The Wnt5a Receptor, Receptor Tyrosine Kinase-Like Orphan Receptor 2, Is a Predictive Cell Surface Marker of Human Mesenchymal Stem Cells with an Enhanced Capacity for Chondrogenic Differentiation.

Multipotent mesenchymal stem cells (MSCs) have enormous potential in tissue engineering and regenerative medicine. However, until now, their development for clinical use has been severely limited as they are a mixed population of cells with varying capacities for lineage differentiation and tissue formation. Here, we identify receptor tyrosine kinase-like orphan receptor 2 (ROR2) as a cell surface marker expressed by those MSCs with an enhanced capacity for cartilage formation. We generated clonal human MSC populations with varying capacities for chondrogenesis. ROR2 was identified through screening for upregulated genes in the most chondrogenic clones. When isolated from uncloned populations, ROR2+ve MSCs were significantly more chondrogenic than either ROR2-ve or unfractionated MSCs. In a sheep cartilage-repair model, they produced significantly more defect filling with no loss of cartilage quality compared with controls. ROR2+ve MSCs/perivascular cells were present in developing human cartilage, adult bone marrow, and adipose tissue. Their frequency in bone marrow was significantly lower in patients with osteoarthritis (OA) than in controls. However, after isolation of these cells and their initial expansion in vitro, there was greater ROR2 expression in the population derived from OA patients compared with controls. Furthermore, osteoarthritis-derived MSCs were better able to form cartilage than MSCs from control patients in a tissue engineering assay. We conclude that MSCs expressing high levels of ROR2 provide a defined population capable of predictably enhanced cartilage production. Stem Cells 2017;35:2280-2291.

Spatially offset Raman spectroscopy for photon migration studies in bones with different mineralization levels.

The ability of Spatially Offset Raman Spectroscopy (SORS) to obtain chemically specific information from below the sample surface makes it a promising technique for non-invasive in vivo diagnosis of bone conditions by sampling bone through the skin. The depth below a surface interrogated by SORS depends on the system's optical properties and is difficult to estimate for complex bone material. This paper uses 830 nm laser excitation to investigate the influence of bone mineralization on photon migration properties in deer antler cortex, equine metacarpal cortex and whale tympanic bulla. Thin slices form each type of bone (thickness: 0.6-1.0 mm) were cut and put together on top of each other forming stacks with a total thickness of 4.1-4.7 mm. A 0.38 mm thin slice of polytetrafluoroethylene (PTFE) served as a test material for Raman signal recovery and was placed in between the individual bone slices within the stack. At SORS offsets of 8.0-9.5 mm Raman bands of materials not present in healthy bone (e.g. PTFE as an example) can be recovered through 4.4-4.7 mm of cortical bone tissue, depending on mineralization level and porosity. These findings significantly increase our understanding of SORS analysis through bones of different composition and provide information that is vital to determine the value of SORS as a medical diagnostic technique. The data serve to define which SORS offset is best deployed for the non-invasive detection of chemically specific markers associated with infection, degeneration and disease or cancer within bone.

Is the Collagen Primed for Mineralization in Specific Regions of the Turkey Tendon? An Investigation of the Protein-Mineral Interface Using Raman Spectroscopy.

The tendons in the turkey leg have specific well-defined areas which become mineralized as the animal ages and they are a thoroughly characterized model system for studying the mineralization process of bone. In this study, nondestructive Raman spectroscopic analysis was used to explore the hypothesis that regions of the turkey tendon that are associated with mineralization exhibit distinct and observable chemical modifications of the collagen prior to the onset of mineralization. The Raman spectroscopy features associated with mineralization were identified by probing (on the micrometer scale) the transition zone between mineralized and nonmineralized regions of turkey leg tendons. These features were then measured in whole tendons and identified in regions of tendon which are destined to become rapidly mineralized around 14 weeks of age. The data show there is a site-specific difference in collagen prior to the deposition of mineral, specifically the amide III band at 1270 cm(-1) increases as the collagen becomes more ordered (increased amide III:amide I ratio) in regions that become mineralized compared to collagen destined to remain nonmineralized. If this mechanism were present in materials of different mineral fraction (and thus material properties), it could provide a target for controlling mineralization in metabolic bone disease.

