Endoscopically assisted transaxillary release of the scalene muscles for thoracic outlet syndromes: a comparison with or without first rib resection.

OBJECTIVES: There are several surgical techniques for thoracic outlet syndrome (TOS). However, there have been no reports of endoscopically assisted transaxillary release of the anterior and middle scalene muscles (EATRS), leaving the first rib intact for TOS. We hypothesized that EATRS would achieve a good Quick Disability of the Arm, Shoulder and Hand score. This study aims to present our experience with a new technique for TOS using endoscopy. METHODS: We chose two surgeries depending on the patient's TOS condition. If the costoclavicular space was under 12 mm, we selected endoscopically assisted transaxillary first rib resection (EAFRR). If the costoclavicular space was over 12 mm, we selected EATRS. Between January 2021 and December 2022, 31 consecutive surgeries for TOS were performed in our institution. Twenty-five patients underwent EAFRR, and six (19%) underwent EATRS. Since July 2022, EAFRR has been performed under differential lung ventilation. RESULTS: Complete and almost complete relief was achieved in 24 patients (77%), and partial relief was conducted in seven patients (23%) at a mean of 19.7 months after surgery. The symptoms improved in all cases. Intraoperative pneumothorax did not occur, and no other complications were observed. Both EAFRR and EATRS were effective and safe surgeries for TOS. Operative time was significantly shorter in EATRS than in EAFRR. CONCLUSIONS: We first report EATRS surgery for TOS. EATRS is indicated for patients whose costoclavicular space is preserved before surgery. Good surgical results were obtained after surgery for this indication.

Preclinical models for studying corticosteroid-induced osteonecrosis of the femoral head.

Nontraumatic osteonecrosis of the femoral head (ONFH) is a refractory condition that commonly results in femoral head collapse and degenerative arthritis of the hip. In the early stages, surgical procedures for hip preservation, including core decompression (CD), have been developed to prevent progressive collapse of the femoral head. Optimization of bone regeneration and biological augmentation may further enhance the therapeutic efficacy of CD for ONFH. Thus, combining CD with cell-based therapy has recently been proposed. In fact, patients treated with cell-based therapy using autologous bone marrow concentrate demonstrate improved survivorship of the femoral head, compared with conventional CD alone. Preclinical research studies to investigate adjunctive therapies for CD often utilize the rabbit model of corticosteroid-induced ONFH. Mesenchymal stem cells (MSCs) are known to promote osteogenesis and angiogenesis, and decrease inflammation in bone. Local drug delivery systems have the potential to achieve targeted therapeutic effects by precisely controlling the drug release rate. Scaffolds can provide an osteoconductive structural framework to facilitate the repair of osteonecrotic bone tissue. We focused on the combination of both cell-based and scaffold-based therapies for bone tissue regeneration in ONFH. We hypothesized that combining CD and osteoconductive scaffolds would provide mechanical strength and structural cell guidance; and that combining CD and genetically modified (GM) MSCs to express relevant cytokines, chemokines, and growth factors would promote bone tissue repair. We developed GM MSCs that overexpress the anti-inflammatory, pro-reconstructive cytokines platelet-derived growth factor-BB to provide MSCs with additional benefits and investigated the efficacy of combinations of these GM MSCs and scaffolds for treatment of ONFH in skeletally mature male New Zealand white rabbits. In the future, the long-term safety, efficacy, durability, and cost-effectiveness of these and other biological and mechanical treatments must be demonstrated for the patients affected by ONFH.

MegaPro, a clinically translatable nanoparticle for in vivo tracking of stem cell implants in pig cartilage defects.

Rationale: Efficient labeling methods for mesenchymal stem cells (MSCs) are crucial for tracking and understanding their behavior in regenerative medicine applications, particularly in cartilage defects. MegaPro nanoparticles have emerged as a potential alternative to ferumoxytol nanoparticles for this purpose. Methods: In this study, we employed mechanoporation to develop an efficient labeling method for MSCs using MegaPro nanoparticles and compared their effectiveness with ferumoxytol nanoparticles in tracking MSCs and chondrogenic pellets. Pig MSCs were labeled with both nanoparticles using a custom-made microfluidic device, and their characteristics were analyzed using various imaging and spectroscopy techniques. The viability and differentiation capacity of labeled MSCs were also assessed. Labeled MSCs and chondrogenic pellets were implanted into pig knee joints and monitored using MRI and histological analysis. Results: MegaPro-labeled MSCs demonstrated shorter T2 relaxation times, higher iron content, and greater nanoparticle uptake compared to ferumoxytol-labeled MSCs, without significantly affecting their viability and differentiation capacity. Post-implantation, MegaPro-labeled MSCs and chondrogenic pellets displayed a strong hypointense signal on MRI with considerably shorter T2* relaxation times compared to adjacent cartilage. The hypointense signal of both MegaPro- and ferumoxytol-labeled chondrogenic pellets decreased over time. Histological evaluations showed regenerated defect areas and proteoglycan formation with no significant differences between the labeled groups. Conclusion: Our study demonstrates that mechanoporation with MegaPro nanoparticles enables efficient MSC labeling without affecting viability or differentiation. MegaPro-labeled cells show enhanced MRI tracking compared to ferumoxytol-labeled cells, emphasizing their potential in clinical stem cell therapies for cartilage defects.

