Background

Bone defects after trauma, infection, or tumour resection present a challenge for patients and clinicians. To date, autologous bone graft (ABG) is the gold standard for bone regeneration. To address the limitations of ABG such as limited harvest volume as well as overly fast remodelling and resorption, a new treatment strategy of scaffold-guided bone regeneration (SGBR) was developed. In a well-characterized sheep model of large to extra-large tibial segmental defects, three-dimensional (3D) printed composite scaffolds have shown clinically relevant biocompatibility and osteoconductive capacity in SGBR strategies. Here, we report four challenging clinical cases with large complex posttraumatic long bone defects using patient-specific SGBR as a successful treatment.

Methods

After giving informed consent computed tomography (CT) images were used to design patient-specific biodegradable medical-grade polycaprolactone-tricalcium phosphate (mPCL-TCP, 80:20 ​wt%) scaffolds. The CT scans were segmented using Materialise Mimics to produce a defect model and the scaffold parts were designed with Autodesk Meshmixer. Scaffold prototypes were 3D-printed to validate robust clinical handling and bone defect fit. The final scaffold design was additively manufactured under Food and Drug Administration (FDA) guidelines for patient-specific and custom-made implants by Osteopore International Pte Ltd.

Results

Four patients (age: 23–42 years) with posttraumatic lower extremity large long bone defects (case 1: 4 ​cm distal femur, case 2: 10 ​cm tibia shaft, case 3: complex malunion femur, case 4: irregularly shaped defect distal tibia) are presented. After giving informed consent, the patients were treated surgically by implanting a custom-made mPCL-TCP scaffold loaded with ABG (case 2: additional application of recombinant human bone morphogenetic protein-2) harvested with the Reamer-Irrigator-Aspirator system (RIA, Synthes®). In all cases, the scaffolds matched the actual anatomical defect well and no perioperative adverse events were observed. Cases 1, 3 and 4 showed evidence of bony ingrowth into the large honeycomb pores (pores >2 ​mm) and fully interconnected scaffold architecture with indicative osseous bridges at the bony ends on the last radiographic follow-up (8–9 months after implantation). Comprehensive bone regeneration and full weight bearing were achieved in case 2 ​at follow-up 23 months after implantation.

Conclusion

This study shows the bench to bedside translation of guided bone regeneration principles into scaffold-based bone tissue engineering. The scaffold design in SGBR should have a tissue-specific morphological signature which stimulates and directs the stages from the initial host response towards the full regeneration. Thereby, the scaffolds provide a physical niche with morphology and biomaterial properties that allow cell migration, proliferation, and formation of vascularized tissue in the first one to two months, followed by functional bone formation and the capacity for physiological bone remodelling. Great design flexibility of composite scaffolds to support the one to three-year bone regeneration was observed in four patients with complex long bone defects.

The translational potential of this article

This study reports on the clinical efficacy of SGBR in the treatment of long bone defects. Moreover, it presents a comprehensive narrative of the rationale of this technology, highlighting its potential for bone regeneration treatment regimens in patients with any type of large and complex osseous defects.

中文翻译：

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4例大长骨缺损患者特异性支架引导骨再生概念的临床转化

背景

创伤、感染或肿瘤切除后的骨缺损给患者和临床医生带来了挑战。迄今为止，自体骨移植（ABG）是骨再生的金标准。为了解决 ABG 的局限性，例如有限的收获量以及过快的重塑和再吸收，开发了一种新的支架引导骨再生 (SGBR) 治疗策略。在具有良好特征的大到超大胫骨节段缺损的绵羊模型中，三维 (3D) 打印复合支架在 SGBR 策略中显示出临床相关的生物相容性和骨传导能力。在这里，我们报告了四个具有挑战性的临床病例，这些病例使用患者特异性 SGBR 作为一种成功的治疗方法，具有大型复杂的创伤后长骨缺损。

方法

在给予知情同意后，计算机断层扫描 (CT) 图像被用于设计患者特定的可生物降解医用级聚己内酯-磷酸三钙 (mPCL-TCP, 80:20 wt%) 支架。使用 Materialise Mimics 对 CT 扫描进行分段以生成缺陷模型，并使用 Autodesk Meshmixer 设计支架部件。支架原型是 3D 打印的，以验证稳健的临床处理和骨缺损配合。最终的支架设计是由 Osteopore International Pte Ltd 根据食品和药物管理局 (FDA) 针对患者特定和定制植入物的指南添加制造的。

结果

4例患者（年龄：23​​-42岁）外伤后下肢大长骨缺损（病例1：股骨远端4cm，病例2：胫骨干10cm，病例3：复杂股骨畸形愈合，病例4：不规则形状缺损胫骨远端）。在给予知情同意后，通过植入装有 ABG 的定制 mPCL-TCP 支架（案例 2：重组人骨形态发生蛋白-2 的额外应用）来对患者进行手术治疗，该支架采用铰刀-灌溉器-抽吸器系统 (RIA,合成®）。在所有情况下，支架都与实际的解剖缺陷很好地匹配，并且没有观察到围手术期不良事件。病例 1、3 和 4 显示骨骼向大蜂窝孔（孔 > 2 毫米）和完全互连的支架结构，在最后一次放射照相随访（植入后 8-9 个月）时，骨末端有指示性骨桥。病例2在植入后23个月的随访中实现了全面的骨再生和完全负重。

结论

这项研究展示了引导骨再生原理到基于支架的骨组织工程的临床转化。SGBR 中的支架设计应具有组织特异性形态特征，可刺激和指导从初始宿主反应到完全再生的阶段。因此，支架提供了具有形态和生物材料特性的物理生态位，允许细胞迁移、增殖和血管化组织在最初的一到两个月内形成，然后是功能性骨形成和生理性骨重塑能力。在四名患有复杂长骨缺损的患者中观察到复合支架具有很大的设计灵活性以支持一到三年的骨再生。

本文的翻译潜力

本研究报告了SGBR治疗长骨缺损的临床疗效。此外，它全面介绍了该技术的基本原理，强调了其在患有任何类型的大型和复杂骨缺损的患者中的骨再生治疗方案的潜力。