Kevin Middleton's research while affiliated with University of Toronto and other places

... Osteocyte lacunae are thought to serve as strain amplifiers [10], leading to nearly 10 times higher strains at the lacunar wall than on the tibial surface because of the stress-concentrating effects [11]. In addition, osteocytes are potentially involved in controlling the calcium and phosphate balance between ECM and interstitial fluid by resorbing their pericellular bone mineral [12][13][14]. Recent findings suggest that the LCN architecture is the result of an interplay between cells and surrounding ECM, closely associated with mechanical loading and indicative of mechanobiological activities and diseases [15][16][17]. ...

... Mei et al presented a study which successfully reduced the ability of MDA-MB-231 breast cancer cells to extravasate into a bone microenvironment composed of osteocyte-like MLO-Y4 cells [111]. By integrating stimulatory bone fluid flow to stimulate the osteocytes, there was a significant reduction in extravasation of the breast cancer cells into the bone microenvironment. ...

... The development of tumor lesions is believed to be driven by the "vicious cycle" between tumors and OCs in the bone microenvironment [139,140]. Now, in vitro and in vivo studies suggest that additional players (Oys, stromal and endothelial cells in bone marrow) could be active participants in bone-cancer crosstalk [141][142][143]. Because Ocys are highly sensitive to mechanical stimulation, they provide a new angle to address the skeletal complications of cancer bone metastasis. ...

... While the current development in imaging systems provides direct evidence of cancer cell extravasation in mouse models, 145,162,163 the lack of a comprehensive understanding of the molecular mechanisms regulating cancer extravasation has hindered the successful targeting of this process by current anti-metastasis strategies. 164 The advancement of microfluidics provides a way for visualizing the process of in vitro extravasation and illuminating the underlying mechanisms [Figs. 3(e) and 3(f)]. ...

... Pioneering work by the You group showed using conditioned media experiments that mechanical stimulation of osteocytes can regulate the behaviour of breast cancer cells in vitro [24], both directly and via intermediate cells, such as endothelial cells [24]. Another recent in vitro study explored potential molecular mechanisms driving this behaviour, applying oscillatory fluid shear stress to osteocytes and finding that the resulting conditioned media enhance proliferation and migration of breast cancer cells with loading, identifying chemokine (C-X-C motif) ligand 1 and 2 (CXCL1 and CXCL2) as mediating the migration [19]. ...

... It was suggested that minimal level of Cx43 was sufficient for signaling molecules transmission, as there were others channel proteins at gap junctions [37]. [46,58,59]. These ions act as signals to be delivered to neighbouring cells through ion channels. ...

... Microfluidic OOCs have also been used in several bone physiology studies aiming to model bone cell migration [27], proliferation [65], and differentiation ( Figure 3E) [20,28], as well as osteocyteosteoclast (OC) crosstalk and mechanotransduction ( Figure 3F) [66]. Microfluidic OOCs give easy access to dynamic culture regimes, stimulating cells with physiological shear stress, the main vector of osteocyte signaling during mechanotransduction [67]. ...

... Micro and nanostructures amenable to non-contact manipulation using external driving fields receive increasing attention across the natural sciences as a consequence of the possibility to generate novel fundamental understandings of mesoscopic phenomena 1,2 and the possibility for novel applications within areas such as biomedicine [3][4][5] , material delivery 6 , and micro/nanomechanical systems [7][8][9] . For example, remotely actuated microstructures have been used to emulate the behavior of biological microorganisms 10,11 while synthetic microstructures operated as untethered micromechanical tools have been explored as micropumps 12 , microgrippers 13,14 , and hydrodynamic propulsion systems 15,16 . ...

... Stress shielding is the loss of bone density caused by an implant removing the usual stress of the bone [19]. This is due to Wolff's law, which states that bone in a healthy human or animal will rebuild in response to the pressures imposed on it [20]. Implants that are too rigid affect the distribution of stresses in the connected bone. ...