The efficiency of genetically modified mesenchymal stromal cells combined with a functionally graded scaffold for bone regeneration in corticosteroid-induced osteonecrosis of the femoral head in rabbits.

Core decompression (CD) with mesenchymal stromal cells (MSCs) is an effective therapy for early-stage osteonecrosis of the femoral head (ONFH). Preconditioning of MSCs, using inflammatory mediators, is widely used in immunology and various cell therapies. We developed a three-dimensional printed functionally graded scaffold (FGS), made of ß-TCP and PCL, for cell delivery at a specific location. The present study examined the efficacy of CD treatments with genetically modified (GM) MSCs over-expressing PDGF-BB (PDGF-MSCs) or GM MSCs co-over-expressing IL-4 and PDGF-BB and preconditioned for three days of exposure to lipopolysaccharide and tumor necrosis factor-alpha (IL-4-PDGF-pMSCs) using the FGS for treating steroid-induced ONFH in rabbits. We compared CD without cell-therapy, with IL-4-PDGF-pMSCs alone, and with FGS loaded with PDGF-MSCs or IL-4-PDGF-pMSCs. For the area inside the CD, the bone volume in the CD alone was higher than in both FGS groups. The IL-4-PDGF-pMSCs alone and FGS + PDGF-MSCs reduced the occurrence of empty lacunae and improved osteoclastogenesis. There was no significant difference in angiogenesis among the four groups. The combined effect of GM MSCs or pMSCs and the FGS was not superior to the effect of each alone. To establish an important adjunctive therapy for CD for early ONFH in the future, it is necessary and essential to develop an FGS that delivers biologics appropriately and provides structural and mechanical support.

Risk factors related to psychological distress among elderly patients with cardiovascular disease.

AIMS: Psychological distress is associated with poor prognosis in patients with cardiovascular disease (CVD). However, factors related to psychological distress in elderly patients with CVD are less understood. We aim to investigate the rate of psychological distress in elderly patients with CVD in comparison with that of patients without CVD and to examine the clinical, socio-economic, and lifestyle factors associated with this condition. METHODS AND RESULTS: Data from a nationwide population-based study in Japan of patients aged ≥60 years were extracted, and 1:1 propensity score matching was conducted of patients with and without CVD. Psychological distress was assessed using the K6 scale, on which a score ≥6 was defined as psychological distress. Of the 24 388 matched patients, the rate of psychological distress was significantly higher among patients with CVD compared with those without CVD (29.8 vs. 20.5%, P < 0.0001). The multivariate analysis revealed that female sex, comorbidities, except for hypertension, current smoking status, daily sleep duration of <6 vs. ≥8 h, home renter vs. owner, retired status, having a walking disability, and lower monthly household expenditure were independently associated with psychological distress. Walking disability was observed to be in greatest association with psychological distress (odds ratio 2.69, 95% confidence interval 2.46-2.93). CONCLUSION: Elderly patients with CVD were more likely to have psychological distress compared with those without CVD. Multiple factors, including clinical, socio-economic, and lifestyle variables, were associated with psychological distress. These analyses may help healthcare providers to identify high-risk patients with psychological distress in a population of older adults with CVD.

[A Case of Stage â £ Pancreatic Head Cancer with Aortic Lymph Node Metastasis Treated with 40 Courses of mFOLFIRINOX Therapy after Surgery and Maintaining PR].

