Regenerative Medicine Products Research Articles

Recreating composition, structure, functionalities of tissues at nanoscale for regenerative medicine.

Nanotechnology offers significant potential in regenerative medicine, specifically with the ability to mimic tissue architecture at the nanoscale. In this perspective, we highlight key achievements in the nanotechnology field for successfully mimicking the composition and structure of different tissues, and the development of bio-inspired nanotechnologies and functional nanomaterials to improve tissue regeneration. Numerous nanomaterials fabricated by electrospinning, nanolithography and self-assembly have been successfully applied to regenerate bone, cartilage, muscle, blood vessel, heart and bladder tissue. We also discuss nanotechnology-based regenerative medicine products in the clinic for tissue engineering applications, although so far most of them are focused on bone implants and fillers. We believe that recent advances in nanotechnologies will enable new applications for tissue regeneration in the near future.

DNA Barcoding of Philippine Herbal Medicinal Products

The Philippine government established the Traditional and Alternative Medicine Act in 1997 to promote traditionally used herbal products and to provide an effective yet affordable alternative to conventional medicines. However, government regulation of herbal medicinal products (HMPs) is not stringent, relying only on submitted quality data from the manufacturer. In this study we validated the taxonomic identity of 26 plant samples contained within 22 HMPs, each produced by different local manufacturers, through DNA barcoding of the nuclear internal transcribed spacer-2 (ITS2) region. We recovered 19 ITS2 barcodes from 26 samples. These were compared to sequences in GenBank using MEGABLAST, but ambiguous results (similar max scores for different species) were phylogenetically analyzed. Twelve of the 19 samples matched the indicated species on the product label, three were equivocal in specific identity but were placed in the expected genus, and four other samples from three manufacturers contained contamination and/or substitution. GenBank's reference database was at times problematic because some sequences were lacking or were misidentified, but the database was still useful. Overall, ITS2 barcoding was successful in authenticating the HMPs, and it is recommended during the premarket evaluation process so as to obtain a certificate of registration from the government. The government should also develop a comprehensive database of barcodes for Philippine plants, and should prioritize the development of the traditional pharmacopeia because many locally produced HMPs are not indigenous.

How Regenerative Medicine Stakeholders Adapt to Ever-Changing Technology and Regulatory Challenges? Snapshots from the World TERMIS Industry Symposium (September 10, 2015, Boston).

Regenerative medicine (RM) is a fascinating area of research and innovation. The huge potential of the field has been fairly underexploited so far. Both TERMIS-AM and TERMIS-EU Industry Committees are committed to mentoring and training young entrepreneurs for more successful commercial translation of upstream research. With this objective in mind, the two entities jointly organized an industry symposium during the past TERMIS World Congress (Boston, September 8-11, 2015) and invited senior managers of the RM industry for lectures and panel discussions. One of the two sessions of the symposium-How to overcome obstacles encountered when bringing products to the commercial phase?-aimed to share the inside, real experiences of leaders from TEI Biosciences (an Integra Company), Vericel (formerly Aastrom; acquirer of Genzyme Regenerative Medicine assets), RegenMedTX (formerly Tengion), Mindset Rx, ViThera Pharmaceuticals, and L'Oreal Research & Innovation. The symposium provided practical recommendations for RM product development, for remaining critical and objective when reviewing progress, for keeping solutions simple, and for remaining relevant and persistent.

Evaluating the Past, Present, and Future of Regenerative Medicine: A Global View.

