Multilayer vascular grafts based on collagen-mimetic proteins.

A major roadblock in the development of an off-the-shelf, small-caliber vascular graft is achieving rapid endothelialization of the conduit while minimizing the risk of thrombosis, intimal hyperplasia, and mechanical failure. To address this need, a collagen-mimetic protein derived from group A Streptococcus, Scl2.28 (Scl2), was conjugated into a poly(ethylene glycol) (PEG) hydrogel to generate bioactive hydrogels that bind to endothelial cells (ECs) and resist platelet adhesion. The PEG-Scl2 hydrogel was then reinforced with an electrospun polyurethane mesh to achieve suitable biomechanical properties. In the current study, initial evaluation of this multilayer design as a potential off-the-shelf graft was conducted. First, electrospinning parameters were varied to achieve composite burst pressure, compliance, and suture retention strength that matched reported values of saphenous vein autografts. Composite stability following drying, sterilization, and physiological conditioning under pulsatile flow was then demonstrated. Scl2 bioactivity was also maintained after drying and sterilization as indicated by EC adhesion and spreading. Evaluation of platelet adhesion, aggregation, and activation indicated that PEG-Scl2 hydrogels had minimal platelet interactions and thus appear to provide a thromboresistant blood contacting layer. Finally, evaluation of EC migration speed demonstrated that PEG-Scl2 hydrogels promoted higher migration speeds than PEG-collagen analogs and that migration speed was readily tuned by altering protein concentration. Collectively, these results indicate that this multilayer design warrants further investigation and may have the potential to improve on current synthetic options.

[1]  D. Keene,et al.  Assessment of prokaryotic collagen-like sequences derived from streptococcal Scl1 and Scl2 proteins as a source of recombinant GXY polymers , 2006, Applied Microbiology and Biotechnology.

[2]  Buddy D Ratner,et al.  The catastrophe revisited: blood compatibility in the 21st Century. , 2007, Biomaterials.

[3]  Heather A. Mitchell,et al.  Activated platelets induce Weibel-Palade-body secretion and leukocyte rolling in vivo: role of P-selectin. , 2005, Blood.

[4]  Y. Wang,et al.  Cell locomotion and focal adhesions are regulated by substrate flexibility. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[5]  J. Tomaszewski,et al.  Human saphenous vein allograft bypass grafts: immune response. , 1998, Journal of vascular surgery.

[6]  G. L’italien,et al.  Matched elastic properties and successful arterial grafting. , 1980, Archives of surgery.

[7]  E Bell,et al.  A blood vessel model constructed from collagen and cultured vascular cells. , 1986, Science.

[8]  S. Greenwald,et al.  Improving vascular grafts: the importance of mechanical and haemodynamic properties , 2000, The Journal of pathology.

[9]  Micah Dembo,et al.  Cell-cell mechanical communication through compliant substrates. , 2008, Biophysical journal.

[10]  R. Darling,et al.  Durability of femoropopliteal reconstructions. Endarterectomy versus vein bypass grafts. , 1972, American journal of surgery.

[11]  Burkel We The challenge of small diameter vascular grafts. , 1988 .

[12]  Lakeshia J Taite,et al.  Nitric oxide-producing polyurethanes. , 2005, Biomacromolecules.

[13]  R. Farndale,et al.  The Collagen-binding A-domains of Integrins α1β1 and α2β1Recognize the Same Specific Amino Acid Sequence, GFOGER, in Native (Triple-helical) Collagens* , 2000, The Journal of Biological Chemistry.

[14]  Sandip Sarkar,et al.  Critical parameter of burst pressure measurement in development of bypass grafts is highly dependent on methodology used. , 2006, Journal of vascular surgery.

[15]  Dougald M Monroe,et al.  Coagulation 2006: a modern view of hemostasis. , 2007, Hematology/oncology clinics of North America.