A biomechanical evaluation of a Hybrid Dynamic Compression Plate and a CastLess Arthrodesis Plate for pancarpal arthrodesis in dogs.

OBJECTIVE: To determine mechanical differences between two plates with different requirements for supplementary casting after pancarpal arthrodesis (PCA): the Veterinary Instrumentation Hybrid Dynamic Compression Plate (HDCP), and the OrthoMed CastLess Arthrodesis Plate (CLP). STUDY DESIGN: In vitro mechanical analysis. SAMPLE POPULATION: HDCP(n = 10), CLP(10). METHODS: Single-cycle load to failure using a materials-testing machine and cyclic loading between 38 and 380 N ± 5% to simulate estimated in vivo loads until failure or 10(6) cycles. RESULTS: Single-cycle to failure: bending stiffness was significantly higher for the HDCP(2269 ± 175 N/mm) than CLP(1754 ± 88 N/mm; P < .001). Bending structural stiffness was higher for the HDCP(3.8 ± 0.3 Nm(2) ) versus CLP(2.9 ± 0.2 Nm(2) ; P= .0022). A difference between the 2 plates for bending strength was not demonstrated; HDCP= 13.9 ± 1.4 Nm, CLP13.2 ± 0.5 Nm (P= .24). Cyclic Loading: no failures occurred with either plate type when plates were cycled to 10(6) cycles. CONCLUSION: There is no mechanical advantage in bending resistance afforded by the CLPover the HDCP. Fatigue failure of either plate during the convalescent period of an estimated 150,000-250,000 cycles is unlikely. Based on the bending performance, there is no evidence to support the use of the CLPover the HDCPfor castless PCA.

Aspartic acid racemization and collagen degradation markers reveal an accumulation of damage in tendon collagen that is enhanced with aging.

Little is known about the rate at which protein turnover occurs in living tendon and whether the rate differs between tendons with different physiological roles. In this study, we have quantified the racemization of aspartic acid to calculate the age of the collagenous and non-collagenous components of the high strain injury-prone superficial digital flexor tendon (SDFT) and low strain rarely injured common digital extensor tendon (CDET) in a group of horses with a wide age range. In addition, the turnover of collagen was assessed indirectly by measuring the levels of collagen degradation markers (collagenase-generated neoepitope and cross-linked telopeptide of type I collagen). The fractional increase in D-Asp was similar (p = 0.7) in the SDFT (5.87 x 10(-4)/year) and CDET (5.82 x 10(-4)/year) tissue, and D/L-Asp ratios showed a good correlation with pentosidine levels. We calculated a mean (+/-S.E.) collagen half-life of 197.53 (+/-18.23) years for the SDFT, which increased significantly with horse age (p = 0.03) and was significantly (p < 0.001) higher than that for the CDET (34.03 (+/-3.39) years). Using similar calculations, the half-life of non-collagenous protein was 2.18 (+/-0.41) years in the SDFT and was significantly (p = 0.04) lower than the value of 3.51 (+/-0.51) years for the CDET. Collagen degradation markers were higher in the CDET and suggested an accumulation of partially degraded collagen within the matrix with aging in the SDFT. We propose that increased susceptibility to injury in older individuals results from an inability to remove partially degraded collagen from the matrix leading to reduced mechanical competence.

Histopathologic features of distal tarsal joint cartilage and subchondral bone in ridden and pasture-exercised horses.