"Evaluating the Past and Present of Regenerative Medicine (RM)" was the first part of an Industry Symposium dedicated to the subject during the 2015 TERMIS World Congress in Boston. This working session presented a critical review of the current RM landscape in Europe and North America with possible projections for the future. Interestingly, the RM development cycle seems to obey the Gartner hype cycle, now at the enlightenment phase, after past exaggerated expectations and discouragements, as suggested by increasing numbers of clinical trials and recent market approvals of RM solutions in both Europe (Glybera and Holoclar® from Chiesi Pharma and Strimvelis® from GSK) and Japan (Remestemcel-L from Mesoblast®). The successful commercial translation of RM research is governed by five major drivers: (i) fully validated manufacturing capability for autologous or allogeneic products, (ii) reimbursement for targeted clinical indications with high and demonstrable medico-economic benefits versus standard of care, (iii) implication of regulatory bodies in the design and development plan of any RM solution, which should be well characterized, robust, with proven consistent efficacy and an acceptable and controlled positive benefit/risk ratio, (iv) collaborations facilitated by multicompetence hubs/consortia of excellence, (v) well-thought-out clinical development plans for reducing the risk of failure. Benefiting from past and present experience, the RM burgeoning industry is expected to accelerate the market release of cost-effective RM products with real curative potential for specific clinical indications with high unmet needs. This should be achieved by wisely leveraging all possible synergies of the different stakeholders, for example, patients, clinicians, reimbursement and health technology assessment (HTA) agencies, regulatory authorities, public/private investors, academia, and companies.

Stem cell therapy clinical research: A regulatory conundrum for academia.

The encouraging pace of discovery and development in the field of regenerative medicine holds tremendous potential for bringing therapies to the clinic that may offer meaningful benefit to patients, particularly in diseases with no or suboptimal therapeutic options. Academic researchers will continue to play a critical role in developing concepts and therapies, thus determining whether regenerative medicine will be able to live up to this potential that clearly excites clinicians, researchers and patients alike. This review summarises recent developments in regulatory frameworks across different countries that aim to ensure adequate oversight of the development of regenerative medicine products, which are unique in structural and functional complexity when compared to traditional chemical drugs and fully characterised biological drugs. It discusses the implications of these developments for researchers aiming to make the challenging transition from laboratory to clinical development of these therapies and considers possible pragmatic solutions that could accelerate this process that is essential to maintain research credibility and ensure patient safety.

Bayesian statistics and clinical trial designs for human cells and tissue products for regulatory approval.

IntroductionIn order to obtain premarket approval for medical products derived from human cells or tissues in the United States (US), the European Union (EU), and Japan, data from clinical trials are typically required to evaluate product efficacy and safety. Clinical investigators or study sponsors often face challenges when designing clinical trials on human cells and tissue products with the goal of obtaining premarket approval owing to the unique characteristics of products in this category. The methods used to administer, infuse and transplant these products vary more widely than the methods used for pharmaceuticals. In addition, final product quality may vary depending on the product source, i.e., patients or donors. These products are generally intended to treat intractable and rare diseases or injuries; therefore, it may not be possible to collect a sufficient number of cases and enrollment may be a long process. Moreover, since the technology for product development in this category is relatively new, knowledge and experience from previous studies are limited.MethodsThe key elements for the design of clinical trials to determine product efficacy were identified by examining clinical trial designs for approving products. Review reports for approved products from regulatory authorities in the US and Japan as well as the European public assessment reports in the EU were analyzed.ResultsFor one product approved in the US, Dermagraft®, Bayesian statistics were used to evaluate product efficacy, instead of traditional (frequentist) statistics. Based on the statistical guidance for clinical trials recently issued by the US Food and Drug Administration, statistical analyses including Bayesian statistics are key elements in the design of clinical trials for products based on human cells and tissues. New regulations regarding human cells and tissue products have recently been implemented in Japan, including conditional and time-limited approval for regenerative medicine products. In these cases, Bayesian statistics are a promising alternative approach to support product development.ConclusionsOur results emphasize the benefit of considering cogitating statistical methods, such as Bayesian statistics, when designing clinical trials for regulatory purposes.

