Department of Materials Science and Engineering, Stanford University, Stanford, CA, 94305, USA.
Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, 94305, USA.
Biomaterials. 2024 Mar;305:122400. doi: 10.1016/j.biomaterials.2023.122400. Epub 2023 Nov 17.
Cervical damage is the most prevalent type of spinal cord injury clinically, although few preclinical research studies focus on this anatomical region of injury. Here we present a combinatorial therapy composed of a custom-engineered, injectable hydrogel and human induced pluripotent stem cell (iPSC)-derived deep cortical neurons. The biomimetic hydrogel has a modular design that includes a protein-engineered component to allow customization of the cell-adhesive peptide sequence and a synthetic polymer component to allow customization of the gel mechanical properties. In vitro studies with encapsulated iPSC-neurons were used to select a bespoke hydrogel formulation that maintains cell viability and promotes neurite extension. Following injection into the injured cervical spinal cord in a rat contusion model, the hydrogel biodegraded over six weeks without causing any adverse reaction. Compared to cell delivery using saline, the hydrogel significantly improved the reproducibility of cell transplantation and integration into the host tissue. Across three metrics of animal behavior, this combinatorial therapy significantly improved sensorimotor function by six weeks post transplantation. Taken together, these findings demonstrate that design of a combinatorial therapy that includes a gel customized for a specific fate-restricted cell type can induce regeneration in the injured cervical spinal cord.
临床上最常见的脊髓损伤类型是颈椎损伤，但很少有临床前研究关注这一解剖学损伤区域。在这里，我们提出了一种组合疗法，由定制的可注射水凝胶和人诱导多能干细胞（iPSC）衍生的深层皮质神经元组成。仿生水凝胶具有模块化设计，包括一个蛋白质工程组件，允许定制细胞黏附肽序列，以及一个合成聚合物组件，允许定制凝胶的机械性能。对包封的 iPSC 神经元进行的体外研究用于选择一种定制的水凝胶配方，该配方既能保持细胞活力，又能促进神经突延伸。在大鼠挫伤模型中注射到损伤的颈椎脊髓后，水凝胶在六周内生物降解，没有引起任何不良反应。与使用生理盐水进行细胞递送相比，水凝胶显著提高了细胞移植的重现性和与宿主组织的整合性。在三个动物行为指标上，这种组合疗法在移植后 6 周显著改善了感觉运动功能。综上所述，这些发现表明，设计一种组合疗法，包括为特定命运受限的细胞类型定制的凝胶，可以诱导损伤颈椎脊髓的再生。
