Next Article in Journal
Induced Dryness Stress on Human Vaginal Epithelium: The Efficacy of a New Vaginal Gel
Previous Article in Journal
Application of “Magnetic Anchors” to Align Collagen Fibres for Axonal Guidance
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Gels
Volume 7
Issue 4
10.3390/gels7040155
gels-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Effect of Micro-/Nanoparticle Hybrid Hydrogel Platform on the Treatment of Articular Cartilage-Related Diseases

by
Xu Han
,
Yongzhi Wu
,
Yue Shan
,
Xu Zhang
and
Jinfeng Liao
*
National Clinical Research Centre for Oral Diseases, State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
*
Author to whom correspondence should be addressed.
Gels 2021, 7(4), 155; https://doi.org/10.3390/gels7040155
Submission received: 16 August 2021 / Revised: 18 September 2021 / Accepted: 23 September 2021 / Published: 27 September 2021
Browse Figures
Review Reports Versions Notes

Abstract

:
Joint diseases that mainly lead to articular cartilage injury with prolonged severe pain as well as dysfunction have remained unexplained for many years. One of the main reasons is that damaged articular cartilage is unable to repair and regenerate by itself. Furthermore, current therapy, including drug therapy and operative treatment, cannot solve the problem. Fortunately, the micro-/nanoparticle hybrid hydrogel platform provides a new strategy for the treatment of articular cartilage-related diseases, owing to its outstanding biocompatibility, high loading capability, and controlled release effect. The hybrid platform is effective for controlling symptoms of pain, inflammation and dysfunction, and cartilage repair and regeneration. In this review, we attempt to summarize recent studies on the latest development of micro-/nanoparticle hybrid hydrogel for the treatment of articular cartilage-related diseases. Furthermore, some prospects are proposed, aiming to improve the properties of the micro-/nanoparticle hybrid hydrogel platform so as to offer useful new ideas for the effective and accurate treatment of articular cartilage-related diseases.

1. Introduction

Cartilage, including hyaline cartilage, fibrous cartilage, and elastic cartilage, is distributed throughout the human body and plays various roles, including lubricating joints, bearing loads, and supporting structures [1]. Nevertheless, plenty of diseases occur in cartilage that are seriously harmful to humans. Due to the unavoidable constant motion of the human body, articular cartilage in the joints is more easily damaged. Due to the aging of the population and modern environmental factors, this problem is becoming increasingly serious [2]. Osteoarthritis (OA), a degenerative disease that causes progressive degeneration of the articular cartilage [3], wears on the body’s structures, afflicting many patients with chronic pain [4] for many years [5]. In addition, rheumatoid arthritis (RA) [6] also results in severe cartilage damage, which affects multiple joints in the body. Moreover, inflammatory arthropathies [7], cartilaginous tumors [8], chondrocalcinosis [9], developmental disorders [10], relapsing polychondritis (RP) [11], and osteochondritis dissecans [12] cause cartilage injury, dysfunction, and severe pain. These diseases commonly involve joints such as the knees, ankles, knuckles, and shoulder joints, as well as temporomandibular joints. It is ineluctable to have trouble with walking, finger, and shoulder movement, and chewing food to different degrees as a daily activity requires the participation of these joints. Figure 1 shows the internal structure of articular cartilage defects in the temporomandibular joint (TMJ) and knee joint.
Due to the features of negatively charged and lacking blood vessels, nerves, and the lymphatic system, it is very difficult for cartilage-related diseases to be cured. At present, drug therapy [13,14] and surgical treatment [15,16] are the main methods to treat articular cartilage-related diseases. However, these clinical treatments are circumscribed and show limited effects. The majority of drugs are used to relieve symptoms such as severe pain [15] and inflammation rather than for an etiological cure. In addition, the function of current drugs in the clinical setting has been proven to be unsatisfactory. Although intra-articular injection is proposed to have a positive effect, unsolved problems still exist, such as safety [17], limited drug effects [18], and poor penetration effects [19]. It is likely to accelerate the progression of joint diseases and damage to joints [17]. Furthermore, surgical treatment tends to cause large wounds and infection, resulting in a limited age for surgery in the clinic [20]. Obviously, tissue regeneration is fairly difficult to entirely realize by the rare methods mentioned above [21]. The lack of an appropriate drug delivery system has already puzzled scientists for a long time. Systemic administration may lead to severe side effects and has a weak effect on the pathological area. However, local injection requires several administrations to ensure a long-lasting effect, and injectable drugs are limited [22].
With the rapid development of materials science, molecular biology, and biomedicine, new choices to improve the aforementioned problem have arisen. Specifically, microparticles [23], nanoparticles [24], and hydrogel [25] are suitable for the tissue regeneration and treatment of localized cartilage diseases due to their capability for controlled drug release, enhanced lubrication, and biocompatibility [26,27,28,29]. Hydrogel offers an appropriate growth environment for chondrocytes and has multiple performances, such as injectability [30], biocompatibility [31], and capability of being environment-sensitive [32] and self-healing [33,34,35]. At the same time, we cannot ignore that they still have limited functions and disadvantages. For example, poor mechanical properties of injectable hydrogel affect its use in joints. The short release time of growth factors in micro-/nanoparticles influences their effect on cartilage repair. Therefore, it is better to combine them into a micro-/nanoparticle hybrid hydrogel platform in order to take advantage of their strengths and compensate for their shortcomings. A great number of researchers have already focused on this for research into multi-field as well as cartilage-related diseases. Some studies show that nanospheres can enhance lubrication [36], ductility, and self-recovery of hydrogel [37]. Microparticles are found to make up for the deficiency of hydrogel in mechanical and stable properties. Meanwhile, the capability of controlled drug release is improved. In addition, the loading efficacy and drug types can be increased [38,39,40]. Current studies have proved the superiority and feasibility of micro-/nanoparticle hybrid hydrogel for the therapy of articular cartilage-related diseases.
Herein, we focus on the treatment of articular cartilage-related diseases based on the micro-/nanoparticle hybrid hydrogel platform in recent years. The effects of the platform are discussed in two parts, including symptomatic treatment and the treatment of articular cartilage defects. Finally, we analyze challenges that the micro-/nanoparticle hybrid hydrogel platform faces in the treatment of articular cartilage-related diseases and proposed prospects in research and clinical application in the future.

2. The Preparation and Main Properties of the Micro-/Nanoparticle Hybrid Hydrogel Platform

There is a variety of micro-/nanoparticles made from multiple materials, which have diverse features and play different roles. Alginate [41], chitosan [27,42], gelatin [43], metal [44], and silk fibroin [45] are representative materials to prepare microparticles or nanoparticles in current research [46,47,48,49]. Different methods are used to prepare porous [50], hollow [51,52], and fuzzy [53] micro-/nanoparticles. Hydrogel, made from chitosan [54], alginate [54], gelatin [55], hyaluronic acid (HA) [56], and cellulose [57], as well as synthesized polymers such as polyethylene glycol (PEG) [58], poly vinyl alcohol (PVA) [33,59], gelatin methacryloyl (GelMA) [60], and poly caprolactone (PCL) [61], have diverse properties. Additionally, bi-layered hydrogel was also designed and showed potential in the repair of osteochondral defects [62,63]. Their abilities to be degradable [64]; self-healing [65]; self-adapting [66]; injectable [57,67]; tunable mechanical [68] and stimuli-responsive, such as pH-responsive [57,69]; thermal-responsive [70]; light-responsive [71]; and magnetic-responsive [72] are crucial for hydrogel research and are expected to be applied in clinical practice. Figure 2 shows the variety of micro-/nanoparticles and hydrogels according to their diverse properties.
Aiming to obtain hydrogels and micro-/nanoparticles with various properties made from different materials requires preparation using several methods. As for hydrogel preparation, physical crosslinking and chemical crosslinking are the main methods, including the freeze–heating cycle [73], Schiff-based reaction [74], and Michael addition [75]. To prepare microparticles, methods such as propylene carbonate emulsification–extraction [76], the membrane emulsification technique [77], liquid jet breakup [78], the electrostatic microdroplet method [79], spray drying, and chemical crosslinking [80] are used by researchers. Furthermore, some techniques are applied to prepare nanoparticles, including emulsification [81], nanoprecipitation [82], the double emulsion solvent evaporation method [83], and the microfluidic technique [84].
In order to understand the benefits of both micro-/nanoparticles and hydrogel, the micro-/nanoparticle hybrid hydrogel platform is being widely studied at present. First, microparticles and nanoparticles were prepared and stowed. Then, to combine micro-/nanoparticles with hydrogel, microparticles and nanoparticles were completely dispersed in a solution to make hydrogel. Finally, we discovered that micro-/nanoparticles were embedded in the hydrogel [38,85,86,87,88,89].
The micro-/nanoparticle hybrid hydrogel platform possesses varying properties due to different selections of materials and the characteristics of specific research interests. Its advantages are mainly as follows: First, the controlled and sustained release property is significant for drug delivery [90,91]. It is beneficial to avoid frequent multiple doses and damage caused by large doses. Second, multiple loads can be transported together by loading in micro-/nanospheres and hydrogel [92]. Figure 3 shows that multiple materials can be added to the micro-/nanoparticle hybrid hydrogel platform. Therefore, different goals can be achieved simultaneously. Third, micro-/nanoparticles are able to compensate for hydrogel’s poor mechanical properties [38,93]. Moreover, this hybrid system is able to release diverse stowage at different stages of treatment [94]. In addition, the injectability ensures localized drug delivery, which is able to enhance the local drug concentration and avoid systemic toxicities [95]. Then, antibacterial and antioxidant properties are important for safety in vivo [96,97]. Accordingly, the micro-/nanoparticle hybrid hydrogel platform is suitable for biomedicine and tissue engineering. Currently, it is popular with research on drug delivery [39,85,98], tumors [99,100,101,102], tissue repair and regeneration [103], and wound healing [94]. Obviously, the hybrid system is promising and effective in the treatment of diseases.

3. Micro-/Nanoparticle Hybrid Hydrogel Platform Applied in Articular Cartilage-Related Diseases

As for articular cartilage-related diseases, the cartilage extracellular matrix (ECM) plays a strong part in their occurrence and development. The abnormity and damage of the ECM are closely correlated with cartilage injury and interrelated diseases [104]. Aging is a factor in a break in homeostasis in the cartilage ECM [105]. Consequently, the ECM can be a signal to imply the risk of the occurrence of cartilage-related diseases, and it is necessary to prevent these and provide corresponding treatment at every stage of the disease. According to the function of the ECM, some attempts have been made to prevent OA [106,107].
Articular cartilage-related diseases are often accompanied by varying degrees of cartilage damage and some symptoms. Therefore, the main manifestation of diseases cannot be neglected. Cartilage degeneration [108,109] and defect [110] need to be more carefully considered as two main factors in articular cartilage-related diseases. They are also related to the occurrence of severe pain, inflammation, and dysfunction, which may seriously impact daily life. Due to the outstanding properties of the micro-/nanoparticle hybrid hydrogel platform, articular cartilage-related diseases are promising for treatment and recovery. Figure 4 shows that it is mainly involved in the symptomatic treatment of pain, inflammation, swelling, and dysfunction, as well as articular cartilage regeneration for cartilage defect. Table 1 exhibits a summary of some relevant research.

