Engineering “cell-particle hybrids” of pancreatic islets and bioadhesive FK506-loaded polymeric microspheres for local immunomodulation in xenogeneic islet transplantation

Nguyen, Tiep Tien,Pham, Tung Thanh,Nguyen, Hanh Thuy,Nepal, Mahesh Raj,Phung, Cao Dai,You, Zhiwei,Katila, Nikita,Pun, Nirmala Tillija,Jeong, Tae Cheon,Choi, Dong-Young,Park, Pil-Hoon,Yong, Chul Soon,K Elsevier 2019 Biomaterials Vol.221 No.-

<P><B>Abstract</B></P> <P>Host immune response remains an obstacle in cell-replacement therapy for treating type I diabetes. Long-term systemic immunosuppression results in suboptimal efficacy and adverse reactions. Thus, “cell-particle hybrids” of pancreatic islets and tissue-adhesive, polydopamine-coated, FK506-loaded biodegradable microspheres (PD-FK506-MS) were developed to locally modulate the immune response at the transplantation site. Coating of FK506-MS with PD enabled the rapid formation of stable cell-particle hybrids without significant changes in islet viability and functionality. Extremely low quantities of FK506 (approximately 600 ng per recipient) sustainably released from cell-particle hybrids effectively prolonged survival of xenogeneic islet graft. Interestingly, FK506 exhibited extended bioavailability in the grafts but was undetectable in systemic circulation and other tissues. Moreover, mRNA expression of inflammatory cytokines was significantly inhibited in the PD-FK506-MS-containing grafts but not in lymphoid organs. This study presents a promising platform that facilitates the translation of local immunomodulation towards an effective strategy with improved safety profiles for treating type I diabetes.</P>

Bioinspired Surface-Engineering of Stem Cell Spheroids with Dexamethasone-Eluting Depots Promotes Bone Regeneration in Murine Calvarial Defect Model

( Nguyen Tien Tiep ),정지헌,육심명 한국공업화학회 2022 한국공업화학회 연구논문 초록집 Vol.2022 No.-

The Role of Zn Doping on the Catalytic Activity of the Nanoparticle Perovskite La0.7Sr0.3MnO3

Tran Thi Minh Nguyet,Nguyen Quang Huan,Tran Que Chi,Do The Chan,Nguyen Doan Thai,Nguyen Cong Trang,Luu Tien Hung,Le Van Tiep,Nguyen Van Qui 한국물리학회 2008 THE JOURNAL OF THE KOREAN PHYSICAL SOCIETY Vol.52 No.5

The nanometer complex oxide La0:7Sr0.3Mn0.6Zn0.₄O₃ was prepared by using a Sol-Gel method with citric acid as a ligand. The in uence of Zn doping of La0.7Sr0.₃MnO₃ on the structure, the morphology, the surface properties and on the catalytic activity of material was studied by using X-ray diraction (XRD), transmission electron microscopy (TEM), a high-resolution images and selected area electron diraction (SAED), physical adsorption and temperature programmed surface reaction (TPSR) methods. The results showed that perovskite La0:7Sr0:3Mn0:6. Zn0.₄O₃ could well catalyse propene oxidation in the temperature range 190 { 280 ℃, which was reduced to 100 { 120 ℃ for catalyst La1-χSrχMnO₃ The nanometer complex oxide La0:7Sr0.3Mn0.6Zn0.₄O₃ was prepared by using a Sol-Gel method with citric acid as a ligand. The in uence of Zn doping of La0.7Sr0.₃MnO₃ on the structure, the morphology, the surface properties and on the catalytic activity of material was studied by using X-ray diraction (XRD), transmission electron microscopy (TEM), a high-resolution images and selected area electron diraction (SAED), physical adsorption and temperature programmed surface reaction (TPSR) methods. The results showed that perovskite La0:7Sr0:3Mn0:6. Zn0.₄O₃ could well catalyse propene oxidation in the temperature range 190 { 280 ℃, which was reduced to 100 { 120 ℃ for catalyst La1-χSrχMnO₃

Evaluation of the Effects of Biodegradable Microspheres Loaded with Quercetin on Adipogenic and Chondrogenic Differentiation of Cellular Spheroids

