A microfluidic model of human dental pulp angiogenesis for preclinical drug and biomaterial testing

Dental pulp homeostasis and regeneration critically depend on angiogenesis, the formation of new capillaries from preexisting blood vessels. Regenerative endodontics has emerged as a clinical strategy to restore damaged or diseased dental pulp tissues using stem cells, signalling molecules, and scaffolds. Enhanced cell viability and angiogenesis are essential for the success of such regenerative therapies. However, their development, as well as efficient drug and biomaterial testing, is limited by the lack of physiologically relevant models. In this study, we developed a microfluidic model of angiogenesis in the human dental pulp to investigate the effects of drugs and biomaterials commonly used in dentistry. We optimised culture conditions influencing angiogenic sprouting and found that the presence of dental pulp cells and lower fibrin concentrations promoted angiogenesis significantly. Furthermore, static culture conditions enhanced sprouting compared with co- or contra-directional hydrostatic pressure-driven flow. Using this platform, we tested drugs (Paclitaxel and Limantrafin) and biomaterials (HEMA and Emdogain®). The model enabled quantitative imaging of angiogenic sprout growth and assessment of cytotoxicity through analysis of the culture medium. Importantly, the timing of drug exposure proved critical: early treatment inhibited sprout formation, whereas later treatment compromised the stability and viability of established vessels. HEMA (10 mM) resulted in cytotoxicity and compromised vessels, whereas Emdogain (1 mg/ml) showed no cytotoxicity and no significant impact on vessel formation. Paclitaxel efficiently inhibited angiogenesis at low concentrations (50 nM) with low cell death while Limantrafin required high concentrations (1 mM) to inhibit angiogenesis while showing elevated cell death and cytotoxicity. In conclusion, this microfluidic model provides a robust tool for studying fundamental angiogenic processes in the human dental pulp and offers an improved platform for safe and effective drug and biomaterial testing, thereby advancing regenerative endodontic therapies.