Induced Experimental Peri-Implantitis and Periodontitis: What Are the Differences in the Inflammatory Response?

This preliminary study investigates the differences between experimental periodontitis and peri-implantitis in a dog model, with a focus on the histopathology, inflammatory responses, and specific immunoregulatory activities driven by Th1/Th2-positive cells. Twelve dental implants were inserted into the edentulated posterior mandibles of 6 beagle dogs and were given 12 weeks for osseointegration. Experimental peri-implantitis and periodontitis (first mandible molar) were then induced using cotton-floss ligatures. Twelve weeks later, alveolar bones were quantitated by cone beam-computer tomography. Histopathologic analysis of the inflamed gingiva and periodontal tissues was performed by light microscopy, and the Th1/Th2 cell populations were investigated by flow cytometry. Peri-implantitis and periodontitis were both found to be associated with pronounced bone resorption effects, both to a similar degree vertically, but with a differential bone resorption pattern mesio-distally, and with a significantly higher and consistent bone resorption result in peri-implantitis, although with a higher variance of bone resorption in periodontitis. The histologic appearances of the inflammatory tissues were identical. The percentages of Th1/Th2 cells in the inflamed gingival tissues of both experimental peri-implantitis and periodontitis were also found to be similar. Experimental periodontitis and peri-implantitis in the dog model show essentially the same cellular pathology of inflammation. However, bone resorption was found to be significantly higher in peri-implantitis; the histopathologic changes in the periodontal tissues were similar in both groups but showed a higher interindividual variation in periodontitis and appeared more uniform in peri-implantitis. This preliminary study indicates that more focused experimental in vivo inflammation models need to be developed to better simulate the human pathology in the 2 different diseases and to have a valuable tool to investigate more specifically how novel treatments/prevention approaches may heal the differential adverse effects on bone tissue and on periodontium in periodontitis and in periimplantitis.

Cells, soluble factors and matrix harmonically play the concert of allograft integration.

Implantation of allograft tissues has massively grown over the last years, especially in the fields related to sports medicine. Beside the fact that often no autograft option exists, autograft related disadvantages as donor-site morbidity and prolonged operative time are drastically reduced with allograft tissues. Despite the well documented clinical success for bone allograft procedures, advances in tissue engineering raised the interest in meniscus, osteochondral and ligament/tendon allografts. Notably, their overall success rates are constantly higher than 80%, making them a valuable treatment option in orthopaedics, especially in knee surgery. Complications reported for allografting procedures are a small risk of disease transmission, immunologic rejection, and decreased biologic incorporation together with nonunion at the graft-host juncture and, rarely, massive allograft resorption. Although allografting is a successful procedure, improved techniques and biological knowledge to limit these pitfalls and maximize graft incorporation are needed. A basic understanding of the biologic processes that affect the donor-host interactions and eventual incorporation and remodelling of various allograft tissues is a fundamental prerequisite for their successful clinical use. Further, the importance of the interaction of immunologic factors with the biologic processes involved in allograft incorporation has yet to be fully dissected. Finally, new tissue engineering techniques and use of adjunctive growth factors, cell based and focused gene therapies may improve the quality and uniformity of clinical outcomes. The aim of this review is to shed light on the biology of meniscus, osteochondral and ligament/tendon allograft incorporation and how collection and storage techniques may affect graft stability and embodiment.Level of evidence V.

Current strategies for integrative cartilage repair.

Osteoarthritis (OA) is a degenerative joint condition characterized by painful cartilage lesions that impair joint mobility. Current treatments such as lavage, microfracture, and osteochondral implantation fail to integrate newly formed tissue with host tissues and establish a stable transition to subchondral bone. Similarly, tissue-engineered grafts that facilitate cartilage and bone regeneration are challenged by how to integrate the graft seamlessly with surrounding host cartilage and/or bone. This review centers on current approaches to promote cartilage graft integration. It begins with an overview of articular cartilage structure and function, as well as degenerative changes to this relationship attributed to aging, disease, and trauma. A discussion of the current progress in integrative cartilage repair follows, focusing on graft or scaffold design strategies targeting cartilage-cartilage and/or cartilage-bone integration. It is emphasized that integrative repair is required to ensure long-term success of the cartilage graft and preserve the integrity of the newly engineered articular cartilage. Studies involving the use of enzymes, choice of cell source, biomaterial selection, growth factor incorporation, and stratified versus gradient scaffolds are therefore highlighted. Moreover, models that accurately evaluate the ability of cartilage grafts to enhance tissue integrity and prevent ectopic calcification are also discussed. A summary and future directions section concludes the review.

