Sufficient oxygen is required to maintain normal cellular and physiological function, such as a creature’s development, breeding, and homeostasis. Lately, some researchers have reported that both pathological hypoxia and environmental hypoxia might affect bone health. Adaptation to hypoxia is a pivotal cellular event in normal cell development and differentiation and in pathological settings such as ischemia. As central mediators of homeostasis, hypoxia-inducible transcription factors (HIFs) can allow cells to survive in a low-oxygen environment and are essential for the regulation of osteogenesis and skeletal repair. From this perspective, we summarized the role of HIF-1 and HIF-2 in signaling pathways implicated in bone development and skeletal repair and outlined the molecular mechanism of regulation of downstream growth factors and protein molecules such as VEGF, EPO, and so on. All of these present an opportunity for developing therapies for bone regeneration.

Physiological microenvironment engineering has shown great promise in combating a variety of diseases. Herein, we present the rational design of reinforced and injectable blood-derived protein hydrogels (PDA@SiO2-PRF) composed of platelet-rich fibrin (PRF), polydopamine (PDA), and SiO2 nanofibers that can act as dual-level regulators to engineer the microenvironment for personalized bone regeneration with high efficacy. From the biophysical level, PDA@SiO2-PRF with high stiffness can withstand the external loading and maintaining the space for bone regeneration in bone defects. Particularly, the reinforced structure of PDA@SiO2-PRF provides bone extracellular matrix (ECM)-like functions to stimulate osteoblast differentiation via Yes-associated protein (YAP) signaling pathway. From the biochemical level, the PDA component in PDA@SiO2-PRF hinders the fast degradation of PRF to release autologous growth factors in a sustained manner, providing sustained osteogenesis capacity. Overall, the present study offers a dual-level strategy for personalized bone regeneration by engineering the biophysiochemical microenvironment to realize enhanced osteogenesis efficacy.

The repair of severe bone defects is still a formidable clinical challenge, requiring the implantation of bone grafts or bone substitute materials. The development of three-dimensional (3D) bioprinting has received considerable attention in bone tissue engineering over the past decade. However, 3D printing has a limitation. It only takes into account the original form of the printed scaffold, which is inanimate and static, and is not suitable for dynamic organisms. With the emergence of stimuli-responsive materials, four-dimensional (4D) printing has become the next-generation solution for biological tissue engineering. It combines the concept of time with three-dimensional printing. Over time, 4D-printed scaffolds change their appearance or function in response to environmental stimuli (physical, chemical, and biological). In conclusion, 4D printing is the change of the fourth dimension (time) in 3D printing, which provides unprecedented potential for bone tissue repair. In this review, we will discuss the latest research on shape memory materials and 4D printing in bone tissue repair.

Periodontitis is a chronic inflammatory condition triggered by oral bacteria. A sustained inflammatory state in periodontitis could eventually destroy the alveolar bone. The key objective of periodontal therapy is to terminate the inflammatory process and reconstruct the periodontal tissues. The traditional Guided tissue regeneration (GTR) procedure has unstable results due to multiple factors such as the inflammatory environment, the immune response caused by the implant, and the operator’s technique. Low-intensity pulsed ultrasound (LIPUS), as acoustic energy, transmits the mechanical signals to the target tissue to provide non-invasive physical stimulation. LIPUS has positive effects in promoting bone regeneration, soft-tissue regeneration, inflammation inhibition, and neuromodulation. LIPUS can maintain and regenerate alveolar bone during an inflammatory state by suppressing the expression of inflammatory factors. LIPUS also affects the cellular behavior of periodontal ligament cells (PDLCs), thereby protecting the regenerative potential of bone tissue in an inflammatory state. However, the underlying mechanisms of the LIPUS therapy are still yet to be summarized. The goal of this review is to outline the potential cellular and molecular mechanisms of periodontitis-related LIPUS therapy, as well as to explain how LIPUS manages to transmit mechanical stimulation into the signaling pathway to achieve inflammatory control and periodontal bone regeneration.

Strontium-containing agents have been demonstrated to elicit both bone anabolic and antiosteoporotic effects, showing great potential for the treatment of bone loss. However, an increased incidence of strontium-induced side effects restricts their clinical applications. Herein, oxidized carbon nitride nanosheets (CN) are delicately used to incorporate Sr2+ for the first time to achieve high osteogenic efficacy. The lamellar structure and enriched nitrogen species of CN provide them with a high surface area-to-volume ratio and abundant anchoring sites for Sr2+ incorporation. Importantly, Sr2+-incorporated CN (CNS) could synergistically promote osteoblast differentiation and bone regeneration at a single, very low Sr2+ dose. Mechanically, CNS could activate the FAK/RhoA signaling pathway to modulate the intracellular tension that stimulates osteoblasts differentiation. The present study will provide a new paradigm to enhance the efficacy of osteogenic metal ions by using lamellar nanocarriers.