Targeted treatment for osteoarthritis: drugs and delivery system

Figures & data

Figure 1. Risk factors of OA prevalence alone with the rising of age.

Figure 2. Schematic representation of healthy knee joint structure and pathological changes of knee osteoarthritis.

Figure 3. Non-pharmaceutical strategies of OA.

Table 1. NSAIDs and delivery system in OA treatment.

Drugs	Delivery system	Physical properties	In vitro findings	Rat model	In vivo performance	Refers
Lnx	PLGA MS	None	None	4% papain induce	Low circulating concentration; long drug retention; biocompatibility safe; reduce joint swelling; histological improvement	Zhang & Huang (2012)
	Chitosan/TPP MS	Particle size (L9): 5.4 µm; EE%: 59.5%	pH and particle size dependent; Sustained release over 8days	3mg/50µl MIA induce	Prolongation of retention time; reduce joint swelling; inhibit IL6; histological improvement	Abd-Allah et al. (2016)
Mlx	CMC-MC-P hydrogels NPs	EE% (N2): 87.5%; Low degradation and swelling behavior	Sustained release: 85-97% after 37days; Promote proliferation and adhesion of chondrocytes	None	None	Fattahpour et al. (2020)
Clx	Acetyl-capped PCLA-PEG-PCLA thermogels	Thermosensitive gel (37 °C)	Sustained release in 90 days	Healthy	Sustained release 4–8 weeks; biocompatibility safe	Petit et al. (2014)
	PEA MS	Particle size: 10–100 µm	More degradation of PEA in inflammatory environment; Sustained release: over 80days	ACLT and pMMx surgery	Biocompatibility safe; sustained release over 12 weeks; reduce degradation of PEA; no cartilage pathology difference	Janssen et al. (2016)
	PEA MS	Average molecular weight: 70 kDa	Sustained release over 28 days	ACLT and pMMx surgery	Dose-dependently release over 120 hours; subchondral bone protection, osteophyte reduction, histological improvement	Tellegen et al. (2018)
	PDLLA MP	20 to 40 μm mean size; 10% to 50% w/w drug loading; EE%> 80%	Sustained release over 90 days; inhibit PGE2 release	None	None	Salgado et al. (2020)
Dcf	PLL/PGA-TriEG	Dfc loading densities: 295 μg/mm3 (30wt%) (40 bilayers); Thickness: 2.7 ± 0.5 μm	Sustained release over 14 months; inhibition of COX-1	None	None	Hsu et al. (2014)
	PEG-ELDI-PHB‐MG co‐monomer	Dfc loading: 38 w/w%	Sustained release 50–120 days	None	None	Sulistio et al. (2017)
	νPVCL nanogel	pH-dependent nanogel size; Temperature sensitive swelling	Temperature-responsive release; sustained release over 24 h at 32 °C	None	None	Zavgorodnya et al. (2017)
	PNIPAM-PMPC nanospheres	Average diameter: 237 ± 97.9; Zeta potential: −16.7 mV; EE%: 41.7%; LC%: 11.1%	Temperature-responsive: 66.8% and 73.4% release with 24 h and 72 h, 81.2% and 87.5% at 37 °C; lubrication; biocompatible, no cytotoxicity and chondroprotective	None	None	Zhang et al. (2020)
	ATP Hybrid-PPR Hydrogel	EE%: 77.3% to 96.4%	Good biocompatibility Sustained release 70%–90% over 4 days	100 µL of carrageenan solution (1%) induced	Prolong retention time to 7 days; Histological improvement	Ha et al. (2021)
Ecx	PCL MP; PCL-CICG MP	Average size: 16.26 ± 10.14 μm; EE%: 83.7 ± 3.27%; LC%: 2.67 ± 0.11%	Controlled release for 28 days; Bio-safe	Healthy	Prolong the retention time to 4 weeks in the synovia	Arunkumar et al. (2016)
	PLGA-PEG-PLGA NPs	Average diameter: 339 nm; Zeta potential: 1.68 ± 0.85 mV	Sustained release over 30 days; Bio-safe	ACLT surgery	Maintain ECM; histological improvement; subchondral bone protection	Liu et al. (2019)
	PLA- chitosan NPs	Smallest size: 420.30 ± 40.16 nm; Zeta potential: 25.95 ± 1.34mv; EE%: 92.15 ± 0.78%	Quick release after first 2 h, sustained release over 28 days; RE%: 55.02%; enhancing the proliferation of MC3T3-E1 cells; enhancing ALP activity and calcium ion concentration	None	None	Salama et al. (2020)
Kpf	UiO-66 metal-organic framework	Particle size: 30-50nm; Loading amount: 38w%	Quick release at the beginning 12 h, slow release in next 60 h; RE%: 65w%; Bio-safe	None	None	Li et al. (2019)

