Biomaterials Science Blog

Most biological organisms depend on electrical signals to function properly. For instance, neurons are electrically active cells that transmit signals to other neurons using electrical signals known as action potentials. Other electrically active cells such as cardiomyocytes in the heart spontaneously generate electrical signals that regulate normal heart rhythm. Additionally, electrical signals are also known to mediate certain processes such as cell migration and cell division. Knowing that biological organisms rely on electrical signals to function, biomaterials scientists are searching for opportunities on how to use innovative electrically conductive materials to deepen our understanding of fundamental biological processes.

Professor Bozhi Tian and his team at the University of Chicago have recently written a mini-review discussing nanoscale semiconductor devices and how they can revolutionize our understanding of cellular electrophysiology. Semiconductor devices such as silicon nanowire field effect transistors (NWFETs) operate at a sufficient resolution to detect the slightest changes in chemical and electrical signals (down to the pico- and femto- unit scales). These devices could theoretically be used as a low-cost strategy for disease marker detection in the clinic.

Ramya Parameswaran, an MD/PhD student at the University of Chicago and second author on the mini-review, explains that the use of nanoscale semiconductor devices in the clinic is not far away. The authors discuss the development of “multiplex sensing” semiconductor devices seek to replace enzyme-linked immunosorbent assays (ELISA) in the future, with the ability to detect concentrations of proteins, nucleic acids, and other ions within cells simultaneously with one device. “Multiplexing nanomaterials can hopefully soon be used to detect biomarkers such as cancer antigens or other important players involved in disease processes in a rapid fashion,” says Parameswaran. “While clinical trials for devices such as these have not been performed as of yet, the proof of concept exists.” These devices would ultimately accelerate patient diagnosis, and would ideally improve patient treatments for a variety of diseases.

The application of nanoscale semiconductor devices in the tissue-engineering field is also emerging. Nanoscale semiconductors embedded in tissue-engineered implants could be used to record electrical information for monitoring and ensuring proper functionality of the implant. Interestingly, nanoelectronic scaffolds can be used for a variety of tissue targets. “Free-standing nanowire nanoelectronic scaffolds can be interfaced with neurons, smooth muscle cells, and cardiomyocytes to monitor local electrical activity within the hybrid scaffolds,” says Parameswaran. Using these nanoelectronic scaffolds, tissue responses to drug treatments could also be “monitored meticulously,” which is another advantage for accelerating the translation of these devices to the clinic.

This mini-review describes the current status of nanoscale semiconductor devices and how they can advance our understanding of cell electrophysiology. Additionally, these devices could have a transformative role in the design of medical devices and tissue engineering scaffolds for clinical applications.

Nanoscale semiconductor devices as new biomaterials
John Zimmerman, Ramya Parmeswaran, and Bozhi Tian
Biomaterial Sci., Advance Article, DOI: 10.1039/C3BM60280J

Brian Aguado is currently a Ph.D. Candidate and NSF Fellow in the Biomedical Engineering department at Northwestern University. He holds a B.S. degree in Biomechanical Engineering from Stanford University and a M.S. degree in Biomedical Engineering from Northwestern University. Read more about Brian’s research publications here.

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One of the primary goals within the field of hard tissue engineering is to create biomaterials that can both promote osteoblast proliferation and support the natural bone mineralization process.  In this study, a trio of researchers at the University of Louisiana at Lafayette has developed a promising, layered hybrid system that contains hydroxyapatite (HAP), chitosan (CS), and graphene oxide (GO).  The GO base provides mechanical strength and biocompatibility while the surface layer which is composed of HAP, a natural constituent of bone, has a high bioactivity.  The intermediate chitosan layer further strengthens the hybrid biomaterial and, perhaps more importantly, has been shown to promote more homogeneous mineralization that mimics the natural biomineralization process.

In order to test the bone forming capabilities of this hybrid material the group soaked it, along with two control materials (HAP-GO and pure GO), in simulated body fluid for three weeks.  Each substrate was then incubated with MC3T3-E1 pre-osteoblast cells.  Among the three biomaterials, the HAP-CS-GO hybrid produced the highest levels of cell proliferation and expansion.   It also induced the greatest expression levels of vinculin, actin, and fibronectin, proteins that are essential for cell adhesion, cytoskeletal organization, and osteoblast morphogenesis and mineralization.  The hybrid material also demonstrated a highly significant increase in mineralized area and bone nodule formation compared to either of the two controls.  This was primarily attributed to the strong electrostatic interactions between the functional groups in the CS-GO base and the calcium ions present in solution.

