Britt Wildemann
Research interests
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InterestsOrthopaedics, Orthopaedic Surgery
Publications
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1.88Impact points
Effect of local Zoledronate on implant osseointegration in a rat model.
BMC musculoskeletal disorders. 03/2012; 13(1):42.
ABSTRACT: 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... [more] ABSTRACT: 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.
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5.95Impact points
Sequential release kinetics of two (gentamicin and BMP-2) or three (gentamicin, IGF-I and BMP-2) substances from a one-component polymeric coating on implants.
Journal of controlled release : official journal of the Controlled Release Society. 07/2011; 156(1):37-45.
The local application of antibiotics in combination with timely controlled growth factor delivery might be beneficial for the prevention of infections and to stimulate bone healing. Therefore, in this study a variable sequential drug delivery system with three distinctly different release profiles w... [more] The local application of antibiotics in combination with timely controlled growth factor delivery might be beneficial for the prevention of infections and to stimulate bone healing. Therefore, in this study a variable sequential drug delivery system with three distinctly different release profiles was developed: i) a burst release of gentamicin, ii) a burst release of IGF-I followed by a sustained release, and iii) a slow sustained release of BMP-2 out of an implant coating. Only one polymer [poly(D,L-lactide)], incorporating gentamicin, IGF-I or BMP-2, was used for two- or three-layer coatings of K-wires. To control the release kinetics, the polymer concentrations in the solvent were varied. The activity of early released gentamicin from a two-layer coating was confirmed microbiologically and BMP-2 stimulated the metabolic activity and alkaline phosphatase activity of C2C12 cells after 2 weeks. From the three-layer coated wires, IGF-I continuously stimulated the cell proliferation, whereas BMP-2 enhanced ALP between 1 and 3 weeks. The sequential release of growth factors revealed an additive effect on the metabolic activity and ALP of primary osteoblast-like cells compared to the single coated controls. The controlled delivery of different factors from one implant might prevent infections and subsequently stimulate the different phases of bone healing.
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1.42Impact points
Changing the release kinetics of gentamicin from poly(D,L-lactide) implant coatings using only one polymer.
The International journal of artificial organs. 03/2011; 34(3):304-16.
Creating orthopedic implants that locally deliver drugs is an appealing approach to induce bone regeneration and prevent or treat infections. In this study, titanium K-wires were coated with poly(D,L-lactide) (PDLLA) solutions with different polymer/solvent/drug ratios to modify the release kinetics... [more] Creating orthopedic implants that locally deliver drugs is an appealing approach to induce bone regeneration and prevent or treat infections. In this study, titanium K-wires were coated with poly(D,L-lactide) (PDLLA) solutions with different polymer/solvent/drug ratios to modify the release kinetics of the antibiotic gentamicin. The concentrations of PDLLA ranged from one-fold (100 mg/1.5 mL solvent, 1X) to four-fold (400 mg/1.5 mL solvent, 4X), where the higher concentrations led to the thickening of the drug-loaded coatings and an increase of total coating mass. Coated wires were incubated in PBS buffer at 37 °C for up to 32 weeks, and the elution kinetics were analyzed at several time points. Different release profiles were observed: I) a burst release within the first hours for the coatings made out of lower concentrations of PDLLA with higher amounts of gentamicin and II) a sustained release of up to 14 weeks for the different coatings with higher polymer amounts with lower concentrations of gentamicin. Moreover, the amounts of remaining gentamicin on the wires after elution were dependent on the coating composition. Nearly complete gentamicin was released from the 1X PDLLA coatings and approximately one-third with respect to initial gentamicin remained in the 4X coatings. Based on these results, we garnered a better understanding of the parameters that influenced release kinetics in this simple system and described how to realize different release patterns by using only one polymer. Using this knowledge, tailored coated implants that can improve infection prophylaxis or stimulate bone healing may be designed.
