Regenerative Medicine Products Research Articles

Is the hepatotoxicity of metamizole significant in clinical practice?

In December 2020 representatives of the responsible entities in consulation with European Medicines Agency and Office for Registration of Medicinal Products, Medical Devices and Biocidal Products published a safety communication on the possible occurrence of drug-induced liver injury (DILI) in the use of metamizolecontaining medicinal products. According to the message, metamizole should not be re-used in patients with a history of liver damage during treatment with metamizole, when no other cause that could lead to liver damage has been identified. Clinical practice, including spontaneous monitoring of side effects, shows that metamizole is still an effective and safe analgesic, which is included in the current recommendations for the treatment of acute, postoperative and cancer patients.

Techno-Economic Analysis of Automated iPSC Production

Induced pluripotent stem cells (iPSC) open up the unique perspective of manufacturing cell products for drug development and regenerative medicine in tissue-, disease- and patient-specific forms. iPSC can be multiplied almost without restriction and differentiated into cell types of all organs. The basis for clinical use of iPSC is a high number of cells (approximately 7 × 107 cells per treatment), which must be produced cost-effectively while maintaining reproducible and high quality. Compared to manual cell production, the automation of cell production offers a unique chance of reliable reproducibility of cells in addition to cost reduction and increased throughput. StemCellFactory is a prototype for a fully automated production of iPSC. However, in addition to the already tested functionality of the system, it must be shown that this automation brings necessary economic advantages. This paper presents that fully automated stem cell production offers economic advantages in addition to increased throughput and better quality. First, biological and technological basics for a fully automated production of iPSC are presented. Second, the basics for profitability calculation are presented. Third, profitability of both manual and automated production are calculated. Finally, different scenarios effecting the profitability of manual and automated production are compared.

Feasibility and safety of the new coronary noncompliant balloon catheter River NC®.

Aim: In this preliminary study, we aimed to confirmthe clinical utility and safety of the new noncompliant balloon catheter River NC® (Balton, Poland). Materials & methods: The primary study end point was to verify balloon diameters calculated in quantitative coronary angiography (QCA) to diameters prespecified by the manufacturer and obtained at given pressures in subjects undergoing percutaneous coronary interventions. Results: Forty-two subjects were enrolled (73.8% multivessel disease;40.5% type B1 lesions; 100% device success). No clinically significant differences between expected balloon diameters and QCA were registered in predilatation (2.36±0.11mm vs 2.43±0.07mm) and postdilatation (3.18±0.19mm vs 3.21±0.31mm). Conclusion: Our study results suggestthat the River NC balloon iseffective and safe. In the QCA evaluation, River NC balloon obtained prespecified diameters and lengths at applied pressures. Study registration: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products (UR.D.WM.DNB.109.2019).

The role of herbal medicines in health care quality and the related challenges

In recent years, there has been a renewed interest in the use of herbal medicines. Quality control and safety are two critical principles to be considered in the production process of herbal medicines. This review study aimed to investigate the condition of the countries other than Iran in terms of observing the safety principles, quality control, and meeting the standard of herbal drug use. In this systematic review, references were selected using the search terms "health-care quality" and "challenges of herbal medicine usage" from the databases "Web of Science" and "PubMed" published between 2000 and 2019. To select the resources among the selected literature, confirmation was accomplished by two researchers and Cohen’s kappa coefficient (κ). The selected papers were classified based on publication year, journal, country, reference standards, regulation, toxicity evaluation, quality control, efficacy, safety, and adverse effects in herbal medicine. From 1532 retrieved papers, 27 papers with an estimated Cohen’s kappa coefficient of 0.81 were confirmed and included in the study. Based on the analysis, the main findings of the papers were thematically classified into seven subcategories as follows: reference standards in herbal medicine, regulation of herbal medicinal products, toxicity evaluation for herbal products, quality control of herbal medicine, efficacy, adverse effects of herbal medicine, and safety. Given the significance of the effects of herbal medicines on health care quality, it is essential to codify guidelines on the proper use of these drugs.

Development of Personalised Medicine within Hospitals: Myth or Reality?

Personalised medicine has become one of the major focal points in global healthcare discourse. Due to its complexity, the use of autologous human materials as well as the need for a variety of specialists, its development and manufacturing has also become an issue of rising interest for hospitals. A comparative analysis on a number of countries in and outside Europe, that looks into legal systems allowing personalised therapies to be manufactured in hospitals, reveals that some countries, such as Russia, are characterised by a strategic approach only, while others, such as Spain or Great Britain, are willing to implement suitable legal instruments and are already developing personalised medicine on site in a non-routine manner. The recent examples of personalised CAR-T cell therapies demonstrate that this can be highly successful – so despite the diversity one can see across different jurisdictions and disparate legal rules on the regulation of medicinal products, hospitals have a central role to play in the production of personalised medical therapies in the future.

