Thermal-crosslinked acellular dermal matrix combined with adipose-derived stem cells to regenerate vascularized adipose tissue

The reconstruction of large-sized soft tissue defects remains a substantial clinical challenge, with adipose tissue engineering emerging as a promising solution. The acellular dermal matrix (ADM), known for its intricate spatial arrangement and active cytokine involvement, is widely employed as a scaffold in soft tissue engineering. Since ADM shares high similarity with decellularized adipose matrix, it holds potential as a substitute for adipose tissue. This study explores the adipogenic ability of a spongy material derived from ADM via vacuum-thermal crosslinking (T-ADM), characterized by high porosity, adjustable thickness, and suitable mechanical strength. Adipose-derived stem cells (ADSCs) are considered ideal seed cells in adipose tissue engineering. Nevertheless, whether pre-adipogenic induction is necessary before their incorporation remains debatable. In this context, ADSCs, both with and without pre-adipogenic induction, were seeded into T-ADM to regenerate vascularized adipose tissue. A comparative analysis of the two constructs was performed to evaluate angiogenesis and adipogenesis<i>in vitro</i>, and tissue regeneration efficacy<i>in vivo</i>. Additionally, RNA-seq analysis was utilized to investigate the potential mechanisms. The results showed that T-ADM exhibited good performance in terms of volume retention and maintenance of adipocyte phenotype, confirming its suitability as a scaffold for adipose tissue engineering.<i>In-vitro</i>outcomes demonstrated that pre-adipogenic induction enhanced the adipogenic level of ADSCs, but reduced their ability to promote vascularization. Furthermore, constructs utilizing pre-induced ADSCs showed an insignificant superiority in<i>in-vivo</i>fat formation, and neovascularization compared with those with non-induced ADSCs, which may be attributed to similar macrophage regulation, and balanced modulation of the proliferator-activated receptor-<i>γ</i>and hypoxia-inducible factor 1<i>α</i>pathways. Consequently, the direct use of ADSCs is advocated to streamline the engineering process and reduce associated costs. The combined strategy of T-ADM with ADSCs proves to be feasible, convenient and effective, offering substantial potential for addressing large-sized tissue deficits and facilitating clinical applications.