Neurosurgical instrument for multi-site biopsies and dynamically adapted localized drug release in the skull via a single access point.

Abstract

Neurosurgical instrument for multi-site biopsies and localized drug delivery in the skull via a single access point, comprising several flexible specialized tubes (6) that can be positioned from a single cranial access point to different target locations in the brain and each designed for tissue sampling and dynamically adapted delivery of drugs, characterized by the fact that the instrument comprises: - a central insertion shaft (1) at the distal end of which interchangeable angle attachments (2) can be fastened to specify different exit angles; - a rotatably mounted central disc (3) which is received between two semicircular base plates (4) and has a central shaft opening (3c) and a radial slot (3b) for lateral deflection of the hoses (6), wherein the base plates (4) have hose holes (4a) and narrowed slot areas (4b) for guiding the specialized hoses (6) and can be locked together by means of connecting slots (4d); - an intermediate guide plate (7) with tube channels (7a), collecting openings (7b) and a central outlet opening (7c) for bundling and orderly routing of the tubes (6) after their placement, as well as lateral attachment points (7d) with bores (7e) for fixation to the skull; and - an external attachment ring (8) to be arranged on soft tissue outside the skull with internal tube inlet openings (8a), upper tube outlet openings (8b) and tube channels running between them for orderly guidance of the proximal tube sections and for receiving access heads (9).

Description

2.1 Technical Area

[0001] The invention relates to neurosurgery and, in particular, to an instrument that enables both multi-site biopsies and targeted drug delivery to multiple localized target sites in the skull via a single access point. Furthermore, the instrument allows for the repeated obtaining of tissue samples and the corresponding dynamic adjustment of drug administration to take into account individual resistance and sensitivity patterns of the tumor tissue. 2.2 State of the art

[0002] Various approaches to biopsy and local drug delivery are known in the prior art, but no system enables multi-site biopsy and localized multi-channel drug delivery via a single access point in the compact device combination proposed here.

[0003] From US 2018 / 0132962 A1, a frameless, stereotactically alignable biopsy instrument is known that allows the precise placement of a biopsy needle; a drug delivery or multi-tube organization system is not provided.

[0004] US 2003 / 0176854 A1 discloses generally implantable controlled-release drug delivery systems without requiring multichannel neurosurgical access for different intracerebral target sites.

[0005] US 5,836,935 describes a refillable, rate-controlled implant reservoir with a delivery tube; the document addresses drug release but not the combination of multi-site biopsy, angle / disc guidance, and multi-tube bundling.

[0006] WO 2020 / 210805 A1 teaches brain-permeable nanoparticles for the distribution of active substances in brain tissue; it is a pharmacological delivery approach and not a mechanical access system.

[0007] US 10,918,720 B2 concerns dendrimer carrier structures for selective drug delivery to brain tumors and mainly claims compositions / methods rather than a surgical multichannel device.

[0008] Several established approaches are available for the local treatment of brain tumors.

[0009] One technique is convection-enhanced delivery (CED). This generates a continuous infusion flow, enabling broader distribution of the drug in the tissue. Several recent reviews confirm the importance of CED in experimental and clinical neuro-oncology (see Jahangiri et al., 2017; Kreatsoulas et al., 2024).

[0010] The Ommaya reservoir is an implant that has been used for decades, allowing repeated intraventricular access for cerebrospinal fluid analysis or drug administration. It is particularly useful for intrathecal chemotherapy or in the treatment of CNS infections (see Zubair & De Jesüs, 2023).

[0011] Biopsy procedures using stereotactic systems are also established. These allow for the precise extraction of tissue samples from different brain regions, but generally require a separate access route for each sample (see Akshulakov et al., 2019).

[0012] In addition, other local therapies have been developed, such as the implantation of BCNU wafers into the resection cavity in glioblastomas to enable direct chemotherapy at the tumor bed (see Ohnishi et al., 2022).

[0013] In summary, existing systems are mostly limited to single functions—either biopsy or drug delivery—and can only be used repeatedly to a limited extent. A combined, flexible system for multi-site biopsy, for obtaining potentially intratumoral fluid, and for dynamically adapted, targeted drug delivery via a single access point is still lacking. 2.3 Object of the invention

[0014] The object of the invention is to provide a tissue-sparing instrument that is particularly suitable for the treatment of malignant brain tumors such as glioblastoma, in which different tumor areas exhibit variable resistance and sensitivity to drugs. The instrument should enable the taking of biopsies from several different locations as well as the targeted and dynamically adapted delivery of specific drugs or drug cocktails via the same access point, based on the respective examination results.

