A new,low cost,locking plate for the long-term fixation of a critical size bone defect in the ratfemur: In vivo performance,biomechanical and finite element analysis

Abstract

BACKGROUND: The optimum fixation device for the critical size bone defect is not established yet.

OBJECTIVE: A reliable, feasible and low-cost fixation device for the long-term maintenance of a critical bone defect.

METHODS: A custom-made plate made of poly-methyl-methacrylate was used for the fixation of a critical defect of rats’ femurs. The screws were securely fixing both on the plate and the bone. A three point bending test, aimed to resemble the in vivo loading pattern, a Finite Element Analysis and a 24-week in vivo monitoring of the integrity of the plate fixation were utilized.

RESULTS: The plate has linear and reproducible behavior. It presents no discontinuities in the stress field of the fixation. Its properties are attributed to the material and the locking principle. It fails beyond the level of magnitude of the normal ambulatory loads. In vivo, 100% of the plates maintained the bone defect intact up to 12 weeks and 85% of them at 24 weeks.

CONCLUSION: This novel locking plate shows optimal biomechanical performance and reliability with high long-term in vivo survival rate. It is fully implantable, inexpensive and easily manufactured. It can be qualified for long term critical defect fixation in bone regeneration studies.

Keywords

Bone tissue engineering segmental bone defects animal models plate critical size defect fixation device

1. Introduction

Bone regeneration and healing of segmental bone defects is a topic of intensive research. The critical size defect – the minimum gap that is unable to be bridged spontaneously by callus – is widely used in experimental protocols for hosting tissue engineering products, which aim to facilitate bone bridging [1–12].

The critical defect requires a bridging fixation device depending on each tissue engineering implants’ needs [1,13]. Implants with enhanced material properties allow a more load sharing fixation, whereas weaker ones require a stiffer bridging bone fixation [14]. The plate fixation is common in the laboratory setting [13–15]. Currently, external fixators seem to meet most of the requirements for critical defect maintenance [5,12,16,17]. In most cases, they are custom-made devices [5–8,16,18–20], serving the needs of each experimental study, providing adequate strength and simple application technique. However, they have some disadvantages which are practically present in all in vivo experiments and as far as we are aware, are not adequately emphasized in the literature. These are mainly with regards to postoperative infections as they inevitably allow the direct contact of the bone with the environment. Increased cost of any fixation device is always another disadvantage especially in large animal series.

The aim of this study is to propose a reliable critical defect-fixation device suitable mainly in tests with experimental animals, which may be used for the interposition of structurally weak implants in the long term. Simple preparation and application technique and low cost were also main objectives in this study. The new locking cement plate functions as an internal-“external fixator”. The biomechanical performance is analyzed with the aid of finite element modelling and a comparison with the literature is presented.

2. Methods

All procedures of this study were performed in compliance with the relevant guidelines of our University and the local veterinary authority, and were approved by the institutional ethics committees.

2.1. Biomechanical tests

Five fresh cadaveric right femurs of male Wistar rats were used [9]. An 8 mm critical defect [1–4] was marked in the middle of the femoral diaphysis. A custom-made cutting jig allowed reproduction of all the drillings and cuttings on the bone. 1 mm diameter parallel holes were drilled for the screws; the holes of each pair were 4 mm apart and the inner hole of each pair was 3 mm apart from the adjacent edge of the marked defect.

All plates used in this study were constructed with Poly-Methyl-Meth-Akrylate (PMMA) in the same mold – 25.0 mm × 5.0 mm × 3.0 mm – under the same conditions (Fig. 1). The PMMA (Palacos^®, Heraeus Medical GmbH, Wehrheim, Germany) was produced by mixing the powder polymer with methyl methacrylate, N,N-dimethyl-p-toluidine, benzoyl peroxide and hydroquinone at 20°C under vacuum.

Fig. 1.

