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Review

Knee Osteoarthritis Therapy: Recent Advances in Intra-Articular Drug Delivery Systems

       

Authors Ma L, Zheng X, Lin R, Sun AR, Song J, Ye Z, Liang D, Zhang M, Tian J, Zhou X, Cui L, Liu Y, Liu Y 

Received 7 January 2022

Accepted for publication 17 April 2022

Published 4 May 2022 Volume 2022:16 Pages 1311—1347

DOI https://doi.org/10.2147/DDDT.S357386

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 3

Editor who approved publication: Prof. Dr. Tin Wui Wong

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Luoyang Ma,1,2 Xiaoyan Zheng,1,3 Rui Lin,1 Antonia RuJia Sun,4 Jintong Song,1 Zhiqiang Ye,1 Dahong Liang,1 Min Zhang,1 Jia Tian,1 Xin Zhou,2 Liao Cui,1 Yuyu Liu,1 Yanzhi Liu1,3,5

1Guangdong Provincial Key Laboratory for Research and Development of Natural Drug, School of Pharmacy, Guangdong Medical University, Zhanjiang City, Guangdong Province, 524023, People’s Republic of China; 2Marine Medical Research Institute of Zhanjiang, Zhanjiang City, Guangdong Province, 524023, People’s Republic of China; 3Zhanjiang Central Hospital, Guangdong Medical University, Zhanjiang city, Guangdong province, 524045, People’s Republic of China; 4Center for Translational Medicine Research and Development, Shenzhen Institute of Advanced Technology, Chinese Academy of Science, Shenzhen City, Guangdong Province, 518055, People’s Republic of China; 5Shenzhen Osteomore Biotechnology Co., Ltd., Shenzhen city, Guangdong Province, 518118, People’s Republic of China

Correspondence: Yanzhi Liu; Yuyu Liu, Tel +86-759-2388405 ; +86-759-2388588, Email [email protected]; [email protected]

Abstract: Drug delivery for osteoarthritis (OA) treatment is a continuous challenge because of their poor bioavailability and rapid clearance in joints. Intra-articular (IA) drug delivery is a common strategy and its therapeutic effects depend mainly on the efficacy of the drug-delivery system used for OA therapy. Different types of IA drug-delivery systems, such as microspheres, nanoparticles, and hydrogels, have been rapidly developed over the past decade to improve their therapeutic effects. With the continuous advancement in OA mechanism research, new drugs targeting specific cell/signaling pathways in OA are rapidly evolving and effective drug delivery is critical for treating OA. In this review, recent advances in various IA drug-delivery systems for OA treatment, OA targeted strategies, and related signaling pathways in OA treatment are summarized and analyzed based on current publications.

Keywords: osteoarthritis, knee, drug delivery, intra-articular

Introduction

Osteoarthritis (OA) is the most common degenerative joint disease that affects approximately more than 300 million people worldwide.1,2 Knee OA(KOA) accounts for approximately 85% of all OA cases worldwide.3 KOA represents a major public health challenge for the coming decades. The disease is ranked as the 10th largest cause of global years lived with disabilities,4 and its prevalence has more than doubled in the last 10 years.5,6 Medication management, hospitalizations, and joint surgery associated with OA treatment cost the healthcare system billions of dollars annually.4,6

OA is a complex and multifactorial disease that involves various tissues lesion of the joint, including degenerative loss of articular cartilage, osteophyte formation, synovitis, subchondral bone remodeling and sclerosis, inflammation and fibrosis of the infrapatellar fat pad in the joints7 (Figure 1) Traditionally, OA has been defined as an abnormal biomechanic-induced disorder causing extensive changes in joint homeostasis; however, it is not merely a passive degenerative disease of “wear-and-tear” as commonly described, but an active dynamic alteration arising from an imbalance between the repair and destruction of joint tissues with complex inflammatory and metabolic factors involved.8,9 Over the last decade, OA has been increasingly recognized as a heterogeneous disease with the combined effects of aging, obesity, mechanical imbalance, gender, inflammation, metabolic imbalance, and genetic background.10,11 The degradation of the articular cartilage is the central feature of KOA.12 The local unbalanced biomechanical microenvironment and various biological factors in OA induce cartilage homeostasis dysregulation, resulting in collagen- and proteoglycan-rich extracellular matrix (ECM) degradation, articular surface fibrosis and erosion, cell death, matrix calcification, and vascular invasion. The progressive destruction of cartilage stimulated chondrocyte compensatory anabolism hypertrophy. Progressive destruction of cartilage stimulates chondrocytes to increase anabolism in the form of compensatory hypertrophy13 and this process simultaneously produce matrix degradation products and pro-inflammatory mediators to accelerate the development of KOA.14 With the further loss of cartilage and the exposure of subchondral bone, the increasing bone remodeling induces occurrence of osteophytosis, subchondral sclerosis, cyst formation, and abnormalities of bone contour in response to the rapid changes of the mechanical environment.15 Pro-inflammatory factors secreted by hypertrophic chondrocytes stimulate synovial cell proliferation and induce T, B lymphocytes and mast cell infiltration in synovial fluid.16 The triggered synovial tissue releases pro-inflammatory mediators to promote the cascade development of KOA.17 The progressive OA also affects the tissues in and around the joint. As the largest intraarticular adipose tissue, Hoffa’s infrapatellar fat pad (IFP) is a very sensitive tissue containing adipocytes, fibroblasts, leukocytes, macrophages and other immune cells.16,18 The IFP of KOA patients presented an increase in inflammatory infiltration, vascularization, fibrotic changes, and thickness of the interlobular septa.19,20 IFP also in turn to produce pro-inflammatory mediators and induce synovitis.20–23 Meniscal/ligament lesion often leads to subsequent cartilage loss, changes in subchondral bone, lesions of bone marrow and synovitis.24 Meniscal/ligament lesion induced biomechanical imbalance is a risk factor causing OA.25 Conversely, the progressive OA usually caused meniscal/ligament lesions. There appears to be a mutually reinforcing relationship between knee osteoarthritis and meniscal/ligament lesion.16,26 In addition, OA caused dysfunctions of the quadriceps muscle, hamstrings and hip muscles.16,27 The weakness of periarticular muscles of OA has a significant impact on knee biomechanics. However, it is not clear whether muscle weakness is associated with OA onset or OA progression.28,29

