Biomechanical and Histological Study of Retrieved LARS Synthetic Ligaments.

BACKGROUND: Synthetic grafts have been used for a number of years in anterior cruciate ligament (ACL) reconstruction surgery. One of the more recent additions to the stable of synthetic ligaments is the Ligament Augmentation and Reconstruction System (LARS) ligament. PURPOSE: To analyze the biomechanics and histology of LARS grafts retrieved due to failure of the device. STUDY DESIGN: Descriptive laboratory study. METHODS: A total of 22 LARS ligament grafts that were explanted from patients were sent for analysis. Five new, unused samples of the standard LARS ACL graft were also analyzed. Biomechanical testing was performed: ultimate tensile force, force versus displacement, and stress versus strain were recorded. Histopathological examination was performed looking for degree of fibrous tissue ingrowth as well as the presence of a foreign body reaction. RESULTS: Of the 22 grafts retrieved, 14 were used for ACL grafts, 1 for a lateral collateral ligament graft, 2 for medial collateral ligament grafts, 4 for gluteal tendon augmentation, and 1 for a supraspinatus augmentation. A severe foreign body reaction was found in 86% of the grafts (18/22) and a mild foreign body reaction in the remaining 14% (4/22). Tissue ingrowth was minimal in the majority of ACL grafts; the other grafts showed moderate tissue ingrowth. Maximal tensile force was significantly higher for the new ACL grafts (mean ± SD, 1667 ± 845 N) compared with the retrieved grafts (897 ± 395 N; P < .05). CONCLUSION: This study demonstrated that the vast majority of retrieved LARS artificial ligaments had a florid foreign body reaction. There was minimal tissue ingrowth in ACL grafts and moderate ingrowth in other grafts. Retrieved grafts had a decreased ultimate tensile force, which increased their risk of rupture. CLINICAL RELEVANCE: Surgeons should be cautious in choosing to use these grafts in reconstructive surgery for patients.

Heterotopic ossification, osteolysis and implant failure following cervical total disc replacement with the M6-C™ artificial disc.

INTRODUCTION: A recent study reported a 34% mid-term revision rate after M6-C™ cervical total disc replacement (CTDR) for wear-related osteolysis. Here, we aim to investigate the prevalence, risk factors, and radiographic characteristics of periprosthetic bony changes and implant failure of the M6-C™ artificial disc. METHODS: We retrospectively analysed radiographic (conventional X-ray, CT scan) and clinical outcomes (EQ-5D-5L, Neck Disability Index (NDI), and Visual Analog Scale (VAS) for neck and arm pain) data collected during routine follow-up of patients who underwent CTDR with the M6-C™ between 2011 and 2015. RESULTS: In total, 85 patients underwent CTDR with the M6-C™. Follow-up data were available for 43 patients (54% female, mean age 44 years) with 50 implants and a mean follow-up of 8.1 years (6.5-11 years). Implant failure with the presence of severe osteolysis was identified in 5 (12%) patients who were all male (p = 0.016) and implanted at the C5/6 level (p = 0.11). All failed implants required revision surgery. The overall prevalence of osteolysis was 44% (22/50 implants) and 34% (17/50 implants) for significant heterotopic ossification. Patients with high-grade osteolysis showed higher VAS arm pain (p = 0.05) and lower EQ-5D-VAS health VAS (p = 0.03). CONCLUSION: We report a lower reoperation rate for failed M6-C™ implants than previously published, but confirmed that osteolysis and heterotopic ossification are common following CTDR with the M6-C™ and may be asymptomatic. Therefore, we strongly recommend ongoing clinical and radiographic monitoring after CTDR with the M6-C™, particularly for male patients implanted at the C5/6 level.

Dissociation of polyethylene liners with the Depuy Pinnacle cup: a report of 26 cases.

