Use of Antibiotic Loaded Biomaterials for the Management of Bone Prosthesis Infections: Rationale and Limits.

BACKGROUND: Periprosthetic joint infection still represents a challenging issue for the orthopedic community. In the United States approximately a million joint arthroplasties are performed each year, with infection rates ranging from 1 to 2%: revisions has significant implications on health care costs and appropriate resource management. The use of locally applied antibiotics as a prophylaxis measure or as a component of the therapeutic approach in primary or revision surgery is finalized at eliminating any microorganism and strengthening the effectiveness of systemic therapy. OBJECTIVE: The present review of clinical and preclinical in vivo studies tried to identify advantages and limitations of the materials used in the clinical orthopedic practice and discuss developed biomaterials, innovative therapeutic approaches or strategies to release antibiotics in the infected environment. METHODS: A systematic search was carried out by two independent observers in two databases (www.pubmed.com and www.scopus.com) in order to identify pre-clinical and clinical reports in the last 10 years. RESULTS: 71 papers were recognized eligible: 15 articles were clinical studies and 56 in vivo studies. CONCLUSION: Polymethylmethacrylate was the pioneer biomaterial used to manage infections after total joint replacement. Despite its widespread use, several issues still remain debated: the methods to combine materials and antibiotics, the choice of antibiotics, releasing kinetics and antibiotics efficacy. In the last years, the interest was directed towards the selection of different antibiotics, loaded in association with more than only one class and biomaterials with special focus on delivery systems as implant surface coatings, hydrogels, ceramics, micro-carriers, microspheres or nanoparticles.

OP-1 application in bone allograft integration: preliminary results in sheep experimental surgery.

UNLABELLED: Massive bone allografts are frequently used in orthopaedic reconstructive surgery. However the failure rate at long term follow-up is around 25%. AIM: Stimulation of allograft incorporation. MATERIALS AND METHODS: In order to stimulate bone remodeling of an allograft we applied recombinant human osteogenic protein-1 (rh-OP-1, also know as bone morphogenetic protein-7, BMP-7) to a long bone critical size defect sheep model. In nine sheep we created a 3 cm osteoperiosteal metatarsal defect replaced with a structural allograft alone (control group, 4 animals), or an allograft added with rh-BMP-7 (BMP group, 5 animals). Radiographic, mechanical, histological and histomorphometric analysis were performed. RESULTS: X-rays in the BMP group showed a better and faster callus formation, compared to the control group within the first 8 weeks after surgery. After 16 weeks there was a higher evidence of bone remodeling in the BMP group. Radiographic healing at junction sites was more evident in the BMP group at 4, 8 and 16 weeks. Mechanical testing on screw extraction showed no statistical differences between the two groups and histomorphometry showed no difference in terms of newly formed bone inside the allograft as well. The resorption rate of the graft was higher in the BMP group in comparison to the control group. The penetration of newly formed vessels was significantly higher in the BMP group. CONCLUSIONS: These findings indicate that BMP-7 added to a structural bone allograft inducing early remodeling of the graft through stimulation of neo-angiogenesis and osteoclastic activity, without negative effects in mechanical strength and clinical outcome.

[Documents and figures about the vaccine in Bologna at the beginning of the nineteenth century]. / Documenti ed immagini sull' innesto del vaiuolo vaccino in Bologna al principio del XIX secolo.

An interesting documentation, related with the campaign for the diffusion of the vaccine in Italy at the beginning of the nineteenth century, is available at the Museum Luigi Cattaneo of Anatomical Waxes of the University of Bologna. In this collection there are two wax models reproducing a cow-udder with pocks and two girl arms with the pocks of a "true" and "false" vaccine rash. The waxes were moulded under the direction of the leading physician Pietro Moscati, and overlap with the engravings of the chief treatise about the cow-pox and vaccine published by Luigi Sacco in 1809. The presence of the same models also in the Museums of the University of Pavia, and the available documentation about these waxes, demonstrate the educational purpose of the preparations. According to Sacco, they would be an effective tool directed to physicians and midwiwes for the learning and the knowledge of the outcomes of vaccination.

In vivo study on critical defects using the sheep model.