Abbreviations: Lnx: Lornoxicam; MS: microspheres; MP: microparticles; PLGA: Poly (lactic-co-glycolic acid); TPP: tripolyphosphate; EE%: entrapment efficiency%; MIA: monosodium iodoacetate; Mlx: Meloxicam; CMC-MC-P: carboxymethyl chitosan-methylcellulose-pluronic; Clx: Celecoxib; PCLA: poly(ε-caprolactone-co-lactide); PCLA-PEG-PCLA: poly(ε-caprolactone-co-lactide)-b-poly(ethylene glycol)-b-poly(ε-caprolactone-co-lactide); PEA: polyester amide; ACLT: anterior cruciate ligament transection; pMMx: partial medial meniscectomy; PDLLA: poly D,L-Lactic Acid; Dcf: Diclofenac; PLL: poly(l-lysine); PGA: poly (l-glutamic acid); TriEG: triethylene glycol; PHB: p-hydroxybenzoate; ELDI: ethyl‐L‐lysine diisocyanate; MG: monoglyceride; PVCL: poly(N-vinylcaprolactam); PNIPAM-PMPC: poly[N-isopropylacrylamide-2-methacryloyloxyethyl phosphorylcholine]; LC: loading capacity; ATP: attapulgite; PPR: pseudopolyrotaxane; Ecx: Etoricoxib; PCL: Poly caprolactone; CICGs: composite injectable Chitosan gel; ECM: extracellular matrix; RE: release efficiency.

Table 2. Cartilage protector and delivery system in OA treatment.

Drugs	Delivery system	Physical properties	In vitro findings	Rat model	In vivo performance	Refers
Dcn	SLN	Particle size: 382 ± 16 nm; Zeta potential: −1966 ± 21 mv TDC (%): 985 ± 02%	Sustained-release up to 12 h	Healthy	Anti-diarrhoeal; enhanced oral bioavailability;	Jain et al. (2013)
	SLNs-GNPs	Particle size: 6.9–9.7 nm; EE%: 79–97%; Zeta potential: −22.7– −38.6 mv	Thermoresponsive release; Sustained-release up to 72 h	None	None	Rehman et al. (2015)
	Glc-TPGS self-nanoemulsifying DDS	Uniform and homogeneous surface; Crystalline anhydrous nature; Drug stability	Enhanced drug release	0.1 mL of 1% w:v λ-carrageenan	Edema and inflammation inhibition; histopathological improvement; TNF-α and caspase-3 inhibition	Eltobshi et al. (2018)
	Niosomal gel- 3% HPMC	Particle size: 7.33- 23.72µm; EE%: 9.52%- 58.43%	Sustained-release up to 8 h	0.1 ml of 1% carrageenan	Edema and inflammation inhibition	El-Say et al. (2016)
	PLGA NPs	Particle sizes: 200– 320 nm; Loading efficiency: 81.76 ± 3.26% DIA (1%) and 80.85 ± 7.51% DIA (5%)	Sustained release up to 63 days; non-toxic; Inhibit IL-1, IL-6, TNF-α, MMP-3, MMP-13, COX-2, and ADAMTS-5	50 μL of 10 mg/mL MIA	Histological improvement; cartilage protection; inhibit inflammation	Jung et al. (2020)
	EA-based vesicular nanocarriers	EE%: 96.25 ± 2.19%; Particle sizes: 506.35 ± 44.61 nm; Zeta potential: −38.65 ± 0.91 mV	Sustained-release up to 8 h;	Transdermal delivery	Biocompatibility safe;	Aziz et al. (2018)
Rhein	PLGA MP	Mean diameter: 4.23 ± 0.87 μm; EE%: 63.8 ± 3.0%; Loading efficiency: 1.60 ± 0.07%; Zeta potential: −21.4 mV	Sustained-release up to 30 days; noncytotoxic; inhibit IL1β, TNFα and ROS	None	None	Gómez-Gaete et al. (2017)
CS	PLGA MS	Particle sizes: 75–500 μm; EE%: 70–80%	Microsphere size-dependent release; multiple burst release noncytotoxic	None	None	Jiang et al. (2011)
	Au-NPs	Average particle size: 13nm	Promote cell proliferation; Increase GAG and collagen production	None	None	Dwivedi et al. (2015)

