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IF 3.2 3区医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Cytotherapy

Pub Date : 2025-09-13 DOI: 10.1016/S1465-3249(25)00821-7

引用次数: 0

Cryopreservation of implantable human skeletal muscle−derived cell-microcarrier combinations for use in clinical regenerative medicine 用于临床再生医学的植入式人体骨骼肌来源细胞-微载体组合的低温保存。

IF 3.2 3区医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Cytotherapy

Pub Date : 2025-09-12 DOI: 10.1016/j.jcyt.2025.09.005

Chara Simitzi , Juzheng Zhang , Rainer Marksteiner , Barry Fuller , Richard M Day

Background aims

Regenerative medicine therapies include tissue-engineered constructs to restore tissue and organ function. Among the different approaches, implantable polymeric microcarriers have been proposed for delivery of anchorage-dependent cells to target tissue locations. Cell-microcarrier combinations produced as fresh advanced therapy medicinal products face significant challenges in terms of manufacturing and time distribution. In the current study, we have explored the feasibility of cryopreservation for human skeletal muscle-derived cells (SMDC)—implantable microcarrier combinations.

Methods

Existing and novel cryoprotectant formulations combined with slow cooling were investigated, along with rapid and slow thawing regimens.

Results

Under specific conditions after cryopreservation and thawing, most SMDC cells were viable and remained attached to the microcarriers. Furthermore, the capacity of human SMDCs to differentiate into myotubes was unaffected. The cryopreservation process did not alter the physico-mechanical properties of the microcarriers enabling them to retain their primary function of an implantable cell substrate.

Conclusions

Overall, these findings pave the way to use cold-chain product supply for future clinical studies with the implantable cell-microcarrier technology.

背景目的：再生医学治疗包括组织工程构建来恢复组织和器官功能。在不同的方法中，植入式聚合物微载体已被提出用于将锚定依赖的细胞递送到目标组织位置。细胞微载体组合作为新鲜的先进治疗药物产品在生产和时间分配方面面临重大挑战。在目前的研究中，我们探索了人类骨骼肌来源细胞(SMDC)-可植入微载体组合冷冻保存的可行性。方法：研究了现有的和新型的冷冻保护剂配方，结合缓慢冷却，以及快速和缓慢解冻方案。结果：在特定条件下，经冷冻和解冻后，大多数SMDC细胞存活并保持附着在微载体上。此外，人smdc分化为肌管的能力不受影响。低温保存过程没有改变微载体的物理力学特性，使其能够保留其作为可植入细胞基质的主要功能。结论：总的来说，这些发现为使用冷链产品供应可植入细胞微载体技术的未来临床研究铺平了道路。

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引用次数: 0

Long-term cryopreservation of hematopoietic stem and progenitor cells: functional viability beyond two decades 造血干细胞和祖细胞的长期冷冻保存：超过二十年的功能活力。

IF 3.2 3区医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Cytotherapy

Pub Date : 2025-09-10 DOI: 10.1016/j.jcyt.2025.09.001

Rebecca Axelsson-Robertson , Thomas Poiret , Lyda M. Osorio , Michael Uhlin

Due to their ability to differentiate into the full diversity of blood cells, CD34+ hematopoietic stem and progenitor cells (HSPC) can be used to treat a variety of diseases. In autologous transplantation CD34+HSPC are harvested when patients are in remission, cryopreserved and later reinfused after therapy. In many cases the harvested cells are cryopreserved for several years. It is unclear how extended, long-term cryostorage affects the quality of CD34+HSPC. This study assessed quality markers in a unique library of 30 CD34+HSPC grafts, cryopreserved for up to 34 years. The samples were divided into 3 groups (<10y, 10-19y and ≥20y) based on their time in cryostorage. Viability indicators, phenotypic as well as functional markers were evaluated. Our results concluded that CD34+HSPC cryostored grafts were resilient to time. No quality marker, except production of selected cytokines, differed between the first and second decade of preservation. After more than two decades of preservation the viability of total leukocytes (CD45+7-AAD-) (P = 0.041), HSPC (CD34+7-AAD-) (P = 0.015), the functionality measured by CFU (P = 0.005) and Th1 and Th2 cytokine production of the grafts were significantly decreased. Despite this, grafts preserved more than twenty years, retained some viability and some ability to form colonies. In addition, most of the live cells retained enzymatic function and capacity to produce cytokines. In conclusion, although more cells die with time, the cells surviving cryopreservation retain some functional capacity after more than two decades of storage. Based on this study, it is hard to identify a time-limit for cryostorage.

