Morphogenetically active polyphosphate, an unexpected nano-/bio-material for successful tissue regeneration Werner E. G. Mueller and Xiaohong Wang University Medical Center of the Johannes Gutenberg University Mainz, Germany Inorganic polyphosphate (polyP) is one of the oldest bio-inorganic molecules, existing in biological systems. This physiological polymer contains longer high-energy phosphate sequences than the universal energy donor adenosine triphosphate (ATP). Therefore, polyP has attracted increasing attention in the field of biomedicine since it promotes diverse metabolic and regulatory cell functions, especially in form of morphogenetically active nano/ microparticles. The polyP nanoparticles transform physiologically into a coacervate phase, which is biologically active. In combination with other materials used in tissue engineering, for example, with hydrogels, polyP is used as bioprintable bio-ink (even for cell printing) or as stable scaffolds (such as with polymethacrylates of polycaprolactone). PolyP can be used not only as a filler (bone or teeth) but also as an implant that is mechanically stable. Furthermore, together with negative polyanions, polyP self-organizes in the presence of divalent cations into stable polymer bundles, which are regeneratively active. Together with suitable hydrogel-forming polymers and divalent cations, polyP is used for the fabrication of hybrid biomaterials with defined porosity and mechanical properties; they display in vitro and in vivo morphogenic activity (promoting cell growth, differentiation, and migration). A distinct property of polyP is to generate metabolic energy, which is utilized by the extracellular macromolecules to organize the complex extracellular matrix. Additionally, polyP was shown to be a strong promoter of chronic wound healing. In our successful application to heal chronic wounds in patients, polyP was integrated into a collagen-based wound dressing as well as into a wound hydrogel. In turn, chronic wounds were supplied with polyP along two routes, firstly via blood platelets and secondly through polyP-enriched wound dressings. Recently, the physiological polymer polyP was disclosed as a member of the innate immune defense system, which prevents the binding of SARS-CoV-2 to their target cells. In parallel, polyP reinforces the metabolism of the epithelial cells in the respiratory system. In turn, polyP has been proven to be a beneficial polymer to be applied for tissue regeneration. References 1. Müller WEG, Schröder HC, Wang XH (2019) Inorganic polyphosphates as storage for and generator of metabolic energy in the extracellular matrix. Chemical Reviews 119: 12337-12374. 2. Schepler H, ……, Wang XH, Müller WEG (2022) Acceleration of chronic wound healing by bio-inorganic polyphosphate: In vitro studies and first clinical applications. Theranostics 12: 18-34.Neufurth M, ......, Wang XH, Müller WEG (2022) 3. 3D bioprinting of tissue units with mesenchymal stem cells, retaining their proliferative and differentiating potential, in polyphosphate-containing bio-ink. Biofabrication 14: 015016. 4. Müller WEG, Schröder HC, Neufurth M, Wang XH (2021) An unexpected biomaterial against SARS-CoV-2: Bio- polyphosphate blocks binding of the viral spike to the cell receptor. Materials Today 51:504-524. 5. Müller WEG, ......, Schröder HC, Wang XH (2019) Biologization of allogeneic bone grafts with polyphosphate: A route to a biomimetic periosteum. Advanced Functional Materials 29: 1905220
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