A novel injectable piezoelectric hydrogel for osteoarthritis treatment

摘要 数以百万计的美国人患有骨性关节炎，目前的药物包括止痛药和抗炎药 炎症性药物只能缓解症状，但不能完全治愈疾病。黄金待遇 到目前为止，已经使用了替换的自体移植物和异体移植物。然而，这些移植物面临的问题是 供体部位发病率、免疫排斥反应、感染，尤其是组织供应受限。工程化软骨 通过将干细胞/软骨生成细胞与生长因子一起种植到生物材料支架上构建的移植物， 已经成为一种引人注目的替代组织来源。尽管有许多令人鼓舞的结果，但临床应用 由于严重依赖有毒生长因子的诱导，工程化软骨移植仍然有限。 软骨生成。因为电信号对促进组织生长有显著作用，而且是生命所固有的 对于生物体，电刺激(ES)可能提供了一种自然和生物相容的诱导方法 软骨再生。具有令人兴奋的将机械变形转化为 电力似乎是创造自供电电刺激器的一个有吸引力的平台，它可以 获取机械关节力或在超声波的外部刺激下产生有用的软骨ES 成长。在这方面，PI最近开发了一种新型的可生物降解的压电聚合物，由 聚乳酸-L-丙交酯(PLLA)是一种著名的生物相容性材料，用于骨支架、外科缝合线和药物. 递送设备。在这里，我们首次提出了一种新的方法，它使用了可注射的 含有脂肪干细胞(ADSCs)和压电纳米材料的压电胶原基水凝胶 聚乳酸纤维，以促进超声刺激下的软骨再生。通过最低限度的- 在侵入性关节镜手术中，混合水凝胶溶液可以被注射到软骨缺损处，并 在体温下自发愈合，形成原位软骨移植。我们的主要假设是；这 超声波可以刺激压电水凝胶产生有用的表面电荷，从而促进 从种植的ADSC细胞分化为软骨细胞。该项目将有三个具体目标。目标1是制造 并对压电水凝胶进行评估。目的2是在超声波作用下评估该水凝胶的软骨形成。 体外刺激。目标3是展示所提出的压电式水凝胶的再生能力 活体，使用具有临界大小的软骨缺损的兔模型。里程碑：第一个里程碑是获得 头12个月后具有所需性能的压电干细胞水凝胶(目标1)。第二个里程碑 是演示使用超声波刺激在体外诱导显著的软骨生成，以及 2年后在体内显示该软骨水凝胶的再生能力(目标2和3)。我们相信 建议的可注射压电水凝胶可以作为治疗和治疗的强大平台 不同组织的再生，不仅包括软骨，还包括神经、骨骼、肌肉等。

Abstract Millions of American suffer from osteoarthritis, and current medicines including analgesics and anti- inflammatory drugs only alleviate the symptoms but do not completely cure the disease. The golden treatment so far has been to use replacement auto-grafts and allo-grafts. These grafts however struggle with problems of donor site morbidity, immune-rejection, infection and especially, limit of tissue supply. Engineered cartilage grafts, constructed by seeding stem/chondrogenic cells onto biomaterial scaffolds along with growth factors, have emerged as a compelling alternative tissue source. Despite many encouraging results, clinical use of the engineered cartilage grafts is still limited due to the heavy dependence on toxic growth factors to induce chondrogenesis. As electrical signal has a significant effect on promoting tissue growth and is inherent in living organisms, electrical stimulation (ES) presumably offers a natural and biocompatible approach for inducing cartilage regeneration. Piezoelectric materials with an exciting ability to convert mechanical deformation into electricity, appear to be an appealing platform to create self-powered electrical stimulators which can either harvest mechanical joint-force or be externally stimulated by ultrasound to generate useful ES for cartilage growth. In this regard, the PI has recently developed a novel biodegradable piezoelectric polymer, made of Poly-L-lactide (PLLA), a well-known biocompatible material used for bone scaffolds, surgical sutures and drug- delivery devices. Here, we propose for the first time, a novel approach which employs an injectable piezoelectric collagen-based hydrogel, containing adipose stem cells (ADSCs) and piezoelectric nano- fibers of PLLA, to enhance cartilage regeneration under ultrasound stimulus. Through a minimally- invasive arthroscopic procedure, the hybrid hydrogel solution could be injected into a cartilage defect and spontaneously cured under body temperature to form a cartilage graft in situ. Our main hypothesis is that; this piezoelectric hydrogel can be stimulated by ultrasound to generate useful surface charge which will promote chondrogenesis from the seeded ADSC cells. The project will have three specific aims. Aim 1 is to fabricate and assess the piezoelectric hydrogel. Aim 2 is to assess chondrogenesis of the hydrogel under ultrasound stimulation in vitro. Aim 3 is to demonstrate regenerative capability of the proposed piezoelectric hydrogel in vivo, using a rabbit model with critical size cartilage defects. Milestones: the first milestone is to obtain the piezoelectric stem-cell hydrogel with desired properties after the first 12 months (aim 1). The second milestone is to demonstrate the use of ultrasound stimulation for inducing a significant chondrogenesis in vitro and demonstrate regenerative capability of this cartilage hydrogel in vivo after 2 years (aims 2 and 3). We believe the proposed injectable piezoelectric hydrogel could serve as a powerful platform for the treatment and regeneration of different tissues including not only cartilages but also nerves, bones, muscles etc.