the biocompatibility properties/superiority/cost/manufacturing of lm105 over other alloys is impressive the future looks very bright for lqmt in the medical market segment. lots of gems below
[0032] Additionally, fabricating the enclosure 302 from a BMG may provide the enclosure 302 with desirable biocompatibility. As an illustration, pre-clinical materials testing has shown that pacemaker enclosures formed from LM105, a BMG with the composition Zr.sub.525Ti.sub.5Cu.sub.179Ni.sub.14.6Al.sub.10 by atomic weight, produced by Liquidmetal Technologies, possess a number of biocompatible properties, as described in more detail below.
[0033] To begin with, a first round of testing was performed on as-molded LM105 specimens based on parts 4, 5, 10, and 11 of the International Organization for Standardization (ISO) 10993 test methods for medical devices. The first round of testing examined the basic biocompatibility of the as-molded LM105 specimens. ISO 10993-4 testing includes hemocompatibility testing (e.g., testing for the rupturing of red blood cells and release of cytoplasm into blood plasma in response to the tested material). The ISO 10993-4 testing included four sets of tests.
[0034] A hemolysis test (based on American Standard for Testing and Materials (ASTM) F756) was conducted on the LM105 specimens. An extraction of the LM105 specimens was immersed in phosphate buffered solution mixed with blood solution. National Committee for Clinical Laboratory Standards (NCCLS) cardiac magnetic resonance (CMR) imaging was then performed to measure the hemolysis of the phosphate buffered solution mixed with the blood solution in response to the extraction. In particular, the hemolysis test measured hemoglobin concentration compared to a negative reference control. The LM105 specimens showed a 0.5% concentration above the negative reference control (pass).
[0035] Complement activation testing was conducted on the LM105 specimens, in particular, a C3a assay and SC5b-9 assay. The complement activation testing measured the ability of the material to trigger complement activation: C3a for anaphylotoxicity and SC5b-9 for cell lysis (e.g., showing tissue breakdown). The test articles were exposed to normal human serum (NHS), and an extraction was plated into triplicate wells of C3a and SC5b-9 plates. The LM105 specimens showed 0.38% activation for the C3a assay and 0% activation for the SC5b-9 assay (pass).
[0036] A partial thromboplastin time (PTT) test and a prothrombin time (PT) test were conducted on the LM105 specimens to measure the ability of the material to cause clot formation (e.g., showing activation of the intrinsic coagulation pathway for the PTT test and activation of the extrinsic pathway for the PT test). For each of these tests, an extraction of the LM105 specimens was exposed to human plasma. For the PTT test, the LM105 specimens showed 32.3% (97 sec.) and 46.1% (138 sec.) of negative plasma control (moderate activation), and for the PT test, the LM105 specimens showed 13 seconds of clotting time and less than a 2-fold increase in PT (pass). As such, the LM105 specimens passed the hemocompability testing as non-hemolytic.
[0037] The ISO 10993-5 testing examined the cytotoxicity (e.g., cellular toxicity) of the tested material. For this testing, in vitro cytotoxicity tests were conducted, specifically to examine MEM elution, which correlates with a material's toxicity to cells. Additionally, an extraction of the LM105 specimens was immersed in cell culture and plated onto L-929 fibroblast cells to test whether the specimens caused cell lysis or inhibited cell growth. For these cytotoxicity tests, the LM105 enclosures were shown to be non-cytotoxic, with a cytotoxicity grade of 0 at 24, 48, and 72 hours.
[0038] The ISO 10993-10 testing examined sensitization and irritation of the material. For sensitization, a guinea pig (GP) maximization test was conducted to determine the skin sensitization of the LM105 specimens (e.g., their ability to cause an allergic response) and elicitation of contact dermatitis. Accordingly, intradermal and topical induction of specimen extracts were performed on guinea pigs. The result of the GP maximization test was a score of 0 for 24 and 48 hours, showing that the materials were non-sensitizing. For irritation, an intracutaneous reactivity test was performed to test the ability of the material to cause intracutaneous irritation (e.g., by the effect of toxic leachables). For this test, an extraction of the LM105 specimens was injected into guinea pigs with observation after 24, 48, and 72 hours. The result was 0.2 for polar and 0.3 for non-polar extractions, which showed that the LM105 specimens were non-irritating.
[0039] The ISO 10993-11 testing examined the systemic toxicity (e.g., the effect on the system from absorption and distribution of a toxicant) of the LM105 specimens. In particular, an acute systemic toxicity test was performed through single exposure with a 72-hour observation period. The result was no effect on test subjects with no abnormalities and no weight loss, showing that the LM105 specimens were non-systemic-toxic. In summary, the results from the ISO 10993-4, 10993-5, 10993-10, and 10993-11 testing suggested that LM105 in the as-molded condition is a potential candidate for surface contact, blood contact, and implantation, and thus is a potential candidate for implantable pacemaker, fibrillation, stimulation, etc. devices as described above.
