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Magnetic field hyperthermia relies on the intra-tumoural delivery of magnetic nanoparticles by interstitial injection, followed by their heating on exposure to a remotely-applied alternating magnetic field (AMF). This offers a potential sole or adjuvant route to treating drug-resistant tumours for which no alternatives are currently available. However, two challenges in nanoparticle delivery currently hinder the effective clinical translation of this technology: obtaining enough magnetic material within the tumour to enable sufficient heating; and doing this accurately to limit or avoid damage to surrounding healthy tissue. A further complication is the lack of established methods to non-invasively quantify nanoparticle biodistribution, which is necessary to evaluate the performance of improved delivery strategies. Here we employ 111In radiolabelling and single-photon emission computed tomography (SPECT) to non-invasively quantify distribution of a clinical grade iron-oxide-based nanoparticle in a mouse model of melanoma. We show that compared to manual injection, ultrasound guided delivery together with syringe-pump-controlled infusion improves both the nanoparticle concentration within the tumour, and the accuracy of delivery - reducing off-target peri-tumoural delivery. Following AMF heating, injected melanomas shrank significantly compared to non-injected controls, validating therapeutic efficacy. Systemic off-target delivery was quantified and extrapolated to predict off-target energy absorbance within safe limits for the main sites of background accumulation. With many nanoparticle-based therapies currently in development for cancer, this image-guided delivery strategy has wide potential impact beyond the field of magnetic hyperthermia. Future use in representative patient cohorts would also be enabled by the high clinical availability of both SPECT and ultrasound imaging.
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Cell therapy is a potential novel treatment for cardiac regeneration and numerous studies have attempted to transplant cells to regenerate the myocardium lost during myocardial infarction. To date, only minimal improvements to cardiac function have been reported. This is likely to be the result of low cell retention and survival following transplantation. This study aimed to improve the delivery and engraftment of viable cells by using an injectable microcarrier that provides an implantable, biodegradable substrate for attachment and growth of cardiomyocytes derived from induced pluripotent stem cells (iPSC). We describe the fabrication and characterisation of Thermally Induced Phase Separation (TIPS) microcarriers and their surface modification to enable iPSC-derived cardiomyocyte attachment in xeno-free conditions is described. The selected formulation resulted in iPSC attachment, expansion, and retention of pluripotent phenotype. Differentiation of iPSC into cardiomyocytes on the microcarriers is investigated in comparison with culture on 2D tissue culture plastic surfaces. Microcarrier culture is shown to support culture of a mature cardiomyocyte phenotype, be compatible with injectable delivery, and reduce anoikis. The findings from this study demonstrate that TIPS microcarriers provide a supporting matrix for culturing iPSC and iPSC-derived cardiomyocytes in vitro and are suitable as an injectable cell-substrate for cardiac regeneration.
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Diferenciación Celular , Células Madre Pluripotentes Inducidas , Miocitos Cardíacos , Células Madre Pluripotentes Inducidas/citología , Miocitos Cardíacos/citología , Diferenciación Celular/fisiología , Humanos , Células Cultivadas , Técnicas de Cultivo de Célula/métodos , Materiales BiocompatiblesRESUMEN
Targeted delivery and retention are essential requirements for implantable tissue-engineered products. Non-invasive imaging methods that can confirm location, retention, and biodistribution of transplanted cells attached to implanted tissue engineering scaffolds will be invaluable for the optimization and enhancement of regenerative therapies. To address this need, an injectable tissue engineering scaffold consisting of highly porous microspheres compatible with transplantation of cells is modified to contain the computed tomography (CT) contrast agent barium sulphate (BaSO4). The trackable microspheres show high x-ray absorption, with contrast permitting whole-body tracking. The microspheres are cellularized with GFP+ Luciferase+ mesenchymal stem cells and show in vitro biocompatibility. In vivo, cellularized BaSO4-loaded microspheres are delivered into the hindlimb of mice where they remain viable for 14 days. Co-registration of 3D-bioluminescent imaging and µCT reconstructions enable the assessment of scaffold material and cell co-localization. The trackable microspheres are also compatible with minimally-invasive delivery by ultrasound-guided transthoracic intramyocardial injections in rats. These findings suggest that BaSO4-loaded microspheres can be used as a novel tool for optimizing delivery techniques and tracking persistence and distribution of implanted scaffold materials. Additionally, the microspheres can be cellularized and have the potential to be developed into an injectable tissue-engineered combination product for cardiac regeneration.
