Bone cement commonly known polymethyl methacrylate or PMMA, is widely used for implant fixation in various orthopaedic and trauma surgery for over 50 years. In reality, “cement” is a misnomer because, the word cement is used to describe a substance that bonds two things together. However, PMMA acts as a space-filler that creates a tight space which holds the implant against the bone and thus acts as a ‘grout’ 1). Bone cements have no intrinsic adhesive properties, but they rely instead on close mechanical interlock between the irregular bone surface and the prosthesis. The primary function of bone cement is to transfer forces from bone to prosthesis 2). Other types of commercially available bone cement like calcium phosphate cements and glass polyalkenoate (ionomer) cements are successfully used in a variety of orthopaedic and dental applications. Calcium phosphate cements are bio-resorbable and biocompatible, but are mainly used in cranial and maxillo-facial surgeries because of their low mechanical strength 3).
One of the major drawbacks of bone cement in joint replacement is cement fragmentation and foreign body reaction to wear debris, resulting in prosthetic loosening and periprosthetic osteolysis. The production of wear particles from roughened metallic surfaces and from the PMMA cement promotes local inflammatory activity, resulting in chronic complications to hip replacements. Histologically, a layer of synovial like cells which line the bone cement interface supported by a stroma containing macrophages and wear particles, has been described in loose prostheses 4). A third of dense fibrous tissue contains polymethyl methacrylate, polyethylene and metallic debris. Activated macrophages express cytokines including interleukin-1, interleukin-6 and tumour necrosis factor alpha, which mediate periprosthetic osteolysis.
Bone cement generates heat as it cures and contracts and later expands due to water absorption. It is neither osteoinductive nor osteoconductive and does not remodel.
The monomer methyl methacrylate (MMA) is toxic and there is a potential for allergic reactions to cement constituents.
PMMA bone cement
PMMA is an acrylic polymer that is formed by mixing two sterile components (Table 1): a liquid methyl methacrylate (MMA) monomer and a powered MMA-styrene co-polymer 5). When the two components are mixed, the liquid monomer polymerizes around the pre-polymerized powder particles to form hardened PMMA. In the process, heat is generated, due to an exothermic reaction.
Additives have been trialed to address problems with modern bone cements such as the loosening of prosthesis, high post-operative infection rates, and inflammatory reduction in interface integrity. Low index (< 15%) vitamin E and low index (< 5 g) antibiotic impregnated additives significantly address infection and inflammatory problems, with only modest reductions in mechanical strength. Chitosan (15% w/w PMMA) and silver (1% w/w PMMA) nanoparticles have strong antibacterial activity with no significant reduction in mechanical strength.
PMMA, along with the presence of various additives, gives the mixture a set of physical and chemical properties. Exposure to light or high temperatures can cause premature polymerization of the liquid component. Hydroquinone therefore is added as a stabilizer or inhibitor to prevent premature polymerization. An initiator, di-benzoyl peroxide (BPO), is added to the powder, and an accelerator, mostly N,N-dimethyl-4-toluidine (DMT), is added to the liquid to encourage the polymer and monomer to polymerise at room temperature (cold curing cement).
In order to make the cement radiopaque, a contrast agent is added. Commercially available cements use either zirconium dioxide (ZrO2) or barium sulphate (BaSO4). Zirconium dioxide is one hundred times less soluble than barium sulphate and has less effect on the mechanical properties of the cement.
During the exothermic free-radical polymerization process, the cement heats up. This polymerization heat reaches temperatures of around 82–86 °C in the body. The cause of the low polymerization temperature in the body is the relatively thin cement coating, which should not exceed 5 mm, and the temperature dissipation via the large prosthesis surface and the flow of blood.