1.10 - Medicinal Product Regulation: Portugal’s Framework

The prescription, supply and use of medicines should centre on their rational use, in order to foster patients’ interests and integrity, and promote public health and national economic sustainability. The pharmaceutical industry is one of the most tightly regulated sectors, and it is essential to know each country’s legislative framework in order to understand the regulation, approval, and marketing of medicinal products for human use. Portugal has played an important role in the European Union and European Economic Area as a Reference Member State (RMS). The aim is to describe the main statutes and procedures governing medicinal products for human use in Portugal, as well as the role of the country's National Medicines and Health Products Authority.

Legislation on the preparation of medicinal products in European pharmacies and the Council of Europe Resolution

IntroductionThe 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...

Medicinal Product Regulation: Portugal׳s Framework

PurposeThe pharmaceutical industry is one of the most tightly regulated sectors, and it is essential to know each country׳s legal framework to understand the regulation, approval, and marketing of medicinal products for human use. This article describes the main statutes and procedures governing medicinal products for human use in Portugal and the role of the country׳s National Medicines and Health Products Authority (Autoridade Nacional do Medicamento e Produtos de Saúde, I.P.; INFARMED). MethodsFrom the most recently available data, an update of requests and approvals concerning marketing authorizations, variations, pricing, and reimbursements is provided. Data were sourced from the INFARMED website, Infomed (database of medicinal products for human use), and periodic reports issued by national authorities. Organic laws, acts, and law decrees published in the government gazette (Diário da República) are cited and reproduced as required. FindingsIn 2015 Portugal ranked fifth in the European System of Medicines Evaluation in terms of the number of completed procedures as a reference member state. Approximately 80% of all approved drug applications in Portugal in 2015 were for generic drugs, mostly pertaining to the nervous system. In Portugal, INFARMED monitors drug quality, safety profile, and efficacy in all stages of the drug life cycle, ensuring patients’ safety. ImplicationsThe Portuguese market for medicinal products for human use has been appreciably changed by the advent of generic drugs. There is an increased trend for new request applications for biological and biotechnological substances.

Expedited approval system for regenerative medicine products - Is it unusual?

Expedited approval system for regenerative medicine products - Is it unusual?

Japan's challenges of translational regenerative medicine: Act on the safety of regenerative medicine.

The first issue of Nature Medicine published 20 years ago featured an article that reported Japan's critical situation regarding clinical trials, calling for major reform. Twenty years later, Japan has enacted three laws to promote the use of regenerative medicine as a national policy. The first law to be enacted was the Regenerative Medicine Promotion Act, which represents the country's determination to work toward the promotion of regenerative medicine. Subsequently, the Pharmaceuticals, Medical Devices, and Other Therapeutic Products Act (PMD Act) and the Act on the Safety of Regenerative Medicine (RM Act) came into effect. The PMD Act created a new category for regenerative medicine products, and established the process for obtaining approval for cell therapy and other regenerative therapies through the implementation of clinical trials. The RM Act specified the regulations that doctors, review committees, and cell culture/processing facilities must adhere to when providing regenerative medicine in medical care, not only in clinical research but also in private practice.Previously, researchers in regenerative medicine only had a set of guidelines to follow for conducting clinical research. Now, with the enactment of the RM Act, all areas for improvement that had been enumerated 20 years ago—such as the lack of appropriate review committees and governmental control—have been addressed by law, creating a system that gives the highest priority to patient safety. In this paper, we present the particularly noteworthy points of the RM Act, along with the actual current conditions of regenerative medicine in Japanese medical care.

Opening the gateways to market and adoption of regenerative medicine? The UK case in context.

Regenerative medicine is a site for opposing forces of gatekeeping and innovation. This applies both to regulation of market entry and to clinical adoption. Key gateways include the EU's Advanced Therapy Medicinal Products Regulation, technology assessment body NICE and commissioning/service contractor National Health Service England. The paper maps recent gatekeeping flexibilities, describing the range of gateways to market and healthcare adoption seen as alternatives to mainstream routes. The initiatives range from exemptions in pharmaceutical and ATMP regulations, through 'adaptive pathways' and 'risk-based' approaches, to special designation for promising innovation, value-based assessment and commissioner developments. Future developments are considered in the UK's 'accelerated access review'. Caution is urged in assessing the impact of these gateway flexibilities and their market and public health implications.

