Effects of glenoid inclination and acromion index on humeral head translation and glenoid articular cartilage strain.

BACKGROUND: Previous clinical studies have reported associations between glenoid inclination (GI), the acromion index (AI), and the critical shoulder angle (CSA) on the one hand and the occurrence of glenohumeral osteoarthritis and supraspinatus tendon tears on the other hand. The objective of this work was to analyze the correlations and relative importance of these different anatomic parameters. METHODS: Using a musculoskeletal shoulder model developed from magnetic resonance imaging scans of 1 healthy volunteer, we varied independently GI from 0° to 15° and AI from 0.5 to 0.8. The corresponding CSA varied from 20.9° to 44.1°. We then evaluated humeral head translation and critical strain volume in the glenoid articular cartilage at 60° of abduction in the scapular plane. These values were correlated with GI, AI, and CSA. RESULTS: Humeral head translation was positively correlated with GI (R = 0.828, P < .0001), AI (R = 0.539, P < .0001), and CSA (R = 0.964, P < .0001). Glenoid articular cartilage strain was also positively correlated with GI (R = 0.489, P = .0004) but negatively with AI (R = -0.860, P < .0001) and CSA (R = -0.285, P < .0473). CONCLUSIONS: The biomechanical shoulder model is consistent with clinical observations. The prediction strength of CSA is confirmed for humeral head translation and thus presumably for rotator cuff tendon tears, whereas the AI seems more appropriate to evaluate the risk of glenohumeral osteoarthritis caused by excessive articular cartilage strain. As a next step, we should corroborate these theoretical findings with clinical data.

Human Bone Progenitor Cells for Clinical Application: What Kind of Immune Reaction Does Fetal Xenograft Tissue Trigger in Immunocompetent Rats?

The potential of human fetal bone cells for successful bone regeneration has been shown in vivo. In particular, it has been demonstrated that the seeding of these cells in porous poly-(l-lactic acid)/ß-tricalcium phosphate scaffolds improved the bone formation compared to cell-free scaffolds in skulls of rats. However, even if the outcome is an improvement of bone formation, a thorough analysis concerning any immune responses, due to the implantation of a xenograft tissue, is not known. As the immune response and skeletal system relationship may contribute to either the success or failure of an implant, we were interested in evaluating the presence of any immune cells and specific reactions of human fetal cells (also called human bone progenitor cells) once implanted in femoral condyles of rats. For this purpose, (1) cell-free scaffolds, (2) human bone progenitor cells, or (3) osteogenic human bone progenitor cells within scaffolds were implanted over 3, 7, 14 days, and 12 weeks. The key finding is that human bone progenitor cells and osteogenic human bone progenitor cells do not trigger any particular specific immune reactions in immunocompetent rats but are noted to delay some bone formation.

Osteogenesis imperfecta: from diagnosis and multidisciplinary treatment to future perspectives.

Osteogenesis imperfecta is an inherited connective tissue disorder with wide phenotypic and molecular heterogeneity. A common issue associated with the molecular abnormality is a disturbance in bone matrix synthesis and homeostasis inducing bone fragility. In very early life, this can lead to multiple fractures and progressive bone deformities, including long bone bowing and scoliosis. Multidisciplinary management improves quality of life for patients with osteogenesis imperfecta. It consists of physical therapy, medical treatment and orthopaedic surgery as necessary. Medical treatment consists of bone-remodelling drug therapy. Bisphosphonates are widely used in the treatment of moderate to severe osteogenesis imperfecta, from infancy to adulthood. Other more recent drug therapies include teriparatide and denosumab. All these therapies target the symptoms and have effects on the mechanical properties of bone due to modification of bone remodelling, therefore influencing skeletal outcome and orthopaedic surgery. Innovative therapies, such as progenitor and mesenchymal stem cell transplantation, targeting the specific altered pathway rather than the symptoms, are in the process of development.

A photopolymerized composite hydrogel and surgical implanting tool for a nucleus pulposus replacement.