Figure 1 Schematic of an osteoarthritis (OA) joint. OA is a disease of the entire joint in which various tissues in the joint are affected and undergoing progressive lesions, including 1) cartilage degradation and breaking down; 2) bone remodeling and sclerosis; 3) osteophytes formation; 4) synovial hypertrophy/synovitis; 5) meniscal damage; 6) ligament dysfunction; 7) muscle atrophy; and 8) inflammation/fibrosis of the infrapatellar fat pad.

Current KOA treatments include surgery, exercise, weight management, training in self-efficacy and pain-coping skills, and medications.12 There is no cure for OA, even no drugs to stop the progress of the disease.30 Current treatments only rely on symptomatic interventions, especially focus on relieve pain and enhance physical function. Intra-articular (IA) injection is one of the pharmacological treatments recommended for KOA in patients who do not respond to oral or topical analgesics31 Compared with oral administration, IA circumvents systemic exposure and potential adverse side effects32 and strengthens the bioavailability of therapeutic drugs direct access to the joint, which reduces treatment costs. In addition, IA is an attractive strategy for delivering drugs with low oral and local bioavailability. Currently, corticosteroids and hyaluronic acid (HA) are the most common drugs administered by IA injection for pain management and joint lubrication. However, the consensus on IA corticosteroids injections among scientific societies have not yet unified and the efficacy and safety of corticosteroids are debated. The balance between GC benefits and potential safety issues have been highlighted among guidelines. (the 2019 American College of Rheumatology (ACR) guideline, the Osteoarthritis Research Society International (OARSI) guideline, the American Academy of Orthopedic Surgeons (AAOS) guideline)33–35 High molecular weight HA has been used to alleviate the symptoms of OA. HA injection has been shown to provide lubrication, protect the cartilage from mechanical degradation, anti-inflammation, increase proteoglycan and HA synthesis, and reduce nerve impulses and nerve sensitivity associated with OA pain.36

Considering long-term efficacy and safety concerns, current IA drug injection treatments (corticosteroids and HA) are only used for a short-term therapy and this strategy cannot reverse the progression of OA. There is an urgent need to develop new IA treatment strategies for OA. IA injection treatment have been rapidly developing with some promising progress in recent years. Several IA treatment small molecules are investigating in different clinical trial stages, of which some exhibited promising results (Table 1). For example, a single injection of CNTX-4975 (a trans-capsaicin that deactivates TRPV1-expressing nociceptive afferents) provided statistically significant improvements in pain with walking for subjects with moderate to severe knee pain associated with OA.37 However, most drug agents only remain in the joint for a few hours and rapidly clear after IA injection owing to the special physiological environment of the joint (Figure 2A).38–42 Multiple IA injections may result in less compliance and inflammation. Ensuring that drugs are consistently and effectively delivered into joint targets remains a significant challenge.43 Drug-delivery systems (DDSs) have evolved rapidly over the past 20 years, and substantial drug loading formulations have been developed to increase drug duration and provide controlled and/or sustained drug release. Some formulations, such as cationic nanoparticle IA formulations, have increased the drug duration from several hours to nearly one month (Figure 2B).44–49

Table 1 Clinical Trials of Small Molecules Delivered by IA Injection as Currently Listed on www.clinicaltrials.gov

Figure 2 Representative half-lives or retention times of intra-articular (IA) drug (A)38–42/intra-articular drug (B)44–49 delivery system in a joint.

In this review, we summarized the IA DDSs development over the past five years (Figure 3) and discuss the application prospects of different types of DDSs for OA treatment.

Figure 3 A statistical chart of the research status of articular injection drug-delivery systems from the past five years.

