Evidence-based uncertainty: do implant-related properties of titanium reduce the susceptibility to perioperative infections in clinical fracture management? A systematic review.

BACKGROUND: Implant-associated infections (IAI) remain a challenging complication in osteosynthesis. There is no consensus or clear evidence whether titanium offers a relevant clinical benefit over stainless steel. PURPOSE: In this systematic review, we sought to determine whether the implant properties of titanium reduce the susceptibility to IAI compared to stainless steel in fracture management. METHODS: A systematic literature search in German and English was performed using specific search terms and limits. Studies published between 1995 and 1st June 2020 in the Cochrane library, MEDLINE and Web of Science databases were included. Only clinical studies comparing titanium and stainless steel implants regarding the susceptibility to infections were selected for detailed review. RESULTS: Five studies out of 384 papers were identified and reviewed. From the studies meeting inclusion criteria one study was a systematic review, two studies were randomized controlled studies (RCT) and two studies were of retrospective comparative nature of level IV evidence. CONCLUSION: Our results show that currently, no proven advantage for titanium implants in respect to IAI can be seen in contemporary literature. Implants preserving periosteal blood-flow and minimising soft-tissue trauma show statistically significant benefits in reducing the incidence of IAI. Clinical studies providing reliable evidence regarding the influence of titanium implants on IAI and investigating the susceptibility of titanium to infection are necessary.

Supplementation with 45S5 Bioactive Glass Reduces In Vivo Resorption of the ß-Tricalcium-Phosphate-Based Bone Substitute Material Vitoss.

Compared to other materials such as 45S5 bioactive glass (BG), ß-tricalcium phosphate (ß-TCP)-based bone substitutes such as Vitoss show limited material-driven stimulation of osteogenesis and/or angiogenesis. The unfavorable degradation kinetics of ß-TCP-based bone substitutes may result in an imbalance between resorption and osseous regeneration. Composite materials like Vitoss BA (Vitoss supplemented with 20 wt % 45S5-BG particles) might help to overcome these limitations. However, the influence of BG particles in Vitoss BA compared to unsupplemented Vitoss on osteogenesis, resorption behavior, and angiogenesis is not yet described. In this study, Vitoss and Vitoss BA scaffolds were seeded with human mesenchymal stromal cells before subcutaneous implantation in immunodeficient mice for 10 weeks. Scaffold resorption was monitored by micro-computed tomography, while osteoid formation and vascularization were assessed by histomorphometry and gene expression analysis. Whilst slightly more osteoid and improved angiogenesis were found in Vitoss BA, maturation of the osteoid was more advanced in Vitoss scaffolds. The volume of Vitoss implants decreased significantly, combined with a significantly increased presence of resorbing cells, whilst the volume remained stable in Vitoss BA scaffolds. Future studies should evaluate the interaction of 45S5-BG with resorbing cells and bone precursor cells in greater detail to improve the understanding and application of ß-TCP/45S5-BG composite bone substitute materials.

[Susceptibility to infections and behavior of stainless steel : Comparison with titanium implants in traumatology]. / Infektanfälligkeit und Verhalten von Stahl : Vergleich mit Titanimplantaten in der Traumatologie.

BACKGROUND: Despite modern treatment options, implant-associated infections (IAI) remain a severe and challenging complication in the treatment of trauma patients. Almost 30 years after the introduction of implants made of titanium alloy into the treatment of trauma patients, there is still no uniform consensus regarding the clinical benefit of titanium alloy in the context of patients with IAI. OBJECTIVE: We sought to determine if implants made of titanium alloy have been proven to be less susceptible regarding IAI in contrast to implants made of stainless steel. MATERIAL AND METHODS: A review of the current literature on IAI in association with the utilized implant material was conducted. Relevant articles from the years 1995 to 2016 were searched in the PubMed database. A total of 183 articles were identified and all abstracts were reviewed for relevance. A total of 14 articles met the inclusion criteria and were stratified according to the level of evidence and furthermore evaluated regarding the influence of the implant material on IAI. RESULTS AND DISCUSSION: Considerable debate remains concerning the influence of the implant material on the susceptibility to IAI; however, the available literature shows that despite slight tendencies, there is no proof of titanium alloy being favorable in the susceptibility to IAI. Furthermore, the literature shows that the design of plates for osteosynthesis might influence IAI. In particular, plates that cause less soft tissue damage and preserve perfusion of the periosteum proved to be beneficial regarding IAI.

