Current Progress on Biological Evaluation for Medical Devices / 中国医疗器械杂志

To broadly understand the new direction of biological evaluation for medical devices, we introduced both domestic and international progress of biological evaluation and focused on illustrating the key points on full life-cycle biological evaluation, toxicological risk evaluation, evaluation endpoints and package material evaluation concern as well as how to use the update vision of ISO 10993-1:2018 scientifically and reasonably in order to provide us better services on performing biological evaluation for medical devices.

Anti-inflammatory target prediction of Gentianae Radix et Rhizoma based on network pharmacology and construction of a bioassay method for its quality control / 中国中药杂志

Based on the heat-clearing and detoxifying effects of Gentianae Radix et Rhizoma, the network pharmacology is mainly used to predict the potential targets of Gentianae Radix et Rhizoma for anti-inflammatory activity and to perform the experimental verification. A method for detecting the biological potency of Gentianae Radix et Rhizoma based on verifiable targets has been established to provide a reference for improving the quality evaluation and control standards of Gentianae Radix et Rhizoma. High performance liquid chromatography can be used to construct chemical fingerprints of different batches of Gentianae Radix et Rhizoma. Constructing a component-target-disease network of Gentianae Radix et Rhizoma for its anti-inflammatory activity was applied to screen potential anti-inflammatory components and related targets of Gentianae Radix et Rhizoma, and to verify the target of Gentianae Radix et Rhizoma by using biological evaluation methods. Detecting the biological potency of different batches of Gentianae Radix et Rhizoma extracts was used to inhibit COX-2 enzyme activity based the verifiable target cyclooxygenase-2(COX-2). The results showed that different batches of Gentianae Radix et Rhizoma accorded with the pharmacopoeia testing regulations, and the chemical fingerprints have a high similarity(similarity>0.93), suggesting that there is no significant difference in the characteristics of the chemical components. Based on network pharmacology predictions, 18 candidate targets were found to have potential direct interactions with the ingredients in Gentianae Radix et Rhizoma. Among them, the most important target is COX-2. Based on the experimental verification of recombinant human COX-2 protease activity inhibition, Gentianae Radix et Rhizoma can inhibit the COX-2 enzyme activity in a dose-dependent manner. It can function with a low concentration(0.75 mg·mL~(-1)), which preliminarily confirmed the accuracy of network pharmacology prediction. The biological potency detection method of Gentianae Radix et Rhizoma based on COX-2 inhibitory activity was optimized and established. The qualitative response parallel line method was used to calculate the biological potency of anti-inflammatory activity, which ranged from 23.04 to 46.60 U·mg~(-1). For network pharmacology prediction, it can screen and clarify the possible targets of traditional Chinese medicine rapidly, which can guide the establishment of a biological evaluation method for the quality of medicinal materials with related activities. Compared with chemical fingerprints, the biological potency testing can better detect quality fluctuations of traditional Chinese medicine.

Research progress on sterilization technology of Chinese materia medica powder based on physicochemical and biological evaluation / 中草药

Chinese materia medica powder (CMMP) is an important intermediate in the preparation of Chinese materia medica (CMM). Sterilization of CMMP is an essential key operation unit, which directly affects the safety, effectiveness and quality stability of CMM. In this paper, the applications, characteristics, important status and the necessity of sterilization of CMMP were summarized, and the classification, advantages and disadvantages and application of existing sterilization technology of CMMP were systematically analyzed from the perspective of sterilization rate, physicochemical and biological evaluation, and chemical residue, so as to further improve the evaluation system of sterilization technology of CMMP. Only by combining the characteristics of CMMP, adopting a multidimensional quality evaluation and selecting appropriate sterilization methods, the internal quality and sterility of CMMP after sterilization can be guaranteed.

Quality evaluation of different processed products of Aconiti Lateralis Radix Praeparata combining bioassay and toxicity detection / 药学学报

