Customized craniofacial stem cell therapy for craniofacial bone defects

 描述（由申请人提供）：细胞疗法在颅面缺损和畸形的重建和再生方面具有巨大的潜力。目前细胞疗法的局限性在于将细胞递送至缺损的模式是粗糙的并且对手术部位是非特异性的。或者，理想的方法是标准化到足以重现，但适应性足够强，可以针对患者和缺陷进行特定。为此，我们有初步的证据表明，MSC可以从肺泡骨髓（aBMSC）中分离出来，使用简单，标准化，可重复的技术。此外，我们已经证明了通过增材制造创建预成形的患者特异性支架的可行性。我们的假设是，临床颅面骨缺损可以通过干细胞移植在三维（3-D）打印支架上再生，该支架在患者特定颅面缺损的形态学维度中产生。为了验证这些假设，拟议的项目有三个具体目标。在SA 1中，我们将优化三维支架的物理和机械性能，以支持aBMSC的细胞接种、附着、生长和分化，并在植入临床骨缺损时保持稳定。SA 2将使用临床相关的原位模型系统评价aBMSC在定制支架上的临床前骨再生潜力。最后，在SA 3中，我们将确定使用个性化3D打印支架将自体aBMSC递送到人类颅面颌骨缺损的可行性和安全性。这项研究的结果将大大推进颅面再生的临床细胞治疗方法。此外，它还将成为使用增材制造这一强大工具开发其他个性化再生方法的重要平台。

 DESCRIPTION (provided by applicant): Cell therapy holds significant potential for the reconstruction and regeneration of craniofacial defects and deformities. A current limitation of cell therapy is that the mode of delivering cells to the defect is crude and non-specific to the surgical site. Alternatively, an ideal approach would be one that is standardized enough to be reproducible, yet adaptable enough to be patient- and defect-specific. To this end, we have preliminary evidence which suggests that MSCs can be predictably isolated from alveolar bone marrow (aBMSCs), using a simple, standardized, reproducible technique. Additionally, we have demonstrated the feasibility of creating pre-shaped, patient-specific scaffolds through additive manufacturing. Our hypothesis is that clinical craniofacial bone defects can be regenerated through stem cell transplantation on 3-dimensional (3-D) printed scaffolds produced in the morphological dimensions of patient-specific craniofacial defects. To test these hypotheses, the project proposed has three Specific Aims. In SA1, we will optimize the physical and mechanical properties of 3-D scaffolds to support cell seeding, attachment, growth, and differentiation of aBMSCs and that will remain stable at the time of placement into clinical bone defects. SA2 will evaluate the preclinical bone regenerative potential of aBMSCs on customized scaffolds using clinically relevant orthotopic model systems. Finally, in SA3, we will determine the feasibility an safety of using personalized 3D printed scaffolds for delivery of autologous aBMSCs to craniofacial jawbone defects in humans. Findings of the proposed study will significantly advance clinical cell therapy approaches for craniofacial regeneration. Additionally, it would serve as an important platform for development of other personalized regenerative approaches using the powerful tool of additive manufacturing.