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1.93Impact points
BMP-2 and BMP-7 affect human rotator cuff tendon cells in vitro.
Journal of shoulder and elbow surgery / American Shoulder and Elbow Surgeons ... [et al.]. 03/2011;
BACKGROUND: Rotator cuff repair is prone to incomplete regeneration. To explore biological improvements of tendon-bone healing, it was the aim of this study to investigate the influence of growth factors bone morphogenetic protein (BMP)-2 and BMP-7 on tenocyte cell activity and matrix gene expressio... [more] BACKGROUND: Rotator cuff repair is prone to incomplete regeneration. To explore biological improvements of tendon-bone healing, it was the aim of this study to investigate the influence of growth factors bone morphogenetic protein (BMP)-2 and BMP-7 on tenocyte cell activity and matrix gene expression and production. A beneficial effect of these factors would be promising to improve tendon-bone healing in vivo. METHODS: Tenocyte-like cells were isolated from human rotator cuff tissue samples (supraspinatus and long head of biceps tendon) and incubated with BMP-2 (100-1000 ng/mL) and BMP-7 (100-2000 ng/mL), both alone and in combination. At days 0, 3, and 6, cell activity was assessed. At day 6, collagen type I production and the expression of several tendon-, bone-, and cartilage-related markers (collagen types I-III, osteocalcin, scleraxis) were evaluated. RESULTS: Dose-dependent effects of both investigated growth factors on tenocyte-like cells were observed. Application of BMP-2 increased collagen type I production significantly but its expression only slightly. Cell activity was decreased in higher doses over time. For BMP-7, a significant increase in collagen type I production and expression, as well as increased cell activity, was observed. The addition of both factors resulted in decreased parameters when compared with BMP-7 alone. The expression of collagen types II and III, osteocalcin, and scleraxis was not significantly affected by application of BMPs. CONCLUSION: Besides the well-known effects of BMP-2 and BMP-7 on osteoblasts, this study describes further effects on rotator cuff tendon cell biology. Both tissue types potentially need to be addressed to improve tendon-bone healing of the rotator cuff.
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1.88Impact points
Local application of BMP-2 specific plasmids in fibrin glue does not promote implant fixation.
BMC musculoskeletal disorders. 01/2011; 12:163.
BMP-2 is known to accelerate fracture healing and might also enhance osseointegration and implant fixation. Application of recombinant BMP-2 has a time-limited effect. Therefore, a gene transfer approach with a steady production of BMP-2 appears to be attractive. The aim of this study was to examine... [more] BMP-2 is known to accelerate fracture healing and might also enhance osseointegration and implant fixation. Application of recombinant BMP-2 has a time-limited effect. Therefore, a gene transfer approach with a steady production of BMP-2 appears to be attractive. The aim of this study was to examine the effect of locally applied BMP-2 plasmids on the bone-implant integration in a non-weight bearing rabbit tibia model using a comparatively new non-viral copolymer-protected gene vector (COPROG). Sixty rabbits were divided into 4 groups. All of them received nailing of both tibiae. The verum group had the nails inserted with the COPROG vector and BMP-2 plasmids using fibrin glue as a carrier. Controls were a group with fibrin glue only and a blank group. After 28 and 56 days, these three groups were sacrificed and one tibia was randomly chosen for biomechanical testing, while the other tibia underwent histomorphometrical examination. In a fourth group, a reporter-gene was incorporated in the fibrin glue instead of the BMP-2 formula to prove that transfection was successful. Implant fixation strength was significantly lower after 28 and 56 days in the verum group. Histomorphometry supported the findings after 28 days, showing less bone-implant contact.In the fourth group, successful transfection could be confirmed by detection of the reporter-gene in 20 of 22 tibiae. But, also systemic reporter-gene expression was found in heterotopic locations, showing an undesired spreading of the locally applied gene formula. Our results underline the transfecting capability of this vector and support the idea that BMP-2 might diminish osseointegration. Further studies are necessary to specify the exact mechanisms and the systemic effects.
