Studies of bone morphogenetic protein-based surgical repair☆
Graphical abstract
Introduction
The repair and replacement of bone is a major clinical problem. The need for functional treatments of fracture non-unions, spinal injuries, and bone loss associated with trauma and cancer has become increasingly common and remains a significant challenge in the field of orthopaedic surgery. In the United States alone, it is estimated that over 10 million fracture-related physician or emergency visits occur every year [1]. These numbers will only continue to grow as human life expentancies increase due to better medical care.
Bone fractures can be treated with a cast because the broken bone needs to be set to improve the healing. Sometimes, surgery is required for bone fractures associated with small bone voids that can be filled with an appropriate bone void filler. For large bone defects, biological grafts such as autologous bone grafts, allografts, and demineralized bone matrix can be used, but each possess their own advantages and disadvantages. Autografts have been recognized as the gold standard in bone grafts because of their high success rate (as high as ~ 80–90%) and unlikelihood of being rejected [2]. However, these grafts are often associated with several shortcomings including donor-site morbidity, limited tissue for harvesting, and increased surgical time [3], [4], [5], [6]. Allografts and demineralized bone matrix have been introduced into clinical practice to overcome the drawbacks of autografts. Allografts are tissues harvested from one individual and implanted into another. Demineralized bone matrix is allograft bone tissue in which the inorganic mineral has been removed by exposure to acid, leaving behind organic collagenous matrix and non-collagenous proteins including growth factors [7], [8], [9]. The advantages of allografts and demineralized bone matrix are that they are readily available in nearly unlimited supply and can be easily processed into a variety of forms for specific applications [9], [10]. However, disease transmission, host immune reaction, and implant rejection remain significant disadvantages of these grafts [11]. As a result of these limitations, there has been significant recent interest in the development of biomaterials that can augment bone healing to preclude the needs for autografts and allografts [12]. For instance, researchers have actively investigated biodegradable polymeric scaffolds combined with growth factors and/or osteoprogenitor cells as a viable alternative to traditional grafts [13], [14], [15], [16], [17].
Tissue engineering can be described as the combination of biological, chemical, and engineering principles toward the repair, restoration, and replacement of tissues using cells, scaffolds, and biologic factors alone or in combination [18]. An important element of successful bone tissue engineering constructs is osteoinduction, or the stimulation of osteoprogenitor cells to differentiate into osteoblasts, which is often accomplished through the use of growth factors [19]. Bone growth factors are usually proteins secreted by cells which provide the necessary driving force for osteoblast functions including proliferation and differentiation. Generally, the mechanism of action of bone growth factors is to interact with membrane receptors on target cells. This interaction triggers an intracellular signaling cascade that ultimately induces the expression of bone associated genes in the nucleus and protein production in the cytoplasm [20], [21]. Over the past several decades, scientists have actively investigated growth factors for use in bone repair and regeneration preclinically. For instance, bone morphogenetic proteins (BMPs), insulin-like growth factors (IGFs), granulocyte–macrophage colony stimulating factor (GM-CSF), basic fibroblast growth factor (bFGF), and platelet-derived growth factor (PDGF) have all demonstrated the ability to induce significant bone formation and hold potential for use in bone reparative therapies [21], [22]. A review of the literature has shown that BMPs are the most effective growth factors in improving healing of non-unions, fractures, spinal fusions, and dental implants [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33]. Although PDGF is currently used in clinical practice, the only osteoinductive materials commercially available today are BMPs. BMPs were discovered by Dr. Marshall Urist when he observed de novo bone formation in rats after the implanation of decalcified bone into soft tissue pouches for which he later named the proteins responsible for the bone formation-BMPs [34]. To date, more than 20 BMPs have been identified, of which 7 appear capable of initiating bone growth [35], [36]. Thanks to notable advances in molecular biology and genomics, human BMP genes have been identified and cloned. rhBMPs can now be produced and purified from E. coli and mammailian cell lines for biochemical analysis and clincial trails [37], [38], [39], [40], [41]. Different animal models have been used to demonstrate the therapeutic potential of rhBMPs in bone repair and regeneration [22], [42], [43]. Presently, rhBMPs remain the most important growth factors in bone formation and repair [44], [45]. Two rhBMP-based commercial products: INFUSE® (rhBMP-2, Medtronic, Minneapolis, MN) and OP-1™ (rhBMP-7, Stryker Biotech, Hopkinton, MA) have received Food and Drug Administration (FDA) clearance for several surgical applications (see Table 1). Since the half-life of rhBMP-2 is about 6.7 min in non-human primates due to enzymatic degradation and rapid clearance rate [46], [47], [48], to increase its effectiveness of healing non-union fractures, rhBMPs are often combined with biocompatible carriers such as aborbable collagen sponges. Loading rhBMP into an absorbable collagen sponge allows for gradual rhBMP release over time, which stimulates new bone formation in the implant site. Current clinical applications of rhBMP-based products include long bone non-unions, spinal fusion, and oral surgeries [49], [50], [51]. In certain open tibial fractures and non-unions, rhBMPs can play an active role in healing broken bones [52]. In spinal surgery, rhBMP induces new bone formation in the disc space to fuse the vertebrae to reduce back pain, restore function, and strengthen the spine [53]. In oral surgery, rhBMP plays a role in the induction of new bone formation in the edentulous area of a missing tooth in order to support a dental implant [54], [55]. Considering the growing number of publications related to the clinical applications of rhBMPs, the purpose of this review is to cover the latest clinical development of rhBMPs including the use of BMP delivery carriers and approved BMP products for surgical repairs.
Section snippets
Long bone fractures
Long bone fractures make up a large portion of clinically reported fractures [1]. While many long bone fractures can be repaired without surgery, a significant portion of fractures are considered critical-size defects meaning they commonly form non-unions without surgical intervention. It should be noted the term critical-size is controversial since a recent study found that the accepted critical-size for human long bones (fracture gap greater than 1 cm and affecting at least 50% of the cortical
Design metrics for BMP delivery devices
While current clinical treatments have been shown to be effective in treating bone and spinal defects or injuries, the research community is actively seeking alternative drug delivery vehicles in order to improve current therapies. The overall aim is to develop an osteoinductive, osteogenic, and osteoconductive scaffold that accelerates bone formation at a similar rate to autologous treatment. To reach this aim, significant research has focused on the local, controlled delivery of rhBMPs
Critical outlook
Applications of BMPs in long bone repairs, spinal fusions, and oral surgeries are becoming increasingly common. While current results and outcomes have shown promise, significant issues with BMP-based therapies remain. One major concern has been the off-label use of BMPs. Over the past decade, at least 85% of the principal procedures using BMPs were off-label applications [235]. rhBMP-2 may lead to early bone resorption around PEEK implants, which can cause loosening and pain [108]. Also, the
Acknowledgements
Dr. Laurencin was the recipient of a Presidential Faculty Fellowship Award from National Science Foundation. Dr. Kevin Lo wishes to thank the Jo-Anne Smith, MD research and education foundation for their funded support of his research. The authors gratefully acknowledge funding from the NSF-EFRI 0736002, and NIH-R21 AR060480.
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This review is part of the Advanced Drug Delivery Reviews theme issue on “Targeted delivery of therapeutics to bone and connective tissues”.
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Contributed equally.