Spinal diseases such as unstable fractures, infections, primary or secondary tumors or deformities require surgical stabilization with implants. The long-term success of this treatment is only ensured by a solid bony fusion. The size of the bony defect, the often poor bone quality and metabolic diseases increase the risk of non-union and make the case a great burden for the patient and a challenge for the surgeon. The goal of spinal fusion can only be achieved if the implants used offer sufficient mechanical stability and the local biological regeneration potential is large enough to form sufficient bone. The lecture will present challenging clinical cases. In addition, implant materials and new surgical techniques are discussed. Local therapeutic effects are achieved through the release of osteopromotive or anti-resorbtive drugs, growth factors and antibiotics. By influencing biological pathways, basic orthopedic research has strong potential to further positively change future spinal surgery

Majority of osteoporosis related fractures are treated surgically using metallic fixation devices. Anchorage of fixation devices is sometimes challenging due to poor osteoporotic bone quality that can lead to failure of the fracture fixation. Using a rat osteoporosis model, we employed neutron tomography and histology to study the biological effects of implant augmentation using an isothermally setting calcium sulphate/hydroxyapatite (CaS/HA) biomaterial with synthetic HA particles as recruiting moiety for systemically administered bisphosphonates. Using an osteoporotic sawbones model, we then provide a standardized method for the delivery of the CaS/HA biomaterial at the bone-implant interface for improved mechanical anchorage of a lag-screw commonly used for hip fracture fixation. As a proof-of-concept, the method was then verified in donated femoral heads and in patients with osteoporosis undergoing hip fracture fixation. We show that placing HA particles around a stainless-steel screw in-vivo, systemically administered bisphosphonates could be targeted towards the implant, yielding significantly higher peri-implant bone formation compared to un-augmented controls. In the sawbones model, CaS/HA based lag-screw augmentation led to significant increase (up to 4 times) in peak extraction force with CaS/HA performing at par with PMMA. Micro-CT imaging of the CaS/HA augmented lag-screws in cadaver femoral heads verified that the entire length of the lag-screw threads and the surrounding bone was covered with the CaS/HA material. X-ray images from fracture fixation surgery indicated that the CaS/HA material could be applied at the lag-screw-bone interface without exerting any additional pressure or risk of venous vascular leakage.: We present a new method for augmentation of lag-screws in fragile bone. It is envisaged that this methodcould potentially reduce the risk of fracture fixation failure especially when HA seeking “bone active” drugs are used systemically

Bioactive glasses, such as 45S5 Bioglass (BG), have been shown to promote bone ingrowth both in vitro and in vivo. The goal of this study was to analyze the effect of a high dose of BG (20%) in Direct Ink Writing (DIW)-produced controlled-geometry PCL-BG composite scaffolds in both their mechanical and biological performance. Porous cubes of 5 × 5 × 5 mm, 50% porosity and pore size and strut diameter of 400 µm were fabricated in a 3D-Bioplotter (EnvisionTec) to investigate their biological performance (n = 3). Additionally, cylindrical specimens (10 mm diameter; 15 mm height) with same internal structure were fabricated for mechanical testing (n = 6). The cylindrical specimens were tested by compression in a universal testing machine (ZwickRoell) with a 10 kN load cell. The tests were performed at 1.00 mm/min with extensometers in both sides. For biological characterization, scaffolds were sterilized in 70% ethanol overnight and pre-incubated with DMEM for 1 hour at room temperature. 1×10. 5. human gingival mesenchymal stem cells (hGMSCs) in 50 µl DMEM were seeded on the scaffolds using agarose molds to improve cell adhesion, and cultured in standard cell-culture conditions for 3, 7 and 14 days. To measure cell proliferation, the reagent CellTiter 96® AQueous One Solution Cell Proliferation Assay (MTS, Promega) was added to the cell-seeded scaffolds at each time point, using non-seeded scaffolds as blank controls. The OD (490 nm) was measured in a BioTek 800 TS plate reader. Both the apparent elastic modulus and yield stress were significantly lower in the scaffolds with 20% BG than their PCL control counterparts (p < 0.0001 for elastic modulus and p < 0.005 for yield stress, t-test). Cell proliferation in the scaffolds by MTS was variable, with the 20% BG scaffolds showing a significantly higher signal after seven days in culture (p < 0.05 by t-test), but a significantly lower signal after 14 days in culture (p < 0.05 by t-test). In conclusion, scaffolds with 20% BG showed a lower mechanical performance than their PCL counterparts in terms of both their apparent elastic modulus and yield stress. Additionally, scaffolds with 20% BG showed variable cell proliferation rates in terms of their metabolic activity over a two-week period. The decrease in proliferation rate after week 2 after an initial increase at the end of week 1 could be due to cytotoxic effects of the BG at this high dose (20%) after long term exposure. These results suggest that a dosage of 20% BG may not necessarily improve the mechanical and biological performance of scaffolds, so future experiments are required in order to characterize the optimum BG dosage in PCL scaffolds for tissue engineering applications