Overall the hybrid HAP-CS-GO material was able to favorably modulate cellular activity in a way that was conducive to bone formation, making it a promising candidate for future bone tissue engineering applications.   However, as the authors have highlighted, there is room for improvement.  A reoccurring issue that many bone tissue engineering materials, including this novel hybrid material, have faced is an inability to attain the proper ratio of mineral deposit to cellular matrix in the regenerated tissue.  This mineral to matrix ratio has been shown to be relatively high in healthy, intact bone (~4.35-5) but was observed in a significantly lower amount (1.76) in the HAP-CS-GO material.  Nonetheless, the hybrid biomaterial reported in this study represents a promising direction forward in the field of bone tissue engineering.

The synergistic effect of a hybrid graphene oxide-chitosan system and biomimetic mineralization on osteoblast functions
D. Depan, T. C. Pesacreta and R. D. K. Misra
Biomater. Sci., 2014, 2, 264-274 DOI: 10.1039/C3BM60192G

Ellen Tworkoski is a guest web-writer for Biomaterials Science.  She is currently a graduate student in the biomedical engineering department at Northwestern University (Evanston, IL, USA).

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This paper by Sunami et al. studies the impact of 3D patterning on cells, and shows that cells grown on 3D micropatterns respond by changing their migration speed, their proliferation rate, and their expression of actin.

It is standard laboratory practice to grow cells outside the body on flat tissue culture plates.  However, cells inside the body are surrounded by other cells and connective tissue organized in three dimensions.  It is therefore very important to develop culture platforms for cells that more accurately capture a cell’s microenvironment inside the body. 

In this paper, the authors developed a three-dimensional culture platform that could be modified to study the properties of fibroblasts (skin cells) in culture. The authors changed only one factor – the area of the three-dimensional triangles that the cells were cultured on – to study the impact of 3D micropatterned areas on fibroblasts. The resultant surfaces that they used were about as adhesive as a smooth glass surface.  Interestingly, they found that fibroblast spreading was very different on surfaces with different areas, with maximum cell spreading observed on a surface with an intermediate pattern area.  The cells primarily adhered to the upper surface of the 3D micropatterns. Further, the density of the cells was also dependent on the micropattern area – as micropattern area increased, the density of the cells correspondingly increased as well. The cells also proliferated faster on surfaces with larger micropattern areas, while cell proliferation slowed on smaller triangles. The authors then used timelapse microscopy to study how these cells migrated over time, and found that while cells migrated more slowly on all of the micropatterned surfaces as compared to a completely flat surface, migration was slowest on the micropatterns with the smallest areas. Similarly, the authors found that f-actin expression was increased on the patterns with the largest areas. The authors hypothesize that this may mean that cells experience less mechanical stress as pattern size decreases.

Influence of the pattern size of micropatterned scaffolds on cell morphology, proliferation, migration and F-actin expression
Hiroshi Sunami, Ikuko Yokota and Yasuyuki Igarashi
Biomater. Sci., 2014, Advance Article DOI: 10.1039/C3BM60237K

Debanti Sengupta recently completed her PhD in Chemistry from Stanford University.  She is currently a Siebel postdoctoral scholar at the University of California, Berkeley.  

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One of the goals of tissue engineers is to manufacture “spare body parts” made of cells and biomaterials to repair damaged or diseased tissues. A current challenge for commercializing cell-biomaterial constructs is maintaining their viability during shipping and/or storage. The storage of cells in liquid suspension is relatively simple with the use of common cryoprotectants (such as dimethyl sulfoxide), but current preservation methods for large cell-biomaterial constructs yield low cell viability in comparison.  More effective preservation methods for cell-biomaterial constructs are needed to produce “off the shelf” tissue engineered products and accelerate the translation of tissue engineered products to the clinic.

In a current study conducted at the Japan Advanced Institute of Science and Technology (JAIST), researchers developed a dextran-based polyampholyte (charged polymer) hydrogel with cryoprotective properties. First, dextran polymers were functionalized with azide groups (azide-Dex) to provide sites for crosslinking. Then, positively charged amine groups were introduced on the dextran using poly-L-lysine to form azide-amino-Dex. To add negatively charged carboxyl groups, succinic anhydride was added at various concentrations to azide-amino-Dex to convert amine groups to carboxyl groups. This newly formed dextran polyampholyte (azide-Dex-PA) polymer was utilized for cryopreservation studies. After encapsulating and freezing cells with various azide-Dex-PA solutions, cell viability post-cryopreservation was shown to increase with higher concentrations of azide-Dex-PA. Viability was also dependent on the ratio of amine and carboxyl groups on the polymer, indicating that the cryoprotective properties of the polyampholyte are likely due to polymer charge.

