The growing worldwide paucity of skin donors for patients with serious wounds highlights the urgent need for alternatives to skin allograft. Skin regeneration research has addressed the unmet demand for artificial skin for the past three decades. Human skin, tissue, and internal organs created artificially may seem like a biomedical fantasy, yet much of it is occurring right now, although in the early stages. Advances in 3D printing, especially bioprinting, are bringing novel therapeutic and scientific study alternatives to the forefront. Bioprinting, in fact, has the potential to be the next big thing in health care and personalized treatment.
Millions of individuals suffer from non-healing skin wounds, which need more expensive treatment. 3D bioprinting is an Additive Manufacturing (AM) technology that is becoming a reality in the medical industry. It allows for the printing of a portion of the skin using suitable cells.
It uses computer-aided design (CAD) model inputs to recreate burn damage layer by layer. This method is being utilized to rebuild and grow cells from a patient’s own stem cells. It has transformed the medical industry while also paving the way for organ and skin tissue printing. This method improves the therapy by producing higher-quality skin grafts at a lower cost.
While bioprinters and 3D printers have many similarities, there is one key difference: bioprinters use living cells. Instead of printing plastics, ceramic or metal, they deposit layers of cell laden biomaterial, to construct complex tissue structures.
3D Scanners are already being used for scanning the mouth to make 3D Printed patient specific dentures and tooth corrections.
WAIT.. Living Cells?
What source do they use to get those? Every tissue in the body is naturally composed of many cell types. The tissue-specific cells are extracted from a patient and cultured to form the ‘bioink’. This is not always feasible, therefore adult stem cells may be employed in certain cases.
Vasculature
The development of a vascular network is an essential step in biofabricating functioning tissue. When the thickness of tissue exceeds 100–200 nm, the vascular network is required to overcome the diffusion limit of oxygen. Engineered tissues would be restricted in their ability to distribute nutrients if their vascular networks were inadequate.
In order to avoid tissue death and facilitate the creation of the endothelium, it is necessary to include vasculature into the created in vitro tissues at an early stage of development. Viable vascular structures are required to mimic the original tissues, including waste and nutrient removal, homeostasis, etc.
In-Vivo Skin Disease
If a person is severely burnt, healthy skin from another area of the body is extracted and utilized to cover the damaged area. However, there isn’t always enough intact skin to go around. Wake Forest School of Medicine researchers have successfully developed, manufactured, and tested a bioprinter that can print skin cells directly into a burn lesion.
The size and depth of the wound is determined by a scanner. This information is provided to the in-vivo bioprinter. Unlike typical skin grafts, a piece of skin one-tenth the area of the burn is needed to produce enough cells for skin printing. While this technology is currently in its early stages, experts anticipate that it will be widely accessible soon.
One American firm has already developed multilayered skin with dermal and epidermal layers. However, there are numerous problems ahead, including how to prevent the printer’s heat from destroying the cells or their vitality. Of all, skin, like most other areas of the human body, is more complicated than it appears—there are nerves, blood arteries, and a plethora of other factors that must be considered.
Challenges of Bioprinting Skin
For Clinical Applications
Current 3D skin tissue structures are unable to mimic the exact microenvironment of skin blood vessels, nerves, and skin appendages). Printed skin structures with highly developed vasculature remain a challenge at the moment.
Nerve regeneration in 3D-printed skin is a difficult yet fascinating subject. It is reliant on newly generated blood vessels throughout the process of 3D-printed skin-induced neo-tissue development. Nerve regeneration can be hindered in the absence of blood supply.
Additionally, Schwann cells are critical for nerve regeneration. Schwann cells contribute to nerve regeneration by proliferating and aggregating to form a tubular structure resembling a “nerve conduit. These induce directional growth of nerve fibers and synthesize and secrete a large number of laminins, which promote nerve growth and can significantly accelerate the regeneration of nerve fibers.
Release of nerve growth factor and other neurotrophic factors to stimulate axon regeneration via upregulation of neuronal cell adhesion molecules. Thus, Schwann cells are added to the 3D printed scaffold in vitro, which is an effective approach for the regeneration of 3D-printed skin sensory nerves.
Vasculature Challenges
One of the most basic issues in tissue engineering is constructing a functioning vascular. The capacity to 3D bioprint vasculature will allow for the creation of a premade microvascular network that can better anastomose to the host circulation and achieve effective perfusion inside tissue-engineered skin constructs. A possible technique is to utilize sacrificial inks to generate 3D interconnecting networks. The ink can be removed after printing the complete construct, leaving empty channels for endothelial cell perfusion and the creation of a blood vessel network.
Miller et al. demonstrated the use of 3D extrusion printing and cast moulding to produce a 3D-interconnected perfusable vasculature. This moulding process, however, is restricted to the creation of basic block tissue structures.
