A novel triptolide analog downregulates NF-κB and induces mitochondrial apoptosis pathways in human pancreatic cancer.

Pancreatic cancer is the seventh leading cause of cancer-related death worldwide, and despite advancements in disease management, the 5 -year survival rate stands at only 12%. Triptolides have potent anti-tumor activity against different types of cancers, including pancreatic cancer, however poor solubility and toxicity limit their translation into clinical use. We synthesized a novel pro-drug of triptolide, (E)-19-[(1'-benzoyloxy-1'-phenyl)-methylidene]-Triptolide (CK21), which was formulated into an emulsion for in vitro and in vivo testing in rats and mice, and used human pancreatic cancer cell lines and patient-derived pancreatic tumor organoids. A time-course transcriptomic profiling of tumor organoids treated with CK21 in vitro was conducted to define its mechanism of action, as well as transcriptomic profiling at a single time point post-CK21 administration in vivo. Intravenous administration of emulsified CK21 resulted in the stable release of triptolide, and potent anti-proliferative effects on human pancreatic cancer cell lines and patient-derived pancreatic tumor organoids in vitro, and with minimal toxicity in vivo. Time course transcriptomic profiling of tumor organoids treated with CK21 in vitro revealed <10 differentially expressed genes (DEGs) at 3 hr and ~8,000 DEGs at 12 hr. Overall inhibition of general RNA transcription was observed, and Ingenuity pathway analysis together with functional cellular assays confirmed inhibition of the NF-κB pathway, increased oxidative phosphorylation and mitochondrial dysfunction, leading ultimately to increased reactive oxygen species (ROS) production, reduced B-cell-lymphoma protein 2 (BCL2) expression, and mitochondrial-mediated tumor cell apoptosis. Thus, CK21 is a novel pro-drug of triptolide that exerts potent anti-proliferative effects on human pancreatic tumors by inhibiting the NF-κB pathway, leading ultimately to mitochondrial-mediated tumor cell apoptosis.

Pancreatic cancer is a major cause of cancer-related deaths worldwide, with only 12% of patients surviving for five years after diagnosis. Individuals generally experience few symptoms of the disease in the early stages and are often diagnosed once the cancer has already spread to other parts of the body. By this point, options for treatment are limited. A molecule known as triptolide has been shown to kill breast, lung, pancreatic and other types of cancer cells. However, triptolide is toxic to humans and other animals, making it unsuitable for use in patients. One way to make drugs safer without compromising their beneficial effects is to modify their molecular structure. By formulating triptolide into an emulsion ­ a mixture of liquids allowing it to dissolve ­ Tian, Zhang et al. synthesized a new analogue called CK21. Experiments showed that CK21 inhibited the growth of human pancreatic cancer cells grown in a laboratory including cells grown in artificial organs similar to the pancreas, known as pancreatic tumor organoids. Furthermore, CK21 killed large tumors in mice pancreases with very few side effects, suggesting the structural modification of triptolide increased safety of the drug. To better understand how CK21 works, Tian, Zhang et al. examined the genes that were induced in the pancreatic tumor organoids at various time points after treatment with the drug. This revealed that CK21 switched off genes involved in the NF-κB cell signaling pathway, which regulates how cells grow and respond to stress. In turn, it triggered programmed cell death, killing the tumor cells in a controlled manner. The findings suggest that CK21 could be a promising candidate for treating pancreatic cancer. In the future, clinical trials will be required to establish whether CK21 is a safe and effective therapy for humans.

Lung cDC1 and cDC2 dendritic cells priming naive CD8+ T cells in situ prior to migration to draining lymph nodes.