3.1. Micro-/Nanoparticle Hybrid Hydrogel Platform in Symptomatic Treatment

Articular cartilage is susceptible to diseases on account of abrasion and coloboma mainly led by constant movement of the joints. Furthermore, trauma, tumor, and other reasons can also cause cartilage diseases. Additionally, the damage of cartilage causes the occurrence of articular cartilage-related diseases. Meanwhile, it can be a symptom of diseases such as OA and RA [118,119]. Additionally, patients suffer from severe pain, inflammation, and dysfunction. As a consequence, timely treatments are needed.
Gels 07 00155 g005 550
Figure 5. Injectable mechanical pillow-attenuated in vivo cartilage damage and osteophyte formation following the development of load-induced osteoarthritis. (A) Mouse tibial cyclic compression model. Schematic of tibia positioned in loading device, ready for in vivo axial loading to be applied. (B) Schematic of the duration of loading, intra-articular injections, and end-point analysis. The five injection formulations were saline, bolus DEX (5 mg/mL in PBS), DEX-loaded PLGA nanoparticles (8 mg/mL), hydrogel with DEX-loaded PLGA nanoparticles, and hydrogel alone. Hydrogel groups were 10% w/v PEG-4MAL with a 1:1 DTT:VPM ratio. The hydrogel group with DEX nanoparticles was ~10% nanoparticles. (C) Safranin O-fast green-stained images of the non-loaded vs. loaded limbs (peak load 9.0 N), indicating cartilage erosion (arrowheads) and osteophyte (ellipses) after 2 weeks of loading in the posterior aspect of the medial tibial plateau. (D) The mean OARSI scores of cartilage in the medial tibial plateau and (E) mean medial–lateral width of the osteophyte from three representative sections in the joint (posterior, middle, and anterior). n = 5 mice/group. Red groups = non-hydrogel injections; blue groups = hydrogel-containing injections. Ψ p < 0.05 for loading; * p < 0.05 for hydrogel vs. no hydrogel nested by loading. Cartilage scale bars = 100 μm. Osteophyte scale bars = 200 μm. This figure was published in [120]—copyright, Elsevier (2019). Permission to share the material has been granted.
Figure 5. Injectable mechanical pillow-attenuated in vivo cartilage damage and osteophyte formation following the development of load-induced osteoarthritis. (A) Mouse tibial cyclic compression model. Schematic of tibia positioned in loading device, ready for in vivo axial loading to be applied. (B) Schematic of the duration of loading, intra-articular injections, and end-point analysis. The five injection formulations were saline, bolus DEX (5 mg/mL in PBS), DEX-loaded PLGA nanoparticles (8 mg/mL), hydrogel with DEX-loaded PLGA nanoparticles, and hydrogel alone. Hydrogel groups were 10% w/v PEG-4MAL with a 1:1 DTT:VPM ratio. The hydrogel group with DEX nanoparticles was ~10% nanoparticles. (C) Safranin O-fast green-stained images of the non-loaded vs. loaded limbs (peak load 9.0 N), indicating cartilage erosion (arrowheads) and osteophyte (ellipses) after 2 weeks of loading in the posterior aspect of the medial tibial plateau. (D) The mean OARSI scores of cartilage in the medial tibial plateau and (E) mean medial–lateral width of the osteophyte from three representative sections in the joint (posterior, middle, and anterior). n = 5 mice/group. Red groups = non-hydrogel injections; blue groups = hydrogel-containing injections. Ψ p < 0.05 for loading; * p < 0.05 for hydrogel vs. no hydrogel nested by loading. Cartilage scale bars = 100 μm. Osteophyte scale bars = 200 μm. This figure was published in [120]—copyright, Elsevier (2019). Permission to share the material has been granted.
Gels 07 00155 g005
In consideration of the movement of joints, the mechanical properties should be ensured. A composite hydrogel system made up of silated hydroxypropylmethyl cellulose (Si-HPMC) and mixed with laponites (XLG) was designed to apply to cartilage tissue engineering. This system allowed an injection into the injured region in vivo to steadily sustain the formation of cartilage tissue [121]. In addition, a nanoparticle hybrid hydrogel platform composed of core-shell nanoparticles, and hydrophobic association hydrogels (MHA gels), presented excellent mechanical properties for articular cartilage repair [122]. Bovine serum albumin (BSA) was embedded in chitosan microspheres (CMs) and released slowly through microspheres combined with injectable CMC-OCS hydrogels. It was also able to transport articular chondrocytes to help cartilage repair [123]. Researchers also designed a suitable micro-/nanoparticle hybrid hydrogel platform to relieve troublesome symptoms. Holyoak et al. [120] created a four-arm maleimide-functionalized polyethylene glycol (PEG-4MAL) hydrogel system loaded with fluorescent fluorescein isothiocyanate (FITC) polystyrene nanoparticles containing dexamethasone as a mechanical pillow (Figure 5). It showed great mechanical properties to relieve stress and protect knee-joint cartilage. This system was also able to release dexamethasone according to the needs of the patient and played a role in anti-inflammatory action at the appropriate times.
Due to immune dysregulation, chronic inflammation and irreversible joint and organ damage may be caused [124]; classical symptoms of immune dysregulation and chronic inflammation are expected to be resolved in the near future in order to avoid further aggravation of the disease. Methotrexate (MTX) is known as a first-line drug for the clinical treatment of RA due to its desirable anti-inflammatory action and ability to enhance the effectiveness of biological agents [125]. A sort of nanoparticle-loaded indomethacin (IND), MTX, and a small-interfering RNA (targeting MMP-9) were added to the hydrogel to form a suitable nanoparticle hybrid hydrogel platform for RA treatment. Relieving swelling, reducing inflammation, and reversing the damage of articular cartilage can be achieved at the same time by injecting the hybrid hydrogel platform into the diseased joint [126]. Yin et al. [127] designed a nanoparticle hybrid hydrogel platform for the synergistic treatment of RA. In this study, the hybrid system was made of temperature-sensitive hydrogel (D-NGel) and nanoparticles (D-NPs), which were loaded with indomethacin (IND) and MTX—specifically, the long-acting hydrogel formed after intra-articular injection. In vivo, it was helpful for reducing joint swelling, inflammation, and bone erosion.
As for articular cartilage-related diseases, including OA and RA, some symptoms, such as inflammation, pain, and swelling, are similar. Therefore, some researchers focused on specific symptoms instead of the type of disease. Platelet lysate (PL), a mixture of growth factors, was designed to load in nanoparticles combined with thermosensitive poly(D,L-lactide)-poly(ethylene glycol)-poly(D,L-lactide) (PLEL) hydrogel. The well-designed system was able to decrease the inflammatory response, avoid the degeneration of cartilage in the early stages of diseases, and enhance the cartilage repair (Figure 6) [128]. In order to make useful, long-acting drugs to protect cartilage and its surrounding tissue, as well as control inflammation, agarose hydrogel and poly(lactic-co-glycolic) acid (PLGA) microspheres were loaded with dexamethasone (DEX) and bonded together to aid the continuous release of the effective drug [129]. The severe pain that patients suffered from should also be alleviated. Long-acting analgesic could be achieved by a microsphere hybrid hydrogel platform. On account of the loading of bupivacaine (BUP) and DEX, the analgesia time was obviously prolonged [86]. Furthermore, the micro-/nanosphere hybrid hydrogel platform can also be used as an applicable implant for orthopedic surgery. Chondrocytes were found to survive and grow in the microsphere hybrid hydrogel platform that comprised cartilaginous hydrogel and PLGA microspheres [130]. Asgari et al. attempted to load curcumin (Cur) in hydrogel to deactivate inflammation, and PLGA microparticles covering kartogenin were embedded within it. Through in vivo experiments, this injectable hybrid hydrogel platform has also been shown to help cartilage regeneration [131].

3.2. Micro-/Nanoparticle Hybrid Hydrogel Platform in Cartilage Defect

It is difficult to heal cartilage defect and regain cartilage function. To solve this problem, researchers focused on two methods, cartilage repair and cartilage regeneration. Some attempted to use other appropriate materials to replace the missing cartilage [132]. Others have been dedicated to regenerating cartilage where it is missing using suitable materials. Although many problems need to be taken into account, biocompatibility, cell attachment, loading capacity, mechanical ability, and other properties are needed. Fortunately, the micro-/nanoparticle hybrid hydrogel platform can satisfy these requirements. It is able to carry the required materials and act as a scaffold for cartilage repair and regeneration.
Regarding cartilage repair, material selection of the micro-/nanoparticle hybrid hydrogel platform is important. Meanwhile, structural design is equally important. The micro-/nanoparticle hybrid hydrogel platform is suggested to be a more suitable scaffold for cartilage tissue engineering. Researchers prepared natural polymers including maleilated chitosan (MCS) and methacrylated silk fibroin (MSF) micro-/nanoparticles and added them into hydrogel. Outstanding biocompatibility and cell adhesion proved that it had great potential for cartilage repair [133]. Liao et al. [134] designed an injectable MPs/Alg-chondrocyte system that consisted of porous poly(ε-caprolactone)−β-poly(ethylene glycol)−β-poly(ε-caprolactone) microspheres (MPs/Alg) and three-dimensional (3D) alginate hydrogel. Many experiments have suggested its usefulness in repairing cartilage defects.
Compared to cartilage repair, cartilage regeneration seems more difficult to achieve. Currently, a great number of studies pay attention to promoting cartilage regeneration by different thoughts. First, as a scaffold, the ability to promote cell growth and differentiation is important. Hydroxyapatite nanoparticle-crosslinked peptide hydrogels designed by Xu et al. [135] presented great potential in cartilage regeneration. Then, choosing a suitable material that possesses the ability to regenerate cartilage to add to a micro-/nanoparticle hybrid hydrogel platform is important. Through a large amount of research, activated skeletal stem cells and mesenchymal stem cells (MSCs) were confirmed to be appropriate to add to the micro-/nanoparticle hybrid hydrogel platform [136].
Kouhi et al. [137] developed an injectable gellan gum/lignocellulose nanofibril hydrogel system mixed with melatonin-loaded forsterite nanoparticles. It showed high mechanical properties and the capability of sustainable drug release. Additionally, this system was able to promote cell adhesion and facilitate proliferation and gene expression, which suggest its appropriateness for cartilage regeneration. Lua et al. [138] attempted to combine collagen hydrogel with carbon dot nanoparticles (CD NPs), which successfully enhance the difficulty to adapt to chondrogenesis (Figure 7). The injectable hybrid hydrogel platform was able to produce reactive oxygen species (ROS) to perfect chondrogenic differentiation and achieve the regeneration of cartilage. Additionally, eggshell microparticles (ESP) were dispersed in hydrogel to obtain better mechanical properties [139].
Drugs, growth factors, and stem cells, as well as chondrocytes, are available to add to the micro-/nanoparticle hybrid hydrogel platform to promote the regeneration of cartilage. Therefore, many researchers are committed to finding means for applicable stowage to load in the system for cartilage regeneration.
In order to regenerate cartilage, it has also been attempted to load drugs that are favorable for cartilage regeneration in the micro-/nanoparticle hybrid hydrogel platform to achieve continuous release. Naghizadeh et al. [140] designed an injectable microparticle hybrid hydrogel platform with the addition of melatonin and methylprednisolone. This system provided a good environment for cell growth, which means that cartilage regeneration is expected to be realized.
Fan et al. [141] designed a nanoparticle hybrid hydrogel platform that loaded kartogenin (KGN) and transforming growth factor β3 (TGF-β3) to stimulate the formation of cartilage. This system mainly acted on the endogenous mesenchymal stem cells (MSCs). TGF-β3-loaded PLGA nanoparticles were added to alginate-poly(acrylamide) hydrogel to create a hybrid system. Then, the controlled release of TGF-β3 showed the effect of enhancing cartilage regeneration (Figure 8) [142]. Furthermore, chondroitin sulfate (ChS) was used to relieve pain and promote cartilage regeneration in joint disease. Radhakrishnan et al. [143] add Ghs-loaded microparticles to porous injectable biphasic semi-interpenetrating polymer network (SIPN) hydrogel for articular hyaline cartilage regeneration.
The micro-/nanoparticle hybrid hydrogel platform is supposed to provide a proper metabolic environment for cells to grow. Therefore, a microparticle hybrid hydrogel platform that was able to release oxygen was created. Researchers placed calcium peroxide in PLA microparticles and dispersed them in the hydrogel. The oxygen released from the system can satisfy the requirements of cell metabolism at the cartilage-to-bone interface [114].
Additionally, magnetic nanocomposite hydrogels were suggested to be applied in cartilage tissue engineering [144]. Huang et al. [145] attempted to add Fe3O4 magnetic nanoparticles to hydrogel to support the adhesion, growth, and proliferation of MSCs due to the effects of the pulsed electromagnetic field. It was able to promote the chondrogenic differentiation of BMSCs and showed a promising opportunity for the clinical treatment of articular cartilage defects. In addition, magnetic poly(lactic-co-glycolic acid) microsphere-gelatin hydrogel designed by Wang et al. [146] was supposed to be able to promote bone repair.
Furthermore, the micro-/nanoparticle hybrid hydrogel platform was expected to be equipped with multiple effects to realize more than one purpose at once. Atoufi et al. [111] created an injectable thermosensitive micro-/nanoparticle hybrid hydrogel platform with triple effects. In this platform, PLGA-ACH micro-/nanoparticles contained melatonin, and PNIPAM/hyaluronic acid hydrogel was thermosensitive. Improving mechanical properties, controlling releasing chondrogenic small molecule melatonin, and reducing the dehydration and shrinkage of hydrogels could be realized through the well-designed hybrid system. Therefore, it had great potential for applications in cartilage tissue engineering.
In addition, there are some current studies focused on improving the performance of micro-/nanoparticle hybrid hydrogels to make it easier to use them in cartilage regeneration. In order to improve the properties of the drug-loaded nanoparticle hybrid hydrogel platform, Leea et al. [147] devised a method to promote stem-cell adherence to the system by means of cold atmospheric plasma (CAP) treatment.

