ERC Advanced Investigator Grant Research Group at the Institute for Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, Duesbergweg 6, 55128 Mainz, GERMANY.
Department of Dermatology, University Medical Center of the Johannes Gutenberg University, Langenbeckstraße 1, 55131 Mainz, GERMANY.
Theranostics. 2024 Aug 19;14(13):5262-5280. doi: 10.7150/thno.100622. eCollection 2024.
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. The contribution of the different forms of energy derived from polyP (metabolic energy, mechanical energy and heat) to regeneration processes was dissected and studied both and in patients. ATP is generated metabolically during the enzymatic cleavage of the energy-rich anhydride bonds between the phosphate units of polyP, involving the two enzymes alkaline phosphatase (ALP) and adenylate kinase (ADK). Exogenous polyP was administered after incorporation into compressed collagen or hydrogel wound coverages to evaluate its regenerative activity for chronic wound healing. In a proof-of-concept study, fast healing of chronic wounds was achieved with the embedded polyP, supporting the crucial regeneration-promoting activity of ATP. In the presence of Ca in the wound exudate, polyP undergoes a coacervation process leading to a conversion of fibroblasts into myofibroblasts, a crucial step supporting cell migration during regenerative tissue repair. During coacervation, a switch from an endothermic to an exothermic, heat-generating process occurs, reflecting a shift from an entropically- to an enthalpically-driven thermodynamic reaction. In addition, mechanical forces cause the appearance of turbulent flows and vortices during liquid-liquid phase separation. These mechanical forces orient the cellular and mineralic (hydroxyapatite crystallite) components, as shown using mineralizing SaOS-2 cells as a model. Here we introduce the energetic triad: metabolic energy (ATP), thermal energy and mechanical energy as a novel theranostic biomarker, which contributes essentially to a successful application of polyP for regeneration processes.
皮肤和骨骼的组织再生是一个能量密集型、需要消耗 ATP 的过程，如果受损，可能导致慢性临床症状的发展。细胞外空间（包括伤口渗出物，尤其是慢性伤口）中的 ATP 水平较低。这种缺乏可以通过无机多磷酸盐（polyP）来补偿，多磷酸盐由血小板供应到再生部位。多磷酸盐（代谢能、机械能和热能）衍生的不同形式能量对再生过程的贡献已在体内和患者中进行了剖析和研究。在多磷酸盐的能量丰富的酐键之间的酶促裂解过程中，ATP 通过代谢产生，涉及两种酶碱性磷酸酶（ALP）和腺苷激酶（ADK）。将外源性 polyP 掺入压缩胶原蛋白或水凝胶伤口覆盖物中后进行给药，以评估其对慢性伤口愈合的再生活性。在一项概念验证研究中，嵌入的 polyP 实现了慢性伤口的快速愈合，支持了 ATP 对再生的关键促进作用。在伤口渗出物中 Ca 的存在下，polyP 会发生凝聚过程，导致成纤维细胞转化为肌成纤维细胞，这是支持再生组织修复期间细胞迁移的关键步骤。在凝聚过程中，会发生从吸热到放热、产生热量的过程的转变，反映了从熵驱动到焓驱动的热力学反应的转变。此外，在液-液相分离过程中，机械力会导致湍流和涡旋的出现。这些机械力使细胞和矿物质（羟基磷灰石微晶）成分定向排列，如使用矿化 SaOS-2 细胞作为模型所示。在这里，我们引入了能量三联体：代谢能（ATP）、热能和机械能作为一种新的治疗诊断生物标志物，这对多磷酸盐成功应用于再生过程至关重要。