이현진,Tiep Tien Nguyen,정지헌,박준범 한국고분자학회 2018 Macromolecular Research Vol.25 No.6

This study was performed to evaluate the effects of quercetin application and the biodegradable poly(lactic-co-glycolic acid)-based microspheres loaded with quercetin on the adipogenic and chondrogenic differentiation of three-dimensional cells composed of gingiva-derived stem cells and osteoblast-like cells. Three-dimensional cell spheroids were fabricated using silicon elastomer-based concave microwells and cultured in adipogenic and chondrogenic media. Quercetin at 1 μg/mL (Q1) and microspheres loaded with quercetin at 1 μg/mL (M1) were used. Quantitative cellular viability was evaluated using Cell Counting Kit-8 assay. Adipogenesis was determined after oil red O staining and chondrogensis was evaluated by measuring relative intensity of Alcian blue staining. Spheroids were well maintained irrespective of quercetin application in silicon elastomer-based concave microwells. The relative Cell Counting Kit-8 assay values for unloaded, Q1, and M1 groups in adipogenic media on Day 1 were 100.0±7.6%, 153.6±11.3%, and 104.7±6.3%, respectively. Relative values of adipogenesis were 114.6%, 116.2%, and 113.4% for unloaded, Q1, and M1 groups on Day 7, respectively, and relative values of adipogenesis were 131.7%, 137.5%, and 133.6% for unloaded, Q1, and M1 groups on Day 14, respectively. The relative Cell Counting Kit-8 assay values for unloaded, Q1, and M1 groups in chondrogenic media on Day 1 were 100.0±3.2%, 162.1±13.0%, and 96.6±3.7%, respectively. Relative values of chondrogensis were 103.6%, 111.0%, and 103.7% for unloaded, Q1, and M1 groups on Day 7, respectively, and the relative values of chondrogensis were 157.4%, 165.3%, and 160.9% for unloaded, Q1, and M1 groups on Day 14, respectively. Application of quercetin produced quercetin at 1 μg/mL and promoted the viability of cell spheroids cultured in adipogenic and chondrogenic media. However, application of quercetin did not reach statistically significant enhancement of adipogenisis or chondrogenesis at the experimental condition.

Advances in alginate encapsulation of pancreatic islets for immunoprotection in type 1 diabetes

쩌우더리디네스,Nguyen Tiep Tien,Yook, Simmyung,정지헌 한국약제학회 2023 Journal of Pharmaceutical Investigation Vol.53 No.5

Background Islet transplantation is a promising minimally invasive approach that dispenses with many challenges, especially immunological complications such as instant blood-mediated inflammatory reaction, autoimmunity, and allogeneic or xenogeneic rejection. Besides, scare of islet donor, side effects of immunosuppressant, and poor angiogenesis are also crucial factors for long-term islet survival and function. Approaches to the encapsulation of islets have been introduced to address aforementioned challenges. Area covered In this review, we summarize the concept of islet encapsulation using alginate to minimize the immunological complications, maintain islet morphology, and exchange of nutrients, hormones, and metabolic waste via isolating pancreatic islets from host immune cells. Alginate encapsulation technologies like dripping, microfluidics, and 3D printing are also briefly introduced. Similarly, this review outlines islet encapsulation strategies (co-encapsulation with other cells, peptides, drugs, etc.,) and approaches (nano-, micro-, and macroencapsulation) using alginate. Alongside this, this review introduces the use of alginate in an oxygenation system to overcome the hypoxic environment faced by encapsulated islets. Finally, challenges and opportunities for islet encapsulation using alginate are also discussed in terms of clinical applications. Expert opinion With the aim of immunoisolation, islet encapsulation using alginate reduces immunological attacks and enhances the survivability of islets after transplantation. Alginate shows promise based on its biocompatibility, non-toxicity, and easy and fast gelation under physiological conditions. Intriguingly, it can also co-encapsulate islets with other biomolecules and shows compatibility with other polymers. With ongoing strides in research on islet encapsulation, alginateencapsulated islets could be available for the treatment of type 1 diabetes in the near future.

Formulation of secretome derived from mesenchymal stem cells for inflammatory skin diseases

Seo Yoojin,Nguyen Tiep Tien,오수정,정지헌,Kim Hyung-Sik 한국약제학회 2023 Journal of Pharmaceutical Investigation Vol.53 No.2

Background Growing evidence has demonstrated that the administration of mesenchymal stem cells (MSCs) in various inflammatory skin diseases caused by autoimmune or allergic reactions can be served as promising therapeutics owing to their immunomodulatory effect as well as tissue regenerative capacity. Area covered In this review, we summarize the therapeutic application of MSCs and their secretome targeting inflammatory skin diseases and current secretome engineering strategies for the clinical translation of cell-free therapeutics. Expert opinion Considering that direct application of MSCs often fails to reproduce stable therapeutic outcomes, partially due to harsh in vivo microenvironment leading to insufficient survival of injected cells, the concept of cell-free approaches utilizing MSC-derived paracrine factors including secretome and exosome has emerged to overcome present issues. Furthermore, various bioengineering techniques with biocompatible materials can be applied to modulate naïve secretome to improve their delivery efficiency and bioavailability in vivo.

