Biofunctionalization of cancellous bone allografts for the therapy of critical size bone defects

由于创伤、感染、退行性疾病、肿瘤切除、假体周围骨丢失或先天性畸形引起的临界尺寸骨缺损的手术治疗是一项特殊的治疗挑战。自体骨移植作为治疗扩展性骨缺损的金标准，提供骨前体细胞、生长因子和用于位点特异性骨再生的结构支架。然而，自体骨移植与供体部位坏死有关（例如，神经血管损伤、血肿、骨折和感染），并且不能提供无限量的骨移植材料（特别是在老年人和/或骨质疏松症患者中）。为了避免供体部位发病率，并且由于骨自体移植物的可用性有限，使用松质骨同种异体移植物（CBA）已成为一种替代策略。然而，无菌CBA缺乏骨形成细胞、生长因子和对骨再生重要的其他有机结构组分，这导致由于骨整合到缺损部位的不足而引起的移植失败率增加。生物活性因子的功能化可以增强CBA的长期骨整合，改善CBA的临床表现。生物活性因子的天然来源是富血小板血浆（PRP）。PRP可以通过各种离心步骤从全血中获得，并且代表与未处理的血液样品相比含有3至5倍高的血小板浓度的血浆部分。通过激活PRP内的血小板，释放出广泛的生长因子、趋化因子、胺、细胞外基质蛋白和核苷酸，所有这些都可以促进早期骨再生。为了实现这些生物活性因子的控制和持续释放，PRP可以与不同的药物递送系统相结合。本项目的目的是开发一种3D多孔CBA与基于水凝胶的药物递送系统的最佳组合，以控制和持续的方式从PRP中释放生物活性因子。因此，将研究PRP与不同市售和临床批准的水凝胶的组合对生长因子释放动力学、生物相容性和对骨髓源性细胞的趋化作用。根据这些结果，最佳的水凝胶结合PRP将与3D多孔CBA相结合，以开发均匀涂覆的生物活性材料。

The surgical treatment of critical-size osseous defects that may arise from trauma, infection, degenerative diseases, tumor resection, periprosthetic bone loss, or congenital deformities is posed to be a special therapeutic challenge. Autologous bone grafting as the golden standard for the treatment of extended bone defects provides both bone precursor cells, growth factors, and a structural scaffold for site-specific bone regeneration. However, autologous bone grafting is associated with donor sitemorbidity (e.g., neurovascular injury, haematoma, fracture, and infection) in up to 30% of the patients and does not provide unlimited amounts of bone graft material (especially in older and/or patients with osteoporosis).To avoid donor site morbidity and due to the limited availability of bone autograft, the use of cancellous bone allografts (CBA) has become an alternative strategy. However, sterilized CBA lacks bone forming cells, growth factors and other organic structural components important for bone regeneration that leads to an increased rate of transplant failure caused by insufficient bony integration into the defect site. Functionalization with bioactive factors may enhance long-term osseointegration and improve the clinical performance of CBA. A natural source of bioactive factors is platelet rich plasma (PRP). PRP can be obtained from whole blood through various centrifugation steps and represents a fraction of plasma containing a 3- to 5-fold higher platelet concentration compared to untreated blood samples. By activating the platelets within the PRP a broad spectrum of growth factors, chemokines, amines, extracellular matrix proteins and nucleotides is released all of which can promote early bone regeneration. To achieve a controlled and sustained release of these bioactive factors PRP can be combined with different drug delivery systems.The aim of this project is to develop an optimal combination of 3D porous CBA with hydrogel based drug delivery systems releasing bioactive factors from PRP in a controlled and sustained manner. Therefore combinations of PRP and different commercially available and clinically approved hydrogels will be investigated concerning growth factor release kinetics, biocompatibility and chemotactic effects on bone marrow-derived cells. Depending on these results the optimal hydrogel incorporating PRP will be combined with 3D porous CBA to develop a homogeneously coated bioactive material.