| As the most effective surgery for treating severe arthritis and otherjoint-related diseases, the number of total joint arthroplasty (TJA) increasessteadily every year. Thus wear debris-induced aseptic loosening and subsequentrevision may be unavoidable, especially in young patients. To understand theprecise mechanism and pursue potential preventive and therapeutic interventions,an animal model that closely mimics the clinical peri-prosthetic environment isessential. Till now, aseptic loosening models include air pouch models, calvarialresorption models, bone harvest chamber models and hemi-arthroplasty models.However, the mechanisms of the first three models are different from clinicalaseptic loosening, because implants and the stimulation of mechanical force orfluid pressure are lacking. Injecting wear debris around implants or into jointscould most closely mimic the clinical peri-prosthetic environment. Therefore, in this study, we tried to establish a more effective and clinicalrelevant aseptic loosening animal model to mimic the clinical peri-prosthetichistological and pathological responses in aseptic loosening patients.Furthermore, we compared this modeling method with others to discuss themechanism of aseptic loosening.After the establishment of the animal model, we prepared analendronate-HA composite coating and investigated the inhibitory effect of thiscomposite coating on peri-implant high bone turnover rate. Then, we preparedtwo kinds of BP-HA composite coatings using either high or lowmineral-binding affinity BPs (ALN and RIS, respectively). We investigated theireffects on peri-implant bone and non-peri-implant bone, so as to make themechanism by which BP-HA composite coatings can inhibit high bone turnoverrate clear and find out the most appropriate indications for different compositecoatings.The problems we need to discuss include:1. Recent aseptic loosening animal models are not clinical relevant.2. Whether we could use reduced particles to induce aseptic looseningsuccessfully.3. The multi-factorial process in aseptic loosening has not been confirmed byanimal experiments.4. Whether the potencies of different modeling methods are different.5. Whether the particle stimulation influences bone anabolism.6. Whether BP-HA composite coatings can inhibit peri-implant high boneturnover rate.7. The mechanisms by which BPs inhibit aseptic loosening. 8. Whether low dose BP inhibits peri-implant bone formation.9. Whether the release characteristic of ALN-HA composite coating can meetthe needs in clinics.10. Whether mineral-binding affinities influence the inhibitory effects on boneturnover rate of different BPs.Therefore, we established an aseptic loosening animal model by injectingUHMWPE particles around implants and into joints simultaneously to mimicclinical peri-implant environment. On the basis of this model, we investigatedthe detailed mechanisms by which BP-HA composite coatings inhibit asepticloosening.The methods used in this study include:1．X-rayX-ray imaging was performed once after sacrificing the animals in order toensure a good position of the implant in the bone tunnel.2．Intra-articular pressure measurementThe pressure-time curves were drawn in order to evaluate the inflammatoryresponse and bone-implant integration.3．HistologySynovial membranes: They were HE stained and observed under normallight and polarized light in order to evaluate the inflammatory response and theinfiltration of particles.Bone-implant interface: On the basis of BIC ratios and toluidine bluestained slices, bone-implant integration was evaluated. 4．Bone histomorphometryDynamic bone histomorphometry: On the basis of tetracyclinedouble-labeled slices and toluidine blue stained slices, OS/BS, BFR/BV andMAR were measured.Static bone histomorphometry: BV/TV, Tb.Th, Tb.N, Tb.Sp and SMI weremeasured by micro-CT imaging.5．Bone mineralizationCortical bone mineralization was evaluated by the average area and areafraction of mineralized bone islands on the basis of Von Kossa stained slices.Cancellous bone mineralization was evaluated by micro-CT imaging.6．Biomechanical measurementsOn the basis of load-displacement curves, MF, ASS and TEA werecalculated.7．Scanning electronic microscopySEM scanning was performed under normal model and back scatteringmodel. Mineralized bone area fraction (M.BAF) was measured in the ranges of0-100μm,100-200μm,200-500μm and500-800μm from the implant surface.8．Cytokine measurementPro-inflammatory cytokines: They were measured using serum or synovialfluid, including TNF-α, IL-1β, IL-6and MMP-1.Bone turnover markers: They were measured using serum or synovial fluid,including OPG, RANKL, B-ALP and TRACP-5b.9．Alendronate release in vitroThe release curve was drawn to evaluate its delivery property. We can conclude:1. The particle stimulation can influence the implant stability through thephysical intervention between bone-implant interface, the secretion ofpro-inflammatory cytokines, intra-articular pressure elevation, inflamedinterfacial membrane formation, chronic inflammation, the impairment ofbone microstructure, bone turnover rate elevation, the inhibition on bonemineralization and collagen metabolism.2. Injecting particles around implants and into joints simultaneously canfacilitate the cooperation among osteolysis-related factors at early modelingperiod that only107particles can successfully induce peri-implant high boneturnover rate.3. Aseptic loosening is a multi-factorial process.4. The migration of particles is crucial to sustain peri-implant chronicinflammatory response and high bone turnover rate.5. Aseptic loosening is not only and bone resorption process but also theimbalance between bone resorption and formation.6. Local released BP can improve peri-implant bone quality and quantity andinhibit particle migration and inflammatory response by inhibitingperi-implant high bone turnover rate.7. Low dose BP can inhibit peri-implant bone resorption without inhibitingbone formation.8. The release of ALN from ALN-HA composite coating is a dual-phaseprocess that it releases quickly in the first week and slowly in the subsequent11weeks. It is good for the early integration of bone-implant interface andthe sustainment of peri-implant low dose drug concentration. 9. ALN-HA composite coating can afford long release time and meet the needsin clinics.10. The mineral-binding affinity is crucial to the delivery property of BPs thatthe BP with high mineral-binding affinity can sustain a stable peri-implantdrug concentration, which is good for improving peri-implant bone quality,the BP with low mineral-binding affinity can diffused far away, which isgood for improving non-peri-implant bone quality.11. It is instructive and meaningful to further clinically relevant studies that wecould compose either/both high-or/and low-affinity BPs with HA coatingdepending on the local and systemic turnover rates of the patients. |
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