Technical drawing of the cement plate and screws incorporating (all the dimensions in relation to the bone). (Colors are visible in the online version of the article; https://dx-doi-org.web.bisu.edu.cn/10.3233/BME-151540.)

After the complete polymerization, 1 mm holes were drilled on the hardened PMMA-plate symmetrically to the bone holes. The plate was fixed on the bone using stainless steel 1.2 mm diameter fine-pitched 8 mm long screws with 1 mm core diameter; the screws were selected in order to resemble the locking screws used in locking plates for humans. Their free-end was configured into a cutting tip to facilitate sequential entry both into the pre-drilled 1 mm diameter PMMA-plate and into the pre-drilled 1 mm bone holes.

The pre-marked bone of the mid-diaphysis was removed using a high speed burr (Rotacraft^®-RC07, Shesto Ltd, London, UK); thus creating the critical defect. Finally, the whole assembly created a fixed construct.

2.1.1. The setup and the bending test

The rat femur is subjected to bending and torsional moments during gait as a result of the weight and the muscle forces [21,22]. After many preliminary testing and trials, a “bio-realistic” modified 3 point bending test configuration [23,24] was established in order to replicate a combined bending–torsion comparable to the one observed at peek loading during stance phase (Fig. 2).

The femoral condyles were symmetrically embedded into a 30 mm-long PMMA block, which was reinforced with a bone piercing KW. The distal block was parallel to both the posterior and the distal surfaces of the femoral condyles. It defined the coronal plane of the femur and it prevented any rotation of the construct during loading (Fig. 2).

A 1.2 mm KW was pierced through the femoral head, followed the axis of the femoral neck and reached the outer cortex of the trochanteric area; aiming to increase the moment arm of the proximal femur (Figs 1, 2). The length of the moment arm, from the free tip of the KW to the longitudinal axis of the femur, was 15 mm. All angles between the distal block and the neck KWs were the same in all bone–plate constructs.

The mounting of the bone–plate constructs on the bending apparatus was done in a 3-point configuration. The femur was lying in a true posterior–anterior direction, as dictated by the distal femoral block (Fig. 2). The loading cell of the bending apparatus was symmetrically centered over the bone gap and was in contact only with the bone stumps; not with the plate.

Fig. 2.

Experimental configuration of biomechanical tests. Note that the moving cross head is in contact only with the bone; not with the plate. The rotational moment which develops during loading is illustrated. (Colors are visible in the online version of the article; https://dx-doi-org.web.bisu.edu.cn/10.3233/BME-151540.)

Due to the maintained femoral neck anteversion, the elevated trochanteric area gradually approached the proximal support during the loading; thus creating a rotational moment on the bone–plate construct. The rotational moment reached its highest value when the trochanter contacted the lower support. Thereafter, the loading continued only with its bending element.

The biomechanical testing generated load/displacement curves for each plate. As “yield point” was considered the point of the stress curve, at which an alteration was noted in the behavior of the construct; indicated with arrows in the plots.

The experiments were carried out with a SHIMADZU Autograph tester (AGS-500NJ standard Unit, Shimadzu Corporation, Tokyo, Japan) with precision of indicated values <1%. The displacement speed was set to 1 mm/min [17]. The applied load and the displacement of the head were continuously recorded with a AGS-J data processing software (Trapezium Lite Software 345-47147, Shimadzu Corporation, Tokyo, Japan). The recording came to a stop whenever a failure of the bone–plate construct took place. Video recording allowed observation of any macroscopic changes (e.g. bolt loosening or screw pullout). After failure, the construct was removed and the type of failure further examined.

The whole process – bone harvest to bending test – was completed within 1 hour postmortem. The specimens were kept moist with 0.9% normal saline throughout. The ambient temperature was 20°C.

2.2. In vivo tests

Twenty Wistar adult male rats were used. The rats were not previously exposed to anything which could affect their bone quality. The average weight of the rats was 266.17 ± 16.44 g.