The Acute Inflammatory Response to Absorbed Collagen Sponge Is Not Enhanced by BMP-2.

Absorbed collagen sponge (ACS)/bone morphogenetic protein-2 (BMP-2) are widely used in clinical practise for bone regeneration. However, the application of this product was found to be associated with a significant pro-inflammatory response, particularly in the early phase after implantation. This study aimed to clarify if the pro-inflammatory activities, associated with BMP-2 added to ACS, were related to the physical state of the carrier itself, i.e., a wet or a highly dehydrated state of the ACS, to the local degree of vascularisation and/or to local biomechanical factors. ACS (0.8 cm diameter)/BMP-2 were implanted subcutaneously in the back of 12 eight-week-old Sprague Dawley rats. Two days after surgery, the implanted materials were retrieved and analysed histologically and histomorphometrically. The acute inflammatory response following implantation of ACS was dependent of neither the presence or absence of BMP-2 nor the degree of vascularization in the surrounding tissue nor the hydration state (wet versus dry) of the ACS material at the time of implantation. Differential micro biomechanical factors operating at the implantation site appeared to have an influence on the thickness of inflammation. We conclude that the degree of the early inflammatory response of the ACS/BMP-2 may be associated with the physical and chemical properties of the carrier material itself.

Transport of anti-IL-6 antigen binding fragments into cartilage and the effects of injury.

The efficacy of biological therapeutics against cartilage degradation in osteoarthritis is restricted by the limited transport of macromolecules through the dense, avascular extracellular matrix. The availability of biologics to cell surface and matrix targets is limited by steric hindrance of the matrix, and the microstructure of matrix itself can be dramatically altered by joint injury and the subsequent inflammatory response. We studied the transport into cartilage of a 48 kDa anti-IL-6 antigen binding fragment (Fab) using an in vitro model of joint injury to quantify the transport of Fab fragments into normal and mechanically injured cartilage. The anti-IL-6 Fab was able to diffuse throughout the depth of the tissue, suggesting that Fab fragments can have the desired property of achieving local delivery to targets within cartilage, unlike full-sized antibodies which are too large to penetrate beyond the cartilage surface. Uptake of the anti-IL-6 Fab was significantly increased following mechanical injury, and an additional increase in uptake was observed in response to combined treatment with TNFα and mechanical injury, a model used to mimic the inflammatory response following joint injury. These results suggest that joint trauma leading to cartilage degradation can further alter the transport of such therapeutics and similar-sized macromolecules.

Human Bone Typing Using Quantitative Cone-Beam Computed Tomography.

INTRODUCTION: Bone typing is crucial to enable the choice of a suitable implant, the surgical technique, and the evaluation of the clinical outcome. Currently, bone typing is assessed subjectively by the surgeon. OBJECTIVE: The aim of this study is to establish an automatic quantification method to determine local bone types by the use of cone-beam computed tomography (CBCT) for an observer-independent approach. METHODS: Six adult human cadaver skulls were used. The 4 generally used bone types in dental implantology and orthodontics were identified, and specific Hounsfield unit (HU) ranges (grey-scale values) were assigned to each bone type for identification by quantitative CBCT (qCBCT). The selected scanned planes were labelled by nonradiolucent markers for reidentification in the backup/cross-check evaluation methods. The selected planes were then physically removed as thick bone tissue sections for in vitro correlation measurements by qCBCT, quantitative micro-computed tomography (micro-CT), and quantitative histomorphometry. RESULTS: Correlation analyses between the different bone tissue quantification methods to identify bone types based on numerical ranges of HU values revealed that the Pearson correlation coefficient of qCBCT with micro-CT and quantitative histomorphometry was R = 0.9 (P = .001) for all 4 bone types . CONCLUSIONS: We found that  qCBCT can reproducibly and objectively assess human bone types at implant sites.

In major joint diseases the human synovium retains its potential to form repair cartilage.

