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346 A. H. Jasni et al.
Table 14.1 (continued)
Reason Specific reason Justification Citation
3. Economic
viability
Cost efficiency Sustainable materials, especially
those derived from abundant
resources like cellulose, can be more
Brown
et al.
(2020)
cost-effective in the long term. They
can reduce the reliance on expensive
synthetic polymers and
the costs
associated with managing
environmental pollution.
Scalability Renewable materials can often be
produced on a larger scale with lower
Kim et al.
(2021a, b)
costs, making advanced tissue
engineering solutions more
accessible and affordable globally.
Regulatory and
4.
social acceptance
Regulations The regulatory demand to lessen the
impact of medical materials on the
environment is growing. Using
Thompson
and Garcia
(2019)
sustainable materials can help meet
these regulatory requirements and
avoid potential legal and financial
penalties.
Consumer and
stakeholder
expectations
There is growing awareness and
demand among consumers and
stakeholders for environmentally
friendly products. Sustainable
materials in tissue engineering can
enhance the reputation of companies
and institutions, fostering trust and
support from the public and
investors.
5. Ethical
responsibility
Moral
imperative:
It is morally required to reduce
environmental damage and advance
the welfare of
Developing
future generations.
sustainable tissue
Martin
et al.
(2020a)
engineering materials aligns with
broader ethical principles of
environmental stewardship and social
responsibility.
Global Health
equity
Sustainable materials can be sourced
and produced
reducing
locally, potentially
disparities in healthcare
Anderson
and Patel
(
2021)
access and quality between highresource and low-resource settings.
This can contribute to more equitable
healthcare outcomes worldwide
6. Innovation and
research
advancement
Interdisciplinary
collaboration:
Collaboration
between
scientists in
fields such as biology, environmental
science, and material science is
Robinson
t al.
e
(2022a)
facilitated by an emphasis on
sustainability. This may result in
novel ideas and advancements in
tissue engineering.
(continued)
14 Sustainable Synthesis of Cellulose-Derived Hydrogels for Tissue Engineering 347
Table 14.1 (continued)
Reason Specific reason Justification Citation
Future-proofing Developing sustainable materials
prepares the field of tissue
engineering for future challenges,
including
regulations and the need for resilient,
adaptive healthcare solutions in the
face of global environmental changes
stricter environmental
Jackson
et al.
(2019)
In summary, pursuing sustainability in tissue engineering materials is not just a
conscientious and forward-thinking strategy to addressing the many difficulties of
the modern world, but it is also a strategic imperative. The tissue engineering sector
can make great strides, protect human and environmental health, maintain economic
viability, and uphold ethical obligations, all at the same time, by putting
sustainability first. This all-encompassing strategy will open the door to a more
inventive, egalitarian, and sustainable future for tissue engineering.
14.1.3 The Aim of this Chapter
This chapter examines the value of sustainability in tissue engineering materials and
how it relates to social welfare, healthcare, and environmental stewardship.
14.2 The Sustainable Biomaterial of Cellulose
14.2.1 Cellulose Structure and Properties
Cellulose-derived hydrogels are fundamentally constructed using cellulose, a polymer common in plant cell walls (Brown et al. 2020) Its distinct structure, which
consists of a series of glucose molecules that are joined by β(1 → 4) glycosidic
linkages, confers intrinsic qualities like hydrophilicity, biocompatibility, and biodegradability (Smith and Jones (2019a, b )). Because of these qualities, cellulose is a
desirable hydrogel synthesis candidate and a sustainable substitute for artificial
polymers (Lee et al. 2021a, b).
Because of its unique connections, cellulose has a molecular structure made up of
straight-chain polymers (Fig. 14.1). By forming hydrogen bonding with oxygen
atoms, hydroxyl groups that are present on glucose molecules combine to form a
strong molecular arrangement that gives the fibers significant tensile strength. These
chains bind together to form microfibrils within plant cell walls (Johnson and Wang
(2020)).
Microfibrils are
and create hydrogen connections between the groups of hydroxyl of neighboring
chains (Joseph et al. 2020). The cellulose structure gains significant tensile strength
created when these linear networks align parallel to one another
348 A. H. Jasni et al.
Fig. 14.1 Cellulose molecular structure. When glucose subunits are linked together, cellulose is
created
and toughness from the subsequent organization of microfibrils into fibers (Johnson
and Wang
2020). Due to the network of hydrogen bonds that form inside and
between the chains, cellulose has a very stiff, crystalline structure that makes it
resistant to hydrolysis and insoluble in water.
