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Additional file 4.

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Clinical implementation of endochondral bone regeneration (EBR) would benefit from the engineering of devitalized cartilaginous constructs of allogeneic origins. Nevertheless, development of effective devitalization strategies that preserves extracellular matrix (ECM) is still challenging. The aim of this study is to investigate EBR induced by devitalized, soft callus-mimetic spheroids. To challenge the translatability of this approach, the constructs are generated using an allogeneic cell source. Neo-bone formation is evaluated in an immunocompetent rat model, subcutaneously and in a critical size femur defect. Living spheroids are used as controls. Also, the effect of spheroid maturation towards hypertrophy is evaluated. The devitalization procedure successfully induces cell death without affecting ECM composition or bioactivity. In vivo, a larger amount of neo-bone formation is observed for the devitalized chondrogenic group both ectopically and orthotopically. In the femur defect, accelerated bone regeneration is observed in the devitalized chondrogenic group, where defect bridging is observed 4 weeks post-implantation. The authors' results show, for the first time, a dramatic increase in the rate of bone formation induced by devitalized soft callus-mimetics. These findings pave the way for the development of a new generation of allogeneic, "off-the-shelf" products for EBR, which are suitable for the treatment of every patient.

BACKGROUND: Limited treatment options exist for patients with locoregional recurrences of head and neck squamous cell carcinoma (HNSCC). In the palliative setting, a single session, minimally invasive, and relatively safe therapy is desirable. This case series illustrates the feasibility of a direct intratumoral injection of radioactive holmium-166 microspheres (HoMS) in patients as a palliative treatment for recurrent HNSCC. PATIENTS AND METHODS: In this retrospective analysis, patients with already reirradiated irresectable recurrent HNSCC, for whom palliative chemotherapy was unsuccessful or impossible, were offered microbrachytherapy with HoMS. The intratumoral injection was administered manually under ultrasound guidance. Parameters scored were technical feasibility (i.e. administration, leakage, and distribution), clinical response (response evaluation criteria in solid tumors 1.1), and complications (Common Terminology Criteria for Adverse Events 4.3). RESULTS: From 2015 to 2017, three patients were treated. None of the patients experienced adverse events; however, therapeutic effects were minimal. Technical difficulties, including precipitating of microspheres and high intratumoral pressure, resulted in suboptimal distribution of the microspheres. CONCLUSION: Intratumoral injections with HoMS are minimally invasive and relatively safe in palliation of HNSCC patients. Careful patient selection and improved administration techniques are required to provide a more effective treatment. Further investigation of this novel treatment modality should be carried out because of the absence of side effects and lack of other treatment options.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/.