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Gold nanoparticles to enhance ophthalmic imaging. Biomaterials science Chen, F., Si, P., de la Zerda, A., Jokerst, J. V., Myung, D. 2020
Abstract

The use of gold nanoparticles as diagnostic tools is burgeoning, especially in the cancer community with a focus on theranostic applications to both cancer diagnosis and treatment. Gold nanoparticles have also demonstrated great potential for use in diagnostic and therapeutic approaches in ophthalmology. Although many ophthalmic imaging modalities are available, there is still a considerable unmet need, in particular for ophthalmic molecular imaging for the early detection of eye disease before morphological changes are more grossly visible. An understanding of how gold nanoparticles are leveraged in other fields could inform new ways they could be utilized in ophthalmology. In this paper, we review current ophthalmic imaging techniques and then identify optical coherence tomography (OCT) and photoacoustic imaging (PAI) as the most promising technologies amenable to the use of gold nanoparticles for molecular imaging. Within this context, the development of gold nanoparticles as OCT and PAI contrast agents are reviewed, with the most recent developments described in detail.

View details for DOI 10.1039/d0bm01063d

View details for PubMedID 33057463
Simultaneous Interpenetrating Polymer Network of Collagen and Hyaluronic Acid as an In Situ-Forming Corneal Defect Filler CHEMISTRY OF MATERIALS Chen, F., Le, P., Lai, K., Fernandes-Cunha, G. M., Myung, D. 2020; 32 (12): 5208?16
View details for DOI 10.1021/acs.chemmater.0c01307

View details for Web of Science ID 000543738500033
Bio-orthogonally crosslinked hyaluronate-collagen hydrogel for suture-free corneal defect repair. Biomaterials Chen, F., Le, P., Fernandes-Cunha, G. M., Heilshorn, S. C., Myung, D. 2020; 255: 120176
Abstract

Biomaterials that mimic corneal stroma could decrease the need for donor corneal tissue and could decrease the prevalence of complications associated with corneal transplantation, including infection and rejection. We developed a bio-orthogonally crosslinked hyaluronate-collagen hydrogel which can fill corneal defects in situ without the need for any sutures, initiators, or catalysts. We studied the effects of biorthogonal crosslinking on the light transmittance of the hydrogel, which was greater than 97% water. The transmittance of the optimized hydrogel in the visible light range was over 94%. We also investigated the mechanical properties, refractive index, morphology, biocompatibility, and corneal re-epithelialization capacity of the hyaluronate-collagen hydrogel. Our in vitro, in vivo, and ex vivo results demonstrated that this bio-orthogonally crosslinked hyaluronate-collagen hydrogel has excellent potential as a biomaterial for cornea repair and regeneration.

View details for DOI 10.1016/j.biomaterials.2020.120176

View details for PubMedID 32559566
Increasing the Efficacy of Stem Cell Therapy via Triple-Function Inorganic Nanoparticles ACS NANO Chen, F., Zhao, E., Hableel, G., Hu, T., Kim, T., Li, J., Gonzalez-Pech, N., Cheng, D. J., Lemaster, J. E., Xie, Y., Grassian, V. H., Sen, G. L., Jokerst, J. V. 2019; 13 (6): 6605?17
Abstract

Stem cell therapy in heart disease is challenged by mis-injection, poor survival, and low cell retention. Here, we describe a biocompatible multifunctional silica-iron oxide nanoparticle to help solve these issues. The nanoparticles were made via an in situ growth of Fe3O4 nanoparticles on both the external surfaces and pore walls of mesocellular foam silica nanoparticles. In contrast to previous work, this approach builds a magnetic moiety inside the pores of a porous silica structure. These materials serve three roles: drug delivery, magnetic manipulation, and imaging. The addition of Fe3O4 to the silica nanoparticles increased their colloidal stability, T2-based magnetic resonance imaging contrast, and superparamagnetism. We then used the hybrid materials as a sustained release vehicle of insulin-like growth factor-a pro-survival agent that can increase cell viability. In vivo rodent studies show that labeling stem cells with this nanoparticle increased the efficacy of stem cell therapy in a ligation/reperfusion model. The nanoparticle-labeled cells increase the mean left ventricular ejection fraction by 11 and 21% and the global longitudinal strain by 24 and 34% on days 30 and 60, respectively. In summary, this multifunctional nanomedicine improves stem cell survival via the sustained release of pro-survival agents.

