Vertebroplasty

6.611. Injectable Bone Cements for Spinal Column Augmentation: Materials for Kyphoplasty/Vertebroplasty J J Verlaan, University Medical Center Utrecht, Utrecht, The Netherlands M A Lopez-Heredia, University Medical Center Nijmegen, Nijmegen, The Netherlands J Alblas and F C Oner, University Medical Center Utrecht, Utrecht, The Netherlands J A Jansen, University Medical Center Nijmegen, Nijmegen, The Netherlands W J A Dhert, University Medical Center Utrecht, Utrecht, The Netherlands ã 2011 Elsevier Ltd. All rights reserved.

6.611.1. 6.611.2. 6.611.2.1. 6.611.2.2. 6.611.2.2.1. 6.611.2.2.2. 6.611.2.2.3. 6.611.3. 6.611.3.1. 6.611.3.1.1. 6.611.3.1.2. 6.611.3.1.3. 6.611.3.1.4. 6.611.3.2. 6.611.3.3. 6.611.3.4. 6.611.4. 6.611.4.1. 6.611.4.2. 6.611.4.3. 6.611.5. 6.611.5.1. 6.611.5.2. 6.611.5.3. 6.611.5.4. 6.611.5.5. 6.611.5.6. 6.611.5.7. 6.611.6. References

Introduction History of Spinal Column Augmentation with Injectable Bone Cements and Currently Accepted Indications History Currently Accepted Indications Painful osteoporotic vertebral compression fractures Painful metastatic/malignant vertebral body lesions Traumatic fractures Overview of Frequently Used Injectable Bone Cements for Spinal Augmentation Acrylate Cements Mixing phase Initial propagation phase Injection phase Curing phase CaP Cements Composite Cements (Hybrid Acrylic/CaP Cements) Miscellaneous Cements Clinical Results of Spinal Column Augmentation with Injectable Bone Cements Osteoporotic Vertebral Compression Fractures Metastatic/Malignant Vertebral Body Lesions Traumatic Fractures Complications in Spinal Column Augmentation Fracture Type Duration of Symptoms Instruments/Instrument Positioning/Spinal Anatomy Viscosity of Cement Injected Volume of Cement Injected Mechanical/Thrombogenic/Thermal Properties of Cement General Patient Health Characteristics Future Directions and Conclusions

Abbreviations CaP CaS CPC DmpT KP

6.611.1.

Calcium phosphate Calcium sulfate Calcium phosphate cement N,N-Dimethyl-p-toluidine Kyphoplasty

Introduction

In contemporary surgical practice, injectable bone cements are increasingly being used to treat a variety of pathological conditions of the spine including osteoporotic vertebral

PMMA SF-36 PCS VAS VP Zn GPC

147 148 148 149 149 149 149 149 150 150 150 150 150 151 152 153 154 154 155 155 155 156 156 156 157 157 157 158 158 158

Polymethyl methacrylate Short form 36 physical component summary Visual analog scale Vertebroplasty Zinc-based glass polyalkenoate cement

compression fractures, metastatic vertebral body lesions, and traumatic fractures. The principal goal of applying these injectable bone cements is to augment impaired bony structures in order to maintain or improve strength and stability of the spinal column. The first type of cement used in the spine,

147

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Orthopedic Surgery – Spinal Treatment

PMMA (polymethyl methacrylate), was originally developed for completely different purposes in humans and used, for example, as the material for dental implants, ocular prosthetics, and later for implant fixation in artificial joints prosthetics. Currently, new injectable bone cements are designed specifically for application in the vertebral body. The clinical results obtained in the last decades by using PMMA bone cement in vertebroplasty (VP) and balloon kyphoplasty (KP) procedures have clearly established a demand for biomaterials better adapted to their function as vertebral body bone void filler. Many biomaterial research centers now focus on incorporating into new bone cements the features notably absent in PMMA, such as the properties for osseointegration, capability of remodeling, and mechanical characteristics better approximating that of cancellous bone. This chapter aims to provide the reader with a brief introduction on the history of injectable bone cements for spinal column augmentation and discusses its currently accepted indications. Furthermore, an overview of frequently used injectable bone cements and their respective technical characteristics are described in detail followed by a summary of the clinical results obtained by this procedure. The clinical implications of cement leakage are discussed together with guidelines for bone cement handling to prevent this complication. A quick glance at possible future directions in the field of injectable bone cements for spinal column augmentation concludes this chapter.

6.611.2. History of Spinal Column Augmentation with Injectable Bone Cements and Currently Accepted Indications 6.611.2.1. History The first published case of VP, a technique referring to the injection of bone cement into a vertebral body, dates back to 1987 when Frenchmen Galibert and Deramond treated a painful hemangioma, refractory to conservative medical treatment, by filling the intravertebral lesion with an injectable bone cement (PMMA) resulting in immediate and long-lasting relief of symptoms.1 This paper is regarded as the index work on injectable bone cements for spinal column augmentation. However, the material used in this case had already been developed in 1928 and the process of polymerizing methyl methacrylate was invented as early as 1877 by Fittig and Paul. PMMA became commercially available in the year 1936 and is widely known to the public as an alternative to glass under the name plexiglas or perspex. The first clinical application of this material was in odontology where it was used to build dental implants. Following the observation by ophthalmologist Ridley during the Second World War that splinters of perspex from shattered aircraft cockpit canopies did not trigger an inflammation reaction in the eyes of wounded pilots, he made the material suitable for implantation in the form of artificial lenses, an operation he first conducted in 1949. Sir Charnley was among the first pioneers to use PMMA in orthopedic surgery to establish a bond between bone and implants in hip replacement surgery: a highly successful practice still in use today.2

Although the landmark paper by Galibert and Deramond, currently cited over 750 times, was followed by several other publications in French journals on this subject, VP as a new treatment for painful osteoporotic vertebral body fractures, did not gain momentum until the late 1990s when the first article in English was published by Jensen and coworkers.3 Jacques Dion, a French Canadian and senior author of the article, became the pivotal link importing the French knowledge into North American medical practice. The year 1999 saw a large number of papers published on various topics related to VP including the expansion of indications to metastatic lesions; the first prospective trials; and the first descriptions of serious complications including infection, pulmonary embolism, and neurological deficits after extravasation of cement.4–7 Around this time, the first critical notes on the (lack of) scientific evidence of the efficacy of injecting PMMA in the spinal column were also expressed.8 Trout and Kallmes raised the question about whether VP caused incidental vertebral fractures but failed to reach strong conclusions due to insufficient quality of data available from the literature.9 It has been estimated that over 1 million procedures have been performed worldwide.10–12 Meanwhile, in 2001 an alternative to VP, balloon KP, was described by Lieberman and coauthors.13 In this technique, balloons were inserted in the vertebral body and inflated prior to injection of the cement. The potential benefits of this procedure consisted of improved restoration of vertebral body anatomy and a reduction in cement extravasation due to the creation of a cavity lined by higher density bone facilitating lower pressures needed to inject bone cement. Subsequent clinical studies have shown results comparable to VP with often lower rates of cement extravasation.14 Virtually all studies described above dealt with the treatment of painful osteoporotic vertebral compression fractures treated by injection of PMMA cement in the affected vertebral level. Notable exceptions published in the same timeframe were the studies by, among others, Nakano et al. in which painful osteoporotic vertebral compression fractures were treated by VP or balloon KP using calcium phosphate (CaP) cement instead of PMMA cement.15–18 The rationale behind the use of CaP cement was the assumed superior biocompatibility, potentially leading to a more intimate bone–cement interface and subsequent remodeling of the biomaterial into bone by creeping substitution.19 In an attempt to combine the favorable characteristics of both PMMA (immediate stability) and CaP cement (superior osseointegration), some manufacturers have designed hybrid cements containing both materials.20 To our best knowledge no clinical data on the performance of these hybrid cements is available from the literature and the application of these biomaterials must currently be regarded to be mostly in the experimental phase.21 Augmentation of the spinal column using either PMMA or CaP cement has, in combination with pedicle screw instrumentation, recently also become an adjunct to the surgical treatment of traumatic burst fractures of the spine. Proponents of this new indication for VP/balloon KP suggested this technique to be able to (partially) restore the anatomy of the intervertebral disk space thereby decreasing the chance for secondary deformity due to disk intrusion into the fractured vertebral body.22