Bone grafting procedures are widely used to repair large defects successfully in humans, but new surgical therapies can be designed to improve allograft integration. The objective of this study was to investigate the best surgical procedure to study bone graft integration in a large animal model. An osteoperiosteal defect of 3 cm in the tibia or in the metatarsal was made in 15 adult crossbreed sheep to investigate osteo-integration of a homologous bone graft in an intercalary critical defect. DCP plates, alone or in association with Scotchcast or external fixator were used as fixation devices. The Scotchcast as was applied after surgery and left for 2 months to avoid torsion stress of the limb during the stand up movement. Metatarsal defect fixed with 7-hole DCP plate and protected with Scotchcast was the best surgical approach to avoid early or late implant failures, and provided good radiographic results after 4 months.

Histomorphometric bone modifications induced by growth hormone treatment in a rabbit model of short bowel syndrome.

The effects of recombinant human growth hormone (rhGH) on cancellous and cortical bone were investigated in an experimental rabbit model of short bowel syndrome (SBS). Eighteen young male New Zealand rabbits, 2.0 +/- 0.2 kg b.w., were divided into three groups: an SBS Group submitted to a 70% midjejunoileal enterectomy and reanastomosis; an SBS-GH Group undergoing the same surgery and receiving 0.4 mg/kg/day rhGH for 28 days; a Control Group which was sham-operated. Thirty-five days after surgery, all the animals were pharmacologically euthanised and their femurs and L5 vertebrae were used for densitometric and histomorphometric studies. Vertebral and femoral densitometric results showed that the SBS Group presented significantly (P<0.01) lower values (10-25%) than the Control and SBS-GH Groups. Significant differences in the cancellous histomorphometric parameters, namely the trabecular bone area (-7% to 46%), trabecular thickness (-21% to 34%) and trabecular separation (17-32%), were observed between the SBS Group and the other groups. Both the SBS and SBS-GH Groups showed significantly (P<0.05) higher values than the Control Group in terms of cross-sectional area (approximately 24%), cortical area (approximately 20%), and periosteal perimeter (approximately 9%), while medullary area (41%) and endocortical perimeter (18%) were significantly higher (P<0.05) in SBS Group than those of Control Group. The current findings are encouraging and suggest that GH administration in SBS animal model used may improve skeletal tissue remodelling.

Osteointegration of bioactive glass-coated and uncoated zirconia in osteopenic bone: an in vivo experimental study.

In elderly and osteoporotic patients an age-related loss of osteoinductivity could be the biological cause of implant failure regardless of the high quality of the implanted device. yttria stabilized tetragonal zirconia (YSTZ), either coated with the bioactive glass named RKKP bioglaze (RKKP) or uncoated, was implanted in the distal femurs of sham-operated and ovariectomized female rats. Animals were sacrificed at 30 and 60 days. Histomorphometry and microhardness tests were performed to assess osteointegration rate as well as bone quality around the implants. Significant decreases (p < 0.0005) in trabecular bone volume, BV/TV (41%), trabecular bone surface BS/TV (33%), trabecular thickness Tb.Th (20%), and trabecular number Tb.N (32%), together with a significant increase in trabecular separation Tb.Sp (184%), were found for the osteopenic rats compared with the sham-operated rats. At both experimental times the RKKP coating ensured a better osteointegration rate with higher AI values than the uncoated YSTZ, even when osteopenic rats were used (48% at 30 days and 12% at 60 days). No differences were observed at the bone-biomaterial interfaces for either material when comparing sham-operated with osteopenic rats. The present results demonstrate that the RKKP bioactive glass used as a coating ensures a high osteointegration rate even in osteoporotic bone, which is already visible from postoperative day 30 and is still apparent on day 60.

Histomorphometric and microhardness assessments of sheep cortical bone surrounding titanium implants with different surface treatments.