Methods

Studies on IA DDSs over the past five years were collected by using the PubMed/Google Scholar/Scopus/Web of Science databases. Search keywords were set as “injection” and “osteoarthritis”. “NoteExpress” software was used to remove the duplicated studies in the collected publications. Then, the publications were categorized into different categories for further analysis (for example: “hydrogel”, “microspheres”, and “nanoparticles”). In addition, the signaling pathway studies related to IA injection for OA treatment over the past five years were also collected by using the PubMed/Google Scholar/Scopus/Web of Science databases, Search keywords were as “Signaling pathway”, “injection” and “osteoarthritis”. Impact factor of the collected publications ≥ 5 were selected and categorized into signaling pathway categories for analysis.

Different Drug-Delivery Systems for Intra-Articular Injection of Knee Joint

At present, biodegradable and bio-eliminable materials have been widely utilized for IA DDSs with diverse benefits, including, but not limited to, enhancing the stability of encapsulated drugs, decreasing toxicity, reducing adverse effects, improving pharmacokinetics, and targeting specific sites. In this study, the current IA DDSs are divided into three categories according to their material characteristics; that is, nanoparticles, microspheres, and hydrogels. We collected 22,040 publications on IA DDSs from the past five years. Of these publications, hydrogels, nanoparticle carriers, and microspheres accounted for 41.2, 40.47, and 18.33%, respectively, of the IA DDSs used for OA treatment (Figure 3).

Hydrogels

Hydrogels are cross-linked 3D polymer networks with a high water content which expand in water-soluble environments and form polymerization systems with targeted substances such as proteins, nucleic acids, small organic molecules, etc. The high water content of hydrogels (typically 70–99%) is physically similar to tissues, providing excellent biocompatibility and the ability to easily encapsulate hydrophilic drugs. Hydrogel DDSs have been applied in different medicinal fields, including cardiology, oncology, immunology, wound healing, and pain management.50 Hydrogel gelation strategies are selected according to the characteristics of various materials and include Schiff-base cross-linking, enzyme-mediated cross-linking, photocrosslinking, or thermosensitive cross-linking.51 Hydrogels have a long application history as a joint lubricant, and were reported in animals as early as 2002.52

Hydrogels Used as a Drug-Delivery System

Hydrogels are generally composed of macromolecules with long retention times in the knee joint compared with small-molecule materials. Therefore, hydrogels are generally used as a DDS for prolonged drug effects in joints. Chondrogenic factors,53 chondroitin sulfate nanoparticles,54 and oligonucleotides55,56 have been commonly loaded into hydrogel delivery systems for therapeutic studies. Some traditional medicines (such as celecoxib,57 meloxicam,58 dexamethasone,59 and triamcinolone60 loaded in hydrogel delivery systems not only provided improved long-term drug release, but also enhanced anti-inflammatory effect than the original formulations (See Table 2 for details).

Table 2 Summary of Hydrogel Drug Delivery System

Hydrogels Used as Cell and Tissue Engineering Scaffolds

Currently, many tissue or cell transplantation techniques have been used for OA cartilage regeneration. However, the cumbersome in vitro cell manipulations and potential cancer risks limit their application.61 In the last few decades, cell and pro-growth factors combined with hydrogel scaffolds applied in tissue engineering has attracted significant attention. As typical representatives, natural hydrogels with high performances are ideal biomaterial scaffolds for cartilage repair because of their preferable reconstructions of cell growth, proliferation, differentiation, and new tissue formation. Hydrogels such as polyglucosamine,62 chitosan,63 hyaluronic acid,64 and acellular cartilage matrix65 showed promising applications in the field of cellular implantation for the treatment of OA.

Functional Hydrogels

Hydrogels made of natural polymer materials have their limited properties (including, rheological, stability, mechanical strength, et al.); therefore, modified hydrogels with different functional groups are rapidly evolving because of the modifications improve the properties of natural polymer. In addition, these modifications create different kinds of smart hydrogels, which could automatically sense and respond to changes in the external environment (include temperature sensitive, pH sensitive, photosensitive, magnetic sensitive and temperature/pH dual sensitivity hydrogels).66–71

Temperature-sensitive hydrogels have always been favored because they are easier to load with drugs or cells and possess more convenient in situ formation properties than other hydrogels.66,67 Thermosensitive hydrogels, such as chitosan with β-glycerol phosphate,72 glycol chitosan,73 PEG-grafted polyalanine or poly(lactide-co-glycolide),74–76 poly(N-isopropylacrylamide-co-acrylic acid) (p(NIPAAm-AA)),77,78 poly(ethyleneglycol)-(p(HPMAm-lac)-PEG),79 poloxamers,80 poly(d,l-lactide)-poly(ethylene glycol)-poly(d,l-lactide) (PLEL),81,82 hyaluronic acid-chitosan-poly(N-isopropylacrylamide),83 and amphiphilic poly(organophosphazene),84 have been increasingly applied in the treatment of OA. A previous study demonstrated that temperature-sensitive PNIPAM (poly(N-isopropylacrylamide)) hydrogels85 could regulate drug release according to the joint temperature. This design offers a novel concept for the hydrogel treatment of OA.