View details for DOI 10.1021/acsnano.9b00653

View details for Web of Science ID 000473248300046

View details for PubMedID 31188564
Cellular toxicity of silicon carbide nanomaterials as a function of morphology BIOMATERIALS Chen, F., Li, G., Zhao, E., Li, J., Hableel, G., Lemaster, J. E., Bai, Y., Sen, G. L., Jokerst, J. V. 2018; 179: 60?70
Abstract

Silicon carbide has been shown to be biocompatible and is used as a coating material for implanted medical devices to prevent biofilms. Silicon carbide nanomaterials are also promising in cell tracking due to their stable and strong luminescence, but more comprehensive studies of this material on the nanoscale are needed. Here, we studied the toxicity of silicon carbide nanomaterials on human mesenchymal stem cells in terms of metabolism, viability, adhesion, proliferation, migration, oxidative stress, and differentiation ability. We compared two different shapes and found that silicon carbide nanowires are toxic to human mesenchymal stem cells but not to cancer cell lines at the concentration of 0.1?mg/mL. Control silicon carbide nanoparticles were biocompatible to human mesenchymal stem cells at 0.1?mg/mL. We studied the potential mechanistic effect of silicon carbide nanowires on human mesenchymal stem cells' phenotype, cytokine secretion, and gene expression. These findings suggest that the toxic effect of silicon carbide nanomaterials to human mesenchymal stem cells are dependent on morphology.

View details for DOI 10.1016/j.biomaterials.2018.06.027

View details for Web of Science ID 000441490200005

View details for PubMedID 29980075

View details for PubMedCentralID PMC6069971
Multifunctional nanomedicine with silica: Role of silica in nanoparticles for theranostic, imaging, and drug monitoring JOURNAL OF COLLOID AND INTERFACE SCIENCE Chen, F., Hableel, G., Zhao, E., Jokerst, J. V. 2018; 521: 261?79
Abstract

The idea of multifunctional nanomedicine that enters the human body to diagnose and treat disease without major surgery is a long-standing dream of nanomaterials scientists. Nanomaterials show incredible properties that are not found in bulk materials, but achieving multi-functionality on a single material remains challenging. Integrating several types of materials at the nano-scale is critical to the success of multifunctional nanomedicine device. Here, we describe the advantages of silica nanoparticles as a tool for multifunctional nano-devices. Silica nanoparticles have been intensively studied in drug delivery due to their biocompatibility, degradability, tunable morphology, and ease of modification. Moreover, silica nanoparticles can be integrated with other materials to obtain more features and achieve theranostic capabilities and multimodality for imaging applications. In this review, we will first compare the properties of silica nanoparticles with other well-known nanomaterials for bio-applications and describe typical routes to synthesize and integrate silica nanoparticles. We will then highlight theranostic and multimodal imaging application that use silica-based nanoparticles with a particular interest in real-time monitoring of therapeutic molecules. Finally, we will present the challenges and perspective on future work with silica-based nanoparticles in medicine.

View details for DOI 10.1016/j.jcis.2018.02.053

View details for Web of Science ID 000430526700029

View details for PubMedID 29510868

View details for PubMedCentralID PMC5899957
Organosilica Nanoparticles with an Intrinsic Secondary Amine: An Efficient and Reusable Adsorbent for Dyes ACS APPLIED MATERIALS & INTERFACES Chen, F., Zhao, E., Kim, T., Wang, J., Hableel, G., Reardon, P., Ananthakrishna, S., Wang, T., Arconada-Alvarez, S., Knowles, J. C., Jokerst, J. V. 2017; 9 (18): 15566?76
Abstract

Nanomaterials are promising tools in water remediation because of their large surface area and unique properties compared to bulky materials. We synthesized an organosilica nanoparticle (OSNP) and tuned its composition for anionic dye removal. The adsorption mechanisms are electrostatic attraction and hydrogen bonding between the amine on OSNP and the dye, and the surface charge of the OSNP can be tuned to adsorb either anionic or cationic dyes. Using phenol red as a model dye, we studied the effect of the amine group, pH, ionic strength, time, dye concentration, and nanomaterial mass on the adsorption. The theoretical maximum adsorption capacity was calculated to be 175.44 mg/g (0.47 mmol/g), which is higher than 67 out of 77 reported adsorbents. The experimental maximum adsorption capacity is around 201 mg/g (0.53 mmol/g). Furthermore, the nanoparticles are highly reusable and show stable dye removal and recovery efficiency over at least 10 cycles. In summary, the novel adsorbent system derived from the intrinsic amine group within the frame of OSNP are reusable and tunable for anionic or cationic dyes with high adsorption capacity and fast adsorption. These materials may also have utility in drug delivery or as a carrier for imaging agents.

