Plates for internal fixation fabricated from biodegradable polymers degrade via an autocatalytic route. When they are used in bone implants of significant size and thickness, hollowing of the implant may occur while the overall dimensions appear unchanged. We hypothesized that incorporation of a cross-linked polypropylene fumarate matrix into polylactide-co-glycolide bone plates may provide an internal molecular network which prevents implant collapse. Cross-linking reagents of varying hydrophilicity including N-vinylpyrrolidone (VP), hydroxyethylmethacrylate (HEMA), and ethyleneglycol dimethacrylate (EGDMA) were employed. With the objective of determining the most biocompatible and structurally sound composition for molecular reinforcement, we investigated tissue responses in both subcutaneous and orthotopic rodent implantation models in relation to maintenance of implant integrity by histologic, histomorphometric, and stereomicroscopic analysis. Results showed that tissue responses were correlated with dimensional stability of the implants. The most favorable results were seen with the hydrophobic cross-linker EGDMA; this may have been related to the initial reduction of the water uptake by the implant. Cross-linking of polypropylene fumarate with EGDMA within a polylactide-co-glycolide bone plate may offer a means to maintain excellent biocompatibility while improving dimensional stability of biodegradable bone plates.