While cell morphology has been recognized as a fundamental regulator of cell behavior, few studies have measured the complex cell morphological changes of chondrocytes using quantitative cell morphometry descriptors in relation to inflammation and phenotypic outcome. Acute vs. persistent exposure to IL-1β and how IL-1β modulated dynamic changes in cell morphology in relation to the phenotype, donor and OA grade in healthy and osteoarthritis (OA) chondrocytes was investigated. A panel of quantitative cell morphometry descriptors was measured using an automated high-throughput method. Absolute quantification of gene expression was measured by ddPCR followed by correlation analyses. In OA chondrocytes, chronic IL-1β significantly decreased COL2A1, SOX9, and ACAN, increased IL-6 and IL-8 levels and caused chondrocytes to become less wide, smaller, longer, slimmer, less round and more circular, consistent with a de-differentiated phenotype. In healthy chondrocytes, 3 days after acute (72 h) IL-1β exposure, COL1A2 and IL-6 significantly increased but had minor effects on cell morphology. However, in healthy chondrocytes, persistent IL-1β led to more profound effects in all cell morphology descriptors and chondrocytes expressed significantly less COL2A1 and more IL-6 and IL-8 vs. controls and acutely-stimulated chondrocytes. In both OA and healthy chronically-stimulated chondrocytes, area, width and circularity were sensitive to the persistent presence of the IL-1β cytokine. Moreover, there were many significant and strong correlations among the measured parameters, with several indications of an IL-1β-mediated mechanism. Cell morphology combined with gene expression analysis could guide researchers interested in understanding inflammatory effects in the complex domain of cartilage/chondrocyte biology. Use of quantitative cell morphometry could complement classical approaches by providing numerical data on a large number of cells, thereby providing a biological fingerprint for describing chondrocyte phenotype, which could help to understand how changes in cell morphology lead to disease progression

After anterior cruciate ligament (ACL) rupture, reconstructive surgery with a hamstring tendon autograft is often performed. Despite overall good results, ACL re-rupture occurs in up to 10% of the patient population, increasing to 30% of the cases for patients aged under 20 years. This can be related to tissue remodelling in the first months to years after surgery, which compromises the graft's mechanical strength. Resident graft fibroblasts secrete matrix metalloproteinases (MMPs), which break down the collagen I extracellular matrix. After necrosis of these fibroblasts, myofibroblasts repopulate the graft, and deposit more collagen III rather than collagen I. Eventually, the cellular and matrix properties converge towards those of the native ACL, but full restoration of the ACL properties is not achieved. It is unknown how inter-patient differences in tissue remodelling capacity contribute to ACL graft rupture risk. This research measured patient-specific tissue remodelling-related properties of human hamstring tendon-derived cells in an in vitro micro-tissue platform, in order to identify potential biological predictors for graft rupture. Human hamstring tendon-derived cells were obtained from remnant autograft tissue after ACL reconstructions. These cells were seeded in collagen I gels on a micro-tissue platform to assess inter-patient cellular differences in tissue remodelling capacity. Remodelling was induced by removing the outermost micro-posts, and micro-tissue compaction over time was assessed using transmitted light microscopy. Protein expression of tendon marker tenomodulin and myofibroblast marker α-smooth muscle actin (αSMA) were measured using Western blot. Expression and activity of remodelling marker MMP2 were determined using gelatin zymography. Cells were obtained from 12 patients (aged 12–51 years). Patient-specific variations in micro-tissue compaction speed or magnitude were observed. Up to 50-fold differences in αSMA expression were found between patients, although these did not correlate with faster or stronger compaction. Surprisingly, tenomodulin was only detected in samples obtained from two patients. Total MMP2 expression varied between patients, but no large differences in active fractions were found. No correlation of patient age with any of the remodelling-related factors was detected. Remodelling-related biological differences between patient tendon-derived cells could be assessed with the presented micro-tissue platform, and did not correlate with age. This demonstrates the need to compare this biological variation in vitro - especially cells with extreme properties - to clinical outcome. Sample size is currently increased, and patient outcome will be determined. Combined with results obtained from the in vitro platform, this could lead to a predictive tool to identify patients at risk for graft rupture

