Standardized release measurements for antibiotics from polymethylmethacrylate bone cement under constant flow

Abstract

Polymethylmethacrylate bone cement is used for shaft fixation of artificial hip and knee joints. The reliable method has the advantage of a nearly immediate loading capacity after the implantation. In cases of hazards due to postoperative biomaterial associated infections [1] anti-inflammatory therapies are difficult [2][3][4], lifelong and often to press an explantation of the implant. A prophylactic measure is the use of antibiotic loaded cement [5,6] with the goal to reach sufficiently high level of antibiotics in the immediate vicinity of the implant, without stressing the organism excessively and the hope to avoid resistance. Oral intakes of antibiotics are mostly ineffectively because of reduced diffusion in the bone sphere. Commercially available are gentamicin loaded bone cements with an antibiotic content of about 2.5 %. In cases, if special antibiotics are required, the active incredients, one or two [7] are added to the cement powder by the physician during the operation. A fraction up to 10 % is in use. There is no knowledge about the influence of constituents of antibiotics to the cement powder with respect to the mechanical stability. But some recommendations are announced which say that a maximum of 10 % of incredients should not be exceeded [8]. The other constraint is the minimal amount of antibiotics to be effective against bacteria. Generally 90 % of the incorporated constituents are retained in the PMMA matrix [9,10], so that only small amounts are available in particular if a long term therapy is aspired. Hence the increase of bacterial resistance, mainly against bacteria responsible for infections on orthopaedic implants, leads to an increasing interest and search for new effective antimicrobial agents which have to be admixed to the cement by the clinician because commercial not available. There are some methods published applied for the determination of the antibiotic release rate. Although not validated results are available, it is generally accepted that the release rate during the first hours shows high values whereas the values strongly decrease in the long term application and finally are stabilized on a very low level over a few weeks [11][12][13]. The release kinetic is controlled by a combination of surface roughness and porosity [14]. A high roughness enlarges the surface and the amount of interfacial bonded agent molecules. Porous materials, permeable by the body electrolyte [15,16] deliver effective molecules out of the region close to the surface. Porosity itself depends on the addition of antibiotics which leave pores after release [17]. Autoren

Real-time and in Situ Drug Release Monitoring from Nanoporous Implants under Dynamic Flow Conditions by Reflectometric Interference Spectroscopy

“…On the other hand, it is not advisable for treatment of conditions that require long-term sustained drug release such as implants (i.e., bone implants, stents, etc. ). ,, …”

“…The experimental data obtained from these experiments were fitted to a typical mathematical model for drug delivery kinetics (i.e. Higuchi model). ,,, This model, which is based on the Fickian diffusion equation, describes the release of drugs from insoluble matrices. Under such assumptions as perfect sink conditions and significantly higher initial drug concentration in the release platform than in the eluting medium, this model can be used to describe the diffusion-controlled release of water-soluble and poorly water-soluble drugs from inert noneroding porous platforms.…”

“…These systems used a continuous flow chamber in which the release kinetics of various antibiotics (i.e. amikacin, vancomycin gentamicin and tobramycin) from a poly-(methyl methacrylate) (PMMA) and calcium phosphate matrix were analyzed. − However, these techniques cannot be automated and multiple aliquots must be taken from the solution continuously throughout the whole release process, making the process labor intensive and less accurate for studying drug release mechanism within a short period of time (e.g. seconds or minutes) .…”

Modeling vancomycin release kinetics from microporous calcium phosphate ceramics comparing static and dynamic immersion conditions

“…However, this testing regime is not close to in vivo situation since the saturation of the immersion liquid with the released drug decreases the concentration gradient between matrix and solution and so retards the release rate. A different testing regime recently described by Rouse et al [18,19] and Braun et al [20] aimed to mimic the natural conditions at the implantation site by using a flow chamber for drug release experiments. In these studies, release kinetics of various antibiotics (amikacin, gentamicin, tobramycin, vancomycin, daptomycin) from PMMA bone cement matrices were investigated using a constant liquid flow rate, which guaranteed maintenance of a high concentration gradient between matrix and solution.…”

Properties of Orthopaedic Cements Biomechanically Little Affected by Exceptional Use of Liquid Antibiotics

“…PRO‐IMPLAN Foundation recommendation) into account 21 , 22 . The recommended upper limit for the addition of AB is 4 g AB per 40 g cement powder (10% rule 23 ).…”