Injectable Bone Cements for Spinal Column Augmentation: Materials for Kyphoplasty/Vertebroplasty

6.611.2.2. Currently Accepted Indications As can be concluded from the considerable media coverage and editorials that rapidly emerged following the publication of the first attempt at randomized controlled trials on VP and balloon KP in 2009, a debate is presently raging concerning the efficacy of augmenting the spinal column with injectable biomaterials for any of the indications stated above.23–25 Notwithstanding the conflicting results gained from many studies conducted in the past two decades, augmentation of the spinal column with injectable biomaterials can presently be divided into the following main categories of indications for treatment: 1. painful osteoporotic vertebral compression fractures; 2. painful metastatic/malignant vertebral body lesions; 3. traumatic fractures.

6.611.2.2.1. fractures

Painful osteoporotic vertebral compression

Most of the spinal augmentations with injectable bone cement are being performed due to painful osteoporotic vertebral compression fractures refractory to conservative medical treatment which mainly consists of bed rest and analgesics.26 The natural history of these types of fractures is frequently benign with progressive resolution of symptoms 6–12 months after the onset of pain regardless of index treatment. It is the immediate and dramatic reduction of pain, typically within 24 h, giving VP or balloon KP the edge over nonoperative treatment strategies in the first 3 months of treatment.27 Currently, the principal hypothesis explaining the beneficial effect of injecting bone cement into osteoporotic vertebral compression fracture holds that cement injected in the vertebral body stabilizes the fracture and the subsequent decrease in residual motion leads to a reduction of perceived pain.28 Supporting this hypothesis, it has been demonstrated by many studies that painful vertebral bodies showing edema on magnetic resonance images, indicating unhealed vertebral body fractures, respond better to VP or balloon KP.29 To prevent cement extravasation, the amount of bone cement injected has steadily decreased in the last decade without affecting the high success rates. It can be argued as to whether everdecreasing volumes of bone cement injected can still adequately stabilize a vertebral body fracture, in which case the ‘stabilizing hypothesis’ may ultimately prove to be incorrect. Alternative hypotheses claim the exothermic and polymerizing effects of curing PMMA to result in thermal and chemical destruction of nociceptors, respectively. These two hypotheses have been refuted by in vivo animal experiments showing little or no tissue necrosis or inflammatory response, after injection of PMMA cement.19,30–32 Furthermore, by using CaP cement as bone void filler for osteoporotic vertebral compression fractures, Nakano et al.18 demonstrated that this isothermic, nonpolymerizing biomaterial leads to identical results compared to PMMA cement when injected in the spinal column.

6.611.2.2.2. Painful metastatic/malignant vertebral body lesions The first lesion to be treated by VP was a painful hemangioma. Many other pathologic lesions including metastatic spinal tumors and multiple myeloma have subsequently been

149

shown to respond favorably to the injection of bone cements provided the pedicles and laminae were not affected and compression of the spinal cord was not present.33 Spinal pain due to metastatic or hematological disease may be caused by a variety of factors and it has been suggested that they include (imminent) pathological fractures, chemical mediators, increased pressure within the bone, microfractures, overstretched periosteum, and compression of neural structures such as the spinal cord and roots.34,35 Similar to the group of osteoporotic vertebral compression fractures, the exact mechanism by which augmentation of the spine with injectable bone cements achieves its beneficial effect in metastatic/malignant spinal disease has not been elucidated. It is possible that stabilization of the vertebral body after VP or balloon KP also underlies the relief of pain for this indication.33 Deducing from the observation that tumor recurrence was rare in vertebral bodies treated with cement injection, some authors have suggested that PMMA has some antitumor properties. These properties could include cytotoxicity, hyperthermia, and local induction of ischemia. In a recently published review, Chi and Gokaslan33 recommend VP or balloon KP in properly selected patients with painful pathologic fractures to be performed as early as possible. Furthermore, they speculate that newer more elastic biomaterials than those currently used may lower the risk for adjacent level collapse and reduce complication rates.

6.611.2.2.3.

Traumatic fractures

Oner et al.36 suggested that recurrent kyphosis after surgical treatment of traumatic thoracolumbar fractures resulted from improperly reduced endplate fractures. It was shown that intervertebral disks adjacent to the fractured segment could intrude through fractured endplates into the burst vertebral body thereby causing spinal deformity.37 Hypothesizing that proper reduction of the endplates and subsequent augmentation of the vertebral body with bone cement could largely prevent this deformity, a technique was developed and subsequently tested to reduce fractured endplates in traumatic thoracolumbar burst fractures by pedicle screw fixation and balloon-assisted endplate reduction.22 After optimal endplate reduction was achieved, the balloons were removed and the intravertebral void was filled with CaP cement. The choice for this filler material was based on the expected average age of patients with traumatic spine fractures, which is significantly lower (mean age
35–40 years) compared to that of patients with osteoporotic vertebral compression fractures.38

6.611.3. Overview of Frequently Used Injectable Bone Cements for Spinal Augmentation The biomaterials used for spinal column augmententation by VP or balloon KP require several characteristics including injectability, biocompatibility, and mechanical stability.21 In selecting the biomaterial, a treating physician considers many parameters: patient condition, patient age, fracture configuration, selection of surgical technique, characteristics of the biomaterial, and environment of implantation site. In the next sections, the characteristics of the cements frequently used in, or with potential use for, VP and balloon KP are discussed.

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6.611.3.1. Acrylate Cements Virtually all cements commercially available for augmentation of the spinal column are based on PMMA, the synthetic polymer of methyl methacrylate. The monomer methyl methacrylate is an organic compound with the formula CH2¼ C(CH3) CO2CH3 (Figure 1(a) and 1(b)) which can be produced by several manufacturing routes. Fittig and Paul, two German physicists, were the first to invent, in 1877, the polymerization reaction leading to PMMA (C5O2H8)n (Figure 2). PMMA is a transparent material with a density of 1180 g l1 and has good resistance against mechanical impact.21 The melting and boiling temperatures are 130  C (403 K) and 200  C (473 K), respectively, while the material autoignites at 460  C (733 K). The polymerization reaction of methyl methacrylate to form PMMA is initiated by benzoyl peroxide, while N,N-dimethyl-p-toluidine (DmpT) is used as a radical-forming activator. Before the bone cement can be injected in the spinal column, its ingredients, a powder (containing polymethyl powder, benzoyl peroxide, and often an opaque material such as barium sulfate to improve radiological visibility) and a liquid (methyl methacrylate and DmpT), must be mixed. In the ensuing process, benzoyl peroxide and DmpT react to produce benzoyl radicals which are highly reactive and readily bind to the C¼C bond of methyl methacrylate. The radicalenhanced methyl methacrylate molecule subsequently starts the polymerization process by reacting with nearby nonradical methyl methacrylate molecules. The resulting (methyl methacrylate)n molecule retains its radical characteristics and continuous addition of new methyl methacrylate molecules leads to the formation of increasingly large chains of PMMA. The addition of each methyl methacrylate molecule to the developing chain is an exothermic process and can lead to temperatures of up to 100  C (373 K) in the core of the polymerizing cement when the maximum number of reactions per time unit is reached.39 As methyl methacrylate molecules eventually become rare in the increasingly viscous cement and radicals start to react with each other, self-extinguishing their reactivity, the chain-forming process decelerates and the chemical

O

O

(a)

(b)

Figure 1 (a) Molecular structure of methyl methacrylate and (b) three-dimensional representation of methyl methacrylate.