View details for DOI 10.1021/acsami.7b04181

View details for Web of Science ID 000401307100039

View details for PubMedID 28422482

View details for PubMedCentralID PMC5443609
Exosome-like silica nanoparticles: a novel ultrasound contrast agent for stem cell imaging NANOSCALE Chen, F., Ma, M., Wang, J., Wang, F., Chern, S., Zhao, E., Jhunjhunwala, A., Darmadi, S., Chen, H., Jokerst, J. V. 2017; 9 (1): 402?11
Abstract

Ultrasound is critical in many areas of medicine including obstetrics, oncology, and cardiology with emerging applications in regenerative medicine. However, one critical limitation of ultrasound is the low contrast of target tissue over background. Here, we describe a novel cup-shaped silica nanoparticle that is reminiscent of exosomes and that has significant ultrasound impedance mismatch for labelling stem cells for regenerative medicine imaging. These exosome-like silica nanoparticles (ELS) were created through emulsion templating and the silica precursors bis(triethoxysilyl)ethane (BTSE) and bis(3-trimethoxysilyl-propyl)amine (TSPA). We found that 40% TSPA resulted in the exosome like-morphology and a positive charge suitable for labelling mesenchymal stem cells. We then compared this novel structure to other silica structures used in ultrasound including Stober silica nanoparticles (SSN), MCM-41 mesoporous silica nanoparticles (MSN), and mesocellular foam silica nanoparticles (MCF) and found that the ELS offered enhanced stem cell signal due to its positive charge to facilitate cell uptake as well as inherently increased echogenicity. The in vivo detection limits were <500 cells with no detectable toxicity at the concentrations used for labelling. This novel structure may eventually find utility in applications beyond imaging requiring an exosome-like shape including drug delivery.

View details for DOI 10.1039/c6nr08177k

View details for Web of Science ID 000391739300049

View details for PubMedID 27924340

View details for PubMedCentralID PMC5179289
Chitosan enclosed mesoporous silica nanoparticles as drug nano-carriers: Sensitive response to the narrow pH range MICROPOROUS AND MESOPOROUS MATERIALS Chen, F., Zhu, Y. 2012; 150 (1): 83?89
View details for DOI 10.1016/j.micromeso.2011.07.023

View details for Web of Science ID 000298721700011
Bioengineered, In Situ-Crosslinked Collagen Gels for Suture-Free Stromal Defect Reconstruction of the Cornea Myung, D., Djalilian, A. R., Heilshorn, S., Chen, F., Le, P., Hull, S., Fernandes-Cunha, G., Na, K. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2020
View details for Web of Science ID 000554528301263
Optimization of an in situ-forming interpenetrating polymer network of collagen and hyaluronic acid hydrogel independently and simultaneously crosslinked by click chemistries Le, P., Chen, F., Cunha, G., Lai, K., Myung, D. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2020
View details for Web of Science ID 000554495700138
In situ-forming bio-orthogonally crosslinked collagen-hyaluronate co-polymeric hydrogel to treat deep corneal stromal defects: in vivo biological response Chen, F., Le, P., Cunha, G., Myung, D. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2020
View details for Web of Science ID 000554495702200
In situ-forming collagen hydrogel crosslinked via multi-functional PEG as a matrix therapy for corneal defects. Scientific reports Fernandes-Cunha, G. M., Chen, K. M., Chen, F., Le, P., Han, J. H., Mahajan, L. A., Lee, H. J., Na, K. S., Myung, D. 2020; 10 (1): 16671
Abstract

