Biointerface Science: Composition-Structure-Function Relationship of Synovial Fluid's Cartilage Boundary Lubricants

生物界面是细胞、分子、组织或生物材料与另一组织或生物材料之间的界面。生物界面科学有助于理解分子和表面之间的相互作用；分子在表面上的相互作用及其产生的功能可能与溶液中的不同。生物界面是自然科学和（生物）工程的核心，在包括生物摩擦学在内的许多领域的研究中都至关重要。生物摩擦学是对滑动生物表面的润滑、摩擦和磨损的研究，它提供了对生物润滑基本机制的洞察。我的研究计划的总体目标是了解蛋白多糖4 （PRG4，一种关键的生物边界润滑剂）在相关生物界面和生物材料上的生物摩擦学和生物物理特性的基本和调控机制。关节软骨是体内的一种组织，它在充满液体的腔内承受载荷并相对于相邻的组织表面滑动，从而形成生物界面。软骨显著的低摩擦和低磨损特性得益于多种润滑模式，包括软骨、周围的滑液及其成分，以及它们之间的相互作用。边界润滑是一种重要的、有效的表面接触方式，由表面的分子提供润滑功能。存在于滑液和软骨表面的两个临界边界润滑分子是PRG4和透明质酸（HA）。两者都作为剂量依赖的软骨边界润滑剂，也共同作用，以减少摩擦水平接近滑液。然而，这种关键功能相互作用的潜在机制仍然未知。我在这里提出的项目的短期目标是通过研究PRG4与自身和HA的相互作用，利用PRG4和HA在溶液和表面的各种结构形式，并评估软骨边界润滑功能，阐明滑液软骨边界润滑剂的组成-结构-功能关系。复杂和互补的生物力学、生化和生物物理生物工程方法将用于i)评估PRG4+HA在溶液中的相互作用的程度和模式；ii)评估和量化表面PRG4+HA复合物的形成；iii)确定PRG4+HA制剂在关节软骨-软骨生物界面上的边界润滑功能。这项基础性工作既新颖又可行，并将在生物界面科学、生物摩擦学和生物工程领域取得重大进展。新颖之处在于实验方法和使用互补和复杂的生化，生物物理和生物力学方法来阐明功能性PRG4+HA相互作用的本质。由于我在PRG4和关节软骨边界润滑方面的独特专业知识和经验，以及实验室内研究PRG4+HA相互作用的其他方法的发展，以及强大的培训环境和培养高素质人才的记录，这项工作是可行的。这项工作的完成将导致生物界面科学、生物摩擦学和生物工程领域的重大进展：1)有助于了解功能性PRG4+HA相互作用的结构-成分依赖性，从而了解基本的关节润滑机制；2)就我的整体研究计划而言，为更广泛地探索生物润滑的基本机制提供一个框架，并有可能在加拿大开发新的含有PRG4+HA的生物材料和/或生物治疗液。

A biointerface is an interface between a cell, molecule, tissue, or biomaterial with another tissue or biomaterial. Biointerface science contributes to the understanding of interactions between molecules and surfaces; interactions of molecules, and their resulting function, at a surface can be different to those in solution. Biointerfaces are central to natural science and (bio)engineering, and crucial in research relating to many fields, including biotribology. Biotribology is the study of lubrication, friction and wear of sliding biological surfaces that provides insight into the fundamental mechanisms of biolubrication. The overall goal of my research program is to understand the fundamental and regulatory mechanisms of the biotribological and biophysical properties of proteoglycan 4 (PRG4, a critical biological boundary lubricant) at relevant biointerfaces and biomaterials. Articular cartilage is a tissue in the body that bears load and slides relative to an apposing tissue surface, thus forming a biointerface, in a fluid-filled cavity. The remarkable low-friction and low-wear properties of cartilage are facilitated by multiple modes of lubrication involving cartilage, the surrounding synovial fluid and its constituents, and their interaction. Boundary lubrication is an important and operative mode where surface-to-surface contact occurs, and molecules at the surface provide lubrication function. Two critical boundary lubricant molecules present in synovial fluid and at the surface of cartilage are PRG4 and hyaluronan (HA). Both function as dose-dependent cartilage boundary lubricants, and also act together to reduce friction to levels near that of synovial fluid. However, the underlying mechanism of this critical functional interaction remains unknown. The short-term objective of my program proposed here is to elucidate the composition-structure-function relationship of synovial fluid’s cartilage boundary lubricants through the study of PRG4 interactions with itself and HA, using various structural forms of PRG4 and HA, both in solution and at a surface, and assessing cartilage boundary lubrication function. Sophisticated and complementary biomechanical, biochemical, and biophysical bioengineering methods will be used to i) evaluate the extent and mode of interactions of PRG4+HA in solution; ii) assess and quantify PRG4+HA complex formation on surfaces; and iii) determine the boundary lubricating function of PRG4+HA preparations at an articular cartilage-cartilage biointerface. This fundamental work is both novel and feasible, and will result in significant advances in biointerface science, biotribology, and bioengineering. The novelty lies in the experimental approach and use of complementary and sophisticated biochemical, biophysical, and biomechanical methods to elucidate the nature of the functional PRG4+HA interaction. This work is feasible due to my unique expertise and experience with PRG4 and articular cartilage boundary lubrication, the development of additional methods within the laboratory for the study of the PRG4+HA interaction, and the strong training environment and record of training highly qualified personnel. Completion of this work will result in significant advances in the fields of biointerface science, biotribology, and bioengineering by 1) contributing to the understanding of the structure-composition dependence of the functional PRG4+HA interaction, and therefore a fundamental joint lubrication mechanism; and 2) with respect to my overall research program, provide a framework for a broader exploration of fundamental mechanisms of biological lubrication, and potentially the development of new PRG4+HA containing biomaterials and/or biotherapeutic fluids in Canada.