Bioorthogonal Radiopaque Hydrogel for Endoscopic Delivery and Universal Tissue Marking (original) (raw)
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Indocyanine green-loaded injectable alginate hydrogel as a marker for precision cancer surgery
Quantitative Imaging in Medicine and Surgery, 2020
Background: Accurate identification of tumor sites and boundaries is of paramount importance during minimally invasive surgery. Although laparoscopic resection is being increasingly and widely performed for early gastric and colorectal cancers, the detection of tumors located inside the stomach and intestine is difficult owing to the lack of tactile sensation. Here, we propose the application of an indocyanine green (ICG)-loaded alginate hydrogel system as a fluorescence surgical marker for precise laparoscopic operations. Methods: A physical complex of ICG and human serum albumin (HSA) was mixed with sodium alginate to form an injectable hydrogel system. Calcium carbonate and D-gluconic acid (GA) were added to the gel to control its strength and gelation time, respectively. The optimal conditions for the preparation of injectable hydrogels were determined by analyzing the fluorescence spectra and sol-gel transition time of the prepared samples at various concentrations and compositions. Next, the aqueous solutions of ICG, ICG-HSA, and ICG-HSA-loaded alginate were subcutaneously injected into nude mice (three mice per group), and nearinfrared (NIR) fluorescence images of the mice (λ ex. =780 nm, λ em. =845 nm) were obtained at different points in time for 8 days. Then, fluorescence intensities at the injection sites, target-to-background ratio, and areas of ICG fluorescence were analyzed. Finally, the potential utility of ICG-HSA-loaded alginate hydrogel as a surgical marker was evaluated in a porcine model. The ICG-HSA-loaded alginate solution was injected into three sites in the submucosal space of the porcine stomach via a catheter. A fluorescent laparoscopic system was installed on the abdomen of the pig 3 days post-injection, and the fluorescence signal generated from the fluorescence surgical marker located inside the stomach was evaluated using the fluorescence laparoscope system (λ ex. =785 nm, λ em. =805 nm). Results: The optimal concentration of ICG-HSA complex was determined to be 30 μM, and maximum fluorescence intensity of the complex was obtained at a 1:1 mole ratio of HSA to ICG. The subcutaneous injection of ICG or ICG-HSA solution in mice resulted in the rapid spread of the fluorescence signal around the injection site in 3 h, and a weak fluorescence was detected at the injection site 24 h post-injection. In contrast, the fluorescence detection time was effectively prolonged up to 96 h post-injection in the case of ICG-HSA-loaded alginate gel, while diffusion of the injected ICG from the injection site was effectively prevented. In the laparoscopic operation, injection sites of the hydrogel in porcine stomach could be accurately detected in real time even after 3 days. Conclusions: This alginate hydrogel system may be potentially useful as an effective surgical marker in terms of accuracy and persistence for laparoscopic operation.
Regional Radiochemotherapy Using In Situ Hydrogel
Pharmaceutical Research, 2005
To evaluate the feasibility of regional radiochemotherapy of mammary tumors using in situ hydrogel loaded with cisplatin (CDDP) and rhenium-188 (188 Re). Methods. Sodium alginate (SA) and calcium chloride were used to create a hydrogel for delivery of CDDP and 188 Re. In vitro studies were performed to evaluate cytotoxic effects of 188 Re-hydrogel and sustained-release ability of the CDDP-hydrogel. Tumor-bearing rats were injected with 188 Re-hydrogel (0.5-1 mCi/rat), 188 Re-perrhenate (0.5-1 mCi/rat, intratumoral, I.T.), CDDP-hydrogel (3 mg/kg), and 188 Re-hydrogel loaded with CDDP (3 mg/kg body weight, 0.5-1 mCi/rat), respectively, and groups receiving 188 Re were imaged at 24 and 48 h postinjection. Tumor volume, body weight, imaging, and kidney function were assessed as required for each group. Results. Successful formation of the hydrogel was demonstrated by cytotoxic effects of 188 Re-hydrogel and slow release of CDDP-hydrogel in vitro. Tumor volume measurements showed significant delay in tumor growth in treated vs. control groups with minimal variation in normal kidney function for the CDDP-hydrogel group. Scintigraphic images indicated localization of 188 Re-hydrogel in the tumor site up to 48 h postinjection. Conclusions. Our data demonstrate the feasibility of using hydrogel for delivery of chemotherapeutics and radiation locally. This technique may have applications involving other contrast modalities as well as treatment in cases where tumors are inoperable.