Visually significant corneal injuries and subsequent scarring collectively represent a major global human health challenge, affecting millions of people worldwide. Unfortunately, less than 2% of patients who could benefit from a sight-restoring corneal transplant have access to cadaveric donor corneal tissue. Thus, there is a critical need for new ways to repair corneal defects that drive proper epithelialization and stromal remodeling of the wounded area without the need for cadeveric donor corneas. Emerging therapies to replace the need for donor corneas include pre-formed biosynthetic buttons and in situ-forming matrices that strive to achieve the transparency, biocompatibility, patient comfort, and biointegration that is possible with native tissue. Herein, we report on the development of an in situ-forming hydrogel of collagen type I crosslinked via multi-functional polyethylene glycol (PEG)-N-hydroxysuccinimide (NHS) and characterize its biophysical properties and regenerative capacity both in vitro and in vivo. The hydrogels form under ambient conditions within minutes upon mixing without the need for an external catalyst or trigger such as light or heat, and their transparency, degradability, and stiffness are modulated as a function of number of PEG arms and concentration of PEG. In addition, in situ-forming PEG-collagen hydrogels support the migration and proliferation of corneal epithelial and stromal cells on their surface. In vivo studies in which the hydrogels were formed in situ over stromal keratectomy wounds without sutures showed that they supported multi-layered surface epithelialization. Overall, the in situ forming PEG-collagen hydrogels exhibited physical and biological properties desirable for a corneal stromal defect wound repair matrix that could be applied without the need for sutures or an external trigger such as a catalyst or light energy.

View details for DOI 10.1038/s41598-020-72978-5

View details for PubMedID 33028837
Stem Cell Tracking with Nanoparticle-Based Ultrasound Contrast Agents. Methods in molecular biology (Clifton, N.J.) Chen, F., Jokerst, J. V. 2020; 2126: 141?53
Abstract

Cell therapy is revolutionizing modern medicine. To promote this emerging therapy, the ability to image and track therapeutic cells is critical to monitor the progress of the treatment. Ultrasound imaging is promising in tracking therapeutic cells but suffers from poor contrast against local tissues. Therefore, it is critical to increase the ultrasound contrast of therapeutic cells over local tissue at the injection site. Here, we describe a method to increase the ultrasound intensity of therapeutic cells with nanoparticles to make the injected therapeutic cells more visible.

View details for DOI 10.1007/978-1-0716-0364-2_13

View details for PubMedID 32112386
Gadolinium Doping Enhances the Photoacoustic Signal of Synthetic Melanin Nanoparticles: A Dual Modality Contrast Agent for Stem Cell Imaging CHEMISTRY OF MATERIALS Lemaster, J. E., Wang, Z., Hariri, A., Chen, F., Hu, Z., Huang, Y., Barback, C. V., Cochran, R., Gianneschi, N. C., Jokerst, J. V. 2019; 31 (1): 251?59
View details for DOI 10.1021/acs.chemmater.8b04333

View details for Web of Science ID 000455558100027
Non-invasive Staging of Pressure Ulcers Using Photoacoustic Imaging. Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society Hariri, A., Chen, F., Moore, C., Jokerst, J. V. 2019
Abstract

Ulcers including pressure ulcers and diabetic foot ulcers damage the skin and underlying tissue in people with compromised blood circulation. They are classified into four stages of severity and span from mild reddening of the skin to tissue damage and muscle/bone infections. Here, we used photoacoustic imaging as a non-invasive method for detecting early tissue damage that cannot be visually observed while also staging the disease using quantitative image analysis. We used a mouse model of pressure ulcers by implanting sub-dermal magnets in the dorsal flank and periodically applying an external magnet to the healed implant site. The magnet-induced pressure was applied in cycles, and the extent of ulceration was dictated by the number of cycles. We used both laser- and LED-based photoacoustic imaging tools with 690 nm excitation to evaluate the change in photoacoustic signal and depth of injury. Using laser-based photoacoustic imaging system, we found a 4.4-fold increase in the photoacoustic intensity in stage I versus baseline (no pressure). We also evaluated the depth of injury using photoacoustics. We measured a photoacoustic ulcer depth of 0.38 � 0.09 mm, 0.74 � 0.11 mm, 1.63 � 0.4 mm, and 2.7 � 0.31 mm (n=4) for stages I, II, III, and IV, respectively. The photoacoustic depth differences between each stage were significant (p < 0.05). We also used an LED-based photoacoustic imaging system to detect early stage (stage I) pressure ulcers and observed a 2.5-fold increase in photoacoustic signal. Importantly, we confirmed the capacity of this technique to detect dysregulated skin even before stage I ulcers have erupted. We also observed significant changes in photoacoustic intensity during healing suggesting that this approach can monitor therapy. These findings were confirmed with histology. These results suggest that this photoacoustic-based approach might have clinical value for monitoring skin diseases including pressure ulcers. This article is protected by copyright. All rights reserved.