[0040] Long-term implant-specific testing was also performed on deburred and passivated LM105 injection molded parts. These tests were selected from parts 3, 6, 10, and 11 for ISO10993. The ISO10993-3 testing examined the genotoxicity, carcinogenicity, and reproductive toxicity of the LM105 specimens. The testing included a mouse lymphoma assay based on 4- and 24-hour treatments. The results showed that the LM105 enclosures were non-mutagenic, as the mutant frequency was less than 90.times.10.sup.-6 of the average mutant frequency of the concurrent negative control. As utilized herein, "long-term implantation" means a contact duration in a body of a human for at least 30 days or 720 hours.
[0041] Passivation is a process by which the already corrosion-resistant surface of a zirconium-based BMG part can be further enhanced to diminish any risk of forming oxidides or leaching ions into the body. The fact that alloys such as LM105 can be commercially passivated as part of the BMG component manufacturing process is extremely valuable to the pacemaker application since resistance to the body fluid environment is critical for the performance of an enclosure device, and a more extended low-risk device lifetime is inherently advantageous for any implantable device.
[0042] The ISO10993-6 and 10993-10 testing evaluated the effects of chronic exposure post-implantation. In particular, the ISO 10993-6 testing examined sub-chronic systemic toxicity 90 days after a test article was implanted in the test subject. Tests were conducted for local effects after the implantation to evaluate organ weight changes, gross necropsy findings, and histopathy results from organs and tissues. No abnormalities were noted at necropsy. All the implanted sites appeared within normal limits, and there were no signs of local and/or general toxicity (pass). The ISO 10993-10 testing evaluated the biological response to chronic exposure of an implanted test article. Devices were implanted in rabbits with paraffin histoprocessing; tests were conducted for irritation and skin sensitization. The final test article score was 0.3, and the test article was determined to be a non-irritant to the subject's tissue as compared to the negative control sample (pass). As such, based on the ISO 10993-6 and 10993-10 testing, the LM150 specimens were determined to be non-irritants.
[0043] The ISO 10993-11 testing was performed to evaluate systemic toxicity. Two sets of tests were performed. (1) Materials mediated pyrogenicity tests were performed according to tests for systemic toxicity from the United States Pharmocopeia (USP)<151> Pyrogen Test Regulatory Standards. The <151> Pyrogen Test Regulatory Standards tests provide general information on the detection of material mediated pyrgenicity of the test article under investigation. Based on the results of this study, the LM105 test article showed no evidence of material mediated pyrogenicity (pass). (2) Sub-chronic systemic toxicity based on an implant after 90 days was tested for local effects after implantation. Similar to the ISO 10993-6 tests discussed above, these tests evaluate organ weight changes, gross necropsy findings, and histopathy results from organs and tissues. No abnormalities were noted at necropsy, all the implanted sites appeared within normal limits, and there were no signs of local and/or general toxicity (pass). As such, the results of the ISO 10993-6 showed that the LM105 specimens were non-systemic-toxic. Accordingly, the ISO 10993-3, 10993-6, 10993-10, and 10993-11 tests discussed above showed that LM105 parts have the appropriate biocompatibility to be considered for implantable pacemaker enclosure applications, as well as applications for other implantable medical devices.
[0044] However, even if potential implantation materials show good biocompatibility, leaching of metal ions into a body fluid environment is also a potential roadblock for implantation of the materials. Because LM105 contains nickel as one of its constituent elements, which can leach into a body fluid environment, the LM105 enclosures were tested for nickel release in a simulated body fluid environment. These tests were conducted according to the EN 1811:2011 test method (which is used to test nickel release in the European Union). The test involves placing the article in an artificial sweat solution for one week and then measuring the nickel in the solution by atomic absorption spectroscopy or inductively coupled plasma mass spectrometry (ICP-MS). The article is then given a pass or fail grading. Both LM105 as-molded and LM105 that had been blasted and passivated were tested. The tests for the LM105 as-molded were all below the measurable limit, while the tests for the blasted and passivated LM105 were 0.0048 or less. These test results indicate that the nickel release rates for as-molded LM105 are below the limit standards for prolonged and piercing body contact, further suggesting that LM105 enclosures would be safe for human implantation.
