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HYDROGEL BIOMATERIALS WITH INDEPENDENT AND COMBINED VARIATIONS IN MODULUS AND CELL ADHESIVE LIGAND GRADIENTS FOR GUIDED NEOVASCULARIZATION OF ENGINEERED TISSUES

机译：模量和细胞粘附配体梯度具有独立和综合变化的水生生物物质，用于指导组织工程化的新血管化

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The engineering of large volume, metabolically demanding tissue requires the formation of rapid, stable, and functional neovascularization (new blood vessel formation) for oxygen and nutrient transport and removal of waste products to support viability, function, and restoration of newly formed tissue. Neovascularization is dependent on cell response to multiple spatiotemporal signals including, soluble and immobilized biochemical factors, as well as gradients of mechanical properties and physical structure provided by the 3D extracellular matrix (ECM); yet the individual and combined effects of these factors is poorly understood. Various polymerization techniques have been developed for creating gradient-based hydrogel scaffolds to promote rapid and guided neovascularization, however, most studies have focused on evaluating 3D cellular responses to scaffold embedded gradients of a single factor (i.e. growth factors). Herein we present free-radical approaches based on visible light frontal photopolymerization to synthesize synthetic poly(ethylene) glycol (PEG) hydrogel scaffolds with controllable, physiologically-relevant continuous gradients of elastic modulus and/or crosslink density, proteolytically mediated scaffold degradation (through incorporation of crosslinks susceptible to degradation by cell-secreted matrix-metalloproteinases) and immobilized concentration of cell adhesive peptide(RGD) ligands (through pendant RGD functionaiized monofunctional acrylates). Scaffolds with desired gradients were created using a dual programmable syringe pump system to control the composition and flow rates of two distinct prepolymer solutions in the feed stream entering a reaction chamber simultaneously exposed to crosslinking via visible light □□=514 nm) using an Argon Ion laser system (Figure 1 A,B). Using this approach proteolytically degradable hydrogel scaffolds were created with (1) gradients of elastic modulus (ranging from 660-1460 Pa) and proteolytic degradation while the immobilized RGD concentration was maintained uniform (2mM), (2) with uniform modulus (600 Pa) and proteolytic degradation with gradients of immobilized RGD concentration (0.48-0.98 mM) and (3) with varying RGD gradient characteristics including magnitude and slope (steep, intermediate and shallow slopes) (Figure 2).The effect of each type of gradient on 3D vascular sprouting parameters (invasion area, sprout length and number) was evaluated using a 3D co-culture spheroid model of sprouting angiogenesis. In scaffolds containing gradients of elastic modulus, the number of vascular sprouts increased in the opposing gradient direction while RGD gradient scaffolds promoted increases in the length of vascular sprouts towards the peptide gradient. Studies are currently underway to elucidate the effects the RGD gradient as scaffold modulus and proteolytic degradation kinetics are independently modulated on vascular sprouting. Finally strategies to spatially incorporate additional gradients such as peptides that enable affinity binding of growth factors or nanoparticles that provide spatiotemporal release of proangiogenic peptides within the scaffolds will be discussed.
机译：大容量，代谢要求高的组织工程需要形成快速，稳定和功能性的新血管形成（新血管形成），用于氧气和营养物的运输以及废物的清除，以支持新形成的组织的活力，功能和恢复。新血管形成取决于细胞对多种时空信号的反应，包括可溶性和固定化生化因子，以及3D细胞外基质（ECM）提供的机械性能和物理结构的梯度；但是，对这些因素的单独影响和综合影响知之甚少。已经开发了各种聚合技术来创建基于梯度的水凝胶支架，以促进快速和引导的新血管形成，但是，大多数研究集中在评估对支架中单个因素（即生长因子）的梯度的3D细胞反应。在本文中，我们提出了基于可见光前光聚合的自由基方法，以合成的，具有可控的，与生理相关的弹性模量和/或交联密度，蛋白水解介导的支架降解（通过掺入）的连续梯度的合成聚（乙二醇）（PEG）水凝胶支架易被细胞分泌的基质金属蛋白酶降解的交联）和固定浓度的细胞粘附肽（RGD）配体（通过RGD侧链官能化的单官能丙烯酸酯）的数量。使用双可编程注射器泵系统创建具有所需梯度的支架，以控制进入反应室的进料流中两种不同的预聚物溶液的组成和流速，同时使用氩离子通过□□= 514 nm可见光进行交联。激光系统（图1 A，B）。使用这种方法创建的蛋白水解可降解水凝胶支架具有（1）弹性模量梯度（从660-1460 Pa）和蛋白水解降解，同时固定的RGD浓度保持均匀（2mM），（2）具有均匀模量（600 Pa）固定的RGD浓度（0.48-0.98 mM）和（3）的梯度具有不同的RGD梯度特征，包括幅度和斜率（陡峭，中间和浅斜率）（图2）。（2）每种梯度对3D的影响使用发芽血管生成的3D共培养球体模型评估血管发芽参数（侵袭面积，发芽长度和数量）。在包含弹性模量梯度的支架中，在相反的梯度方向上，血管发芽的数量增加，而RGD梯度支架促进了向肽梯度的血管发芽长度的增加。目前正在进行研究以阐明RGD梯度的作用，因为支架模量和蛋白水解降解动力学是独立于血管发芽而调节的。最后，将讨论在空间上并入其他梯度的策略，例如能够使生长因子亲和结合的肽或在支架内提供促血管生成肽的时空释放的纳米颗粒。

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