A Pilot First-in-Human Study of Embrace,a Polyethylene Glycol-Based Liquid Embolic Agent,in the Embolization of Malignant and Benign Hypervascular Tumors

PurposeTo investigate the safety and efficacy of an aqueous polyethylene glycol-based liquid embolic agent, Embrace Hydrogel Embolic System (HES), in the treatment of benign and malignant hypervascular tumors.Materials and MethodsA prospective, single-arm, multicenter study included 8 patients, 5 males and 3 females, with a median age of 58.5 years (30–85 years), who underwent embolization in 8 tumors between October 2019 and May 2020. Technical success was defined as successful delivery of HES to the index vessel, with disappearance of >90% of the targeted vascular enhancement or, for portal vein embolization, occlusion of the portal branches to the liver segments for future resection. The volume of HES administered, ease of use (5 point Likert scale), administration time, and adverse events (AEs) were recorded. Evaluation was performed at 7, 30, and 90 days via clinical assessment and blood testing, and follow-up imaging was performed at 30 days.ResultsEight patients were enrolled, and 10 embolizations were performed in 8 lesions. Tumors included hepatocellular carcinoma (n = 4), renal angiomyolipoma (n = 3), and intrahepatic cholangiocarcinoma (n = 1). Technical success was 100%, and the average ease of use was 3.3 ± 1.0 SD. The HES delivery time was 1–28 minutes (median, 16.5 minutes), and the HES volume injected was 0.4–4.0 mL (median, 1.3 mL). All patients reached 30-day follow-up with imaging, and 6 patients reached 90-day follow-up. There were 3 serious AEs in 2 patients that were unrelated to the embolic agent.ConclusionHES resulted in a 100% embolization technical success rate. The product ease of use was acceptable, and no target vessel recanalization was noted on follow-up imaging at 30 days.     

Evaluation of cisplatin-hydrogel for improving localized antitumor efficacy in gastric cancer

Gastric cancer, one of the most common disease, has become a major public health problem worldwide. Cisplatin (DDP) has been a widely used drug for the treatment of cancer, also usually applied in gastric cancer in clinic. However, the side effects including toxicity and drug-resistance restricted the usage of DDP in clinic, so we prepared a DDP-complexed hydrogel (DDP-Gel) and investigated its efficacy in gastric cancer. For in vivo studies, MKN45-Luc cells were injected into BLAB/C node mice subcutaneously to establish gastric cancer with orthotopically grown tumors. Mice bearing tumors were treated with normal saline, DDP and DDP-Gel. Body weight and survival condition were observed and recorded. The treatment efficacy in vivo was detected by luciferase imaging and histological evaluation was performed by H&E staining of different organs. Additionally, normal ICR mice were treated with different doses of DDP/DDP-Gel to calculate their LD₅₀ in vivo. The results showed that DDP-Gel prolonged survival time and ameliorated body weight changes of mice bearing tumors. DDP-Gel exhibited higher efficacy to inhibit tumor growth and metastasis, compared to DDP. Besides, LD₅₀ of DDP-Gel was 166.0?mg/kg, 13.2 folds higher than DDP. As a conclusion, DDP-Gel showed a more effective and safer function than DDP in gastric cancer, which indicating that DDP-Gel might be a novel strategy for gastric cancer therapy.     

N-异丙基丙烯酰胺/N-羟甲基丙烯酰胺共聚物及其水凝胶的合成及其温敏性研究

通过自由基聚合合成了N-异丙基丙烯酰胺(NIPAm)与N-羟甲基丙烯酰胺(NHMPA)的共聚物及其水凝胶。研究发现，调节两单体的配比可得到不同的低临界溶液温度(LCST)值的共聚物及水凝胶。结果表明，NHMPA的加入不改变PNIPAm的温敏性，但可有效的调节其LCST值。     

Développement d’un hydrogel autodurcissant in vivo, en perspective d’un usage biomédicalA new self-hardening gel in prospect of biomedical use

Since 1995, an injectable bone substitute is developed in our laboratory, it is based on a mix of an hydrogel (hydroxypropyl methylcellulose at 3%: cellulose ether) and biphasic calcium phosphate granules (MBCP^® : 60% hydroxyapatite, 40% β-tri calcium phosphate). This first generation of injectable bone substitute is a non-self-hardening past, nevertheless it owns a great osteoconductor potential. But it shows a tendency to the discharge by its initial composition, and involved limited clinical applications. An evolution of this product is presented in this article: the modification is generated by a new self-hardening hydrogel. This hydrogel is a cellulose ether grafted by silane and diluted in an aqueous solution at basic pH. Also it will be presented the general synthesis of this cellulose derivate, the dissolution condition and the self hardening principle in function of the pH and the temperature. As to conclude by preliminary tests, the biocompatibility in vivo and in vitro of the self-hardening hydrogel mixed with biphasic calcium phosphate granules will be studied.     

