Tissue-based Products Research Articles

Autologous Adipose-Derived Tissue Matrix Part I: Biologic Characteristics.

Autologous collagen is an ideal soft tissue filler and may serve as a matrix for stem cell implantation and growth. Procurement of autologous collagen has been limited, though, secondary to a sufficient source. Liposuction is a widely performed and could be a source of autologous collagen. The amount of collagen and its composition in liposuctioned fat remains unknown. The purpose of this research was to characterize an adipose-derived tissue-based product created using ultrasonic cavitation and cryo-grinding. This study evaluated the cellular and protein composition of the final product. Fat was obtained from individuals undergoing routine liposuction and was processed by a 2 step process to obtain only the connective tissue. The tissue was then evaluated by scanning electronic microscope, Western blot analysis, and flow cytometry. Liposuctioned fat was obtained from 10 individuals with an average of 298 mL per subject. After processing an average of 1 mL of collagen matrix was obtained from each 100 mL of fat. Significant viable cell markers were present in descending order for adipocytes > CD90+ > CD105+ > CD45+ > CD19+ > CD144+ > CD34+. Western blot analysis showed collagen type II, III, IV, and other proteins. Scanning electronic microscope study showed a regular pattern of cross-linked, helical collagen. Additionally, vital staing demonstrated that the cells were still viable after processing. Collagen and cells can be easily obtained from liposuctioned fat by ultrasonic separation without alteration of the overall cellular composition of the tissue. Implantation results in new collagen and cellular growth. Collagen matrix with viable cells for autologous use can be obtained from liposuctioned fat and may provide long term results. 5.

Regulatory Advocacy Update: American Society of Plastic Surgeons Comments in Response to the U.S. Food and Drug Administration Draft Guidance Documents on Human Cell and Tissue Products.

The U.S. Food and Drug Administration released draft guidance documents on human cells, tissues, and cellular and tissue-based products regulations. These proposed guidance documents can impact the practice of plastic surgery in the area of tissue grafting procedures. This article describes the relevant issues in these draft guidance documents, and presents the comments provided to the U.S. Food and Drug Administration by the American Society of Plastic Surgeons.

Regulatory Science in Practice (Pharmaceuticals and Medical Devices Agency).

Review, safety, and relief services of the Pharmaceuticals and Medical Devices Agency are primarily focused on scientifically evaluating pharmaceuticals, medical devices, and cellular and tissue-based products referring to their quality, efficacy, and safety, which requires a variety of scientific knowledge and methods. Pharmaceutical regulation should be established based on the most advanced scientific expertise at all times. In order to evaluate products that use cutting-edge technology such as induced pluripotent stem cells and information and communication technology adequately, since fiscal year 2012 the Science Committee has been established as a platform to exchange opinions among members from top-ranking domestic and international academia and to enhance personnel exchanges through the Initiative to Facilitate Development of Innovative Drugs. In addition, the Regulatory Science Center will be established in 2018 to increase the integrity of our services for product reviews and safety measures. In particular, requiring electronic data submissions for clinical trial applications followed by an advanced approach to analysis should not only enhance the quality of reviews of individual products but should also support the development of pharmaceuticals and medical devices by providing pharmaceutical affairs consultations on research and development strategies with various guidelines based on new insights resulting from product-bridging data analysis. Moreover, a database including electronic health records with comprehensive medical information collected mainly from 10 cooperating medical institutions will be developed with the aim of developing safety measures in a more timely manner using methods of pharmacoepidemiological analysis.

Xenogeneic transplantation of human adipose-derived stem cell sheets accelerate angiogenesis and the healing of skin wounds in a Zucker Diabetic Fatty rat model of obese diabetes.

