Advances in the Modification of Injectable Calcium-Phosphate-Based Bone Cements for Clinical Application
The field of bone defect repair has seen significant advancements with the development of bioactive bone replacement materials. Traditional methods such as autografts, allografts, and xenografts, while widely used, come with inherent limitations including limited supply, excessive damage to donor sites, constrained growth, and high complication rates. Injectable bone scaffold materials have emerged as a promising alternative, particularly in orthopedics and dentistry. Among these, calcium-phosphate-based bone cements (CPCs) have garnered substantial attention due to their chemical similarity to the inorganic components of bone, promoting natural bone ingrowth and remodeling.
CPCs mimic the mineral phase of bone, creating a natural lattice that facilitates bone tissue integration. Compared to polymethylmethacrylate (PMMA) cements, CPCs exhibit a lower exothermic reaction temperature and superior osteointegration, making them highly promising for bone repair applications. However, CPCs are not without limitations. Their slow degradation rate and lack of macroporosity hinder sufficient osteoinduction for clinical needs. Additionally, their mechanical strength falls short of that of human cortical bone, necessitating further research into modification strategies.
One approach to enhancing CPCs involves fabricating porous or nanostructured CPC composites and incorporating drug delivery systems to promote bone growth. For osteoporotic patients, modifications aim to promote the differentiation of bone marrow mesenchymal stem cells (BMSCs) and stimulate osteoblast potential. This is achieved by combining CPCs with BMSCs and osteogenic activity factors such as platelet-rich plasma (PRP), bone morphogenetic protein-2 (BMP-2), or metals.
BMP-2, a well-investigated osteogenic active substance, has been loaded onto CPC scaffolds to accelerate bone formation. Studies have shown that CPCs can modulate BMP-2 conformation, enhancing Smad1/5/8 and mitogen-activated protein kinase (MAPK) signaling transduction, which in turn stimulates the expression of osteogenic marker genes. Furthermore, CPCs can inhibit osteoclast-mediated resorption, offsetting the increased osteoclast activity induced by BMP-2. PRP, containing multiple growth factors, has also been used to modify CPCs, promoting bone repair through local delivery of bioactive agents that influence inflammation, angiogenesis, and extracellular matrix synthesis.
Metals such as magnesium, strontium, and their compounds have been explored for their osteogenic activity in bone tissue engineering. Strontium-modified CPCs have been shown to increase the expression levels of osteoblast-related genes and promote alkaline phosphatase activity in osteoblast-like cell lines and BMSCs. Magnesium in CPCs promotes BMSC adhesion and osteogenic differentiation via an integrin-mediated mechanism. Additionally, magnesium/calcium phosphate cements (MCPCs) have been found to enhance the angiogenic potential of human umbilical vein endothelial cells in vitro.
Other bioactive metal ions, including copper, cobalt, and chromium, have also been investigated for their potential to accelerate bone healing. Copper-doped CPCs have demonstrated antibacterial, angiogenic, and bone mineralization-promoting properties. Cobalt and chromium ions have shown mixed results, necessitating further research to confirm their efficacy.
CPCs have also been modified to serve as carriers for antibiotics, addressing post-operative infections through localized drug delivery. While PMMA cements are marginally porous, CPCs offer interconnected microporosity, making them more favorable for antibiotic delivery. However, introducing antibiotics can affect the porosity and mechanical properties of CPCs, and their slow degradation may not synchronize with drug release. To mitigate these issues, CPCs can be modified with drug-loaded polymers, enhancing mechanical properties and degradation rates.
In addition to antibiotics, CPCs have been explored as carriers for anti-tumor drugs and radioactive materials, offering localized treatment options that reduce systemic side effects and patient pain. These modifications aim to simplify the treatment process and improve therapeutic outcomes.
The biodegradability of CPCs is a critical factor, as they are expected to degrade at the same rate as new bone formation. Strategies to accelerate degradation include adding PLGA microspheres, which degrade faster than CPCs, and incorporating organic phases such as allogeneic bone powder or autologous BMSC-PRP. Strontium-modified CPCs have also shown excellent biodegradability and osteoinductive capabilities in clinical tests.
Mechanical properties and fracture toughness are other areas of focus for CPC modification. Reinforcement strategies include adding fibers, crosslinking, and adjusting the hardening liquid. Nanoscale metal oxides, silk fibroin, chemically activated carbon fibers, chitosan fibers, and gelatinized starches have been shown to enhance the compressive strength and anti-washout properties of CPCs. Incorporating type I collagen (coI) into CPCs has been an active area of research, as it promotes bone integration while reinforcing CPCs. However, the addition of coI can negatively impact compressive strength, necessitating secondary modifications such as strontium doping to provide interlocked microstructures and higher compressive strength.
Binary modifications, combining both material and biological modifications, aim to achieve overall efficiency gains. For instance, adding PLGA fibers to CPCs addresses low mechanical strength and fracture toughness issues. Studies have shown that incorporating osteogenic active factors such as BMP-2 and GDF5 protein into PLGA fiber-reinforced CPCs significantly improves bone formation capacity and angiogenic effects.
In conclusion, the modification of injectable calcium-phosphate-based bone cements represents a dynamic and evolving field with significant potential for clinical application. By addressing limitations such as slow degradation, insufficient osteoinduction, and mechanical strength, researchers are paving the way for more effective bone defect repair and regeneration. The integration of bioactive elements, metals, and drug delivery systems into CPCs offers a multifaceted approach to enhancing their performance, ultimately improving patient outcomes in orthopedics and dentistry.
doi.org/10.1097/CM9.0000000000001092
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