Table 1. Constituents of bone cement
Table 2. Summary of polymethyl methacrylate (PMMA) bone cement additives
|Gentamicin||Reduces post-operative infection rates. Powdered format (2/60 g or 2/40 g) shows no significant impact on mechanical strength, however increased gentamicin concentration decreases mechanical strength|
|Vitamin E||Improves cement cytocompatibility and reduces peak temperature. 10% vitamin E concentration does not significantly affect mechanical strength. Increasing concentrations associated with increased setting time and decreased mechanical strength|
|Polymer MMA:AA:AMA||Reduces bone cement shrinkage and improves fracture toughness. 80:20:10 significantly improves mechanical strength vs control|
|NanoMgO and NanoBaSO4||Improves osteoblast adhesion, nanoMgO (12.8 nm) minimizes tissue necrosis and nanoBaSO4 (100 nm) improves mechanical strength|
|Barium sulfate||Allows radiological identification of cement. 10% concentration is not associated with significant decrease in mechanical strength vs control. As concentration increases, mechanical strength decreases|
|Chitosan nanoparticles||In vitro studies show significant antibacterial activity against S. aureus and S. epidermidis with no significant difference in cytoxicity and mechanical strength vs control PMMA|
|Silver nanoparticles||AgNP (1%) has strong and continued antibacterial activity (against Acinetobacter baumannii, Pseudomonas aeruginosa, Proteus mirabilis and Staphylococcus aureus) but with reduction in mechanical strength. Nanosilver (5-50 nm) has antibacterial activity against Staphylococcus epidermidis, MRSE and MRSA with no significant difference in cytotoxicity vs control|
Abbreviations: MRSE = Methicillin-resistant Staphylococcus epidermidis; MRSA = Methicillin-resistant Staphylococcus aureus.
Antibiotic bone cement
Bone cement has proven particularly useful because specific active substances, e.g. antibiotics, can be added to the powder component. This makes bone cement a modern drug delivery system that delivers the required drugs directly to the surgical site. The local active substance levels of bone cements are significantly below the clinical routine dosages for systemic single injections. Research has shown that adding various types of antibiotics to bone cement, in quantities less than 2 g per standard packet of bone cement, does not adversely affect some of the cement’s mechanical properties (compressive or diametrical tensile strengths), although quantities exceeding 2 g did weaken them. Various antibiotics have been successfully mixed and used with bone cements like Gentamycin, Tobramycin, Erythromycin, Cefuroxime, Vancomycin, Colistin etc. The basic requirement, being that the mixable antibiotic should be heat resistant and should last for longer duration of time.
Gentamycin, when used in combination with tobramycin, shows a synergistic effect, with a 68% greater elution of tobramycin and 103% greater elution of vancomycin from the bone cement, compared to controls containing only one antibiotic 6).
van Staden 7) in his study reported that Bacteriocins may be a possible alternative to antibiotics incorporated into bone cement. The in vitro results of the study showed that bacteriocins incorporated into brushite cement did not significantly alter the characteristics of the matrix and that the peptides were released in an active form. Finally it was shown that nisin F-loaded brushite cement controlled S. aureus infection in mice.
Silver containing nanoparticles have also shown promise as effective antibacterial agents which can be added to bone cement 8). Vitamin E additives (10%) have shown a positive effect on free radical oxidation and exothermic activity, with only modest reduction (<5%) in tensile strength 9).
Compared to intramuscular administration, systemic concentration levels of Gentamycin are low with bone cement, usual maximum level being <1 μg/ml (<10%). There are no detectable systemic levels after seven days from administration. Gentamycin levels in urine after bone cement administration range from 10 μg/ml initially to 1–2 μg/ml after seven days.
Different bone cements have different chemical formulations, giving a range of antibiotic bone cements with varying handling characteristics, which are suited to a broad range of clinical requirements and surgical techniques.
Bone cementing techniques
The techniques used to introduce the bone cement into the bone depend on the location or component that is to be fixed, and the surgeon’s preference and experience. Bone cement is generally mixed in the operating room on an ‘as needed’ basis. Because the curing time is fast, the bone cement is usually not prepared until the whole surgery needed to permanently place a component of an artificial joint has been completed. most bone cement is subjected to a mixing environment that reduces the porosity. Initially, this was accomplished by centrifuging the liquid cement to separate the air from the polymer. Mixing the cement in a bowl designed to create a vacuum proved to be a more favorable option; it does not require transfer of the cement, the process takes place during mixing, not separately, thus giving the surgeon more time to work with the material, and eliminates the need for a centrifuge in the operating room.