IntroductionDiabetic patients with foot ulcers often suffer impaired wound healing due to diabetic neuropathy and blood flow disturbances. Direct injection of human adipose-derived stem cells (hASCs) effectively accelerates wound healing, although hASCs are relatively unstable.MethodsWe developed an optimized protocol to engineer hASC sheets using temperature-responsive culture dishes to enhance the function and stability of transplanted cells used for regenerative medicine. Here, we evaluated the efficacy of hASC sheets for enhancing wound healing. For this purpose, we used a xenogeneic model of obese type 2 diabetes, the Zucker Diabetic Fatty rat (ZDF rat), which displays full-thickness skin defects. We isolated hASCs from five donors, created hASC sheets, and transplanted the hASC sheets along with artificial skin into full-thickness, large skin defects (15-mm diameter) of ZDF rats.ResultsThe hASC sheets secreted angiogenic growth factors. Transplantation of the hASC sheets combined with artificial skin increased blood vessel density and dermal thickness, thus accelerating wound healing compared with that in the controls. Immunohistochemical analysis revealed significantly more frequent neovascularization in xenografted rats of the transplantation group, and the transplanted hASCs were localized to the periphery of new blood vessels.ConclusionThis xenograft model may contribute to the use of human cell tissue-based products (hCTPs) and the identification of factors produced by hCTPs that accelerate wound healing.

Development of Cellular and Tissue-based Products for Retinal Regenerative Medicine.

Since the discovery of induced pluripotent stem cells (iPSCs) generation, much progress has been made in the fields of medical and pharmaceutical research, such as cell transplantation therapy. We have generated retinal cells and tissues, including retinal pigment epithelia (RPE), from human iPSCs. The ability to produce iPSCs from patients allows for autologous transplantation without causing immune rejection. The autologous transplantation of iPSC-derived retinal pigment epithelial sheets to a patient with age-related macular degeneration was carried out in Japan in 2014 as a first-in-human clinical study. Biotechnology has enabled the development of a wide range of drugs, including cell-based drugs. We are currently developing iPSC-derived RPE sheets as next-generation cell-based drugs aimed at allogeneic transplantation utilizing iPSC banks of homozygotes of human leukocyte antigen at 3 loci. Regulatory science concerning cellular and tissue-based products is a vital matter associated with the realization of regenerative medicine. Here we review the most recent progress in retinal regeneration and drug development, as well as its future prospects.

Getting Products to Market: Understanding and Navigating the Regulatory Pathway

Orthobiologics are products that include growth factors, stem cells, and matrices that are designed to alleviate symptoms and improve function in the setting of musculoskeletal injury. In the United States, biologics are regulated by the Food and Drug Administration’s (FDA)’s Center for Biologics Evaluation and Research (CBER). In 1997, the CBER established a tiered regulatory framework for the management of human cells, tissues, cellular, and tissue-based products based on perceived risk. Products are separated into those exempted from regulation, those seen as low risk (section 361 products), and those seen as higher risk (section 351 products). The distinctions between section 361 and 351 products are primarily based on the extent to which they are manipulated, used for a nonhomologous purpose, combined with other products, and elicit a systemic effect. Higher risk products require more concrete data supporting product safety and efficacy derived from an investigational new drug application or independent device exemption. Under current regulations, blood products, including platelet-rich plasma (PRP), are exempt and therefore do not follow the FDA’s traditional regulatory pathway and do not have to demonstrate safety and efficacy. Nevertheless, nearly all PRP preparation devices have gained FDA 510(k) clearance for producing PRP intended to be mixed with bone graft to improve graft handling properties. Although PRP can be used by practitioners in other ways (including injection and as additions to tissue scaffolds), these constitute off-label usage. Similarly, mesenchymal stem cells are precursors to cartilage, bone, and other connective tissue cell lines and also have powerful anti-inflammatory and immunomodulatory effects. Although mesenchymal stem cells can be harvested from a number of different tissues including bone marrow, adipose, and synovium, harvest sites vary in their abundance of stem cells and regulatory constraints. Though autologous chondrocyte implantation was successful in making it through the approval process as cultured cells, it is telling that no similar product has been approved since that time. Although the principle objective of the CBER is to ensure safety and efficacy in the use of human cells, tissues, cellular, and tissue-based products, their regulation of orthobiologics has led to an increased abundance of products that enter the market through the 361 pathway.

