biomedicines

Review
Applications of Hydrogels in Osteoarthritis Treatment
Xin Gan 1,† , Xiaohui Wang 2,† , Yiwan Huang 3 , Guanghao Li 1, * and Hao Kang 1, *

1 Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and
Technology, Wuhan 430030, China; d202282263@hust.edu.cn
2 The Center for Biomedical Research, Department of Respiratory and Critical Care Medicine,
NHC Key Laboratory of Respiratory Diseases, Tongji Hospital, Tongji Medical College,
Huazhong University of Science and Technology, Wuhan 430030, China; d202282145@hust.edu.cn
3 School of Materials and Chemical Engineering, Hubei University of Technology, Wuhan 430068, China;
yiwanhuang@hbut.edu.cn
* Correspondence: lifromchina@icloud.com (G.L.); 2010tj0625@hust.edu.cn (H.K.)
† These authors contributed equally to this work.

Abstract: This review critically evaluates advancements in multifunctional hydrogels, particularly

focusing on their applications in osteoarthritis (OA) therapy. As research evolves from traditional
natural materials, there is a significant shift towards synthetic and composite hydrogels, known for
their superior mechanical properties and enhanced biodegradability. This review spotlights novel
applications such as injectable hydrogels, microneedle technology, and responsive hydrogels, which
have revolutionized OA treatment through targeted and efficient therapeutic delivery. Moreover, it
discusses innovative hydrogel materials, including protein-based and superlubricating hydrogels, for
their potential to reduce joint friction and inflammation. The integration of bioactive compounds
within hydrogels to augment therapeutic efficacy is also examined. Furthermore, the review an-
ticipates continued technological advancements and a deeper understanding of hydrogel-based
OA therapies. It emphasizes the potential of hydrogels to provide tailored, minimally invasive
treatments, thus highlighting their critical role in advancing the dynamic field of biomaterial science
for OA management.

Keywords: Hydrogel; Biomaterials; Osteoarthritis; Interdisciplinary therapy; Drug delivery

Citation: Gan, X.; Wang, X.; Huang,
Y.; Li, G.; Kang, H. Applications of
Hydrogels in Osteoarthritis
Treatment. Biomedicines 2024, 12, 923. 1. Introduction
https://doi.org/10.3390/ Osteoarthritis (OA) represents a group of severe degenerative diseases profoundly
biomedicines12040923 affecting human health. It is estimated that OA impacts approximately 500 million people
Academic Editors: Elisa Belluzzi and worldwide, accounting for a prevalence of 7%. Notably, the rate escalates to 30% among
Assunta Pozzuoli elderly populations and postmenopausal women [1,2]. OA predominantly targets knee
and hip joints, with pathological features including articular cartilage degeneration, sub-
Received: 19 March 2024 chondral bone remodeling, osteophyte formation, and synovitis [3,4]. The pathogenesis of
Revised: 18 April 2024
OA encompasses a range of biological processes, such as genetics, metabolism, biomechan-
Accepted: 18 April 2024
ics, and immunity (Figure 1A). These factors interact synergistically, contributing to the
Published: 22 April 2024
disease’s complexity [5–11]. In OA pathogenesis, the roles of cartilage, subchondral bone,
synovium, infrapatellar fat pad and menisci are significant [3,12]. A crucial aspect is the
disruption of the extracellular matrix (ECM) of chondrocytes [13]. There is a decrease in
Copyright: © 2024 by the authors.
the synthesis of Type II collagen (Collagen II) and proteoglycan (Aggrecan), coupled with
Licensee MDPI, Basel, Switzerland. increased production of matrix-degrading enzymes like matrix metalloproteinases (MMPs)
This article is an open access article and A Disintegrin and Metalloproteinase with Thrombospondin Motifs (ADAMTS). This
distributed under the terms and results in the breakdown of ECM and consequently destruction of cartilage [14,15]. Ad-
conditions of the Creative Commons ditionally, macrophages in the synovium and subchondral bone secrete inflammatory
Attribution (CC BY) license (https:// mediators such as tumor necrosis factor-alpha (TNF-α) and interleukin-1β (IL-1β). These
creativecommons.org/licenses/by/ mediators further amplify the destruction of the chondrocyte ECM and induce a marked
4.0/). increase in mitochondrial aerobic metabolism in chondrocytes. The heightened metabolism

Biomedicines 2024, 12, 923. https://doi.org/10.3390/biomedicines12040923 https://www.mdpi.com/journal/biomedicines

 Biomedicines 2024, 12, x FOR PEER REVIEW 2 of 28
Biomedicines 2024, 12, 923 2 of 26

induce a marked increase in mitochondrial aerobic metabolism in chondrocytes. The

leads to excessive
heightened production
metabolism leads toofexcessive
ROS that damageofchondrocytes,
production ultimately
ROS that damage triggering
chondrocytes,
ultimately triggering
chondrocyte apoptosischondrocyte
and autophagyapoptosis and autophagy [16,17].
[16,17].

Figure 1. (A) Schematic Diagram of the Pathogenesis of OA and (B) Various Hydrogel Treatments
Figure 1. (A) Schematic Diagram of the Pathogenesis of OA and (B) Various Hydrogel Treatments
for for
OA.OA.

OAOA affects
affectsmultiple
multiple tissues injoints,
tissues in joints,including
including thethe cartilage,
cartilage, subchondral
subchondral bone, bone,
syn- syn-
ovium, infrapatellar fat pad, and meniscus. OA leads to pain and
ovium, infrapatellar fat pad, and meniscus. OA leads to pain and functional impairment functional impairment
through
through cartilage
cartilagedegeneration, subchondralbone
degeneration, subchondral bone changes,
changes, synovial
synovial inflammation,
inflammation, and and
meniscal
meniscal damage,
damage,hence henceaa comprehensive treatment
comprehensive treatment strategy
strategy is required.
is required. Consequently,
Consequently, a a
holistic
holistic treatmentapproach,
treatment approach, termed
termed “treating
“treatingthethejoint as aaswhole,”
joint a whole,”has been advocated
has been advocated
for for systemic
systemic OA OAmanagement.
management. Subchondral
Subchondralbone bone supports
supports cartilage, absorbs
cartilage, shockshock
absorbs and and
provides joint stability. The synovium produces synovial fluid
provides joint stability. The synovium produces synovial fluid to lubricate and nour-to lubricate and nourish
ishthe
thejoint.
joint.It isIt reported that the
is reported thatinfrapatellar fat pad fat
the infrapatellar andpadthe synovium share the same
and the synovium share the
anatomical functions [18,19]. Synovial cells in IPF can secrete APOE and MDK to regulate
same anatomical functions [18,19]. Synovial cells in IPF can secrete APOE and MDK to
the senescence of chondrocytes, and this is confirmed by single-cell RNA sequencing in
regulate the senescence of chondrocytes, and this is confirmed by single-cell RNA se-
latest findings [20,21]. The meniscus stabilizes the knee joint, distributes load, reduces
quencing
friction in latest
[22]. findings [20,21].
Inflammation of the The meniscus
synovium can stabilizes
exacerbatethe knee joint, distributes
osteoarthritis symptoms. load,
reduces friction [22]. Inflammation of the synovium can exacerbate osteoarthritis symp-
toms. Damage to the infrapatellar fat pad, changes in subchondral bone, and meniscal
injuries can all promote degenerative changes in the joint, accelerating the progression of
osteoarthritis [23,24]. This implies that OA treatment should include the surrounding tis-
sues besides cartilage, forming an integrated treatment approach [25,26]. However, current
primary OA treatments, both pharmacological and surgical, are limited in their ability to re-
Biomedicines 2024, 12, 923 3 of 26