Several factors influence the healing process and the long-term mechanical stability of cementless fixed implants, such as bone remodeling and mineralization processes. Histomorphometric and bone hardness measurements were taken in implants inserted in sheep femoral cortical bone at different times to compare the in vivo osseointegration of titanium screws (diam.; 3.5 x 7 mm length) with the following surface treatments: machined (Ti-MA); acid-etched (Ti-HF); HA vacuum plasma spray (Ti-HA); and Ca-P anodization followed by a hydrothermal treatment (Ti-AM/HA). Ti-MA and Ti-AM/HA implants presented the lowest (Ra = 0.20 +/- 0.01 microm) and highest (Ra = 1.97 +/- 0.64 microm) significant (p < 0.0005) roughness value, respectively. Bone-to-implant contact of Ti-HF was lower than that of the other surface treatments at both experimental times (8 weeks: -20%, ns; 12 weeks: -30%, p < 0.01). Significant differences in MAR (mineral apposition rate) were also found between the different experimental times for Ti-MA (115%, p < 0.01) and Ti-HF (57%, p < 0.01), demonstrating that bone growth had slowed inside the screw threads of Ti-HA and Ti-AM/HA after 12 weeks. No bone microhardness changes in preexisting host bone were found, while Ti-MA showed the lowest value for the inner thread area at 8 weeks (HV(200 microm)= 49.8 +/- 3.8 HV). These findings confirm that osseointegration may be accelerated by adequate surface roughness and bioactive ceramic coating such as Ca-P anodization followed by a hydrothermal treatment, which enhance bone interlocking and mineralization.

Biological assessment of the bone-screw interface after insertion of uncoated and hydroxyapatite-coated pedicular screws in the osteopenic sheep.

The sheep seems to be a promising model of osteoporosis and biomaterial osteointegration in osteopenic bone. The long-term ovariectomized sheep model was used for the biological investigation of bone healing around uncoated and hydroxyapatite (HA)-coated pedicle screws in osteopenic bone. Four sheep were ovariectomized and four sheep were sham-operated. Twenty-four months after surgery, the animals were implanted with uncoated and HA-coated stainless steel screws in the lumbar vertebral pedicles. Four months later, bone-to-implant contact, bone ingrowth, and bone hardness were measured around screws. Uncoated stainless steel presented significantly (p < 0.0005) lower bone-to-implant contact in healthy and osteopenic bone compared with HA-coated stainless steel. HA significantly improved bone ingrowth in healthy bone (p < 0.05) compared with uncoated stainless steel. Osteopenia significantly (p < 0.05) reduced the area of bone ingrowth around the screw threads for both types of implants. In the inner thread area, bone microhardness significantly increased (p < 0.05) in HA-coated surface versus uncoated for healthy and osteopenic bone. HA coating significantly enhances bone-to-implant contact also in osteopenic bone in comparison with uncoated stainless steel surfaces. Bone ingrowth and mineralization are ameliorated by the osteoconductive HA coating. However, osteopenia seems to greatly influence bone ingrowth processes around the implanted screws regardless of the characteristics of the material surface.

Pedicular fixation in the osteoporotic spine: a pilot in vivo study on long-term ovariectomized sheep.

Spinal instrumentation success is greatly affected by the presence of osteoporosis. To date, however, no data exist on in vivo investigations on biomaterial and surgical techniques in the osteoporotic spine. In the present study 24 uncoated and 24 HA-coated screws were implanted in the L3, L4 and L5 pedicles of eight sheep (four ovariectomized, OVX Group; four sham-operated, Control Group). At four months, uncoated screws showed a significant decrease of about -22% in the extraction torque of the OVX Group as compared to the Control Group (p < 0.005). The extraction torque of HA-coated screws significantly (p < 0.0005) improved in both groups when compared to that of uncoated screws and showed increases ranging from 133% to 157%. Pedicle trabecular bone of OVX sheep showed a significant decrease in BV/TV (-30%; p < 0.05) and Tb.Th (-33%; p < 0.01). The affinity index (AI) results revealed significant (p < 0.0005) differences between uncoated and HA-coated screws for both groups: values were lower for uncoated than HA-coated screws by about -35%. A significant difference was also found for the AI data of uncoated screws between the OVX and Control Groups (-13%, p < 0.005). The current findings have demonstrated that long-term ovariectomized sheep can be used to study in vivo osteointegration in the osteoporotic spine. The HA coating has proven to improve bone purchase and bone-screw interface strength in healthy and osteopenic animals.

Osteointegration of bioactive glass-coated zirconia in healthy bone: an in vivo evaluation.

