Sophia Colello
7/26/15
Cluster 7
Current Applications of Bioprinting Technology
As a variety of chronic diseases gain prevalence around the world, members
of the biomedical community have begun searching for a reliable way to
counteract the damage these diseases are causing. Using 3D bioprinting,
researchers are working to create functioning cardiovascular, skeletal, and
hepatocellular (or liver) tissues, among others, for use in organ
transplantation. While major advances have been made, a number of
roadblocks still stand in scientists’ way, many of which may take decades to
overcome.
“Some 18 people die in the United States each day waiting in vain for transplants
because of a shortage of donated organs” (Griggs). As occurrences of heart, liver, and
other chronic diseases continue to rise in America’s population, many sick patients are
finding that organs are simply not available when they need them most. To address this
growing issue, scientists have turned to a variety of forms of regenerative medicine,
including the emerging field of bioprinting. Researchers hope to use this new technology
to engineer a wide variety of specialty organic materials, tissues, and organs, despite the
obstacles this complicated process presents, in order to combat the increase in disease.
In the past decade, a plethora of advances have been made in bioprinting,
specifically concerning skin, cartilage, and bone tissues. “The Hutmacher group was able
to successfully print PCL-based 3D scaffolds” that are able to support both bone and
cartilage growth (Fedorovich et al. 227-228). 3D-printed titanium has also been used
successfully to make bone implants for people with damaged facial bones, as was the
case for one man in England (Gilpin). Interest in bioprinting bone instead of using grafts
or other methods of production has increased because “the ability to create artificial bone
tissue, which can be tailored to fit the shape of a desired bone through bio-printing, may
help to treat damages incurred by diseases such as osteoarthritis, and may replace
demineralized bone grafts for skeletal damage” (Polio, Yoo 16). These bioprinted bones
are one of the most extensively and successfully developed materials in bioprinting, with
implants inserted in mice showing regeneration of both bone and cartilage tissue in
specialized bioprinted compartments after one month (Fedorovich et al. 229). The same
group also found that “3D scaffolds with femoral and tibial plateau articular shape
implanted in rabbit knees successfully support cartilage regeneration and restore joint
functionality” (230). These advances as well as many others have helped solidify the
belief that bioprinting has a major role to play in the coming decades of biomedicine.
Major discoveries such as these also extend beyond just skeletal tissue:
researchers have found that thin tissues without a need for major vascularization, such as
skin, blood vessels, and cartilage can be grown in vitro (Ozbolat). With this knowledge,
scientists have gone on to grow and subsequently bioprint skin cells. Bioprinting has been
used to create “multi-layered engineered tissue composites consisting of human skin
fibroblasts…which mimic skin layers,” which researchers hope will be used for “skin
wound-repair” in the near future (Polio, Yoo 10-11). One team has even created a
specialized bioprinting machine where “skin cells can be placed in an ink cartridge and
printed directly on a wound”, such as a third-degree burn, in a process known as in situ
bioprinting (Gilpin). Scientists at Cornell University have also gone on to bioprint an
artificial ear, which may be used to help treat third-degree burn victims or other
individuals with irreparable damage (Griggs). While these treatments hold great promise,
some researchers have turned their sights on even greater targets; namely, fully
functioning bioprinted organs.
The heart is arguably one of the most important organs in the body, as it is
responsible for pumping nutrient-rich blood around the body and oxygen-poor blood to
the lungs for re-oxygenation. Without sufficient nutrients, cells can die within a matter of
hours, prompting health officials to become increasingly more concerned as heart disease
rates continue to rise. Heart valve disease in particular is becoming much more prevalent,
with no effective biological diagnostics or treatments. A person’s only option is to have a
prosthetic valve inserted which oftentimes needs to be readjusted in subsequent
procedures (Cheung, Duan, and Butcher). To remedy this issue, scientists are currently
working to bioprint a living heart valve, but a deeper understanding of how its complex
structure works is necessary in order to realize this vision (Cheung, Duan, and Butcher).
However, printing the large network of vascularization is also complicating bioprinting
research, with a variety of proposed solutions gaining attention (Gilpin). Some
researchers have been attempting to aid in cardiovascular repair by bioprinting capillary
beds, which have been created using very specific, minute processes and fat-derived cells
(Hiner). These capillary beds can be implanted as is, or used in creating other bioprinted
organs. Because the body does not create bioprinted organs itself, biomedical engineers
must also create some sort of vascularized tissue within their printed organs. This can be
achieved through the integration of bioprinted capillary beds, as mentioned before, but
that can be a time-consuming and inaccurate process. Other approaches include creating
pores inside of base scaffolds to allow for nutrient diffusion and capillary growth, but this
approach does not guarantee vascularization for all cells (Fedorovich et al. 225). Instead,
some researchers have bioprinted “patterned sheets of endothelial cells attached to a
substrate,” which can be used to vascularize printed tissues (van Bitterswijk et al. 168).
