Gerhard Schmidmaier

Publications of Gerhard Schmidmaier

• Effect of local Zoledronate on implant osseointegration in a rat model.

  Authors: David A Back, Stephan Pauly, Lisa Rommel, Norbert P Haas, Gerhard Schmidmaier, Britt Wildemann, Stefan H Greiner

  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 toABSTRACT: 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.

• 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.

  Authors: Catrin Strobel, Nicole Bormann, Anke Kadow-Romacker, Gerhard Schmidmaier, Britt Wildemann

  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, inThe 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.

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

  Authors: Thomas Fuchs, Richard Stange, Gerhard Schmidmaier, Michael J Raschke

  Archives of orthopaedic and trauma surgery. 05/2011; 131(10):1419-25.

  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-loadedThe 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. 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. 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. 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 II.

• Changing the release kinetics of gentamicin from poly(D,L-lactide) implant coatings using only one polymer.

  Authors: Catrin Strobel, Gerhard Schmidmaier, Britt Wildemann

  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 withCreating 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.

• BMP-2 and BMP-7 affect human rotator cuff tendon cells in vitro.

  Authors: Stephan Pauly, Franka Klatte, Catrin Strobel, Gerhard Schmidmaier, Stefan Greiner, Markus Scheibel, Britt Wildemann

  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 growthBACKGROUND: 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.

• Local application of BMP-2 specific plasmids in fibrin glue does not promote implant fixation.

  Authors: Benjamin Faensen, Britt Wildemann, Christian Hain, Julius Höhne, Yvonne Funke, Christan Plank, Axel Stemberger, Gerhard Schmidmaier

  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 transferBMP-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.

• Gentamycin delivered from a PDLLA coating of metallic implants: In vivo and in vitro characterisation for local prophylaxis of implant-related osteomyelitis.

  Authors: Helen Vester, Britt Wildemann, Gerhard Schmidmaier, Ulrich Stöckle, Martin Lucke

  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 ofLocally 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.

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

  Authors: Christoph Heidenhain, Ariyakhagorn Veeravoorn, Blagovest Vachkov, Wilko Weichert, Gerhard Schmidmaier, Britt Wildemann, Peter Neuhaus, Michael Heise

  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 growthReplacing 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.

• Polymer coating of porcine decellularized and cross-linked aortic grafts.

  Authors: Christoph Heidenhain, Wilko Weichert, Gerhard Schmidmaier, Britt Wildemann, Moritz Hein, Peter Neuhaus, Michael Heise

  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, weThis 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.

• The early fracture hematoma and its potential role in fracture healing.

  Authors: Paula Kolar, Katharina Schmidt-Bleek, Hanna Schell, Timo Gaber, Daniel Toben, Gerhard Schmidmaier, Carsten Perka, Frank Buttgereit, Georg N Duda

  Tissue engineering. Part B, Reviews. 03/2010; 16(4):427-34.

  Research regarding the potency and potential of the fracture hematoma has begun to receive increasing attention. However, currently there is a paucity of relevant literature on the capability andResearch regarding the potency and potential of the fracture hematoma has begun to receive increasing attention. However, currently there is a paucity of relevant literature on the capability and composition of the fracture hematoma. This review briefly summarizes the regenerative fracture healing process and the close interplay between the skeletal and immune systems. The role of immune cells in wound healing is also discussed to clarify their involvement in immunological processes during regeneration. We attempt to describe the current state of knowledge regarding the fracture hematoma as the initial stage of the regenerative process of fracture healing. The review discusses how a better understanding of immune reactions in the hematoma may have implications for bone tissue engineering strategies. We conclude the review by emphasizing how additional investigations of the initial phase of healing will allow us to better differentiate between deleterious and beneficial aspects of inflammation, thereby facilitating improved fracture treatment strategies.

• Characterization of a rat osteotomy model with impaired healing.

  Authors: Christine Kratzel, Camilla Bergmann, Georg Duda, Stefan Greiner, Gerhard Schmidmaier, Britt Wildemann

  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 areABSTRACT: 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.

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

  Authors: Stefan H Greiner, Britt Wildemann, David A Back, Mahtala Alidoust, Philipp Schwabe, Norbert P Haas, Gerhard Schmidmaier

  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 theBACKGROUND 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.