Polysaccharides from Marine Algae in Modern Technologies of Regenerative Medicine

The present review considers the physicochemical and biological properties of polysaccharides (PSs) obtained from marine algae (alginates and fucoidans from brown algae; carrageenans from red algae; and ulvans from green algae). These PSs are used in the latest technologies of regenerative medicine (tissue engineering, modulation of drug delivery system, and design of wound dressing materials). Special attention is paid to the ability of PS to form hydrogels, as hydrogel dressings meet the basic requirements for a perfect wound dressing. This review discusses the current trends in the development of a new generation of PS-based materials for creation of drug delivery systems and various tissue-engineering scaffolds; this approach allows one to create human-specific tissues and to develop target-oriented and personalized regenerative medicine products.

Osteochondral scaffolds for early treatment of cartilage defects in osteoarthritic joints: from bench to clinic.

ABSTRACTOsteoarthritis is a degenerative joint disease, typified by the loss in the quality of cartilage and bone at the interface of a synovial joint, resulting in pain, stiffness and reduced mobility. The current surgical treatment for advanced stages of the disease is joint replacement, where the non-surgical therapeutic options or less invasive surgical treatments are no longer effective. These are major surgical procedures which have a substantial impact on patients’ quality of life and lifetime risk of requiring revision surgery. Treatments using regenerative methods such as tissue engineering methods have been established and are promising for the early treatment of cartilage degeneration in osteoarthritis joints. In this approach, 3-dimensional scaffolds (with or without cells) are employed to provide support for tissue growth. However, none of the currently available tissue engineering and regenerative medicine products promotes satisfactory durable regeneration of large cartilage defects. Herein, we discuss the current regenerative treatment options for cartilage and osteochondral (cartilage and underlying subchondral bone) defects in the articulating joints. We further identify the main hurdles in osteochondral scaffold development for achieving satisfactory and durable regeneration of osteochondral tissues. The evolution of the osteochondral scaffolds – from monophasic to multiphasic constructs – is overviewed and the osteochondral scaffolds that have progressed to clinical trials are examined with respect to their clinical performances and their potential impact on the clinical practices. Development of an osteochondral scaffold which bridges the gap between small defect treatment and joint replacement is still a grand challenge. Such scaffold could be used for early treatment of cartilage and osteochondral defects at early stage of osteoarthritis and could either negate or delay the need for joint replacements.

A multiplexed immuno-sensor for on-line and automated monitoring of tissue culture protein biomarkers

Frequent on-line and automated monitoring of multiple protein biomarkers level secreted in the culture media during tissue growth is essential for the successful development of Tissue Engineering and Regenerative Medicine (TERM) products. Here, we present a low-cost, rapid, reliable, and integrable anion-exchange membrane-(AEM) based multiplexed sensing platform for this application. Unlike the gold-standard manual ELISA test, incubation/wash steps are optimized for each target and precisely metered in microfluidic chips to enhance selectivity. Unlike optical detection and unreliable visual detection for the ELISA test, which require standardization for every usage, the AEM ion current signal also offers robustness, endowed by the pH and ionic strength control capability of the ion-selective membrane, such that a universal standard curve can be used to calibrate all runs. The electrical signal is enhanced by highly charged silica nanoparticle reporters, which also act as hydrodynamic shear amplifiers to enhance selectivity during wash. This AEM-based sensing platform is tested with vascular protein biomarkers, Endothelin-1 (ET-1), Angiogenin (ANG) and Placental Growth Factor (PlGF). The limit of detection and three-decade dynamic range are comparable to ELISA assay but with a significantly reduced assay time of 1 h vs 7 h, due to the elimination of calibration and blocking steps. Optimized protocol for each target renders the detection highly reliable with more than 98% confidence. The multiplexed detection capability of the platform is also demonstrated by simultaneous detection of ET-1, ANG and PlGF in 40 μl of the vascular endothelial cell culture supernatants using three-membrane AEM sensor and the performance is validated against ELISA.