Abbreviations: Dcn: Diacerein; SLN: solid lipid nanoparticles; GNPs: gold nanoparticles; Glc: gelucire; TPGS: d-α-tocopheryl polyethylene glycol 1000 succinate; HPMC: hydroxypropylmethyl cellulose; ROS: reactive oxygen species; EA: edge activator; CS: chondroitin sulfate; Au: gold.

Table 3. Novel drug molecules and delivery system in OA treatment.

Drugs	Delivery system	Physical properties	In vitro findings	Rat model	In vivo performance	Refers
rhSDF-1α	Fibrin/hyaluronic acid hydrogel	None	Sustained-release up to 14 days; biocompatible; recruit chondrogenic progenitor cell; regeneration of cartilage tissue	None	None	Yu et al. (2015)
IGF-1	PAMAM dendrimers	Generation 6: 58 kDa	No histotoxicity	ACLT + MMx surgery	Penetrate cartilage; Sustained-release 30.4 days; rescue cartilage degeneration; reduces osteophyte formation	Geiger et al. (2018)
BMP2	GO flakes	Most abundant size: 1,598.5 nm	Sustained-release up to 40 days; inhibit inflammation; promote differentiation	ACLT surgery	Histological improvement; inhibit inflammation	Zhong et al. (2017)
TGF-β3	GO 3D nano-scaffold	Average size 10–40 μm; drug adsorb >99 %	Sustained-release up to 28 days; no cytotoxicity; promote chondrogenic differentiation	None	None	Zhou et al. (2019)
Glutathione	Chitosan-gelatin based hydrogel	Pore size: 1.667 μm	No cytotoxicity; sustained-release up to 48 h; rescue oxidative damage; down-regulate inflammation	None	None	Cheng et al. (2017)
KGN	PEG-PAMAM	Average size: 33.3– 36.4 nm; drug loading: 5.50 ± 0.23 (wt. %); Zeta potentials: +5 mV	Low cytotoxicity; promote chondrogenic differentiation and ECM production;	Healthy and 4% papain injection	Sustained-release up to 21 days	Hu et al. (2017)
	NPPs	Average size: 320 nm; drug loading: 31.5% (w/w)	Sustained release 62% drug in 3 months; bio-safe	DMM surgery	Histological improvement; cartilage protection; inhibit inflammation	Maudens et al. (2018)
	3D Tri-Copolymer Scaffolds	Mean pore size: 20 to 30 µm	Up-regulate Acan, Sox9, and Col2a1; Low cytotoxicity; improve chondrogenesis	None	None	Chen et al. (2021)
TPCA-1	Nanosomes	Average size: 50–200 nm	Low cytotoxicity; inhibit NO, LDH, PGE2, EPAS-1, MMP-13, ACAN and COL2A1	None	None	Bhatti et al. (2019)
Adenosine	PLA-b-PEG NPs	Diameter size: 129–144 nm	None	ACLT surgery	Inhibit NF-kb activation; chondroprotective; histological improvement	Liu et al. (2019)
HCQ	CMFn nanocages	Diameter:22 nm; loading ratio: 48%; embedding ratio: 5%	MMP-13/pH-responsive release; low cytotoxicity; increase Col2a1 and decrease inflammatory factors	None	None	Chen et al. (2019)

