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Biocompatibility: a biomechanical and
biological concept in total hip replacement
I.D. Learmonth
University Department of Orthopaedic
Surgery, Level 5, Bristol Royal Infirmary,
Bristol, BS2 8HW, UK
Correspondence to: I.D. Learmonth, University Department of Orthopaedic
Surgery, Level 5, Bristol Royal Infirmary, Bristol, BS2 8HW, U.K. Email: ian.learmonth@bristol.ac.uk
Keywords: Biocompatibility, biomechanical, biological, hip, particle debris
Surg J R Coll Surg Edinb Irel., 1 February 2003, 1-8
The insertion of any implant or prosthesis into bone usually changes the biomechanical environment and, thus, alters the stresses and strains applied to the bone. Both bone overload and excessive stress protection can result in bone resorption. The material and geometry of any implant should be designed to avoid excessive flexural mismatch. Incompatibility of materials may result in interface and mechanical failure, with the consequent generation of particulate debris, subsequent osteolysis and implant failure. Particulate debris can be generated from articulating surfaces and from any other modular or fixation interface. Larger particles are associated with a foreign body giant cell reaction. Polyethylene particles in the size range of 0.5 to 10µm excite a cytochemical reaction that culminates in osteolysis. The precise pathogenesis of osteolysis has not been characterised, but it is probable that different pathogenetic mechanisms are involved in the different radiological types of osteolysis. A large number of very small metallic particles are released from metal-on-metal couples. These may cause mutagenic damage (chromatid breaks, chromosome translocations, aneuploidy, etc.). In defining implant biocompatibility it is essential to consider the biological response both to an altered mechanical environment and to the liberation of particulate debris
INTRODUCTION
Orthopaedic implants inserted in the 19th
century and the first half of the 20th century were destined to failure, both as a result of metallic
corrosion and of structural failure. Advances in material sciences and bio-engineering greatly
improved the quality of orthopaedic implants, and structural failure of the implants became
the exception rather than the rule. However, having reduced the incidence of failure, it
became necessary to consider the biological implications of metal or plastic prostheses that
survive in the longer term.
Biomaterials should be non-toxic, both locally and systemically, should not be allergenic or carcinogenic and should be bio-acceptable - in particulate and bulk form as well as the breakdown products. In addition, the implant should ideally mimic the tissue it is replacing as closely as possible.
Inserting a metal prosthesis down the medullary cavity of a femur alters the loading pattern and, thus, the stresses and strains in the proximal femur. In accordance with Wolff’s law, this may result in bone remodelling and reduction in bone density.1 Hence, it is important to evaluate the effects of the altered biomechanics in bone caused by the insertion of a stiff metal prosthesis. It is also important to recognise that different materials have different properties - modulus of elasticity, scratch sensitivity, hardness, etc. Certain materials may be incompatible when intermittently loaded in juxtaposition in vivo.
While most materials used today are biocompatible in bulk, they may excite a variable response when presented to the tissues in particulate form. Wear at the articular interface of a metal-plastic couple accounts for the generation of a large number of polyethylene particles (millions of particles may be liberated with each step). The smaller of these particles excite a cytochemical response. Metal particles may be released as a result of corrosion and abrasion. Large numbers of much smaller metal particles are produced which may cause genetic damage.
This article reviews the implications of these considerations in more detail.
Figure 1: (a [above] and b [below]): A finite element analysis model shows the reduced stress protection in the calcar region as the porous coating is reduced from one ninth (a) to one third (b)
Implant design
There was a relatively high
incidence of fracture of the
femoral stems of early Charnley Low Friction Arthroplasties.2 However, while changing the
cross-sectional geometry and increasing the dimensions reduced the incidence of
fracture, it resulted in a stiffer stem and the resultant flexural
mismatch with the surrounding
cement and bone was associated with an increased incidence of aseptic loosening.3 It should be
remembered that the flexibility of an implant depends both on the material composition and
the cross-sectional geometry.4 If the stem of a femoral
component makes contact with the diaphyseal cortex there is
potential for distal load transfer and proximal stress shielding with resultant stress protection
bone resorption. In these circumstances, flexibility of the implant has been
inversely related to thigh pain and stress shielding.5,6 Load transfer is enhanced
if the stem has surface treatment which encourages bone ongrowth (osseointegration).7 The more distal the load is
transferred, the greater the potential for proximal stress protection.8 To
investigate this a two-dimensional model of a cementless stern inserted into the
proximal femur was created using finite elememt analysis. As the extent of the
metaphyseal porous coating was reduced proximally, a commensurate reduction in
the extent of reduced strain was noted in the calcar region. This exactly
mirrored the demineralisation in the calcar region encountered in vivo when
a stiff proximally coated cementless stem was used at total hip replacement
(Figure 1 a-d). A fully coated stiff cementless stem may result in stress protection
of sufficient severity to significantly compromise proximal femoral bone stock and complicate any subsequent
revision surgery.