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2.38Impact points
Gentamycin delivered from a PDLLA coating of metallic implants: In vivo and in vitro characterisation for local prophylaxis of implant-related osteomyelitis.
Injury. 10/2010; 41(10):1053-9.
Locally applied antibiotics support prophylaxis of highly feared implant associated infections. Implant coatings with poly(D,L-lactide) (PDLLA)/gentamicin seem to be a promising approach. Aims of this study were to analyse the release kinetics of gentamicin in vivo, in vitro, to analyse the antibact... [more] Locally applied antibiotics support prophylaxis of highly feared implant associated infections. Implant coatings with poly(D,L-lactide) (PDLLA)/gentamicin seem to be a promising approach. Aims of this study were to analyse the release kinetics of gentamicin in vivo, in vitro, to analyse the antibacterial efficacy,the resistance development and its impact on osteoblasts. For the in vitro release experiments titanium implants were coated with PDLLA/gentamicin and the antibiotic release in aqueous solution was analysed at 20 time points (from 10 s to 110 days). For the in vivo experiments PDLLA/gentamicin-coated kirschner wires were implanted in the tibiae of 18 rats. Gentamicin concentration in the bone was analysed at several time points (n = 3 each, 1 h to 7 days). Bactericidal efficacy, bacterial adhesion on the implants and resistance development were tested. AP activity, cell count and CICP expression of osteoblasts were analysed. Gentamicin was released rapidly with an initial burst in aqueous solution and followed by a slow release. Similarly, in vivo gentamicin concentration reached a high peak initially followed by a decrease to a low level. No development of resistance was observed in the investigated setting, the antibacterial efficacy was not affected by the coating process and significantly fewer bacteria were attached to the implant. Osteoblasts were not negatively affected by the gentamicin released from the coating. PDLLA/gentamicin coating resulted in a desired antibiotic peak concentration within the bone. Bacterial adhesion was successfully prevented. No bacterial resistances were developed. This coating seems to be a suitable supplement for prophylaxis of implant-associated infections.
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1.83Impact points
Fibroblast and vascular endothelial growth factor coating of decellularized vascular grafts stimulates undesired giant cells and graft encapsulation in a rat model.
Artificial organs. 09/2010; 35(1):E1-10.
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 gra... [more] 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.
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2.19Impact points
Polymer coating of porcine decellularized and cross-linked aortic grafts.
Journal of biomedical materials research. Part B, Applied biomaterials. 07/2010; 94(1):256-63.
This article investigates a method of modifying and optimizing the biocompatibility of decellularized vascular bioimplants when treated with a specialized, drug eluting coating. For this purpose, we carried out aortic transplantations using a porcine model. Decellularized, cross-linked aortic grafts... [more] This article investigates a method of modifying and optimizing the biocompatibility of decellularized vascular bioimplants when treated with a specialized, drug eluting coating. For this purpose, we carried out aortic transplantations using a porcine model. Decellularized, cross-linked aortic grafts were coated with poly(D,L-lactide) (PDLLA). To this coating, we added the anticoagulant drug lepirudin which, following transplantation, would be linearly eluted. These aortic grafts are easily manipulated in surgery. It was shown that, as a result of the lepirudin-eluting coating, the rate of thrombogenesis was reduced and the patency rate was significantly improved. However, lumen-stenosing pseudointima developed in all of the transplants and was not effected by PDLLA coating. Furthermore, no evidence of recellularisation was documented. This trial demonstrates that polymer coating of decellularized tissue is possible. Neointimal hyperplasia and the absence of cellular repopulation mark the negative consequences of this concept.
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4.41Impact points
TGF-β1 as possible link between loss of bone mineral density and chronic inflammation.
PloS one. 01/2010; 5(11):e14073.