OBJECTIVE: To determine whether histopathologic characteristics of the osteochondral units of equine distal tarsal joints were associated with exercise history in horses without lameness. SAMPLE POPULATION: 30 cadaver tarsi from horses without lameness and with known exercise history were separated into 3 groups: nonridden, pasture exercise (group P); low-intensity, ridden exercise (group L); and high-intensity, elite competition exercise (group E). PROCEDURES: Standardized sites from the centrodistal and tarsometatarsal joints under went histologic preparation. A grading system was adapted to describe location, depth, and shape of lesions; cellular arrangement; organization at cartilage and subchondral bone (SCB) junctions; and organization of SCB. A high score signified a more severe pathological change than a low score. Exercise groups were compared by calculation of Spearman rank correlations. RESULTS: In the centrodistal joint, lesions were present in groups L and E but only medially. Cellular arrangement scores were higher at the dorsomedial location in group P than in groups L and E. Groups L and E had higher scores than group P for the organization of the cartilage, SCB junctions, and SCB, with higher scores at the dorsomedial location. In the tarsometatarsal joint, lesions were evident across the whole joint surface, with more severe lesions located laterally in all 3 groups. Overall, group E had higher scores for cellular arrangement and SCB organization than groups P and L. CONCLUSIONS AND CLINICAL RELEVANCE: Ridden exercise may increase the risk of osteochondral lesions at distal tarsal sites predisposed to osteoarthritis relative to the risk with nonridden exercise.

Intraosseous transcutaneous amputation prosthesis (ITAP) for limb salvage in 4 dogs.

OBJECTIVE: To report clinical application of intraosseous transcutaneous amputation prosthesis (ITAP) for limb salvage. STUDY DESIGN: Retrospective case series. SAMPLE POPULATION: Client owned dogs with malignant neoplasia of the distal aspect of the limb. METHOD: Distal limb amputation allowed press-fit insertion of the ITAP into the radius (n = 3) or tibia (1). Remaining soft tissues including skin were attached directly to the ITAP. Limb stump and ITAP were protected by bandaging (1) or external skeletal fixation (3) for 5-6 weeks before exoprosthesis attachment. Measures of outcome included subjective assessments of limb function by owners and veterinarians, radiographic (4) and histologic (1) examination. RESULTS: Dermal integration with the ITAP was achieved by 3 weeks and dogs were walking in a pain-free manner by 8 weeks. One dog was administered adjunctive carboplatin chemotherapy. No evidence of local tumor recurrence occurred. In 1 dog, ITAP fracture occurred at 10 weeks and was successfully managed by ITAP replacement. Three dogs were euthanatized because of confirmed or assumed metastatic disease at 8, 12, and 17 months. Histologic examination of the ITAP-limb interface at 1 year documented osseous and dermal integration. CONCLUSION: Implantation of ITAP to the distal limb of dogs is feasible and can result in favorable functional outcomes. Biological integration of osseous and dermal tissues with ITAP is reliable and robust.

Metrenperone enhances collagen turnover and remodeling in the early stages of healing of tendon injury in rabbit.

INTRODUCTION: This study evaluated the effects of metrenperone on healing of unilateral, collagenase-induced lesions in the Superficial Digital Flexor Tendons (SDFT) of rabbits. METHODS: After controlled injury of the left SDFT, nine rabbits received daily treatment with metrenperone for 28 days. Another nine were untreated controls; in both groups the contra-lateral tendons served as uninjured controls. Histological and ultrastructural changes, mechanical properties, dry weight, collagen content, and amount of DNA in healing and control tendons were assessed 28 days after injury. RESULTS: Restoration of structural hierarchy was more organized in treated than in untreated tendons while cellularity was greater in the latter. At the ultrastructural level, collagen in treated lesions was predominantly in the form of small-diameter, new fibrils, with few large, old fibrils; in untreated lesions there was a high proportion of large, old fibrils but relatively few small, new ones. The amount of DNA in untreated injuries was much greater than in normal tendons, while in treated lesions it was not significantly different from that of uninjured controls. There were no significant differences in total collagen, stiffness and ultimate strength of injured, treated, and untreated tendons 28 days after injury. Both were significantly weaker than their corresponding contralaterals. CONCLUSIONS: The findings suggest that metrenperone had positive effects on collagen turnover, remodelling, and organization during acute inflammation and fibroplasia. Provided that the new fibrils subsequently matured in a normal manner, mechanical characteristics of the organized scar should be better than those of an untreated lesion.

