**4. Outlook and perspective**

Though pancreatic islet transplantation has emerged as a promising treatment for diabetes, its clinical application, however, remains limited due to serious side effects of immunosuppressive therapy necessary to prevent host rejection of transplanted islets.

Encapsulation and Surface Engineering of Pancreatic Islets: Advances and Challenges 25

The work was supported by Award #P30EB011319 from the National Institute of Biomedical

Abalovich, A., Jatimliansky, C., Diegex, E., Arias, M., Altamirano, A., Amorena, C.,

Agudelo, C.A., & Iwata, H. (2008).The development of alternative vitrification solutions for microencapsulated islets. *Biomaterials*, Vol.29, No.9, pp.1167-1176, ISSN 0142-9612 Amiji, M., & Park, K. (1993). Surface modification of polymeric biomaterials with

Basta, G., Sarchielli, P., Luca, G., Racanicchi, L., Nastruzzi, C., Guido, L., Mancuso, F.,

Beattie, G. M., Montgomery, A.M.P., Lopez, A.D., Hao, E., Perez, B., Just, M.L., Lakey, J.R.T.,

Beck, J., Angus, R., Madsen, B., Britt, D., Vernon, B., & Nguyen, K.T. (2007). Islet

Bennet, W., Sundberg, B., Groth, C.G., Brendel, M.D., Brandhorst, D., Brandhorst, H.,

Berg, M.C., Yang, S.Y., Hammond, P.T., Rubner, M.F. (2004). Controlling mammalian cell

Bieber, T., Meissner, W., Kostin, S., Niemann, A., & Elsasser, H.P. (2002). Intracellular route

Bünger C.M., Gerlach, C., Freier, T., Schmitz, K.P., Pilz, M., Werner, C., Jonas, L., Schareck,

Martinez, B., & Nacucchio, M. (2001). Pancreatic islets microencapsulation with polylactide-co-glycolide. *Transplant. Proc*., Vol.33, No.1-2, pp.1977–1979, ISSN 0041-

poly(ethylene oxide), albumin, and heparin for reduced thrombogenicity. *Journal of Biomaterials Science - Polymer Edition*., Vol.4, No.3, pp. 217-234, ISSN 0920-5063 Barani, L., Vasheghani-Farahani, E., Lazarjani, H.A., Hashemi-Najafabadi, S., & Atyabi, F.

(2010). Effect of molecular mass of methoxypoly(ethylene glycol) activated with succinimidyl carbonate on camouflaging pancreatic islets. *Biotechnol. Appl. Biochem*.,

Macchiarulo, G., Calabrese, G., Brunetti, P., & Calafiore, R. (2004). Optimized parameters for microencapsulation of pancreatic islet cells: an in vitro study clueing on islet graft immunoprotection in type 1 diabetes mellitus. *Transpl. Immunol*.,

Hart, M.E., & Hayek, A. (2002). A novel approach to increase human islet cell mass while preserving beta-cell function. *Diabetes*, Vol.51, No.12, pp.3435-3439, ISSN

Encapsulation: Strategies to enhance islet cell functions. *Tissue Eng.,* Vol.13, No.3,

Bretzel, R.G., Elgue, G., Larsson, R., Nilsson, B., & Korsgren, O. (1999). Incompatibility between human blood and isolated islets of Langerhans: a finding with implications for clinical intraportal islet transplantation? *Diabetes*, Vol.48,

interactions on patterned polyelectrolyte multilayer surfaces. *Langmuir,* Vol.20,

and transcriptional competence of polyethylenimine-DNA complexes. *J. Control.* 

W., Hopt, U.T., & De Vos, P. (2003). Biocompatibility and surface structure of chemically modified immunoisolating alginate-PLL capsules*. J. Biomed. Mater. Res.* 

**5. Acknowledgment** 

**6. References** 

1345

0012-1797

pp.589-599, ISSN 1076-3279

No.10, pp.1907-1914, ISSN 0012-1797

No.4, pp.1362–1368, ISSN 0743-7463

*Release*, Vol.82, No.2-3, pp.441-454, ISSN 0168-3659

*A*, Vol.67, No.4, pp.1219-1227, ISSN 1549-3296

Imaging and Bioengineering at NIH.

Vol.57, No.1, pp.25-30, ISSN 0885-4513

Vol.13, No.4, pp.289-296, ISSN 0966-3274

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 surfaces, which can interfere with cell function.

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 islets.

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

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 viability and functions.