Recent policies that support clinical application of induced pluripotent stem cell-based regenerative therapies.

In Japan, a research center network consisting of Kyoto University to provide clinical-grade induced Pluripotent Stem Cells (iPSC) and several major research centers to develop iPSC-based regenerative therapies was formed for the clinical application of iPSCs. This network is under the supervision of a newly formed funding agency, the Japan Agency for Medical Research and Development. In parallel, regulatory authorities of Japan, including the Ministry of Health, Labour and Welfare, and Pharmaceuticals and Medical Devices Agency, are trying to accelerate the development process of regenerative medicine products (RMPs) by several initiatives: 1) introduction of a conditional and time-limited approval scheme only applicable to RMPs under the revised Pharmaceuticals and Medical Devices Act, 2) expansion of a consultation program at the early stage of development, 3) establishment of guidelines to support efficient development and review and 4) enhancement of post-market safety measures such as introduction of patient registries and setting user requirements with cooperation from relevant academic societies and experts. Ultimately, the establishment of a global network among iPSC banks that derives clinical-grade iPSCs from human leukocyte antigens homozygous donors has been proposed. In order to share clinical-grade iPSCs globally and to facilitate global development of iPSC-based RMPs, it will be necessary to promote regulatory harmonization and to establish common standards related to iPSCs and differentiated cells based on scientific evidence.

Effect of regulation reform on clinical trials for registering novel therapeutic agents in Taiwan: a chronological analysis.

The registration process for new drugs is crucial in the clinical application of medicines. Previously, the registration of imported novel therapeutic agents in Taiwan depended considerably on their approvals in developed countries. The Taiwanese government enacted Article 38-1 of the Regulations for Registration of Medicinal Products in September 2009. According to the new submission criteria, approvals may be exempted if the number of Taiwanese participants in the clinical trials fulfills the required threshold. The present study compared the profiles of clinical trials of novel therapeutic agents before and after the enactment of this regulation in terms of over-threshold trials, structural types, and therapeutic areas across phases. The outcome-whether the liberalization of the submission criteria functioned as an incentive to launch clinical trials in Taiwan-was also evaluated. The results revealed that the number of clinical trial applications increased after the reformed regulation was enacted, even after the over-threshold criteria were considered; however, the increase disappeared for phase III trials. Most clinical trials were for chemical products and antineoplastic agents across all phases and study periods before and after the enactment of Article 38-1. Furthermore, the increase in the number of international clinical trials conducted in Taiwan was not directly caused by the regulation reform because the percentage of investigational products fulfilling the exemption criteria did not increase. These paradoxical results were interpreted in several aspects, referring particularly to the well-established infrastructure for launching clinical trials as well as the integral environment of medical services in Taiwan.

Tissue-Engineered Products for Skin Regenerative Medicine

In a general wound healing process, foreign bodies and tissue detritus have to be broken down and then a new tissue is produced. However, the new tissue formation sometimes fails to proceed under the impaired conditions such as burn injury and intractable skin ulcer. A major obstruction to wound healing is infection. Another obstruction to wound healing is deficiency of growth factors. The endogenous levels of growth factors are reduced in some chronic wounds. To improve these wound conditions, researchers have been trying to create several types of artificial skins. The tissue-engineered products include three prime constituents, i.e., cells, growth factors, and materials. In this review, the practical design of tissue-engineered products for skin regenerative medicine is introduced. The first design makes it possible to release silver sulfadiazine (AgSD) from a wound dressing. The second design makes it possible to release Epidermal Growth Factor (EGF) from a wound dressing or a skin care product composed of hyaluronic acid spongy sheet containing bioactive ingredients. The third design makes it possible to release several types of growth factors from allogeneic fibroblasts within cultured dermal substitute. This tissue-engineered product is prepared by seeding allogeneic fibroblasts into a collagen and hyaluronic acid spongy sheet. Although allogeneic cells are rejected gradually in immune system, they are able to release some types of growth factors, thereby regenerating a damaged tissue. The clinical study demonstrates that these tissue-engineered products are promising for the treatment of burn injury and intractable skin ulcer.

