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

Area of Science:

• Biomaterials Science
• Tissue Engineering
• Regenerative Medicine

Background:

• Cutaneous tissue engineering aims to create living skin constructs.
• Current limitations include achieving timely and durable perfusion in engineered tissues.
• Existing engineered skin often fails in vivo due to insufficient blood supply.

Purpose of the Study:

• To reframe the field of cutaneous tissue engineering around perfusion as the primary functional endpoint.
• To analyze the vascularization bottleneck in engineered skin.
• To distinguish between implantable skin substitutes and in vitro perfused platforms.

Main Methods:

• Critical narrative review analyzing existing platforms and strategies.
• Assessment of biomaterial design, cell-based strategies, immunomodulation, decellularized matrices, bioprinting, microfluidics, and prevascularization.
• Distinction between implantable skin substitutes and skin-on-chip systems.

Main Results:

• Perfusion, not just vessel density, is the critical factor for engineered skin success.
• The vascularization process involves internal network formation, host inosculation, flow initiation, and perfusion stability.
• Implantable skin substitutes and in vitro perfused platforms have different success criteria.

Conclusions:

• Future research should focus on integrated systems for rapid vascularization and stable perfusion.
• Key areas for advancement include functional perfusion benchmarking, scaffold dynamics, immune-vascular crosstalk, scalable vascular fabrication, and predictive human test platforms.
• Successful translation requires engineered tissues that survive ischemia, connect quickly, and remodel into functional microvasculature.