The rats were anesthetized with intraperitoneal ketamine (30 mg/kg). The ambient temperature was 20°C; a heating table set to 37°C and an isothermal blanket were used. The surgical field was sterilized with 10% povidone iodine solution and the plates were prepared under sterile conditions. The screws and the jig were sterilized together with the whole instrumentation used.

A lateral approach to the femur was performed by the same surgeon for all specimens. The custom-made jig was used for all the drillings, cuttings and the bone-defect creation on the femur. Finally the plate was applied in contact with the bone and stabilized with the screws. Special care was taken not to harm the surrounding soft tissues and the remaining bone. The wound was washed out with sterile normal saline and closed in layers.

All rats were kept in the same type and size of cages and fed with the same food pre- and post-operatively. All experimental-animals received an intraperitoneal bolus dose of Penicillin G (20,000 U/kg) immediately postoperatively. Subcutaneous carprofen (5 mg/kg) was administered on the day of surgery and for 4 days postoperatively for pain management [9].

The integrity of the fixation was radiographically evaluated at 8, 12, 16 and 24 weeks postoperatively (60 kV, 4.5 mA, 1.2 ms, DigitalDiagnost, Phillips Medical Systems, Eindhoven, The Netherlands). The first two time-points represent specific milestones of the bone healing process in rats [25–27] and the last two were chosen in order to investigate the longevity of the bone-defect fixation. Presence of radiolucency around both screws of either pair or any macroscopic loosening of the construct was considered an indicator of plate–bone construct failure.

After the fixation failure or the termination of the 24 week observation period, the rats were humanely sacrificed. The femur was then examined regarding the type of loosening.

2.3. Data analysis

An initial Shapiro–Wilk testing for normality showed that the data from the biomechanical testing as well as rats’ weights followed normal distributions. Descriptive statistical analysis was performed with SPSS package version 16.0 (WinWrap Basic, Copyright 1993–2007, Polar engineering and consulting). A two sample t-test was performed to examine whether the failure of the plates was influenced by the weight of the animals. The level of significance was set to $p ⩽ 0.05$ .

The examination of the biomechanical data was focused on two areas of the whole biomechanical testing. The first concerns features of the plate in the entirety of its behavior under the bending test and the second examines its features up to the “yield point”.

2.4. Finite element analysis

The bone and implant geometries (Fig. 1) were reverse engineered based on the plate and average femur dimensions. The bone matter was allocated into a cortical shell filled with cancellous bone, facilitating bio-realistic stress absorption of the fixation.

The mechanical properties of cortical (and cancellous) bone were considered as unaffected by the implantation and accepted as isotropic materials [28]. All model materials were assumed as linear elastic and the corresponding properties are summarized in Table 1.

Table 1
Mechanical properties of hard tissue and fixation device materials

Cement plate ( $N = 5$ )	Group statistics

	Max load [N]	Deflection at max load [mm]	Deflection until failure [mm]	Yield point [N]	Enlongation at yield point [mm]	Stiffness to yield point [N/mm]
Mean	30.625	2.955	3.419	10.900	1.215	7.480
St.Dev.	8.746	0.333	0.389	1.925	0.094	0.554

Note: This table shows the max-load and the max-deformation which were reached by the cement plates during the initial linear phase of their loading curve. (St.Dev.: Standard Deviation.)

Optimal osseointegration was assumed [29] to facilitate the consideration of a fully bonded contact between bone and implant. A 40 N load was applied on symmetrically centered over the bone gap to mimic the experimental scenario. The surfaces of the distal femur block opposed to the loading direction were constrained of all degrees of freedom, whereas the KW passing through the femoral head was constrained of translational but not rotational movement.

As the verification of a biomechanical finite element model is a fundamental aspect of the analysis itself [30], a mesh independent grid was used [31]. Convergence studies were conducted to determine optimum element size in terms of processing time and results accuracy. The mesh grid was generated in ANSA (by BETA CAE Systems S.A.) allowing tailored meshing and fully conforming interfaces and the model was simulated in ANSYS Workbench^® Academic Research, Release 14.0.

