Elsevier

Advanced Drug Delivery Reviews

Volume 94, 1 November 2015, Pages 41-52
Advanced Drug Delivery Reviews

Extracellular matrix-inspired growth factor delivery systems for bone regeneration

https://doi.org/10.1016/j.addr.2015.04.007Get rights and content

Abstract

Growth factors are very promising molecules to enhance bone regeneration. However, their translation to clinical use has been seriously limited, facing issues related to safety and cost-effectiveness. These problems derive from the vastly supra-physiological doses of growth factor used without optimized delivery systems. Therefore, these issues have motivated the development of new delivery systems allowing better control of the spatiotemporal release and signaling of growth factors. Because the extracellular matrix (ECM) naturally plays a fundamental role in coordinating growth factor activity in vivo, a number of novel delivery systems have been inspired by the growth factor regulatory function of the ECM. After introducing the role of growth factors during the bone regeneration process, this review exposes different issues that growth factor-based therapies have encountered in the clinic and highlights recent delivery approaches based on the natural interaction between growth factor and the ECM.

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.

References (167)

  • T. Cramer et al.

    Expression of VEGF isoforms by epiphyseal chondrocytes during low-oxygen tension is HIF-1 alpha dependent

    Osteoarthritis Cartilage

    (2004)
  • K.N. Malizos et al.

    The healing potential of the periosteum molecular aspects

    Injury

    (2005)
  • U. Noth et al.

    Multilineage mesenchymal differentiation potential of human trabecular bone-derived cells

    J. Orthop. Res.

    (2002)
  • C. Colnot et al.

    Analyzing the cellular contribution of bone marrow to fracture healing using bone marrow transplantation in mice

    Biochem. Biophys. Res. Commun.

    (2006)
  • E.J. Mackie et al.

    Endochondral ossification: how cartilage is converted into bone in the developing skeleton

    Int. J. Biochem. Cell Biol.

    (2008)
  • Y.Y. Yu et al.

    Immunolocalization of BMPs, BMP antagonists, receptors, and effectors during fracture repair

    Bone

    (2010)
  • T.K. Sampath et al.

    Recombinant human osteogenic protein-1 (hOP-1) induces new bone formation in vivo with a specific activity comparable with natural bovine osteogenic protein and stimulates osteoblast proliferation and differentiation in vitro

    J. Biol. Chem.

    (1992)
  • C.M. Edgar et al.

    Autogenous regulation of a network of bone morphogenetic proteins (BMPs) mediates the osteogenic differentiation in murine marrow stromal cells

    Bone

    (2007)
  • H. Seeherman et al.

    Delivery of bone morphogenetic proteins for orthopedic tissue regeneration

    Cytokine Growth Factor Rev.

    (2005)
  • G.M. Calori et al.

    Application of rhBMP-7 and platelet-rich plasma in the treatment of long bone non-unions: a prospective randomised clinical study on 120 patients

    Injury

    (2008)
  • P.V. Giannoudis et al.

    Clinical applications of BMP-7: the UK perspective

    Injury

    (2005)
  • U. Mayr-Wohlfart et al.

    Vascular endothelial growth factor stimulates chemotactic migration of primary human osteoblasts

    Bone

    (2002)
  • M. Orlandini et al.

    Vascular endothelial growth factor-D activates VEGFR-3 expressed in osteoblasts inducing their differentiation

    J. Biol. Chem.

    (2006)
  • Z.S. Patel et al.

    Dual delivery of an angiogenic and an osteogenic growth factor for bone regeneration in a critical size defect model

    Bone

    (2008)
  • T.J. Nash et al.

    Effect of platelet-derived growth factor on tibial osteotomies in rabbits

    Bone

    (1994)
  • S. Pun et al.

    Anabolic effects of basic fibroblast growth factor in the tibial diaphysis of ovariectomized rats

    Bone

    (2000)
  • Y. Tabata et al.

    Bone regeneration by basic fibroblast growth factor complexed with biodegradable hydrogels

    Biomaterials

    (1998)
  • F. Nakajima et al.