Developing Ideal Solution for Acute Wound Treatment by Regenerative Medicine

People tend to get injured, leading to wounds with losses of multiple tissues including skin, subcutaneous tissue, tendons and bones. There effective management is a complex process, but the outcomes many a time remain unpredictable. The complications involve further tissue loss, infections and non healing ulcers leading to huge morbidity. Throughout the world large resources are spent, consuming billions of dollars, towards manage these wounds and lessen the morbidity. A simple therapy for effective wound management if evolved will transform this health problem and save lot of sufferings. Method: The “Sandeep’s Technique’s for Assisted Regeneration of Skin” (STARS) is therapy for complete healing of wounds with Autologous self activated Platelet Rich Plasma (PRP), imparted as local subcutaneous infiltrate in the wound margin or underneath the necrotic Flap, on every 4th day, till complete regeneration takes place and wound heals. The wounds are dressed daily / alternate day with only moist saline. It is a prospective case series of 36 cases of acute wounds over limbs associated with problems such as compound fracture, amputations, infections, post surgical necrotising flaps treated with STARS, treated at Acharya Vinobha Bhave Rural Hospital, J. N. Medical College, Wardha, INDIA. Finding: The final outcome is complete / near complete healing of all the wounds without requiring any surgical or intense medical intervention. Interpretation: This method of treatment assisted with Platelet rich plasma as regenerative medicine product is safe, easy, effective and efficient mode of wound management. It is simple innovation, which can be adopted universally as an ideal treatment for wounds, minimising the morbidity and preserving the resources across the globe.

Development of functional biomaterials using RNA aptamer

Event Abstract Back to Event Development of functional biomaterials using RNA aptamer Yusuke Nomura1, Chie Fukui1, Hitomi Toida1, Yuki Morishita1, Shingo Niimi1, Shin Miyakawa2, Ling Jin2, Yoshikazu Nakamura2, 3 and Yuji Haishima1 1 National Institute of Health Sciences, Division of Medical Devices, Japan 2 RIBOMIC Inc., Japan 3 University of Tokyo, Institute of Medical Science, Japan Introduction: Biomaterials used for implant interact with cells and tissues through the protein layer present at the biointerface. These proteins could adversely affect the function and biocompatibility of the materials. Their adsorption behavior is basically dependent on the physicochemical property of the materials, but it is possible to provide favorable functions to the materials by artificially controlling the protein adsorption behavior on the material surface. In this study, we developed a novel and functional biomaterial immobilized the RNA aptamer (RNA-AP) which specifically captures active FGF2. Materials and Methods: Human FGF2, FGF2 receptor and Lysozyme were purchased from Peprotec, R&D systems and SIGMA, respectively. RNA-APs were prepared by in vitro transcription using the DuraScribe T7 Transcription kit. RNA-AP-SH, poly dT-SH (pdT-SH) and PEG (PEG2k-SH and PEG5k-SH) were immobilized on the Au-coated glass plate. The inhibition of FGF2-mediated phosphorylation in NIH 3T3 cells was analyzed by western blotting using phospho-specific antibody (P-FRS2, P-ERK). RNA-AP/protein interaction and cell proliferation were analyzed using BIAcore2000 and BZ-9000, respectively. Results and Discussion: Candidate of RNA-APs against the human FGF2 were selected by surface plasmon resonance (SPR) method, that did not inhibit the binding of FGF2 to FGF2 receptor in SPR analysis and the phosphorylation of FRS2 and ERK in the NIH 3T3 cells. The several SPR sensor chips were prepared and used for evaluating the protein adsorption. The bare gold and pdT-immobilized surfaces did not show a difference between Lysozyme and FGF2 adsorption, indicating that only nonspecific adsorption of the proteins was observed. Although the specific adsorption of FGF2 was observed on the RNA-AP-immobilized surface, the nonspecific adsorption of Lysozyme was still high. On the other hand, the RNA-AP/PEG2k/PEG5k-coimmobilized surfaces showed a remarkable reduction of the nonspecific adsorption due to the excluded volume effect of the PEG chains[1]. In addition, cell proliferation on the RNA-AP/PEG-coated surfaces was significantly increased in comparison with the pdT/PEG-coated surfaces, indicating that RNA-AP/PEG-immobilized surfaces effectively capture and concentrate the active FGF2. Conclusion: In this study, we succeeded in selectively capturing and concentrating the target protein on the biomaterial surface by immobilizing the functional RNA-AP. It is expected that biomaterials combinationally immobilized several RNA-APs may exhibit the potency to control different function such as proliferation and differentiation of various stem cells. Thus, the innovative biomaterials using RNA aptamer are useful for not only the application to regenerative medicine product, but also other medical devices.