Are You Properly Documenting and Reporting Discarded Cellular and/or Tissue-Based Products?

Are You Properly Documenting and Reporting Discarded Cellular and/or Tissue-Based Products?

Stem Cell Therapy for Knee Pain—What Exactly Are We Injecting, and Why?

Few developments in orthopaedic surgery have been accompanied by as much hype as the use of “stem cells.” While the potential benefits of allogenic tissue-specific cells, stem cells, and progenitor cells are commonly discussed1, and many clinical trials seem to be underway2, few cell preparations have made their way through formal regulatory review and into orthopaedic practice. It is difficult to clearly define the rules for the clinical evaluation of cell products within the regulatory environment, especially in the United States. Focusing just on cell preparations potentially available for cartilage repair, based on draft guidelines from the FDA (U.S. Food and Drug Administration) and the 361 exemption for Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps)3, the processing of minimally manipulated cells of structural tissues must preserve the original relevant characteristics of the tissue relative to reconstruction, repair, or replacement; must be intended for homologous use only (e.g., use of musculoskeletal cells for musculoskeletal restoration); and may not be combined with another article (e.g., scaffold or carrier). The preparation may not have …

Wild, Wild West of Medicare Coverage for Cellular and/or Tissue-Based Products

Wild, Wild West of Medicare Coverage for Cellular and/or Tissue-Based Products

Defining embryo donation: an Ethics Committee opinion

Building families through the adoption of children has been supported by human society throughout history. The ethical appropriateness of patients donating embryos to other patients for family building, or for research, is well established and is affirmed by this Committee. The use of the term ''adoption'' for embryos is inaccurate and should be avoided. This document replaces the ASRM Ethics Committee statement by the same name, last published in 2013 (Fertil Steril 2013;99:1846-7).

Use of Cellular and Tissue-based Product in the Treatment of Diabetic Foot Ulcers

ABSTRACT Introduction The prevalence of diabetes has been rising sharply and the rise in chronic wounds parallels this trend. Lower extremity ulcers present a serious complication for people with diabetes. While debridement of necrotic tissue and off-loading plays an important role in wound healing, many patients with diabetic foot ulcers (DFUs) fail to heal with standard of care (SOC) alone. Unresolved ulcers can lead to complications, such as osteomyelitis and amputation. There continues to be a need for the evaluation of novel wound therapies that can accelerate wound healing and lower the cost of care associated with DFUs. This paper presents recent evidence for the use of cellular and/or tissue-based products (CTPs) and offers an approach for selecting an appropriate CTP. Materials and methods A systematic literature search was conducted using PubMed, Embase, Medline, Cochrane library, and NHS Economic Evaluation Database. Full-length articles in English were assessed for relevance to select studies on effectiveness and economic evaluations. Additionally, Google Scholar was used to gather relevant literature on commonly used CTPs, including Apligraf®, EpiFix®, and Dermagraft®. Findings Results from randomized controlled trials (RCTs) provided evidence for the superior efficacy of CTPs over SOC alone in treatment of chronic DFUs. In recent studies evaluating commonly used CTPs, significantly higher number of DFUs achieved complete closure with EpiFix® when compared to either Apligraf® or Dermagraft®. While cost-effectiveness studies continue to be limited, current literature suggests that CTPs can decrease the long-term costs associated with the care of DFUs by increasing the healing rate, reducing recovery time, and lowering the risk of infection and complications. Cellular and/or tissue-based products (CTPs) may result in higher average number of ulcer-free months and lower average number of amputations or resections compared to SOC alone. How to cite this article Serena TE, Yaakov RA, Mostow EN. Use of Cellular and Tissue-based Product in the Treatment of Diabetic Foot Ulcers. J Foot Ankle Surg (Asia-Pacific) 2016;3(2):92-96.

Treating Clostridium difficile infections: Should fecal microbiota transplantation be reclassified from investigational drug to human tissue?

