Development of an Intratumoral Holmium Microsphere Injection Method in Ex Vivo Human Pancreatic Ductal Adenocarcinoma: A Preclinical Feasibility Study
Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Injection System Design
2.2. Injection System Validation Testing
2.2.1. Microsphere Preparation
2.2.2. Laboratory Validation Testing
2.3. Ex Vivo Human Pancreatic Ductal Adenocarcinoma
2.4. Outcome Measures
Data Processing
3. Results
3.1. Injection System Development
3.2. Injection System Validation
3.3. Ex Vivo Intratumoral Injection
3.3.1. Image Guidance
3.3.2. Injection Volume, Concentration, and Deposits
3.3.3. Leakage
3.3.4. Needle Blockage
3.3.5. Histopathology
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Appendix A. Extensive Injection System Development Results
- Syringe volume: 3.0 mL (range: 1.0–10.0 mL)Syringe volumes of 1.0 mL resulted in less homogeneous suspensions and faster agglomeration, whereas syringes up to 10.0 mL resulted in excessive variation in the volume injected by manual injection due to the larger diameter.
- Rotation time: 120 s (range: ~1–120 s)Visual homogenization of the 165HoMS suspension was achieved after 120 s in all the cases, even if the 165HoMSs accumulated to one side of the syringe before rotation. There were no clear differences in injection concentrations when rotating over 120 s.
- Rotation speed: 60 RPM (range: 30–120 RPM)Since rotation of the syringe was performed manually, a rotation speed was evaluated which could be achieved for multiple minutes without exhausting the operator and did not cause visual agglomeration. Rotation speeds below 60 RPM caused moments of idleness, which resulted in agglomeration. When the suspension was injected, rotation of the syringe was not possible, and agglomeration of the suspension occurred within seconds. Therefore, between every separate injection, or every 0.5 mL of injection volume, the syringe was rotated again for at least 10 s.
- Injection speed: 0.2 mL/s (range: 0.05–1.0 mL/s)Faster injection up to 1.0 mL/s could cause volume overshoots and thus increase the chance of leakage. Since the syringe could not be rotated during injection, lower injection speeds caused more 165HoMS agglomeration and more injection pauses to homogenize the suspension again.
- Injection volumes: 0.3–1.0 mL (range: 0.1–1.0 mL)Because the injection system contains a dead volume, which is the lumen volume between the syringe exit and needle tip in which the 165HoMSs agglomerate, a minimal injection volume of 0.3 mL was used to ensure complete flow through the dead volume, and 0.5 mL when the plastic extension tube was attached.
- System component diameters:System components with adjacent internal diameter changes, especially downstream narrowing, showed increased visual agglomeration of the 165HoMSs. Additionally, relatively large dead volumes, commonly found near Luer-lock connections, showed increased agglomeration when in a horizontal position. 165HoMS agglomeration within dead volumes caused a lower 165HoMS concentration; however, it could unexpectedly dislodge during injection and therefore suddenly increase the injected 165HoMS concentration.
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Characteristic | Holmium-166 Microsphere | Phosphorus-32 Microparticle |
---|---|---|
Material | Poly L-lactic acid | Silicon |
Diameter | 30 µm (15–60 µm) | 30 µm (15–50 µm) |
Isotope | Holmium-166 | Phosphorus-32 |
Half-life | 26.8 h | 14.27 days |
Emission type (yield) | Beta (93.3%), gamma (6.7%) | Beta (100%) |
Maximum beta energy | 1.85 MeV | 1.711 MeV |
Mean β− penetration | 2.5 mm | 2.76 mm |
Maximum β− penetration | 8.7 mm | 8.2 mm |
Imaging modalities | SPECT, CT, MRI | Bremsstrahlung SPECT |
Parameter | Limit | Unit |