聚甲基丙烯酸羟乙酯水凝胶人工晶状体材料的合成与性能

以甲基丙烯酸羟乙酯为原料,过硫酸铵/偏重亚硫酸钠为引发体系,二甲基丙烯酸三乙二醇酯为交联剂,采用溶液聚合法制备了聚甲基丙烯酸羟乙酯水凝胶(PHEMA)人工晶状体材料。系统考察了聚合反应时间、温度及引发剂和交联剂的用量等对该水凝胶材料机械强度、平衡水含量(EWC)的影响,并对PHEMA水凝胶的结构和光学性能进行了表征。实验结果表明,PHEMA水凝胶的最佳合成条件为:引发剂0.5wt%,交联剂1.0wt%,反应温度40℃,反应时间36h。在此条件下制备的PHEMA水凝胶的拉伸强度达到0.57MPa,邵氏A硬度为23.0,平衡含水量超过40%,透光率≥97%。     

Novel nanostructured supramolecular hydrogels for the topical delivery of anionic drugs

A bis-imidazolium-based amphiphilic molecule was used to form novel supramolecular gels in ethanol–water mixtures. The proportion of solvents, the concentration of gellant and the temperature are factors that strongly influence the gelling process. The physical gels that are formed comprise entangled fibers of around 100 nm in diameter, able to incorporate anionic drugs, whose morphology varies depending on the drug they incorporate. These hydrogels are soft and therefore optimum for skin application. They show good stability when compared to previously reported gels. Suitable drug release and skin permeation profiles were obtained, and, moreover, they seem to promote the retention of the drug inside the skin. Finally, effective in vivo anti-inflammatory activity was observed, especially with the indomethacin-incorporated gel, which indicates that these supramolecular hydrogels are a good option for the delivery of poor water soluble drugs for the treatment of acute inflammation or other skin diseases.     

Robust T-tubulation and maturation of cardiomyocytes using tissue-engineered epicardial mimetics

Complex three-dimensional (3-D) heart structure is an important determinant of cardiac electrical and mechanical function. In this study, we set to develop a versatile tissue-engineered system that can promote important aspects of cardiac functional maturation and reproduce variations in myofiber directions present in native ventricular epicardium. We cultured neonatal rat cardiomyocytes within a 3-D hydrogel environment using microfabricated elastomeric molds with hexagonal posts. By varying individual post orientations along the directions derived from diffusion tensor magnetic resonance imaging (DTMRI) maps of human ventricle, we created large (2.5 × 2.5 cm²) 3-D cardiac tissue patches with cardiomyocyte alignment that replicated human epicardial fiber orientations. After 3 weeks of culture, the advanced structural and functional maturation of the engineered 3-D cardiac tissues compared to age-matched 2-D monolayers was evident from: 1) the presence of dense, aligned and electromechanically-coupled cardiomyocytes, quiescent fibroblasts, and interspersed capillary-like structures, 2) action potential propagation with near-adult conduction velocity and directional dependence on local cardiomyocyte orientation, and 3) robust formation of T-tubules aligned with Z-disks, co-localization of L-type Ca²⁺ channels and ryanodine receptors, and accelerated Ca²⁺ transient kinetics. This biomimetic tissue-engineered platform can enable systematic in vitro studies of cardiac structure–function relationships and promote the development of advanced tissue engineering strategies for cardiac repair and regeneration.     

Three-dimensional hydrogel scaffolds facilitate in vitro self-renewal of human skin-derived precursors

Skin-derived precursors (SKPs) are multipotent cells with dermal stem cell properties. These easily available cells possess the capacity to reconstitute the skin in vivo, as well as a broader differentiation potential in vitro, which endows them with great prospects in regenerative medicine. However, the present authors’ group and others previously found that adult human SKPs (hSKPs) expanded deficiently in vitro, which largely counteracted their research and practical values. Taking the physiological micro-environment of hSKPs into consideration, the authors sought to establish a hydrogel scaffold-based three-dimensional (3-D) culture system for hSKPs in the present study. After comparing their morphology, growth characteristics, signature gene expression and differentiation potential in different hydrogels, the present authors found that a chemically defined hyaluronic acid and denatured collagen-based hydrogel system that mimicked the natural niche of hSKPs in the dermis could alleviate hSKP senescence, support hSKP proliferation as spheres, while largely retaining their properties and potential. This study suggested that recapitulating the in vivo stem cell niche by providing them with 3-D extracellular matrix environments could help them achieve better self-renewal in vitro. In addition, the animal-origin-free and biocompatible 3-D hydrogel system will certainly benefit fundamental research and clinical applications of hSKPs in the near future.     

Wound healing potential of a dimeric InlB variant analyzed by in vitro experiments on re-epithelialization of human skin models

A constitutively dimeric truncated variant of internalin B (InlB₃₂₁-CD), acting as stimulator of the receptor tyrosine kinase MET, was tested for dermal wound-healing potential. Due to a lack of the endogenous MET agonist HGF/SF in chronic wounds, HGF/SF substitution by an InlB₃₂₁-CD-loaded hydrogel might be beneficial in chronic wound therapy.In this study, InlB₃₂₁-CD in solution and incorporated in a hydrogel was tested for mitogenic effects on immortalized human dermal keratinocytes (HaCaT) with an MTT assay. Cell migration was investigated with a scratch assay on primary keratinocytes (PHK) and on HaCaT. For the latter, scratching needed to be mitomycin C-controlled. InlB₃₂₁-CD effects on a model of human skin were analyzed histologically with respect to viability.InlB₃₂₁-CD led to dose-dependent proliferative effects on HaCaT cells whereas the equimolar dose of monomeric InlB₃₂₁ did not. Upon hydrogel incorporation of InlB₃₂₁-CD its mitogenic activity for HaCaT cells was maintained thus confirming the hydrogel as a promising drug delivery system. Motogenic effects were shown on both HaCaT and PHK cells. InlB₃₂₁-CD neither possesses cytotoxic effects on the viability of a human skin model nor alters its organotypic cell morphology.