The patient was a male in his 60s who presented with obstructive jaundice and was diagnosed with pancreatic head cancer. He was referred to the Department of Surgery 2 months later due to prolonged jaundice and immediately underwent pylorus-preserving pancreatoduodenectomy with the diagnosis of resectable pancreatic cancer. Pathology showed pN1b (14/37), but 16b1 interaorticocaval was 0/1. The patient was then diagnosed with Stage ⅡB, R0. After completion of adjuvant chemotherapy with S-1, 1 year after surgery, CA19-9 was reelevated and PET/CT-positive enlarged lateroaortic lymph nodes and multiple nodules in both lungs were observed. The lymph nodes were also seen on preoperative CT, and the preoperative diagnosis was Stage Ⅳ. After insertion of an implantable central venous port, mFOLFIRINOX therapy was initiated. The patient had an anaphylactic reaction after 7 courses of L-OHP, and the treatment was continued without L-OHP. After 40 courses of mFOLFIRINOX therapy, the aortic lymph nodes reduced in size, PET results were negative, and the pulmonary nodules partially resolved. We report a case of a patient with Stage Ⅳ pancreatic head cancer who maintained PR for more than 1 year and 7 months after the initiation of mFOLFIRINOX therapy and survived for more than 2 years and 10 months since the initial diagnosis.

Midterm results of endoscopically assisted first rib resection in the zero position for thoracic outlet syndrome.

OBJECTIVES: We have hypothesized that an endoscopically assisted transaxillary approach in the zero position would be able to improve visualization and allow safe surgery for thoracic outlet syndrome. METHODS: We performed surgery only for patients with certain objective findings, including blood flow disruption, low blood flow and accelerated blood flow in the subclavian artery demonstrated using Doppler sonography, narrowing of the scalene interval width between the anterior and middle interscalene muscles (interscalene base) or costoclavicular space demonstrated using Duplex ultrasonography or computed tomography angiography. The present study included 45 consecutive patients (50 limbs) who underwent endoscopic transaxillary first rib resection with scalenotomy and brachial plexus neurolysis. We assessed the intraoperative parameters, including the interscalene base, blood loss, operation time, patient satisfaction, preoperative and postoperative Quick Disability of the Arm, Shoulder and Hand and complications. RESULTS: The mean intraoperatively measured interscalene base width was 6.4 mm. All patients showed improvement after surgery. The outcome was excellent in 40% of cases, good in 48%, fair in 12% and poor in none. Pneumothorax was present in 6%. There were no other complications and no recurrences. Among patients who had been followed up for at least 2 years, the Quick Disability of the Arm, Shoulder and Hand score was significantly improved (42 before surgery vs 12 at final follow-up), especially in athletes relative to non-athletes (0.2 vs 16). The present approach achieved complete relief in 43% of cases overall (91% in athletes and 16% in non-athletes). CONCLUSIONS: Endoscopically assisted transaxillary first rib resection and brachial plexus neurolysis in the zero position are useful and safe for thoracic outlet syndrome, especially in athletes.

Combining Cylindrical Bone Graft and Headless Screw Fixation for Nonunion of the Medial Trochlea of the Elbow: A Case Report.

CASE: A 19-year-old handballer presented with elbow pain and nonunion of the medial trochlea of the elbow. He had undergone earlier surgery for an elbow injury at 6 years of age. Revision surgery for nonunion was performed using an extra-articular method combining cylindrical bone graft and headless screw fixation. Partial union was observed, and he resumed sports after 3 months, with his limb largely pain-free and functional. At the 21-month follow-up, bone healing was complete. CONCLUSIONS: Combining cylindrical bone graft and headless screw fixation using the extra-articular technique is an option for managing nonunion of the medial trochlea of the elbow.

Differential dynamics of bone graft transplantation and mesenchymal stem cell therapy during bone defect healing in a murine critical size defect.

Background: A critical size bone defect is a clinical scenario in which bone is lost or excised due to trauma, infection, tumor, or other causes, and cannot completely heal spontaneously. The most common treatment for this condition is autologous bone grafting to the defect site. However, autologous bone graft is often insufficient in quantity or quality for transplantation to these large defects. Recently, tissue engineering methods using mesenchymal stem cells (MSCs) have been proposed as an alternative treatment. However, the underlying biological principles and optimal techniques for tissue regeneration of bone using stem cell therapy have not been completely elucidated. Methods: In this study, we compare the early cellular dynamics of healing between bone graft transplantation and MSC therapy in a murine chronic femoral critical-size bone defect. We employ high-dimensional mass cytometry to provide a comprehensive view of the differences in cell composition, stem cell functionality, and immunomodulatory activity between these two treatment methods one week after transplantation. Results: We reveal distinct cell compositions among tissues from bone defect sites compared with original bone graft, show active recruitment of MSCs to the bone defect sites, and demonstrate the phenotypic diversity of macrophages and T cells in each group that may affect the clinical outcome. Conclusion: Our results provide critical data and future directions on the use of MSCs for treating critical size defects to regenerate bone.Translational Potential of this article: This study showed systematic comparisons of the cellular and immunomodulatory profiles among different interventions to improve the healing of the critical-size bone defect. The results provided potential strategies for designing robust therapeutic interventions for the unmet clinical need of treating critical-size bone defects.

