The field of tissue engineering and regenerating medicine (TERM) is rapidly evolving with the overarching vision to provide better approaches for the development of personalized therapy for restoration of functionality of organs as well as the screening ex vivo for treatment options for different human diseases. Particularly, the concept of scaffold-guided tissue regeneration has been compelling. A scaffold can act as a porous tissue expander through the defect site, and as a carrier for localised delivery of cells/bioactive molecules to the injured site facilitating tissue regeneration and remodelling [1,2]. More specifically, at the tissue and cell scale, the ideal requirements for scaffolds include (a) appropriate mechanical support and stability while enabling sufficient mechanical stimulation for tissue formation and maturation, (b) being adequately porous with relevant pore size to allow tissue in-growth and vascularization, and (c) degradable at a rate that matches the tissue regeneration rate [1,3].

Over the years, studies have demonstrated the potential to tailor scaffold properties such as degradation rate and mechanical strength, by manipulation of scaffold geometry [2], biomaterial composition, and post-processing treatments, that allow for loading/ functionalization of scaffold surfaces with bioactive components to promote tissue (i.e., bone, cartilage, muscle, or neurons) formation [4]. Many studies have also demonstrated the effectiveness of scaffolds in vivo [5] and for clinical application [6]. Nonetheless, as more results emerge from in vivo studies, it has become apparent that scaffold-guided reparative responses vary considerably depending on animal age and disease comorbidity [6]. For example, a recent study by Reznikow et al. [7] demonstrated that even healthy animals (ovine) responded differently to different geometric scaffolds, with significantly enhanced bone regeneration in octetruss and orthogonal structures compared to stochastic ones. Hence, there is a growing need to understand the implications of the biophysical stimuli of scaffolds at a cellular level that propagates to the tissue and organ level, ultimately affecting the outcome of regeneration.

A major obstacle to investigating cell-biomaterial interface is the difficulty of studying cells in living tissues or 3D microenvironments. In recent years, development of hydrogels and scaffolds that mimic the physiological environment has allowed exploration of the role of 3D features in guiding mechanical signal transduction (3D mechanotransduction) and their downstream epigenetic status. Cell-to-scaffold interaction is governed by the mechanotransduction mechanism, driven by the capacity of cells to adhere to the substratum and react to its features by rearranging cytoskeletal elements and activation of mechanotransduction signalling pathways [8,9]. Thus, when cells are in contact with scaffold surfaces, the mechanical interplay is initiated by dynamic focal adhesion (vinculin, paxillin) or mechanosensitive ion channels leads to force transmission through the cytoskeleton to the nucleus and subsequent change in the composition of the nuclear envelope, nuclear morphology/ ‘stiffness’ and chromatin organization [10], [11], [12], [13]. Chromatin organisation of cells plays a pivotal role in regulating and maintaining cell-specific gene expression patterns. The distinct chromatic landscape of disparate cell types in a multicellular organism is tightly controlled by the cellular epigenomic landscape (i.e., chemical modification of DNA and histone proteins that modulate gene expression) including DNA methylation, histone modification and non-coding RNAs [14]. Moreover, a cell's epigenetic state and gene expression are dynamic and dependent on extracellular biophysical cues, such as biomaterial geometry and dimensionality. However, the epigenetic aspect is often overlooked in the biomaterial science field; much work is required to elucidate the environmental role of 3D dimensionality and geometry on mechanotransduction and epigenetics. The small number of reviews to date addressing biomaterials as an epigenetic factor to direct cellular mechanics and regeneration outcomes [15], [16], [17], [18] have focused mainly on 2D surfaces, or hydrogel's material properties. So far, there is a lack of mechanistic insight into mechanical and epigenetic responses of cells to 3D macro-geometrical cues.

In this review, we first explore mechanotransduction mechanisms and epigenetics before introducing the multi-scale geometry features that could be incorporated on scaffolds leveraging on additive manufacturing (AM) technology. How scaffold geometry has been leveraged to modulate the mechanotransduction mechanism will then be discussed, followed by a summary of a small number of current studies that demonstrate the correlation between 3D mechanotransduction and epigenetics.