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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2870_Библиотеки_им_академика_М_И_Перельмана.pdf
210 New Medical Technology in Patient Care: A Physician’s Guide
Bioinks
Bioinks play a pivotal role in 3D bioprinting, serving as the fundamental
medium through which living tissues are fabricated. These specialized
inks blend biological components that must meet several critical criteria
to effectively create viable, functional tissues.
Composition of Bioinks
Cellular Component
The primary component of bioinks is living cells. See Figure 2. These can
be various cell types, including stem cells, which have the potential to
differentiate into specific tissue cells or mature cells derived from the tissue of interest. The choice of cells depends on the target tissue or organ.
Polymeric Matrix
Cells in bioinks are suspended in a hydrogel matrix typically composed of
natural or synthetic polymers. Natural polymers, such as alginate, collagen,
Figure 2. Bioink development and utilization.
3D Organ Printing: Transforming Transplantation and Tissue Repair 211
gelatin, and fibrin, are often preferred due to their biocompatibility and ability to mimic the natural extracellular matrix (ECM). Synthetic polymers,
such as polyethylene glycol (PEG), can be engineered to have specific
properties but may lack the bioactivity of natural materials.
A study by Gao et al.2 demonstrated the successful use of a gelatin
methacryloyl (GelMA) hydrogel in bioinks, highlighting its suitability for
cell encapsulation and tissue engineering due to its tunable mechanical
properties and biocompatibility.
3
Requirements for Effective Bioinks
Biocompatibility
The bioink must be nontoxic and support cell viability, proliferation, and
differentiation. It should also allow for exchanging nutrients and waste to
keep the cells healthy.
Mechanical Properties
The bioink should possess mechanical properties conducive to the printing process and the stability of the printed structure. It needs the appropriate viscosity to facilitate extrusion, maintain its shape, and support the
cells until they can produce their own ECM and stabilize the tissue. The
bioink should also have the mechanical strength to provide structural support and the flexibility to allow deformation without breaking.
Printability
Good printability is essential for bioinks to ensure precise deposition of
the material and high-resolution tissue structures. This includes appropriate viscosity and gelation properties that allow the ink to flow through the
printer nozzle and solidify in the desired pattern.
Degradation Rate
The bioink degradation rate should match the tissue maturation rate. As
the printed tissue develops, the scaffold material should degrade at a rate
212 New Medical Technology in Patient Care: A Physician’s Guide
that allows for the gradual transfer of mechanical load to the developing
tissue.
Challenges and Innovations
Developing the ideal bioink is a complex task, and researchers continually
experiment with different formulations to enhance their performance.
Innovations in bioink design include incorporating growth factors, developing composite materials combining the best properties of natural and
synthetic polymers, and using advanced techniques such as decellularized
ECM components to provide a more native tissue-like environment. See
Figure 3.
For example, a study by Skylar-Scott et al.4 demonstrated using a
novel bioink formulation for creating vascularized cardiac tissues.
Figure 3. Two techniques for bioprinting: incorporating cells into a hydrogel for extrusion in a bioprinter (top) and creating a scaffold in a bioprinter first and then seeding the
scaffold with cells (bottom).
3D Organ Printing: Transforming Transplantation and Tissue Repair 213
Bioprinters
Bioprinters are specialized devices at the heart of 3D organ printing technology. They are crucial in the precise and controlled bioink deposition to create
complex tissue structures. The functionality and sophistication of bioprinters
are central to the success of 3D bioprinting processes. See Figure 4.
The Integrated Tissue and Organ Printing System (ITOP), developed
at the Wake Forest, is an example of a high-precision bioprinter capable
of printing human-scale tissues.
Types of Bioprinters
Inkjet-Based Bioprinters
These printers function similarly to traditional inkjet printers but use
bioinks instead of conventional ink. Inkjet-based printers use thermal or
acoustic energy to deposit bioink droplets onto a substrate layer by layer.
