Hirano Kyoko, Miyagawa Takaki, Nishida Masahiro, Akiyama Haruhiko
Department of Orthopaedic Surgery, Gifu University Graduate School of Medicine, Gifu, Japan.
Laboratory for Pharmacology, Pharmaceutical Research Center, Asahi Kasei Pharma Corporation, Shizuoka, Japan.
Front Bioeng Biotechnol. 2025 Aug 14;13:1622918. doi: 10.3389/fbioe.2025.1622918. eCollection 2025.
Core decompression (CD) is a minimally invasive procedure widely used to treat early-stage osteonecrosis of the femoral head (ONFH). However, CD alone often yields suboptimal outcomes in promoting bone regeneration in necrotic lesions, highlighting the need for novel therapeutic approaches. In this study, we evaluated the combined effects of CD surgery and local administration of AKDS001, a small-molecule EP4 receptor agonist, in a canine ONFH model. AKDS001 was incorporated into biocompatible, biodegradable polylactic-coglycolic acid microspheres (AKDS001 MSs) for sustained local drug release. The bone-regenerative effects of local administration of AKDS001 MSs combined with CD surgery were evaluated in intact canines or a canine ONFH model, induced by ethanol injection into the femoral head. Safety and local tolerability of the therapy was also investigated in the model. AKDS001 MSs enhanced bone formation in intact dog femurs compared to CD only or MSs without AKDS001. In the ONFH model, CD alone resulted in limited bone repair at 12 weeks postsurgery. In contrast, compared with CD alone, the combination of AKDS001 MSs and CD dose-dependently increased the bone volume, bone mineral density, and tissue mineral density in the CD tunnel. Histological analyses further revealed significant amelioration of the necrotic lesions. Importantly, no systemic or local adverse effects were observed. In conclusion, local administration of AKDS001 MSs combined with CD surgery significantly enhanced bone regeneration in necrotic lesions in a canine ONFH model, demonstrating both efficacy and favorable safety with local tolerability.
髓芯减压术（CD）是一种广泛用于治疗早期股骨头缺血性坏死（ONFH）的微创手术。然而，单纯的髓芯减压术在促进坏死病灶骨再生方面往往效果欠佳，这凸显了新型治疗方法的必要性。在本研究中，我们在犬类ONFH模型中评估了髓芯减压术与小分子EP4受体激动剂AKDS001局部给药的联合效果。AKDS001被包裹在生物相容性、可生物降解的聚乳酸-乙醇酸微球（AKDS001微球）中以实现药物的持续局部释放。在完整犬类或通过向股骨头注射乙醇诱导的犬类ONFH模型中，评估了AKDS001微球局部给药联合髓芯减压术的骨再生效果。还在此模型中研究了该治疗方法的安全性和局部耐受性。与仅进行髓芯减压术或不含AKDS001的微球相比，AKDS001微球增强了完整犬股骨的骨形成。在ONFH模型中，单纯髓芯减压术在术后12周时骨修复有限。相比之下，与单纯髓芯减压术相比，AKDS001微球与髓芯减压术联合使用能剂量依赖性地增加髓芯减压通道内的骨体积、骨矿物质密度和组织矿物质密度。组织学分析进一步显示坏死病灶有明显改善。重要的是，未观察到全身或局部不良反应。总之，在犬类ONFH模型中，AKDS001微球局部给药联合髓芯减压术显著增强了坏死病灶的骨再生，证明了其有效性以及良好的安全性和局部耐受性。
