Department of Biomedical Engineering, University of Massachusetts Lowell, 1 University Avenue, Lowell, MA 01854, USA.
Department of Neuroscience, School of Medicine, Tufts University, 136 Harrison Avenue, Boston, MA 02111, USA.
Acta Biomater. 2023 Sep 1;167:321-334. doi: 10.1016/j.actbio.2023.06.008. Epub 2023 Jun 17.
There is a clinical need to understand the etiologies of periodontitis, considering the growing socio-economic impact of the disease. Despite recent advances in oral tissue engineering, experimental approaches have failed to develop a physiologically relevant gingival model that combines tissue organization with salivary flow dynamics and stimulation of the shedding and non-shedding oral surfaces. Herein, we develop a dynamic gingival tissue model composed of a silk scaffold, replicating the cyto-architecture and oxygen profile of the human gingiva, along with a saliva-mimicking medium that reflected the ionic composition, viscosity, and non-Newtonian behavior of human saliva. The construct was cultured in a custom designed bioreactor, in which force profiles on the gingival epithelium were modulated through analysis of inlet position, velocity and vorticity to replicate the physiological shear stress of salivary flow. The gingival bioreactor supported the long-term in vivo features of the gingiva and improved the integrity of the epithelial barrier, critical against the invasion of pathogenic bacteria. Furthermore, the challenge of the gingival tissue with P. gingivalis lipopolysaccharide, as an in vitro surrogate for microbial interactions, indicated a greater stability of the dynamic model in maintaining tissue homeostasis and, thus, its applicability in long-term studies. The model will be integrated into future studies with the human subgingival microbiome to investigate host-pathogen and host-commensal interactions. STATEMENT OF SIGNIFICANCE: The major societal impact of human microbiome had reverberated up to the establishment of the Common Fund's Human Microbiome Project, that has the intent of studying the role of microbial communities in human health and diseases, including periodontitis, atopic dermatitis, or asthma and inflammatory bowel disease. In addition, these chronic diseases are emergent drivers of global socioeconomic status. Not only common oral diseases have been shown to be directly correlated with several systemic conditions, but they are differentially impacting some racial/ethnic and socioeconomic groups. To address this growing social disparity, the development of in vitro gingival model would provide a time and cost-effective experimental platform, able to mimic the spectrum of periodontal disease presentation, for the identification of predictive biomarkers for early-stage diagnosis.
目前，人们需要深入了解牙周炎的病因，因为这种疾病的社会经济影响日益严重。尽管口腔组织工程学近年来取得了一些进展，但实验方法仍未能开发出一种具有生理相关性的牙龈模型，该模型能够将组织结构与唾液流动动力学以及对有角化和无角化口腔表面的刺激结合起来。在此，我们开发了一种动态牙龈组织模型，该模型由丝质支架组成，复制了人类牙龈的细胞结构和氧分布，并使用模拟唾液的介质来反映人类唾液的离子组成、粘度和非牛顿行为。该构建体在定制设计的生物反应器中进行培养，通过分析入口位置、速度和涡度来调节牙龈上皮的力分布，以复制唾液流动的生理剪切力。该牙龈生物反应器支持牙龈的长期体内特征，并改善了上皮屏障的完整性，这对于抵抗致病菌的入侵至关重要。此外，用牙龈组织挑战 P. gingivalis 脂多糖（作为微生物相互作用的体外替代物）表明，动态模型在维持组织内稳态方面具有更大的稳定性，因此可用于长期研究。该模型将与人类龈下微生物组整合到未来的研究中，以研究宿主-病原体和宿主共生体相互作用。
人类微生物组的主要社会影响已经波及到共同基金的人类微生物组计划的建立，该计划旨在研究微生物群落在人类健康和疾病中的作用，包括牙周炎、特应性皮炎或哮喘和炎症性肠病。此外，这些慢性疾病是全球社会经济地位的新兴驱动因素。不仅常见的口腔疾病与几种系统性疾病直接相关，而且它们对某些种族/族裔和社会经济群体的影响也不同。为了解决这种日益严重的社会差距，体外牙龈模型的开发将为早期诊断提供一种具有成本效益的实验平台，能够模拟牙周病的表现谱，用于识别预测性生物标志物。
