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Background: Aseptic loosening remains a major problem following prosthetic replacement after resection of periarticular tumors. Attempts to decrease the rate of loosening led to the introduction of a composite segmental prosthesis in which the shoulder of the intramedullary stem is porous-coated to allow extracortical bone bridging and bone ingrowth. The purposes of this study were to determine the extent of extracortical bone bridging around, and the amount of bone growth into, the porous-coated shoulder of endoprostheses implanted following the resection of periarticular bone tumors and to correlate the radiographic and histologic findings.Methods: Twenty tumor endoprostheses implanted with use of the extracortical bone-bridging technique were evaluated radiographically to determine the extent of extracortical bone and the amount of bone ingrowth. Five of these endoprostheses were retrieved and subjected to histologic analysis with backscattered electron microscopy and transmitted light microscopy to determine the extent of bone ingrowth.Results: At a mean of twenty-eight months postoperatively, varying amounts of extracortical bone formation were seen radiographically in all patients. Radiographs also appeared to show bone growth into the porous-coated segment of all implants. However, histologic analysis of the five retrieved prostheses revealed that none of the extracortical bone had actually grown into the porous-coated segment of the implant.Conclusions: This study confirmed that autogenous bone-grafting of the bone-implant junction of a tumor endoprosthesis consistently results in the formation of extracortical bone. Although radiographs seemed to indicate that this bone grows into the porous coating, this was not confirmed histologically. Growth of extracortical bone into the extramedullary, porous-coated portion of tumor endoprostheses in humans may not be attainable with the current prosthetic design and surgical technique. [ABSTRACT FROM AUTHOR]

Osteogenesis imperfecta (OI) is a genetic bone fragility disorder that features frequent fractures. Bone healing outcomes are contingent on a proper balance between bone formation and resorption, and drugs such as bone morphogenetic proteins (BMPs) and bisphosphonates (BPs) have shown to have utility in modulating fracture repair. While BPs are used for OI to increase BMD and reduce pain and fracture rates, there is little evidence for using BMPs as local agents for fracture healing (alone or with BPs). In this study, we examined wild-type and OI mice (Col1a2 +/G610C ) in a murine tibial open fracture model with (i) surgery only/no treatment, (ii) local BMP-2 (10 µg), or (iii) local BMP-2 and postoperative zoledronic acid (ZA; 0.1 mg/kg total dose). Microcomputed tomography reconstructions of healing fractures indicated BMP-2 was less effective in an OI setting, however, BMP-2 +ZA led to considerable increases in bone volume (+193% WT, p < 0.001; +154% OI, p < 0.001) and polar moment of inertia (+125% WT, p < 0.01; +248% OI, p < 0.05). Tissue histology revealed a thinning of the neocortex of the callus in BMP-2 treated OI bone, but considerable retention of woven bone in the healing callus with BMP + ZA specimens. These data suggest a cautious approach may be warranted with the sole application of BMP-2 in an OI surgical setting as a bone graft substitute. However, this may be overcome by off-label BP administration., (© 2022 The Authors. Journal of Orthopaedic Research ® published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society.)

Introduction : Osteomyelitis remains a major clinical challenge. Many published rodent fracture infection models are costly compared with murine models for rapid screening and proof-of-concept studies. We aimed to develop a dependable and cost-effective murine bone infection model that mimics bacterial bone infections associated with biofilm and metal implants. Methods : Tibial drilled hole (TDH) and needle insertion surgery (NIS) infection models were compared in C57BL/6 mice (female, N = 150 ). Metal pins were inserted selectively into the medullary canal adjacent to the defect sites on the metaphysis. Free  Staphylococcus aureus  (ATCC 12600) or biofilm suspension (ATCC 25923) was locally inoculated. Animals were monitored for physiological or radiographic evidence of infection without prophylactic antibiotics for up to 14 d. At the end point, bone swabs, soft-tissue biopsies, and metal pins were taken for cultures. X-ray and micro-CT scans were performed along with histology analysis. Results : TDH and NIS both achieved a 100 % infection rate in tibiae when a metal implant was present with injection of free bacteria. In the absence of an implant, inoculation with a bacterial biofilm still induced a 40 %-50 % infection rate. In contrast, freely suspended bacteria and no implant consistently showed lower or negligible infection rates. Micro-CT analysis confirmed that biofilm infection caused local bone loss even without a metal implant as a nidus. Although a metal surface permissive for biofilm formation is impermeable to create progressive bone infections in animal models, the metal implant can be dismissed if a bacterial biofilm is used. Conclusion : These models have a high potential utility for modeling surgery-related osteomyelitis, with NIS being simpler to perform than TDH., Competing Interests: The contact author has declared that none of the authors has any competing interests., (Copyright: © 2023 Aiken Dao et al.)

Background: Spine fusion is a common procedure for the treatment of severe scoliosis, a frequent and challenging deformity associated with Neurofibromatosis type 1 (NF1). Moreover, deficiencies in NF1-Ras-MEK signaling affect bone formation and resorption that in turn impacts on spine fusion outcomes., Methods: In this study we describe a new model for AdCre virus induction of Nf1 deficiency in the spines of Nf1 flox/flox mice. The virus is delivered locally to the mouse spine in a fusion procedure induced using BMP-2. Systemic adjunctive treatment with the MEK inhibitor (MEKi) PD0325901 and the bisphosphonate zoledronic acid (ZA) were next trialed in this model., Results: AdCre delivery resulted in abundant fibrous tissue (Nf1 null  +393%, P < 0.001) and decreased marrow space (Nf1 null  -67%, P < 0.001) compared to controls. While this did not significantly impact on the bone volume of the fusion mass (Nf1 null  -14%, P = 0.999 n.s.), the presence of fibrous tissue was anticipated to impact on the quality of spine fusion. Multinucleated TRAP + cells were observed in the fibrous tissues seen in Nf1 null spines. In Nf1 null spines, MEKi increased bone volume (+194%, P < 0.001) whereas ZA increased bone density (+10%, P < 0.002) versus BMP-2 alone. Both MEKi and ZA decreased TRAP + cells in the fibrous tissue (MEKi -62%, P < 0.01; ZA -43%, P = 0.054). No adverse effects were seen with either MEKi or ZA treatment including weight loss or signs of illness or distress that led to premature euthanasia., Conclusions: These data not only support the utility of an AdCre-virus induced knockout spine model, but also support further investigation of MEKi and ZA as adjunctive therapies for improving BMP-2 induced spine fusion in the context of NF1., (Crown Copyright © 2020. Published by Elsevier B.V. All rights reserved.)