Effectiveness of Bone Marrow-Derived Platelet-Rich Fibrin on Rotator Cuff Healing in a Rabbit Degenerative Model.

BACKGROUND: Platelet-rich fibrin (PRF) is a second-generation platelet concentrate. Although peripheral blood-derived PRF (P-PRF) is commonly applied in biological augmentation, there is no report about the therapeutic effect of bone marrow-derived PRF (BM-PRF) for degenerative rotator cuff tears (RCTs). PURPOSE/HYPOTHESIS: To examine the effects of platelet-rich plasma (PRP), P-PRF, and BM-PRF during rotator cuff repair (RCR) in degenerative RCTs in rabbits. We hypothesized that BM-PRF would accelerate the bone-tendon healing after RCR. STUDY DESIGN: Controlled laboratory study. METHODS: Degenerative RCT models were created 2 weeks before beginning the study, and 68 juvenile rabbits were divided into 4 groups: the control, PRP, P-PRF, and BM-PRF groups. RCR without augmentation was done in the control group. PRP was prepared by centrifuging peripheral blood twice using a plastic tube. P-PRF and BM-PRF were prepared by centrifuging peripheral blood and bone marrow, respectively, using a glass tube. Rabbits from PRP, P-PRF, and BM-PRF groups were administered the augmentation in a similar fashion for RCR, between the rotator cuff and the footprint of the humerus. At 4, 8, and 12 weeks, rabbits were euthanized and histologically assessed using hematoxylin and eosin staining, Alcian blue staining, and immunohistochemical staining for type I and III collagen. The sections were also evaluated with immunofluorescence staining of vascular endothelial growth factor (VEGF) at 4 weeks. RESULTS: The continuity was significantly better in the BM-PRF group at 4 weeks (P < .05). Immunofluorescence staining demonstrated that VEGF-positive stained cells were significantly greater in the BM-PRF group than in the control group (P < .01). The modified tendon maturing score was significantly greater in the BM-PRF group than in the control and PRP groups at 12 weeks (P < .05). There was no significant difference in the modified tendon maturing score of the P-PRF group compared with the control group. CONCLUSION: The rabbit model of degenerative RCTs demonstrated that RCR combined with BM-PRF enhanced tendon-bone continuity and increased the VEGF-positive cells at 4 weeks and obtained preferable tendon-bone maturation at 12 weeks. CLINICAL RELEVANCE: RCR augmented with BM-PRF has the potential to improve clinical outcomes for RCTs.

The Effect of Elbow and Forearm Position on the Resisted Wrist Extension Test and Incidence of Sensory Disturbance of the Superficial Radial Nerve in Patients with Lateral Epicondylitis.

Background: The aim of this study is to determine the effect of elbow and forearm position on the resisted wrist extension test (RWET) in patients with lateral epicondylitis. We also looked at the incidence of associated sensory disturbance of the superficial radial nerve (SRN) and the effect of treatment of lateral epicondylitis on sensory disturbance. Methods: Sixty-three consecutive patients (68 limbs) with lateral epicondylitis and an equal number of age and gender matched volunteers were investigated. Patients with lateral epicondylitis were subdivided into two groups based on history of corticosteroid injection. We performed the RWET in four limb positions namely elbow extended and forearm pronated (EP), elbow flexed and forearm pronated (FP), elbow extended and forearm supinated (ES), elbow flexed and forearm supinated (FS). Sensory disturbance in the SRN was assessed using a Wartenberg pin wheel. Results: The positivity rate of the RWET was significantly higher in the EP position (100%) compared to the FP (66%), ES (62%) and the FS (24%) positions in limbs with lateral epicondylitis. The RWET was positive only in one subject in the EP position in the control group (1.5%). Sensory disturbance in the SRN territory was present in 63.2% of limbs and only two subjects (2.9%) in the control group. The incidence of sensory disturbance was significantly higher (74.5% vs. 48.3%, p < 0.05) in patients who did not have a corticosteroid injection. Conclusions: The sensitivity and specificity of the RWET is better when it is performed with the elbow in extension with the forearm pronated (EP); 63.2% of limbs with lateral epicondylitis were noted to have an associated sensory disturbance of the SRN and a corticosteroid injection seems to decrease the incidence of sensory disturbances. Level of Evidence: Level II (Diagnostic).

