Wound healing is a highly energy-dependent process. Physiologically, the required metabolic energy is supplied by the blood platelets in the form of inorganic polyphosphate, which serves as a source for the generation of the energy carrier adenosine triphosphate (ATP). However, due to metabolic diseases, circulatory disorders, or bacterial wound infections, this energy supply can be insufficient, leading to the development of chronic wounds that are difficult or impossible to treat with conventional methods. It has been shown that this energy deficiency can be remedied by the topical application of synthetic polyP and amorphous polyP nanoparticles that mimic the natural polymer. Initial studies on patients were successful, as summarized in this chapter. Amorphous calcium carbonate particles stabilized with polyP as a source of soluble calcium have proven to be another promising application form of the polymer alongside polyP and polyP nanoparticles.

The repair of alveolar cleft defects remains a formidable challenge in craniofacial surgery, with implications for dental arch continuity, tooth eruption, speech, and facial aesthetics. Traditional bone grafting methods (especially iliac crest autografts) have remained the gold standard, yet donor-site morbidity, graft resorption, and limitations in large defects drive the search for more advanced strategies. In recent years, developments in biomaterials, stem cell-based tissue engineering, and computer-aided surgery have opened new conceptual and practical pathways for alveolar cleft repair. This chapter reviews the embryology and pathophysiology of alveolar clefts, the structural and functional sequelae, and conventional surgical approaches. It then delves into advances in scaffold design, growth factor delivery, mesenchymal stem cell therapies, and 3D bioprinting strategies, highlighting preclinical and early clinical findings. Additionally, the role of CBCT, CAD/CAM, and custom surgical guides is examined in improving graft placement, reducing surgical error, and optimizing outcomes. Clinical successes and persistent challenges are analyzed, including graft integration, long-term stability, tooth eruption, and ethical/regulatory issues. We conclude by identifying key research gaps and proposing future directions-such as scaffold-free regeneration, AI-driven planning, and patient-specific regenerative protocols-that may transform alveolar cleft management in the coming decade.

Platelets play a crucial role in physiological wound healing, providing the energy required for this highly ATP-dependent repair/regeneration process. The formation of these cell fragments, which accumulate the energy-rich polymer inorganic polyphosphate (polyP) in their dense granules, is described. The possible mechanism of storage of the polyanionic polyP in these organelles together with counterions, particularly calcium and serotonin, which is present as a cation in the acidic interior of the granules, is discussed. Synthetic polyP can be used for wound therapy, either as a soluble sodium salt or as calcium-polyP nanoparticles, which are converted into the metabolically active coacervate at the site of injury. A model based on the Donnan equilibrium is presented that explains the uneven distribution of positive and negative charges within the nanoparticulate and coacervate forms of polyP. Another focus of this chapter is on the central role of the enzyme alkaline phosphatase (ALP), present in wound fluid, in polyP metabolism and the conversion of the chemical energy stored in polyP into the metabolically usable energy of the energy carrier ATP. The mechanism of ALP-catalyzed hydrolytic cleavage of the energy-rich phosphoanhydride bonds of polyP is discussed, as are the subsequent reactions that keep this enzyme running.

Epithelial cell damage affects not only the skin, which covers the external surface of the human body, but also the non-keratinized epithelia, the mucosa, that lines the surfaces of internal organs, including the nasopharynx and lungs. This mucosa is characterized by a moist surface formed by the mucus overlying the epithelial cells. In the respiratory tract in particular, mucosa cells are constantly exposed to large amounts of environmental pathogens and stressors, including bacteria and viruses inhaled as aerosols. Therefore, mucins, a group of glycoproteins that constitute a major component of the mucus, play an important role in the innate immune defense provided by the protective mucus shield. This barrier function of the mucus can be disrupted by a number of agents, such as fine dust (particulate matter). Recent results have shown that inorganic polyphosphate (polyP), which can be administered, for example, in the form of a nasopharyngeal spray, offers a promising way to strengthen or repair impaired mucus function. This chapter describes the structure and formation of the mucus and its mucin building blocks, as well as the mode of action of polyP and drug-loaded polyP nanoparticles in restoring the mucus barrier, particularly with regard to their protective function against coronavirus infection.

Exposure to ionizing radiation can cause severe skin damage, leading to the development of cutaneous radiation syndrome. Wound healing of radiation-induced skin injuries proceeds in defined phases that depend on the intensity and type of radiation exposure. Skin damage caused by ionizing radiation can occur not only through accidental exposure, as in the case of the Chernobyl disaster, but also during radiotherapy of tumor patients. The extent of cell damage by ionizing radiation is greater in the presence of oxygen ("oxygen-effect"), most likely by the generation of reactive oxygen species (ROS), which cause damage to macromolecules (nucleic acids, proteins, lipoproteins, and polymeric carbohydrate compounds). If DNA lesions are not repaired, cells can die by apoptosis. This chapter describes the application of sensitive high-throughput microplate assays to determine the frequency of single- and double-strand DNA breaks in individuals exposed during cleanup work at the Chernobyl reactor ("liquidators"), in personnel who had worked in the destroyed Unit IV of the reactor, and in radiotherapy patients. In addition, new materials based on chitin-glucan-melanin complexes (ChGMC) and melanin-glucan complexes (MGC) or on the regeneratively active polymer inorganic polyphosphate (polyP) are presented to prevent the induction and accelerate the healing of radiation-induced skin damage.

