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Novel Ciprofloxacin Releasing SR-PLGA Miniscrews

 

Veiranto, M (1), Tiainen, J (2), Niemelä, S (2), Suokas, E (3), Ikäheimo, I (2), Koskela, M (2), Syrjälä, H (2), Ashammakhi, N (1), Törmälä, P (1)

1 Tampere University of Technology, Tampere, Finland
2 University of Oulu, Oulu, Finland
3 Linvatec Biomaterials, Tampere, Finland

Introduction
Bone infection is a serious clinical complication that may follow surgery or trauma. Besides general measures, and systemic prophylactic antibiotics, a local drug-delivery system is thus needed. Our group has recently developed the first reliable antibiotic-releasing miniscrews for bone surgery in the world. Those screws are bioabsorbable and based on high molecular weight self-reinforced (SR) poly(lactide-co-glycolide) (PLGA). The aims of this study were to study in vitro drug release and mechanical properties, bacterial inhibitory effect and biocompatibility of those recently developed antibiotic releasing SR-PLGA miniscrews.

Materials and methods
The bioabsorbable matrix polymer in studied miniscrews was semicrystalline poly(lactide-co-glycolide) (PLGA 80:20) (Purac) with intrinsic viscosity of 6.3 dl/g (0.1%, chloroform, 25°C). The antibiotic was ciprofloxacin. It has a wide range of activity against osteomyelitis-causing bacteria and good penetration to compact bone. PLGA and ciprofloxacin were extruded into billets and then die-drawn into self-reinforced rods. Screws with the same geometry as that of BioSorbPDXÒ 1.5 Screws (Linvatec Biomaterials, Ltd.) and length of 4.0 mm were machined from self-reinforced rods. The finished screws were gamma sterilized.

To determine the released ciprofloxacin concentration in vitro, screws (500 mg) were placed into 50 ml phosphate buffer solution (KH2PO4 and NaOH) at pH of 7.4. Five parallel samples were kept in an incubator shaker at temperature of 37°C and at the specific sampling times, the released drug concentrations were measured using UV-spectrometer (UNICAM UV 500) at l=270.5 nm. Mechanical properties of the screws were determined using an Instron 4411 materials testing machine. The shear strength of the screws was determined using method modified from standard method ASTM B 769-87. The torsion strength of the screws was measured by the test modified from ASTM F 117-79. Five parallel samples were tested and means were calculated. Biomechanical testing (pull out test) was also carried out using human cadaver bones. Screws were tested for their bacterial inhibitory effect by embedding in agar dishes containing ca. 107 cfu/ml S. epidermidis ATCC 35989 and inhibition areas were measured. Screws were also implanted in cranial bone of rabbits to assess tissue reactions, biodegradation and drug bone concentration.

Results
After 160 days in vitro all loaded ciprofloxacin was released from the studied miniscrews (Fig.1). During that time measured average concentration of released antibiotic per day was between 0.8 and 11.5 µg/ml after the start-up burst peak. The maximum release occurred in the 8th week. In vivo ciprofloxacin released from the studied miniscrews resulted in achieving the highest bone tissue ciprofloxacin concentration of 14100 ng/g of bone at 4 weeks.


Fig.1. Concentration of released ciprofloxacin from studied bioabsorbable gamma sterilized SR-PLGA miniscrews.

Initial mechanical properties of the studied miniscrews were high and their application was easy. Initial shear strength of the studied miniscrews was 172 MPa. Torsion strength of the screws was 65 MPa. Miniscrews retained their mechanical properties 8 weeks in vitro at the level that ensures their fixation properties. Pull-out tests indicated that the early version of the studied antibiotic releasing miniscrew has lower values as compared to controls (non-antibiotic containing SR-PLGA).

Antibiotic releasing SR-PLGA miniscrews inhibited bacteria on average areas of ca. 30 mm in diameter when bacteria growth inhibition properties were studied on agar plates. No inhibition was seen with control screws (non-antibiotic containing bioabsorbable or titanium screws) (Fig.2).


Fig.2. Ciprofloxacin releasing SR-PLGA miniscrew (2) inhibited bacteria on average areas of ca. 30 mm in diameter. No inhibition was seen with control screw (1).

Histology did not show much difference from the control plain SR-PLGA screws except for some increased giant cells at some areas of the implantation site.

Conclusions
Ciprofloxacin releasing SR-PLGA miniscrews are easy to install and they have good drug release profiles, initial and in vitro mechanical strengths, bacterial inhibitory effect in vitro and biocompatibility. They may be useful for clinical use in infection prophylaxis or therapy.