Biophysical Modulation of Mesenchymal Stem Cell Differentiation in the Context of Skeletal Repair

Abstract

A prominent feature of the skeleton is its ability to remodel in response to biophysical stimuli and to repair under varied biophysical conditions. This allows the skeleton considerable adaptation to meet its physiological roles of stability and movement. Skeletal cells and their mesenchymal precursors exist in a native environment rich with biophysical signals, and they sense and respond to those signals to meet organismal demands of the skeleton. While mechanical strain is the most recognized of the skeletal biophysical stimuli, signaling phenomena also include fluid flow, hydrostatic pressure, shear stress, and ion-movement-related electrokinetic phenomena including, prominently, streaming potentials. Because of the complex interactions of these electromechanical signals, it is difficult to isolate the significance of each. The application of external electrical and electromagnetic fields allows an exploration of the effects of these stimuli on cell differentiation and extra-cellular matrix formation in the absence of mechanical strain. This review takes a distinctly translational approach to mechanistic and preclinical studies of differentiation and skeletal lineage commitment of mesenchymal cells under biophysical stimulation. In vitro studies facilitate the examination of isolated cellular responses while in vivo studies permit the observation of cell differentiation and extracellular matrix synthesis.

Stimulation of Chondrogenesis in a Developmental Model of Endochondral Bone Formation by Pulsed Electromagnetic Fields

“…While in vitro studies of cells provide opportunities for studying detailed cell responses to physical stimuli, in vivo studies with developmental models, such as endochondral bone formation, permit the exploration of cell differentiation and signaling in systems that are translationally relevant to the physiological events of embryogenesis, skeletal growth, and fracture repair [ 1 ]. The developmental nature of endochondral bone formation permits the examination of the effects of PEMFs on the timing and magnitude of cell differentiation and ECM synthesis in both cartilage and bone.…”

“…The predictable cell biology of this model lends itself to exploration of the amplification and acceleration of the cell biology of endochondral bone formation by external stimuli. The DBM-EO model has been described many times, most recently in this journal [ 1 ]. In this model, the subcutaneous implantation of DBM granules along the ventral thoracic musculature results in a temporally consistent sequence of mesenchymal stem/stromal cell chemotaxis on days 2–4 after DBM implantation, chondrogenic differentiation by day 6–10, endochondral calcification on days 10–12, and ossification and progressive maturation to an ossicle with cortex, trabecular bone, and marrow elements by days 14–21 after DBM implantation ( Figure 5 ).…”

“…In turn, musculoskeletal tissues are responsive to the physical conditions in which they function and the tasks they have to perform. Notable characteristics of the skeleton are its responsiveness to physical stimuli and its ability to remodel in response to changing biophysical conditions, and thereby fulfill its physiological roles of stability and movement [ 1 ]. This is observed as homeostasis, hypertrophy, and atrophy ( Figure 1 ).…”

“…Skeletal cells at all stages in their development, including stem cells, osteoblasts, osteoclasts, and osteocytes, exist in micro- and macroenvironments extraordinarily rich in biophysical signaling and intercellular communication, facilitating precursor cell differentiation, coordinated osteoblastic and osteoclastic bone remodeling, and osteocyte responses as a functional syncytium to physiologic demands for calcium ( Figure 3 ). While the most recognizable biophysical force functioning in a signaling capacity is mechanical load, applied mechanical stresses are accompanied by strain-related secondary physical and chemical events that may also function as intracellular communication mechanisms, prominently including fluid flow, hydrostatic pressure, shear stress, and ion-movement-related electrokinetic phenomena, notably streaming potentials [ 1 ]. These strain-associated physical events are tightly interrelated, and therefore difficult to isolate.…”

Shape Memory Polyester Scaffold Promotes Bone Defect Repair through Enhanced Osteogenic Ability and Mechanical Stability

“…Moreover, bone repair would be promoted as the initial contact between the scaffold and surrounding tissue can be strengthened during the shape recovery process . Furthermore, mechanical stimuli would also be dynamically generated during the shape recovery process to the defect tissues, which can significantly enhance osteogenesis via mechanotransduction. , …”