Titanium alloys are one of the most used for orthopaedic implants and the fabrication of them by 3D printing technology is a raising technology, which could effectively resolve existing challenges. Surface modification of Ti surfaces is often necessary to improve biocorrosion resistance, especially in inflammatory conditions. Such modification can be made by coatings based on hydrogels, like alginate (Alg) - a naturally occurring anionic polymer. The properties of the hydrogel can be further enhanced with calcium phosphates like octacalcium phosphate (OCP) as a precursor of biologically formed hydroxyapatite. Formed Alg-OCP matrices have a high potential in wound healing, delivery of bioactive agents etc. but their effect on 3D printed Ti alloys performance was not well known. In this work, Alg-OCP coated 3D printed samples were studied with electrochemical measurements and revealed significant variations of corrosion resistance vs. composition of the coating. The potentiodynamic polarization test showed that the Alg-OCP-coated samples had lower corrosion current density than simple Alg-coated samples. Electrochemical impedance spectroscopy indicated that OCP incorporated hydrogels had also a high value of the Bode modulus and phase angle. Hence Alg-OCP hydrogels could be highly beneficial in protecting 3D printed Ti alloys especially when the host conditions for the implant placement are inflammatory. AcThis work was supported by the European Union Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie Actions GA860462 (PREMUROSA). The authors also acknowledge the access to the infrastructure and expertise of the BBCE – Baltic Biomaterials Centre of Excellence (European Union Horizon 2020 programme under GA857287)

The treatment of osteochondral lesions and osteoarthritis remains an ongoing clinical challenge in orthopaedics. This review examines the current research in the fields of cartilage regeneration, osteochondral defect treatment, and biological joint resurfacing, and reports on the results of clinical and pre-clinical studies. We also report on novel treatment strategies and discuss their potential promise or pitfalls. Current focus involves the use of a scaffold providing mechanical support with the addition of chondrocytes or mesenchymal stem cells (MSCs), or the use of cell homing to differentiate the organism’s own endogenous cell sources into cartilage. This method is usually performed with scaffolds that have been coated with a chemotactic agent or with structures that support the sustained release of growth factors or other chondroinductive agents. We also discuss unique methods and designs for cell homing and scaffold production, and improvements in biological joint resurfacing. There have been a number of exciting new studies and techniques developed that aim to repair or restore osteochondral lesions and to treat larger defects or the entire articular surface. The concept of a biological total joint replacement appears to have much potential. Cite this article: Bone Joint Res 2013;2:193–9

