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Antioxidant hydrogels for the treatment of osteoarthritis: mechanisms and recent advances

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Frontiers in Pharmacology
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Articular cartilage has limited self-healing ability, resulting in injuries often evolving into osteoarthritis (OA), which poses a significant challenge in the medical field. Although some treatments exist to reduce pain and damage, there is a lack of effective means to promote cartilage regeneration. Reactive Oxygen Species (ROS) have been found to increase significantly in the OA micro-environment. They play a key role in biological systems by participating in cell signaling and maintaining cellular homeostasis. Abnormal ROS expression, caused by internal and external stimuli and tissue damage, leads to elevated levels of oxidative stress, inflammatory responses, cell damage, and impaired tissue repair. To prevent excessive ROS accumulation at injury sites, biological materials can be engineered to respond to the damaged microenvironment, release active components in an orderly manner, regulate ROS levels, reduce oxidative stress, and promote tissue regeneration. Hydrogels have garnered significant attention due to their excellent biocompatibility, tunable physicochemical properties, and drug delivery capabilities. Numerous antioxidant hydrogels have been developed and proven effective in alleviating oxidative stress. This paper discusses a comprehensive treatment strategy that combines antioxidant hydrogels with existing treatments for OA and explores the potential applications of antioxidant hydrogels in cartilage tissue engineering.
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Antioxidant hydrogels for the
treatment of osteoarthritis:
mechanisms and recent advances
Feng He
1
, Hongwei Wu
1
, Bin He
1
, Zun Han
1
, Jiayi Chen
1
and
Lei Huang
2
*
1
Department of Orthopedics, The Fourth Afliated Hospital of School of Medicine, and International
School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, Zhejiang, China,
2
Department of Critical Care Medicine, The Fourth Afliated Hospital of School of Medicine, and
International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China
Articular cartilage has limited self-healing ability, resulting in injuries often
evolving into osteoarthritis (OA), which poses a signicant challenge in the
medical eld. Although some treatments exist to reduce pain and damage,
there is a lack of effective means to promote cartilage regeneration. Reactive
Oxygen Species (ROS) have been found to increase signicantly in the OA micro-
environment. They play a key role in biological systems by participating in cell
signaling and maintaining cellular homeostasis. Abnormal ROS expression,
caused by internal and external stimuli and tissue damage, leads to elevated
levels of oxidative stress, inammatory responses, cell damage, and impaired
tissue repair. To prevent excessive ROS accumulation at injury sites, biological
materials can be engineered to respond to the damaged microenvironment,
release active components in an orderly manner, regulate ROS levels, reduce
oxidative stress, and promote tissue regeneration. Hydrogels have garnered
signicant attention due to their excellent biocompatibility, tunable
physicochemical properties, and drug delivery capabilities. Numerous
antioxidant hydrogels have been developed and proven effective in alleviating
oxidative stress. This paper discusses a comprehensive treatment strategy that
combines antioxidant hydrogels with existing treatments for OA and explores the
potential applications of antioxidant hydrogels in cartilage tissue engineering.
KEYWORDS
osteoarthritis, hydrogels, reactive oxygen species, antioxidant activity, review
1 Introduction
Osteoarthritis (OA) is a prevalent, progressive, multifactorial joint disease characterized
by chronic pain and dysfunction (James et al., 2018). It is commonly observed in individuals
over the age of 65 and affects approximately 16% of the global population (Cui et al., 2020).
OA primarily manifests as joint pain, dysfunction, and deformity, most often impacting
OPEN ACCESS
EDITED BY
Pier Maria Fornasari,
REGENHEALTHSOLUTIONS, Italy
REVIEWED BY
Xuchang Zhou,
Beijing Sport University, China
Miguel Pereira-Silva,
University of Coimbra, Portugal
*CORRESPONDENCE
Lei Huang,
8019062@zju.edu.cn
RECEIVED 29 August 2024
ACCEPTED 16 October 2024
PUBLISHED 25 October 2024
CITATION
He F, Wu H, He B, Han Z, Chen J and Huang L
(2024) Antioxidant hydrogels for the treatment
of osteoarthritis: mechanisms and
recent advances.
Front. Pharmacol. 15:1488036.
doi: 10.3389/fphar.2024.1488036
COPYRIGHT
© 2024 He, Wu, He, Han, Chen and Huang. This
is an open-access article distributed under the
terms of the Creative Commons Attribution
License (CC BY). The use, distribution or
reproduction in other forums is permitted,
provided the original author(s) and the
copyright owner(s) are credited and that the
original publication in this journal is cited, in
accordance with accepted academic practice.
No use, distribution or reproduction is
permitted which does not comply with these
terms.
