Bioinspired Strategies for Wound Regeneration

Abstract

Regeneration allows animals to replace and restore injured tissues. Animal phyla have evolved different regenerative strategies to increase survival advantages. In contrast to the earlier principle that regeneration recapitulates development, recent studies indicate that wound healing in adult mammals is modified by the inflammatory response to injury, and biochemical signaling from immune and other cellular systems may modulate wound reparative responses to achieve successful tissue regeneration. Here we briefly survey different regenerative strategies used by animals across different phyla. We next focus on skin regeneration using the mouse wound-induced hair neogenesis model as an example to show the circumstances required to rebuild a new, morphogenetically competent field in the adult mammalian skin. Parallel investigations in African spiny mice (Acomys sp.) have further shown that skin rigidity can also modulate wound bed properties to facilitate de novo formation of skin appendages. These regenerating, periodically arranged hair primordia emerge using Turing activator/inhibitor principles with activities derived from sources that differ from those used in embryonic development, including the mechanical environment. Thus, a novel combination of biochemical, immunological, and mechanical signaling strategies can work together to achieve successful cutaneous regeneration in adult animals, potentially inspiring novel therapeutic strategies.

Figure 1.

Distinct regeneration abilities in animals across the animal kingdom. Examples of animals representing different evolutionary stages are shown. Those with regeneration ability are highlighted. Red is for those with regeneration-involved body axis (e.g., Planaria). Orange is for those with regeneration ability of the limb (axolotl) or tail (lizard). Green is for those with regeneration ability in integumentary appendages (tooth, alligator; skin appendages, mouse, spiny mice). The overall trend shows that distinct regenerative strategies in animals have occurred independently multiple times during evolution. Regeneration is not an event that evolved once and then was lost in different animals. Also, the organs exhibiting regeneration ability shift from the central body part to the periphery (limb appendage, then skin appendages) during evolution. (Created with BioRender.com.)

Figure 2.

Mechanochemical events during wound-induced hair follicle neogenesis. The spatial distribution of skin tension, cell type/contractility/density, matrix metalloproteinase (MMP) activity, and extracellular matrix (ECM) components all contribute to the pattern of tissue mechanics and outcome of wound healing. Immune cells secrete cytokines that activate fibroblasts (left inset), some of which eventually differentiate into myofibroblasts. The activated dermal cells express ECM/MMP to locally remodel and modulate the stiffness of the microenvironment. The density and thickness of collagen fibrils in the wound—resulting from a combination of collagen types, extent of cross-linking, and rates of synthesis and degradation—determines the overall mechanical profile of the wound bed from a biomaterials perspective. Wounds also undergo myofibroblast-driven contraction that modulates skin tension and ECM organization (right inset). During epithelial hair placode formation, keratinocytes secrete Wnt, which activates β-catenin and downstream signals such as Twist1 and MMP/ECM, to locally remodel and facilitate morphogenesis of the hair placode (middle inset).

Figure 3.

Turing periodic patterning and the topobiology of epidermal appendage regeneration in wound beds of laboratory mice and Acomys sp. Both micro- and macro-scale tissue mechanics contribute to patterns of repair versus regeneration. Because of the different skin compliance in laboratory mice and Acomys, these species show contrasting spatial patterns of hair regeneration (central vs. peripheral). (A) Conceptual summary of the way we perceive the relationship between tissue stiffness and morphogenetic fields in Mus, Acomys, and a non-regenerating wound (repair). It highlights the different geographic distribution of the morphogenetic field (green) within a wound bed (red frame), and also the periodic appearance of hair primordia (orange) within the permissive morphogenetic field (green). When the wound stiffness is too low (blue), no placodes can form. The stiffness of different wound beds predicts the distribution of morphogenetic field and placode formation. (B) The hair placode is stiffer than its surrounding in the wound center, but not stiffer than the wound margin. Results from atomic force microscopy (AFM) measurements of different regions of the wound, including the hair placodes. (C) Theoretically, for the epidermal hair placode to invaginate into the dermis, the force of the epidermal placode needs to be greater than the force of the dermis. The analogy is the radish, where the soil (dermal environment) needs to be soft enough for the radish (hair placode) to overcome its resistance and grow into it.

Figure 4.

Mechanotransduction of keratinocytes. The mechanotransduction sequence can be divided into three parts: (1) mechanosensing—the extracellular characteristics transmitted by cell surface mechanosensors (integrins, desmosomes, cell junctions), (2) intracellular transduction—the mechanical stimuli that are relayed into the cell and lead to intracellular signaling through pathways such as Smad, FAK, ERK, and Rho, and, ultimately (3) gene expression changes—in which the signals are relayed into the nucleus and lead to altered gene expression. The mechanical signals can be transmitted via mechanochemical cascades or directly connected from the ECM–cell interface to the nucleus via actin filaments and other cytoskeletal components. Cellular mechanotransduction is not exclusive to epidermal or dermal cells.

Figure 5.

Multiple pathways lead to endogenous reprogramming that allow de novo hair follicle regeneration in the injured skin of adult animals. To achieve regeneration, both epidermal and dermal cells within the tissue need to undergo endogenous reprogramming. This can be achieved via various pathways, and it requires the collaboration of different cell types as well as the appropriate mechanical environment. This in turn fosters a morphogenetic field that promotes Turing patterning, leading to folliculogenesis.