4. Prospect and Challenges

The micro-/nanoparticle hybrid hydrogel platform shows tremendous potential in the treatment of articular cartilage-related diseases. Therefore, it is a promising application for cartilage tissue engineering and solving intractable clinical problems. It is certain that the micro-/nanoparticle hybrid hydrogel platform presents great superiority in many ways. Nevertheless, there are still some issues to be considered. First, this hybrid system should be designed to match the complex microenvironment in vivo, including friction, pH and temperature, and its safety should be guaranteed. Nanoparticles may pose toxicity issues through distribution and deposition in cells and different organ systems, such as the lungs, liver, and brain. The route of administration and exposure can influence the toxicity of NPs, and the toxicity of NPs is mainly determined by size, surface area, surface charge, and aggregation state [148]. Therefore, the toxicity of NPs should be considered and analyzed before use. Accordingly, experiments in vitro and in vivo that aim to improve safety and eliminate influencing factors are warranted.
Second, controlled release is an outstanding property of the system. However, the release mechanism and effectiveness remain unclear. Owing to the requirement of a specific quantity of stowage for the system, especially in drugs, whose dosage is closely related to security and efficacy, the release mechanism and effectiveness require rigorous studies. On the other hand, ensuring the difference between micro-/nanoparticles and hydrogel in the micro-/nanoparticle hybrid hydrogel platform is needed. Only in this way can we solve the issue of loading different materials into befitting places and controlling the sequence of releases. Additionally, due to the diversity of micro-/nanoparticles and hydrogels, it becomes difficult to choose the right combination of materials in order to maximize the performance of the hybrid system.
In addition, the kinds of materials that are most appropriate to be loaded in the system should be studied in detail. It is not only necessary to conduct thorough experiments, but the study of mechanisms also cannot be ignored. Suitable cells with desirable effects are expected to be added. Some studies suggest that articular cartilage morphogenesis, cells that are involved in articular cartilage development, may provide insights into cell types and sources of joint injury [149]. Focusing on mechanisms of articular cartilage development and damage may play a significant role in the treatment of articular cartilage-related diseases and cartilage regeneration and provide useful developments.
Furthermore, articular cartilage diseases may cause damage to adjacent bone tissue. Problems of cartilage defects and bone defects are also expected to be solved by the micro-/nanoparticle hybrid hydrogel platform. Therefore, some relevant studies that focused on bone defect repair can be highlighted. Bowen tan’s team designed an injectable curcumin-microsphere/IR820 coloaded hybrid methylcellulose hydrogel (Cur-MP/IR820 gel) platform, which solved the problem of bone defects caused by osteosarcoma by promoting bone reconstruction [100]. Additionally, as a soft tissue, articular capsules can also be damaged. Therefore, it is equally essential to solve this problem. SIS powder (SISP)/chitosan chloride (CSCl)-β-glycerol phosphate (GP)-hydroxyethyl cellulose (HEC) hydrogel was produced and has potential in soft tissue regeneration [150].
Furthermore, previous experiments mainly pay close attention to knee diseases. However, other joint diseases also warrant consideration. The study of the temporomandibular joint lacks suitable animal models [151]. As a special joint, the previously mentioned temporomandibular joint is easily damaged in the condyle cartilage, with no discomfort until the condition becomes highly serious. Compared to knee disease, the temporomandibular joint is harder to treat due to the particularity of its position and structure. Due to the superiority of the micro-/nanoparticle hybrid hydrogel platform in other articular cartilage-related diseases, it may be appropriate to apply in temporomandibular joint diseases, such as temporomandibular joint disorders (TMD) [152], temporomandibular joint osteoarthritis, (TMJOA) [153], and temporomandibular joint ankylosis. There are some studies on cartilage tissue engineering [154,155] that can provide an applicable basis in the micro-/nanoparticle hybrid hydrogel platform for the treatment of the temporomandibular joint. Through experiments, exosomes (Exos) of stem cells from human exfoliated deciduous teeth (SHEDs) were claimed to protect TMJ chondrocytes from inflammation that is mainly caused by TMJOA [156].
In summary, in order to improve the properties of the micro-/nanoparticle hybrid hydrogel platform for use in the treatment of articular cartilage-related diseases, the prospect that should be realized is described as follows: (a) improving safety—it might be helpful to wrap it in secure materials, modify the surface properties of materials that may harm human health, or set up a strain-like structure to avoid harmful substances entering blood circulation; (b) increasing adaptability—improving the lubricity of the surface of materials according to the features of joints and performing vitro experiments under the same conditions as in vivo; (c) studying the mechanism clearly; (d) choosing accurate materials by establishing some conditions such as biocompatibility and mechanical properties and comparing them according to those conditions; (e) solving the problem of adjacent bone destruction; and (f) addressing broader joint diseases.
Additionally, there are still some unresolved challenges. A large amount of effort is required based on the current research status. Before being put into use, the micro-/nanoparticle hybrid hydrogel platform still requires sufficient clinical tests for the hybrid system to be proven to be completely safe for the body and highly effective for these diseases. Moreover, an accurate operating guide should be produced through repeated experiments to instruct the doctor on dosage, duration, and interval. Additionally, we cannot ignore the appropriate methods of therapeutic effect evaluation for humans. Unlike animal experiments, human trials require noninvasive and entirely safe methods to check the efficacy of treatment. At the same time, technical problems of the micro-/nanoparticle hybrid hydrogel platform also exist. We ignored the fact that the internal structure and effect of the micro-/nanoparticle hybrid hydrogel platform may change under the influence of volume and friction. Therefore, guaranteeing that micro-/nanoparticles are uniformly embedded within the hydrogel after injection, extrusion, or friction caused by activity and that the dose of drug release is stable should be resolved. If these issues are resolved completely, the micro-/nanoparticle hybrid hydrogel platform is promising for wide use in the clinic.

5. Conclusions

In this review, we summarize the latest progress of the micro-/nanoparticle hybrid hydrogel platform in the treatment of different types of joint diseases that can cause articular cartilage injury. Due to great biocompatibility, mechanical strength, and syringeability, micro-/nanoparticle hybrid hydrogel presents superiority and a desirable effect on the treatment of articular cartilage-related diseases. This platform shows great potential in symptom control and cartilage repair and regeneration. This review provides a useful strategy for the treatment of articular cartilage-related diseases in cartilage tissue engineering, which may provide researchers with new ideas for clinical treatment.

