Prof. Haobo Pan, Deputy Director of Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Science and also the Director of Research Center for Human Tissues and Organs Degeneration. He has published more than 180 peer-reviewed articles and awarded more than 30 patents, in which 13 patents have been commercialized. He found the alkaline condition is particularly important to enhance bone formation, and thus developed borosilicate bioactive glass. In the meantime, he has developed Healtheme company for biomaterials commercialization.

Topic title: Borosilicate glass(BSG) sequentially modulates immunity, angiogenesis, and osteogenesis to facilitate critical bone defect repair

Abstract:

Introduction：

Treatment methods for pathological fractures arising from infections, tumors, or osteoporosis remain elusive and are a clinical dilemma.  The minimally invasive surgery is often used to insert an implant into the bone defect site to strengthen and fasten the fracture surface.  The success of this surgery heavily relies on the injectable biomaterials, with good syringeability, reasonable coagulation time, sufficient mechanical strength matching the adjacent bone, and their ability to induce new bone formation.  However, for pathological fractures, the bone healing process is delayed.  The imbalance between bone resorption and formation retards certain steps in bone remodeling, where inflammation prevents or delays the generation of new bone.  Therefore, modulation of inflammatory response is the first step in successfully repairing bone defects.

Bioactive glass (BG) can successfully repair bone fractures and defects due to cysts, tumors, and periodontal infections, and BGs can be doped with different elements, such as strontium, iron, copper, lithium, and manganese for different biological effects, such as immunomodulation, angiogenesis, and osteogenesis.  The degradation rate of borosilicate glass (BSG) with a dual network containing [BO3] and [SiO4] can be adjusted by changing the molar ratios of B and Si, which is important to match the degradation rate of the implant and the bone healing rate.  More importantly, BSGs have the potential to sequentially regulate inflammation, angiogenesis, and osteogenesis by releasing B, Sr, and Cu ions.

Methods：

As of now, the construction of new bone remains a challenge.  Recruitment and polarization of the macrophages from M1 to M2, vascularization, and activation of bone marrow stem cells are all essential in bone healing.  Therefore, injectable biomaterials should be designed and fabricated to regulate this process.  Considering the triple functions of Sr and Cu in modulating inflammation, angiogenesis, and osteogenesis, Sr/Cu-doped BSG bone cement was synthesized to not only reduce local inflammation but promote angiogenesis and osteogenesis.  Syringeability, coagulation time, biological activity, and biodegradability of the Sr/Cu-doped BSG bone cement were measured in vitro.  The modulation of RAW 264.7 macrophage polarization and the differentiation of human umbilical cord vein endothelial cells (HUVECs) and human bone marrow stem cells (hBMSCs) due to Sr and Cu ions release were also investigated in vitro.  The bone cement was implanted in a rat femoral condylar bone defect model for 3-28 days to observe short-term and early onset of the inflammatory response, angiogenesis, and osteogenesis.  The bone cement was also studied in a rabbit femoral condylar bone defect model for 8-16 weeks to observe the bone repair in the long term.

Results：

In this study, we designed bone cement comprised of strontium and copper-incorporated borosilicate glass (Sr/Cu-BSG) in the liquid phase of chitosan to modulate bone healing.  In vitro studies showed that the controlled release of Sr and Cu ions up-regulated anti-inflammatory genes(IL-1Ra and TGF-β) while down-regulating pro-inflammatory genes(IL-1β and IL-6) in macrophages at 3 days.  Sr and Cu ions also increased the expressions of angiogenic genes (VEGF and bFGF) in HUVECs at 5 days and osteogenic genes (Runx-2, OCN, and OPN) in hBMSCs at 7, 14, and 21 days.  5Sr3Cu-BSG bone cement exhibited the best anti-inflammatory, angiogenic, and osteogenic properties among the bone cement groups with different Sr and Cu ratios.  Short-term and long-term implantation of Sr/Cu-BSGs in femoral condylar bone defects of rats and rabbits confirmed the in vitro results, where the degradation rate of Sr/Cu-BSG matched the bone healing rate.  Similar to in vitro, the 5Sr3Cu-BSG group also showed the highest bone formation in vivo.  Excellent physical and chemical properties, along with its bone repairing ability, make the Sr/Cu-BSG bone cement a good candidate biomaterial for treating bone defects.

Conclusion：

Specifically, the Sr/Cu-BSG bone cement shows promise in starting bone repair for pathological fractures by correcting the imbalance between osteoblast and osteoclast activities in bone remodeling and avoiding persistent, chronic inflammation.