Regenerative Medicine Products Research Articles

Assessment of Knowledge about Traditional Medicine Reveals Overuse as a Potential Risk for Aggravating COVID-19 and Underlying Diseases in Geriatrics and Women's Health in the Saudi Population.

The devastating COVID-19 pandemic has created several gaps in the management of viral infections, leaving biocontainment and supportive measures as the only resorts for control. As such, there has been a dramatic increase in the use of dietary supplementations and herbal medicine for COVID-19. However, serious concerns regarding the efficacy, safety, and recommended doses of these medicines have been raised. In this study, we aimed to assess the population knowledge about alternative medicine administration for COVID-19 and the associated factors. Using a self-administered cross-sectional survey, we analyzed a total of 2042 valid responses. Most of the included participants were females (69.7%), with an overall mean age of 20.8 ± 11.8 years. Most respondents (62.8%) obtained their knowledge from social media while only 16.6% received knowledge from the health care workers. Half of the participants (50.6%) correctly identified all COVID-19 symptoms, where fever (18.5%) and loss of smell and taste (17.1%) were the most frequent answers. On the use of traditional medicines and supplements for COVID-19, 57.8% did not answer, 23.7% admitted regular use, and 18.5% used sometimes. Family members or friends suggested the use of traditional medicines and dietary supplements to 28.0% of the participants while only 14.7% were advised by a nutritionist, physician, pharmacist, nurse, or a health worker. Moreover, seniors and illiterate portions of society had lower knowledge scores and increased utilization of alternative medicine. Marital status, income, and previous COVID-19 were all significant predictors of the awareness and knowledge score. Thus, this study has identified overuse of unregulated medicinal products in the region, which potentially aggravates COVID-19 or other underlying risks of the disease, making clinical management challenging, particularly in geriatrics and women’s health. Regulation of medicinal products and establishment of educational campaigns about the disease have become imperative.

The Delivery of the Recombinant Protein Cocktail Identified by Stem Cell-Derived Secretome Analysis Accelerates Kidney Repair After Renal Ischemia-Reperfusion Injury.

Recent advances in cell therapy have shown the potential to treat kidney diseases. As the treatment effects of the cell therapies are mainly attributed to secretomes released from the transplanted cells, the delivery of secretomes or conditioned medium (CM) has emerged as a promising treatment option for kidney disease. We previously demonstrated that the controlled delivery of human placental stem cells (hPSC)-derived CM using platelet-rich plasma (PRP) ameliorated renal damages and restored kidney function in an acute kidney injury (AKI) model in rats. The proteomics study of the hPSC-CM revealed that hPSC secrets several proteins that contribute to kidney tissue repair. Based on our results, this study proposed that the proteins expressed in the hPSC-CM and effective for kidney repair could be used as a recombinant protein cocktail to treat kidney diseases as an alternative to CM. In this study, we analyzed the secretome profile of hPSC-CM and identified five proteins (follistatin, uPAR, ANGPLT4, HGF, VEGF) that promote kidney repair. We investigated the feasibility of delivering the recombinant protein cocktail to improve structural and functional recovery after AKI. The pro-proliferative and anti-apoptotic effects of the protein cocktail on renal cells are demonstrated in vitro and in vivo. The intrarenal delivery of these proteins with PRP ameliorates the renal tubular damage and improved renal function in the AKI-induced rats, yielding similar therapeutic effects compared to the CM delivery. These results indicate that our strategy may provide a therapeutic solution to many challenges associated with kidney repair resulting from the lack of suitable off-the-shelf regenerative medicine products.

Establishment of a keratinocyte and fibroblast bank for clinical applications in Japan.

Regenerative medicine products using allogeneic cells, such as allogeneic cultured epidermis (allo-CE), have become a more critical therapeutic method for the treatment of burns. However, there are no clinically available allo-CE products in Japan. Therefore, establishing a quality-controlled cell bank is mandatory to create regenerative medical products using allogeneic cells. In this study, we selected ten patients from the Department of Plastic Surgery of Kyoto University Hospital to become cell donors. We performed medical interviews and blood sampling for the donor to ensure virus safety. We examined the tissues and isolated cells by performing a nucleic acid test (NAT). To establish a master cell bank, quality evaluation was performed according to the International Conference of Harmonization (ICH) Q5A. Serological tests of the blood samples from the ten donors showed that two of them were ineligible. The cells registered in the cell bank were found to be compatible after virus testing was performed, and a master cell bank was constructed. Hence, we established a keratinocyte and fibroblast bank of clinically usable human cultured cells in Japan for the first time.