The growth in the popularity of tissue engineering principles in the treatment of musculoskeletal disorders has been complemented greatly with research investment into tissue specific scaffolds. Biological scaffolds produced by means of decellularising native tissues have the advantage of providing the natural complex hierarchical matrix and, in doing so, replicating the specific biomechanical and biological functions of the tissue in question. Decellularisation treatments are multi-faceted, vary considerably between different processes and may involve many lengthy treatment steps. Some of these bio-processes may cause undesirable structural changes to the extracellular matrix of tissues and, by association, their mechanical properties. Thus, it is of paramount importance to ensure that the properties of the scaffolds are not affected to the extent of reducing their integration, biomechanical performance and longevity. This talk consists of a body of work detailing investigations into bio-process optimisation, sterilisation strategies and the regenerative and functional capacity of decellularised xenogeneic and allogeneic tendon, ligament and bone scaffolds. In addition, on-going work concerning advanced pre-clinical assessment, stratification of these products to particular patient populations and the importance of the manufacturing value chain in their translation will be discussed

Biphasic calcium phosphates (BCP) are the most frequently used materials because of their mineral analogy with bio-mineral part of bones. Their chemical synthesis can be modulated by doping, in order to respond to the biological needs. We present here the biological responses induced by copper ions in solution, to characterize its cytotoxicity and antibacterial activity. We also investigate the antibacterial property of Cu-doped BCP (Ca10 Cu0.1 (PO4)6 (OH)1.8 O0.2) on a strain of clinical interest: S. aureus, compared to undoped BCP. The sol-gel route has been used to prepare the BCP ceramics. Human BMC (Bone Marrow Cells) were obtained from metaphysal cancellous bone collected during hip arthroplasty and used for cytotoxicity evaluations. A strain of Staphylococcus aureus isolated from an osteoarticular infection after total knee arthroplasty was used to evaluate antibacterial activities. Results indicate that 3 ppm of copper ions leads to the death of all cultured bacteria in 24 hours and 25 ppm caused the death of all cells in 15 days. Regarding BCP, the undoped bioceramics increased the bacterial growth compared to a control without bioceramic. After 16 hours of contact, the copper ions released by the Cu-doped BCP induced a significant decrease of the bacterial concentration, indeed no viable bacteria were found. These materials seem to be a promising alternative for the preparation of multifunctional bone substitutes

Improvements in arthroplasty design and materials led to superior lifetime of the implants. Nevertheless, aseptic loosening due to particulate debris is still one of the most frequent late reasons for revision of hip and knee replacements. The complex process of inflammation and osteolysis due to wear particles is not understood in detail so far. A cellular and receptor mediated response to wear particles results in a release of pro-inflammatory cytokines and induces an inflammatory reaction causing periprosthetic osteolysis. The overall cellular response is influenced by particle volume as well as characteristics. But there is still a lack of data concerning all signalling pathways that are involved. To answer some open questions appropriate in vivo models are shown closing the loop between wear simulation, particle analysis, generation of sterile particles and biological evaluation. Beyond that, new aspects of particle effects and deposits in retrieved human tissue are given

In recent years, novel therapies for intervertebral disc (IVD) regeneration have been developed that are based on the delivery of cells, biomaterials or bioactive molecules. The efficacy of these biological therapies depends on the type and degree of IVD degeneration. Whole organ culture bioreactors provide an attractive platform for pre-clinical testing of IVD therapeutics, since the cells are maintained within their native extracellular matrix, and the endplate remains intact to fulfil its function. Moreover, defined regimes of mechanical stress are applied to the IVD, representing either physiological or degenerative, detrimental loading. Different degrees of degeneration can be induced by high load, low nutrition, enzyme injection, and/or mechanical damage; while recent organ culture models also implement an inflammatory component. Using whole organ culture models, we found that mesenchymal stem cell injection into nucleotomized IVDs had an anabolic effect on the IVD cells. Furthermore, hyaluronan hydrogels were beneficial for cell delivery and mechanical support. We also found that anti-inflammatory treatment could partially prevent the induction of cytokines in an inflammatory model. However, chemokine delivery did not induce a significant repair response in an annulus fibrosus defect. In line with 3R principles, relevant ex-vivo models are essential to reliably test biological IVD treatments

Rotator cuff repair has excellent clinical outcomes but continues to be a challenge when it comes to large and massive tears as well as revision procedures. Reported symptomatic retear rates are still too high to be acceptable. The purpose of the present study was to evaluate the effectiveness of a combination of augmentation techniques consisting of microfractures of the greater tuberosity, extracellular matrix (ECM) patch graft and subsequent platelet concentrate (PC) subacromial injections in revision rotator cuff repair.

