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Oxygen Sensitive Trityl Radical OX071

Magnetic resonance imaging (MRI) and electron paramagnetic resonance oxygen imaging (eMRI or EPROI) are fundamentally based upon the same principles, however a key difference is the resonant species. MRI aligns water protons, that are abundant in the body, in a magnetic field to produce exquisite anatomical images whereas eMRI relies on aligning electron spins. Unlike the ubiquity of protons, unpaired electrons sensitive to oxygen are rarely found in living organisms. A nontoxic contrast agents, with high specificity and sensitivity to detect molecular oxygen, is a necessity for EPR-based oxygen imaging; and now, it is being synthesized by O2M Technologies. Introducing incredible molecule: OX071!

Tetrathiatriarylmethyl or “trityl” radicals are not unfamiliar in MRI applications. They have been used as a polarizing agent. Previous versions of trityls, such as the largely used Finland trityl (FT), were unsuitable for in vivo experimentation. Its lipophilic core has a propensity to aggregate with plasma proteins, resulting in some amount of toxicity. In the next iteration, trityl OX063, 12 methyl groups in FT are replaced with hydroxyethyl groups, which greatly increased it’s hydrophilicity. The result is a completely non-toxic, injectable probe. OX063 is used a polarizing agent in 13C MRI.

The latest evolution of trityl is OX071, a partially deuterated analogue of OX063. Deuterium is EPR-silent, which eliminates a source of hyperfine coupling with trityl’s radical center. OX071 retains all the benefits of it’s predecessor while also showing a higher oxygen sensitivity, a higher signal-to-noise ratio, and under physiological conditions, a single-line EPR spectrum with ultra-narrow linewidth. OX071 is especially sensitive in low oxygen conditions. Even a small amount of OX071 will generate signal. The probe can be delivered intravenously, intraperitonially or intratumorally. OX071 is cleared from the animal in 10-30 minutes virtually unchanged.

All these properties make OX071 the probe of choice for a wide array of in vivo EPR oximetry experiments. OX071 has already been published in applications of solid tumor oximetry, viability studies in highly oxygen dependent cell populations like transplanted islets of Langerhansbioscaffold device development, and much more. Reach out to O2M for OX063 or OX071 in your experiments!

Finding the Best Site for Tissue Graft Implantation

Oxygen sensitive LiPc probes implanted within the right dorsum subcutaneously, reporting oxygen tension  over 6 weeks. Data obtained by JIVA-25™ oxygen imager. Oxygen sensitive LiPc probes implanted within the right dorsum subcutaneously, reporting oxygen tension over 6 weeks. Data obtained by JIVA-25™ oxygen imager.

Tissue engineered grafts and cell encapsulation devices have significant potential to improve human health. The site of transplantation is a factor that has profound effect on graft survival. The ideal chosen site should be easy to access for implantation and retrieval, while providing adequate diffusion of nutrients and oxygen for support of cell survival until vascularization is established. The two most commonly used sites for implantation of tissue grafts and cell encapsulation devices are subcutaneous (SC) and intraperitoneal (IP). Evaluating the native oxygenation in these sites is valuable information towards understanding the physiological milieu of implants in vivo.

O2M’s recent peer-reviewed publication in Tissue Engineering Part C: Methods presents the first ever solid probe oxygen imaging, reporting pO2 values, of subcutaneous and intraperitoneal spaces in mice. We observe that solid probe oxygen imaging is a technology that offers researchers oxygenation data in vivo without needing further invasive measures or sacrifice. This study was funded by Juvenile Diabetes Research Foundation (JDRF) and will help scientists develop better therapies for type I diabetes as well as other health conditions.

Visit O2M’s Publication Page to learn about latest research in oxygen imaging.

O2M is at BioFAB and TERMIS!

Come see us in Manchester, New Hampshire!

Spring 2022 Meeting in the Millyard
June 7 – June 9 O2M will be presenting our latest research at the Poster Session
Wednesday June 8, Currier Museum, 5:30pm – 8:00pm

“In Vitro and In Vivo Oxygen Imaging of Islet Encapsulation Devices: Lessons Learned and Path Forward”

Come See Us in Toronto!

TERMIS-AM 2022
July 10 – July 13
Booth #107

Are you at TERMIS 2022? Make sure your plans include a visit to our booth in the Exhibition Hall. We hope to see you there!

