BONE CEMENTS
Submitted by: Işıl Severcan
ABSTRACT
Bone cements are used as bone fillers for skeletal defects and during implantation of hip and knee prosthesis.
Historical development of todays bone cements begins with PMMA that has been produced industrially since 1930’s. Bone cement consists of two major components; A powder containing copolymers based on methacrylate (PMMA), where the powder also contains an initiator (di-benzoylperoxide) and a liquid monomer methylmethacrylate (MMA), where the liquid also contains the activator N,N-dimethyl-p-toluidine.
In order to be suitable for orthopedic and maxillofacial applications, it is crucial that a biodegradable bone cement should meet the following criteria.First, it must initially be shaped, molded or injected in the internal cavities in bone. Second, it must harden in-situ and develop mechanical properties sufficient to permit functional loading of the region. Third, it must be biodegradable not to act as a barrier to bone remodeling or fracture healing so that it can be replaced by host bone over time.
Bulk polymers produced from MMA have special advantages including: low density, resistance to fracture, excellent optical properties, excellent weather resistance, and finally it can be modified in many ways (coloring, pigmenting, surface treartment with scratch-resistant coating).
PMMA acrylic bone cements have been widely used in orthopaedic surgery as filling agents, for the fixation joint prostheses. However they have several drawbacks. These include thermal necrosis of bone, chemical necrosis due to unreacted monomer release, shrinkage of the cement during polymerisation, and property mismatch at the interfaces as bone cement is weaker than the bone or the implant. Therefore recent researches aim to find solutions to these problems.
1. Introduction to Bone Cements
Bone cements are materials used in filling bone defects and in the implantation of hip and knee prostheses. Due to the extended use of acrylic bone cements, its necessary to develop improved formulations in order to resolve their existing drawbacks. A biodegradable bone cement that would provide immediate structural support and in the mean time allow normal bone healing and remodeling is needed.
1.1. Historical Development of Bone cements
Polymethy methacrylate (PMMA), which is the current standard for bone cement, has been produced industrially since the early 1930’s. The history and development of this polymer is closely associated with the chemist Otto Röhm, who is the first to polymerize methyl methacrylate (MMA) into transparent sheets. With many years of intensive research, Otto Röhm finally led to the birth of bone cement in 1943. In the late 1950s Sir John Charnley introduced the concept of low friction arthroplasty. After numerous clinical studies, in late 1960’s the addition of antibiotics to bone cements was first developed by German companies Kulzer and E. Merck. Since then PMMA has not been much changed and its use as a bone cement in orthopaedic surgery has improved the quality of patients life. [3]
1.2. Components of Bone Cements
Bone cements consist of two primary components:
1) A powder containing copolymers based on methacrylate (PMMA), where the powder may also contain an initiator (di-benzoylperoxide)
2) A liquid monomer methylmethacrylate (MMA), where the liquid also contains the activator N,N-dimethyl-p-toluidine to initiate the free radical polymerization of the bone cement
. [2,4]
As radiological detection of bone cements is required, a special opaque agent (zirconium dioxide or barium sulphate) is added to the powder for radiographic contrast.
The powder component in antibiotic loaded bone cements additionally contains an antibiotic such as Gentamicin or a combination of antibiotics such as gentamicin and clindamycin to avoid bacterial disinfections during the application.
1.3. Design Requirements
Certain members of the polymer class possess unsaturation, or potential for controlled crosslinking. Under proper control the polymer can be transformed into a material that has favorable mechanical properties. Compatibility with tissues is another consideration. Additional properties of concern are resilience, plasticity and diffusional transport characteristics.
In order to be suitable for orthopedic and maxillofacial applications, biodegradable bone cement should meet the following criteria:
1) It must behave like a cement that initially can be shaped, molded or infected into the cavities of the bone.
2) It must harden in situ and develop mechanical properties sufficient to permit functional loading of the region.
3) Finally the cement must be biodegradable not to act as a barrier to bone remodeling and fracture healing and it must be replaced by host bone over time. [1]
2. Polymethyl Methacrylates
Bulk polymers produced from methyl methacrylates have special
advantages including low density, resistance to fracture, and above all excellent optical properties (i.e. transparency). PMMA also has favorable processing properties and can be modified in many ways such as coloring, pigmenting, addition of flame retardants, or surface treatment.