Evaluation of the Effects of Synovial Multipotent Cells on Deep Digital Flexor Tendon Repair in a Large Animal Model of Intra-Synovial Tendinopathy.

Intra-synovial tendon injuries are a common orthopedic problem with limited treatment options. The synovium is a specialized connective tissue forming the inner encapsulating lining of diarthrodial joints and intra-synovial tendons. It contains multipotent mesenchymal stromal cells that render it a viable source of progenitors for tendon repair. This study evaluated the effects of autologous implantation of cells derived from normal synovium (synovial membrane cells [SMCs]) in augmenting repair in an ovine model of intra-synovial tendon injury. For this purpose, synovial biopsies were taken from the right digital flexor tendon sheath following creation of a defect to the lateral deep digital flexor tendon. Mononuclear cells were isolated by partial enzymatic digestion and assessed for MSC characteristics. Cell tracking and tendon repair were assessed by implanting 5 × 106 cells into the digital flexor tendon sheath under ultrasound guidance with the effects evaluated using magnetic resonance imaging and histopathology. Synovial biopsies yielded an average 4.0 × 105 ± 2.7 × 105 SMCs that exhibited a fibroblastic morphology, variable osteogenic, and adipogenic responses but were ubiquitously strongly chondrogenic. SMCs displayed high expression of CD29 with CD271NEGATIVE and MHC-IILOW cell-surface marker profiles, and variable expression of CD73, CD90, CD105, CD166, and MHC-I. Implanted SMCs demonstrated engraftment within the synovium, though a lack of repair of the tendon lesion over 24 weeks was observed. We conclude healthy synovium is a viable source of multipotent cells, but that the heterogeneity of synovium underlies the variability between different SMC populations, which while capable of engraftment and persistence within the synovium exhibit limited capacity of influencing tendon repair. © 2019 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society J Orthop Res 38:128-138, 2020.

Effect of exercise on thicknesses of mature hyaline cartilage, calcified cartilage, and subchondral bone of equine tarsi.

OBJECTIVE-To investigate effects of exercise on hyaline cartilage (HC), calcified cartilage (CC), and subchondral bone (SCB) thickness patterns of equine tarsi. SAMPLE POPULATION-30 tarsi from cadavers of horses with known exercise history. PROCEDURES-Tarsi were assigned to 3 groups according to known exercise history as follows: pasture exercise only (PE tarsi), low-intensity general-purpose riding exercise (LE tarsi), and high-intensity elite competition riding exercise (EE tarsi). Osteochondral tissue from distal tarsal joints underwent histologic preparation. Hyaline cartilage, CC, and SCB thickness were measured at standard sites at medial, midline, and lateral locations across joints with a histomorphometric technique. RESULTS-HC, CC, and SCB thickness were significantly greater at all sites in EE tarsi, compared with PE tarsi; this was also true when LE tarsi were compared with PE tarsi. At specific sites, HC, CC, and SCB were significantly thicker in EE tarsi, compared with LE tarsi. Along the articular surface of the proximal aspect of the third metatarsal bone, SCB was thickest in EE tarsi and thinnest in LE tarsi; increases were greatest at sites previously reported to undergo peak strains and osteochondral damage. CONCLUSIONS AND CLINICAL RELEVANCE-Increased exercise was associated with increased HC, CC, and SCB thickness in mature horses. At sites that undergo high compressive strains, with a reported predisposition to osteoarthritic change, there was increased CC and SCB thickness. These results may provide insight into the interaction between adaptive response to exercise and pathological change.