Nucleus pulposus replacements have been subjected to highly controversial discussions over the last 40 years. Their use has not yet resulted in a positive outcome to treat herniated disc or degenerated disc disease. The main reason is that not a single implant or tissue replacement was able to withstand the loads within an intervertebral disc. Here, we report on the development of a photo-polymerizable poly(ethylene glycol)dimethacrylate nano-fibrillated cellulose composite hydrogel which was tuned according to native tissue properties. Using a customized minimally-invasive medical device to inject and photopolymerize the hydrogel insitu, samples were implanted through an incision of 1 mm into an intervertebral disc of a bovine organ model to evaluate their long-term performance. When implanted into the bovine disc model, the composite hydrogel implant was able to significantly re-establish disc height after surgery (p < 0.0025). The height was maintained after 0.5 million loading cycles (p < 0.025). The mechanical resistance of the novel composite hydrogel material combined with the minimally invasive implantation procedure into a bovine disc resulted in a promising functional orthopedic implant for the replacement of the nucleus pulposus.

Anti-Microbial Dendrimers against Multidrug-Resistant P. aeruginosa Enhance the Angiogenic Effect of Biological Burn-wound Bandages.

Multi-drug resistant Pseudomonas aeruginosa has increased progressively and impedes further regression in mortality in burn patients. Such wound infections serve as bacterial reservoir for nosocomial infections and are associated with significant morbidity and costs. Anti-microbial polycationic dendrimers G3KL and G3RL, able to kill multi-drug resistant P. aeruginosa, have been previously developed. The combination of these dendrimers with a class of biological bandages made of progenitor skin cells, which secrete growth factors, could positively impact wound-healing processes. However, polycations are known to be used as anti-angiogenic agents for tumor suppression. Since, neovascularization is pivotal in the healing of deep burn-wounds, the use of anti-microbial dendrimers may thus hinder the healing processes. Surprisingly, we have seen in this study that G3KL and G3RL dendrimers can have angiogenic effects. Moreover, we have shown that a dendrimer concentration ranging between 50 and 100 µg/mL in combination with the biological bandages can suppress bacterial growth without altering cell viability up to 5 days. These results show that antimicrobial dendrimers can be used in combination with biological bandages and could potentially improve the healing process with an enhanced angiogenesis.

A patient-specific model of total knee arthroplasty to estimate patellar strain: A case study.

BACKGROUND: Inappropriate patellar cut during total knee arthroplasty can lead to patellar complications due to increased bone strain. In this study, we evaluated patellar bone strain of a patient who had a deeper patellar cut than the recommended. METHODS: A patient-specific model based on patient preoperative data was created. The model was decoupled into two levels: knee and patella. The knee model predicted kinematics and forces on the patella during squat movement. The patella model used these values to predict bone strain after total knee arthroplasty. Mechanical properties of the patellar bone were identified with micro-finite element modeling testing of cadaveric samples. The model was validated with a robotic knee simulator and postoperative X-rays. For this patient, we compared the deeper patellar cut depth to the recommended one, and evaluated patellar bone volume with octahedral shear strain above 1%. FINDINGS: Model predictions were consistent with experimental measurements of the robotic knee simulator and postoperative X-rays. Compared to the recommended cut, the deeper cut increased the critical strain bone volume, but by less than 3% of total patellar volume. INTERPRETATION: We thus conclude that the predicted increase in patellar strain should be within an acceptable range, since this patient had no complaints 8 months after surgery. This validated patient-specific model will later be used to address other questions on groups of patients, to eventually improve surgical planning and outcome of total knee arthroplasty.

Miniature probe for the delivery and monitoring of a photopolymerizable material.

Photopolymerization is a common method to cure materials initially in a liquid state, such as dental implants or bone or tissue fillers. Recent advances in the development of biocompatible gel- and cement-systems open up an avenue for in situ photopolymerization. For minimally invasive surgery, such procedures require miniaturized surgical endoscopic probes to activate and control photopolymerization in situ. We present a miniaturized light probe in which a photoactive material can be (1) mixed, pressurized, and injected, (2) photopolymerized/photoactivated, and (3) monitored during the chemical reaction. The device is used to implant and cure poly(ethylene glycol) dimethacrylate-hydrogel-precursor in situ with ultraviolet A (UVA) light (365 nm) while the polymerization reaction is monitored in real time by collecting the fluorescence and Raman signals generated by the 532-nm excitation light source. Hydrogels could be delivered, photopolymerized, and monitored by the probe up to a curing depth of 4 cm. The size of the photopolymerized samples could be correlated to the fluorescent signal collected by the probe, and the reproducibility of the procedure could be demonstrated. The position of the probe tip inside a bovine caudal intervertebral disc could be estimated in vitro based on the collected fluorescence and Raman signal.

