Tissue-engineered Medical Products Research Articles

Printable oxygen-generating biodegradable scaffold for thicker tissue-engineered medical products.

Due to the increasing demand to generate thick and vascularized tissue-engineered constructs, novel strategies are currently being developed. An effective example is the fabrication of a 3D scaffold containing oxygen-releasing biomaterials to solve the limitations of gasdiffusion and transport within transplanted tissues or devices. In this study, we developed a biodegradable scaffold made of polycaprolactone (PCL) mixed with oxygen-generating calcium peroxide (CPO) to design new structures for regenerative tissue using a 3D printer capable of forming arbitrarily shapes. When osteoblast progenitor cells (MC3T3-E1 cells) were cultured under hypoxic conditions on scaffolds fabricated with this technique, it was shown that cell death was reduced by the new scaffolds. Therefore, the results suggest that 3D-printed scaffolds made from biodegradable oxygen-releasing materials may be useful for tissue engineering and regeneration.

Automated Characterization of Macroscale Tissue 3D Spatial Material Properties via Robotically-Directed Impedimetric Sensing

Here, we report a novel method for automated characterization of bulk tissue 3D spatial properties based on reverse engineering-driven non-planar tool path planning and robotically-directed sensing. The method incorporates information on object (e.g., tissue) and inspection tool (e.g., sensor) geometry for automated inspection of tissue mechanical and dielectric properties across macroscopic nonplanar domains as large as 44 cm <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$^{2}$</tex-math> </inline-formula> . The process avoids the need for manual sensor-tissue integration processes. The impact and the utility of the method were demonstrated by automated mapping of 3D spatial distributions of mechanical and dielectric properties of plant and animal tissues using multiple complementary impedimetric-based sensors of varying types and form factor, including rigid micro-electromechanical systems (MEMS) and flexible multi-functional fibers. Applications to automated characterization of food quality (e.g., type and age) are provided, including 3D spatial mapping of plant and animal tissue mechanical and dielectric property distributions. Ultimately, automated methods for 3D spatial inspection of plant and animal tissue properties are critical to agriculture, food processing, organ transplantation, and biomanufacturing industries. <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">Note to Practitioners</i> —This article is motivated by the need for automating the inspection of soft 3D biological objects. Here, we present a method that generates 3D quality maps of tissue properties using several sensors. The proposed tool path planning program outputs a customized tissue-conforming path for inspection based on the topographical features of the tissue. Hence, this method enables high-throughput, spatially-resolved, minimally-invasive, and reliable inspection of soft 3D biological objects. Applications to inspection of food quality were provided using two impedimetric-based sensors. Practitioners can directly apply the framework to inspection of other tissue properties and soft objects. This work provides an advance in automated methods for inspection, and real-time monitoring of tissue 3D property distributions, which reduces the need for manual tissue handling and requirement for sensor-product interface prior to characterization. This work can be implemented in various biomanufacturing applications and industries, including food safety and quality control, tissue engineering, and organ transplantation, to ensure the quality and safety of macroscopic tissue-engineered medical and food products.

Three-dimensional, label-free cell viability measurements in tissue engineering scaffolds using optical coherence tomography.

In the field of tissue engineering, 3D scaffolds and cells are often combined to yield constructs that are used as therapeutics to repair or restore tissue function in patients. Viable cells are often required to achieve the intended mechanism of action for the therapy, where the live cells may build new tissue or may release factors that induce tissue regeneration. Thus, there is a need to reliably measure cell viability in 3D scaffolds as a quality attribute of a tissue-engineered medical product. Here, we developed a noninvasive, label-free, 3D optical coherence tomography (OCT) method to rapidly (2.5min) image large sample volumes (1 mm3 ) to assess cell viability and distribution within scaffolds. OCT imaging was assessed using a model scaffold-cell system consisting of a polysaccharide-based hydrogel seeded with human Jurkat cells. Four test systems were used: hydrogel seeded with live cells, hydrogel seeded with heat-shocked or fixed dead cells and hydrogel without any cells. Time series OCT images demonstrated changes in the time-dependent speckle patterns due to refractive index (RI) variations within live cells that were not observed for pure hydrogel samples or hydrogels with dead cells. The changes in speckle patterns were used to generate live-cell contrast by image subtraction. In this way, objects with large changes in RI were binned as live cells. Using this approach, on average, OCT imaging measurements counted 326 ± 52 live cells per 0.288 mm3 for hydrogels that were seeded with 288 live cells (as determined by the acridine orange-propidium iodide cell counting method prior to seeding cells in gels). Considering the substantial uncertainties in fabricating the scaffold-cell constructs, such as the error from pipetting and counting cells, a 13% difference in the live-cell count is reasonable. Additionally, the 3D distribution of live cells was mapped within a hydrogel scaffold to assess the uniformity of their distribution across the volume. Our results demonstrate a real-time, noninvasive method to rapidly assess the spatial distribution of live cells within a 3D scaffold that could be useful for assessing tissue-engineered medical products.