Evaluation of the Effects of Biodegradable Microspheres Loaded with Quercetin on Adipogenic and Chondrogenic Differentiation of Cellular Spheroids

Lee, Hyunjin,Nguyen, Tiep Tien,Jeong, Jee-Heon,Park, Jun-Beom The Polymer Society of Korea 2018 Macromolecular Research Vol.26 No.6

This study was performed to evaluate the effects of quercetin application and the biodegradable poly(lactic-co-glycolic acid)-based microspheres loaded with quercetin on the adipogenic and chondrogenic differentiation of three-dimensional cells composed of gingiva-derived stem cells and osteoblast-like cells. Three-dimensional cell spheroids were fabricated using silicon elastomer-based concave microwells and cultured in adipogenic and chondrogenic media. Quercetin at <TEX>$1{\mu}g/mL$</TEX> (Q1) and microspheres loaded with quercetin at <TEX>$1{\mu}g/mL$</TEX> (M1) were used. Quantitative cellular viability was evaluated using Cell Counting Kit-8 assay. Adipogenesis was determined after oil red O staining and chondrogensis was evaluated by measuring relative intensity of Alcian blue staining. Spheroids were well maintained irrespective of quercetin application in silicon elastomer-based concave microwells. The relative Cell Counting Kit-8 assay values for unloaded, Q1, and M1 groups in adipogenic media on Day 1 were <TEX>$100.0{\pm}7.6%$</TEX>, <TEX>$153.6{\pm}11.3%$</TEX>, and <TEX>$104.7{\pm}6.3%$</TEX>, respectively. Relative values of adipogenesis were 114.6%, 116.2%, and 113.4% for unloaded, Q1, and M1 groups on Day 7, respectively, and relative values of adipogenesis were 131.7%, 137.5%, and 133.6% for unloaded, Q1, and M1 groups on Day 14, respectively. The relative Cell Counting Kit-8 assay values for unloaded, Q1, and M1 groups in chondrogenic media on Day 1 were <TEX>$100.0{\pm}3.2%$</TEX>, <TEX>$162.1{\pm}13.0%$</TEX>, and <TEX>$96.6{\pm}3.7%$</TEX>, respectively. Relative values of chondrogensis were 103.6%, 111.0%, and 103.7% for unloaded, Q1, and M1 groups on Day 7, respectively, and the relative values of chondrogensis were 157.4%, 165.3%, and 160.9% for unloaded, Q1, and M1 groups on Day 14, respectively. Application of quercetin produced quercetin at <TEX>$1{\mu}g/mL$</TEX> and promoted the viability of cell spheroids cultured in adipogenic and chondrogenic media. However, application of quercetin did not reach statistically significant enhancement of adipogenisis or chondrogenesis at the experimental condition.

Tissue adhesive FK506–loaded polymeric nanoparticles for multi–layered nano–shielding of pancreatic islets to enhance xenograft survival in a diabetic mouse model

Pham, Tung Thanh,Nguyen, Tiep Tien,Pathak, Shiva,Regmi, Shobha,Nguyen, Hanh Thuy,Tran, Tuan Hiep,Yong, Chul Soon,Kim, Jong Oh,Park, Pil–,Hoon,Park, Min Hui,Bae, Young Kyung,Choi, Jeong Uk,Byun, IPC Science and Technology Press 2018 Biomaterials Vol.154 No.-

<P><B>Abstract</B></P> <P>This study aims to develop a novel surface modification technology to prolong the survival time of pancreatic islets in a xenogenic transplantation model, using 3,4–dihydroxyphenethylamine (DOPA) conjugated poly(lactide–co–glycolide)–poly(ethylene glycol) (PLGA–PEG) nanoparticles (DOPA–NPs) carrying immunosuppressant FK506 (FK506/DOPA–NPs). The functionalized DOPA–NPs formed a versatile coating layer for antigen camouflage without interfering the viability and functionality of islets. The coating layer effectively preserved the morphology and viability of islets in a co–culture condition with xenogenic lymphocytes for 7 days. Interestingly, the mean survival time of islets coated with FK506/DOPA–NPs was significantly higher as compared with that of islets coated with DOPA–NPs (without FK506) and control. This study demonstrated that the combination of surface camouflage and localized low dose of immunosuppressant could be an effective approach in prolonging the survival of transplanted islets. This newly developed platform might be useful for immobilizing various types of small molecules on therapeutic cells and biomaterial surface to improve the therapeutic efficacy in cell therapy and regenerative medicine.</P>

Timing of magnetic resonance imaging affects the accuracy and interobserver agreement of anterolateral ligament tears detection in anterior cruciate ligament deficient knees