[0045] Salt fog corrosion tests were also conducted on the LM105 test coupons for 336 hours in a salt fog environment according to ASTM test standard B117. The results of the as-molded LM105 are shown in chart 400 illustrated in FIG. 3 (shown as bar 402). Chart 400 also includes the results for blasted and passivated LM105 (shown as bar 404) and other metals used in medical devices, including stainless steels 316, 304, 301 (shown as bar 406), titanium Grades 5, 2 (shown as bar 408), stainless steel 17-4 (shown as bar 410), and aluminum 7075 (shown as bar 412). As shown by bar 402, the as-molded LM105 showed minimum discoloration and no corrosion on LM105 test coupons. This resistance is equal or better than high grade stainless steels and titanium alloys, which are commonly used for long-term human implantation. Additional testing showed no change in LM105 test coupons after over 1,000 hours in the same environment.
[0046] Additionally, LM105 enclosures are geared towards non-ferrous behavior for safety and compatibility in MRI environments. The electromagnetic properties of LM105 make it an MRI-safe material (e.g., the LM105 shows no attractive or repulsive forces in a static B-field), and minimal artifacts are produced around the implant site when imaged using MRI due to the low conductivity and low magnetic susceptibility of the LM105, which is close to the relative magnetic susceptibility of air. For example, FIG. 4 illustrates a graph 500 of the skin depth (mm) versus the electromagnetic radiation frequency (Hz) for LM105, (shown as line 502), copper (shown as line 504), steel (shown as line 506), and titanium (shown as line 508). As illustrated in FIG. 4, the calculated skin depth of injection molded LM105 is very similar to that of titanium, which has been shown to generate fewer (e.g., less intense) artifacts than stainless steel alloys (e.g., as shown by Knott et al., "A Comparison of Magnetic and Radiographic Imaging Artifact After Using Three Types of Metal Rods: Stainless Steel, Titanium, and Vitallium," Spine Journal, Vol. 10, p. 789-794 (2010)). The skin depth calculations indicate the LM105 would have similar "transparency" to electromagnetic signals used for remote communication or power supply charging. The operational band for these devices is around 4.times.10.sup.8 Hz, at which the skin depth is about 0.03 mm for both titanium and LM105, as illustrated in FIG. 4. This indicates that LM105 pacemaker enclosures would have a similar electromagnetic response to MRI environments as well as communication signals and provide comparable image quality as titanium, while maintaining other, advantageous properties over titanium (e.g., in fabrication flexibility).
[0047] Accordingly, as shown by the above-discussed testing, BMGs like LM105 may be a good candidate for enclosures used for implantable medical devices, as well as for other medical device components. Moreover, due to the glass-like nature of LM105 and the larger range of recoverable elastic strain that BMGs such as LM105 can experience, creating pacemaker enclosures out of LM105 may allow for more freedom of design, compact size, and anatomically-favorable geometries over traditional medical device materials (e.g., anatomically-matched geometries rather than geometries dictated by manufacturing methods such as stamping or machining). As such, according to some embodiments, LM105 enclosures may have a number of production advantages, including faster production cycle times with fewer production steps/stages necessary, dimensional repeatability with high yield processes, and allowing for more complex but repeatable geometric features at a reduced cost.
[0048] As an illustration, BMGs often have a larger elastic range than many metals and metal alloys (e.g., LM105 may show around 2% recoverable elastic strain). As such, potential BMG pacemaker enclosure designs can incorporate advantageous elastic features not possible with, for example, titanium alloys. For instance, in some embodiments, a BMG pacemaker enclosure may include interlocking snap-fit features for precise and repeatable alignment of the two halves of the pacemaker during assembly. Utilizing the 2% recoverable elastic strain of the BMG alloy, these features can be locked and unlocked multiple cycles while providing the same amount of locking force each time (e.g., without showing plastic deformation). In one embodiment, these same features can be used to align and lock internal components into place with retaining clips or other support features that are monolithic with the pacemaker enclosure body. For example, these retaining clips or other support features may be used to lock at least one of a pulse generator, battery, wires, or other component of an implantable medical device inside the enclosure. Similarly, support features can be designed to physically separate various internal components from one another for assembly purposes or for design purposes, such as to physically separate the battery of an implantable medical device from other internal components. Alternatively, in another embodiment, the entire pacemaker enclosure rims could be designed to snap together (e.g., similar to a plastic Easter egg). Welding could then be used at these enclosure mating locations to prevent unlocking in some implementations. In other embodiments, potential BMG enclosure designs may include a different type of interlocking fit (e.g., for precisely mating the two enclosure halves together), such as threading for screwing the two halves of the enclosure together.
[0049] As another example, while titanium is often used in implantable medical device enclosures due to its biocompability, the cost of manufacturing high grade titanium enclosures can be significant. As shown by the above-described testing, LM105 enclosures may show similar or better biocompatibility than titanium and can be produced more inexpensively Similar conclusions may be reached for other BMG medical device enclosures, such as LM105 defibrillator enclosures and LM105 stimulation enclosures.