Evaluation of age-related changes in the structure of the equine tarsometatarsal osteochondral unit.

OBJECTIVE: To investigate effects of age on thickness and morphologic characteristics of hyaline cartilage, calcified cartilage, total cartilage, and subchondral bone (SCB) in the equine tarsometatarsal joint. SAMPLE POPULATION: 23 tarsal joints from cadavers of 23 ponies (11 days to 25 years old); ponies were limited to pasture exercise and euthanatized for reasons not related to this study. Procedures-Tarsi were allocated into several age groups (11 days old [n = 3], 6 to 9 months old [4], 2 to 3 years old [3], 6 to 8 years old [4], 11 to 17 years old [6], and 20 to 25 years old [3]). Histologic examination and histomorphometric measurement of hyaline cartilage, calcified cartilage, total cartilage, and SCB were performed at medial and lateral sites. RESULTS: A significant decrease was detected in thickness of hyaline cartilage and total cartilage with increasing age, but there was a significant increase in thickness of calcified cartilage and SCB with increasing age. Differences in chondrocyte and collagen fiber arrangement, tidemark, and osteochondral junction morphology were evident among age groups. CONCLUSIONS AND CLINICAL RELEVANCE: These findings suggested that the various tissues of the osteochondral unit change in different ways with age. The response of each tissue may be related to relative response of the tissues to strains induced by pasture exercise but could have an influence on how the overall properties of the osteochondral unit change with age. The findings may also be suggestive of changes that develop prior to the onset of osteoarthritis.

Physical activity: does long-term, high-intensity exercise in horses result in tendon degeneration?

This study explores the hypothesis that high-intensity exercise induces degenerative changes in the injury-prone equine superficial digital flexor tendon (SDFT), but not in the rarely injured common digital extensor tendon (CDET). The horse represents a large-animal model that is applicable to human tendon and ligament physiology and pathology. Twelve age-matched female horses undertook galloping exercise three times a week with trotting exercise on alternative days (high-intensity group, n = 6) or only walking exercise (low-intensity group, n = 6) for 18 mo. The SDFT, suspensory ligament, deep digital flexor tendon, and CDET were harvested from the forelimb. Tissue from the mid-metacarpal region of the right limb tendons was analyzed for water, DNA, sulfated glycosaminoglycan and collagen content, collagen type III-to-I ratios, collagen cross-links, and tissue fluorescence. Left limb tendons were mechanically tested to failure. The analyses showed matrix composition to have considerable diversity between the functionally different structures. In addition, the specific structures responded differently to the imposed exercise. High-intensity training resulted in a significant decrease in the GAG content in the SDFT, but no change in collagen content, despite a decrease in collagen fibril diameters. There were no signs of degeneration or change in mechanical properties of the SDFT. The CDET had a lower water content following high-intensity training and a higher elastic modulus. Long-term, high-intensity training in skeletally mature individuals results in changes that suggest accelerated aging in the injury-prone SDFT and adaptation in the CDET.

Response of a collagenase-induced tendon injury to treatment with a polysulphated glycosaminoglycan (Adequan).

