Regenerative engineering for complex extremity trauma

项目总结 肢体威胁伤的临床治疗需要复杂的外科处理和终生的治疗。 矫正手术和理疗。复杂下肢创伤的治疗进展 由于缺乏可用于功能性修复双侧肌肉的治疗方法而阻碍了复合组织的丢失 和邻近的骨头。由于治疗选择有限，涉及开放性骨折的复合损伤 伴随的软组织并发症，导致延迟或失败的骨愈合的可能性是对照组的4-5倍。那里 是一种尚未满足的临床需要，需要再生方法来引导和恢复功能性生物物理 两个组织内部和之间的关系。 我们之前的研究已经表明，来自纳米级细胞外基质的空间图案线索可以调制 细胞炎症表型、血管生成潜能和骨骼肌肌发生。我们还有更多 研究表明，当这些图案材料与跑步运动相结合时，大体积的肌肉 小鼠的损伤可以再生和重新神经支配，与天然组织相当。随着越来越多的证据表明 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 在四肢创伤的治疗中，再生生态位可能是改善骨骼和肢体愈合的关键。 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 肌源性和成骨性细胞的再生潜力，导致肌肉和骨骼的再生和功能 修复。这项建议首先在体外研究这些问题，以确定空间模式所起的作用 在指导肌肉和骨祖细胞以及骨髓间充质细胞命运中的作用 干细胞。这些研究将确定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，旁分泌对成骨的调节 将由肌源性细胞在体外和体内表征的一种新型小鼠复合损伤模型 胫骨/胫骨前肌。通过使用空间模式来增强肌肉发生，我们的目标是引导串扰 在损伤和修复过程中，肌肉和骨骼之间会发生这种情况，从而影响邻近骨骼的愈合。此外， 众所周知，肢体康复在成功康复的过程中起着至关重要的作用。 通过改善损伤组织的血流量和通过机械方法提高力量恢复来实现创伤 正在装车。我们的花纹支架已被证明与运动刺激协同工作，以提高 肌肉创伤后的愈合。因此，我们将把花纹脚手架与跑步运动结合起来，以增强 局部肌肉和邻近骨骼再生。共同努力，这项工作将建立一个再生的强大的 为复杂四肢创伤合并复合性组织丢失的治疗提供了创新的方法。

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.