The current paradigm indicates that naive T cells are primed in secondary lymphoid organs. Here, we present evidence that intranasal administration of peptide antigens appended to nanofibers primes naive CD8+ T cells in the lung independently and prior to priming in the draining mediastinal lymph node (MLN). Notably, comparable accumulation and transcriptomic responses of CD8+ T cells in lung and MLN are observed in both Batf3KO and wild-type (WT) mice, indicating that, while cDC1 dendritic cells (DCs) are the major subset for cross-presentation, cDC2 DCs alone are capable of cross-priming CD8+ T cells both in the lung and draining MLN. Transcription analyses reveal distinct transcriptional responses in lung cDC1 and cDC2 to intranasal nanofiber immunization. However, both DC subsets acquire shared transcriptional responses upon migration into the lymph node, thus uncovering a stepwise activation process of cDC1 and cDC2 toward their ability to cross-prime effector and functional memory CD8+ T cell responses.

Identification of HPV16 E1 and E2-specific T cells in the oropharyngeal cancer tumor microenvironment.

BACKGROUND: High-risk human papillomavirus (HPV) is a primary cause of an increasing number of oropharyngeal squamous cell carcinomas (OPSCCs). The viral etiology of these cancers provides the opportunity for antigen-directed therapies that are restricted in scope compared with cancers without viral components. However, specific virally-encoded epitopes and their corresponding immune responses are not fully defined. METHODS: To understand the OPSCC immune landscape, we conducted a comprehensive single-cell analysis of HPV16+ and HPV33+ primary tumors and metastatic lymph nodes. We used single-cell analysis with encoded peptide-human leukocyte antigen (HLA) tetramers to analyze HPV16+ and HPV33+ OPSCC tumors, characterizing the ex vivo cellular responses to HPV-derived antigens presented in major Class I and Class II HLA alleles. RESULTS: We identified robust cytotoxic T-cell responses to HPV16 proteins E1 and E2 that were shared across multiple patients, particularly in HLA-A*01:01 and HLA-B*08:01. Responses to E2 were associated with loss of E2 expression in at least one tumor, indicating the functional capacity of these E2-recognizing T cells and many of these interactions validated in a functional assay. Conversely, cellular responses to E6 and E7 were limited in quantity and cytotoxic capacity, and tumor E6 and E7 expression persisted. CONCLUSIONS: These data highlight antigenicity beyond HPV16 E6 and E7 and nominate candidates for antigen-directed therapies.

Adjuvant-free nanofiber vaccine induces in situ lung dendritic cell activation and TH17 responses.

The current paradigm that subunit vaccines require adjuvants to optimally activate innate immunity implies that increased vaccine reactogenicity will invariably be linked to improved immunogenicity. Countering this paradigm, nanoparticulate vaccines have been reported to act as delivery systems for vaccine antigens and induce immunity without the need for exogenous adjuvants or local inflammation; however, the mechanisms underlying the immunogenicity of nanoparticle vaccines are incompletely identified. Here, we show that antigens displayed on self-assembling nanofiber scaffolds and delivered intranasally are presented by CD103+ and CD11b+ lung dendritic cells that up-regulate CD80 and migrate into the draining lymph node (LN). This was accompanied by a nearly exclusive priming and accumulation of antigen-specific TH17 cells occurring independently in both LN and lung. Thus, self-assembling peptide nanofiber vaccines may represent a novel, needle- and adjuvant-free means of eliciting protective immunity against fungal and bacterial infections at skin and mucosal barrier surfaces.

Inhibition of protective immunity against Staphylococcus aureus infection by MHC-restricted immunodominance is overcome by vaccination.

Recurrent Staphylococcus aureus infections are common, despite robust immune responses. S. aureus infection elicited protective antibody and T cell responses in mice that expressed the Major Histocompatibility Complex (MHC) of the H-2d haplotype, but not H-2b, demonstrating that host genetics drives individual variability. Vaccination with a-toxin or leukotoxin E (LukE) elicited similar antibody and T cell responses in mice expressing H-2d or H-2b, but vaccine-elicited responses were inhibited by concomitant infection in H-2d-expressing mice. These findings suggested that competitive binding of microbial peptides to host MHC proteins determines the specificity of the immunodominant response, which was confirmed using LukE-derived peptide-MHC tetramers. A vaccine that elicited T cell and antibody responses protected mice that expressed H-2d or H-2b, demonstrating that vaccination can overcome MHC-restricted immunodominance. Together, these results define how host genetics determine whether immunity elicted by S. aureus is protective and provide a mechanistic roadmap for future vaccine design.

