Biomedical 3d Printing

From New Media Business Blog

Contents 1 Introduction 2 Description 2.1 Timeline 2.2 Major Players 3 How it Works 3.1 Bioink 3.2 Printer 4 Methods 4.1 Inkjet 4.2 Extrusion 4.3 Laser 4.4 Stereolithography 4.5 Acoustic Bioprinting 4.6 Microvalve Bioprinting 4.7 Scaffold free Bioprinting 4.8 Hybrid Bioprinting 5 3D Bioprinting as a Business 5.1 Market Value 5.2 Costs 5.3 Access 6 Pros & Cons 6.1 Pros 6.2 Cons 7 Promising Projects[48] 8 The Future 9 Authors 10 References

Introduction

3 Dimensional (3D) Printing is a new technology that has reinvented the way we look at printing. Traditional 3D printers involve a form of hot almost liquid filament that is extruded through a nozzle. As the filament cools, it hardens into a new shape or printed object. Biomedical 3D printing is similar, however, the filament used contains organic materials and DNA to create organs and objects that can replace various parts of the human body.

Description

Timeline

With the first 3D printer being invented in 1984, the technology is still very new and has seen major milestones in the last 20 years.^[1].

In 1986, Charles W. Hull, created and patented the first 3D printed for commercial use, after this the ability to research and innovate began. In 1999, the Wake Forest Institute of Regenerative Medicine created the first lab-grown organ (bladder) which saw a successful implementation. ^[2].

In 2008, they reached the milestone of a 3D-printed prosthetic limb. A unique feature is that it contained all the needed biological limb parts and could be printed as it, without needing later assembly. In 2015, Aprecia Pharmaceuticals printed a tablet that gained FDA approval. The tablet was called Spiritam and was used for the treatment of various seizures. A unique feature of this tablet was its ability to immediately dissolve in the mouth, solving problems for people who struggle to swallow pills. ^[3]. In 2019, at Tel Aviv University the first heart was printed. This heart contained a vast network of blood vessels and was capable of contraction. The heart was made from the fatty tissue of the patient and was converted into stem cells.

The cells were then added to a gel to create the unique bioink. The heart was not implemented at this time as the doctors were unsure if the heart's structure could withstand the flow of blood. ^[5]. In 2020, FabRX a United Kingdom-based company launched a product called M3DIMAKER which was the first 3D printed that could be manufactured for personalized medical needs. Similar to the tablet by Aprecia Pharmaceuticals, this printer is able to print multiple prescriptions of medicine into a single 'polypill', making complicated regimens simpler. ^[6].

Major Players

Despite this being a newer industry, there are quite a few major players trying to gain a competitive edge, even in the research field. Three major players include:

3D Biotherapeutics

This New York-based company is a leader in regenerative medicine utilizing a four-part technology to revolutionize 3D bioprinting. Their most groundbreaking milestone is their work in treating Microtia. Microtia is a birth defect where babies' ears aren’t fully developed. Although it is non-life-threatening, there are effects on the children's mental health and self-image. They are now in their clinical trials of printing and implementing a 3D-printed ear. Their four part technology involves a special bioprinter, unique bio-ink, specialized cell structures and an implantable shell. ^[7].

3D Bioprinting Solutions

This company is based in Moscow Russia and has had major success both on Earth and in space. The official opening took place on September 6, 2013, and by the Spring of 2015, they were able to construct a thyroid gland for a mouse. At the beginning of 2016, they invented an entirely new bioprinter which would be used in space.

The lack of gravity in space provides an even better environment for 3D printing, allowing for more complex designs to be printed faster. The printing is done inside the printer, however, is not tethered to any surface. With the object floating in the container, it is able to be more complex in shape, without fear of the print being ruined.

3D Systems

3D Systems is a large company based in Rockhill South Carolina. They operate in a variety of industries, some examples are aerospace, jewellery, motorsport, semiconductors, and service bureaus. Their largest milestone was their ability to successfully print transplantable lungs. The lungs are promised to have a 0% chance of rejection due to the lungs containing DNA from the recipient. They have had success in animals and are projecting to have human trials in the next four years. ^[9].

How it Works

Bioink

The uniqueness of biomedical 3D printing from traditional 3D printing comes from the difference in the filament used. For biomedical 3D printing, the filament is called bio-ink and contains three key components, biological materials, hydrogels and biochemical factors ^[10].