View details for DOI 10.1111/wrr.12751

View details for PubMedID 31301258
Photoacoustic Imaging Quantifies Drug Release from Nanocarriers via Redox Chemistry of Dye-Labeled Cargo. Angewandte Chemie (International ed. in English) Jeevarathinam, A. S., Lemaster, J. E., Chen, F., Zhao, E., Jokerst, J. V. 2019
Abstract

We report a new approach to monitor drug release from nanocarriers via a paclitaxel-methylene blue conjugate (PTX-MB) with redox activity. This construct is in a photoacoustically silent reduced state inside poly(lactic-co-glycolic acid) (PLGA) nanoparticles (PTX-MB@PLGA NPs). During release, PTX-MB is spontaneously oxidized to produce a concentration-dependent photoacoustic signal. An in vitro drug-release study showed an initial burst release (25?%) between 0-24?h and a sustained release between 24-120?h with a cumulative release of 40.6?% and a 670-fold increase in photoacoustic signal. An in vivo murine drug release showed a photoacoustic signal enhancement of up to 649?% after 10?hours. PTX-MB@PLGA NPs showed an IC50 of 78??g?mL-1 and 44.7�4.8?% decrease of tumor burden in an orthotopic model of colon cancer via luciferase-positive CT26 cells.

View details for DOI 10.1002/anie.201914120

View details for PubMedID 31840357
Listening for the therapeutic window: Advances in drug delivery utilizing photoacoustic imaging. Advanced drug delivery reviews Moore, C., Chen, F., Wang, J., Jokerst, J. V. 2019
Abstract

The preclinical landscape of photoacoustic imaging has experienced tremendous growth in the past decade. This non-invasive imaging modality augments the spatiotemporal capabilities of ultrasound with optical contrast. While it has principally been investigated for diagnostic applications, many recent reports have described theranostic delivery systems and drug monitoring strategies using photoacoustics. Here, we provide an overview of the of the progress to date while highlighting work in three specific areas: theranostic nanoparticles, real-time drug monitoring, and stem cell ("living drug") tracking. Additionally, we discuss the challenges that remain to be addressed in this burgeoning field.

View details for DOI 10.1016/j.addr.2019.07.003

View details for PubMedID 31295522
A Mechanistic Investigation of Methylene Blue and Heparin Interactions and Their Photoacoustic Enhancement BIOCONJUGATE CHEMISTRY Wang, J., Jeevarathinam, A., Humphries, K., Jhunjhunwala, A., Chen, F., Hariri, A., Miller, B. R., Jokerst, J. V. 2018; 29 (11): 3768?75
Abstract

We recently reported a real-time method to measure heparin in human whole blood based on the photoacoustic change of methylene blue (MB). Intriguingly, the MB behaved unlike other "turn on" photoacoustic probes-the absorbance decreased as the photoacoustic signal increased. The underlying mechanism was not clear and motivated this study. We studied the binding mechanism of MB and heparin in water and phosphate buffer saline (PBS) with both experimental and computational methods. We found that the photoacoustic enhancement of the MB-heparin mixture was a result of MB-heparin aggregation due to charge neutralization and resulting sequestration of MB in these aggregates. The sequestration of MB in the MB-heparin aggregates led to decreased absorbance-there was simply less free dye in solution to absorb light. The highest photoacoustic signal and aggregation occurred when the number of negatively charged sulfate groups on heparin was approximately equal to the number of positively charged MB molecule. The MB-heparin aggregates dissociated when there were more sulfated groups from heparin than MB molecules because of the electrostatic repulsion between negatively charged sulfate groups. PBS facilitated MB dimer formation regardless of heparin concentration and reprecipitated free MB in aggregates due to ionic strength and ionic shielding. Further molecular dynamics experiments found that binding of heparin occurred at the sulfates and glucosamines in heparin. Phosphate ions could interact with the heparin via sodium ions to impair the MB-heparin binding. Finally, our model found 3.7-fold more MB dimerization upon addition of heparin in MB solution confirming that heparin facilitates MB aggregation. We conclude that the�addition of heparin in MB decreases the absorbance of the sample because of MB-heparin aggregation leading to fewer MB molecules in solution; however, the aggregation also increases the PA intensity because the MB molecules in the MB-heparin aggregate have reduced degrees of freedom and poor heat transfer to solvent.

