Nutter Genevieve P, VanDusen Keith W, Florida Shelby E, Syverud Brian C, Larkin Lisa M
Department of, Molecular & Integrative Physiology, University of Michigan, 2025 BSRB 109 Zina Pitcher Place, Ann Arbor, MI, 48109-2200.
Department of, Biomedical Engineering, University of Michigan, 2025 BSRB 109 Zina Pitcher Place, Ann Arbor, MI, 48109-2200.
Regen Eng Transl Med. 2020 Dec;6(4):365-372. doi: 10.1007/s40883-020-00175-x. Epub 2020 Sep 23.
Volumetric muscle loss (VML) is traumatic, degenerative, or surgical loss of skeletal muscle that exceeds the regenerative capacity of the remaining muscle, thus resulting in impaired muscle function. In humans, the loss of 30% or more mass of any one muscle will result in permanent structural and functional loss. Current VML repair treatments are limited by donor site morbidity and graft tissue availability, necessitating alternative muscle graft sources. To address this need, our lab has fabricated tissue-engineered skeletal muscle units (SMUs) for implantation into a 30 % VML model in the tibialis anterior (TA) muscle of rat. Previous results showed that after 28 days , muscle with a 30% VML repaired with our SMUs produced significantly more force than muscle with acute VML. But repair with our SMU did not fully restore muscle force production to that of native muscle. Thus, we hypothesized that more time for tissue regeneration would allow for greater force recovery. Therefore, the purpose of this study was to examine the long-term (3-month) effects of our SMUs on a 30% VML repair. We also assessed the effects of reinnervation by redirecting a branch of the peroneal nerve to the repair site. Thirty-nine, 2-month old female F344 rats were separated into a nonsurgical control group (n=5) and four surgical experimental groups (VML Only, n=5; VML+Nerve Redirect, n=6; VML+SMU, n=5; VML+SMU+ Nerve Redirect, n=8). Experimental rats were allowed a 3-month recovery period post-surgery before undergoing force testing of the surgical (left) TA. The left TA of the control animals also underwent force testing. Finally, the surgical (left) and contralateral (right) TAs of the experimental animals, as well as the left TA of the control animals, were explanted for histological analysis. Results for specific force showed that while all groups recovered specific forces similar to that of native muscle, the two SMU groups had significantly higher specific forces, on average, compared to the uninjured control group. Histological staining showed small muscle fibers in the repair site in animals that received an SMU. The average cross-sectional area of the native fibers just outside the area of repair (or the equivalent area in control animals) was not significantly different between groups, indicating that hypertrophy of remaining fibers did not contribute to the recovery of force following the VML. Our results suggest that following a 30% VML of the TA muscle, all surgical groups were able to recover TA mass, maximum tetanic and specific force production. Thus, creating a 30% VML in the TA in a rat model is not enough a sufficient VML to produce the sustained VML seen in humans following similar 30% loss of muscle volume.
容积性肌肉损失（VML）是指骨骼肌因创伤、退变或手术导致的损失量超过了剩余肌肉的再生能力，从而造成肌肉功能受损。在人类中，任何一块肌肉损失30%或更多的质量将导致永久性的结构和功能丧失。目前VML修复治疗受到供体部位发病率和移植组织可用性的限制，因此需要替代的肌肉移植来源。为满足这一需求，我们实验室制造了组织工程化骨骼肌单元（SMU），用于植入大鼠胫前肌（TA）30%VML模型。先前的结果表明，28天后，用我们的SMU修复30%VML的肌肉产生的力量明显大于急性VML的肌肉。但用我们的SMU修复并未使肌肉力量产生完全恢复到正常肌肉水平。因此，我们推测更长的组织再生时间将使力量恢复得更多。因此，本研究的目的是检查我们的SMU对30%VML修复的长期（3个月）影响。我们还通过将腓总神经的一个分支重新导向修复部位来评估再支配的效果。将39只2月龄雌性F344大鼠分为非手术对照组（n = 5）和四个手术实验组（仅VML组，n = 5；VML + 神经重定向组，n = 6；VML + SMU组，n = 5；VML + SMU + 神经重定向组，n = 8）。实验大鼠在手术后有3个月的恢复期，然后对手术侧（左侧）TA进行力量测试。对照动物的左侧TA也进行力量测试。最后，将实验动物的手术侧（左侧）和对侧（右侧）TA以及对照动物的左侧TA取出进行组织学分析。比肌力结果显示，虽然所有组恢复的比肌力与正常肌肉相似，但两个SMU组的平均比肌力明显高于未受伤的对照组。组织学染色显示，接受SMU的动物修复部位有小肌纤维。修复区域外的正常纤维平均横截面积（或对照动物的等效区域）在各组之间无显著差异，表明剩余纤维的肥大对VML后力量的恢复没有贡献。我们的结果表明，在TA肌肉发生30%VML后，所有手术组都能够恢复TA质量、最大强直收缩力和比肌力。因此，在大鼠模型中在TA中造成30%VML不足以产生人类在类似30%肌肉体积损失后所见的持续性VML。