O

OO

OO

OO

OO

Figure 2 Molecular structure of polymethyl methacrylate.

O

reaction peters out. The process from mixing the components to finalization of the polymerization reaction can be described in four functional phases: 1. 2. 3. 4.

mixing phase, initial propagation phase, injection phase, curing phase.

6.611.3.1.1.

Mixing phase

In this phase the components of the bone cement are combined and mixed into a low viscosity fluid; radicals form to start the polymerization process.

6.611.3.1.2.

Initial propagation phase

During initial propagation, the number and length of (methyl methacrylate)n chains increase rapidly. The viscosity of the cement, although increasing, is still too low for safe injection.

6.611.3.1.3.

Injection phase

Many polymer chains have now been formed resulting in a substantial increase in cohesion and simultaneously decreased adhesion within the bone cement. To assess whether the bone cement has entered the injection phase, many physicians probe or test the material qualitatively in what is sometimes, frivolously, called the ‘toothpaste test’ or ‘spaghetti test’ as the viscosities of these familiar products accurately resemble the ideal constitution for injection of bone cement into the spinal column.

6.611.3.1.4.

Curing phase

The cement is not injectable anymore and now starts to radiate the heat generated by the exothermic polymerization reaction. Although the cement may appear fully hardened, the polymerization process is not complete for another 24 h. The duration of each phase is highly variable and depends mainly on the temperature of the premixed bone cement components and ambient temperature of the operating theater or radiological suite.40–42 This variability in duration of the various phases of the polymerizing cement poses a problem for physicians since it directly affects the time window available for safe injection.43 It has been noted by many authors that a change of only a few degrees in ambient or cement component temperature may lead to substantial deviations in the duration of the injection phase.44 Several in vitro studies have verified these observations and currently devices are being deployed to intraoperatively probe cement viscosity in real-time.45 Concerns have been expressed regarding the increased risk for adjacent level fractures after spinal augmentation with PMMA cement in osteoporotic vertebral compression fractures.46 Although no study has proven that the occurrence of adjacent level fractures is directly related to a change of the mechanical and elastic characteristics of the spinal column after augmentation (as opposed to the natural history of an already weakened spine where the presence of one vertebral compression fracture is highly predictive for subsequent fractures) many clinical studies have, nonetheless, reported the phenomenon to occur frequently.47 Moreover, in vitro studies assessing the stiffness (Young’s modulus) of human cadaveric

Injectable Bone Cements for Spinal Column Augmentation: Materials for Kyphoplasty/Vertebroplasty

vertebral specimens after VP or balloon KP using PMMA cement have demonstrated significant increases in stiffness after treatment compared to untreated control specimens.48 The stiffness of PMMA cement has been shown in earlier biomechanical experiments to range somewhere between cortical and cancellous bone.48 As a consequence, it has been hypothesized that the increase in stiffness resulting from cement augmentation may contribute to the failure of adjacent levels. Presently, some institutions are in the process of designing and testing PMMA cements with altered biomechanical properties to better approximate the compliancy of cancellous bone found in osteoporotic vertebral bodies, with the aim of reducing the adjacent level fracture rate.49 Boger and coauthors added N-methyl-pyrrolidone to regular PMMA cement and found a significant decrease in Young’s modulus, yield strength, and polymerization temperature while the handling time of the cement (i.e., injection phase) was increased by 200%.50 It was suggested that this type of cement was promising, showing compliancy closer to cancellous bone, while simultaneously exhibiting favorable handling and thermal characteristics compared to unmodified PMMA cement. Other methods to reduce the stiffness of PMMA have been investigated and include increasing cement porosity by addition of ingredients such as hydrogels or oligomers.51 Alternative acrylic cement compositions, such as dimethacrylate-based cements, have been designed showing favorable biomechanical and biocompatible properties compared to regular PMMA cements.52 Currently, most of these biomaterials continue to be studied in a meticulous way. Recent data suggest that the principles underlying their formulation may lead to enhanced clinical performance.53

6.611.3.2. CaP Cements When performing spinal column augmentation with injectable bone cements, several material characteristics including injectability and moldability are required. Heini et al. compiled the requirements for materials in VP and KP (KP). This was later elaborated upon by Lewis.21,54 These requirements can be subdivided into those intrinsically belonging to the material and the desired performance of the material and technique involved. CaP cements satisfy some of the requirements and this category of biomaterials is being considered useful for application in the spinal column. CaP materials have already been used for a long time in dentistry and maxillofacial surgery, but only recently in the field of spinal surgery.55 CaP cements are obtained by mixing a solid phase with a liquid phase, producing a paste that can be injected. Depending on the interaction between the solid and liquid phase and the particle distribution of the CaP powder used, there will be a variability in moldability and pressure filtering effect, the latter phenomenon referring to the undesired separation of the solid and liquid components when put under pressure, thereby greatly influencing injectability of the material.56,57 For application in VP or balloon KP, CaP cement is preferentially tailored to mimic the viscous behavior of PMMA during injection, since this is considered the reference, without displaying the pressure filtering effect.58 Table 1 lists the CaP that can be found in several CaP cement compositions.

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Table 1 Calcium phosphates that may be used in the solid phase of a calcium phosphate cement Name

Formula

Ca/P

Monocalcium phosphate monohydrated Monocalcium phosphate anhydrous Dicalcium phosphate dihydrate Dicalcium phosphate anhydrous Octacalcium phosphate a-Tricalcium phosphate b-Tricalcium phosphate Hydroxyapatite Fluoroapatite Tetracalcium phosphate (TTCP)

Ca(H2PO4)2 H2O Ca(H2PO4)2 CaHPO4 2H2O CaHPO4 Ca8H2(PO4)6 5H2O Ca3(PO4)2 Ca3(PO4)2 Ca10(PO4)6(OH)2 Ca10(PO4)6F2 Ca4(PO4)2O

