Many research studies are directed toward developing safe and efficient collagen-based biomaterials as carriers for drug delivery systems. This article presents a comparative study of the properties of new collagen sponges prepared and characterized by different methods intended for biomedical applications. The structural integrity is one of the main properties for a biomaterial in order for it to be easily removed from the treated area. Thus, the effect of combining a natural polymer such as collagen with an antimicrobial drug such as oxytetracycline or doxycycline and glutaraldehyde as the chemical cross-linking agent influences the cross-linking degree of the material, which is in direct relation to its resistance to collagenase digestion, the drug kinetic release profile, and in vitro biocompatibility. The enzymatic degradation results identified oxytetracycline as the best inhibitor of collagenase when the collagen sponge was cross-linked with 0.5% glutaraldehyde. The drug release kinetics revealed an extended release of the antibiotic for oxytetracycline-loaded collagen sponges compared with doxycycline-loaded collagen sponges. Considering the behavior of differently prepared sponges, the collagen sponge with oxytetracycline and 0.5% glutaraldehyde could represent a viable polymeric support for the prevention/treatment of infections at the application site, favoring tissue regeneration.

Collagen-based biomaterials are increasingly explored in dentistry for their ability to deliver drugs locally and support healing. In this study, we developed chlortetracycline-loaded collagen sponges aimed at preventing postoperative infections. Five formulations were prepared by lyophilization, each with the same collagen-to-drug ratio but different glutaraldehyde (GA) concentrations: 0%, 0.25%, 0.5%, 0.75%, and 1% (w/w) relative to dry collagen. The sponges were characterized using FT-IR and UV–VIS–NIR spectroscopy, and their swelling capacity, enzymatic stability, and drug release kinetics were evaluated. Antibacterial activity was tested against Escherichia coli, Staphylococcus aureus, and Enterococcus faecalis. Statistical differences between formulations were assessed using one-way ANOVA followed by Tukey’s post hoc test (p < 0.05). All sponges released the antibiotic rapidly within the first 60 min, followed by a sustained release for up to 10 h. The non-crosslinked sponge showed the highest antimicrobial effect, while the 0.25% GA formulation offered a good balance between stability and bioactivity. While higher cross-linking enhanced structural stability, it progressively reduced antimicrobial efficacy, highlighting a crucial design trade-off. These findings underline the need to fine-tune cross-linking conditions to achieve both durability and strong antimicrobial action in collagen-based drug delivery systems for dental applications.