The Same but Different: Regulation of Tissue Engineering and Regenerative Medicine in the Context of Regional and International Standards and Expectations.

This commentary places the contributions from several Asian-Pacific countries that constitute this Special Issue in the context of trends in global regulation of tissue engineering and regenerative medicine products and services. It concentrates on the generic issues that face regulation in each jurisdiction and the manner how these issues have to be faced in the light of cultural, political, and economic regional differences.

The early career researcher's toolkit: translating tissue engineering, regenerative medicine and cell therapy products.

Although the importance of translation for the development of tissue engineering, regenerative medicine and cell-based therapies is widely recognized, the process of translation is less well understood. This is particularly the case among some early career researchers who may not appreciate the intricacies of translational research or make decisions early in development which later hinders effective translation. Based on our own research and experiences as early career researchers involved in tissue engineering and regenerative medicine translation, we discuss common pitfalls associated with translational research, providing practical solutions and important considerations which will aid process and product development. Suggestions range from effective project management, consideration of key manufacturing, clinical and regulatory matters and means of exploiting research for successful commercialization.

Concise Review: The U.S. Food and Drug Administration and Regenerative Medicine

Regenerative medicine (RM) is a popular term for a field of scientific and medical research. There is not one universally accepted definition of RM, but it is generally taken to mean the translation of multidisciplinary biology and engineering science into therapeutic approaches to regenerate, replace, or repair tissues and organs. RM products have the potential to provide treatments for a number of unmet needs but have substantial scientific and regulatory challenges that need to be addressed for this potential to be fully realized. FDA has established formal regulatory definitions for biologics, medical devices, and combination products, as well as human cells and tissues. Regenerative medicine products regulated by FDA are classified on the basis of these definitions, and the classification forms the basis for determining the regulatory requirements to each specific product. FDA regulations are generally written to allow the agency flexibility to accommodate new scientific questions raised by novel and evolving technologies. FDA efforts to facilitate product development in this novel and promising area include working with individual sponsors, interacting with the scientific and industry communities, participating in standards development, and developing policy and guidance. Regenerative medicine is generally taken to mean the translation of multidisciplinary biology and engineering science into therapeutic approaches to regenerate, replace, or repair tissues and organs. This article provides an overview of the efforts of the U.S. Food and Drug Administration (FDA) to facilitate product development in the field commonly known was regenerative medicine. It provides an introduction to the processes by which FDA works with individual sponsors, interacts with the scientific and industry communities, participates in standards development, and develops formal FDA policy and guidance.