A flow sensing model for mesenchymal stromal cells using morphogen dynamics.

The differentiation of mesenchymal stromal cells has been shown to be affected by many parameters such as morphogens, flow rate, medium viscosity, and shear stress when exposed to fluid flow. The mechanism by which these cells sense their environment is still under intense discussion. In particular, during flow chamber experiments, it is difficult to interpret the interplay of the above-mentioned parameters in the process of cell differentiation. In this work, we tested the hypothesis that the competition between diffusion and advection of paracrine morphogens could explain the dependency of the cell differentiation to the above-mentioned parameters. To evaluate this hypothesis, we developed a numerical model simulating a simplified version of the advection-diffusion-reaction of morphogens secreted by the cells within a flow chamber. The model predicted a sharp transition in the fraction of receptors bound to the morphogen. This transition was characterized by a new, dimensionless number depending on flow rate, flow viscosity, flow chamber dimensions, and morphogen decay rate. We concluded that the competition between diffusion and advection of paracrine morphogens can act as a probe for the cells to sense their pericellular environment.

Activities of daily living with reverse prostheses: importance of scapular compensation for functional mobility of the shoulder.

HYPOTHESIS: The nonanatomical design of reverse shoulder prostheses induce medial displacement of the center of rotation, impingements and may reduce the mobility of the shoulder. The aim of this study is to test the hypothesis that during activities of daily living functional mobility of the shoulder can be restored by scapular compensation. MATERIAL AND METHODS: A numerical 3-dimensional model was developed to reproduce the movement of the scapula and humerus, during 4 activities of daily living measured experimentally. This hypothesis was tested in 4 configurations of the aequalis reverse prosthesis (standard 36-mm glenosphere, 42-mm glenosphere, lateralized 36-mm glenosphere, lateralized Bony Increased-Offset Reverse Shoulder Arthroplasty [BIO-RSA]), which were implanted in the virtual model. All impingement positions were evaluated, as the required scapular compensation to avoid impingements. RESULTS: With the 36-mm glenosphere, impingements occurred only for rest of hand to back-pocket positions. The 42-mm partly improved the mobility. The 2 lateralized glenospheres were free of impingement. When impingements occurred, the scapular compensation was less than 10°. CONCLUSION: Most reverse prostheses impingements reported in clinical and biomechanical studies can be avoided, either by scapular compensation or by a glenosphere lateralization. After reverse shoulder arthroplasty, a fraction of the mobility of the gleno-humeral is transferred to the scapulo-thoracic joint.

Regulation of proliferation and differentiation of human fetal bone cells.

During the last decade, extensive research has been performed in the field of orthopedic medicine to develop cell-based therapies for the restoration of injured bone tissue. We previously demonstrated that human primary fetal bone cells (HFBCs) associated with porous scaffolds induced a bone formation in critical calvaria defect; however, the environmental factors regulating their behavior in culture have not been identified. HFBCs (human fetal femur,12 week development) were compared to marrow-derived human mesenchymal stem cells (HMSCs) for their capacity to proliferate and differentiate into osteoblasts under various culture conditions. When cultured in standard alphaMEM medium, PDGF and FGF-2 increased cell proliferation of both cell types. Investigation of the differentiating capacity of HFBCs and HMSCs in a normal culture medium indicated that HFBCs expressed higher expression levels of RUNX2, OSX, and osteogenic markers compared with HMSCs, while SOX9 was expressed at very low levels in both cells types. However, HMSCs, but not HFBCs enhanced osteoblastic markers in response to osteogenic factors. Surprisingly, BMP-2 with osteogenic factors increased cell numbers and reduced osteoblastic differentiation in HFBCs with the opposite effect seen in HMSCs. Associated with a higher expression of osteoblastic markers, HFBCs produced a higher calcified extra cellular matrix compared with HMSCs. Taken together, data presented in this study suggest that HFBCs have characteristics of osteoprecursor cells that are more advanced in their osteogenesis development compared with mesenchymal stem cells, making fetal cells an interesting biological tool for treatment of skeletal defects and diseases.

