© 2003 Robert A. Freitas Jr. All Rights Reserved.

Robert A. Freitas Jr., Nanomedicine, Volume IIA: Biocompatibility, Landes Bioscience, Georgetown, TX, 2003

15.3.5.3 Tissue Response to Bulk Alumina and Sapphire

Aside from dental implants, sapphire and alumina ceramics are most commonly employed in a variety of bone implants [1050]. Alumina ceramic surface has shown excellent in vivo tissue compatibility when implanted in the crania of rabbits for 2 months [1043]. In the human jaw, a single-crystal sapphire bone screw was applied for rigid internal fixation of sagittal split osteotomies in 86 cases from 1982-1986 and showed excellent biocompatibility [1035]. There was excellent bone adaptation to the threaded portion and no noticeable bone loss around the screws, which could mechanically support the split mandibular rami until bone union occurred [1035]. (Complications due to the screw were not encountered in follow-up periods of 0.5-3.5 years.) Experiments with alumina ceramic implants designed to reconstruct the bony bridge of the nose and the nasal septum of rabbits found that nasal septum implants were covered with connective tissue and coated with respiratory mucosa, and that implants in bony areas always showed a layer of connective tissue between the implant’s surface and the rebuilt bone [1046]. All implants healed without inflammatory reactions and were solidly fixed to the surrounding tissue after 7.5 months [1046].

Monocrystalline sapphire pins have been used in dozens of patients as an internal fixation device for hand and elbow problems [1034]. In follow-up studies, good bone healing was observed in all cases except for one delayed union in a fracture of the diaphysis of the proximal phalanx. Radiographs showed no pin migration or osteolytic reaction around the pins [1034]. There is some clinical experience using alumina ceramic pins for rib fractures [1047]. Sintered alumina implants inserted into the iliac crests (hip bones) and mandibles of rabbits were well tolerated, although the alumina excited a slightly greater tissue response than did vitreous carbon [782].

Modular total hip prostheses have been successfully employed since the mid-1970s [4806], and often consist of an alumina femoral head (ball) which articulates with an alumina acetabulum (cup) [956, 1048, 1049, 4794]. These show much improved wear characteristics (e.g., wear rates reported from an anomalously-low ~25 nm/year [1105] up to a more probable ~3 microns/year [4762], with up to 38.8 microns/year for early systems implanted in the 1970s [4809]). Such systems produce lower frictional heating [4805] and fewer wear particles [4799] than alternatives such as metal-on-polyethylene [1050, 1051, 4797, 4803] (e.g., ~100 microns/year [1105]), metal on alumina ceramic (e.g., 26.9 microns/year [4809]), or alumina ceramic-on-polyethylene [4803] (e.g., 34 microns/year [4795] to 80-200 microns/year [4810]) systems. By the year 2000, some 2.5 million ceramic femoral heads (mostly 28-mm-diameter BIOLOX heads with a European taper [1049]) had been implanted, mainly in Europe but also in North America and Japan [1049]. Results are generally good [4790], although the orthopedic community has reported (1) a few in vivo mechanical failures of monophase alumina ceramic [4756, 4815], (2) a few cases of moderate [4775] or significant [4771] wear, and (3) mechanical pathological changes in the articular cartilage and menisci from paired alumina knee-joint implants inserted into canine femoral condyles [4760]. Innovations are constantly arising [4776-4782]. By 2002 a new generation of alumina-zirconia nanocomposites were being tested in total hip replacement applications because of their improved crack-growth resistance [4756, 4783] and because zirconia ceramics are known to be highly biocompatible [4757].

As for leg bones, single-crystal sapphire and several other materials implanted into the tibia of rats were subsequently encapsulated by newly formed compact bone [1032], and bone tissue grew deeply into alumina pores [4769]. In another series of experiments [970], three alumina implants – single-crystal alumina (SA), dense polycrystal alumina (DPA), and porous polycrystal alumina (PPA) – were inserted transcortically, extending into the medullary canal of rat tibiae. There was no difference in the degree of maturation of newly formed bone around the three kinds of alumina. SA (sapphire) and DPA were encapsulated with a continuous bone layer, but some bone tissue was attached focally around PPA. Multinucleated giant cells appeared on the surface of DPA and PPA, but not on SA. Quantitative evaluation of bone contact rate, bone contact thickness, and bone contact area ranked SA the highest and PPA the lowest, suggesting that sapphire is superior to the other two as an implant material [970]. In a human clinical study [1052], the metatarsal (foot) bone was elongated by intercalary implantation of a single-crystal alumina ceramic in 7 patients with brachymetatarsy. The implants were encased with new bone 24 months after surgery and resulted in 5.2 mm to 9.2 mm elongation of the metatarsal bone. There was no resorption or pseudoarthrosis of the bones, and no loosening or breakage of the implants. Sapphire bone screws and anchors have been tested in animals and used clinically since at least the late 1970s [1036].

