Hydrogels are increasingly used as three-dimensional (3D) cell culture platforms to mimic the extracellular matrix (ECM) and support cell growth and function. Traditional two-dimensional (2D) cell culture has limitations in replicating the complex 3D environment of native tissues, leading to altered cell behavior. Synthetic and natural hydrogels offer advantages as scaffolds, but each has limitations. Synthetic hydrogels can be engineered to incorporate biochemical and mechanical cues that mimic the native ECM, while natural hydrogels provide biocompatibility and bioactivity. However, both types have challenges, such as limited control over material properties and variability in batch-to-batch performance. Hydrogels are attractive for 3D cell culture due to their ability to mimic the mechanical and biochemical properties of the native ECM. They allow for the controlled presentation of biochemical signals, such as growth factors and integrin-binding ligands, which are essential for cell function and tissue development. Synthetic hydrogels can be tailored to provide specific mechanical and biochemical cues, while natural hydrogels offer inherent biocompatibility and bioactivity. However, synthetic hydrogels often lack the complex signaling networks present in natural ECMs, and natural hydrogels may be too complex to control precisely. To overcome these limitations, synthetic-biologic hydrogels are being developed that combine the benefits of both synthetic and natural materials. These hydrogels can be designed to incorporate multiple biochemical and mechanical cues, allowing for precise control over cell behavior. For example, hydrogels can be engineered to release growth factors in response to specific cellular signals, such as the activity of matrix metalloproteinases (MMPs). This approach allows for the dynamic regulation of cell function and tissue development. The design of hydrogels for 3D cell culture requires careful consideration of mechanical and biochemical properties to ensure that they support cell growth, differentiation, and tissue organization. Hydrogels must be able to provide the right mechanical environment for cells to function properly, while also allowing for the controlled release of growth factors and other signaling molecules. Additionally, hydrogels must be biocompatible and biodegradable to ensure that they do not interfere with cell function or tissue development. In summary, hydrogels are a promising tool for 3D cell culture as they can mimic the complex environment of the native ECM. By incorporating biochemical and mechanical cues, synthetic-biologic hydrogels can provide a more accurate representation of the native ECM, allowing for the study of cell behavior and tissue development in a controlled environment. The development of these hydrogels is essential for advancing tissue engineering and regenerative medicine.Hydrogels are increasingly used as three-dimensional (3D) cell culture platforms to mimic the extracellular matrix (ECM) and support cell growth and function. Traditional two-dimensional (2D) cell culture has limitations in replicating the complex 3D environment of native tissues, leading to altered cell behavior. Synthetic and natural hydrogels offer advantages as scaffolds, but each has limitations. Synthetic hydrogels can be engineered to incorporate biochemical and mechanical cues that mimic the native ECM, while natural hydrogels provide biocompatibility and bioactivity. However, both types have challenges, such as limited control over material properties and variability in batch-to-batch performance. Hydrogels are attractive for 3D cell culture due to their ability to mimic the mechanical and biochemical properties of the native ECM. They allow for the controlled presentation of biochemical signals, such as growth factors and integrin-binding ligands, which are essential for cell function and tissue development. Synthetic hydrogels can be tailored to provide specific mechanical and biochemical cues, while natural hydrogels offer inherent biocompatibility and bioactivity. However, synthetic hydrogels often lack the complex signaling networks present in natural ECMs, and natural hydrogels may be too complex to control precisely. To overcome these limitations, synthetic-biologic hydrogels are being developed that combine the benefits of both synthetic and natural materials. These hydrogels can be designed to incorporate multiple biochemical and mechanical cues, allowing for precise control over cell behavior. For example, hydrogels can be engineered to release growth factors in response to specific cellular signals, such as the activity of matrix metalloproteinases (MMPs). This approach allows for the dynamic regulation of cell function and tissue development. The design of hydrogels for 3D cell culture requires careful consideration of mechanical and biochemical properties to ensure that they support cell growth, differentiation, and tissue organization. Hydrogels must be able to provide the right mechanical environment for cells to function properly, while also allowing for the controlled release of growth factors and other signaling molecules. Additionally, hydrogels must be biocompatible and biodegradable to ensure that they do not interfere with cell function or tissue development. In summary, hydrogels are a promising tool for 3D cell culture as they can mimic the complex environment of the native ECM. By incorporating biochemical and mechanical cues, synthetic-biologic hydrogels can provide a more accurate representation of the native ECM, allowing for the study of cell behavior and tissue development in a controlled environment. The development of these hydrogels is essential for advancing tissue engineering and regenerative medicine.