Over the last several years, significant progress has been made toward understanding the mechanisms involved in the mineralization of hard collagenous tissues, such as bone and dentin. Particularly notable are the identification of transient mineral phases that are precursors to carbonated hydroxyapatite, the identification and characterization of non-collagenous proteins that are involved in controlling mineralization, and significant improvements in our understanding of the structure of collagen. These advances not only represent a paradigm shift in the way collagen mineralization is viewed and understood, but have also brought new challenges to light. In this review, we discuss how recent in vitro models have addressed critical questions regarding the role of the non-collagenous proteins in controlling mineralization, the nature of the interactions between amorphous calcium phosphate and collagen during the early stages of mineralization, and the role of collagen in the mineralization process. We discuss the significance of these findings in expanding our understanding of collagen biomineralization, while addressing some of the limitations that are inherent to in vitro systems.
Collagen biomineralization is a complex process and the controlling factors at the molecular level are still not well understood. A particularly high level of spatial control over collagen mineralization is evident in the anchorage of teeth to the jawbone by the periodontal ligament. Here, unmineralized ligament collagen fibrils become mineralized at an extremely sharp mineralization front in the root of the tooth. A model of collagen biomineralization based on demineralized cryosections of mouse molars in the bone socket is presented. When exposed to metastable calcium and phosphate‐containing solutions, mineral re‐deposits selectively into the natively mineralized tissues with high fidelity, demonstrating that the extracellular matrix retains sufficient information to control the rate of mineralization at the tissue level. While solutions of simulated bodily fluid produce amorphous calcium phosphate within the tissue section, a more highly supersaturated solution stabilized with polyaspartic acid produces oriented, crystalline calcium phosphate with diffraction patterns consistent with hydroxyapatite. The model thus replicates both spatial control of mineral deposition, as well as the matrix‐mineral relationships of natively mineralized collagen fibrils, and can be used to elucidate roles of specific biomolecules in the highly controlled process of collagen biomineralization. This knowledge will be critical in the design of collagen‐based scaffolds for tissue engineering of hard‐soft tissue interfaces.
Hard-soft tissue interfaces pose unique challenges for regeneration due to architectural, mechanical, and compositional changes between tissues, which are difficult to incorporate into tissue engineering scaffolds. Multiphasic scaffolds are needed to better mimic structural and chemical changes through the incorporation of layers with distinct properties. A particular challenge in the production of multilayered constructs is achieving cohesion between layers. Herein, a novel system is developed, which combines sequential collagen self-assembly and diffusion gradients in mineralization to produce multiphasic collagen scaffolds that have intrinsic connectivity and porosity between layers, with no need for adhesives or heat treatments. The scaffolds incorporate mineralized layers, wherein the mineralized collagen fibrils have intrafibrillar oriented mineral resembling bone, alongside unmineralized layers. The interface between mineralized and unmineralized layers is sharp and well defined, with nonmineralized fibrils inserting into the mineralized layer to create mechanical interlock and cohesion. Inspired by the complex architecture of the periodontal attachment apparatus (bone-ligamentcementum), it is demonstrated that the model system can be applied to the development of a trilayered collagen scaffold with potential for periodontal regeneration.
Biomedical polymers face rigid requirements for the biocompatibility of their monomers, the final polymeric product, and their residual reagents from their synthesis schemes. However, their preparation still heavily relies on nonrenewable resources. Itaconate (ITA) is an organic acid that is used as a platform chemical for the production of numerous value-added chemicals and serves as a valuable green chemistry alternative to petrochemical derivatives. In recent years, the multiple roles of this molecule in cell metabolism have generated great attention, particularly as a modulator of inflammation and infection. Recently, we developed a family of ITA polyesters that leverage hydrolytically driven degradation to recapitulate its biofunctionality. This renewable-based material platform warrants characterization of material properties based on synthesis conditions in order to advance their potential application. In this work, we describe the development of ITA polyesters relying on defined reaction feed ratios and reaction times. Material characterization highlighted the significant impact of changing molar feed on molecular weight, which corresponded to increased viscosity and decreased percent degradation. Using 20% excess ITA monomers in the reaction led to optimal outcomes, suggesting opportunities in future material design. Leveraging this characterization, ITA polyesters can be altered through synthesis conditions to achieve appropriate and specific biopolymer applications.
The periodontium is the set of tissues responsible for tooth anchorage, and consists of interconnected layers of mineralized and unmineralized tissues (bone, ligament and cementum). The ligament-cementum interface is a particularly elegant example of biological control of mineralization and the controlling factors are poorly understood. Here we use a tissue-based in vitro model of mineralization, in which sections of demineralized mouse jaw remineralize with the same selectivity as found in vivo, to probe the molecular mechanism of control over collagen mineralization in the periodontium. Removal or enzymatic cleavage of noncollagenous proteins have very similar effects: a reduction in the rate of remineralization that is much more drastic in cementum than in dentin. The periodontal ligament does not mineralize within experimental parameters even after protein removal/digestion. Dephosphorylation results in a slight reduction in mineralization in dentin and cementum. Understanding the mechanisms controlling selective mineralization in the periodontium will help elucidate the molecular factors controlling collagen biomienralization, and provide inspiration for the development of scaffolds for regeneration of hard-soft tissue interfaces.
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