Magnetic resonance-guided cardiac interventions using magnetic resonance-compatible devices: a preclinical study and first-in-man congenital interventions.

BACKGROUND: Percutaneous cardiac interventions are currently performed under x-ray guidance. Magnetic resonance imaging (MRI) has been used to guide intravascular interventions in the past, but mainly in animals. Translation of MR-guided interventions into humans has been limited by the lack of MR-compatible and safe equipment, such as MR guide wires with mechanical characteristics similar to standard guide wires. The aim of the present study was to evaluate the safety and efficacy of a newly developed MR-safe and compatible passive guide wire in aiding MR-guided cardiac interventions in a swine model and describe the 2 first-in-man solely MR-guided interventions. METHODS AND RESULTS: In the preclinical trial, the new MR-compatible wire aided the performance of 20 interventions in 5 swine. These consisted of balloon dilation of nondiseased pulmonary and aortic valves, aortic arch, and branch pulmonary arteries. After ethics and regulatory authority approval, the 2 first-in-man MR-guided interventions were performed in a child and an adult, both with elements of valvar pulmonary stenosis. Catheter manipulations were monitored with real-time MRI sequence with interactive modification of imaging plane and slice position. Temporal resolution was 11 to 12 frames/s. Catheterization procedure times were 110 and 80 minutes, respectively. Both patients had successful relief of the valvar stenosis and no procedural complications. CONCLUSIONS: The described preclinical study and case reports are encouraging that with the availability of the new MR-compatible and safe guide wire, certain percutaneous cardiac interventions will become feasible to perform solely under MR guidance in the future. A clinical trial is underway in our institution.

The removal of Al2O3 particles from grit-blasted titanium implant surfaces: effects on biocompatibility, osseointegration and interface strength in vivo.

For the improvement of surface roughness and mechanical interlocking with bone, titanium prostheses are grit-blasted with Al(2)O(3) particles during manufacturing. Dislocated Al(2)O(3) particles are a leading cause of third-body abrasive wear in the articulation of endoprosthetic implants, resulting in inflammation, pain and ultimately aseptic loosening and implant failure. In the present study, a new treatment for the removal of residual Al(2)O(3) particles from grit-blasted, cementless titanium endoprosthetic devices was investigated in a rabbit model. The cleansing process reduces residual Al(2)O(3) particles on titanium surfaces by up to 96%. The biocompatibility of the implants secondary to treatment was examined histologically, the bone-implant contact area was quantified histomorphometrically, and interface strength was evaluated with a biomechanical push-out test. Conventional grit-blasted implants served as control. In histological and SEM analysis, the Al(2)O(3)-free implant surfaces demonstrated uncompromised biocompatibility. Histomorphometrically, Al(2)O(3)-free implants exhibited a significantly increased bone-implant contact area (p=0.016) over conventional implants between both evaluation points. In push-out testing, treated Al(2)O(3)-free implants yielded less shear resistance than conventional implants at both evaluation points (p=0.018). In conclusion, the new surface treatment effectively removes Al(2)O(3) from implant surfaces. The treated implants demonstrated uncompromised biocompatibility and bone apposition in vivo. Clinically, Al(2)O(3)-free titanium prostheses could lead to less mechanical wear of the articulating surfaces and ultimately result in less aseptic loosening and longer implant life.

Effects of cyclic hydrostatic pressure on the metabolism of human osteoarthritic chondrocytes cultivated in a collagen gel.

Among other parameters, the application of mechanical force may provide an important stimulus in modulating the structure and function of tissue-engineered articular cartilage. We developed a cultivation chamber in which six collagen type-I gel samples, seeded with human osteoarthritic chondrocytes, can be cultivated simultaneously. A cyclic hydrostatic pressure of up to 40 kPa with a frequency of 0.0125 Hz was applied, and cultivation was performed for 1, 4, 7, or 14 days. Histological examinations revealed a spheroidal cell morphology in the treatment group. In contrast, control samples of the same patients represented a more fibroblastic appearance. Collagen type-II (col-II) protein was found in the very pericellular region of all investigated samples; the col-II content did not obviously vary between the control and treatment groups. In the treatment group, col-II and aggrecan gene expression were elevated. A spectrophotometric quantification of proteoglycan concentrations in media supernatants revealed a statistically significant enhancement in the treatment group.

BMP-7 loaded microspheres as a new delivery system for the cultivation of human chondrocytes in a collagen type-I gel.

In recent years, interest in chondrocyte cultures for transplantation has gained increasing attention. We investigated the use of PGLA microspheres as a new delivery system for BMP-7 and the effects on human chondrocytes cultivated in a 3D collagen gel culture. In an in vitro study, human chondrocytes obtained from osteoarthritic knee joints were released, transferred into a collagen type-I gel, and cultivated up to 14 days. In the treatment group PGLA microspheres loaded with human recombinant BMP-7 protein were added to the matrix. After the cultivation period, histological and immunohistochemical investigations were performed. In addition, the aggrecan core protein and type-II collagen mRNA concentrations were measured by real-time PCR. Histological staining for proteoglycan and collagen type-II protein and quantification via digital image processing revealed a significantly higher content in the samples cultivated with BMP-7 loaded microspheres in comparison to the control samples. Moreover, the collagen gel scaffold was partially remodeled by the chondrocytes and replaced by newly synthesized extracellular matrix. Cellular proliferation as well as apoptosis were low. In conclusion, we consider the PGLA microsphere system to be a functional device for the delivery of growth factors during the cultivation of articular chondrocytes leading to an increased content of type-II collagen and proteoglycan in the extracellular matrix.

