Unlocking the Future of Artificial Skin: The Role of 3D Bioprinting

3D Bioprinting Artificial Skin Hydrogels

Written by Michellie Hernandez, MD with the help of ChatGPT

Published: April 03, 2024

Human skin, our body's largest organ, is a marvel of biological engineering, comprising several layers and components that work in harmony to protect us from the radiation, pathogens and chemicals. From the outermost epidermis to the deeper dermis and hypodermis, each layer plays a vital role in maintaining skin integrity, regulating temperature, and facilitating sensory perception. However, when skin is damaged due to injury, burns, or disease, restoring its function and appearance can be a significant challenge. Traditional skin grafts and tissue engineering approaches have made strides in this area, but advancements in 3D bioprinting are now opening new frontiers in artificial skin bio manufacturing. "Three dimensional (3D) bioprinting can deposit biomaterials or bioinks to create scaffolds, spheroids, cell pellets and micro-carriers in a controllable and reproducible manner (Sun et. al 2022)." With the help of machine learning to help design the 3D bio printing scaffolds and evaluate and optimize the process and the biomaterials, 3D bioprinting seems to be gaining traction in multidisciplinary research.

Understanding Human Skin: A Blueprint for 3D Bioprinting

Before delving into the potential of 3D bioprinting, it's essential to understand the intricate architecture of human skin and how it can be replicated in artificial biomimetic constructs. The skin consists of three main layers:

1. Epidermis: The outermost layer of the skin, the epidermis, serves as a protective barrier against environmental insults and pathogens. It is primarily composed of keratinocytes, which undergo constant renewal and differentiation as they migrate from the basal layer within the epidermis to the surface layer consisting of mainly dead keratinocytes. Additionally, the epidermis contains melanocytes, responsible for producing melanin which protects us from ultraviolet radiation (UVR), and Langerhans cells, part of the immune system's defense mechanisms as specialized dendritic cells essential for both the innate and the adaptive immune system (Clayton et. al 2017).

2. Dermis: Beneath the epidermis lies the dermis, a connective tissue layer rich in collagen and elastin fibers. The dermis provides structural support, elasticity, and nourishment to the epidermis. It houses blood vessels, nerve endings, hair follicles, and sweat glands, contributing to thermoregulation and sensory perception  (Brown et al. 2018).

3. Hypodermis: Also known as the subcutaneous tissue, the hypodermis is the deepest layer of the skin, composed mainly of adipose tissue. It serves as insulation, cushioning underlying structures, and storing energy reserves (Kim et. al 2023).

Incorporating the complex structure and functionality of human skin into artificial constructs is a formidable task. However, 3D bioprinting offers a promising solution by enabling the precise deposition of cells, biomaterials, and bioactive factors to create biomimetic tissue substitutes.

Harnessing 3D Bioprinting for Artificial Skin Manufacturing

The principles of 3D bioprinting involve the layer-by-layer deposition of biomaterials and cells to fabricate three-dimensional tissue constructs. In the context of artificial skin, bioprinting techniques can be tailored to replicate the hierarchical organization of natural skin and incorporate key cell types, growth factors, and extracellular matrix components.

1. Customization: One of the potential significant advantages of 3D bioprinting is its ability to customize artificial skin constructs to match individual patient needs. By combining patient-specific data, such as skin thickness, color, and texture, with advanced imaging, AI and Computer-Aided Design and Computer-Aided Manufacturing (CAD/CAM) technologies, researchers can potentially design personalized skin substitutes with precise anatomical features (Tanveer et. al 2023).

2. Cellular Composition: Artificial skin substitutes must contain the appropriate cell types to mimic the functionality of native skin. Keratinocytes, fibroblasts, melanocytes, and endothelial cells are among the key cell populations that can be incorporated into bioprinted constructs to promote epidermal regeneration, collagen synthesis, pigmentation, and vascularization, respectively.