• Carrier systems and application of growth factors in orthopaedics.

  Authors: Gerhard Schmidmaier, Philipp Schwabe, Catrin Strobel, Britt Wildemann

  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 mechanicalWith 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.

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

  Authors: Stefan Greiner, Anke Kadow-Romacker, Britt Wildemann, Philipp Schwabe, Gerhard Schmidmaier

  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 osteoclastNitrogen 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.

• Proliferating and differentiating effects of three different growth factors on pluripotent mesenchymal cells and osteoblast like cells.

  Authors: Britt Wildemann, Nicole Burkhardt, Marc Luebberstedt, Thomas Vordemvenne, Gerhard Schmidmaier

  Journal of orthopaedic surgery and research. 02/2007; 2:27.

  ABSTRACT: Growth factors are in clinical use to stimulate bone growth and regeneration. BMP-2 is used in long bone and spinal surgery, PDGFbb for the treatment of periodontal defects and childrenABSTRACT: Growth factors are in clinical use to stimulate bone growth and regeneration. BMP-2 is used in long bone and spinal surgery, PDGFbb for the treatment of periodontal defects and children with growth hormone receptor deficiency are treated with IGF-I.Aim of the present study was the comparative analysis of the effect of these growth factors released from a local drug delivery system on cells of the osteogenic lineage at differing differentiation stages.The experiments with the mesenchymal cell line C2C12 revealed a proliferating effect of all three growth factors and a differentiating effect of BMP-2 with a dramatic increase in alkaline phosphatase activity. None of the growth factors stimulated cell migration.Human osteoblast like cells showed similar results with an increase in proliferation after stimulation with IGF-I or PDGFbb. The enzymatic activity of alkaline phosphatase was enhanced only in the cells stimulated with BMP-2. This group showed also more mineralized matrix compared to the other groups.In conclusion, the growth factors IGF-I and PDGFbb delivered with a local drug delivery system stimulated cell proliferation, whereas BMP-2 showed a dramatic effect on differentiation on osteoblast precursor cells and osteoblast like cells.

• Biodegradable polylactide membranes for bone defect coverage: biocompatibility testing, radiological and histological evaluation in a sheep model.

  Authors: Gerhard Schmidmaier, Karen Baehr, Svenja Mohr, Martin Kretschmar, Stefan Beck, Britt Wildemann

  Clinical oral implants research. 09/2006; 17(4):439-44.

  Large bony defects often show a delayed healing and have an increasing risk of infection. Several materials are used for the coverage of large defects. These materials must be biocompatible, easy toLarge bony defects often show a delayed healing and have an increasing risk of infection. Several materials are used for the coverage of large defects. These materials must be biocompatible, easy to use, and must have an appropriate stability to present a mechanical hindrance. Aim of this study was to investigate two different biodegradable membranes for defect coverage in a sheep model. Round cranial defects (1.5 cm diameter) were created in sheep. Six different treatments were investigated: defects without membrane, defects covered with a poly(D,L-lactide) or with a 70/30 poly(L/D,L-lactide) membrane and all defects with or without spongiosa filling. The sheep were sacrificed 12 or 24 weeks postoperatively. Bone formation in the defects was quantified by computer-assisted measurements of the area of the residual defect on CT radiographs. Histomorphometry and host-tissue response were evaluated by light microscopy. The biocompatibility was investigated by analyzing the amount of osteoclasts and foreign body cells. Both membranes served as a mechanical hindrance to prevent the prolapse of soft tissue into the defect. The biocompatibility test revealed no differences in the amount and distribution of osteoclasts at the two investigated time points and between the investigated groups. No negative effect on the tissue regeneration was detectable between the investigated groups related to the type of membrane, but a foreign body reaction around the two membrane types was observed. In the membrane-covered defects, the spongiosa showed a progressing remodeling to the native bony structure of the cranium. The groups without spongiosa partly revealed new bone formation, without complete bridging in any group or at any time point. Comparing the 12 and 24 weeks groups, an increased bone formation was detectable at the later time point. In conclusion, the results of the present in vivo study reveal a good biocompatibility and prevention of soft tissue prolapse of the two used membranes without differences between the membranes. An enhanced remodeling of the spongiosa into native bony structures under the membranes was detectable, but no osteopromoting effect was observed due to the membranes.