The study was designed as a retrospective comparative study on prospectively collected data from a consecutive cohort of patients. All patients who underwent arthroscopic revision rotator cuff repair for symptomatic failure of previous posterosuperior rotator cuff repair were considered eligible for the study. Symptomatic failure had been diagnosed according to clinical examination and confirmed by magnetic resonance imaging (MRI). Structural integrity had been assessed on MRI and classified according to Sugaya classification. Only patients affected by stage IV-V were considered eligible. Tear reparability was confirmed during arthroscopy. Only patients with a minimum 2 years follow-up were included. Patients were divided in two groups. In group 1 (control group) a standard arthroscopic revision and microfractures of the greater tuberosity were performed; in group 2 (experimental group), microfractures of the greater tuberosity and a ECM patch graft were used to enhance tendon repair, followed by postoperative PC injections. Minimum follow-up was 12 months. Primary outcome was the Constant-Murley score (CMS) normalized for age and gender. Subjective outcome was assessed with the Disabilities of the Arm, Shoulder and Hand (DASH) score in its short version (Quick-DASH). Tendon integrity was assessed with MRI at 6 months after surgery. Comparison between groups for all discrete variables at baseline and at follow-up was carried out with the Student's t-test for normally distributed data, otherwise Mann-Whitney U-test was used. Within-group differences (baseline vs follow-up) for discrete variables were analyzed by paired t-test, or by Wilcoxon signed-rank test in case of data with non-normal distribution. Differences for categorical variables were assessed by chi-squared test. Significance was considered for p values < 0.05.

Forty patients were included in the study (20 patients for each group). The mean follow-up was 13 ± 1.6 months. No patients were lost at the follow up. Comparison between groups did not show significant differences for baseline characteristics. At follow-up, mean CMS was 80.7 ± 16.6 points in group 1 and 91.5 ± 11.5 points in group 2 (p= 0.022). Mean DASH score was 28.6 ± 21.6 points in group 1 and 20.1 ± 17.4 points in group 2 (p= 0.178). Post-operative MRI showed 6 healed shoulders in Group 1 and 16 healed shoulders in Group 2 (p<0.004). No postoperative complications were reported in both groups.

The combination of microfractures of the greater tuberosity, ECM patch graft, and subsequent PC subacromial injections is an effective strategy in improving tendon healing rate.

Distraction histogenesis (DH) techniques have been widely accepted and practiced in orthopaedics, traumatology, and craniofacial surgery over the last two decades. Using DH methods, many previously untreatable conditions have been successfully managed with outstanding clinical outcomes. The biological mechanisms underlying DH have been studied and the tension-stress principles of tissue regeneration are attributed to upregulated gene expression, enhanced cell proliferation, angiogenesis and tissue remodelling and endogenous stem cell mobilization. The new methods of enhancing bone consolidation in DH are proposed and need further clinical studies. The novel applications of DH have now been extended for the treatment of vascular diseases, cranial defect (with neuronal disorders), hip and spinal deformity corrections and soft-tissue defects in addition to various bone defects and deformities. There are more surprises and novel mechanisms yet to be discovered for these novel applications of DH

Autologous micro-fragmented adipose tissue (MFAT) for the treatment of symptomatic knee osteoarthritis (OA) is gaining interest although there is still a lack of supportive data on safety and clinical efficacy. This study primarily aimed to identify patient- and pathology-related parameters to tighten patient selection criteria for future clinical MFAT application. Secondly, the overall (1) therapeutic response rate (TRR), (2) short-term clinical effect, (3) effect durability and (4) therapeutic safety was investigated at a minimal follow-up of 1 year.