International Journal of Radiation Oncology*Biology*Physics, 2014
We propose using a temperature-sensitive hydrogel (GEL) to allow clinicians to perform direct needlebased injection of micronsize radiation therapy (RT) sources for treating localized tumors. RT-GEL was successfully injected into human tumors by using 30-guage needles. RT-GEL treatment showed much higher residual tumor activities, 170% (200%, respectively) higher than RT-saline at 24 h (48 h, respectively) after injection, with a minimal accumulation of Indium-111 to the kidneys. Purpose: To propose a novel radiation therapy (RT) delivery modality: locally targeted delivery of micron-size RT sources by using temperature-sensitive hydrogel (RT-GEL) as an injectable vehicle. Methods and Materials: Hydrogel is a water-like liquid at room temperature but gels at body temperature. Two US Food and Drug Administration-approved polymers were synthesized. Indium-111 (In-111) was used as the radioactive RT-GEL source. The release characteristics of In-111 from polymerized RT-GEL were evaluated. The injectability and efficacy of RT-GEL delivery to human breast tumor were tested using animal models with control datasets of RT-saline injection. As proof-of-concept studies, a total of 6 nude mice were tested by injecting 4 million tumor cells into their upper backs after a week of acclimatization. Three mice were injected with RT-GEL and 3 with RT-saline. Single-photon emission computed tomography (SPECT) and CT scans were performed on each mouse at 0, 24, and 48 h after injection. The efficacy of RT-GEL was determined by comparison with that of the control datasets by measuring kidney In-111 accumulation (mean nCi/cc), representing the distant diffusion of In-111. Results: RT-GEL was successfully injected into the tumor by using a 30-gauge needle. No difficulties due to polymerization of hydrogel during injection and intratumoral pressure were observed during RT-GEL injection. No back flow occurred for either RT-GEL or RT-saline. The residual tumor activities of In-111 were 49% at 24 h (44% at 48 h, respectively) for RT-GEL and 29% (22%, respectively) for RT-saline. Fused SPECT-CT images of RT-saline showed considerable kidney accumulation of In-111 (2886%, 261%, and 262% of RT-GEL at 0, 24, and 48 h, respectively). Conclusions: RT-GEL was successfully injected and showed much higher residual tumor activity: 170% (200%, respectively), than that of RT-saline at 24 h (48 h, respectively) after injection
2012
We propose using a temperature-sensitive hydrogel (GEL) to allow clinicians to perform direct needlebased injection of micronsize radiation therapy (RT) sources for treating localized tumors. RT-GEL was successfully injected into human tumors by using 30-guage needles. RT-GEL treatment showed much higher residual tumor activities, 170% (200%, respectively) higher than RT-saline at 24 h (48 h, respectively) after injection, with a minimal accumulation of Indium-111 to the kidneys. Purpose: To propose a novel radiation therapy (RT) delivery modality: locally targeted delivery of micron-size RT sources by using temperature-sensitive hydrogel (RT-GEL) as an injectable vehicle. Methods and Materials: Hydrogel is a water-like liquid at room temperature but gels at body temperature. Two US Food and Drug Administration-approved polymers were synthesized. Indium-111 (In-111) was used as the radioactive RT-GEL source. The release characteristics of In-111 from polymerized RT-GEL were evaluated. The injectability and efficacy of RT-GEL delivery to human breast tumor were tested using animal models with control datasets of RT-saline injection. As proof-of-concept studies, a total of 6 nude mice were tested by injecting 4 million tumor cells into their upper backs after a week of acclimatization. Three mice were injected with RT-GEL and 3 with RT-saline. Single-photon emission computed tomography (SPECT) and CT scans were performed on each mouse at 0, 24, and 48 h after injection. The efficacy of RT-GEL was determined by comparison with that of the control datasets by measuring kidney In-111 accumulation (mean nCi/cc), representing the distant diffusion of In-111. Results: RT-GEL was successfully injected into the tumor by using a 30-gauge needle. No difficulties due to polymerization of hydrogel during injection and intratumoral pressure were observed during RT-GEL injection. No back flow occurred for either RT-GEL or RT-saline. The residual tumor activities of In-111 were 49% at 24 h (44% at 48 h, respectively) for RT-GEL and 29% (22%, respectively) for RT-saline. Fused SPECT-CT images of RT-saline showed considerable kidney accumulation of In-111 (2886%, 261%, and 262% of RT-GEL at 0, 24, and 48 h, respectively). Conclusions: RT-GEL was successfully injected and showed much higher residual tumor activity: 170% (200%, respectively), than that of RT-saline at 24 h (48 h, respectively) after injection
Cancers
Background: Tumor-positive surgical margins during primary breast cancer (BCa) surgery are associated with a two-fold increase in the risk of local recurrence when compared with tumor-negative margins. Pathological microscopic evaluation of the samples only assesses about 1/10 of 1% of the entire volume of the removed BCa specimens, leading to margin under-sampling and potential local recurrence in patients with pathologically clean margins, i.e., false negative margins. In the case of tumor-positive margins, patients need to undergo re-excision and/or radiation therapy, resulting in increases in complications, morbidity, and healthcare costs. Development of a simple real-time imaging technique to identify residual BCa in the surgical cavity rapidly and precisely could significantly improve the quality of care. Methods: A small-molecule, fluorescently quenched protease-substrate probe, AKRO-QC-ICG, was tested as part of a thermosensitive imaging gel formulated for topical applicatio...