3. Biomaterial Selection: The choice of biomaterials plays a critical role in the performance and biocompatibility of bioprinted skin constructs. Natural polymers, such as collagen, fibrin, and hyaluronic acid, offer excellent biocompatibility and mimic the extracellular matrix of native skin. Synthetic polymers, such as polycaprolactone (PCL) and polyethylene glycol (PEG), provide mechanical support and structural integrity to printed scaffolds. But ongoing research in natural materials into bioink formulations for 3D bioprinting, such as cellulose (Wan et. al 2022), can be a promising substitute for synthetic polymers for mechanical support offering several advantages, including enhanced biocompatibility, bioactivity, and potential for integration with the host tissue. Placenta derived biomaterials is also a promising field in research for wound care, where the placenta undergoes a decellularization process, followed by preservation techniques and biomaterial cultivation of scaffold sheets, serum and cells (Protzman et. al 2023). The Wyss Institute faculty members Jennifer Lewis, Sc.D., and Christopher Chen, M.D., Ph.D. as well as a multidisciplinary team have an organ engineering department with 3D bioprinting and stem cells research that in 2017 successfully engineered a perfusable 3D vascularized tissues, a key step of the organ engineering process. Ongoing research is yet to be done on bioprinting an organ's extracellular matrix and specialized cells that provide the organ's essential functions. Stable layering is a significant challenge in bioprinting. Stable layering refers to the ability to deposit successive layers of bioink or biomaterials during the bioprinting process without compromising the structural integrity of the printed construct. Since microgravity can provide stabilization of the biomaterial, "conducting bioprinting in space, where the gravity is zero [or microgravity within the International Space Station (ISS)], can enable new frontiers in tissue engineering (Misagh et. al 2023)."

4. Vascularization: One of the key challenges in creating functional artificial skin is the incorporation of vascular networks to support nutrient delivery and waste removal. Bioprinting techniques, such as sacrificial printing and coaxial extrusion, facilitate angiogenesis or blood vessels formation assuring the biomimetic tissue viability. The coaxial extrusion technique simultaneously dispenses two or more bioinks or other biomaterials arranged concentrically in a single filament. While the sacrificial printing technique consists of 4 steps: (1) the conversion of biomaterials or bioinks to microchannels, (2) the development of a tissue block by casting hydrogel with cells over microfibers, (3) the removal of the template and (4) the insertion of endothelial cells within the microchannels (Zhang et. al 2018).

Challenges and Future Directions

While 3D bioprinting holds immense promise for artificial skin bio manufacturing, several challenges remain to be addressed. Achieving sufficient vascularization, optimizing cell viability and functionality, and ensuring regulatory approval are among the key hurdles facing researchers in this field. Additionally, scaling up production and reducing manufacturing costs are essential for the widespread adoption of bioprinted skin substitutes in clinical practice.

Despite these challenges, the potential of 3D bioprinting to revolutionize artificial skin manufacturing cannot be overstated. By leveraging the precision and versatility of bioprinting technologies, researchers are poised to develop next-generation skin substitutes that offer improved aesthetics, functionality, and patient outcomes. As advancements in biomaterials, bioinks, and printing techniques continue to evolve, the future of artificial skin looks brighter than ever before.

In conclusion, 3D bioprinting represents a groundbreaking approach to artificial skin bio manufacturing, offering unprecedented control over tissue architecture and cellular composition. By replicating the complex structure and functionality of native skin, bioprinted constructs have the potential to transform wound healing, regenerative medicine, and cosmetic surgery, paving the way for a new era of personalized healthcare. I propose to consider partnering with maternity wards to harness placental tissues for the production of biomaterials derived from placentas. By this mode, the cost-efficiency of the artificial skin potentially will lower the overall costs compared to traditional 3D printing methods. Ideally, either a protective support layer could be fashioned from a scaffold derived from placenta biomaterial sheet or a cellulose-based hydrogel, with its design crafted by AI through analysis of the placenta's extracellular matrix. This would serve as a temporary artificial skin. Paired with a bottom layer of regenerative hydrogel containing recombinant human granulocyte/macrophage colony-stimulating factor, the objective would be to facilitate the recovery of the patient's own skin whenever feasible. Since 3D bioprinting in microgravity also seems to be a promising combination, I propose improving the speed of 3D bioprinting for the developing a tissue engineering laboratory equipped with a lightning speed 3D bioprinter situated on an artificial microgravity environment here on Earth during NASA parabolic flights that offers microgravity effects for 24 seconds. I also look forward to reading more of the ongoing research of the combination of high-speed centrifuges that can potentially simulate a microgravity environment at sea level on Earth and 3D bioprinting within a Rotating-Wall Vessel Bioreactor (Zhang et. al 2021).

References:

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