Brazilian traditional medicine: Historical basis, features and potentialities for pharmaceutical development

Abstract This article gives a brief overview on the Brazilian traditional medicine, starting from its historical development based on the cultural mixing of indigenous populations, European colonizers, and African slaves. In the sequence, it analyzes some features that contributed to the gradual loss of interest on medicinal plants in Brazil, a process started in the 1950s, and recent initiatives undertaken to valuate the Brazilian traditional medicine. Furthermore, it highlights some drugs developed from or based on constituents of the Brazilian biodiversity and traditional knowledge, which are globally employed, and the perspectives for new drugs development. It also discusses the sanitary requirements currently adopted in Brazil for the development and registration of medicinal products based on the Brazilian biodiversity and associated traditional knowledge, as well as the impact of new technologies. In addition, it is presented a discussion on the regulatory framework to access to genetic heritage and associated traditional knowledge in Brazil, along with its impact on the development of pharmaceutical products. Finally, some attempts are made to indicate the possible causes that limit the development of products based on the genetic heritage of Brazilian plants and associated traditional knowledge.

Off-Label Use of Medicines: A Comparative Study on the Regulation of Medicinal Products in Selected European Union Member States

Many governments have implemented a controlled off-label use of medicines as a tool combined with reimbursement decisions, among other policies, to avoid pharmaceutical firms gaming regulatory systems based on the requirement for marketing authorisation. This article aims to compare the drug regulations in selected European Union countries (France, Italy and Germany) in order to identify specific provisions and concrete solutions implemented by them regarding that matter. The employment of an economic analysis of the law as a theoretical framework allows for the identification of the incentives created in the long run by the referred regulations. The scholarly literature identifies a myriad of drawbacks and advantages associated with off-label practices, and a welfare analysis is ambiguous. Off-label practices are a reality; thus, it is advisable to elaborate policy measures in order to address these practices and condition them on some requirements, taking into account that off-label practices imply trade-offs among access to healthcare, protection of public health, competitiveness and innovation in the industry.

Measurement: the central nervous system of a quality manufacturing line for tissue engineering and regenerative medicine products

Measurement: the central nervous system of a quality manufacturing line for tissue engineering and regenerative medicine products

STUDY OF TOLERANCE OF DRUG BASED ON QUARTZETIN ON CLINICALLY HEALTHY CATS

The article presents the results of clinical trials of tolerability of the drug, containing the flavonoid quercetin, on clinically healthy cats. Quercetin is a biologically active substance found in many plants. Some pharmacological effects of quercetin have been discovered recently and are being intensively studied. The results of numerous studies show that quercetin may possess antioxidant, membraneprotective, gastro-, nephro-, hepato-, cardio-protective, antiplatelet, anti-inflammatory action. The bioavailability of quercetin is highest in combination with pectin and insoluble oligosaccharides, which is associated with changes in the quantitative and qualitative composition of the intestinal microflora. One of the prerequisites for the development and testing of new veterinary medicinal products, both in the context of national legislation and the requirements of the international community for the registration of medicinal products, is to conduct clinical trials in accordance with Good Clinical Practice (GCP). This is especially true of drugs with a new substance, the pharmacological properties and effectiveness of which have not been sufficiently studied. Therefore, to assess the tolerability, safety and efficacy of the drug containing quercetin, a comprehensive clinical trial was performed on small pets (cats). The study was conducted in veterinary clinics on healthy cats of all ages, genders and breeds. The drug was administered orally at a dose of 4 mg/kg body weight with food for 30 days. Blood sampling was performed before drug use and on 30 and 60 days of the experiment. The effect of the drug was assessed by clinical indicators, as well as hematological and biochemical parameters of the blood of cats. Stabilized EDTA blood was used for morphological studies and blood serum for biochemical studies.
 According to the assessment of the animal clinical condition and laboratory data, the tolerability of the studied drug when administered orally to clinically healthy cats was good. According to the results of comparison of clinical, hematological and biochemical parameters obtained on the 30th and 60th day of the experiment, and before the use of the drug, no negative changes were detected.
 The results of biochemical tests of cats serum blood on 30th day indicated a reliable increase, within normal limits, in glucose, urea, creatinine content, increased alanine aminotransferase and catalase activity, decreased gamma-glutamyltransferase activity and decreased content of diene conjugates and malonic dialdehyde – main peroxide oxidation indexes. Serum protein spectrum parameters were stable throughout the experiment. On the 60th day of drug application, recovery to the initial values of majority cats serum parameters was detected, compared with the values obtained on the 30th day of the experiment. According to the indicators of the antioxidant system of cats, the activity of serum superoxide dismutase and the content of diene conjugates during this period of the experiment remained at the level of the 30th day. Serum catalase activity decreased, compared to the values on the 30th day, but did not differ significantly from initial indices, and the content of malonic dialdehyde in the serum of animals decreased reliably. This indicated a decrease in the intensity of the formation of toxic compounds in the cats body and pronounced antioxidant properties of the drug “Hepanephran”. The results of the studies show that when using the drug for 30 days there was an increase in body tone, activation of hematopoiesis and antioxidant protection, stability of protein metabolism, serum biochemical profile and improvement of the physiological state of the study animals as a whole.

