Herein, we report the first citric acid (CA)-derived in situ crosslinkable biodegradable polymer, poly (ethylene glycol) maleate citrate (PEGMC). The synthesis of PEGMC could be carried out via a onepot polycondensation reaction without using organic solvents or catalysts. PEGMC could be insitu crosslinked into elastomeric PPEGMC hydrogels. The performance of hydrogels in terms of swelling, degradation, and mechanical properties were highly dependent on the molar ratio of monomers, crosslinker concentration, and crosslinking mechanism used in the synthesis process. Cyclic conditioning tests showed that PPEGMC hydrogels could be compressed up to 75% strain without permanent deformation and with negligible hysteresis. Water-soluble PEGMC demonstrated excellent cytocompatibilty in vitro. The degradation products of PPEGMC also showed minimal cytotoxicity in vitro. Animal studies in rats clearly demonstrated the excellent injectability of PEGMC and degradability of the in situ-formed PPEGMC. PPEGMC elicited minimal inflammation in the early stages post-injection and was completely degraded within 30 days in rats. In conclusion, the development of CA-derived injectable biodegradable PEGMC presents numerous opportunities for material innovation and offers excellent candidate materials for in situ tissue engineering and drug delivery applications.

Previous studies have confirmed that natural bone apatite crystals are bound with citrate-rich molecules. Citrates on apatite crystals impact bone development and its load-bearing function. However, such understanding has never been translated into bone biomaterials design. Herein, a first citrate-based injectable composite material for orthopedic applications is developed based on our recently developed biodegradable poly(ethylene glycol) maleate citrate (PEGMC) and hydroxyapatite (HA). PEGMC contains rich carboxylic groups that could chelate with calcium-containing HA thus facilitating polymer/HA interactions, similar to natural citrate-bound apatite crystal. The crosslinking of poly(ethylene glycol) diacrylate (PEGDA) with PEGMC/HA composites allows an addition control over degradation and mechanical properties of the crosslinked PEGMC/HA (CPEGMC/HA) composites. CPEGMC/HA composite can serve as an ideal injectable cell carrier as confirmed by the enhanced DNA content, ALP activity, and calcium production through a human fetal osteoblast encapsulation study. Ex vivo study on porcine femoral head demonstrated that PEGMC/HA is a potentially promising injectable biodegradable bone material for the treatment of osteonecrosis of the femoral head. Development of biodegradable citrate-based injectable PEGMC/HA composite is an initial step for the development of the next generation of bone tissue engineering and orthopedic biomaterials.

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Injectable biodegradable hydrogels, which can be delivered in a minimally invasive manner and formed in situ, have found a number of applications in pharmaceutical and biomedical applications, such as drug delivery and tissue engineering. We have recently developed an in situ crosslinkable citric acid-based biodegradable poly (ethylene glycol) maleate citrate (PEGMC)/hydroxyapatite (HA) composite, which shows promise for use in bone tissue engineering. In this study, the mechanical properties of the PEGMC/HA composites were studied in dynamic linear rheology experiments. Critical parameters such as monomer ratio, crosslinker, initiator, and HA concentrations were varied to reveal their effect on the extent of crosslinking as they control the mechanical properties of the resultant gels. The rheological studies, for the first time, allowed us investigating the physical interactions between HA and citric acid-based PEGMC. Understanding the viscoelastic properties of the injectable gel composites is crucial in formulating suitable injectable PEGMC/HA scaffolds for bone tissue engineering, and should also promote the other biomedical applications based on citric acid-based biodegradable polymers.