The Use of Coacervate Technology as a New Drug Delivery System for Musculoskeleta

使用凝聚技术作为肌肉骨骼的新型药物输送系统

基本信息

批准号：
9130004
负责人：
Johnny Huard
金额：
$ 17.85万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-04 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9130004
关键词：
Acute Age Angiogenesis Inhibitors Angiogenic Factor Area Arthritis Autologous Autologous Transplantation BMP2 gene BMP4 Biomedical Engineering Biomimetics Blood Circulation Bone Regeneration Bone Transplantation Calvaria Cell Culture Techniques Cell Therapy Childhood Chondrocytes Clinical Craniofacial Abnormalities Data Defect Degenerative polyarthritis Development Disease Drug Delivery Systems Elderly Engineered Gene Epidemic Etiology Fracture Gene Delivery Genetic Genetic Engineering Goals Gold Grant Growth Factor Harvest Healed Health Heparin Human In Vitro Injection of therapeutic agent Injury Iodoacetates Joints Knee Osteoarthritis Knowledge Lead Mediating Methods Modality Modeling Modification Morbidity - disease rate Mus Muscle Muscle satellite cell Musculoskeletal Natural regeneration Older Population Outcome Pathologic Patients Population Process Proteins Reporting Research Design Site Skeletal Muscle Skeleton Stem cells Supporting Cell Surgeon System Technology Tissue Engineering Tissues Translating Translations Transplantation United States Vascular Endothelial Growth Factor Receptor Vascular Endothelial Growth Factors Viral Woman Work angiogenesis articular cartilage base bone bone healing bone morphogenetic protein 2 bone morphogenetic protein 4 cartilage repair clinically relevant disability gene therapy healing high risk implantation improved in vivo injured interest long bone men novel novel therapeutics operation osteochondral tissue osteogenic osteogenic protein polycation prevent regenerative repaired research study socioeconomics standard of care stem cell technology success therapeutic protein

项目摘要

DESCRIPTION (provided by applicant): Incomplete healing of critical size bone defects, including defects of the craniofacial skeleton, are common. Osteogenic proteins, including bone morphogenetic protein 2 and 4 (BMP2, BMP4), promote bone healing, but the proteins have short half-lives and are rapidly cleared by the bloodstream, which limits their utility. The goals f our previous work were to develop gene therapy and tissue engineering approaches to efficiently deliver osteogenic proteins and improve bone healing using muscle-derived stem cells (MDSCs). We have shown that murine and human MDSCs (hMDSCs) genetically engineered to express BMP2 or 4 could differentiate toward an osteogenic lineage and improve bone healing in calvarial and long bone defects. We also found that concomitant gene delivery of vascular endothelial growth factor (VEGF) improves bone healing after the implantation of BMP2 or 4 expressing MDSCs. Similarly, we have reported that MDSCs isolated from mouse and human skeletal muscle were also capable of chondrogenic differentiation and could be used to promote articular cartilage repair after acute injury (osteochondral defects) and disease (osteoarthritis [OA]), especially when genetically modified to express bone morphogenetic protein 4 (BMP4-MDSC). However, in contrast to bone, our findings also suggested that genetic modification of MDSCs to express both BMP4 and the angiogenic antagonist sFlt-1, could accelerate the AC repair capacity of the cells supporting the fact that blocking angiogenesis is beneficial for AC repair. Although we have made substantial progress in muscle stem cell based therapy for bone and AC healing over the past number of years, most of our previous work involved genetic modification of the stem cells prior to transplantation, a step that limits te clinical translation of the work. We therefore propose a new set of experiments which will aim to circumvent the necessity of using viral transduction via the use of a novel heparin-polycation coacervate delivery system capable of slowly releasing the required therapeutic proteins including BMP2, VEGF and/or sFlt-1 to promote bone and AC repair in conjunction with non- transduced MDSCs. In the first set of experiments we will utilize the heparin-polycation coacervate delivery system to deliver BMP2 and VEGF to enhance hMDSC mediated bone repair. The second set of experiment will aim to promote AC repair after the induction of OA utilizing the heparin-polycation coacervate delivery system to slowly release BMP2 and sFlt-1, in combination with hMDSCs, to enhance AC repair. The efficiency of bone and AC repair with the coacervate-hMDSCs technology will be compared to both hMDSC based gene therapy and hMDSC based free protein therapy (i.e. without the use of the heparin-polycation coacervate). This application outlines a new area of research designed to offer valuable clinically relevant approaches based on novel bioengineering concepts for the treatment of musculoskeletal tissues following injury and disease.

