A Time-Scheduled Oxygen Modulation System Facilitates Bone Regeneration by Powering Periosteal Stem Cells
Academic Background
During tissue repair, chronic hypoxia negatively impacts the functionality of stem cells. Periosteal Stem Cells (PSCs), as the primary contributors to bone repair, exhibit unclear behavior under hypoxic conditions. While hypoxia may be beneficial for certain stem cells in the early stages of tissue repair, prolonged hypoxia can induce apoptosis, thereby hindering bone regeneration. Therefore, developing a system capable of precisely modulating oxygen supply according to temporal demands is crucial for optimizing PSCs function and promoting bone regeneration.
This study aims to address the following questions:
1. Time-dependent effects of hypoxia on PSCs: When does hypoxia transition from beneficial to detrimental?
2. Development of an intelligent oxygen supply system: How to design a system that can remotely control oxygen release to counteract the negative effects of hypoxia on PSCs?
3. Synergistic effects of angiogenesis and bone regeneration: How to promote early angiogenesis through drugs (e.g., Pravastatin) to ensure continuous oxygen supply?
Source of the Paper
This study was conducted by a research team including Yujie Yang, Xue Gao, Yongfeng Zhang, and others from institutions such as the Fourth Military Medical University and Northwestern Polytechnical University. It was published in the journal Advanced Fiber Materials in 2025 and supported by the National Natural Science Foundation of China.
Research Process and Results
1. Time-dependent Effects of Hypoxia on PSCs
Research Process:
Researchers exposed PSCs to a hypoxic environment with 1% oxygen concentration and conducted tests at 12, 24, 36, 48, 60, and 72 hours. Using cell proliferation (CCK-8), cell cycle analysis, immunofluorescence staining (Ki67, TUNEL), and flow cytometry, they assessed the proliferation, apoptosis, and differentiation capabilities of PSCs under hypoxic conditions.
Results:
- Proliferation: PSCs exhibited significantly enhanced proliferation within 48 hours under hypoxia, but this ability gradually declined after 48 hours.
- Apoptosis: Hypoxia significantly increased the apoptosis rate of PSCs after 48 hours.
- Osteogenic differentiation: Hypoxia inhibited the osteogenic differentiation ability of PSCs, as evidenced by reduced alkaline phosphatase (ALP) activity and decreased expression of osteogenic markers (e.g., Runx2, Ocn).
Significance:
The 48-hour mark was identified as the critical time point when hypoxia transitions from beneficial to detrimental, providing a theoretical basis for the design of subsequent oxygen supply systems.
2. Development of an Intelligent Oxygen Supply System
Research Process:
Researchers designed a photothermal-sensitive coaxial fiber-reinforced membrane with a core of Perfluorotributylamine (PFTBA) and a shell of Polycaprolactone (PCL), coated with Polydopamine (PDA). This system uses near-infrared (NIR) light as a switch to initiate oxygen release 48 hours post-implantation to counteract the negative effects of hypoxia.
Results:
- Oxygen release: Under NIR irradiation, the PDA@O2 membrane significantly increased oxygen release, effectively alleviating hypoxia.
- Biocompatibility: The PDA@O2 membrane exhibited excellent biocompatibility, supporting the survival and proliferation of PSCs.
- Photothermal effect: NIR irradiation rapidly increased the membrane temperature, triggering rapid oxygen release.
Significance:
This system achieved remote control of oxygen release, offering new insights for the treatment of hypoxia-related diseases.
3. Pravastatin Promotes Angiogenesis and Bone Regeneration
Research Process:
Researchers encapsulated Pravastatin in PCL fibers to construct the PDA@O2/Pra membrane. In vitro experiments evaluated the effects of Pravastatin on human umbilical vein endothelial cells (HUVECs) and PSCs, while a rat calvarial defect model validated its in vivo efficacy.
Results:
- Angiogenesis: Pravastatin significantly promoted the migration and vessel formation of HUVECs and indirectly enhanced angiogenesis by upregulating VEGF secretion.
- Osteogenic differentiation: Pravastatin directly promoted the osteogenic differentiation of PSCs while also facilitating the formation of type H vessels by regulating Slit3 expression.
- In vivo experiments: Under NIR irradiation, the PDA@O2/Pra membrane significantly accelerated the repair of rat calvarial defects, with newly formed bone tissue exhibiting superior mineralization density and structural integrity compared to the control group.
Significance:
Pravastatin not only directly promoted angiogenesis and bone regeneration but also indirectly enhanced repair effects by modulating the paracrine function of PSCs.
Conclusion and Value
This study developed a time-scheduled oxygen modulation system that, through remote control of oxygen release and sustained Pravastatin release, effectively mitigated the negative effects of hypoxia on PSCs and promoted angiogenesis and bone regeneration. Its scientific value lies in revealing the time-dependent effects of hypoxia on PSCs and proposing an intelligent oxygen supply strategy based on photothermal effects. The application value is reflected in the system’s potential not only for bone regeneration but also for other hypoxia-related diseases and multi-tissue repair.
Research Highlights
- Identification of a critical time point: The study first identified the critical time (48 hours) when hypoxia transitions from beneficial to detrimental for PSCs.
- Intelligent oxygen supply system: Developed a photothermal-sensitive coaxial fiber membrane, enabling remote control of oxygen release.
- Multifunctional Pravastatin: Pravastatin directly promoted angiogenesis and bone regeneration while indirectly enhancing repair effects by modulating the paracrine function of PSCs.
- Innovative experimental design: Combined in vitro experiments and in vivo models to comprehensively validate the system’s efficacy and safety.
Additional Valuable Information
The success of this study provides important references for future development of personalized oxygen supply strategies, particularly in addressing tissue repair under complex pathological conditions such as aging, osteoporosis, and diabetes, offering broad application prospects.