In this review, we broadly define and discuss the preclinical rodent models that are used for orthopedics and bone tissue engineering. These range from implantation models typically used for biocompatibility testing and high-throughput drug screening, through to fracture and critical defect models used to model bone healing and severe orthopedic injuries. As well as highlighting the key methods papers describing these techniques, we provide additional commentary based on our substantive practical experience with animal surgery and in vivo experimental design. This review also briefly touches upon the descriptive and functional outcome measures and power calculations that are necessary for an informative study. Obtaining informative and relevant research outcomes can be very dependent on the model used, and we hope this evaluation of common models will serve as a primer for new researchers looking to undertake preclinical bone studies. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:832-840, 2018., (© 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Background: Bony fixation of cementless orthopaedic implants is not always achieved, particularly in challenging scenarios such as revision surgery, trauma, and tumor reconstruction. An adjunct therapy for improving porous implant fixation could improve the reliability and durability of these reconstructive procedures., Questions/purposes: In this study, we asked whether there is a positive and dose-dependent effect of the local release of the bisphosphonate alendronate from (1) alendronate/hydroxyapatite (HA) porous-coated titanium implants compared with bare metal porous controls; and (2) alendronate/HA on porous-coated titanium implants compared with HA-coated porous controls with respect to extent of bone ingrowth, bone apposition, and periimplant bone formation in a canine model?, Methods: Three-dimensional printed porous-coated cylindrical implants coated with three different doses (0.02, 0.06, and 0.18 mg/cm(2)) of alendronate were inserted bilaterally in the intramedullary canal of the proximal femora of 15 adult mongrel dogs (age range, 3-9 years; mean, 5 years) weighing between 36 kg and 60 kg (mean, 43 kg). In each dog, an implant coated with HA and one of three different doses of alendronate was inserted on one side while the contralateral femur had a bare metal porous control implant and an identical control implant with a coating of HA. The dose effect of locally released alendronate on the extent of bone ingrowth, bone apposition, and periimplant bone was assessed by backscattered electron microscopy of three pairs of cross-sections taken from each implant at 12 weeks after surgery. A linear mixed model was used to perform the statistical analyses to account for the correlation in the data resulting from the multiple measures performed on each dog., Results: Compared with paired bare metal controls, periimplant bone increased by 92% (p = 0.007), and 114% (p < 0.001) in the femora with the alendronate implants with a dose of 0.06 mg/cm(2), or 0.18 mg/cm(2), respectively. At a dose of 0.02 mg/cm(2), there was no difference (46% change; p = 0.184, with the numbers available). The comparison of the alendronate-dosed implants with their HA-coated controls showed that the intermediate dose of 0.06 mg/cm(2) alendronate had the greatest effect on net bone formation. Bone apposition was enhanced with the 0.06-mg/cm(2) alendronate femoral implants (82%; p = 0.008), although there was no change in bone ingrowth (37% change; p = 0.902, with the numbers available). When compared with the HA-coated control implants, the greatest effect of the alendronate-dosed implants was the increased amount of periimplant bone at the intermediate dose of 0.06-mg/cm(2) (108%, p = 0.009). There was no effect of the low (0.02-mg/cm(2)) and high (0.18-mg/cm(2)) alendronate-dosed implants (4%, and 6%, respectively; p = 0.321, p = 0.502). Overall, all three alendronate-dosed implants revealed little to no effect on bone ingrowth compared with the HA-coated control implants., Conclusions: The local release of alendronate from a three-dimensional printed porous-coated implant from the three doses studied showed an overall improvement in bone apposition and periimplant bone at the intermediate dose compared with bare metal or with HA-coated controls, although the effect was more pronounced compared with bare metal. Long-term studies to show the effects of localized alendronate delivery and mechanical fixation would be the next step for future studies., Clinical Relevance: Local release of alendronate from a three-dimensional printed porous-coated implant may improve the reliability of cementless fixation of currently available porous-coated bare metal implants.

To better understand the relative contributions of mesenchymal and endothelial progenitor cells to rhBMP-2 induced bone formation, we examined the distribution of lineage-labeled cells in Tie2-Cre:Ai9 and αSMA-creERT2:Col2.3-GFP:Ai9 reporter mice. Established orthopedic models of ectopic bone formation in the hind limb and spine fusion were employed. Tie2-lineage cells were found extensively in the ectopic bone and spine fusion masses, but co-staining was only seen with tartrate-resistant acid phosphatase (TRAP) activity (osteoclasts) and CD31 immunohistochemistry (vascular endothelial cells), and not alkaline phosphatase (AP) activity (osteoblasts). To further confirm the lack of a functional contribution of Tie2-lineage cells to BMP-induced bone, we developed conditional knockout mice where Tie2-lineage cells are rendered null for key bone transcription factor osterix (Tie2-cre:Osx(fx/fx) mice). Conditional knockout mice showed no difference in BMP-induced bone formation compared to littermate controls. Pulse labeling of mesenchymal cells with Tamoxifen in mice undergoing spine fusion revealed that αSMA-lineage cells contributed to the osteoblastic lineage (Col2.3-GFP), but not to endothelial cells or osteoclast populations. These data indicate that the αSMA+ and Tie2+ progenitor lineages make distinct cellular contributions to bone formation, angiogenesis, and resorption/remodeling., (Crown Copyright © 2015. Published by Elsevier Inc. All rights reserved.)

