Bone-Regeneration Therapy Using Biodegradable Scaffolds: Calcium Phosphate Bioceramics and Biodegradable Polymers.

Calcium phosphate-based synthetic bone is broadly used for the clinical treatment of bone defects caused by trauma and bone tumors. Synthetic bone is easy to use; however, its effects depend on the size and location of the bone defect. Many alternative treatment options are available, such as joint arthroplasty, autologous bone grafting, and allogeneic bone grafting. Although various biodegradable polymers are also being developed as synthetic bone material in scaffolds for regenerative medicine, the clinical application of commercial synthetic bone products with comparable performance to that of calcium phosphate bioceramics have yet to be realized. This review discusses the status quo of bone-regeneration therapy using artificial bone composed of calcium phosphate bioceramics such as ß-tricalcium phosphate (ßTCP), carbonate apatite, and hydroxyapatite (HA), in addition to the recent use of calcium phosphate bioceramics, biodegradable polymers, and their composites. New research has introduced potential materials such as octacalcium phosphate (OCP), biologically derived polymers, and synthetic biodegradable polymers. The performance of artificial bone is intricately related to conditions such as the intrinsic material, degradability, composite materials, manufacturing method, structure, and signaling molecules such as growth factors and cells. The development of new scaffold materials may offer more efficient bone regeneration.

Does re-ossification after palliative radiotherapy for spinal bone metastases help maintain vertebral body height?

BACKGROUND CONTEXT: After palliative radiotherapy of spinal bone metastases, re-ossification is sometimes observed in bone with osteolytic changes. However, it remains unknown whether the re-ossification that is observed after radiotherapy is associated with preservation of vertebral body height. PURPOSE: To investigate whether re-ossification observed after palliative radiotherapy can contribute to the preservation of vertebral body height. STUDY DESIGN: This is a retrospective observational study. PATIENTS SAMPLE: We investigated 111 vertebral bodies in 54 patients that underwent palliative radiotherapy at a single center for painful osteolytic/mixed metastatic spinal tumors in solid tumors between 2016 and 2020. OUTCOME MEASURES: The outcome measures were the presence of re-ossification and vertebral body height reduction on the CT image. METHODS: Re-ossification was evaluated according to the MD Anderson response classification criteria, and sagittal CT images were used to evaluate vertebral body height. A vertebral body ID was assigned to the irradiated vertebral body, and continuous CT images obtained for each vertebral body ID were evaluated. The median number of evaluation periods for each vertebral body was 4, and the total number of periods was 463. Logistic regression analysis was performed to investigate factors related to the occurrence of vertebral body height reduction before the subsequent CT. As a subanalysis, factors related to re-ossification were investigated. RESULTS: The following primary cancer types were observed: lung cancer, 41 vertebral bodies; breast cancer, 19; renal cell cancer, 15; other, 36. A total of 62.2% showed re-ossification. The median time to confirmation of re-ossification by CT was 2 months. Factors significantly associated with vertebral body height reduction were presence of vertebral body height reduction before radiotherapy (odds ratio [OR] 6.8, 95% confidence interval [CI] 2.0-63, p=.01) and no re-ossification (OR 137, 95% CI 22-3469, p<.01). Factors associated with re-ossification were the type of cancer and total radiation dose. Those with lung cancer and those with a total radiation dose of 20 Gy or less were more prone to re-ossification. CONCLUSIONS: Re-ossification was observed in 62.2% of vertebral bodies after palliative radiotherapy for painful osteolytic/mixed metastatic spinal tumors. The re-ossification group demonstrated significantly less vertebral body height reduction when compared with the non-re-ossification group. The presence of re-ossification may potentially serve an important role in maintaining vertebral body height.

Muscle strength and functional recovery for soft-tissue sarcoma of the thigh: a prospective study.

BACKGROUND: This study aimed to investigate changes in muscle strength and functional outcome before and after surgery for soft-tissue sarcoma of the thigh and to examine the timing of recovery. METHODS: From 2014 to 2019, 15 patients who underwent multiple resections of the thigh muscle for soft-tissue sarcoma of the thigh were included in this study. The muscle strength was measured with an isokinetic dynamometer for the knee joint and with a hand-held dynamometer for the hip joint. The functional outcome assessment was based on the Musculoskeletal Tumor Society (MSTS) score, Toronto Extremity Salvage Score (TESS), European Quality of Life-5 Dimensions (EQ-5D), and maximum walking speed (MWS). All measurements were conducted preoperatively and at 3, 6, 12, 18, and 24 months postoperatively, and the ratio of postoperative to preoperative value was used. A repeated-measures analysis of variance was performed to compare changes over time and to investigate the recovery plateau. Correlations between changes in muscle strength and functional outcomes were also examined. RESULTS: The muscle strength of the affected limb, MSTS score, TESS, EQ-5D, and MWS were significantly decreased at 3 months postoperatively. The recovery plateau was subsequently reached at 12 months postoperatively. The changes in muscle strength of the affected limb and functional outcome showed a significant correlation. CONCLUSIONS: The estimated postoperative recovery for soft-tissue sarcoma of the thigh is 12 months after surgery.

