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Term Paper

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adamabraham850
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1.

0 INTRODUCTION

Regenerative medicine is an emerging field that centers on the restoration and


regeneration of functional components of damaged tissue. Tissue engineering is an
application of regenerative medicine and seeks to create functional tissue components and
whole organs. Using 3D printing technologies, native tissue mimics can be created
utilizing biomaterials and living cells. Recently, regenerative medicine has begun to
employ 3D bioprinting methods to create highly specialized tissue models to improve
upon conventional tissue engineering methods. Here, we review the use of 3D bioprinting
in the advancement of tissue engineering by describing the process of 3D bioprinting and
its advantages over other tissue engineering methods. Materials and techniques in
bioprinting are also reviewed, in addition to future clinical applications, challenges, and
future directions of the field.

1
2.0 THREE-DIMENSIONAL (3D) PRINTING AND BIOPRINTING

Three-dimensional (3D) printing uses computer-aided design (CAD) and


segmentation software to sequentially layer 2D medical images (i.e. CT,MRI,etc.) into 3D
models stored as digital files (i.e.,: STL, AMF) that can be printed into physical 3D
structures. The 3D printing technology is being utilized in many specialties of medicine
for surgical planning, educational modeling, and the creation of implantable medical
devices, etc. Conventional 3D printing uses a non-biological, a cellular material such as
powders or gels to create the 3D printed object. However, when a 3D printer uses
biological, living cells (bioink) as the material to print the structure, this process is known
as bioprinting.
Conventional 3D printing techniques and additive manufacturing have been used to print
cell-free scaffolds for implantation in surgery, and 3D bioprinting is now being explored
as a technology to assemble living cells, biomaterials, and biochemicals in functional
tissue-like structures. 3D bioprinting has evolved from the conventional process of first
3Dprinting scaffolds, followed by seeding them with cells to a simultaneous process that
creates 3D-bioprinted matrix and cells concurrently. Upon implantation of these cell-laden
biological structures, 3D bioprinting has the potential to integrate the engineered tissue
into the natural tissue, which will allow for restoration of natural tissue and organ
function. Additionally, cells are precisely layered by CAD and printed by 3D printers to
exactly resemble the patient’s ECM, allowing for precision and customizability with 3D
bioprinting. Overall, it is important to explore 3D bioprinting as an alternative to
conventional tissue engineering methods. The practice of 3D bioprinting has become
increasingly popular in scientific research due to its ability to convert 3D imaging into 3D
models embedded with living cells and active biomaterials, opening a new door in the
realm of TERM applications.

2
2.1 ADVANTAGES OF 3D BIOPRINTING

While conventional tissue engineering approaches have demonstrated success in the past,
it is important to consider the limitations of reconstructing patients’ natural tissues
through these methods. Some limitations of classical tissue engineering methods include
in accurate scaffold creation in comparison to the natural tissue’s anatomy, restrictions on
biomaterials that can be delivered by classical engineering methods, or unreliable delivery
of cells, and improper interactions between different cell lines upon implantation in vivo.
Additionally, some artificial in vitro structures can be incompatible upon application to
different in vivo environments. This can cause undesirable interactions, risking increased
cell damage at the area of interest. Furthermore, while organ transplantations can provide
beneficial results, the risk of graft-versus-host reactions and immunological complications
can hinder successful outcomes in many cases. There are many advantages of 3D
bioprinting over conventional tissue engineering methods. Three-dimensional bioprinting
enhances these older methods to implement a more automated process while also allowing
for high precision and customization for every application Although. scaffolds have
already been well utilized in TERM over the years, they are limited in their ability to fully
replicate the native extracellular matrix (ECM) of the body. The utilization of 3D
bioprinting in scaffold construction has made scaffolds’ microstructures more advanced
and precise in their anatomical features, allowing for more accurate co-deposition of cells
and biomaterials when compared with conventional tissue engineering methods.
Additionally, from a technical standpoint, the process of using a 3D bioprinter to create
models based on medical images allows for the fabrication of complicated and complex
biomimetic tissue systems. The ability to make 3D-printed tissue replicas provides the
engineer and physician more control over the spatiotemporal placement of cells and
biomaterials due to the layer-by-layer construction. This also allows for the customization
of key anatomical features within the tissue replica like the interconnected pores and the
sizing and placement of blood vessels, which can improve neovascularization, perfusion,
and cellular communication while also allowing for larger 3D-bioprinted tissues to be
created.