Cancer screening: Possibility of underscreening in older adult population with a history of cardiovascular disease.

BACKGROUND: Cardiovascular disease and cancer share a number of risk factors and pathophysiologic mechanisms. Although risk management and early detection of cancer in patients with cardiovascular disease are important, preventive efforts in cardiology and oncology have been relatively disconnected. This study aimed to investigate the rate of cancer screening in a population of older adults with cardiovascular disease. METHODS: This study used data from the 2019 Comprehensive Survey of Living Conditions. Data on participants aged 60 years or older were extracted. The rate of cancer screening and cancer type were investigated between participants with and without cardiovascular disease. RESULTS: Of the 132,442 individuals, participants with cardiovascular disease had a significantly lower rate of cancer screening than those without cardiovascular disease [male: 4401 of 7972 participants (55.2%) vs. 33,744 of 52,106 participants (64.8%), p < 0.001; female: 2500 of 4984 participants (50.2%) vs. 41,319 of 67,380 participants (61.3%), p < 0.001]. The rate of cancer screening was significantly lower in participants with cardiovascular disease than in those without cardiovascular disease, regardless of cancer type, including gastric, colorectal, lung, breast, and gynecologic cancer screening. A history of cardiovascular disease was a negative factor for cancer screening (odds ratio 0.71, 95% confidence interval 0.67-0.74 in male participants; odds ratio 0.80, 95% confidence interval, 0.75-0.85 in female participants). CONCLUSIONS: The rate of cancer screening in elderly participants with cardiovascular disease was lower than that in participants without cardiovascular disease. Physicians should raise awareness regarding early cancer detection in patients with cardiovascular disease.

Conservative treatment for stable osteochondritis dissecans of the elbow before epiphyseal closure: effectiveness of elbow immobilization for healing.

BACKGROUND AND HYPOTHESIS: Stable lesions of osteochondritis dissecans (OCD) of the capitellum have been treated with activity restriction (AR), and the complete healing requires 1 or 2 years. Little is known about the effectiveness of elbow immobilization. We hypothesized that elbow immobilization would have positive effects on healing of stable OCD. METHODS: The study subjects were 43 patients (mean age: 12.2 years) with 43 stable OCD lesions of the prematured elbow (mean skeletal age score: 17.1 points of 0-27 points system). The subjects were divided into 3 groups: group A, AR without elbow immobilization, 22 cases; group B, splint (mean: 8.8 weeks) followed by AR, 9 cases; and group C, cast (mean: 3.7 weeks) followed by splint (mean: 7.3 weeks) and AR, 12 cases. The mean nonoperative observation period was 17.5 months (minimum three months). On anteroposterior radiographs of the elbow at 45 degrees of flexion, 5 observers independently assessed the healing of the capitellum, and the interobserver and intraobserver reliabilities were examined. The differences in outcomes among 3 groups were also examined. RESULTS: The interobserver and intraobserver reliabilities of the radiographic assessment were almost perfect (Cohen kappa value: 0.82 and 0.91, respectively). There were no significant differences in age, sports played, or stage of the lesion before the treatment. The proportion of patients returning to sports and the mean period required were 77% and 8.2 months in group A, 78% and 5.7 months in group B, and 83% and 4.4 months in group C, respectively. The proportion of patients showing ossification in the central aspect of the capitellum and the mean period required were 67% and 8.2 months in group A, 63% and 4.9 months in group B, and 91% and 1.9 months in group C, respectively. The proportion of patients showing complete healing and the mean period required were 41% and 16.4 months in group A, 67% and 7.0 months in group B, and 92% and 5.5 months in group C, respectively. Compared to group A, group C showed a significantly earlier return to sports (P = .034), a significantly shorter period required for ossification (P < .001), and significantly higher proportion of patients with complete healing (P = .012) within a significantly shorter period (P = .009). CONCLUSION: Elbow immobilization had positive effects on healing and enabled both an early return to sports and complete healing. Cast immobilization is recommended as a first choice of nonoperative treatment for stable OCD lesions of the elbow before epiphyseal closure.

Staging of osteochondritis dissecans of the elbow based on pathologic progression in the partially detached articular fragment.