Plasticity of fetal cartilaginous cells.

Tissue-specific stem cells found in adult tissues can participate in the repair process following injury. However, adult tissues, such as articular cartilage and intervertebral disc, have low regeneration capacity, whereas fetal tissues, such as articular cartilage, show high regeneration ability. The presence of fetal stem cells in fetal cartilaginous tissues and their involvement in the regeneration of fetal cartilage is unknown. The aim of the study was to assess the chondrogenic differentiation and the plasticity of fetal cartilaginous cells. We compared the TGF-ß3-induced chondrogenic differentiation of human fetal cells isolated from spine and cartilage tissues to that of human bone marrow stromal cells (BMSC). Stem cell surface markers and adipogenic and osteogenic plasticity of the two fetal cell types were also assessed. TGF-ß3 stimulation of fetal cells cultured in high cell density led to the production of aggrecan, type I and II collagens, and variable levels of type X collagen. Although fetal cells showed the same pattern of surface stem cell markers as BMSCs, both type of fetal cells had lower adipogenic and osteogenic differentiation capacity than BMSCs. Fetal cells from femoral head showed higher adipogenic differentiation than fetal cells from spine. These results show that fetal cells are already differentiated cells and may be a good compromise between stem cells and adult tissue cells for a cell-based therapy.

In vivo cyclic loading as a potent stimulatory signal for bone formation inside tissue engineering scaffold.

In clinical situations, bone defects are often located at load bearing sites. Tissue engineering scaffolds are future bone substitutes and hence they will be subjected to mechanical stimulation. The goal of this study was to test if cyclic loading can be used as stimulatory signal for bone formation in a bone scaffold. Poly(L-lactic acid) (PLA)/ 5% beta-tricalcium phosphate (beta-TCP) scaffolds were implanted in both distal femoral epiphyses of eight rats. Right knees were stimulated (10N, 4Hz, 5 min) five times, every two days, starting from the third day after surgery while left knees served as control. Finite element study of the in vivo model showed that the strain applied to the scaffold is similar to physiological strains. Using micro-computed tomography (CT), all knees were scanned five times after the surgery and the related bone parameters of the newly formed bone were quantified. Statistical modeling was used to estimate the evolution of these parameters as a function of time and loading. The results showed that mechanical stimulation had two effects on bone volume (BV): an initial decrease in BV at week 2, and a long-term increase in the rate of bone formation by 28%. At week 13, the BV was then significantly higher in the loaded scaffolds.

Prediction of bone density around orthopedic implants delivering bisphosphonate.

The fixation of an orthopedic implant depends strongly upon its initial stability. Peri-implant bone may resorb shortly after the surgery. This resorption is directly followed by new bone formation and implants fixation strengthening, the so-called secondary fixation. If the initial stability is not reached, the resorption continues and the implant fixation weakens, which leads to implant loosening. Studies with rats and dogs have shown that a solution to prevent peri-implant resorption is to deliver bisphosphonate from the implant surface. The aims of the study were, first, to develop a model of bone remodeling around an implant delivering bisphosphonate, second, to predict the bisphosphonate dose that would induce the maximal peri-implant bone density, and third to verify in vivo that peri-implant bone density is maximal with the calculated dose. The model consists of a bone remodeling equation and a drug diffusion equation. The change in bone density is driven by a mechanical stimulus and a drug stimulus. The drug stimulus function and the other numerical parameters were identified from experimental data. The model predicted that a dose of 0.3 microg of zoledronate on the implant would induce a maximal bone density. Implants with 0.3 microg of zoledronate were then implanted in rat femurs for 3, 6 and 9 weeks. We measured that peri-implant bone density was 4% greater with the calculated dose compared to the dose empirically described as best. The approach presented in this paper could be used in the design and analysis processes of experiments in local delivery of drug such as bisphosphonate.

In vitro characterization of immune-related properties of human fetal bone cells for potential tissue engineering applications.