Abbreviations: OA, Osteoarthritis; ROS, Reactive oxygen species; ECM, Extracellular matrix; PRP,
Platelet-rich plasma; MMPs, Matrix metalloproteinases; ADAMTS4, a disintegrin and
metalloproteinase with thrombospondin motifs 4; NO, Nitric oxide; SOD, Superoxide dismutase;
CAT, Catalase; GPX, Glutathione peroxidase; PEG, Polyethylene glycol; HA, Hyaluronic acid; PLA,
Polylactic acid; PCL, Polycaprolactone; EGCG, ()-Epigallocatechin-3-O-gallate; CeO
2
, Cerium
oxide; SIN, Sinomenium.
Frontiers in Pharmacology frontiersin.org01
TYPE Review
PUBLISHED 25 October 2024
DOI 10.3389/fphar.2024.1488036
load-bearing joints such as the knee and hip. It is one of the leading
causes of lower limb disability in older adults (Hunter and Bierma-
Zeinstra, 2019).
Research indicates that the main pathological features of OA are
cartilage damage and the destruction of the extracellular matrix
(ECM) (Kulkarni et al., 2021). Articular cartilage, a supportive
connective tissue within the joint, is crucial for normal bone
growth, structural support, resistance to deformation, and joint
lubrication (Abramoff and Caldera, 2020). It is predominantly
composed of slowly dividing chondrocytes, which constitute 5%
10% of the total cartilage mass. These chondrocytes maintain the
ECM, a tough gel-like substance containing collagen, proteoglycans,
and matrix proteins (Krishnan and Grodzinsky, 2018). Unlike most
body tissues, cartilage is avascular, lacks nerve supply and has a weak
regenerative capacity. Chondrocytes rely entirely on the diffusion
capacity of the ECM for the necessary nutrients. This nutrient
limitation implies that although cartilage can bear heavy loads
throughout life, it has minimal capacity for recovery after injury
or disease (Zhou et al., 2017;Liu et al., 2021a). Consequently, the
repair and regeneration of cartilage defects remain signicant
clinical challenges. Additionally, Synovial tissue plays a critical
role in the inammatory mechanisms of OA. Inammation
within the synovium leads to the release of pro-inammatory
cytokines and degrading enzymes, which hasten cartilage
breakdown (Sanchez-Lopez et al., 2022). This sets off a
detrimental cycle involving synovitis, cartilage degeneration, and
subchondral bone alterations, exacerbating joint damage and
intensifying OA symptoms (Kurowska-Stolarska and
Alivernini, 2022).
Strategies to treat OA include lifestyle modication, physical
therapy, medication, and surgical intervention. Lifestyle adjustments
and physical therapy aim to improve joint exibility and reduce
pain. Medication typically involves the use of NSAIDs, but long-
term use may cause side effects (Varga et al., 2017). In advanced
stages of the disease or when other treatments have failed, surgical
intervention may be required (Hunziker et al., 2015). Despite the
benecial outcomes of these interventions, the tissue formed is often
brocartilage rather than the original hyaline cartilage, and surgery
can have secondary consequences. Platelet-rich plasma (PRP),
which has a high concentration of platelets, is also injected into
the joint to treat knee osteoarthritis. This treatment leverages the
growth factors in the plasma to promote cartilage regeneration.
However, the effects have been mixed, with most patients not seeing
signicant improvement. Joint replacement is still required in the
late stages of the disease (Jones et al., 2019). Autologous
chondrocytes and mesenchymal stem cells have been studied for
cartilage regeneration, but for cell injection therapy, the main issue is
the rapid clearance of transplanted cells due to lack of adhesion to
cartilage defects (Huey et al., 2012;Vonk et al., 2018).
Recent studies have demonstrated that for larger cartilage
defects, organoid or 3D-printed cartilage scaffold transplantation
is a promising approach for cartilage repair (Yang et al., 2020;Liu
et al., 2021b). Hydrogels are the most commonly used materials for
3D-printed scaffolds. They not only provide components that mimic
the ECM of cartilage but also simulate the biomechanical properties
and three-dimensional structure of cartilage, promoting cell
adhesion, proliferation, and differentiation. Ideally, a hydrogel
could not only relieve the symptoms of OA but also enhance the
regeneration of the cartilage defect (Ding et al., 2022). However,
varying degrees of inammation are commonly present in the OA
joint cavity. Reducing the level of inammation in the joint cavity is
crucial for improving the regenerative performance of biological
scaffolds (Tamaddon et al., 2018).
In this review, we explore the mechanisms by which ROS
contribute to the pathogenesis of OA and discuss recent
advancements in the development of antioxidant hydrogels as a
novel therapeutic approach. We highlight the potential of these
hydrogels to protect chondrocytes, reduce inammation, and
enhance cartilage tissue regeneration, providing a promising
alternative to traditional OA treatments.
2 The role of ROS in the pathogenesis
of OA
ROS have been increasingly recognized as pivotal contributors
to the pathogenesis of OA (Li et al., 2012). The accumulation of ROS
in joint tissues can disrupt cellular homeostasis, leading to oxidative
stress, inammation, and cartilage degeneration. Understanding the
mechanisms of ROS generation and their biological impact is crucial
for developing targeted therapeutic strategies for OA.