Problems of criminal responsibility for violation of patient rights in the field of conducting clinacal trials of drugs

The article is devoted to the problem of criminal liability for violation of patients' rights in the field of clinical trials of medicines.
 The norms formulated in Articles 141 and 321-2 of the Criminal Code (hereinafter - the CC) of Ukraine are studied. It is established that the name of Art. 141 of the Criminal Code of Ukraine is unfounded in terms of the rules of legislative technique. The ambiguity of the phrase " violation of the patient's rights" does not reflect the content set forth in the disposition of Art. 141 of the Criminal Code of Ukraine prohibition. The list of patient rights is quite wide. However, the disposition of the article prohibits only three types of violations of patients 'rights, which can occur only in one of the possible areas of violations of patients' rights, namely in the field of clinical trials of medicines. In particular, liability is provided for: 1) for conducting clinical trials of drugs without the written consent of the patient or his legal representative; 2) for conducting clinical trials of medicinal products in relation to a minor; 3) for conducting clinical trials of drugs against incapacitated. In this case, liability arises only in the event of socially dangerous consequences (death of the patient or other serious consequences).
 Article 321-2 of the Criminal Code of Ukraine “Violation of the established procedure for pre-clinical studies, clinical trials and state registration of medicinal products” also provides for liability for violation of the procedure for clinical trials of medicinal products, but without causing death, other serious consequences (Part 1 and 2 Article 321-2 of the Criminal Code of Ukraine). However, sanctions under Art. 141 and Part 1 of Art. 321-2 of the Criminal Code of Ukraine are the same, and under Part 2 of Art. 321-2 of the Criminal Code of Ukraine - stricter.
 It is established that in part 3 of Art. 321-2 of the Criminal Code of Ukraine actually provides for liability for the same actions as in Art. 141 of the Criminal Code of Ukraine. However, the punishment under Part 3 of Art. 321-2 is much stricter than under Art. 141 of the Criminal Code of Ukraine. Emphasis is placed on the fact that there is competition between norms, in which more socially dangerous acts (which are provided for in Article 141) are punished less severely.
 Soundly the expediency of removing Art. 141 of the Criminal Code of Ukraine with the Criminal Code of Ukraine, as well as differentiation under Art. 321-2 of the Criminal Code of Ukraine liability for an act that is in gross violation of the order of clinical trials of drugs, led to the death of the patient.

Prospective directions for innovative development strategies in pharmacy in the military health system of the Russian Federation

Strengthening the readiness of the medical service system of the Armed Forces of the Russian Federation to fulfill given tasks is possible only with innovative development, which constitutes the scientific and methodological basis for the modernization of military healthcare. In this connection, researchers at the pharmacy department of the Kirov Military medical Academy considered the development of kits and equipment, medical equipment, mobile and special medical equipment, and pharmaceutical technologies as the absolute priority of their scientific development. The requirements for the equipment of different units and military medical organizations both at present conditions and in future wars include high level of mobility, shortened deployment (curtailment) terms, autonomy, increased operational efficiency of units, etc. The realization of these requirements is possible if certain issues are solved, primarily aimed at the digitalization of medical supply system of military forces, improvement of basic equipment, and entering new developments in the field of pharmaceutical technology into the medical service of the Armed Forces of the Russian Federation. The article presents the perspective directions of the innovative development of the medical supply system of the Armed Forces, which is the most important element of military healthcare. Results of the activity such as creation and acceptance for the supply of mobile units for production, accumulation (storage), delivery, distribution of medical gaseous oxygen, registration of medicinal products (medical oxygen, 93%), and acceptance of the corresponding pharmacopoeial article are already represented. Still at the development stage, there are innovative sets of service equipment of airborne troops, sterilization, and distillation unit, allowing the use of water from natural surface sources of domestic and drinking water supply, etc.

