Ultrasound responsive hydrogels for stimulated combinatorial drug delivery

用于刺激组合药物递送的超声响应水凝胶

• 批准号: 10742110
• 负责人: Daniel J. Hayes
• 金额: $ 36.13万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10742110
• 关键词: Address; Allografting; Autologous Transplantation; Blood; Blood Vessels; Bone Morphogenetic Proteins; Bone Regeneration; Bone Resorption; Bone Transplantation; Bone remodeling; Cervical; Clinical; Clinical Treatment; Collagen; Complex; Craniofacial Abnormalities; Defect; Development; Diels Alder reaction; Diffusion; Drug Delivery Systems; Drug Kinetics; Endothelium; Enzyme-Linked Immunosorbent Assay; Enzymes; Femur; Fluorescence; Focused Ultrasound; Gel; Goals; Growth; Heterotopic Ossification; Histologic; Histology; Human; Hydrogels; Immunofluorescence Immunologic; In Vitro; Inflammation; Injections; Kinetics; Link; Liver; Measures; Mediating; Mesenchymal Stem Cells; Methods; Modeling; Organ; Osteoclasts; Osteogenesis; Pathway interactions; Patient-Focused Outcomes; Physiological; Polyethylene Glycols; Porifera; Postoperative Period; Public Health; Reaction; Research Project Summaries; Rheology; Serum; Sprague-Dawley Rats; Stimulus; Swelling; System; Techniques; Technology; Testing; Time; Tissues; Toxic effect; Ultrasonic Therapy; VEGF165; VEGFA gene; Vascular Endothelial Growth Factors; Vascularization; Weight-Bearing state; angiogenesis; biomaterial compatibility; bone; bone marrow mesenchymal stem cell; bone metabolism; bone quality; combinatorial; controlled release; critical period; crosslink; cytokine; cytotoxicity; density; design; healing; image guided; image-guided drug delivery; improved; improved outcome; in vivo; innovation; lipid biosynthesis; microCT; minimally invasive; next generation; novel therapeutics; osteogenic; progenitor; protein metabolism; rational design; reconstruction; repaired; response; side effect; spatiotemporal; stem cell model; success; ultrasound; wound; wound environment

Project Summary This research explores a new and innovative class of ultrasound responsive hydrogels for controlled and sustained delivery of Vascular Endothelial Growth Factor (VEGF) and Bone Morphogenic Protein (BMP) to improve angiogenesis, osteogenesis and healing of segmental bone defects. VEGF and BMP eluting materials and injections have been explored extensively to promote bone regeneration and improve outcomes but the uncontrolled release of these cytokines in bone defects often leads to severe side effects such as postoperative inflammation, heterotopic bone formation, osteoclast-mediated bone resorption, inappropriate adipogenesis and cervical swelling. To address this challenge, we propose rational design of a next generation ultrasound controlled drug delivery system, composed of a VEGF and BMP containing polyethylene glycol (PEG) hydrogel crosslinked by ultrasound sensitive, Diels-Alder (DA) groups. The ultrasound sensitive DA moieties will serve to attach VEGF and BMP-2 into a PEG hydrogel. These DA linkers have been designed such that they are stable under physiological conditions but efficiently undergo a retro reaction when stimulated by focused ultrasound (fUS) at the appropriate energy, resulting in retro DA reaction and VEGF and BMP-2 release. Focused ultrasound stimulation allows for precise spatiotemporal control of activation and repeated ultrasound stimulation allows for sustained delivery during critical periods of bone regeneration. The defined kinetics of retro DA cleavage reaction is the key enabling feature, allowing the hydrogel to remain stable for weeks at physiological conditions, but to undergo a retro reaction and release cytokines with the application of ultrasound energy in regimes that do not damage tissue or inactivate cytokines. There are two hypotheses addressed in this proposal; 1) The retro DA reaction kinetics will correlate with release rates cytokine release when stimulated by fUS, 2) The release of VEGF and BMP-2 can be controlled sequentially by tuning the fUS energy to the DA retro reaction barrier. The hypotheses are tested in two specific aims. Aim 1: Determine the influence of Diels-Alder cross-linkage composition on the fUS response of hydrogels and the associated release kinetics of VEGF and BMP-2. Aim 2: Explore fUS-mediated release of VEGF and BMP-2 from hydrogels on bone regeneration in segmental defect repair. The long-term goal is to develop a new and innovative controlled drug delivery system combining stimuli responsive hydrogels and fUS, to provide a minimally invasive, image guided method to spatially and temporally control the delivery of cytokines in complex, deep tissue wound environments. This technology represents a paradigm shift compared to current autograft or allograft reconstruction methods, which often fail due to poor integration of the graft or the use of BMP eluting sponges wherein the uncontrolled release often results in heterotopic ossification as a consequence of rapid BMP diffusion into surrounding tissue.

项目摘要 这项研究探索了一种新的和创新的超声波响应水凝胶，用于控制 血管内皮生长因子（VEGF）和骨形态发生蛋白的持续递送 (BMP)以改善血管生成、骨生成和节段性骨缺损的愈合。VEGF和BMP 洗脱材料和注射剂已经被广泛地研究以促进骨再生和改善骨再生。 但是这些细胞因子在骨缺损中的不受控制的释放经常导致严重的副作用， 如术后炎症、异位骨形成、破骨细胞介导的骨吸收、不适当的 脂肪形成和颈部肿胀。 为了应对这一挑战，我们提出了下一代超声控制药物输送的合理设计 系统，由通过超声交联的含有VEGF和BMP的聚乙二醇（PEG）水凝胶组成 敏感的Diels-Alder（DA）组。超声敏感的DA部分将用于附着VEGF和BMP-2 聚乙二醇水凝胶这些DA接头已经被设计成使得它们在生理条件下是稳定的。 条件下，但有效地进行逆反应时，刺激的聚焦超声（fUS）在适当的 能量，导致逆DA反应和VEGF和BMP-2释放。聚焦超声刺激允许 激活和重复超声刺激的精确时空控制允许持续递送 在骨再生的关键时期。确定的逆DA裂解反应的动力学是关键， 特征，允许水凝胶在生理条件下保持稳定数周，但要经历逆转， 在不损伤组织的情况下应用超声能量反应并释放细胞因子 或促细胞因子。本研究提出了两个假设：1）DA还原反应动力学 当被fUS刺激时，VEGF和BMP-2的释放与释放速率细胞因子释放相关，2）VEGF和BMP-2的释放 可以通过将fUS能量调节到DA逆反应势垒来顺序地控制。的假设是 在两个具体目标中进行测试。目的1：确定Diels-Alder交联组合物对fUS的影响 水凝胶的响应以及VEGF和BMP-2的相关释放动力学。目的2：探索fUS介导的 从水凝胶中释放VEGF和BMP-2对节段性缺损修复中骨再生的影响。 长期目标是开发一种新的和创新的控制药物输送系统相结合的刺激 响应性水凝胶和fUS，以提供微创的图像引导方法， 在复杂的深层组织伤口环境中控制细胞因子的递送。这项技术代表了 与目前的自体移植物或同种异体移植物重建方法相比，范式转变， 移植物的不良整合或BMP洗脱海绵的使用， 由于BMP快速扩散到周围组织中而导致异位骨化。