Biomedical subjects

Gerhard Schmidmaier

Publications and source records attributed to Gerhard Schmidmaier.

14 recordsLinked to original sources

PubMed2006

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

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 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.

Animals↗

PubMed2006

Locally delivered TGF-beta1 and IGF-1 enhance the fixation of titanium implants: a study in dogs.

BACKGROUND: Osteogenic growth factors have been suggested to enhance the fixation of implants used in joint replacement. We examined the effect of locally delivered transforming growth factor-beta1 and insulin-like growth factor-1 in a biodegradable poly (D, L-lactide) coating. MATERIAL AND METHODS: In a paired study using 9 dogs, unloaded titanium implants surrounded by a 1-mm gap were inserted into the proximal humerus. The growth factors were incorporated in a poly (D, L-lactide) coating at a 1% (w/w) ratio of TGF-beta1 and a 5% (w/w) ratio of IGF-1. Control implants were uncoated. After 4 weeks, the implants were evaluated by mechanical push-out test and by histomorphometry. RESULTS: A twofold increase was seen in mechanical fixation (strength, stiffness, energy absorption) for the growth factor-treated implants (p = 0.04). Similar results were seen in histomorphometry, as bone ongrowth was 2.5 times higher (p = 0.02), and gap healing was 30-110% higher (p = 0.04) for the growth factor-treated implants than for the control implants. Ongrowth of fibrous tissue was eliminated by the treatment. INTERPRETATION: TGF-beta-1 and IGF-1, locally delivered in a biodegradable poly(D,L-lactide) coating, enhance the mechanical fixation and osseointegration of titanium implants in cancellous bone, and no fibrous tissue is produced in the growth factor treated implants.

Animals↗

PubMed2006

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

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 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.

Absorbable Implants↗

PubMed2006

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.

Absorbable Implants↗

PubMed2005

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.

Absorbable Implants↗

PubMed2004

Long-term effects of local growth factor (IGF-I and TGF-beta 1) treatment on fracture healing. A safety study for using growth factors.

Previous studies showed that growth factors dramatically stimulate healing processes in bone. However, the long-term effect of locally applied growth factors on fracture healing remains unclear. In considering the safety of using growth factors, it is necessary to elucidate that after initial stimulation, the effect stops and the result is a normally healed tissue. Therefore, the purpose of the present study was to investigate the long-term time course of healing processes during growth factor (GF) stimulated and unstimulated fracture healing in a closed tibial fracture model in rats. A well established local drug delivery system was used. IGF-I (50 microg) and TGF-beta 1 (10 microg) were locally applied using a 10 microm thin polylactide (PDLLA) coating on intramedullary implants. The biomechanical and histomorphometrical results demonstrated a significant stimulation of the fracture healing due to the locally applied growth factors compared to control at days 28 and 42 in agreement with the literature. At the last time point, 84 days after fracture, no differences were measurable in the biomechanical testing and the callus composition between the groups. The callus was consistently in the late phase of remodeling with no remaining cartilage. In conclusion, local growth factor application enhances the healing in the early phase without alteration of the normal healing process.

Animals↗

PubMed2004

The influence of locally applied platelet-derived growth factor-BB on free tendon graft remodeling after anterior cruciate ligament reconstruction.

BACKGROUND: Ligaments and tendons do not gain mechanical properties of the native tissue after injury or grafting. PURPOSE: To determine the influence of platelet-derived growth factor on tendon graft remodeling. STUDY DESIGN: Laboratory animal study. METHODS: Forty-eight sheep underwent anterior cruciate ligament reconstruction and were sacrificed after 3, 6, 12, and 24 weeks. In 6 animals at each time point, platelet-derived growth factor was locally delivered via coated sutures. After mechanical testing, tissue samples were taken for histologic, immunohistochemical, and electron microscopy evaluations. RESULTS: With platelet-derived growth factor treatment, cross-sectional area was significantly lower at 3 and 12 weeks. Load to failure was significantly higher at 6 weeks. Tensile stress was significantly higher at 3 and 12 weeks. Crimp length was significantly higher at 3 and 6 weeks. Vascular density was significantly higher at 6 weeks. Electron microscopy showed a significantly higher collagen fibril amount at 12 weeks. Differences in these parameters at other time points were not significant. CONCLUSIONS: There were alterations in several but not all time points. The local application of platelet-derived growth factor alters the tissue's mechanical properties during free tendon graft remodeling after anterior cruciate ligament reconstruction. Growth factors present a promising tool toward the complete mechanical restitution of a healing ligament substitute.

Animals↗

PubMed2003

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

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 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.

Angiogenesis Inducing Agents↗

PubMed2003

Synergistic effect of IGF-I and TGF-beta1 on fracture healing in rats: single versus combined application of IGF-I and TGF-beta1.

