**1. Introduction**

The ideal bone graft substitute for spinal fusion would have the safety and effectiveness of autograft when used by itself, be supported by quality published clinical evidence, and be available at a reasonable cost. Most of the options available today fall short of these goals. The number and variety of bone grafting products available to choose from is extensive, totaling more than 400 at the current time. The claims about the function and value of these products are confusing, even to those with the time and expertise to evaluate them in-depth. The preclinical and clinical evidence available for making a clinical use decision is also enormously varied and subject to misinterpretation. A large reason for these challenges is that the regulatory pathways and required evidence leading to FDA approval for spinal bone graft substitutes vary widely.

Nonstructural allograft and cellular allograft products, which do not rely on the metabolic activity of living cells, are considered to be HCT/P products under the United States Code of Federal Regulations Title 21—part 1271 (HUMAN CELLS, TISSUES, AND CELLULAR AND TISSUE-BASED PRODUCTS). Section 361 describes products that are minimally manipulated, are for homologous use only, do not have a systemic effect, and are not dependent on the metabolic activity of living cells for their primary function, in addition to other qualifications. Once a

manufacturer determines a product meets all of these requirements and follows the appropriate regulations, the manufacturer can place the product on the market by simply notifying the FDA of the intent to do so. There is no premarket review by FDA for safety or effectiveness of such products. Therefore, there are no requirements for preclinical or clinical data. Since most HCT/P products have little to no peer-reviewed human clinical data, the surgeons must extrapolate the likely benefits in their clinical use.

Synthetic bone grafts and demineralized bone matrices (DBMs) fall under Class II under Section 510(k) of the Federal Food, Drug and Cosmetic Act. Section 510(k) describes a regulatory process for the clearance of products that have been demonstrated to the FDA's satisfaction to be "substantially equivalent" in safety and effectiveness to another lawfully marketed device when used for the same purpose. Market clearance requires the filing and review of a 510(k) application and a subsequent FDA review. This review is generally based on a single animal study and bench-top testing comparing the subject device with a predicate. Once again, since most 510(k) cleared products have little to no peer-reviewed human clinical data, surgeons must extrapolate the likely benefits in their clinical use.

Drug-device combination bone grafts are Class III and require an investigational device exemption (IDE) clinical trial followed by a premarket approval (PMA) application. The IDE study requirements include strict oversight from the FDA from statistical and protocol design through clinical follow-up, data integrity and analysis. These IDE studies must be prospective, controlled, blinded and statistically-powered prior to the onset. Moreover, the FDA-required outcomes for approval must be stipulated in the clinical design protocol. The review of both the IDE and PMA filings for drug-device combination products involve both the device (CDRH) and drug (CDER) branches of the FDA. The result of this rigorous process is the highest quality Level I human clinical data available. Surgeons may rely upon this data to make clinical use decisions.

## **2. Infuse bone graft: bone morphogenetic protein (BMP)**

#### **2.1 Bone morphogenetic protein: BMP**

In 1965, Dr. Marshall R. Urist showed that demineralized bone matrix (DBM) could induce bone formation when implanted under the skin or intramuscular [1]. Urist pioneered the theory that a substance naturally present in bone was responsible for the osteoinductive bone healing activity of DBM (now Class II). He named this substance, the bone inductive principle, bone morphogenetic protein (BMP) and initiated an extensive and difficult search for these active protein molecules [2]. More than two decades later, advances in molecular biology by Dr. John Wozney's research team at the Genetic Institute described the first isolated extraction and recombinant form of BMP-2 in 1988 [3, 4]. BMP-2 and BMP-7 have been shown to have the most bone forming potential out of the 15 BMPs identified and studied to date [5]. The recombinant protein available commercially today is a synthetic, genetically engineered version of the natural protein.

BMPs are potent bone forming agents in bone regeneration and bone repair activity and are members of the TGF-Beta superfamily of cytokines. BMPs drive mesenchymal stem cells (MSCs) into osteoblastic lineage. These active protein dimeric molecules are osteoinductive and generally require a collagen sponge or ceramic carrier to enhance their handling characteristics. BMPs initiate endochondral bone formation, presumably by stimulating local MSCs and augmenting bone collagen synthesis. The BMP-2 ligand acts as a rigid clamp connecting type I and

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sis or an hourglass configured fusion.