Sapphire implants show good biocompatibility in soft tissues [4768]. Such implants can elicit some foreign body reaction (Section 15.4.3.5), but there is often minimal fibrosis in response to bulk alumina implants [973, 1053]. For example, Akagawa et al [1032] implanted single-crystal sapphire and other materials such as titanium and Co-Cr-Mo alloy into the subcutaneous tissue of rats. The resulting tissue reaction, from early necrotic change and acute inflammation to final encapsulation by fibrous connective tissue, was least pronounced around the sapphire implants. Arvidson et al [1031] found slight or no tissue reaction when sapphire rods were inserted subcutaneously into rats for 4, 8, and 12 weeks. Reuling et al [1054] implanted dental alumina ceramics intramuscularly and subcutaneously in rabbits and guinea pigs. Cylindrical rough surfaces produced the strongest foreign body reactions. Spindle-shaped smooth surfaces elicited bland tissue reactions, including a significant increase in subcapsular adipose tissue and significantly less thickness of the connective tissue capsule [1054]. Small alumina chips (1.6 mm x 6.3 mm) implanted in rat paravertebral muscles produced a 77.5-micron-thick surrounding connective tissue membrane after 2 weeks, subsequently shrinking to 46 microns after 4 weeks, 36 microns after 8 weeks, and 24.4 microns after 26 weeks, with a shifting cell population including a nearly closed layer of macrophages towards the implant [1053]. Up to 1 year, a shifting layer of fatty tissue remained between membrane and muscle, functionally excluding the implant [1053].

A recent series of experiments [1055-1057] at the University of Tokushima School of Medicine and University Hospital, in Japan, investigated the time course of tissue reactions to crystalline alumina implants in the form of Bioceram disks used for synthetic auditory ossicle. In the first of these experiments [1055], the ceramic was implanted subcutaneously in the interscapular region of rats, then removed after 1, 3, 7 and 14 days. Decalcified 6-micron thick sections were stained with hematoxylin and eosin, and cell types around the implants were counted microscopically. An acute inflammatory reaction dominated by macrophages and neutrophils occurred after 1 day, almost disappearing after about 7 days. Fibrosis began at 3 days but foreign body giant cells were seen in only one specimen at 3 days. Chemical irritation to subcutaneous tissue was slight. However, the physical irritation of Bioceram lasted continuously and induced fibrosis around the bioimplant. The second study [1056], which extended the implant durations to 300 days, found that the inflammatory cell reaction decreased rapidly within 14 days, similar to the reaction in control groups. From 30 days to 300 days after implantation, there was continuous reduction of macrophages and lymphocytes to very low levels while the fibrous connective tissue capsule around the implants matured. The third study [1057] extended implantation time to 6-20 months and confirmed that small numbers of macrophages (~2.8% of max) and lymphocytes (~2.7% of max) were observed at 6 months, gradually decreasing to zero at 16, 18 and 20 months. Neither neutrophils nor foreign body giant cells were seen in any specimens. The thickness of fibrous capsules surrounding the implants was closely related to the shape of the implant, but there was no significant change from 6-20 months post-implantation and stereoscopic microscopy revealed no changes in Bioceram surfaces during this period. These results indicate that a sapphire-like ceramic is a satisfactory biocompatible material for reconstructive surgery from the viewpoint of inflammatory cellular and long-term tissue responses.

Alumina ceramic has also been used to provide short- and mid-term biocompatibility in blood-contacting LVAD surfaces [613]. For instance, high-purity alumina was used in the double pivot bearings of the Gyro C1E3 centrifugal blood pump developed as a completely sealless pump for long-term usage [1058]. The ceramic was determined to be a good biocompatible blood-contacting material after a standard in vitro and in vivo analysis including systemic toxicity, sensitization, cytotoxicity, mutagenicity, direct contact hemolysis, and thrombogenicity [1058-1060]. In another application, catheters using alumina-coated Teflon or alumina-coated pyrolytic carbon implanted intraperitoneally in dogs were retrieved after 12 weeks and only thin capsules were observed, of varying thickness and blood supply, surrounding the end of the catheters [895].

Last updated on 30 April 2004