Complex mechanisms are responsible for the biomineralization of skeletal tissues and pathological calcification in the cardiovascular system. In this Review, the physiochemical and biomechanical properties of mineralized tissues, both physiologic and pathophysiologic, and analytical methods to elucidate their finer structure are discussed.

A materials science vision of extracellular matrix mineralization

The natural extracellular matrix (ECM),thanks to its specific properties (e.g., collagenous lattice, a reservoir of growth factors, ECM-cell anchoring areas, an optimal pH and CO2 ),ensures an optimal microenvironment for homeostatic and regenerative cell development. In the context of regenerative medicine, ECM is a lair for residual and infiltrative cells. The aim of the clinical usage of cell-free ECM scaffolds is the enhancement of tissue regeneration with possible minimization of an adverse host reaction on allogeneic or xenogeneic biomaterial. Thus, the objective of decellularization is to obtain acellular grafts characterized by optimal biological properties, such as a lack of remaining cellular elements (e.g., cell membrane phospholipids and proteins, nucleic acids, mitochondria), lack of immunogenicity, lack of calcification promotion and lack of cytotoxicity (e.g., in unrinsed detergents). Furthermore, cell-free ECM scaffolds should present the optimal mechanical and structural properties that may ensure the biocompatibility of the graft. The maintenance of the ultrastructure composition of the ECM is one of the most important goals of decellularization. All physical, chemical, and biological methods proposed (used separately or in combination to extract cells from tissues/organs) are not 100% effective in cell removal and always cause a disruption of the ECM texture, as well as a probable loss of important structure components. Although cell-free ECM scaffolds are generally classified as medical devices, there are no widely accepted or legally defined criteria for quality control/evaluation methods of obtained matrices. Such criteria must be provided. Some of them have been proposed in this manuscript. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 909-923, 2018.

A review of decellurization methods caused by an urgent need for quality control of cell-free extracellular matrix' scaffolds and their role in regenerative medicine.

Cardiovascular diseases have become the leading cause of death worldwide. The increasing burden of cardiovascular diseases has become a major public health problem and how to carry out efficient and reliable treatment of cardiovascular diseases has become an urgent global problem to be solved. Recently, implantable biomaterials and devices, especially minimally invasive interventional ones, such as vascular stents, artificial heart valves, bioprosthetic cardiac occluders, artificial graft cardiac patches, atrial shunts, and injectable hydrogels against heart failure, have become the most effective means in the treatment of cardiovascular diseases. Herein, an overview of the challenges and research frontier of innovative biomaterials and devices for the treatment of cardiovascular diseases is provided, and their future development directions are discussed.

Development of Innovative Biomaterials and Devices for the Treatment of Cardiovascular Diseases

In recent years, valvular heart disease has become a serious disease threatening human life and is a major cause of death worldwide. However, the glutaraldehyde (GLU)-treated biological heart valves (BHVs) fail to meet all requirements of clinical application due to disadvantages such as valve thrombus, cytotoxicity, endothelialization difficulty, immune response, and calcification. Encouragingly, there are a large number of carboxyls as well as a few amino groups on the surface of GLU-treated BHVs that can be modified to enhance biocompatibility. Inspired by natural biological systems, we report a novel approach in which the heart valve was cross-linked with erythrocyte membrane biomimetic drug-loaded nanoparticles. Such modified heart valves not only preserved the structural integrity, stability, and mechanical properties of the GLU-treated BHVs but also greatly improved anti-coagulation, anti-inflammation, anti-calcification, and endothelialization. The in vitro results demonstrated that the modified heart valves had long-term anti-coagulation properties and enhanced endothelialization processes. The modified heart valves also showed good biocompatibility, including blood and cell biocompatibility. Most importantly, the modified heart valves reduced the TNF-α levels and increased IL-10 compared to GLU-treated BHVs. In vivo animal experiments also confirmed that the modified heart valves had an ultrastrong resistance to calcification after implantation in rats for 120 days. The mechanism of anti-calcification in vivo was mainly due to the controlled release of anti-inflammatory drugs that reduced the inflammatory response after valve implantation. In summary, this therapeutic approach based on BHVs cross-linking with erythrocyte membrane biomimetic nanoparticles sparks a novel design for valvular heart disease therapy.

Heart Valves Cross-Linked with Erythrocyte Membrane Drug-Loaded Nanoparticles as a Biomimetic Strategy for Anti-coagulation, Anti-inflammation, Anti-calcification, and Endothelialization.

Polyzwitterion-crosslinked hybrid tissue with antithrombogenicity, endothelialization, anticalcification properties

A novel crosslinking method for improved tear resistance and biocompatibility of tissue based biomaterials

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A novel crosslinking method for improved tear resistance and biocompatibility of tissue based biomaterials