The essential anti-angiogenic strategies in cartilage engineering and osteoarthritic cartilage repair.

In the cartilage matrix, complex interactions occur between angiogenic and anti-angiogenic components, growth factors, and environmental stressors to maintain a proper cartilage phenotype that allows for effective load bearing and force distribution. However, as seen in both degenerative disease and tissue engineering, cartilage can lose its vascular resistance. This vascularization then leads to matrix breakdown, chondrocyte apoptosis, and ossification. Research has shown that articular cartilage inflammation leads to compromised joint function and decreased clinical potential for regeneration. Unfortunately, few articles comprehensively summarize what we have learned from previous investigations. In this review, we summarize our current understanding of the factors that stabilize chondrocytes to prevent terminal differentiation and applications of these factors to rescue the cartilage phenotype during cartilage engineering and osteoarthritis treatment. Inhibiting vascularization will allow for enhanced phenotypic stability so that we are able to develop more stable implants for cartilage repair and regeneration.

Functional aspects of the Eustachian tube by means of 3D-modeling.

The extent of dysfunction of the Eustachian tube (ET) is relevant in understanding the pathogenesis of secondary otological diseases such as acute or chronic otitis media. The underlying mechanism of ET dysfunction remains poorly understood except for an apparent genesis such as a nasopharyngeal tumor or cleft palate. To better describe the ET, its functional anatomy, and the biomechanical valve mechanism and subsequent development of diagnostic and interventional tools, a three-dimensional model based on thin-layer histology was created from an ET in this study. Blackface sheep was chosen as a donor. The 3-D model was generated by the coherent alignment of the sections. It was then compared with the cone-beam computed tomography dataset of the complete embedded specimen taken before slicing. The model shows the topographic relation of the individual components, such as the bone and cartilage, the muscles and connective tissue, as well as the lining epithelium with the lumen. It indicates a limited spiraling rotation of the cartilaginous tube over its length and relevant positional relationships of the tensor and levator veli palatine muscles.

Taxonomic changes in the gut microbiota are associated with cartilage damage independent of adiposity, high fat diet, and joint injury.

Lipodystrophic mice are protected from cartilage damage following joint injury. This protection can be reversed by the implantation of a small adipose tissue graft. The purpose of this study was to evaluate the relationship between the gut microbiota and knee cartilage damage while controlling for adiposity, high fat diet, and joint injury using lipodystrophic (LD) mice. LD and littermate control (WT) mice were fed a high fat diet, chow diet, or were rescued with fat implantation, then challenged with destabilization of the medial meniscus surgery to induce osteoarthritis (OA). 16S rRNA sequencing was conducted on feces. MaAslin2 was used to determine associations between taxonomic relative abundance and OA severity. While serum LPS levels between groups were similar, synovial fluid LPS levels were increased in both limbs of HFD WT mice compared to all groups, except for fat transplanted animals. The Bacteroidetes:Firmicutes ratio of the gut microbiota was significantly reduced in HFD and OA-rescued animals when compared to chow. Nine novel significant associations were found between gut microbiota taxa and OA severity. These findings suggest the presence of causal relationships the gut microbiome and cartilage health, independent of diet or adiposity, providing potential therapeutic targets through manipulation of the microbiome.

T2 mapping of the acetabular cartilage in infants and children with developmental dysplasia of the hip.