Nanoparticles

Nanoparticles (NPs) are also frequently used in OA treatment studies. NPs are submicron particles with dimensions ranging from 1 to 300 nm, which is approximately 1000 times smaller than that of chondrocytes. NPs as carriers can incorporate drugs on the surface or matrix to protect them from enzymatic degradation, improve their penetration across the cartilage matrix, and regulate drug pharmacokinetics, which is beneficial for improving the efficacy and reducing the toxicity of therapeutic compounds.86 By adjusting the physicochemical properties or decorating with moieties, NPs can be modified with functional groups to target the components and/or cells in the cartilage.87 This section reviews the current developments and novel applications of OA-related NP-based DDSs, including liposomes, micelles, dendrimers, polymeric nanoparticles (PNPs), and exosomes.51,88–92

Liposomes

Liposomes are spherical vesicles composed of phospholipids and steroids,93 and are both hydrophilic and lipophilic.94 Liposomes have been proven to prolong drug efficacy, improve bioavailability, and provide tissue/cell targeting.95–98 Some liposome formulations are already commercially available for treating OA. For example, Lipotalon® (Merckle, Germany) is the first used liposome formulation in Germany to clinically treat OA by IA delivery,43 containing dexamethasone palmitate as active ingredient, preferentially taken up by synovial macrophages after IA injection and transformed to its active form by intracellular esterases, thus preventing the side effects of free dexamethasone (synovitis and tissue irritation).99,100

However, the aqueous environment of the synovial fluid may lead to rapid drug release. These shortcomings have limited the application of liposomes.

1). Prolonged duration of drug efficacy

Liposomes can prolong drug retention because the drugs are encapsulated within the phospholipid bilayers and are more difficult to remove than small-molecule drugs. The efficacy of many drugs has reportedly improved through liposome formulations. For example, the liposome formulations for rapamycin,101 fish oil protein,102 diclofenac sodium,103 and d-glucosamine sulfate104 have been reported to enhance the inhibition of pro-inflammatory factors or promote cartilage-related genes expression (See Table 3 for details).

Table 3 Summary of Nanoparticles Drug Loading System

2). Improved bioavailability

The phospholipid bilayer structure of liposomes has a high affinity for the cell membrane and good stability, and the uptake of drugs can be improved by liposome formulations. In recent years, natural molecules, such as curcumin,105,106 lornoxicam,107 and rapamycin,101 with poor bioavailability were also loaded into liposomes for OA treatment. The results showed superior therapeutic effects and better bioavailability than the original forms.

3). Liposome tissue/cell targeting

Modified liposomes with functional groups for targeting are generally based on two strategies.

① Targeting agents loaded in liposome formulation

The targeting agents can be loaded into the liposomes. This strategy typically targets protein receptors or genes, such as CGS21680 (adenosine A2A receptor agonist),108,109 miR-15a (a microRNA that silences SMAD2 gene expression),110 and microRNA-143-3p (targeted regulation of BMPR2 expression).111 The stable lipid bilayer structure of liposomes can help transport sensitive cargo into cells and enhance the effect of the agents.112

② Liposome surface modification with functional targeting groups

Liposome surface modifications with functional targeting groups is another common strategy. The synovium and inflammatory microenvironment can be targeted by modifying with the HAP-1 (ALSQAFRHAFTS; sc-HAP-1) peptide,113 ART-2 (CKPFDRALC) peptide,114 or a specified number of PEG groups.115 Bone-targeted delivery of liposomes can be achieved by modifying with alendronate, pyrophosphate, and oligopeptides.116 Considering that cartilage is rich in type II collagen, liposomes modified with type II collagen antibodies117 reportedly provided cartilage targeting for targeted drug delivery.

Micelles

Micelles are nanoscale materials comprised of amphiphilic polymers that self-assemble in aqueous solvents, and their size range is generally 5–100 nm.118 Micelle formulation requires a critical polymer concentration known as the critical micelle concentration (CMC). The self-assembly process occurs when the amphiphile concentration in the aqueous solution reaches the CMC.119

Micelle formulations are commonly used as a DDS for hydrophobic agents. Wei et al.120 encapsulated the sPLA2 (secretory phospholipase A2) inhibitor into micelles for lesion tissue targeted drug delivery, and Wang et al.121 loaded siRNA in micelles to target p56 of the NF-κB pathway. Oxygen species (ROS)-responsive micelles were developed based on elevated ROS exposure in arthritic joints. For example, the diblock copolymer poly (ethylene glycol)-block-poly (propylene sulfide)122 and PLGA-SeSe-mPEG (poly (lactic-co-glycolic acid-SeSe-poly (ethylene glycol)) were used to modify micelles for ROS-sensitive drug delivery.123 Considering that the folic acid (FA) receptor is highly expressed on arthritic macrophage membranes, FA-modified PSA (polysialic acid)-CC (natural cholesterol) micelles were developed to target macrophages in the synovial inflammatory microenvironment.124 Conjugate polymers of heparin and d-α-tocopheryl succinate (LMWH-TOS) also reportedly target the inflammatory microenvironment.125

The acidic environment and overexpressed matrix metalloproteinases-13 (MMP-13) are typical OA markers, which enable the development of stimulus-responsive drug-delivery systems with high specificity for OA. pH-sensitive amphiphilic methoxy polyethylene glycol-polypropylene fumarate micelles,126 poly (β-amino ester) micelles,127–129 and multiple targeted micelles have been developed for OA drug delivery. For example, Lan et al.130 developed an MMP-13 enzyme and pH-responsive theranostic micelle for OA treatment and a specific collagen type II targeting peptide (WRYGRL) conjugate PPL was used to target the cartilage.

