A 3-D bioprinter extruding a “bioink” with suspended human cells to create a trilayer tissue structure.

Imagine a world where the specter of deadly diseases fades into obscurity and the agonizing wait for life-saving organ transplants becomes a relic of the past; the realm of healthcare undergoes a transformative evolution. Scientists have long harbored dreams of a future where personalized organs can be crafted on demand, reshaping the very fabric of medical care. Gone are the days of patients languishing on transplant lists, their hopes tied to the availability of critical organs like hearts or kidneys. Such is the promise held by bioprinting—a technology whose potential seems to stretch as boundlessly as the sky itself.

Photo by ZMorph All-in-One 3D Printers on Unsplash

The genesis of bioprinting finds its roots in a lineage of innovative manufacturing processes that stretch back decades. Initially dubbed additive manufacturing or three-dimensional (3D) printing in the 1980s, this revolutionary approach involves the gradual construction of objects, layer upon layer, in stark contrast to traditional subtractive methods. It was in the year 1981 that the seeds of modern 3D printing were sown by a visionary Japanese lawyer, Dr. Hideo Kodama. Dr. Kodama's seminal paper, "Automatic Method for Fabricating a 3D Plastic Model with Photo-Hardening Polymer," introduced the concept of layer-by-layer fabrication using photopolymerization—which was a concept ahead of its time.

Photo by Google DeepMind on Unsplash

Despite Dr. Kodama's groundbreaking and visionary work, the true potential of 3D printing remained largely untapped on the global stage. His pioneering efforts may have initially gone unnoticed beyond Japan's shores, but they laid a cornerstone upon which the edifice of modern 3D printing technology would rise. Dr. Kodama's innovative ideas and early research laid the groundwork for the transformative impact that 3D printing would ultimately have on countless industries, from healthcare to aerospace.

But this type of technology is bound to be carried forward. Another luminary individual emerged to carry the torch forward—Charles W. Hull, affectionately known as Chuck Hull. His journey paralleled that of Dr. Kodama, driven by a fervent passion for realizing the potential of 3D printing technology. In 1983, Hull, an American engineer, found himself immersed in experiments with ultraviolet (UV) light, seeking to solidify tabletop coatings. Yet, amidst his endeavors, he encountered the arduous task of prototyping plastic parts destined for injection molding—a process he found to be exceptionally laborious and time-consuming.

Photo by Karl Hörnfeldt on Unsplash

Hull's keen observations of the laborious process before him spurred him to action. Witnessing the considerable time and effort required to complete the task, he became determined to streamline and accelerate the prototyping process. For Hull, the inefficiency of traditional methods became a personal challenge—a barrier standing between him and the realization of his designs. Reflecting on his frustration, he remarked, "I saw it as a big impediment to design a plastic part because I had to design a plastic part now and then so I would get frustrated. I kind of put two and two together. If I could print lots of these layers, I can have a proper plastic part, so that was just the basic ‘aha’ moment." With this epiphany, Hull embarked on a journey to revolutionize manufacturing as we know it.

Chuck Hull, Image from Industryweek

A mere year later, Chuck Hull took a decisive step forward, solidifying his vision in the form of a patent application titled "Apparatus for production of three-dimensional objects by stereolithography," submitted on August 8, 1984. This pivotal moment not only marked the inception of the term "stereolithography" but also heralded the dawn of a new era in manufacturing. Two years elapsed before Hull's dream was officially realized, as the patent was granted on March 11, 1986—a watershed moment that forever altered the trajectory of the print industry.

Bioprinting, a Symbol of Human Advancement

A 3-D-printed heart. Photo by Bryce Vickmark

The evolution of 3D printing from its roots in engineering to its expansive applications across various fields is a testament to human ingenuity. In the realm of medicine, this transformative technology has unlocked new possibilities, allowing biomaterials to replicate the intricate properties of human organs. The genesis of "bioprinting" traces back to a pioneering group of researchers at the Boston Children's Hospital, Harvard Medical School. Here, the researchers embarked on an unprecedented journey that culminated in a groundbreaking achievement: the creation of the first 3D urinary bladders. These milestones marked a departure from conventional manufacturing methods, as each organ was meticulously handcrafted, with scaffolds intricately woven from collagen and polymer, then delicately layered with patient-derived cells, signaling the dawn of functional organs.

Photo by Louis Reed on Unsplash

Guided by visionary leadership, the torchbearer of this initiative, renowned tissue engineer Dr. Anthony Atala, later assumed a pivotal role at the Wake Forest Institute for Regenerative Medicine (WFIRM), fostering a fertile ground for innovation. It was here that machines capable of crafting bespoke scaffolds for human organs were conceived, ushering in an era of limitless potential. Since then, a rich tapestry of research has woven countless categories of tissues and organs by hand, with each thread serving as a testament to human brilliance. As this journey continues towards perfection, the path to clinical application beckons, promising a future where bioprinted organs could transform the healthcare landscape.

Dr. Anthony Atala

Image from Innovation Quarter

Image from Drug Target Review

Here, machines capable of crafting bespoke scaffolds for human organs were conceived, ushering in an era of limitless potential. With the foundation laid by Dr. Atala's pioneering work, the field of bioprinting witnessed exponential growth. As research continued to flourish, a rich tapestry of methodologies emerged, each offering unique approaches to tissue engineering and regenerative medicine.

Bioinks, the Backbone Material

One crucial material amidst the bioprinting process is "bioinks," specialized biomaterials used in the field of 3D bioprinting to create structures resembling living tissues. They typically consist of a combination of cells, biomolecules, and carrier materials such as hydrogels or other biocompatible polymers. Bioinks provide the necessary environment for cells to adhere, proliferate, and differentiate, allowing for the fabrication of complex tissue structures layer by layer. These materials serve as the "ink" in bioprinters, enabling the precise deposition of biological components to build three-dimensional tissue constructs with spatial control and biological relevance.

