Energy level as a theranostic factor for successful therapy of tissue injuries with polyphosphate: the triad metabolic energy - mechanical energy - heat.

Tissue regeneration of skin and bone is an energy-intensive, ATP-consuming process that, if impaired, can lead to the development of chronic clinical pictures. ATP levels in the extracellular space including the exudate of wounds, especially chronic wounds, are low. This deficiency can be compensated by inorganic polyphosphate (polyP) supplied the blood platelets to the regenerating site.

Liquid-liquid phase transition as a basis for novel materials for skin repair and regeneration.

Inorganic materials are of increasing interest not only for bone repair but also for other applications in regenerative medicine. In this study, the combined effects of energy-providing, regeneratively active inorganic polyphosphate (polyP) and also morphogenetically active pearl powder on wound healing were investigated. Aragonite, the mineralic constituent of pearl nacre and thermodynamically unstable form of crystalline calcium carbonate, was found to be converted into a soluble state in the presence of a Ca-containing wound exudate, particularly upon addition of sodium polyP (Na-polyP), driven by the transfer of Ca ions from aragonite to polyP, leading to liquid-liquid phase separation to form an aqueous Ca-polyP coacervate.

Cucurbit[8]uril Mediated Supramolecular and Photocrosslinked Interpenetrating Network Hydrogel Matrices for 3D-Bioprinting.

Printing of biologically functional constructs is significant for applications in tissue engineering and regenerative medicine. Designing bioinks remains remarkably challenging due to the multifaceted requirements in terms of the physical, chemical, and biochemical properties of the three-dimensional matrix, such as cytocompatibility, printability, and shape fidelity. In order to promote matrix and materials stiffness, while not sacrificing stress relaxation mechanisms which support cell spreading, migration, and differentiation, this work reports an interpenetrating network (IPN) bioink design.

Polyphosphate Nanoparticles: Balancing Energy Requirements in Tissue Regeneration Processes.

Nanoparticles of a particular, evolutionarily old inorganic polymer found across the biological kingdoms have attracted increasing interest in recent years not only because of their crucial role in metabolism but also their potential medical applicability: it is inorganic polyphosphate (polyP). This ubiquitous linear polymer is composed of 10-1000 phosphate residues linked by high-energy anhydride bonds. PolyP causes induction of gene activity, provides phosphate for bone mineralization, and serves as an energy supplier through enzymatic cleavage of its acid anhydride bonds and subsequent ATP formation.

The Physiological Inorganic Polymers Biosilica and Polyphosphate as Key Drivers for Biomedical Materials in Regenerative Nanomedicine.

There is a need for novel nanomaterials with properties not yet exploited in regenerative nanomedicine. Based on lessons learned from the oldest metazoan phylum, sponges, it has been recognized that two previously ignored or insufficiently recognized principles play an essential role in tissue regeneration, including biomineral formation/repair and wound healing. Firstly, the dependence on enzymes as a driving force and secondly, the availability of metabolic energy.

Acceleration of Wound Healing through Amorphous Calcium Carbonate, Stabilized with High-Energy Polyphosphate.

Amorphous calcium carbonate (ACC), precipitated in the presence of inorganic polyphosphate (polyP), has shown promise as a material for bone regeneration due to its morphogenetic and metabolic energy (ATP)-delivering properties. The latter activity of the polyP-stabilized ACC ("ACC∙PP") particles is associated with the enzymatic degradation of polyP, resulting in the transformation of ACC into crystalline polymorphs. In a novel approach, stimulated by these results, it was examined whether "ACC∙PP" also promotes the healing of skin injuries, especially chronic wounds.

Development of a 3D simulator for training the mouse in utero electroporation.

In utero electroporation (IUE) requires high-level training in microinjection through the mouse uterine wall into the lateral ventricle of the mouse brain. Training for IUE is currently being performed in live mice as no artificial models allow simulations yet. This study aimed to develop an anatomically realistic 3D printed simulator to train IUE in mice.

Inorganic Polyphosphate: Coacervate Formation and Functional Significance in Nanomedical Applications.

Inorganic polyphosphates (polyP) are long-chain polymers of orthophosphate residues, which, depending on the external conditions, can be present both physiologically and synthetically in either soluble, nanoparticulate or coacervate form. In recent years, these polymers have received increasing attention due to their unprecedented ability to exhibit both morphogenetic and metabolic energy delivering properties. There are no other physiological molecules that contain as many metabolically utilizable, high-energy bonds as polyP, making these polymers of particular medical interest as components of advanced hydrogel scaffold materials for potential applications in ATP-dependent tissue regeneration and repair.