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Células Madre Mesenquimatosas , Microesferas , Ingeniería de Tejidos , Andamios del Tejido , Tomografía Computarizada por Rayos X , Animales , Andamios del Tejido/química , Ingeniería de Tejidos/métodos , Ratones , Ratas , Tomografía Computarizada por Rayos X/métodos , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Sulfato de Bario/química , Medios de Contraste/químicaRESUMEN
Recently, layered rare-earth hydroxides (LRHs) have received growing attention in the field of theranostics. We have previously reported the hydrothermal synthesis of layered terbium hydroxide (LTbH), which exhibited high biocompatibility, reversible uptake of a range of model drugs, and release-sensitive phosphorescence. Despite these favourable properties, LTbH particles produced by the reported method suffered from poor size-uniformity (670 ± 564 nm), and are thus not suitable for therapeutic applications. To ameliorate this issue, we first derive an optimised hydrothermal synthesis method to generate LTbH particles with a high degree of homogeneity and reproducibility, within a size range appropriate for in vivo applications (152 ± 59 nm, n = 6). Subsequently, we apply this optimised method to synthesise a selected range of LRH materials (R = Pr, Nd, Gd, Dy, Er, Yb), four of which produced particles with an average size under 200 nm (Pr, Nd, Gd, and Dy) without the need for further optimisation. Finally, we incorporate Gd and Tb into LRHs in varying molar ratios (1 : 3, 1 : 1, and 3 : 1) and assess the combined magnetic relaxivity and phosphorescence properties of the resultant LRH materials. The lead formulation, LGd1.41Tb0.59H, was demonstrated to significantly shorten the T2 relaxation time of water (r2 = 52.06 mM-1 s-1), in addition to exhibiting a strong phosphorescence signal (over twice that of the other LRH formulations, including previously reported LTbH), therefore holding great promise as a potential multi-modal medical imaging probe.
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Hidróxidos , Metales de Tierras Raras , Tamaño de la Partícula , Hidróxidos/química , Metales de Tierras Raras/química , Imagen por Resonancia Magnética , Imagen Multimodal , HumanosRESUMEN
Perivascular spaces mediate a complex interaction between cerebrospinal fluid and brain tissue that may be an important pathway for solute waste clearance. Their structural or functional derangement may contribute to the development of age-related neurogenerative conditions. Here, we employed a non-invasive low b-value diffusion-weighted ECG-gated MRI method to capture perivascular fluid movement around the middle cerebral artery of the anaesthetised rat brain. Using this method, we show that such MRI estimates of perivascular fluid movement directionality are highly sensitive to the cardiac cycle. We then show that these measures of fluid movement directionality are decreased in the angiotensin-II pharmacological model of acute hypertension, with an associated dampening of vessel pulsatility. This translational MRI method may, therefore, be useful to monitor derangement of perivascular fluid movement associated with cardiovascular pathologies, such as hypertension, in order to further our understanding of perivascular function in neurology.
