**Background:** Adipose-derived stem cells (ADSCs) have emerged as a leading candidate in regenerative medicine due to their easy accessibility via liposuction, multipotency, and robust paracrine activity. First isolated in 2001 from the stromal vascular fraction of adipose tissue, ADSCs are mesenchymal stem cells (MSCs) that can differentiate into adipogenic, osteogenic, chondrogenic, and even non-mesenchymal lineages. Their therapeutic potential extends beyond cell replacement to include angiogenesis, anti-apoptosis, and immunomodulation through secreted factors. However, translating ADSC-based therapies into clinical practice faces challenges, including concerns about tumorigenicity, variability in cell quality due to donor and isolation differences, and lack of standardized protocols. This review provides an update on recent advancements and strategies to overcome these limitations.
**Methods:** This is a narrative review summarizing the current literature on ADSCs in regenerative medicine. The authors discuss the therapeutic potential of ADSCs, current challenges, and novel strategies such as cell-free therapy using the ADSC secretome (including exosomes, microvesicles, and apoptotic bodies), 3D bioprinting for tissue engineering, and optimization of isolation and storage procedures. The review also provides an overview of recent preclinical and clinical studies in specific applications: fat grafting, wound healing, bone regeneration, skeletal muscle repair, tendon reconstruction, cartilage regeneration, cardiac repair, nerve regeneration, and potential use in COVID-19.
**Key Results:** The review highlights several key findings:
- **Fat grafting:** Cell-assisted lipotransfer (CAL) using ADSCs significantly improves fat graft survival. A clinical trial by Kølle et al. (2013) with 10 healthy participants showed that ADSC-enriched fat grafts had significantly higher fat survival than controls over 121 days, without serious adverse events.
- **Wound healing:** In a clinical trial by Moon et al., 59 patients with diabetic foot ulcers were treated with allogeneic ADSC-hydrogel complex or polyurethane film. The complete wound closure rate was distinctly higher in the ADSC group over 12 weeks. Another trial by Zhou et al. (296 patients) showed ADSCs increased granulation tissue coverage rate without adverse events.
- **Bone regeneration:** In a study of 13 patients with craniomaxillofacial defects, autologous ADSCs seeded on scaffolds led to successful bone regeneration in 10 of 13 cases. However, a 6-year follow-up of 5 cranial defect cases showed unsatisfactory long-term results due to graft resorption, tumor recurrence, or infection.
- **Skeletal muscle repair:** A clinical trial by Sarveazad et al. (18 patients with sphincter defects) found that ADSC injection during repair surgery significantly increased muscle tissue area and improved contractile function at 2 months.
- **Tendon reconstruction:** In a trial by Kim et al. (70 patients with rotator cuff tear), ADSC injection during repair significantly decreased the retear rate, though function was similarly improved in both groups. Another trial by Randelli et al. (44 patients) showed microfragmented lipoaspirate containing ADSCs promoted functional repair over 24 months.
- **Cartilage regeneration:** A dose-escalation trial by Pers et al. (18 patients with knee osteoarthritis) found functional improvement and pain relief in all groups, but statistical significance was only in the low-dose group (2 × 10^6 cells). Lee et al. (12 patients) reported significant improvement in pain and function over 6 months.
- **Cardiac repair:** Kastrup et al. (10 patients with ischemic heart failure) found that allogeneic ADSC injection increased left ventricular ejection fraction and exercise capacity over 6 months. Qayyum et al. (60 patients with refractory angina) reported improved cardiac symptoms but unchanged exercise capacity.
- **Nerve regeneration:** One patient with spinal cord injury recovered from American Spinal Injury Association Impairment Scale grade A to grade C after intrathecal autologous ADSC injection over 18 months.
- **COVID-19:** A clinical trial by Sánchez-Guijo et al. (13 patients) showed clinical improvement in 9 patients after allogeneic ADSC administration, with decreased inflammatory parameters.
**Clinical Implications:** ADSC-based therapies hold significant promise for regenerative medicine, with evidence supporting their use in multiple tissue types. However, the review emphasizes that most clinical trials are small, with short follow-up, and lack standardization. The potential tumorigenicity of ADSCs, especially in breast reconstruction, remains a concern, though no clinical trials have yet reported increased oncological recurrence. The development of cell-free therapies using ADSC-derived exosomes may mitigate some risks. Standardized protocols for isolation, storage, and application are urgently needed to ensure consistent cell quality and enable comparison across studies. 3D bioprinting and organoid technologies may further enhance the clinical translation of ADSCs by providing more physiologically relevant models and enabling complex tissue construction. Overall, while ADSCs represent a versatile and accessible cell source, large randomized controlled trials with long-term follow-up are essential to establish safety and efficacy before widespread clinical adoption.