Professor and Associate Vice President Westlake University, United States
Introduction: Citrate-based biodegradable polymers have emerged as a distinctive biomaterial platform with tremendous potential for diverse medical applications. By harnessing their versatile chemistry, these polymers exhibit a wide range of material and bioactive properties, enabling them to regulate cell metabolism and stem cell differentiation through energy metabolism, metabonegenesis, angiogenesis and immunomodulation. Moreover, the recent U.S. Food and Drug Administration (FDA) clearance of the biodegradable poly(octamethylene citrate) (POC)/hydroxyapatite-based orthopedic fixation devices represent a translational research milestone for biomaterial science. POC joins a short list of biodegradable synthetic polymers that have ever been authorized by the FDA for use in humans. The clinical success of POC has sparked enthusiasm and accelerated the development of next-generation citrate-based biomaterials. This talk presents a comprehensive, forward-thinking discussion on the pivotal role of citrate chemistry and metabolism in various tissue regeneration and on the development of functional citrate-based metabotissugenic biomaterials and medical devices for regenerative engineering applications.
Materials and
Methods: The first citrate-based polymer, POC, was synthesized through a cost-effective and catalyst-free polycondensation reaction using citric acid and 1,8-octanediol in two steps. It occurs in two steps, the synthesis of a low molecular weight, solvent soluble prepolymer, followed by further crosslinking to attain the final polymer structure. Citric acid, functioning as a tetrafunctional reactant, contains three carboxyl (-COOH) and one hydroxyl (-OH) group that readily react with mono-, di- or multi-functional monomers containing -COOH, -OH, -NH2, -SH, -NCO et al. through condensation reactions to form new small molecules or polymers. The presence of multiple active sites within the POC prepolymer renders citrate-based materials highly versatile and easily amendable for functionalization, which led to the development of a series of CBBs with tunable mechanical properties and carrying various biofunctions. The in vitro and in vivo biosafety and tissue regenerative effects of citrate-based polymers have been studied using multiple cell and animal models, including stem cells, endothelial cells, macrophages, mice, rats, rabbits, etc. We have also unraveled the biological functions and metabolic implications of citrate. For instance, investigations into its metabonegenic effect have been conducted on osteogenically differentiating human mesenchymal stem cells. To facilitate the commercialization of citrate-based polymers as bioink, the standardization of polymer synthesis and device fabrication were further investigated.
Results, Conclusions, and Discussions: We studied the roles of citrate on regulating osteogenesis, osteoclastogenesis, innervation, immunomodulation, angiogenesis, among others, which culminate to a new concept, metabotissugenesis that recapitulates the previously underexplored roles of exogenous citrate in tissue repair and regeneration. By harnessing citrate's remarkable metabolic properties and its adaptable pendant groups for chemical modification and functionalization, we have also crafted the next generation of biomimetic citrate-based biomaterials including citrate-based polyester, polyurethane and other types of biodegradable polymers and composites. These materials not only present citrate but also deliver other sought-after bioactive molecules crucial during cellular and tissue development under the concept of metabotissugenic biomaterials. Our results also showed that citrate-based polymers are a promising new generation of bioink for medical devices fabrication. While the development and translation of citrate-based biomaterials are still in their infancy, metabotissugenic biomaterials stand ready to tackle the unresolved challenges in intricate tissue repair and regeneration.
