In recent years, bone tissue engineering has emerged as a promising solution to the limitations of current gold standard treatment options for bone related-disorders such as bone grafts. Bone tissue engineering provides a scaffold design that mimics the extracellular matrix, providing an architecture that guides the natural bone regeneration process. During this period, a new generation of bone tissue engineering scaffolds has been designed and characterized that explores the incorporation of signaling molecules in order to enhance cell recruitment and ingress into the scaffold, as well as osteogenic differentiation and angiogenesis, each of which is crucial to successful bone regeneration. Here, we outline and critically analyze key characteristics of successful bone tissue engineering scaffolds. We also explore candidate materials used to fabricate these scaffolds. Different growth factors involved in the highly coordinated process of bone repair are discussed, and the key requirements of a growth factor delivery system are described. Finally, we concentrate on an analysis of scaffold-based growth factor delivery strategies found in the recent literature. In particular, the incorporation of two-phase systems consisting of growth factor-loaded nanoparticles embedded into scaffolds shows great promise, both by providing sustained release over a therapeutically relevant timeframe and the potential to sequentially deliver multiple growth factors.

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We systematically reviewed the currently available evidence on how the design parameters of surface nanopatterns (e.g. height, diameter, and interspacing) relate to their bactericidal behavior. The systematic search of the literature resulted in 46 studies that satisfied the inclusion criteria of examining the bactericidal behavior of nanopatterns with known design parameters in absence of antibacterial agents. Twelve of the included studies also assessed the cytocompatibility of the nanopatterns. Natural and synthetic nanopatterns with a wide range of design parameters were reported in the included studies to exhibit bactericidal behavior. However, most design parameters were in the following ranges: heights of 100-1000 nm, diameters of 10-300 nm, and interspacings of <500 nm. The most commonly used type of nanopatterns were nanopillars, which could kill bacteria in the following range of design parameters: heights of 100-900 nm, diameters of 20-207 nm, and interspacings of 9-380 nm. The vast majority of the cytocompatibility studies (11 out of 12) showed no adverse effects of bactericidal nanopatterns with the only exception being nanopatterns with extremely high aspect ratios. The paper concludes with a discussion on the evidence available in the literature regarding the killing mechanisms of nanopatterns and the effects of other parameters including surface affinity of bacteria, cell size, and extracellular polymeric substance (EPS) on the killing efficiency. Statement of significance The use of nanopatterns to kill bacteria without the need for antibiotics represents a rapidly growing area of research. However, the optimum design parameters to maximize the bactericidal behavior of such physical features need to be fully identified. The present manuscript provides a systematic review of the bactericidal nanopatterned surfaces. Identifying the effective range of dimensions in terms of height, diameter, and interspacings, as well as covering their impact on mammalian cells, has enabled a comprehensive discussion including the bactericidal mechanisms and the factors controlling the bactericidal efficiency. Overall, this review helps the readers have a better understanding of the state-of-the-art in the design of bactericidal nanopatterns, serving as a design guideline and contributing to the design of future experimental studies.

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