Tissue Biology Research Unit, Department of Surgery, University Children's Hospital Zurich, August Forel Str. 7, CH-8008 Zurich, Switzerland.
Department of Molecular Materials, Radboud University Nijmegen, Institute for Molecules and Materials, Heyendaalseweg 135, 6525 Nijmegen, the Netherlands; Noviotech B.V., Molenveldlaan 43, 6523 RJ Nijmegen, the Netherlands.
Acta Biomater. 2018 Apr 1;70:129-139. doi: 10.1016/j.actbio.2018.01.042. Epub 2018 Feb 15.
Molecular and mechanical interactions with the 3D extracellular matrix are essential for cell functions such as survival, proliferation, migration, and differentiation. Thermo-responsive biomimetic polyisocyanopeptide (PIC) hydrogels are promising new candidates for 3D cell, tissue, and organ cultures. This is a synthetic, thermo-responsive and stress-stiffening material synthesized via polymerization of the corresponding monomers using a nickel perchlorate as a catalyst. It can be tailored to meet various demands of cells by modulating its stiffness and through the decoration of the polymer with short GRGDS peptides using copper free click chemistry. These peptides make the hydrogels biocompatible by mimicking the binding sites of certain integrins. This study focuses on the optimization of the PIC polymer properties for efficient cell, tissue and organ development. Screening for the optimal stiffness of the hydrogel and the ideal concentration of the GRGDS ligand conjugated with the polymer, enabled cell proliferation, migration and differentiation of various primary cell types of human origin. We demonstrate that fibroblasts, endothelial cells, adipose-derived stem cells and melanoma cells, do survive, thrive and differentiate in optimized PIC hydrogels. Importantly, these hydrogels support the spontaneous formation of complex structures like blood capillaries in vitro. Additionally, we utilized the thermo-responsive properties of the hydrogels for a rapid and gentle recovery of viable cells. Finally, we show that organotypic structures of human origin grown in PIC hydrogels can be successfully transplanted subcutaneously onto immune-compromised rats, on which they survive and integrate into the surrounding tissue.
Molecular and mechanical interactions with the surrounding environment are essential for cell functions. Although 2D culture systems greatly contributed to our understanding of complex biological phenomena, they cannot substitute for crucial interaction that take place in 3D. 3D culture systems aim to overcome limitations of the 2D cultures and answer new questions about cell functions. Thermo-responsive biomimetic polyisocyanopeptide (PIC) hydrogels are promising new candidates for 3D cell, tissue, and organ cultures. They are synthetic and can be tailor to meet certain experimental demands. Additionally, they are characterized by strain-stiffening, a feature crucial for cell behaviour, but rare in hydrogels. Their thermos-responsive properties enable quick recovery of the cells by a simple procedure of lowering the temperature.
与 3D 细胞外基质的分子和机械相互作用对于细胞的存活、增殖、迁移和分化等功能至关重要。热响应仿生聚异氰酸肽（PIC）水凝胶是用于 3D 细胞、组织和器官培养的有前途的新型候选材料。这是一种通过使用高氯酸镍作为催化剂聚合相应的单体合成的合成的、热响应的和应力增韧材料。通过调节其刚度并通过使用无铜点击化学将短 GRGDS 肽修饰到聚合物上，可以满足细胞的各种需求。这些肽通过模拟某些整合素的结合位点使水凝胶具有生物相容性。本研究重点是优化 PIC 聚合物的特性，以实现高效的细胞、组织和器官发育。筛选水凝胶的最佳刚度和与聚合物偶联的 GRGDS 配体的理想浓度，使各种源自人类的原代细胞类型增殖、迁移和分化。我们证明成纤维细胞、内皮细胞、脂肪来源干细胞和黑色素瘤细胞在优化的 PIC 水凝胶中能够存活、生长和分化。重要的是，这些水凝胶支持复杂结构如体外毛细血管的自发形成。此外，我们利用水凝胶的热响应特性实现了对活细胞的快速温和回收。最后，我们表明在 PIC 水凝胶中生长的源自人体的器官样结构可以成功地皮下移植到免疫缺陷大鼠上，在这些大鼠上它们存活并整合到周围组织中。
与周围环境的分子和机械相互作用对于细胞功能至关重要。尽管 2D 培养系统极大地促进了我们对复杂生物现象的理解，但它们不能替代发生在 3D 中的关键相互作用。3D 培养系统旨在克服 2D 培养的局限性，并回答有关细胞功能的新问题。热响应仿生聚异氰酸肽（PIC）水凝胶是用于 3D 细胞、组织和器官培养的有前途的新型候选材料。它们是合成的，可以根据特定的实验需求进行定制。此外，它们的特点是应变硬化，这是细胞行为的关键特征，但在水凝胶中很少见。它们的热响应特性可以通过简单的降温程序快速回收细胞。
