Project Summary/Abstract The identification of cancer metastases to the bony vertebral column obligates the treating clinician to make a surgical decision. Current spinal stability decision-making is empirical, qualitative, and can be inaccurate. The consequences of that decision for the patient, however, are significant. If the spine is deemed at risk for fracture, then the patient will undergo a major spinal operation. Conversely, the patient whose spine is deemed stable risks fracture and possible paralysis if the analysis was incorrect. This research program addresses both the stability decision and the nature of the treatment. In this renewal application, we will continue our efforts to develop non-invasive, quantitative, and reliable methods to predict the fracture risk of vertebrae with metastatic cancer under physiologically relevant loading conditions, and to optimize minimally invasive techniques using novel biomaterials to reconstitute the load bearing capacity of an affected vertebra. In Aim 1, we propose a novel injectable polymer network that can be self-crosslinked via catalyst-free click chemistry into “click” organic-inorganic nanohybrid (click-ON) bone cement. Compared to our previous injectable system, the novel cement has improved biocompatibility, injectability, and crosslinking efficiency. In Aim 2, we will investigate the efficacy of the optimized click-ON bone cement to both prevent impending fractures and treat existing fractures in cadaveric models using the clinical vertebroplasty and kyphoplasty procedures, respectively (Aim 2a). Intact lumbar spines (L1-S1), spines with simulated lytic defects, and spines with biomaterial augmentation will be tested under accurate and biomimetic loading conditions using a novel robotic testing system. Our previously developed quantitative computerized tomography based finite element analysis (QCT/FEA) models will be expanded to include both kinematic motion evaluation and fracture risk prediction under physiological loading and boundary conditions and validated using the experimental results (Aim 2b). In Aim 3, We will develop a phantom-less calibration technique to account for the effects of QCT protocols on QCT/FEA results (Aim 3a). Using the powerful AnalyzeMD platform, we will implement an automated process to further advance the FEA technique for time efficiency and reproducibility (Aim 3b). We will apply the comprehensive QCT/FEA models in a retrospective cohort of spine metastasis patients and assess the virtual reconstruction using the click-ON bone cement as a first step towards clinical translation. The QCT/FEA technique developed in this work takes into consideration both the quality and quantity of bone and the degeneration status of the intervertebral discs. This technique allows the clinician to counsel her/his patient regarding activities of daily living that can be performed with a low risk of spinal fracture. Our future plans are to expand the clinical implementation ...