PMMA, when used as a bone cement, provides immediate structural support and it is biologically inert. But it has several drawbacks. Being bilogically inert, it acts as a barrier to fracture healing and does not permit direct bonding by host bone. PMMA is also vulnarable to the accumulation of fatigue damage due to repetitive mechanical stresses at the cement-bone interface. [1,3,4]
2.1 End Uses of PMMA
PMMA has a wide range of applications namely:
- Pipelines and vessels made of acrylic glass for the storage and transportation of food due to PMMA’s transperincy and lack of smell and taste.
- Colored and injected molded parts are used in automobile and lightning industries due to PMMA’s heat resistance and excellent mechanical properties.
- Optical components such as lenses are made of PMMA.
- Dental materials for fillings, false teeth and prosthesis are made of PMMA.
- Bone cement for implants. [3]
·
2.2 Toxicology of PMMA
The polymer is regarded as inert and non-toxic. However contact of the mucous membranes with polymer powders may cause allergic and irritating reactions. Liquid monomer is a potent solvent that is highly volatile and flammable. Due to the residual monomer release severe skin reaction may occur. Therefore contact with the monomer should be avoided by taking proper precautions. Monomer vapors may irritate the respiratory tract leading to asthma. The vapors are also potentialy harmful to the liver and may cause reactions with soft contact lenses.
As a bone cement PMMA has a potential carcinogenic effect. In animal implant tests malignant tumors were found at the implant site. But tumors have not yet been observed in humans after many years use. [3,4]
2.3 Mechanical Properties of PMMA
PMMA is preferred for its good mechanical strength, its outstanding optical properties such as clarity, transparency etc. And its excellent weather resistance. Basic physical properties of PMMA are tabulated in Table 1.
Table 1
Property |
|
Density, g/cm3 |
1.18 |
Impact strength, kJ/m2 |
15 |
Elongation at break (v= 5mm /min), % |
5.5 |
Long term tensile strength (t= 10 000h), Mpa |
38 |
Modulus of elasticity (short term value), Mpa |
3300 |
Tensile strength (v= 5mm /min, 1/1 test bar 3), MPa |
80 |
Ball indentation hardness, Mpa |
200 |
Linear themal expansion (0-50 OC), K-1 |
70x10-6 |
Heat distortion temperature (flexural stress of 1.8 MPa), OC |
105 |
Softening point, OC |
115 |
Pure PMMA is an amorphous plastic and is classified as hard, rigid but brittle material. From the table it can be seen that the tensile, compressive and flexural stresses are satisfactorily good.
PMMA is resistant to aliphatic hydrocarbons, nonpolar solvents, aqueous alkalis, and aqueous acids. Aromatic hydrocarbons, chlorinated hydrocarbons, esters, ketones, and other polar solvents may attack PMMA, causing it to dissolve or swell. On the contrary alcohols or water alone are considered as nonsolvents. [3]
2.4. Production of PMMA
Industrially MMA can be polymerized by a free radical mechanism. The polymerization of MMA is comonly initiated by using azo compounds or organic peroxy compounds. A segment of PMMA is shown in figure 1.
Fig. 1 PMMA
During polymerization the viscosity of the reaction medium extremely increases which in turn hinders the diffusion of the free radicals. Chain termination thus becomes very difficult and the concentration of the growing radicals increases by several orders of magnitude. This results in a sharp rise in the polymerization rate and as a result removal of the heat of polymerization becomes a potential hazard. [3]
3. Application of Bone Cements
3.1. Bone Bed Preparation
Before cementing bone bed should be throughly brushed and cleaned. For this purpose high- pressure pulse lavage equipments are preferred. Careful preparation of the bone bed and the bone cavity is needed to achieve the effective microinterlock betwwen the cement and the bone surface. Brushes are used to remove soft tissue and loose cancellous bone. Accidental introduction of blood and tissue debris into the cement may cause laminations which can lower effective strength by 8 - 16%. In figure 2 the preparation of hip and knee is shown. In hip implantation 6 or 7 holes are drilled in order to increase the contact area between the cement and the bone providing a better fixation.
Figure 2. Bone bed preparation for knee and hip prostheses [4]
3.2. Cement Mixing
Cement fracture and subsequent loosening are directly related to the strength of the cement mantle, which acts as an interface between the bone and the prosthetic component. Porosity is an important factor effecting the quality of the bone cement and it has been shown that acrylic bone cement is weakened by its porosity, leading to crack propagation and failure.
Inadequate mixing leads to a high degree of porosity. Traditionally, bone cement was mixed using a spatula and bowl arrangement. However, this process had the consequences of introducing a high degree of porosity into the cement sturcture. Another drawback was that the person mixing the cement was exposed to high level of monomer vapors. After 1980’s closed vacuum mixing technique gained popularity owing to its low degree of porosity and low exposure to monomer vapors.
