As materials technology and the field of biomedical engineering advances, the role of cellular mechanisms, in particular adhesive interactions with implantable devices, becomes more relevant in both research and clinical practice. A key tenet of medical device design has evolved from the exquisite ability of biological systems to respond to topographical features or chemical stimuli, a process that has led to the development of next-generation biomaterials for a wide variety of clinical disorders. In vitro studies have identified nanoscale features as potent modulators of cellular behavior through the onset of focal adhesion formation. The focus of this review is on the recent developments concerning the role of nanoscale structures on integrin-mediated adhesion and cellular function with an emphasis on the generation of medical constructs with regenerative applications. KeywordsFocal adhesions; Biomaterials; Nanotopography; Cell signaling This review highlights the importance and development of the physiomechanical processes that regulate early cell-biomaterial interactions and the influence of nanoscale topographical modification on integrin-mediated cellular adhesion. As materials technology and the field of tissue engineering advance, the role of cellular adhesive mechanisms, in particular the interactions with implantable materials, becomes more relevant in both research and clinical practice.Biomaterials are never truly inert, being at best biotolerable. The cell-substratum interface functions as more than a simple boundary of definition between the host and an implanted device; instead, it presents primary cues for cellular adhesion and the subsequent induction of tissue integration. Indeed, the cytocompatibility of a material can be assessed in vitro by observing the viability and biofunctionality of cells at the substratum interface, paving the way for in vivo studies into device functionality. The range of materials currently designated as biomedically useful and their lack of biofunctionality reflects an increasing need for biomimetic constructs but also indicates the challenges present within the field. In particular a need exists to create truly biocompatible devices and ultimately to control the interactions that occur at the cell-substratum interface.A key tenet of medical device design has evolved from the exquisite ability of biological systems to respond to topographical features or chemical stimuli, a process that has led to the NIH Public Access Author ManuscriptNanomedicine. Author manuscript; available in PMC 2010 October 28. Published in final edited form as:Nanomedicine. 2010 October ; 6(5): 619-633. doi:10.1016/j.nano.2010.01.009. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript development of next-generation biomaterials. Recently published in the journal Science are the prerequisites for third generation biomaterials; not only should they support the healing site (as first-generation biomaterials), but they should be bioactive and possibly biodegradable...

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Stem cells have the capacity to differentiate into various lineages, and the ability to reliably direct stem cell fate determination would have tremendous potential for basic research and clinical therapy. Nanotopography provides a useful tool for guiding differentiation, as the features are more durable than surface chemistry and can be modified in size and shape to suit the desired application. In this paper, nanotopography is examined as a means to guide differentiation, and its application is described in the context of different subsets of stem cells, with a particular focus on skeletal (mesenchymal) stem cells. To address the mechanistic basis underlying the topographical effects on stem cells, the likely contributions of indirect (biochemical signal-mediated) and direct (force-mediated) mechanotransduction are discussed. Data from proteomic research is also outlined in relation to topography-mediated fate determination, as this approach provides insight into the global molecular changes at the level of the functional effectors.

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Polymeric medical devices widely used in orthopedic surgery play key roles in fracture fixation and orthopedic implant design. Topographical modification and surface micro-roughness of these devices regulate cellular adhesion, a process fundamental in the initiation of osteoinduction and osteogenesis. Advances in fabrication techniques have evolved the field of surface modification; in particular, nanotechnology has allowed the development of nanoscale substrates for the investigation into cell-nanofeature interactions. In this study human osteoblasts (HOBs) were cultured on ordered nanoscale pits and random nano "craters" and "islands". Adhesion subtypes were quantified by immunofluorescent microscopy and cell-substrate interactions investigated via immuno-scanning electron microscopy. To investigate the effects of these substrates on cellular function 1.7 k microarray analysis was used to establish gene profiles of enriched STRO-1+ progenitor cell populations cultured on these nanotopographies. Nanotopographies affected the formation of adhesions on experimental substrates. Adhesion formation was prominent on planar control substrates and reduced on nanocrater and nanoisland topographies; nanopits, however, were shown to inhibit directly the formation of large adhesions. STRO-1+ progenitor cells cultured on experimental substrates revealed significant changes in genetic expression. This study implicates nanotopographical modification as a significant modulator of osteoblast adhesion and cellular function in mesenchymal populations.

The surface microtexture of an orthopaedic device can regulate cellular adhesion, a process fundamental in the initiation of osteoinduction and osteogenesis. Advances in fabrication techniques have evolved to include the field of surface modification; in particular, nanotechnology has allowed for the development of experimental nanoscale substrates for investigation into cell nanofeature interactions. Here primary human osteoblasts (HOBs) were cultured on ordered nanoscale groove/ridge arrays fabricated by photolithography. Grooves were 330 nm deep and either 10, 25 or 100 mm in width. Adhesion subtypes in HOBs were quantified by immunofluorescent microscopy and cell-substrate interactions were investigated via immunocytochemistry with scanning electron microscopy. To further investigate the effects of these substrates on cellular function, 1.7 K gene microarray analysis was used to establish gene regulation profiles of mesenchymal stem cells cultured on these nanotopographies. Nanotopographies significantly affected the formation of focal complexes (FXs), focal adhesions (FAs) and supermature adhesions (SMAs). Planar control substrates induced widespread adhesion formation; 100 mm wide groove/ridge arrays did not significantly affect adhesion formation yet induced upregulation of genes involved in skeletal development and increased osteospecific function; 25 mm wide groove/ridge arrays were associated with a reduction in SMA and an increase in FX formation; and 10 mm wide groove/ridge arrays significantly reduced osteoblast adhesion and induced an interplay of up -and downregulation of gene expression. This study indicates that groove/ridge topographies are important modulators of both cellular adhesion and osteospecific function and, critically, that groove/ridge width is important in determining cellular response.

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