The TGF family plays a key role in bone homeostasis. Systemic or topic application of proteins of this family apparently positively affects bone healing in vivo. However, patients with chronic inflammation, having increased TGF-β(1) serum-levels, often show reduced bone mineral content and disturbed... [more] The TGF family plays a key role in bone homeostasis. Systemic or topic application of proteins of this family apparently positively affects bone healing in vivo. However, patients with chronic inflammation, having increased TGF-β(1) serum-levels, often show reduced bone mineral content and disturbed bone healing. Therefore, we wanted to identify intracellular mechanisms induced by chronic presence of TGF-β(1) and their possible role in bone homeostasis in primary human osteoblasts. Osteoblasts were isolated from femur heads of patients undergoing total hip replacement. Adenoviral reporter assays showed that in primary human osteoblasts TGF-β(1) mediates its signal via Smad2/3 and not Smad1/5/8. It induces proliferation as an intermediate response but decreases AP-activity and inorganic matrix production as a late response. In addition, expression levels of osteoblastic markers were strongly regulated (AP↓; Osteocalcin↓; Osteopontin↑; MGP↓; BMP 2↓; BSP2↓; OSF2↓; Osteoprotegerin↓; RANKL↑) towards an osteoclast recruiting phenotype. All effects were blocked by inhibition of Smad2/3 signaling with the Alk5-Inhibitor (SB431542). Interestingly, a rescue experiment showed that reduced AP-activities did not recover to base line levels, even 8 days after stopping the TGF-β(1) application. In spite of the initial positive effects on cell proliferation, it is questionable if continuous Smad2/3 phosphorylation is beneficial for bone healing, because decreased AP-activity and BMP2 levels indicate a loss of function of the osteoblasts. Thus, inhibition of Smad2/3 phosphorylation might positively influence functional activity of osteoblasts in patients with chronically elevated TGF-β(1) levels and thus, could lead to an improved bone healing in vivo.
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2.38Impact points
Bone morphogenetic proteins in critical-size bone defects: what are the options?
Injury. 12/2009; 40 Suppl 3:S39-43.
The recent development of new orthopaedic devices and advanced techniques for soft-tissue reconstruction have clearly improved the outcome in trauma and orthopaedic surgery. Nevertheless, large bone defects are still difficult to treat and require a careful analysis of the situation. Individual plan... [more] The recent development of new orthopaedic devices and advanced techniques for soft-tissue reconstruction have clearly improved the outcome in trauma and orthopaedic surgery. Nevertheless, large bone defects are still difficult to treat and require a careful analysis of the situation. Individual planning of the reconstructive strategy is desirable. Bone morphogenetic proteins (BMPs) have successfully been applied in the clinical setting for the treatment of spinal fusion, fracture healing and delayed and non-unions. Following the 'diamond concept', surgeons have begun using BMPs for treatment of critical-size defects also--in most cases, 'off label'; different treatment strategies are currently being evaluated. BMPs are often used in combination with autogenic, allogenic, xenogenic or synthetic grafting materials and even with mesenchymal stem cells. In addition, gene therapy approaches present an attractive option. Experimental studies and first clinical results are promising in the use of BMPs for treatment of critical-size defects; however, there is obvious need for further controlled studies to define strategies.
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1.12Impact points
In vitro testing of the osteoinductive potential of different bony allograft preparations.