To date, few studies have reported micelle applications for clinical OA treatment,131 which may be related to the common limitations of micelles, including their inability to encapsulate hydrophilic drugs, CMC dependency, and toxicity concerns.

Dendrimers

Dendrimers are highly branched polymers with demonstrated therapeutic potential for drug delivery. Their structure can be divided into three main components: (1) the core or nucleus, (2) inner layers consisting of repetitive molecular units called dendrons, and (3) terminal groups on the surface.132–135 Poly(lysine) (PLL), polypropyleneimine (PPI), polyethylenimine (PEI), poly(arylether), and poly(amidoamine) (PAMAM) are the most popular dendrimers used in oral delivery.136 Dendrimers can steadily incorporate many active compounds and/or ligands that improve their solubility.137 Hu et al.138 conjugated kartogenin (KGN), PAMAM, and PEG to obtain PEG-PAMAM-KGN (PPK) and KGN-PEG-PAMAM (KPP) conjugates. This strategy improved KGN release and enhanced chondrogenic effects in OA joints. In addition, the dendrimer formed by PAMAM is a dense cationic macromolecule that binds anionic cartilage and easy to penetrates anionic cartilage tissues. Geiger et al.49 conjugated insulin-like growth factor 1 and PEG to PAMAM and improved cartilage-targeted drug delivery. Chondrocyte-affinity peptides139 or chondroitin sulfate (CS)-modified PAMAM polymers140 further enhanced polymer cartilage targeting, and azabisphosphonate (ABP)-capped dendrimers selectively targeted monocytes and directed them toward anti-inflammatory activation in the RA joint.141

Dendrimers possess various advantages, such as increased solubility of hydrophobic drugs and tunable physicochemical properties. Currently, there are many pre-clinical studies related to dendrimer applications;135,142–145 however, their application in OA treatment is limited. Disadvantages such as non-entrapment of hydrophilic drugs, cellular toxicity, and rapid drug release (up to 70% of the encapsulated drugs are released within a few hours146) limit their application in OA treatment.

Polymer Nanoparticles (PNPs)

Polymer nanoparticles (PNPs) are solid particles that can be prepared in the range of nanometers to microns.147 There are two structural types: nanocapsules, which consist of a hydrophilic drug reservoir and a polymer shell, and nanospheres, which contain a homogeneous polymer matrix that can load dispersed/intercepted drugs. The release kinetics of both types can be adjusted according to the formulation strategy, chemical composition, and molecular weight of polymers and drugs.148 PNPs have many promising advantages for drug delivery, including:

  1. Improved drug release

Several studies report significantly improved and sustained drug release using PNPs for drug delivery. PLGA,149,150 polylactic acid (PLA),151 polyurethane,152 different polymer combinations,153 silk fibroin,154 and polymer-grafted mesoporous silica155 used to prepare PNPs for drug delivery. These formulations reportedly provide improved and sustained drug-release profiles for celecoxib, curcumin, and KGN by IA drug delivery.

  • 2. Improved drug efficacy by microenvironmental responsive drug delivery (PH/Thermo sensitive)

    • Microenvironmental-sensitive drug-release strategies have been attractive for PNP drug delivery. pH and temperature sensitive PNPs are rapidly evolving, including hollow dextran/poly (N-isopropyl acrylamide) NPs,156 dual-functional poly[N-isopropylacrylamide-2-methacryloyloxyethyl phosphorylcholine] (PNIPAM-PMPC) nanospheres,157 hyaluronic acid-poly(N-isopropylacrylamide) (HA-pNiPAM) nanospheres,158 and chitosan oligosaccharide-conjugated pluronic F127 grafting carboxyl group nanospheres159 which possess temperature-responsive release properties. Previous studies showed that NH4HCO3 laden poly (lactic-co-glycolic acid) (PLGA) NPs demonstrate pH-responsive drug release.160,161

  • 3. PNPs tissue/cell targeting

    • In recent years, more and more PNPs targeted drug-delivery systems have been developed for OA therapy. Cartilage targeting is the most popular strategy that can be achieved by modifying the PNPs with cartilage affinity groups.162 Collagen II-binding peptide-modified formononetin (FMN)-poly (ethylene glycol) (PEG) NPs,163,164 xanthan gum-poly (sulfobetaine methacrylate) (XG-PSBMA) NPs,165 WYRGRL (a short cartilage-targeting peptide sequence)-modified PLGA NPs,164,166 polyethylene glycol (PEG) chains (PEG-SWCNTs) modified with single-walled carbon nanotube (SWCNT) NPs,44 and quaternary ammonium cation modified PLGA NPs167 have been developed for cartilage targeting. In some instances, cartilage targeting originates in the basic material of the PNPs.163–166In addition, dextran sulfate used to target macrophages,168 HAP-1 peptide used to target synovial,169 O-HTCC (O-(2-hydroxyl) propyl-3trimethyl ammonium chitosan chloride) and polyphenol–poloxamer used to target ROS,170,171 C11 peptide (the C-terminal region of rh174) used to target bone,172 PNPs have also been developed to target the specific microenvironment of OA joint.