Multimodal fluorescence lifetime imaging and optical coherence tomography for longitudinal monitoring of tissue-engineered cartilage maturation in a preclinical implantation model.

Cartilage tissue engineering is a promising strategy for effective curative therapies for treatment of osteoarthritis. However, tissue engineers depend predominantly on time-consuming, expensive, and destructive techniques as quality control to monitor the maturation of engineered cartilage. This practice can be impractical for large-scale biomanufacturing and prevents spatial and temporal monitoring of tissue growth, which is critical for the fabrication of clinically relevant-sized cartilage constructs. Nondestructive multimodal imaging techniques combining fluorescence lifetime imaging (FLIm) and optical coherence tomography (OCT) hold great potential to address this challenge. The feasibility of using multimodal FLIm-OCT for nondestructive, spatial, and temporal monitoring of self-assembled cartilage tissue maturation in a preclinical mouse model is investigated. Self-assembled cartilage constructs were developed for 4 weeks in vitro followed by 4 weeks of in vivo maturation in nude mice. Sterile and nondestructive in situ multispectral FLIm and OCT imaging were carried out at multiple time points ( , 4, and 8 weeks) during tissue development. FLIm and 3D volumetric OCT images were reconstructed and used for the analysis of tissue biochemical homogeneity, morphology, and structural integrity. A biochemical homogeneity index was computed to characterize nonhomogeneous tissue growth at different time points. OCT images were validated against histology. FLIm detects heterogenous extracellular matrix (ECM) growth of tissue-engineered cartilage. The outer edge of the tissue construct exhibited longer fluorescence lifetime in 375 to 410 and 450 to 485nm spectral channels, indicating increase in collagen content. Significant ( ) decrease of construct homogeneity index was observed between weeks and weeks. Both FLIm and OCT images revealed defects (voids) at the center of the tissue construct during in vitro culture ( and 4 weeks). Cyst formation during in vivo culture was detected by OCT and confirmed with histology. The ability of multimodal FLIm-OCT to nondestructively monitor the heterogenous growth of engineered tissue constructs in situ is demonstrated. Spatial and temporal variation of construct ECM component was detected by FLIm. OCT reveals structural defects (voids and cysts). This multimodal approach has great potential to replace costly destructive tests in the manufacturing of tissue-engineered medical products, facilitating their clinical translation.

Decellularization of cartilage microparticles: Effects of temperature, supercritical carbon dioxide and ultrasound on biochemical, mechanical, and biological properties.

One of the approaches to restoring the structure of damaged cartilage tissue is an intra-articular injection of tissue-engineered medical products (TEMPs) consisting of biocompatible matrices loaded with cells. The most interesting are the absorbable matrices from decellularized tissues, provided that the cellular material is completely removed from them with the maximum possible preservation of the structure and composition of the natural extracellular matrix. The present study investigated the mechanical, biochemical, and biological properties of decellularized porcine cartilage microparticles (DCMps) obtained by techniques, differing only in physical treatments, such as freeze-thaw cycling (Protocol 1), supercritical carbon dioxide fluid (Protocol 2) and ultrasound (Protocol 3). Full tissue decellularization was achieved, as confirmed by the histological analysis and DNA quantification, though all the resultant DCMps had reduced glycosaminoglycans (GAGs) and collagen. The elastic modulus of all DCMp samples was also significantly reduced. Most notably, DCMps prepared with Protocol 3 significantly outperformed other samples in viability and the chondroinduction of the human adipose-derived stem cells (hADSCs), with a higher GAG production per DNA content. A positive ECM staining for type II collagen was also detected only in cartilage-like structures based on ultrasound-treated DCMps. The biocompatibility of a xenogenic DCMps obtained with Protocol 3 has been confirmed for a 6-month implantation in the thigh muscle tissue of mature rats (n=18). Overall, the results showed that the porcine cartilage microparticles decellularized by a combination of detergents, ultrasound and DNase could be a promising source of scaffolds for TEMPs for cartilage reconstruction.

