Qiang Ao

3D Bioprinting Technologies for Hard Tissue and Organ Engineering

Hard tissues and organs, including the bones, teeth and cartilage, are the most extensively exploited and rapidly developed areas in regenerative medicine field. One prominent character of hard tissues and organs is that their extracellular matrices mineralize to withstand weight and pressure. Over the last two decades, a wide variety of 3D printing technologies have been adapted to hard tissue and organ engineering. These 3D printing technologies have been defined as 3D bioprinting. Especially for hard organ regeneration, a series of new theories, strategies and protocols have been proposed. Some of the technologies have been applied in medical therapies with some successes. Each of the technologies has pros and cons in hard tissue and organ engineering. In this review, we summarize the advantages and disadvantages of the historical available innovative 3D bioprinting technologies for used as special tools for hard tissue and organ engineering.

Efficacy of umbilical cord-derived mesenchymal stem cell-based therapy for osteonecrosis of the femoral head: A three-year follow-up study

This is a retrospective analysis of the clinical effects of transplant of mesenchymal stem cells (MSCs) derived from human umbilical cord-derived MSCs (hUC-MSCs) for the treatment of osteonecrosis of the femoral head (ONFH). The biological characteristics of hUC-MSCs were assessed using flow cytometry. Nine eligible patients were enrolled in the study as they adhered to the Association Research Circulation Osseous (ARCO) classification of stage II–IIIa, and hUC-MSCs were grafted by intra-arterial infusion. Organize effective perfusion was assessed using the oxygen delivery index (ODI). The results showed that the ODI was increased at three days post-operation. The MRI results revealed that at 12 and 24 months after treatment, the necrotic volume of the femoral heads was significantly reduced. No obvious abnormalities were observed. Taken together, these data indicate that intra-arterially infused hUC-MSCs migrate into the necrotic field of femoral heads and differentiate into osteoblasts, thus improving the necrosis of femoral heads. This finding suggested that intra-arterial infusion of hUC-MSCs MSCs is a feasible and relatively safe method for the treatment of femoral head necrosis.

Gelatin-Based Hydrogels for Organ 3D Bioprinting

Three-dimensional (3D) bioprinting is a family of enabling technologies that can be used to manufacture human organs with predefined hierarchical structures, material constituents and physiological functions. The main objective of these technologies is to produce high-throughput and/or customized organ substitutes (or bioartificial organs) with heterogeneous cell types or stem cells along with other biomaterials that are able to repair, replace or restore the defect/failure counterparts. Gelatin-based hydrogels, such as gelatin/fibrinogen, gelatin/hyaluronan and gelatin/alginate/fibrinogen, have unique features in organ 3D bioprinting technologies. This article is an overview of the intrinsic/extrinsic properties of the gelatin-based hydrogels in organ 3D bioprinting areas with advanced technologies, theories and principles. The state of the art of the physical/chemical crosslinking methods of the gelatin-based hydrogels being used to overcome the weak mechanical properties is highlighted. A multicellular model made from adipose-derived stem cell proliferation and differentiation in the predefined 3D constructs is emphasized. Multi-nozzle extrusion-based organ 3D bioprinting technologies have the distinguished potential to eventually manufacture implantable bioartificial organs for purposes such as customized organ restoration, high-throughput drug screening and metabolic syndrome model establishment.

Clinical observation of umbilical cord mesenchymal stem cell treatment of severe idiopathic pulmonary fibrosis: A case report

Idiopathic pulmonary fibrosis (IPF) is a degenerative disease characterized by fibrosis. Cell therapy has been considered within the therapeutic options for IPF. In this study, we explored the potential benefits of human umbilical cord-derived mesenchymal stem cell (HUC-MSC) intravenous infusion in the management of IPF. We describe a case of a 56-year-old man with IPF who was receiving long-term oxygen therapy (LTOT). The patient underwent HUC-MSC intravenous infusion and was followed up for 12 months. Clinical and motor tests, as well as questionnaires assessing quality of life, were performed prior to and following the transplantation. At the end of 12 months, a relevant reduction of LTOT requirement was registered; improvements in terms of physical performance, quality of life, and respiratory parameters were observed in our patient. In conclusion, a program of HUC-MSC intravenous infusion appears to be beneficial to patients with IPF and may be considered as an additional therapeutic option.

