Biomaterials Science Blog

3D Multiscale Fiber Matrices for Bioartificial Livers

07 Mar 2018

The liver is the largest internal organ and gland in the human body and it performs numerous vital functions including metabolism regulation, synthesis, detoxification, excretion, and body homeostasis. Many factors, such as viral hepatitis, drugs, toxins, or cardiac-related hepatic ischemia, can cause liver failure. According to the World Health Organisation (WHO) around 10% of the world’s population is suffering from chronic liver disease. The eventual treatment for chronic liver diseases is liver transplantation; however, an inadequate supply of donors is a major limitation for this therapy. With the large number of patients awaiting a liver transplant, there is urgent need for the development of a temporary liver support system, which could be used until a transplant liver is available, or until the patient’s own liver regains its function. Temporary liver supports can be artificial or bioartificial. Artificial support devices are used for detoxification only, whereas bioartificial support devices are more promising, and have biomaterial and cellular components, allowing for both detoxification and synthetic functions. The aim of this study is to prepare a hollow fiber membrane (HFM) based three-dimension matrix, which is the most crucial part of bioartificial livers, and acts as cell growth promoting material. The microenvironment of the three-dimensional matrix influences the cellular behavior and function, exhibiting proliferation, metabolism and interaction of cells with each other and their environment.

In this study, the authors developed a three-dimensional liver cell (HepG2) compatible bio-matrix which supports the liver cells, allowing them to grow and multiply robustly. The outer surface of indigenously prepared HFM was modified and made accommodating for the growth of the liver cells. Nanofibers of biocompatible compounds including polycaprolactone, chitosan, and gelatin, which mimic the native cell attachment surface, were deposited on the HFMs. The developed material exhibited excellent hemocompatibility with human blood. Minimal induction of inflammatory response and negligible cytotoxicity was observed. Further evaluation of the liver cell functional activity showed that cells exhibited the key characterstics of typical liver cells by secreting urea and albumin in the medium. The specific activity of cytochrome P450 2C9 (detoxifying enzyme) was found to have increased by 2.78-fold. Hence, these results significantly indicate that the three-dimensional fiber matrix developed in this study open up the possibility to use it for the various applications including (1) a membrane material for bio-artificial liver development, (2) cell metabolic studies and (3) drug testing bioreactor.

Three-dimensional multiscale fiber matrices: development and characterization for increased HepG2 functional maintenance for bio-artificial liver application Biomater. Sci., 2018,6, 280-291.

This article is free to read until the 16 April 2018

About the Web/Blog writer:

Dr. Sudip Mukherjee is a Web Writer for Biomaterials Science. He is currently a Postdoctoral Research Associate at the Rice University. His research is involved in the development of advanced nanomaterials for drug/gene delivery in cancer theranostics, immunomodulatory applications & angiogenesis. He published a total of ~30 research articles/patents. He serves as International Advisory Board Member for ‘Materials Research Express‘, IOP Sciences. He is an associate member (AMRSC) of The Royal Society of Chemistry, UK. He serves as reviewer for several international journals like Chem Comm, J Mater Chem A, J Mater Chem B, Journal of Biomedical Nanotechnology, RSC Advances, IOP Nanotechnology etc.

Contact Email: sudip.mukherjee@rice.edu
Twitter: https://twitter.com/sudip_88

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Focus on: Engineered Hydrogels

13 Feb 2018

By Yingfei Xue.

Written by web writer Yingfei Xue

Hydrogels represent one of the most important classes of biomaterials and have been widely used for drug/cell delivery, tissue engineering, and disease models due to their biocompatibility and biodegradability properties. Traditional bulk hydrogels often suffer from drawbacks such as limited injectability, lack of control over morphology, and low cell adherence. Therefore, hydrogels engineered via innovative biomaterial chemistry and biofabrication technologies aim to overcome these obstacles and hold the promise to translate hydrogel based therapy into clinical setting.

This month we focus on three articles published in Biomaterials Science reporting the recent advances in engineered hydrogels as therapeutics, 3D printing platforms, and cell culture systems.

