Seung Hyun Park

Perivascular biodegradable microneedle cuff for reduction of neointima formation after vascular injury

Restenosis often occurs at the site of vascular grafting and may become fatal for patients. Restenosis at anastomosis sites is due to neointimal hyperplasia (NH) and difficult to treat with conventional treatments. Such abnormal growth of smooth muscle cells in tunica media of vascular tissue can be reduced by delivering anti-proliferation drugs such as paclitaxel (PTX) to the inner vascular layer. Drug eluting stents (DES) or drug eluting balloon (DEB) have been developed to treat such vascular diseases. However, they are less efficient in drug delivery due to the drug loss to blood stream and inadequate to be applied to re-stenotic area in the presence of stent or anastomosis sites. Recently, we have introduced microneedle cuff (MNC) as perivascular delivery devices to achieve high delivery efficiency to tunica media. In this study, we investigated in vivo microneedle insertion and efficacy in treating NH using a rabbit balloon injury model. Microneedle shape was optimized for reliable insertion into tunica media layer. Uniform distribution of PTX in tunica media delivered by MNC devices was also confirmed. Animal study demonstrated significant NH reduction by MNC treatments and much higher delivery efficiency than flat type devices.

Rapid and repeatable fabrication of high A/R silk fibroin microneedles using thermally-drawn micromolds

Thermal drawing is a versatile rapid prototyping method that can freely form microneedle (MN) structures with ultra-high aspect ratio without relying on any complex and expensive process. However, it is still challenging to repeatedly produce MNs with identical shapes using this thermal drawing due to small fluctuations in processing conditions such as temperatures, drawing speeds, drawing heights, or parallelism in the drawing setup. In addition, thermal drawing is only applicable to thermoplastic materials and most natural biomaterials are incompatible with this method. Thus, we propose use of thermal drawing to fabricate master molds with high aspect ratios and replicate the shape by micromolding. In this work, high A/R MNs with various body profiles were fabricated by thermal drawing and replicated to silk fibroin (SF) MNs multiple times using micromolding. The original MN shape was precisely copied to the SF MNs. Methanol treatment enhanced the mechanical strength of SF MNs up to about 113% more depending on the treatment duration. We also demonstrated that methanol exposure time could effectively control drug release rates from SF MNs.

Rectal Mucinous Adenocarcinoma: MR Imaging Assessment of Response to Concurrent Chemotherapy and Radiation Therapy—A Hypothesis-generating Study

Purpose To develop a system for assessment of tumor regression grade (TRG) with magnetic resonance (MR) imaging that is applicable to rectal mucinous adenocarcinoma (RMAC) and to obtain a preliminary evaluation of the association of MR imaging assessment of TRG with response to preoperative concurrent chemotherapy and radiation therapy (CCRT). Materials and Methods This retrospective study was approved by the institutional review board, and informed consent was waived. Pre- and post-CCRT MR images of 59 patients with RMAC (median age, 59 years; range, 29-80 years; 42 men [median age, 59 years; range, 36-80 years] and 17 women [median age, 57 years; range, 29-79 years]) who underwent CCRT and subsequent elective resection from July 2005 to June 2015 were analyzed. Two experienced gastrointestinal radiologists independently analyzed imaging parameters such as T stage, mesorectal fascia status, extramural vascular invasion status, and TRG by using modified criteria developed for assessment of RMAC. Interobserver variability was calculated with weighted κ analysis, and disagreement was settled in consensus. MR imaging TRG results were compared with those from pathologic TRG analysis (Mandard grade). Logistic regression analyses were performed to evaluate associations between imaging parameters and pathologic TRG. Results There was moderate to substantial agreement for imaging parameters (post-CCRT T stage-weighted κ, 0.7134; post-CCRT mesorectal fascia status, 0.618; TRG, 0.5023). Modified MR imaging TRG results were significantly associated with pathologic responsiveness (responsive group, Mandard grade 1 or 2; nonresponsive group, Mandard grades 3-5; P = .023). Results of univariate and multivariate logistic regression analyses indicated that MR imaging TRG was the only factor significantly associated with CCRT responsiveness (univariate analysis, P = .023; multivariate analysis, P = .0261). Conclusion The modified MR imaging assessment of TRG was associated with treatment response to CCRT in patients with RMAC.

