Regeneration of tissue interfaces: Biomaterial controlled morphogen gradients for tissue patterning in regeneration

组织界面的再生：生物材料控制的形态发生素梯度用于再生中的组织图案化

• 批准号: 245619036
• 负责人: Professor Dr.-Ing. Georg Duda
• 金额: --
• 依托单位: Julius Wolff Institut für Biomechanik und Muskuloskeletale Regeneration (CVK)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/245619036?language=en
• 关键词: Regeneration; tissue; interfaces; Biomaterial; controlled

The healing of ostechondral defects in the joint still remains a challenge for orthopaedic surgeons and none of the current techniques achieve full reconstruction and functionality of the bone and cartilage phases. A reason for the limited clinical success of treatments is the tight interplay of bone and cartilage tissues at the osteochondral junction, a classical distinct tissue pattern. With the proposed project we want to validate a new concept for distinct tissue patterning in regenerative medicine using osteochondral defects as an example system. We base our concept on a fundamental principle of developmental biology, which includes locally activators and inhibitors acting tightly together to form distinct tissue patterns. For that purpose a multi-layered construct (microsphere-based PLG scaffold) that allows for the controlled release of both stimulatory agents and their antagonists from distinct layers ws developed in cooperation. We plan to employ our biomechanically well controlled osteochondral defect model in sheep to validate the concept in vivo and compare to endogenous factor release. Specifically, the layered scaffold is composed of a cartilage zone containing TGFbeta and anti-BMP4, a middle buffer zone containing anti-BMP and anti-TGFbeta antibodies and an osteogenic inductive layer composed of BMP4 and anti-TGFbeta It is our hypothesis that spatially controlled release of both stimulatory and opposing factors from the PLG scaffold can steer tissue patterning (cartilage like tissue-tidemark-subchondral bone) in an osteochondral defect model in sheep. Basis to our analyses will be the evaluation of the endogenous response to an osteochondral defect by means of the early hematoma formation. Towards that aim, we will investigate the inflammatory response cascade initiated within the first hours after implantation of a scaffold containing either no growth factors or TGFbeta3 or BMP4 alone. We will primarily investigate the cytokine pattern and inflammatory cell response in the hematoma that develops in the freshly created osteochondral defect. In the next step, the suggestibility of this phase by TGFbeta and BMP-4 will be analyzed by implanting the scaffold loaded either with TGFbeta or BMP-4. In summary, the proposed analyses will allow judging on the feasibility of a biomaterial-based strategy to control locally tissue formation at distinct tissue junctions such as in osteochondral repair. Further, it will allow gaining understanding if such approach is helpful to overcome the current clinical shortcomings in osteochondral repair by the growth factors TGFbeta and BMP4. Once validated, this concept of distinct tissue formation may be applied to multiple other even more complex organ structures.

对于骨科医生来说，关节内骨软骨缺陷的修复仍然是一个挑战，目前的技术都没有实现骨和软骨阶段的完全重建和功能。治疗临床成功有限的一个原因是骨软骨交界处骨和软骨组织的紧密相互作用，这是一种经典的独特组织模式。通过提出的项目，我们希望以骨软骨缺失为例系统来验证再生医学中不同组织模式的新概念。我们的概念建立在发育生物学的基本原理上，该原理包括局部激活剂和抑制物紧密结合在一起形成不同的组织模式。为此，合作开发了一种多层结构(基于微球的PLG支架)，允许从不同的层控制释放刺激剂及其拮抗剂。我们计划利用我们的生物力学控制良好的绵羊骨软骨缺损模型在体内验证这一概念，并与内源性因子释放进行比较。具体地说，层状支架由含有TGFbeta和抗BMP4的软骨区，含有抗BMP和抗TGFbeta抗体的中间缓冲区和由BMP4和抗TGFbeta组成的成骨诱导层组成。我们的假设是，从PLG支架中空间控制地释放刺激和反对因子可以引导绵羊骨软骨缺损模型中的组织图案化(软骨样组织-潮标-软骨下骨)。我们分析的基础将是通过早期血肿形成来评估骨软骨缺陷的内源性反应。为此，我们将研究植入不含生长因子或仅含TGFbeta3或BMP4的支架后的第一个小时内引发的炎症反应级联反应。我们将主要研究在新形成的骨软骨缺损处形成的血肿中的细胞因子模式和炎症细胞反应。下一步，将通过植入加载了TGFbeta或BMP-4的支架来分析TGFbeta和BMP-4对这一阶段的暗示作用。总之，拟议的分析将允许对基于生物材料的策略的可行性进行判断，以局部控制不同组织交界处的组织形成，例如在骨软骨修复中。此外，如果这种方法有助于克服目前通过生长因子TGFbeta和BMP4进行的骨软骨修复的临床缺陷，它将允许获得理解。一旦得到验证，这种不同组织形成的概念可能会应用于多种其他甚至更复杂的器官结构。

项目成果

Oxidized alginate beads for tunable release of osteogenically potent mesenchymal stromal cells.

• DOI: 10.1016/j.msec.2019.109911
• 发表时间: 2019-11
• 期刊: Materials science & engineering. C, Materials for biological applications
• 作者: Gao Xiang;E. Lippens;S. Hafeez;G. Duda;S. Geissler;T. Qazi

Dosage and composition of bioactive glasses differentially regulate angiogenic and osteogenic response of human MSCs.

• DOI: 10.1002/jbm.a.36470
• 发表时间: 2018-10
• 期刊: Journal of biomedical materials research. Part A
• 作者: T. Qazi;J. Berkmann;J. Schoon;S. Geissler;G. Duda;A. Boccaccini;E. Lippens