Image from Facellitate

However, great potential often comes with numerous caveats. These bioinks must meet stringent criteria to ensure the success of the bioprinting process and the viability of the resulting tissue constructs. Firstly, they require exceptional mechanical strength and resilience to uphold the structural integrity of printed tissues while faithfully replicating natural mechanical properties. Additionally, bioinks must exhibit adjustable gelation and stabilization properties, crucial for the precise deposition of biological components and maintaining desired structural fidelity during printing.

Biocompatibility is paramount, enabling seamless integration with the biological environment, promoting cell viability, and preventing rejection by the body. Biodegradability is equally vital, facilitating tissue remodeling and regeneration over time to foster integration with host tissue. Lastly, bioinks should be readily amenable to chemical modifications, offering versatility for tailoring specific tissue types to diverse biomedical applications. These criteria collectively emphasize the vital role of bioinks as the foundation of bioprinting innovation, poised to revolutionize regenerative medicine and tissue engineering in profound ways.

Types of 3D Bioprinting

Image from Microbenotes

Meanwhile, such a versatile technology comes with different methods to cater to various needs and applications. Diverse forms of 3D bioprinting have emerged, each with its unique methodology and applications:

• Extrusion-based bioprinting: This method utilizes semi-solid extrusion (SSE) or fused deposition modeling (FDM) techniques to create intricate structures, mimicking soft tissues and bone structures with precision.
• Inkjet-based bioprinting: Employing non-contact technology, inkjet bioprinting ejects liquid droplets onto a substrate with precision, offering cost-effectiveness and compatibility with living materials.
• Pressure-assisted bioprinting: Biomaterials are extruded through a printer nozzle under pressure, enabling the fabrication of 3D biological structures with room temperature processing and direct incorporation of homogeneous cells onto the substrate.
• Laser-assisted bioprinting: This innovative approach deposits biomaterials onto a surface using a pulsed laser beam, facilitating cellular adhesion and sustaining the growth of deposited biomaterials, paving the way for intricate tissue engineering and regenerative medicine applications.
• As bioprinting continues to evolve, fueled by relentless innovation and boundless potential, the horizon of healthcare transforms, promising a future where bioprinted organs could revolutionize patient care.

Transforming Bioprinting Concepts into Real-World Solutions

Image from Carnegie Mellon University

Now, let's explore real-world achievements in the field. A distinguished faculty member in the Departments of Biomedical Engineering and Materials Science and Engineering at Carnegie Mellon University, Professor Adam Feinberg, and his research team accomplished a groundbreaking feat: the bioprinting of a complete human heart. Utilizing their innovative Freeform Reversible Embedding of Suspended Hydrogels (FRESH) technique, they replicated cardiac tissue elasticity and sutures with remarkable realism. This milestone marks the culmination of two years of intensive research, offering immediate promise for surgeons and clinicians while also heralding significant long-term implications for the advancement of bioengineered organ research.

Yet, why hasn't this breakthrough gained widespread attention? Despite Professor Feinberg's demonstration of the versatility and precision of the FRESH technique, the primary challenge in achieving this milestone was the printing of a human heart at full scale. This required the development of a bespoke 3D printer capable of accommodating a gel support bath large enough for printing at the intended size, along with minor software adjustments to ensure optimal printing speed and fidelity.

Image from WFIRM

Another pioneering effort in bioprinting, led by Dr. Atala at WFIRM along with colleagues, showcased the potential of engineered micro hearts, lungs, and livers for drug testing purposes. By integrating these micro-organs into a monitored system, researchers aim to replicate the human body's response to medications. The success reported by the research team involves the engineering of micro-sized 3D organs, termed organoids, which are interconnected on a single platform to monitor their functionality. This achievement marks the first documented success using 3D organ structures, known for their higher functionality and ability to more accurately model the human body.

In this system, the organoids are housed within a sealed, monitored environment equipped with real-time cameras. A nutrient-rich liquid circulates through the system, sustaining the organoids' viability and serving as a medium for introducing potential drug therapies. Through various experimental scenarios, including the introduction of a cancer treatment drug, researchers confirmed that the body-on-a-chip system mimics multi-organ responses. Surprisingly, the drug's effects on lung scarring also impacted the system's heart, leading to increased heart rate and eventual cessation—a revelation of a previously unforeseen toxic side effect. This discovery underscores the system's potential in identifying adverse reactions during the drug development process, as highlighted by Aleks Skardal, PhD, assistant professor at Wake Forest Institute for Regenerative Medicine. Efforts are underway to enhance the system's efficiency for large-scale screening and to incorporate additional organs for comprehensive testing.

In the realm of bioprinting, the journey from concept to real-world application represents a remarkable testament to human ingenuity and innovation. From the pioneering work of Dr. Anthony Atala and his team at WFIRM in engineering micro hearts, lungs, and livers for drug testing, to Professor Adam Feinberg's groundbreaking achievement in bioprinting a complete human heart, these milestones exemplify the transformative potential of bioprinting technology. Yet, despite these strides, challenges persist, such as the need for custom-built 3D printers and meticulous software adjustments to achieve full-scale organ printing. Nevertheless, as evidenced by the successful replication and monitoring of micro-organs in controlled environments, and the elucidation of unforeseen drug effects, bioprinting continues to advance, offering hope for a future where personalized organs and improved drug testing methodologies revolutionize healthcare. With ongoing efforts to refine bioprinting techniques and expand its applications, the horizon of possibilities in tissue engineering and regenerative medicine seems boundless, promising a future where bioprinted organs and tissues play a pivotal role in enhancing patient care and advancing medical research.

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