verse cartilage damage. Addressing cartilage repair and regeneration remains a significant
clinical challenge, highlighting the urgent need for novel therapeutic strategies [2,27].
Hydrogels, a class of hydrophilic, three-dimensional network gels, generally con-
sist of polymer frameworks and water. They serve as ideal carriers for direct drug or
cell therapy delivery to joints [28,29]. Hydrogels enable the sustained release of drugs
and bioactive substances, offering long-term therapeutic effects and aiding in the repair
of damaged cartilage areas [30]. Additionally, they provide support to damaged carti-
lage, reducing stress on the affected area and decelerating OA progression [31–33]. The
development of injectable hydrogels represents a minimally invasive treatment option,
greatly reducing patient discomfort during the treatment process (Figure 1B). The intro-
duction of hydrogel microneedles further refines drug delivery, facilitating non-invasive
treatment [34–36]. Recent research has been investigating the incorporation of bioactive
molecules and nanoparticles into hydrogels to augment their therapeutic efficacy [32,37,38].
Moreover, the emergence of protein-based hydrogels, with their suitable mechanical proper-
ties and excellent biological characteristics, marks a novel approach in OA treatment [39,40].
The concept of “superlubricating” hydrogels has been introduced to innovatively treat OA
by reducing cartilage inflammation through exceptionally low friction [41,42]. Addition-
ally, the novel material Aggregation-Induced Emission (AIE) substantially improves the
responsiveness of hydrogels [43]. Hydrogels, traditional materials with a long history in
materials science, continue to exhibit immense potential in OA treatment, propelled by
continuous innovations.
Recent years have witnessed a marked increase in hydrogel research. Data from the
Science Citation Index (SCI) database reveals that the total number of hydrogel-related
research publications reached 96,864 in the past decade. Notably, 34% of these publica-
tions occurred in the last three years, indicating a consistent upward trend. Specifically,
509 articles (excluding reviews) have focused on hydrogel applications in OA treatment
(Figure 2A), and 1,905 articles have been dedicated to cartilage repair, showing annual
growth in this research domain [6]. Hydrogels derived from natural materials, aparticularly
those based on hyaluronic acid and alginate, are prevalent in OA treatment, largely due
to their superior biocompatibility and bioactivity [44]. Furthermore, the convenience and
adaptability of injectable hydrogels have made them a significant choice in OA therapy
(Figure 2B). Conversely, synthetic hydrogels, despite their unique advantages like cus-
tomizable physicochemical properties, have seen limited practical use. These research
developments not only underscore the relevance of hydrogel technology in biomedicine
Biomedicines 2024, 12, x FOR PEER REVIEW 4 of 28
but also highlight its potential for future advancements in this field [45]. With ongoing
progress in material science and bioengineering, hydrogels are poised to play a pivotal role
in OA treatment and other medical applications.

Figure2.2.(A)
Figure (A)Number
NumberofofSCI
SCIindexed
indexedpublications
publicationson
onvarious
varioustypes
typesof
ofsource-based
source-basedhydrogels
hydrogelsused
used
inOA
in OAtreatment.
treatment.(B)
(B)Number
Numberof ofSCI
SCIindexed
indexedpublications
publicationscomparing
comparinginjectable
injectablehydrogels
hydrogelsto
toother
other
hydrogel-basedtreatment
hydrogel-based treatmentmethods.
methods.

Thisarticle
This articleoffers
offersaacomprehensive
comprehensivereview
reviewof
ofhydrogel
hydrogelapplications
applications in
in OA
OA treatment.
treatment.
Theprimary
The primaryfocus
focusininOAOAtreatment
treatmentisison
onenhancing
enhancingchondrocyte
chondrocytefunction,
function,aasignificant
significant
departure from approaches centered on cartilage regeneration. The review begins by cat-
egorizing hydrogels used in OA therapy, discussing different cross-linking methods in
hydrogel fabrication. It then provides an overview of the incorporation of bioactive sub-
stances in hydrogels, shedding light on how these substances enhance therapeutic effec-
tiveness. Subsequently, the review explores recent advances in various new types of hy-
Biomedicines 2024, 12, 923 4 of 26

departure from approaches centered on cartilage regeneration. The review begins by

categorizing hydrogels used in OA therapy, discussing different cross-linking methods
in hydrogel fabrication. It then provides an overview of the incorporation of bioactive
substances in hydrogels, shedding light on how these substances enhance therapeutic
effectiveness. Subsequently, the review explores recent advances in various new types
of hydrogels within the OA field, examining them in terms of new materials, treatment
techniques, and fundamental principles. It also covers the latest innovations in hydrogel
technology pertinent to OA therapy. Moreover, the article anticipates future research trajec-
tories for hydrogels, offering valuable insights for developing novel hydrogel formulations.
This article highlights the novel hydrogels in OA therapy including hydrogel microneedles,
hydrogel microspheres, multiple responsive hydrogels, decellularized matrix hydrogel,
protein hydrogels and superlubricating hydrogels, distinguished with the former articles,
and plays a key role in inspiring the creation of innovative hydrogels and suggesting
new therapeutic strategies for OA, highlighting the dynamic nature of this field and its
significant potential impact on OA treatment.

2. The Classification of Hydrogels Used in the Treatment of OA

Hydrogels can be classified based on their material origin into natural and synthetic
hydrogels (Figure 3). Regarding their physical structure, they are categorized into homoge-
neous and composite hydrogels. In terms of cross-linking methods, they are divided into
physically and chemically cross-linked hydrogels. Additionally, based on responsiveness to
stimuli, they are differentiated into responsive and non-responsive hydrogels. In practical
applications, hydrogels are predominantly used in their composite form, which may not
align precisely with the aforementioned classifications. For instance, Gelatin Methacryloyl
(GelMA) combines natural gelatin components with synthetic methacrylate, thus discus-
sions here are restricted to whether the raw materials of synthetic hydrogels are naturally
derived or artificially synthesized. Different types of hydrogels exhibit distinct mechanical
properties, which significantly influence their clinical applications in OA therapy [46].
Synthetic hydrogels often boast enhanced strength and durability, making them suitable
for load-bearing applications, whereas natural hydrogels offer better biocompatibility and
bioactivity, ideal for promoting tissue regeneration. Composite hydrogels combine
Biomedicines 2024, 12, x FOR PEER REVIEW 5 of 28
these
advantages, providing both mechanical robustness and biological functionality, thereby
supporting cartilage repair and mitigating OA progression [29].

Figure 3. Classification and Structural Diagram of Hydrogel Raw Material Sources. Natural hydrogels
Figure 3. Classification and Structural Diagram of Hydrogel Raw Material Sources. Natural hydro-
include hyaluronic acid, alginate, chitosan, and gelatin. Synthetic hydrogels encompass poly(N-
gels include hyaluronic acid, alginate, chitosan, and gelatin. Synthetic hydrogels encompass poly(N-
isopropylacrylamide),
isopropylacrylamide), polyvinyl
polyvinylalcohol, polyethyleneglycol,
alcohol, polyethylene glycol,
andand polyacrylic
polyacrylic acidacid hydrogels.
hydrogels.

2.1. Natural Hydrogels

2.1.1. Hyaluronic Acid
Hyaluronic Acid (HA), the main component of the extracellular matrix (ECM) in hu-
man cartilage tissues and joint fluid, has garnered increasing attention in OA research.
Biomedicines 2024, 12, 923 5 of 26

2.1. Natural Hydrogels

2.1.1. Hyaluronic Acid
Hyaluronic Acid (HA), the main component of the extracellular matrix (ECM) in hu-
man cartilage tissues and joint fluid, has garnered increasing attention in OA research. HA
not only provides vital lubrication to joints but also plays an essential role in sustaining joint
health and cartilage function [47]. It is pivotal in regulating the regeneration, proliferation,
metabolism, and apoptosis of chondrocytes, and stimulates ECM synthesis in chondro-
cytes during inflammatory responses [48]. Recent advancements in HA modification and
cross-linking, along with its incorporation into microspheres, 3D printing, and responsive
hydrogels, have broadened its applications in OA therapy [49]. For example, enhancing
HA hydrogels with biocompatible polymers such as Polyethylene Glycol (PEG) increases
their stability. Additionally, forming Methacrylated HA (HAMA) by combining HA with
methacrylic acid yields a temperature-sensitive, injectable material suitable for diverse OA
treatments [50].

2.1.2. Collagen
Collagen, a primary constituent of cartilage tissue and a crucial element of ECM
hydrogels in cartilage, is integral to collagen-based hydrogel development. These hydro-
gels, which emulate the structure and function of natural cartilage, create a conducive
environment for repairing and regenerating damaged joints. Not only are collagen-based
hydrogels biocompatible and biodegradable, but they also facilitate chondrocyte adhesion,
growth, and differentiation, thus aiding the joint cartilage repair process [51]. A notable
advantage of collagen-based hydrogels is their capacity to preserve joint lubrication and
minimize friction in knee joints [52]. This makes collagen-based hydrogels a promising
avenue in hydrogel technology research.

2.1.3. Alginate
Alginate, a natural polysaccharide sourced from seaweed, forms hydrogels by reacting
with polyvalent cations, such as calcium ions (Ca2+ ), to create a stable three-dimensional
network structure. This structure closely resembles the ECM of cartilage tissue, offering
an optimal microenvironment for chondrocyte growth and cartilage repair [53]. Alginate
hydrogels are particularly versatile and innovative in their ability to cross-link with various
ions. Calcium ions are the most common choice for cross-linking alginate, resulting in
a stable gel network that serves as an effective drug delivery carrier, tissue engineering
scaffold, or wound dressing [54–57]. Alginate hydrogels cross-linked with copper ions
(Cu2+ ), known for their wound healing and antibacterial properties, are applied in wound
care where antimicrobial action and accelerated healing are essential [58,59]. Iron ions
(Fe2+ /Fe3+ ), utilized in alginate hydrogels, bestow paramagnetic properties, suitable for
creating magnetically responsive hydrogels [60,61]. Zinc ions (Zn2+ ), when used to cross-
link alginate hydrogels, enhance cell proliferation and differentiation [62,63]. Alginate
hydrogels cross-linked with multivalent ions like aluminum (Al3+ ) or chromium (Cr3+ )
exhibit amphoteric chemical properties, enabling pH-responsive behavior [64,65]. Alginate
hydrogels continue to be a central focus in OA treatment research.