The inner surface layer of human joints, the synovium, is a source of stem cells for the repair of articular cartilage defects. We investigated the potential of the normal human synovium to form novel cartilage and compared its chondrogenic capacity with that of two patient groups suffering from major joint diseases: young adults with femoro-acetabular impingement syndromes of the hip (FAI), and elderly individuals with osteoarthritic degeneration of the knee (OA). Synovial membrane explants of these three patient groups were induced in vitro to undergo chondrogenesis by growth factors: bone morphogenetic protein-2 (BMP-2) alone, transforming growth factor-ß1 (TGF-ß1) alone, or a combination of these two. Quantitative evaluations of the newly formed cartilages were performed respecting their gene activities, as well as the histochemical, immunhistochemical, morphological and histomorphometrical characteristics. Formation of adult articular-like cartilage was induced by the BMP-2/TGF-ß1 combination within all three groups, and was confirmed by adequate gene-expression levels of the anabolic chondrogenic markers; the levels of the catabolic markers remained low. Our data reveal that the chondrogenic potential of the normal human synovium remains uncompromised, both in FAI and OA. The potential of synovium-based clinical repair of joint cartilage may thus not be impaired by age-related joint pathologies.

Crystalline Biomimetic Calcium Phosphate Coating on Mini-Pin Implants to Accelerate Osseointegration and Extend Drug Release Duration for an Orthodontic Application.

Miniscrew implants (MSIs) have been widely used as temporary anchorage devices in orthodontic clinics. However, one of their major limitations is the relatively high failure rate. We hypothesize that a biomimetic calcium phosphate (BioCaP) coating layer on mini-pin implants might be able to accelerate the osseointegration, and can be a carrier for biological agents. A novel mini-pin implant to mimic the MSIs was used. BioCaP (amorphous or crystalline) coatings with or without the presence of bovine serum albumin (BSA) were applied on such implants and inserted in the metaphyseal tibia in rats. The percentage of bone to implant contact (BIC) in histomorphometric analysis was used to evaluate the osteoconductivity of such implants from six different groups (n=6 rats per group): (1) no coating no BSA group, (2) no coating BSA adsorption group, (3) amorphous BioCaP coating group, (4) amorphous BioCaP coating-incorporated BSA group, (5) crystalline BioCaP coating group, and (6) crystalline BioCaP coating-incorporated BSA group. Samples were retrieved 3 days, 1 week, 2 weeks, and 4 weeks post-surgery. The results showed that the crystalline BioCaP coating served as a drug carrier with a sustained release profile. Furthermore, the significant increase in BIC occurred at week 1 in the crystalline coating group, but at week 2 or week 4 in other groups. These findings indicate that the crystalline BioCaP coating can be a promising surface modification to facilitate early osseointegration and increase the success rate of miniscrew implants in orthodontic clinics.

The Synovium of Human Osteoarthritic Joints Retains Its Chondrogenic Potential Irrespective of Age.

The autologous synovium is a potential tissue source for local induction of chondrogenesis by tissue engineering approaches to repair articular cartilage defects that occur in osteoarthritis. It was the aim of the present study to ascertain whether the aging of human osteoarthritic patients compromises the chondrogenic potential of their knee-joint synovium and the structural and metabolic stability of the transformed tissue. The patients were allocated to one of the following two age categories: 54-65 years and 66-86 years (n = 7-11 donors per time point and experimental group; total number of donors: 64). Synovial biopsies were induced in vitro to undergo chondrogenesis by exposure to bone morphogenetic protein-2 (BMP-2) alone, transforming growth factor-ß1 (TGF-ß1) alone, or a combination of the two growth factors, for up to 6 weeks. The differentiated explants were evaluated morphologically and morphometrically for the volume fraction of metachromasia (sulfated proteoglycans), immunohistochemically for type-II collagen, and for the gene expression levels of anabolic chondrogenic markers as well as catabolic factors by a real-time polymerase chain reaction analysis. Quantitative metachromasia revealed that chondrogenic differentiation of human synovial explants was induced to the greatest degree by either BMP-2 alone or the BMP-2/TGF-ß1 combination, that is, to a comparable level with each of the two stimulation protocols and within both age categories. The BMP-2/TGF-ß1combination protocol resulted in chondrocytes of a physiological size for normal human articular cartilage, unlike the BMP-2-alone stimulation that resulted in cell sizes of terminal hypertrophy. The stable gene expression levels of the anabolic chondrogenic markers confirmed the superiority of these two stimulation protocols and demonstrated the hyaline-like qualities of the generated cartilage matrix. The gene expression levels of the catabolic markers remained extremely low. The data also confirmed the usefulness of experimental in vitro studies with bovine synovial tissue as a paradigm for human synovial investigations. Our data reveal the chondrogenic potential of the human knee-joint synovium of osteoarthritic patients to be uncompromised by aging and catabolic processes. The potential of synovium-based clinical engineering (repair) of cartilage tissue using autologous synovium may thus not be reduced by the age of the human patient. Impact statement Our data reveal that in younger and older age groups alike, synovial explants from osteoarthritic joints can be equally well induced to undergo chondrogenesis in vitro; that is, the chondrogenic potential of the human synovium is not compromised by aging. These findings imply that the autologous synovium represents an adequate tissue source for the repair of articular cartilage in clinical practice by tissue engineering approaches in human patients suffering from osteoarthritis, independent of the patient's age.

