). Anti-

encapsulation. *Biomaterials*, Vol.31, No.2, pp.308-314, ISSN 0142-9612 Takemoto, N., Teramura, Y., & Iwata, H. (2011). Islet surface modification with urokinase

Tang, Z., Wang, Y., Podsiadlo, P., & Kotov, N.A. (2006). Biomedical Applications of Layer-

Teramura, Y., & Chen, H. (2010). Control of cell attachment through polyDNA hybridization. *Biomaterials*, Vol.31, No.8, pp.2229-2235, ISSN 0142-9612 Teramura, Y., & Iwata, H. (2008). Islets surface modification prevents blood-mediated

Teramura, Y., & Iwata, H. (2009). Islet encapsulation with living cells for improvement of biocompatibility. *Biomaterials*, Vol.30, No.12. pp.2270-2275, ISSN 0142-9612 Teramura, Y., Kaneda, Y., & Iwata, H. (2007). Islet-encapsulation in ultra-thin layer-by-layer

cell membrane. *Biomaterials,* Vol.28, No.32, pp.4818-4825, ISSN 0142-9612 Teramura, Y., Kaneda, Y., Totani, T., & Iwata, H. (2008). Behavior of synthetic polymers

Teramura, Y., & Minh, L. (2010). Microencapsulation of islets with living cells using

*Bioconjug. Chem*., Vol.18, No.6, pp.1713-1715, ISSN 1043-1802

C culture. *Transplant. Proc.,*Vol.26, No.2, pp.755, ISSN 0041-1345

*Autoimmun*. Vol.16, No.1, pp.47–58, ISSN 0896-8411

No.24, pp.3203-3224, ISSN 0935-9648

0167-0115

1802

1802

0142-9612

1043-1802

1310, ISSN 0142-9612

cryostored encapsulated rat islets. *Regul. Pept*., Vol.166, No.1-3, pp.135-138, ISSN

engineering of pancreatic islets with recombinant azido-thrombomodulin.

composition on encapsulated betaTC3 cells. *Biomaterials*, Vol.22, No.11, pp.1301-

Brunicardi, F.C. (1994). Reduction in immunogenicity of human islets by 24 degrees

Stojkovic, M.M. (2001). Antidiabetogenic effect of pentoxifylline is associated with systemic and target tissue modulation of cytokines and nitric oxide production. *J.* 

(2001). Poly-L-lysine induces fibrosis on alginate microcapsules via the induction of

inflammatory peptide-functionalized hydrogels for insulin-secreting cell

through DNA hybridization. *Bioconjug. Chem*., Vol.22, No.4, pp.673-678, ISSN 1043-

by-Layer Assembly: From Biomimetics to Tissue Engineering. *Adv. Mater*., Vol.18,

inflammatory responses. *Bioconjug. Chem*., Vol.19, No.7, pp.1389-1395, ISSN 1043-

membranes of poly(vinyl alcohol) anchored to poly(ethylene glycol)-lipids in the

immobilized on a cell membrane. *Biomaterials*, Vol.29, No.10, pp.1345-1355, ISSN

polyDNA-PEG-lipid conjugate. *Bioconjug. Chem*., Vol.21, No.4 pp.792-796, ISSN


**1. Introduction** 

and integration,.

much attention in recent years.

**2** 

Rong Jin

*P.R. China* 

**In-Situ Forming Biomimetic Hydrogels** 

Tissue loss or organ failure caused by injury or damage is one of the most serious and costly problems in human health care. Tissue engineering, proposed by Langer *et al.* in the early 1990's (Langer & Vacanti, 1993), is an emerging strategy of regenerative biomedicine that holds promise for the restoration of defect tissues and organs. The concept of tissue engineering is defined as "the application of the principles and methods of engineering and the life sciences towards the fundamental understanding of structure-function relationships in normal and pathological mammalian tissues and the development of biological substitutes that restore, maintain or improve tissue function" (Langer & Vacanti, 1993). In order to accomplish these goals by tissue engineering, three essential components are required, that is, cells for the generation of new tissues, scaffolds for supporting the cell growth and the regeneration of new tissues, and bioactive factors capable of stimulating biological signals *in vivo* for cell proliferation, dfferentiation and tissue growth. Among these, the scaffolds play an important role in the success of tissue regeneration since they serve as temporary temples to mimick the excellular matrix for cell growth and interim mechanical stability for tissue regneration

Hydrogels are one of most used bio-scaffolds in the field of tissue enginereering. They are three-dimensional, water-swollen, crosslinked networks of hydrophilic polymers. Wichterle and Lim for the first time reported on hydrogels based on the hydroxyethyl methacrylate (HEMA) for biological use in 1960 (Wichterle & Lim, 1960). Due to their unique tissue-like properties, such as high water content and good permeability to oxygen and metabolites, hydrogels have been widely studied as biomimetic extracellular matrixes for tissue regeneration. Hydrogels may be used by implantation or injection, which corresponds to socalled preformed hydrogels or in-situ forming hydrogels. From the clinical point of view, insitu forming hydrogels are highly desirable since they gain advantages over preformed hydrogels: (1) Enabling minimally invasive surgeries for implantation; (2) Formation in any desired shape in good alignment with surrounding tissue defects; (3) Easy encapsulation of bioactive molecules and progenic cells. Therefore, in-situ forming hydrogels have received

**for Tissue Regeneration** 

*Institute of Nanochemistry and Nanobiology,* 

*Shanghai University, Shanghai,* 