由于CD34+造血干细胞和祖细胞（HSPC）能够分化成多种血细胞，因此可用于治疗多种疾病。在自体移植中，CD34+HSPC在患者缓解期采集，冷冻保存，治疗后再输注。在许多情况下，收获的细胞被冷冻保存数年。目前尚不清楚长时间的冷冻保存如何影响CD34+HSPC的质量。这项研究评估了30个CD34+HSPC移植物的独特文库中的质量标记，这些移植物冷冻保存长达34年。将样本分为3组(

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引用次数: 0

Impact of pre- and post-thaw processing on recovery and fitness of cord blood mononuclear cells as starting material for cell therapy 解冻前后处理对作为细胞治疗起始材料的脐带血单个核细胞恢复和适应性的影响。

IF 3.2 3区医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Cytotherapy

Pub Date : 2025-09-08 DOI: 10.1016/j.jcyt.2025.09.003

Laurie Coutu-Godbout , Josée Perreault , Diane Fournier , Éric Boilard , Patrick Trépanier

Background

Cord blood units (CBUs) are a well-established source for hematopoietic stem cell transplantation, but key challenges such as post-thaw recovery and functional integrity remain to be addressed for their broader use in emerging cell therapy applications.This study evaluates the impact of pre-cryopreservation mononuclear cell isolation and compares four post-thaw processing methods - Wash-only, Density Gradient, Beads (CD15/CD235 depletion), and EasySep™ Direct Human PBMC Isolation Kit - on CBMC recovery, purity, and functional fitness.

Study Design and Methods

CBUs were processed either by standard volume reduction or by mononuclear cell isolation prior to cryopreservation. Colony-forming Units, metabolic activity, and Live, Apoptosis-Negative (LAN) assays were performed pre-freeze and post-thaw to compare cell fitness across these two pre-cryopreservation approaches. Separately, post-thaw CBMCs were isolated from volume-reduced CBUs using the four different methods, and outcomes were assessed by flow cytometry for immune subset recovery on day 0, as well as T cell proliferation and cell fitness with the apoptosis assay after five days of culture.

Results

Pre-cryopreservation mononuclear cell isolation did not improve post-thaw CBMC recovery or function compared to standard volume-reduced units. Beads and PBMC Isolation Kit achieved the highest depletion, while Wash-Only retained the lowest levels of purity but the highest CBMC yield. PBMC Isolation Kit - processed samples showed the highest percentage of viable LAN cells on Day 0, whereas the Beads method best preserved viability over five days of stimulation. The LAN assay, previously validated only for fresh cells, was successfully applied to post-thaw CBUs. Notably, PBMC Isolation Kit significantly depleted CD14+ cells, which correlated with reduced T cell proliferation.

Discussion

These findings highlight trade-offs between purity, recovery, and functional outcomes in CBU processing. The choice of method should be application specific, particularly when antigen presentation or long-term viability is required. This study provides a framework for optimizing post-thaw processing to enhance CBU suitability for cell therapy.

背景：脐带血单位（CBUs）是一种成熟的造血干细胞移植来源，但其在新兴细胞治疗应用中广泛应用的关键挑战，如解冻后恢复和功能完整性仍有待解决。本研究评估了预低温保存单个核细胞分离的影响，并比较了四种解冻后处理方法-仅水洗，密度梯度，珠（CD15/CD235消耗）和EasySep™直接人PBMC分离试剂盒-对CBMC恢复，纯度和功能适合度的影响。研究设计和方法：在冷冻保存前，对CBUs进行标准体积缩小或单个核细胞分离处理。进行冷冻前和解冻后的集落形成单位、代谢活性和活细胞、凋亡阴性（LAN）检测，比较这两种冷冻前保存方法的细胞适应性。另外，使用四种不同的方法从体积减小的CBUs中分离出解冻后的cbmc，并通过流式细胞术评估第0天免疫亚群恢复的结果，以及培养5天后T细胞增殖和细胞凋亡试验评估细胞适应性。结果：与标准体积缩小单位相比，冷冻保存前分离的单核细胞没有改善解冻后CBMC的恢复或功能。珠和PBMC分离试剂盒达到了最高的损耗，而Wash-Only保留了最低的纯度，但最高的CBMC产量。PBMC隔离试剂盒处理的样品在第0天的LAN细胞存活率最高，而Beads方法在刺激后5天内的存活率最高。LAN实验，以前只在新鲜细胞中验证，成功地应用于解冻后的CBUs。值得注意的是，PBMC隔离试剂盒显著减少CD14+细胞，这与T细胞增殖减少相关。讨论：这些发现强调了CBU处理中纯度、回收率和功能结果之间的权衡。方法的选择应针对具体应用，特别是当需要抗原呈递或长期生存能力时。本研究为优化解冻后处理提供了一个框架，以提高CBU对细胞治疗的适应性。