[16]  Shawn M. Sweeney,et al.  Angiogenesis in Collagen I Requires α2β1 Ligation of a GFP*GER Sequence and Possibly p38 MAPK Activation and Focal Adhesion Disassembly* , 2003, Journal of Biological Chemistry.

[17]  L A Geddes,et al.  Compliance, elastic modulus, and burst pressure of small-intestine submucosa (SIS), small-diameter vascular grafts. , 1999, Journal of biomedical materials research.

[18]  B. Lewis,et al.  Patency of cryopreserved saphenous vein grafts as conduits for coronary artery bypass surgery. , 1995, Chest.

[19]  P. Burger,et al.  Platelet P-selectin facilitates atherosclerotic lesion development. , 2003, Blood.

[20]  J. H. van Bockel,et al.  Saphenous vein versus PTFE for above-knee femoropopliteal bypass. A review of the literature. , 2004, European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery.

[21]  Jennifer L. West,et al.  Physiologic Pulsatile Flow Bioreactor Conditioning of Poly(ethylene glycol)-based Tissue Engineered Vascular Grafts , 2007, Annals of Biomedical Engineering.

[22]  G. Cherr,et al.  Use of Cryopreserved Femoral Vein for In Situ Replacement of Infected Femorofemoral Prosthetic Artery Bypass , 2008, Vascular and endovascular surgery.

[23]  D. Lyman,et al.  Effects of a vascular graft/natural artery compliance mismatch on pulsatile flow. , 1992, Journal of biomechanics.

[24]  M. Furman,et al.  Evaluation of platelet function by flow cytometry. , 2000, Methods.

[25]  H. Berman,et al.  Integrin-collagen complex: a metal-glutamate handshake. , 2000, Structure.

[26]  R. Sebra,et al.  Surface grafted antibodies: controlled architecture permits enhanced antigen detection. , 2005, Langmuir : the ACS journal of surfaces and colloids.

[27]  C. Bowman,et al.  Mechanical properties of hydrogels and their experimental determination. , 1996, Biomaterials.

[28]  A S Hoffman,et al.  Protein adsorption to poly(ethylene oxide) surfaces. , 1991, Journal of biomedical materials research.

[29]  R Langer,et al.  Functional arteries grown in vitro. , 1999, Science.

[30]  Jennifer L West,et al.  Tissue engineered small-diameter vascular grafts. , 2003, Clinics in plastic surgery.

[31]  Joe Tien,et al.  Repositioning of cells by mechanotaxis on surfaces with micropatterned Young's modulus. , 2003, Journal of biomedical materials research. Part A.

[32]  M. C. Rowland,et al.  Photolithographic patterning of polyethylene glycol hydrogels. , 2006, Biomaterials.

[33]  A. Hopfinger,et al.  The collagen-like triple helix to random-chain transition: experiment and theory. , 1972, Journal of molecular biology.

[34]  H Harasaki,et al.  eNOS-overexpressing endothelial cells inhibit platelet aggregation and smooth muscle cell proliferation in vitro. , 2000, Tissue engineering.

[35]  M. Detmar,et al.  The α1β1 and α2β1 Integrins Provide Critical Support for Vascular Endothelial Growth Factor Signaling, Endothelial Cell Migration, and Tumor Angiogenesis , 2002 .

[36]  M. Sefton,et al.  Effect of heparin-PVA hydrogel on platelets in a chronic canine arterio-venous shunt. , 1989, Journal of biomedical materials research.

[37]  G. Rubin,et al.  Coronary artery: quantitative evaluation of normal diameter determined with electron-beam CT compared with cine coronary angiography initial experience. , 2003, Radiology.

[38]  J. Hoxie,et al.  Changes in the platelet membrane glycoprotein IIb.IIIa complex during platelet activation. , 1985, The Journal of biological chemistry.

[39]  S. Bhatia,et al.  Three-Dimensional Photopatterning of Hydrogels Containing Living Cells , 2002 .