0.50 0.50 1.00 1.00 1.33 1.50 1.50 1.67 1.67 2.00

CaP cement holds distinct advantages over PMMA cement by having the potential to undergo resorption while also displaying osteoconductive properties. In recent in vitro studies the effect of CaP cements on vertebral body repair has been investigated.59 Two types of calcium-based materials, namely CaPs and calcium sulfates (CaSs), are used in spinal applications (see also Table 2). CaS cements are sometimes considered not to have osteoconductive properties and, due to their fast dissolution characteristics, achieving adequate mechanical support in the spinal column is found to be more difficult.60 In either case, CaP and CaS cements have demonstrated a superior biocompatibility profile in vitro compared to PMMA cements.61 CaP cements are considered suitable scaffolds for bone substitution since they affect cellular function by virtue of their composition that is similar to the mineral phase of the bone.62,63 CaP allows adhesion and differentiation of osteoblasts while CaP cements are injectable and can be molded to the defect they have to fill. CaP cements exhibit plasticity during their working period allowing the material to occupy the defect well in which they are injected.64,65 In addition, by using different CaP powders, the dissolution/degradation and resorption behavior of CaP cements can be tailored. CaP cements are intended to be used as temporary scaffolds and the initial contact between cement and surrounding bone tissue is considered a key factor for the osseointegration and bone formation at the implantation site.66 CaP cements are required to present a resorption behavior in synchrony with the bone formation.67 CaP cements can be classified into four categories depending on the role and condition of the CaP solid and liquid components.68,69 Among these, hydraulic cements are the most commonly used and usually the term cement refers to this category. Depending on the end solubility product, these CaP cements can be classified into two types: brushite or apatite cements.58,70 Brushite cements contain less favorable mechanical properties but show faster biodegradability when compared to apatite cements.71 Apatite CaP cements have been studied since the early 1970s and by the 1990s started to make inroads into reconstructive surgery.72 When mixing CaP powder with the liquid phase, it will create a partial dissolution of the CaP, causing the creation of a paste with the liquid phase supersaturated with calcium and phosphorus ions, which then will reprecipitate, producing crystal growth and entanglement

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Table 2

Commercially available cements for spine surgery

Cement type

Product name (Company)

PMMA

SpineplexW (Stryker-Howmedica); Corinplast (Corin); SimplexW P (Stryker-Howmedica); PalacosW LV (Zimmer/Heraeus Kulzer); PalacosW R (Zimmer/Heraeus Kulzer); CMWTM (CMW-DePuy); Codman Cranioplastic (CMW-DePuy); KyphXW (Kyphon); HV-R (Kyphon); OsteopalW (Heraeus Kulzer); SymphonyTM VR (Advanced Biomaterial Systems); Osteobond (Zimmer) BSM/BiobonW (ETEX/Merck/Biomet/Lorenz Surgical); Biopex RW (Mitsubishi) BoneSave (Stryker); BoneSource (Orthofix/ Stryker-Howmedica); ChronOS Inject (Synthes), MCPC (Biomatlante); Calcibon (Merck/Biomet); Eurovbone (F-H Orthopedics); NorianW SRSW (Norian/Synthes); Mimix (Lorenz Surgical); Cementek (Teknimed); Fracture Grout (Norian); Collagraft (Zimmer); KyphOs (Kyphon) BonePlast (Interpore Cross Int); MIIGW X3 (Wright Medical) Cortoss (Orthovita), CAP (Kuraray)

Calcium phosphate

Calcium sulfate Composites

Source: Heini, P. F.; Berlemann, U. Eur. Spine J. 2001, 10(Suppl. 2), S205–S213; Lewis, G. J. Biomed. Mater. Res. B Appl. Biomater. 2006, 76(2), 456–468.

providing the initial mechanical properties for the CaP cement. During this phase the CaP cement will be moldable. For CaP cement, solutions of 1–4 wt% Na2HPO4 are commonly used as the liquid phase.69,73 The degree of supersaturation, pH and temperature of the mixture will dictate the endproduct, which can be resorbed and remodeled in vivo. Contrary to acrylic cements, CaP cements have the advantage that the setting phase is an isothermic process reducing the risk of thermal damage to surrounding tissues.21,59 The phase formed after the reprecipitation of the CaP will dictate the resorption properties of the CaP cement.74 Each phase presents a different solubility behavior.75 The injectability and mechanical properties of CaP cements can be changed by modifying the liquid-to-powder ratio, the type of liquid component or the use of a pore generator without affecting the final obtained CaP phase.57,76,77 Porosity is found among the requirements for cements used in VP and balloon KP. After injection, CaP cements present a certain degree of microporosity depending on the dissolution–reprecipitation process which is related to the liquid-to-powder ratio used.73 If the CaP cement is used by itself, comprising only the microporosity, it will take years for the material to degrade since it will do it by a layer-by-layer mechanism, even if it possesses the good chemical characteristics.55 To increase the degradation between the material and the surrounding tissue, an increase in microporosity and/or the incorporation of a macroporous network could be used. This can be achieved by using various techniques.78,79 However, it is important to remember that the mechanical properties of the CaP cement will come mainly from two sides, first from the dissolution– reprecipitation mechanism and further crystallization which creates the microporosity of the material and second from the contribution of additives or pore generators which will influence the macroporosity. CaP cements can withstand compression forces of around 50 MPa after full crystallization which is within the ranges of human bone.71,80 It has been reported that CaP cement loaded with particles, acting as pore generators or drug-delivery systems, can reduce compression values by 80% compared to cements not loaded with particles.71,77 If particles are used for pore generator or drug delivery purposes, the mechanical properties will be dependent on the size, amount, and distribution of the particles in the cement, as well as their compositions.55,71 An agglomeration of these particles should

be avoided to not drastically reduce the mechanical properties of the cement.81 The drug-delivery systems can be used to enhance the biological behavior and activity of CaP cement. Several studies have reported the use of growth factors and proteins in combination with this CaP cement.82–85 Surgical interventions of the spine are typically carried out under radiological guidance; therefore the material used must be radiopaque.59 In contrast to acrylic cements, CaP cements are radiopaque once injected and fully crystallized. However, this action may take 1 day or more days depending upon the characteristics of the cement used. Improving the contrast characteristics of these cements in its early stage is important if CaP cements are aimed to be used in minimal invasive surgery. Tracking the material during the intervention is of high importance in order to avoid leakage of the material that may increase the risk of injuries or adverse effects.86 Some common contrasting agents used are barium, iodine, tantalum, and tungsten.87 Although this approach is relatively new for CaP cement, some groups have already explored this field.88

6.611.3.3. Composite Cements (Hybrid Acrylic/CaP Cements) The goal of adding CaP additives to acrylic cements is to establish a compromise between the desired mechanical and biological properties.89–91 These composite cements may be able to reduce stiffness, polymerization temperature, and potential monomer toxicity of PMMA while strengthening the bone–cement interface by creating a chemical bonding and changing the encapsulation of the acrylic cement to a direct contact with bone.90,92,93 This type of cement has been developed quite recently and the interaction between the components is currently under research.89,91 From the possible CaP candidates, hydroxyapatite (HA) has been most investigated due to the closest similarity of this material to the mineral phase of bone and its high stability.94,95 However, there are also studies directing attention to other CaPs.89,96 Bioactive glass has also been studied.97 All these studies aim to provide a better characterization and understanding of the physical, chemical, mechanical, and biological behaviors of composite materials. It has been proven that the inclusion of CaP additives in the acrylic matrix does not modify the properties of the CaP. CaPs maintain their ability to promote bone ingrowth while the monomer concentration of the acrylic cements stays

Injectable Bone Cements for Spinal Column Augmentation: Materials for Kyphoplasty/Vertebroplasty

