FOR 2180: Graded Implants for Tendon-Bone Junctions (“Graded Implants”)

近年来，移植研究主要集中在同种组织的功能性组织移植上。不太详细的是植入物之间的区域组织具有强烈的不同性质，如。G.腱骨连接处自然组织连接呈现梯度：结构、组成和功能的梯度，这些梯度通过生物力学特性的改变来反映。这种复杂的情况是解决了由研究单位提出的新的，分级无细胞植入。来自宿主的内源性干细胞应被植入物激活并指导重建肌腱-骨连接，并在植入物降解后实现功能性（“再生”）连接。该研究单位的目的是证明原则的可行性，并生成一个模型的分级植入物，为未来的应用在肌腱-骨交界处的肩袖。作为基本材料，将使用具有各向同性（“肌腱侧”）或各向异性（“骨侧”）纤维取向的生物可降解聚合物（主要基于聚己内酯）的静电纺丝纤维垫。纤维垫将配备适当的孔隙率和渗透性，以允许迁移细胞的存活和功能，以及营养物质和代谢产物的交换。此外，纤维的机械性能将根据体内情况进行调整，纤维表面将被修饰并配备不同程度的纳米颗粒：聚合物纳米颗粒将作为生物活性蛋白质的释放系统。除了骨形态发生蛋白（BMP）-2和转化生长因子（TGF）-β外，还将使用新的因子Smad 8连接区+ Mad同源区2（Smad 8 L+ MH 2）。这是一种修饰的转录因子，可诱导细胞分化为肌腱细胞和肌腱组织。通过有针对性地设计纳米颗粒并通过使用将其（分级）固定在纤维垫上的方法，将根据生物需要调整释放动力学因素。为了实现长期释放，还将产生BMP 2聚集体和Smad 8 L+ MH 2的淀粉样蛋白变体。通过市售骨锚将植入物固定在骨侧。在肌腱侧，将使用缝线。将在研究单位通过使用小型和大型动物模型来验证使用植入物后再生组织连接的形成。总之，体内存在的梯度将转化为力学性能的梯度，并结合FOR 2180中生物活性蛋白质的时空控制释放。

Implant research recently focusses on functional tissue implants forhomogenous tissues. Less well elaborated are implants for regionsbetween tissues with strongly differing properties, e. g. tendon-bonejunctions. Natural tissue junctions exhibit gradients: gradients instructure, composition, and resulting functionality which are reflectedby alterations in biomechanical properties. This complex situation isaddressed by the novel, graded cell-free implant presented by theresearch unit. Endogenous stem cells from the host shall be activatedand instructed by the implant to rebuild a tendon-bone junction and toachieve a functional (“regenerated”) junction after degradation of theimplant. Aim of the research unit is to demonstrate the principlefeasibility and to generate a model of a graded implant for futureapplications at the tendon-bone junction of the rotator cuff. As basicmaterial, electrospun fibre mats from biodegradable polymers (mainlybased on polycaprolactone) with isotropic (“on the tendon side”) oranisotropic (“on the bone side”) fibre orientation will be used. The fibremats will be equipped with appropriate porosity and permeability toallow for the survival and functionality of immigrating cells as well asthe exchange of nutrients and products of metabolism. In addition, themechanical properties will be tailored according to the in vivosituation.Fibre surfaces will be modified and equipped with varyingdegrees of nanoparticles: polymeric nanoparticles will serve asrelease systems for biologically active proteins. Apart from BoneMorphogenetic Protein (BMP)-2 and Transforming Growth Factor(TGF)-β, the novel factor Smad8 Linker region + Mad homologyregion 2 (Smad8 L+MH2) will be used. This is a modified transcriptionfactor inducing differentiation of cells into tendon cells and tendontissue. By targeted design of the nanoparticles and by use of methodsfor their (graded) immobilization on the fibre mat release kinetics ofthe factors will be adjusted according to biological needs. In order toachieve long-term release also BMP2-aggregates and amyloidvariants of Smad8 L+MH2 will be produced. Fixation of the implant onthe bone side will by performed by commercially available boneanchors. At the tendon side, sutures will be used. The formation of aregenerated tissue junction after use of the implant will be verified inthe research unit by use of small and large animal models. Inconclusion, gradients existent in vivo will be translated into gradientsof mechanical properties in combination with spatially and temporallycontrolled release of biologically active proteins within FOR 2180.