Sixty-four subjects (91 knees) with symptomatic knee OA (mild-severe on MRI) were enrolled in a prospective single-centre case series. Ethical approval was obtained from the local and academic ethical committee (#B300201733775). After liposuction, the adipose tissue was mechanically processed in a Lipogem® device which eventually produced 6–9cc MFAT. Subjects were clinically assessed by means of the KOOS, NRS, UCLA and EQ-5D at baseline and 1, 3, 6 and 12 months after injection. Adverse events were meticulously recorded. The TRR was defined according to the OMERACT-OARSI criteria. A baseline MRI was scored following the MOAKS system. Paired sample t-tests, independent t-test and Fischer's exact test were applied on appropriate variables. Multiple regression models were fit separately for patient-and pathology-specific factors. Significance level was set at α=0.05.

The overall TRR was 66% at 3 months and 50% at 12 months after injection. Subgroup analysis revealed that specifically patients with no-mild bone marrow lesions (BML) had a TRR of 88% at 3 months and 75% at 12 months after MFAT injection. Therapy responders at these timepoints improved with 29.3±14.1 points and 30.8±15.3 points on KOOS pain, while non-responders deteriorated mildly. All clinical scores were significantly higher at follow-up compared to baseline (p<0.05). BMI (factor 0.17, p=0.002) and age (factor −0.48, p=0.048) were prognosticators for the TRR% at 1 month and for absolute KOOS pain improvement at 6 months, respectively. Posterior horn lesions (PHL) in the medial meniscus (p<0.001) and bone marrow lesions (p=0.003) were negative prognosticators for the TRR at respectively 6 and 12 months post-injection. An inflammatory reaction (pain, swelling or stiffness) to MFAT was reported in 79% knees and resolved spontaneously within 16.6±13.5 days after administration.

The study showed a durable and satisfying TRR (up to 75% at 1 year in selected patients without BML) and clinical improvement after a single intra-articular injection with autologous MFAT. The availability of an index knee MRI is mandatory to select MFAT patients, preferably with no or mild BML and without PHL of the medial meniscus. High BMI and younger age are associated with better early outcomes. In comparison to other injection therapies such as cortisone, hyaluronic acid and PRP, MFAT appears very attractive with an effect durability of at least 1 year.

The development of functional biomaterials scaffolds for bone tissue engineering applications includes the control of specific biological and mechanical parameters that are involved in the growth of bone tissue in a way that mimics the physiological process of healing bone defects. Here, we report on the development of composite scaffolds made from biodegradable natural and synthetic biomaterials with characteristic architectural features, functionalized with the osteoinductive growth factor bone morphogenetic protein BMP-2, and evaluating their osteogenic response in static and dynamic cell culture systems. The results show that scaffold designing with advanced technologies combined with appropriate biochemical and mechanical stimulating factors, results to an enhanced proliferative and osteogenic/chondrogenic differentiation response of cells cultured on the developed scaffolds, and thus controlling the new tissue formation and reconstruction