14.2.2 Properties of Cellulose
1. Mechanical Strength: Cellulose’s remarkable tensile strength is a result of its
abundant hydrogen bonding and linear, fibrous structure. This characteristic is
essential to its function in plant cell walls because it gives the walls the stiffness
and strength they need to endure a variety of stresses (Alberts et al.
2. Crystallinity: Cellulose can
take on
different crystalline forms, or polymorphs,
the most prevalent of which are both cellulose I (native cellulose) and cellulose
II. Its insoluble nature in water and other organic solvents is attributed to its
crystalline structure (Gautam et al. 2010).
3. Hydrophilicity: Since
cellulose has
several hydroxyl groups that can establish
chemical bonds with water molecules, cellulose is hydrophilic even though it is
insoluble. This characteristic is crucial for applications where moisture absorption
as well as retention are crucial, such as the production of paper and textiles (Smith
and Jones (2019a, b)).
Biodegradability: Since cellulose
4.
is a naturally occurring polymer, it can be
broken down by the help of cellulase enzymes, which are made by different
microbes (Brown et al. 2020). In light of this characteristic, it is a sustainable and
environmentally beneficial substitute for synthetic polymers.
2002).
14 Sustainable Synthesis of Cellulose-Derived Hydrogels for Tissue Engineering 349
5. Chemical Reactivity: Esterification and etherification are two examples of the
chemical reactions in which hydroxyl groups that are present on cellulose might
take part. These processes yield cellulose derivatives with a variety of industrial
uses, such as cellulose acetate, and carboxymethyl cellulose (Lee et al.
2021a, b).
Overall, cellulose is a desirable material for the creation of hydrogels with a variety
of uses in biomedical engineering, such as drug delivery, tissue engineering, wound
healing, and regenerative medicine, due to its harmonious combination of hydrophilicity, biocompatibility, renewability, durability, sustainability, chemical adaptability, and flexibility (Jones et al. 2020; Wang and Zhang 2019; Chen et al. 2022).
14.2.3 Sources of Cellulose for Hydrogel Synthesis
Sources of cellulose for hydrogel synthesis can vary widely, encompassing both
natural and synthetic routes. Here are some common sources in Table
Table 14.2 Sources of cellulose for hydrogel synthesis
No. Sources Significant reasons Citation
1 Plant-based cellulose
Wood pulp Obtained from various tree species such as pine,
Cotton Cotton fibres consist almost entirely of
Bamboo Bamboo is another plant source rich in cellulose that
2 Microbial cellulose
Bacterial cultures Certain bacteria, such as Acetobacter xylinum,
3 Cellulose derivatives
Cellulose
nanocrystals
(CNCs)
Carboxymethyl
cellulose (CMC)
Hydroxyethyl
cellulose (HEC)
spruce, and eucalyptus, wood pulp is a primary source
of cellulose for hydrogel synthesis.
making them
production.
can be utilized for hydrogel synthesis
produce cellulose as a natural byproduct of their
metabolism. This microbial cellulose can be harvested
and used for hydrogel formation
CNCs are extracted from cellulose through chemical
or enzymatic treatments, resulting in
crystalline particles.
building blocks for hydrogels with enhanced
properties
CMC is a water-soluble derivative of cellulose,
commonly used in
biocompatibility and rheological properties
HEC
utilized in hydrogel formulations to impart specific
functionalities
a valuable source for hydrogel
These particles can serve as
hydrogel synthesis due to its
is another cellulose
derivative that can be
cellulose,
nano-sized
14.2:
Wang
et al.
(2020a)
Li et al.
(2018)
Zhang
et al.
(2019)
Czaja
et al.
(2006)
Lu et al.
(2019)
Zhang
t al.
e
(2017)
(continued)
350 A. H. Jasni et al.
Table 14.2 (continued)
No. Sources Significant reasons Citation
4 Recycled cellulose
Paper waste Recycled paper materials can be processed to extract
5 Synthetic routes
Regenerated
cellulose
cellulose fibres for hydrogel synthesis, offering a
sustainable alternative to virgin
Cellulose can be dissolved in solvents such as
N-methylmorpholine N-oxide (NMMO) or ionic
liquids and then regenerated to form hydrogels
through processes like coagulation or gelation
cellulose sources
Isobe
et al.
(2016)
14.2.4 Advantages of Using Cellulose-Derived Materials
Traditional biomaterials used in tissue engineering, often derived from
non-renewable resources or produced through energy-intensive processes, pose
significant environmental challenges (Smith et al.