BACKGROUND: T2 mapping is useful for evaluating the cartilage matrix. PURPOSE: To determine the variations in the acetabular cartilage T2 relaxation values between healthy individuals and those with developmental dysplasia of the hip (DDH). MATERIAL AND METHODS: Thirty-three patients with unilateral DDH underwent 3-T magnetic resonance imaging (MRI) between January 2018 and February 2019. Fifteen volunteers (30 hips) were enrolled as controls. T2 values were measured with the T2 mapping sequence in all layers and were equally divided into three layers (deep, middle, and superficial) with equal thickness. We calculated the mean T2 relaxation values for the full thickness, deep, middle, and superficial layers and compared the values between the different groups. In addition, the inter- and intra-observer agreements were calculated. RESULTS: The T2 relaxation values in the DDH arm were significantly lower in the middle, superficial, and full thickness layers compared with those of the volunteers and contralateral hips. The T2 relaxation values of the deep layers showed no significant difference between the different groups. The acetabular cartilage T2 relaxation values increased from the deep layer to the superficial layer in the control and contralateral groups. Both inter- and intra-observer agreements were good. CONCLUSION: MRI T2 mapping may help to diagnose developmental disorders of the acetabular cartilage matrix in infants and children with DDH. Abnormal acetabular cartilage T2 relaxation values may be due to the extraordinary stress load of the femoral head.

Mesenchymal stem cell-derived small extracellular vesicles and bone regeneration.

Mesenchymal stem cells (MSCs) and MSC-derived small extracellular vesicles (sEVs) are promising candidates for cell-based and cell-free regenerative medicine, respectively. By virtue of their multiple lineage differentiation capacity, MSCs have been implicated as an ideal tool for bone and cartilage regeneration. However, later observations attributed such regenerative effects to MSC-secreted paracrine factors. Exosomes, endosomal originated sEVs carrying lipid, protein and nucleic acid cargoes, were identified as components of the MSC secretome and propagated the key regenerative and immunoregulatory characteristics of parental MSCs. Here, exosome biogenesis, the molecular composition of exosomes, sEV-cell interactions and the effects on key bone homeostasis cells are reviewed. MSC-derived sEVs show to promote neovascularization and bone and cartilage regeneration in preclinical disease models. The mechanisms include the transfer of molecules, including microRNAs, mRNAs and proteins, to other key cells. MSC-derived sEVs are interesting candidates as biopharmaceuticals for drug delivery and for the engineering of biologically functionalized materials. Although major exploratory efforts have been made for therapeutic development, the secretion, distribution and biological effects of MSC-derived sEVs in bone and cartilage regeneration are not fully understood. Moreover, techniques for high-yield production, purity and storage need to be optimized before effective and safe MSC-derived sEVs therapies are realized.

Midterm Follow-Up and Assessment of Cartilage Thickness by Arthro-Magnetic Resonance Imaging After Arthroscopic Cam Resection, Labral Repair, and Rim Trimming Without Labral Detachment.

PURPOSE: To evaluate the clinical and radiological outcome, sum of acetabular and femoral cartilage thickness, and rate of failure in the midterm after arthroscopic treatment of femoroacetabular impingement (FAI) syndrome with femoral osteoplasty, labral repair, and rim trimming without labral detachment. METHODS: This retrospective case series included patients with FAI syndrome who had undergone hip arthroscopy from January 2009 to December 2010 by a single surgeon, with a minimum follow-up of 55 months. Data from patients who had undergone arthroscopic hip procedures with labral repair, rim trimming, and femoral osteoplasty were analyzed pre- and postoperatively. Clinical outcome (nonarthritic hip score [NAHS], Short Form 36 [SF-36]), range of motion, progression of osteoarthritis (Tönnis grade), radiological parameters (α angle, lateral center-edge angle [LCEA], Tönnis angle), femoral and acetabular cartilage thickness (using magnetic resonance imaging [MRI]), and intraoperative findings were evaluated. RESULTS: Of 148 hip arthroscopies performed, 97 included rim trimming, labral refixation, and femoral osteoplasty. Ten cases were lost to follow-up, leaving 87 hips. Arthroscopic revision was performed on 4 hips and total hip replacement on 4 hips, and 1 hip underwent both arthroscopic revision and total hip replacement. Excluding these 9 cases of revision, for which follow-up was not possible (retrospective study), the remaining 78 hips were followed up for a minimum of 55 months (77 ± 11.4, mean ± SD; range 55 to 124). Mean NAHS (65 to 88, P < .001), SF-36 physical subscale (65 to 85, P < .001), and the numerical pain rating scale (NRS) (5 to 1, P < .001) improved significantly. Outcome scores of minimal clinical importance (NAHS) were achieved in 67.6% of the patients. Mean range of movement improved significantly in flexion (109 to 122, P < .001) and internal rotation (10 to 22.7, P < .001). NAHS was positively associated with flexion of the hip postoperatively (r = 0.307, P = .011). In 16 cases, microfracture was performed (15 acetabular and 1 femoral). Preoperative α angles (anteroposterior and modified Dunn) were significantly higher in this cohort (P < .001, 95% confidence interval 8.9 to 25.2, P = .001). Twenty hips (28 %) progressed to worse Tönnis grades. Initial Tönnis grades were grade 0, 38; grade 1, 48; grade 2, 8. Pre- or postoperative Tönnis grades did not show any correlation with pre- or postoperative NAHS and NRS. MRI measurements at the latest follow-up (69 patients) of the femoral and acetabular cartilage thickness did not reveal any significant reduction at the 12 o'clock position. CONCLUSION: Arthroscopic cam resection, rim trimming, and labral repair without detachment of the labrum provides good or excellent outcome in 77.1% of hips based on NAHS in the midterm. Higher range of motion in flexion is associated with higher NAHS postoperatively. Arthroscopic cam resection, rim trimming and labral repair without detachment of the labrum is a successful method for the treatment of FAI syndrome in the midterm. LEVEL OF EVIDENCE: IV, retrospective case series.