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Hipertensión , Arteria Cerebral Media , Ratas , Animales , Imagen por Resonancia Magnética , Hipertensión/metabolismo , Difusión , Encéfalo/irrigación sanguínea , Líquido Cefalorraquídeo/metabolismoRESUMEN
Protein-based biomaterial use is expanding within medicine, together with the demand to visualize their placement and behavior in vivo. However, current medical imaging techniques struggle to differentiate between protein-based implants and surrounding tissue. Here a fast, simple, and translational solution for tracking transplanted protein-based scaffolds is presented using X-ray CT-facilitating long-term, non-invasive, and high-resolution imaging. X-ray visible scaffolds are engineered by selectively iodinating tyrosine residues under mild conditions using readily available reagents. To illustrate translatability, a clinically approved hernia repair mesh (based on decellularized porcine dermis) is labeled, preserving morphological and mechanical properties. In a mouse model of mesh implantation, implants retain marked X-ray contrast up to 3 months, together with an unchanged degradation rate and inflammatory response. The technique's compatibility is demonstrated with a range of therapeutically relevant protein formats including bovine, porcine, and jellyfish collagen, as well as silk sutures, enabling a wide range of surgical and regenerative medicine uses. This solution tackles the challenge of visualizing implanted protein-based biomaterials, which conventional imaging methods fail to differentiate from endogenous tissue. This will address previously unanswered questions regarding the accuracy of implantation, degradation rate, migration, and structural integrity, thereby accelerating optimization and safe translation of therapeutic biomaterials.
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Ingeniería de Tejidos , Andamios del Tejido , Ratones , Animales , Bovinos , Porcinos , Andamios del Tejido/química , Ingeniería de Tejidos/métodos , Rayos X , Halogenación , Materiales Biocompatibles/químicaRESUMEN
Fibroblasts in scar tissue elicit myocyte excitation and promote arrhythmia in mouse hearts.
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Arritmias Cardíacas , Cicatriz , Acoplamiento Excitación-Contracción , Fibroblastos , Miocitos Cardíacos , Animales , Ratones , Arritmias Cardíacas/patología , Cicatriz/patología , Fibroblastos/patología , Uniones Comunicantes , Miocitos Cardíacos/patología , Infarto del Miocardio/patologíaRESUMEN
Forensic laboratories need quick and simple technology to improve turnaround times, while delivering reliable results. The goal of this study is first to create a simplified workflow to meet new Academy Standards Board requirements for urine testing in drug-facilitated crime investigations and, second, to create "ready-to-go", "hands-free" testing technology to further streamline analytical procedures. A first of its kind, the ToxBox forensic test kit is used to validate a single analytical procedure for opioids, benzodiazepines, cannabinoids, antidepressants, and several other drug classes. Method performance indicators follow accreditation requirements and include accuracy, precision, measurement uncertainty, calibration models, reportable range, sensitivity, specificity, carryover, interference, ion suppression/enhancement, and analyte stability. "Hands-free" testing platforms require the use of new suspended-state technology to stabilize NIST-traceable standards premanufactured at precise concentrations in the presence of sample preparation reagents. By suspending all reaction components in the solid state, with air gaps between the phases, reference standards and process controls are built in a "ready-to-go" format and stabilized for long-term storage in the presence of a sample matrix, ß-d-glucuronidase, and enzymatic buffers. "Hands-free" test kits are removed from storage, incubated at either ambient temperature or 60 °C, and assayed using validated methods. This is the first example of how complex forensic testing workflows can be streamlined with new "hands-free" testing strategies to meet analytical challenges associated with quantitative and confirmatory analyses.
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The development of near-infrared light responsive conductive polymers provides a useful theranostic platform for malignant tumors by maximizing spatial resolution with deep tissue penetration for diagnosis and photothermal therapy. Herein, the self-assembly of ultrathin 2D polypyrrole nanosheets utilizing dopamine as a capping agent and a monolayer of octadecylamine as a template is demonstrated. The 2D polypyrrole-polydopamine nanostructure has tunable size distribution which shows strong absorption in the first and second near-infrared windows, enabling photoacoustic imaging and photothermal therapy. The hybrid double-layer is demonstrated to increase Raman intensity for 3D Raman imaging (up to two orders of magnitude enhancement and spatial resolution up to 1 µm). The acidic environment drives reversible doping of polypyrrole, which can be detected by Raman spectroscopy. The combined properties of the nanosheets can substantially enhance performance in dual-mode Raman and photoacoustic guided photothermal therapy, as shown by the 69% light to heat conversion efficiency and higher cytotoxicity against cancer spheroids. These pH-responsive features highlight the potential of 2D conductive polymers for applications in accurate, highly efficient theranostics.