Stereologic analysis of tibial-plateau cartilage and femoral cancellous bone in guinea pigs with spontaneous osteoarthritis.

BACKGROUND: Two strains of guinea pig develop spontaneous osteoarthritis of the knee. Although the disease evolves at different rates in the two strains, it is not known whether these differences are reflected in the structure of the cartilage and cancellous bone. QUESTIONS/PURPOSES: We determined whether the three-dimensional structure of the tibial-plateau cartilage and femoral cancellous bone differed between the two strains. METHODS: Six Dunkin-Hartley and six GOHI/SPF guinea pigs were evaluated. The animals were sacrificed at 11 months of age. The 24 proximal tibias were used for a stereologic histomorphometric analysis of the tibial-plateau cartilage. The 24 femurs were used for a site-specific, three-dimensional quantitative analysis of the cancellous bone by micro-CT. RESULTS: Compared to the GOHI/SPF guinea pigs, the tibial-plateau cartilage of the Dunkin-Hartley strain had a larger lesion volume (3.8% versus 1.5%) and a thicker uncalcified cartilage layer (0.042 versus 0.035 mm), but a thinner calcified cartilage zone (0.008 versus 0.01 mm) and a thinner subchondral cortical bone plate (0.035 versus 0.039 mm). The femoral cancellous bone in the Dunkin-Hartley strain had a lower bone mineral density (477 versus 509 mg/cm(3)). However, the trabeculae were thicker (3.91 versus 3.53 pixels) and farther apart (7.8 versus 5.6 pixels). The osteoarthritic changes in the cartilage were topographically mirrored in the subchondral bone. They were most severe on the medial side of the joint, particularly in the anterior region. CONCLUSIONS: Spontaneous osteoarthritis in the guinea pig is associated with site-specific changes in the articular cartilage layer, which are topographically mirrored in the underlying subchondral bone. CLINICAL RELEVANCE: Three-dimensional structural information not revealed by two-dimensional radiography may help characterize the stages of osteoarthritis.

Anticytokine Activity Enhances Osteogenesis of Bioactive Implants.

In dental clinical practice, systemic steroids are often applied at the end of implant surgeries to reduce postsurgical inflammation (tissue swelling, etc.) and to reduce patient discomfort. However, the use of systemic steroids is associated with generalized catabolic effects and with a temporarily reduced immunological competence. We hypothesize that by applying locally anticytokine antibodies (antitumor necrosis factor alpha and anti-interleukin-1 beta) together with a bioactive osteogenic implant at the time of the surgical intervention for the placement of a construct, we will be able to achieve the same beneficial effects as those using systemic steroids but are able to avoid the generalized antianabolic effects and the reduced immunocompetence effects, associated with the systemic use of steroids. In an adult rat model, a collagen sponge, soaked with the osteogenic agent bone morphogenetic protein-2, was used as an example for a bioactive implant material and was surgically placed subcutaneously. In the acute inflammatory phase after implantation (2 days after surgery) we investigated the local inflammatory tissue response, and 18 days postsurgically the efficiency of local osteogenesis (to assess possible antianabolic effects). We found that the negative control groups, treated postsurgically with systemic steroids, showed a significant suppression of both the inflammatory response and the osteogenetic activity, that is, they were associated with significant general antianabolic effects, even when steroids were used only at a low dose level. The local anticytokine treatment, however, was able to significantly enhance new bone formation activity, that is, the anabolic activity, over positive control values with BMP-2 only. However, the anticytokine treatment was unable to reduce the local inflammatory and swelling responses.

Surviving endoplasmic reticulum stress is coupled to altered chondrocyte differentiation and function.