View details for DOI 10.1021/acs.bioconjchem.8b00639

View details for Web of Science ID 000451496400029

View details for PubMedID 30281976
Optics-Free, Non-Contact Measurements of Fluids, Bubbles, and Particles in Microchannels Using Metallic Nano-Islands on Graphene NANO LETTERS Dhong, C., Edmunds, S. J., Ramirez, J., Kayser, L. V., Chen, F., Jokerst, J. V., Lipomi, D. J. 2018; 18 (8): 5306?11
Abstract

Despite the apparent convenience of microfluidic technologies for applications in healthcare, such devices often rely on capital-intensive optics and other peripheral equipment that limit throughput. Here, we monitored the transit of fluids, gases, particles,�and cells�as they flowed through a microfluidic channel without the use of a camera or laser, i.e., "optics-free" microfluidics. We did this by monitoring the deformation of the side walls�caused by the analyte passing through the channel. Critically, the analyte did not have to make contact with the channel walls to induce a deflection. This minute deformation was transduced into a change in electrical resistance using an ultrasensitive piezoresitive film composed of metallic nano-islands on graphene. We related changes in the resistance of the sensor to the theoretical deformation of the channel at varying flow rates. Then, we used air bubbles to induce a perturbation on the elastomeric channel walls and measured the viscoelastic relaxation of the walls of the channel. We obtained a viscoelastic time constant of 11.3 � 3.5 s-1 for polydimethylsiloxane, which is consistent with values obtained using�other techniques. Finally, we flowed silica particles and human mesenchymal stem cells and measured the deformation profiles of the channel. This technique yielded a convenient, continuous, and�non-contact measurement of rigid and deformable particles without the use of a laser or camera.

View details for DOI 10.1021/acs.nanolett.8b02292

View details for Web of Science ID 000441478300094

View details for PubMedID 30024767

View details for PubMedCentralID PMC6174088
Development of a Trimodal Contrast Agent for Acoustic and Magnetic Particle Imaging of Stem Cells ACS APPLIED NANO MATERIALS Lemaster, J. E., Chen, F., Kim, T., Hariri, A., Jokerst, J. 2018; 1 (3): 1321?31
View details for DOI 10.1021/acsanm.8b00063

View details for Web of Science ID 000461400400034
Photoacoustic Imaging for Noninvasive Periodontal Probing Depth Measurements JOURNAL OF DENTAL RESEARCH Lin, C. Y., Chen, F., Hariri, A., Chen, C. J., Wilder-Smith, P., Takesh, T., Jokerst, J. V. 2018; 97 (1): 23?30
Abstract

The periodontal probe is the gold standard tool for periodontal examinations, including probing depth measurements, but is limited by systematic and random errors. Here, we used photoacoustic ultrasound for high-spatial resolution imaging of probing depths. Specific contrast from dental pockets was achieved with food-grade cuttlefish ink as a contrast medium. Here, 39 porcine teeth (12 teeth with artificially deeper pockets) were treated with the contrast agent, and the probing depths were measured with novel photoacoustic imaging and a Williams periodontal probe. There were statistically significant differences between the 2 measurement approaches for distal, lingual, and buccal sites but not mesial. Bland-Altman analysis revealed that all bias values were < �0.25 mm, and the coefficients of variation for 5 replicates were <11%. The photoacoustic imaging approach also offered 0.01-mm precision and could cover the entire pocket, as opposed to the probe-based approach, which is limited to only a few sites. This report is the first to use photoacoustic imaging for probing depth measurements with potential implications to the dental field, including tools for automated dental examinations or noninvasive examinations.

