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; 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创新类型的超声反应性水凝胶，用于受控 血管内皮生长因子（VEGF）和骨形态发生蛋白的持续递送 （BMP）改善节段性骨缺损的血管生成，成骨和愈合。 VEGF和BMP 探索了洗脱材料和注射，以促进骨骼再生并改善 结果，但是这些细胞因子在骨缺损中的不受控制的释放通常会导致严重的副作用 作为术后炎症，异位骨形成，破骨细胞介导的骨吸收，不适当 脂肪生成和宫颈肿胀。 为了应对这一挑战，我们提出了下一代超声控制药物的合理设计 系统，由含有由超声的VEGF和BMP组成的VEGF和BMP组成 敏感的Diels-Alder（DA）组。超声敏感的DA部分将用于连接VEGF和BMP-2 进入PEG水凝胶。这些DA连接器的设计使得它们在生理学下保持稳定 条件但在适当的聚焦超声（FUS）刺激时，有效地经历了复古反应 能量，导致复古反应，VEGF和BMP-2释放。聚焦超声刺激允许 精确的激活和重复超声刺激的时空控制可以持续传递 在骨再生的关键时期。复古裂解反应的定义动力学是启用的关键 特征，使水凝胶在生理条件下保持稳定数周，但要进行复古 反应和释放细胞因子在不损害组织的方案中应用超声能量 或灭活细胞因子。该提案中提出了两个假设。 1）复古反应动力学 当FUS刺激时，将与细胞因子释放相关，2）VEGF和BMP-2的释放 可以通过将FUS能量调谐到DA复古反应屏障来依次控制。假设是 以两个具体目标进行测试。 AIM 1：确定Diels-Alder交叉链接组成对FUS的影响 水凝胶的响应以及VEGF和BMP-2的相关释放动力学。 AIM 2：探索FUS介导的 在节段缺陷修复中，从水凝胶中释放VEGF和BMP-2。 长期目标是开发一种结合刺激的新的和创新的受控药物输送系统 响应敏感的水凝胶和FUS，提供一种微创的，图像引导的方法，用于空间和时间 控制在复杂的深层组织伤口环境中的细胞因子的递送。这项技术代表 与当前自体移植或同种异体重建方法相比，范式转移通常失败 嫁接的整合度不佳或使用BMP洗脱海绵，其中经常不受控制的释放 由于BMP快速扩散到周围的组织中，导致异位骨化。