We describe herein some immunological properties of human fetal bone cells recently tested for bone tissue-engineering applications. Adult mesenchymal stem cells (MSCs) and osteoblasts were included in the study for comparison. Surface markers involved in bone metabolism and immune recognition were analyzed using flow cytometry before and after differentiation or treatment with cytokines. Immunomodulatory properties were studied on activated peripheral blood mononuclear cells (PBMCs). The immuno-profile of fetal bone cells was further investigated at the gene expression level. Fetal bone cells and adult MSCs were positive for Stro-1, alkaline phosphatase, CD10, CD44, CD54, and beta2-microglobulin, but human leukocyte antigen (HLA)-I and CD80 were less present than on adult osteoblasts. All cells were negative for HLA-II. Treatment with recombinant human interferon gamma increased the presence of HLA-I in adult cells much more than in fetal cells. In the presence of activated PBMCs, fetal cells had antiproliferative effects, although with patterns not always comparable with those of adult MSCs and osteoblasts. Because of the immunological profile, and with their more-differentiated phenotype than of stem cells, fetal bone cells present an interesting potential for allogeneic cell source in tissue-engineering applications.

Total shoulder arthroplasty: downward inclination of the glenoid component to balance supraspinatus deficiency.

HYPOTHESIS: Supraspinatus deficiency associated with total shoulder arthroplasty (TSA) provokes eccentric loading and may induce loosening of the glenoid component. A downward inclination of the glenoid component has been proposed to balance supraspinatus deficiency. METHODS: This hypothesis was assessed by a numeric musculoskeletal model of the glenohumeral joint during active abduction. Three cases were compared: TSA with normal muscular function, TSA with supraspinatus deficiency, and TSA with supraspinatus deficiency and downward inclination of the glenoid. RESULTS: Supraspinatus deficiency increased humeral migration and eccentric loading. A downward inclination of the glenoid partly balanced the loss of stability, but this potential advantage was counterbalanced by an important stress increase within the glenoid cement. The additional subchondral bone reaming required to incline the glenoid component indeed reduced the bone support, increasing cement deformation and stress. CONCLUSION: Glenoid inclination should not be obtained at the expense of subchondral bone support.

Biomechanical evaluation of porous biodegradable scaffolds for revision knee arthroplasty.

Tibial bone defect is a critical problem for revision knee arthroplasty. Instead of using metallic spacer or cement, biodegradable scaffolds could be an alternative solution. A numerical model of a revision knee arthroplasty was thus developed to estimate the mechanical resistance of the scaffold in this demanding situation. The tibia, scaffold, and prosthesis were represented by simplified parameterised geometries. The maximal gait cycle force was applied asymmetrically to simulate a critical loading. Several parameters were analysed: 1) inter-individual variability, 2) cortical bone stiffness, 3) cortical bone thickness, 4) prosthesis fixation quality, and 5) scaffold thickness. The calculated scaffold strain was compared to its experimental ultimate strain. Among the tested parameters, failure was only predicted with scaffold thickness below 5 mm. This study suggests that biodegradable bone scaffolds could be used to fill bone defects in revision knee arthroplasty, but scaffold size seems to be the limiting factor.

Wound-healing gene family expression differences between fetal and foreskin cells used for bioengineered skin substitutes.

For tissue engineering, several cell types and tissues have been proposed as starting material. Allogenic skin products available for therapeutic usage are mostly developed with cell culture and with foreskin tissue of young individuals. Fetal skin cells offer a valuable solution for effective and safe tissue engineering for wounds due to their rapid growth and simple cell culture. By selecting families of genes that have been reported to be implicated in wound repair and particularly for scarless fetal wound healing including transforming growth factor-beta (TGF-beta) superfamily, extracellular matrix, and nerve/angiogenesis growth factors, we have analyzed differences in their expression between fetal skin and foreskin cells, and the same passages. Of the five TGF-beta superfamily genes analyzed by real-time reverse transcription-polymerase chain reaction, three were found to be significantly different with sixfold up-regulated for TGF-beta2, and 3.8-fold for BMP-6 in fetal cells, whereas GDF-10 was 11.8-fold down-regulated. For nerve growth factors, midkine was 36-fold down-regulated in fetal cells, and pleiotrophin was 4.76-fold up-regulated. We propose that fetal cells present technical and therapeutic advantages compared to foreskin cells for effective cell-based therapy for wound management, and overall differences in gene expression could contribute to the degree of efficiency seen in clinical use with these cells.