Standardization & analytical tool innovation in the cell & gene therapy field

David McCall, Editor, Cell and Gene Therapy Insights, speaks to Fouad Atouf, Vice President, Global Biologics, United States PharmacopeiaFouad Atouf is Vice President, Global Biologics, for USP. He leads all scientific activities related to the development and maintenance of documentary and reference standards for biologics and advanced therapies as well as the oversees biologics laboratories in USP–US and USP–India. Dr Atouf has been at USP for over 15 years and served in a variety of scientific leadership roles including being the regional champion for the Middle East and North Africa Region, where he helped facilitate, programs designed to enhance the understanding of the role of regulations and standards in the registration of medicinal products. Dr Atouf has a strong background and experience in the development and standardization of cellular and tissue-based products. Prior to joining USP in 2006, his research at the US National Institutes of Health focused on developing methods for the in vitro generation of cell-based therapies for diabetes. Dr Atouf is the author of numerous publications in peer-reviewed journals and a frequent speaker at national and international scientific conferences. Dr Atouf earned his Master’s degree in Biochemistry and his PhD in Cell Biology from the Pierre & Marie Curie University, Paris, France.

Quality Control Platform for the Standardization of a Regenerative Medicine Product.

Adipose tissue is an attractive source of stem cells due to its wide availability. They contribute to the stromal vascular fraction (SVF), which is composed of pre-adipocytes, tissue-progenitors, and pericytes, among others. Because its direct use in medical applications is increasing worldwide, new quality control systems are required. We investigated the ability of the Non-Equilibrium Earth Gravity Assisted Dynamic Fractionation (NEEGA-DF) method to analyze and separate cells based solely on their physical characteristics, resulting in a fingerprint of the biological sample. Adipose tissue was enzymatically digested, and the SVF was analyzed by NEEGA-DF. Based on the fractogram (the UV signal of eluting cells versus time of analysis) the collection time was set to sort alive cells. The collected cells (F-SVF) were analyzed for their phenotype, immunomodulation ability, and differentiation potential. The SVF profile showed reproducibility, and the alive cells were collected. The F-SVF showed intact adhesion phenotype, proliferation, and differentiation potential. The methodology allowed enrichment of the mesenchymal component with a higher expression of mesenchymal markers and depletion of debris, RBCs, and an extracellular matrix still present in the digestive product. Moreover, cells eluting in the last minutes showed higher circularity and lower area, proving the principles of enrichment of a more homogenous cell population with better characteristics. We proved the NEEGA-DF method is a “gentle” cell sorter that purifies primary cells obtained by enzymatic digestion and does not alter any stem cell function.

State-of-the-art knowledge on the regulation of advanced therapy medicinal products.

Advanced therapy medicinal products (ATMPs) constitute therapeutic agents based on obtained cells, tissues or genes representing a novel treatment opportunity in medicine. In addition, ATMPs are administered into the cells or tissues of humans from the patient's own cells, donors, or genetically modified cells. Recently, the field of developing ATMPs has become a point of attention due to the clinical efficacy expected in defeating incurable diseases such as cancers and neurodegenerative disorders. Currently, there are two modes regarding the distribution of ATMPs. First, ATMPs that might be legally authorized for marketing. Second, thepatients are able to access unapproved ATMPs through the hospital exemption (HE) or clinical practice program or through the compassionate use and expanded access program. The aim of this review is to discuss state-of-the-art knowledge on the regulation of ATMPs and provide regulatory recommendations.

Mitomycin-Treated Endothelial and Smooth Muscle Cells Suitable for Safe Tissue Engineering Approaches.