Figure 1: (c [above] and d below]): This reflects the clinical situation. (c) Early post-operative radiograph. (d) The rounding off and "cancellisation" of the calcar that takes place after two years
Various strategies have been used in an attempt to reduce the stiffness of the stem, including slots and the use of composite materials. However, the linear evaluation of bone density in the post-operative period using DEXA has not identied any real difference in the change in periprosthetic bone density with contemporary cementless implants, when compared with earlier generation implants.9
Cortical hypertrophy is a further example of an osseous response to altered mechanical environment. In a recent survey of 109 cemented Muller stems, 43% were found to present with distal cortical hypertrophy. The precise significance of this remains unknown, and there was no correlation with thigh pain.10,11 Specific design features of an implant may predispose to early aseptic loosening and failure. For example, the rounded medial and lateral surfaces below the shoulder of the flanged 3M Capital hip are thought to have predisposed to reduced torsional stability and an increased incidence of aseptic loosening.12 Conversely, however, the long-term survival of an implant may depend on the pattern of loading and the associated bone response.13,14
Materials
Care should also be taken to ensure the compatibility of different
materials. This relates not only to potential electrochemical interaction, but also
to their physical compatibility. Jonck and Grobbelaar (1990, 1992)
investigated the biocompatibility of a bioglass-glass ionomer cement in baboons.15,16
The material was found to be very
biocompatible. However, when used as a bone-cement at total hip replacement, the differential in hardness between the
ceramic and the relatively soft titanium stem resulted in catastrophic wear of the
stem (Figure 2).
Figure 2: Severe abrasive and erosive damage to the femoral stem
Impingement or abrasive movement between any two materials of very different hardness is always associated with the risk of very severe wear.17 The femoral neck of the hip prosthesis shown in Figure 3 was impinging against the ceramic cup, and was found to be heavily notched superiorly. This would have released a considerable amount of metallic debris into the tissues and if this implant had not been revised for aseptic loosening, the neck would almost certainly have fractured with the fullness of time.
Figure 3: The deep notch on the femoral neck (caused by impingement against a ceramic socket)
Simulators are extensively used to test the strength and durability of joint prostheses. While it is clearly critical to avoid structural failure of the implant, it is equally important to consider the interaction between the prosthesis and other materials in the composite reconstruction. In addition, cognisance must be taken of the biological response to the altered biomechanical environment. Furthermore, simulators should replicate the loading profile of activities of daily living, and should produce wear debris with a morphology of similar type and amount to that produced in vivo.18 It is then necessary to consider the biological response to this particulate debris.
BIOLOGICAL RESPONSE TO PARTICULATE DEBRIS OSTEOLYSIS
Osteolysis
In 1987, Jones and Hungerford coined the term “cement disease” to depict the
extensive osteolysis encountered with aseptic loosening of cemented total hip replacements.19 However, the aggressive
osteolysis seen after cementless total hip replacement proved this to be a
misnomer and the term particulate disease was coined.
It is now widely accepted that ultrahigh molecular weight polyethylene is probably the major culprit contributing to particle-mediated osteolysis.20 The majority of these particles are submicron in size and are engulfed by cells which are then stimulated to produce mediators of bone resorption.21,22 The pseudosynovial membrane (PSM) encountered at the component-bone interface of loose prosthesis contains a number of these cells, including macrophages, fibroblasts and lymphocytes. 23,24
Conditioned media (CM) removed from cultures of PSM have been shown to induce bone release in vitro.23,25 Perry et al (1996) demonstrated a relationship between the bone resorbing ability of CM obtained from cultures of periprosthetic tissues and their levels of bone remodelling agents. Bone resorbing activity was determined by measuring the release of Ca++ from45 pre-labelled mouse calvaria in organ culture, while the cytokine prostanoid levels in the CM were measured by immuno-assay (interleukin [IL]-1ß, IL-6, tumour necrosis factor a [TNFa] and prostaglandin [PG]E2). In general, significantly higher levels of cytokines were encountered in those CM with bone resorbing activity. However, interestingly, neither dialysis of the CM nor the addition of neutralising sera to IL-1ß and IL-1a, either alone or in combination, reduced the bone resorbing activity of the CM. This led Perry et al (1996) to conclude that while these agents may act synergistically to mediate osteolysis around failed joint implants, other unidentifed bone resorbing agents must be involved.26
Santavirta et al (1990) identifed an aggressive form of osteolysis, which they ascribed to an unlinking of the normal inflammatory response.27 Schmalzried et al (1992) have described different types of osteolysis - linear, lytic and mixed.28 I believe two further types can be added - discrete osteolysis and “pseudotumour”. The different descriptive radiological types of osteolysis are shown in Figure 4. It is difficult to believe that they all have the same aetiopathogenic mechanism.
