Regenerative engineering for complex extremity trauma

复杂肢体创伤的再生工程

• 批准号: 10584227
• 负责人: Karina Nakayama
• 金额: $ 52.5万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10584227
• 关键词: Aerobic Exercise; Affect; Age; Anisotropy; Biophysics; Blood flow; Bone Regeneration; Bone Tissue; Cause of Death; Cells; Clinical; Clinical Management; Clinical Treatment; Complex; Complication; Coupled; Coupling; Cues; Defect; Dependence; Deposition; Development; Endothelial Cells; Evaluation; Exercise; Extracellular Matrix; Fracture; Functional Regeneration; Gait; Gene Expression; Generations; Genomics; Guided Tissue Regeneration; Hospitalization; In Vitro; Individual; Inflammatory; Injury; Limb Salvage; Limb structure; Lower Extremity; Maintenance; Mediating; Mimetic Muscles; Motion; Mus; Muscle; Muscle Cells; Muscle Fibers; Musculoskeletal; Natural regeneration; Open Fractures; Operative Surgical Procedures; Osteoblasts; Osteogenesis; Outcome; Pathway interactions; Pattern; Persons; Phenotype; Physical Rehabilitation; Physical therapy; Play; Production; Proteins; Proteome; Recovery; Recovery of Function; Regenerative engineering; Regimen; Regulation; Rehabilitation therapy; Research; Resistance; Role; Running; Series; Site; Skeletal Muscle; Skeletal system; Stains; Structure-Activity Relationship; Surgical Management; System; Tissues; Transplantation; Trauma; United States; War; Work; angiogenesis; bone; bone healing; bone marrow mesenchymal stem cell; bone repair; cell fate specification; collagen scaffold; comorbidity; composite restoration; disability; examination questions; functional restoration; healing; improved; in vivo; injury and repair; innovation; limb amputation; limb injury; mechanical load; microCT; mimetics; mouse model; muscle physiology; muscle regeneration; myogenesis; nanofibrillar; nanoscale; nerve supply; novel; osteogenic; paracrine; progenitor; programs; radiological imaging; regeneration potential; regenerative; regenerative approach; reinnervation; repaired; scaffold; severe injury; soft tissue; tibia; tibialis anterior muscle; tissue regeneration

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.

项目概要 肢体威胁性损伤的临床治疗需要复杂的手术治疗和终生治疗 矫正手术和物理治疗。复杂下肢创伤治疗进展 由于缺乏可以功能性修复肌肉的可用疗法，复合组织损失的进展受到阻碍 和相邻的骨头。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，导致骨愈合延迟或失败的可能性高出 4-5 倍。那里 是对可以指导和恢复功能性生物物理的再生方法的未满足的临床需求 两个组织内部和之间的关系。 我们之前的研究表明，纳米级细胞外基质的空间图案线索可以调节 细胞炎症表型、血管生成潜力和骨骼肌肌生成。我们还有进一步 结果表明，当这些图案材料与跑步运动相结合时，大体积的肌肉 与天然组织相比，小鼠的损伤可以再生并重新受神经支配。随着新出现的证据表明 骨骼结果的再生依赖于肌肉细胞和分泌因子，对肌肉的控制 再生生态位可能是四肢创伤治疗中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 肌原细胞和成骨细胞的再生潜力，导致肌肉和骨骼再生和功能 恢复。该提案首先在体外研究这些问题，以确定空间模式所扮演的角色 指导肌肉和骨祖细胞以及骨髓间充质细胞的细胞命运规范 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。与这些研究并行，成骨的旁分泌调节 肌源性细胞的复合损伤的新型小鼠模型将在体外和体内进行表征 胫骨/胫骨前肌。通过使用空间图案来增强肌生成，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，影响邻近骨骼的愈合。此外， 众所周知，身体康复对于下肢的成功身体恢复起着至关重要的作用 通过改善受损组织的血流量和通过机械增加力量恢复来创伤 加载中。我们的图案支架已被证明可以与运动刺激协同作用，以改善 肌肉创伤后的愈合。因此，我们将图案支架与跑步运动结合起来，以增强 局部肌肉和邻近的骨骼再生。这些工作将共同建立一个具有再生能力的强健组织 以及治疗复合组织损失的复杂肢体创伤的创新方法。