BACKGROUND: Osteochondritis dissecans (OCD) is considered to show the following stages of pathologic progression: IA, nearly normal-cartilaginous; IB, deteriorated-cartilaginous; IIA, cartilage-ossifying; and IIB, cartilage-osteonecrotic. However, the validity of this pathologic staging for OCD has yet to be confirmed in a large number of cases. PURPOSE: The aim of the present study was to confirm the clinical validity of the proposed pathologic staging of OCD. METHODS: The subjects were 74 patients (mean age, 14.2 years; mean skeletal age score, 25.6 points) with capitellar OCD. Partially detached articular fragments were surgically removed and were examined histologically. The articular fragments were independently assessed by 5 observers, and the reliability of assessment was examined. The correlation between the pathologic stages and the clinical data was analyzed. RESULTS: The reliability of the assessment among 5 observers was almost perfect. OCD stages of IA, IB, IIA, and IIB were evident in 8, 36, 10, and 20 patients, respectively. OCD-I (cartilaginous) and OCD-II (osteochondral) corresponded significantly to radiographic stage I (radiolucency) and stage II (delayed ossification), respectively. The pathologic OCD stages were significantly correlated with the clinical data, including the period from symptom onset to surgery, patient age, and the skeletal age score (P < .01). CONCLUSION: Our results confirmed that the proposed pathologic staging of OCD corresponds to the observed clinical progression of OCD, thus validating the staging system. Our findings revealed that OCD begins with separation beneath the epiphyseal cartilage, which is programmed to be replaced with bone. When a stage IA articular fragment has remained partially detached for a prolonged period, the epiphyseal cartilage may be deteriorated and become degenerated, and subsequent ossification may not occur, as is evident in OCD-IB. In contrast, stage IA with a vascular supply through the fibrocartilaginous connection can progress to stage IIA. During the prolonged period in which the osteochondral articular fragment remains ununited, microtrauma can cause to disturb the blood supply to the bony fragment, resulting in osteonecrosis (stage IIB).

Macrophages Modulate the Function of MSC- and iPSC-Derived Fibroblasts in the Presence of Polyethylene Particles.

Fibroblasts in the synovial membrane secrete molecules essential to forming the extracellular matrix (ECM) and supporting joint homeostasis. While evidence suggests that fibroblasts contribute to the response to joint injury, the outcomes appear to be patient-specific and dependent on interactions between resident immune cells, particularly macrophages (Mφs). On the other hand, the response of Mφs to injury depends on their functional phenotype. The goal of these studies was to further explore these issues in an in vitro 3D microtissue model that simulates a pathophysiological disease-specific microenvironment. Two sources of fibroblasts were used to assess patient-specific influences: mesenchymal stem cell (MSC)- and induced pluripotent stem cell (iPSC)-derived fibroblasts. These were co-cultured with either M1 or M2 Mφs, and the cultures were challenged with polyethylene particles coated with lipopolysaccharide (cPE) to model wear debris generated from total joint arthroplasties. Our results indicated that the fibroblast response to cPE was dependent on the source of the fibroblasts and the presence of M1 or M2 Mφs: the fibroblast response as measured by gene expression changes was amplified by the presence of M2 Mφs. These results demonstrate that the immune system modulates the function of fibroblasts; furthermore, different sources of differentiated fibroblasts may lead to divergent results. Overall, our research suggests that M2 Mφs may be a critical target for the clinical treatment of cPE induced fibrosis.

Mesenchymal Stem Cells and NF-κB Sensing Interleukin-4 Over-Expressing Mesenchymal Stem Cells Are Equally Effective in Mitigating Particle-Associated Chronic Inflammatory Bone Loss in Mice.

Wear particles from total joint arthroplasties (TJAs) induce chronic inflammation, macrophage infiltration and lead to bone loss by promoting bone destruction and inhibiting bone formation. Inhibition of particle-associated chronic inflammation and the associated bone loss is critical to the success and survivorship of TJAs. The purpose of this study is to test the hypothesis that polyethylene particle induced chronic inflammatory bone loss could be suppressed by local injection of NF-κB sensing Interleukin-4 (IL-4) over-expressing MSCs using the murine continuous polyethylene particle infusion model. The animal model was generated with continuous infusion of polyethylene particles into the intramedullary space of the femur for 6 weeks. Cells were locally injected into the intramedullary space 3 weeks after the primary surgery. Femurs were collected 6 weeks after the primary surgery. Micro-computational tomography (µCT), histochemical and immunohistochemical analyses were performed. Particle-infusion resulted in a prolonged pro-inflammatory M1 macrophage dominated phenotype and a decrease of the anti-inflammatory M2 macrophage phenotype, an increase in TRAP positive osteoclasts, and lower alkaline phosphatase staining area and bone mineral density, indicating chronic particle-associated inflammatory bone loss. Local injection of MSCs or NF-κB sensing IL-4 over-expressing MSCs reversed the particle-associated chronic inflammatory bone loss and facilitated bone healing. These results demonstrated that local inflammatory bone loss can be effectively modulated via MSC-based treatments, which could be an efficacious therapeutic strategy for periprosthetic osteolysis.

