Integrative colloidal gels for cranial defect repair

描述(申请人提供)：这项申请的长期目标是提供一种独特的生物材料，这种材料可以很容易地由外科医生模塑到位，并将在诱导快速组织再生时重新吸收。为了达到这个目标，我们发明了一种基于胶体凝胶技术的生物材料，我们已经证明这种材料在颅骨缺损的再生中是有效的。胶体凝胶区别于两大类支架生物材料(水凝胶和固体支架)的关键特征是它们的糊状流变性，而这又归因于纳米颗粒成分之间的静电相互作用。尽管这类新型支架在可能的合成纳米颗粒和天然纳米颗粒的无限组合中具有高度的多功能性，但我们选择将重点放在自然产生的材料与生物活性信号的受控释放的组合上。因此，本项目的目标是开发一种可延展的材料，这种材料可以在颅骨缺损处铺展到位，同时释放生物活性因子，并允许天然骨穿透和吸收材料。相应的中心假设是，与未加载的胶体凝胶或商品化的羟基磷灰石骨填充物相比，负载生长因子的胶体凝胶将显著更快、更完全地在颅骨缺损处再生骨。为了验证这一假设，我们提出了三个具体的目标：1)合成和表征具有调节流变性的新型胶体凝胶，2)在体外设计和提纯胶体凝胶，以及3)确定胶体凝胶在大鼠颅骨缺损模型中的效果。在我们已发表的原型胶体凝胶表征的基础上，我们的总体战略将是首先通过评估各种特定的硫化糖胺多聚糖(GAG，带负电荷)和羟基磷灰石纳米颗粒(带正电)的组合的流变性和释放性能来显著扩展我们的产品系列，这些组合已被确定为内部粘合的胶体凝胶网络。然后，这些组合的特定子集将在体外彻底评估它们在促进大鼠骨髓间充质干细胞(BMSCs)成骨方面的有效性。这些体外研究中最有希望的小组将在临界大小的大鼠颅骨缺损中进行评估，该项目因此最终确定了GAG、羟基磷灰石以及成骨和血管生成信号的领先组合，用于颅骨缺损的再生。该项目的成功完成将为组织工程支架生物材料的一个全新的子领域奠定基础。这一系列研究的真正影响在于其非凡的通用性和一套相对简单的设计原则，作为一种创造可生物吸收的、具有可调稠度的浆料的手段，具有控制释放生物活性信号的能力。我们和世界各地的其他研究人员将能够探索似乎无限数量的交互式纳米颗粒的创新组合，用于颅骨缺损再生以外的应用，从骨软骨再生到肝脏再生，再到任何其他需要此类材料的可想象的应用。

DESCRIPTION (provided by applicant): The long-term objective of this application is to deliver a unique biomaterial that can easily be molded into place by a surgeon, and will resorb as it induces rapid tissue regeneration. Toward this objective, we invented a biomaterial based on colloidal gel technology, which we have demonstrated to be effective in calvarial defect regeneration. The key feature that distinguishes colloidal gels from the two major classes of scaffolding biomaterials (hydrogels and solid scaffolds) is their paste-like rheology, which in turn is attributed to electrostatic interaction of the nanoparticle constituents. Although this new class of scaffolds is highly versatile in its unbounded combination of possible synthetic and natural nanoparticles, we have elected to focus on a combination of naturally occurring materials with controlled release of bioactive signals. Therefore, the objective of this project is to develop a malleable material that can be spread into place in a cranial defect, while releasing bioactive factors and allowing native bone to penetrate and resorb the material. The corresponding central hypothesis is that the growth factor-loaded colloidal gels will regenerate bone in cranial defects significantly faster and more completely than unloaded colloidal gels or commercial hydroxyapatite bone fillers. To test this hypothesis, we propose three specific aims: 1) to synthesize and characterize novel colloidal gels with modulated rheological properties, 2) to engineer and refine colloidal gels in vitro, and 3) to determine the efficacy of colloidal gels in a rat cranial defect model. Building on our published characterization of prototype colloidal gels, our overall strategy will be to significantly expand our repertoire first by evaluating the rheological and release properties of a variety of combinations of specific sulfated glycosaminoglycans (GAGs, negatively charged) and hydroxyapatite nanoparticles (positively charged), which have been identified as an internally cohesive colloidal gel network. A specific subset of these combinations will then be thoroughly evaluated in vitro for their efficacy in promoting osteogenesis with rat bone marrow-derived mesenchymal stem cells (BMSCs). The most promising groups from these in vitro studies will be evaluated in critical-sized rat calvarial defects, with the project thereby culminating in the identification of the leading combination of GAGs, hydroxyapatite, and osteogenic and angiogenic signals for calvarial defect regeneration. Successful completion of this project will lay the foundation for an entirely new sub-field for tissue engineering scaffolding biomaterials. The true impact of this line of research is its extraordinary versatility and relatively straightforward set of design principles as a means to create bioresorbable, pastes of tunable consistency, with the capability for controlled release of bioactive signals. We and other investigators world- wide will be able to explore a seemingly infinite number of innovative combinations of interactive nanoparticles for applications beyond calvarial defect regeneration, from osteochondral regeneration to liver regeneration to any other conceivable application where such a material is desired.