Table 2. Comparison of vacuum mixing and hand mixing techniques [4]
P o r o s i t y |
Mixing technique |
|
Physical measurement |
|
% Porosity |
Density (g/cm3) |
% Porosity |
Hand mixing |
9.4 |
1.15 |
7.2 |
Vacuum mixing |
0.1 |
1.23 |
0.8 |
References R Wixson, E Lautenschlager, M Novak, North Western University, Chicago, Illinois, USA, 1985 |
Due to residual monomer release, direct contact of the skin or the rubber gloves should be avoided during mixing of the bone cement since liquid monomer is a potent solvent, which is highly volatile and flammable.
Figure 3. Vacuum mixing technique [4]
3.3. Cement Delivery
Achieving an even layer of cement between the bone surface abd the implant is highly important in surgical operations. For this purpose nozzles are used. In order to avoid lamination of the blood cement is applied 3 or 4 minutes after the sart of mixing, although this period may be changed by the type of the cement.
Figure 4. Application of the cement delivery [4]
3.4. Pressurization
The last step in the application of the bone cement is pressurizaition. Researches have shown that high pressurizaiton is needed to achieve microinterlock between the bone surface and the cement. For this purpose acetabular pressurizers are used. In this process pressurization time is an impertant parameter for the sake of the application. The presurization time however will vary depending on the type of the cement used.
Figure 5. Pressurization of the cement [4]
4. Literature Survey on Bone Cements
PMMA bone cement has not substantially changed since it was first introduced . The research has mainly focused on improving its mechanical properties. One way is to optimize the mixing techniques as the physical properties of the cement are greatly influenced by this process.
Dunne et. al. (2000) has investigated the influence of mixing techniques on the physical properties of acrylic bone cement. Inadequate mixing techniques lead to a high degree of porosity, which is a major drawback in reducing the mechanical strength of the cement. In their study Palacos RÒ bone cement was prepared using three commercially available mixing techniques. At the end, mechanical properties and porosity contents of the bone cements was determined. The compressive strengths, bending strengths and flexural moduli were expressed as a function of void content. In Table 3 cement mixing systems and the corresponding reduced pressure levels are tabulated. Here first generation mixing technique corresponds to traditional mixing technique, where spatula/bowl arrangement was used at atmospheric pressure. This technique has the consequences of introducing high content of porosity and also the
person mixing the cement is exposed to a high level of monomer vapours. In second generation mixing systems the cement is mixed under a low reduced pressure (-30 kPa) to reduce the monomer fumes. But these systems still produced highly porous bone cement. In third generation mixing systems cement is mixed under further reduced pressure (-70 kPa). As can be seen from figure 6 the lower the pressure, the lower is the porosity content.
Table 3.
Lewis (1999) investigated the effect of mixing method and storage temperature of cement constituents on the fatigue and porosity of acrylic bone cement. They compared four types of bone cement and their parameters were storage temperature (either 21 or 4 OC) and mixing method (either hand mixed (HM) or vacuum mixed (VM)). As a result they have found that storage temperature prior to mixing had no significant influence, however vacuum mixed bon cements showed a remarkable decrease in areal porosity, as can be seen in figure 7.
Fig. 7. The areal porosity results
Harper et. al. (2000) investigated the tensile characteristics of ten commercial acrylic bone cements. These cements differ in chemical composition and physical properties of both powder and monomer constituents. The cements were prepared by hand mixing and testing was performed in air at room temperature. As a result significant differences in both static and fatigue properties were found between the cements. Tensile tests revealed that Palacos RÒ, Sulfix-60Ò, and Simplex-PÒhad the highest valus of ultamate tensile strength. The weakness of this study is that there must be further study on cements mixed by vacuum. Also the tests must be repeated in-vivo conditions.
Ratier et.al. (2001) investigated the setting characteristics and mechanical behaviour of a calcium phosphate bone cement containing tetracycline. Calcium phosphate bone cements may be used as a carrier or delivery system for active ingredients such as antibiotics or anticancer drugs. For this study tetracycline was chosen for its large bacteriostatic spectrum. The antibiotic can be loaded on calcium phosphate compound however the presence of chloride ions strongly influence the behaviour of the cement. Chemical characterization, x-ray diffraction analysis, compressive strength and tensile strength was performed. Researches have shown that adding more than 1% (w/w) of 95% pure tetracyline hydrochloride in the solid phase led to a cement with poor mechanical properties. The results are tabulated in Table 4. It can be seen that there is a significant decrease in both compressive and tensile strengths as the amount of teracycline was increased regardless of the duration of specimens in water.
