Currently, OA is likely to be treated with lifestyle modification, pharmaceutical drugs, surgery, and also in combination. In the early stage of OA, lifestyle modifications such as swimming or Tai chi show to help patients with OA to alleviate pain and recover functions (Vignon et al., 2006). Orthotics have been shown to alleviate discomfort and increase function (Hussain et al., 2016). Besides these physical treatments, acetaminophen and non-steroidal anti-inflammatory drugs are widely used to resist inflammatory reactions and relieve pain, glucocorticoids, hyaluronic acid, chondroitin sulfate and glucosamine are also frequently used. Oral NSAIDs are the mainstay of the pharmacologic management of OA at present. NSAIDs can exert anti-inflammatory effects (Liu et al., 2013; Chen et al., 2017; Zhang et al., 2020a), and have been demonstrated to improve central and peripheral sensory thresholds and lessen pain. NSAIDs can diminish hyperalgesia by reducing the inflammatory and cellular immunological reactions generated by inflammatory mediators (Argoff, 2011). Furthermore, researchers discovered that NSAIDs preserve cartilage by efficiently inhibiting the damage caused by local inflammatory reactions to chondrocytes and synovial cells (Gunson et al., 2012). All of these drugs, however, have the potential for gastrointestinal, hepatic, and cardiorenal side effects, which increase with dose and treatment duration (Bjarnason, 2013; Ghosh et al., 2015; García-Rayado et al., 2018; Tai and McAlindon, 2018; Bindu et al., 2020). Chondroitin sulfate (CS) is a natural glycosaminoglycan present in cartilage and the ECM. In chondrocytes and synovial membranes, CS inhibits NF-κB activation and nuclear translocation (Uwe, 2008). To treat OA, CS is frequently combined with glucosamine (Bishnoi et al., 2016). Its capacity to relieve symptoms or reduce the structural progression of OA has been studied in clinical trials. The results have been contradictory, owing to variances in patient demographics and CS purity (Uebelhart et al., 2004; Henrotin et al., 2014; Singh et al., 2015; Simental-Mendía et al., 2018). The safety of CS, on the other hand, is guaranteed. Researchers discovered that giving glucosamine hydrochloride to OA mice prevented not only the loss of GAGs and proteoglycans in articular cartilage but also bone resorption by inhibiting RANKL (Ivanovska and Dimitrova, 2011; Henrotin et al., 2012). Glucosamine hydrochloride was also demonstrated to block the production of IL-6 and to upregulate the production of IL-10 by the synovial membrane in the same study. And scholars have developed a controlled drug delivery system that co-delivers diacerein and GS, for the treatment of osteoarthritic knee. Based on the results, it can be concluded that this new formulation could induce chondroprotection with a downturn effect on inflammatory biomarkers. Despite that the effectiveness of glucosamine is controversial (Towheed et al., 2005; Bruyère et al., 2016; Roman-Blas et al., 2017; Runhaar et al., 2017; Ogata et al., 2018), glucosamine is widely considered to be safe, and no serious or fatal adverse events have ever been reported. Glucocorticoids (GCs) also alter whole-body homeostasis, modulate immunological responses and brain functions, change tissue integrity, and affect the skeletal system (Hartmann et al., 2016). The glucocorticoid receptor can interact with NF-κB and AP-1 to limit the transcription of these genes, according to researchers (Mihailidou et al., 2016). In addition, GC inhibited the expression of proinflammatory mediators TNF-α, IL-6, and MMP-9, indicating that it has anti-inflammatory properties (Zimmermann et al., 2009). Furthermore, GC can inhibit IL-1-induced collagen breakdown and suppress MMP-1 and MMP-3 production. As a result, it has the ability to protect articular cartilage, prevent ECM breakdown, enhance ECM production, and stimulate chondrocyte proliferation (Lu et al., 2011; Li et al., 2015). Long-term use of GCs, as well as disrupted negative feedback loops or persistent stress, can lead to serious consequences (McDonough et al., 2008). Insulin resistance, muscular and skin atrophies, depression, and severe skeletal consequences are among them. As a result, the use of GCs should be closely regulated. Many tissues and fluids contain hyaluronic acid (HA). The amount of HA in different joints and species varies greatly (Gupta et al., 2019). By binding to CD44, HA can preserve cartilage, because HA-CD44 inhibits IL-1β, MMP-1, MMP-2, MMP-3, MMP-9, and MMP-13 expression is reduced (Brun et al., 2012; Pohlig et al., 2016). HA has been shown in numerous studies to have anti-inflammatory properties (Litwiniuk et al., 2016; Pontes-Quero et al., 2019; How et al., 2020). IL-1 was suppressed after HA binding to CD44. Furthermore, MMPs were downregulated after IL-1β suppression, which contributed to the anti-inflammatory action of HA. The binding of HA to CD44 can block inflammatory factors such as IL-8, IL-6, and TNF-α, as well as upregulate the anti-inflammatory impact (Chang et al., 2012). Table 1 is a summary of properties of the above pharmaceutical reagents.