Investigating dielectric spectroscopy and soft sensing for nondestructive quality assessment of engineered tissues

Non-destructive, inline quality monitoring techniques that can overcome the limitations of traditional, offline assays are essential to support the scale-up production of tissue engineered medical products (TEMP). In this work, we investigate a new soft-sensing approach with non-destructive dielectric spectroscopy (DS) that synergistically utilizes inline sensor data and predictive analytics to estimate unmeasured TEMP quality profiles. First, the performance of DS during the assessment of gelatin methacrylate (GelMA) constructs containing human adipose-derived stem cells was investigated in comparison to a traditional biochemical assay. The effects of two critical biofabrication parameters (photocrosslinking duration and volume of growth media) on a key scalar metric (Δϵ) were determined over 11 days of in vitro culture, where the metric was associated with the permittivity response of cells to alternating electric fields during DS and corresponding cellular metabolic activity. To enable accurate quality prediction while minimizing direct data collection to reduce the risk of cytotoxicity from prolonged exposure to the DS sensor electrodes and electric fields, we then developed a bilinear basis mixed model (BBMM) as a soft sensor. With comprehensive consideration of different variation sources, this model was designed to estimate missing permittivity profiles of constructs based on the measured DS dataset and biofabrication parameters. Results of benchmarking showed that BBMM outperformed state-of-the-art vector-prediction methods from literature in two different missing data estimation mechanisms. The high-accuracy BBMM provides a novel DS-driven soft sensing system as an inline monitoring tool suitable for scaled-up or scaled-out TEMP production systems.

A Bioengineered Organized Collagen-Based Microfibrous Implant Designed for Tendon Regeneration

Category:Basic Sciences/Biologics; SportsIntroduction/Purpose:Tendon healing is a slow and complicated process that results in inferior structural and functional properties compared to healthy tissue. It may be possible to improve outcomes of tendon healing with enhancement of biological repair through the development of tissue engineered medical products (TEMPs). Although many tendons heal with satisfactory outcomes, others do not, leading to pain and additional cost. Current augments for repair lack either native tissue structure or composition, limiting their potential effectiveness. For example, in tendon healing, restoring native organized and dense collagen composition is a primary goal; however, most TEMPs, such as lyophilized collagen or electrospun pure collagen fibers, are mechanically weak and unstable. For optimizing stability and biocompatibility, collagen can be combined with a high-performance co-biopolymer, such as poly(D,L-lactide) (PDLLA).Methods:The purpose of this study was to demonstrate the efficacy of a novel biointegrative construct, composed of type I collagen and PDLLA for Achilles tendon repair. PDLLA is biocompatible, has shown to support cell growth, and degrades to CO2 and H2O in vivo. The electrospun copolymer constructs were post-processed with low-temperature annealing to enhance their porosity and mechanical stability. The constructs were first tested for their ability to absorb blood and platelet-rich-plasma (PRP). Additionally, the constructs were tested in vivo by implantation in a rabbit Achilles tendon injury model by creating a 7 mm midsubstance Achilles defect. For each tendon defect, a copolymer construct was circumferentially wrapped around the defect and sutured into place. Finally, human cadaver testing was performed to assess implant handling and fixation characteristics.Results:Collagen-PDLLA constructs absorbed more than ten times their weight in blood and PRP. Histologically, rabbit tendons showed rapid implant cellularization by 2-8 weeks, along with de novo collagen deposition. By 16 weeks, dense collagenous connective tissue was seen integrating at the tendon-implant interface and throughout the implant. Movin-Bonar scores for the collagen-PDLLA-implanted and sham-operated tendons were identical from 16-72 weeks post-operatively, indicating a return to normal tendon morphology. Overall, surgical application of the collagen-PDLLA constructs demonstrated dense collagenous fibrous connective tissue ingrowth into and around the implant. Moreover, cadaver surgical implantation of the implant in a minimally invasive Achilles tendon repair and arthroscopic rotator cuff repair, allowed easy graft orientation and delivery as well as excellent handleability and suture fixation to the native tendon.Conclusion:Electrospun biointegrative implants were tissue-engineered to enhance cell infiltration for promoting tissue integration and functional remodeling. When implanted in the rabbit Achilles tendon, the implants demonstrated new in situ tissue generation and remodeled into dense, regularly oriented connective tissue at the tendon-implant interface. Collagenous ingrowth may be crucial in tendon protection and significantly progresses towards improving clinical outcomes following tendon injury.Moreover, the implants demonstrated additional clinical utility by absorbing greater than ten times their weight in biologic fluids which demonstrates the potential to combine this novel biointegrative implant with additional fluid based biologic therapies.

