Li Cuidi, Li Changwei, Ma Zhenjiang, Chen Hongfang, Ruan Huitong, Deng Lianfu, Wang Jinwu, Cui Wenguo
Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, PR China.
Shanghai Key Laboratory of Orthopedic Implant, Department of Orthopedic Surgery, Shanghai Ninth People's Hospital Affiliated Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, PR China.
Bioact Mater. 2022 May 2;19:474-485. doi: 10.1016/j.bioactmat.2022.04.028. eCollection 2023 Jan.
The 3D printing technique is suitable for patient-specific implant preparation for bone repair after bone tumor resection. However, improving the survival rate due to tumor recurrence remains a challenge for implants. The macrophage polarization induction to M2-type tumor-associated macrophages (TAMs) by the tumor microenvironment is a key factor of immunosuppression and tumor recurrence. In this study, a regenerative scaffold regulating the macrophage immune microenvironment and promoting bone regeneration in a dual-stage process for the postoperative treatment of bone tumors was constructed by binding a colony-stimulating factor 1 receptor (CSF-1R) inhibitor GW2580 onto in situ cosslinked hydroxybutylchitosan (HBC)/oxidized chondroitin sulfate (OCS) hydrogel layer covering a 3D printed calcium phosphate scaffold based on electrostatic interaction. The hydrogel layer on scaffold surface not only supplied abundant sulfonic acid groups for stable loading of the inhibitor, but also acted as the cover mask protecting the bone repair part from exposure to unhealthy growth factors in the microenvironment at the early treatment stage. With local prolonged release of inhibitor being realized via the functional material design, CSF-1R, the main pathway that induces polarization of TAMs, can be efficiently blocked, thus regulating the immunosuppressive microenvironment and inhibiting tumor development at a low therapeutic dose. At the later stage of treatment, calcium phosphate component of the scaffold can facilitate the repair of bone defects caused by tumor excision. In conclusion, the difunctional 3D printed bone repair scaffold regulating immune microenvironment in stages proposed a novel approach for bone tumor postoperative treatment.
3D打印技术适用于骨肿瘤切除术后骨修复的个性化植入物制备。然而，提高因肿瘤复发导致的生存率对植入物来说仍然是一个挑战。肿瘤微环境将巨噬细胞极化为M2型肿瘤相关巨噬细胞（TAM）是免疫抑制和肿瘤复发的关键因素。在本研究中，通过基于静电相互作用将集落刺激因子1受体（CSF-1R）抑制剂GW2580结合到覆盖3D打印磷酸钙支架的原位交联羟丁基壳聚糖（HBC）/氧化硫酸软骨素（OCS）水凝胶层上，构建了一种用于骨肿瘤术后治疗的双阶段调节巨噬细胞免疫微环境并促进骨再生的再生支架。支架表面的水凝胶层不仅为抑制剂的稳定负载提供了丰富的磺酸基团，还在治疗早期起到覆盖屏障的作用，保护骨修复部位免受微环境中有害生长因子的影响。通过功能材料设计实现抑制剂的局部长效释放，可有效阻断诱导TAM极化的主要途径CSF-1R，从而在低治疗剂量下调节免疫抑制微环境并抑制肿瘤发展。在治疗后期，支架的磷酸钙成分可促进肿瘤切除引起的骨缺损修复。总之，这种分阶段调节免疫微环境的双功能3D打印骨修复支架为骨肿瘤术后治疗提出了一种新方法。