The extraction and processing of these materials contribute to habitat destruction,
pollution, and greenhouse gas emissions, exacerbating the global environmental
crisis. Furthermore, the elimination of non-biodegradable biomaterials exacerbates
environmental deterioration, underscoring the pressing requirement for sustainable
substitutes.
Sustainable biomaterials offer a promising solution to mitigate the environmental
footprint of tissue engineering. These biomaterials are derived from renewable
resources, such as plant-based polymers like cellulose, chitosan, and alginate, or
synthesized using eco-friendly processes that minimize energy consumption and
waste generation (Wang et al. 2022).
By harnessing nature-inspired design principles and green chemistry techniques,
sustainable biomaterials such as cellulose enable the development of biocompatible
and b iodegradable scaffolds that promote tissue regeneration while minimizing
adverse environmental impacts (Lee and Kim 2020). Here’s a comparison of the
advantages of using cellulose-derived materials compared to other types of materials
in Table 14.3.
2020); Johnson and Patel 2018).
14.3 Cellulose Hydrogel Formation Techniques
14.3.1 Synthesis Methods
Cellulose-derived hydrogels can be synthesized through various methods, each
offering distinct advantages and tailored properties. Chemical crosslinking methods
involve the introduction of crosslinking agents to form covalent bonds between
cellulose chains, resulting in hydrogel networks with tunable mechanical and
swelling properties. Physical crosslinking methods, such as freeze-thawing and
14 Sustainable Synthesis of Cellulose-Derived Hydrogels for Tissue Engineering 351
Table 14.3 A comparison of the advantages and disadvantages between cellulose-derived
materials and other types of materials
Aspects Cellulose-derived materials Other types of materials
Renewability
and
sustainability
Biocompatibility Cellulose-derived materials are
Versatility Cellulose-derived materials offer
Low cost Cellulose-derived materials are
Environmental
impact
Sourced from
offers a sustainable alternative to
petroleum-based materials, which
are derived from finite fossil fuel
resources (Chen et al. 2020a, b)
inherently biocompatible and pose
minimal risks of adverse reactions or
immune responses compared to
some synthetic materials (Smith and
Jones
versatility in terms of properties and
functionalities, allowing for
customization to meet specific
application requirements (Wang
et al. 2021a, b)
often more cost-effective compared
to synthetic polymers, as cellulose is
abundant in nature and can be
obtained from various sources at
relatively low cost
Cellulose-derived materials have
lower environmental
compared to synthetic alternatives,
as they are biodegradable and
contribute to reducing plastic waste
(Martin et al. 2020b)
renewable biomass,
2018a, b)
footprint
May contribute to environmental
pollution and resource depletion
such as petroleum-derived materials
May exhibit cytotoxicity or cause
inflammatory responses in
biological systems, limiting their
suitability for biomedical
applications (Johnson and Patel
(
2021))
While both natural and synthetic
materials can be versatile, cellulosebased materials can be modified or
engineered with greater ease to
achieve desired characteristics, such
as mechanical strength or
degradability (Brown et al. 2022)
Synthetic materials may involve
higher production costs due to the
need for petrochemical feedstocks
and energy-intensive processes,
making them less economically
viable (Kim et al. 2021b)
Synthetic polymers often persist in
a
the environment for long periods,
causing pollution and ecological
harm, whereas cellulose-based
materials degrade naturally,
minimizing environmental impact
(Robinson et al. 2022b)
self-assembly, utilize non-covalent interactions to form hydrogel stru ctures, offering
simplicity and versatility in synthesis. Furthermore, hybrid crosslinking technologies
have arisen that combine physical and chemical crosslinking strategies, giving
hydrogel qualities fine control for particular applications (Ali et al. 2022).
14.3.1.1 Chemical Crosslinking Methods
The process of creating covalent connections between polymer chains is known as
chemical crosslinking. Strong and stable hydrogels are produced by this process. For
instance, in the process of generating a network of monomers by the use of free
radical initiators, covalent connections are formed between them. For example,
polyacrylamide hydrogels can be created by polymerizing acrylamide monomers
with free radicals (Peppas et al. 2000) The click chemistry technique is an additional
chemical crosslinking method that uses azide-alkyne cycloaddition processes to
crosslink polymers. The effectiveness and specificity of this approach are well-
352 A. H. Jasni et al.
known. For instance, click chemistry can be used to crosslink hydrogels based on
Polyethylene glycol (PEG) (Kolb et al.
2001). Glutaraldehyde Crosslinking is also
mentioned since it utilizes glutaraldehyde to produce cross-linking between polymer
chains, as seen in chitosan hydrogels (Rinaudo 2006).