Sex Differences in Mesenchymal Stem Cell Therapy With Gelatin-Based Microribbon Hydrogels in a Murine Long Bone Critical-Size Defect Model.

Mesenchymal stem cell (MSC)-based therapy and novel biomaterials are promising strategies for healing of long bone critical size defects. Interleukin-4 (IL-4) over-expressing MSCs within a gelatin microribbon (µRB) scaffold was previously shown to enhance the bridging of bone within a critical size femoral bone defect in male Balb/c mice. Whether sex differences affect the healing of this bone defect in conjunction with different treatments is unknown. In this study, we generated 2-mm critical-sized femoral diaphyseal bone defects in 10-12-week-old female and male Balb/c mice. Scaffolds without cells and with unmodified MSCs were implanted immediately after the primary surgery that created the bone defect; scaffolds with IL-4 over-expressing MSCs were implanted 3 days after the primary surgery, to avoid the adverse effects of IL-4 on the initial inflammatory phase of fracture healing. Mice were euthanized 6 weeks after the primary surgery and femurs were collected. MicroCT (µCT), histochemical and immunohistochemical analyses were subsequently performed of the defect site. µRB scaffolds with IL-4 over-expressing MSCs enhanced bone healing in both female and male mice. Male mice showed higher measures of bone bridging and increased alkaline phosphatase (ALP) positive areas, total macrophages and M2 macrophages compared with female mice after receiving scaffolds with IL-4 over-expressing MSCs. Female mice showed higher Tartrate-Resistant Acid Phosphatase (TRAP) positive osteoclast numbers compared with male mice. These results demonstrated that sex differences should be considered during the application of MSC-based studies of bone healing.

The effect of genetically modified platelet-derived growth factor-BB over-expressing mesenchymal stromal cells during core decompression for steroid-associated osteonecrosis of the femoral head in rabbits.

BACKGROUND: Approximately one third of patients undergoing core decompression (CD) for early-stage osteonecrosis of the femoral head (ONFH) experience progression of the disease, and subsequently require total hip arthroplasty (THA). Thus, identifying adjunctive treatments to optimize bone regeneration during CD is an unmet clinical need. Platelet-derived growth factor (PDGF)-BB plays a central role in cell growth and differentiation. The aim of this study was to characterize mesenchymal stromal cells (MSCs) that were genetically modified to overexpress PDGF-BB (PDGF-BB-MSCs) in vitro and evaluate their therapeutic effect when injected into the bone tunnel at the time of CD in an in vivo rabbit model of steroid-associated ONFH. METHODS: In vitro studies: Rabbit MSCs were transduced with a lentivirus vector carrying the human PDGF-BB gene under the control of either the cytomegalovirus (CMV) or phosphoglycerate (PGK) promoter. The proliferative rate, PDGF-BB expression level, and osteogenic differentiation capacity of unmodified MSCs, CMV-PDGF-BB-MSCs, and PGK-PDGF-BB-MSCs were assessed. In vivo studies: Twenty-four male New Zealand white rabbits received an intramuscular (IM) injection of methylprednisolone 20 mg/kg. Four weeks later, the rabbits were divided into four groups: the CD group, the hydrogel [HG, (a collagen-alginate mixture)] group, the MSC group, and the PGK-PDGF-BB-MSC group. Eight weeks later, the rabbits were sacrificed, their femurs were harvested, and microCT, mechanical testing, and histological analyses were performed. RESULTS: In vitro studies: PGK-PDGF-BB-MSCs proliferated more rapidly than unmodified MSCs (P < 0.001) and CMV-PDGF-BB-MSCs (P < 0.05) at days 3 and 7. CMV-PDGF-BB-MSCs demonstrated greater PDGF-BB expression than PGK-PDGF-BB-MSCs (P < 0.01). However, PGK-PDGF-BB-MSCs exhibited greater alkaline phosphatase staining at 14 days (P < 0.01), and osteogenic differentiation at 28 days (P = 0.07) than CMV-PDGF-BB-MSCs. In vivo: The PGK-PDGF-BB-MSC group had a trend towards greater bone mineral density (BMD) than the CD group (P = 0.074). The PGK-PDGF-BB-MSC group demonstrated significantly lower numbers of empty lacunae (P < 0.001), greater osteoclast density (P < 0.01), and greater angiogenesis (P < 0.01) than the other treatment groups. CONCLUSION: The use of PGK-PDGF-BB-MSCs as an adjunctive treatment with CD may reduce progression of osteonecrosis and enhance bone regeneration and angiogenesis in the treatment of early-stage ONFH.