    Over the past decade, significant progress has been made in the functional modification of PNPs. However, the side effects, toxicity, and complicated preparation processes of PNPs continue to challenge their application in OA treatment.

    Exosomes

    Exosomes are extracellular vesicles (loading content including lipids, nucleic acids, and proteins) secreted by cells for cell-to-cell communication.92 The size of exosomes is generally between 30–150 nm.173 Previous studies demonstrated the utility of exosomes as drug-delivery systems. Compared with other nanoparticles, exosomes possess higher stability, biocompatibility, biological barrier permeability, and lower immunogenicity,174 and can overcome some challenges, such as toxicity and a high clearance rate.175 Current studies on exosomes for OA treatment are mainly focused on two aspects: 1) to investigate the diagnostic significance and biological effects of endogenous exosomes in OA patients; 2) to investigate stem cell-derived exosomes for OA treatment.92

    On the other hand, in recent years, the utility of exosomes as drug-delivery systems has become increasingly attractive for OA treatment. Tao et al.82 prepared circRNA3503 loaded exosomes from synovial mesenchymal stem cells and further incorporated the exosomes into an injectable thermosensitive hydrogel. This composite gel strategy successfully delivered small-molecule RNAs, improved drug targeting, and prevented OA progression. Liang et al.176 reported chondrocyte-affinity peptides (CAP) and lysosome-associated membrane glycoprotein 2b (Lamp2b) protein-modified exosomes (CAP-exosomes) that can efficiently encapsulate miR-140 and target chondrocytes in vitro. The CAP-exosomes successfully delivered miR-140 to deep cartilage regions and alleviated OA progression, demonstrating a potential organelle-based, cell-free therapy for OA. Xu et al.177 reported KGN-loaded MSC-binding peptide E7 modified exosomes (E7-Exo) that targeted synovial fluid-derived mesenchymal stem cells. The E7-Exo induced a higher MSC cartilage differentiation than KGN alone or KGN-loaded unmodified exosomes.

    Exosomes have shown promising potential as drug carriers in OA treatment. However, studies of using exosome as drug-delivery systems are still limited. The greatest technical challenge is the difficulty in obtaining sufficient amounts of exosomes for in vivo studies. Table 3 demonstrated more details of the nanoparticle drug delivery systems mentioned in this review.

    Microspheres

    Microspheres are skeletal spherical drug-delivery systems formulated by dispersing or dissolving a drug in a polymer, with a particle size of approximately 1–200 μm. Microspheres are commonly used in OA treatment to prolong the retention time of drugs and lubricate joints.178,179

    Liang et al.180 reported that mometasone furoate-loaded PLGA microspheres increased the drug retention time in joints by up to 35 days. Stefani et al.181 developed an acellular agarose hydrogel incorporated with dexamethasone-loaded PLGA microspheres for OA treatment. Combining microspheres and hydrogels improved the sustained drug-release properties for OA treatment for up to 99 days. Li et al.182 demonstrated that super-activated platelet lysate (sPL)-loaded PLGA/chitosan/gelatin microspheres improved the sustained drug release, inhibited osteoarthritis, and promoted cartilaginous repairs. Park et al.183 reported the utility of gelatin microspheres that are responsive to proteolytic enzymes typically expressed in arthritic flares, resulting in the on-demand and spatiotemporally controlled release of anti-inflammatory cytokines for cartilage preservation and repair.

    On the other hand, IA DDS are not only committed to improving drug effectiveness, but also focus on improving joint lubrication properties. Bio-lubricants have been designed for the treatment of early OA by improving the lubrication performance of synovial joints. Therefore, some people have also improved the lubricating properties of hydrogels by modifying polymer materials. Sulfone-modified HA,184 lactose modified chitosan185 and gellan gum186 could modulate viscoelastic properties of osteoarthritis synovial fluids and improve OA joint lubrication. Han et al.179 reported photocrosslinked methyl methacrylate gelatin (GelMA) hydrogel microspheres incorporated into a self-adhesive polymer (DMA-MPC) to prepare a new composite microsphere (GelMA@DMA-MPC). This biomimetic injectable hydrogel microsphere enhanced lubrication and controlled the drug release for OA treatment. Zhang et al.187 demonstrated that YAP (Yes-associated protein)-selective inhibitor-loaded chitosan microspheres could target subcellular YAP activity and alleviate OA progression. Yang et al.188 reported ball-bearing-inspired polyampholyte-modified microspheres with a super lubricated ability (MGS@DMA-SBMA). The MGS@DMA-SBMA microspheres significantly enhanced joint lubrication and improved the sustained drug release, which are highly desirable for IA OA treatment.