Archives of orthopaedic and trauma surgery. 07/2009;
INTRODUCTION: Bony allografts are used frequently in the clinic for bone defect filling, however, less comparative data concerning their osteoinductive potential are available. AIM: The purpose of the present study was the comparative analysis of different allograft preparations. From five donors, w... [more] INTRODUCTION: Bony allografts are used frequently in the clinic for bone defect filling, however, less comparative data concerning their osteoinductive potential are available. AIM: The purpose of the present study was the comparative analysis of different allograft preparations. From five donors, we investigated fresh-frozen cancellous bone (native), peracetic acid-ethanol sterilized (PES) cancellous bone, cortical bone and demineralised bone matrix (DBM). In addition, two commercially available DBM products from five different donors were analyzed: Allomatrix((R)) (Wright Medical Technology Inc.) and DBX putty((R)) (Synthes GmbH). For positive control and as a clinically used growth factor, BMP-2 was chosen. METHOD: To investigate the osteoinductivity C2C12 cells were cultured with the different materials and the effect on cell proliferation and alkaline phosphatase activity were measured. RESULT: Proliferation was significantly enhanced by the native cancellous bone, Allomatrix, and BMP-2 and decreased by the PES-processed cancellous bone. The osteogenic differentiation was significantly enhanced by BMP-2 and the two commercial DBM products and decreased by PES-sterilized cancellous bone. All tested materials revealed a high donor-dependent variability. This is the first comparative study on the osteoinductivity of bony allografts frequently used in clinic.
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6.04Impact points
Experimental Folate and Vitamin B12 Deficiency Does Not Alter Bone Quality in Rats.
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 01/2009;
Abstract Introduction: Hyperhomocysteinemia (HHCY) has been linked to fragility fractures and osteoporosis. Folate and vitamin B(12) deficiencies are among the main causes of HHCY. However, the impact of these vitamins on bone health is poorly investigated. This study analyzed the effect of folate a... [more] Abstract Introduction: Hyperhomocysteinemia (HHCY) has been linked to fragility fractures and osteoporosis. Folate and vitamin B(12) deficiencies are among the main causes of HHCY. However, the impact of these vitamins on bone health is poorly investigated. This study analyzed the effect of folate and vitamin B(12) deficiency on bone in rats. Methods: We used 2 groups of rats: a control group (Co, n=10) and a vitamin deficient group (VitDef, n=10). VitDef animals were fed for 12 weeks with a folate and vitamin B(12) free diet. Co animals received an equicaloric control diet. Tissue and plasma concentrations of HCY, S-adenosyl-homocysteine (SAH) and S-adenosyl-methionine (SAM) were measured. Bone quality was assessed by biomechanical testing [maximum force of an axial compression test (Fmax)], histomorphometry [bone area/total area (B.Ar./T.Ar.)] and the measurement of biochemical bone turnover markers [osteocalcin, collagen I C-terminal crosslaps (CTx)]. Results: VitDef animals developed a significant HHCY (Co vs. VitDef: 6.8+/-2.7 vs. 61.1+/-12.8 mumol/L, p<0.001) that was accompanied by a high plasma concentration of SAH (Co vs. VitDef: 24.1+/-5.9 vs. 86.4+/-44.3 nmol/L, p<0.001). However, bone tissue concentrations of HCY, SAH and SAM were similar in the two groups. Fmax, B.Ar./T.Ar., OC and CTx did not differ between VitDef and Co animals indicating that bone quality was not affected. Conclusions: Folate and vitamin B12 deficiency induces a distinct HHCY but has no effect on bone health in otherwise healthy adult rats. The unchanged HCY-metabolism in bone is the most probable explanation for the missing effect of the vitamin free diet on bone.
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4.09Impact points
Hyperhomocysteinemia induces a tissue specific accumulation of homocysteine in bone by collagen binding and adversely affects bone.
