*5.1.1 Factor-based substitutes*

 Factor-based bone grafts include natural and recombinant growth factors and hormones, which are generally used alone and/or together with other materials. The bone morphogenetic proteins (BMPs), platelet-derived growth factor (PDGF), parathyroid hormone (PTH), transforming growth factor-beta proteins (TGF-β), and many more come under this category. This group too does not come without associated disadvantages, such as protein instability, risk of uncontrolled proliferation or cancer, and high cost.

#### *5.1.1.1 Bone morphogenic proteins*

Nearly 30 human proteins fall under the BMP name and this group comprises the largest division of transforming growth factor (TGF)-β family of ligands. Since the last 40 years, the significance of BMP signaling in skeletal development has received immense approval [32]. It was first identified as a substance in extracellular matrix of bone, which stimulates new bone formation by Marshall R. Urist, and later named BMPs. In the United States, in 2002, the Food and Drug Administration (FDA) approved the first bone graft substitute, which was the recombinant human (rh) BMP-2 for single-level anterior lumbar interbody fusion (ALIF) within a titanium cage of implant grade. Subsequently, the increased use of BMP-2 for various spine

fusion injuries as an alternative to autograft acted to be a savior as bone substitute. Despite that, starting from 2006, independent research groups started reporting complications associated with the use of rhBMP-2. The side effects ranged from seroma formation [33, 34], ectopic bone growth [35–37], osteolysis [38, 39], and increased risk of cancer [40, 41]. This led to a systematic review and meta-analysis, which was reported in Annals of Internal Medicine in June 2013. It was conducted as joint work of Medtronic and Yale University Open Data Access Project (YODA), and reported biased results in earlier industry-funded publications [42, 43]. Now, the use of rhBMP-2 (INFUSE) is limited to oblique lateral interbody fusion (OLIF) and anterior lumbar interbody fusion (ALIF) upon nonavailability of autograft. Also, BMP-7 or human osteogenic peptide-1 (OP-1) was given an FDA Humanitarian Device Exemption in 2004 [44, 45], but later studies [46] ultimately led to the FDA rejection of Pre-Market Approval of OP-1 in April 2009.