Human muscular fetal cells: a potential cell source for muscular therapies.

Myoblast transfer therapy has been extensively studied for a wide range of clinical applications, such as tissue engineering for muscular loss, cardiac surgery or Duchenne Muscular Dystrophy treatment. However, this approach has been hindered by numerous limitations, including early myoblast death after injection and specific immune response after transplantation with allogenic cells. Different cell sources have been analyzed to overcome some of these limitations. The object of our study was to investigate the growth potential, characterization and integration in vivo of human primary fetal skeletal muscle cells. These data together show the potential for the creation of a cell bank to be used as a cell source for muscle cell therapy and tissue engineering. For this purpose, we developed primary muscular cell cultures from biopsies of human male thigh muscle from a 16-week-old fetus and from donors of 13 and 30 years old. We show that fetal myogenic cells can be successfully isolated and expanded in vitro from human fetal muscle biopsies, and that fetal cells have higher growth capacities when compared to young and adult cells. We confirm lineage specificity by comparing fetal muscle cells to fetal skin and bone cells in vitro by immunohistochemistry with desmin and 5.1 H11 antibodies. For the feasibility of the cell bank, we ensured that fetal muscle cells retained intrinsic characteristics after 5 years cryopreservation. Finally, human fetal muscle cells marked with PKH26 were injected in normal C57BL/6 mice and were found to be present up to 4 days. In conclusion we estimate that a human fetal skeletal muscle cell bank can be created for potential muscle cell therapy and tissue engineering.

Repair of critical size defects in the rat cranium using ceramic-reinforced PLA scaffolds obtained by supercritical gas foaming.

Bioresorbable scaffolds made of poly(L-lactic acid) (PLA) obtained by supercritical gas foaming were recently described as suitable for tissue engineering, portraying biocompatibility with primary osteoblasts in vitro and interesting mechanical properties when reinforced with ceramics. The behavior of such constructs remained to be evaluated in vivo and therefore the present study was undertaken to compare different PLA/ceramic composite scaffolds obtained by supercritical gas foaming in a critical size defect craniotomy model in Sprague-Dawley rats. The host-tissue reaction to the implants was evaluated semiquantitatively and similar tendencies were noted for all graft substitutes: initially highly reactive but decreasing with time implanted. Complete bone-bridging was observed 18 weeks after implantation with PLA/ 5 wt % beta-TCP (PLA/TCP) and PLA/5 wt % HA (PLA/HA) scaffolds as assessed by histology and radiography. We show here for the first time that this solvent-free technique provides a promising approach in tissue engineering demonstrating both the biocompatibility and osteoconductivity of the processed structures in vivo.

Biocompatibility of bioresorbable poly(L-lactic acid) composite scaffolds obtained by supercritical gas foaming with human fetal bone cells.

The aim of this investigation was to test the biocompatibility of three-dimensional bioresorbable foams made of poly(L-lactic acid) (PLA), alone or filled with hydroxyapatite (HA) or beta-tricalcium phosphate (beta-TCP), with human primary osteoblasts, using a direct contact method. Porous constructs were processed by supercritical gas foaming, after a melt-extrusion of ceramic/polymer mixture. Three neat polymer foams, with pore sizes of 170, 310, and 600 microm, and two composite foams, PLA/5 wt% HA and PLA/5 wt% beta-TCP, were examined over a 4-week culture period. The targeted application is the bone tissue-engineering field. For this purpose, human fetal and adult bone cells were chosen because of their highly osteogenic potential. The association of fetal bone cells and composite scaffold should lead to in vitro bone formation. The polymer and composite foams supported adhesion and intense proliferation of seeded cells, as revealed by scanning electron microscopy. Cell differentiation toward osteoblasts was demonstrated by alkaline phosphatase (ALP) enzymatic activity, gamma-carboxylated Gla-osteocalcin production, and the onset of mineralization. The addition of HA or beta-TCP resulted in higher ALP enzymatic activity for fetal bone cells and a stronger production of Gla-osteocalcin for adult bone cells.