Ideal graft characteristics




Autologous bone




Allograft bone








Platelet gels

DBM demineralized bone matrix, BMP bone morphogenetic proteins, BMA bone marrow aspirate

29.2 Autografts

The first spinal surgery using autograft bone was done by Hibbs in 1911. Three types of autograft bone have been used since then: cancellous, cortical, and vascularized cortical [4]. Autograft bone has all properties for an ideal spine graft material: osteoinduction (bone morphogenic proteins (BMPs), particularly BMP2 and BMP7), osteoconduction (bone matrix/collagen), and most importantly osteogenic potential (stem cells and osteoblasts). Accordingly, autografts can provide immediate and long-term mechanical stability. Autografts used for spine fusion can be classified in two categories: local bone, which is harvested from the lamina, facets, or processes during decompression, and extraspinal material, most commonly an iliac crest bone graft (ICBG). With both grafts there are no issues with donor compatibility and the costs are low. Local bone is a cortical graft and provides immediate mechanical stability, but due to the pore size, cell migration and differentiation is impaired. This leads to lower rates of bone remodeling and long-term instability. The advantage of local bone over ICBG is that no extra procedure or harvest site is needed, causing fewer complications. In contrast, ICBG is the most commonly used graft and often referred to as a “gold standard” for spinal fusion. A purely cancellous structure is easily revascularized, and the large surface provides an ideal environment for bone formation. Although ICBG lacks compressive strength, the rapid bone formation leads to an increase in fusion mass that provides mechanical stability. If the fusion approach is posterior, ICBG can be harvested without an additional surgical incision. An important parameter when choosing the autologous bone graft is the patient’s age, as elderly patients will have less ICBG and a lower bone quality. A challenge with both types of autografts is the large amount of material needed for multilevel fusions. Sengupta and co-workers found that the ICBG was superior in overall fusion rates and that both grafts performed similarly for single-level fusions. In multilevel fusions ICBG outperformed the local bone graft (fusion rates of 66 % vs. 20 %) [5]. However, ICBG grafts carry more complications than local bone grafts. The most serious complications are related to the harvest and can lead to subsequent fractures, hernia, ureteral injury, instability, infection, and prolonged length of stay [6]. Even though postoperative pain at the donor site is one of the most common issues, Howard et al. found that the pain incidence was similar in patients with or without ICBG harvest [7]. A study done by Gruskay found that an increase in blood transfusion rates, surgical time, and length of stay were the only short-term complications associated with the use of ICBG as a graft material [8].

29.3 Allograft Bone

This bone graft is harvested from cadaver tissues and is usually used for anterior cervical and lumbar fusions. Allografts are depleted of cells and growth factors and therefore have osteoconductive and minor osteoinductive properties. Allograft bones can be fresh, fresh frozen, or freeze-dried. The mechanical properties of fresh-frozen allografts are superior to freeze-dried ones, but have higher immunogenicity. In the posterolateral approach, freeze-dried allografts failed to produce fusion, whereas ICBG led to an 80 % fusion rate [9]. Cortical allografts can provide immediate stabilization, but the remodeling process is slow and the resorption of the graft is increased. On the other hand, corticocancellous grafts do not have an immediate mechanical benefit, but due to the large contact area, they are easily integrated and can promote bone remodeling. One of the main health concerns with allografts is the transmission of diseases. Mroz reported that between 1994 and 2007, 96.5 % of musculoskeletal allografts were recalled due to contamination and recipient infection [10]. Furthermore, a study done by Jurgensmeier found frequent inconsistencies in tissue banks, with 39 % accepting samples from elderly donors (≤80 years of age) and only 50 % of banks excluding grafts from osteoporotic patients [11]. Those discrepancies in graft collection have a significant impact on the mechanical properties of the graft and can contribute to fusion failure. However, the use of allografts in surgeries avoids complications associated with ICBG harvest. Allografts are manufactured in various forms as strips, chips, or demineralized bone matrix.

