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WIREs Nanomed Nanobiotechnol
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Self‐assembly in nature: using the principles of nature to create complex nanobiomaterials

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Self‐assembly is a ubiquitous process in biology where it plays numerous important roles and underlies the formation of a wide variety of complex biological structures. Over the past two decades, materials scientists have aspired to exploit nature's assembly principles to create artificial materials, with hierarchical structures and tailored properties, for the fabrication of functional devices. Toward this goal, both biological and synthetic building blocks have been subject of extensive research in self‐assembly. In fact, molecular self‐assembly is becoming increasingly important for the fabrication of biomaterials because it offers a great platform for constructing materials with high level of precision and complexity, integrating order and dynamics, to achieve functions such as stimuli‐responsiveness, adaptation, recognition, transport, and catalysis. The importance of peptide self‐assembling building blocks has been recognized in the last years, as demonstrated by the literature available on the topic. The simple structure of peptides, as well as their facile synthesis, makes peptides an excellent family of structural units for the bottom‐up fabrication of complex nanobiomaterials. Additionally, peptides offer a great diversity of biochemical (specificity, intrinsic bioactivity, biodegradability) and physical (small size, conformation) properties to form self‐assembled structures with different molecular configurations. The motivation of this review is to provide an overview on the design principles for peptide self‐assembly and to illustrate how these principles have been applied to manipulate their self‐assembly across the scales. Applications of self‐assembling peptides as nanobiomaterials, including carriers for drug delivery, hydrogels for cell culture and tissue repair are also described. WIREs Nanomed Nanobiotechnol 2013, 5:582–612. doi: 10.1002/wnan.1227 This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Implantable Materials and Surgical Technologies > Nanotechnology in Tissue Repair and Replacement Biology-Inspired Nanomaterials > Peptide-Based Structures

