It was the aim of the study to compare the effectiveness of autologous conditioned serum (ACS) and dextrose prolotherapy (DP) solutions, in treating patients with TMJ internal derangement (ID). 24 participants with TMJ ID (Wilkes II-V) were recruited and randomized into study and control groups, with 12 patients each, treated with IA injection of ACS and DP, respectively. Pain, mouth opening, joint sounds, and jaw deviation were evaluated, with patients reviewed at 2 weeks, 1 month, and 2 months intervals. Based on the nature of the variables, appropriate descriptive statistics and statistical tests were applied. The pain score was zero in the study group after 2 months of treatment, which was statistically significant (p = 0.006). Deviation was also significantly reduced (p < 0.001) and mouth opening significantly improved (p = 0.004) in the ACS-treated patients. ACS demonstrated superiority over DP in the management of TMJ dysfunction. Therefore, ACS can be considered an ideal, minimally invasive treatment option for TMJ ID. Clinical trial registry number: (CTRI/2021/10/037043).
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