A scaffold-free, collagen-guided self-assembling adipose construct for functional soft tissue reconstruction

Reconstruction of large-volume soft tissue defects remains a significant challenge in plastic and reconstructive surgery. Autologous fat grafting, though widely used, often suffers from poor volume retention and slow vascularization. This study presents an innovative collagen-guided self-assembling adipose construct from clinical lipoaspirate to create structurally stable engineered fat flaps-Self-Assembly Fat (SAF), driven by the intrinsic crosslinking of type I collagen within the lipoaspirated fat. Supplementation with exogenous type I collagen (SAF⁺) further enhanced the mechanical properties and biological activity of these constructs, increasing their stiffness, elasticity, and resilience. The self-assembly process facilitated collagen network formation, which not only improved tissue stability but also provided a favorable microenvironment for cell adhesion, proliferation, and differentiation. In vitro, SAF⁺ exhibited enhanced adipogenic differentiation and superior stem cell recruitment. In vivo, SAF⁺ significantly accelerated tissue repair by promoting M2 macrophage polarization, angiogenesis, and stem cell homing. Mechanistically, these effects were mediated through activation of the integrin α2β1-FAK/Src signaling pathway. This study provides a mechanistic understanding of adipose tissue self-assembly and presents an autologous, collagen-guided approach for engineering implantable, scaffold-free adipose constructs with enhanced regenerative capacity for soft-tissue repair. STATEMENT OF SIGNIFICANCE: Soft‑tissue reconstruction is hindered by unpredictable resorption and poor vascularization of autologous fat grafts. Biomaterial approaches using synthetic scaffolds or exogenous matrices often suffer biocompatibility issues, foreign‑body responses, and limited integration. We identify an intrinsic, type I collagen-driven self‑assembly capacity in human lipoaspirate and establish a collagen-guided, scaffold-free adipose strategy. By elucidating collagen signaling via integrin α2β1-FAK/Src axis, we link structural consolidation, mechanical tuning, and a pro‑regenerative microenvironment. Modulating collagen availability and crosslinking strengthens cohesion while preserving implantability and handling. The resulting constructs maintain adipose lineage, support vascularization, and integrate with host tissue. Bypassing synthetic scaffolds, this platform advances ECM‑guided assembly and offers a practical, autologous approach to soft‑tissue repair with improved handling, stability, and translational potential.