Molecular and biochemical approach for understanding the transition of amorphous to crystalline calcium phosphate deposits in human teeth.

Calcium phosphate (CaP) deposition during bone mineralization starts with the aggregation of Posner's clusters Ca(PO) into amorphous Ca-phosphate (ACP), which then transforms into crystalline CaP and finally maturates to hydroxyapatite (HA). Using dentin/enamel of human teeth as a model system, we show that the physiological inorganic polymer polyphosphate (polyP), a phosphate donor in mineralization, prevents the transition from amorphous to crystalline CaP at concentrations> 15 wt%. Stabilization of the amorphous phase of CaP by polyP is reversed by hydrolysis of the polymer by alkaline phosphatase (ALP), an enzyme that releases phosphate for mineralization.

Functional importance of coacervation to convert calcium polyphosphate nanoparticles into the physiologically active state.

Inorganic polyphosphates (polyP) are of increasing medical interest due to their unprecedented ability to exhibit both morphogenetic and ATP-delivering properties. However, these polymers are only physiologically active in the coacervate state, but not as amorphous nanoparticles (NP), the storage form of the polymer. Little is known about the mechanism of formation and interconversion of these two distinct polyP phases in the presence of metal ions.

Polyphosphate in Antiviral Protection: A Polyanionic Inorganic Polymer in the Fight Against Coronavirus SARS-CoV-2 Infection.

Polyanions as polymers carrying multiple negative charges have been extensively studied with regard to their potential antiviral activity. Most studies to date focused on organic polyanionic polymers, both natural and synthetic. The inorganic polymer, polyphosphate (polyP), despite the ubiquitous presence of this molecule from bacteria to man, has attracted much less attention.

Polyphosphate in Chronic Wound Healing: Restoration of Impaired Metabolic Energy State.

Many pathological conditions are characterized by a deficiency of metabolic energy. A prominent example is nonhealing or difficult-to-heal chronic wounds. Because of their unique ability to serve as a source of metabolic energy, inorganic polyphosphates (polyP) offer the opportunity to develop novel strategies to treat such wounds.

Inorganic Polymeric Materials for Injured Tissue Repair: Biocatalytic Formation and Exploitation.

Two biocatalytically produced inorganic biomaterials show great potential for use in regenerative medicine but also other medical applications: bio-silica and bio-polyphosphate (bio-polyP or polyP). Biosilica is synthesized by a group of enzymes called silicateins, which mediate the formation of amorphous hydrated silica from monomeric precursors. The polymeric silicic acid formed by these enzymes, which have been cloned from various siliceous sponge species, then undergoes a maturation process to form a solid biosilica material.

Acceleration of chronic wound healing by bio-inorganic polyphosphate: studies and first clinical applications.

The healing of chronic wounds is impaired by a lack of metabolic energy. In previous studies, we showed that physiological inorganic polyphosphate (polyP) is a generator of metabolic energy by forming ATP as a result of the enzymatic cleavage of the high-energy phosphoanhydride bonds of this polymer. Therefore, in the present study, we investigated whether the administration of polyP can substitute for the energy deficiency in chronic wound healing.

3D bioprinting of tissue units with mesenchymal stem cells, retaining their proliferative and differentiating potential, in polyphosphate-containing bio-ink.

The three-dimensional (3D)-printing processes reach increasing recognition as important fabrication techniques to meet the growing demands in tissue engineering. However, it is imperative to fabricate 3D tissue units, which contain cells that have the property to be regeneratively active. In most bio-inks, a metabolic energy-providing component is missing.

An unexpected biomaterial against SARS-CoV-2: Bio-polyphosphate blocks binding of the viral spike to the cell receptor.

No other virus after the outbreak of the influenza pandemic of 1918 affected the world's population as hard as the coronavirus SARS-CoV-2. The identification of effective agents/materials to prevent or treat COVID-19 caused by SARS-CoV-2 is an urgent global need. This review aims to survey novel strategies based on inorganic polyphosphate (polyP), a biologically formed but also synthetically available polyanionic polymeric material, which has the potential of being a potent inhibitor of the SARS-CoV-2 virus-cell-docking machinery.

Triple-target stimuli-responsive anti-COVID-19 face mask with physiological virus-inactivating agents.

