The microstructure of polyphosphoesters controls polymer hydrolysis kinetics from minutes to years

The stability and degradation rates of polymers in aqueous media are critical factors for their biomedical applications, as they must remain intact for a specific period of time before degrading or degrading on-demand to prevent potential accumulation and harmful effects. Polyphosphoesters (PPEs) are highly compatible with biological systems, and the ester bonds in the backbone allow for hydrolytic degradation. In this study, we have demonstrated that the degradation rate of various PPEs can be precisely controlled by minor modifications to the side-chain and the binding pattern around the phosphorous center in the polymer backbone. We synthesized a systematic library of water-soluble PPEs using ring-opening polymerization, resulting in polyphosphates and in-chain or side-chain polyphosphonates. Specifically, we investigated the degradation rates of side-chain polyphosphonates with different side-chain structures (methyl, ethyl, allyl, iso- or n-propyl) at pH = 8 and pH = 11. Our results indicate that the degradation mechanism is influenced by the type and size of the side-chain, as well as the pH. At pH = 11, hydrophilicity is a key factor, while at pH = 8, electron density on the phosphorus is crucial, leading to a random chain scission or a backbiting mechanism. We also observed that changing the binding pattern of the phosphorus or incorporating additional "breaking points" allowed us to tune the half-life times of the polymer from less than a day to several years. This study highlights the versatile stability of water-soluble PPEs, making them a promising option for various applications that require different hydrolysis rates, such as tissue regrowth.