During the last few decades, knowledge about growth factors and their function has increased. However, little is known about the interaction of these factors during bone growth and fracture healing. In vitro studies have shown a higher rate of cell proliferation and cell metabolism after the use of IGF-I and TGF-beta1 in combination, as compared to the single use of these factors. The purpose of this study was to investigate a possible synergistic effect of these growth factors in vivo, using a fracture model. A midshaft fracture of rat tibia (n = 84) was intramedullary stabilized with poly(D,L-lactide)-coated or uncoated titanium K-wires. The growth factors IGF-I and TGF-beta1, singly or in combination, were incorporated in the coating and continuously released during fracture healing. 28 days after fracture, we performed mechanical tests and histomorphological analyses. We found a greater stimulating effect of IGF-I on fracture healing than of TGF-beta1. The combined application of both growth factors resulted in a significantly higher maximum load and torsional stiffness than the use of only one of them. The histomorphometric analyses showed an increase in remodeling of the fracture callus in this group with less cartilaginous and more mineralized tissue than in the other groups. Both growth factors seem to have a synergistic effect on fracture healing in this model.

Animals↗

PubMed2002

IGF-I and TGF-beta1 application by a poly-(D,L-lactide)-coated cage promotes intervertebral bone matrix formation in the sheep cervical spine.

STUDY DESIGN: A sheep cervical spine interbody fusion model was used to determine the effect of combined insulin-like growth factor-I (IGF-I) and transforming growth factor-beta-1 (TGF-beta1) applied by a poly-(D,L-lactide) (PDLLA)-coated cage. OBJECTIVES: The purpose of this study was to determine the effect of a new PDLLA carrier system, and to evaluate the effect of combined IGF-I and TGF-beta1 application in a sheep cervical spine model. SUMMARY AND BACKGROUND DATA: Growth factors such as bone morphogenic protein-2 have been shown to promote spine fusion and to overcome the disadvantages of an autologous bone graft. The optimum growth factor for promoting spinal fusion and the optimum method for delivering such growth factors are still a matter of discussion. METHOD: In this study, 32 sheep underwent C3-C4 discectomy and fusion: Group 1 (autologous tricortical iliac crest bone graft; n = 8), Group 2 (titanium cage; n = 8), Group 3 (titanium cage coated with a PDLLA carrier; n = 8), and Group 4 (titanium cage coated with a PDLLA carrier including IGF-I [5% w/w] and TGF-beta1 [1% w/w; n = 8). Blood samples, body weight, and body temperature were analyzed. Radiographic scans were performed before and after surgery, then at 1, 2, 4, 8, and 12 weeks, respectively. At the same time points, the disc space height, intervertebral angle, and lordosis angle were measured. After 12 weeks, the animals were killed, and fusion sites were evaluated using functional radiographic views of the animals in flexion and extension. Quantitative computed tomographic scans were performed to assess bone mineral density, bone mineral content, and bony callus volume. Biomechanical testing of the motion segment C3-C4 was performed in flexion, extension, axial rotation, and lateral bending. The stiffness, range of motion, neutral zone, and elastic zone were determined. Histomorphologic and histomorphometric analysis was performed, and polychrome sequential labeling was used to determine the time frame of new bone formation. RESULTS: There were no differences between the groups in terms of blood counts, body weight, and temperature. Over a 12-week period, cage Groups 2 to 4 showed significantly higher values for the intervertebral angle than for the bone graft. Functional radiographic assessment showed significantly lower residual flexion-extension movement in Group 4 than in any other group. The PDLLA-coated cages with IGF-I and TGF-beta1 showed significantly higher values for bone mineral density, bone mineral content, and bony callus volume. The average stiffness in rotation and bending was significantly higher, and the range of motion, neutral zone, and elastic zone in rotation were significantly lower in Group 4 than in any other group. Although only one animal in Group 4 demonstrated solid bony fusion after 12 weeks, histomorphometric evaluation showed a more progressed bone matrix formation in the group that had PDLLA-coated cages with IGF-I and TGF-beta1 than in any other group. Polychrome sequential labeling showed accelerated intervertebral bone matrix formation in Group 4. CONCLUSIONS: The findings showed that PDLLA coating of cervical spine interbody fusion cages as a delivery system for growth factors was effective. Although IGF-I and TGF-beta1 application by a PDLLA-coated interbody cage was not able to achieve solid bony fusion during the 12-week follow-up period, these growth factors significantly increased the results of interbody bone matrix formation. Additional longer-term studies are required to determine whether combined IGF-I and TGF-beta1 application leads to a successful spinal fusion.

Absorbable Implants↗

PubMed2002

Quantitative measurement of the splice variants 120 and 164 of the angiogenic peptide vascular endothelial growth factor in the time flow of fracture healing: a study in the rat.

