What Is Bioprinting?

Bioprinting is an additive manufacturing process that builds artificial body parts out of filaments made from living cells. Typically, these biomaterial filaments (called bio-ink) are extruded layer by layer to create a synthetic biomedical part, similar to 3D printing. The idea is to build biomimetic structures that accurately replicate those naturally occuring in our bodies. So far, bioprinting can produce living tissue, bone and blood vessels, with the aim to eventually fabricate entire organs from scratch.

Bioprinting is the process of creating 3D, cellular structures out of bio-inks. It’s used to build functional, biological replicas of body parts, like living tissues, bone and blood vessels.

In 3D printing, a printer can be used to build tools and structures, like tech accessories, jewelry or toys, out of metals, plastics or ceramics.

“Bioprinting takes this a step further,” said Ryan Creek, a certified physician associate with experience in regenerative medicine at biotech startups. “The ‘printing’ is done using biologically derived materials that can then replicate some of the properties of specific tissues in the body.”

Bioprinting is thought to be a vanguard for regenerative medicine, and it will likely be used to repair or restore damaged and diseased tissues. Currently, it’s being put to the test in lab-based research to trial drugs and explore treatments. Just last year, surgeons in San Antonio, Texas became the first team to implant a 3D-bioprinted structure — an ear, grown from the patient’s own cells — onto a human.

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Before the actual printing starts, a biopsy must be taken from the organ. Certain ‘“desired” cells are isolated, then multiplied via a culturing process that promotes growth in an artificial environment. Certain cell types are singled out, depending on the project. For example, if a researcher wanted to fabricate a meniscus, fibrocartilage cells would be required for the job.

These cells will then be mixed in a hydrogel solution, which provides oxygen and nutrients to the cells to keep them alive, and loaded into a cartridge.

“Bio-ink formulations are typically made of [a combination of biomaterials] that help cells grow and mature as tissue,” explained Didarul Bhuiyan, a biomaterial and tissue engineering scientist at West Pharmaceutical Services. These biomaterials usually include different biopolymers, proteins and growth factors. Together, they help build the scaffold that the living cells then populate.

In the meantime, a digital blueprint is created using a computer-aided design (CAD) file that splices the subject into thin layers. This prepares the three-dimensional framework as a set of instructions that construct the object from the bottom up.

At this point, the project is print ready. A nozzle guided by a robotic arm horizontally moves along an X-Y-Z axis, extruding filament as it follows the CAD file blueprint. Layer by layer, the bio-ink builds the final structure onto a scaffolding tray or a liquid base.

While some biomaterials may cure in real-time, others may require more care in vivo to ensure full functionality and overall cell viability. In post-production, bioprinted structures may be placed in bioreactors for optimal tissue maturation, vascularization and stability. Depending on the complexity of a biomedical part, this final step may take weeks or even months.

The above describes the most common bioprinting method, which is called material extrusion. Other methods include inkjet 3D bioprinting, which builds pieces in droplets, and stereolithography, a technique that cures an object by projecting ultraviolet light through a vat of resin.

It’s no secret that creating whole, functional organs is the holy grail of bioprinting.

This is why researchers at the University of São Paulo in Brazil explored the use of blood cells in order to develop miniature versions of the human liver, producing a viable organ in just 90 days. The “hepatic organoids” can produce vital proteins, store vitamins and secrete bile.

In animal trials, researchers in Poland have bioprinted a functional pancreas prototype, dubbed the ‘Bionic Pancreas,’ that demonstrated blood flow in pigs over a two-week period.

Meanwhile, San-Diego-based bioengineering startup Trestle Biotherapeutics earned its license to manufacture human kidney tissues that can treat those in end-stage renal disease, wean less severe cases off of dialysis, give more time to those on the transplant list and eventually replace the organ entirely.

Researchers at the United Therapeutics Corporation made way toward the world’s first 3D-printed, cellularized lungs with their construction of a human lung scaffold, complete with 4,000 kilometers of capillaries and 200 million alveoli, capable of oxygen exchange in animal models. They expect the project to be cleared for human trials in the next five years, according to the report.