In our previous study, we showed that discarded cardiac tissue from the right atrial appendage and right ventricular myocardium is an available source of functional endothelial and smooth muscle cells for regenerative medicine and tissue engineering. In the study, we aimed to find out what benefits are given by vascular cells from cardiac explants used for seeding on vascular patches engrafted to repair vascular defects in vivo. Additionally, to make the application of these cells safer in regenerative medicine we tested an in vitro approach that arrested mitotic division to avoid the potential tumorigenic effect of dividing cells. A tissue-engineered construction in the form of a patch based on a polycaprolactone-gelatin scaffold and seeded with endothelial and smooth muscle cells was implanted into the abdominal aorta of immunodeficient SCID mice. Aortic patency was assessed using ultrasound, MRI, immunohistochemical and histological staining. Endothelial and smooth muscle cells were treated with mitomycin C at a therapeutic concentration of 10 μg/ml for 2 h with subsequent analysis of cell proliferation and function. The absence of the tumorigenic effect of mitomycin C-treated cells, as well as their angiogenic potential, was examined by injecting them into immunodeficient mice. Cell-containing patches engrafted in the abdominal aorta of immunodeficient mice form the vessel wall loaded with the appropriate cells and extracellular matrix, and do not interfere with normal patency. Endothelial and smooth muscle cells treated with mitomycin C show no tumorigenic effect in the SCID immunodeficient mouse model. During in vitro experiments, we have shown that treatment with mitomycin C does not lead to a decrease in cell viability. Despite the absence of proliferation, mitomycin C-treated vascular cells retain specific cell markers, produce specific extracellular matrix, and demonstrate the ability to stimulate angiogenesis in vivo. We pioneered an approach to arresting cell division with mitomycin C in endothelial and smooth muscle cells from cardiac explant, which prevents the risk of malignancy from dividing cells in vascular surgery. We believe that this approach to the fabrication of tissue-engineered constructs based on mitotically inactivated cells from waste postoperative material may be valuable to bring closer the development of safe cell products for regenerative medicine.

Mutual Recognition Procedure for the Registration of Medicines: New Challenges or Opportunities

Introduction. An important task for pharmaceutical manufacturers is to bring high quality, effective and safe medicines to the market. In the event that the country's resources are not enough, drugs that have been successfully registered in other countries come to the rescue.Aim. To study the possibilities and advantages of the procedure of mutual recognition of registration medicinal products as a potential for the development of domestic producers.Materials and methods. The materials of the study were available publications in peer-reviewed journals on thematic queries based on keywords of the selected topic, official websites, regulatory legal acts, regulating the procedure for registering medicinal products in the EU and the Russian Federation.Results and discussion. New approaches to registration within the framework of the Eurasian Economic Union (using the example of the mutual recognition procedure) are considered from the perspective of new opportunities and emerging problems for domestic manufacturers of generic drugs. A comparative analysis of the mutual recognition procedure and the national procedure for registration of medicinal products revealed a number of advantages for domestic manufacturers, favoring the introduction of medicinal products into circulation on the territory of the EAEU.Conclusion. The review of the process of harmonization of the registration practice of medicinal products in the EAEU speaks of the prospects of using the mutual recognition procedure for developing the potential of domestic manufacturers and facilitating access to effective and safe drugs.

Regulation & registration of drugs and biologics in Brazil

Registration of medicinal products is a challenging task in various countries as the regulatory requirements differ from country to country around the world. Like in regulated countries medicinal products regulation is a difficult piece of work in Semi-regulated countries as they are not coordinated. Being the sixth most populous country, Brazil gives a great opportunity for the bio/pharmaceutical market. Superior health maintenance, high quality, and modern medicines are being demanded by Brazilians which gives a huge opportunity for overseas investment. Medicinal products registration is a lengthy process in Brazil. Obtaining access to the marketing of drugs and biologics from the Brazilian Regulatory Authority is not an easy business for bio/pharmaceutical companies. One of the most difficult tasks facing regulatory agencies is ensuring that medications are manufactured in accordance with the country's regulatory requirements. This Review article's primary objective is to explain how pharmaceuticals and biologics are regulated and registered in Brazil. Keywords: Brazil, ANVISA, Drugs, Biologics, Regulation.

Single-chain tandem macrocyclic peptides as a scaffold for growth factor and cytokine mimetics

Mimetics of growth factors and cytokines are promising tools for culturing large numbers of cells and manufacturing regenerative medicine products. In this study, we report single-chain tandem macrocyclic peptides (STaMPtides) as mimetics in a new multivalent peptide format. STaMPtides, which contain two or more macrocyclic peptides with a disulfide-closed backbone and peptide linkers, are successfully secreted into the supernatant by Corynebacterium glutamicum-based secretion technology. Without post-secretion modification steps, such as macrocyclization or enzymatic treatment, bacterially secreted STaMPtides form disulfide bonds, as designed; are biologically active; and show agonistic activities against respective target receptors. We also demonstrate, by cell-based assays, the potential of STaMPtides, which mimic growth factors and cytokines, in cell culture. The STaMPtide technology can be applied to the design, screening, and production of growth factor and cytokine mimetics.