Legislation On The Preparation Of Medicinal Products In European Pharmacies And The Council Of Europe Resolution

The rights of patients should be sufficiently protected even when an appropriate authorised medicine does not exist or is unavailable on the market. The Resolution, which was adopted by the Committee of Ministers of the Council of Europe in 2011, aims at harmonising quality and safety standards for pharmacy preparation of medicinal products in Europe. Two pillars of EU regulation and the exceptions to them The system of regulation of medicinal products is built upon two pillars: the marketing authorisation of the medicinal product and the licence for manufacturing and wholesale. This article provides insight into the recent interpretation of the European Court of Justice concerning the scope of European Union (EU) regulation of medicinal products and the circumstances in which the EU regulation does not apply: pharmacy preparations, specialties and the compassionate use of medicines, including manufacturing licence. EU regulation and the Resolution concerning pharmacy preparation Pharmacy preparations are allowed under certain strict conditions according to EU regulations. However, pharmacies specialised in preparation and distributing medicinal products to local pharmacies do not fulfil these strict conditions in EU regulation. Apart from the legal context, relevant standards for safety and quality assurance are needed in Europe in order to protect patients’ rights and to avoid risks from pharmacy preparations. Discussion and conclusions The Council of Europe Resolution provides a means of establishing standards for safety and quality assurance for pharmacy preparations through Good Manufacturing Practice Guidelines. The Resolution is available to authorities and pharmacists in order to prevent incidents with medicines prepared in pharmacies which may threaten patients’ safety. The authors conclude that pharmacy practices have changed over time in Europe and this may imply a reason for a reform of EU regulation on medicinal products.

Stem Cells, Cell Therapies, and Bioengineering in Lung Biology and Disease 2019.

A workshop entitled “Stem Cells, Cell Therapies and Bioengineering in Lung Biology and Diseases” was hosted by the University of Vermont Larner College of Medicine in collaboration with the National Heart, Lung and Blood Institute, the Alpha-1 Foundation, the Cystic Fibrosis Foundation, the International Society for Cell and Gene Therapy and the Pulmonary Fibrosis Foundation. The event was held from July 15 to 18, 2019 at the University of Vermont, Burlington, Vermont. The objectives of the conference were to review and discuss the current status of the following active areas of research: 1) technological advancements in the analysis and visualisation of lung stem and progenitor cells; 2) evaluation of lung stem and progenitor cells in the context of their interactions with the niche; 3) progress toward the application and delivery of stem and progenitor cells for the treatment of lung diseases such as cystic fibrosis; 4) progress in induced pluripotent stem cell models and application for disease modelling; and 5) the emerging roles of cell therapy and extracellular vesicles in immunomodulation of the lung. This selection of topics represents some of the most dynamic research areas in which incredible progress continues to be made. The workshop also included active discussion on the regulation and commercialisation of regenerative medicine products and concluded with an open discussion to set priorities and recommendations for future research directions in basic and translation lung biology.

Balancing Safety and Efficacy With Early Availability in the Regulation of Regenerative Medicine Product.

Balancing Safety and Efficacy With Early Availability in the Regulation of Regenerative Medicine Product.

Mesenchymal Stromal Cell-Produced Components of Extracellular Matrix Potentiate Multipotent Stem Cell Response to Differentiation Stimuli.

Extracellular matrix (ECM) provides both structural support and dynamic microenvironment for cells regulating their behavior and fate. As a critical component of stem cell niche ECM maintains stem cells and activates their proliferation and differentiation under specific stimuli. Mesenchymal stem/stromal cells (MSCs) regulate tissue-specific stem cell functions locating in their immediate microenvironment and producing various bioactive factors, including ECM components. We evaluated the ability of MSC-produced ECM to restore stem and progenitor cell microenvironment in vitro and analyzed the possible mechanisms of its effects. Human MSC cell sheets were decellularized by different agents (detergents, enzymes, and apoptosis inductors) to select the optimized combination (CHAPS and DNAse I) based on the conservation of decellularized ECM (dECM) structure and effectiveness of DNA removal. Prepared dECM was non-immunogenic, supported MSC proliferation and formation of larger colonies in colony-forming unit-assay. Decellularized ECM effectively promoted MSC trilineage differentiation (adipogenic, osteogenic, and chondrogenic) compared to plastic or plastic covered by selected ECM components (collagen, fibronectin, laminin). Interestingly, dECM produced by human fibroblasts could not enhance MSC differentiation like MSC-produced dECM, indicating cell-specific functionality of dECM. We demonstrated the significant integrin contribution in dECM-cell interaction by blocking the stimulatory effects of dECM with RGD peptide and suggested the involvement of key intracellular signaling pathways activation (pERK/ERK and pFAK/FAK axes, pYAP/YAP and beta-catenin) in the observed processes based on the results of inhibitory analysis. Taken together, we suppose that MSC-produced dECM may mimic stem cell niche components in vitro and maintain multipotent progenitor cells to insure their effective response to external differentiating stimuli upon activation. The obtained data provide more insights into the possible role of MSC-produced ECM in stem and progenitor cell regulation within their niches. Our results are also useful for the developing of dECM-based cell-free products for regenerative medicine.