Nature communications, 2017
Tissue adhesives have emerged as an alternative to sutures and staples for wound closure and reconnection of injured tissues after surgery or trauma. Owing to their convenience and effectiveness, these adhesives have received growing attention particularly in minimally invasive procedures. For safe and accurate applications, tissue adhesives should be detectable via clinical imaging modalities and be highly biocompatible for intracorporeal procedures. However, few adhesives meet all these requirements. Herein, we show that biocompatible tantalum oxide/silica core/shell nanoparticles (TSNs) exhibit not only high contrast effects for real-time imaging but also strong adhesive properties. Furthermore, the biocompatible TSNs cause much less cellular toxicity and less inflammation than a clinically used, imageable tissue adhesive (that is, a mixture of cyanoacrylate and Lipiodol). Because of their multifunctional imaging and adhesive property, the TSNs are successfully applied as a hemos...
Biomaterials, 1987
The synthesis and properties of spherical radiopaque hydrogel particles designed for endovascular occlusion are reported. These particles were prepared by the hydroxyl acylation of low crosslinked poly (2-hydroxyethyl methacrylate) beads with a nontoxic radiopaque compound based on triiodobenzoic acid, without affecting their properties which are advantages in medical practice. The effect of the iodine content on the size of dry and swollen particles is discussed. It has been found that an iodine content of about 25-30 wt% is desirable in order to obtain an easily recognizable X-ray image. These particles make the immediate control of embolus application easy and enable periodical inspection of the polymer to check the successful blockage of the vessel. They also open up the method of endovascular occlusion to further improvement.
Research Square (Research Square), 2024
Liver cancer ranks as the fth leading cause of cancer-related death globally. Direct intratumoral injections of anti-cancer therapeutics may improve therapeutic e cacy and mitigate adverse effects compared to intravenous injections. Some challenges of intratumoral injections are that the liquid drug formulation may not remain localized and have unpredictable volumetric distribution. Thus, drug delivery varies widely, highly-dependent upon technique. An x-ray imageable poloxamer 407 (POL)-based drug delivery gel was developed and characterized, enabling real-time feedback. Utilizing three needle devices, POL or a control iodinated contrast solution were injected into an ex vivo bovine liver. The 3D distribution was assessed with cone beam computed tomography (CBCT). The 3D distribution of POL gels demonstrated localized spherical morphologies regardless of the injection rate. In addition, the gel 3D conformal distribution could be intentionally altered, depending on the injection technique. When doxorubicin (DOX) was loaded into the POL and injected, DOX distribution on optical imaging matched iodine distribution on CBCT suggesting spatial alignment of DOX and iodine localization in tissue. The controllability and localized deposition of this formulation may ultimately reduce the dependence on operator technique, reduce systemic side effects, and facilitate reproducibility across treatments, through more predictable standardized delivery.
Cell therapy is promising to treat many conditions, including neurological and osteoarticular diseases. Encapsulation of cells within hydrogels facilitates cell delivery and can improve therapeutic effects. However, much work remains to be done to align treatment strategies with specific diseases. The development of imaging tools that enable monitoring cells and hydrogel independently is key to achieving this goal. Our objective herein is to longitudinally study an iodine-labeled hydrogel, incorporating gold-labeled stem cells, by bicolor CT imaging afterin vivoinjection in rodent brains or knees. To this aim, an injectable self-healing hyaluronic acid (HA) hydrogel with long-persistent radiopacity was formed by the covalent grafting of a clinical contrast agent on HA. The labeling conditions were tuned to achieve sufficient X-ray signal and to maintain the mechanical and self-healing properties as well as injectability of the original HA scaffold. The efficient delivery of both cel...