2.1.4. Chitosan
Chitosan, a natural polysaccharide extracted from crustacean exoskeletons, primarily
consists of N-acetyl-D-glucosamine units. Its distinctive polysaccharide structure facilitates
the formation of a three-dimensional networked gel in water, providing an excellent
hydration environment [66]. Chitosan’s strong nucleophilic characteristics enable the
addition of functional side chains through electrophilic reactions. It can be processed
into hydrogels using both physical and chemical cross-linking methods. Owing to its
outstanding biocompatibility, biodegradability, non-toxicity, and gel-forming properties,
chitosan hydrogels are widely employed in OA treatment [67].
Biomedicines 2024, 12, 923 6 of 26

2.1.5. Gelatin
Gelatin, a natural protein derived from the partial hydrolysis of collagen in animal
skin, bones, and connective tissues, contains the amino acid sequence arginine-glycine-
aspartic acid. In water, gelatin forms a stable three-dimensional network structure akin to
the ECM of natural cartilage tissues. This structure promotes the adhesion and growth of
chondrocytes, thus facilitating the repair of damaged cartilage tissue. When cross-linked
with methacrylic acid, gelatin forms GelMA hydrogels, notable for their photosensitivity
and injectability. Post-injection, GelMA can solidify into a gel within the body under UV
irradiation. It can also be pre-formed into microspheres using microfluidic technology
before injection, establishing it as a versatile and widely used multifunctional hydrogel [68].
Due to their cost-effectiveness and exceptional biological properties, gelatin hydrogels are
extensively researched in OA treatment.

2.2. Synthetic Hydrogels

Synthetic hydrogels are typically produced through the chemical synthesis of or-
ganic polymers. They often exhibit superior mechanical properties and more precisely
controllable chemical and physical characteristics compared to natural hydrogels. Ex-
amples of synthetic hydrogels include Polyvinyl Alcohol (PVA), Polyacrylic Acid (PAA),
Poly(N-isopropylacrylamide) (PNIPAM), and Polyethylene Glycol (PEG). These synthetic
hydrogels can be cross-linked with other materials to enhance their functionality and
performance in various applications.

2.2.1. Polyvinyl Alcohol

Polyvinyl Alcohol (PVA) is distinguished by its excellent water solubility. PVA hy-
drogels, known for their biocompatibility and tunable mechanical properties, closely re-
semble the hydration and mechanical characteristics of soft tissues, making them ideal for
replicating natural articular cartilage. These hydrogels are synthesized through physical
cross-linking methods, such as freeze-thaw cycles, or chemical cross-linking to form stable
three-dimensional network structures. In OA treatment, PVA hydrogels are predominantly
utilized as artificial substitutes or repair materials for joint cartilage, providing effective
cushioning and shock absorption that mitigate joint inflammation and pain [69]. How-
ever, PVA hydrogels exhibit relatively low bioactivity, and their mechanical strength and
durability may be insufficient for long-term joint pressure and wear, particularly in knee
applications. Their non-biodegradable nature also considerably restricts their use [70].
Therefore, current research is directed towards enhancing PVA hydrogels with suitable
material technologies to better fulfill therapeutic requirements.

2.2.2. Polyacrylic Acid

Polyacrylic Acid (PAA) is characterized by its high hydrophilicity, forming a three-
dimensional network capable of significant water absorption. The mechanical strength and
stability of PAA hydrogels are relatively robust, enabling them to emulate essential carti-
lage properties such as cushioning and elasticity. This renders PAA hydrogels suitable as
artificial substitutes for joint cartilage. Nevertheless, the biocompatibility of PAA hydrogels
is somewhat limited, potentially causing local tissue inflammatory responses. Further-
more, their pronounced hydrophilicity may lead to excessive water uptake, resulting in a
volumetric increase that could impact their stability and function within the joint cavity.
Moreover, the mechanical strength and durability of PAA hydrogels sometimes fall short,
necessitating cross-linking with side chain groups to improve their performance [71,72].

2.2.3. Poly(N-isopropylacrylamide)
Poly(N-isopropylacrylamide) (PNIPAM) hydrogels are extensively studied in OA
treatment due to their unique temperature-sensitive properties. They exhibit a phase transi-
tion that allows them to switch from a solution state to a gel state below their lower critical
solution temperature (LCST). This feature grants PNIPAM hydrogels excellent injectable
Biomedicines 2024, 12, 923 7 of 26

properties [73]. This phase transition enables PNIPAM hydrogels to form a stable gel at
body temperature, offering support and cushioning to damaged joints. They are conve-
nient and cost-effective [74]. However, the biocompatibility and bioactivity of PNIPAM
hydrogels are relatively limited, and their stability in the body requires improvement.
Thus, modifications through cross-linking or blending with other polymers are essential to
enhance their durability under the continuous mechanical stress of joints [74,75].

2.2.4. Polyethylene Glycol

Polyethylene Glycol (PEG) is known for its high-water solubility, exceptional biocom-
patibility, and versatility. The molecular weight of PEG can be varied through synthetic
techniques, permitting control over its physicochemical properties, including viscosity, sol-
ubility, and permeability. Additionally, PEG’s chemical structure can be covalently altered
to introduce specific functional groups [76]. PEG-based materials are widely used in clinical
settings. PEG hydrogels, by forming highly hydrated three-dimensional network structures,
emulate the natural environment of joint cartilage. They provide support and protection
to damaged cartilage, buffer joint stress, and are unlikely to cause immune responses or
inflammation. Due to the tunability of their chemical structure, PEG hydrogels are also
effective in drug delivery systems, enabling the controlled release of anti-inflammatory
agents or growth factors [77–80]. However, the mechanical strength and stability of PEG
hydrogels are somewhat inadequate for enduring joint stresses, necessitating modifications
in practical applications to bolster their mechanical robustness.

2.2.5. Polyphosphazene
Polyphosphazene, a synthetic polymer with a backbone of alternating nitrogen and
phosphorus atoms, displays unique chemical and physical properties, including high
adaptability, good biocompatibility, and biodegradability. Tailoring the polyphosphazene
side chains via chemical modification can adjust its characteristics, such as water solubility,
elasticity, and degradability, thus enhancing its applicability in medical materials [81].
Employed as a novel therapeutic carrier, polyphosphazene hydrogels have been used in
wound repair, attributed to their excellent antibacterial properties. Researchers, including
Ni et al., have utilized these hydrogels in drug delivery systems for the controlled release
of anti-inflammatory drugs and growth factors [82,83]. However, as an emerging hydrogel
material, research into its biosafety and effectiveness is still limited. Its mechanical strength
remains somewhat lacking, necessitating more comprehensive studies to fully explore its
potential applications.

3. Cross-Linking Methods of Hydrogels

Hydrogel synthesis is an interdisciplinary endeavor that combines chemistry, biology,
and material science, striving to create polymer networks with specific functionalities and
properties. Recognizing that natural hydrogels often exhibit lower mechanical performance
and synthetic hydrogels may pose biocompatibility challenges, researchers are focusing on
developing composite hydrogel systems. These systems merge the benefits of both natural
and synthetic polymers, incorporating bioactive substances to more effectively address
OA treatment. The cross-linking methods of hydrogels are primarily divided into physical
and chemical cross-linking (Figure 4). Physical cross-linking typically involves reversible
and non-covalent bonding structures, brought about by temperature changes or physical
agents. Conversely, chemical cross-linking creates covalent bonds between polymer chains,
yielding a more robust and enduring network structure. This method allows for enhanced
control of the hydrogel’s properties, including mechanical strength, degradation rate, and
drug release profiles.
 both natural and synthetic polymers, incorporating bioactive substances to more effec-
tively address OA treatment. The cross-linking methods of hydrogels are primarily di-
vided into physical and chemical cross-linking (Figure 4). Physical cross-linking typically
involves reversible and non-covalent bonding structures, brought about by temperature
changes or physical agents. Conversely, chemical cross-linking creates covalent bonds be-
Biomedicines 2024, 12, 923 tween polymer chains, yielding a more robust and enduring network structure. This 8 of 26
method allows for enhanced control of the hydrogel’s properties, including mechanical
strength, degradation rate, and drug release profiles.

