Improving multiparametric MR-transrectal ultrasound guided fusion prostate biopsies with hyperpolarized 13 C pyruvate metabolic imaging: A technical development study.

PURPOSE: To develop techniques and establish a workflow using hyperpolarized carbon-13 (13 C) MRI and the pyruvate-to-lactate conversion rate (kPL ) biomarker to guide MR-transrectal ultrasound fusion prostate biopsies. METHODS: The integrated multiparametric MRI (mpMRI) exam consisted of a 1-min hyperpolarized 13 C-pyruvate EPI acquisition added to a conventional prostate mpMRI exam. Maps of kPL values were calculated, uploaded to a picture archiving and communication system and targeting platform, and displayed as color overlays on T2 -weighted anatomic images. Abdominal radiologists identified 13 C research biopsy targets based on the general recommendation of focal lesions with kPL >0.02(s-1 ), and created a targeting report for each study. Urologists conducted transrectal ultrasound-guided MR fusion biopsies, including the standard 1 H-mpMRI targets as well as 12-14 core systematic biopsies informed by the research 13 C-kPL targets. All biopsy results were included in the final pathology report and calculated toward clinical risk. RESULTS: This study demonstrated the safety and technical feasibility of integrating hyperpolarized 13 C metabolic targeting into routine 1 H-mpMRI and transrectal ultrasound fusion biopsy workflows, evaluated via 5 men (median age 71 years, prostate-specific antigen 8.4 ng/mL, Cancer of the Prostate Risk Assessment score 2) on active surveillance undergoing integrated scan and subsequent biopsies. No adverse event was reported. Median turnaround time was less than 3 days from scan to 13 C-kPL targeting, and scan-to-biopsy time was 2 weeks. Median number of 13 C targets was 1 (range: 1-2) per patient, measuring 1.0 cm (range: 0.6-1.9) in diameter, with a median kPL of 0.0319 s-1 (range: 0.0198-0.0410). CONCLUSIONS: This proof-of-concept work demonstrated the safety and feasibility of integrating hyperpolarized 13 C MR biomarkers to the standard mpMRI workflow to guide MR-transrectal ultrasound fusion biopsies.

Development of specialized magnetic resonance acquisition techniques for human hyperpolarized [13 C,15 N2 ]urea + [1-13 C]pyruvate simultaneous perfusion and metabolic imaging.

PURPOSE: This study aimed to develop and demonstrate the in vivo feasibility of a 3D stack-of-spiral balanced steady-state free precession(3D-bSSFP) urea sequence, interleaved with a metabolite-specific gradient echo (GRE) sequence for pyruvate and metabolic products, for improving the SNR and spatial resolution of the first hyperpolarized 13 C-MRI human study with injection of co-hyperpolarized [1-13 C]pyruvate and [13 C,15 N2 ]urea. METHODS: A metabolite-specific bSSFP urea imaging sequence was designed using a urea-specific excitation pulse, optimized TR, and 3D stack-of-spiral readouts. Simulations and phantom studies were performed to validate the spectral response of the sequence. The image quality of urea data acquired by the 3D-bSSFP sequence and the 2D-GRE sequence was evaluated with 2 identical injections of co-hyperpolarized [1-13 C]pyruvate and [13 C,15 N2 ]urea formula in a rat. Subsequently, the feasibility of the acquisition strategy was validated in a prostate cancer patient. RESULTS: Simulations and phantom studies demonstrated that 3D-bSSFP sequence achieved urea-only excitation, while minimally perturbing other metabolites (<1%). An animal study demonstrated that compared to GRE, bSSFP sequence provided an ∼2.5-fold improvement in SNR without perturbing urea or pyruvate kinetics, and bSSFP approach with a shorter spiral readout reduced blurring artifacts caused by J-coupling of [13 C,15 N2 ]urea. The human study demonstrated the in vivo feasibility and data quality of the acquisition strategy. CONCLUSION: The 3D-bSSFP urea sequence with a stack-of-spiral acquisition demonstrated significantly increased SNR and image quality for [13 C,15 N2 ]urea in co-hyperpolarized [1-13 C]pyruvate and [13 C,15 N2 ]urea imaging studies. This work lays the foundation for future human studies to achieve high-quality and high-SNR metabolism and perfusion images.

Failure modes and effects analysis of mechanical thrombectomy for stroke discovered in human brains.

OBJECTIVE: Despite advancement of thrombectomy technologies for large-vessel occlusion (LVO) stroke and increased user experience, complete recanalization rates linger around 50%, and one-third of patients who have undergone successful recanalization still experience poor neurological outcomes. To enhance the understanding of the biomechanics and failure modes, the authors conducted an experimental analysis of the interaction of emboli/artery/devices in the first human brain test platform for LVO stroke described to date. METHODS: In 12 fresh human brains, 105 LVOs were recreated by embolizing engineered emboli analogs and recanalization was attempted using aspiration catheters and/or stent retrievers. The complex mechanical interaction between diverse emboli (elastic, stiff, and fragment prone), arteries (anterior and posterior circulation), and thrombectomy devices were observed, analyzed, and categorized. The authors systematically evaluated the recanalization process through failure modes and effects analysis, and they identified where and how thrombectomy devices fail and the impact of device failure. RESULTS: The first-pass effect (34%), successful (71%), and complete (60%) recanalization rates in this model were consistent with those in the literature. Failure mode analysis of 184 passes with thrombectomy devices revealed the following. 1) Devices loaded the emboli with tensile forces leading to elongation and intravascular fragmentation. 2) In the presence of anterograde flow, small fragments embolize to the microcirculation and large fragments result in recurrent vessel occlusion. 3) Multiple passes are required due to recurrent (15%) and residual (73%) occlusions, or both (12%). 4) Residual emboli remained in small branching and perforating arteries in cases of alleged complete recanalization (28%). 5) Vacuum caused arterial collapse at physiological pressures (27%). 6) Device withdrawal caused arterial traction (41%), and severe traction provoked avulsion of perforating and small branching arteries. CONCLUSIONS: Biomechanically superior thrombectomy technologies should prevent unrestrained tensional load on emboli, minimize intraluminal embolus fragmentation and release, improve device/embolus integration, recanalize small branching and perforating arteries, prevent arterial collapse, and minimize traction.

A human brain test bed for research in large vessel occlusion stroke.

OBJECTIVE: Endovascular removal of emboli causing large vessel occlusion (LVO)-related stroke utilizing suction catheter and/or stent retriever technologies or thrombectomy is a new standard of care. Despite high recanalization rates, 40% of stroke patients still experience poor neurological outcomes as many cases cannot be fully reopened after the first attempt. The development of new endovascular technologies and techniques for mechanical thrombectomy requires more sophisticated testing platforms that overcome the limitations of phantom-based simulators. The authors investigated the use of a hybrid platform for LVO stroke constructed with cadaveric human brains. METHODS: A test bed for embolic occlusion of cerebrovascular arteries and mechanical thrombectomy was developed with cadaveric human brains, a customized hydraulic system to generate physiological flow rate and pressure, and three types of embolus analogs (elastic, stiff, and fragment-prone) engineered to match mechanically and phenotypically the emboli causing LVO strokes. LVO cases were replicated in the anterior and posterior circulation, and thrombectomy was attempted using suction catheters and/or stent retrievers. RESULTS: The test bed allowed radiation-free visualization of thrombectomy for LVO stroke in real cerebrovascular anatomy and flow conditions by transmural visualization of the intraluminal elements and procedures. The authors were able to successfully replicate 105 LVO cases with 184 passes in 12 brains (51 LVO cases and 82 passes in the anterior circulation, and 54 LVO cases and 102 passes in the posterior circulation). Observed recanalization rates in this model were graded using a Recanalization in LVO (RELVO) scale analogous to other measures of recanalization outcomes in clinical use. CONCLUSIONS: The human brain platform introduced and validated here enables the analysis of artery-embolus-device interaction under physiological hemodynamic conditions within the unmodified complexity of the cerebral vasculature inside the human brain.

Construction of a comprehensive endovascular test bed for research and device development in mechanical thrombectomy in stroke.

OBJECTIVE: The development of new endovascular technologies and techniques for mechanical thrombectomy in stroke has greatly relied on benchtop simulators. This paper presents an affordable, versatile, and realistic benchtop simulation model for stroke. METHODS: A test bed for embolic occlusion of cerebrovascular arteries and mechanical thrombectomy was developed with 3D-printed and commercially available cerebrovascular phantoms, a customized hydraulic system to generate physiological flow rate and pressure, and 2 types of embolus analogs (elastic and fragment-prone) capable of causing embolic occlusions under physiological flow. RESULTS: The test bed was highly versatile and allowed realistic, radiation-free mechanical thrombectomy for stroke due to large-vessel occlusion with rapid exchange of geometries and phantom types. Of the transparent cerebrovascular phantoms tested, the 3D-printed phantom was the easiest to manufacture, the glass model offered the best visibility of the interaction between embolus and thrombectomy device, and the flexible model most accurately mimicked the endovascular system during device navigation. None of the phantoms modeled branches smaller than 1 mm or perforating arteries, and none underwent realistic deformation or luminal collapse from device manipulation or vacuum. The hydraulic system created physiological flow rate and pressure leading to iatrogenic embolization during thrombectomy in all phantoms. Embolus analogs with known fabrication technique, structure, and tensile strength were introduced and consistently occluded the middle cerebral artery bifurcation under physiological flow, and their interaction with the device was accurately visualized. CONCLUSIONS: The test bed presented in this study is a low-cost, comprehensive, realistic, and versatile platform that enabled high-quality analysis of embolus-device interaction in multiple cerebrovascular phantoms and embolus analogs.

Analysis of human emboli and thrombectomy forces in large-vessel occlusion stroke.

OBJECTIVE: This study's purpose was to improve understanding of the forces driving the complex mechanical interaction between embolic material and current stroke thrombectomy devices by analyzing the histological composition and strength of emboli retrieved from patients and by evaluating the mechanical forces necessary for retrieval of such emboli in a middle cerebral artery (MCA) bifurcation model. METHODS: Embolus analogs (EAs) were generated and embolized under physiological pressure and flow conditions in a glass tube model of the MCA. The forces involved in EA removal using conventional endovascular techniques were described, analyzed, and categorized. Then, 16 embolic specimens were retrieved from 11 stroke patients with large-vessel occlusions, and the tensile strength and response to stress were measured with a quasi-static uniaxial tensile test using a custom-made platform. Embolus compositions were analyzed and quantified by histology. RESULTS: Uniaxial tension on the EAs led to deformation, elongation, thinning, fracture, and embolization. Uniaxial tensile testing of patients' emboli revealed similar soft-material behavior, including elongation under tension and differential fracture patterns. At the final fracture of the embolus (or dissociation), the amount of elongation, quantified as strain, ranged from 1.05 to 4.89 (2.41 ± 1.04 [mean ± SD]) and the embolus-generated force, quantified as stress, ranged from 63 to 2396 kPa (569 ± 695 kPa). The ultimate tensile strain of the emboli increased with a higher platelet percentage, and the ultimate tensile stress increased with a higher fibrin percentage and decreased with a higher red blood cell percentage. CONCLUSIONS: Current thrombectomy devices remove emboli mostly by applying linear tensile forces, under which emboli elongate until dissociation. Embolus resistance to dissociation is determined by embolus strength, which significantly correlates with composition and varies within and among patients and within the same thrombus. The dynamic intravascular weakening of emboli during removal may lead to iatrogenic embolization.

Development of an advanced microfluidic micropipette aspiration device for single cell mechanics studies.

Various micro-engineered tools or platforms have been developed recently for cell mechanics studies based on acoustic, magnetic, and optical actuations. Compared with other techniques for single cell manipulations, microfluidics has the advantages with simple working principles and device implementations. In this work, we develop a multi-layer microfluidic pipette aspiration device integrated with pneumatically actuated microfluidic control valves. This configuration enables decoupling of cell trapping and aspiration, and hence causes less mechanical perturbation on trapped single cells before aspiration. A high trapping efficiency is achieved by the microfluidic channel design based on fluid resistance model and deterministic microfluidics. Compared to conventional micropipette aspiration, the suction pressure applied on the aspirating cells is highly stable due to the viscous nature of low Reynolds number flow. As a proof-of-concept of this novel microfluidic technology, we built a microfluidic pipette aspiration device with 2 × 13 trapping arrays and used this device to measure the stiffness of a human breast cancer cell line, MDA-MB-231, through the observation of cell deformations during aspiration. As a comparison, we studied the effect of Taxol, a FDA-approved anticancer drug on single cancer cell stiffness. We found that cancer cells treated with Taxol were less deformable with a higher Young's modulus. The multi-layer microfluidic pipette aspiration device is a scalable technology for single cell mechanophenotyping studies and drug discovery applications.