Table 4.
The solution they have found to this problem is that treating the tetracyline HCl with calcium sulphate solution prior to reaction conserved the activity of the antibiotic and retained the properties of the cement. The researches have also shown that the phase evolution is dependent on the amount of tetracycline added. As a result TTC influences the morphology of the cement, which is evidenced by SEM on figure 8.
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Deb et. al. (2001) investigated the effect of crosslinking agents on acrylic bone cements containing radiopacifiers. Intrinsic radiopacity is difficult to achieve in bone cements due to the constituent elements of the PMMA polymer. However radiopacity is essential, therefore PMMA is rendered radiopaque by blending heavy metal ion salts, which tends to adversely effect the mechanical and biological properties of the cement. The main reason for this is barium sulphate, which lowers the ultimate tensile strength and fracture toughness. In this study dimethacrylate cross-linking agents were added to the monomer phase and a x-linked matrix was generated, with barium sulphate as a radiopaque agent. Two types of crosslinking agents were investigated, namely, triethylene glycol dimethacrylate (TEGDMA) and poly(ethyleneglycol dimethacrylate) (PEGDMA). The results were tabulated in Table 5, which suggest that the mechanical properties could be improved or retained with the addition of such crosslinking agents. According to these results the bone cement with 5% of TEGDMA gave the best mehanical properties. For further research these materials can be tested for other mechanical properties such as fatigue under cyclic loadig or fracture tests prior to coming up with a final conclusion.
Table 5.
This research has also shown that the peak temperatures did not change sisgnificantly in the presence of crosslinking agents. This result can be seen in figure 9, where changes in polymerization exotherms were plotted with increasing amount of PEGDMA.
Shinzato et. al. investigated the bioactive bone cement and the effect of surface curing properties on bone-bonding strength. The cement under study was wollastonite containing glass ceramic (AW-GMA) with a bisphenol-a-glycidyl methacrylate (bis-GMA) based resin. The bone bending strength of cement plates having an uncured surface on one side and a cured surface on the other side had been evaluated. It was believed that an uncured surface played an important role when determining the surface curing properties of cement. In vivo tests were performed in rabits by preparing these cements an inserting in tribial bone. The results showed that uncured surfaces show an effective way to induce bone bonding. However uncured surface may be mechanically weak since the bone bonding strength for the uncures surface was lower compared to that of abraded surfaces. The bone strengths of AWC for its both cured and uncured surfaces were higher compared to that of hydroxy apatite (HAC) as can be seen in figure 10 and in figure 11 uncured surfaces of AWC and HAC can be seen 8 weeks after implantation.
Fig. 10. The detaching failure loads for AWC and HAC of the uncured and of the cured surfaces.
Fig. 11. CMR photographs of a) AWC and b) HAC of the uncured surfaces in rabbit tibiae 8 weeks after implantation.
PMMA acrylic bone cements introduces high exotherm release of toxic chemical constituents during the in-vivo polymerization. Also initial bone necrosis and impaired blood flow in tubular bone have been reported. Residual chemical constituents that chemically damage are mainly MMA and the activator N,N-dimethyl-4-toluidine (DMT). Liso et. al. (1997) performed the analysis of the leaching and toxicity of new amine activators for curing of acrylic bone cements and composites. The leaching of the amine compounds from cured cements was analysed by concentration of the corresponding amine in a physiological saline solution after 3 months of immersion. The acute toxicity was determined by intraveneous injection of saline solutions in mice and the cytotoxicity was evaluated by the evolution of specific culture media. The activators that were used in the current study was N,N-dimethylaminobenzyl alcohol (DMOH) and N,N-dimethylaminobenzyl methacrylate (DMMO). These activators were chosen as they were found to be less toxic than DMT. The results obtained showed much lower exotherms for both activator comparing to DMT, which is beneficial for less tissue damage. The acute toxicity levels and cytotoxicity levels of the new activators were much lower than that of DMT. Finally an antiseptic action of these new compounds were found, which may be investigated as a further research.
Two studies were performed to investigate the mechanical properties of PMMA bone cements. McCormack et. al. (1996) performed an experimental study of damage accumulation in cemented hip prosthesis, which was mainly focused on developing a methodology to characterize the pattern of crack initiation and damage accumulation in intramedulary cemented prosthesis. 6 types of cements were tested in mantle, cement/bone interface, and cement/prostheses interface. According to these results number of cracks in mantle were significantly higher compared to the other two interfaces. However a thorough stress analysis is needed prior to complete interpretation of the results.