Multiple techniques designed to induce scoliotic deformity have been applied across many animal species. We have undertaken a review of the literature regarding experimental models of scoliosis in animals to discuss their utility in comprehending disease aetiology and treatment. Models of scoliosis in animals can be broadly divided into quadrupedal and bipedal experiments. Quadrupedal models, in the absence of axial gravitation force, depend upon development of a mechanical asymmetry along the spine to initiate a scoliotic deformity. Bipedal models more accurately mimic human posture and consequently are subject to similar forces due to gravity, which have been long appreciated to be a contributing factor to the development of scoliosis. Many effective models of scoliosis in smaller animals have not been successfully translated to primates and humans. Though these models may not clarify the aetiology of human scoliosis, by providing a reliable and reproducible deformity in the spine they are a useful means with which to test interventions designed to correct and prevent deformity., (© 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Background: Fixation of cementless orthopaedic implants is not always achieved, particularly in challenging scenarios such as revision surgery, trauma, and tumor reconstruction. An adjunct therapy for improving implant fixation would improve the reliability and durability of certain reconstructive procedures., Questions/purposes: The purpose of this study was to determine the effect of local elution of the bisphosphonate alendronic acid on bone formation around porous titanium implants in an animal model., Methods: Porous-coated cylindrical rods were coated with either 0.2 mg or 1.0 mg alendronic acid before bilateral surgical implantation into the femoral intramedullary canals of 10 experimental dogs. Twelve weeks after surgery, the femora were harvested and scanned with micro-CT to quantify the percentage volume of bone within the immediate periimplant space. Four femora from two dogs were also processed for undecalcified thin-section histology and analysis with backscattered scanning electron microscopy. Three histologic sections from each of these four femora were anatomically matched with transverse micro-CT sections to enable direct comparison of the area fraction of bone within the periimplant space., Results: Compared with paired controls, micro-CT analysis showed that local elution of alendronic acid increased periimplant bone at both doses of 0.2 mg (+52%, p = 0.01) and 1.0 mg (+152%, p = 0.004) with 1.0 mg resulting in a 2.9-fold greater mean relative increase compared with 0.2 mg (p = 0.002). Micro-CT measurements of periimplant bone formation correlated very strongly with the backscattered scanning electron microscopy measurements (R = 0.965, p < 0.001)., Conclusions: Local elution of alendronic acid causes a dose-dependent net increase in periimplant bone formation in an animal model., Clinical Relevance: This concept has potential to improve the biologic fixation of porous reconstructive implants.

Background: Noncemented revision arthroplasty is often complicated by the presence of bone implant gaps that reduce initial stability and biologic fixation. Demineralized bone matrix has osteoinductive properties and therefore the potential to enhance gap healing and porous implant fixation., Questions/purposes: We determined at what times and to what extent demineralized bone matrix promotes gap healing and bone ingrowth around a porous implant., Methods: We inserted porous titanium implants into the proximal metaphyses of canine femora and humeri, with an initial 3-mm gap between host cancellous bone and implants. We left the gaps empty (control; n = 12) or filled them with either demineralized bone matrix (n = 6) or devitalized demineralized bone matrix (negative control; n = 6) and left them in situ for 4 or 12 weeks. We quantified volume healing of the gap with new bone using three-dimensional micro-CT scanning and quantified apposition and ingrowth using backscattered scanning electron microscopy., Results: The density of bone inside gaps filled with demineralized bone matrix reached 64% and 93% of surrounding bone density by 4 and 12 weeks, respectively. Compared with empty controls and negative controls at 4 and 12 weeks, gap healing using demineralized bone matrix was two to three times greater and bone ingrowth and apposition were up to 15 times greater., Conclusions: Demineralized bone matrix promotes rapid bone ingrowth and gap healing around porous implants., Clinical Relevance: Demineralized bone matrix has potential for enhancing implant fixation in revision arthroplasty.

Neurofibromatosis type 1 (NF1) is a common genetic condition caused by mutations in the NF1 gene. Patients often suffer from tissue-specific lesions associated with local double-inactivation of NF1. In this study, we generated a novel fracture model to investigate the mechanism underlying congenital pseudarthrosis of the tibia (CPT) associated with NF1. We used a Cre-expressing adenovirus (AdCre) to inactivate Nf1 in vitro in cultured osteoprogenitors and osteoblasts, and in vivo in the fracture callus of Nf1(flox/flox) and Nf1(flox/-) mice. The effects of the presence of Nf1(null) cells were extensively examined. Cultured Nf1(null)-committed osteoprogenitors from neonatal calvaria failed to differentiate and express mature osteoblastic markers, even with recombinant bone morphogenetic protein-2 (rhBMP-2) treatment. Similarly, Nf1(null)-inducible osteoprogenitors obtained from Nf1 MyoDnull mouse muscle were also unresponsive to rhBMP-2. In both closed and open fracture models in Nf1(flox/flox) and Nf1(flox/-) mice, local AdCre injection significantly impaired bone healing, with fracture union being <50% that of wild type controls. No significant difference was seen between Nf1(flox/flox) and Nf1(flox/-) mice. Histological analyses showed invasion of the Nf1(null) fractures by fibrous and highly proliferative tissue. Mean amounts of fibrous tissue were increased upward of 10-fold in Nf1(null) fractures and bromodeoxyuridine (BrdU) staining in closed fractures showed increased numbers of proliferating cells. In Nf1(null) fractures, tartrate-resistant acid phosphatase-positive (TRAP+) cells were frequently observed within the fibrous tissue, not lining a bone surface. In summary, we report that local Nf1 deletion in a fracture callus is sufficient to impair bony union and recapitulate histological features of clinical CPT. Cell culture findings support the concept that Nf1 double inactivation impairs early osteoblastic differentiation. This model provides valuable insight into the pathobiology of the disease, and will be helpful for trialing therapeutic compounds., (Copyright © 2012 American Society for Bone and Mineral Research.)