3
2.2 PROCESS OF BIOPRINTING

The process of 3D bioprinting involves several important steps, which can be described as
three important stages:

(1) Preprocessing—the creation of the digital 3D model to be printed;

(2)processing—the creation of the bioink, and the actual process of bioprinting;

(3)post processing—the stabilization, and maturation of the bioprinted 3Dmodel.Each of


these stages includes several important steps that are crucial for the proper preparation of
the materials used in bioprinting, the actual process of printing, as well as the maturation
of the bioprinted model post-production

4
2.3 DESIGNING THE 3D MODEL

The second step of preprocessing is the designing of the 3D model using computer aided
design (CAD) software. This step is crucial in ensuring a high level of accuracy of the
physical properties upon creating the 3D tissue mimic. There are many CAD software
programs that are in use in medicine today, and the use of CAD software allows for
increased efficiency by partially automating the design of the 3D structure in a way that
follows the exact internal and external geometry while also ensuring low porosity of the
structure in order to avoid future problems. Firstly, the 2D images are segmented and split
into different masks by anatomical region. Once all of the necessary masks have been
segmented, this file can be converted to a stereolithography file (STL) format, the typical
file format accepted by most bioprinters, for 3D reconstructions by CAD software. The
image layers are stacked to create a digital 3D structure through CAD that can be modified
manually to confirm the presence of details, smooth out any imperfections, and correct
any computer errors that may have been generated by the automated process. The 3D
model is rendered by the segmentation of volumetric units, also known as voxels, which
are digitally put together to build the 3D mimic. The size of the voxels can be adjusted to
accommodate for fine details by smaller triangles making up the 3D structure, while larger
voxels can be assembled more quickly at the cost of minute details. Additionally, the
correct internal anatomy and pore structure must also be verified manually to ensure
proper cell proliferation and tissue growth upon implantation of the bioprinted material.
This step is integral to the rest of the bioprinting process because it will assemble the
physical structure of the tissue mimic, which will act as the scaffold.

5
2.4 METHODS OF BIOPRINTING
While bioprinting includes several different processes and methodologies, the three most
commonly used bioprinting technologies include (1) inkjet bioprinting, (2) laserassisted
bioprinting, and (3) extrusion-based bioprinting (or pressure-assisted bioprinting). Each of these
methodologies has its own technical characteristics and determines the types of biomaterials that
are compatible with the printer . Some methodologies are favored over others to create certain
tissues rather than others due to the type of bioinks that can be used. Inkjet bioprinting was
derived from typical desktop printers, replacing the conventional ink cartridges with specialized
bioinks to print living cells on a 3D structure. Inkjet bioprinting functions as a non-contact
printing process in which the liquid bioink is loaded into the nozzle and droplets are carefully
deposited onto the surface of the tissue construct. This process fabricates rapidly at a larger scale
compared with other techniques. Advantages of inkjet printing include the high resolution at
about 50 µm, fast printing speeds, and low overall costs of production. However,the low
viscosity of the bioink, which is required to avoid clogging then ozzlein inkjet
bioprinting,weakens the structural integrity of the bioink and requires additional crosslinking to
stabilize its structure. Laser-assisted bioprinting uses monochromatic laser energy, either pulsed
or continuous, to illuminate a ribbon-carrying bioink and a photoabsorbing layer, resulting in the
creation of the 3D construct. This process is non-contact and does not use a nozzle for the
delivery of bioinks, resulting in high resolution, high cell viability, high cell densities, and fast
production speeds. However, disadvantages include high costs of maintenance, as well as the risk
of cell damage caused by laser energy. Depending on the laser source, laser-assisted bioprinting
can be further classified as laser-induced forward transfer (LIFT), laser-guided direct writing (LG
DW), matrix-assisted pulsed laser evaporation–direct writing (MAPLE DW), etc.. Extrusion-
based bioprinting is the most commonly used form of bio printing and utilizes mechanical
compressions or pneumatic pressure to continuously eject the bioink from the nozzle and deposit
it in a layer-by-layer pattern. The consistency of the bioinks used in extrusion-based bioprinting
tends to be assembled as pastes or dispersions with higher viscosities compared to the other
method. Due to the wide range of bioink viscosities, extrusion bioprinting is widely used to
create large stable 3D tissue constructs. In addition to the high viscosity of bioink that can be
used, other advantages of extrusion-based bioprinting include low costs of production and high
densities of cells that can be deposited. However, disadvantages include slower production times
and increased risk of the extrusion nozzle blockage by the bioink. Most importantly, extrusion-
based bioprinting has a very low resolution at about 100 µm.It has also been thought that the
stress of pressure forces may negatively impact cell viability and functionality.

