A novel injectable piezoelectric hydrogel for osteoarthritis treatment

摘要 数以百万计的美国人患有骨关节炎，目前的药物，包括止痛药和抗骨关节炎药物， 消炎药只能减轻症状，但不能完全治愈疾病。黄金待遇 迄今为止一直是使用替代性自体移植物和同种异体移植物。然而，这些移植物存在以下问题： 供区发病率、免疫排斥、感染，特别是组织供应受限。工程软骨 通过将干细胞/软骨细胞与生长因子一起接种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。尽管取得了许多令人鼓舞的结果，但临床使用的 工程化软骨移植物仍然是有限的，由于严重依赖于毒性生长因子来诱导 软骨形成由于电信号对促进组织生长具有显著的作用，并且是生物体内固有的， 电刺激（ES）可能提供了一种天然的和生物相容的方法，用于诱导 软骨再生压电材料具有将机械变形转化为 电，似乎是一个有吸引力的平台，以创造自我供电的电刺激器， 获得机械关节力或通过超声外部刺激以产生对软骨有用的ES 增长在这方面，PI最近开发了一种新型的可生物降解的压电聚合物， 聚-L-丙交酯（PLLA）是一种众所周知的生物相容性材料，用于骨支架、手术缝合线和药物， 输送装置。在这里，我们第一次提出了一种新的方法，该方法采用可注射的 压电胶原基水凝胶，含有脂肪干细胞（ADSC）和压电纳米- PLLA纤维，以增强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，可以将混合水凝胶溶液注射到软骨缺损中， 在体温下自发固化以原位形成软骨移植物。我们的主要假设是： 压电水凝胶可以通过超声刺激以产生有用的表面电荷， 从接种的ADSC细胞的软骨形成。该项目将有三个具体目标。目标1：制造 并评估压电水凝胶。目的2是评估超声下水凝胶的软骨形成 体外刺激。目的3是证明所提出的压电水凝胶的再生能力， 体内，使用具有临界尺寸软骨缺损的兔模型。里程碑：第一个里程碑是 压电干细胞水凝胶在最初12个月后具有所需的特性（目标1）。第二个里程碑 是为了证明使用超声刺激在体外诱导显著的软骨形成， 证明2年后该软骨水凝胶在体内的再生能力（目的2和3）。我们认为 所提出的可注射压电水凝胶可以作为治疗的有力平台， 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.