Controlled release of hydrogen by implantation of magnesium induces P53-mediated tumor cells apoptosis.

Hydrogen has been used to suppress tumor growth with considerable efficacy. Inhalation of hydrogen gas and oral ingestion of hydrogen-rich saline are two common systemic routes of hydrogen administration. We have developed a topical delivery method of hydrogen at targeted sites through the degradation of magnesium-based biomaterials. However, the underlying mechanism of hydrogen's role in cancer treatment remains ambiguous. Here, we investigate the mechanism of tumor cell apoptosis triggered by the hydrogen released from magnesium-based biomaterials. We find that the localized release of hydrogen increases the expression level of P53 tumor suppressor proteins, as demonstrated by the in vitro RNA sequencing and protein expression analysis. Then, the P53 proteins disrupt the membrane potential of mitochondria, activate autophagy, suppress the reactive oxygen species in cancer cells, and finally result in tumor suppression. The anti-tumor efficacy of magnesium-based biomaterials is further validated in vivo by inserting magnesium wire into the subcutaneous tumor in a mouse. We also discovered that the minimal hydrogen concentration from magnesium wires to trigger substantial tumor apoptosis is 91.2 µL/mm3 per day, which is much lower than that required for hydrogen inhalation. Taken together, these findings reveal the release of H2 from magnesium-based biomaterial exerts its anti-tumoral activity by activating the P53-mediated lysosome-mitochondria apoptosis signaling pathway, which strengthens the therapeutic potential of this biomaterial as localized anti-tumor treatment.

Multifunctional Magnesium Anastomosis Staples for Wound Closure and Inhibition of Tumor Recurrence and Metastasis.

Biodegradable magnesium (Mg) implants spontaneously releasing therapeutic agents against tumors are an intriguing therapeutic approach for both tissue repair and tumor treatment. Anastomotic staples are extensively used for wound closure after surgical resection in patients with colorectal tumors. However, the safety of Mg anastomosis implants for intestinal closure and the effect of tumor suppression remain elusive. Here, we used a high-purity Mg staple to study these issues. Based on the results, we found that it has the potential to heal wounds produced after colorectal tumor resection while inhibiting relapse of residual tumor cells in vitro and in vivo. After implantation of Mg staples for 7 weeks in rabbits, the intestinal wound gradually healed with no adverse effects such as leakage or inflammation. Furthermore, the implanted Mg staples inhibit the growth of colorectal tumor cells and block migration to normal organs because of the increased concentration of Mg ions and released hydrogen. Such an antitumor effect is further confirmed by the in vitro cell experiments. Mg significantly induces apoptosis of tumor cells as well as inhibits cell growth and migration. Our work presents a feasible therapeutic opinion to design Mg anastomotic staples to perform wound healing and simultaneously release tumor suppressor elements in vivo to decrease the risk of tumor recurrence and metastasis.

Degradable magnesium implants inhibit gallbladder cancer.

Gallbladder cancer can be difficult to detect in its early stages and is prone to metastasize, causing bile duct obstruction, which is usually treated by stent implantation in clinic. However, the commonly used biliary stents are non-degradable, which not only prone to secondary blockage, but also need to be removed by secondary surgery. Biodegradable magnesium (Mg) is expected to one of the promising candidates for degradable biliary stents due to its excellent physicochemical property and biocompatibility. In this work, we studied the influence of high-purity Mg wires on gallbladder cancer through in vitro and in vivo experiments and revealed that the degradation products of Mg could significantly inhibit the growth of gallbladder cancer cells and promote their apoptosis. Our findings indicate that Mg biliary stent possesses the function of draining bile and treating gallbladder cancer, suggesting that Mg has good application prospects in biliary surgery. STATEMENT OF SIGNIFICANCE: Current research and development of biomedical magnesium are mainly concentrated in the cardiovascular and orthopedics field. Degradable magnesium bile duct stents have great application prospects in the treatment of bile duct blockage caused by bile duct-related cancers. At present, the effect of magnesium implants on gallbladder cancer is not clear. Our work verified the effectiveness of magnesium wire implants in inhibiting gallbladder cancer through in vivo and in vitro experiments, and studied the effect of magnesium degradation products on gallbladder cancer cells from the perspective of cell proliferation, apoptosis and cycle. This study provided new understanding for the application of magnesium in biliary surgery.

A novel lean alloy of biodegradable Mg-2Zn with nanograins.

Lean alloy (low alloyed) is beneficial for long-term sustainable development of metal materials. Creating a nanocrystalline microstructure is a desirable approach to improve biodegradability and mechanical properties of lean biomedical Mg alloy, but it is nearly impossible to realize. In the present study, the bulk nanocrystalline Mg alloy (average grain size: ~70 nm) was successfully obtained by hot rolling process of a lean Mg-2wt.%Zn (Z2) alloy and both high strength ((223 MPa (YS) and 260 MPa (UTS)) and good corrosion resistance (corrosion rate in vivo: 0.2 mm/year) could be achieved. The microstructure evolution during the rolling process was analyzed and discussed. Several factors including large strain, fine grains, strong basal texture, high temperature and Zn segregation conjointly provided the possibility for the activation of pyramidal slip to produce nanocrystals. This finding could provide a new development direction and field of application for lean biomedical Mg alloys.

Biodegradable Mg Implants Suppress the Growth of Ovarian Tumor.

The common treatment of epithelial ovarian cancer is aggressive surgery followed by platinum-based cytotoxic chemotherapy. However, residual tumor cells are resistant to chemotherapeutic drugs during postoperative recurrence. The treatment of ovarian cancer requires breakthroughs and advances. In recent years, magnesium alloy has been widely developed as a new biodegradable material because of its great potential in the field of medical devices. From the degradation products of magnesium, biodegradable magnesium implants have great potential in antitumor. According to the disease characteristics of ovarian cancer, we choose it to study the antitumor characteristics of biodegradable magnesium. We tested the anti-ovarian tumor properties of Mg through both in vivo and in vitro experiments. According to the optical in vivo imaging and relative tumor volume statistics of mice, high-purity Mg wires significantly inhibited the growth of SKOV3 cells in vivo. We find that the degradation products of Mg, Mg2+, and H2 significantly inhibit the growth of SKOV3 cells and promote their apoptosis. Our study suggests a good promise for the treatment of ovarian cancer.

Translational status of biomedical Mg devices in China.

Magnesium (Mg) and its alloys as temporary medical implants with biodegradable and properly mechanical properties have been investigated for a long time. There are already three kinds of biodegradable Mg implants which are approved by Conformite Europeene (CE) or Korea Food and Drug Administration (KFDA), but not China Food and Drug Administration (CFDA, now it is National Medical Products Administration, NMPA). As we know, Chinese researchers, surgeons, and entrepreneurs have tried a lot to research and develop biodegradable Mg implants which might become other new approved implants for clinical applications. So in this review, we present the representative Mg implants of three categories, orthopedic implants, surgical implants, and intervention implants and provide an overview of current achievement in China from academic publications and Chinese patents. We would like to provide a systematic way to translate Mg and its alloy implants from experiment designs to clinical products.