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An illustration showing the noncovalent interactions involved in supramolecular chemistry and their strength.
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In vivo studies showing the potential of self‐assembling peptides as regenerative biomaterials and their advanced testing stages toward clinical applications. (a) Bone regeneration mediated by a self‐assembling peptide nanofiber gel matrix that has the capacity to mineralize; A critical‐size (5 mm wide) defect (a1, a3 empty defect) in a rat femoral was treated with these gels (a2, a4); Microcomputed tomography analysis of the rat femurs after 4 weeks of gel implantation revealed the formation of new bone (a6, a8) when compared with empty defects (a5, a7). (Reprinted with permission from Ref . Copyright 2010 Elsevier) (b) Cartilage regeneration in a full thickness articular cartilage defect (microfracture rabbit model, b1) treated with a PA gel (b2) displaying a high density of binding epitopes to transforming growth factor β‐1 (TGFβ‐1) a growth factor known to maintain articular cartilage in the differentiated phenotype; Histological evaluation of cartilage samples 12 weeks after treatment with PA gels (b3), containing the TGFβ‐1 epitope (TGFBPA) with or even without the addition of exogenous growth factor, showed formation of hyaline‐like tissue within the defect space, as observed by the glycosaminoglycans (GAGs) and collagen II stainings. (Reprinted with permission from Ref . Copyright 2010 National Academy of Sciences, USA) (c) IKVAV PA promotes regeneration of sensory axons after spinal cord injury (SCI); Brightfield images of biotinylated dextran amine‐labeled tracts from IKVAV PA‐injected (c1), EQS PA (nonbioactive PA)‐injected (c2) and sham (c3) animals at 11 weeks postinjury; Sensory axon tracing (fibers through the lesion indicated by red arrows) was only observed in the IKVAV PA‐injected group and just up to and slightly into the lesion in EQS PA‐injected and sham groups; Approximately 55% of labeled dorsal column axons in the IKVAV PA group entered the lesion compared with only about 18% of the fibers in sham controls and less than 10% in EQS PA injected animals (c4). (Reprinted with permission from Ref . Copyright 2010 John Wiley and Sons, Inc.) (d) Nanofiber (NF) peptide (RAD16‐II) scaffolds with vascular endothelial growth factor (VEGF) create a microenvironment for cardiac repair; Immunostained images at myocardium border zone for each treated group at 28 h after myocardial infarction (MI) shows a higher number of newly generated cardiomyocyte‐like cells (GFP/cTnl+, small cells indicated by arrows and magnified in the inset images) derived from endogenous stem/progenitors cells in the animals treated with NF/VEGF that is favorable for induction of endogenous cardiomyocyte regeneration. (Reprinted with permission from Ref . Copyright 2012 AAAS)
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Examples of peptide hydrogels used for in vitro 3D cell culture and delivery of protein molecules. (a) Cell (human dermal fibroblasts) adhesion and morphology in Fmoc‐FF/Fmoc‐RGD (a1) and Fmoc‐FF/Fmoc‐RGE (a2) hydrogels; Cells are well spread in the Fmoc‐FF/Fmoc‐RGD hydrogels while in Fmoc‐FF/Fmoc‐RGE maintain a round morphology. Integrin (α5β1) blocking experiments proved direct interaction of the cells with RGD after 20 h (a3, a4). (Reprinted with permission from Ref . Copyright 2009 Elsevier) (b) Enzymatically degradable peptide hydrogels allows cleavage of self‐assembled peptide structures by specific enzymes, as visualized by cryo‐TEM images which show intact nanofibers of a multi‐domain peptide containing enzyme cleavage sites before (b1) and after incubation with MMP‐2 (b2) resulting in the disintegration of the nanofibrous network; The presence of a MMP‐2 cleavage site allows cell migration into the peptide hydrogels (b5, b6) whereas in nondegradable hydrogels green‐fluorescent cells remain as monolayer on top (b3, b4). (Reprinted with permission from Ref . Copyright 2010 American Chemical Society) (c) Effect of mechanical properties of self‐assembled peptide (Q11) hydrogels on the growth and proliferation of primary human umbilical vein endothelial cells (HUVECs) seeded on top of the gels; HUVECs were nearly confluent on the stiffer gels (c1, storage modulus G′ = 48 kPa) and expressed significantly higher levels of the cell–cell adhesion protein PECAM (CD31, expression of CD31 at cell–cell contacts is expected in normally functional endothelial cells) (c3) whereas on less stiffer gels (G′ = 10 kPa) cells are sparse and spindle‐shaped (C2) (green‐CD31, blue‐DAPI); (Reprinted with permission from Ref . Copyright 2008 Elsevier) (d) Two‐layered (d1) self‐assembling peptide (d2) nanofiber (d4) hydrogel (d3) for the long‐term sustained delivery of antibodies such as immunoglobulin G (d5). (Reprinted with permission from Ref . Copyright 2012 Elsevier)
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Advances in peptide self‐assembly have contributed to the generation of nanostructured biomaterials enabling their expansion into different applications in regenerative medicine.
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Examples of spontaneous self‐assembly in solution (a) and directed by external forces (b) or by a chemical/physical template (c). DSA can be used to guide the self‐assembly process and lead to specific orientation, alignment, ordering, or new microdomain structures. (b) DSA using energy (electric and magnetic fields, shear, temperature gradients). (c‐i) TSA on chemically patterned substrates. (c‐ii) Self‐assembly across the length scales, from nano to microscale. (c‐iii) TSA of a multi‐domain peptide in the presence of hyaluronic acid on topographically patterned soft substrate to fabricate freestanding thin membranes. (c‐iv) TSA using microfluidics (confined space) to precisely generate spherical capsular structures with monodispersed size.
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Length scales of the forces involved in self‐assembly (first panel) and the hierarchical complex structures generated by peptide self‐assembly (second panel). Spectroscopy and microscopy techniques used for structural characterization of peptide molecules and assemblies from the nanometer to centimeter length scales (third panel). NMR, nuclear magnetic resonance; X‐ray, X‐ray diffraction; CD, circular dichroism; AFM, atomic force microscopy; TEM, transmission electron microscopy; SEM, scanning electron microscopy.
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Examples of self‐assembling peptides with β‐sheet secondary structure: Molecular structure (a) of peptide building blocks, molecular graphics (b) showing their self‐assembly mechanism and TEM/AFM images (c) of corresponding self‐assembled nanostructures. (b‐i, c‐i: Reprinted with permission from Ref . Copyright 2005 National Academy of Sciences, USA; c‐ii: Reprinted with permission from Ref . Copyright 2010 National Academy of Sciences, USA; b‐iii, c‐iii: Reprinted with permission from Ref . Copyright 2009 American Chemical Society; b‐iv, c‐iv: Reprinted with permission from Ref . Copyright 2002 National Academy of Sciences; b‐iv: Reprinted with permission from Ref . Copyright 2002 Elsevier and Reprinted with permission from Ref . Copyright 2002 American Chemical Society; b‐vi, c‐vi: Reprinted with permission from Ref . Copyright 2013 American Chemical Society; b‐vii, c‐vii: Reprinted with permission from Ref . Copyright 2007 American Chemical Society; (b‐viii, c‐viii: Reprinted with permission from Ref . Copyright 2009 Elsevier)
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Examples of biological self‐assembled structures showing the building blocks and the relevant interactions involved in the self‐assembly process. (a) Protein folding; (b) ds‐DNA; (c) tobacco mosaic virus (TMV); and (d) cell membrane.
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Implantable Materials and Surgical Technologies > Nanotechnology in Tissue Repair and Replacement
Nanotechnology Approaches to Biology > Nanoscale Systems in Biology
Biology-Inspired Nanomaterials > Peptide-Based Structures

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