the surgeons modelling with their hands bone cement in order to obtain handmade devices with a prosthesis-like geometry. The device was created to replace temporar- ily the removed septic prosthesis. The positioning in the septic site of an antibiotic- loaded bone cement device aimed at strengthening the systemic antibiotic therapy.
As a matter of fact systemic antibiotic therapy is not always able to guarantee optimal antibiotic concentration in the infected site. After some months from implantation, the device was removed replacing it with a new prosthesis, giving back to the patient an healed joint and a certain functional recovery. This devices were called “spacers”
[1, 7, 13, 14].
Mechanical Failure
Unfortunately in many cases it was possible to see also bad situations, determined by the mechanical failure of the hand-made devices. If on one side breakage was a fear- some and undesired complication, on the other side surgeons were very satisfied with the anti-septic effectiveness of the device. In other words the “spacer “ and the sys- temic treatment increased the probability of infection healing compared to systemic antibiotic therapy alone.
Spacer-G
The positive results described led Tecres to start the research and study systematically the spacers made by the surgeon in order to design a device which could be at a time mechanically safe and pharmacologically effective: in other words a “reproducible effective device”. A device which could also give the patient a better quality of life.
With these key features the Spacer-G was designed (Fig. 1). Its geometry was stud-
ied to permit an optimal interaction between the acetabulum and the femur: anatom-
ical stem-neck angle chosen to limit as much as possible dislocation; saddle shape
neck to limit the possible acetabular protrusion; extreme smoothness of the head to
reduce the possible generation of debris. An inner stainless steel bar (Fig. 2) was
Fig. 1. Spacer-G, hip spacer
Fig. 2. Inner core present in Spacer-G
inserted to provide high mechanical strength and gentamicin was chosen as antibi- otic due to the wide spectrum of activity and the good properties of release from PMMA.
Mechanical and pharmacological testing confirmed the good performances of the
device which is solid and allows partial weight-bearing and releases effective amount
of antibiotic in the infected site [2, 3, 4, 5, 9]. Soon after the first positive cases, the
one-size spacer was joined by a smaller and a bigger head size, which permitted to
improve the head-acetabulum coupling and reducing dislocation. Then the long-
stem version was introduced which allowed to use the device also in the absence of a
proximal support, in the presence of large metaphyseal defects and after a trans-fem-
oral approach [12].
which is generally achieved by hardware removal with debridement and local deliv-
Fig. 3. Spacer-K, knee spacer
Fig. 4. Spacer-S, shoulder spacer
Fig. 5. Spacer-E, elbow spacer
ery of antibiotics by antibiotic beads [8], an irrigation-perfusion technique [6], or an antibiotic cement nail beads [11], and fracture union, which is usually accomplished by providing alternative fixation, mostly external fixation.
The infective problems induced by endomedullar nails have also been faced with the same principle of the local release of antibiotic bone cement-mediated. In this case the system has been designed with a different approach: for mechanical and dimensional reasons, the supporting internal structure is the nail itself onto which a cement clothing is placed. Everything is assembled in the operating theatre in a few minutes. The device (Nail Clothing) is made of industrially preformed tubular antibiotic-loaded bone cement segments (Fig. 6a): the surgeon inserts the segments onto the nail till to cover it all and with a special glue, fix them on the nail itself (Fig. 6b).
Fig. 6a. Nail clothing a
Concentration Surface Porosity
RELEASE
b Fig. 6b. Nail clothing
glued to nail
Bone Cement Elution from PMMA
The mechanism or the mechanisms of elution of antibiotic from PMMA are not so clear yet. Therefore it is more correct to speak of experimental observations which show the conditions which lead to an increase or the decrease in the release of antibi- otic. Synthetically, keeping fixed solvent and temperature, the increase of the release occurs when:
) increases the concentration of the antibiotic in PMMA;
) increases the surface at the interface cement-solvent;
) increases the permeability of the cement matrix.
Permeability = porosity + chemical/physical properties (of matrix) A reduction in the release will occur when in the opposite situation (Fig. 7).
Fig. 7. Factors influencing the release of antibiotic from a PMMA matrix
As an example, the preparation of bone cement under vacuum determines a reduction in the cement porosity and therefore a reduction in the antibiotic release [10].
In addition to the above mentioned parameters, other experimental observations show that the antibiotic (drug) molecule is able to migrate in the cement matrix even in the absence of a solvent following a diffusion behaviour (Fig. 8). The relation which better satisfies such experimental observations is the Fick’s equation:
J = D (C1 – C2)
X
Gentamicin elution from PMMA
0 2 4 6 8 10 12
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Days
Concentration mg/L
Fig. 8. Elution kinetics of an antibiotic loaded cement: after an elu- tion period in saline, the specimen is dried and left in the open air. A second elution period is then started showing an initial release higher than expected: the migra- tion of the antibiotic in the PMMA matrix occurs also in absence of a liquid solvent.
