Hierarchically Porous Osteoinductive Poly(hydroxyethyl methacrylate-co-methyl methacrylate) Scaffold with Sustained Doxorubicin Delivery for Consolidated Osteosarcoma Treatment and Bone Defect Repair

A bifronted cure system for osteosarcoma, a common aggressive bone tumor, is highly in demand to prevail the postsurgical adversities in connection with systemic chemotherapy and repair of critical-size bone defects. The hierarchically porous therapeutic scaffolds presented here are synthesized by free radical-initiated copolymerization of hydroxyethyl methacrylate and methyl methacrylate [HEMA/MMA 80:20 and 90:10 mM, H 2 O/NaCl porogen], which are further surface-phosphorylated [P-PHM] and transformed to bifunctional by impregnating doxorubicin (DOX) [DOXP-PHM]. The P-PHM scaffolds exhibited porous microarchitecture analogous to native cancellous bone (scanning electron microscopy analysis), while X-ray photoelectron spectroscopy analysis authenticated surface phosphorylation. Based on pore characteristics, swelling attributes and slow-pace degradation, P-PHM9163 and P-PHM8263 (HEMA/MMA 90:10 and 80:20 with H 2 O/NaCl: 60/3.0 weight %, respectively) were chosen from the series and evaluated for osteoinductive efficacy in vitro . Both P-PHM9163 and P-PHM8263 invoked calcium phosphate mineralization in simulated physiological conditions (day 14) with Ca/P ratios of 1.58 and 1.66 respectively, comparable to human bone (1.67). Early biomineralization (Alizarin Red S and von Kossa staining) was evidenced at day 7, while osteoblast differentiation was verified by time-dependent expression of the typical late marker, osteocalcin, at day 14 and 21 in rat bone marrow mesenchymal cells. DOX-loaded P-PHM9163 (DOXP-PHM9163) exhibited pH-responsive (tumor analogous pH; 6.5) sustained release of DOX for prolonged time (up to 45 days) and invoked cellular alterations by cortical stress fiber formation and DNA fragmentation in human osteosarcoma cells leading to early apoptosis (24 h), validated by annexin V/PI staining (FACS) and immunostaining (F-actin/DAPI). Subsequent to DOX release tenure, the scaffold induced the formation of well-organized, porous post-release Ca-P apatite coating (Ca/P is 1.3) in simulated body fluid (day 14) which further endorses the dual functionality of the system. Altogether, the results accentuate that DOXP-PHM9163 is a potential bifunctional therapeutic scaffold capable of extended localized chemotherapeutic delivery in-line with inherent osteogenesis for efficient bone cancer treatment.