The effect of surface modification of a porous TiO2/perlite composite on the ingrowth of bone tissue in vivo.

The porous TiO2/perlite composite Ecopore is a synthetic biomaterial with possible clinical application in bone substitution. In our previous work, we demonstrated that surface modification of Ecopore with fibronectin (FN) enhanced spreading and growth of human osteoblasts in vitro. In the present study, we implanted untreated, alkaline-etched and FN-coated Ecopore cylinders into critical size defects of rabbit femora and applied pulsed polychrome sequence staining. After 6 weeks, sections of the implants were investigated via conventional and fluorescence microscopy. A partial ingrowth of bone matrix into the pore system of the Ecopore implants was observed. At the contact zones, the bone appeared to be directly connected to the implant without detectable gaps. Defect healing was complete within 6 weeks, while fibrous tissue generation or inflammation were absent in the implant modification groups, demonstrating basic Ecopore biocompatibility. The mean bone apposition rates within the implant cross-section were 4.1+/-0.6 microm/day (p<0.001) in the FN-coated group and 3.3+/-0.5 microm/day (p<0.05) in the NaOH-etched group. In both treated Ecopore modification groups, the apposition rates were significantly higher than in the non-modified control (2.9+/-0.6 microm/day), indicating bone growth stimulation by pre-treatment. Energy-dispersive X-ray analysis confirmed that significantly more bone tissue was formed inside the pores of the FN-coated implants compared to the unmodified control. The cross-sectional areas identified as ingrown bone amounted to 18.5+/-6.1% (p<0.05) in the FN group, 13.4+/-5.1% (p>0.05) in the NaOH-etched group and 10.2+/-5.5% in the unmodified group. In summary, we conclude that bone tissue tolerates Ecopore well and that tissue ingrowth can be enhanced by etching and coating with FN.

Structural, mechanical and in vitro characterization of individually structured Ti-6Al-4V produced by direct laser forming.

Direct laser forming (DLF) is a rapid prototyping technique which enables prompt modelling of metal parts with high bulk density on the base of individual three-dimensional data, including computer tomography models of anatomical structures. In our project, we tested DLF-produced material on the basis of the titanium alloy Ti-6Al-4V for its applicability as hard tissue biomaterial. To this end, we investigated mechanical and structural properties of DLF-Ti-6Al-4V. While the tensile and yield strengths of untreated DLF alloy ranged beyond 1000 MPa, a breaking elongation of 6.5+/-0.6% was determined for this material. After an additional post-DLF annealing treatment, this parameter was increased two-fold to 13.0+/-0.6%, while tensile and yield strengths were reduced by approx. 8%. A Young's modulus of 118.000+/-2.300 MPa was determined for post-DLF annealed Ti-6Al-4V. All data gained from tensile testing of post-DLF annealed Ti-6Al-4V matched American Society of Testing and Materials (ASTM) specifications for the usage of this alloy as medical material. Rotating bending tests revealed that the fatigue profile of post-DLF annealed Ti-6Al-4V was comparable to casted/hot isostatic pressed alloy. We characterized the structure of non-finished DLF-Ti-6Al-4V by scanning electron microscopy and observed a surface-associated layer of particles, which was removable by sandblasting as a finishing step. We manufactured porous specimens with nominal pore diameters of 500, 700 and 1000 microm. The diameters were reduced by the used DLF processing by approx. 300 microm. In an in vitro investigation, we cultured human osteoblasts on non-porous and porous blasted DLF-Ti-6Al-4V specimens to study morphology, vitality, proliferation and differentiation of the cells. The cells spreaded and proliferated on DLF-Ti-6Al-4V over a culture time of 14 days. On porous specimens, osteoblasts grew along the rims of the pores and formed circle-shaped structures, as visualized by live/dead staining as well as scanning electron microscopy. Overall, the DLF-Ti-6Al-4V approach proved to be efficient and could be further advanced in the field of hard tissue biomaterials.

In vitro behavior of a porous TiO2/perlite composite and its surface modification with fibronectin.

In this study, we introduce a porous composite material, termed "Ecopore", and describe in vitro investigation of the material and its modification with fibronectin. The material is a sintered compound of rutile TiO2 and the volcanic silicate perlite with a macrostructure of interconnecting pores. It is both inexpensive and easy to manufacture. We first investigated Ecopore for corrosion and leaching of elements in physiological saline. The corrosion supernatants did not contain critical concentrations of toxic trace elements. In an in vitro model, human primary osteoblasts (HOB) were cultured directly on Ecopore. HOB grew on the composite as well as on samples of its single constituents, TiO2 and perlite glass, and remained vital, but cellular spreading was less than on tissue culture plastic. The pro-inflammatory cytokines IL-1 and TNF-alpha were below detection limits in HOB culture supernatants, whereas IL-6 was detectable on a low level. To enhance cellular attachment and growth, the surface of the composite was modified by etching, functionalization with aminosilane and coupling of fibronectin. This modification greatly enhanced the spreading of HOB, indicated by vital staining and Sodium 3'-[1-(phenylaminocarbonyl)-3,4-tetrazolium]-bis (4-methoxy-6-nitro) benzene sulfonic acid hydrate (XTT) metabolism assays. HOB grew on the entire visible surface of porous fibronectin-modified composite, expressing alkaline phosphatase, a mature osteoblast marker. We conclude that Ecopore is non-toxic and sustains HOB growth, cellular spreading being improvable by coating with fibronectin. The composite may be usable in the field of bone substitution.