Up to now, some of the above drugs have been carried out for clinical trials (Table 2). These drugs have the potential to treat OA. Margreet found that Lutikizumab (an IL-1 inhibitor) treatment compared with placebo was associated with significant reductions in serum IL-1α and IL-1β levels (Kloppenburg et al., 2019). What’s more, Lutikizumab can significantly decrease the levels of neutrophils, high-sensitivity C reactive protein and serum collagen type I compared with placebo and Serum collagen type were also reduced. However, despite the adequate blockade of IL-1, lutikizumab did not improve pain or imaging outcomes in erosive Hand OA compared with placebo. In another phase II multicenter double-blind study, knee OA patients received a single intra-articular injection of placebo or CNTX-4975 (an injectable form of highly purified trans-capsaicin). The results show that a single intra-articular injection of CNTX-4975 was effective in providing a significant and clinically meaningful reduction in pain that occurs while walking on a flat surface in patients with chronic moderate-to-severe OA knee pain (Stevens et al., 2019). The improvement in pain was associated with a reduction in knee stiffness and an improvement in function compared to placebo. To evaluate the efficacy, safety, and tolerability of MIV-711 in participants with symptomatic, radiographic knee osteoarthritis. Philip designed a 26-week randomized, double-blind, placebo-controlled phase 2a study (Conaghan et al., 2020). Progression of medial femoral bone area was significantly reduced in both MIV-711 treatment groups compared with placebo, and medial femoral cartilage thinning was reduced in the group receiving 100 mg/d. Significant reductions in bone resorption and cartilage degradation biomarkers were also observed. In conclusion, MIV-711 showed no beneficial effects on osteoarthritic knee pain in this study. However, statistically significant reductions in bone and cartilage osteoarthritis manifestations were observed, along with a reassuring safety profile. Marie-Pierre’s group want to explore if inhibition of inducible nitric oxide synthase (iNOS) with cindunistat hydrochloride maleate will slow the progression of osteoarthritis (Hellio le Graverand et al., 2013). Their statistics show that irreversible iNOS inhibitor Cindunistat did not reduce the rate of joint space narrowing in patients with knee OA in comparison with placebo and iNOS inhibition did not slow OA progression. What’s more, the loss of efficacy over time and lack of effect in patients suggest that alternative biochemical catabolic pathways overcame the effects of NO inhibition and/or that the consequences of the increased intra-articular stress may not have been amenable to iNOS inhibition alone. In Felix Eckstein’s clinic trial, they applied the recombinant human fibroblast growth factor 18 (sprifermin) to patients, compared with placebo (Eckstein et al., 2020). The current results support the concept that sprifermin increases cartilage thickness, and reduces cartilage loss. They showed structural modification of cartilage thickness with sprifermin. Sprifermin should be evaluated further in clinical trials as a potential DMOAD for knee OA. To explore the disease modifying effect of strontium ranelate (SrRan) treatment on cartilage volume loss and bone marrow lesions in a subset of OA patients, Pelletier conducted a phase III clinical trial (Pelletier et al., 2015). They find that treatment with SrRan 2 g/day can reduce knee OA cartilage volume loss predominantly in the plateau and that in patients with bone marrow lesions, a protective effect of SrRan was found to substantially reduce the cartilage volume loss in the medial plateau. Taken together, these findings showed that SrRan has a DMOAD effect in knee OA patients. Tanezumab, a monoclonal antibody, inhibits nerve growth factors and reduces chronic pain. Balanescu conducted a study to evaluate the efficacy and safety of tanezumab added to oral diclofenac sustained release in patients with hip or knee OA pain (Balanescu et al., 2014). The study reported that the addition of tanezumab to diclofenac sustained release resulted in significant improvements in pain, function and global assessments in patients with OA. Although no new safety signals were observed, the higher incidence of adverse events in the tanezumab + diclofenac group suggests that combination therapy is unfavorable. Further investigations of tanezumab monotherapy for OA pain treatment are required. Yazici conducted a phase II clinical trial to assess the safety and efficacy of the novel Wnt/β pathway modulator lorecivivint (SM04690) for treating pain and inhibiting structural progression in moderate-to-severe symptomatic knee OA. The results data indicated that lorecivivint have improvements in pain and function compared with placebo. This study identified a target group of subjects with unilateral symptomatic knee OA and a potentially optimal dose of LOR (0.07 mg). The clinical and radiographic outcomes warrant additional studies of the potential of LOR for both analgesia and disease-modifying activity in knee OA. Paula’s study assessed the efficacy, general safety, and joint safety of fasinumab, an anti-nerve growth factor monoclonal antibody, in OA pain (Dakin et al., 2019). In this phase IIb/III study, fasinumab demonstrated a substantial degree of analgesia in patients with moderate-to-severe pain from OA, without clear evidence of dependence on dose level for efficacy. This represents an important, previously unaddressed patient population. Fasinumab was well tolerated by most patients, with a clear dose-dependent increase in joint-related abnormalities. The observation that the efficacy of lower doses was similar to that of higher doses but was associated with lower rates of arthropathy demands that future studies explore the benefit versus risk at these lower doses of fasinumab. When lifestyle modification and drug treatment do not work, surgery is needed. Arthroscopy is a minimally invasive surgery for eliminating meniscal tears and debridement of loose articular cartilage and it is one of the most prevalent surgeries (Chang et al., 2012; Kloppenburg et al., 2019). Nonspecific treatment for OA is not suggested because of the multiple factors that influence success rates (Hellio le Graverand et al., 2013; Stevens et al., 2019; Conaghan et al., 2020; Eckstein et al., 2020). Knee replacement surgery has been performed consistently for more than four decades. Because severe arthritis of the knee usually affects only one compartment, it can be treated with either unicompartmental (UKA) or complete knee arthroplasty (TKA). UKA has a speedier recovery, fewer problems, and better function (Balanescu et al., 2014; Pelletier et al., 2015; Dakin et al., 2019). While TKA is only used as a last resort for patients with OA. TKA is typically advised for older patients who have terrible knee pain, unacceptable activity limitations that result in the loss of important activities, and severe end-stage OA of the joint (Song et al., 2018).