Cell therapy for cerebral hemorrhage: Five year follow-up report

The aim of the study was to examine treatment of cerebral hemorrhages with bone-marrow or human umbilical cord-derived mesenchymal stem cells (BMSCs or Hu-MSCs) and conventional surgical approaches, and determine and compare the effectiveness, feasibility, safety and reproducibility of each method. A retrospective analysis was performed on a cohort of cell-treated cerebral hemorrhage patients from October 1, 2007 to October 1, 2009. A total of 24 patients, all of whom received conventional surgical treatment, were classified as follows: i) The control group consisted of 8 patients who received only hematoma removal surgery, ii) the autologous group consisted of 7 patients who received additional autologous bone marrow mononuclear cell transplantation, and iii) the allograft group consisted of 9 patients who received additional umbilical cord mononuclear cell transplantation. After conventional hematoma removal surgery and X-ray supervision within 24 h and at 7 days, neurological disability and function tests were completed 3, 6, 12, 36 and 60 months later. The T-cell marker plasma levels were analyzed after 60 months. The results showed that, at approximately 3.5 months after graft the hematomas in all the groups were completely reabsorbed as observed on computed tomography scans. However, the functional outcomes in the cell-transplanted groups were better than in the control group after 5 years. While the National Institutes of Health Stroke Scale, modified Rankin score and modified Barthel index scores were simliar in the cell-transplanted groups, patients in the allograft group had better outcomes than those in the autologous graft group starting at 3 months and until the end of the follow-up period. The serum levels of T-cell markers CD4, CD56 and human leukocyte antigen-DR in the allograft group showed no signs of immunogenic graft complications and there were no significant differences in T-cell subtypes among the patient groups. The results of the present study suggest that, treatment of cerebral hemorrhage patients can be safely and effectively accomplished using Hu-MSC grafting and larger clinical trials should be considered in the future.

Functional characterization of human umbilical cord-derived mesenchymal stem cells for treatment of systolic heart failure

Congestive heart failure (HF) is a leading cause of morbidity and mortality worldwide. Although advances in medical therapy, mechanical support and heart transplantation have been made, almost half of all patients with HF succumb to the disease within five years of the initial diagnosis. Therefore, treatment methods need to be identified to restore the structure and function of cardiac muscle. Three patients with HF caused by ischemic cardiomyopathy received human umbilical cord-derived mesenchymal stem cell (HUC-MSC) intravenous infusion were included in the present study. Two patients demonstrated a 65.1% increase in left ventricular ejection fraction (LVEF) at the end of 3 months, which was maintained increasing 47.8% at the end of 12 months post-HUC-MSC intravenous infusion. LVEF of patient 1 decreased slowly in the observation period. This LVEF improvement was associated with significant improvements in the clinical parameters of the New York Heart Association class, and six-minute walk test in the coupled time. The third patient showed significant improvement in the six-minute walk test at the end of 12 months, while the other parameters did not change obviously. There were no severe adverse events during and post-HUC-MSC transplantation. During follow-up, no other immunosuppressive drugs were used. In conclusion, HUC-MSC therapy is a reasonable salvage treatment in HF. Future large-scale randomized clinical trials are likely to be designed to elucidate the efficacy of the HUC-MSC transplantation therapy on HF.

Intravenous infusion umbilical cord-derived mesenchymal stem cell in primary immune thrombocytopenia: A two-year follow-up

Four patients with chronic refractory immune thrombocytopenic purpura (ITP) received human umbilical cord-derived mesenchymal stem cells (hUC-MSCs). The hUC-MSC dose was 5×107 to 1×108. Complete remission (CR) was achieved in three patients in 12 months and one patient in 24 months. Three patients received the second hUC-MSC transplantation with the same dose. The median time between hUC-MSC transplantation and response was 12.5 days (range, 7–16). There were no severe adverse events during and post hUC-MSC transplantation. During follow-up (median, 17 months; range, 13–24) no other immunosuppressive drugs were used post-first hUC-MSCs transplantation. In conclusion, hUC-MSC transplantation is a reasonable salvage treatment in chronic refractory ITP. Prospective randomized large-scale clinical trials are needed to further elucidate the efficacy of hUC-MSCs transplantation therapy on ITP.