Three-dimensional polymer coated 45S5-type bioactive glass scaffolds seeded with human mesenchymal stem cells show bone formation in vivo.

45S5-type bioactive glasses are a promising alternative to established substitutes for the treatment of bone defects. Because the three-dimensional (3D) structure of bone substitutes is crucial for bone ingrowth and formation, we evaluated the osteoinductive properties of different polymer coated 3D-45S5 bioactive glass (BG) scaffolds seeded with human mesenchymal stem cells (hMSC) in vivo. BG scaffolds coated with gelatin, cross-linked gelatin, and poly(3-hydroxybutyrate-co-3-hydroxyvalerate) were seeded with hMSC prior to implantation into severe combined immunodeficiency mice. Newly formed bone was evaluated with histomorphometry and micro-computed tomography. Bone formation was detectable in all groups, whereas the gelatin-coated BG scaffolds showed the best results and should be considered in further studies.

Establishment of a new methicillin resistant Staphylococcus aureus animal model of osteomyelitis.

PURPOSE: The increase in methicillin-resistant Staphylococcus aureus (MRSA) infections is currently a major health care problem. Vancomycin is still often the first-line anti-microbiological agent for treating such infections; however, a recent decline in efficacy of vancomycin in MRSA infections has raised concerns and accelerated the search for new antibiotics. The aim of this study was to establish a MRSA peri-implant osteomyelitis animal model for future testing of new anti-microbiological agents under typical MRSA infection conditions. METHODS: Eighteen randomised NZW-rabbits underwent a standardised surgical procedure with the insertion of a femoral bone implant. Animals were then divided into group 1 (MRSA inoculation, no antibiotics; M/N), group 2 (MRSA inoculation, Vancomyin; M/V), and group 3 (no MRSA inoculation, no antibiotics; N/N). The primary study outcome parameters were animal leucocyte count, animal weight, and animal body temperature at one, seven, and 42 days after surgery. Additionally, a histo-morphometrical score was established and adjusted to a modified histological Smeltzer score. RESULTS: Macroscopic and histo-morphometrical findings showed a peri-implant osteomyelitis in group 1 with both increased acute and chronic infection parameters in M/N, as compared to M/V and N/N, indicating that vancomycin treatment prevented typical morphological changes of MRSA peri-implant osteomyelitis. Similarly, there was a reduction in animal weight and increase in leucocyte count and body temperature in group 1 (each p < 0.005). Vancomycin treatment again resulted in significantly reduced leucocyte count and body temperature, and increased animal body weight. CONCLUSIONS: Here we have established a peri-implant MRSA osteomyelitis model that successfully combined clinical and laboratory outcome parameters of infection with histo-morphometrical results; this model appears to be valuable for future experimental use and therapeutic monitoring of new anti-microbiological MRSA drugs.

Stimulation of bone healing by sustained bone morphogenetic protein 2 (BMP-2) delivery.