Perry et al (1997) measured the levels of bone remodelling agents in CM from cultures of PSM and correlated these with the radiographic appearances of the failed joint implants.29 Significant correlations of specific bone remodelling agents were found in different types of osteolysis. It was suggested, therefore, that co-regulation of these bone remodelling agents differs with the radiographic appearances of the failed joint implants.
Other factors have been incriminated in osteolysis. These include leukaemia inhibitory factor (LIF), oncostatin M, atypical fibroblasts (similar to those seen in the pannus of rheumatoid arthritis) and increased joint pressure. Although the precise aetiopathogenesis of osteolysis remains unclear, it is evident that particulate debris plays a central role. Abnormal stresses and strains associated with loosening and abnormal movement may be an aggravating factor, but are clearly not responsible for initiating the process. It is necessary, therefore, to explore means of reducing the particulate load and preventing access to the fixation interface. It may also be possible to modulate the biological response pharmacologically (e.g. with bisphosphonates).30
Figure 4a
Figure 4b Figure 4c Figure 4d
Figure 4: Different radiological types of osteolysis: (a) discrete (b) linear (c) erosive (d) mixed
Figure 4ei Figure 4eii Figure 4eiii Figure 4iv
Figure 4: Different radiological types of osteolysis: (e) i-iv pseudotumour: (i) Early post-operative radiograph. (ii) Five-year follow-up. (iii-iv) The appearances shown on the AP and lateral radiographs at eight years are reminiscent of a malignant neoplasm
Metallic debris
Modular metal interfaces and corrosion and abrasion, as a result of differential
micromovement, liberate a large amount of metallic debris into the system. While the volumetric
wear of a metal-on-metal articulation is much lower than that of metal-on-plastic, it produces
a far greater number of particles.31 These particles
are very much smaller than the size of the average plastic particle, and do not excite
an inflammatory response. However, metallic particles do accumulate in cells and may cause
mutagenic damage. Metal particles have been identifed in tissues adjacent to the implant,
in the regional and distant lymph nodes, liver and spleen.32,33 In addition, increased levels of
trace metals have been reported in the serum and urine especially if there is loosening of the
prosthesis.34,35
Hypersensitivity has been well documented following total hip replacement, particularly with stainless steel implants. The prevalence of metal sensitivity in eight studies varied between 3% and 43% (average +/- 25%) - approximately double the prevalence found in the normal population. The prevalence documented in seven publications reporting metal sensitivity in poorly functioning implants varied between 13% and 71% (average 60%). This was five times greater than that found in the general population.
Using inductively coupled mass spectrometry, Case et al (1994) measured metal levels in the body (synovium, pelvic lymph nodes, para-aortic lymph nodes, liver, spleen etc) at post-mortem and compared them with controls.36 The lymph node concentration was many times higher than in the control cases - as much as cobalt X 2000, chromium X 362, molybdenum X 58 and iron X 15. The material which is disseminated is not inert and may provoke cytokine-mediated bone resorption and nuclear pyknosis and cell death.37-39 Necrosis and fibrosis of local lymph nodes could compromise the local immune response and impair the host response to infection. Indeed, Bravo et al (1990) have demonstrated inhibition of T cell activities in tissue culture.40
Case et al (1996) analysed blood and bonemarrow samples from 71 patients at revision arthroplasty of a loose or worn prosthesis, and 30 control patients at primary arthroplasty with cytogenetic and molecular biological techniques. 41 There was a higher chromosomal aberration rate in cells adjacent to the prosthesis at revision surgery, compared with iliac crest biopsies from the same patients or with femoral bone marrow at primary arthroplasty.