Novel Insights Into the Role of N6-Methyladenosine RNA Modification in Bone Pathophysiology.

Thus far, there are more than known 150 modifications to RNA, in which common internal modifications of mRNA include N6-methyladenosine (m6A), N1-methyladenosine, and 5-methylcytosine. Among them, m6A RNA modification is one of the highest abundance modifications in eukaryotes, regulating mechanisms controlling gene expression at the post-transcription level. As an invertible and dynamic epigenetic marker, m6A base modification influences almost all vital biological processes, cellular components, and molecular functions. Once the m6A modification process is abnormal, a series of diseases-including cancer, neurological diseases, and growth disorders-will be caused. Besides, several base modification activities also have been created by noncoding RNAs (ncRNAs), for instance, microRNAs, and circular RNAs, long ncRNAs, which were dynamically regulated during bone and cartilage pathophysiology processes. Therefore, it has now been clear that dynamic modification on coding RNAs and ncRNAs represents a completely new way to modulate genetic information. In this review, we highlight up-to-date progress and applications of m6A RNA modification in bone and cartilage pathophysiology, and we discuss the pathological roles and underlying molecular mechanism of m6A modifications in osteoarthritis and osteoporosis and osteosarcoma pathogenesis.

Short term outcomes of hip arthroscopy on hip joint mechanics and cartilage health in patients with femoroacetabular impingement syndrome.

BACKGROUND: Femoroacetabular acetabular impingement syndrome consists of abnormal hip joint morphology resulting in painful hip joint impingement. Hip arthroscopy corrects the abnormal morphology and reduces clinical symptoms associated with femoroacetabular impingement syndrome yet the effects of hip arthroscopy on gait mechanics and cartilage health are not well understood. METHODS: Ten femoroacetabular impingement syndrome patients and 10 matched asymptomatic controls underwent gait analysis consisting of three-dimensional hip joint kinematics and kinetics. Femoroacetabular impingement syndrome patients underwent gait analysis and quantitative magnetic resonance imaging of the surgical hip joint before and seven months post-surgery. Patient reported outcomes were obtained from all study participants and were used to quantify hip joint pain, function and quality of life. FINDINGS: Prior to surgery, femoroacetabular impingement syndrome patients demonstrated hip joint kinematics or kinetics as the control group. After surgery, femoroacetabular impingement syndrome patients exhibited improved patient reported outcomes, similar hip joint kinematic patterns, increased hip flexion and decreased hip extension moment impulses within the surgical limb. The femoroacetabular impingement syndrome patients that ambulated with increased HFMI post-surgery demonstrated a decrease in femoral cartilage T1ρ and T2 values. INTERPRETATION: Femoroacetabular impingement syndrome patients exhibited improved clinical symptoms yet ambulated with altered sagittal plane hip joint loading after hip arthroscopy. Increased hip flexion moment impulse post-surgery was associated with improved cartilage health within the surgical limb. These study findings suggest that sagittal plane hip joint loading at short-term follow-up after hip arthroscopy is associated with cartilage health and may be an important biomechanical parameter in post-operative rehabilitation programs.