[0015] The invention further aims to enable not only a single biopsy and drug administration, but also repeated diagnostic and therapeutic procedures via the same access point. This allows for the taking of multiple tissue samples and the administration of different drugs or drug combinations at staggered intervals, ensuring treatment tailored to the course of therapy. In addition, the instrument should also allow for the collection of intratumoral fluid, if necessary, to enable further analysis.

[0016] Furthermore, the instrument is intended to offer a gentle and flexible method for targeted biopsies and drug administration in cases of recurrent tumors, particularly recurrent glioblastoma after primary tumor resection. This supports treatment even in cases where repeat open resection is not possible or desired. 2.4 Solution to the task

[0017] The task is accomplished using a neurosurgical instrument that allows access to multiple locations in the brain through a single cranial access point. The instrument combines guiding and fixation elements that permit the precise manual placement of flexible tubes, which can be used for both tissue sampling and the targeted delivery of drugs. Modular components ensure secure anchoring, precise orientation, and gentle handling of the tissue. 2.5 Advantages of the invention

[0018] The instrument requires only a single, relatively small access point, which makes the procedure significantly less damaging to the tissue than procedures that require either multiple or larger access points.

[0019] The instrument can be oriented using markings on the insertion shaft, center disc, and tubing, even without sophisticated neuronavigation systems. This ensures the device remains functional even when such systems are unavailable or cannot be used due to hardware or software malfunctions.

[0020] A key advantage is that a single device combines the capability of multi-site biopsy with targeted drug delivery. This is particularly important for malignant tumors with heterogeneous resistance patterns, as it allows for the precise extraction of different tissue samples and the targeted application of specific drug combinations.

[0021] Furthermore, the detachable design of the access heads (9) increases flexibility: they can be removed as needed to insert a biopsy needle or to connect a syringe directly to the tube ends (6). This allows not only for drug administration but also for the collection of intratumoral fluid, if necessary, to obtain additional diagnostic information—such as molecular markers or resistance analyses.

[0022] Furthermore, the instrument allows for repeated diagnostic and therapeutic interventions via the same access point. Thus, after an initial biopsy, further samples can be taken at different times, while the drug treatment can be flexibly adjusted in parallel – for example, through the sequential application of different active substances or drug cocktails, depending on the current findings regarding the sensitivity or resistance of the tumor tissue.

[0023] Each specialized tube (6) has an imaging-detectable marking ring (6c) at its tip (6a), which allows position control using imaging techniques, thereby increasing the safety and precision of the procedure.

[0024] A further advantage lies in the multifunctional design of the tube tips (6a). The hollow lumen (6b) is dimensioned such that the introducer wire is held in front of the distal end of the tip during placement. This prevents the wire from protruding from the tip and potentially injuring surrounding brain tissue. At the same time, however, the lumen (6b) is dimensioned to allow both the insertion of a biopsy needle for obtaining tissue samples and the aspiration of fluids, such as cerebrospinal fluid or intratumoral fluid. Furthermore, it allows for the targeted delivery of fluids, particularly drug solutions. Thus, the lumen of the tube tip fulfills three key roles: protection during placement, enabling diagnostic procedures, and enabling therapeutic interventions.

[0025] The specialized tubes (6) are manually and gradually advanced into the tumor tissue, with the introducer wire serving as a guide. This allows for a particularly tissue-sparing procedure, as the advancement is entirely under the surgeon's control.

[0026] The adjustable platform elements (5) enable precise leveling of the base plates (4) even on uneven bone surfaces. This ensures stable fixation and increases the precision of instrument guidance.

[0027] The flexible design of the intermediate guide plate (7) and outer fastening ring (8) allows adaptation to the uneven surface of the skull and thus facilitates the secure fixation of the instrument.

[0028] A key advantage of the instrument lies in its ability to precisely target different levels of a brain tumor. The movable insertion shaft (1) along the Y-axis allows for the precise targeting of not only horizontal target locations but also various depth levels (e.g., deep areas near the tumor, intermediate levels, or superficial regions). This significantly improves the accuracy of the placement of the tubes (6), as the entry points in the brain can be selected close to the target locations, thus increasing both the therapeutic accuracy and the safety of the procedure.