Abbreviations: rhSDF-1α): Human stromal cell-derived factor 1α; PAMAM: Amine terminal polyamidoamine; GO: Graphene oxide; KGN: Kartogenin; NPPs; nanocrystal–polymer particles; TPCA-1: [5-(p-Fluorophenyl)-2-ureido] thiophene-3-carboxamide; LDH: lactic dehydrogenase; PGE2: Prostaglandin E2; HCQ: hydroxychloroquine; CMFn: ferritin nanocages; DMM: Destabilization medial meniscus.

Table 4. Chinese herb extracts and gene delivery in OA treatment.

Drugs	Delivery system	Physical properties	In vitro findings	Rat model	In vivo performance	Refers
Curcumin	Gelatin/silk fibroin microspheres	EE%: 55–59%; Low degradation	Low degradation; SUSTAINED release over 14 days	50 µl of MIA (60 mg/ml)	Inhibit development of OA; Histological improvement	Ratanavaraporn et al. (2017)
PSO	MRC-PPL NPs	Average size: 121.5 ± 26.1 nm Zeta potential: −5.75 mV; Loading percentage: 16.9%	pH responsive release; No cytotoxicity with 15 μM PSO; Increase Col2a1 and decrease MMP-13 and TNF-α	Papain solution (8% W/V) and l-cysteine (0.03 mol/L)	Sustained-release up to 21 days; low organ uptake; cartilage protection; reduce osteophyte; histological improvement	Lan et al. (2020)
Hes	PDA-Gd2(CO3)3 NPs	Loading percentage: 9.32%; anchoring efficiency: 67.86 %	Nontoxic; cartilage affinity; attenuate apoptosis and inflammation; inhibit TLR-2 and NF-κB/Akt	ACLT surgery	MR suitability; low organ uptake; biocompatibility and low cytotoxicity; histological improvement	Ouyang et al. (2019)
mASOs	PEG-SWCNT-anti-GFP	An average value of hm: 3.1 ± 1.2 nm	None	DMM surgery	Inhibit development of OA; prolonged retention time; enter the ECM; deliver gene into chondrocytes	Sacchetti et al. (2014)
Ihh	Lipid NPs	EE%: above 95%; diameters: 67 ± 4.3 nm;	Excellent penetration; low cytotoxicity;	Healthy and ACLT surgery	Inhibit Ihh expression; increase anabolic factors; attenuate OA pathogenesis	Thompson et al. (2015)
antimiR-221	fibrin/HA hydrogel	None	Sustained release over 14 days; miR-221 knockdown in 7 days; increase anabolic factors	Osteochondral biopsy	Enhanced cartilage repair	Lolli et al. (2019)
NF-κB p65 siRNA	Self-assembling peptidic NPs	Average size: 55 ± 18 nm; zeta potential: 12 ± 0.7 mV	Suppresses p65; preserve chondrocyte viability; maintains cartilage homeostasis	None	None	Yan et al. (2019)

Abbreviations: PSO: psoralidin; MR-PPL: MR-Cy5.5-BHQ-3-PPL; Gd2(CO3)3: PDA: polydopamine; Hes: Hesperetin; SAA: Salvianolic acid A; SWCNTs: single-walled carbon nanotubes; anti-GFP: anti-green fluorescent protein; Ihh: Indian Hedgehog.