Distal tuberosity osteotomy in open-wedge high tibial osteotomy does not exacerbate patellofemoral osteoarthritis on arthroscopic evaluation.

PURPOSE: The purpose of the present study was to use arthroscopy to evaluate the effect of distal tuberosity osteotomy (DTO) in open-wedge high tibial osteotomy (OW-HTO) on patellofemoral (PF) cartilage degradation. METHODS: Between 2012 and 2017, 46 knees underwent DTO in OW-HTO, and 65 knees underwent conventional OW-HTO (cOW-HTO). To assess changes in patellar height, the Blackburne-Peel (BP) ratio and the Caton-Deschamps (CD) index were measured. Arthroscopic evaluation on the PF joint was performed at the initial osteotomy and at the second-look procedure 1 year later. Statistical analyses were performed to compare difference between the DTO and the cOW-HTO group. RESULTS: In the cOW-HTO group, the mean BP ratio and CD index decreased significantly from 0.81 and 0.89 preoperatively, respectively, to 0.69 and 0.76 postoperatively, respectively (p < 0.001). In contrast, the DTO group maintained a consistent patellar height; the mean BP ratio and CD index were 0.77 and 0.83 preoperatively, respectively, and 0.73 and 0.80 postoperatively, respectively. Upon arthroscopic evaluation, 39 of 46 patients (84.8%) in the DTO group showed no progression of PF cartilage degradation at the second look; indeed, five of 46 patients (10.9%) even demonstrated improvement. In contrast, 21 of 65 patients (32.3%) in the cOW-HTO group exhibited increased PF cartilage degradation. There was a significant difference in progression of PF cartilage degradation between DTO and cOW-HTO (p < 0.001). CONCLUSION: DTO in OW-HTO maintained the preoperative patellar height, which could help prevent progression of cartilage degeneration in the PF joint after surgery. In respect of the biplanar osteotomy direction in OW-HTO, the DTO, rather than cOWHTO, is the preferred technique for the treatment of varus knee osteoarthritis to avoid progression of PF cartilage degradation. LEVEL OF EVIDENCE: III.

Demographic and Radiographic Factors Associated With Intra-articular Hip Cartilage Injury: A Cross-sectional Study of 1511 Hip Arthroscopy Procedures.

BACKGROUND: Moderate to severe (grade 3-4) hip joint cartilage injury seems to impair function in patients with femoroacetabular impingement syndrome. PURPOSE: To investigate whether demographic and radiographic factors were associated with moderate to severe hip joint cartilage injury. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: Patients were identified in the Danish Hip Arthroscopy Registry. The outcome variables were acetabular cartilage injury (modified Beck grade 0-2 vs 3-4) and femoral head cartilage injury (International Cartilage Repair Society grade 0-2 vs 3-4). Logistic regressions assessed the association with the following: age (<30 vs 30-50 years); sex; sport activity level (Hip Sports Activity Scale); alpha angle (AA) assessed as normal (AA <55°), cam (55°≤ AA <78°), or severe cam (AA ≥78°); lateral center-edge angle (LCEA) assessed as normal (25°≤ LCEA ≤ 39°), pincer (LCEA >39°), or borderline dysplasia (LCEA <25°); joint space width (JSW) assessed as normal (JSW >4.0 mm), mild reduction (3.1 mm ≤ JSW ≤ 4.0 mm), or severe reduction (2.1 mm ≤ JSW ≤ 3.0 mm). RESULTS: A total of 1511 patients were included (mean ± SD age: 34.9 ± 9.8 years). Male sex (odds ratio [OR], 4.42), higher age (OR, 1.70), increased AA (cam: OR, 2.23; severe cam: OR, 4.82), and reduced JSW (mild: OR, 2.04; severe: OR, 3.19) were associated (P < .05) with Beck grade 3-4. Higher age (OR, 1.92), increased Hip Sports Activity Scale (OR, 1.13), borderline dysplasia (OR, 3.08), and reduced JSW (mild: OR, 2.63; severe: OR, 3.04) were associated (P < .05) with International Cartilage Repair Society grade 3-4. CONCLUSION: Several demographic and radiographic factors were associated with moderate to severe hip joint cartilage injury. Most notably, increased cam severity and borderline dysplasia substantially increased the risk of grade 3-4 acetabular and femoral head cartilage injury, respectively, indicating that specific deformity may drive specific cartilage injury patterns in the hip joint.