In protein folding and secretion disorders, activation of endoplasmic reticulum (ER) stress signaling (ERSS) protects cells, alleviating stress that would otherwise trigger apoptosis. Whether the stress-surviving cells resume normal function is not known. We studied the in vivo impact of ER stress in terminally differentiating hypertrophic chondrocytes (HCs) during endochondral bone formation. In transgenic mice expressing mutant collagen X as a consequence of a 13-base pair deletion in Col10a1 (13del), misfolded alpha1(X) chains accumulate in HCs and elicit ERSS. Histological and gene expression analyses showed that these chondrocytes survived ER stress, but terminal differentiation is interrupted, and endochondral bone formation is delayed, producing a chondrodysplasia phenotype. This altered differentiation involves cell-cycle re-entry, the re-expression of genes characteristic of a prehypertrophic-like state, and is cell-autonomous. Concomitantly, expression of Col10a1 and 13del mRNAs are reduced, and ER stress is alleviated. ERSS, abnormal chondrocyte differentiation, and altered growth plate architecture also occur in mice expressing mutant collagen II and aggrecan. Alteration of the differentiation program in chondrocytes expressing unfolded or misfolded proteins may be part of an adaptive response that facilitates survival and recovery from the ensuing ER stress. However, the altered differentiation disrupts the highly coordinated events of endochondral ossification culminating in chondrodysplasia.

Mechanical insertion properties of calcium-phosphate implant coatings.

OBJECTIVES: To investigate the influence of protein incorporation on the resistance of biomimetic calcium-phosphate coatings to the shear forces that are generated during implant insertion. MATERIALS AND METHODS: Thirty-eight standard (5 × 13 mm) Osseotite® implants were coated biomimetically with a layer of calcium phosphate, which either lacked or bore a co-precipitated (incorporated) depot of the model protein bovine serum albumin (BSA). The coated implants were inserted into either artificial bone (n=18) or the explanted mandibles of adult pigs (n=12). The former set-up was established for the measurement of torque and of coating losses during the insertion process. The latter set-up was established for the histological and histomorphometric analysis of the fate of the coatings after implantation. RESULTS: BSA-bearing coatings had higher mean torque values than did those that bore no protein depot. During the insertion process, less material was lost from the former than from the latter type of coating. The histological and histomorphometric analysis revealed fragments of material to be sheared off from both types of coating at vulnerable points, namely, at the tips of the threads. The sheared-off fragments were retained within the peri-implant space. CONCLUSION: The incorporation of a protein into a biomimetically prepared calcium-phosphate coating increases its resistance to the shear forces that are generated during implant insertion. In a clinical setting, the incorporated protein would be an osteogenic agent, whose osteoinductive potential would not be compromised by the shearing off of coating material, and the osteoconductivity of an exposed implant surface would not be less than that of a coated one.

Enhanced biocompatibility and improved osteogenesis of coralline hydroxyapatite modified by bone morphogenetic protein 2 incorporated into a biomimetic coating.

OBJECTIVES: (1) To determine whether the biocompatibility of coralline hydroxyapatite (CHA) granules could be improved by using an octacalcium phosphate (OCP) coating layer, and/or functionalized with bone morphogenetic protein 2 (BMP-2), and (2) to investigate if BMP-2 incorporated into this coating is able to enhance its osteoinductive efficiency, in comparison to its surface-adsorbed delivery mode. METHODS: CHA granules (0.25 g per sample) bearing a coating-incorporated depot of BMP-2 (20 µg/sample) together with the controls (CHA bearing an adsorbed depot of BMP-2; CHA granules with an OCP coating without BMP-2; pure CHA granules) were implanted subcutaneously in rats (n = 6 animals per group). Five weeks later, the implants were retrieved for histomorphometric analysis to quantify the volume of newly generated bone, bone marrow, fibrous tissue and foreign body giant cells (FBGCs). The osteoinductive efficiency of BMP-2 and the rates of CHA degradation were also determined. RESULTS: The group with an OCP coating-incorporated depot of BMP-2 showed the highest volume and quality or bone, and the highest osteoinductive efficacy. OCP coating was able to reduce inflammatory responses (improve biocompatibility), and also simple adsorption of BMP-2 to CHA achieved this. CONCLUSIONS: The biocompatibility of CHA granules (reduction of inflammation) was significantly improved by coating with a layer of OCP. Pure surface adsorption of BMP-2 to CHA also reduced inflammation. Incorporation of BMP-2 into the OCP coatings was associated with the highest volume and quality of bone, and the highest biocompatibility degree of the CHA granules. CLINICAL SIGNIFICANCE: Higher osteoinductivity and improved biocompatibility of CHA can be obtained when a layer of BMP-2 functionalized OCP is deposited on the surfaces of CHA granules.

