Dienes Jack, Browne Shane, Farjun Bruna, Amaral Passipieri Juliana, Mintz Ellen L, Killian Grant, Healy Kevin E, Christ George J
Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia 22908, United States.
Department of Bioengineering, University of California, Berkeley, Berkeley, California 94720, United States.
ACS Biomater Sci Eng. 2021 Apr 12;7(4):1587-1599. doi: 10.1021/acsbiomaterials.0c01751. Epub 2021 Mar 4.
Volumetric muscle loss (VML) injuries are characterized by a degree of tissue loss that exceeds the endogenous regenerative capacity of muscle, resulting in permanent structural and functional deficits. Such injuries are a consequence of trauma, as well as a host of congenital and acquired diseases and disorders. Despite significant preclinical research with diverse biomaterials, as well as early clinical studies with implantation of decellularized extracellular matrices, there are still significant barriers to more complete restoration of muscle form and function following repair of VML injuries. In fact, identification of novel biomaterials with more advantageous regenerative profiles is a critical limitation to the development of improved therapeutics. As a first step in this direction, we evaluated a novel semisynthetic hyaluronic acid-based (HyA) hydrogel that embodies material features more favorable for robust muscle regeneration. This HyA-based hydrogel is composed of an acrylate-modified HyA (AcHyA) macromer, an AcHyA macromer conjugated with the bsp-RGD(15) peptide sequence to enhance cell adhesion, a high-molecular-weight heparin to sequester growth factors, and a matrix metalloproteinase-cleavable cross-linker to allow for cell-dependent remodeling. In a well-established, clinically relevant rat tibialis anterior VML injury model, we report observations of robust functional recovery, accompanied by volume reconstitution, muscle regeneration, and native-like vascularization following implantation of the HyA-based hydrogel at the site of injury. These findings have important implications for the development and clinical application of the improved biomaterials that will be required for stable and complete functional recovery from diverse VML injuries.
容积性肌肉损失（VML）损伤的特征是组织损失程度超过肌肉的内源性再生能力，导致永久性的结构和功能缺陷。此类损伤是创伤以及一系列先天性和后天性疾病及病症的结果。尽管对多种生物材料进行了大量临床前研究，以及对脱细胞细胞外基质植入进行了早期临床研究，但在VML损伤修复后更完全地恢复肌肉形态和功能方面仍存在重大障碍。事实上，鉴定具有更有利再生特性的新型生物材料是改进治疗方法发展的关键限制因素。作为朝这个方向迈出的第一步，我们评估了一种新型的基于半合成透明质酸（HyA）的水凝胶，其具有更有利于强健肌肉再生的材料特性。这种基于HyA的水凝胶由丙烯酸酯修饰的HyA（AcHyA）大分子单体、与bsp-RGD(15)肽序列共轭以增强细胞粘附的AcHyA大分子单体、用于螯合生长因子的高分子量肝素以及用于实现细胞依赖性重塑的基质金属蛋白酶可裂解交联剂组成。在一个成熟的、与临床相关的大鼠胫前肌VML损伤模型中，我们报告了在损伤部位植入基于HyA的水凝胶后观察到的强健功能恢复，同时伴有体积重建、肌肉再生和类似天然的血管化。这些发现对于开发和临床应用改进的生物材料具有重要意义，这些生物材料是从各种VML损伤中实现稳定和完全功能恢复所必需的。