Current Methods in the Study of Nanomaterials for Bone Regeneration.

Nanomaterials show great promise as bone regeneration materials. They can be used as fillers to strengthen bone regeneration scaffolds, or employed in their natural form as carriers for drug delivery systems. A variety of experiments have been conducted to evaluate the osteogenic potential of bone regeneration materials. In vivo, such materials are commonly tested in animal bone defect models to assess their bone regeneration potential. From an ethical standpoint, however, animal experiments should be minimized. A standardized in vitro strategy for this purpose is desirable, but at present, the results of studies conducted under a wide variety of conditions have all been evaluated equally. This review will first briefly introduce several bone regeneration reports on nanomaterials and the nanosize-derived caveats of evaluations in such studies. Then, experimental techniques (in vivo and in vitro), types of cells, culture media, fetal bovine serum, and additives will be described, with specific examples of the risks of various culture conditions leading to erroneous conclusions in biomaterial analysis. We hope that this review will create a better understanding of the evaluation of biomaterials, including nanomaterials for bone regeneration, and lead to the development of versatile assessment methods that can be widely used in biomaterial development.

Antitumor Effect of Sclerostin against Osteosarcoma.

Various risk factors and causative genes of osteosarcoma have been reported in the literature; however, its etiology remains largely unknown. Bone formation is a shared phenomenon in all types of osteosarcomas, and sclerostin is an extracellular soluble factor secreted by osteocytes that prevents bone formation by inhibiting the Wnt signaling pathway. We aimed to investigate the antitumor effect of sclerostin against osteosarcoma. Osteosarcoma model mice were prepared by transplantation into the dorsal region of C3H/He and BALB/c-nu/nu mice using osteosarcoma cell lines LM8 (murine) and 143B (human), respectively. Cell proliferations were evaluated by using alamarBlue and scratch assays. The migratory ability of the cells was evaluated using a migration assay. Sclerostin was injected intraperitoneally for 7 days to examine the suppression of tumor size and extension of survival. The administration of sclerostin to osteosarcoma cells significantly inhibited the growth and migratory ability of osteosarcoma cells. Kaplan-Meier curves and survival data demonstrated that sclerostin significantly inhibited tumor growth and improved survival. Sclerostin suppressed the proliferative capacity and migratory ability of osteosarcoma cells. Osteosarcoma model mice inhibited tumor growth and prolonged survival periods by the administration of sclerostin. The effect of existing anticancer drugs such as doxorubicin should be investigated for future clinical applications.

Evaluation of MC3T3-E1 Cell Osteogenesis in Different Cell Culture Media.

Many biomaterials have been evaluated using cultured cells. In particular, osteoblast-like cells are often used to evaluate the osteocompatibility, hard-tissue-regeneration, osteoconductive, and osteoinductive characteristics of biomaterials. However, the evaluation of biomaterial osteogenesis-inducing capacity using osteoblast-like cells is not standardized; instead, it is performed under laboratory-specific culture conditions with different culture media. However, the effect of different media conditions on bone formation has not been investigated. Here, we aimed to evaluate the osteogenesis of MC3T3-E1 cells, one of the most commonly used osteoblast-like cell lines for osteogenesis evaluation, and assayed cell proliferation, alkaline phosphatase activity, expression of osteoblast markers, and calcification under varying culture media conditions. Furthermore, the various media conditions were tested in uncoated plates and plates coated with collagen type I and poly-L-lysine, highly biocompatible molecules commonly used as pseudobiomaterials. We found that the type of base medium, the presence or absence of vitamin C, and the freshness of the medium may affect biomaterial regeneration. We posit that an in vitro model that recapitulates in vivo bone formation should be established before evaluating biomaterials.

Anti-PD-1 antibody decreases tumour-infiltrating regulatory T cells.