The purpose of this study was to characterize a technique to effectively mask surface chemistry without modifying surface topography. A thin layer of titanium was deposited by physical vapor deposition (PVD) onto different biomaterial surfaces. Commercially pure titanium disks were equally divided into three groups. Disks were either polished to a mirror finish, grit blasted with alumina particles, or grit blasted and subsequently plasma sprayed with a commercial grade of hydroxyapatite (HA). A subgroup of each of these treatment types was further treated by masking the entire disk surface with a thin layer of commercially pure titanium deposited by PVD. A comparison of surface topography and chemical composition was carried out between disks within each treatment group. Canine marrow cells were seeded on all disk surfaces to determine the stability of the PVD Ti mask under culture conditions. The PVD process did not significantly alter the surface topography of any samples. The thin titanium layer completely masked the underlying chemistry of the plasma sprayed HA surface and the chemistry of the plasma vapor deposited titanium layer did not differ from that of the commercially pure titanium disks. Aliquots obtained from the media during culture did not indicate any significant differences in Ti concentration amongst the Ti and Ti-masked surfaces. The PVD application of a Ti layer on HA coatings formed a stable, durable, and homogenous layer that effectively masked the underlying surface chemistry without altering the surface topography., (Copyright 2007 Wiley Periodicals, Inc.)

Virtually all contemporary cementless femoral hip stems are designed with the goals of achieving immediate and long-term stability, restoring hip mechanics, and minimizing thigh pain. However, the incorporation of features specifically intended to minimize stress-mediated bone resorption (stress shielding) has been variable. Attempts to reduce bone loss through stem design have yielded inconsistent results and, in certain instances, early and catastrophic failure. Prior beliefs regarding the determinants of stress shielding were based upon the qualitative assessment of bone loss using plain radiographs. These are being challenged, particularly with regard to the role of porous coating level. This is in large part due to the refinement and widespread availability of dual-energy xray absorptiometry (DEXA), which allows quantitative assessment of bone mineral density both pre- and postoperatively. The available evidence indicates stem stiffness plays a dominant role. Progressive bone loss through stress shielding has potentially dire consequences. While such problems have not manifested as severe or widespread clinical issues, the preservation of femoral bone stock is an important and desirable goal.

The influence of microstructure on the wear of cobalt-based alloys used in metal-on-metal hip implants was investigated in a boundary lubrication regime designed to represent the conditions that occurred some of the time in vivo. These cobalt-chromium-molybdenum alloys were either wrought, with a total carbon content of 0.05 or 0.23 wt %, cast with a solution-annealing procedure or simply as-cast but not solution annealed. Bars of these different alloy grades were subjected to various heat treatments to develop different microstructures. The wear was evaluated in a linear-tracking reciprocating pin-on-plate apparatus with a 25 per cent bovine serum lubricant. The wear was found to be strongly affected by the dissolved carbon content of the alloys and mostly independent of grain size or the carbide characteristics. The increased carbon in solid solution caused reductions in volumetric wear because carbon helped to stabilize a face-centred cubic crystal structure, thus limiting the amount of strain-induced transformation to a hexagonal close-packed crystal structure. Based on the observed surface twining in and around the contact zone and the potentially detrimental effect of the hexagonal close-packed phase, it was postulated that the wear of cobalt-based alloys in the present study was controlled by a deformation mechanism.

Detailed characterization of wear particles is necessary to understand better the implant wear mechanisms and the periprosthetic tissue response. The purposes of the present study were to compare particle characteristics of current with older designs of metal-on-metal (MM) total hip replacements (THRs), and to determine the effect of implantation time on wear particle characteristics. Metal wear particles isolated from periprosthetic tissues from 19 patients with MM THRs of current and older designs and at different implantation times (very short, longer, and very long) were studied using transmission electron microscopy and energy dispersive X-ray analysis. The particles from the current design implants with implantation times of not more than 15 months (very short-term) were almost exclusively round to oval chromium oxide particles. In all other cases, although the predominance was still round to oval chromium oxide particles, greater proportions of cobalt-chromium-molybdenum (Co-Cr-Mo) particles, mainly needle-shaped, were detected. Very long-term THRs implanted for more than 20 years had the highest percentage of needle-shaped Co-Cr-Mo particles. Particle lengths were not markedly different between the different designs and implantation times except for the current design implants of not more than 15 months, which had a significantly smaller mean length of 39 nm. In conclusion, the implant design did not seem to have a significant influence on particle characteristics whereas the implantation time appeared to have the most effect on the particles. It should be noted that, because of the limited number of tissue retrievals available, some uncertainty remains regarding the generality of these findings.

The microstructure and its effect on the friction behavior of a medical grade wrought cobalt-chromium-molybdenum (CoCrMo) alloy for surgical implants were studied in this work. In particular, the effects of compression and carbon (C) content on the above characteristics were analyzed. Increasing amounts of deformation resulted in a decrease in the number of annealing twins in the microstructures. In addition, there was an increase in the volume fraction of the hexagonal closed-packed (HCP) phase due to a strain-induced transformation (SIT) from the metastable face-centered cubic (FCC) phase. The high C (HC) alloy had a lower volume fraction of this SIT phase. Friction studies conducted on these alloys revealed a higher coefficient of friction for the HC alloy and no significant effect of SIT on the friction characteristics., (Copyright 2005 Wiley Periodicals, Inc.)

The bisphosphonate zoledronic acid chemically and physically was bound to hydroxyapatite-coated porous tantalum implants. The zoledronic acid elution characteristics in saline were determined as a function of time and the in vivo effects of elution were quantified at 12 weeks in a canine ulnar implant model. Intramedullary implants surgically were implanted bilaterally into the ulnae of a control group of five dogs and a zoledronic acid-dosed (0.05 mg zoledronic acid) group of four dogs. Computerized image analysis of undecalcified histologic sections was used to quantify the amount of peri-implant bone within the intramedullary canal, the percentage of available pore space filled with new bone, and the number and size of the individual bone islands within the implant pores. The data were analyzed using a hierarchical analysis of variance with 95% confidence intervals. The peri-implant bone occupied a mean of 13.8% of the canal space in controls and 32.2% of the canal space in zoledronic acid-dosed dogs, a relative difference of 134% (2.34-fold) that was significant. The mean extent of bone ingrowth was 12.5% for the control implants and 19.8% for the zoledronic acid-dosed dogs, a relative difference of 58% that was statistically significant. Individual islands of new bone formation with the implant pores were similar in number in both implant groups but were 71% larger on average in the ZA-dosed group. We are the first authors to show that local elution of a bisphosphonate can cause substantial bone augmentation around and within porous orthopaedic implants. The concept represents a potential tool for restoration of bone stock and enhancement of implant fixation in primary and revision cementless joint arthroplasty surgeries in the face of compromised or deficient bone.