Comprehensive collagen crosslinking comparison of microfluidic wet-extruded microfibers for bioactive surgical suture development

Collagen microfiber-based constructs have garnered considerable attention for ligament, tendon, and other soft tissue repairs, yet with limited clinical translation due to strength, biocompatibility, scalable manufacturing, and other challenges. Crosslinking collagen fibers improves mechanical properties; however, questions remain regarding optimal crosslinking chemistries, biocompatibility, biodegradation, long-term stability, and potential for biotextile assemble at scale, limiting their clinical usefulness. Here, we assessed over 50 different crosslinking chemistries on microfluidic wet-extruded collagen microfibers made with clinically relevant collagen to optimize collagen fibers as a biotextile yarn for suture or other medical device manufacture. The endogenous collagen crosslinker, glyoxal, provides extraordinary fiber ultimate tensile strength near 300MPa, and Young's modulus of over 3GPa while retaining 50% of the initial load-bearing capacity through 6 months as hydrated. Glyoxal crosslinked collagen fibers further proved cytocompatible and biocompatible per ISO 10993-based testing, and further elicits a predominantly M2 macrophage response. Remarkably these strong collagen fibers are amenable to industrial braiding to form strong collagen fiber sutures. Collagen microfluidic wet extrusion with glyoxal crosslinking thus progress bioengineered, strong, and stable collagen microfibers significantly towards clinical use for potentially promoting efficient healing compared to existing suture materials. Statement of SignificanceTowards improving clinical outcomes for over 1 million ligament and tendon surgeries performed annually, we report an advanced microfluidic extrusion process for type I collagen microfiber manufacturing for biological suture and other biotextile manufacturing. This manuscript reports the most extensive wet-extruded collagen fiber crosslinking compendium published to date, providing a tremendous recourse to the field. Collagen fibers made with clinical-grade collagen and crosslinked with glyoxal, exhibit tensile strength and stability that surpasses all prior reports. This is the first report demonstrating that glyoxal, a native tissue crosslinker, has the extraordinary ability to produce strong, cytocompatible, and biocompatible collagen microfibers. These collagen microfibers are ideal for advanced research and clinical use as surgical suture or other tissue-engineered medical products for sports medicine, orthopedics, and other surgical indications.

Standards efforts and landscape for rapid microbial testing methodologies in regenerative medicine

The Standards Coordinating Body for Gene, Cell, and Regenerative Medicines and Cell-Based Drug Discovery (SCB) supports the development and commercialization of regenerative medicine products by identifying and addressing industry-wide challenges through standards. Through extensive stakeholder engagement, the implementation of rapid microbial testing methods (RMTMs) was identified as a high-priority need that must be addressed to facilitate more timely release of products. Since 2017, SCB has coordinated efforts to develop standards for this area through surveys, weekly meetings, workshops, leadership in working groups and participation in standards development organizations. This article describes the results of these efforts and discusses the current landscape of RMTMs for regenerative medicine products.Based on discussions with stakeholders across the field, an overview of traditional culture-based methods and limitations, alternative microbial testing technologies and current challenges, fit-for-purpose rapid microbial testing and case studies, risk-based strategies for selection of novel rapid microbial test methods and ongoing standards efforts for rapid microbial testing are captured here. To this end, SCB is facilitating several initiatives to address challenges associated with rapid microbial testing for regenerative medicine products. Two documentary standards are under development: an International Organization for Standardization standard to provide the framework for a risk-based approach to selecting fit-for-purpose assays primarily intended for cell and gene therapy products and an ASTM standard guide focused on sampling methods for microbial testing methods in tissue-engineered medical products. Working with the National Institute of Standards and Technology, SCB expects to facilitate the process of developing publicly available microbial materials for inter-laboratory testing. These studies will help collect the data necessary to facilitate validation of novel rapid methods. Finally, SCB has been working to increase awareness of, dialog about and participation in efforts to develop standards in the regenerative medicine field.