The aim of the study was to investigate the effect of a sustained release of bone morphogenetic protein2 (BMP-2) incorporated in a polymeric implant coating on bone healing. In vitro analysis revealed a sustained, but incomplete BMP-2 release until Day 42. For the in vivo study, the rat tibia osteotomy was stabilized either with control or BMP-2 coated wires, and the healing progress was followed by micro computed tomography (µCT), biomechanical testing and histology at Days 10, 28, 42 and 84. MicroCT showed an accelerated formation of mineralized callus, as well as remodeling and an increase of mineralized/total callus volume (p=0.021) at Day 42 in the BMP-2 group compared to the control. Histology revealed an increased callus mineralization at Days 42 and 84 (p=0.006) with reduced cartilage at Day 84 (p=0.004) in the BMP-2 group. Biomechanical stiffness was significantly higher in the BMP-2 group (p=0.045) at Day 42. In summary, bone healing was enhanced after sustained BMP-2 application compared to the control. Using the same drug delivery system, but a burst release of BMP-2, a previous published study showed a similar positive effect on bone healing. Distinct differences in the healing outcome might be explained due to the different BMP release kinetics and dosages. However, further studies are necessary to adapt the optimal release profiles to physiological mechanisms.

Influence of statins locally applied from orthopedic implants on osseous integration.

BACKGROUND: Simvastatin increases the expression of bone morphogenetic protein 2 (BMP-2) in osteoblasts, therefore it is important to investigate the influence of statins on bone formation, fracture healing and implant integration. The aim of the present study was to investigate the effect of simvastatin, locally applied from intramedullary coated and bioactive implants, on bone integration using biomechanical and histomorphometrical analyses. METHODS: Eighty rats received retrograde nailing of the femur with titanium implants: uncoated vs. polymer-only (poly(D,L-lactide)) vs. polymer plus drug coated (either simvastatin low- or high dosed; "SIM low/ high"). Femurs were harvested after 56 days for radiographic and histomorphometric or biomechanical analysis (push-out). RESULTS: Radiographic analysis revealed no pathological findings for animals of the control and SIM low dose group. However, n=2/10 animals of the SIM high group showed osteolysis next to the implant without evidence of bacterial infection determined by microbiological analysis. Biomechanical results showed a significant decrease in fixation strength for SIM high coated implants vs. the control groups (uncoated and PDLLA). Histomorphometry revealed a significantly reduced total as well as direct bone/implant contact for SIM high- implants vs. controls (uncoated and PDLLA-groups). Total contact was reduced for SIM low vs. uncoated controls. Significantly reduced new bone formation was measured around SIM high coated implants vs. both control groups. CONCLUSIONS: This animal study suggests impaired implant integration with local application of simvastatin from intramedullary titanium implants after 8 weeks when compared to uncoated or carrier-only coated controls.

Effect of local zoledronate on implant osseointegration in a rat model.

BACKGROUND: An implant coating with poly(D, L-lactide) (PDLLA) releasing incorporated zoledronic acid (ZOL) has already proven to positively effect osteoblasts, to inhibit osteoclasts and to accelerate fracture healing. Aim of this study was to investigate the release kinetics of the chosen coating and the effect of different concentrations of ZOL locally released from this coating on the osseointegration of implants. METHODS: For release kinetics the release of C14-labled ZOL out of the coating was monitored over a period of six weeks in vitro. For testing the osseointegration, titanium Kirschner wires were implanted into the medullary canal of right femurs of 100 Sprague Dawley rats. The animals were divided into five groups receiving implants either uncoated or coated with PDLLA, PDLLA/ZOL low (1.2% w/w) or PDLLA/ZOL high (2% w/w). Additionally, a group with uncoated implants received ZOL intravenously (i.v.). After 56 days animals were sacrificed, femurs dissected and either strength of fixation or histological bone/implant contacts and newly formed bone around the implants were determined. RESULTS: Release kinetics revealed an initial peak in the release of C14-ZOL with a slight further progression over the following weeks. There was no significant enhancement of osseointegration for both groups who received ZOL-coated implants or ZOL i.v. compared to the controls in biomechanical or histological analyses, except for a significant raise in strength of fixation of ZOL i.v. versus PDLLA. CONCLUSIONS: Even though the investigated local ZOL application did not enhance the osseointegration of the implant, the findings might support its application in fracture treatment, since fracture stabilization devices are often explanted after consolidation.

Fibroblast and vascular endothelial growth factor coating of decellularized vascular grafts stimulates undesired giant cells and graft encapsulation in a rat model.