Degradation behaviors and cytocompatibility of Mg/ß-tricalcium phosphate composites produced by spark plasma sintering.

Magnesium (Mg)-based materials have shown great potentials for bioresorbable implant applications. Previous studies showed that Mg with 10 and 20 vol % ß-tricalcium phosphate (ß-TCP) composites produced by spark plasma sintering, improved mechanical properties when compared with pure Mg. The objectives of this study were to evaluate the degradation behaviors of Mg/10% ß-TCP and Mg/20% ß-TCP composites in revised stimulated body fluid (rSBF), and to determine their cytocompatibility with bone marrow derived mesenchymal stem cells (BMSCs) using the direct culture method. During the 11 days of immersion in rSBF, Mg/ß-TCP composites showed different degradation behaviors at different immersion periods, that is, the initial stage (0-1 hr), the mid-term stage (1 hr to 2 days), and the long-term stage (2-11 days). The counter effects of mass loss due to microgalvanic corrosion and mass gain due to deposition of Ca-P containing layers resulted in slower Mg2+ ion release for Mg/20% ß-TCP than Mg/10% ß-TCP in the mid-term, but eventually 16% mass loss for Mg/20% ß-TCP and 10% mass loss for Mg/10% ß-TCP after 11 days of immersion. The in vitro studies with BMSCs showed the highest cell adhesion density (i.e., 68% of seeding density) on the plate surrounding the Mg/10% ß-TCP sample, that is, under the indirect contact condition of direct culture. The ß-TCP showed a positive effect on direct adhesion of BMSCs on the surface of Mg/ß-TCP composites. This study elucidated the degradation behaviors and the cytocompatibility of Mg/ß-TCP composites in vitro; and, further studies on Mg/ceramic composites are needed to determine their potential for clinical applications. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 2238-2253, 2019.

Nano-to-Submicron Hydroxyapatite Coatings for Magnesium-based Bioresorbable Implants - Deposition, Characterization, Degradation, Mechanical Properties, and Cytocompatibility.

Magnesium (Mg) and its alloys have shown attractive biocompatibility and mechanical strength for medical applications, but low corrosion resistance of Mg in physiological environment limits its broad clinical translation. Hydroxyapatite (HA) nanoparticles (nHA) are promising coating materials for decreasing degradation rates and prolonging mechanical strength of Mg-based implants while enhancing bone healing due to their osteoconductivity and osteoinductivity. Conformal HA coatings with nano-to-submicron structures, namely nHA and mHA coatings, were deposited successfully on Mg plates and rods using a transonic particle acceleration (TPA) process under two different conditions, characterized, and investigated for their effects on Mg degradation in vitro. The nHA and mHA coatings enhanced corrosion resistance of Mg and retained 86-90% of ultimate compressive strength after in vitro immersion in rSBF for 6 weeks, much greater than non-coated Mg that only retained 66% of strength. Mg-based rods with or without coatings showed slower degradation than the respective Mg-based plates in rSBF after 6 weeks, likely because of the greater surface-to-volume ratio of Mg plates than Mg rods. This indicates that Mg-based plate and screw devices may undergo different degradation even when they have the same coatings and are implanted at the same or similar anatomical locations. Therefore, in addition to locations of implantation, the geometry, dimension, surface area, volume, and mass of Mg-based implants and devices should be carefully considered in their design and processing to ensure that they not only provide adequate structural and mechanical stability for bone fixation, but also support the functions of bone cells, as clinically required for craniomaxillofacial (CMF) and orthopedic implants. When the nHA and mHA coated Mg and non-coated Mg plates were cultured with bone marrow derived mesenchymal stem cells (BMSCs) using the in vitro direct culture method, greater cell adhesion densities were observed under indirect contact conditions than that under direct contact conditions for the nHA and mHA coated Mg. In comparison with non-coated Mg, the nHA and mHA coated Mg reduced BMSC adhesion densities directly on the surface, but increased the average BMSC adhesion densities under indirect contact. Further long-term studies in vitro and in vivo are necessary to elucidate the effects of nHA and mHA coatings on cell functions and tissue healing.