Currently, to reduce porosity, most bone cement is mixed using various vacuum mixing systems. Many of the vacuum mixing systems are designed to release the mixed cement into a cartridge, which is then placed in what is essentially a caulking gun. If the cement is to be placed in a femur to fix the femoral component of an artificial hip joint, for example, the cement can be injected into the femoral canal. This is generally done in a ‘retrograde’ fashion. The nozzle of the cement gun is placed into the distal or far end of the femoral canal, and the gun is withdrawn as the cement is injected distally to proximally. The surgeon may opt to ‘hand pack’ the cement, as in the case of a tibial component of an artificial knee. In this case, the cement can be ejected from the cement gun onto the surgeon’s hand and manipulated into the appropriate site. The state of the bone cement (predough, dough, etc.) when applied to the bone depends on the site of use, surgeon’s preference, etc.
Overall, advancements in cementing can be classified to have occurred from ‘first generation’ to ‘third generation techniques’, with changes occurring in bone bed preparation, cement preparation and cement delivery 10).
Once the cement is in place, the surgeon has a limited time to insert the device into the bone cement and ensure that the device is correctly placed and aligned. Although the time may be short, the surgeon must also ensure that the device does not move once it is in place, and must maintain a stable position until the bone cement is fully cured. The time from when the components of the bone cement are mixed until it is not possible to further manipulate either the prosthesis or bone cement is sometimes called the ‘working time.’ Once the cement has cured, its job is primarily structural – to hold the device in place permanently and facilitate load transfer from the device into the remaining bone. Bone cement fracture and/or loosening of the device within the cement mantle can lead to failure of the artificial joint and require a revision surgery. Thus, we discuss the mechanical properties of bone cement in detail in this chapter.
Radiographic examinations of patients with loosened prostheses may reveal a radiolucent line in the bulk of the cement, indicating that the cement has fractured. In the 15-year follow-up study by Kavanagh et al., cement fracture was identified as the ‘most frequent mode of failure.’ There are examples where cement fracture was indicated on a radiograph, yet the patient retained function of the prosthesis for over 3 years. A subsequent examination revealed that the extent of the cement fracture had escalated, the prosthesis had loosened, and revision surgery was necessary.
First generation bone cementing technique
It involved the hand mixing of cement in bowels. There was only a minimal preparation of the femoral canal and cancellous bone was left in-situ. The canal was irrigated and suctioned prior to the digital application of cement. The prosthesis was then inserted into the femoral canal. During the 1980’s these techniques were refined. Steps were taken to reduce the porosity of the cement and thereby increase the fatigue life. Pressurization of the cement was introduced to improve osseo-integration of the cement and the importance of a good cement mantle around the prosthesis was more clearly understood.
Second generation bone cementing techniques
All cancellous bone is removed as near to the endosteal surface and distal cement restrictor was also used. There is pulsatile irrigation, packing and drying of the femoral canal followed by retrograde insertion of cement with a cement gun. The prosthesis is again positioned manually 11). Further improvement lead to the development of third generation cementing techniques.
Third generation bone cementing techniques
Cement is now prepared using a vacuum-centrifugation, which further reduces porosity. The femoral canal is irrigated with pulsatile lavage and then packed with adrenaline soaked swabs. After insertion of the cement in a retrograde fashion, the cement is pressurised. Finally the prosthesis is inserted using distal and proximal centralizers to ensure an even cement mantle (4th generation).
Bone cement curing process
The curing process is divided into 4 stages:
- a) mixing,
- b) sticky/waiting,
- c) working, and
- d) hardening.
The mixing can be done by hand or with the aid of centrifugation or vacuum technologies.
Bone cements are heat sensitive. Any increase or decrease in temperature (either ambient, and/or of the cement components and mixing equipment) from the recommended temperature of 73 °F (23 °C) affects the handling characteristics and setting time of the cement. Manual handling and body temperature reduces the final setting time. Variations in humidity affect the cement handling characteristics and setting time. It is recommended that the unopened cement components are stored at 73 °F (23 °C) for a minimum of 24 h before use. Vacuum mixing of cement can also accelerate the setting time of the cement.