Zhang Z, Huang G. (2012). Intra-articular lornoxicam loaded PLGA microspheres: enhanced therapeutic efficiency and decreased systemic toxicity in the treatment of osteoarthritis. Drug Deliv 19:255–63.

 PubMed Web of Science ®Google Scholar

Abd-Allah H, Kamel AO, Sammour OA. (2016). Injectable long acting chitosan/tripolyphosphate microspheres for the intra-articular delivery of lornoxicam: optimization and in vivo evaluation. Carbohydr Polym 149:263–73.

 PubMed Web of Science ®Google Scholar

Fattahpour S, Shamanian M, Tavakoli N, et al. (2020). An injectable carboxymethyl chitosan-methylcellulose-pluronic hydrogel for the encapsulation of meloxicam loaded nanoparticles. Int J Biol Macromol 151:220–9.

 PubMed Web of Science ®Google Scholar

Petit A, Sandker M, Müller B, et al. (2014). Release behavior and intra-articular biocompatibility of celecoxib-loaded acetyl-capped PCLA-PEG-PCLA thermogels. Biomaterials 35:7919–28.

 PubMed Web of Science ®Google Scholar

Janssen M, Timur UT, Woike N, et al. (2016). Celecoxib-loaded PEA microspheres as an auto regulatory drug-delivery system after intra-articular injection. J Control Release 244:30–40.

 PubMed Web of Science ®Google Scholar

Tellegen AR, Rudnik-Jansen I, Pouran B, et al. (2018). Controlled release of celecoxib inhibits inflammation, bone cysts and osteophyte formation in a preclinical model of osteoarthritis. Drug Deliv 25:1438–47.

 PubMed Web of Science ®Google Scholar

Salgado C, Guénée L, Černý R, et al. (2020). Nano wet milled celecoxib extended release microparticles for local management of chronic inflammation. Int J Pharm 589:119783.

 PubMedGoogle Scholar

Hsu BB, Park MH, Hagerman SR, Hammond PT. (2014). Multimonth controlled small molecule release from biodegradable thin films. Proc Natl Acad Sci U S A 111:12175–80.

 PubMed Web of Science ®Google Scholar

Sulistio A, Reyes-Ortega F, D’Souza AM, et al. (2017). Precise control of drug loading and release of an NSAID-polymer conjugate for long term osteoarthritis intra-articular drug delivery. J Mater Chem B 5:6221–6.

 PubMed Web of Science ®Google Scholar

Zavgorodnya O, Carmona-Moran CA, Kozlovskaya V, et al. (2017). Temperature-responsive nanogel multilayers of poly(N-vinylcaprolactam) for topical drug delivery. J Colloid Interface Sci 506:589–602.

 PubMed Web of Science ®Google Scholar

Zhang K, Yang J, Sun Y, et al. (2020). Thermo-sensitive dual-functional nanospheres with enhanced lubrication and drug delivery for the treatment of osteoarthritis. Chemistry 26:10564–74.

 PubMed Web of Science ®Google Scholar

Ha W, Wang ZH, Zhao XB, Shi YP. (2021). Reinforced supramolecular hydrogels from attapulgite and cyclodextrin pseudopolyrotaxane for sustained intra-articular drug delivery. Macromol Biosci 21:e2000299.

 PubMed Web of Science ®Google Scholar

Arunkumar P, Indulekha S, Vijayalakshmi S, Srivastava R. (2016a). Synthesis, characterizations, in vitro and in vivo evaluation of etoricoxib-loaded poly (caprolactone) microparticles – a potential intra-articular drug delivery system for the treatment of osteoarthritis. J Biomater Sci Polym Ed 27:303–16.

 PubMed Web of Science ®Google Scholar

Liu P, Gu L, Ren L, et al. (2019). Intra-articular injection of etoricoxib-loaded PLGA-PEG-PLGA triblock copolymeric nanoparticles attenuates osteoarthritis progression. Am J Transl Res 11:6775–89.

