3-D printed hyperelastic bone composites for bone regeneration and spine fusion

 描述(由申请人提供)：这项研究的目标是改变退行性和创伤性骨病患者的临床护理。尽管骨移植技术最近取得了进步，但对于执行需要骨愈合的手术的骨科外科医生来说，仍然存在一个重大空白。目前市场上的生物制剂，如重组人骨形态发生蛋白-2(rhBMP-2；INUSE(Tm))是有效的，但与不良反应有关。陶瓷和脱钙骨基质(DBM)作为脊柱融合的骨移植替代品还不够有效。我们的目标是开发一种安全、易于操作、在诱导骨形成和脊柱融合方面比现有产品更有效的无外源生长因子的陶瓷复合支架。为此，我们团队开发了一种独特的3D可打印羟基磷灰石(HA)墨水，可用于创建坚固的复合支架，不仅促进骨再生，还具有超弹性机械性能，改善开放和微创脊柱融合术中的功能和交付。由于油墨合成、3D打印和处理是在环境温度下进行的，因此这种3D打印技术很容易扩展，并便于加入其他生物活性因子或药物。在前期工作中，我们开发了一种策略来3D打印这种超弹性HA(HHA)的变体，它将脱矿骨基质(DBM)颗粒结合到3D墨水中，从DBM中存在的天然生物活性生长因子中提供额外的骨诱导刺激。结果是一种灵活而有弹性的HHA-DBM复合材料，我们认为这是开放和微创脊柱融合手术的高效骨移植替代品的基础。根据这一建议，我们将1)开发用于骨再生的最佳3D-ink配方和打印参数，并评估这种超弹性骨复合材料(HBC)在大鼠脊柱融合模型中诱导脊柱融合的能力；2)比较其疗效(骨再生和脊柱融合能力)与已建立的阳性对照(rhBMP-2；Inuse(Tm))；以及3)比较超弹性骨复合材料与rhBMP-2的促成骨作用和炎症反应的机制。我们假设，由此产生的HBC将引起与rhBMP-2类似的融合率和再生能力，但将引起显著较低的炎症宿主反应。这项转化性研究旨在开发一种可以使临床护理方法现代化的技术，同时促进我们对复杂3D打印颗粒基复合材料的行为和功能的理解。这项研究不仅将为安全、有效和成本效益高的脊柱关节融合术疗法奠定基础，而且设计的多功能性和快速的制造速度也将使患者能够高效地定制。我们预计，这项技术的全面发展将改变脊柱退行性和创伤性疾病患者的临床实践，并最终转化为需要骨再生的其他骨科和非骨科环境。

 DESCRIPTION (provided by applicant): The goal of this research is to transform clinical care for patients with degenerative and traumatic bone pathologies. Despite recent advances in bone graft technology, a major void remains for orthopaedic surgeons who perform procedures that require bone healing. Current biologics on the market, such as recombinant human bone morphogenetic protein-2 (rhBMP-2; INFUSE(tm)), are effective but are associated with adverse effects. Ceramics and demineralized bone matrices (DBM) are insufficiently effective as bone graft substitutes for spine fusion. Our goal is to develop an exogenous growth factor-free ceramic composite scaffold that is safe, easy to manipulate, and more effective at inducing bone formation and spine fusion than currently available products. To this end, our group has developed a unique 3D-printable hydroxyapatite (HA) ink that can be used to create a robust composite scaffold that not only promotes bone regeneration, but also has hyperelastic mechanical properties that improves functionality and delivery in both open and minimally invasive spine fusion procedures. This 3D-printed technology is easily scalable and facilitates incorporation of other bioactive factors or drugs, since ink synthesis, 3D-printing, and processing are carried out at ambient temperatures. In preliminary work, we developed a strategy to 3D-print a variation on this hyperelastic HA (hHA) that incorporates demineralized bone matrix (DBM) particles into the 3D-ink, which imparts an added osteoinductive stimulus from the native bioactive growth factors present within the DBM. The result is a flexible and elastic hHA-DBM composite that we believe is the basis for a highly effective bone graft substitute for both open and minimally invasive spine fusion procedures. With this proposal, we will 1) develop the optimal 3D-ink formulation and printing parameters for bone regeneration and evaluate the capacity of this hyperelastic bone composite (HBC) to elicit spine fusion in a rat spine fusion model; 2) compare its efficacy (bone regenerative and spine fusion capacities) with an established positive control (rhBMP-2; INFUSE(tm)); and 3) compare the mechanisms of pro-osteogenic action and inflammatory host response of the hyperelastic bone composite with that of rhBMP-2. We hypothesize that the resulting HBC will elicit comparable fusion rates and regenerative capacity to rhBMP-2, but will provoke a significantly lower inflammatory host response. This translational study aims to develop a technology that could modernize clinical care approaches, while advancing our understanding of the behavior and functionality of complex 3D-printed particle-based composites. Not only would this investigation lay the groundwork for a safe, efficacious, and cost-effective therapy for spinal arthrodesis, but the versatility of design and rapid rate of manufacturing would also allow for efficient customizabilit to individual patients. We expect that full development of this technology would transform clinical practice for patients with degenerative and traumatic conditions of the spine, and would ultimately translate to other orthopaedic and non-orthopaedic settings where bone regeneration is required.