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WIREs Nanomed Nanobiotechnol
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Nanoscale surfacing for regenerative medicine

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Abstract Cells in most tissues reside in microenvironment surrounded with specific three‐dimensional features. The extracellular matrix or substratum with which cells interact often includes topography at the nanoscale. For example, the basement membrane of many tissues displays features of pores, fibers and ridges in the nanometer range. The nanoscale topography has significant effects on cellular behavior. Knowledge of the cell–substratum interactions is crucial to the understanding of many fundamental biological questions and to regenerative medicine. Rapid advances in nanotechnology enable cellular study on engineered nanoscale surfaces. Recent findings underscore the phenomenon that mammalian cells do respond to nanosized features on a synthetic surface. This review covers the commonly used techniques of engineering nanoscale surface and the techniques which have not been adapted but are of great potential in regenerative medicine, surveys the applications of nanoscale surface in regenerative medicine including vascular, bone, neural and stem cell tissue engineering, and discusses the possible mechanisms of cellular responses to nanoscale surface. A better understanding of the interactions between cells and nanoscale surfacing will help advance the field of regenerative medicine. WIREs Nanomed Nanobiotechnol 2010 2 478–495 This article is categorized under: Nanotechnology Approaches to Biology > Cells at the Nanoscale Implantable Materials and Surgical Technologies > Nanomaterials and Implants Implantable Materials and Surgical Technologies > Nanotechnology in Tissue Repair and Replacement

(a) Schematic illustration of the electrospinning process. Taylor cone (inset a) forms in an applied electric field and ejects fluid jet (inset b). The jet stream starts out in stable straight region (inset c), then becomes unstable, partly owing to charge repulsion, typically showing a whipping or spiralling motion.66 (Reproduced with permission from Ref 66. Copyright 2006 Annual Reviews). SEM micrographs of (b) randomly oriented polyvinylpyrrolidone (PVP) nanofibers, (c) aligned polycaprolactone nanofibers, (d) electrospun pseudowoven polyglycolic acid (PGA) (∼500 nm in diameter with spacing between fibers ranging from 7 to 10 um) mats with 30 layers alternating 0°/90° layup.67 (Reproduced with permission from Ref 67. Copyright 2008 American Chemical Society). (e) TiO2/PVP hollow fibers prepared by electrospinning a PVP solution that contained 0.5 g/ml of Ti(OiPr)4.68 (Reproduced with permission from Ref 68. Copyright 2004 American Chemical Society). (f) TiO2 tubes with the multichannels divided by a Y‐shape inner ridge.69 (Reproduced with permission from Ref 69. Copyright 2007 American Chemical Society).

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(a) Schematic of DPN. An alkanethiol ink‐coated AFM tip is brought into contact with a gold substrate. Molecules diffuse from the tip to the surface through or over a water meniscus and assemble in the wake of the tip path to form a stable nanostructure.31 (Reproduced with permission from Ref 31. Copyright 2007 Macmillan Publishers Ltd.). (b) Optical micrograph of a small portion of the 2D array of 55,000 AFM cantilevers in parallel used for patterning. The inset shows an SEM image of the tips. (c) SEM image of a portion of an 88,000,000 gold dot array (40 × 40 within each block) on an oxidized silicon substrate. On the right‐hand side is a representative AFM topographical image of part of a block.32 Scale bars: 100 µm. (Reproduced with permission from Ref 32. Copyright 2006 Wiley‐VCH Verlag GmbH & Co. KGaA).

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(a) AFM image of the template (a parallel 2D array of trenches that were 150 and 150 nm in width and depth, respectively, that was fabricated using near‐field optical lithography. (b) SEM micrograph of the linear chains that were formed by templating 150‐nm PS beads against the trenches shown in (b).37 (Reproduced with permission from Ref 37. Copyright 2001 American Chemical Society). (c) AFM image of 38 nm high nanoislands prepared by PS/PBrS demixing.39 (Reproduced with permission from Ref 39. Copyright 2007 Elsevier). (d) SEM micrograph of self‐assembled lines from PS‐b‐PMMA on resist patterns (PS = 57.5 nm). The averaged resist line widths are 10.4 nm.40 (Reproduced with permission from Ref 40. Copyright 2008 Wiley‐VCH Verlag GmbH & Co. KGaA). (e) SEM micrograph of 3D macroporous and nanofibrous poly(L‐lactic acid) (PLLA) scaffolds prepared from sugar fiber template leaching and phase separation.41 (Reproduced with permission from Ref 41. Copyright 2000 John Wiley & Sons, Inc.).

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Schematic illustration of conventional lithography techniques. (a) SEM micrograph of a mold with a 10 nm diameter pillar array fabricated with electron beam lithography (EBL). (b) SEM micrograph of hole arrays imprinted in poly(methylmethacrylate) (PMMA) by the such mold.11 (Reproduced with permission from Ref 11. Copyright 1997 American Institute of Physics). (c) SEM micrograph of a microcoil structure having a wire diameter of 80 nm with a 600 nm coil diameter and a 700 nm coil pitch.12 (Reprinted with permission from Ref 12. Copyright 2005 Wiley‐VCH Verlag GmbH & Co. KGaA).

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(a) Scanning electron micrograph (SEM) of a corneal epithelial basement membrane of Macaque monkey.6 (Reproduced with permission from Ref 6. Copyright 2000 Springer Science). (b) Transmission electron microscopy (TEM) image of dense collagen fibrillar matrices of the trabecular beam of a 75‐year‐old normal donor eye. The collagen network is spanned by the cross‐bridge of proteoglycans, at a periodicity of 60 nm (magnification = 66,430).7 (Reprinted with permission from Ref 7. Copyright 1992 Elsevier).

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SEM micrographs of the human corneal epithelial cell cultured on gratings with 400 nm pitch (a–c) and 4000 nm pitch (d and e). On patterns with 400 nm pitch, (a) cell aligned along nanostructured substrate, (b) cross‐sectional image of cell on patterned substrate, (c) filopodia extend along the top of ridges and bottom of grooves. Lamellipodia protrude into the grooves at the cell edge along the topographic patterns but bridge the grooves at the leading edge of the cell. On patterns with 4000 nm pitch, (d) cell aligned along microstructured substrate and (e) at the cell edges perpendicular to the patterns, lamellipodia were able to adhere to the floor of the grooves on 2100 nm wide grooves.115 (Reproduced with permission from Ref 115. Copyright 2003 Journal of Cell Science).

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Illustration of cell response to nanogratings. (a) The cell orients and elongates along the grating direction and (b)–(e) shows how the cell interact with the nanotopography.

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Nanotechnology Approaches to Biology > Cells at the Nanoscale
Implantable Materials and Surgical Technologies > Nanotechnology in Tissue Repair and Replacement
Implantable Materials and Surgical Technologies > Nanomaterials and Implants

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