There are many kinds of processed products of Aconiti Lateralis Radix Praeparata (ALRP), but their differences in toxicity and efficacy have not been identified. The minimum premature ventricular contraction (PVC) method was used to evaluate the biological toxicity of eight processed products. The results showed that the minimal toxic dose (MTD) of an ethanol extract of Shengfupian (SFP) was 0.16 g·kg-1, which was much lower than that of Heishunpian (HSP), Baifupian (BFP), Baofupian (BAP), Paofuzi (PFZ) or Zhengfupian (ZFP), with MTDs ranging from 2.64 to 5.75 g·kg-1. No cardiotoxicity was detected with Chaofupian (CFP) and Paotianxiong (PTX). A novel +dp/dtmax assay for acute heart failure in rats was developed to evaluate the cardiac activity. It was found that all eight processed products had cardiac effects, with Shengfupian showing the strongest cardiotonic effect and the ability to restore damaged cardiac function to normal within 15 minutes of injection. Heishunpian, Baifupian and the three other products displayed moderate activity, while Paofuzi and Paotianxiong were the weakest. An LC-MS/MS method was utilized to determine the content of 13 alkaloids in water extracts. The results demonstrated that hypertoxic aconitine, mesaconitine, and hypaconitine could not be detected, higenamine was only present in Shengfupian, and salsolinol was about 4-56 times higher in Shengfupian than in other products. A correlation analysis showed that salsolinol had the best correlation with the cardiotonic index, with a correlation coefficient as high as 0.817, while the three monoester alkaloids failed to correlate with the cardiotonic effect. Higenamine and salsolinol were cardiotonic, while the 11 other components had no cardiotonic activity. This study establishes methods for precise evaluation of cardiotoxicity and cardiac activity, reveals the toxicity and efficacy of common processed products, and identifies the key quality markers for cardiac activity, providing scientific support for the quality evaluation and clinical application of processed products of aconite.

The in vivo thrombosis evaluation for the biodegradable polymer stent / 生物医学工程学杂志

New biodegradable intravascular stent can reduce risk of foreign bodies retained, thus, it is widely concerned and some of the products have been introduced into the clinic. However, the characteristic of biodegradable may lead to more safety concerns associated with thrombosis. To ensure the safety, the thrombus formation experiment needs to be carefully designed and evaluated based on GB/T 16886.4 standard, but current standard do not provide explicit testing and evaluating methods. Establishing animal model with experimental pigs, the study compares biodegradable coronary stents and metal stents by simulating clinical implantation on the thrombus formation in the implanting process, and after the short-term and long-term implantation. The evaluation methods include gross observation, digital subtraction angiography intraoperative analysis, optical coherence tomography analysis, scanning electron microscopy and so on. The results show that combining these methods could comprehensively evaluate the whole process of the thrombus formation from the beginning of implantation to the end of preclinical animal experiments, so that, it may better predict the clinical thrombosis risk, and the selection of the control was very important. The study tries to use the comparison examples of thrombosis on the new medical instrument to provide the clue for thrombosis evaluation on similar instruments and show the methodology on the preclinical evaluation.

Application of the Threshold of Toxicological Concern (TTC) to Biological Evaluation of Medical Devices / 中国医疗器械杂志

The threshold of toxicological concern (TTC), a risk estimation method based on compound structurally-related toxicity data, has been widely used by many countries and regions for the safety risk assessment of food packaging materials and additives etc. Toxicological risk estimation is of importance in the biological evaluation of medical devices. Application of the TTC approach to leachable from medical devices may reduce or replace some unnecessary biocompatibility tests, but consideration should be taken for contact duration and route differences, which could affect the applicability of TTC. We herein focused on analyzing the eligibility of TTC for its further application in biological evaluation of medical devices.

Design, synthesis and biological evaluation of five-membered heterocyclopyrimidines as MTH1 inhibitors / 中国药科大学学报

@#Based on the reported inhibitors TH287, 17 five-membered heterocyclopyrimidine derivatives were designed and synthesized by cyclization, scaffold hopping, bioisosterism and molecular docking technology. The bioassays determined by malachite green method demonstrated that the target compounds displayed good inhibitory activity against MTH1. Among them, the IC50 value of 7 compounds was less than 1 μmol/L, suggesting that these compounds may be candidates for further investigation.

Design,synthesis and biological evaluation of phenylsulfonamide-based IDO1 inhibitors / 中国药科大学学报

Based on the reported IDO1 inhibitor U-3i,11 phenylsulfonamide derivatives were designed and syn-thesized by adopting bioisosterism and molecular docking technology.The inhibitory activities of the target compounds against IDO1 were determined by the HeLa cell-based kynurenine assay.The results demonstrated that most compounds showed different degrees of inhibitory effects on IDO1.Among them,compounds 3b and 3e displayed the most potent activity and could reverse IDO1-mediated immune suppression,which might be worth of further investigation.