Sodium orthovanadate induces the apoptosis of SH-SY5Y cells by inhibiting PIWIL2

PIWIs have been shown to be abnormally expressed in a variety of cancers and may be important in the maintenance and invasion of cancer cells. The high expression of PIWIL2 contributed to the resistance effect of cisplatin in colon cancer cells, and the knockout of the PIWIL2 gene reduced the aggressive nature and malignant degree of colon cancer cells. Sodium orthovanadate (SOV) is a vanadium compound, and exhibited antineoplastic activity in certain types of human cancer cells, including lung, kidney and prostate cancer cells. However, its effects in human neuroblastoma (NB) cells have not yet been reported. The objective of this study was to investigate the effect of SOV on the apoptosis of NB cells and to explore how PIWIL2 is involved in the mechanism underlying this effect. In the present study, SH‑SY5Y cells were treated with SOV and the optimal concentration was determined for further assays. Cell apoptosis, cell count, viability, the cell cycle, and the expression of PIWIL2 mRNA and protein were then determined. The results showed that SOV could induce cell apoptosis, reduce the percentage of viable cells, induce accumulation of SH‑SY5Y cells at the G2/M and S phase of the cell cycle, and inhibit the expression of PIWIL2 and Bcl‑2 mRNA and protein. The results suggested that the underlying mechanisms may be, at least in part, due to SOV inhibiting the expression of PIWIL2. These findings demonstrated the effect of SOV and supported its further evaluation as a treatment for human NB.

Modulation of Immune-Inflammatory Responses in Abdominal Aortic Aneurysm: Emerging Molecular Targets

Abdominal aortic aneurysm (AAA), a deadly vascular disease in human, is a chronic degenerative process of the abdominal aorta. In this process, inflammatory responses and immune system work efficiently by inflammatory cell attraction, proinflammatory factor secretion and subsequently MMP upregulation. Previous studies have demonstrated various inflammatory cell types in AAA of human and animals. The majority of cells, such as macrophages, CD4+ T cells, and B cells, play an important role in the diseased aortic wall through phenotypic modulation. Furthermore, immunoglobulins also greatly affect the functions and differentiation of immune cells in AAA. Recent evidence suggests that innate immune system, especially Toll-like receptors, chemokine receptors, and complements are involved in the progression of AAAs. We discussed the innate immune system, inflammatory cells, immunoglobulins, immune-mediated mechanisms, and key cytokines in the pathogenesis of AAA and particularly emphasis on a further trend and application of these interventions. This current understanding may offer new insights into the role of inflammation and immune response in AAA.

Curcumin attenuates the development of thoracic aortic aneurysm by inhibiting VEGF expression and inflammation

Angiogenesis is an important process in the pathogenesis of aortic aneurysm. The aim of the present study was to investigate the angiogenic balance and the expression of vascular endothelial growth factor (VEGF) in thoracic aortic aneurysm (TAA). A previous study demonstrated that curcumin exerts a marked effect on aortic aneurysm development. Therefore, the present study determined whether curcumin is able to modulate angiogenesis and inflammatory signaling in TAA by collecting human TAA samples and establishing a rat TAA model using periaortic application of CaCl2. TAA rats were treated with curcumin or 1% carboxymethyl cellulose and were sacrificed 4 weeks after the operation. All tissue specimens were analyzed by histological staining, immunohistochemistry and western blotting. Human TAA samples exhibited increased neovascularization and VEGF expression when compared with normal aortic walls. In rat tissues, treatment with curcumin resulted in reduced aneurysm size and restored the wavy structure of the elastic lamellae. In addition, curcumin decreased neovascularization and the expression of VEGF. Immunohistochemical analysis indicated that curcumin significantly inhibited infiltration of cluster of differentiation (CD)3+ and CD68+ cells in TAA. Furthermore, curcumin treatment decreased the expression of vascular cell adhesion molecule-1, intracellular adhesion molecule-1, monocyte chemoattractant protein-1 and tumor necrosis factor-α. Collectively, the results demonstrated that angiogenesis and VEGF expression were increased in the aortic wall in TAA. Treatment with curcumin inhibited TAA development in rats, which was associated with suppression of VEGF expression. In addition, curcumin attenuated inflammatory cell infiltration and suppressed inflammatory factor expression in the periaortic tissue of TAA.