A Newly Modified Salter Osteotomy Technique for Treatment of Developmental Dysplasia of Hip That Is Associated with Decrease in Pressure on Femoral Head and Triradiate Cartilage.

BACKGROUND AND PURPOSE: The Salter innominate osteotomy has been an effective method to treat the developmental dysplasia of hip (DDH) over the past decades; however, several postoperative complications and deficiencies were reported. In this study, we evaluated outcome of a newly modified Salter osteotomy in patients presenting with DDH. METHODS: We reviewed retrospectively 76 patients (90 hips) with DDH aged ≥ 18 months, who underwent open reduction and a modified osteotomy by a single surgeon. The distal osteotomy segment of pelvis was shifted anterolaterally in the amount of osteotomy cross-section, but not downwards. The mean age at surgery was 2 years and 11 months (1.5 to 16 years). Femoral shortening was conducted when necessary. The duration of operation varied between 60 and 90 minutes. The mean follow-up was 4 years and one month (range 15 months to 7 years and 9 months). All patients were followed up both clinically (based on the modified MacKay criteria) and radiologically (based on the modified Severin criteria). RESULTS: Clinically, 94.5% of hips had excellent and good results at final follow-up, and only 5.5% had a fair condition. Radiographically, at the final follow-up 77.8% of hips were grade IA (excellent), 12.2% were grade IB, 6.7% were grade II, and 3.3% were grade III (fair). The preoperative mean acetabular index was 47.85° (41° to 59), which decreased to 17.16° (13° to 22°) immediately after the surgery (p<0.0001) and progressed to 11.24° (7° to 19°) at the final follow-up (p<0.0001). The mean initial postoperative center-edge angle was 30.3° (25° to 42°) significantly improved to 39.1 (31° to 56°) at the final follow-up (p<0.0001). Avascular necrosis of femoral head occurred in 4.4% of hips (4 patients). CONCLUSION: The results show that our modified Salter osteotomy is safe and associated with significant benefit for the management of patients suffering from DDH.

Multi-scale modeling of an upper respiratory airway: Effect of mucosal adhesion on Eustachian tube function in young children.

BACKGROUND: The Eustachian tube is a collapsible upper respiratory airway that is periodically opened to maintain a healthy middle ear. Young children, <10 years old, exhibit reduced Eustachian tube opening efficiency and are at risk for developing middle ear infections. Although these infections increase mucosal adhesion, it is not known how adhesion forces alters the biomechanics of Eustachian tube opening in young children. This study uses computational techniques to investigate how increased mucosal adhesion alters Eustachian tube function in young children. METHODS: Multi-scale finite element models were used to simulate the muscle-assisted opening of the Eustachian tube in healthy adults and young children. Airflow during opening was quantified as a function of adhesion strength, muscle forces and tissue mechanics. FINDINGS: Although Eustachian tube function was sensitive to increased mucosal adhesion in both adults and children, young children developed Eustachian tube dysfunction at significantly lower values of mucosal adhesion. Specifically, the critical adhesion value was 2 orders of magnitude lower in young children as compared to healthy adults. Although increased adhesion did not alter the sensitivity of Eustachian tube function to tensor and levator veli palatini muscles forces, increased adhesion in young children did reduced the sensitivity of Eustachian tube function to changes in cartilage and mucosal tissue stiffness. INTERPRETATIONS: These results indicate that increased mucosal adhesion can significantly alter the biomechanical mechanisms of Eustachian tube function in young children and that clinical assessment of adhesion levels may be important in therapy selection.