2.1 Generation and sources of ROS
ROS primarily include superoxide anion (O
2
), hydrogen
peroxide (H
2
O
2
), and hydroxyl radical (·OH). These are natural
by-products of normal oxygen metabolism and play critical roles in
cell signaling and homeostasis. They are generated under both
physiological and pathological conditions (Sies et al., 2022). The
primary sources of ROS in biological systems include mitochondria,
peroxisomes, and the endoplasmic reticulum.
Mitochondria is the primary source of ROS, particularly
superoxide anions (O
2
), which are produced during the normal
operation of the electron transport chain. Complex I and Complex
III of the mitochondrial respiratory chain are the major sites of
superoxide production (Hayyan et al., 2016). Peroxisomes produce
hydrogen peroxide (H
2
O
2
) as a by-product of fatty acid oxidation
and other metabolic processes. Catalase, an enzyme within
peroxisomes, converts H
2
O
2
into water and oxygen, thereby
mitigating its potential damage (Basri İla, 2022). The
endoplasmic reticulum produces ROS during the protein folding
process, with superoxide and hydrogen peroxide being generated as
by-products during disulde bond formation (Smirnova
et al., 2018).
Additionally, NADPH oxidase produces superoxide anions in
phagocytes during immune responses by catalyzing the reaction 2O
2
+ NADPH 2O
2
+ NADP
+
+H
+
. Upon activation, the cytosolic
components translocate to the cell membrane to form the enzyme
complex (Begum et al., 2022). Xanthine oxidase, a key enzyme in
uric acid metabolism, catalyzes the conversion of xanthine to uric
acid, concurrently producing H
+
and H
2
O
2
, thereby increasing ROS
levels in the body (Bortolotti et al., 2021). Understanding the
generation and sources of ROS is crucial for developing targeted
therapies to mitigate oxidative stress-related damage in
diseases like OA.
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Previous studies have shown that in most OA
microenvironments, there are varying degrees of elevated ROS
levels. High levels of ROS can damage chondrocytes, leading to
dedifferentiation, senescence, and apoptosis (Zhao et al., 2020). ROS
and/or reactive nitrogen species (RNS) play signicant roles in many
physiological, biological, and pathological processes (Sies et al.,
2022). ROS is not only by-products of normal cell metabolism
but also essential components of cell signaling (Schieber and
Chandel, 2014;Azzi, 2022). In a healthy state, the generation and
clearance of ROS are dynamically balanced to maintain cell function
and tissue structure stability. However, in a diseased state, this
balance is disrupted, leading to abnormally elevated ROS levels
that trigger oxidative stress (Sies and Jones, 2020). ROS plays a key
role in the pathogenesis of OA by inuencing the aging and
apoptosis of chondrocytes, destroying the ECM, regulating cell
signal transduction, and promoting inammatory responses
(Henrotin et al., 2005;Rahmati et al., 2017;Blanco et al., 2018;
Bolduc et al., 2019;Yao et al., 2019;Zhang et al., 2021). Therefore,
controlling ROS levels and alleviating oxidative stress in the
hydrogel materials is a critical strategy for treating OA.
Therapeutic strategies for ROS include the development of novel
biomaterials and drugs, utilizing antioxidants or specic therapeutic
compounds. Hydrogels are an ideal carrier material due to their
excellent biocompatibility, adjustable physicochemical properties,
and effective drug delivery capability (Parmar et al., 2015;Vega et al.,
2017). Recent research has focused on the development of
antioxidant hydrogels to combat ROS-induced damage in OA.
These hydrogels aim to protect chondrocytes, reduce
inammation, and enhance cartilage tissue regeneration. By
applying these innovative materials, ROS damage in OA can be
directly targeted, offering patients more effective treatment options.
2.2 Mechanisms of ROS in the pathogenesis
of OA
Previous studies have shown that the progression of OA is
signicantly associated with oxidative stress and ROS. Oxidative
stress exacerbates cartilage damage and degradation by promoting
chondrocyte apoptosis and inammatory responses (Ahmad et al.,
2020). In articular chondrocytes, ROS are typically produced at low
levels, primarily generated by NADPH oxidase. These ROS are
crucial components of intracellular signaling and are essential for
maintaining cartilage homeostasis. They regulate various processes
including chondrocyte apoptosis, gene expression, ECM synthesis
and degradation, and cytokine production (Rahmati et al., 2017;
Yamamoto et al., 2016;Sun et al., 2021). The role of ROS in
chondrocyte damage and the progression of osteoarthritis is
illustrated in Figure 1.
2.2.1 Effects of ROS on chondrocyte senescence
and apoptosis
Elevated levels of ROS cause oxidative stress, leading to damage
in the DNA, proteins, and lipids of chondrocytes (Grishko et al.,
FIGURE 1
The role of ROS in chondrocyte damage and osteoarthritis progression.