The first component of biological material is made of two properties, living cells and tissue/extracellular matrix (ECM). The living cells come from the recipient of the organ. This will allow for no rejection of the organ and the recipient's own DNA will be in the product. The tissue and ECM will provide a natural microenvironment for the cells.

The second component is the hydrogels. Hydrogels are water-based polymers that are used to provide structure at support to the bio-ink. They must be made of a biocompatible material. Some examples include gelatin, alginate, collagen, and hyaluronic acid ^[11]. Hydrogels will also often contain some synthetic materials such as Polyethylene Glycol (PEG), which is used to give the cells and bio-ink more structure and support overall. ^[12].

The third component of bio-ink the biochemical factors. These are a variety of factors with the purpose to keep the bioink alive, and healthy. There are growth factors to focus on proliferation and tissue development, nutrient and cytokines such as amino acids, vitamins, and interleukins to create cellular responses .^[13]. Lastly, there are bioactive materials such as antibodies to prevent cell decay.

Printer

The printer has many moving parts that work harmoniously together to create the simulated tissue with remarkable precision. The hydrogel plays a crucial role by providing bio-ink, a specialized biomaterial, with essential nutrients and oxygen. The bio-ink, infused with cells that mimic the target tissue, forms the building blocks of the printed structure.

The process takes place within the bioprinter, where an elevator, a metal shaft at the back, allows for the vertical movement of the print, enabling the stacking of multiple layers^[15].To monitor and control the printing process, a control screen displays vital information such as progress, duration, and other relevant data. Throughout the printing procedure, the platform serves as the base that holds the printed tissue, often integrating a petri dish for support^[16]. The nozzle is a critical element from which the bio-ink is precisely ejected, contributing to the intricate design of the tissue. Lastly, the reservoir plays a pivotal role as it holds both the bio-ink and hydrogel, ensuring a continuous supply throughout the printing process. The harmonious interplay of these components facilitates the creation of intricate and functional simulated tissue with great promise in various fields of medicine and research.

Methods

Inkjet

Inkjet-based printers deposit cells or biomaterials using heating reservoirs or piezoelectric actuators ^[18]. The first type is thermal which is heating-based and small bubbles are generated by heating the printhead which then forcefully prints out as droplets ^[19]. The other type is called piezoelectric printers which use pressure pluses to print droplets ^[20]. These techniques are more affordable, more compatible with living materials and much faster. However, their application is limited due to the limited range of printable biomaterial since heat-based and piezoelectric-based printers may cause damage to cells during the printing process ^[21].

Extrusion

This bioprinting uses pneumatic pressure (pressure from pressurized gas) or mechanical tools(screw and piston) to deposit material in a fast and controlled manner. They can handle high cell density, thick and sticky fluids, and crosslinking mechanisms ^[22]. This type of bioprinting mimics soft tissue and bone structures. However, the limitations include lower resolution and damage to cells due to the force being exerted by the printing nozzle ^[23]. Resolution refers to the fine details and precision the printer will capture and print.

Laser

Laser-assisted bioprinting method puts the biomaterials onto a surface using a laser beam. By using the laser beam it causes the liquid biomaterial to evaporate and reach droplet form ^[24]. This method is also known to be highly accurate and nozzle clogging is eliminated as it is a nozzle-free printing process, however, the heat generated from this method could impact the cells negatively. ^[25].

Stereolithography

This method uses light to crosslink bio-ink in a layer-by-layer process ^[26]. However, it is limited to light-responsive bio-ink and therefore has fewer options for bio-inks compared to other methods. Some advantages include a higher degree of accuracy and lower printing time. However, it uses UV light, which has a higher intensity and longer processing time ^[27].

Acoustic Bioprinting

This method is a type of droplet-based method that uses acoustic waves to generate force that ejects the droplets filled with bio-ink ^[28]. This printer has a piezoelectric component and gold rings which generate acoustic waves ^[29]. Droplets are ejected when the force of the acoustic radiation is generated. The advantages are they do not expose the cells to heat or high pressure which causes cell damage ^[30]. Some disadvantages are the loss of control over droplet ejection and gentle acoustic waves, which may not eject thicker bio-inks ^[31].