This study explored the hypothesis that local administration of a polysulphated glycosaminoglycan (PSGAG) in the early phase of healing of a standard collagenase-induced tendon injury in the superficial digital flexor tendon of the rabbit would reduce the degenerative effects of inflammatory mediators and proteases and preserve normal tendon morphology, composition, and biomechanical properties. Histological and ultrastructural changes together with the mechanical properties, dry weight, collagen content, and amount of DNA in healing tissue at the site of the lesion were assessed in treated and untreated animals. In treated lesions 28 days after injury, the normal orientation of tenoblasts and collagen fibrils was well preserved compared with the disorganized scar formation seen in untreated animals. The degree of cellularity was significantly higher in the untreated lesions. At the ultrastructural level the collagen in the healing tissue of the treated animals consisted of a mixture of small diameter, new regenerated fibrils intermingled with well-preserved large diameter, old fibrils, aligned to the long axis of the tendon; in untreated animals small, randomly arranged new fibrils predominated. The diameters of treated tendons had returned to normal, but in untreated animals the injured tendons remained significantly thicker than their controls. The percentage dry weight and collagen contents of treated injured tendons approximated those of control normal tendons, whereas those of untreated tendons were significantly less than those of the control values. The DNA content of injured treated tendons was not significantly different from that of normal contralateral controls, while in the untreated tendons it was significantly higher. There were no significant differences between the normal and the contralateral treated injured tendons in ultimate strength, fatigue strength, stiffness, and maximum absorbed energy. However in the untreated animals, although the tendon diameter was significantly greater, the ultimate strength, fatigue strength, stiffness, and maximum absorbed energy were significantly lower than the contralateral control. These data suggest that polysulphated glycosaminoglycans are effective in restoring the morphological, biochemical, and biomechanical properties of injured soft connective tissues and may be of clinical value in the treatment of acute tendon injury.

Polar bears (Ursus maritimus), the most evolutionary advanced hibernators, avoid significant bone loss during hibernation.

Some hibernating animals are known to reduce muscle and bone loss associated with mechanical unloading during prolonged immobilisation,compared to humans. However, here we show that wild pregnant polar bears (Ursus maritimus) are the first known animals to avoid significant bone loss altogether, despite six months of continuous hibernation. Using serum biochemical markers of bone turnover, we showed that concentrations for bone resorption are not significantly increased as a consequence of hibernation in wild polar bears. This is in sharp contrast to previous studies on other hibernating species, where for example, black bears (Ursus americanus), show a 3-4 fold increase in serum bone resorption concentrations posthibernation,and must compensate for this loss through rapid bone recovery on remobilisation, to avoid the risk of fracture. In further contrast to black bears, serum concentrations of bone formation markers were highly significantly increased in pregnant female polar bears compared to non-pregnant,thus non-hibernating females both prior to and after hibernation. However, bone formation concentrations in new mothers were significantly reduced compared to pre-hibernation concentrations. The de-coupling of bone turnover in favour of bone formation prior to hibernation, suggests that wild polar bears may posses a unique physiological mechanism for building bone in protective preparation against expected osteopenia associated with disuse,starvation, and hormonal drives to mobilise calcium for reproduction, during hibernation. Understanding this physiological mechanism could have profound implications for a natural solution for the prevention of osteoporosis in animals subjected to captivity with inadequate space for exercise,humans subjected to prolonged bed rest while recovering from illness, or astronauts exposed to antigravity during spaceflight.© 2008 Elsevier Inc. All rights reserved.

The effect of early training and the adaptation and conditioning of skeletal tissues.

Horses as equine athletes must be conditioned and trained to optimize the whole animal for the particular type of athletic activity. An extremely high proportion of all injuries in the equine athlete in general, and in the racehorse in particular, are associated with the skeletal system, many of which are believed to arise from a mismatch between the prevailing exercise levels and adaptation. To maximize performance, yet minimize injury, it is important to understand and apply the principles of functional adaptation of the component tissues of the skeletal system (bone, cartilage, tendons, and ligaments), which differ in their responses to changes in mechanical environment. With appropriate monitoring owners, trainers, and veterinarians can apply the science underlying functional adaptation to the training of specific equine athletes, and so improve equine welfare.

Bone marrow mesenchymal stem cells do not enhance intra-synovial tendon healing despite engraftment and homing to niches within the synovium.