BACKGROUND: Although the Pinnacle Acetabular Hip System (DePuy Synthes) has demonstrated excellent survivorship results since it was first introduced in 2003, there have been a growing number of cases indicating that Pinnacle liners may be subject to a higher-than-expected rate of early dissociation failure. Between 2006 and 2020, our Centre received 212 retrieved Pinnacle liners from Western Australian hospitals. Of these, 26 were removed due to liner dissociation. METHODS: To better understand the frequency and cause of this complication we assessed all retrieved Pinnacle acetabular components for type, damage modes and patient demographics. The leverage force required to dissociate Pinnacle liners was also measured and compared with another commonly used acetabular system, the Trident (Stryker Orthopaedics). RESULTS: The estimated minimum incidence of liner dissociation from our data was 0.35%. Characterisation of dissociated Pinnacle cases (n = 26) revealed 73% were female with an average age of 59 compared to all retrieved Pinnacle cases (n = 212) where 58% were female with an average age of 66. Retrieval analysis indicated plastic deformation of the liner into an ovoid shape, signs of impingement on the rim postero-superiorly and shearing of the liner's anti-rotation tabs was common. Mechanical testing indicated that the dissociation strength of Pinnacle cups decreases at approximately 6.6 N/year in situ (p = 0.01). CONCLUSION: The survival rate of Pinnacle acetabular cups is exceptional with only 5% revised at 10 years. However, surgeons should be aware of the clinical symptoms and high-risk demographics when assessing patients with polyethylene Pinnacle liners.

The effect of trunnionosis on the risk of re-revision following femoral head exchange in hip arthroplasty.

BACKGROUND: Fretting corrosion at modular junctions contributes to arthroplasty failure. Currently, no evidence-based guidelines are available regarding the acceptable level of trunnion corrosion that can occur in vivo. We aimed to examine the relationship between trunnion corrosion and risk of re-revision to assist surgeons with intraoperative decision making. METHOD: Grading by 3 independent examiners of revised and re-revised head components was performed using a modified Goldberg corrosion scale. Samples were separated into low-grade (LG) and high-grade (HG) corrosion. Mechanical testing determined the relationship between corrosion severity and pull-off strength at the head-stem junction. RESULTS: 529 retrieved femoral heads were analysed. A positive association was detected between males and HG corrosion (OR 2.07; 95% CI, 1.45-2.94; p < 0.001). No difference between the survivorship of LG and HG heads was detected (p-value = 0.247). In the re-revised sample, the first implant had a time in situ that was on average 7.97 years longer (95% CI, 5.4-10.6) than that of the subsequent re-revised femoral head. Severe corrosion on the first head was associated with a 37.5 (95% CI, 4.00-1944) fold increase of HG on the subsequent head (p < 0.001). Femoral disassembly force had a positive correlation with stem taper corrosion grade (p = 0.001). CONCLUSIONS: A well-fixed stem with corrosion may remain in situ.

Erratum: Author Correction: The influence of HLA genotype on the development of metal hypersensitivity following joint replacement.

[This corrects the article DOI: 10.1038/s43856-022-00137-0.].

The influence of HLA genotype on the development of metal hypersensitivity following joint replacement.

Background: Over five million joint replacements are performed across the world each year. Cobalt chrome (CoCr) components are used in most of these procedures. Some patients develop delayed-type hypersensitivity (DTH) responses to CoCr implants, resulting in tissue damage and revision surgery. DTH is unpredictable and genetic links have yet to be definitively established. Methods: At a single site, we carried out an initial investigation to identify HLA alleles associated with development of DTH following metal-on-metal hip arthroplasty. We then recruited patients from other centres to train and validate an algorithm incorporating patient age, gender, HLA genotype, and blood metal concentrations to predict the development of DTH. Accuracy of the modelling was assessed using performance metrics including time-dependent receiver operator curves. Results: Using next-generation sequencing, here we determine the HLA genotypes of 606 patients. 176 of these patients had experienced failure of their prostheses; the remaining 430 remain asymptomatic at a mean follow up of twelve years. We demonstrate that the development of DTH is associated with patient age, gender, the magnitude of metal exposure, and the presence of certain HLA class II alleles. We show that the predictive algorithm developed from this investigation performs to an accuracy suitable for clinical use, with weighted mean survival probability errors of 1.8% and 3.1% for pre-operative and post-operative models respectively. Conclusions: The development of DTH following joint replacement appears to be determined by the interaction between implant wear and a patient's genotype. The algorithm described in this paper may improve implant selection and help direct patient surveillance following surgery. Further consideration should be given towards understanding patient-specific responses to different biomaterials.

Loosening of tibia baseplates after total knee arthroplasty: Evaluation of pull-out strength of tibia baseplate-cement Interface.