Chronic wounds, pathological states failing to heal promptly, are especially prevalent among the elderly. This impaired healing in the senescent tissue is predominately attributed to the accumulation of senescent cells and a concomitant decline in energy metabolism, ultimately leading to functional impairment. Existing clinical practices-including debridement, hyperbaric oxygen, antibiotics, and wound dressings-cannot fundamentally resolve this cellular decline. In this context, advanced biomaterials designed to enhance cellular energy metabolism emerge as a viable strategy. This chapter details strategies by which biomaterials enhance skin wound healing in aging environments by modulating energy metabolism. It explains that delayed healing primarily stems from age-associated metabolic and mitochondrial dysregulation, which compromises cellular repair functions. Furthermore, it reviews advanced biomaterial-based approaches that promote healing by delivering metabolites, restoring mitochondrial function, and indirectly modulating stem cells. By targeting energy metabolism to reverse the low-energy state of aged skin, these approaches fundamentally address cellular functional decline and actively foster tissue regeneration. Therefore, this chapter outlines design principles for energy metabolism-modulating biomaterials to aid wound healing in aged skin and highlights recent advances in this field.

Collagen is a biocompatible, biodegradable, and low-immunogenic protein, making it an ideal candidate for regenerative medicine. Due to ethical/religious concerns and the risk of disease transmission from traditional terrestrial mammal sources (bovine/porcine), scientific interest has increasingly shifted toward the vast marine ecosystem as a sustainable and alternative source. This chapter explores the primary applications of marine-derived collagen in wound healing, detailing its unique biochemical and structural characteristics compared to terrestrial collagen. Collagen, a fibrous protein of the extracellular matrix (ECM), is defined by its triple-helix structure, stabilized by hydroxyproline. Marine collagen shows significant diversity between vertebrates (fish) and invertebrates (Porifera, Cnidaria, Mollusca, Annelida, Echinodermata). For instance, fish collagen, though abundant from fishing industry waste, often has lower thermal stability due to a reduced imino acid content. However, specific invertebrate collagens, such as those from sponges (Chondrosia reniformis) or mollusk byssal threads, exhibit unique mechanical properties and surprising thermal resistance. The chapter comprehensively reviews the latest innovative applications using marine collagen (from fish, jellyfish, sponges, and mollusks) or gelatin in scaffolds, films, and bioactive peptides to promote skin regeneration and wound repair. This highlights the vast, unexplored potential of marine biodiversity for developing more efficient and sustainable biomaterials.

Inorganic polyphosphate (polyP), a linear polymer of orthophosphoric acid residues, is essential for living cells from bacteria to humans. It forms complexes with metal ions, DNA, and polyhydroxybutyrate. The interaction of polyP with proteins includes polyphosphorylation at lysine and histidine residues, as well as participation in amyloid formation. The enzymes of polyP metabolism are polyfunctional, and their substrates include second messenger compounds and nucleoside phosphates. PolyP is a universal regulatory compound and plays an important role in bone tissue development, thrombosis and inflammation, signal transmission in nerve cells, carcinogenesis, and amyloid formation. PolyP participates in biofilm formation and other processes occurring during the interaction of pathogenic microorganisms with the host. PolyP of the gut microbiome is involved in maintaining intestinal functions. PolyP and the enzymes of its metabolism are promising targets for developing drugs against infections and novel approaches to treat bone, cardiovascular, and neurodegenerative diseases.

The corneal epithelium, a stratified squamous non-keratinized layer of 50-60μm thickness, forms the outermost barrier of the cornea and provides both optical clarity and protection against trauma, infection, and fluid imbalance. It plays a vital role in protecting the eye and maintaining visual clarity. A range of conditions, including trauma, metabolic disorders, microbial infection, and limbal stem cell deficiency, can lead to chronic corneal epithelial defects and subsequent visual impairment. Epithelial renewal is a continuous process, primarily sustained by stem cells located at the limbus. These stem cells give rise to transient amplifying cells, which migrate centripetally and superficially to maintain epithelial integrity. Wound healing follows a highly regulated sequence, superficial cells slide to cover the defect, basal cells proliferate, and corneal nerves realign to support epithelial stratification. This process is orchestrated by cytoskeletal remodeling, integrin-matrix interactions, and growth factor signaling. The epithelium relies on glucose from the corneal stroma, primarily metabolized through glycolysis, while mitochondrial oxidative phosphorylation generates the ATP required for repair. Thus, epithelial regeneration is closely tied to cellular energy availability. Enhancing this process involves supporting mitochondrial function, metabolic signaling pathways, and stem cell activity. Emerging strategies in regenerative ophthalmology include NAD+ replenishment, activation of AMP-activated protein kinase (AMPK), application of growth factors, targeted nanotherapies, and photobiomodulation. This chapter explores these cutting-edge approaches aimed at promoting energy-driven regeneration of the corneal surface.

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. The basis is the generation of ATP from the polymer through the joint action of two extracellular or plasma membrane-bound enzymes alkaline phosphatase and adenylate kinase, which enable the transfer of energy-rich phosphate from polyP to AMP with the formation of ADP and finally ATP. Building on these findings, it was possible to develop novel regeneratively active materials for wound therapy, which have already been successfully evaluated in first studies on patients.