BACKGROUND: Intra-synovial tendon injuries display poor healing, which often results in reduced functionality and pain. A lack of effective therapeutic options has led to experimental approaches to augment natural tendon repair with autologous mesenchymal stem cells (MSCs) although the effects of the intra-synovial environment on the distribution, engraftment and functionality of implanted MSCs is not known. This study utilised a novel sheep model which, although in an anatomically different location, more accurately mimics the mechanical and synovial environment of the human rotator cuff, to determine the effects of intra-synovial implantation of MSCs. METHODS: A lesion was made in the lateral border of the lateral branch of the ovine deep digital flexor tendon within the digital sheath and 2 weeks later 5 million autologous bone marrow MSCs were injected under ultrasound guidance into the digital sheath. Tendons were recovered post mortem at 1 day, and 1-2, 4, 12 and 24 weeks after MSC injection. For the 1-day and 1-2-week groups, MSCs labelled with fluorescent-conjugated magnetic iron-oxide nanoparticles (MIONs) were tracked with MRI, histology and flow cytometry. The 4, 12 and 24-week groups were implanted with non-labelled cells and compared with saline-injected controls for healing. RESULTS: The MSCs displayed no reduced viability in vitro to an uptake of 20.0 ± 4.6 pg MIONs per cell, which was detectable by MRI at minimal density of ~ 3 × 104 cells. Treated limbs indicated cellular distribution throughout the tendon synovial sheath but restricted to the synovial tissues, with no MSCs detected in the tendon or surgical lesion. The lesion was associated with negligible morbidity with minimal inflammation post surgery. Evaluation of both treated and control lesions showed no evidence of healing of the lesion at 4, 12 and 24 weeks on gross and histological examination. CONCLUSIONS: Unlike other laboratory animal models of tendon injury, this novel model mimics the failed tendon healing seen clinically intra-synovially. Importantly, however, implanted stem cells exhibited homing to synovium niches where they survived for at least 14 days. This phenomenon could be utilised in the development of novel physical or biological approaches to enhance localisation of cells in augmenting intra-synovial tendon repair.

Immediate functional loading of single-tooth TIO2 grit-blasted implant restorations: a controlled prospective study in a porcine model. Part I: Clinical outcome.

BACKGROUND: Although favorable integration occurs with immediately loaded implants, the relationship between implant outcome, levels of occlusion, and diet requires optimization. PURPOSE: Pertubating load on single implant restorations immediately after placement by a hard food diet will increase the strains at the bone-implant interface, increasing the risk for failure. MATERIALS AND METHODS: Forty-eight implants replaced the first and third mandibular premolars in 12 pigs, allocated into two groups based on soft- and hard-diet feeding. Cylindrical and tapered implants replaced the first and third premolars, respectively. Each animal received at random four different masticatory loading conditions (group 1 control]: implant with either a cover screw or a healing abutment, and group 2 test]: implant with a crown either with or without occlusal contacts). RESULTS: Thirteen implants out of 44 failed in 11 animals (one with a cover screw, one with a healing abutment, three with nonocclusal, and eight with occlusal restorations). The failure rate of restored implants (either in occlusion or not) was significantly higher in the third premolar sites (p=.007), although diet had no significant effect (p=.421). CONCLUSIONS: While diet had no effect on the failure pattern of immediately loaded single implants, the position and type of load under the masticatory mode were significant. Immediately loaded implants both in and out of occlusion were less successful than the controls, and this is probably attributed to detrimental strain induced on the bone-implant interface.

Immediate functional loading of single-tooth TiO2 grit-blasted implant restoration. A controlled prospective study in a porcine model. Part II: Histology and histomorphometry.

