Development of a GMP-conform, biocompatible corneal stroma replacement for ocular surface reconstruction

开发符合 GMP 要求、生物相容性的角膜基质替代物，用于眼表重建

• 批准号: 280173526
• 负责人: Dr. Christian Lotz
• 金额: --
• 依托单位: Institut für Pharmazeutische Technologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/280173526?language=en
• 关键词: Development; GMP; conform; biocompatible; corneal

Ocular surface disorders are the fourth leading cause of blindness worldwide. The allogeneic corneal transplantation and the use of the amniotic membrane for ocular surface reconstruction are the most frequently used treatment methods to date. However, there is a worldwide discrepancy of 1:70 between the available and required corneal donor material. As a result, around 12.7 million patients are currently waiting for a donor cornea. The small total number of corneal donors, but also the limitations of the quality and the standardizable of the donor material as well as transplant rejection due to immune reactions are some reasons for this shortage of material. The need for clinically usable, alternative tissue substitutes for ocular surface reconstruction is higher than ever and of high clinical relevance. Using human cells to generate an artificial tissue followed by decellularization is a very promising approach. Due to the possibility of obtaining a large number of cells from a small tissue biopsy, there is almost no restriction on tissue availability for this approach. Furthermore, it is also possible to produce autologous tissue substitute by using a small biopsy from the patient and thus prevent a possible rejection reaction. In this follow-up study, the previously successfully established and in vitro tested matrices based on human corneal keratocytes will be tested in a mouse model with regard to their biocompatibility. Furthermore, with regard to the application in patients, the bioreactor system will be further improved in order to enable a standardized, GMP-compliant production of corneal substitute tissue under in vivo like conditions. In addition, the culture conditions will be adapted further in order to achieve an increased thickness through cell sheet stacking and an improved transparency by directed growth of the keratocytes in the cell sheets in a shorter time. In the feasibility study for this application it could already be shown that the generation of these cell sheets is possible and that they have promising properties with regard to the usability as replacement tissue. The anticipated outcome of this project is to generate a patient-specific, transparent and GMP-compliant tissue substitute as an alternative to amniotic membrane and to donor corneal material, which can be used in the treatment of ocular surface diseases.

眼表疾病是全球第四大致盲原因。异体角膜移植和使用羊膜重建眼表是迄今为止最常用的治疗方法。然而，在世界范围内，可用的角膜供体材料与所需的角膜供体材料之间的差异为1：70。因此，目前约有1270万患者正在等待捐献角膜。角膜供体的总数很少，而且供体材料的质量和可重复性的限制以及由于免疫反应引起的移植排斥是材料短缺的一些原因。临床上可用的替代组织替代物用于眼表重建的需求比以往任何时候都高，并且具有高度的临床相关性。使用人类细胞产生人工组织，然后进行脱细胞化是一种非常有前途的方法。由于从小组织活检获得大量细胞的可能性，这种方法对组织可用性几乎没有限制。此外，还可以通过使用来自患者的小活检来产生自体组织替代物，从而防止可能的排斥反应。在本后续研究中，将在小鼠模型中测试先前成功建立并体外测试的基于人角膜基质细胞的基质的生物相容性。此外，关于在患者中的应用，将进一步改进生物反应器系统，以便能够在类似体内的条件下标准化、符合GMP的角膜替代组织的生产。此外，培养条件将进一步适应，以便通过细胞片层堆叠实现增加的厚度，并通过在较短时间内细胞片层中角膜细胞的定向生长实现改善的透明度。在该应用的可行性研究中，已经表明这些细胞片的产生是可能的，并且它们在作为替代组织的可用性方面具有有前途的特性。该项目的预期成果是产生一种患者特异性、透明且符合GMP的组织替代物，作为羊膜和供体角膜材料的替代品，可用于治疗眼表疾病。