Prof. Lewis’ research group recently published a paper describing a bioprinting method that allows for simultaneous printing of the vascular structure and surrounding cells for heterogeneous cell-laden tissue constructions. They created a technology that uses Pluronic F-127 as a fugitive bioink. This fugitive can be printed and dissolved under moderate circumstances. This allows them to print heterogeneous cell-laden tissue structures with interconnected vascular networks.
Zhang et al. recently reported on direct bioprinting of vessel-like cellular microfluidic channels using hydrogels such as alginate and chitosan utilising a coaxial nozzle. Prof. Lewis’ team has published research showing bioprinting of 3D cell-laden, vascularized tissues. These are more than 1 cm thick and can be perfused on a chip for more than 6 weeks.
Multicell printing is employed which uses human mesenchymal stem cells and human neonatal dermal fibroblasts within a customized fibrin-gelatin matrix alongside embedded vasculature, which was then lined with human umbilical vein endothelial cells to create a single thick tissue that combined parenchyma, stroma, and endothelium into a single thick tissue. This might open up new possibilities for pre-vascularized skin tissue printing.
The print resolution must be enhanced and printing time lowered in order to print vascularized skin models with complexity and resolution that match in vivo structures. For the construction of transplantable organs, the capacity to bioprint hierarchical vascular networks while creating complex tissues and the ability to replicate vascular flow in vitro are important.
Learn More About Bioprinting Vasculature in Module 6 of our Online Course in 3D Bioprinting
| Learn About the diverse challenges in 3D Bioprinting, how researchers are looking to overcome these hurdles and the latest advances made in the field |
Application & Research Challenges
It is possible to use 3D bioprinting technology in the area of tissue repair and regeneration. Bioprinting skin, avoiding donor site morbidity and producing in vitro tumour models like malignant melanoma might have major health advantages due to its ability to eliminate donor site morbidity. Replicating skin and cancer microenvironment using 3D bioprinting, researchers can examine cell growth, metastasis, and drug detection. In the long run, 3D bioprinting can directly print skin on lesions produced by cancer excision or burns.
So far, research has proven that 3D bioprinting will allow for precision insertion of all native skin cell types as well as precise repeatability of constructs to replace skin. However, replicating natural skin’s microenvironment and performance for wound recovery and temperature management is still a work in progress. 3D bioprinting is predicted to overcome these hurdles and play a significant role in bioengineering and skin bionics as related technologies advance and interdisciplinary collaboration is explored.
Regulatory Challenges
Even if human cells are used to create 3D bioprinted tissues and organs, who would own the finished product? Is it the cell donor, the doctor, the firm, or the institution that bears responsibility? In addition, there are a number of safety concerns that must not be overlooked.
Intellectual property is estimated to be lost at a rate of around $100 billion each year. This raises questions about how and by whom this technology will be used. CAD files for The Liberator, the world’s first 3D-printable pistol, have been made available online.
As a result, there is a serious risk that bioprinting of organs can be used as a weapon for bioterrorism in the future. There are much more questions than solutions when it comes to bioethical and legal problems around 3D bioprinting. Initially, challenges will emerge for categorizing these products, as this determines the review and approval procedure for such devices. A complicated bioprinting product is not a device, biologic, or pharmaceutical product.
Perhaps it falls under the general and imprecise category of “combination product”. Therefore, do we need a new category to include such products? To add to the complexity, the FDA makes a passing reference to the possibility that some items “may need extra manufacturing process considerations and various regulatory routes.” Although the FDA often consults with the CBER (Center for Biologics Evaluation and Research) throughout the decision-making process, there are currently no particular rules for 3D bioprinted organs or transplants.
3D bioprinting is a fast-developing sector that has the potential to assist both human and veterinary care. Improvements in vascularization of printed tissues, bioprinters with greater resolution and tissue models in vitro and in vivo have all resulted from bioprinting advancements. Despite the chasm between societal promise and technical development, the social and ethical problems surrounding 3D printing have received little focus. 3D bioprinting technology, on the other hand, has the potential to revolutionise the way in which the human body is fixed or replaced. Despite this, there are still concerns about universal access and equity, biological and engineering responsibilities in terms of functioning matching with in vivo organs, as well as the ethical control of the process, object, and consequences.
Author
Ms. Prachi Khamkar
Ms. Prachi is a scientific content writer for Next Big Innovation Labs®.She also serves as Project head in Pharmaceutical Manufacturing Operations at CiREE, Pune. Her area of interest Pharmaceutical 3D Printing and 3D Bioprinting. Received numerous awards for Scientific and Professional bodies at National and International Platforms for 3D Printng in Healthcare sector. She has published several review articles and book chapters based on 3D Printing Technology in Pharmaceutical for International Publication.
