Layer-by-layer assembly: advancing skin repair, one layer at a time

Abstract

Skin wound management remains a critical global healthcare challenge, with annual costs exceeding £30 billion. Traditional treatments like autografts face limitations in cost, availability, and recovery times. This review explores spray-assisted Layer-by-Layer (LbL) technology as a transformative approach for wound healing, emphasising its ability to deposit natural- and synthetic-polyelectrolytes such as chitosan, alginate, hyaluronic acid, and collagen into nanoscale coatings. These biocompatible multilayers integrate therapeutic agents to accelerate healing, reduce infections, and mimic native extracellular matrix structures. The work highlights emerging spray device innovations that optimise spray parameters to enhance cell viability, coverage, and clinical outcomes. While LbL techniques demonstrate versatility across substrates and scalability via immersion, spray, and microfluidic methods, challenges persist in manufacturing uniformity and clinical translation. The review underscores the urgent need for clinical trials to validate Lbl-based coatings in real-world settings and addresses gaps in portable, sustainable device development. By bridging advanced materials science with clinical practice, spray-assisted LbL technology offers a roadmap to overcome current wound care limitations, prioritising biocompatibility, cost-efficiency, and improved patient safety in regenerative medicine.

Fig. 1. Layer-by-Layer (LbL) assembly of polyelectrolytes (PEs) on a charged substrate (in grey, indicated by black arrows) is used to construct multiple layers (blue and red, process indicated by grey arrows). This process allows for a variety of oppositely charged substrates with materials as PEs, to be used in fabrication.

Fig. 2. Illustration of the three commonly used Layer-by-layer methods in biomedical technologies: (A) immersion or dipping, (B) spray and (C) microfluidic, showing the iterative deposition of material 1, washing step and material onto substrates, being in a microfluidic system, micro or nanoparticles passing through the PEs solutions.

Fig. 3. Schematic approach of spray‐assisted layer‐by‐layer assembly on hyaluronic acid scaffolds for skin tissue engineering. Keratinocytes are seeded on top of the membrane, forming a cell monolayer. The LbL membrane acts as an epidermal substitute, which adheres to the dermal component (the porous hyaluronic acid scaffold). Reproduced from ref. with permission from John Wiley and Sons, Journal of Biomedical Materials Research Part A, copyright 2023.

Fig. 4. Schematic overview of the therapeutic skin Layer-by-layer assembly onto skin tissue or meshes as substrates to deposit an extensive choice of therapeutic materials using handheld technologies to treat the wound and assist in the wound healing process for skin burns and trauma injuries. Created in https://BioRender.com.

Elias Hasan

Christopher J. Lewis

Piergiorgio Gentile

Ana M. Ferreira