 PubMed Web of Science ®Google Scholar

Salama AH, Abdelkhalek AA, Elkasabgy NA. (2020). Etoricoxib-loaded bio-adhesive hybridized polylactic acid-based nanoparticles as an intra-articular injection for the treatment of osteoarthritis. Int J Pharm 578:119081.

 PubMed Web of Science ®Google Scholar

Li L, Yang X, Yang L, et al. (2019). Biomechanical analysis of the effect of medial meniscus degenerative and traumatic lesions on the knee joint. Am J Transl Res 11:542–56.

 PubMed Web of Science ®Google Scholar

Jain A, Singh SK, Singh Y, Singh S. (2013). Development of lipid nanoparticles of diacerein, an antiosteoarthritic drug for enhancement in bioavailability and reduction in its side effects. J Biomed Nanotechnol 9:891–900.

 PubMed Web of Science ®Google Scholar

Rehman M, Madni A, Ihsan A, et al. (2015). Solid and liquid lipid-based binary solid lipid nanoparticles of diacerein: in vitro evaluation of sustained release, simultaneous loading of gold nanoparticles, and potential thermoresponsive behavior. Int J Nanomed 10:2805–14.

 PubMed Web of Science ®Google Scholar

Eltobshi AA, Mohamed EA, Abdelghani GM, Nouh AT. (2018). Self-nanoemulsifying drug-delivery systems for potentiated anti-inflammatory activity of diacerein. IJN 13:6585–602.

 Google Scholar

El-Say KM, Abd-Allah FI, Lila AE, et al. (2016). Diacerein niosomal gel for topical delivery: development, in vitro and in vivo assessment. J Liposome Res 26:57–68.

 PubMed Web of Science ®Google Scholar

Jung JH, Kim SE, Kim HJ, et al. (2020). A comparative pilot study of oral diacerein and locally treated diacerein-loaded nanoparticles in a model of osteoarthritis. Int J Pharm 581:119249.

 PubMed Web of Science ®Google Scholar

Aziz DE, Abdelbary AA, Elassasy AI. (2018). Fabrication of novel elastosomes for boosting the transdermal delivery of diacerein: statistical optimization, ex-vivo permeation, in-vivo skin deposition and pharmacokinetic assessment compared to oral formulation. Drug Deliv 25:815–26.

 PubMed Web of Science ®Google Scholar

Gómez-Gaete C, Retamal M, Chávez C, et al. (2017). Development, characterization and in vitro evaluation of biodegradable rhein-loaded microparticles for treatment of osteoarthritis. Eur J Pharm Sci 96:390–7.

 PubMed Web of Science ®Google Scholar

Jiang T, Petersen RR, Call G, et al. (2011). Development of chondroitin sulfate encapsulated PLGA microsphere delivery systems with controllable multiple burst releases for treating osteoarthritis. J Biomed Mater Res B Appl Biomater 97:355–63.

 PubMedGoogle Scholar

Dwivedi P, Nayak V, Kowshik M. (2015). Role of gold nanoparticles as drug delivery vehicles for chondroitin sulfate in the treatment of osteoarthritis. Biotechnol Prog 31:1416–22.

 PubMed Web of Science ®Google Scholar

Yu Y, Brouillette MJ, Seol D, et al. (2015). Use of recombinant human stromal cell-derived factor 1α-loaded fibrin/hyaluronic acid hydrogel networks to achieve functional repair of full-thickness bovine articular cartilage via homing of chondrogenic progenitor cells. Arthritis Rheumatol 67:1274–85.

 PubMed Web of Science ®Google Scholar

Geiger BC, Wang S, Padera RF, Jr, et al. (2018). Cartilage-penetrating nanocarriers improve delivery and efficacy of growth factor treatment of osteoarthritis. Sci Transl Med 10:eaat8800.

 PubMed Web of Science ®Google Scholar

Zhong C, Feng J, Lin X, Bao Q. (2017). Continuous release of bone morphogenetic protein-2 through nano-graphene oxide-based delivery influences the activation of the NF-κB signal transduction pathway. IJN Volume 12:1215–26.