Polymeric mesh and insulin-like growth factor 1 delivery enhance cell homing and graft-cartilage integration.

Cartilage injury, such as full-thickness lesions, predisposes patients to the premature development of osteoarthritis, a degenerative joint disease. While surgical management of cartilage lesions has improved, long-term clinical efficacy has stagnated, owing to the lack of hyaline cartilage regeneration and inadequate graft-host integration. This study tests the hypothesis that integration of cartilage grafts with native cartilage can be improved by enhancing the migration of chondrocytes across the graft-host interface via the release of chemotactic factor from a degradable polymeric mesh. To this end, a polylactide-co-glycolide/poly-ε-caprolactone mesh was designed to localize the delivery of insulin-like growth factor 1 (IGF-1), a well-established chondrocyte attractant. The release of IGF-1 (100 ng/mg) enhanced cell migration from cartilage explants, and the mesh served as critical structural support for cell adhesion, growth, and production of a cartilaginous matrix in vitro, which resulted in increased integration strength compared with mesh-free repair. Further, this neocartilage matrix was structurally contiguous with native and grafted cartilage when tested in an osteochondral explant model in vivo. These results demonstrate that this combined approach of a cell homing factor and supportive matrix will promote cell-mediated integrative cartilage repair and improve clinical outcomes of cartilage grafts in the treatment of osteoarthritis.

Tenomodulin is necessary for tenocyte proliferation and tendon maturation.

Tenomodulin (Tnmd) is a member of a new family of type II transmembrane glycoproteins. It is predominantly expressed in tendons, ligaments, and eyes, whereas the only other family member, chondromodulin I (ChM-I), is highly expressed in cartilage and at lower levels in the eye and thymus. The C-terminal extracellular domains of both proteins were shown to modulate endothelial-cell proliferation and tube formation in vitro and in vivo. We analyzed Tnmd function in vivo and provide evidence that Tnmd is processed in vivo and that the proteolytically cleaved C-terminal domain can be found in tendon extracts. Loss of Tnmd expression in gene targeted mice abated tenocyte proliferation and led to a reduced tenocyte density. The deposited amounts of extracellular matrix proteins, including collagen types I, II, III, and VI and decorin, lumican, aggrecan, and matrilin-2, were not affected, but the calibers of collagen fibrils varied significantly and exhibited increased maximal diameters. Tnmd-deficient mice did not have changes in tendon vessel density, and mice lacking both Tnmd and ChM-I had normal retinal vascularization and neovascularization after oxygen-induced retinopathy. These results suggest that Tnmd is a regulator of tenocyte proliferation and is involved in collagen fibril maturation but do not confirm an in vivo involvement of Tnmd in angiogenesis.

Elongation of the Long Bones in Humans by the Growth Plates.

The disk of hyaline cartilage that is interposed between the epiphysis and the metaphysis of each of the long bones is responsible for its elongation, and, thus, when the lower limbs are concerned, for increases in bodily height. This so-called growth plate is avascular, aneural, and alymphatic. It consists solely of chondrocytes and an extracellular matrix which the cells elaborate. The growth plate is architectonically striking in so far as the chondrocytes are aligned in strictly vertical columns, which represent the functional units of longitudinal bone growth. The growth process begins with the slow division of chondrocytes in the resting ("stem cell") zone and proceeds with their rapid proliferation in the adjacent zone. These cells then undergo a process of progressive enlargement, which culminates in the zone of terminal hypertrophy. The life history of any given cell is recapitulated in a vertical column. The neoformation of cartilage in the axial direction is synchronized with its destruction at the vascular invasion front of the metaphysis and results in an elongation of the bony trabeculae. The mechanism that governs the highly coordinated sequence of events that underlies the growth of the long bones is complex; it is subject to influence by genetic, hormonal, nutritional, environmental, and pathological factors.

A Novel Experimental Dental Implant Permits Quantitative Grading of Surface-Property Effects on Osseointegration.