Replacing an infected prosthesis with a bioimplant provides a hopeful alternative in septic vascular surgery. The objective of this study was to determine the effect of fibroblast endothelial growth factors (FGF) and vascular endothelial growth factors (VEGF) coating on a decellularized vascular graft in a rat model and the possible impact on recellularization processes. Rat aortas were decellularized, crosslinked with genipin, and coated with poly-(D, L) lactide containing either FGF or VEGF. Observation periods were 6 and 12 weeks. Surprisingly, we found moderate accumulation of giant cells around the grafts that contained poly-(D, L) lactide acid. FGF and VEGF grafts showed massive stimulation of giant cells and eosinophils leading to complete graft encapsulation (P < 0.05). Pseudointmal hyperplasia was significantly increased in the FGF group (P < 0.05). Both results can only be interpreted as very negative. We achieved a situation in diametric opposition to that which we had hoped for. These data demonstrate that the use of growth factors may produce harmful side effects.

The use of gentamicin-coated nails in the tibia: preliminary results of a prospective study.

BACKGROUND: The use of antibiotic-coated implants may reduce the rate of infection and facilitate fracture healing after surgical treatment of tibial shaft fractures. A new biodegradable gentamicin-loaded coating of an implant (UTN PROtect) was CE-certified in August 2005. In this prospective, non-randomized case series, we investigated the clinical, laboratory and radiological outcomes of 21 patients who underwent surgical treatment in closed or open tibial fractures, as well as revisions with the UTN PROtect gentamicin-coated intramedullary nail. METHODS: Of 21 patients (13 men, 8 women), 19 completed the 6-month follow-up. The study population included patients with complex tibial fractures and late revision cases. Clinical outcomes comprised adverse events, including infections and the SF-36 physical score. Laboratory outcomes, including C-reactive protein and leukocyte count as inflammatory markers, haemoglobin and serum gentamicin, were measured at baseline and up to 6 months post operatively. Radiographic assessments of fracture healing and weight-bearing capacity were determined at 5 weeks, 3 and 6 months after surgery. RESULTS: No implant-related infections occurred; one patient had superficial wound healing problems. Mean C-reactive protein levels remained below 5 mg/L throughout the study, with a peak at 4-7 days after surgery (4.4 mg/L; range 0.5-16.1 mg/L). Leukocyte counts and haemoglobin levels did not vary over time during the study. The mean SF-36 physical score at 6 months was 42.6 (range 19.4-56.7). Radiographic union defined as three or four bridged cortices was achieved in 11 patients (58%) after 6 months. The remaining eight patients showed partial fracture healing with one or two bridged cortices. Additionally, 13 patients (68%) demonstrated full weight-bearing capacity after 6 months. CONCLUSIONS: The use of the UTN PROtect intramedullary nail was associated with good clinical, laboratory and radiological outcomes after 6 months. These preliminary results support the use of gentamicin-coated implants as a new potential treatment option for the prevention of infection in trauma patients and in revision cases. LEVEL OF EVIDENCE: Level II.

Systemic Administration of PTH Supports Vascularization in Segmental Bone Defects Filled with Ceramic-Based Bone Graft Substitute.

Non-unions continue to present a challenge to trauma surgeons, as current treatment options are limited, duration of treatment is long, and the outcome often unsatisfactory. Additionally, standard treatment with autologous bone grafts is associated with comorbidity at the donor site. Therefore, alternatives to autologous bone grafts and further therapeutic strategies to improve on the outcome and reduce cost for care providers are desirable. In this study in Sprague-Dawley rats we employed a recently established sequential defect model, which provides a platform to test new potential therapeutic strategies on non-unions while gaining mechanistic insight into their actions. The effects of a combinatorial treatment of a bone graft substitute (HACaS+G) implantation and systemic PTH administration was assessed by µ-CT, histological analysis, and bio-mechanical testing and compared to monotreatment and controls. Although neither PTH alone nor the combination of a bone graft substitute and PTH led to the formation of a stable union, our data demonstrate a clear osteoinductive and osteoconductive effect of the bone graft substitute. Additionally, PTH administration was shown to induce vascularization, both as a single adjuvant treatment and in combination with the bone graft substitute. Thus, systemic PTH administration is a potential synergistic co-treatment to bone graft substitutes.

