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3D cell-to-cell interactions form potentially providing new in vitro approaches to study and mimic the response of biological and cellular processes. One particularly interesting area to study is mechanical stimulation due to its importance in a wide range of physiological systems from cardiac to neural areas. In the neural domain, previous approaches for examining the effects of in vitro mechanical loading on cells have focused mostly on local stimulation of single or multiple neurons cultured on planar substrates. These approaches have proven to be useful for understanding how mechanical stimuli are transduced to biochemical signals including being integrated with micro-fabricated environments. [5-8] While much of the knowledge of cellular biomechanics focuses on our understanding from planar substrates, these 2D systems unfortunately lack physiological aspects such as three dimensionality as well as the complexity of tissue and neuronal function. 3D culture systems can enhance the analysis of integrated interactions between tissue and neural response to recapitulate the natural microenvironment with spatiotemporal details, which may be relevant in understanding many issues including Alzheimer's disease and traumatic brain injury (TBI). [9,10,11] This type of understanding of biomechanics is particularly important as TBI can result from a diversity of situations such as a car crash, an innocuous fall, sports injury, and sudden jolts or blows to the head. Annually these types of issues affect ≈1.5 million people in the United States and 69 million individuals worldwide as well as accounting for one third of all injury-related deaths in the United States affecting every stage of life from adolescents to the elderly. [12,13] Precisely identifying the importance of dysfunction and pathomorphological expressions after external mechanical insult is very important. These responses include a variety of factors such as compressive strains and subcellular responses. The approaches with tissue-on-a-chip systems could help in these areas as representative building blocks for assessing in vitro, multi-dimensional organ architectures toward physiological understanding and treatment. Understanding cell responses under mechanical stimulation can be probed through many techniques. One approach involves an important molecular signature related

treatment strategies should inform the surgical treatment of spine metastases and the predicted prognosis to guide personalized approaches.METHODS: This is a multi-institutional, retrospective, observational cohort study of patients who underwent spine surgery for symptomatic breast cancer spine metastases from 2008-2020. We studied overall survival, stratified by breast cancer molecular subtype and calculated hazard ratios adjusting for demographics, tumor characteristics, treatments, and laboratory values. We tested the performance of established models (Tokuhashi, Bauer, SORG, NESMS) to predict and compare all-cause mortalities using time-dependent performance metrics.RESULTS: A total of 98 patients surgically treated for breast cancer spine metastases were identified. The 1-year probabilities of survival for HR+, HR+/HER2+, HER2+, and TNBC were 63%, 83%, 0%, and 12% (P <0.001). Postoperative chemotherapy and endocrine therapy were associated with prolonged survival. The SORG prognostic model had the highest discrimination. The performance of all prognostic scores improved when preoperative molecular data was considered in addition to postoperative systemic treatment data.CONCLUSIONS: Advanced HR+, HR+/HER2+ breast cancer portended significantly longer overall survival compared with HER2+ and TNBC tumors after surgery for symptomatic spine metastases. Hormone receptor status and postoperative systemic therapy should be considered in prediction models for a more accurate assessment of prognosis.

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The evolution of tissue on a chip systems holds promise for mimicking the response of biological functionality of physiological systems. One important direction for tissue on a chip approaches are neuron based systems that could mimic neurological responses and lessen the need for in vivo experimentation. For neural research, more attention has been devoted recently to understanding This article is protected by copyright. All rights reserved. 2 mechanics due to issues in areas such as traumatic brain injury and pain, among others. To begin to address these areas, we developed a 3D Nerve Integrated Tissue on a Chip approach combined with a Mechanical Excitation Testbed System to impose external mechanical stimulation toward more realistic physiological environments. We used PC12 cells differentiated with nerve growth factor, which were cultured in our controlled 3D scaffolds. We labelled the cells with Fluo-4-AM to examine their calcium response under mechanical stimulation. We imposed mechanical stimulation synchronized with image capturing to examine the cellular response in our 3D nerve integrated tissue on a chip system. Understanding the neural responses to mechanical stimulation beyond 2D systems is very important for neurological studies and future personalized strategies. We feel that this work will have implications in a diversity of areas including tissue on a chip systems, biomaterials, and neuromechanics.