Biological evaluation of scaffold materials for external skeletal fixation / 医疗卫生装备

Objective To provide integral biological assessment on carbon fiber,aluminum alloy (6061)and stainless steel (05Cr17Ni4Cu4Nb)for external skeletal fixation.Methods According to biological evaluation criterion of medical devices, four tests in vitro and vivo were selected on the basis of the GB/T 14233.2—2005 and GB/T 16886 serial standards. The cytotoxicity test determined with MTT method. Acute general toxicity test, tests for irritation and delayed -type hypersensitivity were to evaluate biological safety by two leaching media of polar solvent (sodium chloride) and nonpolar solvent (cottonseed oil).Results The scaffold materials of external skeletal fixation had no cell toxicity in vitro.The three materials had none of acute general toxicity, skin irritation and sensitization in sodium chloride and cottonseed oil. Conclusion Carbon fiber,aluminum alloy (6061)and stainless steel (05Cr17Ni4Cu4Nb)are kinds of bone external scaffold materials with high biocompatibility and can be safely applied for clinical use.

Design, synthesis and biological evaluation of pyridine-based IRAK4 inhibitors / 中国药科大学学报

Based on the known IRAK4 inhibitors MK-32 and AU-5,we designed and synthesized 12 pyridine-based target compounds by adopting open-ring and hybrid strategies,and combining molecular docking technology.The bioassays determined by radioisotope labeling demonstrated that the target compounds displayed good inhibitory activity against IRAK4.Among them,the IC50 value of 5 compounds was less than 1 μmol/L,suggesting that these compounds may be candidates for further investigation.

Consistency evaluation method for Lianhua Qingwen Capsule based on microcalorimetry / 中草药

Objective: To study the effect of Lianhua Qingwen Capsule (LQC) on the growth and metabolism of Pseudomonas aeruginosa and to establish a new method to evaluate the consistency of LQC. Methods: The power-time curves and corresponding thermodynamic parameters such as appearance time (T), total heat output (Q), maximum power output (P), and growth rate constant (k) of P. aeruginosa were determined by microcalorimetry. The regression analysis was carried out with T, P, Q, and k as parameters, and the optimal parameters were selected according to the correlation coefficient to calculate the antibacterial effective rate. The effects of 11 batches of LQC and specially treated LQC samples on growth and metabolism of P. aeruginosa were determined by an index antibacterial effective rate to evaluate the antibacterial activity of LQC. Results: LQC had obvious inhibitory effect on P. aeruginosa in the range of 10.00 to 47.68 mg/mL, and the bacteriostatic efficacy and dosage of LQC had good correlation. By regression analysis, it was found that T was the best parameter in the four thermodynamic parameters, r = 0.990. The change of this parameter could directly evaluate the effect of LQC on the growth and metabolism of P. aeruginosa, with good stability. The appearance time was selected as a parameter to calculate its antibacterial effective rate (E). The results showed that there was no significant difference in E of different batches of LQC samples. And the E value was significantly changed when the sample was placed in a humid/high temperature environment. Conclusion: The microcalorimetric method can be used to evaluate the antibacterial activity and the quality consistency of LQC capsule, which has the high precision and good accuracy. The study has provided a new method to evaluate the quality consistency of TCM.

Correlation between Serum Phosphorylated High-molecular-weight Neurofilament and Severity of Spinal Cord Injury in Rats / 中国康复理论与实践

Objective To investigate the level of phosphorylated high-molecular-weight neurofilament (pNF-H) after spinal cord injury (SCI), and explore the relationship between pNF-H and severity of SCI. Methods 20 Sprague-Dawley rats were equally divided into control group (group A), mild SCI group (group B), moderate SCI group (group C) and severe SCI group (group D). The level of pNF-H in serum, BBB score and remaining area of white matter were obtained at different time points. Results The level of serum pNF-H in groups B, C and D arrived at peaks 12 hours and 3 days after SCI, and there was significant difference among them (P<0.05). Both BBB score and remaining area of white matter 14 days after SCI negatively correlated with the level of pNF-H 3 days after SCI (r=-0.987 and r=-0.978, respective-ly). Conclusion The pNF-H increases twice after SCI in rats, and may be associated with the severe of SCI, which can be considered as a biomarker.

A Quick Evaluation of Comprehensive Toxicity of Traditional Chinese Medical Injections Based on Microtox Technology / 世界科学技术-中医药现代化

Microtox technology is one of quick toxicity test methods for determining the poisonous or toxic substances in the environment by luminous bacteria as a indicator organism.This paper reviewed the appearance and development of microtox technology.Besides,we expounded the methods and stepwise technique map and addressed key questions of microtox technology for the evaluation of the comprehensive toxicity of Chinese medicinal materials.In conclusion,microtox technology is a promising method from a vantage point of the toxicity detection of Chinese medicinal materials.