Gelatin coating increases in vivo bone formation capacity of three-dimensional 45S5 bioactive glass-based crystalline scaffolds.

Recent studies have demonstrated that surface characteristics, porosity, and mechanical strength of three-dimensional 45S5-type bioactive glass (BG)-based scaffolds are directly correlated with osteogenic properties. Three-dimensional BG-based scaffolds obtained from maritime natural sponges (MNSs) as sacrificial templates exhibit the required morphological properties; however, no in vivo data about the osteogenic features are available. In this study, uncoated (Group A) and gelatin-coated (Group B) crystalline MNS-obtained BG-based scaffolds were evaluated mechanically and seeded with human mesenchymal stem cells prior to subcutaneous implantation in immunodeficient mice. Before implantation and after explantation, micro-computed tomography scans were conducted, and scaffolds were finally subjected to histomorphometry. Scaffolds of both groups showed bone formation. However, Group B scaffolds performed distinctly better as indicated by a significant increase in scaffold volume (8.95%, p = 0.039) over the implantation period compared with a nonsignificant increase of 5.26% in Group A scaffolds in micro-computed tomography analysis. Furthermore, percentage bone area was 10.33% (±1.18%) in the Group B scaffolds, which was significantly (p = 0.007) higher compared with the 8.53% (±0.77%) in the Group A scaffolds in histomorphometry. Compressive strength was enhanced significantly by gelatin coating (9 ± 2 vs. 4 ± 1 MPa; p = 0.029). The presence of gelatin on the remnant parts was verified by scanning electron microscopy and X-ray spectroscopy, demonstrating the coatings' resilience. MNS-obtained BG-based scaffolds were thus confirmed to exhibit osteogenic properties in vivo that can significantly be enhanced by gelatin coating.

Osteogenic differentiation of mesenchymal stem cells is enhanced in a 45S5-supplemented ß-TCP composite scaffold: an in-vitro comparison of Vitoss and Vitoss BA.

Since the amount of autologous bone for the treatment of bone defects is limited and harvesting might cause complications, synthetic bone substitutes such as the popular ß-tricalcium phosphate (ß-TCP) based Vitoss have been developed as an alternative grafting material. ß-TCPs exhibit osteoconductive properties, however material-initiated stimulation of osteogenic differentiation is limited. These limitations might be overcome by addition of 45S5 bioactive glass (BG) particles. This study aims to analyze the influence of BG particles in Vitoss BA (20 wt% BG particles with a size of 90-150 µm) on osteogenic properties, cell vitality and cell proliferation in direct comparison to Vitoss by evaluation of the underlying cellular mechanisms. For that purpose, Vitoss and Vitoss BA scaffolds were seeded with human mesenchymal stem cells (MSC) and underwent osteogenic differentiation in-vitro for up to 42 days. Cell vitality, proliferation, and osteogenic differentiation were monitored by quantitative gene expression analysis, determination of alkaline phosphatase activity, PrestoBlue cell viability assay, dsDNA quantification, and a fluorescence-microscopy-based live/dead-assay. It was demonstrated that BG particles decrease cell proliferation but do not have a negative impact on cell vitality. Especially the early stages of osteogenic differentiation were significantly improved in the presence of BG particles, resulting in earlier maturation of the MSC towards osteoblasts. Since most of the stimulatory effects induced by BG particles took place initially, particles exhibiting another surface-area-to-volume ratio should be considered in order to provide long-lasting stimulation.

Local application of zoledronic acid incorporated in a poly(D,L-lactide)-coated implant accelerates fracture healing in rats.

