Regenerative engineering for complex extremity trauma

项目摘要 临床治疗肢体威胁性损伤需要复杂的手术治疗和终身的 矫正手术和物理治疗复杂下肢创伤的治疗进展 由于缺乏可以在功能上修复两种肌肉的可用疗法， 和邻近的骨头。由于有限的治疗选择，涉及开放性骨折的复合损伤， 伴随的软组织共病，导致骨愈合延迟或失败的可能性高4 - 5倍。那里 是一个未满足的临床需要再生的方法，可以引导和恢复功能的生物物理 两种组织内部和之间的关系。 我们先前的研究表明，来自纳米细胞外基质的空间图案线索调节 细胞炎症表型、血管生成潜能和骨骼肌肌生成。我们进一步 显示当这些图案化的材料与跑步锻炼相结合时， 小鼠中的损伤可以再生和再神经支配，与天然组织相当。有证据表明 骨骼结果对肌肉细胞和分泌因子的再生依赖性，对肌肉的控制 再生小生境可能是改善肢体创伤治疗中骨和肢体愈合的关键。 我们相信，来自各向异性纤维支架的纳米级空间图案线索将增强 再生潜力的肌细胞和成骨细胞，导致肌肉和骨骼再生和功能 修复这个建议首先在体外研究这些问题，以确定空间模式所扮演的角色 在指导肌肉和骨祖细胞以及骨髓源性间充质干细胞的细胞命运特化中， 干细胞这些研究将定义纳米级图案和亚细胞之间的生物物理关系。 组织特异性细胞表型的调节。在这些研究的同时，骨生成的旁分泌调节 将在体外和体内在一种新的复合损伤的小鼠模型中表征肌源性细胞的作用。 胫骨/胫骨前肌通过使用空间图案化来增强肌生成，我们的目标是引导串扰 在损伤和修复过程中发生在肌肉和骨骼之间，影响相邻骨骼的愈合。此外，委员会认为， 众所周知，身体康复在下肢的成功身体恢复中起着关键作用 通过改善受损组织的血流和通过机械恢复增加力量恢复来治疗创伤 加载中我们的图案化支架已被证明与运动刺激协同作用，以改善 肌肉创伤后的愈合因此，我们将结合模式支架与跑步运动，以提高 局部肌肉和邻近骨再生。总之，这项工作将建立一个再生强大的 和创新的方法来治疗复杂的四肢创伤与复合组织损失。

PROJECT SUMMARY The clinical treatment of limb threatening injuries requires complex surgical management and a lifetime of corrective surgeries and physical therapy. Advancements in the treatment of complex lower extremity trauma with composite tissue loss are hindered by the lack of available therapies that can functionally repair both muscle and adjacent bone. As a result of limited treatment options, composite injuries involving open bone fractures with concomitant soft tissue co-morbidities, are 4-5 times more likely to result in delayed or failed bone union. There is an unmet clinical need for regenerative approaches that can guide and restore the functional biophysical relationship within and between both tissues. Our prior research has shown that spatial patterning cues from nanoscale extracellular matrices modulate the cellular inflammatory phenotype, angiogenic potential, and skeletal muscle myogenesis. We have further shown that when these patterned materials are combined with running exercise, that large volumetric muscle injuries in mice can be regenerated and re-innervated comparable to native tissue. With emerging evidence of a regenerative dependency of bone outcomes on muscle cells and secreted factors, control over the muscle regenerative niche may be the key to improved bone and limb healing in the management of extremity trauma. We believe that nanoscale spatial patterning cues from anisotropic fibrillar scaffolds will enhance the regenerative potential of myogenic and osteogenic cells, leading to muscle and bone regeneration and functional restoration. This proposal first examines these questions in vitro to identify the role that spatial patterning plays in guiding cell fate specification of muscle and bone progenitors as well as bone marrow-derived mesenchymal stem cells. These studies will define the biophysical relationship between nanoscale patterning and subcellular regulation of tissue-specific cell phenotype. In parallel with these studies, paracrine regulation of osteogenesis by myogenic cells will be characterized in vitro and in vivo in a novel mouse model of composite injury of the tibia/tibialis anterior. Through the use of spatial patterning to enhance myogenesis, we aim to guide the crosstalk that occurs between muscle and bone during injury and repair to impact adjacent bone healing. Furthermore, physical rehabilitation is known to play a critical role in the successful physical recovery from lower extremity trauma by improving blood flow to damaged tissues and increasing strength recovery through mechanical loading. Our patterned scaffolds have been shown to synergistically work with exercise stimulation to improve healing following muscle trauma. Therefore, we will couple patterned scaffolds with running exercise to enhance local muscle and adjacent bone regeneration. Together, this body of work will establish a regeneratively robust and innovative approach for the treatment of complex extremity trauma with composite tissue loss.