Fecal microbiota transplantation (FMT) has emerged as a highly effective treatment for Clostridium difficile infection (CDI), the most frequent cause of hospital-acquired infectious diarrhea in developed countries and the cause of nearly 30,000 annual deaths in the US. FMT is proving to be more effective at treating CDI than traditional antibacterial therapy, and reduces the exposure of valuable antibiotics to potential resistance. A systematic review to assess the efficacy of FMT for CDI treatment showed that across all studies for recurrent CDI, symptom resolution was observed in 85% of patients. The United States Food and Drug Administration currently classifies FMT as an investigational drug, which imparts overly restrictive regulations that are impossible to apply to FMT in the same manner as conventional drugs. Reclassification of FMT to a human cell, tissue, and cellular and tissue-based product could potentially expand access to this important treatment while maintaining rigorous safety standards.

Regulation of Cell- and Tissue-Based Therapeutic Products in Singapore.

The regulatory environment for cell- and tissue-based therapeutic (CTT) products is rapidly evolving and drug regulatory agencies are working toward establishing a risk-based system in their regulatory approach. In Singapore, CTT products such as cell therapy products, stem cell products, and tissue-engineered products in regenerative medicine are regulated as medicinal products. CTT products are defined as articles containing or consisting of autologous or allogeneic human or xenogeneic cells or tissues that are used for or administered to, or intended to be used for or administered to human beings for the diagnosis, treatment, or prevention of human diseases or conditions. Currently, we have applied a risk-based tiered approach whereby high-risk CTT products (substantially manipulated products, products intended for nonhomologous use or combined/used in conjunction with a drug, biologic, or device) are regulated under the Medicines Act. A new standalone regulation for CTT products is being proposed under the Health Products Act where we propose to regulate the entire spectrum (high and low risk) of CTT products.

BioT™ cryopod carrier: standardized cryogenic temperature handling of cellular therapies

personnel and process flows, and resulting air flow patterns. Within the BSC critical zone, sites should be in close proximity to operations such as centrally located settle plates and particle sensors not more than 1 foot from the work site. Surface viable sites should be in close proximity to processing activity, at locations contacted by operator gloves, areas where materials transfer from lower classification, and other facility surfaces (e.g. floors, walls) to assess disinfectant efficacy. Suggested sampling frequencies are shown in Tables 1 and 2. EM Levels: Cell therapy areas typically will have ISO 5 BSCs placed within an ISO 7 room with ISO 8 support such as a gowning airlock. This classification scheme is outlined in USP Cellular and Tissue-Based Products. Suggested EM levels for cell therapy aseptic processing are shown in Table 3. Conclusion: Considerations are offered to help cell therapy manufacturers to set-up and an appropriate risk-based EM sampling program that meets criteria of being meaningful, manageable, and defendable.

New Japanese Initiatives on Stem Cell Therapies

Two laws aiming to provide a new legal framework to promote regenerative medicine, while ensuring the efficacy and safety of the treatments, came into effect in Japan on November 25, 2014. The scope of these laws is briefly described here.

Regulation Policy on Cell- and Tissue-Based Therapy Products in Korea.

Extensive investment on research and development of cell therapy products (CTPs) and tissue-engineered products (TEPs) has been made in Korea, and various commercial products are born in market. The Ministry of Food and Drug Safety (MFDS) in Korea regulates CTPs and TEPs as biological products under the authority of the Pharmaceutical Affairs Act. The Korean MFDS approved 16 CTPs and 4 stem CTPs and authorized 135 clinical trials, including 60 sponsor-investigator trials. Currently, the advent of stem cell technology and new biomaterials gives an impetus to develop more innovative CTPs and TEPs to treat intractable and serious diseases. This article deals about the regulatory process for approving CTPs and TEPs in Korea. Regulatory policies of the MFDS for supporting the development of novel products and ensuring the safety of the CTPs and TEPs are reviewed.

FDA regulation of adult stem cell therapies as used in sports medicine.