Summary. Wear particles from joint replacements may result in loosening and periprosthetic osteolysis. Interference with systemic macrophage trafficking to the implant, modulation of macrophage phenotype from M1 to M2, and inhibition of NFκB may mitigate these adverse effects. Introduction. Joint replacement of the lower extremity is highly successful in alleviating pain, and improving ambulation and function. However, prosthetic byproducts of different materials, in sufficient amounts, may lead to loosening and periprosthetic osteolysis. Debris from polymers (such as polyethylene and PMMA), metals and ceramics are capable of inciting an adverse tissue reaction, which is orchestrated by cells of the monocyte/macrophage lineage. Three experimental approaches have been taken by our group to potentially mitigate the adverse biological sequela of particle disease. These include: 1) interfering with ongoing migration of monocyte/macrophages to the implant site by inhibiting the chemokine system 2) altering the functional activities of local macrophages by converting pro-inflammatory M1 macrophages to an anti-inflammatory pro-tissue healing M2 phenotype and 3) modulating the production and release of pro-inflammatory cytokines, chemokines and other potentially harmful factors by inhibiting the key transcription factor NFκB. Methods. First, a murine model of systemic trafficking of remotely infused macrophages to locally infused clinically relevant wear particles was established. After preliminary in vitro studies in which a key macrophage chemokine, MCP-1 was identified, blocking of this chemokine ligand-receptor axis using antagonists and knockouts was undertaken. Second, in vitro and in vivo studies were performed to convert M1 pro-inflammatory macrophages (associated with wear particles ± endotoxin) to an M2 alternative phenotype by the infusion of the anti-inflammatory cytokine Interleukin-4 (IL-4). Third, in vitro studies were undertaken in which activated macrophages were exposed to an NFκB decoy oligodeoxynucleotide (ODN), which interferes with the production of pro-inflammatory mediators. The analytical techniques used included bioluminescence, microCT, immunohistochemical and immunofluorescent microscopy, histomorphometry, ELISA, rT-PCR and cell sorting. Results. Interference of the MCP-1-CCR2 ligand-receptor axis decreased systemic macrophage migration to the area of particle infusion, and subsequent osteolysis at the implant site. Local delivery of IL-4 promoted an alternative anti-inflammatory M2 macrophage phenotype (rather than a pro-inflammatory M1 phenotype), mitigating inflammation and osteolysis. Preliminary studies exposing activated macrophages to NFκB ODN decreased pro-inflammatory cytokine production. Discussion/Conclusion. Macrophage-induced inflammation and osteolysis due to wear byproducts limit the longevity of joint replacements. The interventions outlined above may be useful in preventing these events. For example, coatings that limit macrophage migration to the implant site or local delivery of biologics that alter macrophage phenotype might facilitate osseointegration and provide a more robust bone-implant interface initially. Early osteolysis with a salvageable joint replacement might be mitigated by local infusion of IL-4 or an NFκB ODN. These treatments are less invasive compared to surgical revision, and might prolong the lifetime of a joint replacement in humans

The recent description of progenitor/stem cells in degenerated intervertebral discs (IVDs) raised the possibility of harnessing their regenerative capacity for endogenous repair. The aim of this work is to develop an intradiscal polysaccharide microbead-based delivery system for the sequential release of chemokines and nucleopulpogenic factors. This delivery system would sequentially contribute to 1) the recruitment of resident progenitors (CXCL12 or CCL5), 2) the differentiation of the mobilized progenitors (TGF-β1 and GDF5), and 3) the subsequent regeneration of NP. To determine the effects of chemokines on in vitro cell recruitment, human mesenchymal stem cells (MSC) were cultured in Transwells for 4h, with or without CXCL12 or CCL5. In parallel, pullulan microbeads (PMBs) (100µm) were prepared by a simultaneous crosslinking protocol coupled to a water-in-oil emulsification process. Freeze-dried PMBs were loaded with biological factors then release assays were performed at 37°C for 21 days and supernatant concentrations were measured by ELISA. As compared to untreated MSC, MSC migration was improved with a 3.9 (CXCL12) and 7.5 (CCL5) fold increase, respectively. All factors were successfully adsorbed on PMBs and a burst release within the 1. st. day was observed. At day 7, 27.5% and 83% of CXCL12 and CCL5 were released, respectively and at day 21, 20% and 100% of TGF-β1 and GDF5 were released, respectively. Currently, released cytokine bioactivity is being analysed and an ex vivo ovine IVD model is developed to determine the repair potential of this controlled release approach

Long-term survival of massive prostheses used to treat bone cancers is associated with extra-cortical bone growth and osteointegration into a grooved hydroxyapatite coated collar positioned adjacent to the transection site on the implant shaft [1]. The survivorship at 10 years reduces from 98% to 75% where osteointegration of the shaft does not occur. Although current finite element (FE) methods successfully model bone adaption, optimisation of adventitious new bone growth and osteointegration is difficult to predict. There is thus a need to improve existing FE models by including biological processes of osteoconduction and osteoinduction. The principal bone adaptation criteria is based on the standard strain-energy remodeling algorithm, where the rate of remodeling is controlled by the difference in the stimulus against the reference value [3]. The additional concept of bone connectivity was introduced, to limit bone growth to neighbouring elements (cells) adjoining existing bone elements. The algorithm was developed on a cylindrical model before it was used on an ovine model. The geometry and material properties from two ovine tibiae were obtained from computed tomography (CT) scans and used to develop FE models of the tibiae implanted with a grooved collar. The bones were assigned inhomogeneous material properties based on the CT grey values and typical ovine walking load conditions were applied. The FE results show a region of bone tissue growth below the implanted collar and a small amount of osteointegration with the implant, which is in good agreement to clinical results. Some histological results suggest that further bone growth is possible and potential improvements to the model will be discussed. In summary, by including an algorithm that describes osteoconduction, adventitious bone growth can be predicted