The effect of zoledronic acid on bone ingrowth was examined in an animal model in which porous tantalum implants were placed bilaterally within the ulnae of seven dogs. Zoledronic acid in saline was administered via a single post-operative intravenous injection at a dose of 0.1 mg/kg. The ulnae were harvested six weeks after surgery. Undecalcified transverse histological sections of the implant-bone interfaces were imaged with backscattered scanning electron microscopy and the percentage of available pore space that was filled with new bone was calculated. The mean extent of bone ingrowth was 6.6% for the control implants and 12.2% for the zoledronic acid-treated implants, an absolute difference of 5.6% (95% confidence interval, 1.2 to 10.1) and a relative difference of 85% which was statistically significant. Individual islands of new bone formation within the implant pores were similar in number in both groups but were 69% larger in the zoledronic acid-treated group. The bisphosphonate zoledronic acid should be further investigated for use in accelerating or enhancing the biological fixation of implants to bone.

The purpose of the present study was to compare wear particles isolated from metal-metal (MM) hip implants worn in an orbital bearing simulator with particles from similar MM total hip replacement (THR) implants worn in vivo. Comparison of these particles is important because it will help to assess the overall suitability of this type of hip simulator for reproducing in vivo wear and for producing physiological wear particles suitable for biological studies of in vitro cellular response. Commercial grade components made of ASTM F75 (cast) alloy were evaluated. Simulator tests were performed in 95% bovine calf serum with a 28-mm-diameter implant. Wear particles were collected from 0 to 0.25 million cycles (run-in wear period) and 1.75 to 2 million cycles (steady-state wear period). Tissues from seven patients with MM implants (surface replacement or stem type) were harvested at revision surgeries (after 1-43 months). Metal wear particles were isolated from serum lubricant or tissues using an enzymatic protocol that was previously optimized to minimize particle changes due to reagents. After isolation, particles were centrifuged, embedded in epoxy resin, and characterized by transmission electron microscopy (TEM) and energy dispersive X-ray analysis (EDXA). Results of EDXA on particles from the hip simulator primarily indicated a predominance of particles containing Cr and O but no Co (most likely chromium oxide particles), and fewer CoCrMo particles presenting varying ratios of Co and Cr. Image analysis of TEM micrographs demonstrated that the majority of the particles from the simulator were round to oval, but a substantial number of needle-shaped particles were also found, especially from 0 to 0.25 Mc. The particles generated from 0 to 0.25 Mc had an average length of 53 nm, whereas those generated from 1.75 to 2 Mc had an average length of 43 nm. In vivo, EDXA and TEM analysis of particles that were retrieved from two patients at 23 and 43 months respectively, revealed that they were the most comparable in composition, average length (57 nm), and shape to particles generated in the hip simulator during the run-in wear period. Because a large clinical retrieval study in the literature suggested that a run-in wear regime might occur in vivo for some 6-36 months, the fidelity of the simulator of the present study was strongly supported. However, some uncertainties existed, including the finding that the particles isolated from the other five patients generated from 1 month up to 15 months (shorter implantation times than the other two patients) were smaller and mostly contained only Cr and O (no Co). In the opinion of the authors, this particular very short term patient group was somewhat atypical. Therefore, despite these uncertainties, the present study was deemed to support the ability of the orbital bearing hip simulator to produce physiological wear particles., (Copyright 2004 Wiley Periodicals, Inc.)

We designed an in vivo study to determine if the superimposition of a microtexture on the surface of sintered titanium beads affected the extent of bone ingrowth. Cylindrical titanium intramedullary implants were coated with titanium beads to form a porous finish using commercial sintering techniques. A control group of implants was left in the as-sintered condition. The test group was etched in a boiling acidic solution to create an irregular surface over the entire porous coating. Six experimental dogs underwent simultaneous bilateral femoral intramedullary implantation of a control implant and an acid etched implant. At 12 weeks, the implants were harvested in situ and the femora processed for undecalcified, histological examination. Eight transverse serial sections for each implant were analysed by backscattered electron microscopy and the extent of bone ingrowth was quantified by computer-aided image analysis. The extent of bone ingrowth into the control implants was 15.8% while the extent of bone ingrowth into the etched implants was 25.3%, a difference of 60% that was statistically significant. These results are consistent with other research that documents the positive effect of microtextured surfaces on bone formation at an implant surface. The acid etching process developed for this study represents a simple method for enhancing the potential of commonly available porous coatings for biological fixation.

There has been a revived interest in metal-metal total hip replacements because of their potential for improved wear performance compared with conventional metal-polyethylene implants. The aim of the present study was to characterize metal wear particles isolated from metal-metal hip simulator testing of various clinically relevant alloys and to analyze the effects of these alloys and the number of loading cycles on wear particle characteristics. Implants were manufactured using medical-grade cobalt-chromium-molybdenum (CoCrMo) alloys that were high-carbon wrought, low-carbon wrought, or cast (with solution annealing). Testing was performed in a MATCO orbital bearing hip simulator in 95% bovine calf serum. The wear particles were isolated from the serum at test periods of 0-0.25 million cycles (Mc) (run-in wear) and 1.75-2 Mc (steady-state wear) using an enzymatic protocol previously optimized to minimize particle changes due to reagents. Isolated particles embedded in epoxy resin were characterized by transmission electron microscopy (TEM) and energy dispersive X-ray analysis (EDXA). The EDXA results revealed the predominance of "lighter" particles containing Cr and O (most likely chromium oxide particles from the passivation layer) and fewer darker CoCrMo particles, with varying ratios of Co and Cr (possibly from carbides and from implant matrix material). More CoCrMo particles were observed with the low-carbon wrought alloy, but the majority of the particles for all three alloys was chromium oxides, especially for the 1.75-2 Mc test period. Image analysis of TEM micrographs revealed that for 0-0.25 Mc, there was up to 21% needle-shaped particles but that the majority remained round to oval in shape, reflecting the predominance of chromium oxide particles. Particle length averaged about 52 +/- 4 nm, with only small differences due to the alloy. For 1.75-2 Mc, most particles were round to oval in shape. They were even less needle-shaped than at 0.25 Mc, and they had a slightly smaller length, averaging 46 +/- 3 nm. In addition to characterizing the size and shape of particles from a MATCO simulator, this study is the first to demonstrate that particles that do not contain Co (presumably chromium oxides) can be predominant in the wear of metal-metal hip implants. It is therefore recommended that future in vitro and in vivo studies include the effects of these particles rather than just the effects of CoCrMo particles on the overall tissue response., (Copyright 2003 Wiley Periodicals, Inc. J Biomed Mater Res 67A: 312-327, 2003)