Funding

This work was financially supported by the National Natural Science Foundation (31972925), Chengdu International Science and Technology Cooperation Project (2020-GH02-00048-HZ), Sichuan Science and Technology Program (2020YJ0065), and the Fundamental Research Funds for Central Universities.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not Applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Krishnan, Y.; Grodzinsky, A.J. Cartilage diseases. Matrix Biol. 2018, 71–72, 51–69. [Google Scholar] [CrossRef]
  2. Berenbaum, F.; Wallace, I.J.; Lieberman, D.E.; Felson, D.T. Modern-day environmental factors in the pathogenesis of osteoarthritis. Nat. Rev. Rheumatol. 2018, 14, 674–681. [Google Scholar] [CrossRef]
  3. Guilak, F.; Nims, R.J.; Dicks, A.; Wu, C.L.; Meulenbelt, I. Osteoarthritis as a disease of the cartilage pericellular matrix. Matrix Biol. 2018, 71–72, 40–50. [Google Scholar] [CrossRef]
  4. Zhu, S.; Zhu, J.; Zhen, G.; Hu, Y.; An, S.; Li, Y.; Zheng, Q.; Chen, Z.; Yang, Y.; Wan, M.; et al. Subchondral bone osteoclasts induce sensory innervation and osteoarthritis pain. J. Clin. Investig. 2019, 129, 1076–1093. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  5. Barnett, R. Osteoarthritis. Lancet 2018, 391, 1985. [Google Scholar] [CrossRef]
  6. Schett, G.; Tanaka, Y.; Isaacs, J.D. Why remission is not enough: Underlying disease mechanisms in RA that prevent cure. Nat. Rev. Rheumatol. 2021, 17, 135–144. [Google Scholar] [CrossRef] [PubMed]
  7. Wu, X. Innate Lymphocytes in Inflammatory Arthritis. Front. Immunol. 2020, 11, 565275. [Google Scholar] [CrossRef]
  8. Zhu, G.G.; Nafa, K.; Agaram, N.; Zehir, A.; Benayed, R.; Sadowska, J.; Borsu, L.; Kelly, C.; Tap, W.D.; Fabbri, N.; et al. Genomic Profiling Identifies Association of IDH1/IDH2 Mutation with Longer Relapse-Free and Metastasis-Free Survival in High-Grade Chondrosarcoma. Clin. Cancer Res. 2020, 26, 419–427. [Google Scholar] [CrossRef] [Green Version]
  9. Latourte, A.; Rat, A.C.; Ngueyon Sime, W.; Ea, H.K.; Bardin, T.; Mazières, B.; Roux, C.; Guillemin, F.; Richette, P. Chondrocalcinosis of the Knee and the Risk of Osteoarthritis Progression: Data From the Knee and Hip Osteoarthritis Long-term Assessment Cohort. Arthritis Rheumatol. 2020, 72, 726–732. [Google Scholar] [CrossRef]
  10. Dai, J.; Yu, D.; Wang, Y.; Chen, Y.; Sun, H.; Zhang, X.; Zhu, S.; Pan, Z.; Heng, B.C.; Zhang, S.; et al. Kdm6b regulates cartilage development and homeostasis through anabolic metabolism. Ann. Rheum. Dis. 2017, 76, 1295–1303. [Google Scholar] [CrossRef] [PubMed]
  11. Haslag-Minoff, J.; Regunath, H. Relapsing Polychondritis. N. Engl. J. Med. 2018, 378, 1715. [Google Scholar] [CrossRef] [PubMed]
  12. Nguyen, J.C.; Liu, F.; Blankenbaker, D.G.; Woo, K.M.; Kijowski, R. Juvenile Osteochondritis Dissecans: Cartilage T2 Mapping of Stable Medial Femoral Condyle Lesions. Radiology 2018, 288, 536–543. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Burmester, G.R.; Pope, J.E. Novel treatment strategies in rheumatoid arthritis. Lancet 2017, 389, 2338–2348. [Google Scholar] [CrossRef]
  14. Zeng, C.; Wei, J.; Persson, M.S.M.; Sarmanova, A.; Doherty, M.; Xie, D.; Wang, Y.; Li, X.; Li, J.; Long, H.; et al. Relative efficacy and safety of topical non-steroidal anti-inflammatory drugs for osteoarthritis: A systematic review and network meta-analysis of randomised controlled trials and observational studies. Br. J. Sports Med. 2018, 52, 642–650. [Google Scholar] [CrossRef] [PubMed]
  15. Conaghan, P.G.; Cook, A.D.; Hamilton, J.A.; Tak, P.P. Therapeutic options for targeting inflammatory osteoarthritis pain. Nat. Rev. Rheumatol. 2019, 15, 355–363. [Google Scholar] [CrossRef]
  16. Palmer, J.S.; Monk, A.P.; Hopewell, S.; Bayliss, L.E.; Jackson, W.; Beard, D.J.; Price, A.J. Surgical interventions for symptomatic mild to moderate knee osteoarthritis. Cochrane Database Syst. Rev. 2019, 7, Cd012128. [Google Scholar] [CrossRef]
  17. Kompel, A.J.; Roemer, F.W.; Murakami, A.M.; Diaz, L.E.; Crema, M.D.; Guermazi, A. Intra-articular Corticosteroid Injections in the Hip and Knee: Perhaps Not as Safe as We Thought? Radiology 2019, 293, 656–663. [Google Scholar] [CrossRef]
  18. Mehta, S.; He, T.; Bajpayee, A.G. Recent advances in targeted drug delivery for treatment of osteoarthritis. Curr. Opin. Rheumatol. 2021, 33, 94–109. [Google Scholar] [CrossRef]
  19. Bajpayee, A.G.; Grodzinsky, A.J. Cartilage-targeting drug delivery: Can electrostatic interactions help? Nat. Rev. Rheumatol. 2017, 13, 183–193. [Google Scholar] [CrossRef]
  20. Chahal, J.; Lansdown, D.A.; Davey, A.; Davis, A.M.; Cole, B.J. The Clinically Important Difference and Patient Acceptable Symptomatic State for Commonly Used Patient-Reported Outcomes After Knee Cartilage Repair. Am. J. Sports Med. 2021, 49, 193–199. [Google Scholar] [CrossRef]
  21. Kwon, H.; Brown, W.E.; Lee, C.A.; Wang, D.; Paschos, N.; Hu, J.C.; Athanasiou, K.A. Surgical and tissue engineering strategies for articular cartilage and meniscus repair. Nat. Rev. Rheumatol. 2019, 15, 550–570. [Google Scholar] [CrossRef] [PubMed]
  22. Jones, I.A.; Togashi, R.; Wilson, M.L.; Heckmann, N.; Vangsness, C.T., Jr. Intra-articular treatment options for knee osteoarthritis. Nat. Rev. Rheumatol. 2019, 15, 77–90. [Google Scholar] [CrossRef] [PubMed]
  23. Neufurth, M.; Wang, X.; Wang, S.; Steffen, R.; Ackermann, M.; Haep, N.D.; Schröder, H.C.; Müller, W.E.G. 3D printing of hybrid biomaterials for bone tissue engineering: Calcium-polyphosphate microparticles encapsulated by polycaprolactone. Acta Biomater. 2017, 64, 377–388. [Google Scholar] [CrossRef]
  24. Deng, C.; Xu, C.; Zhou, Q.; Cheng, Y. Advances of nanotechnology in osteochondral regeneration. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 2019, 11, e1576. [Google Scholar] [CrossRef] [PubMed]
  25. Zhang, X.; Tan, B.; Wu, Y.; Zhang, M.; Liao, J. A Review on Hydrogels with Photothermal Effect in Wound Healing and Bone Tissue Engineering. Polymers 2021, 13, 2100. [Google Scholar] [CrossRef] [PubMed]
  26. Gupta, V.; Khan, Y.; Berkland, C.J.; Laurencin, C.T.; Detamore, M.S. Microsphere-Based Scaffolds in Regenerative Engineering. Annu. Rev. Biomed. Eng. 2017, 19, 135–161. [Google Scholar] [CrossRef]
  27. Shoueir, K.R.; El-Desouky, N.; Rashad, M.M.; Ahmed, M.K.; Janowska, I.; El-Kemary, M. Chitosan based-nanoparticles and nanocapsules: Overview, physicochemical features, applications of a nanofibrous scaffold, and bioprinting. Int. J. Biol. Macromol. 2021, 167, 1176–1197. [Google Scholar] [CrossRef]
  28. He, T.; Zhang, C.; Vedadghavami, A.; Mehta, S.; Clark, H.A.; Porter, R.M.; Bajpayee, A.G. Multi-arm Avidin nano-construct for intra-cartilage delivery of small molecule drugs. J. Control. Release 2020, 318, 109–123. [Google Scholar] [CrossRef]
  29. Han, Y.; Yang, J.; Zhao, W.; Wang, H.; Sun, Y.; Chen, Y.; Luo, J.; Deng, L.; Xu, X.; Cui, W.; et al. Biomimetic injectable hydrogel microspheres with enhanced lubrication and controllable drug release for the treatment of osteoarthritis. Bioact. Mater. 2021, 6, 3596–3607. [Google Scholar] [CrossRef]
  30. Zhao, Y.; Cui, Z.; Liu, B.; Xiang, J.; Qiu, D.; Tian, Y.; Qu, X.; Yang, Z. An Injectable Strong Hydrogel for Bone Reconstruction. Adv. Healthc. Mater. 2019, 8, e1900709. [Google Scholar] [CrossRef]
  31. Adak, A.; Ghosh, S.; Gupta, V.; Ghosh, S. Biocompatible Lipopeptide-Based Antibacterial Hydrogel. Biomacromolecules 2019, 20, 1889–1898. [Google Scholar] [CrossRef] [PubMed]
  32. Hendi, A.; Umair Hassan, M.; Elsherif, M.; Alqattan, B.; Park, S.; Yetisen, A.K.; Butt, H. Healthcare Applications of pH-Sensitive Hydrogel-Based Devices: A Review. Int. J. Nanomed. 2020, 15, 3887–3901. [Google Scholar] [CrossRef]
  33. Yang, L.; Zeng, Y.; Wu, H.; Zhou, C.; Tao, L. An antioxidant self-healing hydrogel for 3D cell cultures. J. Mater. Chem. B 2020, 8, 1383–1388. [Google Scholar] [CrossRef] [PubMed]
  34. Yang, J.; Zhang, Y.S.; Yue, K.; Khademhosseini, A. Cell-laden hydrogels for osteochondral and cartilage tissue engineering. Acta Biomater. 2017, 57, 1–25. [Google Scholar] [CrossRef] [PubMed]
  35. Hong, H.; Seo, Y.B.; Kim, D.Y.; Lee, J.S.; Lee, Y.J.; Lee, H.; Ajiteru, O.; Sultan, M.T.; Lee, O.J.; Kim, S.H.; et al. Digital light processing 3D printed silk fibroin hydrogel for cartilage tissue engineering. Biomaterials 2020, 232, 119679. [Google Scholar] [CrossRef] [PubMed]
  36. Chen, H.; Sun, T.; Yan, Y.; Ji, X.; Sun, Y.; Zhao, X.; Qi, J.; Cui, W.; Deng, L.; Zhang, H. Cartilage matrix-inspired biomimetic superlubricated nanospheres for treatment of osteoarthritis. Biomaterials 2020, 242, 119931. [Google Scholar] [CrossRef] [PubMed]
  37. Ge, P.; Cai, Q.; Zhang, H.; Yao, X.; Zhu, W. Full Poly(ethylene glycol) Hydrogels with High Ductility and Self-Recoverability. ACS Appl. Mater. Interfaces 2020, 12, 37549–37560. [Google Scholar] [CrossRef] [PubMed]
  38. Xing, L.; Sun, J.; Tan, H.; Yuan, G.; Li, J.; Jia, Y.; Xiong, D.; Chen, G.; Lai, J.; Ling, Z.; et al. Covalently polysaccharide-based alginate/chitosan hydrogel embedded alginate microspheres for BSA encapsulation and soft tissue engineering. Int. J. Biol. Macromol. 2019, 127, 340–348. [Google Scholar] [CrossRef]
  39. Wang, F.; Zhang, Q.; Li, X.; Huang, K.; Shao, W.; Yao, D.; Huang, C. Redox-responsive blend hydrogel films based on carboxymethyl cellulose/chitosan microspheres as dual delivery carrier. Int. J. Biol. Macromol. 2019, 134, 413–421. [Google Scholar] [CrossRef]
  40. Gong, Y.; Zhang, Y.; Cao, Z.; Ye, F.; Lin, Z.; Li, Y. Development of CaCO(3) microsphere-based composite hydrogel for dual delivery of growth factor and Ca to enhance bone regeneration. Biomater. Sci. 2019, 7, 3614–3626. [Google Scholar] [CrossRef]
  41. Uyen, N.T.T.; Hamid, Z.A.A.; Tram, N.X.T.; Ahmad, N. Fabrication of alginate microspheres for drug delivery: A review. Int. J. Biol. Macromol. 2020, 153, 1035–1046. [Google Scholar] [CrossRef]
  42. Fu, Y.N.; Li, Y.; Li, G.; Yang, L.; Yuan, Q.; Tao, L.; Wang, X. Adaptive Chitosan Hollow Microspheres as Efficient Drug Carrier. Biomacromolecules 2017, 18, 2195–2204. [Google Scholar] [CrossRef]
  43. Kudva, A.K.; Dikina, A.D.; Luyten, F.P.; Alsberg, E.; Patterson, J. Gelatin microspheres releasing transforming growth factor drive in vitro chondrogenesis of human periosteum derived cells in micromass culture. Acta Biomater. 2019, 90, 287–299. [Google Scholar] [CrossRef]