1. Protein-engineered hydrogels enhance the survival of induced pluripotent stem cell-derived endothelial cells for treatment of peripheral arterial disease
Abbygail A. Foster, Ruby E. Dewi, Lei Cai, Luqia Hou, Zachary Strassberg, Cynthia A. Alcazar, Sarah C. Heilshorn and Ngan F. Huang
Biomater. Sci., 2018, Advance Article
DOI: 10.1039/C7BM00883J

Cell therapies via direct cell transplantation often resulted in limited therapeutic effects due to low cell viability and retention. Therefore, the authors utilized the platform technology of injectable shear-thinning hydrogel (termed as SHIELD) to mitigate such problems. SHIELD consists of engineered recombinant protein and polyethylene glycol modified proline-rich peptide domains, and it promoted cell-matrix interaction to improve cell viability and retention. Additionally, SHIELD was further strengthened by thermoresponsive poly(N-isopropylacrylamide). The encapsulation of human induced pluripotent stem cell-derived endothelial cells in SHIELD protected cells from membrane damage caused by injection and augmented cell proliferation under hypoxia. In a rodent model of peripheral arterial disease, cell injection with SHIELD had significantly higher cell retention in vivo and further promoted microvessel formation to relieve ischemic insult when compared to saline control.

2. Applying macromolecular crowding to 3D bioprinting: fabrication of 3D hierarchical porous collagen-based hydrogel constructs
Wei Long Ng, Min Hao Goh, Wai Yee Yeong, May Win Naing
Biomater. Sci., 2018, Advance Article
DOI: 10.1039/C7BM01015J

It has been well recognized that scaffold architecture plays a critical role in determining the cellular behavior. Tradition hydrogels fabricated by freeze drying, solvent casting, and phase separation were often confined to less controllable architectures. Utilizing 3D bioprinting via drop-on-demand (DOD) technique, the authors printed 3D hierarchical porous collagen scaffolds with finely controlled pore size and porosity . In this process, droplets of polyvinylpyrrolidone (PVP) were uniformly printed to facilitate the rapid and homogeneous cross-linking, enhance collagen fibrillogenesis, and tune the collagen architecture in a controlled manner. This printing strategy yielded a cytocompatible construct as demonstrated by a primary human dermal fibroblasts model.

3. Evaluation of RGD functionalization in hybrid hydrogels as 3D neural stem cell culture systems
Emanuele Mauri, Alessandro Sacchetti, Nunzio Vicario, Luca Peruzzotti-Jametti, Filippo Rossi and Stefano Pluchino
Biomater. Sci., 2018, Advance Article
DOI: 10.1039/C7BM01056G

To improve the stem cell based therapy for the repair and regeneration of central nervous system, the authors engineered hydrogels which composed of polyethylene glycol, agarose, and polyacrylic acid with cell-adhesive and cell-recognition Arg-Gly-Asp (RGD) motif. When interfacing with neural stem cells, the RGD modified hydrogels enabled a higher ratio of active proliferating cell population compared to a 2D laminin surface or non-RGD hydrogel throughout the 21 day in vitro culture. Additionally, the examination of conditioned media obtained from the in vitro culture revealed the higher level of nutrients contained in the RGD modified hydrogels group, indicating the superior biocompatibility of RGD modified hydrogel construct.

Read these articles for free until 19 March

About the webwriter

Yingfei Xue is a web writer for Biomaterials Science. Currently, he is a PhD candidate and graduate student researcher in Dr. Shilpa Sant lab at the University of Pittsburgh, USA. His research focus on nano-/micro-technology in novel heart valve therapy. Find him on Twitter: @Phil_Xue or connect with him on ResearchGate.

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Bio-mimicking melanin-manganese nanoparticles for tumor targeting MRI agent

31 Jan 2018

By Sudip Mukherjee.