O2M is Presenting at TERMIS! Keynote Talk by Dr. Mrignayani Kotecha
“In Vitro and In Vivo Oxygen Imaging assessment of Islet Transplantation Devices”
Sessions 7, Non-invasive Imaging and Analysis of Engineered Tissues
Wednesday, July 13, 8:00 AM – 8:30 AM Poster Presentation by Team O2M
“In Vivo Oxygen Imaging Of Oxygen Generating Cellular Implant Devices”
Poster Session 3
Tuesday, July 12, 4:30pm – 6:00pm

Upcoming O2M Webinar

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Moderator: Dr. Martyna Elas, Jagiellonian University, Krakow, Poland

About the Speaker:
Dr. Mark “Marty” Pagel has focused on molecular imaging research during the last 20 years in industry and academia.  He is a Professor in the Departments of Cancer Systems Imaging and Imaging Physics at the University of Texas MD Anderson Cancer Center.  In addition, Dr. Pagel has held leadership positions in professional societies, funding agencies, and scientific journals that focus on molecular imaging.  Dr. Pagel’s current research focuses on CEST MRI, PET/MRI, photoacoustic imaging, and EPR imaging, for studies of tumor hypoxia, acidosis, vascular perfusion and enzyme activity, with mouse models of cancer and for clinical trials with cancer patients.

Abstract: Previous studies with EPR imaging have shown that measurements of tumor pO2 can indicate the status of hypoxia in the tumor microenvironment, which can be used to predict response to radiation therapy.  To build on these previous studies, we are developing Oxygen Enhanced (OE) EPR imaging that challenges a pre-clinical tumor model with 21% O2 (medical grade air) and 100% O2 in the anesthetic carrier gas, which can be a useful biomarker for evaluating early response to radiation therapy.  In addition, we are developing Dynamic Contrast Enhanced (DCE) EPR imaging that measures tumor vascular perfusion, as a complimentary biomarker for evaluating early response to cancer treatment.  This presentation will also discuss our ongoing research studies that show how tumor hypoxia causes resistance to immunotherapy, and how reducing hypoxia can improve tumor control with immune checkpoint blockade.

Biomaterial Assessment Using Oxygen Imaging

Biomaterials that host live cells must overcome the crucial hurdle of sustaining sufficient oxygenation for cell survival. Several approaches for improving oxygenation within the biomaterials have been developed and investigated for improved cell survival in artificial tissue constructs. Regardless of the method of addressing the oxygen needs of the cells, all three-dimensional constructs require in situ pO2 assessment in vitro and in vivo to gauge the success of the approach. In addition, in vivo models can have very divergent results because of inherent variability between the animals, which demands a greater understanding for the breadth of variation in normal and diseased states.  O2M’s oxygen imaging technology can improve the outcome of cell and tissue engineering by providing real time in vitro and in vivo oxygen maps for improved therapy outcome.
O2M’s “Oxygen Measurement Core” partners with research labs to provide critical oxygenation and associated biological data to accelerate their development of better biomaterials, cell replacement devices, and tissue constructs. Recent publications from these partnerships have been published at Nature CommunicationsScience Advances, and Journal of Biomedical Materials Research.
Reach out to O2M to find out how oxygen imaging can advance the development of your biomaterial research!

O2M is at SFB!

Come see us in Baltimore! If you are at SFB 2022, make sure your plans include a visit to us. Get a hands-on demonstration with our in-vivo oxygen imager, JIVA-25™. We hope to see you there!

O2M is Presenting at SFB!
Come learn about our latest research!

Biomaterial-Tissue Interaction
Thursday, April 28, 11:00am – 11:15am
In Vivo pO2 Assessment of Implantation Site: SubQ vs IP
Oral Presentation by CEO Dr. Mrignayani Kotecha

Biomaterials for Pancreatic Islet Replacement and Immune Tolerance in T1D
Saturday, April 30, 12:15-12:30pm
In Vivo pO2 Measurement of Islet Encapsulation Devices in Oxygen Measurement Core
Oral Presentation by CEO Dr. Mrignayani Kotecha

Accelerating Towards a Cure for Type 1 Diabetes

Type 1 diabetes mellitus (T1D) is an autoimmune disease causing insufficient or no production of insulin from the pancreas; this impedes glucose metabolism, generating several life-long health sequelae in nearly every organ system. Tools such as automated exogenous insulin delivery systems and constant glucometers, alongside diligent self-care, do improve outcomes. However, additional therapies are needed to improve the management of therapeutic goals and eliminate the risks or consequences of wide swings in glycemia. Transplantation of human islets  has offered a proof-of-concept for beta-cell replacement therapy. But a number of hurdles remain in realizing the full potential of beta-cell replacement therapy, one of which being ensuring an adequate supply of nutrients and oxygen to the islet graft.

