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Abstract

Hemostasis is the body’s natural process for stopping bleeding after vascular injuries. It involves interactions between blood vessels, platelets, and coagulation factors. Imbalance in this process leads to pathological conditions such as thrombosis. Antiplatelets and anticoagulants are clinically used to treat thrombosis by targeting various steps in platelet activation and blood coagulation. However, these therapies carry a significant bleeding risk, highlighting the need for safer strategies. Polyanions have emerged as promising targets for safer antithrombotic therapies due to their role in enhancing blood coagulation through the contact activation system. We previously introduced macromolecular polyanion inhibitors (MPIs), which were successful in inhibiting polyphosphate (polyP) and reducing thrombotic risks. While successful, MPIs’ potential bioaccumulation in vital organs (e.g., spleen and liver) raises concerns about their long-term safety. The development of biodegradable polymers provides a solution for the above challenge. Due to their ability to degrade into smaller, non-toxic fragments, biodegradable polymers are widely used in various biomedical applications, such as tissue engineering and drug delivery systems. However, many biodegradable polymers have limitations, such as poor water solubility and biocompatibility and toxic byproduct generation upon degradation, which impact their effectiveness. To address this, I report the design and synthesis of a new class of branched biodegradable polymers with incorporated acid-labile ketal groups. A new monomer (OTPE) containing one ketal group was synthesized through a multi-step protocol and was further copolymerized with glycidol using anionic ring-opening multi-branching polymerization (ROMBP) to generate branched biodegradable copolymers with high water-solubility and controlled degradation. Copolymers with various ketal contents (2, 5 and 10 mol%) were synthesized, and the OTPE incorporation within the polymer was confirmed by nuclear magnetic resonance (NMR) spectroscopy. Copolymers were characterized by the gel permeation chromatography (GPC) technique. Copolymers were stable at physiological pH and showed controllable pH-dependent degradation profiles at lower pH values. Copolymers showed excellent biocompatibility, as measured by coagulation studies, platelet activation, red blood cell lysis and aggregation, and cell viability measurements in-vitro. Their promising hemocompatibility, degradation profiles, and high water solubilities make them attractive for future biomedical applications such as drug delivery, bioconjugation, and tissue engineering.