3D Printing of Bacteriophage‐Loaded Hydrogels: Development of a Local and Long‐Lasting Delivery System

Multiple drug-resistant bacteria are a growing life-threatening problem and novel treatment strategies are urgently needed. One promising option is the use of lytic bacteriophages, viruses that infect and kill bacteria with high specificity. To efficiently utilize bacteriophage therapy for the treatment of implant-associated infections, an effective strategy for the local, long-lasting administration of bacteriophages at the site of infection is required. With the aim of developing a defined delivery system, this study investigates the feasibility of 3D extrusion printing of bacteriophages embedded in biomaterial inks by using a Staphylococcus aureus-specific phage strain as model. It is demonstrated that a bacteriophage-loaded hydrogel blend consisting of alginate and methylcellulose (AlgMC) can be printed with high shape fidelity. After cross-linking, the hydrogel constructs release bacteriophages that maintain their activity against S. aureus over a period of 35 days when incubated in human-plasma-like medium (HPLM). The integration of the nanoclay Laponite into the AlgMC blend, known for its high binding capacity for biomolecules, does not further prolong the release under (near) physiological conditions in HPLM but may protect bacteriophages under nonphysiological conditions. In conclusion, bacteriophage-loaded AlgMC inks fulfill the requirements for local bacteriophage therapy as they release active bacteriophages in a sustained manner.