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引用次数: 0

Automated vertical wheel bioreactor integrated with process analytics for T-cell manufacturing 集成了t细胞制造过程分析的自动垂直轮式生物反应器。

IF 3.2 3区医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Cytotherapy

Pub Date : 2025-08-31 DOI: 10.1016/j.jcyt.2025.08.007

Bryan Wang , Bharat Kanwar , Annie C. Bowles-Welch , Walker Byrnes , Paloma Casteleiro Costa , Caroline Filan , Reginald Tran , Theresa Kotanchek , Francisco Robles , Krishnendu Roy , Stephen Balakirsky

Background aims

Biomanufacturing of cell therapies involves highly complex and labor-intensive processes, where process parameters and biological variabilities can significantly influence product quality, reproducibility and therapeutic efficacy. Here, we developed a vertical wheel-based bioreactor platform with automated controls and in-line process analytical technologies (PAT) to demonstrate successful closed-system T cell biomanufacturing.

Methods

By identifying the critical process parameters (CPP), a process development strategy was optimized for expanding primary human unmodified and chimeric antigen receptor (CAR) T cells using multiple activation systems, including degradable microscaffolds.

Results

Spent media analysis combined with symbolic regression identified CPPs, which were validated through small-scale experiments and large-scale expansions in the bioreactor platform. Closed-loop automation with analytics such as real-time imaging also was integrated into the bioreactor platform for continuous monitoring and process control.

Conclusions

This integrated bioreactor platform provides a proof-of-concept design for multiplexed PAT integration, process optimization and feedback-controlled intelligent automation to enable discovery, monitoring and control of critical quality attributes and critical process parameters for cell therapy manufacturing.

背景目的：细胞疗法的生物制造涉及高度复杂和劳动密集型的过程，其中工艺参数和生物学变异可以显著影响产品质量、可重复性和治疗效果。在这里，我们开发了一个垂直轮式生物反应器平台，具有自动控制和在线过程分析技术（PAT），以展示成功的封闭系统T细胞生物制造。方法：通过确定关键工艺参数（CPP），优化了使用多种激活系统（包括可降解微支架）扩增原代人未修饰和嵌合抗原受体（CAR） T细胞的工艺开发策略。结果：废媒分析结合符号回归识别出CPPs，并通过小规模实验和生物反应器平台的大规模扩展验证。具有实时成像等分析功能的闭环自动化也被集成到生物反应器平台中，用于连续监测和过程控制。结论：该集成生物反应器平台为多路PAT集成、工艺优化和反馈控制的智能自动化提供了概念验证设计，可以发现、监测和控制细胞治疗制造的关键质量属性和关键工艺参数。

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引用次数: 0

Optimizing cryopreservation in hematopoietic cell therapy: the case for evaluating DMSO concentration alongside freezing methodology 优化冷冻保存在造血细胞治疗：评估DMSO浓度与冷冻方法的情况。

IF 3.2 3区医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Cytotherapy

Pub Date : 2025-08-30 DOI: 10.1016/j.jcyt.2025.08.009

Rongmei Wang

引用次数: 0

Universities can do more to prepare the biomedical workforce for the cell-, tissue- and gene-manufacturing industry 大学可以做更多的工作，为细胞、组织和基因制造行业培养生物医学人才。

IF 3.2 3区医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Cytotherapy

Pub Date : 2025-08-29 DOI: 10.1016/j.jcyt.2025.08.004

Ashley How , Min Thu Ta , Duc Tuan Thanh Phan , Andy Tay

Background and Aims

Precision medicine is poised to revolutionize the treatment of complex diseases, with cell, tissue and gene therapy products (CTGTP) emerging as a major driver of innovation. As industry demand for skilled professionals grows, academic institutions must adapt to equip graduates with the necessary expertise. This study examines the undergraduate curricula and internship programs of top English-speaking universities globally to assess their alignment with industry needs in the CTGTP sector.

Methods

We conducted a comparative analysis of undergraduate programs in biomedical sciences, bioengineering and life sciences, identifying CTGTP-related coursework and evaluating the depth of theoretical training offered. In addition, we mapped major biomedical companies to determine the availability of internship and research opportunities, highlighting discrepancies between academic preparation and workforce requirements.

Results

Our findings indicate that although some universities are trying to integrate CTGTP as a teaching component, many institutions offer limited coursework, leaving students to seek specialization through electives, special programs or postgraduate education.

Conclusions

To address this bottleneck in skilled labor, we propose curriculum enhancements, stronger industry-academic partnerships and expanded practical training opportunities to better prepare graduates for careers in the cell, tissue and gene manufacturing industry.