Lewis et. al. (2000) investigated the correlation between the impact strength and fracture toughness of PMMA based bone cements. 4 commercially available bone cements were tested and as a result a power relationship between fracture toughness (KIC) and impact strength IS were found.
KIC = 0.795(IS)0.59 (eq 1)
Another work aimed to improve the mechanical properties and to decrease the toxicity of acrylic bone cements is that of Torrado et. al. (2001), where characterisation and release of gentamicin bone cements were investigated both in vitro and in vivo assays. The selected bone cements were CMW1 Radiopaque CMW1 Gentamicin (De Puy International Ltd.). The constituents of the cement were:
Powder: gentamicin sulphate, PMMA, benzoil peroxide and barium sulphate.
Liquid: MMA, N,N-dimethyl-p-toluidine, ethanol, ascorbic acid and hydroquinona.
In this study powder size, shape and distribution that could effect the properties of the cement were studied with the aid of SEM, laser diffraction spectroscopy, and powder X-ray diffraction. The possible release mechanism is elucidated by fitting to a semi-emprical equation.The cumulative amount released increased with a sharp rate in the first days and that reached a steady state in 50 days. In vivo release studies the tibia and femur segments, both from the healthy pows and subjected to surgery were investigated for their gentamicin content. As a result, no gentamicin was found in the healthy paws, however bones subjected to the implantation showed a large amount of gentamicin release.
5. Conclusions
PMMA acrylic bone cements have been widely used in orthopaedic surgery as filling agents, for the fixation joint prostheses. However they have several drawbacks. These include thermal necrosis of bone, chemical necrosis due to unreacted monomer release, shrinkage of the cement during polymerisation, and property mismatch at the interfaces as bone cement is weaker than the bone or the implant. Recent researches are mainly focused to solve these problems. Modifications in the formulations of the commercially available bone cements are required and further research is needed in this area.
REFERENCES
1. Gresser J.D., Trantolo D.J., “Bone Cement Part 1- Bio Polymer for Avulsive Maxillofacial Repair”, Human Biomaterials Applications, Humana Press Inc., Totowa, NJ
2. Gresser J.D., Trantolo D.J., “Bone Cement Part 2- Biomaterials to Restore Function in People with Physical Disabilities”, Human Biomaterials Applications, Humana Press Inc., Totowa, NJ
3. Polymethacrylates, “Ullmann’s Encyclopedia of Industrial Chemistry”, Vol A21, VCH Publishers Inc., 1992
4. http://www.bonecement.com
5. http://www.immedica.com
6. Deb S., Vazquez B., “Effect of Crosslinking Agents on Acrylic Bone Cements Containing Radiopacifiers”, Biomaterials 22 (2001) pp- 2177-2181.
7. Dunne N.J., “Influence Of Mixing Techniques On The Physical Properties Of Acrylic Bone Cement”, Biomaterials 22 (2001), pp 1819-1826.
8. Harper E.J., Bonfield W., “Tensile Characteristics of Ten Commercial Acrylic Bone Cements”, Appl. Biomaterials 53 (2000), pp- 605-616.
9. Lewis G., “Effect Of Mixing Method And Storage Temperature Of Cement Constituents On The Fatigue And Porosity Of Acrylic Bone Cement”, Appl. Biomaterials 48 (1999), pp 143-149.
10. Lewis G., Mladsi S., “Correlation Between the Impact Strength and Fracture Toughness of PMMA Based Bone Cements”, Biomaterials 21 (2000) pp 775-781.
11. Liso P.A., Vazquez B., “Analysis of the Leaching and Toxicity of New Amine Activators for Curing of Acrylic Bone Cements and Composites”, Biomaterials 18 (1997) pp 15-20.
12. McCormack B.A., Prendergast P.J., “An Experimental Study of Damage Accumulation in Cemented Hip Prosthesis”, Clinical Biomechanics Vol. 11, No. 4, pp 214-219, 1996.
13. Ratier A., Gibson I.R., “Setting Characteristics and Mechanical Behaviour of a Calcium Phosphate Bone Cement Containing Tetracycline”, Biomaterials 22 (2001), pp 897-901
14. Shinzato S., Kobayashi M., “Bioactive Bone Cement and the Effect of Surface Curing Properties on Bone-Bonding Strength”, John Wiley and Sons Inc., 2000.
15. Torrado S., Frutos P., “Gentamicin Bone Cements: Characterisation and Release (in vitro and in Vivo Assays”, International Journal of Pharmaceutics 217 (2001) pp 57-69.