描述（由申请人提供）：临界尺寸骨缺损的不完整愈合，包括颅面骨骼的缺陷，是常见的。成骨蛋白，包括骨形态发生蛋白2和4（BMP2，BMP4），可促进骨骼愈合，但蛋白质的半衰期短，并被血液迅速清除，这限制了它们的效用。我们以前的工作的目标是开发基因疗法和组织工程方法，以有效地提供成骨蛋白并使用肌肉衍生的干细胞（MDSC）改善骨骼愈合。我们已经表明，通过基因设计以表达BMP2或4的鼠和人类MDSC（HMDSC）可以区分成骨的谱系，并改善钙和长骨缺损的骨骼愈合。我们还发现，血管内皮生长因子（VEGF）伴随基因递送可改善BMP2或4表达MDSC的植入后的骨骼愈合。同样，我们报道说，从小鼠和人骨骼肌中分离出的MDSC也能够与软骨成生成分化，并且可用于促进急性损伤后的关节软骨修复（骨软骨缺损）和疾病（骨关节炎）（骨关节炎[OA]），尤其是当遗传上以表达骨形骨形成骨形蛋白4（bmds）。然而，与骨骼相反，我们的发现还表明，MDSC对表达BMP4和血管生成拮抗剂SFLT-1的遗传修饰可以加速支持造成的细胞的AC修复能力，这些细胞支持阻断血管生成有益于AC修复。尽管在过去的几年中，我们在基于肌肉干细胞的骨骼和AC愈合方面取得了重大进展，但我们先前的大多数工作都涉及在移植前对干细胞的遗传修饰，这一步骤限制了工作的临床翻译。因此，我们提出了一套新的实验，该实验将通过使用新型肝素 - 聚会凝聚输送系统来规避使用病毒转导的必要性，该系统能够缓慢释放所需的治疗蛋白，包括BMP2，VEGF和/或SFLT-1，并与非传递MDSCS促进骨骼和AC修复。在第一组实验中，我们将利用肝素 - 聚凝聚液输送系统传递BMP2和VEGF，以增强HMDSC介导的骨修复。第二组实验将旨在促进OA诱导后，利用肝素聚凝胶凝聚液递送系统慢慢释放BMP2和SFLT-1，并结合HMDSC，以增强AC修复。将与基于HMDSC的基因疗法和基于HMDSC的基于HMDSC的游离蛋白质治疗相比，将骨和交流修复的效率将其比较（即不使用肝素 - 溶解凝聚）。该应用程序概述了一个新的研究领域，旨在根据新型生物工程概念提供有价值的临床相关方法，用于治疗受伤和疾病后肌肉骨骼组织的治疗。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The use of heparin/polycation coacervate sustain release system to compare the bone regenerative potentials of 5 BMPs using a critical sized calvarial bone defect model.

DOI：
10.1016/j.biomaterials.2022.121708
发表时间：
2022-09
期刊：
Biomaterials
影响因子：
14
作者：
通讯作者：

Influence of fixation on CA4+ contrast enhanced microCT of articular cartilage and subsequent feasibility for histological evaluation.

DOI：
发表时间：
2021
期刊：
American journal of translational research
影响因子：
2.2
作者：
Xueqin Gao;Amit N. Patwa;Zhenhan Deng;Hajime Utsunomiya;M. Grinstaff;Joseph J. Ruzbarsky;B. Snyder;S. Ravuri;M. Philippon;J. Huard
通讯作者：
Xueqin Gao;Amit N. Patwa;Zhenhan Deng;Hajime Utsunomiya;M. Grinstaff;Joseph J. Ruzbarsky;B. Snyder;S. Ravuri;M. Philippon;J. Huard