In sports medicine, adult stem cells are the subject of great interest. Several uses of stem cells are under investigation including cartilage repair, meniscal regeneration, anterior cruciate ligament reconstruction, and tendinopathy. Extensive clinical and basic science research is warranted as stem cell therapies become increasingly common in clinical practice. In the United States, the Food and Drug Administration (FDA) is responsible for regulating the use of stem cells through its "Human Cells, Tissues, and Cellular and Tissue-Based Products" regulations. This report provides a brief overview of FDA regulation of adult stem cells. Several common clinical case scenarios are then presented that highlight how stem cells are currently being used in sports medicine and how current FDA regulations are likely to affect the physicians who use them. In the process, it explains how a variety of factors in sourcing and handling these cells, particularly the extent of cell manipulation, will affect what a physician can and cannot do without first obtaining the FDA's express approval.

Regulatory Oversight of Cell- and Tissue-Based Therapeutic Products and Gene Therapy Products in Singapore.

The regulatory environment for cell- and tissue-based therapeutic products and gene therapy products is rapidly evolving and drug regulatory agencies are working towards establishing a risk-based system in the regulatory framework. Similarly in Singapore, a risk-based tiered approach has been applied whereby clinical trials and product licence of high-risk cell- and tissue-based therapeutic products (substantially manipulated products, products intended for nonhomologous use or combined products) and gene therapy products are regulated as medicinal products under the Medicines Act. There is no legal definition for cell- and tissue-based therapeutic and gene therapy products. The current working definition for a cell- and tissue-based therapeutic product is an article containing or consisting of an autologous or allogeneic human cell or tissue that are used for or administered to, or intended to be used for or administered to, human beings for the diagnosis, treatment, or prevention of human diseases or conditions. Gene therapy products are included under the current biological medicinal product definition.

Future Prospective of Cancer Vaccination Technology in Japan

Dendritic cell (DC)-based immunotherapy has been developed against various types of cancers. To develop and promote regenerative medicine and cell therapy in Japan, the Act on the Safety of Regenerative Medicine and the Revised Pharmaceutical Affairs Law have been enforced since November 25, 2014. Therapeutic vaccination with active DCs was evaluated under the legal framework. Cancer vaccination therapies with autologous monocyte-derived mature DCs are principally attributed to the presence of tumor-associated antigens. Clinical studies and trials should be conducted in accordance with legislation for approval of either DC-based cancer therapy or DC vaccine products. The following issues with regards to DC-based vaccination and vaccine products for clinical use may be raised: 1) Manufacturing of DCs according to the standard grade of Good Gene, Cellular, and Tissue-based Products (GCTP) Manufacturing Practice; 2) Peptides that target cancer-associated antigens for any cancer patient; 3) Quality of immunological analyses as proof of concept; and 4) Optimization of DC vaccines as add-ons to chemotherapeutic drugs and/or radiotherapy to predict potential biomarkers of response. Phase II clinical trials that are covered by Advanced Medical Care System would be conducted on DC vaccine pulsed with Wilms’ tumor 1-specific MHC class I/II-restricted epitopes for pancreatic cancer. The designed clinical trial adopted with new technology could reveal the efficacy of DC vaccine in combination with optimized therapies. This would be relevant to the development of personalized therapy in cancer patients.

Dehydrated Amniotic Membrane Allograft for Treatment of Chronic Leg Ulcers in Patients With Multiple Comorbidities: A Case Series

Cellular and/or tissue-based products (CTPs) are emerging treatment options for chronic non-healing wounds. Dehydrated amniotic membrane allograft (DAMA) was used in 7 patients whose wounds had not responded adequately to standard and adjuvant therapies; four VLUs, 2 surgical wounds, and 1 DFU. Patients had multiple comorbidities, including 2 with autoimmune disorders (CREST syndrome and systemic lupus erythematosus). Patients received 3–8 applications of DAMA at weekly to biweekly intervals (average, 5.4 applications). Complete wound healing was observed in 6 of 7 patients during study period, with an average time to closure of 7.9 weeks. Closure was achieved in 3 of 7 patients after 3 DAMA applications. In the patient with CREST syndrome who did not completely close, DAMA reduced the area and volume by nearly 50% and later went on to closure. These cases suggest that DAMA is a viable option for recalcitrant DFUs, VLUs, and surgical wounds.