14.3.1.2 Physical Crosslinking Methods
Non-covalent interactions like as ionic bonds, hydrogen bonds, or hydrophobic
interactions are involved in physical crosslinking. For instance, divalent cations
like calcium ions (Ca
2+
) can be used to create ionically crosslinked networks by
the use of alginate hydroge ls in the ionic crosslinking process. Polyvinyl alcohol
(PVA) hydrogels can be formed through repeated freeze-thaw cycles, which promote hydrogen bonding between polymer chains (Hassan and Peppas 2000).
Hydrogels formed by block copolymers like Pluronic F127 utilize hydrophobic
interactions, where the hydrophobic blocks self-assemble in aqueous environments
to form physically crosslinked networks (Jeong et al. 1997).
14.3.1.3 Hybrid Approaches
Hybrid crosslinking methods combine chemical and physical crosslinking to
enhance the properties of hydrogels. Examples include dual crosslinking, where
Gelatin methacryloyl (GelMA) hydroge ls can be crosslinked using both photopolymerization (chemical) and thermal gelation (physical) (Yue et al.
2015) and
enzyme-mediated and ionic crosslinking, where hydrogels are formed using
transglutaminase (enzyme-mediated chemical crosslinking) along with ionic
crosslinking agents for alginate gels (Boontheekul et al.
2005). Here is Table 14.4
summarizing recent studies on chemical cross linking, physical crosslinking, and
hybrid approaches for hydrogel synthesis. This table provides a concise overview of
recent studies on various hydrogel crosslinking methods, highlighting key findings.
14.4 Tissue Engineering Applications
14.4.1 Scaffold Design Considerations
Designing cellulose hydrogels as scaffolds for tissue engineering involves several
critical considerations to ensure they meet the desired mechanical, biological, and
functional properties. Here are the key design considerations for cellulose hydrogels:
1. Biocompatibility
• Ensuring the hydroge l is non-toxic and supports cell adhesion, proliferation,
and differentiation is paramount. Cellulose inherently possesses good biocompatibility, making it a favourable scaffold material (Lin et al. 2012).
2. Mechanical Properties
•
The scaffold must
intended to replace or support. This includes tensile strength, elasticity, and
compressive strength (Wang et al. 2018).
mimic the mecha nical properties of the native tissue it is
14 Sustainable Synthesis of Cellulose-Derived Hydrogels for Tissue Engineering 353
Table 14.4 Recent studies on hydrogel crosslinking methods
Crosslinking
method Study Key findings Citation
No.
via
Peppas et al.
(2020)
Kolb et al.
(2019)
Rinaudo
(2021)
Hassan and
Peppas
(2019)
Jeong et al.
(2020)
al.
Yue et
(2015)
Boontheekul
2005).
et al. (
1 Chemical Synthesis of
polyacrylamide
hydrogels
2 Chemical Click chemistry
in PEG-based
hydrogels
3 Chemical Glutaraldehyde
crosslinking of
chitosan
4 Physical Ionic
crosslinking of
alginate
hydrogels
5 Physical Hydrogen
bonding in PVA
hydrogels
6 Physical Hydrophobic
interactions in
Pluronic gels
7 Hybrid GelMA dual
crosslinking
8 Hybrid Enzyme and
ionic
crosslinking of
alginate
Free radical polymerization
provides robust and stable
hydrogels for various applications
Click chemistry offers efficient and
specific crosslinking, enhancing
hydrogel properties
Glutaraldehyde creates strong
crosslinked networks, suitable for
biomedical applications
2+
Ca
ions effectively crosslink
alginate, creating biocompatible
and mechanically stable hydrogels
Freeze-thaw cycles induce
hydrogen bonding, resulting in
highly elastic and resilient
hydrogels
Pluronic F127 forms physically
crosslinked hydrogels through selfassembly in aqueous environments
GelMA hydrogels crosslinked
photo-polymerization and thermal
gelation
exhibit enhanced
properties
Combined
Ca
hydrogel stability and
biocompatibility
transglutaminase and
2+
crosslinking improves
3. Porosity and Pore Size
• The scaffold should have an appropriate porosity to facilitate nutrient and
waste transport, and an interconnected pore structure to support vascularization and tissue integration. Optimal pore size varies depending on the tissue
type but generally ranges from 100 to 500 micrometres for most tissues (Loh
and Choong 2013))
4. Degradation Rate
• The rate of scaffold degradation ought to correspond with the rate of regeneration of tissue. Cellulose hydrogels can be blended with different polymers or
chemically crosslinked to change how quickly they degrade.