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Nanopartículas , Neoplasias , Técnicas Fotoacústicas , Humanos , Polímeros/química , Terapia Fototérmica , Fototerapia/métodos , Pirroles/farmacología , Nanopartículas/química , Técnicas Fotoacústicas/métodos , Neoplasias/diagnóstico por imagen , Neoplasias/terapia , Nanomedicina Teranóstica/métodosRESUMEN
The protein kinase PKN2 is required for embryonic development and PKN2 knockout mice die as a result of failure in the expansion of mesoderm, cardiac development and neural tube closure. In the adult, cardiomyocyte PKN2 and PKN1 (in combination) are required for cardiac adaptation to pressure-overload. The specific role of PKN2 in contractile cardiomyocytes during development and its role in the adult heart remain to be fully established. We used mice with cardiomyocyte-directed knockout of PKN2 or global PKN2 haploinsufficiency to assess cardiac development and function using high resolution episcopic microscopy, MRI, micro-CT and echocardiography. Biochemical and histological changes were also assessed. Cardiomyocyte-directed PKN2 knockout embryos displayed striking abnormalities in the compact myocardium, with frequent myocardial clefts and diverticula, ventricular septal defects and abnormal heart shape. The sub-Mendelian homozygous knockout survivors developed cardiac failure. RNASeq data showed up-regulation of PKN2 in patients with dilated cardiomyopathy, suggesting an involvement in adult heart disease. Given the rarity of homozygous survivors with cardiomyocyte-specific deletion of PKN2, the requirement for PKN2 in adult mice was explored using the constitutive heterozygous PKN2 knockout. Cardiac hypertrophy resulting from hypertension induced by angiotensin II was reduced in these haploinsufficient PKN2 mice relative to wild-type littermates, with suppression of cardiomyocyte hypertrophy and cardiac fibrosis. It is concluded that cardiomyocyte PKN2 is essential for heart development and the formation of compact myocardium and is also required for cardiac hypertrophy in hypertension. Thus, PKN signalling may offer therapeutic options for managing congenital and adult heart diseases.
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Cardiomiopatías , Hipertensión , Proteína Quinasa C/metabolismo , Angiotensina II/metabolismo , Angiotensina II/farmacología , Animales , Cardiomegalia/metabolismo , Cardiomiopatías/metabolismo , Cardiomiopatías/patología , Femenino , Hipertensión/metabolismo , Hipertensión/patología , Ratones , Ratones Noqueados , Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , EmbarazoRESUMEN
PURPOSE: To assess the safety and tolerability of a vandetanib-eluting radiopaque embolic (BTG-002814) for transarterial chemoembolization (TACE) in patients with resectable liver malignancies. MATERIALS AND METHODS: The VEROnA clinical trial was a first-in-human, phase 0, single-arm, window-of-opportunity study. Eligible patients were aged ≥18 years and had resectable hepatocellular carcinoma (HCC) (Child-Pugh A) or metastatic colorectal cancer (mCRC). Patients received 1 mL of BTG-002814 transarterially (containing 100 mg of vandetanib) 7-21 days prior to surgery. The primary objectives were to establish the safety and tolerability of BTG-002814 and determine the concentrations of vandetanib and the N-desmethyl vandetanib metabolite in the plasma and resected liver after treatment. Biomarker studies included circulating proangiogenic factors, perfusion computed tomography, and dynamic contrast-enhanced magnetic resonance imaging. RESULTS: Eight patients were enrolled: 2 with HCC and 6 with mCRC. There was 1 grade 3 adverse event (AE) before surgery and 18 after surgery; 6 AEs were deemed to be related to BTG-002814. Surgical resection was not delayed. Vandetanib was present in the plasma of all patients 12 days after treatment, with a mean maximum concentration of 24.3 ng/mL (standard deviation ± 13.94 ng/mL), and in resected liver tissue up to 32 days after treatment (441-404,000 ng/g). The median percentage of tumor necrosis was 92.5% (range, 5%-100%). There were no significant changes in perfusion imaging parameters after TACE. CONCLUSIONS: BTG-002814 has an acceptable safety profile in patients before surgery. The presence of vandetanib in the tumor specimens up to 32 days after treatment suggests sustained anticancer activity, while the low vandetanib levels in the plasma suggest minimal release into the systemic circulation. Further evaluation of this TACE combination is warranted in dose-finding and efficacy studies.
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Carcinoma Hepatocelular , Quimioembolización Terapéutica , Neoplasias Hepáticas , Adolescente , Adulto , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/terapia , Quimioembolización Terapéutica/efectos adversos , Quimioembolización Terapéutica/métodos , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/terapia , Piperidinas , Inhibidores de Proteínas Quinasas/efectos adversos , Quinazolinas/efectos adversos , Resultado del TratamientoRESUMEN
Medical therapies achieve their control at expense to the patient in the form of a range of toxicities, which incur costs and diminish quality of life. Magnetic resonance navigation is an emergent technique that enables image-guided remote-control of magnetically labeled therapies and devices in the body, using a magnetic resonance imaging (MRI) system. Minimally INvasive IMage-guided Ablation (MINIMA), a novel, minimally invasive, MRI-guided ablation technique, which has the potential to avoid traditional toxicities, is presented. It comprises a thermoseed navigated to a target site using magnetic propulsion gradients generated by an MRI scanner, before inducing localized cell death using an MR-compatible thermoablative device. The authors demonstrate precise thermoseed imaging and navigation through brain tissue using an MRI system (0.3 mm), and they perform thermoablation in vitro and in vivo within subcutaneous tumors, with the focal ablation volume finely controlled by heating duration. MINIMA is a novel theranostic platform, combining imaging, navigation, and heating to deliver diagnosis and therapy in a single device.
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Imagen por Resonancia Magnética Intervencional , Neoplasias , Humanos , Imagen por Resonancia Magnética/métodos , Imagen por Resonancia Magnética Intervencional/métodos , Neoplasias/diagnóstico por imagen , Neoplasias/cirugía , Calidad de VidaRESUMEN
Engineered heart tissue (EHT) strategies, by combining cells within a hydrogel matrix, may be a novel therapy for heart failure. EHTs restore cardiac function in rodent injury models, but more data are needed in clinically relevant settings. Accordingly, an upscaled EHT patch (2.5 cm × 1.5 cm × 1.5 mm) consisting of up to 20 million human induced pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) embedded in a fibrin-based hydrogel was developed. A rabbit myocardial infarction model was then established to test for feasibility and efficacy. Our data showed that hPSC-CMs in EHTs became more aligned over 28 days and had improved contraction kinetics and faster calcium transients. Blinded echocardiographic analysis revealed a significant improvement in function in infarcted hearts that received EHTs, along with reduction in infarct scar size by 35%. Vascularization from the host to the patch was observed at week 1 and stable to week 4, but electrical coupling between patch and host heart was not observed. In vivo telemetry recordings and ex vivo arrhythmia provocation protocols showed that the patch was not pro-arrhythmic. In summary, EHTs improved function and reduced scar size without causing arrhythmia, which may be due to the lack of electrical coupling between patch and host heart.
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Insuficiencia Cardíaca , Infarto del Miocardio , Miocardio/citología , Ingeniería de Tejidos/métodos , Animales , Arritmias Cardíacas/etiología , Arritmias Cardíacas/fisiopatología , Arritmias Cardíacas/prevención & control , Procedimientos Quirúrgicos Cardíacos , Regeneración Tisular Dirigida/métodos , Insuficiencia Cardíaca/prevención & control , Insuficiencia Cardíaca/terapia , Humanos , Hidrogeles/uso terapéutico , Células Madre Pluripotentes Inducidas , Contracción Miocárdica/fisiología , Infarto del Miocardio/fisiopatología , Infarto del Miocardio/terapia , ConejosRESUMEN
Interleukin (IL)-6 is an emerging therapeutic target in myocardial infarction (MI). IL-6 has 2 distinct signaling pathways: trans-signaling, which mediates inflammation, and classic signaling, which also has anti-inflammatory effects. The novel recombinant fusion protein sgp130Fc achieves exclusive trans-signaling blockade, whereas anti-IL-6 antibodies (Abs) result in panantagonism. In a rat model of reperfused MI, sgp130Fc, but not anti-IL-6-Ab, attenuated neutrophil and macrophage infiltration into the myocardium, reduced infarct size, and preserved cardiac function 28 days after MI. These data demonstrate the efficacy of exclusive IL-6 trans-signaling blockade and support further investigation of sgp130Fc as a potential novel therapy in MI.
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Early measurements of tissue viability after myocardial infarction (MI) are essential for accurate diagnosis and treatment planning but are challenging to obtain. Here, manganese, a calcium analogue and clinically approved magnetic resonance imaging (MRI) contrast agent, is used as an imaging biomarker of myocardial viability in the first hours after experimental MI. Safe Mn2+ dosing is confirmed by measuring in vitro beating rates, calcium transients, and action potentials in cardiomyocytes, and in vivo heart rates and cardiac contractility in mice. Quantitative T1 mapping-manganese-enhanced MRI (MEMRI) reveals elevated and increasing Mn2+ uptake in viable myocardium remote from the infarct, suggesting MEMRI offers a quantitative biomarker of cardiac inotropy. MEMRI evaluation of infarct size at 1 h, 1 and 14 days after MI quantifies myocardial viability earlier than the current gold-standard technique, late-gadolinium-enhanced MRI. These data, coupled with the re-emergence of clinical Mn2+ -based contrast agents open the possibility of using MEMRI for direct evaluation of myocardial viability early after ischemic onset in patients.
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Supervivencia Celular/efectos de los fármacos , Medios de Contraste/farmacología , Corazón/diagnóstico por imagen , Manganeso/farmacología , Infarto del Miocardio/diagnóstico , Animales , Gluconato de Calcio/farmacología , Modelos Animales de Enfermedad , Corazón/fisiopatología , Humanos , Imagen por Resonancia Magnética , Ratones , Infarto del Miocardio/diagnóstico por imagen , Infarto del Miocardio/patología , Miocardio/patología , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patologíaRESUMEN
Glioblastomas (GBMs) are refractory to current treatments and novel therapeutic approaches need to be explored. Proapoptotic tumor necrosis factorrelated apoptosisinducing ligand (TRAIL) is tumorspecific and has been shown to induce apoptosis and subsequently kill GBM cells. However, approximately 50% of GBM cells are resistant to TRAIL and a combination of TRAIL with other therapeutics is necessary to induce mechanismbased cell death in TRAILresistant GBMs. The present study examined the ability of the tumor cell surface receptor, interleukin (IL)13 receptor α2 (IL13Rα2) and epidermal growth factor receptor (EGFR)targeted pseudomonas exotoxin (PE) to sensitize TRAILresistant GBM cells and assessed the dual effects of interleukin 13PE (IL13PE) or EGFR nanobodyPE (ENbPE) and TRAIL for the treatment of a broad range of brain tumors with a distinct TRAIL therapeutic response. Receptor targeted toxins upregulated TRAIL death receptors (DR4 and DR5) and suppressed the expression of antiapoptotic FLICEinhibitory protein (FLIP) and Xlinked inhibitor of apoptosis protein (XIAP). This also led to the induction of the cleavage of caspase8 and caspase9 and resulted in the sensitization of highly resistant established GBM and patientderived GBM stem cell (GSC) lines to TRAILmediated apoptosis. These findings provide a mechanismbased strategy that may provide options for the cellmediated delivery of bifunctional therapeutics to target a wide spectrum of TRAILresistant GBMs.
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Toxinas Bacterianas/farmacología , Exotoxinas/farmacología , Glioblastoma , Subunidad alfa2 del Receptor de Interleucina-13 , Interleucina-13/farmacología , Proteínas de Neoplasias , Pseudomonas/química , Anticuerpos de Dominio Único/farmacología , Ligando Inductor de Apoptosis Relacionado con TNF , Toxinas Bacterianas/química , Muerte Celular/efectos de los fármacos , Muerte Celular/genética , Línea Celular Tumoral , Receptores ErbB/genética , Receptores ErbB/metabolismo , Exotoxinas/química , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Inmunotoxinas/química , Inmunotoxinas/farmacología , Interleucina-13/química , Subunidad alfa2 del Receptor de Interleucina-13/genética , Subunidad alfa2 del Receptor de Interleucina-13/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Anticuerpos de Dominio Único/química , Ligando Inductor de Apoptosis Relacionado con TNF/genética , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismoRESUMEN
Cell-based therapies have been making great advances toward clinical reality. Despite the increase in trial activity, few therapies have successfully navigated late-phase clinical trials and received market authorization. One possible explanation for this is that additional tools and technologies to enable their development have only recently become available. To support the safety evaluation of cell therapies, the Health and Environmental Sciences Institute Cell Therapy-Tracking, Circulation and Safety Committee, a multisector collaborative committee, polled the attendees of the 2017 International Society for Cell & Gene Therapy conference in London, UK, to understand the gaps and needs that cell therapy developers have encountered regarding safety evaluations in vivo. The goal of the survey was to collect information to inform stakeholders of areas of interest that can help ensure the safe use of cellular therapeutics in the clinic. This review is a response to the cellular imaging interests of those respondents. The authors offer a brief overview of available technologies and then highlight the areas of interest from the survey by describing how imaging technologies can meet those needs. The areas of interest include imaging of cells over time, sensitivity of imaging modalities, ability to quantify cells, imaging cellular survival and differentiation and safety concerns around adding imaging agents to cellular therapy protocols. The Health and Environmental Sciences Institute Cell Therapy-Tracking, Circulation and Safety Committee believes that the ability to understand therapeutic cell fate is vital for determining and understanding cell therapy efficacy and safety and offers this review to aid in those needs. An aim of this article is to share the available imaging technologies with the cell therapy community to demonstrate how these technologies can accomplish unmet needs throughout the translational process and strengthen the understanding of cellular therapeutics.
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SIGNIFICANCE: Tumor detection and margin delineation are essential for successful tumor resection. However, postsurgical positive margin rates remain high for many cancers. Raman spectroscopy has shown promise as a highly accurate clinical spectroscopic diagnostic modality, but its margin delineation capabilities are severely limited by the need for pointwise application. AIM: We aim to extend Raman spectroscopic diagnostics and develop a multimodal computer vision-based diagnostic system capable of both the detection and identification of suspicious lesions and the precise delineation of disease margins. APPROACH: We first apply visual tracking of a Raman spectroscopic probe to achieve real-time tumor margin delineation. We then combine this system with protoporphyrin IX fluorescence imaging to achieve fluorescence-guided Raman spectroscopic margin delineation. RESULTS: Our system enables real-time Raman spectroscopic tumor margin delineation for both ex vivo human tumor biopsies and an in vivo tumor xenograft mouse model. We then further demonstrate that the addition of protoporphyrin IX fluorescence imaging enables fluorescence-guided Raman spectroscopic margin delineation in a tissue phantom model. CONCLUSIONS: Our image-guided Raman spectroscopic probe-tracking system enables tumor margin delineation and is compatible with both white light and fluorescence image guidance, demonstrating the potential for our system to be developed toward clinical tumor resection surgeries.