Introduction. 20 cases of bone defect have been treated by the induced membrane technique avoiding allograft, microsurgery and amputation. Material and Methods. 9 cases of long bone defect (humerus and 2 bones arm) and 11 cases of bone defct at the hand have been included in this multicentric prospective study (3 centers). 11 cases were traumatic, 7 cases were septic non union and 2 cases were tumor. At hand level's bone reached at least one phalanx, and for long bone the mean defect was 5cm (3–11). All cases were treated by the induced membrane technique which consists in stable fixation, flap if necessary and in filling the void created by the bone defect by a cement spacer (PMMA). This technique needs a second stage procedure at the 2. nd. month where the cement is removed and the void is filled by cancellous bone. The key point of this induced membrane technique is to respect the foreign body membane which appeared around the cement spacer and which create a biologic chamber after the second time. Bone union was evaluated prospectively in each case by an surgeon not involved in the treatment by Xray and CT scan. Failure was defined as a non union at 1 year, or an uncontrolled sepsis at 1 month. Results. 3 cases failed to achieve bone union, 2 at hand level and 1 for long bone. No septic complications occured and all septic cases werre stopped. In 14 cases bone union was achieved with a delay of 5 months (1, 5–12). 2 biopsies allowed to proove us that osteoid tissue was created by the technic. At hand level all fingers have included. At shoulder and elbow level, function reached 75% of motion than controlateral side. Discussion. Masquelet first reported 35 cases of large bone defect of tibia non union treated by the induced membrane technic which allow to fill bone defect with cancellous bone alone. The cement spacer allows to induce a foreign body membrane which constitute a biological chamber. Works on animal model reported by Pellissier and Viatteau showed the properties of the membrane: secretion of growths factors (VEGF, TGFbéta1, BMP2) and osteoinductive activitie of the cells. The induced membrane seem to play the role of a neo periosteum. Using this technic is possible in emergency or in septic condition where bone defect can not been solved by shortening. This technic avoids to use microsurgical technic and the limit is the quantity of avalaible cancellous bone

Industrialized countries experience a population aging. Elderly patients, due to the experienced immunity, have a constant pro-inflammatory milieu. Little is known on how adaptive immunity impacts the tissue homeostasis and regeneration. The standardized housing of lab animals is specific pathogen free (SPF). However, this housing condition hinders antigen exposure and thus an aging of the adaptive immune system. We hypothesized that exposure to antigens and a developing adaptive immunity will impact tissue homeostasis and regeneration in mice. Mice kept under SPF housing or non-SPF were examined towards their immune status via flow cytometry, bone structure via microCT and bone competence via biomechanical torsional testing. MSCs from these mice were analyzed regarding their differentiation potential and ECM production under various immune cell signaling. Bone regeneration was analyzed in vivo in a mouse osteotomy model. The memory and effector compartment of the adaptive immunity was significantly increased in mice under non-SPF housing. This housing led to an increased femoral cortical thickness and torsional stiffness (p<0,05), whereas the tissue mineral density was not affected. The differentiation potential of stem cells under the influence of an aged immune milieu was significantly reduced. Bone formation was highly affected by the immune status and availed of a naïve immune cell milieu. Adaptive immunity directly impacts bone tissue formation, by exhibiting a constant stress, leading to structural differences in bone tissue organization as well as mechanical competence. For experimental settings, it appears highly relevant if mouse models have had the chance to develop an experienced immune system.