5. Functionalization and Bioactivity
Bioactive substances
•
like peptides or growth factors can be added to the
scaffold to improve its capacity to encourage tissue regeneration. The cellulose
backbone can be chemically modified to produce functionalization (Ma et al.
2014).
354 A. H. Jasni et al.
6. Swelling Behavior
• The swelling ratio of the hydrogel influences cell survival and operation by
affecting its capacity to hold onto water and nutrients. The scaffold must be
properly balanced to maintain its structural stability and to provide a wet
environment that promotes cell development.
14.4.2 The Biocompatibility of Cellulose-Based Hydrogels
Owing of their remarkable biocompatibility, cellulose-based hydrogels are wellsuited for a wide range of biomedical applications, such as drug delivery, tissue
engineering, and wound healing. The salient features of their biocompatibility are as
follows:
1. Non-Toxicity
• The inherent non-toxicity of cellulose and its analogs is essential for any
material used in biomedical applications. In addition to being non-toxic,
their breakdown products guarantee safety for in vivo applications (Lin et al.
2012).
2. Support for Cell Adhesion and Proliferation
• Cell adhesion, proliferation, and differentiation are all aided by the environment that cellulose hydrogels create. Cell-material interactions can be
improved by introducing bioactive compounds through the modification of
the hydroxyl groups on cellulose chains (Wang et al. 2018).
3. Minimal Immune Response
• Research has demonstrated that when utilized as implantation or wound
dressings, cellulose-based hydrogels cause the least amount of immunological
reactions, which is essential for avoiding inflammation and rejection (Czaja
et al. 2006).
4. Biodegradability
• Cellulose hydrogels are compostable; the body can naturally absorb or eliminate them when they break down into non-toxic components. You can control
its biodegradability by changing the crosslinking density or cellulose structure
(Pandey et al. 2012).
5. Customization for Specific Applications
• The hydrogels’ biocom
them for certain biomedical applications thanks to the chemical composition of
cellulose (Ma et al. 2014).
patibility
and usefulness can be improved by tailoring
14.4.3 Case Studies of Tissue Engineering with Hydrogels Generated from Cellulose
The use of environmentally friendly biomaterials in tissue engineering has significant effects on society well-being and healthcare. Improved compatibility with the
14 Sustainable Synthesis of Cellulose-Derived Hydrogels for Tissue Engineering 355
host tissue is provided by biocompatible and biodegradable scaffolds made of
renewable resources, which lowers the possibility of immunological rejection and
unfavorable reactions. Furthermore, these materials’ biodegradability promotes tissue remodeling and regeneration, which improves the long-term efficacy of tissue
engineering treatments. Beyond the realm of medicine, the transition to sustainable
biomaterials advances social justice by guaranteei
ng that everyone has access to
reasonably price and ecologically friendly medical treatment.
1. Case Study 1 Chitosan-Reinforced Nanocrystalline Cellulose Hydrogel for Anti-
toxin Wound Dressing
Application Researchers created a hydrogel of activated carbon and chitosanreinforced nanocrystalline cellulose (NCC), which has great potential as an antitoxin
wound dressing. The problem of chronic wounds brought on by endotoxins and
infections—specifically, lipopolysaccharides, or LPS—from Gram-negative
bacteria—is discussed in this study.
Key Findings
1. The incorporation of activated carbon into the NCC-chitosan matrix enhances the
hydrogel’s ability to absorb bacterial toxins, thereby reducing infection and
promoting faster healing.
2. Demonstrated desirable mechanical properties, excellent swelling capacity, and
low cytotoxicity towards human fibroblasts and keratinocytes.
3. Effectively removed up to 85% of endotoxins in vitro, highlighting their potential
in clinical applications for managing infected chronic wounds (Rameli et al.
2024).
2. Case Study 2 Cellulose Nanofibril Hydrogel for Cartilage Regeneration
Application In order to facilitate cartilage tissue creation, researchers created a
cellulose nanofibril (CNF) hydrogel composite reinforced with gelatin. In order to
promote chondrocyte proliferation and differentiation—which are necessary for
cartilage regeneration—the hydrogel offered a favorable environment.
Key Findings
• Improved structural integrity and mechanical qualities appropriate for cartilage
restoration.
• Encouraged the growth and high cell viability of chondrocytes.
• In animal models, cartilage tissue has successfully regenerated, indicating prom-
ise for therapeutic (Slila et al. 2023).
3. Case S
tudy 3 B
Application This
acterial Cellulose Hydrogel for Wound Healing
study investigated the application of silver nanoparticle-
impregnated bacterial cellulose hydrogels for enhanced wound healing. The goal