The purpose of the current study was to ascertain the relative contributions of surface chemistry and topography to the osseointegration of hydroxyapatite-coated implants. A canine femoral intramedullary implant model was used to compare the osseous response to commercially pure titanium implants that were either polished, grit-blasted, plasma-sprayed with hydroxyapatite, or plasma-sprayed with hydroxyapatite and masked with a very thin layer of titanium using physical vapor deposition (titanium mask). The titanium mask isolated the chemistry of the underlying hydroxyapatite layer without functionally changing its surface topography and morphologic features. At 12 weeks, the bone-implant specimens were prepared for undecalcified thin section histologic evaluation and serial transverse sections were quantified with backscattered scanning electron microscopy for the percentage of bone apposition to the implant surface. Bone apposition averaged 3% for the polished implants and 23% for the grit-blasted implants. Bone apposition to the hydroxyapatite-coated implants averaged 74% whereas bone apposition to the titanium mask implants averaged 59%. Although there was significantly greater osseointegration with the hydroxyapatite-coated implants, 80% of the maximum bone forming response to the implant surfaces developed with the titanium mask implants. This simple, controlled experiment revealed that topography is the dominant factor governing bone apposition to hydroxyapatite-coated implants.

We evaluated 59 hips that underwent a primary total hip arthroplasty using an S-ROM modular femoral component at a mean follow-up of 101 months (range, 72-145 months). All cases showed radiographic evidence of bone ingrowth, and there were no femoral revisions for aseptic loosening. The Harris hip score improved from a mean of 40 preoperatively to 89 at final follow-up. Some degree of proximal femoral disuse atrophy from stress shielding occurred in 46 hips (78%), and some degree of femoral osteolysis occurred in 25 hips (42%). Only additional follow-up will reveal whether there is a consequence of both types of proximal femoral bone loss.

We prospectively assessed femoral bone remodeling using dual-energy x-ray absorptiometry for 2 years after total hip arthroplasty. Thirty-nine hips were randomized to receive a titanium proximally porous-coated femoral component with or without hydroxyapatite-tricalcium phosphate coating. Although both stems resulted in alterations in the periprosthetic bone mineral density, the hydroxyapatite-tricalcium phosphate coated stems had significantly less femoral bone loss than the uncoated stems at 2-year follow-up. This reduced femoral bone loss may provide short-term and long-term advantages over noncoated stems.

Isolation of metal wear particles from hip simulator lubricants or tissues surrounding implants is a challenging problem because of small particle size, their tendency to agglomerate, and their potential for chemical degradation by digestion reagents. To provide realistic measurements of size, shape, and composition of metal wear particles, it is important to optimize particle isolation and minimize particle changes due to the effects of the reagents. In this study (Part I of II), transmission electron microscopy (TEM) was used to examine and compare the effects of different isolation protocols, using enzymes or alkaline solutions, on the size and shape of three different types of cobalt-based alloy particles produced from metal-metal bearings. The effect on particle composition was examined in a subsequent study (Part II). Large particles (<1200 nm) were generated by dry abrasion of CoCrMo alloy against itself and small particles (<300 nm) were generated by hip simulator testing of a metal-metal implant pair in the presence of either distilled-deionized water or a 95% bovine serum solution. The reagents changed particle size and to a lesser extent particle shape. For both large particles and small particles generated in water, the changes in size were more extensive after alkaline than after enzymatic protocols and increased with alkaline concentration and time in solution, up to twofold at 2 h and threefold at 48 h. However, when isolating particles from 95% serum, an initial protective effect of serum proteins and/or lipids was observed. Because of this protective effect, there was no significant difference in particle size and shape for both oval and needle-shaped particles after 2 h in 2N KOH and after enzymatic treatments. However, round particles were significantly smaller after 2 h in 2N KOH than after enzymatic treatments. Particle composition may also have been affected by the 2N KOH treatment, as suggested by a difference in particle contrast under TEM, an issue examined in detail in Part II., (Copyright 2001 John Wiley & Sons, Inc. J Biomed Mater Res 55: 320-329, 2001)

The isolation of metal wear particles from hip simulator lubricants is important for understanding wear mechanisms and the tissue response to particulate material. Part I of this study demonstrated that isolation protocols involving digestion reagents can chemically attack metal-metal wear particles, reducing their size and changing their shape. In part II of this study, Co and Cr ion concentrations in solution after each digestion protocol were measured by flame atomic absorption spectrometry, and wear particle composition was determined by X-ray analysis spectra. The exposure of wear particles in water to alkaline solutions caused an increasing release of Cr ions in solution with alkaline concentration and time, and a corresponding decrease in particle Cr peak intensity on X-ray spectra. As a result, particles exposed to 12N KOH for 48 h displayed Co peaks and no Cr. In contrast, enzymatic protocols caused a release of Co ions in solution and a corresponding decrease in particle Co peak intensity on X-ray spectra, especially with sodium phosphate as a buffer. However, when isolating particles from 95% serum, there was an initial protective effect of serum proteins, presumably because of their binding to Co and Cr. As a result, the extent of Cr ion release from metal wear particles in 95% serum after alkaline treatments was diminished, although still present, whereas both enzymatic protocols resulted in a negligible release of Co and Cr ions into solution. Particle composition analysis after enzymatic treatments revealed the presence of chromium oxide particles and CoCrMo particles with variable Co/Cr ratios. After alkaline treatments, the chromium oxide particles increasingly disappeared with time and alkaline concentration, demonstrating a change in particle composition after these treatments. This study demonstrated that digestion reagents can induce chemical changes that affect particle composition. Of all the protocols tested, the enzymatic protocols were the least damaging to the particles and appeared to be the best compromise for isolation and characterization of metal particles, especially in 95% serum. Special care on the choice of buffers should be taken when isolating particles from a lower concentration of serum., (Copyright 2001 John Wiley & Sons, Inc. J Biomed Mater Res 55: 330-337, 2001)

