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.

<p>Icariin-loaded porous scaffolds for bone regeneration through the regulation of the coupling process of osteogenesis and osteoclastic activity</p>

“…Local drug delivery systems are applied for inducing and accelerating bone formation by releasing a variety of osteoinductive molecules such small molecules, DNA, RNA, proteins, etc 10. Nevertheless, most of these small molecules are often easily degraded during the preparation process in vitro or fail in translational trials because of the unpredictable side effects 11. BMP-2 protein delivery enhanced bone formation in bone defects, but some adverse effects were also reported, including ectopic ossification, soft tissue swelling, immune responses and an incidence of cancer 12.…”

Medium-Intensity Treadmill Exercise Exerts Beneficial Effects on Bone Modeling Through Bone Marrow Mesenchymal Stromal Cells

“…The osteoblasts activity is improved with increased ALP secretion (Shen et al, 2007). Exercise stimulates the ALP production by osteogenic cells in order to increase the mineralization of the newly forming bone (Roussignol et al, 2012;Wang et al, 2018). Supposedly, the increase in bone formation and the number of osteoblasts may be mediated by the increase in the number of osteogenic BMMSCs (Zhang et al, 2017).…”

Adjuvant Drug-Assisted Bone Healing: Advances and Challenges in Drug Delivery Approaches

“…Targeted drug delivery approaches are needed to increase the therapeutic drug efficacy and decrease adverse side effects [6,[23][24][25]. Ideal scaffolds should fulfill several biological and structural requirements including biocompatibility, biomimicry, mechanical support, and porosity to permit cell adhesion as well as nutrient supply, biodegradability after successful therapy, and controlled drug delivery [1,13,17,[26][27][28][29][30][31].…”

“…Estrogen deficiency reduces bone mineral density, making the bone more fragile. If bone defects are of critical size or patients have an impaired bone healing due to metabolic or inflammatory diseases such as diabetes mellitus and osteoporosis, the defects will not heal completely without additional surgical intervention [1][2][3][4][5][6].…”

“…Bone, as a complex structured tissue, requires a well-orchestrated healing process regarding timeframe and localization. In the literature, the bone healing process and defining molecular pathways are already described extensively [2,3,[6][7][8][9][10][11][12][13]. Briefly, bone regeneration can be sectioned into an inflammatory, reparative, and remodeling phase.…”