Nature-Inspired Scarless Healing: Guiding Biomaterials Design for Advanced Therapies.

The use of biomaterials in the treatment of skin wounds has been steadily increasing over the last two decades. The key to the successful application of biomaterials in scar reduction is the up-to-date knowledge of the actors involved in accelerated healing and the cellular factors that can be implemented in bioinspired materials. Natural models of scarless healing such as oral mucosa, fetal skin and the skin of amphibians, fish, and reptiles are a great source of information. By investigating their microenvironments, cellular factors, and inflammatory self-regulatory systems, a general model of scarless healing can be defined. This review introduces the basic and current concepts of skin wound healing and focuses on providing a detailed overview of the main processes of accelerated healing without scarring. The article outlines the common features and key points that develop and promote scar-free healing. The tissues and healing processes of the selected natural models are described individually (tissue organization, structural components, ratios of cellular factors such as Collagen and transforming growth factor and their mechanisms of regulation of inflammation and scar overgrowth). A comparative work of each natural model concerning healing in human skin is included in the discussion. Finally, the patterns identified through the analysis of each model and their differences from normal healing are presented to facilitate the knowledge for the implementation of new treatments.

Bioinspired design of mannose-decorated globular lysine dendrimers promotes diabetic wound healing by orchestrating appropriate macrophage polarization.

A large number of cytokines or growth factors have been used in the treatment of inflammation. However, they are highly dependent on an optimal delivery system with sufficient loading efficiency and protection of growth factors from proteolytic degradation. To develop the immunotherapy capacity of peptide dendrimers themselves, inspired by the structure and immunoregulatory functions of mannose-capped lipoarabinomannan (ManLAM), we thus propose a hypothesis that mannose-decorated globular lysine dendrimers (MGLDs) with precise molecular design can elicit anti-inflammatory activity through targeting and reprogramming macrophages to M2 phenotype. To achieve this, a series of mannose-decorated globular lysine dendrimers (MGLDs) was developed. Size-controlled MGLDs obtained were spherical with positive surface charges. The mean size ranged from 50-200 nm in varying generations and modification degrees. The initial screening study revealed that MGLDs have superior biocompatibility. When cocultured with MGLDs, mouse bone marrow-derived macrophages (BMDMs) acquired an anti-inflammatory M2 phenotype characterized by significant mannose receptor (MR) clustering on the cell surface and the elongated shape, an increased production of transforming growth factor (TGF)-ß1, interleukin (IL)-4 and IL-10, a downregulated secretory of IL-1ß, IL-6, and tumor necrosis factor (TNF)-α, and increased ability to induce fibroblast proliferation. Then in vivo studies further demonstrated that topical administration of optimized MGLDs accelerates wound repair of full-thickness cutaneous defects in type 2 diabetic mice via M2 macrophage polarization. Mechanistically, MGLDs treatment showed an enhanced closure rate, collagen deposition, and angiogenesis, along with mitigated inflammation modulated by a suppressed secretory of pro-inflammation cytokines, and increased production of TGF-ß1. These findings provide the first evidence that the bioinspired design of MGLDs can direct M2 macrophage polarization, which may be beneficial in the therapy of injuries and inflammation.

Injectable Adhesive Self-Healing Multicross-Linked Double-Network Hydrogel Facilitates Full-Thickness Skin Wound Healing.

The development of natural polymer-based hydrogels, combining outstanding injectability, self-healing, and tissue adhesion, with mechanical performance, able to facilitate full-thickness skin wound healing, remains challenging. We have developed an injectable micellar hydrogel (AF127/HA-ADH/OHA-Dop) with outstanding adhesive and self-healing properties able to accelerate full-thickness skin wound healing. Dopamine-functionalized oxidized hyaluronic acid (OHA-Dop), adipic acid dihydrazide-modified HA (HA-ADH), and aldehyde-terminated Pluronic F127 (AF127) were employed as polymer backbones. They were cross-linked in situ using Schiff base dynamic covalent bonds (AF127 micelle/HA-ADH network and HA-ADH/OHA-Dop network), hydrogen bonding, and π-π stacking interactions. The resulting multicross-linked double-network design forms a micellar hydrogel. The unique multicross-linked double-network structure endows the hydrogel with both improved injection abilities and mechanical performance while self-healing faster than single-network hydrogels. Inspired by mussel foot adhesive protein, OHA-Dop mimics the catechol groups seen in mussel proteins, endowing hydrogels with robust adhesion properties. We also demonstrate the potential of our hydrogels to accelerate full-thickness cutaneous wound closure and improve skin regeneration with reduced scarring. We anticipate that our hydrogel platform based on a novel multicross-linked double-network design will transform the future development of multifunctional wound dressings.