Aberrant expression of OATP1B3 in colorectal cancer liver metastases and its clinical implication on gadoxetic acid-enhanced MRI

Purpose To investigate the factors associated with hepatobiliary phase (HBP) enhancement at gadoxetic acid-enhanced magnetic resonance imaging (MRI) and to determine whether HBP images could be used to predict prognosis in patients with colorectal cancer liver metastasis (CRLM). Results Of the 96 total nodules, 65 and 31 nodules were in the mixed and clearly hypointense groups, respectively. In the 55 nodules without preoperative chemotherapy, organic anionic transporting polypeptide 1B3 (OATP1B3) expression was a significant factor regarding the HBP enhancement (P=0.042). In this subgroup, nodules with OATP1B3 expression displayed a significantly higher relative intensity ratio on the HBP image (RIRpost) and relative enhancement ratio (RER) than those lacking this marker (P=0.024, 0.003, respectively). No significant factor was associated with the enhancement pattern in the chemotherapy group. The mixed hypointense group displayed worse survival rates (P=0.002). Materials and Methods Ninety-six patients who underwent pre-operative liver MRI and surgical resection for CRLM from January 2010 to June 2012 were retrospectively analyzed. We qualitatively evaluated the HBP enhancement pattern of CRLMs and classified them into mixed and clearly hypointense groups. For quantitative measurement, the RIRpost and RER were analyzed. To investigate factors associated with HBP enhancement, tumor components (fibrosis, necrosis, and cellularity) and OATP1B3 expression were scored on a 4-point scale. Univariate and multivariate analyses were done to determine significant factors for visual enhancement and quantitative parameters. Conclusions OATP1B3 expression is associated with mixed hypointense CRLMs without chemotherapy. Signal intensity on HBP has potential usefulness to predict prognosis in CRLMs.

Abdominal seeding of renal cell carcinoma: radiologic, pathologic, and prognostic features

PurposeWe analyzed radiologic and histologic characteristics, and prognosis of abdominal seeding from renal cell carcinoma (RCC).MethodsConsecutive 25 patients with RCC and histologically or radiologically diagnosed abdominal seeding were analyzed. No patient had another type of malignancy. Histologic subtype, Fuhrman grade, sarcomatoid differentiation, and T-stage of primary tumors were assessed. Pre- or postoperative presentation of seeding was investigated. Median survival time and RCC-specific survival rates were evaluated.ResultsOf 25 patients, 15 (60%) died and 4 (16%) were hopelessly discharged (median follow-up time, 6 months; range 1–62 months). Histologic subtypes were clear cell (76%, 19/25), papillary (16%, 4/25), chromophobe (4%, 1/25), and poorly differentiated (4%, 1/25). Fuhrman grades were 4 (48%, 12/25), 3 (36%, 9/25), 2 (12%, 3/25), and unknown (4%, 1/25). T-stage of the four patients with grade 2 or unknown was 3a. Sarcomatoid differentiation and postoperative occurrence were found in 32% (8/25) and 80% (20/25), respectively. Median survival time was 13 months, and 1-year, 2-year, and 3-year RCC-specific survival rates were 51%, 41%, and 31%, respectively.ConclusionAbdominal seeding may occur in various subtypes of RCC with high Fuhrman grade including sarcomatoid differentiation or high T-stage, and appears to be related to poor prognosis.

A Biodegradable Microneedle Cuff for Comparison of Drug Effects through Perivascular Delivery to Balloon-Injured Arteries

Restenosis at a vascular anastomosis site is a major cause of graft failure and is difficult to prevent by conventional treatment. Perivascular drug delivery has advantages as drugs can be diffused to tunica media and subintima while minimizing the direct effect on endothelium. This in vivo study investigated the comparative effectiveness of paclitaxel, sirolimus, and sunitinib using a perivascular biodegradable microneedle cuff. A total of 31 New Zealand white rabbits were used. Rhodamine was used to visualize drug distribution (n = 3). Sirolimus- (n = 7), sunitinib- (n = 7), and paclitaxel-loaded (n = 7) microneedle cuffs were placed at balloon-injured abdominal aortae and compared to drug-free cuffs (n = 7). Basic histological structures were not affected by microneedle devices, and vascular wall thickness of the device-only group was similar to that of normal artery. Quantitative analysis revealed significantly decreased neointima formation in all drug-treated groups (p < 0.001). However, the tunica media layer of the paclitaxel-treated group was significantly thinner than that of other groups and also showed the highest apoptotic ratio (p < 0.001). Proliferating cell nuclear antigen (PCNA)-positive cells were significantly reduced in all drug-treated groups. Sirolimus or sunitinib appeared to be more appropriate for microneedle devices capable of slow drug release because vascular wall thickness was minimally affected.

