Umbilical cord-derived mesenchymal stem cell secretome in combination therapy for acute ankle ligament injuries: a two-patient case series

Lateral ankle ligament injuries are common and can cause functional impairment. Although most low-grade injuries recover with structured conservative rehabilitation, adjunctive biologic approaches have been proposed to support tissue healing in selected patients. Mesenchymal stem cell-derived secretome has demonstrated regenerative and immunomodulatory potential, but clinical evidence for its use in ankle ligament injuries remains scarce. We describe two patients with acute ankle ligament injuries treated nonoperatively with structured rehabilitation and adjunctive umbilical cord-derived secretome. The first patient was a 19-year-old Indonesian male military cadet with high functional demands and a severe multi-ligament injury involving the anterior talofibular (ATFL), calcaneofibular (CFL), and posterior talofibular (PTFL) ligaments, whereas the second patient was a 37-year-old Indonesian female non-athlete with a milder grade I–II multi-ligament ankle sprain characterized by a partial ATFL tear and associated sprain-related abnormalities of the CFL, PTFL, and deltoid ligament components. Both patients underwent initial conservative treatment consisting of ankle immobilization, protected weight-bearing, swelling control, and progressive rehabilitation. Umbilical cord-derived secretome was administered as two peri-ligamentous injections of 3 mL each, at 2 and 3 months after injury, with a 1-month interval between injections. Clinical outcomes were assessed at baseline and at 3, 6, and 9 months after injury. Despite differences in injury severity and functional demands, both patients showed progressive improvement in pain, ankle range of motion, and functional scores throughout the 9-month follow-up. The 3-month assessment represented an early rehabilitation milestone during completion of the injection protocol, while the 6- and 9-month assessments reflected later follow-up after completion of the two-injection protocol and rehabilitation. AOFAS scores improved from 55 at baseline to 93 at 9 months in the first patient and from 64 to 95 in the second patient. Pain scores progressively decreased, ankle range of motion improved, and both patients returned to activity without recurrence or major complications. One patient experienced transient mild fever after the second injection, which resolved spontaneously. Umbilical cord-derived secretome combined with structured rehabilitation was associated with favorable functional recovery in these two patients with ankle ligament injuries of differing severity. However, because this report included only two patients and lacked a comparator group, the observed improvements cannot be attributed independently to secretome therapy and may also reflect natural healing and rehabilitation. Further controlled studies are warranted to evaluate its clinical efficacy.