Recognising that the long-term biological effects of wear debris were largely unknown, Doherty et al (2001) investigated whether there was any evidence of cumulative mutagenic damage in peripheral blood lymphocytes of patients undergoing revision arthroplasty of predominantly metal-on-metal hip replacements, compared with those at primary arthroplasty (Figure 5).42 Using a chromosome painting technique they demonstrated a threefold increase in aneuploidy and a two-fold increase in chromosomal translocations that could not be explained by the confounding variables of smoking, gender, age and diagnostic radiographs. In patients with Ti Va A1 prostheses they noted a five-fold increase in aneuploidy but no increase in chromosomal translocations. By contrast, in patients with cobalt chrome prostheses there was a 2.5-fold increase in aneuploidy and a 3.5-fold increase in chromosomal translocations. In six patients with stainless steel prostheses there was no increase in either aneuploidy or chromosomal translocations.
Figure 5a
Figure 5b
Figure 5: (a) A reciprocal translocation between chromosomes 1 and 2 (b) There are three copies of the chromosome I to gove 47 chromosomes. This is aneuploidy
It is clear, therefore, that metallic debris does provoke a biological response, and the nature of the response is influenced by the type of alloy used in the prosthesis. These factors need to be considered when assessing the long-term implications of joint replacement.
DISCUSSION
In considering a new prosthetic design,
strategies should be formulated to ensure that
biocompatibility embraces both biomechanical and biological imperatives. We are currently
evaluating a metaphyseal loading implant to assess how it affects the pattern of loading in
the proximal femur, quantitatively and
qualitatively. More conservative options (such as resurfacing arthroplasty) are likely to provide
more normalised loading regimens in the proximal femur.
It has been shown that a highly polished double tapered stem converts the shear stresses (in the cement, in the bone and at the fixation interface) into compressive stresses. This beneficial effect is sustained by the ability of the prosthesis to subside and re-engage the taper - thus restoring the compressive loading regimen. It is probable that the beneficial inuence of the stem design on the mechanical environment has contributed to the excellent 10-year results reported recently.43
Wroblewski et al (2001) have recently observed that reduced loading of the calcar is associated with loss of bone stock in the long-term using the Charnley Low Friction Arthroplasty. They suggested that using a cemented stem with a triple taper will provide more effective loading of the calcar in the longer term - and their seven-year results are most encouraging.44
It would be highly desirable to have a model that was predictive of the biological effects of altering the biomechanical environment. This could perhaps be achieved by linear monitoring of the movement (RSA) and bone density changes (DEXA) around an implant and then iteratively and dynamically evolving a finite element analysis model. This could provide validation to a predictive theoretical model that is often .awed by untenable assumptions. Aseptic loosening is the commonest cause of failure of total joint replacement, and osteolysis is the commonest cause of aseptic loosening. It behoves us, therefore, to address this issue. Current strategies to reduce the particulate load include minimising the generation of debris by optimising the materials, design and surgical implantation of the prosthesis. In addition, an attempt should be made to seal the interfaces (cement, circumferential bioactive coatings etc.) and so prevent particle access and ingress. A better understanding of the aetiopathogenesis of osteolysis would allow us to pharmacologically manipulate and modulate the biological response to the debris.
The success of total joint replacement has created its own nemesis. Indications have been relaxed, and joint replacement is increasingly being carried out in younger cohorts of patients. Particle-driven disease (asbestosis, etc.) only becomes clinically apparent after a long-term interval. The adverse experience with silicone in North America (although somewhat nebulous) suggests that there is no room for complacency. There can be little doubt about the carcinogenic potential of metallic substances, particularly chromium, cobalt and nickel, released from implants.45 However, it should be stressed that the fact that there are mutagenic changes in peripheral blood lymphocytes does not prove that there will be clinical expression of disease in the patient in the long-term. Of perhaps greater significance is the emerging evidence that organometallic ions produced by implants constitute a chronic stress on the immune system.46 Donati et al (1998) have demonstrated a selective decrease in the numbers of T and B lymphocytes and natural killer cells in response to increased levels of chromium, cobalt and nickel ions.47 The association between implant-generated wear debris-and the development of disease remains uncertain and controversial.
It is clearly essential to establish ongoing communication between clinicians, scientists and manufacturers. A surgeon should be as knowledgeable about the biological implications of the material and prosthesis he/she is implanting as the physician is about the side effects of any drug he prescribes.
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Copyright: 12 August 2002