[0029] The combination of the insertion shaft (1), angled attachments (2), and rotatable central disc (3) allows for precise control in all three spatial axes (X, Y, Z). This makes it possible to position the tubes (6) so that they exit with minimal deviation from the calculated target points. This is particularly important because, due to the flexibility of the tissue, the exact exit angles of the tubes after they emerge from the angled attachments do not remain stable over longer distances.

[0030] Another advantage is that the brain's anatomy is largely preserved. Since the device does not rely on the suction or removal of cerebrospinal fluid, displacements or structural changes to the brain, such as those that can occur during conventional surgery, are avoided.

[0031] Finally, the design with sterilizable main components - in particular insertion shaft (1), angle attachments (2), center disc (3) and base plates (4) - as well as with elements designed as single-use items - adaptable platforms (5), specialized tubing (6), intermediate guide plate (7), outer retaining ring (8) and access heads (9) - contributes significantly to clinical practicality, patient safety and hygienic safety. 2.6 Example of Implementation

[0032] The task is accomplished by a neurosurgical instrument comprising an insertion shaft (1). This shaft has height markings (1a), a central lumen (1b) for guiding the tubes, and a connection interface (1c) at its proximal end.

[0033] Different angle attachments (2) can be attached to the insertion shaft (1), which in embodiments are designed as, for example, angle attachment 0° (2a), angle attachment 15° (2b), angle attachment 30° (2c) or angle attachment 45° (2d).

[0034] A rotatable central disc (3) is provided for controlling the hoses. The central disc (3) has a circumferential edge projection (3a) arranged along its outer edge in the central region of the disc edge. This projection is annular in shape but interrupted at one point by a radially extending slot (3b), forming an opening between the central shaft opening (3c) and the disc edge. The central disc (3) also has angular reference grooves (3d).

[0035] The central disc (3) is mounted between two semicircular base plates (4). Each base plate (4) has hose openings (4a), narrowed slot areas (4b), a central recess (4c), and a connecting slot (4d). The two base plates (4) can be slid together and locked via the connecting slots (4d), so that a total of twelve hose openings (4a) are available when assembled. The central recess (4c) serves to positively engage the circumferential edge projection (3a) of the central disc (3), thus enabling its rotatability. The base plates (4) have lateral mounting lugs (4e), each containing a mounting bore (4f).

[0036] To compensate for different anatomical features of the skull, an adjustable platform (5) is provided beneath the base plates (4). The platform (5) is available in five sizes (5a-e) with heights of approximately 1, 2, 3, 4, and 5 mm. Several platforms (5) can be stacked on top of each other to achieve the desired height. Each platform (5) has a central through-hole (5f) that serves as a connection between the mounting holes of the base plates (4) and the skull, allowing screws to be inserted through the platform.

[0037] Each specialized tube (6) has a tip (6a) at its distal end with a continuous hollow lumen (6b). A circumferential, image-visible marking ring (6c) is arranged between the tip (6a) and the proximally adjacent connection area, enabling imaging-based position verification. The distal tube inlet (6d) is located on the side of the tip facing the tube body, through which the lumen (6b) is fluidically connected to the tube body. The tube body features distance markings (6e) for monitoring the insertion depth.

[0038] After placement of the tubes (6), the correct positioning of the distal tube tips (6a) can be verified using imaging techniques, in particular MRI. This verification can be performed both immediately during the insertion procedure and directly after completion of placement to ensure the exact position in the target area.

[0039] The insertion shaft (1), the center disc (3), and the base plates (4) are then removed. The hoses (6) located in the hose holes (4a) of the base plates (4) are carefully exposed and transferred to the hose channels (7a) of the intermediate guide plate (7).

[0040] The specialized tubes (6) are guided from below through the intermediate guide plate (7). They first enter through the central opening (7a), are gathered in the collecting openings (7b), and then routed via the tube channels (7c) to the lateral tube openings. In this way, the proximal tube sections are guided in an orderly fashion from the inside of the skull towards the outside.

[0041] For fixation, the intermediate guide plate (7) has lateral fastening projections (7d) in which fastening holes (7e) are arranged, via which the plate can be fixed to the skull.

[0042] Outside the skull, the specialized tubes (6) are guided through the outer mounting ring (8). This ring has internal tube inlet openings (8a) and upper tube outlet openings (8b) that ensure orderly routing of the tubes. Additionally, the mounting ring (8) has four evenly spaced mounting points (8c) with mounting holes (8d) for secure fixation.

[0043] In the mounting ring (8), the proximal ends of the tubes (6) are cut to the desired length and each fitted with an access head (9). Each access head (9) comprises a base section (9a), a dome section (9c), an internal cavity (9b), and, optionally, a central opening (9d). The cavity (9b) serves as a receiving space for the proximal tube ends and is accessible via the central opening (9d). After temporary removal of the access head (9), medications can be administered via a Luer-lock interface, or biopsy needles can be inserted.

[0044] Unlike the intermediate guide plate (7), which is fixed directly to the skull, the fastening ring (8) is designed to be positioned on the soft tissue. There, it ensures the orderly guidance of the proximal tube sections and the secure retention of the access heads (9).

[0045] At their proximal ends, the tubes (6) are connected to an access head (9) comprising a base section (9a), a dome section (9c), an internal cavity (9b), and optionally a central opening (9d). The cavity (9b) serves as a receiving space for the proximal tube ends and is accessible via the central opening (9d).

[0046] After completion of the diagnostic and therapeutic procedures, the instrument can be completely removed. To do this, the access heads (9) are detached and the tubes (6) are carefully withdrawn from the brain tissue. The intermediate guide plate (7), the outer retention ring (8), and any remaining components are then disconnected and removed. The access point can then be surgically closed and the wound sutured. This ensures that the instrument does not remain permanently in the body and allows for postoperative monitoring and further treatment of the patient. 3. Drawing list with reference symbols and views Fig. 1: Introduction wave (1) - Front view 1st wave of introduction 1a Height markings 1b Central lumen 1c connection interface Fig. 2: Angle attachments (2) - Front view 2 Angle attachments in general 2a Angle attachment 0° 2b Angle attachment 15° 2c Angle attachment 30° 2D angle attachment 45° Fig. 3: Middle disc (3) - oblique front / side view 3 Middle disc 3a Edge projection (circumferential, central area) 3b Radial slot 3c Central shaft opening 3D angular reference grooves Fig. 4: Middle disk (3) - Top view showing the features (3a-3d) from above. Fig. 5: Base plate left (4) - Top view 4a Hose holes 4b Narrowed slot areas 4c Central Deepening 4D connection slot 4e Mounting points 4f mounting holes Fig. 6: Base plate right (4) - Top view Features accordingly Fig. 5. Fig. 7: Adjustable platform (5) - angled front / side view 5 Platform in general 5a-e platform sizes (approximately 1-5 mm height) 5f Central through hole Fig. 8: Specialized hose (6) - Side view 6 Specialized Hose 6a Peak 6b Hollow lumen of the tip (see Fig. 9) 6c Imaging-depictable marker ring 6d Distal hose inlet 6e Distance markers Fig. 9: The tip of the specialized hose (6a) - bottom view showing the features (6b, 6d) from below. Fig. 10: Intermediate guide plate (7) - Top view (obliquely from above) 7a Central opening (see Fig. 11) 7b Collection openings 7c Hose channels 7d Mounting Approaches 7e Mounting holes Fig. 11: Intermediate guide plate (7) - Underside view (obliquely from below) Representation of features (7a-7e) from a lower perspective. Fig. 12: Outer mounting ring (8) - Top view 8a Hose outlet openings (inside) 8b Hose inlet openings (top) 8c Mounting points 8d Mounting holes Fig. 13: Outer fastening ring (8) - Oblique side view showing features (8a-8d). Fig. 14: Access head (9) - Front view 9a Basic Section 9b Cavity 9c Dome section 9d Central Opening Fig. 15: Access head (9) - Bottom view showing the specific features (9a and 9d) from below Table of contents 1. Claims for protection 1.1 Main claim 1.2 Subclaims 2. Description 2.1 Technical Area 2.2 State of the art 2.3 Object of the invention 2.4 Solution to the task 2.5 Advantages of the invention 2.6 Example of Implementation 3. Drawing list with reference symbols and views 4. Sources / References for the State of the Art 5. Drawings 4. Sources / References for the State of the Art Akshulakov, SK; Kerimbayev, TT; Biryuchkov, MY; Urunbayev, Y. A.; Farhadi, DS; Byvaltsev, VA Current Trends for Improving Safety of Stereotactic Brain Biopsies: Advanced Optical Methods for Vessel Avoidance and Tumor Detection. Front. Oncol., 02 October 2019. Vol 9. doi:10.3389 / fonc.2019.00947 Jahangiri, A; Chin, AT; Flanigan, PM; Chen, R; Bankiewicz, K; Aghi, MK Convection-enhanced delivery in glioblastoma: a review of preclinical and clinical studies. J Neurosurg. 2017 Jan;126 (1):191-200. doi: 10.3171 / 2016.1.JNS151591 Kreatsoulas, D; Damante, M; Cua, S; Lonser, RR Adjuvant convection-enhanced delivery for the treatment of brain tumors Journal of Neuro-Oncology 2024: 166:243-255. doi:10.1007 / s11060-023-04552-8 Ohnishi, T.; Okada, M.; Ohno, T.; Kohno, S Is Interstitial Chemotherapy with Carmustine (BCNU) Wafers Effective against Local Recurrence of Glioblastoma? A Pharmacokinetic Study by Measurement of BCNU in the Tumor Resection Brain Sci. 2022; 12(5): 567. doi: 10.3390 / brainsci12050567 Zubair, M.; De Jesús, O. Ommaya Reservoir. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023. PMID: : 32644437 Patente US 5,836,935 - Multi-lumen catheter for drug delivery to the brain and spinal cord US 1091 8720B2 - Selective dendrimer delivery to brain tumors US20030176854A1 - Apparatus and method for delivering therapeutic agents into the brain US20180132962A1 - Method and system for stereotactic biopsy WO2020210805A1 - Nanoparticle-based delivery systems for the treatment of brain tumors ZITATE ENTHALTEN IN DER BESCHREIBUNG

[0000] This list of documents cited by the applicant was automatically generated and is included solely for the reader's convenience. The list is not part of the German patent or utility model application. The DPMA accepts no liability for any errors or omissions. Cited patent literature

[0000] US 2018 / 0132962 A1 [0003, 0046] US 2003 / 0176854 A1 [0004, 0046] US 5,836,935 [0005, 0046] WO 2020 / 210805 A1 [0006, 0046] US 10,918,720 B2 [0007, 0046] Cited non-patent literature

[0000] Jahangiri et al., 2017; Kreatsoulas et al., 2024

[0009] Zubair & De Jesüs, 2023

[0010] Akshulakov et al., 2019

[0011] Ohnishi et al., 2022

[0012] Akshulakov, SK; Kerimbayev, TT; Biryuchkov, MY; Urunbayev, YA; Farhadi, DS; Byvaltsev, VA Current Trends for Improving Safety of Stereotactic Brain Biopsies: Advanced Optical Methods for Vessel Avoidance and Tumor Detection

[0046] Front. Oncol., 02 October 2019. Vol 9. doi:10.3389 / fonc.2019.00947

[0046] Jahangiri, A; Chin, AT; Flanigan, PM; Chen, R; Bankiewicz, K; Aghi, MK Convection-enhanced delivery in glioblastoma: a review of preclinical and clinical studies. J Neurosurg. 2017 Jan;126 (1) :191-200. doi: 10.3171 / 2016.1.JNS151591

[0046] Kreatsoulas, D; Damante, M; Cua, S; Lonser, RR Adjuvant convection-enhanced delivery for the treatment of brain tumors Journal of Neuro-Oncology 2024: 166:243-255. doi:10.1007 / s11060-023-04552-8

[0046] Ohnishi, T.; Okada, M.; Ohno, T.; Kohno, S Is Interstitial Chemotherapy with Carmustine (BCNU) Wafers Effective against Local Recurrence of Glioblastoma? A Pharmacokinetic Study by Measurement of BCNU in the Tumor Resection Brain Sci. 2022; 12(5): 567. doi: 10.3390 / brainsci12050567

[0046] Zubair, M.; De Jesús, O

[0046] Ommaya Reservoir. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023. PMID: : 32644437

[0046]

Claims

[1] Neurosurgical instrument for multi-site biopsies and localized drug delivery in the skull via a single access point, comprising several flexible specialized tubes (6) that can be positioned from a single cranial access point to different target locations in the brain and are each designed for tissue sampling and dynamically adapted delivery of drugs, characterized by , that the instrument includes: - a central insertion shaft (1) at the distal end of which interchangeable angle attachments (2) can be fastened to specify different exit angles; - a rotatably mounted central disc (3) which is received between two semicircular base plates (4) and has a central shaft opening (3c) and a radial slot (3b) for lateral deflection of the hoses (6), wherein the base plates (4) have hose holes (4a) and narrowed slot areas (4b) for guiding the specialized hoses (6) and can be locked together by means of connecting slots (4d); - an intermediate guide plate (7) with tube channels (7a), collecting openings (7b) and a central outlet opening (7c) for bundling and orderly routing of the tubes (6) after their placement, as well as lateral attachment points (7d) with bores (7e) for fixation to the skull; and - an external attachment ring (8) to be arranged on soft tissue outside the skull with internal tube inlet openings (8a), upper tube outlet openings (8b) and tube channels running between them for orderly guidance of the proximal tube sections and for receiving access heads (9). [2] Instrument according to claim 1, characterized by , that the tubes (6) are provided at the distal end with a tip (6a) and a circumferential marking ring (6d) that can be visualized using imaging. [3] Instrument according to any of the preceding claims, characterized by , that the insertion shaft (1) has height markings (1a), the center disc (3) has angle reference grooves (3d) and the specialized hoses (6) have distance markings (6g). [4] Instrument according to any of the preceding claims, characterized by , that the angle attachments (2) specify different exit angles, in particular 0°, 15°, 30° or 45°. [5] Instrument according to any of the preceding claims, characterized by , that the base plates (4) have a central recess (4c) for the form-fitting reception of an edge projection (3a) of the central disc (3). [6] Instrument according to any of the preceding claims, characterized by , that the outer fastening ring (8) has fastening projections (8c) with fastening holes (8d) and is intended for placement on soft tissue. [7] Instrument according to any of the preceding claims, characterized by, that the access heads (9) are detachably connectable to the proximal ends of the tubes (6), wherein the proximal tube ends have a Luer-lock or functionally equivalent compatibility that allows both dynamically adapted drug administration and the withdrawal of fluids, in particular intratumoral fluid, if necessary, and wherein for these applications as well as for the withdrawal of tissue samples the access head (9) can be temporarily removed in order to insert a biopsy needle through the tube (6). [8] Instrument according to any of the preceding claims, characterized by , that adjustable, stackable platform elements (5) with defined heights (5a-5e) are provided under the base plates (4) by means of which leveling of the base plates (4) on uneven bone surfaces can be adjusted. [9] Instrument according to any of the preceding claims, characterized bythat at least six, preferably twelve, tube guides are provided for performing multi-site biopsies and for dynamically adjusted drug release. [10] Instrument according to any of the preceding claims, characterized by , that the adaptable platform elements (5), the specialized hoses, the intermediate guide plate (7), the outer retaining ring (8) and the access heads (9) are designed as single-use items, while the insertion shaft (1), the angle attachments (2), the center disc (3) and the base plates (4) are reusable and sterilizable. [11] Instrument according to any of the preceding claims, characterized by that the metallic components are made of stainless steel or titanium and the polymeric components are made of biocompatible plastic. [12] Instrument according to any of the preceding claims, characterized by, that it is designed for repeated procedures, in particular for multiple tissue sampling and for the sequential application of different drugs or drug combinations via the placed specialized tubes (6). [13] Instrument according to any of the preceding claims, characterized by , that the distal end of the specialized tubes (6) has a hollow lumen (6b) which is designed to - that an insertion wire is retained within the tip (6a) during placement and does not escape, - that a biopsy needle can be inserted to take tissue samples, - that medications or drug cocktails can be administered in a targeted manner, and - that fluids, especially cerebrospinal fluid or intratumoral fluid, can be withdrawn. [14] Instrument according to any of the preceding claims, characterized bythat it is designed to perform highly precise local therapy by enabling targeted tissue sampling and the delivery of drugs to multiple different areas and levels of the same tumor with high local accuracy.

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