• Prophylaxis and treatment of implant-related infections by antibiotic-coated implants: a review.

  Authors: Gerhard Schmidmaier, Martin Lucke, Britt Wildemann, Norbert P Haas, Michael Raschke

  Injury. 06/2006; 37 Suppl 2:S105-12.

  Implant-related infection is a feared complication in orthopedic and trauma surgery with tremendous consequences for the patient. To reduce this risk, administration of perioperative antibioticImplant-related infection is a feared complication in orthopedic and trauma surgery with tremendous consequences for the patient. To reduce this risk, administration of perioperative antibiotic prophylaxis is a routine procedure in orthopedic surgery. A local delivery system for antibiotics based on a polymer implant coating has been developed to optimize the prophylaxis. In an animal experiment, the efficacy of local prophylaxis of gentamicin was compared to a systemic single shot of gentamicin and to a combination of both administrations. The medullary cavities of rat tibiae were contaminated with Staphylococcus aureus and titanium K-wires were implanted into the medullary canals. For local antibiotic therapy, the implants were coated with poly(D,L-Lactide) (PDLLA) loaded with gentamicin. All the animals not treated with local and systemic application of the antibiotic developed osteomyelitis and all cultures of the implants tested positive for S. aureus. Onset of infection was prevented in 80-90% of animals treated with gentamicin-coated K-wires, with and without systemic prophylaxis. Gentamicin-coated intramedullary tibial nails are CE-certified for Europe and Canada and several patients have already been treated for implant-related infection. Up to now, eight patients with open tibia fractures have been treated with an unreamed tibial nail (UTN) coated with PDLLA and gentamicin. In the 1-year follow up, none of the patients developed an infection. A prospective randomized clinical documentation is currently in progress. So far, the results suggest that a local application of gentamicin from PDLLA-coated implants might support systemic antibiotic prophylaxis in preventing implant-associated osteomyelitis.

• 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.

  Authors: Gerhard Schmidmaier, Martin Lucke, Philipp Schwabe, Michael Raschke, Norbert P Haas, Britt Wildemann

  Journal of long-term effects of medical implants. 02/2006; 16(1):61-9.

  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 traumaDemographic 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.

  Authors: Britt Wildemann, Andre Sander, Philipp Schwabe, Martin Lucke, Ulrich Stöckle, Michael Raschke, Norbert P Haas, Gerhard Schmidmaier

  Biomaterials. 07/2005; 26(18):4035-40.

  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 beenFracture 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.

• The angiogenic peptide pleiotrophin (PTN/HB-GAM) is expressed in fracture healing: an immunohistochemical study in rats.

  Authors: Wolf Petersen, Britt Wildemann, Thomas Pufe, Michael Raschke, Gerhard Schmidmaier

  Archives of orthopaedic and trauma surgery. 12/2004; 124(9):603-7.

  INTRODUCTION: Formation of new blood vessels is essential for the process of fracture healing. MATERIALS AND METHODS: We investigated the expression of the angiogenic factor pleiotrophin/HB-GAM in aINTRODUCTION: Formation of new blood vessels is essential for the process of fracture healing. MATERIALS AND METHODS: We investigated the expression of the angiogenic factor pleiotrophin/HB-GAM in a closed fracture model in rats by immunohistochemical methods. RESULTS: Histologically, 5 days after fracture the callus was predominantly composed of fibrous tissue. On day 10 a prominent chondral callus connected both ends of the fractured tibia. There was a continuous transition from the chondral callus to the newly formed bone adjacent to the corticalis of the tibia. On day 15 the amount of woven bone had increased, and in 3 of 5 animals the proximal and distal tibiae were connected by a bridge of woven bone. Pleiotrophin could be immunostained in fibroblasts and endothelial cells of the fibrous tissue between the fractured tibia ends. The chondral callus remained largely pleiotrophin-negative. Only single chondrocytes adjacent to the newly formed bone were pleiotrophin-positive. On days 10 and 15 strong immunoreactivity for pleiotrophin in the well vascularized, newly formed, woven bone was detectable. Osteoblasts, endothelial cells and fibroblasts were strongly pleiotrophin-positive. CONCLUSIONS: These results show the presence of the angiogenic peptide pleiotrophin during fracture healing.