视神经损伤
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Figure 1｜Cell replacement therapy shows promise as an emerging retinal therapeutic that can help the growth of global market for retinal therapeutics.
Introduction: The rapidly growing field of regenerative medicine incorporates fundamental principles of stem cell biology and biomedical engineering to repair tissues damaged by genetic disorder, degeneration, or traumatic injury. The global market for stem cell therapies is expanding at an accelerating rate and projected to triple to over 100 Billion USD by the end of the decade (No author listed, 2019), as per Figure 1A. However, the full market and health potential of regenerative therapies depends upon successful clinical translation of contemporary treatments, such as cell replacement therapy. Replacement strategies offer newfound promise to treat vision loss caused by degeneration of the retina, a photosensitive tissue that lines the back of the human eye to convert light into bioelectrical signals for vision. Retinal disorders, such as macular degeneration and diabetic retinopathy, are leading causes of irreversible blindness in adults and are projected to increase in prevalence in the coming decades (GBD 2019 Blindness and Vision Impairment Collaborators, 2021). Emerging cell replacement strategies (No author listed, 2019; GBD 2019 Blindness and Vision Impairment Collaborators and Vision Loss Expert Group of the Global Burden of Disease Study, 2021) showcase innovative treatments for vision loss that will dramatically increase the current market share for retinal therapeutics.
Cell replacement therapy: Regenerative medicine seeks to restore vision by replacing damaged retinal neurons with healthy, functional stem cells. Previous studies have demonstrated the ability of precursor cells, progenitor cells, and adult mesenchymal stem cells to be safely transplanted, in vivo, without tumorigenic capacity (Oswald and Baranov, 2018). The human retina is a highly cellular structure with millions of cells positioned across a maximum thickness of 250 μm. The outer, non-neural tissue is called the retinal pigment epithelium (RPE), a single cell layer that helps regulate the flow of nutrients, transport waste, and relieve oxidative stress (Baden et al., 2020). The neural retina contains millions of neurons and glia synaptically interconnected across three nuclear layers, as shown in Figure 1B. Vision occurs when incident light is absorbed and transduced into electrical signals by rod and cone photoreceptors of the outer nuclear layer. Rods/cones then synapse with secondary neurons of the inner nuclear layer, such as bipolar, horizontal and amacrine cells, which in turn network with cells in the ganglion layer to transmit signals along the optic nerve to the visual cortex. Damage to neurons in any portion of this sophisticated network leads to progressive vision loss, which is incurable using current treatment options.Microfluidic models of collective behaviors: Microfluidic systems are highly customizable, in vitro assays with characteristic lengths of less than 1000 microns, or 1 millimeter. The microfluidic scale is highly applicable to the study of retinal cells and the migration scales desired during cell replacement therapy. Previous work from our group has developed microfluidic systems to examine the collective and individual behaviors of replacement cells in response to numerous factors and stimuli (Zhang et al., 2020). Further, contemporary fabrication readily facilitates the custom design and manufacture of microfluidics with nanometer structures able to model complex retinal anatomy during retinogenesis and in adulthood. Our laboratory recently developed a microsystem to model the in vivo geometry of the optic stalk (Zhang et al., 2020), a precursor to the optic nerve where retinal neuroblasts migrate from the developing brain to form the retina. As shown in Figure 1C and D, the full device is smaller than a coin and can be readily fabricated using elastomeric molding to characteristic lengths of less than 100 μm. The device can be seeded with cells and matrix on one side and used to observe migration across the central channel array under precise conditions. Our experiments have demonstrated that neuroblasts migrated collectively in clusters of cells with both neuronal and glial lineage in response to FGF concentration gradients (Pena et al., 2019; Zhang et al., 2020), as per Figure 1E. Moreover, smaller cohesive clusters (typically of 3–5 cells) were able to detach from larger cell groups to chemotax longer distances in the same gradient field, as shown in Figure 1F. These exciting results illustrate that collective behaviors observed in development can be modeled within microfluidic models to enable quantitative study of the role of cohesion in the migration of transplanted cells. These data further suggest an optimal cluster size for migration of de/differentiated retinal cells that may be correlated with N-cadherin activation and require further investigation. Taken together, these studies highlight how microfluidic study of inter-dependent collective chemotaxis and cohesion can produce novel insights to inform emerging strategies in retinal cell replacement (Zhang et al., 2020).