J-TEC's efforts to industrialize regenerative medicine in Japan

J-TEC was launched in 1999 to industrialize regenerative medicine in Japan. We developed the first regenerative medicine product, JACE (autologous cultured epidermis), which received PMDA approval for treating serious burns in 2007. Then, JACC (autologous cultured cartilage), the second product, was approved in 2012 for efficacy on traumatic cartilage defects. In 2014, the Pharmaceutical Affairs Law was revised to the Pharmaceutical and Medical Device Act, and regenerative medicine products, including gene therapies, were newly classified to accelerate productization. Subsequently, Nepic (autologous cultured corneal epithelium) and Ocural (autologous cultured oral mucosal epithelium) for epithelialization of limbal stem cell deficiencies in ophthalmology were approved in 2020 and 2021, respectively. To develop regenerative medicine products, it is necessary to ensure the safety of raw materials, standardize the cultivation process, examine cell characteristics on GLP tests, construct transportation methods, build facilities, and conduct clinical trials.

Comparative study of medicinal products registration in USA and Europe

A pharmaceutical drug regulatory Affairs is mainly involved in registration process parameters of different pharmaceutical products and new drug application. Regulatory affairs professionals play vital roles in a pharmaceutical field as; it is related to healthcare products. The present article mainly focuses to provide similarities and differences in the registration of medicinal products in USA and European countries.This also provide details to protect public health in terms of safety, quality, and efficacy of products like medical devices, pharmaceuticals, veterinary medicines, pesticides, cosmetics & complementary medicines, agrochemicals, etc.

Gene and Cell Therapies Overview Under the Light of Health Economics

With the increase in drug development studies for rare diseases, gene therapies have recently come to the fore more frequently. In addition to orphan drugs used in the treatment of rare diseases, advanced therapy medicinal products have been developed. Advanced therapy medicinal products are a fast-growing field. Although it is not a treatment method used only in the field of rare diseases, it is also used in the fields of oncology and cardiovascular diseases, musculoskeletal diseases. Regenerative medicine can be promising in cases where advanced therapy medicinal products are difficult and clinically uncertain. There are various cell therapies related to regenerative medicine and cell-based therapies are one of them. Gene therapies, cell-based therapies, advanced therapy medicinal products and regenerative medicine products have high producer price and high production cost. Because all these treatments have limited clinical evidence and high costs, they are difficult to evaluate in terms of health technology assessment (HTA), and special considerations are needed for evaluation. As a solution, costs should be limited and clinical developments should be provided in cooperation with the society. SAVE (equivalent to young life saved) is recommended to evaluate the lifetime health profiles of curative treatments such as gene therapies. In order to reduce the budgetary burden of gene therapies, outcome-directed entry agreements with income-based payments are recommended. Compulsory use of gene therapies and non-reimbursement of these drugs can lead to catastrophic health expenditures. Various payment methods are offered to avoid catastrophic health expenditures. Income-based payment and outcome-based payment are some of these methods. It is also advocated that high prices should be accepted by the society, since gene therapies to be applied in the treatment of rare diseases will be applied to a small population. Both the support of the society to accept the high price of gene therapies, the support of the producer and the support of the payer are important in the development of gene therapies and their supply to the market.

Design, fabrication, and testing of a low-cost extrusion based 3D bioprinter for thermo-sensitive and light sensitive hydrogels

3D bioprinting consists of the fabrication of complex biological structures, with animal cells cultured in vitro. It has enormous potential in developing animal tissues and organs for drug testing, regenerative medicine, and food products. Limitations on the technology include the cost of the commercial equipment’s and the lack of flexibility required in R&D labs. Design, fabrication, and testing of a 3D bioprinter with temperature control and UV curing is presented. Printer acceptance tests were performed using hydrogel biomaterials including gelatine methacrylate (GelMA) and algae-derived polysaccharides. The designed equipment presents positive overall results, namely in printability, operation, and user-friendliness.