  44. Mao, W.; Son, Y.J.; Yoo, H.S. Gold nanospheres and nanorods for anti-cancer therapy: Comparative studies of fabrication, surface-decoration, and anti-cancer treatments. Nanoscale 2020, 12, 14996–15020. [Google Scholar] [CrossRef]
  45. Wu, M.; Yang, W.; Chen, S.; Yao, J.; Shao, Z.; Chen, X. Size-controllable dual drug-loaded silk fibroin nanospheres through a facile formation process. J. Mater. Chem. B 2018, 6, 1179–1186. [Google Scholar] [CrossRef]
  46. Wang, X.; Cao, Y.; Yan, H. Chlorambucil loaded in mesoporous polymeric microspheres as oral sustained release formulations with enhanced hydrolytic stability. Mater. Sci. Eng. C Mater. Biol. Appl. 2018, 91, 564–569. [Google Scholar] [CrossRef]
  47. Tawagi, E.; Ganesh, T.; Cheng, H.M.; Santerre, J.P. Synthesis of degradable-polar-hydrophobic-ionic co-polymeric microspheres by membrane emulsion photopolymerization: In vitro and in vivo studies. Acta Biomater. 2019, 89, 279–288. [Google Scholar] [CrossRef]
  48. Li, Z.; Ma, S.; Zhang, G.; Wang, D.; Zhou, F. Soft/Hard-Coupled Amphiphilic Polymer Nanospheres for Water Lubrication. ACS Appl. Mater. Interfaces 2018, 10, 9178–9187. [Google Scholar] [CrossRef] [PubMed]
  49. Allen, S.D.; Bobbala, S.; Karabin, N.B.; Scott, E.A. On the advancement of polymeric bicontinuous nanospheres toward biomedical applications. Nanoscale Horiz. 2019, 4, 258–272. [Google Scholar] [CrossRef] [PubMed]
  50. Cong, H.; Xing, J.; Ding, X.; Zhang, S.; Shen, Y.; Yu, B. Preparation of porous sulfonated poly(styrene-divinylbenzene) microspheres and its application in hydrophilic and chiral separation. Talanta 2020, 210, 120586. [Google Scholar] [CrossRef] [PubMed]
  51. Lengert, E.; Kozlova, A.; Pavlov, A.M.; Atkin, V.; Verkhovskii, R.; Kamyshinsky, R.; Demina, P.; Vasiliev, A.L.; Venig, S.B.; Bukreeva, T.V. Novel type of hollow hydrogel microspheres with magnetite and silver nanoparticles. Mater. Sci. Eng. C Mater. Biol. Appl. 2019, 98, 1114–1121. [Google Scholar] [CrossRef] [PubMed]
  52. Wang, H.; Lin, G.; Li, X.; Lu, W.; Peng, Z. Self-standing hollow porous AuPt nanospheres and their enhanced electrocatalytic performance. J. Colloid Interface Sci. 2019, 554, 396–403. [Google Scholar] [CrossRef] [PubMed]
  53. Zhang, D.; Zheng, H.; Geng, K.; Shen, J.; Feng, X.; Xu, P.; Duan, Y.; Li, Y.; Wu, R.; Gou, Z.; et al. Large fuzzy biodegradable polyester microspheres with dopamine deposition enhance cell adhesion and bone regeneration in vivo. Biomaterials 2021, 272, 120783. [Google Scholar] [CrossRef] [PubMed]
  54. Ahsan, S.M.; Thomas, M.; Reddy, K.K.; Sooraparaju, S.G.; Asthana, A.; Bhatnagar, I. Chitosan as biomaterial in drug delivery and tissue engineering. Int. J. Biol. Macromol. 2018, 110, 97–109. [Google Scholar] [CrossRef] [PubMed]
  55. Satapathy, M.K.; Manga, Y.B.; Ostrikov, K.K.; Chiang, W.H.; Pandey, A.; Lekha, R.; Nyambat, B.; Chuang, E.Y.; Chen, C.H. Microplasma Cross-Linked Graphene Oxide-Gelatin Hydrogel for Cartilage Reconstructive Surgery. ACS Appl. Mater. Interfaces 2020, 12, 86–95. [Google Scholar] [CrossRef] [PubMed]
  56. Pandit, A.H.; Mazumdar, N.; Ahmad, S. Periodate oxidized hyaluronic acid-based hydrogel scaffolds for tissue engineering applications. Int. J. Biol. Macromol. 2019, 137, 853–869. [Google Scholar] [CrossRef]
  57. Chen, N.; Wang, H.; Ling, C.; Vermerris, W.; Wang, B.; Tong, Z. Cellulose-based injectable hydrogel composite for pH-responsive and controllable drug delivery. Carbohydr. Polym. 2019, 225, 115207. [Google Scholar] [CrossRef]
  58. Huynh, C.T.; Liu, F.; Cheng, Y.; Coughlin, K.A.; Alsberg, E. Thiol-Epoxy “Click” Chemistry to Engineer Cytocompatible PEG-Based Hydrogel for siRNA-Mediated Osteogenesis of hMSCs. ACS Appl. Mater. Interfaces 2018, 10, 25936–25942. [Google Scholar] [CrossRef]
  59. Chou, H.Y.; Tsai, H.C. Development of hydrogels with thermal-healing properties using a network of polyvinyl alcohol and boron nitride composites. Mater. Sci. Eng. C Mater. Biol. Appl. 2021, 118, 111364. [Google Scholar] [CrossRef]
  60. Zhao, X.; Sun, X.; Yildirimer, L.; Lang, Q.; Lin, Z.Y.W.; Zheng, R.; Zhang, Y.; Cui, W.; Annabi, N.; Khademhosseini, A. Cell infiltrative hydrogel fibrous scaffolds for accelerated wound healing. Acta Biomater. 2017, 49, 66–77. [Google Scholar] [CrossRef] [Green Version]
  61. Chen, M.; Feng, Z.; Guo, W.; Yang, D.; Gao, S.; Li, Y.; Shen, S.; Yuan, Z.; Huang, B.; Zhang, Y.; et al. PCL-MECM-Based Hydrogel Hybrid Scaffolds and Meniscal Fibrochondrocytes Promote Whole Meniscus Regeneration in a Rabbit Meniscectomy Model. ACS Appl. Mater. Interfaces 2019, 11, 41626–41639. [Google Scholar] [CrossRef] [PubMed]
  62. Yu, X.; Hu, Y.; Zou, L.; Yan, S.; Zhu, H.; Zhang, K.; Liu, W.; He, D.; Yin, J. A bilayered scaffold with segregated hydrophilicity-hydrophobicity enables reconstruction of goat hierarchical temporomandibular joint condyle cartilage. Acta Biomater. 2021, 121, 288–302. [Google Scholar] [CrossRef] [PubMed]
  63. Liao, J.; Tian, T.; Shi, S.; Xie, X.; Ma, Q.; Li, G.; Lin, Y. The fabrication of biomimetic biphasic CAN-PAC hydrogel with a seamless interfacial layer applied in osteochondral defect repair. Bone Res. 2017, 5, 17018. [Google Scholar] [CrossRef] [Green Version]
  64. Liu, X.; Steiger, C.; Lin, S.; Parada, G.A.; Liu, J.; Chan, H.F.; Yuk, H.; Phan, N.V.; Collins, J.; Tamang, S.; et al. Ingestible hydrogel device. Nat. Commun. 2019, 10, 493. [Google Scholar] [CrossRef] [PubMed]
  65. Zhang, A.; Liu, Y.; Qin, D.; Sun, M.; Wang, T.; Chen, X. Research status of self-healing hydrogel for wound management: A review. Int. J. Biol. Macromol. 2020, 164, 2108–2123. [Google Scholar] [CrossRef]
  66. Li, Y.; Wang, X.; Fu, Y.N.; Wei, Y.; Zhao, L.; Tao, L. Self-Adapting Hydrogel to Improve the Therapeutic Effect in Wound-Healing. ACS Appl. Mater. Interfaces 2018, 10, 26046–26055. [Google Scholar] [CrossRef]
  67. Wu, C.H.; Sun, M.K.; Kung, Y.; Wang, Y.C.; Chen, S.L.; Shen, H.H.; Chen, W.S.; Young, T.H. One injection for one-week controlled release: In vitro and in vivo assessment of ultrasound-triggered drug release from injectable thermoresponsive biocompatible hydrogels. Ultrason. Sonochem. 2020, 62, 104875. [Google Scholar] [CrossRef]
  68. Xu, P.; Xu, H.; Yang, Y.; Wang, X.; An, W.; Hu, Y.; Xu, S. A nonswellable gradient hydrogel with tunable mechanical properties. J. Mater. Chem. B 2020, 8, 2702–2708. [Google Scholar] [CrossRef]
  69. Hu, J.; Zheng, Z.; Liu, C.; Hu, Q.; Cai, X.; Xiao, J.; Cheng, Y. A pH-responsive hydrogel with potent antibacterial activity against both aerobic and anaerobic pathogens. Biomater. Sci. 2019, 7, 581–584. [Google Scholar] [CrossRef]
  70. Pham, L.; Dang, L.H.; Truong, M.D.; Nguyen, T.H.; Le, L.; Le, V.T.; Nam, N.D.; Bach, L.G.; Nguyen, V.T.; Tran, N.Q. A dual synergistic of curcumin and gelatin on thermal-responsive hydrogel based on Chitosan-P123 in wound healing application. Biomed. Pharmacother. 2019, 117, 109183. [Google Scholar] [CrossRef] [PubMed]
  71. Roth-Konforti, M.E.; Comune, M.; Halperin-Sternfeld, M.; Grigoriants, I.; Shabat, D.; Adler-Abramovich, L. UV Light-Responsive Peptide-Based Supramolecular Hydrogel for Controlled Drug Delivery. Macromol. Rapid Commun. 2018, 39, e1800588. [Google Scholar] [CrossRef] [PubMed]
  72. Silva, E.D.; Babo, P.S.; Costa-Almeida, R.; Domingues, R.M.A.; Mendes, B.B.; Paz, E.; Freitas, P.; Rodrigues, M.T.; Granja, P.L.; Gomes, M.E. Multifunctional magnetic-responsive hydrogels to engineer tendon-to-bone interface. Nanomedicine 2018, 14, 2375–2385. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  73. Talló, K.; Bosch, M.; Pons, R.; Cocera, M.; López, O. Preparation and characterization of a supramolecular hydrogel made of phospholipids and oleic acid with a high water content. J. Mater. Chem. B 2020, 8, 161–167. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  74. Lin, P.; Liu, L.; He, G.; Zhang, T.; Yang, M.; Cai, J.; Fan, L.; Tao, S. Preparation and properties of carboxymethyl chitosan/oxidized hydroxyethyl cellulose hydrogel. Int. J. Biol. Macromol. 2020, 162, 1692–1698. [Google Scholar] [CrossRef]
  75. Pupkaite, J.; Rosenquist, J.; Hilborn, J.; Samanta, A. Injectable Shape-Holding Collagen Hydrogel for Cell Encapsulation and Delivery Cross-linked Using Thiol-Michael Addition Click Reaction. Biomacromolecules 2019, 20, 3475–3484. [Google Scholar] [CrossRef]
  76. Grizić, D.; Lamprecht, A. Microparticle preparation by a propylene carbonate emulsification-extraction method. Int. J. Pharm. 2018, 544, 213–221. [Google Scholar] [CrossRef]
  77. Niu, R.; Yang, Y.; Wang, S.; Zhou, X.; Luo, S.; Zhang, C.; Wang, Y. Chitosan microparticle-based immunoaffinity chromatography supports prepared by membrane emulsification technique: Characterization and application. Int. J. Biol. Macromol. 2019, 131, 1147–1154. [Google Scholar] [CrossRef]
  78. Xia, Y.; Yuan, M.; Chen, M.; Li, J.; Ci, T.; Ke, X. Liquid jet breakup: A new method for the preparation of poly lactic-co-glycolic acid microspheres. Eur. J. Pharm. Biopharm. 2019, 137, 140–147. [Google Scholar] [CrossRef]
  79. Zhang, R.; Xie, L.; Wu, H.; Yang, T.; Zhang, Q.; Tian, Y.; Liu, Y.; Han, X.; Guo, W.; He, M.; et al. Alginate/laponite hydrogel microspheres co-encapsulating dental pulp stem cells and VEGF for endodontic regeneration. Acta Biomater. 2020, 113, 305–316. [Google Scholar] [CrossRef]
  80. Wei, H.; Li, W.; Chen, H.; Wen, X.; He, J.; Li, J. Simultaneous Diels-Alder click reaction and starch hydrogel microsphere production via spray drying. Carbohydr. Polym. 2020, 241, 116351. [Google Scholar] [CrossRef]
  81. Shao, Y.; Wu, C.; Wu, T.; Li, Y.; Chen, S.; Yuan, C.; Hu, Y. Eugenol-chitosan nanoemulsions by ultrasound-mediated emulsification: Formulation, characterization and antimicrobial activity. Carbohydr. Polym. 2018, 193, 144–152. [Google Scholar] [CrossRef] [PubMed]
  82. Feng, J.; Markwalter, C.E.; Tian, C.; Armstrong, M.; Prud’homme, R.K. Translational formulation of nanoparticle therapeutics from laboratory discovery to clinical scale. J. Transl. Med. 2019, 17, 200. [Google Scholar] [CrossRef] [PubMed]