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In response, Juvenile Diabetes Research Foundation (JDRF) is collaborating with a wide spectrum of partners to develop a replacement product using an unlimited source of beta cells without needing broad spectrum immunosuppression. A critical challenge is to protect beta cells from their host’s immune system, while still preserving consistent gas permeability, and permitting glucose-responsive insulin secretion. Novel designs are emerging that try to strike this delicate balance between diffusion, perfusion, and protection (see figure). Non-invasive tools that can directly map oxygen levels in vivo could prove very useful in evaluating and optimizing new technologies that extend the viability of beta-cell implants. In an effort to accelerate the development of beta cell replacement therapies, JDRF is supporting O2M Technologies’ “Oxygen Measurement Core” to test the therapeutic potential of implantable cell delivery systems. The technology developed by O2M has already proven to be successful in providing oxygen maps of islet encapsulation devices in vitro and in mice.

JDRF is committed to achieving their vision of “a world without T1D.” By connecting multidisciplinary collaborations and investing in diverse strategies, JDRF is closing research gaps. See a discussion by VP of Research Dr. Esther Latres on how JDRF is accelerating towards a cure for T1D.

O2M is at RSNA 2021!

Come meet Team O2M at RSNA 2021! Our Demo JIVA-25 allows you to capture oxygen images of a "mouse." We are located in the New Vendors Exhibition Hall, booth #2402.

A Lesson From Insects on Overcoming Cell Encapsulation Hypoxia

Inadequate oxygenation is a major challenge in cell encapsulation, a therapy which holds potential to treat many diseases including type I diabetes. In such systems, cellular oxygen (O2) delivery is limited to slow passive diffusion from transplantation sites through a poorly O2-soluble encapsulating matrix, usually a hydrogel. This constrains the maximum permitted distance between encapsulated cells and their host site to within a few hundred micrometers to ensure cellular function.

To solve the problem of poor oxygen penetration, the Dr. Minglin Ma's group at Cornell University took inspiration from mealworm beetle larvae! As opposed to the blood circulatory system of vertebrates, many insects transport oxygen through a tracheal system (Fig. 1): a gas-filled, ladder-like channel network that permits O2 distribution across multi-millimeter scales. Critically significant to this design, gaseous O2 has a 104 times higher diffusion coefficient than dissolved O2. Ma's group designed a biomimetic scaffold featuring internal continuous air channels endowed with 10,000-fold higher O2 diffusivity than hydrogels (Fig. 2). They named the scaffold SONIC (Speedy Oxygenation Network for Islet Constructs), reported in last month's Nature Communications.

Figure 1: Beetle larva tracheal system. Figure 2: 3D mold cast for SONIC device
Figure 1: Mealworm beetle larva tracheal system. Figure 2: 3D cast of SONIC device.
Figure 1: Mealworm beetle larva tracheal system. Figure 2: 3D cast of SONIC device.

The SONIC scaffold is comprised of a hydrophobic polymer (vinylidene fluoride-co-hexafluoropropylene), and the internal continuous air channels were created by a phase separation process in a 3D printed mold. A hydrophilic polydopamine coating was applied to the scaffold surface, providing a compatible interface between the hydrophobic scaffold and hydrophilic hydrogel. SONIC's internal hydrophobicity avoids water penetration into the air channels, an essential feature for enabling high O2 permeability. Finally, a cell-laden hydrogel was applied via a simple in situ cross-linking procedure by pre-deposited CaSO4 crystals on the scaffold surface.

pO2 map and average pO2 of SONIC and control devices
pO2 map and average pO2 of SONIC and control devices

A spiral SONIC device was designed for delivering a clinically relevant islet dose for islet replacement therapy, which computational models predict could support a curative islet dose of 500 k IEQ human islets within a disk approximately 11 cm in diameter.

In summary, the SONIC scaffold provides a solution to the poor transport of O2 in traditionally employed bulk hydrogels of cell encapsulation systems and represents a promising platform for translatable encapsulation devices requiring high cell payloads.

Reach out to O2M™ for your experiments. We provide high resolution oxygen maps for in vitro and in vivo samples, among many other Core services.

