Rejuvenation of Aged Human Skin by Injection of Cross-linked Hyaluronic Acid

Background: Dermal injection of chemically cross-linked hyaluronic acid (CL-HA) is a common procedure to smooth wrinkles and add fullness to the face. Due to its physical properties, CL-HA both fills space and exerts mechanical forces within the dermis. Dermal fibroblasts produce the collagen-rich extracellular matrix (ECM), which comprises the bulk of skin. Attachment to the ECM allows fibroblasts to achieve a stretched, morphology, which confers a functional phenotype that maintains collagen production. In aged/photoaged skin, collagen fibril fragmentation impairs fibroblast attachment, resulting in a collapsed morphology and reduced collagen production. This article describes investigations of the impact of CL-HA injection on fibroblast morphology and function in the aged/photoaged human skin. Methods: Fifty-three subjects, age 70 years or older, received a single injection of saline (vehicle control) and CL-HA (0.5 ml each) in separate adjacent skin sites on photodamaged forearm or sun-protected buttock skin. Full-thickness punch biopsies were obtained from injected skin sites at various times and analyzed for molecular and cellular changes. Results: Injected CL-HA forms discreet pockets that localize to areas of the dermis that contain fragmented, loosely organized collagen fibrils. These CL-HA pockets fill space and apply mechanical forces on adjacent ECM that induce stretching of fibroblasts. This stretching is associated with increased collagen gene expression and deposition of mature collagen fibril bundles, which resemble those observed in young skin. Conclusions: CL-HA injected into aged/photoaged human dermis acts by both filling space and inducing production of collagen by dermal fibroblasts. Deposition of mature collagen, which remains in the skin for decades, likely confers long-term benefits. Reduced collagen production in aged/photoaged skin is an adaptive response of fibroblasts to ECM fragmentation, rather than inherent cellular aging mechanisms.