Three‐Dimensional Bioprinting in Regenerative Medicine: Reality, Hype, and Future

Regenerative medicine aims to repair or restore function to tissues and organs. The field has seen major advances recently even if serious challenges still remain, stemming primarily from the inherent complexity of the human body. The organs in our body are results of millions of years of evolution in the course of which nature experimented until it “got it right.” This experimentation was not without victims: many of the shapes and forms that appeared eventually were eliminated by natural selection, favoring those with the most relevant function and compatible intricate structure. As a consequence, present day tissues and organs are all complex, and their complexity varies depending on the cell type and organization, architecture, and function. Flat tissues (e.g., skin) are the least complex, tubular structures (e.g., blood vessels) more complex, hollow nontubular organs (e.g., bladder) even more complex, and solid organs (e.g., liver or heart) the most complex. Just three decades ago, most human cell types could not be grown and expanded outside the body, human stem cells had not yet been identified, and technologies such as cloning had not yet been developed. Today, with advances in cell and molecular biology, most types of cells can be grown in vitro, multiple types of human stem cells have been established and organs have been engineered in the laboratory. Engineered organs such as skin, urethra, blood vessel, bladder, and vagina have been implanted in patients in limited numbers in clinical trials. Several tissue-engineered products are advancing through the regulatory pathway so they can be eventually commercialized and disseminated widely. However, most of the engineered tissues now in the more advanced stages of the regulatory pathway were made by hand. The engineering of a living tissue and its fabrication by hand require several steps, each with its own hurdles. The undertaking starts with the sourcing of the seed population of cells. For this, typically, a tissue biopsy is performed. The resulting cells then have to be grown and expanded in vitro. This may sound easy. However, reliably obtaining cells with similar release criteria that will perform with the expected level of function requires extensive knowledge of cell and molecular biology. Harvesting and cell expansion techniques, culture media protocols, growth factor additives, environmental conditions, and sterility are just a few of the many details necessary to have the right cells as a starting material. Furthermore, an adult liver for example contains approximately 100 billion cells, and is composed of multiple cell types, including hepatocytes, stellate cells, and Kupffer cells. In order to create such an organ, the various cells need to be expanded at the same time, to large numbers and thus divided many times outside of the body. Extreme care needs to be exercised to make sure that the resulting cells do not become transformed and remain functional consistent with their intended use. Equally complex are the biomaterials that are necessary to make normal tissues. They need to have the right properties to support cells in vitro but also characteristics to make them biocompatible and suitable for impantation into the patient. Finally, adding the cells to the biomaterials with the interactions necessary to have the right environment for tissue formation in bioreactors and incubators adds yet another level of complexity to the process. In parallel to the development of regenerative medicine, the field of three-dimensional (3D) printing has also advanced. Three-dimensional printing has been used in the manufacturing industry for decades. It was first applied to make plastic samples to be used as prototypes for more complex parts that would typically be later mass produced. This was a laborious and costly process. The printers initially were cumbersome and expensive pieces of machinery, some with a cost of more than a million dollars, and technically difficult to operate. Technological advances have led to the current state-of-the-art printers that are being used to manufacture a wide range of products, from complex tools to automotive parts and entire buildings. The design and operation of 3D printers have been markedly simplified. Desktop 3D printers can now be used even by children and are being sold in toy stores at a low cost, some for less than $100. Three-dimensional printing, now also a major component of additive manufacturing, led to the more recent advent of bioprinting, the specific Dr. Atala is the Editor‐in‐Chief of Stem Cells Translational Medicine and Director of the Wake Forest Institute for Regenerative Medicine, and the W. Boyce Professor and Chair of Urology at Wake Forest University. Dr. Atala is a practicing surgeon and a researcher in the area of regenerative medicine. His work focuses on growing human cells, tissues and organs. Dr. Atala heads a team of over 450 physicians and researchers. Over twelve applications of technologies developed in Dr. Atala's laboratory have been used clinically.