Abstract
As life expectancy increases, the population experiences progressive ageing. Ageing, in turn, is connected to an increase in bone-related diseases (i.e., osteoporosis and increased risk of fractures). Hence, the search for new approaches to study the occurrence of bone-related diseases and to develop new drugs for their prevention and treatment becomes more pressing. However, to date, a reliable in vitro model that can fully recapitulate the characteristics of bone tissue, either in physiological or altered conditions, is not available. Indeed, current methods for modelling normal and pathological bone are poor predictors of treatment outcomes in humans, as they fail to mimic the in vivo cellular microenvironment and tissue complexity. Bone, in fact, is a dynamic network including differently specialized cells and the extracellular matrix, constantly subjected to external and internal stimuli. To this regard, perfused vascularized models are a novel field of investigation that can offer a new technological approach to overcome the limitations of traditional cell culture methods. It allows the combination of perfusion, mechanical and biochemical stimuli, biological cues, biomaterials (mimicking the extracellular matrix of bone), and multiple cell types. This review will discuss macro, milli, and microscale perfused devices designed to model bone structure and microenvironment, focusing on the role of perfusion and encompassing different degrees of complexity. These devices are a very first, though promising, step for the development of 3D in vitro platforms for preclinical screening of novel anabolic or anti-catabolic therapeutic approaches to improve bone health.
Highlights
The ageing of global population is increasing steadily, thanks to the progress in medicine and therapy
These are regulated by bone cells: the osteoblasts, that have a mesenchymal origin and that deposit collagen type I and the mineralized matrix; the osteocytes, the most differentiated form of osteoblasts, and that are embedded in the mineralized bone matrix; the osteoclasts, that have a hematopoietic origin, and that degrade bone via secretion of acid and proteolytic enzymes
High resolution live imaging Reproducibility Accurately mimic the effect of interstitial fluid flow Simulate mechanical stress at microscale level Possibility to model paracrine communication, cell-cell interaction, cell-extracellular matrix (ECM) interaction Possibility to combine multiple biochemical and biophysical stimuli to model complex biological phenomena Reduction of the amount of reagents and cells Small number of cells allow insertion patient tissue biopsies, or cells isolated from biopsies, that are available in small quantities
Summary
The ageing of global population is increasing steadily, thanks to the progress in medicine and therapy. The ECM allows the transmission of physical forces to the cell cytoskeleton via physical mechanotransduction, activating a signalling cascade, which affects cellular functions such as proliferation, migration, differentiation, and apoptosis (Sikavitsas et al, 2001; Mccoy and O’brien, 2010; Wittkowske et al, 2016) Among these mechanical strains, fluid shear stress is induced by interstitial perfusion, which, in turn, results from pressure gradients produced by vascular and hydrostatic pressure, and ca be induced by mechanical loading (Hillsley and Frangos, 1994; Mccoy and O’brien, 2010; Yao et al, 2012; Wittkowske et al, 2016; Yuste et al, 2021). We gave particular attention to the impact of perfusion on directing the chemical and physical behaviour of the models and on dictating biological processes
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