PURPOSE: To test the hypothesis if a novel single-chamber experimental dental implant allows in vivo the quantitative assessment of osseointegration over time and as a function of different surface properties (physical, chemical, geometric, biologic [osteoconductive or osteoinductive]) in a biologically unfavorable environment (local osteoporosis). MATERIALS AND METHODS: Three prototypes of a novel experimental implant with different chamber sizes (small, medium, and large) were compared with each other to find out the minimum size of bone chambers needed to allow a discriminative quantification of osseointegration over time. For the comparison of low and high surface osteoconductivity properties, conventional sandblasted, acid-etched chamber surfaces (low surface osteoconductivity) were compared with biomimetically (calcium phosphate) coated ones (high surface osteoconductivity). The implants (4 implants per animal; 88 implants per time point) were inserted into the edentulous maxillae of a total of 66 adult goats with a physiologically osteoporotic masticatory apparatus. Two, 4, and 8 weeks later, they were excised and prepared for a histomorphometric analysis of the volume of neoformed bone within the chamber space and of the bone-to-implant contact (BIC) area. RESULTS: The implants with small chambers did not show significant differences in bone coverage (BIC) nor bone volume (relative and absolute volume), neither as a function of time nor as of implant surface property (low versus high surface osteoconductivity). However, medium and large chambers revealed significant differences respecting both of these parameters over the 8-week postoperative time period. CONCLUSION: The new implant model permits a discriminative quantification of osseointegration in vivo in an osteoporotic bone environment for implants with medium-sized and large-sized chambers. Quantitative assessment of osseointegration is possible, both over time and as a function of low and high surface osteoconductivity properties.

The kinetics and mechanism of bone morphogenetic protein 2 release from calcium phosphate-based implant-coatings.

Biomimetically deposited calcium phosphate-based coatings of prostheses can serve as a vehicle for the targeted delivery of growth factors to the local implant environment. Based on indirect evidence in previous studies we hypothesize that such agents are liberated gradually from the coating via a cell-mediated degradation. In the present study, we tested this hypothesis by investigating the release mechanism and its kinetics by use of a radiolabeled osteogenic agent (131 I-BMP-2) under conditions in which native cell populations with a coating-degradative potential were either absent or present. The release of 131 I-BMP-2 was monitored for 5 weeks, either in vitro or after implantation at an ectopic (subcutaneous) site in rats in vivo. Only from implants that bore a coating-incorporated depot of bone morphogenetic protein 2 (BMP-2) was the agent released slowly and steadily over 5 weeks, that is, 50% of the loaded dose was liberated in vivo (5 to 10% weekly), as against 14.6% in vitro (less than 1% weekly). The coatings bearing an incorporated depot of BMP-2 underwent significant cell-mediated degradation, whereas under cell-free conditions no degradation occurred, and the spontaneous release of BMP-2 was negligible. Our findings confirm this carrier system to be a suitable vehicle for the sustained and cell-mediated delivery of BMP-2. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A:2363-2371, 2018.

The influence of BMP-2 and its mode of delivery on the osteoconductivity of implant surfaces during the early phase of osseointegration.

Osteogenic agents, such as bone morphogenetic protein-2 (BMP-2), can stimulate the degradation as well as the formation of bone. Hence, they could impair the osteoconductivity of functionalized implant surfaces. We assessed the effects of BMP-2 and its mode of delivery on the osteoconductivity of dental implants with either a naked titanium surface or a calcium-phosphate-coated one. The naked titanium surface bore adsorbed BMP-2, whilst the coated one bore incorporated, adsorbed, or incorporated and adsorbed BMP-2. The implants were inserted into the maxillae of adult miniature pigs. The volume of bone deposited within a defined "osteoconductive" (peri-implant) space, and bone coverage of the implant surface delimiting this space, were estimated morphometrically 1-3 weeks later. After 3 weeks, the volume of bone deposited within the osteoconductive space was highest for coated and uncoated implants bearing no BMP-2, followed by coated implants bearing incorporated BMP-2; it was lowest for coated implants bearing only adsorbed BMP-2. Bone-interface coverage was highest for coated implants bearing no BMP-2, followed by coated implants bearing either incorporated, or incorporated and adsorbed BMP-2; it was lowest for uncoated implants bearing adsorbed BMP-2. Hence, the osteoconductivity of implant surfaces can be significantly modulated by BMP-2 and its mode of delivery.