Responses of human urothelial cells to magnesium-zinc-strontium alloys and associated insoluble degradation products for urological stent applications.

Current urological devices such as ureteral stents and catheters still face serious problems, such as encrustation and biofilm formation. Magnesium (Mg) and its alloys showed great potentials as an alternative material for urological devices, due to their excellent biodegradability and antibacterial property. In this study, a serial of four promising Mg alloys which contain zinc (Zn) and strontium (Sr), i.e., Mg-4Zn-xSr (ZSr41) alloys, were investigated in vitro for potential ureteral stent application. Specifically, these four alloys have 4 wt% Zn in all and 0.15 wt% Sr in ZSr41_A, 0.5 wt% Sr in ZSr41_B, 1.0 wt% Sr in ZSr41_C and 1.5 wt% Sr in ZSr41_D. The cytocompatibility and degradation behaviors of Mg-4Zn-xSr alloys were studied by culturing with human urothelial cells (HUCs) for 24 h and 48 h using exposure culture method. ZSr41_B showed a better cytocompatibility with HUCs among all the Mg-4Zn-xSr alloys in both 24-hour and 48-hour cultures. Moreover, the cytocompatibility of insoluble degradation products of Mg, i.e., MgO and Mg(OH)2, was also investigated by culturing different concentrations of MgO and Mg(OH)2 nanoparticles with HUCs for 24 h and 48 h. The concentration of MgO and Mg(OH)2 particles at 0.5 mg/mL and above, showed a significant decrease of cell density and cell size after 24-hour and 48-hour cultures. The concentration of MgO and Mg(OH)2 at 1.0 mg/mL and above, showed no viable cells after 24-hour culture. Collectively, it is recommended to further reduce the degradation rates of Mg alloys in order to control possible side effects of the soluble and insoluble degradation products and to take the benefits of Mg-based biodegradable ureteral stents toward the future clinical translation.

Electrophoretic Deposition of Magnesium Oxide Nanoparticles on Magnesium: Processing Parameters, Microstructures, Degradation, and Cytocompatibility.

Magnesium (Mg) and its alloys are a class of promising materials for biodegradable orthopedic and craniomaxillofacial implants; however, rapid release of hydrogen gas remains a key challenge for clinical translation. This study reported the optimal parameters of electrophoretic deposition (EPD), at which magnesium oxide nanoparticles (nMgO) could be deposited onto Mg substrates with homogeneous surface morphology and elemental distribution. The results showed that the distribution and uniformity of the nMgO coatings on Mg improved when the nMgO concentration in ethanol increased and the time of applied voltage decreased. The nMgO-coated Mg showed a homogeneous surface and distinct degradation mode during the 9-day immersion studies in revised simulated body fluid (r-SBF) and Dulbecco's modified Eagle's medium (DMEM), when compared with the noncoated Mg controls. The nMgO coating initially mitigated hydrogen gas formation. The degradation layer on nMgO-coated Mg was thicker than the noncoated Mg and enriched with Ca and P that are favorable for skeletal implant applications. In the direct culture study with bone marrow derived mesenchymal stem cells (BMSCs) in vitro, the cell adhesion density and morphology were not affected by the solubilized degradation products released by the nMgO-coated Mg under indirect contact. However, at the cell-biomaterial interface, the cell spreading decreased under direct contact, possibly because of the continuous dynamic degradation of the samples. The electrophoretically deposited nMgO coatings on Mg-based medical implants should be further studied to improve the coating-substrate and cell-material interfaces for clinical applications.