Rapid inflammation and early degeneration of bone and cartilage revealed in a time-course study of induced haemarthrosis in haemophilic rats.

OBJECTIVES: Detailed knowledge of the sequential cell and tissue responses following haemarthrosis is important for a deep understanding of the pathological process initiated upon extensive bleeding into the joint causing haemophilic arthropathy (HA). The underlying pathobiology driving haemarthrosis towards HA has been difficult to establish in detail, although animal models have shed light on some processes. Previous studies have focused on a single or a few distant time points and often only characterizing one tissue type of the joint. The objective of this study was, therefore, to carefully map early onset of synovitis and HA following induced haemarthrosis. METHODS: One hundred and thirty haemophilia A rats were subjected to induced haemarthrosis or a sham procedure in full anaesthesia and euthanized from 30 min to 7 days after the procedure. Pathological changes of the joints were visualized using micro-computed tomography, histology and immunohistochemistry. RESULTS: Synovitis developed within 24 h and was dominated by myeloid cell infiltrations. Cartilage and bone pathology were evident as early as 48-96 h after haemarthrosis, and the pathology rapidly progressed with extensive periosteal bone formation and formation of subchondral cysts. CONCLUSION: Fast, extensive and simultaneous cartilage and bone degeneration developed shortly after haemarthrosis, as shown by the detailed mapping of the early pathogenesis of HA. The almost immediate loss of cartilage and the pathological bone turnover suggest a direct influence of blood on these processes and are unlikely to be attributed simply to an indirect effect of inflammation.

Analysis of the mechanical effects of defect shape on damage evolution of articular cartilage under rolling load.

To study the mechanical effects of defect shape on the damage evolution of knee cartilage and find the causes of fragments, so as to obtain damage evolution rules and determine the most appropriate shape used in a clinical repair. A porous viscoelasticity fiber-reinforced 2D numerical model with different micro-defect shapes was established which considered the depth-dependent Young's modulus, fiber distribution, porosity and permeability. The stress-strain relationship, interstitial hydraulic and interstitial flow velocity was obtained under rolling load. The results showed that damage developed at the bottom corner of the defect, preferentially deep within the cartilage tangential to the fibers direction, and then extended to the surface along adjacent fibers, finally forming fragments. In the early stages of damage, the shear stress and interstitial flow velocity within cartilage with a rectangular cross-sectional defect were the lowest, while interstitial hydraulic pressure was the highest, followed by 100° trapezoid and semicircle, and finally 80° trapezoid defects. In the later stage of damage, the results were very similar. The shear strain, interstitial flow velocity and interstitial hydraulic pressure decreased with increasing defect depth. Therefore, defect shape only affected damage evolution in the early stages. The fragments in cartilage were the result of the damage evolution which sizes were correlated with the initial defect depth. The damage velocity of cartilage with a rectangular section-incision was the slowest. Finally, we concluded that cylindrical incisions are optimal in clinical surgery. These results provide a theoretical basis for the clinical interpretation of pathological degeneration and repair therapy.

TGF-ß/SMAD signaling inhibits intermittent cyclic mechanical tension-induced degeneration of endplate chondrocytes by regulating the miR-455-5p/RUNX2 axis.

