Synergistic microenvironments for non-union bone defects

骨不连缺损的协同微环境

基本信息

批准号：
MR/L022710/1
负责人：
Manuel Salmeron-Sanchez
金额：
$ 128.11万
依托单位：
University of Glasgow
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2014
资助国家：
英国
起止时间：
2014 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FL022710%2F1
关键词：
Synergistic microenvironments non union bone

项目摘要

Long bone fractures involve damage to the surrounding tissues and vascular networks and, as a result, the natural bone healing capacity is lost and non-union defects are formed. The prevalence of this clinical problem is 2.5% for bone fractures but this rate increases up to 15% and 45% when there is collateral soft tissue and vascular injuries respectively. Current treatments comprise bone autografts, bone substitutes and the use of growth factors (GFs), specially bone morphogenetic proteins (BMP) with limited success and significant drawbacks.Thus, there is an unmet clinical need to develop new therapeutic approaches for bone regeneration and vascularisation in non-union bone defects. The role of GFs in bone regeneration is broadly recognised but the delivery of these factors to enhance tissue healing, while maintaining their activity, has not been successful. Soluble administration or controlled delivery (including hydrogels and scaffolds) have failed to meet the need due to the breakdown and clearance of GFs from tissue sites. More importantly, however, catastrophic collateral risks have been reported due to the high dose used. This unsatisfactory clinical translation of growth factors demands robust, safe and effective systems that control delivery. Human bone morphogenetic protein-2 (BMP-2) is a powerful growth factor that is essential in tissue morphogenesis and is involved in a myriad of cellular processes, including cell recruitment, cell differentiation, and angiogenesis. The use of recombinant BMP-2 (rhBMP-2) has been generalised to promote bone growth in a broad range of clinical applications (spine, oral-maxillofacial and trauma). Current clinical delivery involves the incorporation of the protein in a collagen sponge carrier at a concentration of 1.5 mg/cm3. However, serious clinical complications have been reported that even led the FDA to issue a Public Health Notification of life threatening complications associated with rhBMP-2 (respiratory, neurological, inflammatory).7 Reports since then include observations of uncontrolled bone formation and carcinogenic risks associated to the high doses used. Notwithstanding collateral risks and controversy between health agencies, clinical researchers and industry, the use of rhBMP-2 continues to increase in clinical practice.8Here we present a simple and robust materials-based strategy to induce bone regeneration in non-union defects. It is based on engineered constructs that tune the interaction between GFs and their receptors and it allows very small rhBMP-2 doses to be used (< 0.1 mg/cm3) while maintaining cell activation. This will clearly make treatments cheaper, safer and more effective. It is important to note that our approach does not tune GF delivery per se, but rather it tunes the effective presentation of growth factors to cell receptors, and hence prevents collateral risks associated with the delivery of soluble rhBMP-2 at the regenerating site. The final strategy involves the implant of a cell-free 3D construct that incorporates synthetic-biodegradable polymers, extracellular matrix proteins and rhBMP-2. The system is designed to recruit stem cells in vivo (no pre-loading the construct with stem cells needed) and to promote bone regeneration in non-union defects, as well as aiding in revascularisation of the new tissue.

长骨骨折涉及对周围组织和血管网络的损害，因此，自然骨愈合能力丢失并形成了非工会缺陷。骨折的临床问题的患病率为2.5％，但是当存在附带软组织和血管损伤时，该速率高达15％和45％。当前的处理包括骨自体移植，骨骼替代品和生长因子的使用（GFS），特别是成功和显着缺点的骨形态发生蛋白（BMP）。 GF在骨骼再生中的作用得到了广泛的认可，但是这些因素在维持活性的同时增强组织愈合的传递并没有成功。由于组织部位的GF分解和清除，可溶性给药或受控的输送（包括水凝胶和支架）未能满足需求。然而，更重要的是，由于使用的高剂量，已经报道了灾难性的附带风险。这种增长因素的这种不令人满意的临床翻译需要控制交付的强大，安全有效的系统。人骨形态发生蛋白-2（BMP-2）是一个强大的生长因子，在组织形态发生中至关重要，并且参与了无数的细胞过程，包括细胞募集，细胞分化和血管生成。重组BMP-2（RHBMP-2）的使用已被推广，以促进广泛的临床应用（脊柱，口腔墨西哥叶和创伤）的骨骼生长。当前的临床递送涉及将蛋白质掺入胶原蛋白海绵载体中，浓度为1.5 mg/cm3。但是，已经报道了严重的临床并发症，即使FDA也发出了与RHBMP-2（呼吸道，神经系统，炎症性）有关的威胁生命并发症的公共卫生通知。尽管卫生机构，临床研究人员和行业之间存在附带风险和争议，但RHBMP-2的使用仍在继续增加临床实践。8，我们提出了一种简单，强大的材料策略，以诱导非工会缺陷中的骨骼再生。它基于调整GFS及其受体之间相互作用的工程构建体，并且可以在保持细胞激活的同时使用非常小的RHBMP-2剂量（<0.1 mg/cm3）。这显然会使治疗更便宜，更安全，更有效。重要的是要注意，我们的方法本身不会调整GF的递送，而是调节生长因子向细胞受体的有效表示，因此防止了与再生位点上可溶性RHBMP-2相关的附带风险。最终策略涉及无细胞的3D构建体的植入物，该构建体融合了合成 - 基因降解聚合物，细胞外基质蛋白和RHBMP-2。该系统旨在在体内募集干细胞（无需干细胞预载构建体），并促进非工会缺陷中的骨再生，并有助于新组织的血运重建。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Material-driven fibronectin assembly for high-efficiency presentation of growth factors.

DOI：
10.1126/sciadv.1600188
发表时间：
2016-08
期刊：
Science advances
影响因子：
13.6
作者：
Llopis-Hernández V;Cantini M;González-García C;Cheng ZA;Yang J;Tsimbouri PM;García AJ;Dalby MJ;Salmerón-Sánchez M
通讯作者：
Salmerón-Sánchez M

Receptor control in mesenchymal stem cell engineering