In vitro evaluation of MgSr and MgCaSr alloys via direct culture with bone marrow derived mesenchymal stem cells.

Magnesium (Mg) and its alloys have been widely investigated as the most promising biodegradable metals to replace conventional non-degradable metals for temporary medical implant applications. New Mg alloys have been developed for medical applications in recent years; and the concept of alloying Mg with less-toxic elements have aroused tremendous interests due to the promise to address the problems associated with rapid degradation of Mg without compromising its cytocompatibility and biocompatibility. Of particular interests for orthopedic/spinal implant applications are the additions of calcium (Ca) and strontium (Sr) into Mg matrix because of their beneficial properties for bone regeneration. In this study, degradation and cytocompatibility of four binary MgSr alloys (Mg-xSr, x = 0.2, 0.5, 1 and 2 wt%) and four ternary MgCaSr alloys (Mg-1Ca-xSr, x = 0.2, 0.5, 1 and 2 wt%) were investigated and compared via direct culture with bone marrow-derived mesenchymal stem cells (BMSCs). The influence of the alloy composition on the degradation rates were studied and compared. Moreover, the cellular responses to the binary MgSr alloys and the ternary MgCaSr alloys were comparatively evaluated; and the critical factors influencing BMSC behaviors were discussed. This study screened the degradability and in vitro cytocompatibility of the binary MgSr alloys and the ternary MgCaSr alloys. Mg-1Sr, Mg-1Ca-0.5Sr and Mg-1Ca-1Sr alloys are recommended for further in vivo studies toward clinical translation due to their best overall performances in terms of degradation and cytocompatibility among all the alloys studied in the present work. STATEMENT OF SIGNIFICANCE: Traditional Mg alloys with slower degradation often contain aluminum or rare earth elements as alloying components, which raised safety and regulatory concerns. To circumvent unsafe elements, nutrient elements such as calcium (Ca) and strontium (Sr) were selected to create Mg-Sr binary alloys and Mg-Ca-Sr ternary alloys to improve the safety and biocompatibility of bioresorbable Mg alloys for medical implant applications. In this study, in vitro degradation and cellular responses to four binary Mg-xSr alloys and four ternary Mg-1Ca-xSr alloys with increasing Sr content (up to 2 wt%) were evaluated in direct culture with bone marrow derived mesenchymal stem cells (BMSCs). The roles of Sr and Ca in tuning the alloy microstructure, degradation behaviors, and BMSC responses were collectively compared in the BMSC direct culture system for the first time. The most promising alloys were identified and recommended for further in vivo studies toward clinical translation.

Development of a Novel Loading Device for Studying Magnesium Degradation under Compressive Load for Implant Applications.

Medical implants play a key role in treating bone fractures. Permanent implants are currently used for immobilization of fractures and bearing physiological loads during bone healing. After bone has healed, these implants, if not removed, often cause complications in the long run; and secondary surgeries for removing them pose additional discomfort and expenses for patients. Magnesium (Mg)-based bioresorbable implants, can potentially eliminate the need for additional surgeries by degrading safely over time in the human body. When studying the degradation behaviors of Mg-based implants in vitro, it is important to simulate physiological conditions in vivo closely, including loading. Considering that implants often carry physiological loads in vivo and mechanical stresses affect the degradation rate of Mg, a novel loading device was designed and manufactured for studying Mg degradation under load over a long period of time in a simulated body fluid in vitro. Degradation of Mg rods were investigated by immersing in a revised simulated body fluid (rSBF) for two weeks while a consistent compressive load was applied using the loading device. The results showed that the loading device provided a consistent load of 500 ± 45 N during the two weeks of immersion. Mg rods showed a significant faster degradation rate under the applied load, as demonstrated by a higher mass loss of the sample, a higher pH increase and Mg2+ ion release in the rSBF.

Electrochemical deposition of conductive polymers onto magnesium microwires for neural electrode applications.