Bone. 12/2008;
BACKGROUND: Recently, hyperhomocysteinemia (HHCY) has been suggested to have adverse effects on bone. This study investigated if an experimental HHCY in rats induces an accumulation of homocysteine (HCY) in bone tissue that is accompanied by bone loss and reduced bone strength. MATERIAL AND METHODS:... [more] BACKGROUND: Recently, hyperhomocysteinemia (HHCY) has been suggested to have adverse effects on bone. This study investigated if an experimental HHCY in rats induces an accumulation of homocysteine (HCY) in bone tissue that is accompanied by bone loss and reduced bone strength. MATERIAL AND METHODS: HHCY was induced in healthy rats by either a methionine (Meth)- or a homocystine (Homo)-enriched diet and compared with controls. Homocystine is the product of two disulfide linked HCY molecules. Tissue and plasma concentrations of HCY, S-adenosylhomocysteine (SAH) and S-adenosylmethionine (SAM) were measured. Bones were assessed by biomechanical testing, histomorphometry, muCT and the measurement of biochemical bone turnover markers in plasma. RESULTS: Meth and Homo animals developed a significant HHCY that was accompanied by a tissue specific accumulation of HCY (1300 to 2000% vs. controls). 65% of HCY in bone was bound to collagen of the extracellular matrix. The SAH / SAM-ratio in bone and plasma of Meth and Homo animals exhibited a tissue specific increase indicating a reduced methylation capacity. Accumulation of HCY in bone was characterized by a distinct reduction of cancellous bone (proximal femur: -25 to -35%; distal femur -56 to -58%, proximal tibia: -28 to -43%). Accordingly, bone strength was significantly reduced (-9 to -12%). CONCLUSION: A tissue specific accumulation of HCY in bone may be a promising mechanism explaining adverse effects of HHCY on bone. A reduced methylation capacity of bone cells might be another relevant pathomechanism.
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1.88Impact points
Characterization of a rat osteotomy model with impaired healing.
BMC musculoskeletal disorders. 11/2008; 9(1):135.
ABSTRACT: BACKGROUND: Delayed union or nonunion are frequent and feared complications in fracture treatment. Animal models of impaired bone healing are rare. Moreover, specific descriptions are limited although understanding of the biological course of pathogenesis of fracture nonunion is essential ... [more] ABSTRACT: BACKGROUND: Delayed union or nonunion are frequent and feared complications in fracture treatment. Animal models of impaired bone healing are rare. Moreover, specific descriptions are limited although understanding of the biological course of pathogenesis of fracture nonunion is essential for therapeutic approaches. METHODS: A rat tibial osteotomy model with subsequent intramedullary stabilization was performed. The healing progress of the osteotomy model was compared to a previously described closed fracture model. Histological analyses, biomechanical testing and radiological screening were undertaken during the observation period of 84 days (d) to verify the status of the healing process. In this context, particular attention was paid to a comparison of bone slices by histological and immunohistological (IHC) methods at early points in time, i.e. at 5 and 10 d post bone defect. RESULTS: In contrast to the closed fracture technique osteotomy led to delayed union or nonunion until 84 d post intervention. The dimensions of whole reactive callus and the amounts of vessels in defined regions of the callus differed significantly between osteotomized and fractured animals at 10 d post surgery. A lower fraction of newly formed bone and cartilaginous tissue was obvious during this period in osteotomized animals and more inflammatory cells were observed in the callus. Newly formed bone tissue accumulated slowly on the anterior tibial side with both techniques. New formation of reparative cartilage was obviously inhibited on the anterior side, the surgical approach side, in osteotomized animals only. CONCLUSIONS: Tibial osteotomy with intramedullary stabilisation in rats leads to pronounced delayed union and nonunion until 84 d post intervention. The early onset of this delay can already be detected histologically within 10 d post surgery. Moreover, the osteotomy technique is associated with cellular and vascular signs of persistent inflammation within the first 10 d after bone defect and may be a contributory factor to impaired healing. The model would be excellent to test agents to promote fracture healing.
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1.91Impact points
Local application of zoledronic acid incorporated in a poly(D,L-lactide)-coated implant accelerates fracture healing in rats.
Acta orthopaedica. 11/2008; 79(5):717-25.
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... [more] 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.
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2.38Impact points
Carrier systems and application of growth factors in orthopaedics.
Injury. 10/2008; 39S2:S37-S43.