Non-destructive quality monitoring of 3D printed tissue scaffolds via dielectric impedance spectroscopy and supervised machine learning

Majority of methods currently used for quality assessment of tissue engineered medical products (TEMPs) are offline and destructive in nature, which is one of the factors impeding the scale up and translation of these technologies. In this study, we investigate quality assessment of TEMP via dielectric impedance spectroscopy (DIS) and supervised machine learning (ML) as a non-destructive alternative that requires minimal human intervention. 3D printed, NaOH-treated polycaprolactone (PCL) scaffolds seeded with human adipose-derived stem cells (hASC), NIH 3T3, MG63, and human chondrocyte cells were assessed via DIS over 4 days of in vitro culture. The results showed that the cell type and duration in culture had a significant effect on the delta permittivity (Δε, an important DIS metric. Five supervised ML algorithms – K Nearest Neighbors (KNN), Logistic Regression, Random Forest Classifiers, Support Vector Machines, and artificial neural network – were then used to analyze the comprehensive structured permittivity datasets to determine their ability to discern between different cell types and culture durations. The KNN algorithm demonstrated the best accuracy (99%). The outcomes of this study demonstrate the approach of using DIS and supervised ML in conjunction for assessment of TEMPs in an automated manufacturing system.

Tissue Engineering Measurands.

A metrological perspective for thinking about the characterization of tissue engineered medical products (TEMPs) may help improve communication between researchers. During the development lifecycle of a TEMP, many product properties are measured over the long path to a product release. The selection of each measurement is designed to establish that the product is safe and efficacious (i.e., successful). However, there is often miscommunication during discussions of product characterization. The miscommunication stems from inherent assumptions that are made about the measurements. A "measurand chart" can help clarify these assumptions to enable a more coherent discussion of the value of each measurement. A measurand is defined as "the quantity or property intended to be measured". Tissue engineering measurands are discussed in terms of three case studies including "cell viability in a scaffold", "potency", and "biocompatibility". Topics including a measurement model, defining tissue engineering measurands and definitional uncertainty, are discussed to further refine thinking about tissue engineering measurands. Awareness of these concepts while discussing product characterization can enhance communication and strategic thinking so that the resulting plan is clear and purposeful.

Workshop on the characterization of fiber-based scaffolds: Challenges, progress, and future directions.

A critical component of many tissue-engineered medical products (TEMPs) is the scaffold or biomaterial. The industry's understanding of scaffold properties and their influence on cell behavior has advanced, but our technical capability to reliably characterize scaffolds requires improvement, especially to enable large-scale manufacturing. In response to the key findings from the 2013 ASTM International Workshop of Standards and Measurements for Tissue Engineering Scaffolds, the National Institute of Standards and Technology (NIST), ASTM International, BiofabUSA, and the Standards Coordinating Body (SCB) organized a workshop in 2018 titled, "Characterization of Fiber-Based Scaffolds". The goal was to convene a group of 40 key industry stakeholders to identify major roadblocks in measurements of fiber-based scaffold properties. This report provides an overview of the findings from this collaborative workshop. The four major consensus findings were that (a) there is need for a documentary standard guide that would aid developers in the selection of test methods for characterizing fiber-based scaffolds; (b) there is a need for a strategy to assess the quality of porosity and pore size measurements, which could potentially be ameliorated by the development of a reference material; (b) there are challenges with the lexicon used to describe and assess scaffolds; and (d) the vast array of product applications makes it challenging to identify consensus test methods. As a result of these findings, a working group was formed to develop an ASTM Standard Guide for Characterizing Fiber-Based Constructs that will provide developers guidance on selecting measurements for characterizing fiber-based scaffolds.

