A Roadmap to Perfused Skin: Defining the Next Generation of Research Questions in Cutaneous Tissue Engineering

Cutaneous tissue engineering has advanced from simple coverage substitutes to increasingly complex living constructs, yet the field remains constrained by a decisive problem: timely and durable perfusion. Many engineered skin substitutes can appear vascular in static culture or in small-animal models. However, they still fail when blood flow must be established quickly enough to rescue cells across clinically relevant tissue thickness. Rather than re-catalog platforms already summarized in recent reviews, this critical narrative review reframes the field around perfusion as the master functional endpoint rather than vessel density alone. We analyze the vascularization bottleneck as a sequence, internal network formation, host inosculation, flow initiation, and perfusion stability-and use that sequence to reassess biomaterial design, cell-based strategies, immunomodulation, decellularized matrices, bioprinting, microfluidics, and prevascularization. We intentionally distinguish implantable skin substitutes from perfused in vitro platforms such as skin-on-chip systems, arguing that these are linked but non-interchangeable application spaces with different success criteria. Building on this distinction, we propose a research agenda centered on functional benchmarking of perfusion, spatiotemporal coordination of scaffold dynamics, immune-mural-lymphatic-vascular crosstalk, scalable hierarchical vascular fabrication, and predictive human test platforms. The central argument is that translation will depend not on ever more isolated pro-angiogenic interventions but on integrated systems that survive the ischemic interval, connect rapidly, tolerate blood entry, maintain a workable inflow-outflow balance, and remodel into a stable, skin-specific microvasculature.