Ehsanipour Arshia, Sathialingam Mayilone, Rad Laila M, de Rutte Joseph, Bierman Rebecca D, Liang Jesse, Xiao Weikun, Di Carlo Dino, Seidlits Stephanie K
Department of Bioengineering, University of California, Los Angeles, California 90095, USA.
APL Bioeng. 2021 Mar 9;5(1):016104. doi: 10.1063/5.0035291. eCollection 2021 Mar.
Biomaterials are being developed as therapeutics for spinal cord injury (SCI) that can stabilize and bridge acute lesions and mediate the delivery of transgenes, providing a localized and sustained reservoir of regenerative factors. For clinical use, direct injection of biomaterial scaffolds is preferred to enable conformation to unique lesions and minimize tissue damage. While an interconnected network of cell-sized macropores is necessary for rapid host cell infiltration into-and thus integration of host tissue with-implanted scaffolds, injectable biomaterials have generally suffered from a lack of control over the macrostructure. As genetic vectors have short lifetimes , rapid host cell infiltration into scaffolds is a prerequisite for efficient biomaterial-mediated delivery of transgenes. We present scaffolds that can be injected and assembled from hyaluronic acid (HA)-based, spherical microparticles to form scaffolds with a network of macropores (∼10 m). The results demonstrate that addition of regularly sized macropores to traditional hydrogel scaffolds, which have nanopores (∼10 nm), significantly increases the expression of locally delivered transgene to the spinal cord after a thoracic injury. Maximal cell and axon infiltration into scaffolds was observed in scaffolds with more regularly sized macropores. The delivery of lentiviral vectors encoding the brain-derived neurotrophic factor (BDNF), but not neurotrophin-3, from these scaffolds further increased total numbers and myelination of infiltrating axons. Modest improvements to the hindlimb function were observed with BDNF delivery. The results demonstrate the utility of macroporous and injectable HA scaffolds as a platform for localized gene therapies after SCI.
生物材料正被开发用作脊髓损伤（SCI）的治疗手段，它可以稳定和桥接急性损伤，并介导转基因的递送，提供一个局部且持续的再生因子储存库。对于临床应用而言，直接注射生物材料支架更可取，这样能够使其适应独特的损伤情况并将组织损伤降至最低。虽然细胞大小的大孔相互连接的网络对于宿主细胞快速浸润到植入支架中并因此实现宿主组织与植入支架的整合是必要的，但可注射生物材料通常在宏观结构控制方面存在不足。由于基因载体寿命较短，宿主细胞快速浸润到支架中是生物材料介导的转基因高效递送的先决条件。我们展示了一种可以从基于透明质酸（HA）的球形微粒注射并组装而成的支架，以形成具有大孔网络（约10微米）的支架。结果表明，在具有纳米孔（约10纳米）的传统水凝胶支架中添加规则尺寸的大孔，可显著提高胸段损伤后脊髓中局部递送转基因的表达。在具有更规则尺寸大孔的支架中观察到细胞和轴突向支架内的最大浸润。从这些支架中递送编码脑源性神经营养因子（BDNF）而非神经营养因子-3的慢病毒载体，进一步增加了浸润轴突的总数和髓鞘形成。BDNF递送后观察到后肢功能有适度改善。结果证明了大孔可注射HA支架作为SCI后局部基因治疗平台的实用性。