Formation of new blood vessels is essential for the process of wound and fracture healing. Little is known about the time-dependent expression and the involved splice variants of the vascular endothelial growth factor (VEGF). We therefore quantified and differentiated the angiogenic factor VEGF and its receptors (VEGFR) in a rat fracture model by immunohistochemical, biochemical and molecular biological methods. VEGF could be immunostained in chondrocytes and osteoblasts of the callus, but not in fibrous callus. In the capillaries, VEGFR-1 (flt-1) and VEGFR-2 (flk-1/KDR) were also visualized. Both receptors were also detectable in some chondrocytes and in osteoclasts. Enzyme-linked immunosorbent assay (ELISA) measurements showed high levels of VEGF in fractured tibiae and negligible ones in non-injured bone. Reverse transcriptase-polymerase chain reaction (RT-PCR) revealed expression of the rat splice variants VEGF(120) and VEGF(164) during the course of fracture healing, which corresponds to human VEGF121 and VEGF165 splice variants. VEGF plays the most important role during the early phase of fracture healing, but VEGF concentrations decrease further after day 5.

Alternative Splicing↗

PubMed2002

Systemic application of growth hormone for enhancement of secondary and intramembranous fracture healing.

Hormones are known to influence bone metabolism and cellular mechanisms of fracture healing. Recent technologies in molecular biology offer recombinant production of hormones, which makes them applicable for pharmacological use. To investigate the effect of systemic growth hormone (GH) application experiments were performed in micropig animal models. Systemic daily subcutaneous injection of species-specific recombinant GH was investigated in Yucatan micropigs to evaluate the effect on secondary fracture healing in a standardized gap model (1 cm) and on intramembranous bone formation in distraction osteogenesis (DO). Quantitative computed tomography (qCT), biomechanical testing, measurement of systemic insulin-like growth factor 1 (IGF-1) levels as well as histomorphometric analyses were performed to investigate differences in regenerate formation. Systemic GH administration significantly increased the torsional stability of the regenerate in comparison to the contralateral side in both experiments. qCT showed accelerated fracture bridging in the GH-treated animals in bone defect healing, while in DO histomorphometry elicited larger callus areas in the case of GH application. Systemic IGF-1 levels were significantly increased in both GH-treated groups. These experiments show that the systemic administration of recombinant GH accelerates fracture healing in standardized animal models. Clinical studies have now been initiated in order to prove the safety and the effectiveness of this therapeutical option.

Animals↗

PubMed2002

Influence of cage design on interbody fusion in a sheep cervical spine model.

OBJECT: The purpose of this study was to compare the characteristics of interbody fusion achieved using an autologous tricortical iliac crest bone graft with those of a cylinder- and a box-design cage in a sheep cervical spine model. This study was designed to determine whether there are differences between three interbody fusion procedures in: 1) ability to preserve postoperative distraction; 2) biomechanical stability; and 3) histological characteristics of intervertebral bone matrix formation. METHODS: Twenty-four sheep underwent C3-4 discectomy and fusion in which the following were used: Group 1, autologous tricortical iliac crest bone graft (eight sheep); Group 2, titanium cylinder-design cage filled with autologous iliac crest bone graft (eight sheep); and Group 3, titanium box-design cage filled with autologous iliac crest graft (eight sheep). Radiography was performed 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 12 weeks, the sheep were killed, and fusion sites were evaluated by obtaining functional radiographs in flexion and extension. Quantitative computerized tomography scans were acquired to assess bone mineral density, bone mineral content, and bone callus volume. Biomechanical testing was performed in flexion, extension, axial rotation, and lateral bending. Stiffness, range of motion, neutral zone, and elastic zone were determined. Histomorphological and histomorphometric analyses were performed, and polychrome sequential labeling was used to determine the time frame of new bone formation. Over a 12-week period significantly higher values for disc space height and intervertebral angle were shown in cage-treated sheep than in those that received bone graft. Functional radiographic assessment revealed significantly lower residual flexion-extension movement in sheep with the cylinder cage-fixed spines than in those that received bone graft group. The cylinder-design cages showed significantly higher values for bone mineral content, bone callus content, and stiffness in axial rotation and lateral bending than the other cages or grafts. Histomorphometric evaluation and polychrome sequential labeling showed a more progressed bone matrix formation in the cylindrical cage group than in both other groups. CONCLUSIONS: Compared with the tricortical bone graft, both cages showed significantly better distractive properties. The cylindrical cage demonstrated a significantly higher biomechanical stiffness and an accelerated interbody fusion compared with the box-design cage and the tricortical bone graft. The differences in bone matrix formation within both cages were the result of the significantly lower stress shielding on the bone graft by the cylinder-design cage.

Animals↗

PubMed2002

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.

Animals↗