BACKGROUND: Evidently, there is a fast-moving shift from delayed to immediate implant loading. The hypothesis to be tested was that bone reactions adjacent to single TiO2-microthreaded implants exposed to immediate masticatory loading for 10 weeks after placement would modulate osseointegration. MATERIALS AND METHODS: Cylindrical- and tapered-designed implants (Astra Tech AB, Mölndal, Sweden) replaced first and third mandibular premolars respectively in 12 pigs. The animals were allocated into two groups based on soft and hard diet feeding. Each animal received, at random positions, four different masticatory loading conditions: implant with either (1) a cover screw only, (2) a healing abutment, (3) an implant with a crown without occlusal contact, or (4) an implant with a crown in contact with the antagonistic teeth. RESULTS: Histomorphometry showed that there were no statistically significant differences in bone-implant contact (BIC), bone mass inside/outside of the threads and soft tissue ingrowth ratio for all the implants at 10 weeks after placement irrespective of masticatory loading condition. Bone loss showed a trend of progressive increase for implants with a healing abutment toward implants with occlusal contact. CONCLUSIONS: The results of this study rejected the hypothesis and could be explained by the fact that grit-blasted acid-etched implants were already placed in dense bone.

Repair of Torn Avascular Meniscal Cartilage Using Undifferentiated Autologous Mesenchymal Stem Cells: From In Vitro Optimization to a First-in-Human Study.

Meniscal cartilage tears are common and predispose to osteoarthritis (OA). Most occur in the avascular portion of the meniscus where current repair techniques usually fail. We described previously the use of undifferentiated autologous mesenchymal stem cells (MSCs) seeded onto a collagen scaffold (MSC/collagen-scaffold) to integrate meniscal tissues in vitro. Our objective was to translate this method into a cell therapy for patients with torn meniscus, with the long-term goal of delaying or preventing the onset of OA. After in vitro optimization, we tested an ovine-MSC/collagen-scaffold in a sheep meniscal cartilage tear model with promising results after 13 weeks, although repair was not sustained over 6 months. We then conducted a single center, prospective, open-label first-in-human safety study of patients with an avascular meniscal tear. Autologous MSCs were isolated from an iliac crest bone marrow biopsy, expanded and seeded into the collagen scaffold. The resulting human-MSC/collagen-scaffold implant was placed into the meniscal tear prior to repair with vertical mattress sutures and the patients were followed for 2 years. Five patients were treated and there was significant clinical improvement on repeated measures analysis. Three were asymptomatic at 24 months with no magnetic resonance imaging evidence of recurrent tear and clinical improvement in knee function scores. Two required subsequent meniscectomy due to retear or nonhealing of the meniscal tear at approximately 15 months after implantation. No other adverse events occurred. We conclude that undifferentiated MSCs could provide a safe way to augment avascular meniscal repair in some patients. Registration: EU Clinical Trials Register, 2010-024162-22. Stem Cells Translational Medicine 2017;6:1237-1248.

Development of a soft tissue seal around bone-anchored transcutaneous amputation prostheses.

Conventional amputation prosthetics are problematic because they rely on the stump-socket interface for attachment. Intraosseous transcutaneous amputation prostheses (ITAP) could solve these problems; however they rely on the integrity of the soft tissue-implant interface as a barrier to exogenous agents, and in the prevention of downgrowth and marsupilisation. We have used an in vivo animal model to study the soft tissue interfaces around bone-anchored transcutaneous implants. We hypothesise that by facilitating and increasing the area of dermal attachment to the implant epithelial down-growth will be reduced. A flange with a series of 24, 0.7 mm holes positioned immediately below the epithelium was used to increase dermal attachment. This significantly reduced downgrowth and optimised the integrity of the collagenous tissue-implant interface at the dermal level. We postulate that the flange reduces relative interfacial movement at the epithelium-implant interface by providing increased surface area for dermal tissue attachment. A tight seal at the dermal tissue level reduces the degree of downgrowth around ITAP, eliminating marsupilisation as a potential failure modality. Surface topography and coatings did not affect the degree of downgrowth or dermal attachment to straight or flanged implants. A significant negative correlation was observed between downgrowth and both epithelial and dermal attachment. This study shows that a soft tissue-implant interface capable of preventing downgrowth and marsupilisation can develop around a bone-anchored transcutaneous implant, given the incorporation of a porous flange positioned in the dermal tissues immediately below the epithelium. This will benefit applications where bone-anchored transcutaneous implants are used.