Experiments have also begun using human umbilical vein endothelial cells in bioprinting,
as they “can spontaneously form a complex vascular system which displays an
unexpected degree of self-organization” in the right conditions (van Bitterswijk et al.
169). Using these and other methods, scientists hope to create more viable bioprinted and
endothelial tissues to encourage natural cell growth and differentiation within and around
the organs upon implantation. Still others have attempted to print the heart itself.
Scientists at the University of Louisville’s Cardiovascular Institute have made a printer
that can print multiple parts of a heart and move them around as necessary during the
printing process (Gilpin). This machine allows researchers to print heart valves directly
on top of smooth muscle, or generally use two different cell types at the same time, thus
avoiding the long, arduous process of incorporating different types of tissues that have
been maturing at different times into one whole organ. While the team has yet to create a
fully functioning human heart, they have been able to assemble certain parts of the heart,
with hopes of success in the next few years.
Perhaps one of the most complicated tissues researchers are attempting to
engineer, though, is the human liver. “Liver failure…is a significant cause of morbidity
and mortality for which liver transplantation is considered the ultimate treatment.
However, a shortage of donors, the relatively risky operation and the high cost reduce the
benefits of liver transplantation. Liver disease accounts for 2.5% of total deaths in the
world, and their incidence and the health burden they impose are continuously
increasing” (Lee). With this in mind, the San Diego-based company Organovo has
pioneered research in bioprinting hepatic cells, creating very small strips of tissue that
only take five minutes to print but can survive for roughly forty days (Griggs). Other
researchers have also been able to bioprint prototypes of liver tissue with primitive
organization and microanatomies similar to those of human hepatic tissue (Lee).
However, many continue to run into the same issues concerning lack of vascularization to
printed cells, particularly in the interiors of the printed tissue, and unpredictable cellular
restructuring.
Beyond the three major research areas of skeletal, cardiovascular, and hepatic
repair, some individuals have also applied bioprinting technologies to help in printing a
wide variety of more specialized tissues. For instance, scientists have been able to make
windpipe splints out of absorbable plastic for a baby with a collapsed trachea (Gilpin).
Researchers have also been able to print a prototype, or non-functioning, human kidney
(Gilpin). Others have also been able to print several lymph nodes successfully (Hiner). A
2-year-old girl born without a trachea received a windpipe 3D printed from her own stem
cells in 2013 (Griggs). Neural cells have also been grown in culture and printed after 7
days, highlighting not only the incredible versatility of bioprinters, but also the large
quantity of time required to produce a small amount of products (Polio, Yoo 12).
While bioprinting is widely used to create living tissues for transplantation, it can
also be used to create tissues used for pharmacological purposes. As a spokesperson form
Organovo told Lyndsey Gilpin of TechRepublic, “Since the technology is not advanced
enough yet to create a full organ, the tissue samples are perfect to test drugs and other
medical advancements” (Gilpin). These tissues would actually provide more accurate
results than current methods involving rats as they use actually human cells that produce
a more realistic human response to a desired drug. By using bioprinted human tissues,
companies can also minimize the conflicts they experience with animal rights advocates.
Yet other researchers are using bioprinters to isolate specific bacterium from complicated
cultures from human infections or the environment for further testing (Biffinger et al.
243). Unfortunately, though, there are a few major problems that researchers continue to
come across while working with bioprinters and their products.
While there are many different ways to bioprint, most involve a base scaffold
made from organic materials. Unfortunately, “many of these materials dissolve in culture
or require the use of high temperatures and demanding post-processing techniques to
achieve formation of stable scaffold structures” (Fedorovich et al. 231), and “the high
temperatures involved during fabrication of melted polymers remain still critical and
limit the possibilities for direct incorporation of biological factors to enhance the
scaffolds’ bioactivity” (Fedorovich et al. 230). This obviously makes it more difficult to
work with scaffold materials when bioprinting. Even when a scaffold has been printed
correctly, “problems related to biomaterial use (inflammation, infections, aseptic
loosening, etc.)” can occur (Chollet et al. 107-14). As the cells grow on the scaffold, they
can also form “systems that are not necessarily stable and will remodel or reorganize over
time” (van Bitterswijk et al. 163), making it difficult to control exactly how the cells
grow and possibly interfering with the intended structure the tissue is already constructed
to have.
While scientists still face many challenges ahead as they work to create fullybioprinted organs, including cellular remodeling and scaffold imperfections, the benefits
of bioprinting organs far outweigh the obstacles that lie in researchers’ paths. With the
rise of chronic diseases and the need for more accurate ways to test drugs humanely,
bioprinted tissues will undoubtedly become major tools in advancing current knowledge
of tissues and how these complex structures function. Even though fully printed organs
are still quite far off, the discoveries leading up to their successful creation remain both
inspiring and crucial for the advancement of science as more scientists turn to bioprinting
to give mankind a second chance.
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