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He et al. 10.3389/fphar.2024.1488036
2009;Loeser et al., 2016;McCulloch et al., 2017). This accumulated
damage activates multiple cellular senescence pathways, such as
Pathways such as ERK and p38 MAPK drive chondrocyte
dedifferentiation and senescence, while pro-inammatory
signaling. Particularly via NF-κB, exacerbates the inammatory
response and accelerates cartilage degradation and the
development of degenerative diseases like arthritis (Hossain et al.,
2022;Lepetsos et al., 2019;Choi et al., 2019). The feedback loop
between inammation and oxidative stress accelerates cartilage
degradation and chondrocyte senescence. ROS damage the
mitochondria, leading to the loss of mitochondrial membrane
potential and the release of cytochrome c, which activates caspase
family proteins, ultimately resulting in apoptosis (Wang G. et al.,
2021). Mitochondria are not only a primary source of ROS but also
one of their main targets. Excessive ROS inhibit the mitochondrial
respiratory chain, reducing ATP production and causing
mitochondrial DNA mutations. This establishes a vicious cycle
where mitochondrial dysfunction and ROS production exacerbate
each other, leading to cell damage and death (Blanco et al., 2018;
López-Armada et al., 2006;Kim et al., 2010). Excessive ROS also
induce ER stress, activating the unfolded protein response (UPR),
which in turn activates CHOP (a transcription factor associated with
apoptosis), thereby inducing chondrocyte apoptosis (Lin
et al., 2021).
Autophagy and Apoptosis Imbalance ROS inhibit autophagy, a
cellular degradation mechanism that allows cells to repair
themselves by degrading and recycling damaged organelles and
proteins. Autophagy is regulated by pathways like mTOR, which
is a major regulator of cell growth and metabolism and a negative
regulator of autophagy. Suppression of mTOR can activate
autophagy and delay aging (He et al., 2023). When autophagy is
inhibited, the accumulation of damaged components exacerbates
oxidative stress and cell damage. Imbalances between autophagy and
apoptosis may be a key mechanism leading to chondrocyte death
(Sun et al., 2021;Chen et al., 2016).
Ferroptosis is a form of programmed cell death characterized
by iron-dependent lipid peroxidation, with ROS playing a central
role in this process (Su et al., 2019). Excessive ROS promote the
peroxidation of polyunsaturated fatty acids, leading to the
accumulation of lipid peroxides, a hallmark of ferroptosis. Iron
generates more ROS through the Fenton reaction, further
accelerating lipid oxidation (ZhangX.etal.,2023). The
depletion of glutathione (GSH) and the inactivation of
GPX4 are also crucial in this process, leading to chondrocyte
death (Ruan et al., 2024).
2.2.2 Destruction of the ECM in chondrocytes
In OA, the excessive production of ROS exerts a dual effect on
the ECM, leading to its destruction and inhibiting its synthesis. ROS
radicals, particularly hydroxyl radicals (OH·), directly attack
proteoglycans and collagen molecules within the ECM. This not
only prevents the formation of collagen brils but also degrades
existing collagen and alters its amino acid composition (Bates et al.,
1984). ROS further exacerbate ECM degradation by activating
matrix metalloproteinases (MMPs). MMPs are a family of at least
28 zinc-dependent endopeptidases capable of degrading all ECM
components, including collagens, non-collagenous proteins, and
proteoglycans (Rose and Kooyman, 2016).
ROS also promote the expression of inammatory cytokines
such as IL-1βand TNF-α, which stimulate the overproduction of
MMPs, a major cause of cartilage loss. Current research indicates
that MMP-1 and MMP-13 are primary contributors to ECM
degradation. MMP-1 is produced by the synovial lining, whereas
MMP-13 is produced by chondrocytes. MMP-13 is involved in the
degradation of type II collagen and proteoglycans, thereby playing a
dual role in ECM destruction (Yamamoto et al., 2016;Ryu et al.,
2011;Mehana et al., 2019;Hu and Ecker, 2021).
Inammatory cytokines like IL-1βand TNF-αalso induce the
expression and increase the activity of a disintegrin and
metalloproteinase with thrombospondin motifs 4 (ADAMTS4),
leading to ECM degradation, particularly of proteoglycans (Xue
et al., 2013). Moreover, the accumulation of ROS affects chondrocyte
function, reducing their ability to synthesize ECM components.
Previous studies have shown that nitric oxide (NO) mediates the
inhibitory effect of IL-1βon proteoglycan synthesis (Cipolletta et al.,
1998). By decreasing the production of critical ECM components,
ROS not only accelerate the degradation of the existing ECM but
also inhibit the synthesis of new ECM, further exacerbating cartilage
degeneration (Zhang et al., 2020).