Good quality MRI contrast agents require profound tumor-targeting ability, well relaxivity, along with rapid clearance properties. In this context, endogenous biological mimicking biomaterials, with high biodegradability and biocompatibility hold enormous potential for the development of clinically translatable nanotheranostics platforms. Manganese plays a crucial role in mitochondrial and cellular function and recently, manganese (Mn)-based contrast agents have been receiving significant attention, due to improved biosafety and superior contrast abilities. However, the long term toxicity and non-biodegradability of these inorganic nanoplatforms have significantly halted their clinical progress. In contrast to this, melanin, an asymmetrical natural biopolymer, has garnered enormous attention due to good biocompatibility, biodegradability and MRI contrast imaging abilities. Hence, exploring endogenous natural materials with high contrast properties seems promising as clinically translatable in vivo MRI imaging contrast agent.

The Wang group developed an ultra small and water soluble Mn²⁺ chelating pegylated melanin nanoparticles (MNP-PEG-Mn) demonstrating excellent tumor-targeting Magnetic Resonance Imaging (MRI) ability. The MNP-PEG-Mn nanoparticles show a size of 5.6 nm displaying high chelating stability and low cytotoxicity. Interestingly, the MNP-PEG-Mn nanoparticles show improved longitudinal relaxivity compared to clinically approved MRI contrast agent Gadodiamide. In vivo studies further showcased excellent tumor targeting abilities upon intravenous administration of MNP-PEG-Mn nanoparticles in mouse model. The author further showed that the MNP-PEG-Mn nanoparticles could be excreted via hepatobiliary and renal routes. In this process negligible toxicity was generated to body tissues that indicate high biocompatibility. Altogether, these results clinically validate the tumor targeted T1 MRI contrast properties of bio-mimicking melanin conjugated manganese nanoparticles.

Melanin-manganese nanoparticles with ultrahigh efficient clearance in vivo for tumor-targeting T1 magnetic resonance imaging contrast agent . Biomater. Sci., 2018, 6, 207-215.

This article is free to read until 28 February!

About the Web writer:

Dr. Sudip Mukherjee is a Web Writer for Biomaterials Science. He is currently a Postdoctoral Research Associate working at the Department of Bioengineering at the Rice University. His research is involved in the development of advanced nanomaterials for drug/gene delivery in cancer theranostics, immunotherapy, immunomodulatory applications & angiogenesis. He published a total of ~30 research articles/patents. He serves as International Advisory Board Member for ‘Materials Research Express‘, IOP Sciences. He is an associate member (AMRSC) of The Royal Society of Chemistry, UK. He serves as reviewer for several international journals like Chem Comm, J Mater Chem A, J Mater Chem B, Journal of Biomedical Nanotechnology, RSC Advances, IOP Nanotechnology etc. He can be contacted by email at sudip.mukherjee@rice.edu or on Twitter.

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Focus on: Controlled micro-/nano-geometry

03 Jan 2018

By Yingfei Xue.

Written by Webwriter Yingfei Xue

The geometry of micro- or nano-materials determine their physico-chemical properties and play crucial roles in directing an array of in vivo biological activities. Historically, the significance of micro-/nano-geometry for biomaterials has not been adequately appreciated due to the limitations in manufacturing techniques. Recent years have witnessed the exponential growth of micro-/nano-fabrication technologies which allow closer scrutiny of the relationship between the micro-/nano-geometry and the biological effects of materials. This month the focus is on three articles published in Biomaterials Science reporting the recent advances to achieve controlled micro-/nano-geometry of biomedical devices including microdisks, nanosheets, and microcapsules.

1. Advanced manufacturing of microdisk vaccines for uniform control of material properties and immune cell function

Qin Zeng, Peipei Zhang, Xiangbin Zeng, Lisa H. Tostanoski and Christopher M. Jewell
Biomater. Sci., DOI: 10.1039/c7bm00520b

The heterogeneity in the geometry and loading level represents one major drawback of synthetic vaccine constructs. Therefore, taking advantage of the facile and flexible technique of soft lithography, the authors designed and fabricated PLGA microdisks with controllable dimension and payload loading. Compared to the conventional PLGA microparticles made by emulsion, microdisks possessed highly uniform diameter with less variation. Importantly, microdisks could safely co-deliver vaccine antigen and molecular adjuvants to primary dendritic cells. As a result, dendritic cells could be activated according to the composition of antigen and adjuvants. This controllable and programmable microdisk system will serve as platform to probe the relationship between the vaccine design parameters and immune responses in vivo.