Table 3

Factors affecting CaP–acrylic composite cement behavior

Molecular structure of CaP Characteristics of the CaP (e.g., porous, thermally treated, doped, etc.) Amount added Particle size of the CaP Fabrication process

stable.96 When considering composites, understanding the properties related to the interaction between the phases will be essential to better understand the composite material, overall. In the case of the acrylic composites, this interaction will affect setting times, temperature, and mechanical properties. Table 3 shows the factors affecting the acrylate–CaP composites. The setting time of these composites will be affected mainly by the amount of CaP added while the exact type of CaP will only have a minor effect.89,96 While PMMA by itself can reach temperatures up to 100  C (373 K), the addition of CaP can reduce it to room temperature.89,92,96 The addition of CaP will interfere with the polymerization of the acrylic cement and can therefore act as a heat absorber.89 The mechanical behavior will be a complex interaction between the shape of the additive, and its dissolution and transformation properties as well as its distribution within the sample, amount within the sample, and the anisotropy created.98 CaP particles may act as stress concentration factors or fracture energy absorbers, hence affecting the mechanical properties in several ways.91 Some authors reported that the addition of CaP does not change the mechanical properties significantly, while others report an improvement or even a decrease in these properties.90,95,96 These differences may be related to the type and size of the CaP and their bonding to the acrylic matrix. Standard ISO 5833 indicates that acrylic cements must present a minimum compressive, tensile, and bending strength of 70, 30, and 50 MPa, respectively. Concerning porosity, acrylic cements by themselves have low porosity.91,96,99 When the CaP is added, an important factor is the porosity and interconnectivity between the CaP particles. If particles are embedded in the acrylic matrix without contact to surrounding tissue, the properties of the CaP, and the reason for including them, will not be utilized. Here the CaP particle size and amount included will play a significant role, as it happens when loading a CPC with particles for pore generator or drug-delivery systems.92,96 It has been demonstrated that including HA particles causes a void increment.91 Therefore, CaP additives per se will have an effect on the pore size in the cement also. This effect will be related to the additive content and its wettability toward the acrylic material.96 CaP materials are hydrophilic, so they are partially covered by the liquid monomer that later will polymerize with the powder polymer embedding the CaP into the acrylic matrix but without a strong interface.89,95 Treated and untreated CaP additives (silinazed) have proven to have a different interaction with the acrylic matrix and influence the mechanical behavior of the composites.95 However, these treatments may modify the hydrophobicity of the CaP additives, which could affect their biological properties. Thermal treatments affect the surface properties of CaP.70 This approach could be used to increase the interaction of the CaP with the liquid monomer

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without affecting the biological properties of the CaP. Another approach that has been studied to modify the mechanical properties of this type of cement is the creation of a porous acrylic cement by preparing the PMMA with a biodegradable gel.100,101 In this last approach, if combined with the loading of CaP particles, the structure will be affected on the mechanical properties due to the porous network and type, size, and amount of the particles included.50,89 Acrylic cements with lower modulus are attractive since they allow better stress distribution in the filled vertebral body, thus potentially reducing the risk of fractures on the vertebrae adjacent to the operated sites.102 In the case of using radiopaque agents for tracking the material during the surgical intervention, composite cements show a higher degree of complexity since the cement will be a three-phase composite system; hence the interaction of each component will not be one-to-one but one-to-two. Although studied to some extent by some groups the characterization of these three-phase systems is an area that needs to be researched further in order to fully validate the use of these composites.91

6.611.3.4. Miscellaneous Cements Acknowledging the several drawbacks found in commonly used biomaterials for spinal augmentation (i.e., PMMA and CaP cement) consisting of difficult handling characteristics, thermal issues, potential for toxic reactions, mismatched Young’s modulus, and limited mechanical strength, researchers have recently started to focus on entirely different materials to be used for this application.21,103 Boyd and coauthors suggested aluminum-free, zinc-based glass polyalkenoate cements (Zn-GPC) to be a suitable alternative for use in VP.104 In their recent work, comparing polymerization temperature, strength, Young’s modulus, and biocompatibility of this cement formulation with three commercially available bone cements (two PMMA cements and one composed of resins and glass ceramic particles) it was found that, although setting times precluded clinical use in the current composition, thermal behavior of the new material was benign, its stiffness exhibited values similar to cancellous bone while biocompatibility was superior. The authors suggested Zn-GPC to be a suitable candidate material for further development as bone cement once the setting parameters were optimized. In recent studies by Perry et al.105 two new biomaterials, polypropylene fumarate cement and CaS cement, were tested as alternatives for PMMA cement in a model for human cadaveric osteoporotic vertebral compression fractures treated by balloon KP. The authors concluded from their biomechanical tests, showing similar mechanical properties to PMMA, that both polypropylene fumarate and CaS were potential new candidates for this application. In 2004 Zhao and coworkers reported on the properties of a strontium-containing HA cement with surface treatment using methyl methacrylate to be used for VP and found favorable biomechanical results.106 Other promising cement compositions include glass–ceramic-based cements.52,107 The studies described in this section cover just a small selection of several biomaterials currently under study, but it can be expected that many more new biomaterials will be designed, tested and eventually qualify for clinical investigation in the near future. The prospect of the availability of biomaterials better adapted to

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the needs of both the treating physicians, in terms of superior handling profiles, and patients, in terms of improved safety, efficacy, and biocompatibility, is encouraging.

6.611.4. Clinical Results of Spinal Column Augmentation with Injectable Bone Cements 6.611.4.1. Osteoporotic Vertebral Compression Fractures In 1994 Gangi and coauthors described one of the first, smallscale, series of patients treated for various indications including osteoporotic vertebral body collapse and spinal metastasis treated with VP using PMMA cement.108 They noted immediate relief of pain and absence of further vertebral body compression during follow-up in all. Jensen et al.3 published a series of 47 spinal levels treated in 29 patients suffering from osteoporotic vertebral compression fracture and found relief of pain immediately after treatment. Identical results were reported by Martin and coworkers in their series of 68 levels treated in 40 patients with 80% of the patients experiencing substantially improved symptoms.5 According to the authors, failures were related to insufficient pretreatment, clinical evaluation, and excessive injection of PMMA. In 2003 a prospective controlled trial was published by Diamond and coauthors, describing VP as a safe technique resulting in prompt relief of pain when compared to conservative medical treatment.109 The same year a review was published, in which it was emphasized that this technique should be reserved for carefully selected patients who do not respond to conservative treatment.110 In 2006, a review of the treatment of osteoporotic vertebral compression fractures by VP summarized 15 studies (11 prospective, 3 retrospective, and 1 controlled trial) containing a total of 1136 procedures in 793 patients.111 The visual analog scale (VAS) for pain, a validated pain measuring tool, ranging from 0 to 10, with 0 meaning no pain and 10 the worst pain imaginable, improved from a mean of 7.8 to 3.1. The rate of complications ranged between 0.4% and 75.6%, and was frequently related to cement extravasation and included major adverse events. It was concluded that long-term, properly controlled trials were required to address the lack of sound scientific and clinical understanding of this technique. Hochmuth and coauthors performed yet another review on VP, describing the results from 30 studies and 2086 patients and, again, concluded that although spinal augmentation with PMMA cement seemed to dramatically improve symptoms in patients with osteoporotic vertebral compression fractures, randomized controlled trials were needed to confirm the efficacy of the procedure.112 In 2006 Bouza and coworkers published a review of the literature on balloon KP presenting the pooled clinical data of 26 previously published articles.113 It was found that, although the methodological quality of the papers on which their review was based was generally low, balloon KP for the treatment of painful vertebral compression fractures led to significant improvements in pain intensity, vertebral height, sagittal alignment, functional capacity, and quality of life. The authors concluded the review suggesting that balloon KP was safe and effective. Hulme and coworkers, in their review of 69 articles published in the literature on the outcome of VP and balloon KP, refuted this claim, stating that definite proof of safety and efficacy of both procedures could not be obtained without