    Several microsphere formulations have been commercially available or proved to be promising for OA treatment. A triamcinolone acetonide sustained-release microsphere formulation (Triamcinolone acetonide extended-release (ER), Zilretta®) was approved for OA treatment in the United States.189 In addition, several microsphere formulations, such as fluvastatin,190 celecoxib,191 and etoricoxib,192 are planning to tested in clinical trials.

    Generally, different polymers (such as polylactic acid, gelatin, and chitosan) can be developed into microspheres, which can also be modified with different functional groups to help improve drug delivery/targeting.193 Table 4 demonstrated more details of the microsphere drug delivery system mentioned in this review.

    Table 4 Summary of Microspheres Drug Delivery System

    Current Active and Passive Targeting Strategies for IA DDSs

    Tissue/cell-specific active and passive targeting technologies have been developed to improve drug retention and efficacy in joints. We collected and analyzed 36 studies with clear target mechanisms. The results demonstrated that targeted synovium/synoviocytes, cartilage and chondrocytes, and joint microenvironments (synovial fluid) accounted for 61.11, 33.33, and 5.56%, respectively, of the IA DDSs used for OA treatment (Figure 4). The details are listed in Table 5.

    Table 5 Representative Research Targets of IA DDSs

    Figure 4 Representative research targets of IA DDSs.

    Different strategies have been used to target cartilages/chondrocytes, including the passively targeting anionic cartilage ECM/collagen type II.49,194–196 For example, a six-amino acid collagen II-binding peptide (WYRGRL)-conjugated drug-delivery system targets collagen and provides significantly longer joint retention than a normal control peptide.195,196 In addition, drug retention increased with the collagen II-binding peptide content in the drug-delivery system. Antibodies for collagen II197,198 have also been used as ligands in drug-delivery systems to target cartilage.117,199 A drug-delivery system incorporating a cell-penetrating peptide (YGRKKRRQRRR-C) significantly enhanced the drug uptake by chondrocytes by approximately 4-folds compared to the non-targeting formulation.200 A passive, electrostatic-based strategy was also developed for targeting cartilage.49,139,201,202 For example, drug-delivery systems with cationic surface charges (especially dendrimers136,139) significantly improved the joint retention of drugs, as the cartilage ECM accumulated anionic charges because of the dense sulfated proteoglycan networks.49,141,203

    The OA targeting strategy not only focuses on the cartilage/chondrocytes, but also on other joint tissues/cells, such as the synovium/synoviocytes, owing to the complicated disease progression in OA. This strategy focused on targeting surface receptors in two major cells: 1) the minor type A synovial macrophages that significantly proliferate and activate under inflammatory conditions; 2) and the dominant type B fibroblast-like cells which produce ECM components of the synovial membrane and synovial fluid. Previous studies have demonstrated tuftsin peptide incorporated nanoparticles that target macrophages in the joint;204 copolymer nanoparticles incorporated with IL-1Ra proteins targeted synoviocytes through the IL-1 receptor and increased drug retention in the joint;45 RGD (Arg-Gly-Asp) peptide-modified liposomes targeted vascular endothelial cells of synovium though RGD peptide binding to αvβ3 integrins,205 which are strongly up-regulated on angiogenic endothelium at the inflammatory sites; αvβ3-targeted fumagillin nanoparticles significantly decreased inflammation and angiogenesis, and preserved proteoglycan integrity in synovial tissues.206

    Overexpressed activated macrophages and acidic microenvironments are two significant features of RA joints. Multifunctional FA receptor-targeting and pH-responsive nanocarriers have been developed for RA IA treatment. Folate-incorporated nanoparticles promoted drug uptake of macrophages compared to untargeted nanoparticles,207 and drug-delivery systems incorporated with macrophage-derived micro-vesicles can target macrophages in the synovium or pannus of inflamed tissues.208 Drug deliveries were also designed to target synovial fluid by ionic cross-linking with endogenous/exogenous hyaluronic acid.48,209

    Evidently, numerous targeted strategies have been developed to deliver and improve the efficacy of drugs in joints. Active and passive targeting strategies for OA joints have rapidly evolved over the past decades (Figure 4 and Table 5).

    Current Signaling Pathways Targeted by IA Drug-Delivery Systems

    Many pathways are involved in the pathogenesis of OA, and drug delivery system targeting different pathways have been used in IA drug-delivery systems. Articular drug-delivery systems provide significant support for the precise targeting of key sites in OA.210–221 We searched 14,160 studies on articular drug-delivery systems with clear signaling pathways from the 1st of January 2016 to the 13th of July 2021. The results demonstrated that the current research on articular drug-delivery systems mainly focus on five signaling pathways. TGF-β is the leading signaling pathway accounting for up to 26.35% of the studies (3730), followed by the NF-κB, PI3K, Wnt, and p38 MAPK (1790) signaling pathways which account for 21.97 (3109), 19.64 (2786), 19.39 (2745), and 12.65% (1790), respectively, of the studies (3109) (Figure 5, Table 6). None of the signaling pathways were proven to play the dominant role in OA initiation and progression. The mechanism of action of OA has yet to be fully elucidated.