Metals are widely used in electrode design for recording neural activities because of their excellent electrical conductivity and mechanical strength. However, there are still serious problems related to these currently used metallic electrodes, including tissue damage due to the mechanical mismatch between metals and neural tissues, fibrosis, and electrode fouling and encapsulation that lead to the loss of signal and eventual failure. In this study, a biocompatible, biodegradable, and conductive electrode was created. Specifically, pure magnesium (Mg) microwire with a diameter of 127 µm was used as the electrode substrate and the conductive polymer, that is, poly(3,4-ethylenedioxythiophene) (PEDOT), was electrochemically deposited onto Mg microwires to decrease corrosion rate and improve biocompatibility of the electrodes for potential neural electrode applications. Both chronopotentiometry and cyclic voltammetry (CV) methods and the associated parameters for electrochemical deposition of PEDOT onto Mg microwires were investigated, such as deposition current, deposition temperature, voltage, sweep rate, cycle number, and duration. The CV method from -2.0 to 1.25 V for 1 cycle at a cycle duration of 600 s with a sweep rate of 5 mV/s at 65°C led to a consistent, uniform, and complete PEDOT coating on Mg microwires. The surface conditions of Mg microwires also affected the quality of PEDOT coating. The corrosion rate of PEDOT-coated Mg microwire was 0.75 mm/year, much slower than the noncoated Mg microwire that showed a corrosion rate of 1.78 mm/year. The optimal Mg microwires with PEDOT coating could potentially serve as biodegradable electrodes for neural recording and stimulation applications. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1887-1895, 2018.

Comparison Study on Four Biodegradable Polymer Coatings for Controlling Magnesium Degradation and Human Endothelial Cell Adhesion and Spreading.

Magnesium (Mg)-based bioresorbable cardiovascular scaffold (BCS) is a promising alternative to conventional permanent cardiovascular stents, but it faces the challenges of rapid degradation and poor endothelium recovery after device degradation. To address these challenges, we investigated poly(l-lactic acid) (PLLA), poly(lactic-co-glycolic acid) (PLGA) (90:10), PLGA (50:50), and polycaprolactone (PCL) coatings on Mg, respectively, and evaluated their surface and biological properties. Intact polymer coatings with complete coverage on Mg substrate were achieved. The biological performance of the materials was evaluated by culturing with human umbilical vein endothelial cells (HUVECs) in vitro using the direct culture method. The pH of the culture media and Mg2+ and Ca2+ ion concentrations in the media were measured after culture to characterize the degradation rate of the materials in vitro. The results showed that the PLGA (50:50) coating improved the adhesion and spreading of HUVECs the most among the four polymer coatings. Moreover, we found three possible factors that promoted HUVECs directly attached on the surface of PLGA (50:50)-coated Mg: (1) the higher concentration of Mg2+ ions released into culture media with a concentration range of 9-15 mM; (2) the lower Ca2+ ion concentration in culture media at 1.3-1.6 mM; and (3) the favorable surface conditions of PLGA (50:50), when compared with the other sample groups. This in vitro study provided the first evidence that the PLGA (50:50) is a promising coating material for Mg-based biodegradable metals toward potential cardiovascular or neurovascular applications.

Cytocompatibility of Magnesium Alloys with Human Urothelial Cells: A Comparison of Three Culture Methodologies.