2. The biodistribution, excretion and potential toxicity of different-sized Pd nanosheets in mice following oral and intraperitoneal administration

Xiaolan Chen, Jingchao Li, Yizhuan Huang, Jingping Wei, Duo Sun and Nanfeng Zheng
Biomater. Sci., 2017, 5, 2448. DOI: 10.1039/c7bm00769h

To elucidate the in vivo behaviors of Pd nanosheets (NSs), the authors synthesized size-specific Pd NSs (with 5 nm, 30 nm, or 80 nm in diameter) by controlling the chemical reaction conditions. Those NSs were then administrated via oral feeding or intraperitoneal injection to reveal different biodistribution, excretion, and toxicity profiles of those size-specific NSs. Interestingly, when intraperitoneally delivered, larger sized Pd NSs (80 nm) had higher accumulation in liver and spleen than the smaller sized Pd NSs (5 nm), which had higher accumulation in tumor tissue. In addition, the smaller sized NSs (5 nm) exhibited more excretion through urine than larger sized Pd NSs (30 and 80 nm). Overall, this study indicated that the size of nanomaterials could have significant influence on their biodistribution and bioavailability in vivo.

3. Development of drug-loaded polymer microcapsules for treatment of epilepsy

Yu Chen, Qi Gu, Zhilian Yue, Jeremy M. Crook, Simon E. Moulton, Mark J. Cook and Gordon G. Wallace
Biomater. Sci., 2017, 5, 2159. DOI: 10.1039/c7bm00623c

To achieve the goal of developing controllable local delivery system for treating epilepsy, the authors developed drug-loaded PLGA based microspheroids, microspheres, and microfibers by tuning the solution concentration during electrojetting (electrospinning and/or electrospraying) process. All the resultant microcapsules had excellent shape and size uniformity with high controllability and low variance. Different microcapsule geometry led to various sustained drug release profiles in vitro without compromising their cytocompatibility. This study highlighted the potential of programmable and controllable delivery system and suggested the potential role of geometry in controlling the drug release profile of micron-sized biomedical device.

Read these articles for free until 3 February

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Biocompatible CuS-based nanoplatforms for multifunctional theranostics

18 Dec 2017

By Sudip Mukherjee.

Written by Dr Sudip Mukherjee

The rationale for combination therapy is to employ various therapeutic methods which work using different mechanisms, thereby decreasing the chance of developing resistant cancer cells. Photothermal therapy (PTT) is the use of electromagnetic radiation to eradicate cancer cells which can also be utilized to increase the effectiveness of chemotherapy or radiation therapy. The application of targeted and functional nanoparticles can be used to overcome the existing limitations of nonspecific toxicity which is associated with PTT. Therefore, functional nanomaterials with near-infrared (NIR) PTT, high biocompatibility and excellent photothermal conversion efficiency can be dynamic tools for cancer ablation without affecting normal healthy tissue.

The Chen group used core-shell water-soluble copper sulphide nanoparticles (CuSNPs) coated with mesoporous silica nanoshells (MSNs) for effective delivery of anti-cancer drug doxorubicin (DOX) towards H22 liver cancer. Cleverly, the hollow cavity of MSN was utilized for the loading of anti-cancer drug DOX. CuS@MSN-DOX demonstrated good water dispersibility, high stability, excellent biocompatibility and strong NIR absorption. Its excellent photothermal and NIR thermal imaging properties are due its strong NIR photothermal conversion efficiency. The anti-tumor activity of CuS@MSN-DOX was extensively studied in both in vitro and in vivo therapeutic models which supports excellent chemotherapeutic activity. Complete eradication of the liver tumor was observed by combination therapy of PTT and chemotherapy using CuS@MSN-DOX. Infrared thermal imaging was used to monitor the photothermal treatment. These results clinically validate the multifunctional cancer theranostics property of CuS@MSN-DOX that has enormous potential for clinically translatable thermochemotherapy and enhanced drug delivery in the future.