    Table 6 Summary of Previous Studies on Signaling Pathway in IA DDSs

    Figure 5 Statistics over the past five years on the current research status of IA DDSs target signaling pathways.

    Discussion

    IA injections play an important role in the treatment of OA owing to their significant advantages. In this review, we summarized the current drug-delivery systems for IA DDSs. We collected and analyzed studies that reported the application of different nanoparticle-based IA DDSs in pre-clinical/clinical trials. Polymeric microspheres were the leading nanoparticles and accounted for 35.17% of IA DDSs. Nanoparticle and hydrogel/gel formulations accounted for 28.57 and 14.29%, respectively, of IA DDSs (Figure 6A). Although OA treatment remains a challenge in clinical practice, there are many IA drug delivery formulations for clinical application are ongoing, and several formulations including ZILRETTA, TIVORBEX, ZORVOLEX, and VIVLODEX have been approved222–225 (Figure 6B, Table 7).

    Table 7 Recent IA DDSs Reported in Preclinical and Clinical Trials

    Figure 6 Recent reported IA DDSs in pre-clinical/clinical trials/approved stages. (A) Proportion of different formulation of recent reported IA DDSs in pre-clinical/clinical trials/approved stages; (B) proportion of recent reported IA DDSs in pre-clinical/clinical trials/approved stages.

    Different IA drug delivery systems have their advantages and disadvantages. Hydrogel often used as lubricant as its high water content and rheological properties. The excellent biocompatibility of hydrogel is also attractive for loading live cells and drugs. However, the loose network and high water content of hydrogels makes it difficult to increase drug retention time in joint. Microspheres are widely used for controlled delivery of therapeutics via different routes of administration (mainly subcutaneous and intramuscular) for augmenting effectiveness and reducing toxicity of the incorporated agents to non-targeted cells and tissues. However, the stability of microspheres is a challenge issue and they are not easily to mass-produce. Nanoparticle is a promising drug delivery system as its unique ability to penetrate tissues and easy to modify functional groups. However, some challenge issues still hinder the application of these nanoparticles. For example, 1) the sustained release and retention properties of most nanoparticles are still weak; 2) the drug leakage issue of liposome formulations; 3) the entrapment efficiency issue of hydrophilic drug micelles; 4) drug release too fast issue of dendrimer. Although exosomes have unique advantages in biocompatibility and non-toxicity, it is difficult to address the large quantities production issue, which significant hinder its future application. At present, significant challenges remain regarding to the safety, efficacy duration, and targeting properties to all IA DDSs. There is another important issue that may raise significant concerns: how to sterilize DDs while maintaining their effectiveness? Liposomes and microspheres are more suitable for gamma ray sterilization.226 For unstable nanoparticles, aseptic filtration is recommended.227 High-pressure steam sterilization and ethylene oxide sterilization are not suitable for most drug delivery systems as the properties of DDSs and its loaded drugs would easy to be destroy.227 However, there still are some formulations had been proved that their properties maintained their properties after autoclave.228

    A multifunctional drug-delivery system with excellent biosafety and drug-targeting properties is a promising direction of future IA drug delivery system development. Combined different strategies to prepare drug delivery systems for IA injection treatment are increasingly attractive. However, the more complex strategy of the drug delivery system, the more it is required to address synergies effects between different strategies.

    Conclusions

    Different IA drug delivery systems are developing rapidly with some significant progress. The ideal performance of an IA DDS depends on the nature of the drug delivery platform. Desirable properties of an IA DDS for OA included excellent continuous and controlled drug delivery, lubrication performance, and disease-targeting that could significantly improve the treatment of OA. At last, the most important issue is the benefits of new IA treatments must be carefully weighed against their cost and potential risks.

    Data Availability Statement

    The original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding author/s.

    Funding

    This research was funded by grants from the National Natural Science Foundation of China (No. 81703584); The regional joint fund of natural science foundation of Guangdong province (No. 2020B1515120052); Guangdong Province Natural Science Foundation of China (No. 2017A030310614, 2018A030313390, 2016ZC0178, 2021A1515010975); Discipline construction project of Guangdong Medical University (No. 4SG22002G, 4SG21156G); Special Funds for Scientific Technological Innovation of Undergraduates in Guangdong Province (No. pdjh2022a0214); Affiliated Hospital of Guangdong Medical University “Clinical Medicine+” CnTech Co-operation Project (No. CLP2021B012); Guangdong Medical University scientific research fund (No. B2017001); the Fund of Southern Marine Science and Engineering Guangdong Laboratory (Zhanjiang) (No. ZJW-2019-007).

    Disclosure

    The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this review.

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