comparative, blinded, randomized trials.114 Taylor and coauthors found, in contrast again, Level III evidence to support balloon KP and VP as effective therapies in the management of patients with symptomatic osteoporotic vertebral compression fractures refractory to conventional medical therapy.14 Moreover, balloon KP was suggested to offer a better profile with respect to adverse events than VP. The first randomized controlled trial on this subject was the FREE trial published in the Lancet in 2009 describing the efficacy and safety of balloon KP compared with nonsurgical care for the treatment of osteoporotic vertebral compression fractures, metastatic spinal lesions, and multiple myeloma.115 In this trial a total of 300 patients were enrolled and randomly assigned to receive balloon KP with PMMA cement or optimal nonsurgical care. A total of 266 patients completed the 1-month follow-up and a significant difference in SF-36 PCS was found between the two groups favoring the surgical intervention group. At 12 months, 38 out of 115 patients in the balloon KP group and 24 out of 95 in the nonoperative group had new or worsening vertebral fractures. It was concluded that balloon KP with PMMA cement was an effective and safe technique for patients with acute vertebral fractures. In the same year two studies were published in one issue of the New England Journal of Medicine.10,11 These papers generally received a critical reception.23,25 In the paper by Buchbinder and coauthors, a randomized, double-blind, placebo-controlled trial was performed to study the efficacy of VP using PMMA cement for the treatment of painful osteoporotic vertebral compression fractures in 78 patients. In this study patients were randomly assigned to receive regular VP or a sham operation in which the needle used to inject cement was not advanced in the vertebral body but rested upon the lamina but cement was not injected. During follow-up, the authors found no significant difference in perceived pain between the groups at any time-point while incidental vertebral fractures occurred in both groups (three in the VP group and four in the placebo group). The authors concluded that VP had no beneficial effect when compared to the sham procedure used. The study by Kallmes included a total of 131 patients who were assigned to undergo VP with PMMA cement (n ¼ 68) or infiltration of the skin and periosteum with the possibility to crossover from either group at 1-month posttreatment. After 1 month no difference was found in disability scores or pain rating. At 3 months a significantly higher rate of crossover was found in patients from the control group than in the VP group. No incidental fractures were reported for any of the groups. The authors concluded that improvements in the VP study group were similar to improvements in the control group. Both studies have been criticized by virtue of a number of limitations: the low percentage of cases included from the total number of patients eligible; the improvement in pain after receiving treatment being unusually small for both the treatment and control arm, indicating that patients might have undergone inadequate or suboptimal VP procedures; the insufficient statistical power; the potential bias in patient selection; the inclusion of patients possibly not indicated for the treatment; and the sham not being a proper control.23,25 Studies describing the clinical results following VP using CaP cement to treat painful osteoporotic vertebral compression fractures are relatively rare.

Injectable Bone Cements for Spinal Column Augmentation: Materials for Kyphoplasty/Vertebroplasty

Nakano and coauthors were, to our best knowledge, the first to describe the treatment of 65 osteoporotic vertebral compression fractures with VP using CaP cement.18,116 Their results were indistinguishable from studies describing similar cohorts of patients treated with VP based on PMMA cement. Hillmeier and coauthors reported on the treatment of 102 patients with 192 osteoporotic vertebral compression fractures treated by balloon KP with PMMA cement in 138 cases and with CaP cement in 54 cases.16 Again, the results were comparable for both groups and led to immediate, substantial, and long-term relief of pain in 89% of the patients. In 7% of all treated vertebral bodies cement leakage occurred, however, without clinical sequelae. Grafe et al.15 performed a prospective comparative trial in which 20 patients received balloon KP with CaP cement and 20 patients with PMMA cement. After 3 years of follow-up, no differences were detected at any timepoint between the two groups. It was concluded that CaP cement was as effective as PMMA cement to achieve pain reduction and improvement of mobility in this category of patients. Furthermore, since CaP cement has the potential of being resorbed and replaced by new bone, they concluded this type of cement to be a promising alternative for PMMA cement especially in younger patients.

6.611.4.2. Metastatic/Malignant Vertebral Body Lesions Metastatic vertebral body lesions and pathological fractures are exclusively being treated with VP or balloon KP in combination with PMMA cement. In 2003 Fourney and coworkers described the treatment of 97 vertebral levels in 56 patients with multiple myeloma (n ¼ 21) or other primary malignancies (n ¼ 35) by VP or balloon KP.35 At a median follow-up length of 4.5 months, 84% of the patients noted marked or complete relief of pain while no patient was worse after treatment. Asymptomatic cement leakage was observed in six cases of VP; no cement leakage was observed in the KP group. The authors concluded that both procedures provided significant and durable pain relief in a high percentage of patients. In a recent review on cement injection for spinal metastases Heini and Pfa¨ffli stated VP and balloon KP with PMMA cement to be extremely efficient procedures provided that treatment is restricted to osteolytic lesions in the presence of mechanically challenged bony structures. In a review of the literature, Bouza and coauthors reported on the pooled data of seven studies describing the clinical outcome of balloon KP with PMMA cement for the treatment of malignant spinal fractures and concluded, despite the limited methodological quality of the original studies, that balloon KP is a well-tolerated, relatively safe, and effective technique to provide early relief of pain and improved functional outcomes in this category of patients.34

6.611.4.3. Traumatic Fractures Traumatic fractures of the spine are mostly seen in young and active individuals and bone void fillers used for vertebral body augmentation in this group of patients are likely to remain in situ for many decades and will be subjected to many load cycles.117,118 Concerns on the detrimental long-term effects of acrylic cements in the spine, including short-term inflammation or thermal necrosis and long-term particle-induced

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osteolysis, have prompted researchers and clinicians to revert to alternative biomaterials. In 2005 Verlaan and coworkers reported on the application of CaP cement after pedicle screw fixation and balloon-assisted endplate reduction in a small series of 20 patients with traumatic thoracolumbar fractures.119 It was found that the procedure was relatively undemanding for patients, a significant restoration of the vertebral body anatomy was achieved, and major complications were not observed except for an adjacent level fracture in one patient necessitating a secondary surgical intervention. All patients underwent elective removal of their pedicle instrumentation between 12 and 18 months posttrauma as part of the study protocol. At a minimum of 6 years follow-up it was found that recurrence of kyphosis had not occurred. Similar studies were published by Korovessis et al.120 and Marco and Kushwaha,121 respectively. In the series by Korovessis and coauthors, a total of 23 patients with thoracolumbar burst fractures underwent pedicle screw instrumentation followed by balloon KP with CaP cement and it was concluded after a minimum of 2 years follow-up that the technique provided excellent immediate reduction of posttraumatic kyphosis, provided significant spinal canal clearance, and restored vertebral body height of the fractured level. Marco and coauthors described a series of 38 patients with unstable thoracolumbar burst fractures with and without associated neurological deficits treated with short-segment pedicle screw fixation followed by transpedicular balloon-assisted endplate reduction and injection of CaP cement. It was concluded that the procedure led to maintained or improved neurological function in all patients with preexistent neurological deficits and a low rate of instrumentation failure or loss of correction. Maestretti and coauthors reported on a series of patients with traumatic thoracolumbar fractures treated with standalone (i.e., without pedicle screw fixation) balloon KP using CaP cement.122 Although the clinical results were good, it was noted that CaP cement had distinctive biomechanical disadvantages compared to PMMA cement sometimes leading to loss of fracture correction and unpredictable resorption behavior. Currently, Blattert et al.123 recommend against standalone treatment of traumatic thoracolumbar fractures by VP or balloon KP. To our knowledge, only one article has been published on the treatment of traumatic thoracolumbar fractures treated by pedicle screw fixation and VP using PMMA cement.124 In this work, Cho and coworkers report on a series of 70 patients of which 20 underwent VP additional to pedicle screw fixation and 50 underwent regular pedicle screw fixation.124 The authors concluded from their work that reinforcement of the anterior column with VP using PMMA cement may achieve and maintain kyphosis correction and decrease instrument failure rate.