*Class III Spine Grafts*

*2.1.1 rhBMP-2 pre-clinical*

models by Sandhu et al. [7, 8].

in rhBMP-2 dose [7].

*DOI: http://dx.doi.org/10.5772/intechopen.87706*

type II BMP receptor chains (BMPRs) together for transactivation. This activation causes intracellular signaling by phosphorylation of downstream signaling molecules (Smads). Smads ultimately mediate and regulate the transcription of target genes by binding to specific DNA sequences (BMP-responsive elements) [6].

The next direction of rhBMP-2 research was to attempt to define proper dosing of the potent protein and to determine if this dosage would be specific to site or to carrier/scaffold. Formative work in this inquiry was performed in two different

The investigators first attempted to characterize the dose-response relationship of rhBMP-2 in a canine intertransverse spine fusion model. They compared increasing logarithmic rhBMP-2 doses (58, 115, 230, 460, and 920 mg) on a porous polylactic acid polymer carrier. Successful fusions postoperatively at 3 months were shown throughout this dosing range. A prior study done by this same

research team demonstrated superiority of a 2300 mg rhBMP-2 dose to autologous iliac crest bone graft (ICBG) using this same technique. Quality differences above a threshold dose were not reflected in the mechanical, radiographic, or histologic features in the canine intertransverse spine fusion model from a 40-fold variation

Learning from the canine work, the investigators continued their work in an ovine lumbar interbody fusion model in conjunction with a cylindrical fenestrated titanium interbody fusion cage (INTER FIX, Medtronic Sofomor Danek, Inc., Memphis, TN). The cage was filled with rhBMP-2-collagen or ICBG (control). The sheep all appeared radiographically fused at 6 months. However, the histologic evaluation revealed that 33% (2/6) of the control group were fused as compared with 100% (6/6) of the rhBMP-2 group (*P* < 0.001). The scar involving the control group was 16-fold more than that seen with the rhBMP-2 group (*P* < 0.01) [8]. A rhesus monkey nonhuman primate model with rhBMP-2 on a collagen carrier within a titanium cage (Sofomor Danek, Memphis, TN) was the subsequent evolutionary step from the ovine model [9]. As optimal dosing for rhesus monkeys had not been previously established, three concentrations of rhBMP-2 [0.00 mg/ mL sham (buffer only), 0.75 mg/mL low dose, or 1.50 mg/mL high dose) were tested. The results demonstrated that both the investigational rhBMP-2 groups achieved arthrodesis at 6 months histologically as compared to the sham group. As before with the ovine model, the blinded nonhuman primate model radiographic assessment was suboptimal but the sagittal CT assessment was consistent with the histology. The higher dose rhBMP-2 (1.5 mg/mL) caused faster and denser bone formation; this study established the dose used in the upcoming US IDE trial.

Fusion environments differ. A cage environment places the contained collagen

A standard compression resistant carrier with concomitant dosing concentration

for rhBMP-2 was deemed necessary. Boden et al. studied a ceramic carrier [60% hydroxyapatite and 40% tricalcium phosphate (TCP)] in a nonhuman primate laminectomy model. Concentrations of rhBMP-2 (0, 6, 9, or 12 mg) were compared to ICBG. Fusion occurred with each rhBMP-2 carrier including the 0 mg/rhBMP-2 ceramic carrier alone group [10]. No significant overgrowth occurred involving the

carrier under protected direct compression forces between large vascularized opposing bony vertebral endplate surfaces. Posterolateral fusion presents a difficult environment with limited surface area and an intertransverse process fusion gap under distraction forces. Moreover, the surrounding muscle envelope applies mechanical compression on the graft material and may contribute to a pseudarthrotype II BMP receptor chains (BMPRs) together for transactivation. This activation causes intracellular signaling by phosphorylation of downstream signaling molecules (Smads). Smads ultimately mediate and regulate the transcription of target genes by binding to specific DNA sequences (BMP-responsive elements) [6].