29.3.1 Demineralized Bone Matrix

Demineralized bone matrix (DBM) is a human, demineralized, cell-free allograft bone graft. During the extraction process, antigenic markers are removed, making DBM less immunogenic. The bone type used for DBM production is crucial, as tubular and cortical bones are more osteoinductive than flat bones [12]. The demineralized matrix consists of collagen (93 %), glycoproteins (3 %), debris, and calcium phosphate. The collagen matrix provides osteoconductivity to DBM; it is mainly composed of collagen I and a small fraction of collagen IV and X. Growth factors contribute to the osteoinductivity of DBM and include bone sialoprotein, osteopontin, and TGF-β superfamily [13]. BMP2 and BMP7 play a central role in cell differentiation toward osteoblasts. However, aging leads to decreased amounts of BMPs in DBM matrix. Conversely, tumor growth factor beta (TGF-β) and insulin growth factor 1 (IGF-1) are not affected by aging and thus have an important role in bone osteoinduction and interaction with major BMPs [14]. After bone demineralization, DBM is produced in powder form. Studies have shown that the particle size of DBM determines its osteoinductive properties by affecting host interaction and the release of growth factors. A size range between 420 and 840 μm was found to be the most osteoinductive [15]. DBM is mixed with various carriers at a ratio of 15 % DBM and 85 % carrier for easier delivery, precise surgical localization, and containment. The type of the carrier defines the final form of the DBM graft such as chips, putty, gel-filled syringes, and powder. Common carriers are calcium sulfate, glycerol, gelatin, and hyaluronic acid. DBM graft potentials have been evaluated in a large number of animal studies and clinical trials. Morone and co-workers have found that in a rabbit fusion model, a DBM gel (Grafton) alone or in combination with ICBG produced similar fusion rates compared to ICBG alone [16]. Studies have shown that the Grafton DBM in form of putty or flex led to higher fusion rates, even achieving 100 % when mixed with a small percentage of autologous bone. Both putty and flex are fibrous in structure, promote better osteoconductivity, and are similar to the native tissue. In our study we found that both the Grafton putty and the Osteofil paste led to fusion, whereas Dynograft did not promote fusion [17]. Furthermore, Osteofil induced fusion at earlier time points (4 weeks) and had the highest overall fusion rate (Fig. 29.1).


Fig. 29.1
L4–5 posterolateral fusion at 6 weeks in athymic rat using various DBMs: Osteofil paste, Grafton putty, and Dynograft (Reproduced from Wang et al. [17])

In spine orthopedics DBM is commonly used as bone filler or graft extender. Because the DBM is biodegradable, the scaffold can be used as a slow-release delivery vehicle for growth factors, antibiotics, cells (with/without gene modifications), and other active components. DBM has been used as an exogenous delivery system in numerous studies. In our study DBM was combined with an adenoviral Nel-like molecule 1 (NELL-1), BMP2, or BMP7. NELL-1, one of the key proteins in osteoblastic differentiation, caused the formation of a well-defined tissue mass similar to cortical bone and a continuous connection of newly formed bone and transverse processes [18]. We observed significantly higher fusion rates in the NELL-1 group compared to other studies that used BMP (Fig. 29.2).


Fig. 29.2
Lumbar X-rays (a, d) and micro-CT scans (b, c, e, and f) of Nell-1 and LacZ (control) 6-week fusion samples. The red arrows identify the radiopaque tissue masses on both sides of spine at L4 and L5 segments. The medial edge (green arrows) of each mass displayed the highest density similar to cortical bone (Reproduced from Lu et al. [18])

Clinical trials for cervical and lumbar fusion have shown that DBM can act as a bone graft leading to fusion and that there are no differences in the complication rates or duration of surgery when compared to ICBG. For example, Sassard and co-workers reported similar fusion rates in patients with autologous bone graft and Grafton putty vs. autologous graft only, with no significant differences in bone mineralization [19]. However, DBM’s disadvantage is a large variability due to donor demographics, type of bone, carrier, amount of growth factors, and the extraction procedure.

29.4 Ceramics

Ceramics are osteoconductive grafts deficient in growth factors and cells. They are easily obtainable in large amounts, are disease-free, and are with a pore size that is suitable for cell and blood vessel ingrowth. Hydroxyapatite and β-tricalcium phosphate (β-TCP) are mainly used for spine surgeries due to their prolonged rate of resorption, up to a year for hydroxyapatite and several months for β-TCP. Furthermore, the structure and pore size of hydroxyapatite and β-TCP are very similar to cancellous bone. Once implanted, β-TCP is populated with a fibrovascular stroma that is soon replaced with osteogenic cells, leading to bone formation. Several clinical studies have found that both ceramic grafts induced similar fusion rates compared to patients who received ICBG [20, 21]. One of the most commonly used hydroxyapatites is Pro Osteon Coralline Hydroxyapatite (Interpore Cross International, Irvine, CA). It is derived from a sea coral and mainly consists of calcium carbonate. Another graft mixture is Collagraft (NeuColl, Inc., Palo Alto, CA), consisting of collagen and a mixture of hydroxyapatite and β-TCP closely resembling the natural bone structure. Silicate-substituted calcium phosphate and calcium sulfate have been used in the recent years as synthetic graft extenders, showing variable fusion rates. The general disadvantage of ceramic grafts is its brittleness and inability to sustain heavy loads. Due to the low mechanical stability, ceramics are usually combined with fixation instruments. Because ceramics lack osteogenic and osteoinductive properties, they are often combined with materials containing growth factors and cells.

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Sep 23, 2017 | Posted by in NEUROLOGY | Comments Off on Osteobiologics
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