The azide groups on the azide-Dex-PA were utilized to crosslink the dextran polyampholytes to form hydrogels. After synthesizing alkyne-functionalized dextran with dibenzylcyclooctyne (DBCO-Dex), the two components were mixed with cells to form hydrogels with azide-alkyne click chemistry. Encapsulated cells in the hydrogel were cryopreserved, thawed, and evaluated for viability. Compared to the 0% viability observed with collagen hydrogel and non-polyampholyte dextran hydrogel controls, the dextran polyampholyte hydrogels substantially increased cell viability to 93-94%. The increased viability post-cryopreservation may be due to the polyampholyte polymer adsorbing onto the cell membrane, providing a polymer “shell” of protection during thawing. Images of cells coated with FITC labeled azide-Dex-PA provide evidence to support this hypothesis.

All in all, dextran polyampholyte hydrogels have cryoprotective properties, and are able to preserve cell viability during the cryopreservation process. The dramatic increase in cell viability post-cryopreservation justifies future studies for using these hydrogels for preserving larger cell-biomaterial constructs for long term storage.

Hydrogelation of dextran-based polyampholytes with cryoprotective properties via click chemistry
Minkle Jain, Robin Rajan, Suong-Hyu Hyon, and Kazuaki Matsumura
Biomaterials Science, 2014, Advance Article DOI: 10.1039/C3BM60261C

Brian Aguado is currently a Ph.D. Candidate and NSF Fellow in the Biomedical Engineering department at Northwestern University. He holds a B.S. degree in Biomechanical Engineering from Stanford University and a M.S. degree in Biomedical Engineering from Northwestern University. Read more about Brian’s research publications here.

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Cancer is the second leading cause of death worldwide, and continues to be a challenging disease to treat therapeutically. One strategy to treat cancer patients is to surgically remove the primary tumor and attempt to prevent the spread of cancer cells to other organs in the body. Unfortunately, surgical resection of tumors may be difficult in sensitive organs (e.g. the brain), and tumors may need to be treated directly with chemotherapy drugs to inhibit growth.

Recently, there has been an increased interest in utilizing biomaterials to deliver chemotherapy drugs directly to the primary tumor. Current research at the Indian Institute of Technology explores the use of nanohydrogels supplemented with iron oxide magnetic nanoparticles as a vehicle to deliver chemotherapy drugs to the primary tumor. Interestingly, these thermo-responsive nanohydrogels could release their anticancer drug cargo when heated with a magnetic field. Although this study did not use chemotherapy drugs, the magnetic hydrogels were used to heat the tumor locally to reduce tumor size – upon stimulation with a magnetic field. This study focused on characterizing the material properties of the magnetic nanohydrogels, in addition to analyzing the effects of the nanohydrogel on inhibiting tumor growth.

The magnetic nanohydrogel is composed of iron oxide nanoparticles, chitosan, and poly-N-isopropylacrylamide (NIPAAm).  The chitosan-poly-(NIPAAm) nanohydrogels are hydrophilic below the lower critical solution temperature (LCST) of 42^oC. When stimulated with the appropriate magnetic field, the magnetic nanoparticles heat the hydrogel above the LCST. When the temperature is increased above the LCST, the polymers in the hydrogel change from “expanded coils” to “compact globules,” and cause the release of the aqueous contents of the hydrogel. The hydrophilic to hydrophobic transition is the main mechanism by which the anticancer drug cargo could be released from the hydrogel.

The biocompatibility and efficacy of the hydrogel in reducing tumor growth in vivo were analyzed. Using a mouse model of fibrosarcoma, the magnetic nanohydrogels were delivered via injection to the primary tumor site, and then stimulated with a magnetic field. Various biocompatibility studies were conducted, showing that serum protein concentrations and blood cell counts were not affected. The biodistribution of the magnetic hydrogel was also quantified, with minimal accumulation of the nanohydrogel in various organs (14 days post-delivery). Additionally, the magnetic nanohydrogel decelerated the growth of the primary tumor. After magnetic stimulation, the magnetic particles in the nanohydrogel successfully heated the tumor locally with minimal damage to the surrounding tissues. Despite not containing chemotherapy drugs, the magnetic nanohydrogels were still efficient in inhibiting the primary tumor growth.

