Table 4.

Preclinical in vivo models studying models to increase n-3 PUFA bioavailability or intra-articular applications. Up arrows refer to increase and down arrows to decrease.

Molecule	In Vivo Model	Dose/Delivery Route	Main Effects	Specific Outcomes	Indications for Preventive-Therapeutic Strategies for ObOA	Ref.
RvD1	ObOA model: DMM model C57Bl/J6 mice + HFD (45 kcal% fat) vs. control diet (10 kcal% fat).	20 ng/μL (one week before and on weeks 1 and 6 after OA induction). IA injection	Protective role of IA injection of the pro-resolving RvD1 in modulating macrophage phenotype to counteract inflammation.	▪↓Cell density and thickness in the synovium; ▪↓ IL-1β, Cxcl10, TNF, IL6 and Ccr7 (M1 markers); ▪↓F4/80+CD11b+MHC II high; ▪↓ COL10, DIPEN, NITEGE; ▪↓ M1 in synovium; ▪↑ M2 polarization.	The potential of targeting macrophage phenotypes to prevent OA aggravation.	[161]
RvD1-loaded nano-liposomal formulation (Lipo-RvD1)	Post-traumatic OA model: DMM model in male C57BL/6 mice.	Liposomes (~1 mg per joint in a total volume of 10 μL). IA injection.	Lipo-RvD1 formulation could be a therapeutic candidate thanks to its anti-inflammatory and analgesic properties.	▪Liposomes increased the IA retention of RvD1; ▪↓ M1 macrophage; ▪↑ M2 macrophage; ▪↓ Osteophyte formation; ▪↓ Pain.	The potential of targeting macrophage phenotypes to prevent OA aggravation with analgesic effects.	[222]
RvD1	ObOA model: DMM model + HFD.	RvD1 encapsulated in liposomes (lipo-RvD1).	Improved joint health following the treatment with the lipo- than the free RvD1 treatment.	▪↓ Cartilage degradation; ▪↑ M2/M1 ratio in synovium.	The potential of lipo-RvD1 as an anti-OA agent.	[234]
MaR-1	Inflammatory model of OA: MIA model in Sprague–Dawley rats.	10 ng MaR-1 + 50 µL sterile saline (two treatments per week for 4 weeks). IA injection.	Chondroprotective effects in mitigating OA progression.	▪↑ Coll II; ▪↓ MMP13 in the synovium.	The potential of promoting cartilage repair.	[124]
Gelatin hydrogels with EPA	Post-traumatic OA: DMM model in mice.	Group 1—SHAM. Group 2—DMM. Group 3—DMM + corn oil. Group 4—EPA-I (DMM + corn oil and EPA). Group 5—control (DMM + gelatin hydrogels). Group 6—EPA-G (DMM + gelatin hydrogels containing EPA). IA injection.	Hydrogel incorporating EPA was more effective in attenuating the inflammatory effects underlying the progression of OA.	Gelatin hydrogels containing EPA were more potent compared with a single EPA injection through: ▪↓ M1 macrophage; ▪↓ CD86+ cells; ▪↓ F4/F80; ▪↓ IL-1β, p-IKK, MMP-13; ▪Gradual release of EPA (average of ~ 3 weeks).	IA administration of controlled-release EPA can be a new therapeutic approach to target inflammatory and catabolic markers also in patients with ObOA.	[235]
Seed oil (DSO) in niosomes	Carrageenan-induced paw oedema in rats.	0.5 g/kg DSO pure extract a day. i.p. injection.	Controlled release and therapeutic effective level of DSO niosomes in mitigating OA progression	▪Good stability, optimum entrapment efficiency and sustained release pattern; ▪↓ Inflammation.	Nanoparticles as a targeted delivery system can be a valuable tool for ObOA.	[236]
Cel-MEs@MNs (microemulsion-incorporated dissolving microneedle co-loading celecoxib and α-linolenic acid)	OA model.	Transdermal injection vs. oral administration of celecoxib and α-linolenic acid.	Synergistic anti-inflammation and potent transdermal delivery,	▪↓ Inflammatory cytokines; ▪↓ Cartilage damage, paw swelling; ▪M2 repolarization; ▪↓ M1 macrophages; ▪↓ Chondrocyte apoptosis; ▪↓ PGE-2.	Microemulsion with improved transdermal injection potency holds great potential in the solubilization of water-insoluble drugs.	[240]