BACKGROUND AND PURPOSE: Zoledronic acid (ZOL) has been shown in vitro and in vivo to inhibit osteoclastic activity and to regulate osteoblasts. Its antiresorptive effect is used clinically in the treatment of bone-consuming pathologies to prevent skeletal complications. Because of its effect on bone cells, there might be a possible benefit in treatment of fractures by local application from a biodegradable poly(D,L-lactide) (PDLLA) coating of osteosynthetic implants. We analyzed the effect of locally applied ZOL from a PDLLA coating of intramedullary implants on fracture healing. MATERIAL AND METHODS: Standardized midshaft fractures of the right tibia of 5-month-old rats were stabilized either with uncoated, PDLLA-coated, or ZOL-coated implants. Animals were killed 42 or 84 days after fracture. Tibiae were dissected and mechanically tested. Results Radiographs taken 42 days after fracture showed at least unilateral bridging in all groups. Maximum load and torsional stiffness were highest in the group treated with ZOL. 84 days after fracture, the torsional stiffness of the ZOL-treated group remained higher than that of the uncoated group whereas the maximum load for the control groups reached the results for the ZOL-coated group. INTERPRETATION: Local application of ZOL from PDLLA coating appears to accelerate the achievement of mechanical stability in fractures.

Evaluation of the clinical effectiveness of bioactive glass (S53P4) in the treatment of non-unions of the tibia and femur: study protocol of a randomized controlled non-inferiority trial.

BACKGROUND: Treatment of non-union remains challenging and often necessitates augmentation of the resulting defect with an autologous bone graft (ABG). ABG is limited in quantity and its harvesting incurs an additional surgical intervention leaving the risk for associated complications and morbidities. Therefore, artificial bone graft substitutes that might replace autologous bone are needed. S53P4-type bioactive glass (BaG) is a promising material which might be used as bone graft substitute due to its osteostimulative, conductive and antimicrobial properties. In this study, we plan to examine the clinical effectiveness of BaG as a bone graft substitute in Masquelet therapy in comparison with present standard Masquelet therapy using an ABG with tricalciumphosphate to fill the bone defect. METHODS/DESIGN: This randomized controlled, clinical non-inferiority trial will be carried out at the Department of Orthopedics and Traumatology at Heidelberg University. Patients who suffer from tibial or femoral non-unions with a segmental bone defect of 2-5 cm and who are receiving Masquelet treatment will be included in the study. The resulting bone defect will either be filled with autologous bone and tricalciumphosphate (control group, N = 25) or BaG (S53P4) (study group, N = 25). Subsequent to operative therapy, all patients will receive the same standardized follow-up procedures. The primary endpoint of the study is union achieved 1year after surgery. DISCUSSION: The results from the current study will help evaluate the clinical effectiveness of this promising biomaterial in non-union therapy. In addition, this randomized trial will help to identify potential benefits and limitations regarding the use of BaG in Masquelet therapy. Data from the study will increase the knowledge about BaG as a bone graft substitute as well as identify patients possibly benefiting from Masquelet therapy using BaG and those who are more likely to fail, thereby improving the quality of non-union treatment. TRIAL REGISTRATION: German Clinical Trials Register (DRKS), ID: DRKS00013882 . Registered on 22 January 2018.

Bisphosphonates incorporated in a poly(D,L-lactide) implant coating inhibit osteoclast like cells in vitro.