An in vivo study was designed to determine if non-invasive low intensity ultrasound could enhance bone growth into porous intramedullary implants. Fully porous intramedullary rods were implanted bilaterally into the ulnae of six dogs. In each dog, one ulna served as a control and the other was treated with 20 min of daily ultrasound stimulation for 6 consecutive weeks. Analysis of serial transverse sections indicated an average of 119% more bone growth into the ultrasound-treated implants compared with the contralateral controls (P < 0.001). In each of the 6 dogs, there was a significantly greater amount of bone ingrowth on the ultrasound-stimulated side. These data indicate a clear potential for externally applied ultrasound therapy to augment biological fixation.

This study determined the soft tissue attachment strength and extent of ingrowth to a porous tantalum biomaterial. Eight dorsal subcutaneous implants (in two dogs) were evaluated at 4, 8, and 16 weeks. Upon retrieval, all implants were surrounded completely by adherent soft tissue. Implants were harvested with a tissue flap on the cutaneous aspect and peel tested in a servo-hydraulic tensile test machine at a rate of 5 mm/min. Following testing, implants were dehydrated in a solution of basic fuschin, defatted, embedded in methylmethacrylate, and processed for thin-section histology. At 4, 8, and 16 weeks, the attachment strength to porous tantalum was 61, 71, and 89 g/mm respectively. Histologic analysis showed complete tissue ingrowth throughout the porous tantalum implant. Blood vessels were visible at the interface of and within the porous tantalum material. Tissue maturity and vascularity increased with time. The tissue attachment strength to porous tantalum was three- to six-fold greater than was reported in a similar study with porous beads. This study demonstrated that porous tantalum permits rapid ingrowth of vascularized soft tissue, and attains soft tissue attachment strengths greater than with porous beads., (Copyright 2000 John Wiley & Sons, Inc.)

Accurate restoration of normal limb alignment is crucial for the long-term survivorship of total knee arthroplasty (TKA). A mathematical model was used to evaluate the maximum error in varus and valgus alignment that could occur when cutting the tibia or femur during TKA using intramedullary (IM) guides of varying length and diameter. Minor deviations in the insertion point of IM instrumentation during TKA can result in malalignment of several degrees. This error can be minimized by careful attention to the entry point of the IM instrumentation or by increasing the IM rod diameter and length used during primary TKA.

The implication of polyethylene wear particles as the dominant cause of periprosthetic osteolysis has created a resurgence of interest in metal-on-metal implants for total hip arthroplasty because of their potential for improved wear performance. Twenty-two cobalt chromium molybdenum metal-on-metal implants were custom-manufactured and tested in a hip simulator. Accelerated wear occurred within the first million cycles followed by a marked decrease in wear rate to low steady-state values. The volumetric wear at 3 million cycles was very small, ranging from 0.15 to 2.56 mm3 for all implants tested. Larger head-cup clearance and increased surface roughness were associated with increased wear. Independent effects on wear of material processing (wrought, cast) and carbon content were not identified. Implant wear decreased with increasing lambda ratio, a parameter used to relate lubricant film thickness to surface roughness, suggesting some degree of fluid film lubrication during testing. This study provided important insight into the design and engineering parameters that affect the wear behavior of metal-on-metal hip implants and indicated that high quality manufacturing can reproducibly lead to very low wear.

We have studied the characteristics of bone ingrowth of a new porous tantalum biomaterial in a simple transcortical canine model using cylindrical implants 5 x 10 mm in size. The material was 75% to 80% porous by volume and had a repeating arrangement of slender interconnecting struts which formed a regular array of dodecahedron-shaped pores. We performed histological studies on two types of material, one with a smaller pore size averaging 430 microm at 4, 16 and 52 weeks and the other with a larger pore size averaging 650 microm at 2, 3, 4, 16 and 52 weeks. Mechanical push-out tests at 4 and 16 weeks were used to assess the shear strength of the bone-implant interface on implants of the smaller pore size. The extent of filling of the pores of the tantalum material with new bone increased from 13% at two weeks to between 42% and 53% at four weeks. By 16 and 52 weeks the average extent of bone ingrowth ranged from 63% to 80%. The tissue response to the small and large pore sizes was similar, with regions of contact between bone and implant increasing with time and with evidence of Haversian remodelling within the pores at later periods. Mechanical tests at four weeks indicated a minimum shear fixation strength of 18.5 MPa, substantially higher than has been obtained with other porous materials with less volumetric porosity. This porous tantalum biomaterial has desirable characteristics for bone ingrowth; further studies are warranted to ascertain its potential for clinical reconstructive orthopaedics.

The purpose of this study was to examine the radiographic and histologic response to corundum blasted implant surfaces of varying roughness in a canine total hip arthroplasty model. Three types of tapered femoral implants were made from titanium alloy and were identical in every respect except surface finish. The entire surface of the femoral implant had a 2.9-, 4.2-, or 6.7-micron average surface roughness (Ra) from blasting with 60-, 24-, or 16-grit corundum particles, respectively. Twenty-two stems in 11 dogs were evaluated at 6 months. Twenty-one of the stems showed osseointegration, whereas in one stem a fibrous interface developed. Abundant new periimplant bone formation occurred, particularly within the intramedullary canal where trabeculae spanned implant to endosteal cortex gaps as large as 5 mm. Bone apposition with the 60-, 24-, and 16-grit stems averaged 31.7%, 32%, and 27.9%, respectively; the differences were not statistically significant. However, the pattern of new bone formation was different in that the average length of each region of bone apposition for the 60- and 24-grit surfaces was 50% greater than that for the coarser 16-grit surface. The observations of this study indicate that because of their highly osteoconductive nature, corundum blasted surfaces represent an important and valuable technology for the design of noncemented implants.

