Author Archive

Focus on: Engineered Hydrogels

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.

neural stem cells (NSCs) in cell therapy

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 XueYingfei 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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Focus on: Controlled micro-/nano-geometry

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.

Focus on controlled micro/nano-geometry

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

About the webwriter

Yingfei XueYingfei 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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Focus on: Nanoparticle Delivery Systems

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.

Nanoparticle delivery system

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

About the webwriterYingfei Xue

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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Congratulations to Biomaterials Science Award Winners at ICBZM2017

Biomaterials Science was proud to sponsor ICBZM2017, which took place this year in Tokyo, from the 18th to the 20th 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

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

Erik Liu with Professor Shaoyi Jiang

 

Congratulations to both Sarah and Erik!

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Repurposing Drug Action with Targeted Nanomedicine

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.

Melanoma Regression in Mice

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 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

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.

Figure 1

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:

  1. 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.
  2. 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.
  3. 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 WDr. Sudip Mukherjee ebwriter:

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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