Studies and Application of Biological Evaluation in the Quality Standardization of Chinese Medicines / 世界科学技术-中医药现代化

Biological evaluation is a critical approach by which the quality standardization of traditional Chinese medicines can be linked to the clinical efficacy and safety, which has become an important aspect in the develop-ment of quality standardization of Chinese medicines. In this article, the necessity and feasibility of the biological e-valuation research were analyzed. Further, the main progress achieved as well as the major problems about the re-search and applications of the biological evaluation of traditional Chinese medicines were discussed, to bring forward a point for consideration or discussion.

Biological evaluation of thermoplastic starch / 重庆医学

Objective To evaluate the Biological properties of thermoplastic starch(TPS).Methods According the standard of the government,operate three biological evaluation(acute toxicity,haemocompatibility and short-time toxicity)compound with SPSS analyse.Results The rate of haemocompatibility was 2.06%,no more different weight between trail and control in acute toxicity or short-time toxicity in any key period time.Conclusion TPS is acceptable biology materials.

DESIGN, SYNTHESES, AND BIOLOGICAL EVALUATION OF 14-N-SUBSTITUTED NALTREXONE DERIVATIVES AS OPIOID RECEPTOR LIGANDS / Монголын эм зүй, эм судлал

Introduction: Morphine, the main active ingredient of opium, and other clinically useful opioid analgesics all mediate their effects by activating the mu opioid receptor (MOR). Studies involving MOR knockout mice have shown that the interaction with the MOR is also responsible for the many notorious side effects associated with these drugs including dependence and addiction [1]. Therefore, selective antagonists for the MOR are needed to study its function in drug abuse and addiction.Goal: Design and synthesis of a series of naltrexone derivatives and determination of their pharmacological profile at all three opioid receptors.Material and methods: Based on the lead compound that was previously identified in our lab, a series of 14-N-substituted naltrexone derivatives were synthesized. Thebaine was used as the starting material and the naltrexone derivatives were synthesized in multiple steps using various organic synthesis methods. The final compounds were purified using column chromatography and characterized using IR, NMR, mass spectroscopy, HPLC, and melting point. The final compounds were then tested in a competitive radioligand binding assay at the mu, kappa, and delta opioid receptors using [3H]naloxone, [3H]diprenorphine, and [3H]naltrindole to label the receptors respectively. The [35S]GTPγS binding assay was employed to determine the relative efficacy of these compounds at the MOR.Results: Competitive binding assay results showed that the naltrexone derivatives with amide linkageto various heterocyclic aromatic rings have a subnanomolar to nanomolar affinity for all three opioid receptors. The lead compound of the series was shown to be dually selective for the mu and kappa opioid receptors over the delta opioid receptor. Furthermore in the [35S]GTPγS binding functional assay, the lead compound was determined to be an antagonist at both mu and kappa opioid receptors.Conclusion: It is well established that MOR antagonists by themselves can be effective at treating various forms of drug addiction [2]. Furthermore, there is growing evidence that suggests KOR antagonists may be beneficial in lowering drug cravings and preventing relapse in addicts [3]. MOR-KOR dual-antagonists may find novel clinical utility as therapeutic agents in the treatment of opioid dependence.References:1. Matthes H. “Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the mu-opioid-receptor gene” Nature [383], 1996.2. Garbutt, J. “Efficacy and tolerability of naltrexone in the management of alcohol dependence” Current Pharmaceutical Design [16], 2010.3. Redila, V. “Stress-induced reinstatement of cocaine seeking is mediated by the kappa opioid system” Psychopharmacology [200], 2008.

In vitro evaluation of new terpenoid derivatives against Leishmania infantum and Leishmania braziliensis

The activity of five (1-5) abietane phenol derivatives against Leishmania infantum and Leishmania braziliensis was studied using promastigotes and axenic and intracellular amastigotes. Infectivity and cytotoxicity tests were performed with J774.2 macrophage cells using Glucantime as a reference drug. The mechanisms of action were analysed by performing metabolite excretion and transmission electron microscopy ultrastructural studies. Compounds 1-5 were more active and less toxic than Glucantime. The infection rates and mean number of parasites per cell observed in amastigote experiments showed that derivatives 2, 4 and 5 were the most effective against both L. infantum and L. braziliensis. The ultrastructural changes observed in the treated promastigote forms confirmed that the greatest cell damage was caused by the most active compound (4). Only compound 5 caused changes in the nature and amounts of catabolites excreted by the parasites, as measured by ¹H nuclear magnetic resonance spectroscopy. All of the assayed compounds were active against the two Leishmania species in vitro and were less toxic in mammalian cells than the reference drug.

