Review
Role of angiogenesis in bone repair

https://doi.org/10.1016/j.abb.2014.07.006Get rights and content

Highlights

  • Bone vasculature is essential for bone development, remodeling and homeostasis.

  • Inadequate blood vessel formation impairs bone remodeling and fracture repair.

  • Review illustrates the importance of vascularization in bone remodeling and repair.

  • We elaborate on research in improving vascularization in engineered bone grafts.

Abstract

Bone vasculature plays a vital role in bone development, remodeling and homeostasis. New blood vessel formation is crucial during both primary bone development as well as fracture repair in adults. Both bone repair and bone remodeling involve the activation and complex interaction between angiogenic and osteogenic pathways. Interestingly studies have demonstrated that angiogenesis precedes the onset of osteogenesis. Indeed reduced or inadequate blood flow has been linked to impaired fracture healing and old age related low bone mass disorders such as osteoporosis. Similarly the slow penetration of host blood vessels in large engineered bone tissue grafts has been cited as one of the major hurdle still impeding current bone construction engineering strategies. This article reviews the current knowledge elaborating the importance of vascularization during bone healing and remodeling, and the current therapeutic strategies being adapted to promote and improve angiogenesis.

Section snippets

Bone Circulation and Angiogenesis

Vasculature is essential for embryonic skeletal development, bone growth and remodeling [1], [2], [3], [4]. Apart from supplying the bone tissue with nutrients, growth factors, hormones, cytokines and chemokines as required; and removing waste products, bone vasculature acts as a communicative network between the bone and neighboring tissues [3], [5]. Depending on their origin, bone development occurs via two distinct modes of ossification: Intramembranous (flat bones such as skull and

Normal bone repair and microenvironment

In the event of an injury, bones have the unique ability to heal by regenerating new bone sans development of fibrotic scars, a common phenomenon during soft tissue healing [1], [5], [38]. The development of fibrotic scars during bone repair results in critical-sized bone defects if left untreated and it would ultimately compromise the mechanical properties of the skeleton [5]. Hence adult bone repair mimics bone formation during organogenesis, consisting of a series of interdependent healing

Pro-angiogenic signaling in bone wound micro-environment

A plethora of pro-angiogenic factors such as the VEGF, Platelet-Derived Growth Factor (PDGF), Transforming Growth Factor β (TGF-β), Fibroblast Growth Factors (FGF) and Bone Morphogenetic Proteins (BMPs) are involved in the bone repair cascade (see Fig. 2). Their role in initiating angiogenesis and/or regulating osteogenesis has been summarized in Table 1.

Among these, VEGF, whose production is frequently stimulated by most osteoinductive factors [67], [68], [69], has been suggested to possibly

Endothelial progenitor cells in bone repair

EPCs are a population of cells that is found circulating in the bone marrow and peripheral blood, which has the ability to differentiate into mature EC. New blood vessels during fracture repair can be formed either via angiogenesis or vasculogenesis. The latter process occurs when new blood vessels form without a pre-existing vascular component and occurs via the differentiation of local or/and circulating EPCs [132], [133], [134], [135], [136]. EPC are comprised of a heterogeneous population

Current therapeutic tools in bone repair and their limitations

The treatment for restoring bone function is often dependent on the type of orthopedic injury. Although bone fractures generally undergo repair via the process of callus formation [38], severe cases of bone damage (traumatic fractures, bone tumors etc) mostly require surgical reconstruction [52]. Current therapy involves bone grafting, a procedure that replaces missing bone with either autologous (bone material sourced from patients own body), allogenic (bone material sourced from a donor) or

Strategies for improving vascularization in Bone tissue engineering

Biomaterial scaffolds in bone tissue engineering serve as templates for the establishment of the vascular system and bone-forming cell growth [160]. Lack of de novo tissue growth, insufficient nutrient supply and poor waste removal in 3D scaffolds are some of the limitations still hampering successful bone engineering and transplantation. The efficacy of the scaffolds for successful bone regeneration critically depends on their ability to induce and support vascular infiltration. Various

Incorporation pro-angiogenic factors in scaffolds

The close association between angiogenesis and osteogenesis, makes angiogenic growth factors that are implicated in both neovascularization and endochondral ossification, important therapeutic agents for bone regeneration. The ability of pro-angiogenic factors like VEGF, FGF-2, BMP-2 and BMP-7 to accelerate fracture repair when administered exogenously is well established [45], [46], [67], [70], [89], [99], [100]. For example injecting FGF-2 into larger animal models was reported to

‘Biocoating’ of scaffolds

Generating vascularized engineered bone tissue constructs by culturing MSCs or co-culturing ECs and bone cells in scaffolds presents another approach to simultaneously promote osteogenesis and vascularization [194], [195], [196]. ECs are well established to play a key role in angiogenesis, thus enhancing EC migration into the matrix to develop vascular beds is critical for the survival of implanted bone constructs. Schechner et al. [197] observed that in vivo implantation of primitive vascular

Gene therapy

The application of gene therapy as a mean to deliver growth factors for the clinical management of orthopedic disorders is another promising area in the field of bone tissue engineering [226]. The transference of genetic material can be performed by either in vivo or ex vivo gene-transfer procedure, implemented via viral (transfection) or non-viral (transduction) vectors [227], [228]. The in vivo technique where the genetic material is directly transferred to the host is generally the easier of

Conclusions

In conclusion, while much of the current strategies for fabricating functional vascularized bone grafts are still in their infancy, experimental data offers great potential for their future application in treatment of bone repair. However, in order to accelerate our progress in the field it is imperative to obtain a better understanding of bone wound microenvironment, which is the home of biological processes underlying vascularization and bone regeneration during fracture repair. This will in

Acknowledgments

The authors would like to acknowledge the help of Saranya Rajendran, Prattusha Sengupta, Sneha Srinivas and Ilaria Salvati for editing the manuscript. This work was partially supported by FP7-PEOPLE-2011-IRSES; Grant No 295181 – Acronym: INTERBONE, and a grant from University Grant Commission (UGC) Faculty Recharge Programme, Government of India to SC.

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