Biocompatible CuS-based nanoplatforms for efficient photothermal therapy and chemotherapy in vivo Biomater. Sci., 2017, 5, 475 – 484

About the Webwriter

Dr. Sudip Mukherjee is a Web Writer for Biomaterials Science. He is currently a Postdoctoral Research Associate working alongside Dr. Omid Veiseh at the Department of Bioengineering at the Rice University. His research is involved in the development of advanced nanomaterials for drug/gene delivery in cancer theranostics, immunomodulatory applications & angiogenesis. He published a total of ~30 research articles/patents. He serves as International Advisory Board Member for‘Materials Research Express‘, IOP Sciences. He is an associate member (AMRSC) of RSC, UK. He serves as reviewer for several international journals like Chem Comm, J Mater Chem A, J Mater Chem B, Journal of Biomedical Nanotechnology, RSC Advances, IOP Nanotechnology etc.
Contact Email: sudip.mukherjee@rice.edu

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Focus on: Nanoparticle Delivery Systems

08 Dec 2017

By Yingfei Xue.

Written by web writer Yingfei Xue

Developing nanoparticle formulations that can deliver drugs more effectively to the target sites with enhanced efficacy and reduced side effects has been an overarching goal in the field of nanobiotechnology. Dendrimers, micelles, and liposomes represent three major classes of nanoparticles that have shown promising results in drug delivery and bio-sensing. Each type of nanoparticle has its own strengths and limitations in terms of the desirable payload, site of action, duration of action, release profile, and dosing frequency. Therefore, it is imperative to engineer these classical nanoparticle delivery systems for specific drug delivery application.

This month we focus on four articles published in Biomaterials Science reporting the recent advances in leveraging those different nanoparticle delivery systems for efficient, controlled, and targeted delivery of therapeutic agents.

1. Nucleobase-modified polyamidoamine-mediated miR-23b delivery to inhibit the proliferation and migration of lung cancer
Haobo Han, Jiebing Yang, Yudi Wang, Wenqi Chen, Jiawen Chen, Yan Yang and Quanshun Li
Biomater. Sci., 2017, 5, 2268. DOI: 10.1039/c7bm00599g

In the current study, the authors aimed to further improve the transfection efficiency and biocompatibility of conventional polyamidoamine (PAMAM) dendrimers. To this end, the surface of PAMAM was chemically modified with 2-amino-6-chloropurine. This modification further enhanced the carrier/DNA interaction via the fine balance of hydrogen bonding and electrostatic interaction. Compared to the prototype PAMAM, the modified PAMAM demonstrated higher transfection efficiency. In an in vitro model, this gene carrier delivered miR-23b, a potent anti-proliferative and anti-invasive agent, more efficiently into A549 cancer cells, indicating the potential of this carrier in cancer nanotherapy.

2. Novel poly(vinyl alcohol)-based amphiphilic nanogels by non-covalent boric acid crosslinking of polymeric micelles
Hen Moshe, Yuval Davizon, Maya Menaker Raskin and Alejandro Sosnik
Biomater. Sci., 2017, 5, 2295. DOI: 10.1039/c7bm00675f

Poor physical stability often presents as a major drawback for polymeric micelles. The authors addressed this issue by non-covalent crosslinking of a poly(vinyl alcohol) (PVA) based polymeric micelles system with boric acid. Compared to the non-crosslinked control, this novel micelles demonstrated improved physical stability under harsh environment. More interestingly, these micelles could be spray-dried and efficiently consolidated into dry powders which were able to regenerate back into the original nanoparticles upon re-dispersion. This non-covalently crosslinked micelles also maintained good mucoadhesiveness and cytocompatibility.

3. Codelivery of sorafenib and GPC3 siRNA with PEI-modified liposomes for hepatoma therapy
Weitong Sun, Yong Wang, Mingyue Cai, Liteng Lin, Xiaoyan Chen, Zhong Cao, Kangshun Zhu and Xintao Shuai
Biomater. Sci., 2017, 5, 2468. DOI: 10.1039/c7bm00866j

Combination therapy using chemotherapeutic drugs and siRNA represents a promising strategy that can potentially induce and/or enhance the synergistic anticancer effects. To overcome the individual drawbacks of sorafenib and gene therapy, the authors developed a PEI based liposome system which allow the co-delivery of GPC3 siRNA and hydrophobic sorafenib molecule. The drug loaded liposomal delivery system displayed enhanced anticancer effects by suppressing the expression of the anti-apoptotic GPC3 gene and the proliferative cyclin D1 gene simultaneously in human hepatocellular carcinoma (HCC) HepG2 cells. Further, the improved therapeutic effects of this delivery system was demonstrated in an in vivo xenograft model.

