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Bone Tissue Engineering Strategies To Treat Critically Sized Defects in Compromised Wound Healing Environments
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    Bone Tissue Engineering Strategies To Treat Critically Sized Defects in Compromised Wound Healing Environments
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    • Sara E. Munkwitz
      Sara E. Munkwitz
      University of Miami Miller School of Medicine, Miami, Florida 33136, United States
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    • Hana Shah
      Hana Shah
      University of Miami Miller School of Medicine, Miami, Florida 33136, United States
      Florida International University Herbert Wertheim College of Medicine, Miami, Florida 33199, United States
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    • Nicholas J. Iglesias
      Nicholas J. Iglesias
      DeWitt Daughtry Family Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida 33136, United States
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      Orcidhttps://orcid.org/0000-0002-5935-997X
    • Michelle Camacho
      Michelle Camacho
      Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, Florida 33136, United States
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    • Taylor Fix
      Taylor Fix
      Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, Florida 33136, United States
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    • Cesar Pavon
      Cesar Pavon
      Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, Florida 33136, United States
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    • Vasudev Vivekanand Nayak*
      Vasudev Vivekanand Nayak
      Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, Florida 33136, United States
      Dr. John T. Macdonald Foundation Biomedical Nanotechnology Institute (BioNIUM), University of Miami, Miami, Florida 33136, United States
      *Email: [email protected]
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      Orcidhttps://orcid.org/0000-0003-2739-0339
    • Lukasz Witek
      Lukasz Witek
      Biomaterials and Regenerative Biology Division, NYU College of Dentistry, New York, New York 10010, United States
      Department of Biomedical Engineering, NYU Tandon School of Engineering, Brooklyn, New York 11201, United States
      Hansjörg Wyss Department of Plastic Surgery, NYU Grossman School of Medicine, New York, New York 10016, United States
      Department of Oral and Maxillofacial Surgery, NYU College of Dentistry, New York, New York 10010, United States
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      Orcidhttps://orcid.org/0000-0003-1458-6527
    • Paulo G. Coelho
      Paulo G. Coelho
      Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, Florida 33136, United States
      Dr. John T. Macdonald Foundation Biomedical Nanotechnology Institute (BioNIUM), University of Miami, Miami, Florida 33136, United States
      DeWitt Daughtry Family Department of Surgery, Division of Plastic Surgery, University of Miami Miller School of Medicine, Miami, Florida 33136, United States
      Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida 33136, United States
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    ACS Biomaterials Science & Engineering

    Cite this: ACS Biomater. Sci. Eng. 2026, XXXX, XXX, XXX-XXX
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acsbiomaterials.5c02130
    Published April 6, 2026
    © 2026 The Authors. Published by American Chemical Society
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    Abstract

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    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.

    © 2026 The Authors. Published by American Chemical Society

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    ACS Biomaterials Science & Engineering

    Cite this: ACS Biomater. Sci. Eng. 2026, XXXX, XXX, XXX-XXX
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acsbiomaterials.5c02130
    Published April 6, 2026
    © 2026 The Authors. Published by American Chemical Society
    Request reuse permissions

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