2.2.3 The effects of ROS on synovial cells
In OA, synovial cells play a critical role in both the production of
ROS and the amplication of inammatory responses (Mathiessen
and Conaghan, 2017). Synovial inammation drives increased ROS
generation, which, in turn, activates key signaling pathways such as
NF-κB, leading to the upregulation of pro-inammatory cytokines
like IL-1βand TNF-α(Sanchez-Lopez et al., 2022;Kurowska-
Stolarska and Alivernini, 2022). This exacerbates the
inammatory environment and creates a vicious cycle where
ROS and inammation perpetuate each other, causing
progressive tissue damage. Moreover, ROS stimulate the
expression and activation of MMPs, particularly MMP-1 and
MMP-13, in synovial cells (Kwapisz et al., 2023). These enzymes
are directly involved in the degradation of ECM components, such
as type II collagen and proteoglycans, further contributing to
cartilage destruction and joint degradation in OA. Additionally,
the release of chemokines like IL-8 and MCP-1 attracts immune cells
to the inamed site, intensifying the inammatory response and
ROS production (Russo et al., 2014;Miller et al., 2012). This cascade
of events drives both inammation and tissue degradation,
perpetuating a cycle of joint destruction that worsens the
progression of OA.
2.2.4 ROS and antioxidant defense mechanisms
In OA, patients, the levels of antioxidant enzymes such as
superoxide dismutase (SOD), catalase (CAT), and glutathione
peroxidase (GPX) are signicantly reduced (Koike et al., 2015;
Ighodaro and Akinloye, 2018). The reduction of these
antioxidant enzymes leads to excessive accumulation of ROS,
resulting in cellular and tissue damage. To combat oxidative
stress, organisms have developed a series of antioxidant
mechanisms, including enzymatic antioxidants (such as SOD,
CAT, and GPX) and non-enzymatic antioxidants (e.g., vitamin C
and E). These antioxidants neutralize ROS, maintaining redox
balance within cells and protecting them from damage (Ighodaro
and Akinloye, 2018;Halliwell et al., 2005). In OA patients, increased
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He et al. 10.3389/fphar.2024.1488036
ROS production and associated oxidative stress levels have been
observed (Altay et al., 2015;Ertürk et al., 2017). Conversely, the
levels of antioxidant enzymes like SOD, CAT, and GPX are reduced
in OA patients, conrming the role of oxidative stress in the
pathogenesis of OA (Ostalowska et al., 2006;Altindag et al.,
2007;Scott et al., 2010). In OA, elevated ROS production and
associated oxidative stress are well-documented, while reduced
levels of antioxidant enzymes exacerbate this imbalance,
contributing to the pathogenesis of the disease (Chen et al.,
2020). Proteins like SIRT1, which regulate oxidative stress and
inammation, also play a protective role by maintaining cartilage
homeostasis and promoting chondrocyte survival under oxidative
conditions (Sun et al., 2021). Downregulation of SIRT1 in OA
further impairs the cells ability to combat ROS.
Other key regulatory proteins involved in antioxidant defenses
include Nrf2 (Khan et al., 2018), which governs the expression of
enzymes like SOD and CAT, and FOXO transcription factors (e.g.,
FOXO1 and FOXO3), which help regulate cellular survival under
stress (Shen et al., 2015). AMPK also contributes to oxidative
balance by supporting mitochondrial health and reducing ROS
accumulation, but its activity is diminished in OA (Chen
et al., 2018).
Enhancing these antioxidant defense mechanisms, particularly
through supplementation of exogenous antioxidants, offers a
promising strategy to slow OA progression and protect
chondrocytes from oxidative damage. Additionally, targeting
regulatory pathways like SIRT1 and Nrf2 could provide novel
therapeutic approaches for managing OA by mitigating ROS-
induced damage and preserving joint health (see Figure 2).
3 Applications of antioxidant hydrogels
in the treatment of OA
Antioxidant hydrogels possess several advantageous properties,
including biocompatibility, biodegradability and physical stability,
making them ideal for therapeutic use in OA. These hydrogels are
specically designed to scavenge excess ROS in the body. They offer
signicant benets in their physicochemical properties, as they are
typically made from biocompatible polymers such as polyethylene
glycol (PEG) (Bryant et al., 2004), hyaluronic acid (HA), and gelatin
(Yang et al., 2024), ensuring they do not cause immune reactions or
toxicity during application. Many of these materials use natural or
synthetic degradable polymers, such as chitosan (Rajabi et al., 2021),
polylactic acid (PLA), and polycaprolactone (PCL) (Li M. et al.,
2023), which gradually degrade and are metabolized in the body,
avoiding the need for secondary surgery. Hydrogels also maintain
good mechanical strength and shape retention, ensuring that they
hold their structure and function during joint movement (Yang
et al., 2020).