[40]  S. Milz,et al.  Autologous Endothelialized Vein Allograft: A Solution in the Search for Small-Caliber Grafts in Coronary Artery Bypass Graft Operations , 2001, Circulation.

[41]  Shelly R. Peyton,et al.  Extracellular matrix rigidity governs smooth muscle cell motility in a biphasic fashion , 2005, Journal of cellular physiology.

[42]  A Giudiceandrea,et al.  The Mechanical Behavior of Vascular Grafts: A Review , 2001, Journal of biomaterials applications.

[43]  B D Ratner,et al.  In vivo evaluation of artificial surfaces with a nonhuman primate model of arterial thrombosis. , 1980, The Journal of laboratory and clinical medicine.

[44]  Yi Hong,et al.  Fabrication of cell microintegrated blood vessel constructs through electrohydrodynamic atomization. , 2007, Biomaterials.

[45]  C. West,et al.  A biomechanical study of the human vertebral artery with implications for fatal arterial injury. , 2000, Forensic science international.

[46]  Byung-Soo Kim,et al.  Mechano-active tissue engineering of vascular smooth muscle using pulsatile perfusion bioreactors and elastic PLCL scaffolds. , 2005, Biomaterials.

[47]  Elliot L Chaikof,et al.  Elastin-mimetic protein polymers capable of physical and chemical crosslinking. , 2009, Biomaterials.

[48]  Stuart K. Williams,et al.  Migration of individual microvessel endothelial cells: stochastic model and parameter measurement. , 1991, Journal of cell science.

[49]  F A Auger,et al.  A completely biological tissue‐engineered human blood vessel , 1998, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[50]  Dany J. Munoz-Pinto,et al.  Impact of endothelial cells and mechanical conditioning on smooth muscle cell extracellular matrix production and differentiation. , 2009, Tissue engineering. Part A.

[51]  J. Porter,et al.  Antigenicity of Venous Allografts , 1979, Annals of surgery.

[52]  A. Mikos,et al.  Electrospinning of polymeric nanofibers for tissue engineering applications: a review. , 2006, Tissue engineering.

[53]  N. L'Heureux,et al.  Human tissue-engineered blood vessels for adult arterial revascularization , 2007, Nature Medicine.

[54]  S. Baldwin,et al.  Coagulation on biomaterials in flowing blood: some theoretical considerations. , 1997, Biomaterials.

[55]  D. Wagner,et al.  Pro-coagulant state resulting from high levels of soluble P-selectin in blood. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[56]  L. Niklason,et al.  Effect of pulse rate on collagen deposition in the tissue-engineered blood vessel. , 2003, Tissue engineering.

[57]  Larry V. McIntire,et al.  Effect of flow on polymorphonuclear leukocyte/endothelial cell adhesion , 1987 .

[58]  N. Lamba Polyurethanes in Biomedical Applications , 1997 .

[59]  A. Mikos,et al.  Platelet adhesion on a bioresorbable poly(propylene fumarate-co-ethylene glycol) copolymer. , 1999, Biomaterials.

[60]  J. Bujnicki,et al.  Streptococcal Scl1 and Scl2 Proteins Form Collagen-like Triple Helices* , 2002, The Journal of Biological Chemistry.

[61]  Dany J. Munoz-Pinto,et al.  Bioactive hydrogels based on Designer Collagens. , 2010, Acta biomaterialia.

[62]  M. Tuttle,et al.  Controlled release of water-soluble macromolecules from bioerodible hydrogels. , 1983, Biomaterials.

[63]  Jennifer H Elisseeff,et al.  Collagen mimetic peptide-conjugated photopolymerizable PEG hydrogel. , 2006, Biomaterials.

[64]  P. D. de Groot,et al.  Cell-collagen interactions: the use of peptide Toolkits to investigate collagen-receptor interactions. , 2008, Biochemical Society transactions.