Tumor Hypoxia Imaging

Axial slices of SCC7 squamous cell carcinoma in mouse leg of MRI, PO2 by JIVA-25™, and CT. Tumor contoured in pink.
Photo credit: Howard Halpern Lab, The University of Chicago
Axial slices of SCC7 squamous cell carcinoma in mouse leg of MRI, PO2 by JIVA-25™, and CT. Tumor contoured in pink. Photo credit: Howard Halpern Lab, The University of Chicago

Tissue oxygenation is determined by the balance of oxygen delivery to tissues against oxygen consumption by those tissues. Normally, this is a well-maintained balance through several homeostatic mechanisms. However, solid tumors are unable to maintain oxygen balance due to the aberrant structure and function of a tumor’s vascular supply, the tumor microenvironment, and the intense metabolic demands of tumor cells. In some cases, tumor cells develop adaptive strategies to escape oxygen deficiency, whereby hypoxic environments act as a selective pressure resulting in clonogenic expansion of tumor cells with hypoxia tolerance. This establishes a vicious cycle of hypoxia and malignant progression. Moreover, hypoxic tumor environments reduce the effectiveness of radiation therapy, as oxygen needs to be present within milliseconds of radiation to observe the “oxygen effect” - whereby oxygen radicals enhance radiation induced DNA damage. It has been well demonstrated in sarcomas of the cervix, breast, and prostate that hypoxia can be considered an independent predictor of disease progression, treatment failure, and metastatic potential. Electron paramagnetic resonance oxygen imaging is a technology 20 years in the making, that can non-invasively capture real time absolute-value images of oxygen tension in solid tumors (see figure).

Learn more about tumor oximetry at Dr. Martyna Elas's webinar.

The First Publication from “Oxygen Measurement Core”

Cell encapsulation represents a promising therapeutic strategy for many hormone-deficient diseases such as type I diabetes (T1D). However, adequate oxygenation of the encapsulated cells remains a challenge, especially in the poorly oxygenated subcutaneous site.

Recently, our collaborator, Dr. Minglin Ma's group at Cornell University, published a paper “An inverse-breathing encapsulation system for cell delivery” in Science Advances. This work reported a novel oxygen delivery system that generates oxygen (O2) for the islet cells from their own waste product, carbon dioxide (CO2), in a self-regulated (i.e. “inverse breathing”) way, supporting the long-term function of islets in the cell encapsulation device.

As lead author, Dr. Longhai Wang designed and fabricated the inverse-breathing device (iBED) by employing a gas-solid (CO2-lithium peroxide) reaction that was completely separated from the aqueous cellular environment by a gas-permeable membrane (Fig. a and b). Doctoral student Alexander Ernst performed computational modeling which guided device design optimizations (Fig. c).

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Oxygen mapping was performed using O2M's preclinical oxygen imager JIVA-25™ instrument at O2M's “Oxygen Measurement Core” facility to validate the CO2-regulated O2 release in the inverse-breathing devices (Fig. d).

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The iBED restored normoglycemia of immunocompetent diabetic mice for over 3 months. And functional islets were observed in scaled-up device implants in minipigs retrieved after 2 months (Fig. e). Furthermore, O2 supply may be extended indefinitely by the introduction of a tank replacement or formulation refilling modular design.

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This inverse breathing device provides a potential system to support long-term cell function in the clinically attractive subcutaneous site by overcoming several outstanding challenges in oxygenating encapsulated cells and thus represents considerable progress in the use of translatable long-term O2-supplementing technologies for cell replacement therapies.

Read the complete article here: https://advances.sciencemag.org/content/7/20/eabd5835

First Publication from “Oxygen Measurement Core”

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Did you know that JIVA-25™ can provide in vivo partial oxygen pressure (pO2) maps of an implanted devices in a rodent? The pO2 maps provide a crucial missing information to assess the success of all transplanted devices. Reach out to us if you are interested in performing such study in collaboration with us at our "Oxygen Measurement Core" facility or at your lab by bringing a JIVA-25™ to your lab. Looking forward to talk to you about what excites you in your journey of developing new cell- and tissue-based therapies!

In Vivo Oxygen Imaging of Islet Encapsulation Devices using JIVA-25™

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Did you know that JIVA-25™ can provide in vivo partial oxygen pressure (pO2) maps of an implanted devices in a rodent? The pO2 maps provide a crucial missing information to assess the success of all transplanted devices. Reach out to us if you are interested in performing such study in collaboration with us at our "Oxygen Measurement Core" facility or at your lab by bringing a JIVA-25™ to your lab. Looking forward to talk to you about what excites you in your journey of developing new cell- and tissue-based therapies!

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