Development of controlled drug delivery systems for bone fracture-targeted therapeutic delivery: A review

Abstract

Impaired fracture healing is a major clinical problem that can lead to patient disability, prolonged hospitalization, and significant financial burden. Although the majority of fractures heal using standard clinical practices, approximately 10% suffer from delayed unions or non-unions. A wide range of factors contribute to the risk for nonunions including internal factors, such as patient age, gender, and comorbidities, and external factors, such as the location and extent of injury. Current clinical approaches to treat nonunions include bone grafts and low-intensity pulsed ultrasound (LIPUS), which realizes clinical success only to select patients due to limitations including donor morbidities (grafts) and necessity of fracture reduction (LIPUS), respectively. To date, therapeutic approaches for bone regeneration rely heavily on protein-based growth factors such as INFUSE, an FDA-approved scaffold for delivery of bone morphogenetic protein 2 (BMP-2). Small molecule modulators and RNAi therapeutics are under development to circumvent challenges associated with traditional growth factors. While preclinical studies has shown promise, drug delivery has become a major hurdle stalling clinical translation. Therefore, this review overviews current therapies employed to stimulate fracture healing pre-clinically and clinically, including a focus on drug delivery systems for growth factors, parathyroid hormone (PTH), small molecules, and RNAi therapeutics, as well as recent advances and future promise of fracture-targeted drug delivery.

Figure 1. Schematic of fracture healing stages, various risking factors for development of non-union healing, as well as an overview of current clinical treatments

* indicate FDA-approved therapies for fractures. (Abbreviations: ACP5: Acid Phosphatase 5; ALPL: Alkaline Phosphatase; ANG: Angiopoietin; BGLAP: Bone Gamma-Carboxyglutamate Protein (Osteocalcin); BMP: Bone Morphogenetic Proteins; COL1A1: Collagen Type I, alpha 1; DKK-1: Dickkopf-related Protein 1; IL: Interleukin; LIPUS: Low-Intensity Pulsed Ultrasound; M-CSF: Macrophage Colony-Stimulating Factor; MSC: Mesenchymal Stem Cell; OPG: Osteoprotegerin; PPARG: Peroxisome Proliferator-Activated Receptor Gamma; PTH: Parathyroid Hormone; RANKL: Receptor Activator of Nuclear Factor Kappa-B Ligand; RUNX2: Runt-Related Transcription Factor 2; SOX-9: Sex Determining Region Y-Box 9; SP7: Osterix; TNFα: Tumor Necrosis Factor Alpha; VEGF: Vascular Endothelial Growth Factor; Wnt: Wingless-Related Integration Site)

Figure 2. Release of fluorescein-labeled PSMA-b-PS NPs from PEG-PLA-DM-based hydrogels

(A) NP release was quantified by measuring fluorescence intensity using a microplate reader (470/515), mean ± SD, n=3. Dashed lines indicated release curves fitting into 1^st order release model. (B) Release profile (day 4 to day 23) extracted from (A) and fitted into zero order release model. (C) Summary of rate constants for 2 models, half-lives from 1^st order model and R² from zero order release model.