Tuning mesenchymal stem cell secretome therapeutic potential through mechanotransduction

Mesenchymal stem cells (MSCs) and their byproducts have been widely validated as potential therapeutic products for regenerative medicine. The therapeutic effects result mainly from the paracrine activity of MSCs, which consists of the secretion of bioactive molecules, whether dispersed in medium conditioned by cell culture or encapsulated in extracellular vesicles. The composition of the MSC secretome, which represents the set of these secreted cellular products, is crucial for the performance of the desired therapeutic functions. Different cell culture strategies have been employed to adjust the secretome composition of MSCs to obtain the best therapeutic responses for different clinical contexts. However, the manipulation of culture conditions has focused mainly on the use of different biochemical elements for the preconditioning of MSCs and less on the physical conditions of the cell culture environment. Herein, we offer our point of view regarding the importance of the physical properties of cell culture substrates and their mechanotransduction responses in preconditioning the MSCs secretome. We highlight the relevance of studying mechanotransduction events associating cell morphology and the modulation of gene expression to customize and expand the use of MSCs secretomes.

Prospects and Applications of Natural Blood-Derived Products in Regenerative Medicine.

Currently, there are a number of therapeutic schemes used for the treatment of various types of musculoskeletal disorders. However, despite the use of new treatment options, therapeutic failure remains common due to impaired and delayed healing, or implant rejection. Faced with this challenge, in recent years regenerative medicine started looking for alternative solutions that could additionally support tissue regeneration. This review aims to outline the functions and possible clinical applications of, and future hopes associated with, using autologous or heterologous products such as antimicrobial peptides (AMPs), microvesicles (MVs), and neutrophil degranulation products (DGP) obtained from circulating neutrophils. Moreover, different interactions between neutrophils and platelets are described. Certain products released from neutrophils are critical for interactions between different immune cells to ensure adequate tissue repair. By acting directly and indirectly on host cells, these neutrophil-derived products can modulate the body’s inflammatory responses in various ways. The development of new formulations based on these products and their clinically proven success would give hope for significant progress in regenerative therapy in human and veterinary medicine.

Polymer Nanofibers for Biomedical Applications: Advances in Electrospinning

Background: The demand for novel biomaterials has been exponentially rising in the last years as well as the searching for new technologies able to produce more efficient products in both drug delivery systems and regenerative medicine. Objective: The technique that can pretty well encompass the needs for novel and high-end materials with a relatively low-cost and easy operation is the electrospinning of polymer solutions. Methods: Electrospinning usually produces ultrathin fibers that can be applied in a myriad of biomedical devices including sustained delivery systems for drugs, proteins, biomolecules, hormones, etc that can be applied in a broad spectrum of applications, from transdermal patches to cancer-related drugs. Results: Electrospun fibers can be produced to mimic certain tissues of the human body, being an option to create new scaffolds for implants with several advantages. Conclusions: In this review, we aimed to encompass the use of electrospun fibers in the field of biomedical devices, more specifically in the use of electrospun nanofibers applications toward the production of drug delivery systems and scaffolds for tissue regeneration.

American Medical Society for Sports Medicine Position Statement: Principles for the Responsible Use of Regenerative Medicine in Sports Medicine.

Many sports medicine physicians are currently considering introducing regenerative medicine into their practice. Regenerative medicine and the subclassification of orthobiologics are a complicated topic and have produced widely varying opinions. Although there is concern by government regulators, clinicians, scientists, patient advocacy organizations, and the media regarding the use of regenerative medicine products, there is also excitement about the potential benefits with growing evidence that certain regenerative medicine products are safe and potentially efficacious in treating musculoskeletal conditions. Sports medicine physicians would benefit from decision-making guidance about whether to introduce orthobiologics into their practice and how to do it responsibly. The purpose of this position statement is to provide sports medicine physicians with information regarding regenerative medicine terminology, a brief review of basic science and clinical studies within the subclassification of orthobiologics, regulatory considerations, and best practices for introducing regenerative medicine into clinical practice. This information will help sports medicine physicians make informed and responsible decisions about the role of regenerative medicine and orthobiologics in their practice.