  83. Jang, J.H.; Jeong, S.H.; Lee, Y.B. Preparation and In Vitro/In Vivo Characterization of Polymeric Nanoparticles Containing Methotrexate to Improve Lymphatic Delivery. Int. J. Mol. Sci. 2019, 20, 3312. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  84. Arduino, I.; Liu, Z.; Rahikkala, A.; Figueiredo, P.; Correia, A.; Cutrignelli, A.; Denora, N.; Santos, H.A. Preparation of cetyl palmitate-based PEGylated solid lipid nanoparticles by microfluidic technique. Acta Biomater. 2021, 121, 566–578. [Google Scholar] [CrossRef] [PubMed]
  85. Chen, X.; Fan, M.; Tan, H.; Ren, B.; Yuan, G.; Jia, Y.; Li, J.; Xiong, D.; Xing, X.; Niu, X.; et al. Magnetic and self-healing chitosan-alginate hydrogel encapsulated gelatin microspheres via covalent cross-linking for drug delivery. Mater. Sci. Eng. C Mater. Biol. Appl. 2019, 101, 619–629. [Google Scholar] [CrossRef] [PubMed]
  86. Zhang, W.; Xu, W.; Ning, C.; Li, M.; Zhao, G.; Jiang, W.; Ding, J.; Chen, X. Long-acting hydrogel/microsphere composite sequentially releases dexmedetomidine and bupivacaine for prolonged synergistic analgesia. Biomaterials 2018, 181, 378–391. [Google Scholar] [CrossRef]
  87. Feng, J.; Wu, Y.; Chen, W.; Li, J.; Wang, X.; Chen, Y.; Yu, Y.; Shen, Z.; Zhang, Y. Sustained release of bioactive IGF-1 from a silk fibroin microsphere-based injectable alginate hydrogel for the treatment of myocardial infarction. J. Mater. Chem. B 2020, 8, 308–315. [Google Scholar] [CrossRef] [PubMed]
  88. Fu, J.; Wu, B.; Wei, M.; Huang, Y.; Zhou, Y.; Zhang, Q.; Du, L. Prussian blue nanosphere-embedded in situ hydrogel for photothermal therapy by peritumoral administration. Acta Pharm. Sin. B 2019, 9, 604–614. [Google Scholar] [CrossRef] [PubMed]
  89. Trinh, T.A.; Duy Le, T.M.; Ho, H.G.V.; To, T.C.T.; Nguyen, V.V.L.; Huynh, D.P.; Lee, D.S. A novel injectable pH-temperature sensitive hydrogel containing chitosan-insulin electrosprayed nanosphere composite for an insulin delivery system in type I diabetes treatment. Biomater. Sci. 2020, 8, 3830–3843. [Google Scholar] [CrossRef]
  90. Zhang, X.; Pan, Y.; Li, S.; Xing, L.; Du, S.; Yuan, G.; Li, J.; Zhou, T.; Xiong, D.; Tan, H.; et al. Doubly crosslinked biodegradable hydrogels based on gellan gum and chitosan for drug delivery and wound dressing. Int. J. Biol. Macromol. 2020, 164, 2204–2214. [Google Scholar] [CrossRef]
  91. Simão, A.R.; Fragal, V.H.; Lima, A.M.O.; Pellá, M.C.G.; Garcia, F.P.; Nakamura, C.V.; Tambourgi, E.B.; Rubira, A.F. pH-responsive hybrid hydrogels: Chondroitin sulfate/casein trapped silica nanospheres for controlled drug release. Int. J. Biol. Macromol. 2020, 148, 302–315. [Google Scholar] [CrossRef]
  92. Nazemi, Z.; Nourbakhsh, M.S.; Kiani, S.; Heydari, Y.; Ashtiani, M.K.; Daemi, H.; Baharvand, H. Co-delivery of minocycline and paclitaxel from injectable hydrogel for treatment of spinal cord injury. J. Control. Release 2020, 321, 145–158. [Google Scholar] [CrossRef]
  93. Vedadghavami, A.; Minooei, F.; Mohammadi, M.H.; Khetani, S.; Rezaei Kolahchi, A.; Mashayekhan, S.; Sanati-Nezhad, A. Manufacturing of hydrogel biomaterials with controlled mechanical properties for tissue engineering applications. Acta Biomater. 2017, 62, 42–63. [Google Scholar] [CrossRef]
  94. Ma, Z.; Song, W.; He, Y.; Li, H. Multilayer Injectable Hydrogel System Sequentially Delivers Bioactive Substances for Each Wound Healing Stage. ACS Appl. Mater. Interfaces 2020, 12, 29787–29806. [Google Scholar] [CrossRef]
  95. Seo, J.H.; Lee, S.Y.; Kim, S.; Yang, M.; Jeong, D.I.; Hwang, C.; Kim, M.H.; Kim, H.J.; Lee, J.; Lee, K.; et al. Monopotassium phosphate-reinforced in situ forming injectable hyaluronic acid hydrogels for subcutaneous injection. Int. J. Biol. Macromol. 2020, 163, 2134–2144. [Google Scholar] [CrossRef] [PubMed]
  96. Deng, Y.; Hu, J.; Qu, Z.; Tao, R.; Wang, G.; Liu, W. Niacin Metal-Organic Framework-Laden Self-Healing Hydrogel for Wound Healing. J. Biomed. Nanotechnol. 2020, 16, 1719–1726. [Google Scholar] [CrossRef]
  97. Wei, J.; Wang, Y.; Jiang, J.; Yan, Y.; Fan, D.; Yang, X.; Zuo, Y.; Li, Y.; Gu, H.; Li, J. Development of an Antibacterial Bone Graft by Immobilization of Levofloxacin Hydrochloride-Loaded Mesoporous Silica Microspheres on a Porous Scaffold Surface. J. Biomed. Nanotechnol. 2019, 15, 1097–1105. [Google Scholar] [CrossRef] [PubMed]
  98. Saeedi Garakani, S.; Davachi, S.M.; Bagher, Z.; Heraji Esfahani, A.; Jenabi, N.; Atoufi, Z.; Khanmohammadi, M.; Abbaspourrad, A.; Rashedi, H.; Jalessi, M. Fabrication of chitosan/polyvinylpyrrolidone hydrogel scaffolds containing PLGA microparticles loaded with dexamethasone for biomedical applications. Int. J. Biol. Macromol. 2020, 164, 356–370. [Google Scholar] [CrossRef]
  99. García-Fernández, L.; Olmeda-Lozano, M.; Benito-Garzón, L.; Pérez-Caballer, A.; San Román, J.; Vázquez-Lasa, B. Injectable hydrogel-based drug delivery system for cartilage regeneration. Mater. Sci. Eng. C Mater. Biol. Appl. 2020, 110, 110702. [Google Scholar] [CrossRef] [PubMed]
  100. Tan, B.; Wu, Y.; Wu, Y.; Shi, K.; Han, R.; Li, Y.; Qian, Z.; Liao, J. Curcumin-Microsphere/IR820 Hybrid Bifunctional Hydrogels for In Situ Osteosarcoma Chemo-co-Thermal Therapy and Bone Reconstruction. ACS Appl. Mater. Interfaces 2021, 13, 31542–31553. [Google Scholar] [CrossRef] [PubMed]
  101. Liao, J.; Shi, K.; Jia, Y.; Wu, Y.; Qian, Z. Gold nanorods and nanohydroxyapatite hybrid hydrogel for preventing bone tumor recurrence via postoperative photothermal therapy and bone regeneration promotion. Bioact. Mater. 2021, 6, 2221–2230. [Google Scholar] [CrossRef]
  102. Liao, J.; Han, R.; Wu, Y.; Qian, Z. Review of a new bone tumor therapy strategy based on bifunctional biomaterials. Bone Res. 2021, 9, 18. [Google Scholar] [CrossRef]
  103. Ingavle, G.C.; Gionet-Gonzales, M.; Vorwald, C.E.; Bohannon, L.K.; Clark, K.; Galuppo, L.D.; Leach, J.K. Injectable mineralized microsphere-loaded composite hydrogels for bone repair in a sheep bone defect model. Biomaterials 2019, 197, 119–128. [Google Scholar] [CrossRef]
  104. Peng, Z.; Sun, H.; Bunpetch, V.; Koh, Y.; Wen, Y.; Wu, D.; Ouyang, H. The regulation of cartilage extracellular matrix homeostasis in joint cartilage degeneration and regeneration. Biomaterials 2021, 268, 120555. [Google Scholar] [CrossRef]
  105. Rahmati, M.; Nalesso, G.; Mobasheri, A.; Mozafari, M. Aging and osteoarthritis: Central role of the extracellular matrix. Ageing Res. Rev. 2017, 40, 20–30. [Google Scholar] [CrossRef]
  106. Shen, S.; Wu, Y.; Chen, J.; Xie, Z.; Huang, K.; Wang, G.; Yang, Y.; Ni, W.; Chen, Z.; Shi, P.; et al. CircSERPINE2 protects against osteoarthritis by targeting miR-1271 and ETS-related gene. Ann. Rheum. Dis. 2019, 78, 826–836. [Google Scholar] [CrossRef] [Green Version]
  107. Song, E.K.; Jeon, J.; Jang, D.G.; Kim, H.E.; Sim, H.J.; Kwon, K.Y.; Medina-Ruiz, S.; Jang, H.J.; Lee, A.R.; Rho, J.G.; et al. ITGBL1 modulates integrin activity to promote cartilage formation and protect against arthritis. Sci. Transl. Med. 2018, 10. [Google Scholar] [CrossRef] [Green Version]
  108. Asghar, S.; Litherland, G.J.; Lockhart, J.C.; Goodyear, C.S.; Crilly, A. Exosomes in intercellular communication and implications for osteoarthritis. Rheumatology 2020, 59, 57–68. [Google Scholar] [CrossRef] [PubMed]
  109. Varela-Eirín, M.; Varela-Vázquez, A.; Guitián-Caamaño, A.; Paíno, C.L.; Mato, V.; Largo, R.; Aasen, T.; Tabernero, A.; Fonseca, E.; Kandouz, M.; et al. Targeting of chondrocyte plasticity via connexin43 modulation attenuates cellular senescence and fosters a pro-regenerative environment in osteoarthritis. Cell Death Dis. 2018, 9, 1166. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  110. Culvenor, A.G.; Øiestad, B.E.; Hart, H.F.; Stefanik, J.J.; Guermazi, A.; Crossley, K.M. Prevalence of knee osteoarthritis features on magnetic resonance imaging in asymptomatic uninjured adults: A systematic review and meta-analysis. Br. J. Sports Med. 2019, 53, 1268–1278. [Google Scholar] [CrossRef] [PubMed]
  111. Atoufi, Z.; Kamrava, S.K.; Davachi, S.M.; Hassanabadi, M.; Saeedi Garakani, S.; Alizadeh, R.; Farhadi, M.; Tavakol, S.; Bagher, Z.; Hashemi Motlagh, G. Injectable PNIPAM/Hyaluronic acid hydrogels containing multipurpose modified particles for cartilage tissue engineering: Synthesis, characterization, drug release and cell culture study. Int. J. Biol. Macromol. 2019, 139, 1168–1181. [Google Scholar] [CrossRef]
  112. Lourenço, A.H.; Torres, A.L.; Vasconcelos, D.P.; Ribeiro-Machado, C.; Barbosa, J.N.; Barbosa, M.A.; Barrias, C.C.; Ribeiro, C.C. Osteogenic, anti-osteoclastogenic and immunomodulatory properties of a strontium-releasing hybrid scaffold for bone repair. Mater. Sci. Eng. C Mater. Biol. Appl. 2019, 99, 1289–1303. [Google Scholar] [CrossRef]
  113. Li, Y.; Liu, Y.; Guo, Q. Silk fibroin hydrogel scaffolds incorporated with chitosan nanoparticles repair articular cartilage defects by regulating TGF-β1 and BMP-2. Arthritis Res. Ther. 2021, 23, 50. [Google Scholar] [CrossRef]
  114. Khorshidi, S.; Karkhaneh, A. A hydrogel/particle composite with gradient in oxygen releasing microparticle for oxygenation of the cartilage-to-bone interface: Modeling and experimental viewpoints. Mater. Sci. Eng. C Mater. Biol. Appl. 2021, 118, 111522. [Google Scholar] [CrossRef] [PubMed]
  115. Min, Q.; Liu, J.; Zhang, Y.; Yang, B.; Wan, Y.; Wu, J. Dual Network Hydrogels Incorporated with Bone Morphogenic Protein-7-Loaded Hyaluronic Acid Complex Nanoparticles for Inducing Chondrogenic Differentiation of Synovium-Derived Mesenchymal Stem Cells. Pharmaceutics 2020, 12, 613. [Google Scholar] [CrossRef] [PubMed]
  116. Awasthi, S.; Gaur, J.K.; Pandey, S.K.; Bobji, M.S.; Srivastava, C. High-Strength, Strongly Bonded Nanocomposite Hydrogels for Cartilage Repair. ACS Appl. Mater. Interfaces 2021, 13, 24505–24523. [Google Scholar] [CrossRef] [PubMed]
  117. Abou-ElNour, M.; Soliman, M.E.; Skouras, A.; Casettari, L.; Geneidi, A.S.; Ishak, R.A.H. Microparticles-in-Thermoresponsive/Bioadhesive Hydrogels as a Novel Integrated Platform for Effective Intra-articular Delivery of Triamcinolone Acetonide. Mol. Pharm. 2020, 17, 1963–1978. [Google Scholar] [CrossRef]
  118. Harre, U.; Schett, G. Cellular and molecular pathways of structural damage in rheumatoid arthritis. Semin. Immunopathol. 2017, 39, 355–363. [Google Scholar] [CrossRef] [PubMed]
  119. Bolduc, J.A.; Collins, J.A.; Loeser, R.F. Reactive oxygen species, aging and articular cartilage homeostasis. Free Radic. Biol. Med. 2019, 132, 73–82. [Google Scholar] [CrossRef] [PubMed]