Table 2 is a summary of properties of the above pharmaceutical reagents.

As a topical disease, innovative delivery options such as intra-articular injection or transdermal delivery have been extensively researched in addition to the traditional oral and systemic administration routes. Many biomaterials have been investigated for the design of novel drug delivery systems for the treatment of OA to improve the efficacy of the delivery vehicles.

Oral delivery is still the most common approach in drug administration for OA (Sastry et al., 2000; Sant et al., 2012). However, oral distribution is hampered by physiological hurdles such as the harsh gastrointestinal environment, as well as enzymatic degradation and tolerance, which make it difficult to use oral delivery methods in clinical settings (Homayun et al., 2019). For example, the most popular and traditional therapy for OA pain relief is NSAIDs. However, NSAIDs have a number of serious adverse effects, including toxicity and a severe gastrointestinal response (Meng and Li, 2017; Polderman et al., 2019). Improved oral administration such as by the nano or micro formulations can enhance medication absorption with long effects and lessen gastrointestinal side effects and frequent administrations. For example, HA-Liposomal (Lipo)-DIC has been shown to achieve an effective working concentration in 4 h and maintain it for at least 168 h (Chang et al., 2021).

As a localized disease, OA may be treated through intra-articular (IA) injections (Gerwin et al., 2006). Intra-articular drug delivery offers a variety of advantages, including higher local bioavailability, less systemic exposure, fewer side effect, and lower cost (Evans et al., 2014; Emami et al., 2018). However, because of the dense avascular cartilage matrix made up of negatively charged glycosaminoglycans (GAGs), medicines injected locally will quickly leave the joint region and disperse and travel slowly. The need for biomaterial-based drug delivery vehicles that can increase medication bioavailability in target tissues notwithstanding the challenges (Maudens et al., 2018). IA injectable formulations of glucocorticoids and hyaluronic acid are available (Zhang et al., 2020b). And the majority of them are in the form of solutions or suspensions. Due to the fast disappearance of classic injectable formulations in joints, new drug delivery methods are expected to be developed yet.