Biological evaluation of crude and degummed oil from Moringa oleifera seeds

The aim of this work was to evaluate the oil extracted from Moringa oleifera (fam. Moringaceae) seeds from the nutritional standpoint. Nutritional evaluation of crude or degummed moringa oil or soybean oil (as a control) involved the determination of the Food Efficiency (FE) in male Fisher rats and the fatty acid composition of the moringa oil. Hepatic and renal functions were assessed by measuring serum transaminases activity and urea and creatinine concentrations, respectively. Serum cholesterol and triglycerides, alkaline phosphatase, total proteins and albumine were also measured. Results showed that FE was slightly increased by the crude moringa oil while no differences were found between the soybean and degummed moringa oil regarding this parameter. Renal or hepatic injures as well as major alterations in serum proteins were not induced by the tested oils. These results suggested that degummed M. oleifera oil possessed adequate biological quality as compared to the crude oil.

Preparation of compound tissue-engineering scaffolds of PLA/silk fibroin and evaluation of its biological features / 吉林大学学报(医学版)

Objective To study the preparation method of compound tissue-engineering scaffolds of the PLA/silk fibroin and evaluate its biological features.Methods The PLA scaffolds matrix were dipped into the silk fibroin solution,then dried,and PLA/silk fibroin scaffolds were prepared.There were two groups in the experiment,one group was PLA group,and the other one was compound scaffolds group.According to ISO-10993 standard,hematolysis test,dynamic coagulation time test,cell toxicity test,stimulation test and pyrogen test were performed in two groups,and the results were compared betwen two groups.Results In the stimulation test,the two kinds of materials had equally not aroused the obvious animal skin stimulation,it showed that the experiment was in accordance with the standard.In the pyrogen test,the two scaffolds material aroused the animal temperature rising without exception under 0.2℃ and the total number of degree was under 1.0℃,therefore there was no obvious difference between two groups.In the hematolysis test,the hemolysis rates of the two scaffolds samples were smaller than 5% equally(P=0.000),which indicated that the hemolysis of the compound scaffolds was better than that of the PLA scaffolds.In the dynamic coagulation time test,the coagulation time of the compound scaffolds(37 min) was longer than that of the PLA scaffolds(26 min).The anti-coagulation ability of the compound scaffolds was better than that of the PLA scaffdds.In the cell toxicity test,the cell growth situation of the compound scaffolds group was obviously better than that of the PLA group,and at the meantime the cell toxicity of the compound scaffolds was obviously smaller than that of the PLA scaffolds.Conclusion The material of PLA/silk fibroin compound scaffolds has the advanced biological consistent compared with the simplex scaffolds.Accordingly,the PLA/silk fibroin can be used as a scaffolds matrix to be transplanted into the body.

Exposição a agentes químicos e ruído em indústria de couro / Exposure to chemical agents and noise in tanneries

Este estudo tem como objetivo investigar a relação entre a perda auditiva e a exposição ocupacional ao ruído e ao tolueno. A população em estudo foi composta por 73 trabalhadores de curtume. Para conhecer a história clínica e ocupacional dos trabalhadores, aplicou-se um questionário. Para avaliação da exposição ocupacional, realizaram-se avaliações ambiental e biológica do tolueno e avaliações audiológica e dos níveis de ruído. Os valores obtidos na avaliação ambiental e biológica estavam abaixo dos limites estabelecidos pelas NR 7 e 15. Os níveis de ruído em diversos setores da indústria foram superiores ao máximo permitido pela NR 15, chegando a 97.8 dB(A). As perdas auditivas encontradas no grupo ruído (GR) e no grupo ruído e agente químico (GRAQ) foram significativas quando comparadas ao grupo controle através da análise estatística SPSS®, T-Test p<0,01. Este estudo demonstrou fatores de impacto na saúde e na qualidade de vida dos trabalhadores. Portanto, fazem-se necessárias a revisão dos programas e a implementação de medidas que reduzam os riscos de forma a prevenir e evitar danos à saúde do trabalhador.

This study aims at investigating the relationship between the hearing loss and the occupational exposition to noise and toluene. Seventy-three tannery workers were the subject of this study. A questionnaire was used to obtain information on the workers' clinical and occupational history. To evaluate the occupational exposition, an environmental and biological survey on toluene was held, together with noise and audiologycal evaluations. The results of the environmental and biological evaluations were below the levels established by NR 7 and 15. The noise levels in several sections of the industry were above the maximum allowed by NR 15, reaching 97.8dB(A). The hearing losses found in the noise group (GR) and noise and chemical agents (GRAQ) groups were significant when compared, through the statistic analysis SPSS®, T-Test p<0,01, to the control group. This study demonstrated impact factors in workers' health and life quality. Due to this, the programs must be revised and measures to reduce the risks must be implemented in order to prevent hazards to workers' health.