Figure 4. Schematic Diagram of Hydrogel Cross-Linking Methods. (A) Classification and principles
Figure 4. Schematic
of chemical Diagram
cross-linking of Hydrogel
in hydrogels. Cross-Linking
(B) Classification Methods.
and principles(A) Classification
of physical and principles
cross-linking in
of chemical
hydrogels.cross-linking
The small ballsinrepresent
hydrogels. (B) Classification
different and principles
atoms or ions involved of physical
in cross-linking. cross-linking
The gray ar-
rows represent
in hydrogels. Thecrosslinking
small ballsreactions.
representRed and green
different arrows
atoms or represent electrostatic
ions involved forces.
in cross-linking. The gray
arrows represent crosslinking reactions. Red and green arrows represent electrostatic forces.

3.1. Physical Cross-Linking

Physical cross-linking encompasses freeze-thaw cycles, ionic interactions, and self-
assembling cross-linking. Self-assembling cross-linking depends on non-covalent inter-
actions between molecules, such as hydrogen bonding, hydrophobic interactions, and
electrostatic forces.

3.1.1. Ionic Interaction

Ionic cross-linking hinges on the interactions between ions of opposite charges to
create cross-linking points. Its advantages include simplicity, the absence of complex
chemical reagents, and the capacity to proceed under mild conditions. This method employs
multivalent cations (e.g., calcium and aluminum ions) to cross-link with multivalent anion
polymers (like alginate) [84]. Huang used Zr4+ to cross-link polyampholyte to fabricate
mechanically strengthened hydrogel with a Young’s modulus of 39.2 MPa and 3.7 MPa
of tensile strength [85]. In this approach, oppositely charged ions attract, establishing
stable connection points between polymer chains, which culminate in a three-dimensional
network structure.

3.1.2. Self-Assembling Cross-Linking

This method utilizes non-covalent interactions, including hydrogen bonding and hy-
drophobic interactions, which prompt molecular self-assembly into a stable hydrogel struc-
ture. Hydrogen bond cross-linking, a prevalent physical cross-linking approach in polymer
and hydrogel materials, is contingent on hydrogen bond formation [86]. Hydrophobic
interaction cross-linking in the hydrogel arises from hydrophobic groups, typically due
to water molecule repulsion that facilitates the attraction of non-polar or weakly polar
molecules. In the case of Polyethylene Glycol (PEG) hydrogels, PEG chains modified
Biomedicines 2024, 12, 923 9 of 26

with hydrophobic groups, such as methyl and ethyl, aggregate in water to form stable
cross-linking points [87].

3.1.3. Freeze-Thaw Cycles

The freeze-thaw method, frequently utilized for preparing materials like Polyvinyl
Alcohol (PVA), relies on physical changes induced by temperature variations without
involving chemical reactions or requiring chemical cross-linking agents. During the freez-
ing phase, water molecules within the hydrogel crystallize into ice, prompting polymer
chains to aggregate and form dense regions. These regions, stabilized through physical
entanglement and interactions such as hydrogen bonds, create cross-linking points. Upon
thawing, as the ice melts, the polymer chains maintain the physically cross-linked structure
formed during the freeze. Repeated freeze-thaw cycles further reinforce this structure,
enhancing the hydrogel’s mechanical strength and stability. The microphase separation
occurring in the freeze-thaw process facilitates the formation of hydrogels with distinctive
porous structures and network morphologies [88,89].

3.2. Chemical Cross-Linking

Chemical cross-linking encompasses covalent cross-linking, radiation cross-linking,
and enzyme-catalyzed cross-linking. It involves the creation of stable covalent bonds
linking polymer chains via chemical reactions. Covalent cross-linking necessitates cross-
linking agents, commonly including glutaraldehyde, sodium periodate, and isocyanates.
Radiation cross-linking is initiated using ultraviolet light, gamma rays, or electron beam
radiation. Enzyme-catalyzed cross-linking employs specific enzymes, like transglutaminase,
to catalyze the cross-linking of proteins or peptides.

3.2.1. Covalent Cross-Linking

Covalent cross-linking, a method that forms stable covalent bonds between polymer
chains, typically involves reactive groups such as hydroxyl, amine, and carboxyl groups
reacting with cross-linking agents like glutaraldehyde, sodium periodate, and isocyanates.
The Schiff base reaction enables grafting functional groups onto hydrogels, creating mul-
tifunctional composite hydrogels [90,91]. Jung et al. utilized this reaction to develop
oxidized alginate and gelatin hydrogels (COS-SA) with excellent biocompatibility and
cartilage-protective effects [92]. These reactions create permanent connections between
polymer chains, conferring lasting mechanical and chemical stability to the hydrogels.
Hydrogels formed by covalent cross-linking are notably stable and can be tailored for
specific applications.

3.2.2. Light Cross-Linking

Light cross-linking uses light, typically ultraviolet, to initiate chemical reactions that
cross-link polymer chains. This method involves polymers with photosensitive groups or
the addition of photoinitiators, with common groups including epoxy and benzophenone
derivatives. Upon exposure to specific light wavelengths, these groups activate and form
covalent cross-links. Photocross-linking provides precise spatial and temporal control and
can be executed without high temperatures or harmful solvents. This precision makes
photocross-linking particularly apt for creating complex three-dimensional structures in
applications like 3D printing and the fabrication of microspheres for precision medicine [93].
However, this method often produces cytotoxic oxygen free radicals.

3.2.3. Enzyme-Catalyzed Cross-Linking

Enzyme-catalyzed cross-linking employs specific enzymes, such as transglutaminase,
to catalyze reactions between groups (e.g., lysine and glutamic acid residues in peptide
chains) to create stable covalent cross-links. This technique typically uses biocompatible
natural polymers, like proteins or peptides, under mild conditions, thus preserving bioac-
Biomedicines 2024, 12, 923 10 of 26

tive substances. Hydrogels cross-linked via enzyme catalysis are useful as carriers for
bioactive substances, cell culture matrices, or adhesives in tissue engineering [94].

4. Hydrogel Drug Delivery Systems and Cell Carrier Therapies

In OA treatment, the intrinsic bioactivity of hydrogels is limited and often inadequate
for alleviating cartilage damage independently. Hence, the use of hydrogels as carriers for
drugs or bioactive substances is widespread. The application of drug-loaded nanoparticles
in hydrogels enables targeted release and controlled drug release rates, improving thera-
peutic effects [95]. Additionally, hydrogels function as cell carriers in11tissue
Biomedicines 2024, 12, x FOR PEER REVIEW of 28 engineering for
OA treatment (Figure 5).

Figure 5. (A) Drugs and bioactive substances in hydrogel delivery systems used for treating OA. (B)
Figure 5.and
Principles (A) Drugs and
mechanisms bioactive
of hydrogel substances
treatment for OA. in hydrogel delivery systems used for treating OA.
(B) Principles and mechanisms of hydrogel treatment for OA.
4.1. Drugs
4.1. A
Drugs
variety of drugs, including anti-inflammatory agents such as non-steroidal anti-
inflammatory drugs
A variety of(NSAIDs)
drugs, and corticosteroids,
including along with cartilage
anti-inflammatory repair-promoting
agents such as non-steroidal anti-
drugs, are used in OA treatment [96]. Research often combines anti-inflammatory drugs
inflammatory drugs (NSAIDs) and corticosteroids, along with cartilage repair-promoting
with cartilage repair agents to more effectively address joint damage and support cartilage
drugs,
repair areNSAIDs,
[97]. used in OA treatment
particularly selective[96].
COX-2Research
inhibitorsoften combines
like celecoxib anti-inflammatory drugs
and rofecoxib,
with cartilage
are commonly repair through
delivered agents composite
to more effectively address
hydrogels. Their joint
generally damage
good and support cartilage
water solu-
repair
bility [97]. direct
enables NSAIDs,
mixingparticularly
with hydrogels selective COX-2
for sustained inhibitors
effectiveness likeCorticoster-
[98,99]. celecoxib and rofecoxib, are
oids, such as hydrocortisone
commonly and prednisone,
delivered through compositeare also prevalent. Moreover,
hydrogels. drugs likegood
Their generally di- water solubility
acerein, an IL-1 receptor antagonist, demonstrate clinical efficacy, but their slightly poor
enables direct mixing with hydrogels for sustained effectiveness [98,99]. Corticosteroids,
water solubility may necessitate encapsulation in microspheres or liposomes before incor-
such as into
poration hydrocortisone and prednisone,
hydrogels for prolonged are also prevalent. Moreover, drugs like diacerein,
release [100,101].
an IL-1 receptor antagonist, demonstrate clinical efficacy, but their slightly poor water
solubility may necessitate encapsulation in microspheres or liposomes before incorporation
into hydrogels for prolonged release [100,101].
Biomedicines 2024, 12, 923 11 of 26