6
3.0 TISSUE ENGINEERING AND REGENERATIVE MEDICINE

The ability to regenerate tissue has become increasingly more important as a novel
method to restore the functional components of damaged tissues and organs. Tissue
engineering is an application of regenerative medicine that aims to use in vitro and in situ
methods to regenerate specific tissues and restore normal biological functionality. The
classical approaches to tissue engineering include the implantation of (a) scaffolds alone,
(b) isolated cells and other bioactive molecules, or (c) a combination of cells implanted
within or on scaffolds to model the body’s natural extracellular matrix (ECM) and
promote tissue engineering. There are different advantages and potential uses of each
approach. On the one hand, the combination approach of cells seeded onto scaffolds tends
to be the most widely used approach due to its ability to culture cells and observe the
maturation process outside of the body, followed by implanting this cell-seeded 3D
structural support within the body. On the other hand, the implantation of a scaffold alone
can provide structural support while also promoting natural cell recruitment to the area in
situ. The field of regenerative medicine focuses on providing support to the body’s own
self-healing abilities to promote cell and tissue growth in vivo. This is accomplished using
tissue engineering methods in combination with other in vivo therapies such as cell or
gene therapy, pharmaceutically optimized diets, or immunomodulation. Tissue
engineering and regenerative medicine (TERM) is the integration of medicine and
bioengineering, which has resulted in the two having become widely interchangeable
terms, as both fields focus on restoring tissue functionality to the body. While TERM
research has been conducted for decades now, its practice is still relatively new. It is a
rapidly developing area of research that is being widely applied to nearly every specialty
in medicine.

7
3.1 CLASSICAL APPROACHES TO TISSUE ENGINEERING
The most common approaches to tissue engineering include using:
(1) cells, such as for stem cell implantation,
(2) Bioactive molecules for the delivery of growth factors or other regulators
(3)a combination of cell sand biomaterials seeded into a porous 3D scaffold
that can be implanted in vivo to promote natural cell growth. It is important to
gain a complete understanding of these traditional methods in order to identify
optimal bioprinting applications.

3.2 POTENTIAL CLINICAL APPLICATIONS OF TISSUE REGENERATION


There has been much progress in the realm of 3D bioprinting in the past
decade, allowing for future applications within many areas of clinical medicine
and, potentially, every major system in thebody. Due to the in ability of certain
tissues to regenerate naturally, surgical repair or artificial restoration are the
mainstays of treatment. Consequently, bioprinting has shown vast success in
cases where organ transplant is difficult or not a viable option. Major body
tissues such as the heart, blood vessels, and skin have seen success with 3D-
bioprinted tissue implantation.

8
4.0 CONCLUSION
The 3D bioprinting technology has established itself as a promising innovation in the realm of
tissue regeneration and even has additional potential applications beyond tissue regeneration.
Bioprinting is already being used in cancer research, drug development and delivery, prosthetics,
and even clinician/patient education. Although bioprinting has many advantages compared with
conventional tissue engineering methods, challenges in implementation and utilization still exist.
For example, 3D-bioprinted tissue
Constructs are not yet seen in human clinical settings in practice due to the poor mechanical
properties and the lack of long-term data to support sufficient stability of the bio fabricated tissue.
These challenges are also related to the types of cells and biomaterials chosen as well as the
method of bioprinting utilized. There are many limitations of bioinks and bioprinters that make it
difficult to choose an ink that exhibits all of the desired characteristics of a particular application.
The method of bioprinting chosen must be compatible with the tissue being printed as well as the
selected bioink. Current bioprinting technologies must also be enhanced to increase printing
speeds, resolution, and the scalability of the cells of the bioprinted structures [44,48]. A focus on
improving these issues can result in a breakthrough for 3D bioprinting. Additionally, the cost
efficiency of 3D bioprinting must also be considered, particularly in regard to the high costs of
3D printers, cellular materials, and even computer software [46]. Some organizations have hired
dedicated engineers to design and segment the 3D models due to the considerable amount of time
and training needed to properly create 3D models. Overall, the costs of maintenance and
expansion of bioprinting technologies make it challenging to readily bring 3D printing
capabilities to clinics.

REFERENCES

1. Rider, P.; Kacarevic, Z.P.; Alkildani, S.; Retnasingh, S.; Barbeck, M. Bioprinting of tissue
engineering scaffolds. J. Tissue Eng. 2018, 9, 2041731418802090. [CrossRef] [PubMed]
2. Caddeo, S.; Boffito, M.; Sartori, S. Tissue Engineering Approaches in the Design of Healthy and
Pathological In Vitro Tissue Models. Front. Bioeng. Biotechnol. 2017, 5, 40. [CrossRef]
[PubMed]
3. Han, F.; Wang, J.; Ding, L.; Hu, Y.; Li, W.; Yuan, Z.; Guo, Q.; Zhu, C.; Yu, L.; Wang, H.; et al.
Tissue Engineering and Regenerative Medicine: Achievements, Future, and Sustainability in
Asia. Front. Bioeng. Biotechnol. 2020, 8, 83. [CrossRef] [PubMed]

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