Integrative colloidal gels for cranial defect repair

描述（由申请人提供）：本申请的长期目标是提供一种独特的生物材料，该材料可由外科医生轻松模制到位，并在诱导快速组织再生时吸收。为了实现这一目标，我们发明了一种基于胶体凝胶技术的生物材料，我们已经证明它在颅骨缺损再生中是有效的。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，这又归因于纳米颗粒成分的静电相互作用。虽然这类新的支架在其可能的合成和天然纳米颗粒的无限组合方面具有高度的通用性，但我们选择专注于天然材料与生物活性信号的受控释放的组合。因此，本项目的目标是开发一种可延展的材料，该材料可以在颅骨缺损中扩散到位，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业羟基磷灰石骨填充物相比，加载生长因子的胶体凝胶将显著更快且更完全地再生颅骨缺损中的骨。为了验证这一假设，我们提出了三个具体的目标：1）合成和表征新的胶体凝胶与调制的流变性能，2）工程和完善胶体凝胶在体外，和3）确定胶体凝胶在大鼠颅骨缺损模型的疗效。基于我们已发表的原型胶体凝胶的表征，我们的总体策略将是首先通过评估特定硫酸化糖胺聚糖（GAG，带负电荷）和羟基磷灰石纳米颗粒（带正电荷）的各种组合的流变学和释放特性来显着扩展我们的库，这些组合已被确定为内部内聚胶体凝胶网络。这些组合的一个特定子集，然后将在体外彻底评估其在促进大鼠骨髓间充质干细胞（BMSC）的成骨作用。这些体外研究中最有前途的组将在临界大小的大鼠颅骨缺损中进行评估，该项目最终确定了用于颅骨缺损再生的GAG、羟基磷灰石以及成骨和血管生成信号的主要组合。 该项目的成功完成将为组织工程支架材料这一全新的研究领域奠定基础。这一系列研究的真正影响是其非凡的多功能性和相对简单的设计原则，作为一种手段来创建生物可吸收的，可调一致性的糊剂，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看似无限数量的相互作用纳米颗粒的创新组合，用于颅骨缺损再生以外的应用，从骨软骨再生到肝再生，再到任何其他需要这种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.