Nitrogen containing bisphosphonates such as zoledronic acid (ZOL) are clinically used to prevent osteoclast induced bone loss. Previous studies indicated that bisphosphonates prevent osteoclast formation, decreases their resorption activity and lead to osteoclast apoptosis. Aim of the study was to investigate the effect of ZOL on fusion and resorption activity of osteoclast like cells (OLC) derived from human peripheral blood mononuclear cells (PBMNC) in vitro. For application of ZOL a local drug delivery system based on a coating for medical devices was used. ZOL was incorporated in the coating based on Poly(D,L-Lactide) (PDLLA) in different concentrations (10-50 microM). Control groups were treated without ZOL or ZOL pure substance in corresponding concentrations. Human PBMNCs were isolated and stimulated to form OLCs. After an experimental period of 144 h, TRAP staining of polynucleated cells was performed and TRAP positive cells were counted. A pit formation assay was performed and resorption lacunas on dentin chips were counted. Results showed a significant dose dependent decrease in the number of TRAP positive cells after exposure to ZOL incorporated in the drug delivery system or applied as pure substance. The amount of resorption lacunas was also dose dependent decreased using both application methods. In conclusion, exposure to specific concentrations of ZOL incorporated in a drug delivery system showed a significant decrease in OLC formation and activity comparable to the effect of pure substance. The effect on osteoclasts might be of clinical benefit to reduce orthopedic implant loosening and to support fracture healing.

Collective review: bioactive implants coated with poly(D,L-lactide) and growth factors IGF-I, TGF-beta1, or BMP-2 for stimulation of fracture healing.

Demographic data reveal that due to the increasing aging of the population, complications with the musculoskeletal system will increase in the next years. One major problem in orthopedic and trauma surgery are the delayed healing or non-unions of long bone fractures. The exogenous application of growth factors can stimulate the bone healing to reduce these complications. Beside the choice of the optimal growth factor the application system is important. Therefore, we developed a new bioactive coating method for implants, which is based on a biodegradable poly(D,L-lactide) (coating thickness: 10 mum). This coating allows the incorporation of growth factors and the controlled release of these factors during the healing process without the need for further devices. The effect of different growth factors (IGF-I, TGF-beta1, and BMP-2) locally released from coated intramedullary implants on fracture healing was investigated with biomechanical and histological analysis in rats. All investigated growth factors stimulated the fracture healing as assessed with biomechanical tests and histological analysis. The local application of combined IGF-I and TGF-beta1 had the most stimulating effect on fracture healing, followed by the effect of BMP-2, IGF-I, and TGF-beta1 alone. Bioactive coating of biomechanical well-established implants can on the one hand stabilize the fracture and on the other hand stimulate healing processes to increase healing and to reduce the rate of complications.

Short term in vivo biocompatibility testing of biodegradable poly(D,L-lactide)--growth factor coating for orthopaedic implants.

Fracture healing can be stimulated by exogenous application of growth factors. Using porcine and rat models the efficacy of locally delivered IGF-I and TGF-beta1 from an implant coating has been demonstrated. A thin and biomechanical stable biodegradable poly(D,L-lactide) was used to coat implants and serve as a drug carrier. Due to reports of possible foreign body reactions caused by polymer materials in orthopedic surgery, this study investigated the biocompatibility of the polylactide implant coating and the locally released growth factors during the time course of rat tibial fracture healing (days 5, 10, 15, and 28 after fracture). Monocytes/macrophages and osteoclast were detected using an monoclonal antibody against ED1 (comparable to CD68 in mice and human). The antibody ED1 stains monocytes, macrophages and osteoclast in the bone marrow and in the newly formed fracture callus. A moderate density of the monocytes/macrophages was seen in the proximal part of the medullary canal, but almost no cells were detectable in the region distal to the fracture. The amount of stained cells increased during the observation time with a maximum at days 10 and 15 followed by a decrease at day 28. No differences were detectable between the investigated groups from day 5 to 15 post fracture indicating, that the used poly(D,L-lactide) or the incorporated growth factors do not evoke an elevated immunological response compared to the uncoated titanium implant at the investigated time points. A significantly higher amount of ED1 positive cells was measured 28 days after fracture in the control group compared to the groups with the coated implants. In conclusion, no indication of a foreign body reaction due to the use of the polylactide or the growth factors was found indicating a good short-term biocompatibility of this bioactive coating.

Bone morphogenetic protein-2 application by a poly(D,L-lactide)-coated interbody cage: in vivo results of a new carrier for growth factors.