Inkjet bioprinters are known for their high speed and ability to print with
relatively high resolution. However, they may be less suitable for highly
viscous bioinks or applications requiring the deposition of large cell
volumes.
5
Figure 4. 3D bioprinting process.
214 New Medical Technology in Patient Care: A Physician’s Guide
Inkjet bioprinting has created layered skin tissue constructs using
Chinese hamster ovary cells and embryonic motor neuron cells in predefined patterns.
4
Another example of inkjet-based bioprinting is the work by Organovo,
which specializes in developing functional human tissues using 3D bioprinting technology. They have successfully printed liver tissues that are
used for drug toxicity testing, providing a more accurate and ethical alternative to animal testing.
6
Extrusion-Based Bioprinters
These printers use a continuous flow of bioink extruded through one or
more nozzles. This type is more versatile regarding the range of bioinks it
can handle, including highly viscous materials. Extrusion bioprinters can
create more structurally robust tissues but often at a lower resolution than
inkjet printers. However, the pressure and shear stress during extrusion
can be challenging for cell viability. See Figure 5.
Figure 5. Three types of extrusion printers.
3D Organ Printing: Transforming Transplantation and Tissue Repair 215
A notable example of extrusion-based bioprinting is the work done by
researchers at the University of Toronto. They developed a skin bioprinter
that precisely places skin cells onto wounds to improve healing. This bioprinter deposited layers of skin tissue directly onto a wound, significantly
aiding the healing process.
7
An extrusion-based bioprinter was also used to fabricate a functional
human-scale bone and cartilage structure.
8
Laser-Assisted Bioprinters
In this type of printer, a laser pulse is used to deposit bioink onto the substrate. This method is known for its high precision and minimal mechanical stress on the cells, making it suitable for sensitive cell types. However,
laser-assisted bioprinters can be more complex and costly.
An example of laser-assisted bioprinting can be seen in the work con-
ducted by Poietis, a French biotechnology company. They have developed
a laser-assisted bioprinting technology to create complex tissue models,
including multilayered skin and bone tissues.
9
Vital Functional Requirements of Bioprinters
1. Precision and Accuracy: Bioprinters must deposit cells and biomaterials with high precision to replicate the complex architecture of natural
tissues. This includes accurate control over the size and placement of
each printed droplet or filament.
2. Cell Viability: The printing process must maintain high cell viability.
This involves gentle handling of the bioink to avoid damaging the
cells during printing. Parameters such as temperature, pressure, and
shear forces must be carefully controlled.
3. Speed and Efficiency: Precision and cell viability are paramount, but
printing must also be efficient. A balance must be struck between the
printing speed and the printed tissues’ resolution and viability.
4. Compatibility with Bioinks: Bioprinters must be compatible with
various bioinks, each having different properties and requirements.
This includes handling varying viscosities and compositions without
clogging or damaging the bioink.
216 New Medical Technology in Patient Care: A Physician’s Guide
Challenges and Innovations
Developing bioprinters that meet all these requirements is a significant
engineering challenge. Innovations in this field include the development
of multinozzle systems that can print different types of cells and materials
simultaneously and the integration of real-time monitoring systems to
adjust printing parameters for optimal cell viability and tissue formation.
Bioprinters are sophisticated devices that require a high degree of
precision and control to successfully create viable, functional tissues. The
ongoing advancements in bioprinter technology are crucial for the continued growth and success of 3D organ printing in regenerative medicine and
tissue engineering.
Scaffolds
Scaffolds in bioprinting play a critical role in the successful creation of
functional tissues and organs. They serve as a temporary framework that
supports the cells during the initial stages of tissue formation and maturation. The design and composition of these scaffolds are crucial, as they
must meet several key requirements to ensure the viability and proper
functioning of the printed tissues.
