Abstract
The repair of critical bone defects remains challenging worldwide. Three canonical pillars (biomaterial scaffolds, bioactive molecules, and stem cells) of bone tissue engineering have been widely used for bone regeneration in separate or combined strategies, but the delivery of bioactive molecules has several obvious drawbacks. Biophysical stimuli have great potential to become the fourth pillar of bone tissue engineering, which can be categorized into three groups depending on their physical properties: internal structural stimuli, external mechanical stimuli, and electromagnetic stimuli. In this review, distinctive biophysical stimuli coupled with their osteoinductive windows or parameters are initially presented to induce the osteogenesis of mesenchymal stem cells (MSCs). Then, osteoinductive mechanisms of biophysical transduction (a combination of mechanotransduction and electrocoupling) are reviewed to direct the osteogenic differentiation of MSCs. These mechanisms include biophysical sensing, transmission, and regulation. Furthermore, distinctive application strategies of biophysical stimuli are presented for bone tissue engineering, including predesigned biomaterials, tissue-engineered bone grafts, and postoperative biophysical stimuli loading strategies. Finally, ongoing challenges and future perspectives are discussed.
Highlights
After trauma, bone tissue shows self-healing property, but this ability is limited for critical bone defects caused by serious injury, tumor excision, or other orthopedic diseases (Lopes et al, 2018)
These results suggest that the osteoinductive window of Low-intensity pulsed ultrasound (LIPUS) is primarily determined by duty cycle and intensity, and 20% duty cycle and 90–150 mW/cm2 intensity may be optimal for the osteogenic differentiation of mesenchymal stem cells (MSCs)
Mechanotransduction and electrocoupling have been separately proposed to interpret their molecular mechanisms. Considering that both signaling show high comparability and that they simultaneously occur in physiological microenvironment, we propose a new concept of biophysical transduction that integrates mechanotransduction and electrocoupling
Summary
Bone tissue shows self-healing property, but this ability is limited for critical bone defects (average diameter over 2 cm in humans) caused by serious injury, tumor excision, or other orthopedic diseases (Lopes et al, 2018). The delivery of bioactive molecules shows some limitations: 1) initial burst release, 2) declined biological activity, 3) high therapeutic dosage, and 4) potential side effects (Krishnan et al, 2017; Bertrand et al, 2020) Another pillar showing osteoinductive properties needs to be incorporated into bone tissue engineering for bone regeneration or bone healing. We first update the fourth pillar of bone tissue engineering as biophysical stimuli and summarize distinctive biophysical stimuli with their osteoinductive windows for MSC osteogenesis, including internal structural stimuli, external mechanical stimuli, and electromagnetic stimuli. This review aims to propose a novel and comprehensive concept that biophysical stimuli show potential to be used as the fourth pillar of bone tissue engineering
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