This study investigates the impact of PEG sensitization on the efficacy of PEG hydrogel-mediated tissue engineering, particularly in bone regeneration. PEG hydrogels are generally considered biologically inert, but concerns about their immunogenicity are growing. The study immunizes mice against PEG to stimulate anti-PEG antibody production and evaluates bone defect regeneration after treatment with BMP-2-loaded PEG hydrogels. Quantitative analysis shows that PEG sensitization increases bone formation compared to naive controls, while histological analysis reveals abnormally porous bone morphology in males. Immune cell recruitment is higher in PEG-sensitized mice. Naive controls also develop anti-PEG antibodies. Sex differences in bone formation and immune cell recruitment are apparent. These findings suggest that anti-PEG immune responses can impact tissue engineering efficacy. PEG hydrogels are widely used in medical devices, drug delivery, and tissue engineering due to their injectability, high water content, and soft-tissue-like properties. However, concerns about PEG immunogenicity have grown, with high prevalence of anti-PEG antibodies in the general population. This can lead to anaphylactic reactions and reduced efficacy of PEGylated drugs. The study shows that PEG sensitization increases bone formation and causes differences in bone morphology in mice treated with BMP-2-loaded PEG hydrogels, particularly in males. Sex-dependent differences in anti-PEG antibody production and immune cell recruitment are observed. These findings highlight the need for further investigation into PEG immunogenicity in tissue engineering. The study also shows that PEG hydrogel-based implants can induce anti-PEG antibody formation in vivo, which has implications for the use of PEG hydrogels in delivering osteoinductive therapeutics. The results suggest that patients with anti-PEG antibodies could be at risk for complications if PEG hydrogels are used as a vehicle for BMP-2 delivery. The study concludes that PEG-based delivery systems should be screened for anti-PEG antibodies before clinical use.This study investigates the impact of PEG sensitization on the efficacy of PEG hydrogel-mediated tissue engineering, particularly in bone regeneration. PEG hydrogels are generally considered biologically inert, but concerns about their immunogenicity are growing. The study immunizes mice against PEG to stimulate anti-PEG antibody production and evaluates bone defect regeneration after treatment with BMP-2-loaded PEG hydrogels. Quantitative analysis shows that PEG sensitization increases bone formation compared to naive controls, while histological analysis reveals abnormally porous bone morphology in males. Immune cell recruitment is higher in PEG-sensitized mice. Naive controls also develop anti-PEG antibodies. Sex differences in bone formation and immune cell recruitment are apparent. These findings suggest that anti-PEG immune responses can impact tissue engineering efficacy. PEG hydrogels are widely used in medical devices, drug delivery, and tissue engineering due to their injectability, high water content, and soft-tissue-like properties. However, concerns about PEG immunogenicity have grown, with high prevalence of anti-PEG antibodies in the general population. This can lead to anaphylactic reactions and reduced efficacy of PEGylated drugs. The study shows that PEG sensitization increases bone formation and causes differences in bone morphology in mice treated with BMP-2-loaded PEG hydrogels, particularly in males. Sex-dependent differences in anti-PEG antibody production and immune cell recruitment are observed. These findings highlight the need for further investigation into PEG immunogenicity in tissue engineering. The study also shows that PEG hydrogel-based implants can induce anti-PEG antibody formation in vivo, which has implications for the use of PEG hydrogels in delivering osteoinductive therapeutics. The results suggest that patients with anti-PEG antibodies could be at risk for complications if PEG hydrogels are used as a vehicle for BMP-2 delivery. The study concludes that PEG-based delivery systems should be screened for anti-PEG antibodies before clinical use.