4. Dimeric camptothecin-loaded RGD-modified targeted cationic polypeptide-based micelles with high drug loading capacity and redox-responsive drug release capability
Zhaopei Guo, Xingzhi Zhou, Mengze Xu, Huayu Tian, Xuesi Chen and Meiwan Chen
Biomater. Sci., 2017, 5, 2501. DOI: 10.1039/c7bm00791d

To tackle the low bioavailability problem of camptothecin, the authors devised a novel polymeric micelles system composed of cationic polypeptide poly-lysine-block-poly-leucine, polyethylene glycol (PEG), and arginine-glycine-aspartic acid (RGD) peptide. The micelles system increased drug encapsulation efficiency, drug loading capacity, and physical stability of camptothecin. The RGD moiety further enhanced the intracellular uptake of micelles due to the cellular targeting capability of RGD sequence. Importantly, the drug loaded micelles effectively inhibited the proliferation of malignant MDA-MB-231 breast cancer cells by inducing cellular apoptosis and decreasing mitochondrial membrane potential.

Read these articles for free until 10 January 2018

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2018 Biomaterials Science Lectureship is now open for nominations!

16 Nov 2017

By Laura Fisher, Deputy Editor.

Do you know an early-career researcher who deserves recognition for their contribution to the biomaterials field?

Now is your chance to put them forward for the accolade they deserve.

Biomaterials Science is pleased to announce that nominations are now being accepted for its 2018 Lectureship award. This annual award was established in 2014 to honour an early-stage career scientist who has made a significant contribution to the biomaterials field.

2017 winner Zhuang Liu receives his certificate from Executive Editor Neil Hammond

Previous winners

2017 – Zhuang Liu, Soochow University, China

2016 – Fan Yang, Stanford University, USA

2015 – Joel Collier, Duke University, USA

2014 – Suzie Pun, University of Washington, USA

Qualification

To be eligible for the Biomaterials Science Lectureship, the candidate should be in the earlier stages of their scientific career, typically within 7 years of attaining their first independent research position, and will have made a significant contribution to the field.

Description

The recipient of the award will be asked to present a lecture at the European Society for Biomaterials Annual Meeting in Maastricht in September 2018, where they will also be presented with the award. The Biomaterials Science Editorial Office will provide financial support to the recipient for travel and accommodation costs.

The recipient will also be asked to contribute a lead article to the journal and will have their work showcased free of charge on the front cover of the issue in which their article is published.

Selection

The recipient of the award will be selected and endorsed by the Biomaterials Science Editorial Board.

Nominations

Those wishing to make a nomination should send details of the nominee, including a brief C.V. and a letter supporting the nomination, to the Biomaterials Science Editorial Office by 28^thFebruary 2018. Self-nomination is not permitted.

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Congratulations to Biomaterials Science Award Winners at ICBZM2017

31 Oct 2017

By Garima Sharma, Deputy Editor.

The 3rd International Conference on Bioinspired and Zwitterionic Materials

Biomaterials Science was proud to sponsor ICBZM2017, which took place this year in Tokyo, from the 18^th to the 20^th October. During the conference two Biomaterials Science Poster prizes were awarded.

Winners of the Biomaterials Science poster prize were;

Sarah Ward, (University of Massachusetts), for her poster presentation on ‘Polymer Zwitterion Prodrugs as Chemotherapeutics’.

Sarah Ward with Professor Todd Emrick

Erik Liu, (University of Washington), for his poster presentation on ‘Expression of EK Fusion Proteins to Enhance Protein Kinetics and Stability’.

Erik Liu with Professor Shaoyi Jiang

Congratulations to both Sarah and Erik!