BACKGROUND: Aseptic loosening is reported as the leading cause of revision total knee arthroplasty on the Australian National Joint Replacement Registry. Loosening of cemented tibial baseplates has been correlated with type of cement used, cementing technique, and cement contamination with biological material. The aim of this study was to evaluate the effect of cementing application and techniques including surface contamination and cement viscosity on fixation strength of tibia baseplates/cement interface. METHODS: Mechanical assessment of the fixation strength of tibia baseplates/cement interface was tested using a pull-out test on a material testing system. Different tibial baseplate design, cementing techniques, cement viscosity and contamination of the implant/cement interface with bone marrow were assessed to determine if they influenced force required to disrupt the cement/implant interface (pull-out strength). FINDINGS: The model with contamination of the cement prosthesis interface demonstrated a lower pull-out strength (p < 0.001). The model with the keel and baseplate cemented showed a higher pull-out strength compared to cementing the baseplate alone (p < 0.001). The use of low-viscosity cement resulted in a significantly higher failure force (p = 0.002) compared to high-viscosity cement when cementing the baseplate alone. INTERPRETATIONS: Biomechanical testing demonstrated improved fixation with cementing the tibial keel and keeping surfaces free from contamination during the cementation process.

Tibial tray debonding from the cement mantle is associated with deformation of the backside of polyethylene tibial inserts.

AIMS: The aim of this study was to investigate whether wear and backside deformation of polyethylene (PE) tibial inserts may influence the cement cover of tibial trays of explanted total knee arthroplasties (TKAs). METHODS: At our retrieval centre, we measured changes in the wear and deformation of PE inserts using coordinate measuring machines and light microscopy. The amount of cement cover on the backside of tibial trays was quantified as a percentage of the total surface. The study involved data from the explanted fixed-bearing components of four widely used contemporary designs of TKA (Attune, NexGen, Press Fit Condylar (PFC), and Triathlon), revised for any indication, and we compared them with components that used previous generations of PE. Regression modelling was used to identify variables related to the amount of cement cover on the retrieved trays. RESULTS: A total of 114 explanted fixed-bearing TKAs were examined. This included 76 used with contemporary PE inserts which were compared with 15 used with older generation PEs. The Attune and NexGen (central locking) trays were found to have significantly less cement cover than Triathlon and PFC trays (peripheral locking group) (p = 0.001). The median planicity values of the PE inserts used with central locking trays were significantly greater than of those with peripheral locking inserts (205 vs 85 microns; p < 0.001). Attune and NexGen inserts had a characteristic pattern of backside deformation, with the outer edges of the PE deviating inferiorly, leaving the PE margins as the primary areas of articulation. CONCLUSION: Explanted TKAs with central locking mechanisms were significantly more likely to debond from the cement mantle. The PE inserts of these designs showed characteristic patterns of deformation, which appeared to relate to the manufacturing process and may be exacerbated in vivo. This pattern of deformation was associated with PE wear occurring at the outer edges of the articulation, potentially increasing the frictional torque generated at this interface. Cite this article: Bone Joint J 2021;103-B(12):1791-1801.

Catastrophic failure of the Accolade I hip arthroplasty stem: a retrieval analysis study.

PURPOSE: Modular Morse tapered femoral arthroplasty stems have been used for many years with great success and minimal complications. 1 stem, the Accolade by Stryker is noted to have increased failure when used in combination with LFIT V40 CoCr or the MITCH CoCr femoral heads. The failure has been in the form of corrosion, metallosis, fretting and trunnion fracture. This paper explores 10 cases with trunnion failure. METHODS: A retrospective retrieval analysis of ten femoral stems retrieved at four different centres across Western Australia over a 3-year time frame. Inclusion criteria for this analysis included the use of Accolade 1 TMZF femoral stem plus either a MITCH or LFIT modular head. RESULTS: 10 Accolade I (Stryker) stems were retrieved as part of the analysis, 6 with the LFIT V40 36-mm femoral head and 4 with a MITCH TRH femoral head. Average in situ time was 8.9 years. The hips were revised for either trunnion dislocation (6 cases) or trunnion fracture (4 cases). A characteristic destructive wear pattern of the femoral taper (trunnion) a "bird beak" appearance was present in all stems. This wear pattern created excessive movement and loosening resulting in a trunnion/head dislocation or brittle fracture of the trunnion. CONCLUSIONS: Catastrophic femoral neck fracture was likely due to a combination of material composition mismatch and mechanically assisted fretting corrosion at the head-neck junction leading to gross metallosis and failure. We suggest a recall on patients with an Accolade 1 stems in combination with a 36-mm or above LFIT or MITCH head, and for these patients to have clinical and radiological review.

The effect of implant modification: the low contact stress experience.