The working mechanisms of antioxidant hydrogels involve
several interconnected processes that manage oxidative stress
while also protecting cells and promoting tissue repair. First,
these hydrogels provide a controlled release of antioxidants,
allowing gradual scavenging of excess reactive oxygen species
(ROS) to maintain oxidative balance and reduce long-term tissue
damage (Valentino et al., 2022). Many antioxidant hydrogels are
ROS-responsive, meaning they can detect elevated ROS levels and
automatically release antioxidants or therapeutic agents. This
ensures timely and precise antioxidant protection when oxidative
stress is high (Wu et al., 2022). Beyond managing oxidative stress,
these hydrogels offer critical protection to cells by inhibiting ROS-
induced apoptosis and tissue degradation. They achieve this by
mitigating inammatory responses, chelating metal ions that drive
ROS production, and regulating cellular signaling pathways (Xu
et al., 2022;Zhang C. et al., 2023). In particular, antioxidant
hydrogels protect mitochondrial integrity, preventing oxidative
damage to the cells energy center. Additionally, they support
cartilage ECM repair by promoting chondrocyte function,
reducing MMP activity, and preserving the structural
components of the ECM (Jiang et al., 2023). The detailed
mechanisms and potential applications of antioxidant hydrogels
for osteoarthritis treatment are outlined in Table 1. Moreover, we
have created a gure that summarizes the various mechanisms and
therapeutic applications of different types of antioxidant hydrogels
in the treatment of OA (see Figure 3).
FIGURE 2
Antioxidant defense mechanisms for osteoarthritis.
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3.1 Hydrogels for scavenging ROS
The direct scavenging of ROS by hydrogels involves
incorporating antioxidants that neutralize ROS, mitigating
cellular damage and inammation associated with osteoarthritis
(OA). Antioxidants such as vitamin C and glutathione are known to
react directly with ROS, reducing oxidative stress. Vitamin C, for
instance, neutralizes free radicals by donating electrons (Na et al.,
TABLE 1 Mechanisms and applications of antioxidant hydrogels in osteoarthritis treatment.
Type of
hydrogel
Mechanism of action Targeted
outcome
Bioactive agents References
Hydrogels for
Scavenging ROS
Controlled release of antioxidants to
neutralize ROS and maintain oxidative
balance
Reduced oxidative stress,
protection of
chondrocytes
Vitamin C, Glutathione, Polyphenols
(Hydroxytyrosol, EGCG), Selenium
nanoparticles, Cerium oxide (CeO2)
nanoparticles
Valentino et al. (2022), Na et al.
(2006), Chang et al. (2015), Cheng
et al. (2017), Li et al. (2023b), Hu et al.
(2023), Nelson et al. (2016), Lin et al.
(2020)
Hydrogels for Cell
and Mitochondria
Protection
Protects against ROS-induced
apoptosis, regulates autophagy,
enhances mitochondrial function
Reduced apoptosis,
improved chondrocyte
survival
Chitosan microspheres, GelMA
hydrogels encapsulating sinomenium
(SIN), Microcapsules to enhance
mitochondrial activity, Reprogrammed
macrophage hydrogel microspheres
Chen et al. (2016), Hao et al. (2023),
López De Figueroa et al. (2015), Liu
et al. (2023), Xiao et al. (2024), Shi
et al. (2022)
Hydrogels for
Promoting Cartilage
Repair
Provides an environment for cartilage
repair and regeneration through
reducing oxidative stress and
inammation
Promotes cell
proliferation and
differentiation, ECM
repair
Growth factors, Allicin, Decellularized
cartilage powder, Poly (gallic acid)-
manganese nanoparticles, Silk-based
hydrogels infused with polyphenols,
Bone marrow mesenchymal stem cells
(BMSCs), Manganese nanoparticles
Jain et al. (2019), Yang et al. (2023),
Cheng et al. (2023), Chen et al.
(2024), Zhang et al. (2022), Wu et al.
(2023)
Hydrogels for
Inhibiting
Inammation
Locally releases anti-inammatory
agents, scavenges ROS, modulates
inammatory pathways, responsive to
OA microenvironment
Reduces inammation
protects cartilage,
promotes regeneration
NSAIDs, Corticosteroids, Chondroitin
sulfate, Novel hyaluronic acid granular
hydrogel (n-HA), LDH@TAGel
hydrogel, ChsMA+CLX@Lipo@
GelMA
Miao et al. (2024), Wang et al.
(2021b), Seo et al. (2022), Koh et al.
(2020), Liu et al. (2024)
FIGURE 3
Mechanisms and therapeutic applications of antioxidant hydrogels in osteoarthritis treatment.
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2006;Chang et al., 2015), while glutathione acts as a reducing agent,
playing a crucial role in cellular redox homeostasis (Cheng et al.,
2017). Polyphenols, such as hydroxytyrosol (Valentino et al., 2022)
and ()-epigallocatechin-3-O-gallate (EGCG) (Li H. et al., 2023),
exhibit signicant antioxidant activity. Hydroxytyrosol is known for
its ability to protect chondrocytes from oxidative damage, while
EGCG, the main active component in green tea, is recognized for its
potent antioxidant properties that contribute to the reduction of
oxidative stress in cells. Some antioxidants enhance the bodys
antioxidant activity indirectly by activating the antioxidant
enzyme systems, such as superoxide dismutase SOD and CAT.