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Repurposing Drug Action with Targeted Nanomedicine

12 Oct 2017

By Garima Sharma, Deputy Editor.

Written by Dr. Sudip Mukherjee

In cancers, rapid tumour growth is attributed to overexpression of anti-apoptotic proteins, inhibition or functional inefficiency of apoptotic proteases like caspases. Among caspases, caspase-8 signalling cascade is vital and interesting because of its ability to induce cell death by involving both mitochondria mediated intrinsic as well as death receptor (DR) – mediated extrinsic pathways. Notably, among ovarian cancer patients, tumors with low levels of caspase 8 are inherently resistant to chemotherapies. Incidentally, aggressive melanoma cells have functional expression of both Folate receptor (FR) on cell membrane and Estrogen receptor (ER) in cytoplasm. Stitching these basic facts one can deliver anti-cancer drugs, possibly targeting ER, using a liposomal system which will carry FR-targeting ligand to treat the aggressive melanoma cells.

In this present work, the Banerjee group used a hydrophobic drug molecule called NME2 (a recently developed ER-targeted anticancer drug for the treatment in breast cancer). Using a special FR-targeted liposome, the drug was successfully delivered to FR-moderately expressing melanoma cells.

The efficient targeting to FR-moderately expressed melanoma cells was accomplished by a new robust, cationic folate ligand named FA8. This efficiency of delivery is in stark contrast to other available FR-targeted liposomes which target only FR-over expressing cancer cells. The concoction of NME2 in FA8-associated liposome selectively induced caspase-8 expression-mediated apoptotic cell death in melanoma cancer cells (in vitro and in vivo). However, the drug in pristine state or in non-targeted liposome could not induce caspase-8 mediated apoptosis. Preliminarily, docetaxel, another potent anticancer drug, showed a similar result upon FA8-mediated delivery. Clearly, the given FR-targeted, liposomal delivery methodology indicated a change in mechanism of anticancer action of drug cargo and hence exemplified an interesting possibility to elude impending drug resistance (if any) against the given drug.

Tips from the authors:

1) In MDR cancers repurposing drug’s mechanistic pathway is essential, as acquired drug resistance is one of the major obstacles in fruitful cancer treatment.

2) The given FR-targeted formulation affected the change of mechanism of action of drug cargo (here, NME2) from non-caspase 8 to caspase-8 mediated apoptosis, thereby repurposing the apoptotic pathway of encapsulated drug.

3) The unique cationic lipid-conjugated folic acid based-ligand facilitated a) targeting to FR-moderately expressed melanoma cells; b) modification of mechanistic action of drug-cargo.

4) The liposomal delivery system with an FR-targeting ligand instigated an independent cell death pathway through the up-regulation of caspase-8 with subsequent cleavage of pro-survival factor RIP-1.

Article Link:

Cationic folate-mediated liposomal delivery of bis-arylidene oxindole induces efficient melanoma tumor regression Biomater. Sci., 2017, 5, 1898-1909

About the Webwriter:

Dr. Sudip Mukherjee is a Webwriter for Biomaterials Science. He is currently a Postdoctoral Research Associate working alongside Dr. Omid Veiseh at the Department of Bioengineering at the Rice University. His research is involved in the development of advanced nanomaterials for drug/gene delivery in cancer theranostics, immunomodulatory applications & angiogenesis. He published a total of ~30 research articles/patents. He serves as International Advisory Board Member for ‘Materials Research Express‘, IOP Sciences. He is an associate member (AMRSC) of The Royal Society of Chemistry, UK. He serves as reviewer for several international journals like Chem Comm, J Mater Chem A, J Mater Chem B, Journal of Biomedical Nanotechnology, RSC Advances, IOP Nanotechnology etc.

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Mapping Oxygen Gradients in 3D Cell Cultures

03 Oct 2017

By Garima Sharma, Deputy Editor.