Microspheres can not only protect pharmaceuticals in vivo from numerous causes but also slow down their release. It reduces delivery durations and doses while avoiding the harmful side effects of systemic absorption, providing essential theoretical support for OA research and therapy. Triamcinolone acetonide (TAA), a traditional corticosteroid, relieves synovitis and discomfort, but only temporarily. Local release of TAA based on biomaterials may extend pain relief without the need for numerous injections (Burt et al., 2009).

Scholars discovered that hyaluronic acid nanoparticle/hydrogel (HA-NP) exhibited resistance to hyaluronidase digestion in vitro and long-term retention ability in the knee joint in vivo. The injectable hydrogel-based drug delivery system-dexamethasone hydrogels have a consistent release profile from the start, with a content of 22 percent of the original medication released in 5 days. Furthermore, these drug delivery methods are less cytotoxic and support good cell viability in chondrocytes and osteoblast cells. Intra-articular injection can reduce gastrointestinal reactions, avoid the first-pass effect, and ensure that drugs can be delivered to the articular cavity. However, intra-articular injection needs to puncture the skin, which is invasive and may cause inflammation and bring secondary damage to OA patients. What’s more, 50% of the clinical intra-articular injections will be injected outside the joint cavity. Therefore, it is still necessary to develop new delivery systems to prolong the drug retention time in the joint and reduce the frequency of drug delivery. Above all, Figure 3 have shown oral and intra-articular delivery systems for OA.

OA is a localized disease that often occurs in the knee, hand and hip joints. Therefore, skin penetration-based topical administration may commonly meet the needs of OA treatment. Transdermal drug administration can allow the medication to enter circulation at a steady pace and continuously via the skin. Compared to the oral route or intra-articular injection, transdermal administration offers a number of benefits (Prausnitz and Langer, 2008). Transdermal administration can minimize administration frequency, improve slow-release effectiveness, and improve patient compliance (Yin and Smith, 2016; Brown and Williams, 2019). However, the stratum corneum, which functions as the first protective layer of the skin and limits medication absorption, poses the biggest obstacle in drug administration via the transdermal method (Hadgraft and Lane, 2005). To enhance the skin penetration of drugs, various physical and chemical means of promoting permeation have been attempted for transdermal delivery of OA drugs.

Numerous chemical enhancers are capable of disrupting the highly ordered bilayer structures of intracellular lipids found in the stratum corneum by inserting amphiphilic molecules into these bilayers to disrupt molecular packing or by extracting lipids using solvents and surfactants to create nanometer-scale lipid packing defects (Prausnitz and Langer, 2008). However, the most significant limitation of this technique is that skin irritation may induce allergic responses in individuals. Iontophoresis is another technique for improving transdermal penetration by supplying an electrical driving force. Due to the fact that iontophoresis does not affect the epidermal barrier directly, it is often applied to tiny charged molecules and certain macromolecules up to a few thousand Daltons (Kalia et al., 2004).

Cavitational ultrasound that uses the bubbles to oscillate and collapse at the skin surface to generate localized shock waves and liquid microjets directed at the stratum corneum induces the disruption in the lipid structure of the stratum corneum and can increase skin permeability for many hours. Additionally, thermal effects from ultrasound have been suggested to impact sonophoretic skin contact favorably by increasing the drug diffusion and the skin permeability coefficients (Canavese et al., 2018; Park et al., 2016).

Articular thermotherapy induces vasodilation and increases blood flow around the joints, thereby reducing pain and joint stiffness (Choi et al., 2015). Besides this, heaters can also help drugs cross the skin. When the thermos therapy is applied, solubility and diffusivity of inorganic and organic drugs increase from the drug-containing layer (Bagherifard et al., 2016). Transdermal drug permeation is increased by the application of heat, which enhances the circulation of bodily fluid, the permeability of blood vessel walls, and the rate-limiting membrane permeability (Lee et al., 2018).

Microneedles are tiny and cheap needles that can carry medications through the skin in the least invasive way (HS et al., 2014; Kennedy et al., 2017). Furthermore, microneedles allow for the regulated and sustained release of medications based on the demands of the patients. Microneedles, in general, could increase skin permeability by creating micron-scale pathways into the skin, and actively drive drugs into the skin either as coated or encapsulated cargo introduced during microneedle insertion or via convective flow through hollow microneedles. Skin penetration enhancement strategies are shown in Figure 4. And we have summarized the advantages and disadvantages between different delivery systems in Table 4.