AIMS: The aim of this study was to conduct the largest low contact stress (LCS) retrieval study to elucidate the failure mechanisms of the Porocoat and Duofix femoral component. The latter design was voluntarily recalled by the manufacturer. MATERIALS AND METHODS: Uncemented LCS explants were divided into three groups: Duofix, Porocoat, and mixed. Demographics, polyethylene wear, tissue ingrowth, and metallurgical analyses were performed. RESULTS: In 104 implants, a decrease in the odds of loosening and an increase in metallosis and tissue staining in the Duofix group relative to Porocoat group was detected (p = 0.028). There was an increased presence of embedded metallic debris in the Duofix group (p < 0.001). Decreased tissue ingrowth was associated with the Duofix surface (p < 0.001). The attached beads had reduced microhardness, indicative of adverse thermal processing, which resulted in bead shedding, particulate debris, and metallosis. CONCLUSION: Hydroxyapatite coating of the LCS femoral component produced unexpected results and led to its recall. The root cause was likely a combination of retained alumina grit and a reduction in bead microhardness (mechanical strength) resulting in increased particle debris, metallosis, and early revision. The Duofix LCS femoral component was not equivalent to the Porocoat version despite its approval through the Food and Drug Administration (FDA) 510(k) equivalance approval process. Regulation of the introduction of modified existing devices needs to be improved and the Duofix LCS should have been considered to be a new device for which equivalence had not been demonstrated at the point of introduction. Cite this article: Bone Joint J 2019;101-B:1248-1255.

Foreign Body Reaction Associated With Artificial LARS Ligaments: A Retrieval Study.

BACKGROUND: Artificial ligaments have been developed and used in the treatment of ligamentous injuries since the 1970s. The early generation of artificial ligaments showed promising short-term results but resulted in high rates of rupture and inflammatory reaction in the surrounding tissues. PURPOSE: To determine whether the use of Ligament Augmentation and Reconstruction System (LARS) ligaments is associated with the development of intra-articular foreign body reaction. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: LARS ligaments were explanted from 15 patients under 6 consultant orthopaedic surgeons at 8 surgical centers. Of these, 14 explanted samples were sent for macroscopic and histological analysis, with the 1 remaining sample sent for scanning electron microscopy, to assess for inflammatory change as well as the degree of fibrous tissue ingrowth. RESULTS: We observed a foreign body reaction in 10 of 14 explanted LARS ligaments. Seven samples demonstrated fibrous tissue ingrowth, with 5 producing only focal or incomplete ingrowth. The 2 samples with extensive fibrous coverage were completely free of any foreign body reaction, while all 5 remaining samples with only focal or partial fibrous ingrowth were associated with at least some degree of harmful immune response. CONCLUSION: The LARS ligament is still associated with a clinically significant degree of foreign body reaction despite the LARS Company's efforts to reduce complications through improved design. The development and completion of fibrous tissue ingrowth may work to reduce the occurrence of a foreign body reaction.

Failure and Fatigue Fracture at the Femoral Stem-Metaphyseal Sleeve Junction in a Modular Knee Prosthesis: A Case Report.

CASE: A 66-year-old active man had undergone revision total knee replacement surgery with a femoral metaphyseal sleeve and a cemented stem in 2013 after loosening of the implant following the primary knee arthroplasty. He was overweight and had a high activity level, and there had been progressive osteolysis surrounding the distal aspect of the femoral sleeve. In 2017, the metaphyseal sleeve had loosened, resulting in corrosion of the threaded taper and catastrophic failure of the implant, with a fracture of the stem at the junction of the sleeve. CONCLUSION: This unique method of failure in this knee implant highlights a weak point in the design. Clinicians must be aware of the increased likelihood of this type of failure with these implants in patients who have contributory factors.

Taper Corrosion and Adverse Local Tissue Reactions in Patients with a Modular Knee Prosthesis.

