Biological performance of mussel-inspired adhesive in extrahepatic islet transplantation.

There is significant need for effective medical adhesives that function reliably on wet tissue surfaces with minimal inflammatory insult. To address these performance characteristics, we have generated a synthetic adhesive biomaterial inspired by the protein glues of marine mussels. In-vivo performance was interrogated in a murine model of extrahepatic syngeneic islet transplantation, as an alternative to standard portal administration. The adhesive precursor polymer consisted of a branched poly(ethylene glycol) (PEG) core, whose endgroups were derivatized with catechol, a functional group abundant in mussel adhesive proteins. Under oxidizing conditions, adhesive hydrogels formed in less than 1 min from catechol-derivatized PEG (cPEG) solutions. Upon implantation, the cPEG adhesive elicited minimal acute or chronic inflammatory response in C57BL6 mice, and maintained an intact interface with supporting tissue for up to one year. In-situ cPEG adhesive formation was shown to efficiently immobilize transplanted islets at the epididymal fat pad and external liver surfaces, permitting normoglycemic recovery and graft revascularization. These findings establish the use of synthetic, biologically-inspired adhesives for islet transplantation at extrahepatic sites.

[1]  J. Waite,et al.  Polyphenolic Substance of Mytilus edulis: Novel Adhesive Containing L-Dopa and Hydroxyproline. , 1981, Science.

[2]  A. Rezania,et al.  Development of an ectopic site for islet transplantation, using biodegradable scaffolds. , 2005, Tissue engineering.

[3]  P. Vos,et al.  THE EFFICACY OF INTRAPERITONEAL PANCREATIC ISLET ISOGRAFTS IN THE REVERSAL OF DIABETES IN RATS , 1991, Transplantation.

[4]  E. Chaikof,et al.  Layer-by-layer assembly of a conformal nanothin PEG coating for intraportal islet transplantation. , 2008, Nano letters.

[5]  J Herbert Waite,et al.  Adhesion à la Moule1 , 2002, Integrative and comparative biology.

[6]  P. Messersmith,et al.  Rational design of transglutaminase substrate peptides for rapid enzymatic formation of hydrogels. , 2003, Journal of the American Chemical Society.

[7]  Akira Mochizuki,et al.  Model polypeptide of mussel adhesive protein. I. Synthesis and adhesive studies of sequential polypeptides (X-Tyr-Lys)n and (Y-Lys)n , 2000 .

[8]  Kristi S Anseth,et al.  Effects of PEG hydrogel crosslinking density on protein diffusion and encapsulated islet survival and function. , 2009, Journal of biomedical materials research. Part A.

[9]  O. Korsgren,et al.  Isolated Human Islets Trigger an Instant Blood Mediated Inflammatory Reaction: Implications for Intraportal Islet Transplantation as a Treatment for Patients with Type 1 Diabetes , 2000, Upsala journal of medical sciences.

[10]  Yu,et al.  Synthetic Polypeptide Mimics of Marine Adhesives. , 1998, Macromolecules.

[11]  Norbert F Scherer,et al.  Single-molecule mechanics of mussel adhesion , 2006, Proceedings of the National Academy of Sciences.

[12]  N. Barshes,et al.  islet transplantation: implications for intrahepatic grafts , 2022 .

[13]  E. Ryan,et al.  Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. , 2000, The New England journal of medicine.

[14]  R. van Schilfgaarde,et al.  Causes of limited survival of microencapsulated pancreatic islet grafts. , 2004, The Journal of surgical research.

[15]  Bruce P. Lee,et al.  Thermal gelation and tissue adhesion of biomimetic hydrogels , 2007, Biomedical materials.

[16]  J. Stockman,et al.  International Trial of the Edmonton Protocol for Islet Transplantation , 2008 .

[17]  Jing Wang,et al.  Co-polypeptides of 3,4-dihydroxyphenylalanine and L-lysine to mimic marine adhesive protein. , 2007, Biomaterials.

[18]  J. Waite,et al.  Cross-linking in adhesive quinoproteins: studies with model decapeptides. , 2000, Biochemistry.

[19]  Changsheng Liu,et al.  Development of mussel adhesive polypeptide mimics coating for in-situ inducing re-endothelialization of intravascular stent devices. , 2009, Biomaterials.

[20]  J. Hubbell,et al.  In Vitro and in Vivo Performance of Porcine Islets Encapsulated in Interfacially Photopolymerized Poly(Ethylene Glycol) Diacrylate Membranes , 1999, Cell transplantation.

[21]  D. Kaufman,et al.  In Vivo Bioluminescence Imaging of Transplanted Islets and Early Detection of Graft Rejection , 2006, Transplantation.

[22]  Jonathan J. Wilker,et al.  Simplified Polymer Mimics of Cross-Linking Adhesive Proteins , 2007 .

[23]  R. Munday,et al.  Relative importance of transport and alkylation for pancreatic beta-cell toxicity of streptozotocin , 2000, Diabetologia.

[24]  Bruce P. Lee,et al.  Synthesis and gelation of DOPA-modified poly(ethylene glycol) hydrogels. , 2002, Biomacromolecules.

[25]  D. Kaufman,et al.  The epididymal fat pad as a transplant site for minimal islet mass. , 2007, Transplantation.

[26]  Kent N Bachus,et al.  A water-borne adhesive modeled after the sandcastle glue of P. californica. , 2009, Macromolecular bioscience.

[27]  K. Anseth,et al.  Synthesis of immunoisolation barriers that provide localized immunosuppression for encapsulated pancreatic islets. , 2006, Bioconjugate chemistry.

[28]  A. Shapiro,et al.  Five-year follow-up after clinical islet transplantation. , 2005, Diabetes.

[29]  R. Bottino,et al.  Rapid loss of intraportally transplanted islets: an overview of pathophysiology and preventive strategies , 2007, Xenotransplantation.

[30]  Miaoer Yu,et al.  Role of l-3,4-Dihydroxyphenylalanine in Mussel Adhesive Proteins , 1999 .

[31]  A. Shapiro,et al.  Optimal implantation site for pancreatic islet transplantation , 2008, The British journal of surgery.

[32]  Youngro Byun,et al.  Functional and histological evaluation of transplanted pancreatic islets immunoprotected by PEGylation and cyclosporine for 1 year. , 2007, Biomaterials.

[33]  S. Burks,et al.  Hemostats, sealants, and adhesives: components of the surgical toolbox , 2008, Transfusion.

[34]  O. Korsgren,et al.  Neutrophilic granulocytes are the predominant cell type infiltrating pancreatic islets in contact with ABO‐compatible blood , 2005, Clinical and experimental immunology.

[35]  J. Ijzermans,et al.  The Choice of Anatomical Site for Islet Transplantation , 2008, Cell transplantation.

[36]  J. Waite,et al.  Polyphosphoprotein from the adhesive pads of Mytilus edulis. , 2001, Biochemistry.

[37]  Abner Louis Notkins,et al.  Immunologic and Genetic Factors in Type 1 Diabetes* , 2002, The Journal of Biological Chemistry.

[38]  K. Biemann,et al.  Hydroxyarginine-containing Polyphenolic Proteins in the Adhesive Plaques of the Marine Mussel Mytilus edulis(*) , 1995, The Journal of Biological Chemistry.