3. Results

3.1. Biomechanical performance

The final failure of the construct occurred at the proximal bone–plate junction with a spiral fracture configuration, while the screws remained tightly fixed on the plate. The plate reached a maximum load of 30.625 ± 8.746 N; the deflection at that point was 2.954 ± 0.333 mm. The plates deflection to failure was 3.419 ± 0.389 mm. The average yield point is at 10.900 ± 1.925 N, which takes place at 1.215 ± 0.094 mm (Table 2).

Table 2
Mechanical properties of hard tissue and of the materials of fixation-devices

Material type	Young modulus [GPa]	Poisson ratio
Cortical rat bone	15.000	0.3
Cancellous rat bone	5.000	0.3
Stainless steel	210.000	0.28
PMMA	2.944	0.375

The plate shows a reproducible behavior under the biomechanical loading, since the plots of the 5 tests almost coincide to each other up to approximately 1.0–1.2 mm displacement and loads up to ∼10 N; the yield point (Fig. 3). The stiffness of the construct (reflected by the slope of the curves) remained constant up to ∼1.2 mm of displacement. The calculated stiffness values within this linear region had a low scattering with average value 7.48 ± 0.554 N/mm (Table 2).

Fig. 3.

Experimental results of biomechanical tests (load versus displacement) of the cement plate. Five independent tests – in a different construct each – were performed.

3.2. In vivo performance

At 8 weeks all plates were intact (Fig. 4). At 12 weeks two specimens showed signs of radiolucency around one of their screws. There was no evidence of any macroscopic deformity of the construct, the critical bone defect was intact, there was no abnormal movement of the rats’ femur and its ambulation was unchanged. Despite the intact bone defect, those specimens were removed from further evaluation. One plate showed loosening in the proximal screws at 16 weeks. Finally, at 24 weeks, 85% (17/20) of the plates successfully maintained their initial position (Fig. 5) and the critical defect intact.

Fig. 4.

Results of the in vivo tests of the cement plate at 8, 12, 16 and 24 weeks. The survival rate (%) is presented in the histogram (total number of animals tested = 20). CSD – Critical Size Defect, PMMA – Poly-Methyl-Meth-Akrylate. (Colors are visible in the online version of the article; https://dx-doi-org.web.bisu.edu.cn/10.3233/BME-151540.)

Fig. 5.

Radiographs of the cement plate of the right rat femur obtained 24 weeks postoperatively, showing the intact cement plate fixation.

As expected, no spontaneous callus formation was noted. No abnormal movement or altered gait of the rats was observed at any stage. All wounds showed no signs of swelling, collection or inflammation. Statistical analysis revealed no correlation of the animals’ weight and the plates’ failures; $p = 0.537$ .

3.3. Finite element analysis

The experimental results of the in vivo and the biomechanical tests agree with the finite element analysis. The similar applied loads and boundary conditions to those of the experimental set-up resulted in comparable analytical and experimental deformation values (Fig. 6).

Fig. 6.

Qualitative comparison of the developing stress values of the cement plate under a 40 N load with the locking plate principle and without. Note the increased stresses developed in the non-locking plate scenario. (Colors are visible in the online version of the article; https://dx-doi-org.web.bisu.edu.cn/10.3233/BME-151540.)

The strength properties of the plate are within one magnitude of the animals’ bone properties (Table 1). This provided a smooth stress transition from bone to plate and back to bone, evenly distributing deformation and the developing stresses. The plates’ behavior can also be attributed to the locking plate principle, as the pre-drilled 1 mm holes into the plate facilitated a strongly bonded screw–plate interface. A fixation scenario with the same plate and larger diameter pre-drilled holes on the plate was simulated, allowing no fixation of the screws on the plate itself but fixation only on the bone. This scenario led to losing of the locking plate effect and increased the stresses by 12% (Fig. 6).