  120. Holyoak, D.T.; Wheeler, T.A.; van der Meulen, M.C.H.; Singh, A. Injectable mechanical pillows for attenuation of load-induced post-traumatic osteoarthritis. Regen. Biomater. 2019, 6, 211–219. [Google Scholar] [CrossRef] [PubMed]
  121. Boyer, C.; Figueiredo, L.; Pace, R.; Lesoeur, J.; Rouillon, T.; Visage, C.L.; Tassin, J.F.; Weiss, P.; Guicheux, J.; Rethore, G. Laponite nanoparticle-associated silated hydroxypropylmethyl cellulose as an injectable reinforced interpenetrating network hydrogel for cartilage tissue engineering. Acta Biomater. 2018, 65, 112–122. [Google Scholar] [CrossRef] [PubMed]
  122. Chen, J.; An, R.; Han, L.; Wang, X.; Zhang, Y.; Shi, L.; Ran, R. Tough hydrophobic association hydrogels with self-healing and reforming capabilities achieved by polymeric core-shell nanoparticles. Mater. Sci. Eng. C Mater. Biol. Appl. 2019, 99, 460–467. [Google Scholar] [CrossRef] [PubMed]
  123. Fan, M.; Ma, Y.; Tan, H.; Jia, Y.; Zou, S.; Guo, S.; Zhao, M.; Huang, H.; Ling, Z.; Chen, Y.; et al. Covalent and injectable chitosan-chondroitin sulfate hydrogels embedded with chitosan microspheres for drug delivery and tissue engineering. Mater. Sci. Eng. C Mater. Biol. Appl. 2017, 71, 67–74. [Google Scholar] [CrossRef]
  124. Sparks, J.A. Rheumatoid Arthritis. Ann. Intern. Med. 2019, 170, itc1–itc16. [Google Scholar] [CrossRef]
  125. Cronstein, B.N.; Aune, T.M. Methotrexate and its mechanisms of action in inflammatory arthritis. Nat. Rev. Rheumatol. 2020, 16, 145–154. [Google Scholar] [CrossRef]
  126. Yin, N.; Tan, X.; Liu, H.; He, F.; Ding, N.; Gou, J.; Yin, T.; He, H.; Zhang, Y.; Tang, X. A novel indomethacin/methotrexate/MMP-9 siRNA in situ hydrogel with dual effects of anti-inflammatory activity and reversal of cartilage disruption for the synergistic treatment of rheumatoid arthritis. Nanoscale 2020, 12, 8546–8562. [Google Scholar] [CrossRef]
  127. Yin, N.; Guo, X.; Sun, R.; Liu, H.; Tang, L.; Gou, J.; Yin, T.; He, H.; Zhang, Y.; Tang, X. Intra-articular injection of indomethacin-methotrexate in situ hydrogel for the synergistic treatment of rheumatoid arthritis. J. Mater. Chem. B 2020, 8, 993–1007. [Google Scholar] [CrossRef]
  128. Tang, Q.; Lim, T.; Shen, L.Y.; Zheng, G.; Wei, X.J.; Zhang, C.Q.; Zhu, Z.Z. Well-dispersed platelet lysate entrapped nanoparticles incorporate with injectable PDLLA-PEG-PDLLA triblock for preferable cartilage engineering application. Biomaterials 2021, 268, 120605. [Google Scholar] [CrossRef]
  129. Stefani, R.M.; Lee, A.J.; Tan, A.R.; Halder, S.S.; Hu, Y.; Guo, X.E.; Stoker, A.M.; Ateshian, G.A.; Marra, K.G.; Cook, J.L.; et al. Sustained low-dose dexamethasone delivery via a PLGA microsphere-embedded agarose implant for enhanced osteochondral repair. Acta Biomater. 2020, 102, 326–340. [Google Scholar] [CrossRef] [PubMed]
  130. Nie, X.; Chuah, Y.J.; He, P.; Wang, D.A. Engineering a multiphasic, integrated graft with a biologically developed cartilage-bone interface for osteochondral defect repair. J. Mater. Chem. B 2019, 7, 6515–6525. [Google Scholar] [CrossRef]
  131. Asgari, N.; Bagheri, F.; Eslaminejad, M.B.; Ghanian, M.H.; Sayahpour, F.A.; Ghafari, A.M. Dual functional construct containing kartogenin releasing microtissues and curcumin for cartilage regeneration. Stem. Cell Res. Ther. 2020, 11, 289. [Google Scholar] [CrossRef]
  132. Armiento, A.R.; Stoddart, M.J.; Alini, M.; Eglin, D. Biomaterials for articular cartilage tissue engineering: Learning from biology. Acta Biomater. 2018, 65, 1–20. [Google Scholar] [CrossRef] [PubMed]
  133. Zhou, Y.; Liang, K.; Zhao, S.; Zhang, C.; Li, J.; Yang, H.; Liu, X.; Yin, X.; Chen, D.; Xu, W.; et al. Photopolymerized maleilated chitosan/methacrylated silk fibroin micro/nanocomposite hydrogels as potential scaffolds for cartilage tissue engineering. Int. J. Biol. Macromol. 2018, 108, 383–390. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  134. Liao, J.; Wang, B.; Huang, Y.; Qu, Y.; Peng, J.; Qian, Z. Injectable Alginate Hydrogel Cross-Linked by Calcium Gluconate-Loaded Porous Microspheres for Cartilage Tissue Engineering. ACS Omega 2017, 2, 443–454. [Google Scholar] [CrossRef]
  135. Xu, Y.; Wu, X.; Wang, S.; Yang, C.; Li, Y.; Cao, Y. Hydroxyapatite Nanoparticle-Crosslinked Peptide Hydrogels for Three-Dimensional Culture and Differentiation of MC3T3-E1 Osteoblasts. J. Biomed. Nanotechnol. 2019, 15, 2351–2362. [Google Scholar] [CrossRef]
  136. Nasiri, N.; Hosseini, S.; Alini, M.; Khademhosseini, A.; Baghaban Eslaminejad, M. Targeted cell delivery for articular cartilage regeneration and osteoarthritis treatment. Drug Discov. Today 2019, 24, 2212–2224. [Google Scholar] [CrossRef]
  137. Kouhi, M.; Varshosaz, J.; Hashemibeni, B.; Sarmadi, A. Injectable gellan gum/lignocellulose nanofibrils hydrogels enriched with melatonin loaded forsterite nanoparticles for cartilage tissue engineering: Fabrication, characterization and cell culture studies. Mater. Sci. Eng. C Mater. Biol. Appl. 2020, 115, 111114. [Google Scholar] [CrossRef]
  138. Lu, Z.; Liu, S.; Le, Y.; Qin, Z.; He, M.; Xu, F.; Zhu, Y.; Zhao, J.; Mao, C.; Zheng, L. An injectable collagen-genipin-carbon dot hydrogel combined with photodynamic therapy to enhance chondrogenesis. Biomaterials 2019, 218, 119190. [Google Scholar] [CrossRef]
  139. Wu, X.; Stroll, S.I.; Lantigua, D.; Suvarnapathaki, S.; Camci-Unal, G. Eggshell particle-reinforced hydrogels for bone tissue engineering: An orthogonal approach. Biomater. Sci. 2019, 7, 2675–2685. [Google Scholar] [CrossRef]
  140. Naghizadeh, Z.; Karkhaneh, A.; Nokhbatolfoghahaei, H.; Farzad-Mohajeri, S.; Rezai-Rad, M.; Dehghan, M.M.; Aminishakib, P.; Khojasteh, A. Cartilage regeneration with dual-drug-releasing injectable hydrogel/microparticle system: In vitro and in vivo study. J. Cell. Physiol. 2021, 236, 2194–2204. [Google Scholar] [CrossRef] [PubMed]
  141. Fan, W.; Yuan, L.; Li, J.; Wang, Z.; Chen, J.; Guo, C.; Mo, X.; Yan, Z. Injectable double-crosslinked hydrogels with kartogenin-conjugated polyurethane nano-particles and transforming growth factor β3 for in-situ cartilage regeneration. Mater. Sci. Eng. C Mater. Biol. Appl. 2020, 110, 110705. [Google Scholar] [CrossRef] [PubMed]
  142. Saygili, E.; Kaya, E.; Ilhan-Ayisigi, E.; Saglam-Metiner, P.; Alarcin, E.; Kazan, A.; Girgic, E.; Kim, Y.W.; Gunes, K.; Eren-Ozcan, G.G.; et al. An alginate-poly(acrylamide) hydrogel with TGF-β3 loaded nanoparticles for cartilage repair: Biodegradability, biocompatibility and protein adsorption. Int. J. Biol. Macromol. 2021, 172, 381–393. [Google Scholar] [CrossRef] [PubMed]
  143. Radhakrishnan, J.; Subramanian, A.; Sethuraman, S. Injectable glycosaminoglycan-protein nano-complex in semi-interpenetrating networks: A biphasic hydrogel for hyaline cartilage regeneration. Carbohydr. Polym. 2017, 175, 63–74. [Google Scholar] [CrossRef] [PubMed]
  144. Huang, J.; Liang, Y.; Jia, Z.; Chen, J.; Duan, L.; Liu, W.; Zhu, F.; Liang, Q.; Zhu, W.; You, W.; et al. Development of Magnetic Nanocomposite Hydrogel with Potential Cartilage Tissue Engineering. ACS Omega 2018, 3, 6182–6189. [Google Scholar] [CrossRef] [PubMed]
  145. Huang, J.; Liang, Y.; Huang, Z.; Zhao, P.; Liang, Q.; Liu, Y.; Duan, L.; Liu, W.; Zhu, F.; Bian, L.; et al. Magnetic Enhancement of Chondrogenic Differentiation of Mesenchymal Stem Cells. ACS Biomater. Sci. Eng. 2019, 5, 2200–2207. [Google Scholar] [CrossRef]
  146. Wang, J.; Li, P.; Li, K.; Xu, J.; Liu, M.; Fan, Y. The Effect of Magnetic Poly(lactic-co-glycolic acid) Microsphere-Gelatin Hydrogel on the Growth of Pre-Osteoblasts Under Static Magnetic Field. J. Biomed. Nanotechnol. 2020, 16, 1658–1666. [Google Scholar] [CrossRef]
  147. Lee, S.J.; Yan, D.; Zhou, X.; Cui, H.; Esworthy, T.; Hann, S.Y.; Keidar, M.; Zhang, L.G. Integrating cold atmospheric plasma with 3D printed bioactive nanocomposite scaffold for cartilage regeneration. Mater. Sci. Eng. C Mater. Biol. Appl. 2020, 111, 110844. [Google Scholar] [CrossRef]
  148. Najahi-Missaoui, W.; Arnold, R.D.; Cummings, B.S. Safe Nanoparticles: Are We There Yet? Int. J. Mol. Sci. 2020, 22, 385. [Google Scholar] [CrossRef]
  149. Decker, R.S. Articular cartilage and joint development from embryogenesis to adulthood. Semin. Cell Dev. Biol. 2017, 62, 50–56. [Google Scholar] [CrossRef]
  150. Deng, X.Q.; Chao, N.N.; Ding, W.; Qin, T.W.; Wang, W.; Zhang, Y.; Luo, J.C. Production and Characterization of Composite Chitosan Hydrogel Containing Extracellular Matrix Particles for Tissue Engineering Applications. J. Biomed. Nanotechnol. 2019, 15, 756–768. [Google Scholar] [CrossRef]
  151. Almarza, A.J.; Brown, B.N.; Arzi, B.; Ângelo, D.F.; Chung, W.; Badylak, S.F.; Detamore, M. Preclinical Animal Models for Temporomandibular Joint Tissue Engineering. Tissue Eng. Part B Rev. 2018, 24, 171–178. [Google Scholar] [CrossRef] [PubMed]
  152. Zhang, Y.; Shao, S.; Zhang, J.; Wang, L.; Wang, K.; Svensson, P. Temporal summation and motor function modulation during repeated jaw movements in patients with temporomandibular disorder pain and healthy controls. Pain 2017, 158, 1272–1279. [Google Scholar] [CrossRef] [PubMed]
  153. Cui, C.; Zheng, L.; Fan, Y.; Zhang, J.; Xu, R.; Xie, J.; Zhou, X. Parathyroid hormone ameliorates temporomandibular joint osteoarthritic-like changes related to age. Cell Prolif. 2020, 53, e12755. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  154. Vapniarsky, N.; Huwe, L.W.; Arzi, B.; Houghton, M.K.; Wong, M.E.; Wilson, J.W.; Hatcher, D.C.; Hu, J.C.; Athanasiou, K.A. Tissue engineering toward temporomandibular joint disc regeneration. Sci. Transl. Med. 2018, 10. [Google Scholar] [CrossRef] [Green Version]
  155. Acri, T.M.; Shin, K.; Seol, D.; Laird, N.Z.; Song, I.; Geary, S.M.; Chakka, J.L.; Martin, J.A.; Salem, A.K. Tissue Engineering for the Temporomandibular Joint. Adv. Healthc. Mater. 2019, 8, e1801236. [Google Scholar] [CrossRef]
  156. Luo, P.; Jiang, C.; Ji, P.; Wang, M.; Xu, J. Exosomes of stem cells from human exfoliated deciduous teeth as an anti-inflammatory agent in temporomandibular joint chondrocytes via miR-100-5p/mTOR. Stem Cell Res. Ther. 2019, 10, 216. [Google Scholar] [CrossRef] [Green Version]
Gels 07 00155 g001 550
Figure 1. Articular cartilage defects in the temporomandibular joint (TMJ) and knee joint.