Human Platelet Lysate Supports Efficient Expansion and Stability of Wharton's Jelly Mesenchymal Stromal Cells via Active Uptake and Release of Soluble Regenerative Factors.

Manufacturing of mesenchymal stromal cell (MSC)-based therapies for regenerative medicine requires the use of suitable supply of growth factors that enhance proliferation, cell stability and potency during cell expansion. Human blood derivatives such as human platelet lysate (hPL) have emerged as a feasible alternative for cell growth supplement. Nevertheless, composition and functional characterization of hPL in the context of cell manufacturing is still under investigation, particularly regarding the content and function of pro-survival and pro-regenerative factors. We performed comparative analyses of hPL, human serum (hS) and fetal bovine serum (FBS) stability and potency to support Wharton’s jelly (WJ) MSC production. We demonstrated that hPL displayed low inter-batch variation and unique secretome profile that was not present in hS and FBS. Importantly, hPL-derived factors including PDGF family, EGF, TGF-alpha, angiogenin and RANTES were actively taken up by WJ-MSC to support efficient expansion. Moreover, hPL but not hS or FBS induced secretion of osteoprotegerin, HGF, IL-6 and GRO-alpha by WJ-MSC during the expansion phase. Thus, hPL is a suitable source of factors supporting viability, stability and potency of WJ-MSC and therefore constitutes an essential raw material that in combination with WJ-MSC introduces a great opportunity for the generation of potent regenerative medicine products.

Pharmacokinetic Characterization to Enable Medicine Use in Pregnancy, the Potential Role of Physiologically-Based Pharmacokinetic Modeling: A Regulatory Perspective.

It is generally recommended that use of medicines should be avoided during pregnancy, sometimes however use of a medicine is essential to safeguard the health of mother and baby. A very limited number of medicines are however specifically licensed for use in pregnancy. This article considers the potential of PBPK modelling as a predictive tool to investigate the expected systemic exposure of medicines in pregnant women and to support possible dosing adjustment to maintain efficacy.

Coronavirus disease 2019: A tissue engineering and regenerative medicine perspective.

Current therapies for novel coronavirus disease (COVID‐19) are generally used to manage rather than cure this highly infective disease. Therefore, there is a significant unmet medical need for a safe and effective treatment for COVID‐19. Inflammation is the driving force behind coronavirus infections, and the majority of deaths caused by COVID‐19 are the result of acute respiratory distress syndrome (ARDS). It is crucial to control the inflammation as early as possible. To date, numerous studies have been conducted to evaluate the safety and efficacy of tissue engineering and regenerative medicine (TERM) products, including mesenchymal stem cells (MSCs), and their derivatives (eg, exosomes) for coronavirus infections, which could be applied for the COVID‐19. In this review, first, the impacts of the COVID‐19 pandemic in the present and future of TERM research and products are briefly presented. Then, the recent clinical trials and the therapeutic benefits of MSCs in coronavirus‐induced ARDS are critically reviewed. Last, recent advances in the field of tissue engineering relevant to coronavirus infections, including three‐dimensional platforms to study the disease progression and test the effects of antiviral agents, are described. Moreover, the application of biomaterials for vaccine technology and drug delivery are highlighted. Despite promising results in the preclinical and clinical applications of MSC therapy for coronavirus infections, controversy still exists, and thus further investigation is required to understand the efficacy of these therapies.

Effectiveness of autologous platelet-rich plasma gel in the treatment of hard-to-heal leg ulcers: a randomised control trial

Objective: Regenerative medicine products such as autologous platelet-rich plasma (autologous PRP) gel may speed up the process of healing. Clinical studies show promising results in the treatment ...