Microvalve Bioprinting

This is a type of droplet-based bioprinter and this uses an electromagnetic micro-valve with a coil and plunger to eject droplets ^[32]. The magnetic field forces the plunger upwards pressurizing the bio-inks in the barrel and ejecting the ink ^[33]. The advantages are they do not expose the cells to heat or high pressure which causes cell damage. However, the droplets produced by micro-value bioprinters are larger compared to inkjet bioprinters resulting in lower resolution ^[34].

Scaffold free Bioprinting

Unlike traditional bioprinting methods that use scaffolds to hold and guide the growth of cells, scaffold-free bioprinting does not rely on such external structures. Scaffolds refer to the printable hydrogels commonly referred to as bio-inks ^[35].In scaffold-free bioprinting, cells are aggregated into three-dimensional clusters or spheroids. These spheroids are formed by allowing cells to self-assemble and interact with each other, creating a microenvironment that resembles the natural tissue ^[36]. The spheroids are then carefully deposited layer by layer to build complex tissue structures without the need for supporting materials.^[37]. This approach offers several advantages, including faster tissue fabrication as cells can organize themselves into functional structures more efficiently, better cell-cell interactions that mimic native tissue behavior, and the potential to create more intricate and biomimetic tissues. ^[38]

Hybrid Bioprinting

Although each approach has its very own strengths and weaknesses, combining different methods may be useful in specific conditions. For instance, a hybrid bioprinting machine that integrates inkjet-based and extrusion-based has been proposed for developing 3-D in vitro skin models^[39]. However, it is vital to be aware that these hybrid strategies involve extra complex fabrication methods and require advanced software and hardware controllers, which may pose challenges for researchers who desire to utilize them ^[40].

3D Bioprinting as a Business

Market Value

As a business, 3D bioprinting will not only create its own market value, but also tap into multiple current markets. Since it is still in the experimental phase we can only make assumptions about the potential business value based on these current markets. The 3D bioprinting in the medical application market size is expected to have a compounded annual growth rate (CAGR) of 23.28% from 2022 to 2030 ^[42]. The global transplantation market is expected to have a CAGR of 9.3% from 2023 to 2030 ^[43]. Both markets stretch into the billions of dollars in market size. By using these statistics, we can assume 3D bioprinting will likely become a market that will grow in a similar upward trend. This shows it could be a worthy investment from a business perspective.

Costs

The average 3D bioprinter costs approximately $100,000 ^[44]. The cost of tissue printing is relatively inexpensive at an average of $1000 ^[45]. However, the unknown variable costs of printer operators as well as transplantation is where monetizing the technology becomes blurry. What we do know is that the average cost of a kidney transplant in the United States is $442,500 ^[46]. With that being said, there is roughly $300,000 that can be allotted for these unknown costs. This is leading industry professionals to assume 3D bioprinting will be a cheaper option for patients despite the unknowns.

Access

Another unknown for 3D bioprinting is who will have access and will it be covered? From a business perspective, we know private firms have the opportunity to make more revenues rather than being a government owned public firm ^[47]. They typically have higher efficiencies which lead to those higher revenues. By keeping 3D bioprinting private it would also allow for competition between multiple firms. This competition allows for constant innovations within the field in order to stay relevant. This also allows this innovation to occur without external influences. For example, as a public business political influence and power can change and impact the development of the technology. Overall, the best business value for 3D bioprinting would be through keeping firms private.

The next question we face surrounds coverage. The best hypothesis we can derive is that the technology will not be covered for patients until it is widely accepted and regulated. However, we already see regulations being placed on 3D printing in the medical application. In Canada, transplants are covered by public healthcare. Since 3D bioprinting is expected to be cheaper than traditional practices, we hypothesize eventual public coverage being offered for Canadians. However, combining this with business value we see 3D bioprinting being outsourced and covered by the government, but ultimately privately owned.