Selenium is an essential component of glutathione peroxidase,
while zinc acts as a cofactor for SOD, promoting the activity of
these enzymes. For instance, Injectable hydrogels containing
selenium nanoparticles can continuously activate glutathione
peroxidase, enhancing OA treatment (Hu et al., 2023). Cerium
oxide (CeO2) nanoparticles are another powerful ROS scavenger,
with their unique ability to switch between Ce3+ and Ce4+
oxidation states, mimicking the action of SOD (Nelson et al.,
2016). In vitro experiments have shown that CeO
2
nanoparticles
can prevent H
2
O
2
-induced chondrocyte damage and exhibit
superoxide dismutase-mimetic activity (Lin et al., 2020).
3.2 Hydrogels for cell and mitochondria
protection
In the context of OA, both apoptosis and autophagy imbalances
play critical roles in disease progression (Su et al., 2019). Cell-
protective hydrogels are designed to shield chondrocytes from ROS-
induced damage, regulate autophagy, and support mitochondrial
function. By maintaining intracellular ROS levels and enhancing the
cellular antioxidant defense system, these hydrogels help reduce
apoptosis and promote cell survival. For example, hydrogels
developed by Hao et al. possess superior ROS scavenging
capabilities, providing a protective environment that preserves
cell integrity under oxidative stress (Hao et al., 2023).
Additionally, chitosan microspheres and photocrosslinked GelMA
hydrogels encapsulating sinomenium (SIN) have been shown to
regulate autophagy and improve OA progression by targeting
chondrocytes (Chen et al., 2016).
Mitochondria-regulating hydrogels extend the protective role by
specically targeting mitochondrial dysfunction, which is intricately
linked to OA pathology (López De Figueroa et al., 2015). These
hydrogels are designed to improve mitochondrial function, reduce
ROS production, and enhance cellular resistance to oxidative stress.
This not only protects chondrocytes but also promotes tissue repair
and regeneration. Liu et al. developed a hydrogel formulation
incorporating microcapsules that enhance mitochondrial activity,
breaking the cycle of cellular senescence in OA by delivering
therapeutic agents directly to the mitochondria (Liu et al., 2023).
Similarly, Xiao et al. (2024) reprogrammed macrophages using
hydrogel microspheres, impacting mitochondrial function to
reduce inammation and cartilage matrix degradation.
Moreover, advanced hydrogel systems such as those developed
by Shi et al. combine cell and mitochondrial protection mechanisms
(Shi et al., 2022). These hydrogels protect chondrocytes from ROS-
induced gene expression changes, maintaining anabolic activities
essential for cartilage repair while simultaneously preventing the
upregulation of catabolic genes. By incorporating bioactive
molecules that regulate mitochondrial dynamics, these hydrogels
restore cellular energy balance, enhance chondrocyte viability, and
reduce apoptotic signals. Future research will likely focus on
optimizing these delivery systems and exploring combination
therapies to further enhance clinical outcomes in OA treatment.
3.3 Hydrogels for promoting cartilage repair
and regeneration
These hydrogels aim to provide a favorable environment for the
repair and regeneration of damaged cartilage by reducing oxidative
stress and inammation. Many hydrogels incorporate bioactive
molecules that promote cell proliferation and differentiation, such
as growth factors (Jain et al., 2019), or provide physical support to
facilitate new cartilage formation (Yang et al., 2023). For example,
Cheng et al. (2023) developed a double-network hydrogel with
antibacterial and anti-inammatory properties, enhancing
cartilage repair by incorporating allicin and decellularized
cartilage powder. Similarly, Chen et al. (2024) designed a nano-
composite hydrogel with poly (gallic acid)-manganese (PGA-Mn)
nanoparticles, which strengthens the hydrogel while scavenging
ROS, protecting chondrocytes from oxidative stress. In addition,
hydrogels like the silk-based design by Zhang et al. (2022), infused
with polyphenols, support cartilage regeneration by reducing
oxidative stress and modulating inammation. Other hydrogels,
such as those carrying bone marrow mesenchymal stem cells
(BMSCs), promote chondrogenic differentiation and tissue repair,
offering regenerative potential for damaged cartilage (Wu et al.,
2023). Temperature-sensitive hydrogels and those mimicking the
ECM of cartilage, like those based on hyaluronic acid or chitosan,
further enhance chondrocyte survival and function. Hydrogels with
manganese nanoparticles and oxidized sodium alginate reduce
MMP-13 expression and maintain collagen production,
improving joint lubrication and antioxidation (Chen et al., 2024).
By combining anti-inammatory, antioxidant, and regenerative
properties, these hydrogels offer a multifaceted approach to
restoring cartilage integrity, making them a promising tool in
osteoarthritis treatment.