Transfer-molded wrappable microneedle meshes for perivascular drug delivery

&NA; After surgical procedures such as coronary/peripheral bypass grafting or endarterectomy for the treatment of organ ischemia derived from atherosclerosis, intimal hyperplasia (IH) which leads to restenosis or occlusion at the site of graft anastomosis frequently occurs. In order to inhibit IH caused by abnormal growth of smooth muscle cells (SMCs) in tunica media, various perivascular drug delivery devices are reported for delivery of anti‐proliferation drugs into vascular tissue. However, there still remain conflicting requirements such as local and unidirectional delivery vs device porosity, and conformal tight device installation vs pulsatile expansion and constriction of blood vessels. In this study, a biodegradable microneedle (MN) array is developed on a flexible woven surgical mesh using a transfer molding method. Mechanical properties of ‘wrappable’ MN meshes are investigated and compared to the properties of blood vessels. Ex vivo and in vivo animal studies demonstrate enhanced drug delivery efficiency, efficacy for IH reduction, and safety of MN mesh. In particular, MN mesh showed significantly reduced neointiamal formation (11.1%) compared to other competitive groups (23.7 and 22.2%) after 4‐week in vivo animal study. Additionally, wrappable MN meshes effectively suppressed side effects such as IH due to mechanical constriction, loss of toxic drug to the surroundings, and cell death that were frequently observed with other previous perivascular drug delivery devices. Graphical abstract Figure. No caption available.

Linear Micro-patterned Drug Eluting Balloon (LMDEB) for Enhanced Endovascular Drug Delivery

In-stent restenosis (ISR) often occurs after applying drug eluting stents to the blood vessels suffering from atherosclerosis or thrombosis. For treatment of ISR, drug eluting balloons (DEB) have been developed to deliver anti-proliferative drugs to the lesions with ISR. However, there are still limitations of DEB such as low drug delivery efficiency and drug loss to blood flow. Although most researches have focused on alteration of drug formulation for more efficient drug delivery, there are few studies that have attempted to understand and utilize the contact modality of DEB drug delivery. Here, we developed a linear micro-patterned DEB (LMDEB) that applied higher contact pressure to enhance drug stamping to vascular tissue. Ex vivo and in vivo studies confirmed that higher contact pressure from micro-patterns increased the amount of drug delivered to the deeper regions of vessel. Finite element method simulation also showed significant increase of contact pressure between endothelium and micro-patterns. Quantitative analysis by high performance liquid chromatography indicated that LMDEBs delivered 2.3 times higher amount of drug to vascular tissue in vivo than conventional DEBs. Finally, efficacy studies using both atherosclerotic and ISR models demonstrated superior patency of diseased vessels treated with LMDEB compared to those treated with DEB.

Depthwise-controlled scleral insertion of microneedles for drug delivery to the back of the eye

&NA; To treat retinal diseases, intravitreal injection is commonly performed to deliver therapeutic agents to the eye. However, intravitreal injection poses potential risks of ocular complications such as endophthalmitis, retinal detachment, and ocular hemorrhage. Thus, it is desired to develop a minimally invasive and therapeutically effective ocular drug delivery system without full penetration into the sclera. Here, we studied the possibility of precisely‐controlled insertion of microneedles (MNs) into the sclera to different levels of depths and how different insertion depths could affect drug delivery into the sclera and to the back of the eye. A microneedle pen (MNP) was developed for depth‐controlled scleral delivery by controlling insertion speeds, and it was confirmed that the insertion depths of MNs could be finely controlled by insertion speeds in ex vivo studies. Finite element modeling analyses were also conducted to understand how the depth‐controlled insertion of MNs could significantly influence the diffusion distances of drug molecules. Finally, in vivo experiments demonstrated that this MNP system could be applied to the beagle eyes comparable to human ones for the scleral administration of therapeutic agents through the scleral tissues. Graphical abstract Figure. No caption available.