Han Audrey Xinyun,Tan Tien Jin,Nguyen Tiep,Lee Dave Yee Han 대한슬관절학회 2020 대한슬관절학회지 Vol.32 No.-

We aimed to identify the anterolateral ligament (ALL) tears in anterior cruciate ligament (ACL)-deficient knees using standard 1.5-Tesla magnetic resonance imaging (MRI). We included all patients who underwent primary ACL reconstruction at our center between 2012 and 2015. Exclusion criteria included patients with multiple ligament injuries, lateral collateral ligament, posterolateral corner, and infections, and patients who underwent MRI more than 2 months after their injury. All patients ( n = 148) had ACL tears that were subsequently arthroscopically reconstructed. The magnetic resonance (MR) images of the injured knees performed within 2 months of injury were reviewed by a musculoskeletal radiologist and an orthopedic surgeon. The patients were divided into two groups. The first group of patients had MRI performed within 1 month of injury. The second group of patients had MRI performed 1–2 months after the index injury. Both assessors were blinded and the MR mages were read separately to assess the presence of ALL, presence of a tear and the location of the tear. Based on their readings, interobserver agreement (kappa statistic (K)), sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were compared. The ALL was identified in 100% of the patients. However, there was a discrepancy of up to 15% in the identification of tear of the ALL. In the first group in which MRI scans were performed within 1 month of injury, the ALL tear was identified by the radiologist in 92% of patients and by the surgeon in 90% of patients (Κ = 0.86). In the second group in which MRI scans were performed within 1–2 months of the injury, the ALL tear was identified by the radiologist in 78% of patients and by the surgeon in 93% of patients (K = 0.62).The ALL can be accurately identified on MRI, but the presence and location of ALL tear and its location cannot be reliably identified on MRI. The accuracy in identification and characterization of a tear was affected by the interval between the time of injury and the time when the MRI was performed.Diagnostic, level IIIb, retrospective.

Polymeric microsphere-facilitated site-specific delivery of quercetin prevents senescence of pancreatic islets <i>in vivo</i> and improves transplantation outcomes in mouse model of diabetes

Pathak, Shiva,Regmi, Shobha,Nguyen, Tiep Tien,Gupta, Biki,Gautam, Milan,Yong, Chul Soon,Kim, Jong Oh,Son, Youlim,Kim, Jae-Ryong,Park, Min Hui,Bae, Young Kyung,Park, So Young,Jeong, Daewon,Yook, Simmyu Elsevier 2018 ACTA BIOMATERIALIA Vol.75 No.-

<P><B>Abstract</B></P> <P>Attenuation of senescence progression may be attractive way to preserve the functionality of pancreatic islets (PI) after transplantation. In this study, we developed a model for <I>in vitro</I> induction of premature senescence in rat PI and showed the effectiveness of quercetin (QU) to prevent the senescence. To provide targeted-delivery of QU to the PI after transplantation, we prepared the hybrid clusters (HC) of islet single cells (ISC) and QU-loaded polymeric microspheres (QU; ∼7.55 ng HC<SUP>−1</SUP>). Long-term culture of the HC revealed reduced levels of reactive oxygen species and decreased expression of senescence-associated beta galactosidase, Rb, p53, p16, and p21 compared to that of the control islets. Transplantation of HC into subcutaneous space of the immune-deficient mice produced better glycemic control compared to the control islets or the ICC-transplanted mice. SA-β-Gal staining of the <I>in vivo</I> transplanted HC sample showed lower intensity compared to that of the control islets or the islet cell clusters. Thus, <I>in situ</I> delivery of therapeutic agent may be a promising approach to improve therapeutic outcomes in cell therapy.</P> <P><B>Statement of Significance</B></P> <P>In this study, we aimed to improve outcomes in islet transplantation using <I>in situ</I> delivery of quercetin to pancreatic islets, using polymeric microspheres. We prepared prolonged release-type microspheres and constructed hybrid clusters of pancreatic islets and the microspheres using hanging drop method. The presence of quercetin in the cellular microenvironment attenuated the progression of senescence in the pancreatic islets in a long-term <I>in vitro</I> culture. Moreover, transplantation of the hybrid clusters in the diabetic mice produced better glycemic control compared to that of the control islets. In addition, quercetin delayed the progression of senescence in the pancreatic islets after <I>in vivo</I> transplantation. Thus, local delivery of antioxidants like quercetin may be an attractive way to improve outcomes in cell therapy.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Quercetin prevents senescence of pancreatic islets <I>in vitro</I>. </LI> <LI> PLGA microspheres provide quercetin into the cellular microenvironment. </LI> <LI> Transplantation of the hybrid clusters produces better glycemic control. </LI> <LI> Hybrid clusters of cells and microspheres exhibit reduction of senescence. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>