Molecular Mechanism Study on Effect of Biodegradable Amino Acid Ester–Substituted Polyphosphazenes in Stimulating Osteogenic Differentiation

Abstract

Amino acid ester substituted polyphosphazenes are osteoactive benefiting from their phosphorus‐containing chemical structure, which highlights interests in bone tissue engineering. To correlate their chemical structures with cell activities, in this study, poly[(ethyl alanato)0.3(ethyl glycinato)0.7phosphazene] (PAGP) and poly[(ethyl phenylalanato)0.3(ethyl glycinato)0.7phosphazene] (PPGP) are synthesized to carry out studies on cell osteogenic differentiation. In the non‐contact culture manner, bone mesenchymal stromal cells (BMSCs) are cultured in transwell chambers containing PAGP or PPGP films, while the cells and the materials do not contact. In the contact culture manner, BMSCs are cultured on the PAGP or PPGP films. In the meantime, solutions containing PAGP or PPGP degradation products (i.e., phosphate, ammonium, and corresponding amino acids) are applied for cell culture using inorganic phosphate (Pi) ion as control. Thus, the influences from substrate surface and degradation products can be identified separately. The results reveal that both the phosphorus‐containing surface of PAGP and PPGP films and their degradation products play significant roles in regulating cell behaviors. In comparison with PAGP, PPGP seems able to provide relatively stable phosphorus‐containing surface to strengthen the cell‐scaffold interaction because of its slower degradation rate and higher Young's modulus, leading to greater promotion in osteogenic differentiation via contact effect.

Antibacterial, conductive, and osteocompatible polyorganophosphazene microscaffolds for the repair of infectious calvarial defect

“…Biodegradable POPPs, including nonconductive PAGP and conductive PATGP, were synthesized to meet the targets in consideration of the flexibility in polyphosphazene chemistry and the inherent phosphorus‐rich feature of POPPs for bone tissue engineering. Compared with other polymeric biomaterials, amino acid ester substituted POPPs are osteocompatible thanks to their bioactive compositions, such as phosphorus, nitrogen, and amino acids, which display upregulation effects on cell/tissue biological activities 19,20 . Through nucleophilic substitution reactions, various functional groups can be grafted onto polyphosphazene backbones to endow the polymers with diverse properties, such as degradability and conductivity.…”

“…Compared with other polymeric biomaterials, amino acid ester substituted POPPs are osteocompatible thanks to their bioactive compositions, such as phosphorus, nitrogen, and amino acids, which display upregulation effects on cell/tissue biological activities. 19,20 Through nucleophilic substitution reactions, various functional groups can be grafted onto polyphosphazene backbones to endow the polymers with diverse properties, such as degradability and conductivity. Based on amino acid ester substituted polyphosphazenes (e.g., PAGP), the conductive PATGP was readily obtained by introducing the conductive AT as side groups, with glycine ethyl ester as co-substituent to adjust the polymer degradation.…”

“…Comparatively, polyorganophosphazenes (POPPs) are good choices for the purpose, thanks to their chemical flexibility, phosphorus‐rich compositions and diverse side groups. The backbone of POPPs was built up with alternate phosphorus and nitrogen elements, and biodegradable POPPs usually bear amino acid esters as side groups 19 . The pH‐buffered degradation products of POPPs, namely, amine, phosphate, and corresponding pendant groups (e.g., amino acid), are biocompatible for in vivo implantation, 20 and the polymers have an inherent capacity to promote osteogenesis 21,22 .…”

“…The backbone of POPPs was built up with alternate phosphorus and nitrogen elements, and biodegradable POPPs usually bear amino acid esters as side groups. 19 The pH-buffered degradation products of POPPs, namely, amine, phosphate, and corresponding pendant groups (e.g., amino acid), are biocompatible for in vivo implantation, 20 and the polymers have an inherent capacity to promote osteogenesis. 21,22 POPPs are easily functionalized through the substitution of different side groups onto the linear polydichlorophosphazene (PDCP), 23,24 and in our previous study, conductive poly[(aniline tetramer)(ethylglycyl)]phosphazene (PATGP) was synthesized, which demonstrated antioxidant capacity, achieving higher efficiency in osteogenesis than the nonconductive poly[(ethylalanine)(ethylglycyl)]phosphazene (PAGP).…”

Main-Chain Phosphorus-Containing Polymers for Therapeutic Applications

“…The main premise of using polyphosphazenes is their tuneable degradation rates, which can in principle be tailored to match cell growth. The most investigated PPzs are functionalized with amino acid esters (Figure 43i), with the release of amino acids upon hydrolysis helping to boost cell growth [200]. A wide range of cells has been successfully cultivated on amino acid ester-substituted PPz-based matrices [197].…”