Pros & Cons

Pros

An obvious pro of 3D bioprinting is it will combat the organ shortage. Patients would no longer need to wait for matches or donors. We wouldn’t lose lives while people remain on these lists for years. By offering personalized organs, patients run a significantly lower risk of transplant rejection due to this technology. By printing organs, it would also reduce medical wait times. Patients could get definite transplant dates rather than being put on a seemingly endless timeline. They would not need to wait for the perfect donor, rather an open printer. 3D bioprinting can also revolutionize drug testing and medical research. We can use bioprinted organs for drug trials and see how the medicine will directly impact human cells. We can also give our future doctors and practitioners hands-on practice with printed organs. This can make our surgeries more efficient and our education engaged. Finally, this technology can reduce human organ trafficking. Simply put, printing organs will reduce the demand for new organs. Organ transplants would be available and accessible, thus reducing the need for this illegal activity.

Cons

To balance out the pros we must also understand the cons. Although 3D bioprinting is expected to be less costly than current practices, it will still be expensive which limits accessibility. The process is also highly complex. Each organ is individualized which means we can’t just mass produce excess organs. Ultimately, the long term safety and efficacy remains unknown. These organs have not been tested for long enough for us to understand how long they will remain working. This limits the implementation timeline for this technology. There are also legal concerns that come with this technology. For example, who can print organs? Who will regulate them? There also come ethical concerns. Who will be helped first? Will cosmetic procedures be held with importance? Ultimately, the unknowns as a whole are what gives 3D bioprinting its cons. With future development we hope to see the number of cons reduce.

Promising Projects^[48]

• Boston University has created a miniature heart out of human stem cells. Their new invention of the “miniPUMP” allows the heart to function and pump blood.

• Tongi Hospital in China has used hydrogel to build ovaries for mice. The purpose of this is to study the impacts of diseases.

• A research group out of India has used human corneal tissue to create 3D bioprinted corneas. They have found success by experimenting with rabbits. This could mean a cure for certain eye diseases. One day it could ultimately mean giving the gift of sight to those without.

• Trestle Biotherapeutics in the U.S. have used stem cells to create 3D bioprinted kidneys. An interesting point they are making is 3D printed kidneys may only be a temporary solution. This means patients would rely on their 3D bioprinted kidney while ultimately waiting for a donor match.

These innovations seem far away from implementation, however we have seen examples of the reality of this technology. Luke Masella was born with Spina Bifida which led to his bladder becoming defective. Doctors in 2004 were able to make a collagen scaffold of a bladder and allowed Luke’s cells to grow over it for two months, it was then successfully transplanted. Now in his twenties, Luke’s bladder is still working and has allowed him to “live a normal life after.” ^[49]

The Future

In conclusion, the future of 3D bioprinting is promising. With experiments running in multiple countries, the technology will surely continue to expand. With effort being made on the International Space Station the possibilities are being pushed further than ever. The investment into this technology may seem far-fetched however, “even though rockets cost tens of millions of dollars per mission, NASA’s organs are still expected to cost less than what patients pay to treat chronic disease." ^[50]

Authors

Guneet Gill	Madison Rieger	Sonya Vasan
Beedie School of Business Simon Fraser University Burnaby, BC, Canada	Beedie School of Business Simon Fraser University Burnaby, BC, Canada	Beedie School of Business Simon Fraser University Burnaby, BC, Canada

References

1. ↑ https://www.bcn3d.com/the-history-of-3d-printing-when-was-3d-printing-invented
2. ↑ https://school.wakehealth.edu/research/institutes-and-centers/wake-forest-institute-for-regenerative-medicine/research/abcs-of-organ-engineering#:~:text=In%202016%2C%20the%20institute%20announced,a%20system%20of%20blood%20vessels
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5. ↑ https://www.nbcnews.com/mach/science/israeli-scientists-create-world-s-first-3d-printed-heart-using-ncna996031
6. ↑ https://www.fabrx.co.uk/2020/04/06/fabrxs-pharmaceutical-3d-printer-for-personalised-medicines-m3dimaker-is-now-available
7. ↑ https://3dbiocorp.com/company/#our-story
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33. ↑ https://www.mdpi.com/2073-4360/12/12/2958
34. ↑ https://www.mdpi.com/2073-4360/12/12/2958
35. ↑ https://www.researchgate.net/publication/323781459_Progress_in_scaffold-free_bioprinting_for_cardiovascular_medicine
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38. ↑ https://sites.esm.psu.edu/~ito1/assets/files/Scaffold-Based_or_Scaffold-Free_Bioprint-2.pdf
39. ↑ https://www.mdpi.com/2073-4360/12/12/2958
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