 Google Scholar

Zhou M, Lozano N, Wychowaniec JK, et al. (2019). Graphene oxide: a growth factor delivery carrier to enhance chondrogenic differentiation of human mesenchymal stem cells in 3D hydrogels. Acta Biomater 96:271–80.

 PubMed Web of Science ®Google Scholar

Cheng YH, Chavez E, Tsai KL, et al. (2017). Effects of thermosensitive chitosan-gelatin based hydrogel containing glutathione on Cisd2-deficient chondrocytes under oxidative stress. Carbohydr Polym 173:17–27.

 PubMed Web of Science ®Google Scholar

Hu Q, Ding B, Yan X, et al. (2017). Polyethylene glycol modified PAMAM dendrimer delivery of kartogenin to induce chondrogenic differentiation of mesenchymal stem cells. Nanomedicine 13:2189–98.

 PubMed Web of Science ®Google Scholar

Maudens P, Seemayer CA, Thauvin C, et al. (2018). Nanocrystal-polymer particles: extended delivery carriers for osteoarthritis treatment. Small 14.

 PubMed Web of Science ®Google Scholar

Chen CY, Li C, Ke CJ, et al. (2021). Kartogenin enhances chondrogenic differentiation of MSCs in 3D tri-copolymer scaffolds and the self-designed bioreactor system. Biomolecules 11.

 Web of Science ®Google Scholar

Bhatti FUR, Hasty KA, Cho H. (2019). Anti-inflammatory role of TPCA-1 encapsulated nanosomes in porcine chondrocytes against TNF-α stimulation. Inflammopharmacology 27:1011–9.

 PubMed Web of Science ®Google Scholar

Chen H, Qin Z, Zhao J, et al. (2019). Cartilage-targeting and dual MMP-13/pH responsive theranostic nanoprobes for osteoarthritis imaging and precision therapy. Biomaterials 225:119520.

 PubMed Web of Science ®Google Scholar

Ratanavaraporn J, Soontornvipart K, Shuangshoti S, et al. (2017). Localized delivery of curcumin from injectable gelatin/Thai silk fibroin microspheres for anti-inflammatory treatment of osteoarthritis in a rat model. Inflammopharmacology 25:211–21.

 PubMed Web of Science ®Google Scholar

Lan Q, Lu R, Chen H, et al. (2020). MMP-13 enzyme and pH responsive theranostic nanoplatform for osteoarthritis. J Nanobiotechnology 18:117.

 PubMed Web of Science ®Google Scholar

Ouyang Z, Tan T, Liu C, et al. (2019). Targeted delivery of hesperetin to cartilage attenuates osteoarthritis by bimodal imaging with Gd2(CO3)3@PDA nanoparticles via TLR-2/NF-κB/Akt signaling. Biomaterials 205:50–63.

 PubMed Web of Science ®Google Scholar

Sacchetti C, Liu-Bryan R, Magrini A, et al. (2014). Polyethylene-glycol-modified single-walled carbon nanotubes for intra-articular delivery to chondrocytes. ACS Nano 8:12280–91.

 PubMed Web of Science ®Google Scholar

Thompson CL, Patel R, Kelly TA, et al. (2015). Hedgehog signalling does not stimulate cartilage catabolism and is inhibited by Interleukin-1β. Arthritis Res Ther 17:373.

 PubMed Web of Science ®Google Scholar

Lolli A, Sivasubramaniyan K, Vainieri ML, et al. (2019). Hydrogel-based delivery of antimiR-221 enhances cartilage regeneration by endogenous cells. J Control Release 309:220–30.

 PubMed Web of Science ®Google Scholar

Yan H, Duan X, Pan H, et al. (2019). Development of a peptide-siRNA nanocomplex targeting NF- κB for efficient cartilage delivery. Sci Rep 9:442.

 PubMed Web of Science ®Google Scholar