A mechanical stimulation plays a pivotal role in maintaining normal cartilage function. Our objective was to reveal the mechanism of action of the tension-sensitive molecule miR-455-5p in the degeneration of endplate chondrocytes and to identify whether the transforming growth factor beta (TGF-ß)/SMAD signaling pathway has a regulatory effect on it. The expression profiles of members of the TGF-ß/SMAD pathway, miR-455-5p, and RUNX2 were determined by microRNA microarray analysis, reverse transcription quantitative polymerase chain reaction, luciferase reporter assay, and Western blot analysis. Intermittent cyclic mechanical tension (ICMT) induced the degeneration of endplate chondrocytes without affecting their viability. The tension-sensitive molecule miR-455-5p specifically bound to RUNX2, a gene involved in the degeneration of endplate chondrocytes. Activation of the TGF-ß/SMAD signaling pathway upregulated miR-455-5p expression and thus inhibited RUNX2 levels. Therefore, the TGF-ß/SMAD signaling pathway inhibits the ICMT-induced degeneration of endplate chondrocytes by regulating the miR-455-5p/RUNX2 axis.

Gene therapy for repair and regeneration of bone and cartilage.

Gene therapy refers to the use of viral and non-viral vectors to deliver nucleic acids to tissues of interest using direct (in vivo) or transduced cell-mediated (ex vivo) approaches. Over the past few decades, strategies have been adopted to express therapeutic transgenes at sites of injury to promote or facilitate repair of bone and cartilage. Targets of interest have typically included secreted proteins such as growth factors and anti-inflammatory mediators; however, work has also begun to focus intracellularly on signaling components, transcription factors and small, regulatory nucleic acids such as microRNAs (miRNAs). In recent years, a number of single therapeutic gene approaches (termed 'monotherapies') have proven effective in preclinical models of disease, and several are being evaluated in clinical trials. In particular, an ex vivo TGF-ß1 gene therapy was approved in Korea in 2017 for treatment of moderate-to-severe osteoarthritis (OA). The ability to utilize viral vectors for context-specific and combinatorial gene therapy is also being investigated, and these strategies are likely to be important in more robustly addressing the complexities of tissue repair and regeneration in skeletal disease. In this review, we provide an overview of viral gene therapies being developed for treatment of bone and cartilage pathologies, with an emphasis on emerging combinatorial strategies as well as those targeting intracellular mediators such as miRNAs.

Sialoglycoprotein isolated from eggs of Carassius auratus promotes fracture healing in osteoporotic mice.

In this study, open tibial fracture surgery was performed on mice with ovariectomy induced osteoporosis to investigate the effect of a treatment with sialoglycoprotein isolated from Carassius auratus eggs (Ca-SGP) on fracture healing. Dynamic histological analysis showed that Ca-SGP promoted the generation of cartilage callus on day 5 post-surgery, then facilitated the transformation of the cartilage callus to bony callus on days 11 and 24 post-surgery, and enhanced the remodeling of bony callus on 35 day post-surgery. Moreover, Ca-SGP significantly decreased the secretion of TNF-α and IL-1ß in serum on day 5 post-surgery, thus inhibiting the negative spread of the inflammatory reaction. On day 11 post-surgery, Ca-SGP clearly decreased the serum level and the mRNA expression of Aggrecan but also increased the secretion and the expression of VEGF and MMP13, thus promoting the degradation of the cartilage matrix and vascular invasion. On day 24 post-surgery, Ca-SGP remarkably increased the mRNA expression of osteogenesis markers Col1a and OCN, and increased callus BV/TV and Tb.N, this facilitating the formation of woven bone. On day 35 post-surgery, Ca-SGP enhanced the transformation of woven bone into lamellar bone and improved the callus biomechanical property. In conclusion, Ca-SGP promoted fracture healing in osteoporotic mice by accelerating endochondral ossification.

Peptide-Based Materials for Cartilage Tissue Regeneration.