Development of an immunodeficient pig model allowing long-term accommodation of artificial human vascular tubes

Before they are used in the clinical setting, the effectiveness of artificially produced human-derived tissue-engineered medical products should be verified in an immunodeficient animal model, such as severe combined immunodeficient mice. However, small animal models are not sufficient to evaluate large-sized products for human use. Thus, an immunodeficient large animal model is necessary in order to properly evaluate the clinical efficacy of human-derived tissue-engineered products, such as artificial grafts. Here we report the development of an immunodeficient pig model, the operational immunodeficient pig (OIDP), by surgically removing the thymus and spleen, and creating a controlled immunosuppressive protocol using a combination of drugs commonly used in the clinical setting. We find that this model allows the long-term accommodation of artificial human vascular grafts. The development of the OIDP is an essential step towards a comprehensive and clinically relevant evaluation of human cell regeneration strategies at the preclinical stage.

Beyond the Present Constraints That Prevent a Wide Spread of Tissue Engineering and Regenerative Medicine Approaches.

Despite the success of tissue engineered medical products (TEMPs) in preclinical translational research, very few have had success in the clinical market place. This gap, referred to as the “valley of death” is due to the large number of ventures that failed to attract or retain investor funding, promotion, and clinical acceptance of their products. This loss can be attributed to a focus on a bench to bedside flow of ideas and technology, which does not account for the multitude of adoption, commercial, and regulatory constraints. The implementation of an alternative bedside to bench and back again approach permits investigators to focus on a specific unmet clinical need, defining crucial translation related questions early in the research process. Investigators often fail to accurately identify critical clinical adoption criteria due to their focus on improved patient outcomes. Other adoption criteria (such as price, time, ethical concerns, and place in the workflow) can cause a product to fail despite improved patient outcomes. By applying simplified business principles such as the build-measure-learn loop and the business model canvas to early-stage research projects, investigators can narrow in on appropriate research topics and define design constraints. Additionally, 86% of all clinical trials fail to result in Federal Drug Administration approval, resulting in significant economic burdens. On the reverse side, approval through the European Medical Agency is widely considered to be more direct but has its challenges. The Committee for Advanced Therapies within the European Medical Agency has received 22 market authorization applications for advanced therapy medicinal products, of which only 10 received authorization. A thorough understanding of the various regulatory pathways permits investigators to plan for future regulatory obstacles and potentially increase their chances of success. By utilizing a bedside to bench and back again approach, investigators can improve the odds that their research will have a meaningful clinical impact.

Phytochemical Incorporated Drug Delivery Scaffolds for Tissue Regeneration

Tissue-engineered scaffolds are platforms for drug delivery and potential candidates for skin, musculoskeletal, bone and cardiac tissue engineering. Though scaffolds incorporated with drugs, growth factors and cytokines are reported, research focusing on phytochemical-incorporated tissue-engineered scaffolds for tissue regeneration and repair are scarce. Phytochemicals used in traditional medicine are treasure houses which have a wide range of biochemical and functional activities that are yet to be explored and if tagged to innovative technologies can easily enable a new generation of tissue-engineered products. Moreover, well characterised and standardised phytochemicals are economic and non-toxic alternatives to synthetic growth factors and cytokines. This review brings into focus—(1) the potential phytochemical candidates for future tissue engineering applications and (2) the incorporation strategies that could be adopted for the synthesis of de novo phytochemical releasing biomaterials and tissue-engineered medical products (TEMP). Tissue-engineered scaffolds are platforms for drug delivery and have immense applications in skin, musculoskeletal, bone and cardiac tissue regeneration. Though such scaffolds incorporated with drugs and growth factors are available, research focusing on phytochemical-incorporated tissue-engineered scaffolds for stem cells and tissue regeneration are scarce. Phytochemicals in traditional medicine are treasure houses with varied biochemical and functional activities that are yet to be explored and this review highlights the gateway of the potential phytochemical candidates for future tissue engineering applications. Phytochemical incorporation strategies are also adopted for the new generation of drug releasing biomaterials and tissue-engineered medical products (TEMP). Future research aims at synthesising and developing biocompatible ceramic/polymeric scaffolds incorporated with easily available, economic and non-toxic formulation of phytochemicals which are effectively used in traditional medicine. Proof of burden studies for safety and efficacy of these scaffolds will be performed in suitable animal models to promote tissue regeneration and repair.