BACKGROUND: There are many types of therapies for cancer. In these days, immunotherapies, especially immune checkpoint inhibitors, are focused on. Though many types of immune checkpoint inhibitors are there, the difference of effect and its mechanism are unclear. Some reports suggest the response rate of anti-PD-1 antibody is superior to that of anti-PD-L1 antibody and could potentially produce different mechanisms of action. On the other hand, Treg also express PD-1; however, their relationship remains unclear. METHODS: In this study, we used osteosarcoma cell lines in vitro and osteosarcoma mouse model in vivo. In vitro, we analyzed the effect of IFNγ for expression of PD-L1 on the surface of cell lines by flowcytometry. In vivo, murine osteosarcoma cell line LM8 was subcutaneously transplanted into the dorsum of mice. Mouse anti-PD-1 antibody was intraperitoneally administered. we analysed the effect for survival of anti-PD-1 antibody and proportion of T cells in the tumour by flowcytometry. RESULTS: We discovered that IFNγ increased PD-L1 expression on the surface of osteosarcoma cell lines. In assessing the relationship between anti-PD-1 antibody and Treg, we discovered the administration of anti-PD-1 antibody suppresses increases in tumour volume and prolongs overall survival time. In the tumour microenvironment, we found that the administration of anti-PD-1 antibody decreased Treg within the tumour and increased tumour-infiltrating lymphocytes. CONCLUSIONS: Here we clarify for the first time an additional mechanism of anti-tumour effect-as exerted by anti-PD-1 antibody decreasing Treg- we anticipate that our findings will lead to the development of new methods for cancer treatment.

Carbon fibers for treatment of cancer metastasis in bone.

When cancer metastasizes to bone, the resulting pain and functional disorders due to bone destruction adversely affect the patient's quality of life. We have developed a new cancer metastasis control system consisting of anticancer agents conjugated to carbon fibers (CFs), which are nonbiodegradable, carriers of a wide variety of molecules with extremely high affinity for bone. In the evaluation of cancer suppression effects on Walker 256 cancer cells, cisplatin (CDDP)-conjugated CFs (CF-CDDP) were found to be as effective in cancer suppression as CDDP. In the evaluation of the cancer suppression effects of local injection in the rat model of tibial cancer bone metastasis, similar cancer suppression was noted in the CF-CDDP group and CDDP group; however, blood Pt concentrations were significantly lower in the CF-CDDP group. Experiments with CDDP and CF-CDDP injected into bone actually destroyed by cancer metastases revealed the presence of significantly more newly formed bone tissue with the administration of CF-CDDP. Local administration of CF-CDDP is expected to become the first therapy to suppress cancer growth with low prevalence of adverse reactions, and to repair bone damaged by metastasis.

Clinical outcome of osteosarcoma and its correlation with programmed death-ligand 1 and T cell activation markers.

PURPOSE: Although both anti-PD-1 antibody and treatments using anti-PD-L1 antibody are currently in clinical use, their therapeutic effects vary according to cancer type. One of the factors accounting for this variability is the expression level of the immune checkpoint molecule that differs between cancer types; thus, it is important to clarify the relationship between clinical outcomes and immune checkpoint molecules for all types of human cancer. The purpose of this study is to evaluate the clinical outcome of osteosarcoma in relation to PD-L1, PRF, GZMB, and IFNγ expression. METHODS: Using 19 clinical specimens of osteosarcoma, we examined the expression of PD-L1, PRF, GZMB, and IFNγ in relation to their clinical outcomes. RESULTS: PD-L1 expression correlated with early metastatic formation in clinical specimens of osteosarcoma, and the group with highly expressed functional markers for T cells such as PRF and GZMB resulted in a long overall survival time. CONCLUSION: This is the first study to elucidate the clinical outcomes of osteosarcoma in relation to PD-L1, PRF, GZMB, and IFNγ expression. This study provides valuable information regarding the clinical indication and prediction of effect for anti-PD-1 antibody in osteosarcoma.

Painful locking of the wrist in a patient with pseudoachondroplasia confirmed by COMP mutation.

We report the case of a 40-year-old woman with pseudoachondroplasia (PSACH), with a heterozygous mutation (c.806A > G, p.Asp269Gly) located in the Type 3 repeats domain of the cartilage oligomeric matrix protein gene, who complained of the unusual symptom of painful locking of the wrist. Her condition was caused by a non-traumatic enlargement of the extensor carpi radialis longus (ECRL) and brevis (ECRB) tendons along with bulbous swelling of the synoviums around them. Surgical treatment resolved these unusual tendon-related symptoms. Repetitive mechanical loading of the wrist in daily activities, including distal intersection tenosynovitis between the extensor pollicis longus tendon and ECRL and ECRB tendons, may have contributed to changes in the structural integrity of the tendons. We should pay more attention to tendon-related symptoms in patients with PSACH.