BACKGROUND: Corrosion has been documented in modular knee implants, but it has not been related to negative patient outcomes. We performed an observational retrieval investigation of 13 Stryker Triathlon TS modular knee implants, 3 of which were revised because of osteolysis and adverse local tissue reactions secondary to fretting corrosion at the modular junctions. METHODS: Modular surfaces were examined for the presence and severity of corrosion, and factors that may influence the development of corrosion were investigated. Scanning electron microscopy and energy-dispersive x-ray spectroscopy were performed to evaluate implants with severe corrosion, and tissue samples were sent for histopathological analysis. RESULTS: Mild to severe corrosion was present in association with 62% of modular tibial components and 75% of modular femoral components. Although tibial corrosion was less prevalent than femoral corrosion, it occurred earlier and with greater severity. Scanning electron microscopy and energy-dispersive x-ray spectroscopy demonstrated the appearances of fretting and corrosion of the modular junctions. Histopathological analysis of specimens from the 3 patients with adverse local tissue reactions demonstrated severe reactions to metal debris, including 1 reaction that was consistent with an aseptic lymphocyte-dominated vasculitis-associated lesion (ALVAL). CONCLUSIONS: To our knowledge, ALVAL and pseudotumors have not previously been reported secondary to corrosion of modular knee replacements. The threaded taper design and the release of cobalt-chromium ions and/or debris are implicated in the occurrence of the adverse local tissue reactions, osteolysis, and soft-tissue damage that we observed in our investigation. Clinicians should be aware of this possible complication associated with modular knee implants. CLINICAL RELEVANCE: This article should raise clinician awareness of adverse local tissue reactions secondary to corrosion, potentially resulting in earlier recognition of this complication.

Oxidation of Second Generation Sequentially Irradiated and Annealed Highly Cross-Linked X3™ Polyethylene Tibial Bearings.

Since the first use of ultra-high-molecular-weight polyethylene as a bearing material, research and development efforts have sought to improve wear resistance, increase longevity and lessen the potential for debris mediated adverse tissue responses. A series of second generation sequentially cross-linked and annealed tibial bearings were analysed after several bearings sent for routine retrieval analysis showed oxidative degradation including subsurface whitening, cracking and gross material loss. Evaluation incorporated visual and white banding assessment, mechanical testing and spectroscopy analysis. Whilst visual observation and white banding assessment confirmed oxidative changes, a decrease in mechanical properties and increasing ketone oxidation index as a function of time in vivo suggest time dependent oxidative degradation. Clinically relevant degradation of the sequentially cross-linked and annealed tibial bearings was observed.

Repair of meniscal cartilage white zone tears using a stem cell/collagen-scaffold implant.

Injuries to the avascular region of knee meniscal cartilage do not heal spontaneously. To address this problem we have developed a new stem cell/collagen-scaffold implant system in which human adult bone marrow mesenchymal stem cells are seeded onto a biodegradable scaffold that allows controlled delivery of actively dividing cells to the meniscus surface. Sandwich constructs of two white zone ovine meniscus discs with stem cell/collagen-scaffold implant in between were cultured in vitro for 40 days. Histomorphometric analysis revealed superior integration in the stem cell/collagen-scaffold groups compared to the cell-free collagen membrane or untreated controls. The addition of TGF-beta1 to differentiate stem cells to chondrocytes inhibited integration. Biomechanical testing demonstrated a significant 2-fold increase in tensile strength in all constructs using the stem cell/collagen-scaffold compared to control groups after 40 days in culture. Integration was significantly higher when collagen membranes were used that had a more open/spongy structure adjacent to both meniscal cartilage surfaces, whereas a collagen scaffold designed for osteoinduction failed to induce any integration of meniscus. In conclusion, the stem cell/collagen-scaffold implant is a potential therapeutic treatment for the repair of white zone meniscal cartilage tears.

The synergistic effects of lysophosphatidic acid receptor agonists and calcitriol on MG63 osteoblast maturation at titanium and hydroxyapatite surfaces.

Successful osseointegration stems from the provision of a mechanically competent mineralised matrix at the implant site. Mature osteoblasts are the cells responsible for achieving this and a key factor for ensuring healthy bone tissue is associated with prosthetic materials will be 1 alpha,25 dihydroxy vitamin D3 (calcitriol). However it is known that calcitriol per se does not promote osteoblast maturation, rather the osteoblasts need to be in receipt of calcitriol in combination with selected growth factors in order to undergo a robust maturation response. Herein we report how agonists of the lysophosphatidic acid (LPA) receptor, LPA and (2S)-OMPT, synergistically co-operate with calcitriol to secure osteoblast maturation for cells grown upon two widely used bone biomaterials, titanium and hydroxyapatite. Efforts could now be focussed on functionalizing these materials with LPA receptor agonists to support in vivo calcitriol-induced osseointegration via heightened osteoblast maturation responses.

Induction of cartilage integration by a chondrocyte/collagen-scaffold implant.