J is the molecular flux which is directly proportional to the diffusion coefficient (D), which depends from antibiotic, matrix and temperature; interface area (A); concen- tration difference (C 1–C2) where C1
8C 2, and inversely proportional to the distance between C1 and C2 (X).
If we consider to keep C and X constant, the formula becomes:
J = D A K
Therefore if we want to increase the antibiotic release it is sufficient to increase the diffusion coefficient D and the interface area A. This has been the route followed to design the new spacers.
High-release Matrix for the Spacers
In 2006 the distribution of the spacers with increased antibiotic release started. The
absolute amount of antibiotic in the devices is identical, but the new spacers have an
increased release capacity. The release can be as high as 4 – 5 times the release of the
previous spacers. This result has been achieved in two ways: 1) the external surface,
e.g. the interface area with the biological liquids, has been increased thanks to a spe-
cial finishing which increases the interface area. Figure 9 shows the surfaces of Spac-
er-G stem before and now; 2) the bone cement matrix which includes the antibiotic is
made with a new generation of polymers which are structured in a way to increase
permeability.
left, old version with smooth surface; right, new version with textured surface
Microscopy of the High-porosity Spacers
Before turnig into a compact and solid structure, the spacer is a powder of spheroidal particles made of a mixture of PMMA, barium sulphate and gentamicin sulphate.
Only with a colorimetric method it is possible to discriminate the components. Fig- ure 10 shows a group of spheroidal particles which constitutes the powder used to manufacture the spacers. The colourless particles are PMMA, the blue ones are genta- micin. When the liquid monomer, MMA, is added to the powder a mouldable dough is obtained which in a few minutes gets hard and solid. In the hardened mass the spheroidal particles of PMMA cannot be distinguished any more, but the gentamicin ones can. Figure 11a shows the particles of gentamicin coloured in red. Actually these spheroidal particles act as micro-reservoirs from which gentamicin flows outside the
Fig. 10. Bone cement powder: PMMA pearls are colourless, genta- micin sulphate pearls are blue
a
b Fig. 11. Cured genta- micin bone cement:
a reservoir with genta- micin in red; b empty reservoir (after con- tact with solvent)
cement mass. Figure 11b shows the empty micro-reservoir of gentamicin after the contact with the solvent.
Conclusions
The constant work carried out over the years has led towards an extension of the use of bone cement in fields hardly immaginable a few years ago. Today it is possible to manufacture with this material medical devices with different properties which can be modulated at pleasure. Bone cement as a drug delivery system can be designed and specific elution kinetics can be achieved.
This aspect expands the concept of cementation and if the right synergy among
specialists of different disciplines it will be possible to strengten the surgical and the-
rapeutical tools and increase the healing expectances of the patient.
Orthop Trauma Surg 95(1 – 2):31 – 35
7. Cohen JC, Hozack W, Cuckler JM et al (1988) Two-stage reimplantation of septic total knee arthroplasty. Report of three cases using an antibiotic-PMMA spacer block. J Arthroplasty 3(4):369 – 377
8. Henry SL, Ostermann PA, Seligson D (1990) The prophylactic use of antibiotic impregnated beads in open fractures. J Trauma 30(10):1231 – 1238
9. Magnan B, Regis D, Biscaglia R et al (2001) Preformed acrylic bone cement spacer loaded with antibiotics: use of two-stage procedure in 10 patients because of infected hips after total replacement. Acta Orthop Scand 72(6):591 – 594
10. Neut D, van de Belt H, van Horn JR et al (2003) The effect of mixing on gentamicin release from polymethylmethacrylate bone cements. Acta Orthop Scand 74(6):670 – 676
11. Ohtsuka H, Yokoyama K, Higashi K et al (2002) Use of antibiotic-impregnated bone cement nail to treat septic nonunion after open tibial fracture. J Trauma 52(2):364 – 366
12. Roman`o C, Meani E (2004) The use of preformed long stem antibiotic loaded cement spacers and modular non-cemented prosthesis for two-stage revisions of infected hip prosthesis Pro- ceedings of the AAOS 2004 San Francisco (USA)
13. Wilde AH, Ruth JT (1988) Two-stage reimplantation in infected total knee arthroplasty. Clin Orthop Relat Res (236):23 – 35
14. Zilkens KW, Casser HR, Ohnsorge J (1990) Treatment of an old infection in a total hip replacement with an interim spacer prosthesis. Arch Orthop Trauma Surg 109(2):94 – 96.