Written by Dr. Sudip Mukherjee

Microenvironmental oxygen levels and gradients within three-dimensional (3D) tissue cultures directly influence cellular behavior and function, dictating the mode of proliferation, metabolism and interaction of cells with each other and their environment. While advances and prevalence of in vitro generated 3D cultures have spurred new techniques and systems for biological interrogation, it is necessary to develop and implement parallel systems to monitor and characterize the oxygen microenvironment within the tissue cultures and around them in the vessel used for the cultures. Conventional oxygen evaluation platforms can be ill-suited for continuous oxygen evaluation in custom tissue cultures. The Takayama group was able to robustly evaluate multiple 3D culture platforms by combining the use of phase-fluorimetry and lab-fabricated dispersible oxygen responsive microparticles. Oxygen microsensors were used to evaluate two spheroid culture vessels, hanging-drop and low-adhesion microwell plates, to highlight the variations in the oxygen levels peripheral to the spheroids in the two culture techniques. Dramatic differences can be seen in the steady state oxygen levels between the two culture techniques because of the difference in distance between the spheroids and the air-liquid interface in these two vessel types. These results highlighted the importance of minding the gas exchange location as compared to the cell culture to ensure appropriate tissue culture microenvironments.

Furthermore, these microsensors were used to map radial oxygen distribution across a circular, cell-patterned hydrogel by dispersing the microsensors within the culture. Coupling the spatial oxygen mapping to computational models of oxygen diffusion, the authors were able to estimate oxygen uptake behavior of the tissue culture. While 3D tissue culture platforms leverage the in vitro tissue architecture to produce more physiologically similar phenomena, integrated design and analysis of these 3D cell cultures from both biomaterial and oxygen supply aspects will be paramount in enabling researchers to effectively recreate some of the complexities present within both healthy and diseased tissues.

Tips from the authors:

When fabricating oxygen microsensing beads, infusion with Dichloromethane enabled large amount of Ruthenium caging within the PDMS microspheres, while leaving them oxygen sensitive. While other solvents swell PDMS more readily and enabled higher efficiency infusion of ruthenium, these solvents resulted in oxygen unresponsive ruthenium loaded PDMS beads.
Microsensors cannot be effectively integrated in the multicellular spheroids we tried with HEK293T, HS-5 and MDA-MB-231 cells; as the spheroids contract microsensors are ejected out of the spheroids.
The only limitation of phase-fluorimetry for the oxygen measurements is sufficient signal output that it can be detected by the photodiode, or other detection system. This was generally not a problem with beads greater than 80 microns assuming the culture systems was less than 1-mm thick. However, we were unable to effectively infuse beads under 80 microns with enough ruthenium to have enough output signals from the microsensors to get robust readings with cultures > 1 mm.

Article Link:

Dispersible oxygen microsensors map oxygen gradients in three-dimensional cell cultures Biomater. Sci., 2017,5, 2106-2113

About the Webwriter:

Dr. Sudip Mukherjee is a Web Writer for Biomaterials Science. He is currently a Postdoctoral Research Associate working alongside Dr. Omid Veiseh at the Department of Bioengineering at the Rice University. His research is involved in the development of advanced nanomaterials for drug/gene delivery in cancer theranostics, immunomodulatory applications & angiogenesis. He published a total of ~30 research articles/patents. He serves as International Advisory Board Member for ‘Materials Research Express’, IOP Sciences. He is an associate member (AMRSC) of RSC, UK. He serves as reviewer for several international journals like Chem Comm, J Mater Chem A, J Mater Chem B, Journal of Biomedical Nanotechnology, RSC Advances, IOP Nanotechnology etc.

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Biomaterials Science Blog

3D Multiscale Fiber Matrices for Bioartificial Livers

Focus on: Engineered Hydrogels

Bio-mimicking melanin-manganese nanoparticles for tumor targeting MRI agent

Focus on: Controlled micro-/nano-geometry

Biocompatible CuS-based nanoplatforms for multifunctional theranostics

Focus on: Nanoparticle Delivery Systems

2018 Biomaterials Science Lectureship is now open for nominations!

Do you know an early-career researcher who deserves recognition for their contribution to the biomaterials field?

Congratulations to Biomaterials Science Award Winners at ICBZM2017

Repurposing Drug Action with Targeted Nanomedicine

Mapping Oxygen Gradients in 3D Cell Cultures

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