4.2. Bioactive Substances

The bioactive substances utilized in OA treatment predominantly include proteins, cy-
tokines, biologics, and exosomes. Agents such as Transforming Growth Factor-beta (TGF-β)
and Bone Morphogenetic Proteins (BMPs) have proven effective in promoting cartilage
regeneration and repair [102,103]. Glucosamine and chondroitin sulfate can significantly
alleviate joint cartilage degeneration. Small molecule compounds, like Kartogenin, encour-
age mesenchymal stem cells to differentiate into chondrocytes. Platelet-Rich Plasma (PRP)
aids in reducing inflammation in cartilage and subchondral bone. Hydrogels incorporating
these bioactive components have demonstrated substantial therapeutic efficacy in OA
treatment [104–110]. For instance, Yuan et al. developed a temperature-sensitive, injectable
hydrogel using hydroxypropyl chitosan (HPCH) loaded TGF-β, stromal cell-derived fac-
tor 1α (SDF-1α) as well as poly(lactic-co-glycolic) acid (PLGA) microspheres containing
kartogenin (KGN). This hydrogel facilitated controlled drug release and exhibited cartilage-
protective effects, offering significant clinical translation potential [111–113]. Additionally,
hydrogels containing small interfering RNA and transcription-regulating viruses have been
developed. J. Maihöfer et al. used an alginate hydrogel (IGF-I/AlgPH155) loaded with
recombinant adeno-associated virus (rAAV) vectors encoding human Insulin-like Growth
Factor I (IGF-I) in large animal models, showing substantial efficacy in alleviating knee
OA [114].
Exosomes, tiny vesicles secreted by cells containing proteins, miRNA, and other
bioactive components, exhibit anti-inflammatory, antioxidant, immune-modulating, and
cell proliferation-enhancing properties. They represent a novel approach in OA treat-
ment research. Zhang et al. formulated a hydrogel from alginate-dopamine, chondroitin
sulfate, and regenerated silk fibroin (AD/CS/RSF) loaded with MSC-derived exosomes
(EXO) [115]. Pang et al. developed GelMA-based hydrogels photo-crosslinked to encapsu-
late mesenchymal stem cell-derived nanovesicles (MSC-NVs) for animal injections [116].
Zeng et al. created a modified chitosan dual-drug hydrogel system loaded with mes-
enchymal stem cell-derived exosomes (MSC-exo) and icariin (ICA). Similarly, Yin et al.
produced polyethylene glycol-hyaluronic acid hydrogel microspheres infused with mir-
99a-3p modified adipose-derived stem cell exosomes [117]. These studies indicate that
hydrogels enriched with exosomes effectively promote cartilage regeneration and mitigate
joint inflammation, offering promising applications. However, challenges such as high
production costs and limited availability hinder their widespread application, and further
clinical validation is necessary.

4.3. Stem Cell Carrier Therapy

Hydrogels, with their ECM-like structure, excellent biocompatibility, and porosity,
are ideal as cellular scaffolds in stem cell-based therapies for OA. Mesenchymal stem
cells (MSCs) are frequently employed for cell loading, with adipose-derived stem cells
also being widely used due to their abundant availability [118]. Yan et al. developed
a DNA supramolecular hydrogel embedded with MSCs to reduce friction in knee joint
cartilages [24]. Zhong et al. utilized extracellular matrix hydrogels loaded with bone
marrow-derived MSCs for direct treatment of damaged menisci in OA [119]. Zhang et al.
facilitated OA treatment by incorporating xenogeneic MSCs into HA hydrogels [120]. In
cartilage defect repair, loaded cells actively contribute to cartilage regeneration at the defect
site. In contrast, OA treatment primarily focuses on improving chondrocyte function rather
than cartilage structure repair. Thus, compared to OA treatment, cell carrier therapy has
broader applications in cartilage repair.

5. Advanced Applications of Hydrogels in OA Treatment

As hydrogel applications continue to advance, the sophistication of composite hy-
drogels is increasing, with widespread applications in treating conditions like OA, burns,
ulcers, tumors, diabetes, ophthalmic disorders, and cardiovascular diseases. Hydrogels
used as cellular scaffolds in tissue engineering have proven effective in repairing nerves
Biomedicines 2024, 12, 923 12 of 26

Biomedicines 2024, 12, x FOR PEER REVIEW 13 of 28

and blood vessels. They show immense potential in facilitating tissue repair and enhancing
drug delivery, offering promising avenues in various medical fields [121,122]. However, a
used as cellular scaffolds in tissue engineering have proven effective in repairing nerves
primary limitation in their biological efficacy is the relatively low mechanical strength of
and blood vessels. They show immense potential in facilitating tissue repair and enhanc-
hydrogels. Ongoing
ing drugresearch
delivery,and development
offering are expected
promising avenues to yield
in various new
medical approaches
fields for
[121,122]. How-
OA treatment,ever,
withainnovations in hydrogel materials, drug delivery methods, processes,
primary limitation in their biological efficacy is the relatively low mechanical
and structures strength
significantly enhancing
of hydrogels. hydrogel
Ongoing researchfunctionality.
and development are expected to yield new ap-
proaches for OA treatment, with innovations in hydrogel materials, drug delivery meth-
5.1. Hydrogel Microneedles
ods, processes, and structures significantly enhancing hydrogel functionality.
Hydrogel5.1.
microneedle is a novel method in drug administration. As a drug delivery
Hydrogel Microneedles
system, microneedle technology, typically involves creating fine, needle-like structures on
Hydrogel microneedle is a novel method in drug administration. As a drug delivery
the skin’s surface using
system, materials
microneedle with good
technology, biocompatibility
typically involves creatingand biodegradability
fine, suchon
needle-like structures
as hyaluronic acid and polyethylene glycol (Figure 6). 3D-printing is the most
the skin’s surface using materials with good biocompatibility and biodegradability such frequently
used method to as form microneedles.
hyaluronic Combineglycol
acid and polyethylene the microneedle with proper
(Figure 6). 3D-printing hydrogel,
is the most it
frequently
enables painless drug delivery [123]. In contrast to conventional hydrogel injections forit
used method to form microneedles. Combine the microneedle with proper hydrogel,
OA treatment,enables painless
hydrogel drug delivery
microneedles [123].substantial
offer In contrast to conventionalincluding
advantages, hydrogel injections
minimal for
OA treatment, hydrogel microneedles offer substantial advantages, including minimal in-
invasiveness, reduced infection risk, and ease of use. Enhanced with nanotechnology, hy-
vasiveness, reduced infection risk, and ease of use. Enhanced with nanotechnology, hy-
drogel microneedles can also enable more precise drug delivery and treatment monitoring.
drogel microneedles can also enable more precise drug delivery and treatment monitor-
Zhang et al. developed
ing. Zhang etpolydopamine hydrogel microneedles
al. developed polydopamine that function
hydrogel microneedles similarly
that function to
similarly
traditional plasters, providing sustained release and prolonged effects, thereby
to traditional plasters, providing sustained release and prolonged effects, thereby enhanc-enhancing
patient qualitying
ofpatient
life during
qualitytreatment [124].
of life during Lin [124].
treatment et al.Lin
applied hydrogels
et al. applied in traditional
hydrogels in traditional
Chinese acupuncture, effectively penetrating rat and rabbit cartilage cell layers, managing
Chinese acupuncture, effectively penetrating rat and rabbit cartilage cell layers, manag-
inflammation
ing inflammation in both superficial
in both superficial and deepand deep cartilage,
cartilage, andandreducing
reducing subchondral
subchondral bone scle-
bone
rosis [125]. These advancements underscore the potential of hydrogel microneedle tech-
sclerosis [125]. These advancements underscore the potential of hydrogel microneedle
nology in OA therapy. Its non-invasive nature is likely to improve patient quality of life
technology in and
OA treatment
therapy. adherence,
Its non-invasive
marking nature is likelyresearch
it as a significant to improve area inpatient quality of
OA therapy.
life and treatment adherence, marking it as a significant research area in OA therapy.