Figure 1. Articular cartilage defects in the temporomandibular joint (TMJ) and knee joint.
Gels 07 00155 g001
Gels 07 00155 g002 550
Figure 2. The variety of micro-/nanoparticles and hydrogels.
Figure 2. The variety of micro-/nanoparticles and hydrogels.
Gels 07 00155 g002
Gels 07 00155 g003 550
Figure 3. Drugs, growth factors, and stem cells can be added to the micro-/nanoparticle hybrid hydrogel platform.
Figure 3. Drugs, growth factors, and stem cells can be added to the micro-/nanoparticle hybrid hydrogel platform.
Gels 07 00155 g003
Gels 07 00155 g004 550
Figure 4. Micro-/nanoparticle hybrid hydrogel platform applied in articular cartilage-related diseases.
Figure 4. Micro-/nanoparticle hybrid hydrogel platform applied in articular cartilage-related diseases.
Gels 07 00155 g004
Gels 07 00155 g006 550
Figure 6. In vitro anti-inflammatory performance of the PLEL@PL-NP system. (A) Diagram of the co-cultural method for gel (upper) and chondrocytes (lower, 2D or 3D culture). (B) Secretory protein levels of IL-6, TNF-α, collagen II, and MMP13 in chondrocyte culture medium with different treatment after 14 days of co-culture. (C,D) Protein levels of iNOS and COX-2 in chondrocytes after 14 days of co-culture with different treatments. (E) Immunofluorescence staining of cells co-cultured with different treatments as indicated at day 14. (F) Histological staining (H&E), GAG staining (Alcian blue and Safranin O), and immunohistochemistry staining of collagen II in pellets with different treatments, as indicated at day 21. (G) Quantification of pellet size. (H) Quantification of dsDNA content. (I) Quantification of sGAG content. (J) Quantification of the ratio of sGAG/dsDNA. All quantitative results are presented as means ± SD of five replicate experiments. * p < 0.05, ** p < 0.01. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.) This figure was published in [128]—copyright, Elsevier (2021). Permission to share the material has been granted.
Figure 6. In vitro anti-inflammatory performance of the PLEL@PL-NP system. (A) Diagram of the co-cultural method for gel (upper) and chondrocytes (lower, 2D or 3D culture). (B) Secretory protein levels of IL-6, TNF-α, collagen II, and MMP13 in chondrocyte culture medium with different treatment after 14 days of co-culture. (C,D) Protein levels of iNOS and COX-2 in chondrocytes after 14 days of co-culture with different treatments. (E) Immunofluorescence staining of cells co-cultured with different treatments as indicated at day 14. (F) Histological staining (H&E), GAG staining (Alcian blue and Safranin O), and immunohistochemistry staining of collagen II in pellets with different treatments, as indicated at day 21. (G) Quantification of pellet size. (H) Quantification of dsDNA content. (I) Quantification of sGAG content. (J) Quantification of the ratio of sGAG/dsDNA. All quantitative results are presented as means ± SD of five replicate experiments. * p < 0.05, ** p < 0.01. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.) This figure was published in [128]—copyright, Elsevier (2021). Permission to share the material has been granted.
Gels 07 00155 g006
Gels 07 00155 g007 550
Figure 7. Cartilage regeneration promoted by PDT after implantation with CGN. (a,b) Gross macroscopic observation (a) and O’Driscoll score (b) of engineered cartilage (scale bar = 2 mm). (c) Mechanical evaluation of the engineered cartilage after 8 weeks of treatment. (d) Histological score of the engineered cartilage after 4 and 8 weeks of treatment. (e,f) HE (e) and Safranin O/fast green (f) staining of the engineered cartilage (scale bar = 200 μm). Mean ± SD, n = 6; *, # indicate p < 0.05, ## indicates p < 0.01, ***, ### indicates p < 0.001. (C = collagen; CN = collagen mixed with CD NPs; CG = collagen crosslinked with genipin; CGN = collagen crosslinked with genipin and CD NPs; CGN + PDT=CGN after 808 nm laser irradiation at a power density of 8.3 mW/cm2 for 3 min.) (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.) This figure was published in [138]—copyright, Elsevier (2019). Permission to share the material has been granted.
Figure 7. Cartilage regeneration promoted by PDT after implantation with CGN. (a,b) Gross macroscopic observation (a) and O’Driscoll score (b) of engineered cartilage (scale bar = 2 mm). (c) Mechanical evaluation of the engineered cartilage after 8 weeks of treatment. (d) Histological score of the engineered cartilage after 4 and 8 weeks of treatment. (e,f) HE (e) and Safranin O/fast green (f) staining of the engineered cartilage (scale bar = 200 μm). Mean ± SD, n = 6; *, # indicate p < 0.05, ## indicates p < 0.01, ***, ### indicates p < 0.001. (C = collagen; CN = collagen mixed with CD NPs; CG = collagen crosslinked with genipin; CGN = collagen crosslinked with genipin and CD NPs; CGN + PDT=CGN after 808 nm laser irradiation at a power density of 8.3 mW/cm2 for 3 min.) (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.) This figure was published in [138]—copyright, Elsevier (2019). Permission to share the material has been granted.
Gels 07 00155 g007
Gels 07 00155 g008 550
Figure 8. In vivo representative photomicrographs of tissue sections in the experimental groups stained with (A–C) H&E; (D–F) Safranin O/fast green, (G–I) Gomori’s trichrome stains, TB (J–L), and PAS (M–O). (A,D,G) Control group demonstrates mostly fibrous tissue with limited tissue repair in the chondral region. (B,E,H) PAAm-Alg group shows fibrous tissue with few fibroblast and chondrocyte-like cells in the joint surface chondral regions. (E) Fibrous tissue in the deeper regions is still observed in some rats. (C,F,I) PAAm-Alg-NPTGF-β3 group reveals fibrous tissue with some fibrocartilage and hyaline cartilage groups in the chondral regions. PAAm-Alg and PAAm-Alg-NPTGF-β3 groups demonstrated higher (K,L) glycosaminoglycan deposition and (N,O) glycoprotein and proteoglycan contents compared to control group (the arrows indicate the margins of the defect area; scale bars: 100 μm). The histological lesion scores in regard to the morphology of (P) new surfaces, (Q) cartilage tissues, (R) tissue thickness, (S) surface regularity, (T) chondrocyte distribution, and (U) cellularity. ns > 0.05, * p < 0.05, ** p < 0.01, *** p < 0.001; Kruskal–Wallis test. This figure was published in [142]—copyright, Elsevier (2021). Permission to share the material has been granted.
Figure 8. In vivo representative photomicrographs of tissue sections in the experimental groups stained with (A–C) H&E; (D–F) Safranin O/fast green, (G–I) Gomori’s trichrome stains, TB (J–L), and PAS (M–O). (A,D,G) Control group demonstrates mostly fibrous tissue with limited tissue repair in the chondral region. (B,E,H) PAAm-Alg group shows fibrous tissue with few fibroblast and chondrocyte-like cells in the joint surface chondral regions. (E) Fibrous tissue in the deeper regions is still observed in some rats. (C,F,I) PAAm-Alg-NPTGF-β3 group reveals fibrous tissue with some fibrocartilage and hyaline cartilage groups in the chondral regions. PAAm-Alg and PAAm-Alg-NPTGF-β3 groups demonstrated higher (K,L) glycosaminoglycan deposition and (N,O) glycoprotein and proteoglycan contents compared to control group (the arrows indicate the margins of the defect area; scale bars: 100 μm). The histological lesion scores in regard to the morphology of (P) new surfaces, (Q) cartilage tissues, (R) tissue thickness, (S) surface regularity, (T) chondrocyte distribution, and (U) cellularity. ns > 0.05, * p < 0.05, ** p < 0.01, *** p < 0.001; Kruskal–Wallis test. This figure was published in [142]—copyright, Elsevier (2021). Permission to share the material has been granted.
Gels 07 00155 g008
Table
Table 1. Application of micro-/nanoparticle hybrid hydrogel platform in articular cartilage-related diseases.
Table 1. Application of micro-/nanoparticle hybrid hydrogel platform in articular cartilage-related diseases.
Micro-/NanoparticlesHydrogelPropertyStowageApplicationEffectRef.
Chitosan-acrylic acid-coated PLGA (ACH-PLGA) micro-/nanoparticlesPNIPAM/hyaluronic acidinjectable, thermosensitive,
biocompatibility		melatonincartilage tissue engineeringsustained drug release[111]
Hydroxyapatite (HAp) microparticlesRGD-alginateinjectable, viscoelasticSrbone repairosteogenic, anti-osteoclastogenic and immunomodulatory[112]
Chitosan (CS) nanoparticlessilk fibroin (SF) biocompatibilityTGFβ1@CS, BMP-2@SFrepair knee joint cartilage defectsrelease TGF-β1 and BMP-2, promoted chondrogenic ability of BMSCs[113]
Polylactic acid (PLA) microparticleshydrogel of functionalized pectin and fibroin\calcium peroxidea promoting step for regeneration of cartilage-to-bone interfaceoxygenation of the cartilage-to-bone interface[114]
Hyaluronic acid (HA)/chitosan-poly(dioxanone)(CH-PDO) complex nanoparticlesALG-POL/SF dual networkelastic, tough and strongbone morphogenic protein-7 (BMP-7)cartilage tissue engineeringcontrolled release of BMP-7[115]
CNT nanoparticlespolyacrylamide (PAM)bioactivity and cytocompatibilityTiO2cartilage repaircartilage replacement[116]
Poly(lactic acid) (PLA)/methoxy-polyethylene glycol-poly(δdecalactone) (mPEG−PDL) microparticlespoly(PEGMA) Copolymerthermoresponsive, bioadhesivetriamcinolone acetonide (TA)RAanti-inflammatory[117]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Han, X.; Wu, Y.; Shan, Y.; Zhang, X.; Liao, J. Effect of Micro-/Nanoparticle Hybrid Hydrogel Platform on the Treatment of Articular Cartilage-Related Diseases. Gels 2021, 7, 155. https://doi.org/10.3390/gels7040155

AMA Style

Han X, Wu Y, Shan Y, Zhang X, Liao J. Effect of Micro-/Nanoparticle Hybrid Hydrogel Platform on the Treatment of Articular Cartilage-Related Diseases. Gels. 2021; 7(4):155. https://doi.org/10.3390/gels7040155

Chicago/Turabian Style

Han, Xu, Yongzhi Wu, Yue Shan, Xu Zhang, and Jinfeng Liao. 2021. "Effect of Micro-/Nanoparticle Hybrid Hydrogel Platform on the Treatment of Articular Cartilage-Related Diseases" Gels 7, no. 4: 155. https://doi.org/10.3390/gels7040155

APA Style

Han, X., Wu, Y., Shan, Y., Zhang, X., & Liao, J. (2021). Effect of Micro-/Nanoparticle Hybrid Hydrogel Platform on the Treatment of Articular Cartilage-Related Diseases. Gels, 7(4), 155. https://doi.org/10.3390/gels7040155

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop