Imaging of large volume subcutaneous deposition using MRI: exploratory clinical study results.

Subcutaneous (SC) delivery is a preferred route of administration for biotherapeutics but has predominantly been limited to volumes below 3 mL. With higher volume drug formulations emerging, understanding large volume SC (LVSC) depot localization, dispersion, and impact on the SC environment has become more critical. The aim of this exploratory clinical imaging study was to assess the feasibility of magnetic resonance imaging (MRI) to identify and characterize LVSC injections and their effect on SC tissue as a function of delivery site and volume. Healthy adult subjects received incremental injections of normal saline up to 5 mL total volume in the arm and up to 10 mL in the abdomen and thigh. MRI images were acquired after each incremental SC injection. Post-image analysis was performed to correct imaging artifacts, identify depot tissue location, create 3-dimensional (3D) SC depot rendering, and estimate in vivo bolus volumes and SC tissue distention. LVSC saline depots were readily achieved, imaged using MRI, and quantified via subsequent image reconstructions. Imaging artifacts occurred under some conditions, necessitating corrections applied during image analysis. 3D renderings were created for both the depot alone and in relation to the SC tissue boundaries. LVSC depots remained predominantly within the SC tissue and expanded with increasing injection volume. Depot geometry varied across injection sites and localized physiological structure changes were observed to accommodate LVSC injection volumes. MRI is an effective means to clinically visualize LVSC depots and SC architecture allowing assessment of deposition and dispersion of injected formulations.Trial Registration: Not applicable for this exploratory clinical imaging study.

Enabling faster subcutaneous delivery of larger volume, high viscosity fluids.

OBJECTIVES: Many current subcutaneous (SC) biologic therapies may require >1 mL volume or have increased viscosity, necessitating new delivery system approaches. This study evaluated 2-mL large-volume autoinjector (LVAI) delivery performance across varying solution viscosities and design inputs to assess the design space and identify configurations that produce practical injection times. METHODS: Investigational LVAI delivery duration and volume, depot location, and tissue effects were examined in both air and in vivo models across various pre-filled syringe (PFS) cannula types (27 G Ultra-thin wall [UTW], 27 G special thin wall [STW], or 29 G thin-wall [TW]), drive spring forces (SFLOW or SFHIGH), and Newtonian solutions (2.3-50 centipoise [cP]). RESULTS: Within each design configuration, increasing PFS internal diameters and spring forces reduced delivery times, while increasing viscosity increased times. The 27 G UTW PFS/SFHIGH combination achieved shorter delivery times across all injection conditions, with 2 mL in vivo durations <15 seconds at ≤31 cP and routinely <20 seconds at 39 and 51 cP, with nominal and transitory tissue effects. CONCLUSION: PFS cannula and spring force combinations can be tailored to achieve various injection durations across viscosities, while UTW PFS enables faster rates to potentially better accommodate human factors during LVAI injection, especially at high viscosity.

Initial clinical results of an in vivo dosimeter during external beam radiation therapy.

PURPOSE: An implantable radiation dosimeter has been developed to monitor dose delivered at depth in patients undergoing external beam therapy. A clinical pilot study was conducted to test the safety, efficacy, and utility of the device. METHODS AND MATERIALS: Ten patients, all with unresectable malignant disease, were enrolled to assess implantation risk and movement of the device in the body and to compare the in vivo measured dose to the value predicted by the treatment planning system software. RESULTS: Migration of the sensor away from the point of original placement was noted in only 1 patient (due to unconsolidated host tissue) and no adverse events were recorded during the implantation procedure or thereafter. Daily dose measurements were recorded successfully for all sensors in all patients. Variance between measured and predicted dose values was reported as a frequency of error at the > or =5% and > or =8% levels. The error frequency at the > or =8% level was as high as 47%, 29%, and 21% for lung, prostate, and rectal tumors, respectively. CONCLUSIONS: The implantable dosimeter was found to be safe and effective in measuring dose at depth. There are many factors that can influence delivered dose, and the implantable dosimeter measures the net effect of these factors. The daily sensor readings provide a new tool for rigorous treatment quality assurance.

An implantable radiation dosimeter for use in external beam radiation therapy.

An implantable radiation dosimeter for use with external beam therapy has been developed and tested both in vitro and in canines. The device uses a MOSFET dosimeter and is polled telemetrically every day during the course of therapy. The device is designed for permanent implantation and also acts as a radiographic fiducial marker. Ten dogs (companion animals) that presented with spontaneous, malignant tumors were enrolled in the study and received an implant in the tumor CTV. Three dogs received an additional implant in collateral normal tissue. Radiation therapy plans were created for the animals and they were treated with roughly 300 cGy daily fractions until completion of the prescribed cumulative dose. The primary endpoints of the study were to record any adverse events due to sensor placement and to monitor any movement away from the point of placement. No adverse events were recorded. Unacceptable device migration was experienced in two subjects and a retention mechanism was developed to prevent movement in the future. Daily dose readings were successfully acquired in all subjects. A rigorous in vitro calibration methodology has been developed to ensure that the implanted devices maintain an accuracy of +/-3.5% relative to an ionization chamber standard. The authors believe that an implantable radiation dosimeter is a practical and powerful tool that fosters individualized patient QA on a daily basis.

Theoretical analysis of adsorption thermodynamics for hydrophobic peptide residues on SAM surfaces of varying functionality.

At a fundamental level, protein adsorption to a synthetic surface must be strongly influenced by the interaction between the peptide residues presented by the protein's surface (primary protein structure) and the functional groups presented by the synthetic surface. In this study, semi-empirical molecular modeling was used along with experimental wetting data to theoretically approach protein adsorption at this primary structural level. Changes in enthalpy, entropy, and Gibbs free energy were calculated as a function of residue-surface separation distance for the adsorption of individual hydrophobic peptide residues (valine, leucine, phenylalanine) on alkanethiol self-assembled monolayers on gold [Au-S(CH(2))(15)-X; X = CH(3), OH, NH(3)(+), COO(-)]. The results predict that the adsorption of each type of hydrophobic residue is energetically favorable and entropy dominated on a methyl-terminated hydrophobic surface, energetically unfavorable and enthalpy dominated on a hydroxyl-terminated neutral hydrophilic surface, and very slightly favorable to unfavorable and enthalpy dominated on charged surfaces. These theoretical results provide a basis for understanding some of the fundamental effects governing protein adsorption to synthetic surfaces. This level of understanding is needed for the proactive design of surfaces to control protein adsorption and subsequent cellular response for both implant and tissue engineering applications.