Extracellular matrix-inspired growth factor delivery systems for bone regeneration☆
Graphical abstract
Introduction
Unlike most tissues, bone possesses an intrinsic capacity to regenerate after injury [1], [2]. The majority of bony injuries, when properly treated by re-apposition, heal without a permanent lesion, and the pre-existing properties of the bone tissue are restored through remodeling. In the clinical setting, the most common form of bone regeneration is fracture healing, during which the pathway of normal fetal skeletogenesis, including intramembranous (primary) and endochondral (secondary) ossification, is recapitulated to some extent [3]. However, there are many situations where complete bone regeneration cannot occur. For example, up to 13% of fractures occurring in the tibia are associated with delayed healing or fail to heal [4]. When a broken bone does not heal properly, it is called a “non-union”, and this happens if the fracture is non-stabilized or if the bone defect is too large following a trauma or a tumor resection. Other reasons for non-union include avascular necrosis, infection, soft-tissue imposition, osteoporosis, or co-morbidities such as diabetes [5], [6], [7], [8]. In those cases, the bone regeneration needs to be further stimulated. Standard approaches widely used in clinical practice include distraction osteogenesis, bone transport [9], and bone-grafting methods such as autologous or allogeneic bone grafts [10]. While autologous bone grafting is currently the gold standard, harvesting bone requires an additional surgical procedure, with well-documented complications and discomfort for the patient. Moreover, the quantity of bone that can be harvested is clearly limited. Therefore, extensive efforts have been made to develop bone-graft substitutes, which consist of natural or synthetic biomaterial scaffolds that promote bone regeneration. A wide range of biomaterials such as fibrin, collagen, gelatin, alginate, hydroxyapatite, β-tricalcium phosphate, and glass ceramics are currently used alone or combined [11], [12]. While these biomaterials have some intrinsic osteogenic capacities, they are often not sufficient to promote complete regeneration. Indeed, optimal bone regeneration not only depends on mechanical stability and on an osteoconductive matrix, but also on osteoinductive factors and osteogenic cells [13], [14]. Therefore, common strategies to promote better or faster healing consist of delivering osteoinductive growth factors and/or stem/progenitor cells through osteoconductive biomaterials.
Stem/progenitor cells are very promising to enhance bone regeneration, but showing statistically significant efficacy in clinical trials has been difficult [15], [16], most likely because of stem/progenitor cell selection criteria variations and because their regenerative capability cannot readily be controlled once transplanted [15]. On the other hand, growth factors may have better capacities to promote bone regeneration [17], and several products containing recombinant growth factors have been used in orthopedic applications such as spinal fusions, non-unions, and oral surgery [18], [19], [20], [21], [22]. In this review, after introducing the roles of growth factors during the bone regeneration process, we will concentrate on their potential to promote bone healing and on their clinical limitations. Specifically, we will present growth factor delivery strategies inspired from the natural interaction between extracellular matrix (ECM) and growth factors.
Section snippets
Inflammatory phase
Bone injury is typically associated with disruption of the local soft and vascular tissue integrity. This damage induces the activation of non-specific wound healing pathways that accompany non-skeletal injuries (Fig. 1A). The bleeding within the injury site develops into a hematoma, which coagulates between and around the broken bone ends forming a fibrinous clot. The first cells recruited are polymorphonuclear neutrophils, which are attracted by dead cells and debris and rapidly accumulate
Extensively explored growth factors to enhance bone regeneration
As we have seen above, a multitude of growth factors are involved in regulating the different phases of the bone regeneration process; some of these growth factors have been extensively used in pre-clinical models. Numerous studies using critical-sized defect have demonstrated the great potential of BMP-2 [61], BMP-7 [61], VEGF-A [35], PDGF-BB [62], FGF-2 [41], and IGF-1 [63]. While TGF-βs are strongly implicated in the regeneration process, it has been difficult to draw conclusions regarding
Clinical limitations of growth factors
As we have seen above, a number of growth factors have entered into clinical trials and some of them are approved for specific applications in orthopedic surgery. However, the promising outcomes of studies in animal models has only partially been translated to the human situation, due to safety and cost-effectiveness issues.
In spinal surgery, several serious complications have been reported regarding the use of BMPs due to post-operative edema leading to dysphagia and dyspnea, ectopic bone
Recreating the bone regenerative microenvironment with growth factors coupled to ECM components
Numerous ways have been explored both in research and clinical phases to deliver growth factors [115], [116], [117]. Currently, the ECM has become a source of inspiration for designing optimal delivery systems, because it plays a fundamental role in coordinating growth factor signaling in vivo. Indeed, the ECM displays and releases growth factors in a highly spatio-temporal controlled manner. Moreover, the ECM also modulates the signaling of growth factors. Thus, understanding how the ECM
Future directions
Another way to reduce dose is to exploit the cooperative signaling between growth factors, cytokines, and ECM proteins. The natural process of bone regeneration involves the sequential signaling of multiple cytokines and growth factors, which control each other and shape the regenerative microenvironment (Fig. 1). Therefore, instead of delivering a single type of signaling molecule at high dose, delivering low doses of multiple key players simultaneously or sequentially could be more optimal
Conclusion
When delivering growth factors to augment bone regeneration, the first challenge is to know which optimal concentrations of the right growth factors should be detected by the right cells at the right time. Therefore, as a first critical step, substantial attention should be given to understand basic information about the dynamic of the bone regenerative microenvironment, to further develop growth factor-based therapies. This understanding is particularly important to gain insights about the
Abbreviations
- BMP
bone morphogenetic protein
- ECM
extracellular matrix
- FGF
fibroblast growth factor
- GDF
growth/differentiation factor
- HIF
hypoxia-inducible factor
- IGF
insulin-like growth factor
- M-CSF
macrophage colony-stimulating factor
- MSC
mesenchymal stem cells
- OPG
osteoprotegerin
- PDGF
platelet-derived growth factor
- PEG
polyethylene glycol
- PlGF
placental growth factor
- PTH
parathyroid hormone
- RANKL
receptor activator of nuclear factor κB ligand
- SDF
stromal cell-derived factor
- TGF
transforming growth factor
- TNF
tumor necrosis factor
- VEGF
Acknowledgements
This work was supported in part by the European Research Council under the Advanced Grant Cytrix, by the Swiss National Science Foundation (P300P3-151198), and the International Joint Research Promotion Program of Osaka University.
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This review is part of the Advanced Drug Delivery Reviews theme issue on “Drug delivery to bony tissue”.