Department of Oral and Maxillofacial Surgery & Special Dental Care, University Medical Center Utrecht, Utrecht University, G05.222, PO Box 85500, Utrecht, 3508 GA, The Netherlands.
Regenerative Medicine Center Utrecht, Utrecht, 3584 CT, The Netherlands.
Adv Sci (Weinh). 2022 Feb;9(6):e2103284. doi: 10.1002/advs.202103284. Epub 2021 Dec 28.
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.
临床应用软骨内骨再生（EBR）将受益于同种异体来源去细胞软骨构建体的工程化。然而，开发保留细胞外基质（ECM）的有效去细胞化策略仍然具有挑战性。本研究旨在研究去细胞化、软愈伤组织样球体诱导的 EBR。为了挑战这种方法的可翻译性，使用同种异体细胞源生成构建体。在免疫活性大鼠模型中，皮下和股骨临界尺寸缺损中评估新骨形成。将活球体用作对照。此外，还评估了球体成熟向肥大的影响。去细胞化程序成功诱导细胞死亡，而不会影响 ECM 组成或生物活性。在体内，去细胞化软骨形成组在异位和原位都观察到更多的新骨形成。在股骨缺损中，去细胞化软骨形成组观察到骨再生加速，植入后 4 周即可观察到缺损桥接。作者的结果首次表明，去细胞化软愈伤组织样物质诱导的骨形成率显著增加。这些发现为开发新一代适用于每位患者的同种异体、“现成”EBR 产品铺平了道路。
