A microphysiological system for studying human bone biology under simultaneous control of oxygen tension and mechanical loading.

Throughout life, continuous remodelling is part of human bone biology and depends on the simultaneous action of physicochemical parameters such as oxygen tension and varying mechanical load. Thus, suitable model systems are needed, which allow concomitant modulation of these factors to recapitulate in vivo bone formation. Here, we report on the development of a first microphysiological system (MPS) that enables perfusion, environment-independent regulation of the oxygen tension as well as precise quantification and control of mechanical load. To demonstrate the use of the MPS for future studies on the (patho-)biology of bone, we built a simplified 3D model for early de novo bone formation. Primary human osteoblasts (OBs), which are the key players during this process, were seeded onto type I collagen scaffolds and cultured in the MPS. We could not only monitor cell viability and metabolism of OBs under varied physicochemical conditions, but also visualise the mineralisation of the extracellular matrix. In summary, we present a MPS that uniquely combines the independent control of physicochemical parameters and allows investigation of their influence on bone biology. We consider our MPS highly valuable to gain deeper insights into (patho-)physiological processes of bone formation in the future.

Reinventing the Penumbra - the Emerging Clockwork of a Multi-modal Mechanistic Paradigm.

The concept of the ischemic penumbra was originally defined as the area around a necrotic stroke core and seen as the tissue at imminent risk of further damage. Today, the penumbra is generally considered as time-sensitive hypoperfused brain tissue with decreased oxygen and glucose availability, salvageable tissue as treated by intervention, and the potential target for neuroprotection in focal stroke. The original concept entailed electrical failure and potassium release but one short of neuronal cell death and was based on experimental stroke models, later confirmed in clinical imaging studies. However, even though the basic mechanisms have translated well, conferring brain protection, and improving neurological outcome after stroke based on the pathophysiological mechanisms in the penumbra has yet to be achieved. ï»¿Recent findings shape the modern understanding of the penumbra revealing a plethora of molecular and cellular pathophysiological mechanisms. We now propose a new model of the penumbra, one which we hope will lay the foundation for future translational success. We focus on the availability of glucose, the brain's central source of energy, and bioenergetic failure as core pathophysiological concepts. We discuss the relation of mitochondrial function in different cell types to bioenergetics and apoptotic cell death mechanisms, autophagy, and neuroinflammation, to glucose metabolism in what is a dynamic ischemic penumbra.