# Advances in Three Dimensional Bioprinting for Wound Healing: A Comprehensive Review
## 2 Structure and Function of Skin  
Skin consists of three layers: the epidermis, the dermis, and the hypodermis (Figure 1A). These layers protect the skin from various stresses such as injuries, thermal trauma, surgical wounds, or medical conditions such as HIV/AIDS, sickle cell anemia, [PERSON] syndrome, rheumatoid disease, anemia, [PERSON], Cutis Laxa syndrome, ischemia, or diabetes mellitus [20; 21]. The outermost layer, the epidermis is composed of the stratum basale, the stratum spinosum, the stratum granulosum, and the stratum corneum layers, which are epithelial cell layers up to a depth of 75 to 150 \(\upmu\)m. The corneocytes in the epidermis layer are embedded in a multilayer organized lipid matrix. Through this mechanism, the outer layer of the skin can stretch and move. This layer is at risk from pathogens and physical activities on a regular basis. The second layer of the skin, the dermis, is composed of the papillary dermis and the reticular dermis [22; 23; 24; 25]. The papillary layer consists of a loose network of collagen and elastin fibers. It contains fibroblasts, a small number of fat cells, capillaries, lymphatic capillaries, nerve fibers, and touch receptors called Meissner bodies. The reticular layer lies beneath the papillary layer densely vascularized, composed of irregular connective tissue with the abundance of sensory and sympathetic nerves. While the elastin fibers in the layer provide some flexibility to the skin and allow movement, the collagen fibers extend to both the papillary layer and the hypodermis. Elastin fibers also provide tensile strength and keep the skin moist by facilitating water transmission [26]. The mechanical behavior of the skin is determined by collagen and elastic fibers. Collagen fibers make up 75% of the fat-free dry mass, while elastic fibers make up 4%. Collagen fibers are also more abundant in the dermis, making up 18-30% of its constitution, while elastic fibers  
Figure 1: Schematic representation of wound treatment with 3D bioprinted hydrogel-based dressings. (**A**) The first diagram illustrates the cross-section of human skin, including the epidermis, dermis, and subcutaneous tissue layers. The epidermis is the outermost layer of the skin that protects from environmental damage, whereas the dermis is the layer that provides structural support and contains the hair follicles, sweat glands, and blood vessels. Fat and connective tissues are found in the subcutaneous tissue layer. (**B**) The second schematic illustrates the wound healing process, composed of four stages: hemostasis, inflammation, proliferation, and remodeling. As part of the initial stage of wound healing, hemostasis involves the formation of blood clots to stop the bleeding. During the second stage of the process, immune cells are responsible for cleaning the wound and preventing infection. Following that proliferation occurs, in which new tissue forms and blood vessels grow to restore the damaged area. Re-organization and strengthening of the new tissue constitute the final stage of remodeling. (**C**) An example of a solution to wound healing using hydrogel-based 3D bioprinting can be seen in the third schematic. The technology allows the precise placement of cells and biomaterials to create wound dressings that closely mimic natural tissue. The biocompatibility of hydrogel-based bioinks, their ability to respond to external stimuli, and their similarity to natural tissue make them an ideal choice for wound healing. (**D**) The fourth schematic depicts the components of the 3D bioprinting process, including the 3D printer and computer-aided design software (CAD). The CAD software enables the design of the bioink cartridge using hydrogel-based bioink deposited layer by layer onto the printing bed. These 3D printers provide a high level of precision in the creation of wound dressings, ensuring their perfect fit. This figure was created using [[https://app.biorender.com/](https://app.biorender.com/)]([https://app.biorender.com/](https://app.biorender.com/)) (accessed on 1 August 2023).