Boston University researchers bioprinted a miniature human heart that beats on its own. Dubbed the ‘miniPump,’ researchers fabricated the bantam heart out of living stem cell-derived human heart cells and 3D-printed acrylic parts on the microscale. Moving forward, these tiny, artificial hearts will be used to study the human body up close and personal, allowing insight on their embryonic growth, how cardiac diseases progress or how the blood-pumping organ reacts to new drugs.

In 2019, researchers at the Rensselaer Polytechnic Institute developed fully vascularized skin patches, successfully creating a synthetic stand-in of the body’s largest organ. The skin liquid-gel consisted of a human-cell cocktail suspended in collagen extracted from rat tails. When grafted to rodent test subjects, the bioengineered skin patches organically developed blood vessels, which connected to the host’s vascular system in a matter of weeks. Findings from the study promise better burn care and accelerated wound healing in the near future.

Elsewhere, scientists at the Wake Forest Institute for Regenerative Medicine created a mobile skin bioprinting system that can print pseudo-skin directly into a wound from a patient’s bedside.

Corneal opacities are the fifth leading cause of blindness worldwide, according to the World Health Organization. To support the 4.2 million people suffering with treatable vision impairment, a team of India-based researchers developed a bioprinted corneal implant that cleared animal trials. For every human cornea donated, three artificial corneas can be printed, researchers claim.

Reprinting parts of the female reproductive system could help fill in the gaps of the underfunded, under researched area that is women’s healthcare. Doing their part, a team of Northwestern University researchers have successfully implanted an ovarian bioprosthesis that can boost hormone production, restore fertility and rehabilitate endocrine health in mice. In the experiment, healthy ovaries were removed, then replaced with the bioprinted, gelatin-based scaffolds that housed immature mouse eggs. The bioprosthesis were capable of ovulation, fertilization and carrying out a live birth.

One out of every six deaths is caused by cancer. Yet, how these cells communicate and behave remains somewhat of a mystery to the medical community at large.

To better understand the myriad of mutated cells, scientists have adapted ‘on-a-chip’ technology, established by the Wyss Institute in 2007, to study cancer cell behavior. These microfluidic culture devices, which come in the form of tumor-on-a-chip or cancer-on-a-chip, provide a window into the microenvironments in which metastasis proliferates in order to grasp a better understanding in how to develop anti-cancer agents.

According to Creek, cancer research is an often overlooked bioprinting application.

“Most of the media interest is directed at implanted technologies,” Creek said. “But if you could replicate human tissue, organs or specific cancerous tumors in a test-tube environment, you could then study the effects of medications and other treatments before trying them in human beings.”

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Bioprinting isn’t just about producing look-alikes — these living cellular structures are also functional, biological replicas of their naturally occurring counterparts. Biomimicry is achieved when an artificial twin successfully recreates cellular interactions found in the sample tissue by replicating identical structural elements from the same cell types set in uniform placement under controlled conditions. Scientists rely on scaffolds and bioreactors to aid in this process.

Any technology developed within the 3D-printing space enjoys a high level of control. These machines are designed to replicate CAD models down to the cell position along an X-Y-Z axis, recreating architecturally complex microstructures capable of biomimicry.

“Also, bioprinting is better suited for creating tissue with multiple sets of different cell types,” Bhuiyan said, “that other traditional fabrication techniques typically lack.”

Research looking into the implementation of artificial intelligence — more specifically, machine learning — to create the perfect digital dupe is already underway.

The highly customizable nature of 3D printing infers the eventual availability of patient-specific treatments. From an extracting biopsy, doctors culture the cells before mixing them into a bio-ink, that’s used to construct the desired organ or tissue out of the patient’s own DNA. These personalized tissues and organs are tailor-made matches to each patient, decreasing the likelihood of rejection.

Aside from the pre- and post-production required of tissue engineering, bioprinting is highly amenable to automation. Mass producing organs could mean the difference of life and death for those waiting on the transplant list — of which 17 die every day, according to the Health Resources and Services Administration. The promise of bioprinting is in its scalable delivery of on-demand transplants, as simple as harvesting cells, uploading a digital file and pressing print. Also, the more computerized a procedure becomes, lowering the probability of human error.