3.4 Hydrogels for inhibiting inammation
Anti-inammatory hydrogels play a crucial role in alleviating
the progression of OA by reducing inammation through various
mechanisms, thereby preventing further joint damage. These
hydrogels can locally release anti-inammatory drugs such as
non-steroidal anti-inammatory drugs (NSAIDs) (Miao et al.,
2024), corticosteroids (Wang Q-S. et al., 2021;Seo et al., 2022),
or natural anti-inammatory molecules, ensuring the drugs act
directly at the site of inammation to improve efcacy while
minimizing systemic side effects. Moreover, many anti-
inammatory hydrogels can modulate inammatory signaling
pathways by scavenging ROS, thereby inhibiting the production
of pro-inammatory cytokines, effectively reducing inammation
and tissue damage (Koh et al., 2020). Studies show that LDH@
Frontiers in Pharmacology frontiersin.org07
He et al. 10.3389/fphar.2024.1488036
TAGel hydrogel is an inammation-responsive carrier that protects
chondrocytes from oxidative stress and apoptosis by activating the
Nrf2/Keap1 system and the Pi3k-Akt pathway (Liu et al., 2024).
Additionally, the ChsMA+CLX@Lipo@GelMA hydrogel degrades
in the OA microenvironment, inhibiting inammatory factors while
releasing chondroitin sulfate, which promotes chondrocyte
proliferation and cartilage repair (Miao et al., 2024). Similarly,
the novel hyaluronic acid granular hydrogel (n-HA) exhibits
enhanced resistance to degradation and can be injected less
frequently, while still providing anti-inammatory effects (Zhang
C. et al., 2023). By reducing chondrocyte senescence and blocking
TLR-2 expression and NF-κB activation, n-HA effectively attenuates
inammation and protects joint tissues. These hydrogels share the
common feature of responsive drug or factor release in inamed
environments, and by reducing inammation and oxidative stress,
they protect chondrocytes and promote tissue regeneration.
4 Advancements in antioxidant
hydrogel technologies for
OA treatment
The development of advanced antioxidant therapies targeting ROS
mechanisms, such as gene therapy, nanotechnology, and novel drug
delivery systems, holds tremendous potential for OA treatment. Given
that ROS play essential roles in both physiological and pathological
processesacting as key mediators in inammation and oxidative
stresstargeting these pathways can signicantly inuence OA
progression. Studies have shown that regulating the production and
clearance of ROS can prevent cartilage degradation, providing an
effective intervention for OA (Davalli et al., 2016). Combining
antioxidant hydrogels with existing OA treatments such as physical
therapy, pharmacotherapy, and surgery could provide a more
comprehensive treatment approach. Hydrogels, as one of the most
promising biomaterials in biomedical applications, have shown
signicant progress in cartilage tissue regeneration. Serving as
biological scaffolds, drug carriers, and delivery vehicles for stem cells,
hydrogels can also be combined with nanomaterials for targeted delivery.
These innovative constructs hold promise for improving the repair and
regeneration of damaged cartilage in OA (Xue et al., 2022).
5 Challenges and future directions for
antioxidant hydrogel applications
Given the central role of ROS in cartilage damage, the application of
antioxidant hydrogels in cartilage tissue engineering presents exciting
new research opportunities. Studies indicate that these hydrogels could
dramatically improve cartilage repair by reducing oxidative stress and
preventing further degradation (Forrester et al., 2018). However,
challenges remain regarding their clinical translation, including
potential toxicity, achieving redox balance, and ensuring stability and
biocompatibility. Moreover, manufacturing costs and the complexity of
hydrogel-based treatments pose additional hurdles (Almawash
et al., 2022).
Future research directions should focus on developing more
precise hydrogel constructs, such as nanospheres or hybrid systems
that better mimic human cartilage structure. These advanced
hydrogels should aim to provide seamless integration with native
tissues, thereby promoting efcient cartilage repair and regeneration
(Eleftheriadou et al., 2020). Furthermore, combining basic research
with clinical applications will be crucial to advancing the
development of antioxidant hydrogels. Collaborative efforts
across disciplines could lead to signicant breakthroughs, helping
shift the clinical paradigm from traditional OA treatments to
innovative, biomaterial-based therapies (Xu et al., 2020).
Shifting clinical perspectives toward incorporating these
advanced antioxidant hydrogels in OA management will be vital
in optimizing treatment strategies. A focus on innovation in
cartilage repair technologies may redene the future landscape of
OA treatment, providing new hope for patients suffering from this
degenerative disease (Lin et al., 2022).
Author contributions
FH: Writingreview and editing, Writingoriginal draft. HW:
Writingreview and editing. BH: Writingreview and editing. ZH:
Visualization, Writingreview and editing. JC: Visualization,
Writingreview and editing. LH: Writingoriginal draft.
Funding
The author(s) declare that no nancial support was received for
the research, authorship, and/or publication of this article.
Conict of interest
The authors declare that the research was conducted in the
absence of any commercial or nancial relationships that could be
construed as a potential conict of interest.
Publishers note
All claims expressed in this article are solely those of the authors and
do not necessarily represent those of their afliated organizations, or
those of the publisher, the editors and the reviewers. Any product that
may be evaluated in this article, or claim that may be made by its
manufacturer, is not guaranteed or endorsed by the publisher.
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