Cartilaginous tissue requires structural and metabolic support after traumatic or chronic injuries because of its limited capacity for regeneration. However, current techniques for cartilage regeneration are either invasive or ineffective for long-term repair. Developing alternative approaches to regenerate cartilage tissue is needed. Therefore, versatile scaffolds formed by biomaterials are promising tools for cartilage regeneration. Bioactive scaffolds further enhance the utility in a broad range of applications including the treatment of major cartilage defects. This chapter provides an overview of cartilage tissue, tissue defects, and the methods used for regeneration, with emphasis on peptide scaffold materials that can be used to supplement or replace current medical treatment options.

Femoroacetabular impingement causes osteoarthritis of the hip by migration and micro-instability of the femoral head.

Femoroacetabular impingement is the condition whereby parts of the proximal femur mechanically collide with the acetabular rim leading to adjacent and contrecoup acetabular damage. Evidence is growing that at least for cam impingement, and perhaps less so for pincer impingement, there is a relation to the development of osteoarthritis. It has been demonstrated that surgery for impingement can improve function and decrease pain. Intuitively, it would then make sense that surgical intervention would prevent further degeneration. However, available literature to date cannot assure that it does. Therefore, the impingement itself seems not a sufficient cause to consistently cause osteoarthritis. For many years we have observed a phenomenon whereby the femoral head 'migrates' anteriorly and superiorly in the acetabulum in patients with cam impingement. The same, but less constant, can be observed in pincer impingement, where the head may migrate posteriorly and medially. Migration of the femoral head is known in the literature and seen as caused by, or as part of, osteoarthritis of the hip. We suggest that the migration is caused by the impingement, and that the femoral head wanders into the impingement-related area with cartilage damage. In cam impingement this may be anterolateral, in pincer impingement posteromedial. The effect must be a huge increase in compression forces, especially in cam impingement. The migration may even lead to, or be a sign of, micro-instability of the femoral head in the acetabulum, which may produce an increase in shear forces. We therefore hypothesise that impingement may lead to osteoarthritis by means of migration and the possible existence of micro-instability of the femoral head. Detecting and quantifying these phenomena seem of uttermost importance and may add a new dimension to conservative hip surgery.

Preparation of a biphase composite scaffold and its application in tissue engineering for femoral osteochondral defects in rabbits.

PURPOSE: Three-dimensional bioactive scaffolds are useful tools for stem cell implant in tissue-engineering. For chondral and subchondral repair, the chondroinductive and osteoinductive property of a scaffold is a major challenge. The scaffolds that aim to osteogenic differentiation have been well studied. However, cartilage cells can hardly be induced for osteogenesis, and monophase scaffolds cannot ideally repair both cartilage and subchondral defects at the same time. METHODS: We developed a novel biphase composite scaffold and observe its application osteochondral defects. We combined the advantages of silk-fibroin/chitosan (SF/CS) scaffold in chondrogenic differentiation and the silk-fibroin/chitosan/nano-hydroxyapatite (SF/CS/nHA) scaffold in osteogenic differentiation and bone regeneration, and synthesized a SF/CS-SF/CS/nHA scaffold, which contained both the chondrocytic phase (SF/CS) and the osteoblastic phase (SF/CS/nHA). RESULTS: The biphase scaffold exhibited a porosity ratio around 90% and a water absorption ratio about 822%. A similar degradation property to traditional monophase scaffolds was observed. Bone mesenchymal stem cells (BMSCs) showed a good proliferation on this scaffold. Expression of two types of collagen was inducable for BMSCs on the scaffold. Neoformative extracellular matrix integrated with the scaffold was observed by the scanning electron microscope. When implanted in the lesion site in the rabbit femur with cartilage injury, mixing and filling function were exerted by the cell-scaffold constructs (CSCs). Micro-CT scanning revealed both chondral and subchondral layers were repaired. Moreover, type I and II collagens were both expressed in the implanted CSCs. CONCLUSIONS: Chondral and subchondral repair can be achieved using the biphase scaffold implant that permits both chondrogenesis and osteogenesis from BMSCs. This approach has the potential to be clinically used for tissue engineering implantation.