With optimal surgical treatment within an appropriate time frame, bony tissue has the potential to regenerate defects without the formation of scar tissue. However, even under optimal mechanical circumstances and appropriate operative treatment, healing can fail and delayed or non-union occur. In Eu... [more] With optimal surgical treatment within an appropriate time frame, bony tissue has the potential to regenerate defects without the formation of scar tissue. However, even under optimal mechanical circumstances and appropriate operative treatment, healing can fail and delayed or non-union occur. In Europe delayed bone healing leads to socio-economic costs of up to euro14.7 billion per year. In addition to the optimal clinical treatment, the success of bone regeneration depends on the following main aspects: (1) adequate mechanical stabilization and biological competence of the organism, (2) osteogenic cells, (3) osteoconductive structures or scaffolds, and (4) growth factors (Diamond Concept)(1). Further, (5) a sufficient vascularisation is essential for the nutritive supply. Within the last years two growth factors, BMP-2 and BMP-7, were approved for clinical use in orthopaedic and trauma surgery for different indications.(2,3) The establishment of carrier systems and application techniques for growths factors is the focus of current research. The combination of a well established stabilization system and local drug delivery system for bioactive factors could be a therapeutical strategy to optimize bone healing and reduce the complication rate, in the future.
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5.23Impact points
Stimulation of osteoblast activity by homocysteine.
Journal of cellular and molecular medicine. 08/2008; 12(4):1205-10.
Homocysteine (HCY) has recently been linked to fragility fractures. Moreover, HCY activates osteoclasts. Little is known about the effect of HCY on activity of human osteoblasts (OBs). We hypothesized that HCY decreases the activity of OBs. Osteoblasts obtained from tra-becular human bone specimens ... [more] Homocysteine (HCY) has recently been linked to fragility fractures. Moreover, HCY activates osteoclasts. Little is known about the effect of HCY on activity of human osteoblasts (OBs). We hypothesized that HCY decreases the activity of OBs. Osteoblasts obtained from tra-becular human bone specimens of eight donors were cultured with conditioned medium. Culture medium was adjusted to 0, 100, 500, 1000 and 2000 muM HCY. After 14 days alkaline phosphatase (AP) activity, pro-collagen type I N-terminal peptide (PINP) and osteocalcin (OC) secretion in the supernatant were measured. After 20 days the formation of mineralized matrix was analyzed. HCY-stimulated AP activity gradually (100 muM HCY: 118%, P= 0.006; 500 muM HCY: 125%, P < 0.001). At 1000 and 2000 muM HCY the increase of AP activity was reversible (1000 muM HCY: 106%, P= 0.317; 2000 muM HCY: 102%, P < 0.737). The PINP secretion was also stimulated by HCY reaching a maximum of 260 +/- 154 mug/l at 500 mumol/l versus 205 +/- 94 mu,g/l in controls. After 20 days of culture the formation of bone matrix was increased at 100 and 500 muM HCY. OC secretion was not significantly changed. The results of the present study consistently demonstrate a moderate stimulation of primary human OB activity by increasing concentrations of HCY. However, the magnitude of this effect seems to be less pronounced than recent observations on primary human osteoclasts, suggesting a dysbalance between OBs and osteoclasts in favour of osteoclasts.
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2.82Impact points
Bisphosphonates incorporated in a poly(D,L-lactide) implant coating inhibit osteoclast like cells in vitro.
Journal of biomedical materials research. Part A. 01/2008; 83(4):1184-91.
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 i... [more] 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.
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2.54Impact points
Accumulation of homocysteine by decreasing concentrations of folate, vitamin B12 and B6 does not influence the activity of human osteoblasts in vitro.
Clinica chimica acta; international journal of clinical chemistry. 10/2007; 384(1-2):129-34.