Composition and Properties of Scaffolds
1. Biocompatibility: Scaffolds must be made from biocompatible materials, meaning they do not provoke an immune response or cause
toxicity in the body. This ensures that the scaffold can integrate seamlessly with the body’s tissues without causing inflammation or
rejection.
2. Biodegradability: An essential feature of scaffolds in bioprinting is
their biodegradability. They are designed to degrade at a rate that
matches the growth and development of the new tissue. As the cells
proliferate and start forming their ECM, the scaffold gradually dissolves, leaving behind a fully functional tissue or organ. The degradation products should be nontoxic and safely absorbed or excreted by
the body.
3D Organ Printing: Transforming Transplantation and Tissue Repair 217
3. Mechanical Strength and Flexibility: The scaffold must possess adequate mechanical strength to maintain structural integrity during the
printing process and initial tissue formation. It should also have
enough flexibility to mimic the mechanical properties of the natural
tissue it is replacing or supporting.
4. Pore Structure and Size: The porosity of the scaffold, including the
pore size and distribution, is critical for cell migration, nutrient and
oxygen diffusion, and waste removal. A well-designed pore structure
facilitates vascularization, which is essential for the survival of thicker
tissues.
Materials used in Scaffold Design
1. Natural Polymers: Materials such as collagen, gelatin, alginate, fibrin,
and chitosan are commonly used due to their excellent biocompatibility and biodegradability. They closely mimic the natural ECM, promoting cell attachment and growth.
2. Synthetic Polymers: Polymers such as polylactic acid (PLA), polyglycolic acid (PGA), and polycaprolactone (PCL) are used for their
tunable degradation rates and mechanical properties. They can be
engineered to meet specific requirements of different tissues.
3. Composite Materials: Combining natural and synthetic polymers can
create scaffolds that possess both the biocompatibility of natural
materials and the mechanical stability of synthetic ones. This approach
allows for the customization of scaffolds for specific applications.
Challenges and Innovations
Developing scaffolds that meet all these requirements is a significant challenge. Innovations in scaffold design include incorporating growth factors
or other bioactive molecules to promote tissue growth and using advanced
fabrication techniques to create more complex and precise structures. See
Figure 6.
A study by Murphy and Atala6 discusses various materials used for
scaffolds in bioprinting. These include gel-cast hydroxyapatite (HA)
218 New Medical Technology in Patient Care: A Physician’s Guide
Figure 6. Creating a scaffold of donor cells to mimic human myocardial tissues.
foams, bioactive glass foam, and biodegradable polymer foam, as well as
the “electrospinning” of polymers to form an electrostatic field that mimics the structure and physiochemical features of natural fibers. These
materials and techniques highlight the importance of scaffold design in
tissue engineering.6 See Figure 7.
In another example, a study by Hospodiuk et al.10 highlighted the use
of a composite scaffold made from a blend of gelatin and PCL,
3D Organ Printing: Transforming Transplantation and Tissue Repair 219
Precursor
Pendant drop of polymer
Jet initiation and
extension
Figure 7. Electrospinning fibers for bioprinted scaffolding.
Bending instability and
further elongation
Solidification of the jet
into fibers
V
Power supply
demonstrating improved cell viability and structural integrity for tissue
engineering applications.
Scaffolds in bioprinting are fundamental to the creation of viable,
functional tissues and organs. Their design and material composition are
critical to supporting cell growth, tissue development, and integration
with the body, making them a key area of focus in the field of 3D
bioprinting.
3D organ printing, as we can see, is evolving from traditional manu-
facturing to bioprinting, and it involves complex interplays between
bioinks, printers, and scaffolds. Each component plays a crucial role in
creating viable, functional tissues and organs, marking a significant
advancement in medical technology and treatment possibilities.
The Science behind 3D Organ Printing
Cell Biology in Organ Printing: Stem Cells and Differentiated Cells
The foundation of 3D organ printing lies in cell biology, specifically the
use of stem cells and differentiated cells.