Magnesium (Mg) is a biodegradable metallic material, which has shown great potential for medical device applications. In this study, human urothelial cells (HUCs) were cultured in vitro with Mg-based substrates to investigate their cytocompatibility for potential urological device applications. Three different in vitro culture methodologies were explored to mimic different in vivo conditions, in an attempt to establish standard methods of evaluating cytocompatibility of Mg-based biomaterials for urological device applications. Direct culture is a suitable in vitro method when it is important to evaluate direct cell attachment on the biomaterial surfaces. Direct exposure culture is a desirable in vitro method for investigating the response of well-established cells in the body with newly implanted biomaterials. The exposure culture method is appropriate for evaluating cell-biomaterial interactions in the same environment, where they are not in direct contact with each other. The results showed differences in HUC behaviors with the same Mg-based substrates when different culture methods were used. The Mg-based substrates inhibited the HUC viability with direct contact at the cell-material interface in direct culture and direct exposure culture. The faster degrading Mg alloys containing yttrium reduced HUC density in direct culture, direct exposure culture, and exposure culture. The major soluble degradation products of Mg-based materials reduced HUC density significantly when the pH increased to 8.6 and above or the Mg2+ ion concentration reached 10 mM and above. Mg-based biomaterials, especially the slower degrading alloys such as AZ31, should be further studied to determine their potential to be used for bioresorbable urological devices.

Nanostructured calcium phosphate coatings on magnesium alloys: characterization and cytocompatibility with mesenchymal stem cells.

This article reports the deposition and characterization of nanostructured calcium phosphate (nCaP) on magnesium-yttrium alloy substrates and their cytocompatibility with bone marrow derived mesenchymal stem cells (BMSCs). The nCaP coatings were deposited on magnesium and magnesium-yttrium alloy substrates using proprietary transonic particle acceleration process for the dual purposes of modulating substrate degradation and BMSC adhesion. Surface morphology and feature size were analyzed using scanning electron microscopy and quantitative image analysis tools. Surface elemental compositions and phases were analyzed using energy dispersive X-ray spectroscopy and X-ray diffraction, respectively. The deposited nCaP coatings showed a homogeneous particulate surface with the dominant feature size of 200-500 nm in the long axis and 100-300 nm in the short axis, and a Ca/P atomic ratio of 1.5-1.6. Hydroxyapatite was the major phase identified in the nCaP coatings. The modulatory effects of nCaP coatings on the sample degradation and BMSC behaviors were dependent on the substrate composition and surface conditions. The direct culture of BMSCs in vitro indicated that multiple factors, including surface composition and topography, and the degradation-induced changes in media composition, influenced cell adhesion directly on the sample surface, and indirect adhesion surrounding the sample in the same culture. The alkaline pH, the indicator of Mg degradation, played a role in BMSC adhesion and morphology, but not the sole factor. Additional studies are necessary to elucidate BMSC responses to each contributing factor.

Electrophoretic deposition and characterization of nanocomposites and nanoparticles on magnesium substrates.

This study introduces a triphasic design of biodegradable materials composed of nanophase hydroxyapatite (nHA), poly(lactic-co-glycolic acid) (PLGA), and magnesium (Mg) substrates for musculoskeletal implant applications. Specifically, nHA_PLGA composites and nHA nanoparticles were synthesized, deposited on three-dimensional Mg substrates using electrophoretic deposition (EPD), and characterized. The three components involved, that is, nHA, PLGA, and Mg are all biodegradable in the human body, thus promising for biodegradable implant and device applications. Mg and its alloys are attractive for musculoskeletal implant applications due to their comparable modulus and strength to cortical bone. Controlling the interface of Mg with the biological environment, however, is the key challenge that currently limits this biodegradable metal for broad applications in medical implants. This article particularly focuses on creating nanostructured interface between the biodegradable Mg and surrounding tissue for the dual purposes of (1) mediating the degradation of the Mg-based substrates and (2) potentially enhancing osteointegration. Nanophase hydroxyapatite (nHA) is an excellent candidate as a coating material due to its osteoconductivity, while the polymer phase promotes interfacial adhesion between the nHA and Mg. Moreover, the degradation products of PLGA and Mg neutralize each other. Surface characterization showed successful deposition of nHA_PLGA composite microspheres and nHA nanoparticles on Mg substrates using EPD. Mg substrates coated with nHA_PLGA composites showed greater adhesion strength when compared with nHA coating, and slower corrosion rate than nHA coated Mg and non-coated Mg. The triphasic composites of nHA, PLGA and Mg are promising as the next-generation biodegradable materials for medical applications.