Page 275 - Advances in Biomechanics and Tissue Regeneration

14.3 MATERIALS 273

Alginate is a polysaccharide distributed generally in the cell walls of brown algae. It is a popular hydrogel for
bioprinting processes due to its high biocompatibility and various choices of cross-linking. It undergoes ionic
cross-linking in the presence of calcium chloride or sulfate (CaCl 2 or CaSO 4 , respectively) [31]. Alginate is a very good
candidate for extrusion-based [32, 33] and laser-based bioprinting [34, 35]. However, it lacks cellular adhesion signals.
Collagen is the main structural protein in the extracellular space in the various connective tissues in animal bodies.
It consists of polypeptide chains self-assembled to form triple helices of elongated fibrils. There are 28 types of collagen,
which are categorized as fibrillar (such as collagen type I) and nonfibrillar (such as Collagen type IV). Collagen type I is
fibrillar and the most common type of collagen in many tissues. It is obtained from natural sources (e.g., tails of rats,
calf hide, or pork skin) [36]. Collagen matrix enables cell adhesion, attachment, and growth due to abundant integrin-
binding domains. However, there are some limitations of the use of collagen type I in the 3-D bioprinting in function of
the slow gelation rate, which can cause nonhomogeneity of cell distribution in collagen [23]. Another inconvenience is
the tendency of collagen to gel with small fluctuations in temperature. Nevertheless, it has been used as a bioink for
extrusion-based [37] and inkjet-based [38] bioprinting.
Gelatin, a thermoreversible natural polymer, is a mixture of peptides and proteins produced by partial hydrolysis
of collagen extracted from the skin, bones, and connective tissues. It is a good candidate for bioink used in extrusion-
based printing as it is highly accessible and cheap and has good biocompatibility. However, gelatin is hardly
bioprinted in its native form because of its poor mechanical properties. To improve its bioprintability and stability
in physiological conditions, several chemicals (such as cross-linking with glutaraldehyde) and physical cues
(temperature-induced gelation) have been used [17, 39].

14.3.2 Synthetic Hydrogels
®
Pluronic F-127 is a trademark for poloxamers that can be defined as nonionic triblock copolymers composed of a
central hydrophobic chain of polyoxypropylene (poly(propylene oxide)) flanked by two hydrophilic chains of poly-
oxyethylene (poly(ethylene oxide)). Poloxamers have temperature dependents gelation and self-assembly properties.
A particularly useful property of poloxamers is that at low temperatures, high-concentration poloxamer solutions are
in liquid, whereas at higher temperatures, they form reversible gels [40, 41]. The reversible properties of Pluronic are
very useful for creating perfusable channels within bulky cell-laden constructs. At room temperature or at higher tem-
peratures, it is in solid form, so it can be surrounded by a second type of hydrogel and then placed at 4°C to liquefy it.
Pluronic is used in extrusion-based bioprinting [42].
Gelatin methacrylated (GelMA) was developed in response to some limitations presented by natural hydrogels,
such as extensive contraction, poor mechanical properties, and rapid degradation and stability at body temperature
[26, 43]. The photo-cross-linkable methacrylated gelatin hydrogels are synthesized by adding methacrylate groups to
the amine-containing side groups of gelatin [44]. Chen et al. demonstrated ECFC-driven vascular morphogenesis in
GelMA hydrogels for vascular tissue engineering [45]. The polymerization of GelMA hydrogels can be achieved in 15s
of UV light exposure in the presence of a photoinitiator. With this rapid polymerization, it would be a critical feature to
avoid hydrogel dissemination at the implantation site (for potential in situ bioprinting applications) [46]. GelMA
hydrogels have been bioprinted by inkjet-based [47] and extrusion-based [21] techniques to manufacture cell-laden
constructs with high cell viability.
Poly ethylene glycol (PEG) is a linear polyether compound with many applications from industrial manufacturing
to medicine. It can be conjugated with many biomolecules as proteins, enzymes, and lipids [23]. A research developed
by Benoit et al. showed that cells encapsulated in PEG survive even without the addition of biological constituents
although they are unable to remodel the hydrogel [48]. The advantage PEG is its mechanical properties that can be
manipulated by changing its chemistry. For that, the addition of diacrylate and methacrylate groups is beneficial
for improving the mechanical property of the resulting photo-cross-linkable hydrogels. However, those additives
require photo-cross-linking by exposure to UV light, which can dramatically reduce cell viability. PEG hydrogels
can be printable in all types of bioprinting: extrusion-based, inkjet-based, and laser-based [27].
Beyond the replacement of tissues, generally, another common medical need is structural support to the tissues in the
form of implants. Some common examples of such structures are tracheal, esophageal, and vascular stents and dental,
orthopedic, and breast implants. Although the industrialized implants are currently in use, the anatomical and struc-
tural variations between the patients result in implants and medical devices that are not perfect fits, which result in prob-
lemssuchasmechanicalmismatch-relatedcomplications,pain,excessive inflammation,pseudotumors,andgranuloma
formation. Thus, there is a great need for personalization of such implants. In soft tissues, one of the most widely used
materials for such implants is polydimethylsiloxane. In the next section, we will demonstrate its use in otorhinolaryn-
gology setting as an example of 3-D printing in medical implants where the presence of cells is not required.

II. MECHANOBIOLOGY AND TISSUE REGENERATION