4. Discussion

4.1. Interpretation of the results

There is agreement and counter-support of all the biomechanical loading, the in vivo performance, the radiography and the finite element analysis results.

The load–displacement curves (Fig. 3) suggest that the initial linear part up to the yield point represents the regime of secure and reliable performance of the plate. Thereafter, some kind of failure is apparent; however the load/displacement curves remain linear. This constant stiffness seems to facilitate a smooth transition of the loads from the one bony part of the construct to the other; a fact which is highly desirable and important in the biological environment. The results of the finite element analysis suggest that this can be attributed to the locking plate principle. Moreover, the fixation of the screws both in the plate and in the bone seems to eliminate any screw–plate movement and to minimize any screw–bone gross movement. At maximum loading, the failure of the plate construct at the bone–screw interface was expected due to stress concentration arising in the fixed side of the plate, where a stiffer element is set to collaborate with a more flexible one (Fig. 6).

With regards to the forces applied on the plate, the combined sagittal and coronal forces acting on the rats’ femur during gait do not exceed 2 × BW (body weight) in all areas of the femur [21]. The modified 3 point bending test, aiming to incorporate that combined sagittal and coronal plane loading, reached approx. (15 × BW) 7.5 times the maximum normal force acting on the femur on that plane during gait. The maximum torsional deformation was reached at approx. 3 N (approx. the BW) of loading. The maximum rotational moment at that point was approximately 3 times the normal torsional moment, which the femur is subjected to during gait. The average yield point of the plate is at 3.6 BW, which is beyond the normal loading of the femur on that plane during gait. This point lies within the constant stiffness area of all plates; in the predictable behaviour span. This is the reason why the plate withstands successfully the in vivo loading.

The cyclic loading of the plate was achieved by the normal ambulation during its in vivo implantation. The results showed that the plate successfully withstands all the loads of ambulation without early mechanical failure. It has a high survival rate, as the defect remains intact at 12 weeks and 85% of the constructs remain stable at 24 weeks; a survival limit investigated for the first time.

4.2. Discussion

The goal of this study was the introduction of a reliable and feasible fixation device with reproducible behavior regarding its ability to safely withstand the normal laboratory animal ambulation needs, considering that the properties of the intact bone surpass the needs of the normal laboratory animal ambulation [21,23,32]. The 3-point bending test is a generally sensitive and widely used method for assessing bone and various materials biomechanical properties [23,24,33]. The “bio-realistic” modification used in this study, aimed to simulate the bending and torsional stresses acting simultaneously on the rat femur [21–24,33–36]. The axial loading was not evaluated by this single testing; however, the in vivo survival of the cement plate indicates that it safely withstands this type of loading as well.

Acrylic PMMA cement is a biocompatible, inert non-absorbable material, which is widely used in human and veterinary surgery [10] and its biomechanical properties, e.g. Young’s modulus, are in the same of similar order of magnitude to those of bones [37]. Thus, stiffness curves are almost linear, they last over relatively long deflections and high loads, and resemble the linear stiffness curve of intact rat femurs [23,24,33]. The screws were securely fixed both in the cement plate and in the bone. Therefore the construct behaves as an internal “external fixator”, which results in a wider distribution of loads applied on the bone–plate junctions, satisfying the principles of the locking plates used in humans [38–40]. In comparison to the external fixator devices, it has the advantage of not allowing any contact of the bone with the environment; a cause of potential postoperative infection, which could jeopardize and influence any experimental results. Moreover, the spiral fracture at maximum loading resembles the one that would happen in a normal bone subjected to the same bending and torsional loading pattern; implying a normal load transmission through the bone–plate construct [22,41].

