Chemically and structurally directed shape morphosis in hybrid aerogels for bone tissue engineering - Toward designing smart biomimetic 3D scaffold for bone cancer therapy and bone repair

恶性骨肿瘤的治疗及肿瘤切除后骨缺损的修复仍是一个重大的临床挑战。这种肿瘤引发的大骨缺损的治疗通常需要植入具有双重功能的仿生3D多孔材料，该双重功能是通过局部化学/光热治疗杀死残留的骨肿瘤细胞，随后使骨缺损再生。此外，除了在缺损部位的成骨之外，血管化或血管形成是骨形成过程中的另一个主要挑战，这需要在支架中考虑特定的结构。3D支架的治疗和新骨再生能力（骨生成和血管生成）都受其微观结构、细胞反应性和治疗功能的控制。为了应对这些挑战，制造满足最佳生物学和肿瘤治疗功能的所有要求的合适的细胞支架材料是至关重要的。从物理和微观结构方面来看，即由于其高的孔体积、孔连通性和广泛的内表面积，气凝胶是骨组织工程中有前途的生物材料。在这项工作中，主要目标是开发一系列双功能表面改性丝素蛋白（SF）复合气凝胶支架，通过表面改性，自组装和3D打印策略的协同组合，结合了高光热效应和新骨组织和血管形成。细胞粘附肽修饰的SF在溶液中的特殊自组装能力，以及所得SF聚合物与作为无机纳米填料的1D（电纺中空二氧化硅纳米纤维）和2D纳米片（锑烯）的杂交，以及所得复合凝胶的3D打印，可以提供具有互连通道的3D材料，如孔隙率、癌细胞光热消融和骨再生潜力。作为设想工作的主要部分，将探索最先进的技术，如互穿网络或表面接枝以及新型3D打印和基于SF的混合支架的临时模板的组合，以推进当前的支架微制造技术。最有前途的三维支架将从骨再生和治疗方面进行研究。这包括体外测试，主要是成骨分化、血管生成、刺激响应性药物释放和骨癌细胞消融。预计3D打印和SF的自组装以及将无机纳米填料并入最终支架的组合赋予材料独特的治疗和骨再生的双功能特性。

The treatment of malignant bone tumors and the regeneration of the bone defects resulted from tumor resection is still a significant clinical challenge. The treatment of such a tumor-initiated large bone defect typically requires implanting the biomimetic 3D porous materials with the dual functionality of killing the residual bone tumor cells through local chemo-/photothermal therapy followed by subsequent regeneration of the bone defects. In addition, vascularization or blood vessel formation beside osteogenesis in the defect site is another major challenge in the process of bone formation, which requires a specific structural consideration in the scaffold. Both therapeutic and new bone regeneration competence (osteogenesis and angiogenesis) of the 3D scaffold are governed by control on its micro-structural, cell responsivity, and therapeutic functionalities. To address these challenges, the fabrication of appropriate cell scaffolding materials meeting all requirements for optimal biological and tumor therapeutic functions are vitally important. Aerogels from physical and microstructural aspects, namely for their high pore volume, pore interconnectivity, and extensive internal surface area, are promising biomaterials in bone tissue engineering. In this work, the principle goal is to develop a series of bifunctional surface-modified silk fibroin (SF) composite aerogel scaffolds combining a high photothermal effect and new bone tissue and vasculature formation through a synergistic combination of surface-modification, self-assembly, and 3D-printing strategies. The particular self-assembling capabilities of cell adhesive peptide modified SF in solution together with hybridization of the resulted SF polymer with 1D (electrospun hollow silica nanofiber) and 2D nanosheets (antimonene) as inorganic nanofillers, and 3D printing of the resulted composite gel could afford 3D materials with an interconnected channel like porosity, cancer cells photothermal ablation and bone regeneration potential. As a major part of the envisaged work, state-of-the-art techniques such as interpenetrating networks or surface grafting and a combination of novel 3D printing and temporary templating of SF-based hybrid scaffolds will be explored to advance current scaffold microfabrication techniques. The most promising 3D scaffold will be studied from bone regeneration and therapeutic aspects. This includes in-vitro tests, mainly osteogenic differentiation, angiogenesis, stimuli-responsive drug-releasing, and bone cancer cell ablation. It is expected that the combination of 3D printing and self-assembling of SF and incorporation of inorganic nanofillers to the final scaffold endow the materials with distinct bifunctional properties of therapy and bone regeneration.