View details for DOI 10.1177/0022034517729820

View details for Web of Science ID 000418548700003

View details for PubMedID 28880116

View details for PubMedCentralID PMC5755810
Photoacoustic Imaging of Human Mesenchymal Stem Cells Labeled with Prussian Blue-Poly(L-lysine) Nanocomplexes ACS NANO Kim, T., Lemaster, J. E., Chen, F., Li, J., Jokerst, J. V. 2017; 11 (9): 9022?32
Abstract

Acoustic imaging is affordable and accessible without ionizing radiation. Photoacoustic imaging increases the contrast of traditional ultrasound and can offer good spatial resolution when used at high frequencies with excellent temporal resolution. Prussian blue nanoparticles (PBNPs) are an emerging photoacoustic contrast agent with strong optical absorption in the near-infrared region. In this study, we developed a simple and efficient method to label human mesenchymal stem cells (hMSCs) with PBNPs and imaged them with photoacoustic imaging. First, PBNPs were synthesized by the reaction of FeCl3 with K4[Fe(CN)6] in the presence of citric acid and complexed with the cationic transfection agent poly-l-lysine (PLL). The PLL-coated PBNPs (PB-PLL nanocomplexes) have a maximum absorption peak at 715 nm and could efficiently label hMSCs. Cellular uptake of these nanocomplexes was studied using bright field, fluorescence, and transmission electron microscopy. The labeled stem cells were successfully differentiated into two downstream lineages of adipocytes and osteocytes, and they showed positive expression for surface markers of CD73, CD90, and CD105. No changes in viability or proliferation of the labeled cells were observed, and the secretome cytokine analysis indicated that the expression levels of 12 different proteins were not dysregulated by PBNP labeling. The optical properties of PBNPs were preserved postlabeling, suitable for the sensitive and quantitative detection of implanted cells. Labeled hMSCs exhibited strong photoacoustic contrast in vitro and in vivo when imaged at 730 nm, and the detection limit was 200 cells/?L in vivo. The photoacoustic signal increased as a function of cell concentration, indicating that the number of labeled cells can be quantified during and after cell transplantations. In hybrid ultrasound/photoacoustic imaging, this approach offers real-time and image-guided cellular injection even through an intact skull for brain intraparenchymal injections. Our labeling and imaging technique allowed the detection and monitoring of 5 � 104 mesenchymal stem cells in living mice over a period of 14 days.

View details for DOI 10.1021/acsnano.7b03519

View details for Web of Science ID 000411918200050

View details for PubMedID 28759195

View details for PubMedCentralID PMC5630123
A Nanoscale Tool for Photoacoustic-Based Measurements of Clotting Time and Therapeutic Drug Monitoring of Heparin. Nano letters Wang, J., Chen, F., Arconada-Alvarez, S. J., Hartanto, J., Yap, L. P., Park, R., Wang, F., Vorobyova, I., Dagliyan, G., Conti, P. S., Jokerst, J. V. 2016; 16 (10): 6265?71
Abstract

Heparin anticoagulation therapy is an indispensable feature of clinical care yet has a narrow therapeutic window and is the second most common intensive care unit (ICU) medication error. The active partial thromboplastin time (aPTT) monitors heparin but suffers from long turnaround times, a variable reference range, limited utility with low molecular weight heparin, and poor correlation to dose. Here, we describe a photoacoustic imaging technique to monitor heparin concentration using methylene blue as a simple and Federal Drug Administration-approved contrast agent. We found a strong correlation between heparin concentration and photoacoustic signal measured in phosphate buffered saline (PBS) and blood. Clinically relevant heparin concentrations were detected in blood in 32 s with a detection limit of 0.28 U/mL. We validated this imaging approach by correlation to the aPTT (Pearson's r = 0.86; p < 0.05) as well as with protamine sulfate treatment. This technique also has good utility with low molecular weight heparin (enoxaparin) including a blood detection limit of 72 ?g/mL. We then used these findings to create a nanoparticle-based hybrid material that can immobilize methylene blue for potential applications as a wearable/implantable heparin sensor to maintain drug levels in the therapeutic window. To the best of our knowledge, this is the first use of photoacoustics to image anticoagulation therapy with significant potential implications to the cardiovascular and surgical community.

View details for DOI 10.1021/acs.nanolett.6b02557

View details for PubMedID 27668964

View details for PubMedCentralID PMC5623117

Fang Chen (Rosy)

Postdoctoral Research Fellow, Ophthalmology

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