Figure 6. A possible and feasible method of creation and therapeutic process of hydrogel micronee-
Figure 6. A possible and feasible method of creation and therapeutic process of hydrogel micronee-
dles for treatingdles
OAforcan be described
treating as follows:
OA can be described After After
as follows: successful loading
successful loadingof
ofdrugs orbioactive
drugs or bioactive
sub-
substances and stances
subsequent crosslinking, hydrogel is formed into a microneedle array using 3D
and subsequent crosslinking, hydrogel is formed into a microneedle array using 3D printing
printing technology. These microneedles, exceedingly small in size, are designed to penetrate the
stratum corneum, the outermost layer of the skin, without affecting underlying nerves. Specifically
engineered for targeted joint areas, these hydrogel microneedles, upon penetrating the skin, facili-
tate the release of the encapsulated medication into the body, thereby providing more precise and
localized treatment for OA [126].
 technology. These microneedles, exceedingly small in size, are designed to penetrate the str
corneum, the outermost layer of the skin, without affecting underlying nerves. Specifically
neered for targeted joint areas, these hydrogel microneedles, upon penetrating the skin, faci
the release of the encapsulated medication into the body, thereby providing more precise and l
Biomedicines 2024, 12, 923 ized treatment for OA. [126]. 13 of 26

5.2. Hydrogel Microspheres

5.2. Hydrogel Microspheres
Hydrogel microspheres are created by processing hydrogel materials into tiny, sp
Hydrogel microspheres
ical are created
particles. These by processing
microspheres, notable hydrogel
for theirmaterials intocontent
high-water tiny, spher-
and biocom
ical particles.bility,
Thesearemicrospheres, notable for their
capable of systematically high-water
releasing content7).and
drugs (Figure biocom-
Their applications
patibility, aredrug
capable of systematically
delivery releasing drugs
and tissue engineering, making (Figure
them 7). Their
a focal applications
point in recent hydroge
span drug delivery and tissue engineering, making them a focal point
search [127,128]. Common methods for preparing microspheres include in recent hydro-
emulsion t
gel research [127,128]. Common methods for preparing microspheres include emulsion
niques and microfluidic technology. Post-formation, hydrogels can be cross-linked
techniques and microfluidic
various technology.
functional Post-formation,
groups to augment hydrogels can
their functionalities. HA bemicrospheres,
cross-linked for insta
with various facilitate
functional groups to augment their functionalities. HA microspheres,
sustained drug release, enhancing treatment efficacy and duration. for Xia et al
instance, facilitate
veloped sustained drug release,
dual-responsive enhancing
hydrogel treatment
microspheres byefficacy and methacrylated
anchoring duration. ge
Xia et al. developed dual-responsive hydrogel microspheres by anchoring methacrylated
(GelMA) and phenylboronic acid (PBA) onto hyaluronic acid methacrylate (HAM
gelatin (GelMA) and phenylboronic acid (PBA) onto hyaluronic acid methacrylate (HAMA),
loaded with dihydromyricetin (DMY). These microspheres activate the SIRT3 signa
loaded with dihydromyricetin (DMY). These microspheres activate the SIRT3 signaling
pathway, preserving organelle balance in chondrocytes, and reducing autophagy
pathway, preserving organelle balance in chondrocytes, and reducing autophagy and
apoptosis [129]. Xiao et al. incorporated chemokines, macrophage antibodies, and e
apoptosis [129]. Xiao et al. incorporated chemokines, macrophage antibodies, and en-
neered cell membrane vesicles (sEVs) into HAMA hydrogel microspheres, achieving
gineered cell membrane vesicles (sEVs) into HAMA hydrogel microspheres, achieving
cise macrophage reprogramming and regulation [130,131]. Zuo et al. synthesized hi
precise macrophage reprogramming and regulation [130,131]. Zuo et al. synthesized
permeable nanogel microspheres using triphenylphosphine (TPP) and HAMA, enhan
highly permeable nanogel microspheres using triphenylphosphine (TPP) and HAMA,
cartilage and subchondral bone metabolism via ROS scavenging [132]. Li et al. develo
enhancing cartilage and subchondral bone metabolism via ROS scavenging [132]. Li et al.
liposome-anchored teriparatide (PTH (1-34)) encapsulated in GelMA hydrogel m
developed liposome-anchored teriparatide (PTH (1-34)) encapsulated in GelMA hydrogel
spheres, mitigating IL-1β-induced inflammation in ATDC5 cells by modulating
microspheres, mitigating IL-1β-induced inflammation in ATDC5 cells by modulating the
PI3K/AKT signaling pathway [133].
PI3K/AKT signaling pathway [133].

Figure 7. Illustration
Figure of the Principles
7. Illustration of Microfluidic
of the Principles ofTechnology and
Microfluidic Photocuring
Technology andMolding Tech-Molding T
Photocuring
nique Using GelMA Hydrogel
nique Using GelMAMicrospheres
Hydrogel as an Example.asGelMA,
Microspheres combined
an Example. GelMA,withcombined
the desired
with the de
drugs
drugs or bioactive or bioactive
substances, substances,
passes throughpasses through the micro-orifices
the micro-orifices in thedevice
in the microfluidic microfluidic
to formdevice to
uniformly textured microspheres loaded with the drug. These are then solidified and molded under
ultraviolet light radiation.

5.3. Responsive Hydrogels

Hydrogel microspheres can be tailored to modify their structure, offering a broad
spectrum of functionalities. Owing to their large specific surface area, they provide more
Biomedicines 2024, 12, 923 14 of 26

efficient drug release properties than traditional hydrogels and can more effectively achieve
joint lubrication. Responsive hydrogels constitute a class of hydrogels that respond to
specific environmental stimuli [134]. In the field of OA treatment, responsive hydro-
gels primarily encompass temperature-responsive, pH-responsive, enzyme-responsive,
magnetic-responsive, ROS-responsive, and mechanical-responsive hydrogels (Figure 8A).
Temperature-responsive hydrogels expand or contract at a critical temperature (LCST) and
solidify under body temperature conditions (Figure 8B), providing localized treatment, a
feature inherent in most injectable hydrogels [135]. Yi et al. developed a robust thermosen-
sitive hydrogel by cross-linking collagen with PLGA and polyethylene glycol (PEG) [136].
Y. H. et al. synthesized a thermosensitive chitosan-gelatin hydrogel that, through delivering
glutathione, mitigated mitochondrial dysfunction, thereby reducing chondrocyte apoptosis
and autophagy [137]. HA is also frequently used in thermosensitive hydrogels; Zhou et al.
formulated an injectable HAMA hydrogel microsphere responsive to hypoxia and MMP13
(Figure 8E) that degrades under MMP13 and releases drugs in hypoxic conditions [138].
Mechanical-responsive hydrogels react to pressure and friction (Figure 8B). Liu et al.’s
mechanical stress-responsive hydrogel, created by cross-linking PAA with polyaniline
(PANI), instantaneously hardens under pressure, providing support for stressed areas of
cartilage during walking [139]. Wu et al.’s HSPC nanoliposome-encapsulated gelatin (HG)
facilitates friction force-responsive drug release [140]. In OA, cartilage cells under inflamma-
tion generate significant amounts of ROS; Scognamiglio et al.’s ROS-responsive hydrogel,
engineered with borate-crosslinked lactose-modified chitosan (CTL), releases drugs in
the presence of ROS (Figure 8G), exhibiting excellent biocompatibility and antioxidant
properties [141]. Jiang et al. incorporated magnetic responsiveness into GelMA-HAMA
hydrogels using boronized neodymium iron boron (NdFeB) (Figure 8F), enhancing the sim-
ulation of pressure on OA cartilage and establishing a groundwork for future research [142].
AIE materials, distinguished from traditional luminescent materials, shine brightly in
aggregated or solid states. Employing AIE, exceptionally sensitive and biocompatible
pH-responsive (Figure 8D), temperature-responsive, and enzyme-responsive hydrogels
can be engineered [143–145]. The responsiveness of hydrogels enables precision treatment.
Various responses contribute to hydrogel formation, drug release, and degradation. This
lays the foundation for the precision and diversification of hydrogel functions and signifies
a key future research direction in hydrogel development [122].