6.611.5. Complications in Spinal Column Augmentation Within 2 years after the widespread use of VP with PMMA bone cement, the first descriptions of serious complications occurred. Two independent cases of symptomatic pulmonary embolism resulted from extravasation of bone cement into the pulmonary circulation.6,7 Shortly after, it was found that the incidence of asymptomatic pulmonary embolism could

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be as high as 87.9% and was predominantly related to an excessive volume of cement injected.125,126 It is a currently accepted notion that during VP or balloon KP, leakage of cement into the surrounding soft tissue, venous circulation, or pulmonary system often goes unnoticed by both the physician and the patient. Complications arising from VP or balloon KP can be divided into categories of minor and major severity.12 Minor complications include wound hematoma, superficial infection, rib fracture due to patient manipulation, needle malpositioning, and asymptomatic cement extravasation. These minor complications are responsible for an estimated 95–98% of all adverse events. Major complications include symptomatic pulmonary embolism, cement infection, symptomatic spinal cord or root compression, myocardial infarction, and death. Many studies have reported cement emboli to be present in the pulmonary circulation after augmentation of the spinal column by VP or balloon KP. In a recent metaanalysis of the literature, Lee et al.12 reported on a total of 3078 cases of cement leakage found in 4097 patients treated with VP using PMMA leading to an unusually high leakage percentage of 75%. Symptomatic leakage of cement was, however, found in only 1.5% of cases reported. The number of asymptomatic versus symptomatic cement leakage after treatment with balloon KP was found to be 14% and 0.06%, respectively. The review by McGirt and coauthors confirmed these results and, moreover, reported neurological decline to occur in less than 1% of cases treated by VP and balloon KP.127 These results raise the question as to why cement leakage is apparently tolerated so well by the majority of patients. It is currently, for example, not known what factors are involved or necessary for pulmonary embolism to become symptomatic after cement leakage has occurred. Patient-related factors, such as decreased pulmonary capacity and heart failure, may lead to a predilection for symptomatic pulmonary embolism but do not explain the actual occurrence since these highly prevalent conditions may be present in the asymptomatic group as well. Many reviews of the pertinent literature have, however, shown almost all complications, both of minor and major severity, to be related to leakage of bone cement. Two groups of factors have been identified to potentially influence the risk of adverse events following VP or balloon KP. Factors increasing the risk of cement leakage are 1. 2. 3. 4. 5.

fracture type, duration of symptoms, instruments/instrument positioning/spinal anatomy, viscosity of cement injected, volume of cement injected.

Factors not increasing the risk of cement leakage are 6. mechanical/thrombogenic/thermal properties of cement, 7. general patient health characteristics.

6.611.5.1. Fracture Type Osteoporotic vertebral compression fractures are associated with less cement extravasation than malignant spinal lesions, which in turn are less prone to cement leakage than traumatic fractures.128 The explanation for the differences may be found

in the varying degree of fracture comminution, cortical disruption, and surrounding soft tissue damage for these three categories.129 It is hypothesized that postural reduction and subsequent ligamentotaxis may decrease the risk of cement extravasation due to minimization of fracture gaps and (partial) restoration of the vertebral anatomy thereby facilitating unimpeded cement flow.29

6.611.5.2. Duration of Symptoms It has been suggested that the duration of symptoms influences both clinical outcome and incidence of cement extravasation in osteoporotic vertebral compression fractures. It is generally accepted that the optimal window for treatment ranges approximately between 6 and 12 weeks after the onset of symptoms. Performing spinal augmentation at an earlier stage is, considering the generally benign nature of these lesions showing full resolution in the majority of patients, considered overtreatment while after 3 months the effect of postural reduction is diminished. The optimal timing of intervention for metastatic spinal disease or traumatic fractures by VP or balloon KP is unknown but, considering the natural history of the lesions in this category of patients, is rather on acute or emergency basis than elective.121

6.611.5.3. Instruments/Instrument Positioning/Spinal Anatomy In order to minimize the resistance of bone cement to flow, short, large-diameter cement delivering needles are recommended, regardless of the type of biomaterial used. Assuming laminar flow of a liquid with a given viscosity through a tube, the following equation can be applied (nonalgebraic version of Poiseuille’s law): Flow ¼ Pressure*diameter4 =viscosity*length Assuming a limitation of the pressure that can be generated by human force using a manually operated syringe and assuming a lower threshold of viscosity needed for safe injection of the biomaterial in the vertebral body, shortening the length of the needle while increasing its diameter will increase flow. Since the increase in flow is proportional to needle diameter by the fourth power, it is clear that using large-bore needles optimally facilitates injection of higher viscosity cement. The topic of cement viscosity and flow in relation to cement extravasation is described in more detail elsewhere in this chapter. The optimal positioning of the needle(s) is considered to be close to the midline in the anterior third of the vertebral body. Deviating from this position may lead to uneven distribution of cement and increased risk for cement extravasation due to the proximity of venous structures (anterior vertebral venous plexus; intraspinal extradural venous plexus).130 Unipedicular, bipedicular, or extrapedicular procedures are currently being performed for both VP and balloon KP and are showing identical results.131 It can be argued that the utilization of the unipedicular approach would decrease the chance of instrument malposition by 50%. However, controlled clinical trials showing this theoretical advantage to lead to better clinical results and less cement extravasation or complications have

Injectable Bone Cements for Spinal Column Augmentation: Materials for Kyphoplasty/Vertebroplasty

not been performed. Variations in patient anatomy, most notably small-diameter or aberrant pedicles, can lead to difficulties in proper access to the vertebral body and may, in case of pedicle wall fracture, increase the risk of false routes and subsequent leakage of cement.