If bioprinting is able to yield living tissues that emulate those naturally occurring in humans, then the possibility of removing animal testing from life science labs altogether becomes more of a reality. One organization, a European project known as BRIGHTER, coordinated by the Institute of Bioengineering of Catalonia, hopes to eliminate animal experimentation with its novel tech that uses light-sheet lithography to fabricate functional human skin.

Given the fact that the technology and hardware used in bioprinting are simply adaptations from basic 3D-printing systems designed for plastics and metals, this aspect of development faces severe limitations. When working with building materials made out of bio-ink, the design of these machines fall short in areas vital to biomaterials, which require low viscosity filaments, a highly controlled, emissionless environment and near-perfect droplet placement.

“Currently, most of the materials that are good for 3D printing are not very good for cells,” Bhuiyan said. “Similarly, most of the materials that cells really love are not good for 3D printing. So, there is a real need for developing [more compatible] bio-ink materials.”

Cells endure a significant amount of stress during bioprinting. Making sure that a certain percentage of cells remain viable is crucial to the success of a project. Undersized nozzles, high pressures and nutrient-deficient environments may result in damage or cell death, potentially compromising a part’s functionality in post production. Bioprinting techniques that involve light, such as stereolithography or laser-assisted methods, can also inflict thermal and radiative stress to the cell cultures.

Fabricating biomedical parts is costly. Bioprinting is a labor-intensive science that also relies on high-caliber machinery. According to additive manufacturing hardware marketplace Aniwaa, topline printers, like the Poietis NGB-R, are priced at $200,000 — a significant price jump to those commonly used in non-bio, polymer-based 3D printing. More affordable models, like Regemat Bio V1, land around $25,000, which are most commonly geared toward university researchers. Also consider the costs that come with acquiring both human cells and property rights in working with biomaterials.

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The greatest successes in bioprinting today are in simple biomedical structures that are flat and hollow, like blood vessels, capillaries and other tubes responsible for nutrient and waste exchange.

As of now, researchers are attempting to traverse two major barriers in tissue engineering, according to Stanford bioengineering professor Mark Skylar-Scott. The first is how to best place cell types in order to eventually build complex tissues, like whole organs. The second is figuring out how to print artificial models with built-in blood vessels. That way, cellular structures could rely on the vascular networks to stay well fed and oxygenated during lengthy production processes.

These challenges have spurred unconventional projects, fusing human-cell bio-inks with plant-based, algae cells or applying cryobioprinting to extend a living structure’s shelf-life mid production, in the race to the world’s first bioengineered organ. That race will likely involve AI-programming with machine learning to produce defectless, anatomically accurate models at automated speeds.

Looking ahead, experts say that bioprinted human transplants may only be a decade away.

But before then, there’s a lot of work to do.

“We will need to complete extensive clinical trials before bioprinted technologies can be used on humans, and this process can take many years,” Creek said. This includes thorough safety and efficacy reviews from all accredited regulatory bodies. Once approved, that’s when the battle of the bottom line begins. This is when the research teams and the biotech startups breaking ground will not only have to prove the science behind their methodology, but how it makes financial sense.

“Hospital systems and insurance companies need to see that a product they pay for is ‘worth it,’” Creek added. “Otherwise there will be considerable pushback to adoption.”

Even when medical innovations actualize the impossible, treatments can remain financially out of reach to the patient populations that need it most.

On the bright side, bioprinting’s future is bound for a happy ending — it's not a question of if this tech can relieve the global organ shortage, but when.

Bioprinting is used for tissue engineering and drug research, specific to regenerative medicine. It can produce living tissue, bone and blood vessels — but not whole organs just yet.

Three-dimensional printing methods were developed before the concept of bioprinting, so much of the systems and hardware in place are playing catch up with the needs of tissue engineering.

Although both use similar methods to create three-dimensional structures, 3D printing uses non-biological materials, like metals, plastics and ceramics, while bioprinting uses a cell-based filament, known as bio-ink, made out of living biomaterials.