BACKGROUND: Homocysteine (HCY) has recently been linked to fragility fractures. Elevated circulating HCY is mainly caused by folate, vitamin B12 and B6 deficiencies. However, little is known about the effect of these vitamins on the activity of osteoblasts. We hypothesized that decreasing concentrat... [more] BACKGROUND: Homocysteine (HCY) has recently been linked to fragility fractures. Elevated circulating HCY is mainly caused by folate, vitamin B12 and B6 deficiencies. However, little is known about the effect of these vitamins on the activity of osteoblasts. We hypothesized that decreasing concentrations of folate, vitamin B12 and B6 decrease osteoblasts activity by accumulation of HCY. METHODS: Osteoblasts obtained from trabecular human bone specimens of 8 donors were cultured with decreasing concentrations of folate, vitamin B12 and B6. Vitamin concentrations were modified in combination or one vitamin only (8 repetitions x 8 donors, n=64). After 14 days alkaline phosphatase (AP) activity, pro-collagen type I N-terminal peptide (PINP) and osteocalcin secretion in the supernatant was measured. After 20 days, the formation of mineralized matrix was analyzed. RESULTS: Decreasing B-vitamin concentrations induced a significant accumulation of HCY in the supernatant reaching up to 160%. The increase in HCY was not accompanied by changes of AP, osteocalcin and PINP. Moreover, mineralized matrix formation was not affected. CONCLUSION: Accumulation of HCY by decreasing concentrations of folate, vitamin B12 and B6 does not affect the activity of human osteoblasts. Consequently, other mechanisms have to be responsible for the reduced bone quality in hyperhomocysteinemic subjects.
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4.09Impact points
Stimulation of osteoclast activity by low B-vitamin concentrations.
Bone. 10/2007; 41(4):584-91.
BACKGROUND: Homocysteine (HCY) has recently been linked to fragility fractures. Moreover, HCY activates osteoclasts (OC). Elevated HCY concentrations are mainly caused by folate, vitamin B12 (B12) and B6 (B6) deficiencies. We hypothesized that folate, B12 and B6 deficiencies stimulate OC activity. M... [more] BACKGROUND: Homocysteine (HCY) has recently been linked to fragility fractures. Moreover, HCY activates osteoclasts (OC). Elevated HCY concentrations are mainly caused by folate, vitamin B12 (B12) and B6 (B6) deficiencies. We hypothesized that folate, B12 and B6 deficiencies stimulate OC activity. MATERIALS AND METHODS: OC were cultured from peripheral blood mononuclear cells (10 healthy male donors, 34+/-5 years) for 20 days. Culture medium was conditioned with decreasing concentrations of folate, B12 and B6 (in combination or variation of only one vitamin) starting at physiologic concentrations. Moreover, we tested increasing concentrations of HCY. OC activity was measured by dentine resorption activity (DRA), tartrate-resistant acid phosphatase (TRAP) and cathepsin K (CK) activity. RESULTS: The combined reduction of folate, B12 and B6 stimulated DRA up to 211% (p<0.001). This observation was confirmed by TRAP (maximum increase 24%, p<0.001) and CK (maximum increase 24%, p<0.001). Reduction of only one vitamin stimulated DRA up to 250% (folate: maximum increase 248%, p<0.018; B12: maximum increase 252%, p<0.001, B6: maximum increase 247%, p<0.001). However, only for folate this effect could be confirmed by TRAP (maximum increase 33%, p<0.001). HCY stimulated DRA up to 395% (p<0.001). TRAP (maximum increase 49%, p<0.001) and CK analyses confirmed this observation (maximum increase 50%, p<0.001). CONCLUSION: Our results demonstrate a strong stimulatory effect of low concentrations of folate, B12 and B6 on OC activity, suggesting a mechanistic role of low B-vitamin concentrations for bone degradation. Consequently, OC stimulation by low folate, B12 and B6 concentrations could be an important adverse factor for bone health.
Following (4)
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Catrin Strobel
Charité Universitätsmedizin Berlin -
Christoph Heidenhain
Universitätsklinikum Aachen -
Andreas K Nussler
Eberhard-Karls-Universität Tübingen -
Markus Neumaier
Technische Universität München
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