5.4. Novel Hydrogel Materials

The sources of hydrogels have expanded beyond conventional natural substances and
synthetically produced polymers, with emerging materials markedly improving their func-
tionality. The decellularized matrix, obtained from natural tissues by eliminating cellular
elements, consists of extracellular matrix components. This matrix maintains the structure
and bioactivity of the original tissues, offering a conducive environment for cell adhesion,
proliferation, and differentiation [119,146–148]. As a result, decellularized matrices are
increasingly utilized in the fabrication of biological scaffolds, aiding in the repair and regen-
eration of damaged tissues (Figure 9). Hydrogels, in contrast, provide adjustable physical
characteristics and drug delivery capacities, thereby enhancing the matrices’ functionality.
Yuan et al. crafted a hydrogel from human mesenchymal stem cell extracellular matrix
that demonstrated significant efficacy in mitigating cartilage damage in the meniscus of
immunodeficient mice, markedly improving cartilage repair in the affected areas [149].
Similarly, Qiang et al. employed the extracellular matrix of porcine menisci chondrocytes,
combined with polyethylene glycol diacrylate (PEGDA), to synthesize a decellularized
matrix hydrogel that successfully treated OA in rat knee joints [150]. Integrating hydro-
gels with ECM materials to formulate composites with outstanding physicochemical and
biological properties emerges as a promising strategy in OA therapy [151,152].
Biomedicines 2024, 12,2024,
Biomedicines 923 12, x FOR PEER REVIEW 16 of 28 15 of 26

Figure
Figure 8. MultipleResponsive
8. Multiple Responsive Hydrogels
Hydrogelsfor Treating
for OA.OA.
Treating (A) Diagrammatic representation
(A) Diagrammatic of OA. of OA.
representation
(B–G) Illustrations depicting the principles of temperature-responsive, mechanical-responsive, pH-
(B–G) Illustrations depicting the principles of temperature-responsive, mechanical-responsive, pH-
responsive, enzyme-responsive, magnetic-responsive, and ROS-responsive hydrogels, respectively.
Biomedicines 2024, 12, x FOR PEER REVIEW 17 of 28
responsive, enzyme-responsive,
Black arrows represent responsivemagnetic-responsive,
reactions. and ROS-responsive hydrogels, respectively.
Black arrows represent responsive reactions.
5.4. Novel Hydrogel Materials
The sources of hydrogels have expanded beyond conventional natural substances
and synthetically produced polymers, with emerging materials markedly improving their
functionality. The decellularized matrix, obtained from natural tissues by eliminating cel-
lular elements, consists of extracellular matrix components. This matrix maintains the
structure and bioactivity of the original tissues, offering a conducive environment for cell
adhesion, proliferation, and differentiation [119,146–148]. As a result, decellularized ma-
trices are increasingly utilized in the fabrication of biological scaffolds, aiding in the repair
and regeneration of damaged tissues (Figure 9). Hydrogels, in contrast, provide adjustable
physical characteristics and drug delivery capacities, thereby enhancing the matrices’
functionality. Yuan et al. crafted a hydrogel from human mesenchymal stem cell extracel-
lular matrix that demonstrated significant efficacy in mitigating cartilage damage in the
meniscus of immunodeficient mice, markedly improving cartilage repair in the affected
areas [149]. Similarly, Qiang et al. employed the extracellular matrix of porcine menisci
chondrocytes, combined with polyethylene glycol diacrylate (PEGDA), to synthesize a
decellularized matrix hydrogel that successfully treated OA in rat knee joints [150]. Inte-
grating hydrogels with ECM materials to formulate composites with outstanding physi-
cochemical and biological properties emerges as a promising strategy in OA therapy
[151,152].

Figure
Figure 9. PreparationofofDecellularized
9. Preparation Decellularized Matrix
MatrixHydrogel
Hydrogel Derived fromfrom
Derived Rat Chondrocytes and Its and Its
Rat Chondrocytes
Application in OA Treatment. Rat cartilage undergoes decellularization to form a sol containing the
Application in OA Treatment. Rat cartilage undergoes decellularization to form a sol containing the
extracellular matrix of chondrocytes. This is then cross-linked with PEGDA to form an injectable,
extracellular matrix
photosensitive of chondrocytes.
decellularized This is then
matrix hydrogel drug cross-linked with
delivery system, PEGDA
which to form
gels inside thean injectable,
body
photosensitive decellularized
under blue light radiation. matrix hydrogel drug delivery system, which gels inside the body
under blue light radiation.
Protein hydrogels are a distinct class of hydrogels, distinct from earlier variants. They
consist of either purely synthetic proteins or combinations with other polymers to estab-
lish composite network structures. These hydrogels demonstrate customizable biochemi-
cal and mechanical properties, with notable degradability and biocompatibility. Fu and
colleagues devised protein sequences using ferredoxin-like protein (FL) as a foundation.
Individual monomers assemble into octamers via dityrosine bonds. In polar solutions,
Biomedicines 2024, 12, 923 16 of 26

Protein hydrogels are a distinct class of hydrogels, distinct from earlier variants. They
consist of either purely synthetic proteins or combinations with other polymers to establish
composite network structures. These hydrogels demonstrate customizable biochemical and
mechanical properties, with notable degradability and biocompatibility. Fu and colleagues
devised protein sequences using ferredoxin-like protein (FL) as a foundation. Individual
monomers assemble into octamers via dityrosine bonds. In polar solutions, these FL oc-
tamers ((FL)8 ) remain in a folded state. Upon chemical denaturation, (FL)8 transforms
into chain-like structures. In concentrated solutions, the interweaving of these protein
chains results in robust cross-linking, a widely used physical cross-linking technique in
polymer hydrogel preparation. This method depends on the physical entanglement and
interaction of polymer chains, contrasting with the covalent bonds in traditional chemical
cross-linking. Furthermore, denatured (FL)8 in dilute solutions reverts to its folded form
under hydrogen bonding, forming collapsed structures. The refolded N-DC ((FL)8 ) exhibits
enhanced physical properties and is transformed into a protein hydrogel resembling carti-
lage (Figure 10). This hydrogel exhibits exceptional mechanical properties, melding high
hardness and toughness with biocompatibility. It has demonstrated promising therapeutic
effects in treating OA in rats. The development of this hydrogel represents a significant
Biomedicines 2024, 12, x FOR PEER REVIEW 18 of 28
advancement in OA treatment, heralding the use of artificially designed sequence protein
hydrogels in this field. It provides valuable insights for future research and applications of
hydrogels [40].

Figure 10. Schematic Diagram of Entangled Cross-Linked Protein Hydrogels. The gelation process of
Figure 10. Schematic
entangled Diagramincludes
protein hydrogels of Entangled Cross-Linked
four stages: ProteinofHydrogels.
concentration The gelation
solution, chemical process
denaturation,
of entangled protein hydrogels includes four stages:
denaturation cross-linking, and renaturation folding. concentration of solution, chemical denatura-
tion, denaturation cross-linking, and renaturation folding.
5.5. Superlubricating Hydrogels
5.5. Superlubricating
SuperlubricationHydrogels
is typically defined as a friction coefficient lower than 0.01, also
termed ‘ultra-low friction’. Superlubricating
Superlubrication is typically defined as hydrogels attain this extremely
a friction coefficient lower thanlow friction
0.01, also
coefficient through innovative chemical and physical designs, eclipsing the lubricative
termed ‘ultra-low friction’. Superlubricating hydrogels attain this extremely low friction
capabilitiesthrough
coefficient of conventional
innovative hydrogel materials
chemical (Figure
and physical 11). These
designs, hydrogels
eclipsing often replicate
the lubricative ca-
natural lubrication
pabilities mechanisms,
of conventional hydrogelespecially
materialsthose in cartilage
(Figure 11). Thesetissue. Primarily
hydrogels oftenconsisting
replicate
natural lubrication mechanisms, especially those in cartilage tissue. Primarily consisting
of polymer networks, they can imbibe significant water quantities, forming stable, water-
rich gels [153]. Incorporating specific lubricating molecules into the hydrogel, such as hy-
aluronic acid or polyethylene glycol, drastically reduces the surface friction coefficient.
Biomedicines 2024, 12, 923 17 of 26

of polymer networks, they can imbibe significant water quantities, forming stable, water-
rich gels [153]. Incorporating specific lubricating molecules into the hydrogel, such as
hyaluronic acid or polyethylene glycol, drastically reduces the surface friction coefficient.
Lin and colleagues, mimicking the boundary lubrication of liposomes in joint cartilage,
developed liposome-integrated hydrogel microspheres with a friction coefficient of about
0.01 [154]. Yang, drawing on the concept of bearing lubrication, synthesized porous am-
phiphilic ionic microspheres capable of releasing platelet-derived growth factor BB (PDGF-
BB), markedly reducing knee joint friction upon intra-articular injection [155]. Inspired
by the lubricative properties of ice, Zhao and team employed microfluidics to generate
2-methacryloyloxyethyl phosphorylcholine (MPC) modified hydroxyethyl methacrylate
(HEMA) microspheres loaded with diclofenac sodium, achieving superlubrication and
prolonged drug release in knee joints [156]. Han and associates utilized DMA and MPC to
create branch crosslinked GelMA hydrogel microspheres, effectively reducing joint friction
Biomedicines 2024, 12, x FOR PEER REVIEW 19 of 28
upon intra-articular administration, thus serving as joint lubricants [157]. These hydrogels
act as joint lubricants, diminishing friction and wear on joint surfaces, thereby mitigating
pain and retarding disease progression.

