Professor and Associate Vice President Westlake University, United States
Introduction: Tissue regeneration is integral to clinical practice, yet current biomaterials often fall short in replicating tissue compositions and coordinating biomechanical, biochemical, and biological factors crucial for healing. Overcoming this challenge, citrate, recognized for its versatile applications in food, pharmaceuticals, and cosmetics, as well as its role in intracellular metabolism and bone formation, has emerged as a key component in synthesizing a new generation of biodegradable and bioactive materials since the early 2000s. In the past two decades, citrate-based polymers (CBPs) have gained considerable traction in biomaterials and regenerative engineering. Their versatility extends to applications in vascular tissue engineering, wound healing, muscle and nerve regeneration, bone repair, and drug delivery. CBPs offer tunable properties, enabling adjustments in elasticity, strength, and degradation rate, while also facilitating the incorporation of bioactive molecules and the introduction of biophysical traits like photoluminescence and electrical conductivity. The recent FDA clearance of poly(octamethylene citrate) (POC)/hydroxyapatite-based orthopedic fixation devices marks a significant milestone in translational research, as POC becomes one of few biodegradable synthetic polymers authorized for human use by the FDA. This success has spurred the development of next-generation citrate-based biomaterials. Concurrently, researchers are delving into the intricate biological functions and metabolic implications of citrate across various cell types and tissues.
Materials and
Methods: The first generation CBP, POC, is 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 CBPs with tunable mechanical properties and carrying various biofunctions. The in vitro and in vivo biosafety and tissue regenerative effects of CBPs 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. Moreover, ongoing research is examining citrate's impact on various aspects of tissue regeneration, utilizing relevant in vitro and in vivo models.
Results, Conclusions, and Discussions: Drawing from the diverse roles that citrate assumes in orchestrating intracellular metabolic pathways and facilitating tissue regeneration by regulating a spectrum of cell activities pivotal to the regenerative process，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 and dynamic citrate-based biomaterials including citrate-based polyester, polyurethane and other types of biodegradable polymers and composites. These materials not only showcase citrate but also deliver other sought-after bioactive molecules crucial during cellular and tissue development under the concept of metabotissugenic biomaterials. 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.
