Calcium Hydroxylapatite in Facial Rejuvenation: A Review from Multi-Layered Aging Mechanisms to Material-Property-Guided Clinical Practice

Contemporary research on facial aging is undergoing a profound paradigm shift, transitioning from macroscopic descriptive phenotyping to refined cellular-molecular mechanistic dissection. This review reveals these frontiers across multi-omics and structural dimensions, highlighting single-cell transcriptomic alterations (e.g., KLF6 and HES1 dysregulation), proteomic hubs (e.g., KNG1), epigenetic causal chains, and microbiome community succession within the cutaneous microenvironment. Concurrently, we map the progressive biomechanical failure of deeper tissues, including sequential adipose atrophy, SMAS-muscle complex degeneration, and sex-specific skeletal remodeling. Within the evolving landscape of regenerative aesthetics, calcium hydroxylapatite (CaHA) has emerged not merely as a passive space-occupying volumizer but as a dynamic biostimulatory material. We examine how CaHA’s morphology and rheological properties govern its biological behavior. Human histological studies provide evidence that CaHA is associated with fibroblast activity and temporal extracellular-matrix remodeling, particularly changes in type III and type I collagen expression. Changes in elastin- and angiogenesis-related markers have also been reported, whereas the mechanotransduction and immune-regulatory pathways proposed to underlie these responses remain supported predominantly by in vitro, ex vivo, and preclinical evidence and have not been fully validated in human facial tissue. Finally, we translate these material-driven interactions into advanced clinical strategies, including rheologically programmed dilution, layer-specific vectoring, and synergistic therapies. By bridging intricate aging biology with material-guided regeneration, this review provides a robust conceptual framework for individualized and precise rejuvenation.