Comparative Effectiveness of Autologous Blood Clot Therapy (ActiGraft), Autologous Micrograft Therapy (Rigenera), and Advanced Wound Dressings for Refractory Chronic Lower Limb Ulcers: A Real-World Evidence Study

<b>Background/Objectives</b>: Chronic lower limb ulcers represent a significant clinical challenge, with conventional therapies achieving healing in only 30-40% of complex cases. This study evaluated the comparative effectiveness of autologous blood clot therapy (ActiGraft, delivering platelet- and leukocyte-derived growth factors) and autologous micrograft therapy (Rigenera, containing viable progenitor cells) versus advanced wound dressings for refractory chronic wounds. <b>Methods</b>: This retrospective analysis of a prospectively collected, non-randomized clinical cohort included 132 patients with chronic lower limb ulcers refractory to prior therapy, who were treated between 2019 and 2024 at a single wound care center. The patients received ActiGraft (n = 32), Rigenera (n = 33), or advanced wound dressings (n = 67) based on their choice after informed discussion. The primary outcome was complete wound closure at 52 weeks. Multivariable Poisson regression with robust variance was performed, adjusting for baseline wound area (log-transformed), chronic renal failure, age, and peripheral vascular disease. Cox proportional hazards was used to model time to closure. Bonferroni correction (threshold <i>p</i> < 0.0167) was applied for three pairwise comparisons. This study was not pre-registered, and the results should be considered hypothesis-generating. <b>Results</b>: Unadjusted wound closure rates were 68.8% (ActiGraft; RR = 1.71, 95% CI: 1.17-2.48, <i>p</i> = 0.015), 60.6% (Rigenera; RR = 1.50, 95% CI: 1.01-2.25, <i>p</i> = 0.089), and 40.3% (advanced dressings). After multivariable adjustment, ActiGraft showed attenuated benefit (adjusted RR = 1.38, 95% CI: 0.86-2.21, <i>p</i> = 0.179), while the beneficial effect of Rigenera became non-significant (adjusted RR = 1.19, 95% CI: 0.73-1.94, <i>p</i> = 0.488). However, the adjusted Cox regression revealed significantly faster healing for ActiGraft (HR = 10.67, 95% CI: 4.17-27.30, <i>p</i> < 0.001) and Rigenera (HR = 4.12, 95% CI: 1.75-9.73, <i>p</i> = 0.001). Sensitivity analyses restricted to comparable wound sizes (≤10 cm²) showed a consistent direction of effect (ActiGraft 71.4% vs. Advanced 37.5%). Infection rates were lower in the autologous therapy groups (0-3.0% vs. 11.9%; Fisher's exact <i>p</i> = 0.006). <b>Conclusions</b>: ActiGraft autologous blood clot therapy showed trends toward superior wound closure and demonstrated significantly faster healing compared to advanced dressings in patients with refractory chronic lower limb ulcers, with autologous micrograft therapy (Rigenera) showing intermediate results. Significant baseline imbalances in wound size limit causal inference from the closure rate comparisons. These hypothesis-generating findings from a non-randomized cohort warrant confirmation in adequately powered randomized controlled trials with stratification by wound characteristics.