This study describes the thermo-responsive properties of magnetic nanohydrogels, and demonstrates the ability to reduce tumor size using nanohydrogels heated with a magnetic field. Future studies are needed to show efficacy in delivering chemotherapy drugs using the magnetic nanohydrogels as a delivery vehicle. Still, the magnetic nanohydrogels are a promising platform for a minimally invasive method of decreasing tumor growth in vivo.

Biocompatibility, biodistribution and efficacy of magnetic nanohydrogels in inhibiting growth of tumors in experimental mice models
Manish K. Jaiswal, Manashjit Gogoi, Haladhar Dev Sarma, Rinti Banerjee and D. Bahadur
Biomater. Sci., 2014, Advance Article DOI: 10.1039/C3BM60225G

Brian Aguado is currently a Ph.D. Candidate and NSF Fellow in the Biomedical Engineering department at Northwestern University. He holds a B.S. degree in Biomechanical Engineering from Stanford University and a M.S. degree in Biomedical Engineering from Northwestern University. When he’s not in the lab, Brian enjoys traveling, cooking, swimming, and spending time with family and friends. Read more about Brian’s research publications here.

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The next generation of diagnostic devices is currently being realized in the form of ‘smart’ biosensors.  These sensors use logic gates to digitalize biochemical signals and produce a binary output that either indicates the presence or absence of a disease.  The biochemical signals, which are often the product of enzymatic cascades, are also capable of triggering drug release from stimuli-responsive materials, thus creating a device that is capable of both sensing and treating a particular condition.

However, these integrated sense and treat biosensors have a major obstacle to overcome if they are to be successfully implemented.  Many of the enzymatic cascades used for input will produce low, but non-zero concentrations of the sensing analytes under normal, physiological conditions.  Over time, the accumulation of these background signals can rise to a level that is high enough to trigger drug release, resulting in the dosage of a perfectly healthy patient which often has adverse consequences.  In this work, a team from Clarkson University and Oak Ridge National Laboratory propose a novel solution to this problem which involves the incorporation of an enzymatic filter into these devices.

The group created a system that was designed to detect and treat liver injury using input from two known biomarkers of liver disease: alanine transaminase (ALT) and aspartate transaminase, type I (AST).  When both ALT and AST are present in elevated concentrations, they will produce high levels of molecules which can be used to synthesize citric acid and another enzyme known as CoA-SH.  While CoA-SH can be readily detected and used to generate a positive signal indicating liver injury, citric acid can be used to trigger drug release by dissolving the iron-cross-linked alginate beads which were used in this study to simulate drug release capsules.  The group then introduced an enzymatic filter, malate dehydrogenase (MDH), into the system.  MDH is able to regulate the production of citric acid, thus controlling the degradation of the alginate beads and subsequent drug release.  In the test cases listed, the modified system generated the correct diagnostic result 100% of the time.  However, the filter was not able to completely eliminate bead dissolution and drug release under conditions associated with a normal, healthy environment.

To tackle this problem, the group decided to try improving the stability of the beads themselves.  By alternately depositing layers of poly-L-lysine with additional layers of alginate, PLA bi-layers were formed on the surface of the alginate cores.   The group found that, as more layers were added, the speed of bead dissolution and the amount of drug released were reduced.  The combination of the filter and the PLA coatings showed enhanced suppression of the negative signals while continuing to have a minimal effect on the positive signal.

Although the group was unable to completely eliminate drug release under normal conditions due to long-term noise accumulation, they were able to reduce it significantly.  Their approach marks a promising step forwards in addressing one of the major obstacles faced by smart biosensor systems.

Enzymatic filter for improved separation of output signals in enzyme logic systems towards ‘sense and treat’ medicine
Shay Mailloux, Oleksandr Zavalov, Nataliia Guz, Evgeny Katz and Vera Bocharova  
Biomater. Sci., 2014, Advance Article DOI: 10.1039/C3BM60197H

Ellen Tworkoski is a guest web-writer for Biomaterials Science.  She is currently a second year Ph.D. student in the biomedical engineering department at Northwestern University (Evanston, IL, USA).

Follow the latest journal news on Twitter @BioMaterSci or go to our Facebook page.

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