Osteointegration of yttria stabilised tetragonal zirconia (YSTZ), either coated with bioactive glass named RKKP bioglaze (RKKP) or uncoated, was evaluated in an animal model. RKKP-coated and uncoated (controls) YSTZ cylinders were implanted in the distal femoral epiphyses of 14 Sprague Dawley rats under general anaesthesia. At the experimental times of 30 and 60 days after sacrifice, histomorphometry and SEM microanalysis were performed on methylmethacrylate-embedded undecalcified sections to determine the osteointegration rate. At 30 days, a significantly higher affinity index was demonstrated in vivo by histomorphometric evaluation in RKKP-coated versus uncoated YSTZ implants p < 0.05); at 60 days, the coated implants behaved better than controls (affinity index of + 32%), but the difference observed lay within the statistical uncertainty. SEM analysis demonstrated better bone adhesion to the material in RKKP-coated YSTZ at both 30 and 60 days. These findings suggest that YSTZ coated with the bioactive glass named RKKP enhances osteointegration of ceramics.

Improvement in zirconia osseointegration by means of a biological glass coating: An in vitro and in vivo investigation.

The biocompatibility and osseointegration of zirconia (ZrO(2)), either coated with RKKP bioglazeor uncoated, were evaluated in vitro and in vivo. The in vitro test was performed in human osteoblasts, whereas maximal sensitization was performed in 23 Dunkin Hurtley guinea pigs. RKKP bioglaze-coated and uncoated (controls) ZrO(2) cylinders were implanted in the distal femoral epiphyses of 14 Sprague-Dawley rats under general anesthesia, and animals were sacrificed at 30 and 60 days. Lactate dehydrogenase, alkaline phosphatase, and Thiazolyl Blue (MTT) were tested in vitro. A graded score was used for evaluating the results of the sensitization test. Histomorphometry and microhardness testing were performed to quantify the osseointegration rate, as well as bone quality around the implants. Neither in vitro cytotoxicity nor sensitization were observed. Histomorphometry demonstrated that at 30 days, the affinity index was significantly higher in coated implants than in uncoated ones (p < 0.05); at 60 days, the behavior of coated implants was better than that of uncoated ones, but differences were not significant. Significant increases in bone microhardness were found at 1000 microm from the interface area for both uncoated (p < 0.0005) and RKKP bioglaze-coated (p < 0.0005) ZrO(2), and also within 200 microm from the interface (p = 0.014) but only for coated ZrO(2.) These results suggest that RKKP bioglaze-coated ZrO(2) permits biocompatible devices with improved osseointegration properties to be manufactured.

Glubran 2: a new acrylic glue for neuroradiological endovascular use. Experimental study on animals.

SUMMARY: A new acrylic glue, Glubran 2, is now available on the European market. It bears the CE mark with several surgical indications and the specific indication for neuroradiological endovascular use. Despite this approval, to our knowledge its use is still limited to surgery and no injections have been made in human patients. This study was designed to evaluate the behavior of Glubran 2 in endovascular injection in a simulation of brain AVM. Six sheep were operated on opening a fistula between the right common carotid artery and the jugular vein. This fistula modifies blood flow in the skull base rete mirabilis, which then functions as an AVM. In two sheep, the rete mirabilis was occluded by injection of 1.5 ml of Histoacryl diluted 1:1 and 1:3 with Lipiodol. In two sheep, the rete was embolized by injection of 1.5 ml of Glubran 2 diluted 1:1 with Lipiodol. The last two sheep were embolized by injection of Glubran 2 diluted 1:3 with Lipiodol. The procedures were documented by DSA angiographic acquisitions and by fluoroscopic VHS. The sheep were killed immediately after the procedures and the rete mirabilis isolated for histologic examination. Embolization was obtained with both kinds of glue. Glubran 2 diffuses in a very similar way to Histoacryl with an apparently more complete diffusion. Reflux in the ascending pharyngeal artery showed that Glubran 2 tended not to produce bubbles but diffused more homogeneously. The subjective conclusion of this work is that Glubran 2 can be used in endovascular embolizations. Before approaching brain AVMs, a further study will investigate embolization of the external carotid territory.