Different types of external fixator constructs and plates have been used in the literature for the fixation of a critical defect. According to the list prices of those implants, the final cost of each PMMA plate is 130–140 times less than the cost of the commercially available 1.3 mm or 1.5 mm titanium/steel mini-plates [13,14]; designed for the fixation of human small bone fractures. The cost of the custom-made plates and external fixator frames were not evaluated by the authors [2,14,15,17,22]; however, it is appreciated that the overall cost of the design, the manufacturing and the metal is more expensive than this of a PMMA plate. The latter requires only a mold which is the same for all plates while a single dose of reconstituted PMMA cement is able to produce more than 90 plates.

Other advantages of the cement plate include that it has the same application to all other plates and that it is fully implantable, allowing no contact of the bone to the environment. It is not fully radiopaque; thus allowing the radiographic monitoring of the bone healing/regeneration within the bone-defect. The custom-made manufacturing is easy and it allows adjusting the plates’ dimensions according to the size of the animal or the biomechanical needs. PMMA is a material which can be impregnated with other substances (e.g. Antibiotics) and can be used as local drug delivery system.

Many custom-manufactured devices have been published which aim to stabilize bone defects [11,15,17,22]. Similar plates made out of PLLA, have already been used in the literature [11,22]. However, they were non-locking and they functioned in vivo with a load sharing principle since the interposed scaffold was structurally durable.

Glatt et al. [17] showed the safe maintenance of a critical defect with an own manufactured external fixator device, biomechanically and in vivo, for a period of 8 weeks. However, this work provides no description about the stabilization and the plane of loading on the 3 point bending test, which did not include torsional forces. Torsional strength is a common area of vulnerability of external fixators, due to the increased distance of the main frame from the bone [42–44]. We believe that an internal-“external fixator” provides a better biomechanical response to torsion.

Russel et al. [15] presented a steel plate for the fixation of a 5 mm bone defect which showed approx. 94% survival in 15 weeks. This result is similar to our plate, where 1 fixation out of 20 failed at 16 weeks (95%). However, our strict criteria excluded from the study the plates which showed even an element of radiolucency. Therefore, we believe that the 85% survival in 24 weeks is an expected outcome in line with other published fixation devices for the same purpose.

5. Conclusions

This cement plate is a locking plate with high survival rate and optimal load transmitting behavior managing to maintain the Critical defect intact within the range of normal ambulatory loading. It has low manufacturing cost, it has similar application to all other plates and it is fully implantable. It allows adjustment of its dimensions according to the size of the bone or the biomechanical needs and may be used as a drug delivery device.

Therefore, the novel PMMA plate can be qualified for studies with experimental animals for the study of critical size defects because it provides an inexpensive, reliable and feasible option for long-term fixation in bone regeneration studies, allowing safe maturation of weak tissue engineering implants within the bone defects.

Conflict of interest

The authors confirm that there are no conflicts of interest associated with this work and its publication. The work was realized within our Institutions and no third party funding took place in any of the stages of this study.

Footnotes

Acknowledgements

The authors would like to express their gratitude to Nancy Saranti, John Matsaidonis, Venetia Mataliotaki, Anthony Theodorides and to all people who contributed to this study. The authors would also like to acknowledge BETA CAE Systems SA, for providing them with the CAE pre-processor ANSA, used during surface and volume generation and meshing of the introduced model.

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A new,low cost,locking plate for the long-term fixation of a critical size bone defect in the ratfemur: In vivo performance,biomechanical and finite element analysis

Abstract

Keywords

1. Introduction

2. Methods

2.1. Biomechanical tests

2.3. Data analysis

2.4. Finite element analysis

Table 1 Mechanical properties of hard tissue and fixation device materials

3.1. Biomechanical performance

Table 2 Mechanical properties of hard tissue and of the materials of fixation-devices

4.1. Interpretation of the results

4.2. Discussion

5. Conclusions

Conflict of interest

Footnotes

Acknowledgements

References

Table 1
Mechanical properties of hard tissue and fixation device materials

Table 2
Mechanical properties of hard tissue and of the materials of fixation-devices