Bone cell mechanobiology
Bone remodeling depends on changes in interstitial fluid pressure. Macroscopically, venous stasis or applied pressurization by external loading was associated with increased bone formation. However, there is limited understanding of the cellular level response to changes of fluid pressure in bone.
We are investigating the capacity of osteocytes to cyclic hydrostatic pressure, and low-magnitude, high-frequency vibrations loadings. By understanding the fundamental cellular mechanisms involving osteocyte mechanosensitivity, pharmaceutical agents and exercise regimens that control bone cell activity could be developed for novel treatments of detrimental bone diseases such as osteoporosis and osteopetrosis, designing tissue engineered bone implants, and enhancement of bone health.
Bone cell mechanobiology and angiogenesis
Osteocytes (OCYs) are believed to sense loading-induced fluid flow in their canaliculi network and transduce the signals to osteoclasts (OCs) and osteoblasts to regulate bone resorption and formation. In vivo studies have shown that bone disuse causes OCY apoptosis, which precedes OC activity at the local remodeling site. However, the specific mechanism by which osteoclast precursors (OCPs) are transported from the bone marrow to the site of remodeling in response to flow conditions is not clearly elucidated.
OCPs travel from the bone marrow to the local site of remodeling via blood vessels. In order for OCPs to reach the local site of remodeling, they must travel from the capillary across the Haversian canal to the adjacent bone lining surface. While bone capillaries are on average of 8 µm in diameter and human Haversian canals range from 30-170 µm in diameter5, OCPs would have to migrate unreasonable large distances to reach their destination. This suggests that without angiogenesis (local endothelial cell (EC) proliferation, migration and tubule formation) OCPs will have great difficulty reaching the targeted remodeling site. In this study, we examine the role of oscillatory fluid flow on OCY apoptosis and the downstream EC response to aid in the transport of OCPs. We hypothesize that OCY apoptosis is a flow-regulated process and that apoptotic OCYs will play a critical role in initiating and regulating angiogenesis to provide a conduit for OCP transport.
Microfluidic culturing systems for physiologically relevant mechanobiology
We designed a microfluidic co-culture chamber system that provides a well-controlled spatial and temporal gradient of soluble factors. Such a system overcomes the problem of half-life and decay of soluble proteins, which is often seen in conventional conditioned media studies. The microchamber system delivers oscillatory fluid flow (OFF) to mimic physiological mechanical loading conditions imposed on osteocytes.
Recent studies have indicated that the unique lacunar-canalicular structure, as well as the osteocytic processes extending from lacunar space to the canaliculi, played important roles in the mechanotransduction [3, 4]. However, the current 2-D cell culture is very different from the 3-D in vivo growth environment of ostoecytes. To provide an optimized 3-D scaffold for bone tissue, we employed soft lithography and hot embossing technique to construct a one-layer micro flow chamber-channel structure using biomaterial PLA. This structure has a basic chamber-channel feature that mimics the in vivo osteocytic lacunar-canalicular structure, which has been indicated as one of the key factors in the bone mechanotransduction
Breast Cancer Bone Metastasis
Breast cancer is the most common cancer in women worldwide. Approximately 70% of advanced breast cancer patients experience bone metastasis, which is the process of breast cancer cells (BCC) break away from the primary tumor, travel through the blood vessel and spread to the bone as a secondary site. BCC that invaded across the endothelial lining of blood vessel to the bone have devastating impacts on bone quality by interacting with bone cells to alter the bone remodeling process. Exercise, an often-used cancer intervention strategy, applies mechanical stimulation to bone and regulates bone remodeling process such that it could affect BCC bone metastasis. As the major mechanosensory cell in bone, osteocytes can be a key regulator. Advancements in microfluidic technology had allowed the construction of physiological relevant tumor microenvironment and rapid experimentation without expensive animal models. However, there lacks a microfluidic model to study mechanoregulation of breast cancer bone metastasis. We aim to develop a microfluidic model for studying mechanical regulation of breast cancer metastasis. This platform will enable us to study the effects of physiological relevant mechanical loading on osteocytes’ regulation of BCC metastasis, and to identify the specific mechanisms in which osteocytes regulate BCCs through. The development of this microfluidic platform will allow real-time signaling between osteocytes and BCCs in vascular lumen outside living animal models. Results from this study will elucidate the effects of bone mechanical loading on BCC metastasis and determine the key mechanisms involved in osteocytes’ regulation of BCC metastasis to bone. Consequently, this study will provide insight into the impact of exercise on bone metastasis and assist in breast cancer intervention strategies.