Department of Biomedical Engineering, University of Connecticut, Storrs, Connecticut, USA.
Connecticut Convergence Institute for Translation in Regenerative Engineering, UCONN Health, Farmington, Connecticut, USA.
J Biomed Mater Res A. 2023 Aug;111(8):1200-1215. doi: 10.1002/jbm.a.37508. Epub 2023 Feb 2.
Cell therapy is emerging as an effective treatment strategy for many diseases. Here we describe a novel approach to bone tissue repair that combines hydrogel-based cell therapy with low intensity pulsed ultrasound (LIPUS), an FDA approved treatment for fracture repair. Bone marrow-derived stromal cells (BMSCs) have been encapsulated in type I collagen hydrogels and mechanically stimulated using LIPUS-derived acoustic radiation force (ARF). We observed the expression and upward trend of load-sensitive, osteoblast-specific markers and determined that the extent of cell response is dependent on an optimal combination of both hydrogel stiffness and ARF intensity. Specifically, cells encapsulated in hydrogels of optimal stiffness respond at the onset of ultrasound by upregulating early bone-sensitive markers such as calcium, cyclooxygenase-2, and prostaglandin E , and later by supporting mineralized tissue formation after 21 days of culture. In vivo evaluation of a critical size calvarial defect in NOD scid gamma (NSG) mice indicated that the implantation of BMSC-laden hydrogels of optimal stiffness improved healing of calvarial defects after daily administration of ARF over 4 weeks. Collectively, these findings validate the efficacy of our system of localized cell delivery for treating bone defects where undifferentiated BMSCs are induced to the osteoblastic lineage. Further, in vivo healing may be enhanced via non-invasive transdermal mechanical stimulation of implanted cells using ARF.
细胞疗法作为许多疾病的有效治疗策略正在兴起。在这里，我们描述了一种新的骨组织修复方法，将基于水凝胶的细胞疗法与低强度脉冲超声（LIPUS）相结合，LIPUS 是一种经 FDA 批准用于骨折修复的治疗方法。骨髓基质细胞（BMSCs）已被包裹在 I 型胶原水凝胶中，并使用 LIPUS 衍生的声辐射力（ARF）进行机械刺激。我们观察到负载敏感的成骨细胞特异性标志物的表达和上升趋势，并确定细胞反应的程度取决于水凝胶刚度和 ARF 强度的最佳组合。具体来说，在超声开始时，最佳刚度的水凝胶中包裹的细胞通过上调钙、环氧化酶-2 和前列腺素 E 等早期骨敏感标志物来上调，在 21 天的培养后，通过支持矿化组织的形成来进一步响应。在 NOD scid gamma（NSG）小鼠的临界大小颅骨缺损的体内评估表明，在 4 周的时间内每天给予 ARF 后，负载最佳刚度 BMSC 的水凝胶的植入可改善颅骨缺损的愈合。总的来说，这些发现验证了我们局部细胞递送系统治疗未分化 BMSCs 诱导成骨细胞谱系的骨缺损的疗效。此外，通过使用 ARF 对植入细胞进行无创经皮机械刺激可能会增强体内愈合。