Figure 11. Schematic

Schematic Diagram
Diagramof ofSuperlubricating
SuperlubricatingHydrogels.
Hydrogels.The Thediagram
diagram illustrates thethe
illustrates design of
design
ball
of bearing-inspired
ball superlubricated
bearing-inspired microsphere,
superlubricated which
microsphere, whichsynergistically treats
synergistically OAOA
treats in rats. TheThe
in rats. ad-
vent of of
advent this hydrogel
this marks
hydrogel a significant
marks milestone
a significant milestonein the treatment
in the of OA,
treatment through
of OA, enhanced
through hy-
enhanced
dration lubrication and sustained drug release [144].
hydration lubrication and sustained drug release [144].

6. Prospective and Outlook

OA,
OA, a prevalent
prevalentdegenerative
degenerativedisease
diseaseininthe
theelderly,
elderly,severely
severelycompromises
compromises their quality
their qual-
of
itylife. TheThe
of life. incidence
incidenceof of
OA OA rises
risessignificantly
significantlywithwithage
ageandandisismore
morecommon
commonin in women
women
than
than ininmen.
men.This
Thisdiscrepancy
discrepancy is is
often linked
often to reduced
linked estrogen
to reduced levels
estrogen during
levels menopause,
during meno-
which
pause,contributes to osteoporosis,
which contributes while genetics,
to osteoporosis, trauma, trauma,
while genetics, and prolonged use are also
and prolonged use key
are
factors in the development of knee OA [1,2,158]. Treating joint damage poses
also key factors in the development of knee OA [1,2,158]. Treating joint damage poses a a considerable
clinical challenge:
considerable Cartilage,
clinical challenge:being terminally
Cartilage, beingdifferentiated, exhibits limited
terminally differentiated, self-renewal
exhibits limited
capacity
self-renewal capacity and is challenging to regenerate once damaged. Additionally,in
and is challenging to regenerate once damaged. Additionally, alterations the
alter-
force lines in the affected area further hasten the degeneration of joint cartilage
ations in the force lines in the affected area further hasten the degeneration of joint carti- [3,159,160].
Existing conventional
lage [3,159,160]. OAconventional
Existing treatments, including
OA treatments,pharmacotherapy and surgery, failand
including pharmacotherapy to
cure the condition. In this context, hydrogels, as established biomaterials, have
surgery, fail to cure the condition. In this context, hydrogels, as established biomaterials, attracted
have attracted significant interest in OA research. Their excellent biocompatibility, resem-
blance to cartilage cell extracellular matrix, adjustable properties, drug delivery capabili-
ties, and functional versatility render them a compelling option in OA therapy. The ability
of hydrogels to simulate the natural tissue environment and their potential in targeted
Biomedicines 2024, 12, 923 18 of 26

significant interest in OA research. Their excellent biocompatibility, resemblance to cartilage

cell extracellular matrix, adjustable properties, drug delivery capabilities, and functional
versatility render them a compelling option in OA therapy. The ability of hydrogels to
simulate the natural tissue environment and their potential in targeted drug delivery and
tissue engineering highlight their importance in evolving OA treatment strategies. Current
research and development in this field indicate a future where hydrogels may play a crucial
role in effectively managing and potentially reversing OA’s effects.
Many studies have highlighted the potential of advanced hydrogels in treating OA,
yet only a limited number of these materials have progressed to clinical trials. This gap
primarily stems from the challenges associated with scaling laboratory findings to practical,
clinical applications. However, there has been some success in using HA as a cell carrier in
clinical settings. HA-based treatments for OA have demonstrated high biocompatibility,
evidenced by a range of studies [161–163]. One notable example of an HA-based hydrogel
that has received FDA approval for commercial use is HYMOVIS®. This hydrogel repre-
sents a significant advancement in OA treatment options available to patients, showcasing
the effectiveness of such materials in clinical applications. Currently, more hydrogels
are undergoing clinical studies to explore their potential for wider clinical use [164,165].
These emerging technologies are well-positioned for OA treatment, tackling the current
challenges in hydrogel molding. Microfluidics technology enables precise control over
hydrogel particle size. The integration of nanotechnology is expected to enhance the ef-
ficiency and specificity of hydrogel drug delivery at the microscopic level. The adoption
of microneedle technology could revolutionize conventional drug delivery methods, im-
proving safety and compliance in post-optimization treatments, thus facilitating painless
OA treatment. Responsive hydrogels offer more accurate treatment aligned with disease
conditions. Novel protein hydrogels are providing novel insights into treating cartilage
inflammation [166]. Superlubricating hydrogels, focused on reducing friction between
cartilages, have demonstrated significant efficacy in alleviating OA symptoms, particularly
pain [145]. These developments have substantially enriched the hydrogel research field,
injecting new energy and directions. With these advancements, hydrogels are increasingly
recognized as key components of innovative medical solutions, especially in addressing
the complexities and challenges of OA treatment.
As technological progress and medical needs advance, the limited mechanical strength
of traditional hydrogels has proven inadequate for clinical applications. This necessitated
the exploration and development of new hydrogel types, yielding several innovations
recently. Mikyung and colleagues have introduced an injectable tissue interface prosthesis
(IT-IC) with immediate gelation properties, utilizing multiple cross-linking methods. The IT-
IC hydrogel incorporates biphenyl bonds and coordination bonds formed from conductive
gold nanoparticles (AuNPs) interacting with PB groups in situ through biphenyl reduction,
providing modest electrical conductivity suitable for various tissue repairs [167]. Advanced
technologies like 3D printing and microfluidics have further amplified hydrogel efficacy.
The use of 3D printing enables hydrogel structure customization to individual patient
requirements, enhancing treatment personalization and precision. Zhang has developed
a sono-ink that facilitates self-reinforcing cross-linking in hydrogels. Utilizing this, the
deep-penetration acoustic volumetric printing (DAVP) technique was created, differing
markedly from traditional 3D printing and not relying on photosensitive materials, making
a wider range of hydrogels printable [168]. Ni and colleagues have ingeniously produced
hydrogels with memory and delayed recovery features through 3D printing, capable of
shape-responsive action and timed reversion to their original state [169].
Recent advancements in hydrogel research and application have markedly diversified
their sources and enhanced their physical properties. This development has revolutionized
traditional hydrogels. In OA treatment, hydrogels must fulfill criteria for biocompatibility,
mechanical strength, biodegradability, and therapeutic convenience, elevating standards
in the field. Traditional hydrogels, such as hyaluronic acid (HA), previously exhibited
inferior mechanical properties, which have been greatly enhanced through modifications.
Biomedicines 2024, 12, 923 19 of 26

Current research primarily focuses on discovering new hydrogel materials and improving
existing ones. Prospects involve a deeper comprehension of hydrogel theory and ongoing
advancements in materials science, anticipating more effective and precise hydrogel-based
OA treatments. This promises improved options for OA patients and marks a significant
evolution in biomaterial science. In summary, hydrogels, as versatile and adaptable bioma-
terials, are poised to play a crucial role in OA treatment. Their potential for personalized
medicine, increased therapeutic efficacy, and minimally invasive application places them at
the forefront of innovative treatments, promising to revolutionize OA management.

7. Conclusions
This review comprehensively examines hydrogels in OA therapy. The development of
hydrogel applications in osteoarthritis treatment has progressed significantly over several
decades. Initially, in the 1980s, research focused on natural hydrogels like hyaluronic acid
and collagen, prized for their biocompatibility. By the late 1990s and early 2000s, synthetic
hydrogels such as PVA and PEG emerged, offering enhanced mechanical properties and
customization. The mid-2000s marked a pivotal advancement with the introduction of
injectable hydrogel systems, minimizing invasiveness while maximizing therapeutic effi-
cacy. The 2010s saw the development of multi-responsive hydrogels, capable of reacting to
various biological stimuli like pH and temperature changes, which enabled more precise
drug delivery. Most recently, the 2020s have integrated 3D printing with hydrogel fabrica-
tion, facilitating personalized treatment approaches by tailoring hydrogels to individual
patient needs, thus optimizing therapeutic outcomes in osteoarthritis management. The
advancements in hydrogel technology have significantly enriched treatment strategies
for osteoarthritis, providing innovative and valuable approaches that hold considerable
promise for enhancing therapeutic outcomes.

Author Contributions: Conceptualization, X.G., Y.H. and G.L.; investigation, H.K.; writing—original
draft preparation, G.L. and X.W.; writing—review and editing, X.G., Y.H. and H.K.; supervision and
funding, H.K. All authors have read and agreed to the published version of the manuscript.
Funding: This research was funded by the National Natural Science Foundation of China grant
number 81472106.
Acknowledgments: We acknowledge the financial support from the National Natural Science Foun-
dation of China.
Conflicts of Interest: The authors declare no conflicts of interest.

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