OBJECT: Growth factors such as bone morphogenetic protein-2 (BMP-2) have been proven to promote spine fusion and to overcome the disadvantages of an autologous bone graft. The optimum method to deliver such growth factors remains a matter of discussion. The purpose of this study was to determine the safety and efficacy of a new poly(D,L-lactide) (PDLLA) carrier system for BMP-2 and to compare this carrier system with a collagen sponge carrier in a sheep cervical spine interbody fusion model. METHODS: Thirty-two sheep underwent C3-4 discectomy and fusion: Group 1, titanium cage (eight animals); Group 2, titanium cage coated with a PDLLA carrier (eight animals); Group 3, titanium cage coated with a PDLLA carrier including BMP-2 (150 microg) (eight animals); and Group 4, titanium cage combined with a collagen sponge carrier including BMP-2 (150 microg) (eight animals). Blood samples, body weight, and temperature were assessed. Radiographs were obtained pre- and postoperatively and after 1, 2, 4, 8, and 12 weeks. At the same time points, disc space height, intervertebral angle, and lordosis angle were measured. After the sheep were killed 12 weeks postoperatively, flexion-extension radiography was performed to evaluate fusion sites. Quantitative computerized tomography scans were obtained to assess bone mineral density (BMD), bone mineral content (BMC), and bone callus volume (BCV). Biomechanical testing was performed in flexion, extension, axial rotation, and lateral bending. Stiffness, range of motion, neutral, and elastic zone were determined. Histomorphological and -morphometrical analyses were performed, and polychrome sequential labeling was used to determine the timeframe of new bone formation. There were no differences among the groups concerning blood counts, body weight, and temperature. Compared with the noncoated cages, all PDLLA-coated cages showed significantly higher values for BMD of the callus, as well as slightly higher values for BMC, BCV, and the bone volume/total volume ratio. In comparison with the cage-alone group, the BMP-2 groups showed significantly higher values for BMD and biomechanical stiffness. Histomorphological, -morphometrical, and polychrome sequential labeling analyses demonstrated greater progression of callus formation in the BMP-2 groups than in any other group. Compared with BMP-2 delivered using a collagen sponge carrier, BMP-2 application with a PDLLA carrier resulted in a higher BCV and a greater progression of interbody callus formation in the histomorphometrical analysis. CONCLUSIONS: The use of cervical spine interbody fusion cages coated with PDLLA as a delivery system for growth factors was effective. In this 12-week follow-up study, the PDLLA coating showed no adverse effects. The slight but not significant positive effect of the PDLLA carrier on interbody fusion might be a result of the degradation process of the biodegradable carrier. Compared with collagen sponge delivery of BMP-2, the PDLLA-coated interbody cages significantly increased the results of interbody bone matrix formation. In this new combination (implant + PDLLA + growth factor) the cage represents a "real fusion" cage, because it not only serves as a mechanical device for spinal fixation but also as a local drug delivery system.

What should be the characteristics of the ideal bone graft substitute? Combining scaffolds with growth factors and/or stem cells.

Reconstruction of large bone defects or non-unions resulting from biochemical disorders, tumour resections or complicated fractures is still a challenge for orthopaedic and trauma surgery. On the one hand, autografts harbour most features of ideal bone graft substitutes but on the other hand, they have a lot insurmountable disadvantages. An ideal bone graft substitute should be biomechanically stable, able to degrade within an appropriate time frame, exhibit osteoconductive, osteogenic and osteoinductive properties and provide a favourable environment for invading blood vessels and bone forming cells. Whilst osteoconductivity of biomaterials for bone tissue engineering strategies can be directed by their composition, surface character and internal structure, osteoinductive and osteogenic features can be provided by growth factors originally participating in fracture healing and/or multipotent mesenchymal stromal/stem cells (MSC) capable of rebuilding bone and marrow structures. In this review, aspects of the clinical application of the most commonly used growth factors for bone repair, the bone morphogenetic proteins (BMPs), and the potential use of human MSC for clinical application will be discussed.