Qualitative and quantitative assessments of radiographic healing of osteochondritis dissecans of the humeral capitellum.

BACKGROUND: Little is known about the optimal timing of early return to sports after which the osteochondritis dissecans (OCD) lesion can completely heal. The aims of this study were to investigate the clinical outcomes of nonoperative treatment and elucidate the relationship between the radiographic findings and the timing for the return to sports. METHODS: We performed a retrospective review of 32 patients who presented with stable OCD of the capitellum and were treated nonoperatively for a minimum of 3 months. The mean follow-up period was 22.1 months. OCD lesions were assessed qualitatively and quantitatively on anteroposterior radiographs of the elbow at 45° of flexion every 3 months. The width of the OCD lesion (OCDw) and lateral width of the normal capitellum were measured and were associated with return to sports activities. RESULTS: In 21 patients (66%), the progression of ossification was seen at a mean period of 4.1 months. Eighteen (56%) had partial union at a mean period of 4.3 months. Twenty-nine cases (91%) returned to sports activities after a mean of 4.6 months. Nine cases (28%) achieved complete union after a mean period of 15.0 months. Fifteen (47%) required surgery after a mean period of 11.8 months. The mean OCDw (%) was 10.2 ± 3.9 mm (56%) at the initial presentation and 8.0 ± 6.0 mm (41%) at the final follow-up examination, and the decrease in OCDw was 2.2 ± 3.1 mm (15%). The mean decrease in OCDw in patients with progression of ossification during the first 3 months was significantly larger than in patients without progression of ossification (4.9 ± 4.7 mm and -0.7 ± 4.5 mm, respectively; P = .002). In patients who had both an OCDw value of <8.0 mm and a lateral width value of >2.0 mm at the time of the return to sports, the rate of successful nonoperative treatment (86%) and complete union (71%) was significantly higher in comparison with other patients (P = .03 and P = .02). CONCLUSIONS: OCD lesions showed difficult healing in the middle one-third of the capitellum. The progression of ossification during the first 3 months was a significant predictor of successful nonoperative treatment and complete union. Surgery should be considered for lesions without the progression of ossification during the first 3 months. We propose both an OCD lesion width of <8.0 mm and a lateral normal width of >2.0 mm as radiographic landmarks of the timing of the return to sports.

The efficacy of lapine preconditioned or genetically modified IL4 over-expressing bone marrow-derived mesenchymal stromal cells in corticosteroid-associated osteonecrosis of the femoral head in rabbits.

Cell-based therapy for augmentation of core decompression (CD) using mesenchymal stromal cells (MSCs) is a promising treatment for early stage osteonecrosis of the femoral head (ONFH). Recently, the therapeutic potential for immunomodulation of osteogenesis using preconditioned (with pro-inflammatory cytokines) MSCs (pMSCs), or by the timely resolution of inflammation using MSCs that over-express anti-inflammatory cytokines has been described. Here, pMSCs exposed to tumor necrosis factor-alpha and lipopolysaccharide for 3 days accelerated osteogenic differentiation in vitro. Furthermore, injection of pMSCs encapsulated with injectable hydrogels into the bone tunnel facilitated angiogenesis and osteogenesis in the femoral head in vivo, using rabbit bone marrow-derived MSCs and a model of corticosteroid-associated ONFH in rabbits. In contrast, in vitro and in vivo studies demonstrated that genetically-modified MSCs that over-express IL4 (IL4-MSCs), established by using a lentiviral vector carrying the rabbit IL4 gene under the cytomegalovirus promoter, accelerated proliferation of MSCs and decreased the percentage of empty lacunae in the femoral head. Therefore, adjunctive cell-based therapy of CD using pMSCs and IL4-MSCs may hold promise to heal osteonecrotic lesions in the early stage ONFH. These interventions must be applied in a temporally sensitive fashion, without interfering with the mandatory acute inflammatory phase of bone healing.