IPS/ES細胞を用いた再生医療研究 －安全性評価技術の現状と課題－

iPS/ES細胞を用いた再生医療研究 －安全性評価技術の現状と課題－

Premarket Regulation of Tissue Engineered Medical Products in China.

Tissue engineered medical products (TEMPs) use state-of-the-art technologies and offer the patients with alternative clinical options for diseases that conventional treatments may fail or be incompetent. However promising, this technology is comparatively new with very limited hands-on experiences with both manufacturing and clinical therapy. Of great significance to products with such complexity and novelty is the establishment of a complete jurisdiction framework and a standardization database so that the safety of the technique in clinical treatment can be ensured. Although different regulatory routes are adopted in different countries, risks are generally considered to be derived from the cellular components within the product, the material scaffolds, and potentially from the final products. This article is to provide an insight of the regulatory considerations and the role of China Food and Drug Administration (CFDA) in the supervision of TEMPs.

Tissue engineered constructs: perspectives on clinical translation.

In this article, a "bedside to bench and back" approach for developing tissue engineered medical products (TEMPs) for clinical applications is reviewed. The driving force behind this approach is unmet clinical needs. Preclinical research, both in vitro and in vivo using small and large animal models, will help find solutions to key research questions. In clinical research, ethical issues regarding the use of cells and tissues, their sources, donor consent, as well as clinical trials are important considerations. Regulatory issues, at both institutional and government levels, must be addressed prior to the translation of TEMPs to clinical practice. TEMPs are regulated as drugs, biologics, devices, or combination products by the U.S. Food and Drug Administration (FDA). Depending on the mode of regulation, applications for TEMP introduction must be filed with the FDA to demonstrate safety and effectiveness in premarket clinical studies, followed by 510(k) premarket clearance or premarket approval (for medical devices), biologics license application approval (for biologics), or new drug application approval (for drugs). A case study on nerve cuffs is presented to illustrate the regulatory process. Finally, perspectives on commercialization such as finding a company partner and funding issues, as well as physician culture change, are presented.

ASTM international workshop on standards and measurements for tissue engineering scaffolds.

The "Workshop on Standards & Measurements for Tissue Engineering Scaffolds" was held on May 21, 2013 in Indianapolis, IN, and was sponsored by the ASTM International (ASTM). The purpose of the workshop was to identify the highest priority items for future standards work for scaffolds used in the development and manufacture of tissue engineered medical products (TEMPs). Eighteen speakers and 78 attendees met to assess current scaffold standards and to prioritize needs for future standards. A key finding was that the ASTM TEMPs subcommittees (F04.41-46) have many active "guide" documents for educational purposes, but few standard "test methods" or "practices." Overwhelmingly, the most clearly identified need was standards for measuring the structure of scaffolds, followed by standards for biological characterization, including in vitro testing, animal models and cell-material interactions. The third most pressing need was to develop standards for assessing the mechanical properties of scaffolds. Additional needs included standards for assessing scaffold degradation, clinical outcomes with scaffolds, effects of sterilization on scaffolds, scaffold composition, and drug release from scaffolds. Discussions highlighted the need for additional scaffold reference materials and the need to use them for measurement traceability. Workshop participants emphasized the need to promote the use of standards in scaffold fabrication, characterization, and commercialization. Finally, participants noted that standards would be more broadly accepted if their impact in the TEMPs community could be quantified. Many scaffold standard needs have been identified and focus is turning to generating these standards to support the use of scaffolds in TEMPs.

Glycomics in Quality Control of Tissue-engineered Medical Products

Glycosylation of cells is known to alter with several biological events such as cell differentiations and proliferations as well as some diseases. "Glycomic approaches", comprehensive qualitative and quantitative glycan analyses of the cells, have become increasingly important as a means of discovering biomarkers that have the potential of being used as disease diagnostic markers and molecular markers for cell characterizations. In this paper, we introduce a method of quantitative glycan profiling by liquid chromatography/mass spectrometry with a combination of an isotope tagging method. In addition, we demonstrate the potential of glycan profiling as a tool for the identification of differentiated human bone marrow mesenchymal stem cell (hMSC) and non-differentiated hMSC.