High viscosity cements are sometimes pre-chilled for use with mixing systems for easier mixing and prolonged working phase. This will also increase the setting time. The relative humidity might also influence the handling properties. That is the reason why the working time and setting time of the cement might vary in winter and summer.
Unlike the polymerization reaction of PMMA, calcium phosphate cements are hardened through a dissolution and precipitation process that produces hardening with entanglement of precipitated crystals 12).
Bone cement side effects
Hypotensive episodes and cardiac arrest have been reported during cement insertion 13).
Pressurization and thorough cleaning of the bone with expulsion of bone marrow has been associated with the occurrence of pulmonary embolisms, and this risk has been found to be increased in patients with highly osteoporotic bone and patients diagnosed with femoral neck fracture. Reaming of the marrow cavity can have similar effects on mean arterial pressure as the introduction of the bone cement. Marrow cavities should be vented when the cement is introduced digitally. The premature insertion of bone cement may lead to a drop in blood pressure, which has been linked to the availability of methyl methacrylate at the surface of the product 14), although this has not been proven. This drop in blood pressure, on top of hypotension induced either accidentally or intentionally, can lead to cardiac arrhythmias or to an ischemic myocardium. However, according to a report, the possible risk of death associated with the use of cemented implant is confined to early postoperative and perioperative period 15).
The hypotensive effects of methyl methacrylate are potentiated if the patient is suffering from hypovolemia.
The most frequent adverse reactions reported with acrylic bone cements are:
- Transitory fall in blood pressure.
- Elevated serum gamma-glutamyl-transpeptidase (GGTP) upto 10 days post-operation.
- Loosening or displacement of the prosthesis.
- Superficial or deep wound infection.
- Trochanteric bursitis.
- Short-term cardiac conduction irregularities.
- Heterotopic new bone formation.
- Trochanteric separation.
Other known adverse effects 16):
- Bone cement implantation syndrome (BCIS) is characterized by a number of clinical features that may include hypoxia, hypotension, cardiac arrhythmias, increased pulmonary vascular resistance and cardiac arrest. It is most commonly associated with, but is not restricted to, hip arthroplasty 17). It usually occurs at one of the five stages in the surgical procedure; femoral reaming, acetabular or femoral cement implantation, insertion of the prosthesis or joint reduction. It is an important cause of intraoperative mortality and morbidity in patients undergoing cemented hip arthroplasty and may also be seen in the postoperative period in a milder form causing hypoxia and confusion.
- Cardiac arrhythmia.
- Adverse tissue reaction.
- Bladder fistula.
- Local neuropathy.
- Local vascular erosion and occlusion.
- Transitory worsening of pain due to heat released during polymerization.
- Delayed sciatic nerve entrapment due to extrusion of the bone cement beyond the region of its intended application.
- Intestinal obstruction because of adhesions and stricture of the ileum due to the heat released during cement polymerization.
A common complication of cemented arthroplasty is loosening of the cemented prosthesis. Mechanical weakness in the bone cement, primarily attributed to the addition of barium sulphate and zirconium oxides (for radiological detection), increases the risk of loosening 18). Stabilisation of the bone cement matrix improves the transfer of load across the cement-prosthesis interface, reducing the likelihood of crack formation in the cement. Various additives such as steel fibers, glass fibers, carbon fibers and titanium fibers have been developed to improve mechanical strength 19). Rubber toughened cement (PMMA matrix interspersed with rubber particles) has 167% greater fracture toughness (the structural strength to withstand further cracking in fractured materials) than non-reinforced control (PMMA), although compressive strength and elasticity are compromised (raw data not available) 20). PMMA reinforced with embedded continuous stainless steel coil (2.5 turns of coil; distal tip of prosthesis) significantly increases compressive stress 4.5-fold (control vs reinforced; 0.039 ± 0.001 MPa vs 0.009 ± 0.001 MPa) and tensile stress 4.5-fold (control vs reinforced; 4.272 ± 0.015 MPa vs 0.95 ± 0.005 MPa) on 3-dimensional finite element computational analysis 21). This reinforcement increases mechanical strength, thus decreasing the likelihood of fracture formation. The use of additives with rubber toughened cements and stainless steel coils may improve other properties and needs to be investigated.
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