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Cells are inherently sensitive to multiple chemical signals and topography of the external environment. However, conventional methods of making biomaterials only concern in mimicking the mechanical properties of tissues on the macroscopic level, without considering the nanoscopic details of the cell surface interface. The review paper (Stevens & George, 2005) seeks to explore the recent developments in nanoscale engineering of material surfaces to the regulation of cell fate and to better create biomimetic cellular environments.
Multiple chemical signals come from 3 different sources; ligands presented by the surrounding extracellular matrix (ECM), neighboring cells, and secreted signaling molecules, which stimulate intracellular signaling pathways leading to determination of cell fate. Together, the extrinsic signal creates a highly defined and specialized cell microenvironment essential for tissue development and function.
ECM has a variety of form depending on tissue types and stages of development. The diversity partly governs by Extracellular Matrix Proteins (ECM proteins), such as fibronectin and collagen. The multiple motifs of ECM proteins, encoded by specific amino acid sequences, are recognized and bound to specific cell transmembrane surface receptors, such as integrins, to trigger the intracellular signaling pathways leading to gene expression. Different cell types may respond differently to the same combination of these signals and may lead to differentiation, proliferation, further expression of ECM proteins, or the maintenance of survival signals to prevent apoptosis.
Engineering ECM ligands into the biomaterial surfaces greatly enhances cell behaviors. Ligand surface densities and binding affinities also influence diverse cellular responses (Palecek et al, 1997; Benoit et al, 2005; Kesolowsky et al, 2005). Precise spatial distribution of the motifs is also a determinant factor in cell behavior as 2D and 3D structures possess substantially different cellular response due to different patterns in integrin binding (Cukierman et al, 2001).
Nanoscale Engineering Surface
Nanoscale alterations in topography (surface landscape) of features such as grooves, ridges, steps and wells induce diverse cell behaviors such as changes in cell adhesion, cell orientation, cell proliferation, expression of antigens on cell surface and modulation of intercellular signaling pathways (Curtis & Wilkinson. 1999). The scale of topography (the size and depth of features from nanometer to micrometer range), and their symmetry are also responsible for different cell behaviors.
Simple modification of topography has already been shown to increase cellular response such as cell adhesion, cell differentiation and cell proliferation. Many approaches to incorporate biological signals into nanostructured scaffolds are capable of enhancing the functionality of biomaterials even further.
Potentially, naturally derived biopolymers are the best candidate for nanofiber scaffolds because they already possess the nanostructure and incorporated with ECM proteins. However, the extraction, processing and remodeling of these biopolymers have been proven challenging, and also there are regulatory issues over the direct use of animal-derived material in a medical setting.
Synthetic materials offer the alternative to the naturally-derived ones. One technique, electrospinning is used to produce fibers with diameter ranging from a few nanometers to micrometers which become basis for nanofibrous scaffolds. The 3D structures contain high porosity, high interconnectivity and controlled alignment of fibers to direct cell orientation and migration. The nanofibrous scaffolds produced by thermally induced phase separation technique have been shown to adsorb a wider spectrum and a greater quantity of integrin-binding proteins than do solid wall scaffolds.
Another approach to synthesize nano-sized polymers is to mimic the natural biopolymersââ‚¬â„¢ ability to self-assemble in multiple steps from the bottom up. This technique can produce thinner fibers when compared with electrospinning. One such example is amphiphilic self-assembling scaffold which uses molecules with thin hydrophobic tails and thick hydrophilic heads. In aqueous solution, hydrophobic tails form a core to shield themselves and assemble into extended nanocylinders. In bone regeneration, hydrophilic heads contain phosphorylated serine, encouraging hydroxyapatite nucleation and act like ECM motifs to aid bone cell adhesion and survival (Hartgerink et al, 2001). Effectively, the system mimics the natural process.
Cryptic Binding Site
ECM proteins may be hidden within cryptic binding site which become exposed when cleaved by enzyme proteases released by cells or mechanically distort during tissue damage. The revealed ligands give dynamic information to direct cell behavioral response. Recreating these dynamic mechanisms is challenging but proved to encourage cell invasions into artificial scaffolds (Lutolf et al, 2003). The proteolytic fragments released maybe biologically active to cell membrane receptors and further enhance cell proliferation within the scaffold.
Significance of paper at time of published
Third-generation biomaterials are materials with the abilities to activate gene expression or cellular response which will lead to gene expression (Hench & Polak, 2002). This illustrates that the idea has been around before the time of publishing of the review. Hench, applicable numbers of studies are available as was demonstrated in the review. This renders the review information dense and would have proven to be very significant in terms of giving the readers current situations during the time of publish.
Find out when biomaterials first studied. How far has it come up until 2005.
Errors and Improvement
Need more studies to confirm the ideas
How nanoscale topography modulates cell behaviors is still unclear. But some suggestions such as modulation of interfacial forces that guide cytoskeletal formation and membrane receptor organization in the cell, which in turn can modify intracellular signaling.
However, it undertakes and the studies usually focus on one factor at a time where in fact nature is much more complex.
3D structure of nanofibrous matrix.
ââ‚¬Å“Great disparity between the experimental approaches taken by different groups, making it difficult to compare data on nominally similar systemsââ‚¬Â
Being able to control the expression of ligands on ECM will greatly enhance the worthiness of this scaffold.
Topography alone is capable of augmenting different cellular response from the same cell phenotype shown by an experiment with smooth and modified topography on titanium surfaces by Anderson et al (2003). The uroepithelial cells had modified release of cytokine and chemokine in response to bacterial infection with the same surface chemistry. Yet how cells detect and respond to nanoscale topography is still unclear, but it is suggested that the interfacial forces that guide cytoskeleton formation and receptor organization, consequently lead to modulated intracellular signaling, are modified (Curtis et al, 2004).