---|---|---|
Syringe volume | 3.0 | mL |
Minimal rotation time | 120 | seconds |
Intermittent rotation time 1 | 10 | seconds |
Rotation speed | 60 | RPM |
Minimal flush volume | 1.0 | mL |
Minimal injection volume without tube | 0.3 | mL |
Minimal injection volume with tube | 0.5 | mL |
Injection speed | 0.2 | mL/s |
Parameter | Limit | Unit |
---|---|---|
Tumor volume 1 | 2.5–15.6 | mL |
Maximum injection volume | 20.0 | % of tumor volume |
Maximum syringe angle to horizontal | 10.0 | Degrees |
Number of needle insertions | 1–3 | - |
Number of deposits | 1–3 | - |
Volume per deposit 1 | 0.3–1.0 | mL |
Holmium microsphere concentration in syringe 1 | 5.0–50.0 | mg/mL |
Needle diameter 1 | 18–21 | Gauge |
Needle length 1 | 50–150 | mm |
Characteristics | Unit | Sample 1 | Sample 2 | Sample 3 | Sample 4 | Sample 5 | Sample 6 | Sample 7 | Sample 8 | Sample 9 | Sample 10 | |
---|---|---|---|---|---|---|---|---|---|---|---|---|
Tumor volume | mL | 14.3 | 6.7 | 9.6 | 2.5 | 15.6 | 3.6 | 5.6 | 11.6 | 7.1 | 2.5 | |
Extratumoral leakage observed | Yes/no | yes | yes | no | no | no | yes | no | no | yes | yes | |
Observation remark | - | Over fractionated deposits | Needle overshoot | - | HVC 2 instead of injection fluid | - | Intentionally increased injection volume | Needle blockage due to syringe angle | - | Leakage through pancreatic duct | Intentionally increased injection volume | |
Image guidance | - | - | - | US | US | US | US + CT | US + CT | US + CT | US + CT | US + CT | |
Injection volume (as % of tumor volume) | mL (%) | 4.5 (31) | 2.3 (35) | 1.8 (19) | 0.2 (8) | 3.0 (19) | 3.0 (83) | 0.7 (13) | 2.0 (17) | 0.7 (10) | 1.0 (40) | |
Number of needle insertions | - | 13 | 5 | 3 | 1 | 3 | 1 | 1 | 2 | 1 | 2 | |
Number of deposits × volume per deposit | mL | 45 × 0.1 | 3 × 0.5 2 × 0.3 | 1 × 0.8 2 × 0.5 | 1 × 0.2 | 3 × 1.0 | 6 × 0.5 | 1 × 0.7 | 2 × 1.0 | 1 × 0.7 | 2 × 0.5 | |
Concentration of 165HoMSs in syringe | mg/mL | 5.0 | 5.0 | 5.0 | 10.0 | 10.0 | 10.0 | 20.0 | 20.0 | 25.0 | 25.0 | 50.0 |
HoMSs injected 1 | mg (mg/mL) | 18.5 (4.1) | 9.4 (4.1) | 7.4 (4.1) | 2.0 (10.0) 2 | 24.6 (8.2) | 24.6 (8.2) | 11.5 (16.4) | 32.8 (16.4) | 13.4 (20.5) | 10.3 (20.5) | 20.5 (41.0) |
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Willink, C.Y.; Jenniskens, S.F.M.; Klaassen, N.J.M.; Stommel, M.W.J.; van Laarhoven, C.J.H.M.; Fütterer, J.J.; Nijsen, J.F.W. Development of an Intratumoral Holmium Microsphere Injection Method in Ex Vivo Human Pancreatic Ductal Adenocarcinoma: A Preclinical Feasibility Study. Cancers 2025, 17, 1028. https://doi.org/10.3390/cancers17061028
Willink CY, Jenniskens SFM, Klaassen NJM, Stommel MWJ, van Laarhoven CJHM, Fütterer JJ, Nijsen JFW. Development of an Intratumoral Holmium Microsphere Injection Method in Ex Vivo Human Pancreatic Ductal Adenocarcinoma: A Preclinical Feasibility Study. Cancers. 2025; 17(6):1028. https://doi.org/10.3390/cancers17061028
Chicago/Turabian StyleWillink, Coen Ysbrand, Sjoerd Franciscus Maria Jenniskens, Nienke Johanna Maria Klaassen, Martijn Willem Jan Stommel, Cornelis Johannes Henricus Martinus van Laarhoven, Jurgen J. Fütterer, and Johannes Frank Wilhelmus Nijsen. 2025. "Development of an Intratumoral Holmium Microsphere Injection Method in Ex Vivo Human Pancreatic Ductal Adenocarcinoma: A Preclinical Feasibility Study" Cancers 17, no. 6: 1028. https://doi.org/10.3390/cancers17061028
APA StyleWillink, C. Y., Jenniskens, S. F. M., Klaassen, N. J. M., Stommel, M. W. J., van Laarhoven, C. J. H. M., Fütterer, J. J., & Nijsen, J. F. W. (2025). Development of an Intratumoral Holmium Microsphere Injection Method in Ex Vivo Human Pancreatic Ductal Adenocarcinoma: A Preclinical Feasibility Study. Cancers, 17(6), 1028. https://doi.org/10.3390/cancers17061028