6.611.5.4. Viscosity of Cement Injected The viscosity of the bone cement injected in the spinal column is of utmost importance to achieve even flow and controlled distribution of the biomaterial in the vertebral cancellous bone. However, during polymerization of PMMA cement (or formation of HA crystals during setting in the case of calcium phophate cements), the viscosity increases slowly but exponentially with time from the moment of mixing the components until the fully cured state.132 The interval in which bone cement can safely be injected is often called the working time or injection phase and is dependent on

• • • • • •

the initial ratio of ingredients (monomer-to-polymer in PMMA cement and ratio of liquid-to-CaP in CaP cement);40,133 the presence of additives in PMMA cement or alternative solutions for CaP cement;134,135 the temperature of the components before mixing;136 the mixing process itself;132 the temperature of the environment (‘room temperature’) during polymerization/setting;136 considering the significant variations in working time under apparently identical circumstances: miscellaneous yet unidentified factors.45

By trial and error, clinicians have found, rather unscientifically, that the optimal viscosity for safe injection resembles that of toothpaste or spaghetti; cement of lower viscosity (before the injection phase) led to frequent extravasation while cement displaying higher viscosity (after the injection phase) substantially reduced injectability.137 Baroud and coauthors quantified this observation using cements of different viscosities in an in vitro model of VP.138 It was demonstrated that the highest viscosity cement stabilized flow and prevented extravasation but was no longer injectable using human force. An experimental study by Loeffel and coauthors, published in 2008, assessed distribution of PMMA cement in the vertebral body as a function of cement viscosity, bone porosity, and injection speed.139 Their main conclusion was that viscosity was the key factor to reduce cement extravasation and should be adapted to each patient individually according to the degree of osteoporosis present. It was advised to use high-viscosity cement combined with high injecting speed to safely augment the vertebral body. The experimental work by Krebs and coworkers, investigating bone marrow fat embolism in an in vivo VP model, however, suggests that increasing cement viscosity and injection speed could lead to different, yet no less harmless, adverse events.140,141

6.611.5.5. Volume of Cement Injected In the first decade following the invention of VP, nearcomplete filling of a vertebral body with bone cement was

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considered necessary for good clinical outcome. However, soon it was realized that smaller amounts of cement injected led to identical good results while substantially decreasing the occurrence of adverse events related to cement extravasation. Injection of 3–4 ml bone cement in the thoracic spine and of 4–6 ml cement in the lumbar spine is presently recommended by many authors and this practice has, thus far, been shown to yield the optimal compromise between clinical outcome and adverse events related to cement leakage.142 No data are yet available on the efficacy and safety of spinal augmentation using even less cement.

6.611.5.6. Mechanical/Thrombogenic/Thermal Properties of Cement Limited data are available on whether the contribution of bone cement to the development of pulmonary embolism after extravasation is by direct mechanical blockage of pulmonary vessels or by promotion of thromboembolic processes downstream. In multiple in vitro studies conducted by Cenni et al. it was demonstrated that several acrylic cements, when tested for hemolytic activity, antithrombotic properties, and the plasmatic phase of coagulation, did not seem to influence these parameters.143–145 Further work by the same group showed that, in general, products released from acrylic cements were not able to elicit a specific immune or endothelial response.146 The lack of thrombogenic activity in PMMA cement was confirmed by the work of Blinc and coauthors, adding that liquid components of this type of cement inhibited platelet aggegration and plasma clotting in vitro.147 Concluding from these studies it seems plausible that mechanical blocking of the pulmonary circulation by cement particles, as opposed to chemical induction of thrombogenesis, is responsible for the development of pulmonary embolism when using PMMA cement. Large cement particle size (>2 mmr) in combination with preexistent risk factors for symptomatic pulmonary embolism can be hypothesized to constitute the key etiological factors for the occurrence of this complication.86 With respect to CaP cements and the occurrence of pulmonary embolism, two experimental in vivo studies have been conducted to test the hypothesis that extravasation of CaP cement into the venous circulation may result in uncontrolled activation of the coagulation cascade.148,149 In the study by Bernards et al.,148 CaP was injected directly into the venous system of 21 pigs to investigate any cardiopulmonary insults. An overall mortality of 13 out of 21 pigs was observed following a profound increase in pulmonary artery pressure and subsequent drop in left atrial and systemic blood pressure after cement injection. On autopsy, massive thromboemboli were found in the arterial pulmonary circulation and right ventricle. The authors hypothesized that semiliquid, curing CaP cement may have acted as a powerful scaffold for blood clot formation. Furthermore, it was suggested that the release of significant amounts of calcium in the circulation, being an important cofactor in the coagulation cascade, may have further stimulated the coagulation process. The occurrence of neurological deterioration after leakage of cement into the spinal canal or neural foramina has been suggested to result from mechanical compression of neural structures (i.e., spinal cord, cauda equina, or neural roots)

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or thermal damage. Currently, the damage by mechanical compression of neural structures, resulting from cement extravasation after VP or balloon KP, is undisputed and warrants immediate surgical decompression.150 Patients in any of the three indication categories presenting with neurological deficits are not considered good candidates for spinal augmentation with injectable bone cements without additional surgical decompressive measures, since leakage of cement into the spinal canal may further compromise neurological function. The often suggested possibility that local heat, produced during the exothermic polymerization of PMMA, may cause neural tissue damage has received considerable attention in recent in vitro and in vivo studies.30,32,151 Several experimental investigations have demonstrated conductive and convective mechanisms by the circulation and flow of cerebrospinal fluid to effectively dispose of the excessive thermal energy generated by the curing cement. The heat effect of large quantities of polymerizing PMMA cement located in the spinal canal, however, was not studied and may still pose a considerable threat to neural tissue integrity. CaP cements set isothermically and concerns about thermal damage therefore do not apply.

6.611.5.7. General Patient Health Characteristics Health hazards that are generally prevalent in the frail and elderly include hypertension, osteoporosis, diabetes mellitus, coronary artery disease, heart failure, coagulation disorders, and chronic obstructive pulmonary disease. These are obvious patient-related factors associated with an increased complication risk for virtually any surgical treatment and may account for, at least, some of the complications occurring after spinal augmentation including both minor and major events such as rib fracture, infection, hematoma, pulmonary embolism, and myocardial infarction.12

6.611.6.

Future Directions and Conclusions

The number of articles published in basic scientific and clinical journals on injectable bone cements for spinal column augmentation has expanded immensely in the last decade. Despite all this work, no generally accepted explanations have emerged as to why augmenting the vertebral body leads, in general, to such good clinical results; whether adjacent fractures occur more frequently after augmentation of the spine; why cement leakage sometimes, but certainly not always, leads to serious complications. Acknowledging the logistic (study enrollment) and ethical (sham operations) difficulties in conducting randomized controlled trials to find an effect of VP or balloon KP, investigators could focus on well-controlled dose-dependent studies. In these studies the minimal amount of cement needed for adequate pain reduction could be established which could serve as a basis to support or refute the fracture stabilization theory and find the optimum balance between treatment effect and complication rate. If augmentation of the spinal column indeed leads to pain reduction, by stabilization or other means, the next step would be to identify the key factors that determine success or failure. Considering the exceedingly large number of procedures of VP and balloon KP performed each year, establishing a registry

(similar to the large total hip/knee replacement databases in worldwide use today) may help clinicians identify factors leading to the occurrence of adjacent level fractures and symptomatic pulmonary embolism, for example. Such analyses are generally useful for suggesting better performing biomaterial characteristics. It is a tempting concept that the biomechanical and biological properties of an ideal bone cement more closely match the individual patient requirements. Factors such as cement stiffness and capacity for osseointegration may be adapted to unique individual characteristics including easily quantifiable variables such as gender, age, and bone mineral density and further including more qualitative concepts such as activities of daily life, workload, risk of major intraoperative complications, and life expectancy. As the medical community is slowly gaining a better understanding of the specific needs for patients with spinal lesions, it is possible that, in time, more individualized vertebral bone void fillers may become available. The last two decades have brought us promising new minimal invasive techniques and biomaterials to augment the spinal column of patients who otherwise would be confined to longterm immobilization and analgesics or subjected to major surgery. By virtue of sheer need, these techniques and biomaterials were introduced and became widely accepted. Well-controlled studies addressing safety and efficacy were not routinely performed. Continued progress in this exciting field should depend on rigorous scientific and clinical studies.

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