Adjunctive Therapies in Long-Bone Distraction Osteogenesis: Clinical Evidence for Biophysical and Biologic Treatment...

Objectives: Distraction osteogenesis (DO) is an established technique for bone regeneration but is associated with prolonged consolidation time and extended external fixation. Biophysical and biologic adjuncts have been proposed to accelerate regenerative maturation. This systematic review aimed to comparatively evaluate the available clinical evidence regarding low-intensity pulsed ultrasound (LIPUS) and biologic augmentation strategies in distraction osteogenesis. Methods: A systematic review was conducted in accordance with PRISMA 2020 guidelines and prospectively registered in PROSPERO (CRD420251125456). MEDLINE, Embase, Scopus, and Google Scholar were searched from inception to October 2025. Randomized controlled trials and cohort studies evaluating LIPUS, platelet-rich plasma (PRP), bone marrow aspirate concentrate (BMAC), culture-expanded mesenchymal stem cells, or hyperbaric oxygen therapy in distraction osteogenesis were included. Risk of bias was assessed using RoB 2 for randomized trials and structured domain-based criteria for observational studies. Due to substantial clinical and methodological heterogeneity, findings were synthesized narratively. Results: Nine studies involving 304 participants met the inclusion criteria, including randomized controlled trials and cohort studies across multiple anatomical sites and fixation techniques. Randomized trials evaluating LIPUS demonstrated inconsistent reductions in healing index and consolidation time, with no consistent effect on complication rates. Biologic adjuncts such as PRP, BMAC, and cell-based therapies showed signals of improved consolidation parameters in selected studies; however, evidence was limited by small sample sizes and methodological heterogeneity. Hyperbaric oxygen therapy lacked sufficient high-quality evidence to support routine use. Overall, the certainty of evidence was constrained by variability in study design, outcome definitions, and risk of bias. Conclusions: Although both biophysical and biologic adjuncts demonstrate compelling biological rationale, current clinical evidence in distraction osteogenesis remains heterogeneous and inconclusive. Biologic strategies may offer theoretical advantages through direct cellular and growth factor supplementation, whereas LIPUS provides non-invasive mechanotransductive stimulation; however, neither approach can currently be recommended for routine clinical use. High-quality, adequately powered trials with standardized outcome reporting are required to define their true clinical role. Level of Evidence: Level III (Systematic review of Level I-III studies).