Engineering Skeletal Muscle with Biodegradable Hydrogels

描述（由申请人提供）：通知编号（NOT-OD-09-058）和通知标题：NIH宣布恢复法案资金可用于竞争性修订申请。颅面重建手术中经常需要骨骼肌组织，申请人研究的长期目标是再生功能性颅面骨骼肌。母基金的目标是将特定生长因子的局部呈现与使用可生物降解的聚合物载体的细胞移植相结合，所述可生物降解的聚合物载体用于控制因子对宿主和移植细胞的可用性，控制移植细胞的活化和迁移以重新填充和再生受损的宿主组织，并调节肌肉血管化和神经再支配。许多可以从这种疗法中受益的患者年龄较大，但父母资助解决了年轻动物的骨骼肌再生问题。衰老与骨骼肌再生能力的丧失、血管生成反应的减弱以及损伤后神经再支配潜力的丧失有关。这一修订解决了我们的方法在老龄化背景下的相关性。更具体地说，该项目增加了一个新的目标（目标4），我们将确定如何在中年（10个月）和老年（20个月）动物中改变持续的卫星细胞和生长因子递送诱导的肌肉再生。这一目标是基于新的子假设，即老年动物将表现出受损的内在再生能力，强调了本项目中开发的积极策略的重要性。此外，将检查局部和持续的IGF-1递送增强老年小鼠骨骼肌内在再生能力的能力。实验方法的这一补充是基于我们新的初步数据，该数据表明材料的局部和持续的IGF-1递送可增强幼鼠的再生。拟议的研究将提高目前对VEGF和IGF-1信号传导以及卫星细胞激活在受损肌肉再生中的作用的理解，特别是在衰老的背景下。与组织工程和再生研究中通常使用的年轻动物相比，预期在临床前研究中使用老年动物更接近于模拟人类患者。 公共卫生相关性：拟议的研究将提高目前对VEGF和IGF-1信号传导以及卫星细胞激活在受损肌肉再生中的作用的理解，特别是在衰老的背景下。与组织工程和再生研究中通常使用的年轻动物相比，预期在临床前研究中使用老年动物更接近于模拟人类患者。

DESCRIPTION (provided by applicant): Notice Number (NOT-OD-09-058) and Notice Title: NIH Announces the Availability of Recovery Act Funds for Competitive Revision Application. Skeletal muscle tissue is often required in reconstructive craniofacial surgery, and the long-term goal of the applicants' research is to regenerate functional craniofacial skeletal muscle. The parent grant has the goal is combining localized presentation of specific growth factors with cell transplantation using biodegradable polymer vehicles that serve to control the availability of the factors to host and transplanted cells, control the activation and migration of the transplanted cells to repopulate and regenerate damaged host tissue, and regulate muscle vascularization and reinnervation. Many of the patients who could benefit from this therapy are older, but the parent grant addresses skeletal muscle regeneration in young animals. Aging is associated with a loss of regenerative ability in skeletal muscle, diminishing angiogenic response, and loss of reinnervation potential following injury. This revision addresses the relevance of our approach in the context of aging. More specifically, a new aim has been added to the project (Aim 4), in which we will determine how sustained satellite cell and growth factor delivery-induced muscle regeneration is altered in middle age (10 months) and old (20 months) animals. This aim is based on the new sub-hypothesis that aged animals will demonstrate an impaired intrinsic regenerative capacity, emphasizing the importance of the active strategy developed in this project. In addition, local and sustained IGF-1 delivery will be examined for its ability to enhance the intrinsic regenerative ability of skeletal muscle in aged mice. This addition to the experimental approach is based on our new Preliminary Data that demonstrates localized and sustained IGF-1 delivery from the materials enhances regeneration in young mice. The proposed studies will improve the current understanding of the roles of VEGF and IGF-1 signaling, and satellite cell activation in regeneration of damaged muscle, particularly in the context of aging. The use of aged animals in pre-clinical studies is expected to more closely mimic human patients than the young animals typically used in tissue engineering and regeneration studies. PUBLIC HEALTH RELEVANCE: The proposed studies will improve the current understanding of the roles of VEGF and IGF-1 signaling, and satellite cell activation in regeneration of damaged muscle, particularly in the context of aging. The use of aged animals in pre-clinical studies is expected to more closely mimic human patients than the young animals typically used in tissue engineering and regeneration studies.