Engineering Immunomodulatory Biomaterials to Drive Skin Wounds toward Regenerative Healing

Abstract

The healing of human skin wounds is designed for a rapid fibroproliferative response at the expense of tissue complexity and is therefore prone to scar formation. Moreover, wound healing often goes awry when excessive inflammation leads to chronic nonhealing wounds or when excessive repair results in uncontrolled tissue fibrosis. The immune system plays a central role in orchestrating wound healing, and, thus, controlling immune cell activities holds great potential for reducing scars and enhancing regeneration. Biomaterial dressings directly interact with immune cells in the wound and have been shown to improve the repair process. A few studies have even shown that biomaterials can induce complete regeneration through mechanisms involving immune cells. Here, we review the role of the immune system in skin repair and regeneration and describe how advances in biomaterial research may uncover immunomodulatory elements to enhance fully functional skin regeneration.

Figure 1.

Natural extracellular matrix (ECM)-based materials. (A) Schematic representations of natural biomaterial fabrication processes including (i) acellular dermal substitute production by removal of cells, (ii) collagen scaffold production by self-assembly, (iii) hyaluronic acid (HA) scaffold production, and (iv) fibrin matrix production from fibrinogen and thrombin. (B) Features of natural biomaterials beneficial for wound healing include its degradability, molecular interactions with cells, and biocompatibility.

Figure 2.

Synthetic and hybrid biomaterials. (A) Chemistry of common synthetic biomaterial scaffolds including PEG (poly(ethylene glycol)), PLGA (poly(lactic-co-glycolic acid)), PCL (polycaprolactone), and PGA (polyglycolic acid). (B) Features of synthetic biomaterials beneficial for wound healing include the ability to conjugate peptides or proteins and control of physical properties. (C) Synthetic materials can be combined with natural biomaterials to create hybrid materials and used to deliver immunomodulatory cells or biological agents.

Figure 3.

Biomaterials for skin regeneration. Wounding of skin typically leads to scarring (top), but treatment with biomaterials such as microporous annealed particle (MAP) hydrogels that elicit immune cell activation leads to hair follicle regeneration (bottom).

Figure 4.

Engineering biomaterials to enhance skin regenerative wound healing. (A) Key immune and repair cells in wound healing. Wounding initiates inflammation with the release of danger signals, mast cell degranulation, and influx of neutrophils and monocyte-derived inflammatory macrophages. Inflammation is resolved following apoptosis of neutrophils, their clearance by macrophages, and macrophage conversion into anti-inflammatory and reparative activation. T cells are also recruited and skew toward anti-inflammatory activation with time. Macrophages promote angiogenesis and a fibroproliferative process, but the reparative activity must be limited for wound resolution and regeneration of functional tissue. Macrophage and T-cell activities are essential for regenerative repair mechanisms including hair neogenesis. (B) Biomaterial properties that modulate wound inflammation and repair. Biomaterials contain biophysical and biochemical properties that modulate the immune response and may be leveraged to encourage regeneration. Biomaterial compatibility is key to avoiding inflammatory response with excess recruitment and activation of immune cells and instead, enhancing the resolution of inflammation and repair process. Biomaterial permeability and degradability facilitate the infiltration of host cells to promote reepithelialization, angiogenesis, and ECM deposition in a timely fashion to skew fibrosis toward the regeneration of functional skin.