Plantar Fasciitis Pathophysiology and the Potential Role of Mesenchymal Stem Cell-Derived Extracellular Vesicles as Therapy

Abstract

Plantar fasciitis is a common condition characterized by inflammation and degeneration of the plantar fascia, leading to heel pain and reduced mobility. Affecting both athletic and non-athletic populations, it is a leading cause of foot-related medical visits. Conservative treatments, including rest, physical therapy, and corticosteroid injections, provide relief for most patients, but a subset experiences persistent symptoms requiring advanced therapies. Emerging biologic treatments, such as platelet-rich plasma (PRP) and mesenchymal stem/stromal cell (MSC) therapy, have demonstrated potential in promoting tissue regeneration and reducing inflammation. Recently, MSC-derived extracellular vesicles (MSC-EVs) have gained attention for their regenerative properties, offering a promising, cell-free therapeutic approach. EVs mediate tissue repair through immunomodulation, anti-inflammatory signaling, and extracellular matrix stabilization. Preclinical studies suggest that EV therapy may improve tendon and ligament healing by promoting M2 macrophage polarization, inhibiting excessive metalloproteinase activity, and enhancing vascular remodeling. This review explores the potential of MSC-EVs as an innovative, non-surgical treatment for plantar fasciitis, addressing their mechanisms of action and current evidence in musculoskeletal regeneration.

Keywords: biologics; extracellular vesicles; mesenchymal stem/stromal cells; plantar fasciitis.

Figure 1

Conservative treatments remain the first-line approach for plantar fasciitis and include NSAIDs, stretching, orthotics, and physical therapy. In cases resistant to conservative measures, advanced therapies such as ESWT, MSC-EVs, and PRP injections may be utilized and prevent the necessity of surgical intervention. NSAIDS = non-steroidal anti-inflammatory drugs; ESWT = extracorporeal shockwave therapy; MSC-EVs = mesenchymal stem/stromal cell-derived extracellular vesicles; PRP = platelet-rich plasma.

Figure 2

Extracellular vesicles (EVs) contain a diverse cargo, including proteins, growth factors, and nucleic acids. They can be engineered to deliver specific therapeutic molecules to target tissues, offering anti-inflammatory, antifibrotic, and pro-angiogenic effects. Engineered EVs have been shown to degrade substance P via CD10, contributing to analgesic outcomes.

Figure 3

Emerging role of mesenchymal stem/stromal cell-derived extracellular vesicles (MSC-EVs) in pathophysiology and treatment of plantar fasciitis.