Trends in hydrogel-based encapsulation technologies for advanced cell therapies applied to limb ischemia

Ischemia occurs when blood flow is reduced or restricted, leading to a lack of oxygen and nutrient supply and removal of metabolites in a body part. Critical limb ischemia (CLI) is a severe clinical manifestation of peripheral arterial disease. Atherosclerosis serves as the main cause of CLI, which arises from the deposition of lipids in the artery wall, forming atheroma and causing inflammation. Although several therapies exist for the treatment of CLI, pharmacotherapy still has low efficacy, and vascular surgery often cannot be performed due to the pathophysiological heterogeneity of each patient. Gene and cell therapies have emerged as alternative treatments for the treatment of CLI by promoting angiogenesis. However, the delivery of autologous, heterologous or genetically modified cells into the ischemic tissue remains challenging, as these cells can die at the injection site and/or leak into other tissues. The encapsulation of these cells within hydrogels for local delivery is probably one of the promising options today. Hydrogels, three-dimensional (3D) cross-linked polymer networks, enable manipulation of physical and chemical properties to mimic the extracellular matrix. Thus, specific biostructures can be developed by adjusting prepolymer properties and encapsulation process variables, such as viscosity and flow rate of fluids, depending on the final biomedical application. Electrostatic droplet extrusion, micromolding, microfluidics, and 3D printing have been the most commonly used technologies for cell encapsulation due to their versatility in producing different hydrogel-based systems (e.g., microgels, fibers, vascularized architectures and perfusable single vessels) with great potential to treat ischemic diseases. This review discusses the cell encapsulation technologies associated with hydrogels which are currently used for advanced therapies applied to limb ischemia, describing their principles, advantages, disadvantages, potentials, and innovative therapeutic ideas.