Different dense and porous biodegradable matrices based oh solely atelocollagen, or with different atelocollagen and hyaluronic acid derivative ratios, were obtained by varying feeding formulations, cross-linking reaction parameters, and preparative protocols. The compositions.. and methods for forming hydrogels through a combination of physical and chemical cross-linking processes are provided. The chemical cross-linking was mainly mediated by a synthetic component, a poly(e-caprolactone) reactive derivative, aiming the development of new hybrid hydrogels with tailored characteristics by an appropriate use of the advantages offered by the included natural and synthetic components and the selection of the preparative procedure. The structure and morphology of the 3D hybrid materials were comparatively investigated by means of Fourier-transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), X-ray diffraction (XRD), and environmental scanning electron microscopy (ESEM). FTIR and XRD analysis showed no signs of collagen denaturation during the formation of, 3D structures. The influence of various factors, such as the chemical composition of the resulted hydrogels and their morphology, on water uptake and water vapor sorption, mechanical behavior, as well as on in vitro degradation characteristics, was systematically investigated. The experimental results point on the advantage offered by the high and modular physicochemical stability of the ternary hydrogels cross-linked by combined approaches. All newly developed materials show no hemolytic effect, which recommends them for potential biomedical applications.