    Spatial and temporal gene expression in chondrogenesis during fracture healing and the effects of basic fibroblast growth factor

    J. Orthop. Res.

    (2001)
  • F. Shapiro

    Bone development and its relation to fracture repair. The role of mesenchymal osteoblasts and surface osteoblasts

    Eur. Cell Mater.

    (2008)
  • L. Audige et al.

    Path analysis of factors for delayed healing and nonunion in 416 operatively treated tibial shaft fractures

    Clin. Orthop. Relat. Res.

    (2005)
  • C. Lu et al.

    Effect of age on vascularization during fracture repair

    J. Orthop. Res.

    (2008)
  • J.R. Lynch et al.

    Femoral nonunion: risk factors and treatment options

    J. Am. Acad. Orthop. Surg.

    (2008)
  • D.K. Wukich et al.

    The management of ankle fractures in patients with diabetes

    J. Bone Joint Surg. Am. Vol.

    (2008)
  • J. Aronson

    Limb-lengthening, skeletal reconstruction, and bone transport with the Ilizarov method

    J. Bone Joint Surg. Am. Vol.

    (1997)
  • C.R. Perry

    Bone repair techniques, bone graft, and bone graft substitutes

    Clin. Orthop. Relat. Res.

    (1999)
  • C. Laurencin et al.

    Bone graft substitutes

    Expert Rev. Med. Devices

    (2006)
  • J.I. Dawson et al.

    Concise review: bridging the gap: bone regeneration using skeletal stem cell-based strategies - where are we now?

    Stem Cells

    (2014)
  • E. Ratcliffe et al.

    Current status and perspectives on stem cell-based therapies undergoing clinical trials for regenerative medicine: case studies

    Br. Med. Bull.

    (2013)
  • J.C. Reichert et al.

    A tissue engineering solution for segmental defect regeneration in load-bearing long bones

    Sci. Transl. Med.

    (2012)
  • J. Even et al.

    Bone morphogenetic protein in spine surgery: current and future uses

    J. Am. Acad. Orthop. Surg.

    (2012)
  • M. Kitamura et al.

    FGF-2 stimulates periodontal regeneration: results of a multi-center randomized clinical trial

    J. Dent. Res.

    (2011)
  • M. Nevins et al.

    Platelet-derived growth factor promotes periodontal regeneration in localized osseous defects: 36-month extension results from a randomized, controlled, double-masked clinical trial

    J. Periodontol.

    (2013)
  • Y.R. Yun et al.

    Administration of growth factors for bone regeneration

    Regen. Med.

    (2012)
  • L. Claes et al.

    Fracture healing under healthy and inflammatory conditions

    Nat. Rev. Rheumatol.

    (2012)
  • Z.S. Ai-Aql et al.

    Molecular mechanisms controlling bone formation during fracture healing and distraction osteogenesis

    J. Dent. Res.

    (2008)
  • T.J. Cho et al.

    Differential temporal expression of members of the transforming growth factor beta superfamily during murine fracture healing

    J. Bone Miner. Res.

    (2002)
  • P.M. Mountziaris et al.

    Modulation of the inflammatory response for enhanced bone tissue regeneration

    Tissue Eng. B Rev.

    (2008)
  • G.E. Glass et al.

    TNF-alpha promotes fracture repair by augmenting the recruitment and differentiation of muscle-derived stromal cells

    Proc. Natl. Acad. Sci. U. S. A.

    (2011)
  • Y. Liu et al.

    Mesenchymal stem cell-based tissue regeneration is governed by recipient T lymphocytes via IFN-gamma and TNF-alpha

    Nat. Med.

    (2011)
  • H. Xie et al.

    PDGF-BB secreted by preosteoclasts induces angiogenesis during coupling with osteogenesis

    Nat. Med.

    (2014)
  • Cited by (220)

    • Particle carriers for controlled release of peptides

      2023, Journal of Controlled Release
    View all citing articles on Scopus

    This review is part of the Advanced Drug Delivery Reviews theme issue on “Drug delivery to bony tissue”.

    View full text