Treating cartilage damage is challenging as its ability for self-regeneration is limited. Left untreated, it can progress to osteoarthritis (OA), a joint disorder characterized by the deterioration of articular cartilage and other joint tissues. Surgical options, such as microfracture and cell/tissue transplantation, have shown promise as techniques to harness the body’s endogenous regenerative capabilities to promote cartilage repair. Nonetheless, these techniques have been scrutinized due to reported inconsistencies in long-term outcomes and the tendency for the defects to regenerate as fibrocartilage instead of the smooth hyaline cartilage native to joint surfaces. Orthobiologics are medical therapies that utilize biologically derived substances to augment musculoskeletal healing. These treatments are rising in popularity because of their potential to enhance surgical standards of care. More recent developments in orthobiologics have focused on the role of exosomes in articular cartilage repair. Exosomes are nano-sized extracellular vesicles containing cargo such as proteins, lipids, and nucleic acids, and are known to facilitate intercellular communication, though their regenerative potential still needs to be fully understood. This review aims to demonstrate the advancements in cartilage regeneration, highlight surgical and biological treatment options, and discuss the recent strides in understanding the precise mechanisms of action involved.

Fisetin is a natural flavonoid that possesses antioxidant, anti-inflammatory, anti-senescence, and neuroprotective effects in preclinical studies. This double-blind randomized clinical trial investigated the effects of two fisetin dosing regimens on senescent gene expression in peripheral blood mononuclear cells (PBMCs) in elderly humans (> 55 years old). Participants were randomized to Daily dose (100mg/day, N = 41) or Bolus dose (20mg/kg for two consecutive days on and 28 days off, N = 40) for 60 days. Blood draw, PBMC isolation, RNA extraction and quantitative polymerase chain reaction (Q-PCR) for 5 target genes were performed at baseline, and days 15, 35, 45 and 60. At the primary endpoint, day 45, both fisetin dosing regimens significantly decreased galactosidase beta 1 (GLB1) and P16 ^INK4A (P16) gene expression. Bolus dose also significantly reduced macrophage migration inhibition factor (MIF) and alpha-L-fucosidase 1 (FUCA1) compared to baseline and decreased MIF compared to daily dose. Further, Bolus dose significantly decreased GLB1 and MIF at days 15, 35, 60, and P16 at days 15, 35 as well as FUCA1 at day 35 compared to baseline. Hence, Bolus dosing of fisetin is more effective than Daily dosing for reducing cellular senescent genes in PBMCs isolated from elderly human blood.