Conventional face masks to prevent SARS-CoV-2 transmission are mostly based on a passive filtration principle. Ideally, anti-COVID-19 masks should protect the carrier not only by size exclusion of virus aerosol particles, but also be able to capture and destroy or inactivate the virus. Here we present the proof-of-concept of a filter mat for such a mask, which actively attracts aerosol droplets and kills the virus.

The therapeutic potential of inorganic polyphosphate: A versatile physiological polymer to control coronavirus disease (COVID-19).

The pandemic caused by the novel coronavirus SARS-CoV-2 is advancing rapidly. In particular, the number of severe courses of the disease is still dramatically high. An efficient drug therapy that helps to improve significantly the fatal combination of damages in the airway epithelia, in the extensive pulmonary microvascularization and finally multiorgan failure, is missing.

Polyphosphate Reverses the Toxicity of the Quasi-Enzyme Bleomycin on Alveolar Endothelial Lung Cells In Vitro.

The anti-cancer antitumor antibiotic bleomycin(s) (BLM) induces athyminic sites in DNA after its activation, a process that results in strand splitting. Here, using A549 human lung cells or BEAS-2B cells lunc cells, we show that the cell toxicity of BLM can be suppressed by addition of inorganic polyphosphate (polyP), a physiological polymer that accumulates and is released from platelets. BLM at a concentration of 20 µg ml causes a decrease in cell viability (by ~70%), accompanied by an increased DNA damage and chromatin expansion (by amazingly 6-fold).

Caged Dexamethasone/Quercetin Nanoparticles, Formed of the Morphogenetic Active Inorganic Polyphosphate, are Strong Inducers of .

Inorganic polyphosphate (polyP) is a widely distributed polymer found from bacteria to animals, including marine species. This polymer exhibits morphogenetic as well as antiviral activity and releases metabolic energy after enzymatic hydrolysis also in human cells. In the pathogenesis of the coronavirus disease 2019 (COVID-19), the platelets are at the frontline of this syndrome.

Morphogenetic (Mucin Expression) as Well as Potential Anti-Corona Viral Activity of the Marine Secondary Metabolite Polyphosphate on A549 Cells.

The mucus layer of the nasopharynx and bronchial epithelium has a barrier function against inhaled pathogens such as the coronavirus SARS-CoV-2. We recently found that inorganic polyphosphate (polyP), a physiological, metabolic energy (ATP)-providing polymer released from blood platelets, blocks the binding of the receptor binding domain (RBD) to the cellular ACE2 receptor in vitro. PolyP is a marine natural product and is abundantly present in marine bacteria.

The biomaterial polyphosphate blocks stoichiometric binding of the SARS-CoV-2 S-protein to the cellular ACE2 receptor.

The effect of the polyanionic polymer of inorganic polyphosphate (polyP) involved in innate immunity on the binding of the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein to the cellular ACE2 receptor was studied. The RBD surface comprises a basic amino acid stretch of four arginine residues which interact with the physiological polyP (polyP) and polyP. Subsequently, the interaction of RBD with ACE2 is sensitively inhibited.

Biomimetic Alginate/Gelatin Cross-Linked Hydrogels Supplemented with Polyphosphate for Wound Healing Applications.

In the present study, the fabrication of a biomimetic wound dressing that mimics the extracellular matrix, consisting of a hydrogel matrix composed of non-oxidized and periodate-oxidized marine alginate, was prepared to which gelatin was bound via Schiff base formation. Into this alginate/oxidized-alginate-gelatin hydrogel, polyP was stably but reversibly integrated by ionic cross-linking with Zn ions. Thereby, a soft hybrid material is obtained, consisting of a more rigid alginate scaffold and porous structures formed by the oxidized-alginate-gelatin hydrogel with ionically cross-linked polyP.

Amplified morphogenetic and bone forming activity of amorphous versus crystalline calcium phosphate/polyphosphate.

Amorphous Ca-phosphate (ACP) particles stabilized by inorganic polyphosphate (polyP) were prepared by co-precipitation of calcium and phosphate in the presence of polyP (15% [w/w]). These hybrid nanoparticles showed no signs of crystallinity according to X-ray diffraction analysis, in contrast to the particles obtained at a lower (5% [w/w]) polyP concentration or to hydroxyapatite. The ACP/15% polyP particles proved to be a suitable matrix for cell growth and attachment and showed pronounced osteoblastic and vasculogenic activity in vitro.