The integration of implanted cartilage is a major challenge for the success of tissue engineering protocols. We hypothesize that in order for effective cartilage integration to take place, matrix-free chondrocytes must be induced to migrate between the two tissue surfaces. A chondrocyte/collagen-scaffold implant system was developed as a method of delivering dividing cells at the interface between two cartilage surfaces. Chondrocytes were isolated from bovine nasal septum and seeded onto both surfaces of a collagen membrane to create the chondrocyte/collagen-scaffold implant. A model of two cartilage discs and the chondrocyte/collagen-scaffold sandwiched in between was used to effect integration in vitro. The resulting tissue was analysed histologically and biomechanically. The cartilage-implant-cartilage sandwich appeared macroscopically as one continuous piece of tissue at the end of 40 day cultures. Histological analysis showed tissue continuum across the cartilage-scaffold interface. The integration was dependent on both cells and scaffold. Fluorescent labeling of implanted chondrocytes demonstrated that these cells invade the surrounding mature tissue and drive a remodelling of the extracellular matrix. Using cell-free scaffolds we also demonstrated that some chondrocytes migrated from the natural cartilage into the collagen scaffold. Quantification of integration levels using a histomorphometric repair index showed that the chondrocyte/collagen-scaffold implant achieved the highest repair index compared to controls, reflected functionally through increased tensile strength. In conclusion, cartilage integration can be achieved using a chondrocyte/collagen-scaffold implant that permits controlled delivery of chondrocytes to both host and graft mature cartilage tissues. This approach has the potential to be used therapeutically for implantation of engineered tissue.

A comparison of colorimetric and DNA quantification assays for the assessment of meniscal fibrochondrocyte proliferation in microcarrier culture.

We have developed and refined a rapid, reliable method for the evaluation of attachment and proliferation of ovine meniscal chondrocytes in microcarrier culture. Assays measuring both mitochondrial activity, using MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] and MTS [3-(4,5-dimethylthiazol-2-yl)5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium], and DNA synthesis with a PicoGreen assay were compared. The MTT assay was the most sensitive at lower cell concentrations and enabled accurate assessment of cell proliferation over 14 day culture.

Effect of silicon doping on bone formation within alumina porous domains.

The effect of doping a porous bioinert bioceramic with silicon (Si) on tissue ingrowth, differentiation, and osteogenesis was studied using a rat intramedullary model. Alumina tubes (1.3-mm outer diameter, 0.6-mm inner diameter, 15-mm length) doped with Si at nominal concentrations of 0.5 and 5.0 mol % were implanted into femoral medullary canals of female rats for 16 weeks. Tissue formation within the tubes was determined by histology and histomorphometry. Addition of 0.5 mol % Si to alumina stimulated cellular activity at the bone-ceramic interface and impaired osteogenic maturation within the tubes. In contrast, osteogenesis was enhanced in the 5.0 mol % Si-doped alumina tubes. It is considered that effect of Si is related to surface chemistry rather than microstructure. This work demonstrates that doping a bioinert ceramic with small amounts of Si can significantly alter tissue ingrowth, differentiation, and osteogenesis within a porous implant.

Bone formation within alumina tubes: effect of calcium, manganese, and chromium dopants.

Alumina tubes (1.3mm outer diameter, 0.6mm inner diameter, 15 mm length) doped with Ca, Mn, or Cr at nominal concentrations of 0.5 and 5.0 mol% were implanted into femoral medullary canals of female rats for 16 weeks. Tissue formation within tubes was determined by histology and histomorphometry. Addition of Ca to alumina promoted hypertrophic bone formation at the advancing tissue fronts and tube entrances, and appeared to retard angiogenesis by limiting ongoing cellular migration into the tube. It is speculated that the presence of a secondary phase of calcium hexaluminate, probably having a solubility greater than that of alumina, possibly increased the level of extracellular Ca and, consequently, stimulated osteoclastic activity at the bone-ceramic interface. Addition of Mn significantly enhanced osteogenesis within the tubes. However, it is not possible to determine whether phase composition or microstructure of the ceramic was responsible for this because both were significantly altered by Mn addition. Addition of Cr to the alumina apparently stimulated bone remodelling as indicated by increased cellular activity and bone resorption at the tissue-implant interface. Cr was incorporated into the alumina as a solid solution and the tissue response was speculated to be an effect of surface chemistry rather than microstructure. The work demonstrates that doping a bioinert ceramic with small amounts of specific elements can significantly alter tissue ingrowth, differentiation, and osteogenesis within a porous implant.