This study evaluated the osseous tissue response to a noncemented metal-backed acetabular component made of a new porous tantalum biomaterial. Eleven dogs with bilateral total hip arthroplasties (22 acetabular implants) were studied for a period of 6 months. Thin section histology, high-resolution radiography, and backscattered scanning electron microscopy revealed that all 22 implants had stable bone-implant interfaces. Regions of bone ingrowth were present in all histologic sections. The depth of bone ingrowth varied from 0.2 mm to the maximal limit of 2 mm. Analyzing contiguous regions of interest across the full bone-implant interface, the mean bone ingrowth for all sections was 16.8% +/- 5.7%. In the peripheral regions of the cup where bone-implant contact was most consistent, bone ingrowth averaged 25.1% +/- 10.1%. The data indicate that the porous tantalum material is effective for biologic fixation in the dog and may provide a suitable alternative to other porous materials used in acetabular cup design.

The objective of this prospective study was to determine if bone densitometry can detect disparities in regional adaptive bone remodelling surrounding the cementless porous-coated femoral component of a hip prosthesis in two titanium alloy implants of different design . These prostheses were the S-ROM (n=69) and the Multilock (n=65). The Multilock implants consisted of two groups; 25 had a 50 micron layer of hydroxyapatite (HA) sprayed over the porous surface of the femoral component and the remaining 40 femoral components were not coated with HA. Densitometry was performed with dual energy X-ray absorptiometry (DXA) utilizing the LUNAR ORTHO software to analyse the seven Gruen zones. Bone mineral density measurements were obtained within a week of surgery as a baseline reference and at 6, 12, 24, 36 and 48 months thereafter. At 6 months there was significant mineral loss in all Gruen zones in the three prostheses. By 48 months there were differences in mineral loss between the three prostheses. In the zones adjacent to the porous surface, predominantly zones 1 and 7, the S-ROM exhibited 60% less mineral loss than the Multilock in zone 1, and there was no significant difference in zone 7. Compared to the Multilock-HA, the S-ROM lost 35% less mineral in zone 1, but the Multilock lost 70% less mineral than the S-ROM in zone 7. The Multilock-HA lost 37% and 75% less mineral than the Multilock in zones 1 and 7, respectively, i.e., hydroxyapatite coating tended to preserve bone stalk. Using the Gruen zone area measurements provided by the software, the S-ROM had significantly greater bone resorption in zone 7 at 24 months than either of the Multilocks, which did not differ from each other. In conclusion, DXA has shown differences in periprosthetic adaptive bone remodelling between implants of different design and composition as a function of time.

The purpose of this study was to compare, with regard to fixation of the implant and femoral bone resorption, two fully porous-coated stems of different stiffnesses in a canine total hip arthroplasty model. A bilateral arthroplasty was carried out with insertion of a titanium-alloy stem (which had stiffness properties comparable with those of the canine femur) on one side and with insertion of a composite stem (which was three to fivefold more flexible than the canine femur) on the contralateral side. Eight femora were evaluated at six months and eight, at eighteen months after the operation, to determine the extent of bone ingrowth, periprosthetic cortical area, intracortical porosity, and bone-remodeling. Despite the markedly greater flexibility of the composite stems, no significant difference could be detected (with the numbers available), with regard to the overall degree of femoral stress-shielding, cortical area, or cortical porosity, between these stems and the stiffer, titanium-alloy stems at either time-period. However, the composite stems had less bone ingrowth and more formation of radiopaque lines than did the titanium-alloy stems. At eighteen months, the values for bone ingrowth were 9.7 +/- 5.38 percent (mean and standard deviation) for the composite stems compared with 28.1 +/- 5.31 percent for the titanium-alloy stems (p = 0.003). Furthermore, the histological sections from the femora containing a composite stem showed radiopaque lines indicative of fibrous ingrowth approximately threefold more often than did those from the femora containing a titanium-alloy stem (p = 0.02).

Bone mineral density changes surrounding a porous-coated proximal modular sleeved hip prosthesis were determined as a function of time over a 24-month period. The periprosthetic bone regions were defined by the 7 Gruen zones. Measurements were obtained with a dual-energy x-ray densitometer using a dedicated software program. Inclusion criteria required that the patients had primary implants, were asymptomatic with Harris hip scores of > or =95 for the duration of the study, and showed no radiographic evidence of loosening. The protocol specified that bone measurements be obtained within 1 week after surgery as a baseline reference and at 3, 6, 9, 12, 18, and 24 months thereafter. A total of 111 consecutive patients were enrolled in this ongoing prospective study, of whom 52 had 4 or more measurements after the initial baseline determination for statistical analysis. At 3 months, all zones showed a significant decrease in bone mineral density relative to the baseline measurements, and their mean loss ranged from 6.5% to 11.2%. By 24 months, mineral losses relative to baseline varied from 0 to 11% for Gruen zones 1 to 6. Relative to the 3-month levels, there was no significant change in zones 1, 4, and 6; a significant improvement in zones 3 and 5; and a small but significant loss in zone 2 at 24 months. Gruen zone 7, the medial femoral neck cortex, differed in that it was the site of greatest bone mineral loss, attaining a mean of 20.2% at 24 months. It was found that the amount of periprosthetic mineral loss at 12 months was independent of the initial baseline reference bone mineral levels. Results of this study show the normal temporal bone mineral changes surrounding a proximally modular porouscoated femoral implant. The pattern of change demonstrated may be peculiar to the prosthesis used in this study because it might differ in implants of different design and material composition.