Bone Tissue Engineering Strategies To Treat Critically Sized Defects in Compromised Wound Healing Environments

Critically sized bone defects are difficult to treat, necessitating tissue engineering strategies to restore form and function. However, translation of these approaches is often constrained by preclinical models that fail to replicate systemic comorbidities commonly seen in clinical practice, such as diabetes, prior irradiation, osteonecrosis, and osteoporosis, and instead favor healthy wound environments that may overestimate efficacy. This comprehensive review aimed to provide a detailed overview of in vivo bone regeneration strategies for critically sized defects specifically within compromised healing environments, summarizing how animal models are developed and how biomaterial, cellular, and drug delivery platforms are tailored to these disease states. Recent work has sought to address key pathological barriers including chronic inflammation, oxidative stress, poor vascularization, hypocellularity, and the limited efficacy of cell-seeding approaches through a range of bioengineered solutions. Strategies include nanoengineered drug delivery systems, bioactive ion-releasing scaffolds, immunomodulatory and antioxidant biomaterials, advanced cell provisioning, and extracellular vesicle-based therapies designed to restore redox balance, promote angiogenesis, and reestablish osteogenesis. Remaining challenges include heterogeneity and poor standardization of defect models, underrepresentation of multimorbidity and treatment-related injury, ethical and logistical barriers to large animal studies, and uncertainty in how best to bridge emerging platforms with regulatory expectations. Future directions will require coordinated refinement of disease-relevant models and development of multifunctional, context-responsive constructs to more reliably predict and improve clinical translation of bone tissue engineering therapies.