背景和目的：精密医学有望彻底改变复杂疾病的治疗，细胞、组织和基因治疗产品（CTGTP）正在成为创新的主要驱动力。随着行业对熟练专业人员的需求不断增长，学术机构必须适应，为毕业生提供必要的专业知识。本研究考察了全球顶级英语大学的本科课程和实习项目，以评估它们与CTGTP行业需求的契合度。方法：对生物医学、生物工程和生命科学本科专业进行对比分析，确定ctgtp相关课程，并对理论培训的深度进行评价。此外，我们绘制了主要生物医学公司的地图，以确定实习和研究机会的可用性，突出了学术准备和劳动力需求之间的差异。结果：我们的研究结果表明，尽管一些大学试图将CTGTP作为教学组成部分，但许多机构提供的课程有限，让学生通过选修课、特殊课程或研究生教育寻求专业。结论：为了解决熟练劳动力的瓶颈问题，我们建议加强课程设置，加强产学研合作，扩大实践培训机会，以更好地为毕业生在细胞、组织和基因制造行业的职业生涯做好准备。

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引用次数: 0

Quality indicators for cell collections for immune effector cell and gene therapy: recommendations from the American Society for Apheresis 用于免疫效应细胞和基因治疗的细胞收集的质量指标：来自美国血液分离学会的建议。

IF 3.2 3区医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Cytotherapy

Pub Date : 2025-08-29 DOI: 10.1016/j.jcyt.2025.08.006

Nicole A. Aqui , Patricia A. Shi , Yara A. Park , Yvette C. Tanhehco , Suzanne R. Thibodeaux , Joseph Schwartz , Leon Su , Gaurav K. Gupta , Jeffrey L. Winters , Yan Yun Wu , Jennifer Schneiderman , Nour AlMozain , Saadiya Nazli , Theodros Mamo , Wen Lu , Divjot Singh Lamba , Jan C. Hofmann , Hien D. Liu

Immune effector cell (IEC) therapies provide increasingly important treatment options for patients with certain hematologic malignancies. Apheresis comprises a critical step, providing the starting material from which peripheral-blood derived IEC therapies are manufactured. Regulatory and accreditation bodies providing laws, regulations, guidance, and standards appropriately impose high quality goals for apheresis collection facilities, but they are often not all congruent with clinical trial requirements. Multiple efforts are underway to standardize apheresis procedures for IEC therapies. However, few publications give practical guidance on establishing quality indicators for apheresis collection facilities. Recognizing this, the American Society for Apheresis (ASFA) Clinical Applications Committee (Immune Effector Cell Therapy Subcommittee) sought to review and define the quality indicators that can be applied at each phase of the collection process. This paper is primarily focused on apheresis collection facilities in the United States (US), but general concepts may be applicable outside of the US as well. These recommendations are also endorsed by the Foundation for the Accreditation of Cellular Therapy (FACT), Association for the Advancement of Blood and Biotherapies (AABB), and International Society for Cell & Gene Therapy (ISCT).

免疫效应细胞（IEC）疗法为某些血液系统恶性肿瘤患者提供了越来越重要的治疗选择。血液分离是关键的一步，它提供了制造外周血源性IEC疗法的起始材料。提供法律、法规、指导和标准的监管和认证机构适当地对采血收集设施施加高质量目标，但它们往往不完全符合临床试验要求。目前正在进行多项努力，以使IEC治疗的采回程序标准化。然而，很少有出版物对建立采血收集设施的质量指标提供实际指导。认识到这一点，美国采血学会（ASFA）临床应用委员会（免疫效应细胞治疗小组委员会）寻求审查和定义可应用于收集过程的每个阶段的质量指标。本文主要关注美国的采血收集设施，但一般概念也可能适用于美国以外的地区。这些建议也得到了细胞治疗认证基金会（FACT）、血液与生物治疗促进协会（AABB）和国际细胞与基因治疗学会（ISCT）的认可。

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引用次数: 0

Cell and gene therapy approvals in Asia: regulatory landscape, access and affordability 亚洲的细胞和基因治疗审批：监管格局、获取和负担能力。

IF 3.2 3区医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Cytotherapy

Pub Date : 2025-08-22 DOI: 10.1016/j.jcyt.2025.08.005

William Ying Khee Hwang , Sudipto Bari , Shin Kawamata , Bryan Choi , Chaiyong Koaykul , He Huang , Pawan Gupta

Cell and gene therapies (CGTs) are revolutionizing the treatment paradigm for a range of life-threatening and rare conditions, offering curative potential where conventional therapies have fallen short. In Asia, the CGT landscape has matured significantly in recent years, driven by regulatory reforms, increased local development and a growing number of product approvals. This updated review presents a comprehensive analysis of CGT regulatory frameworks, product approvals, pricing trends and reimbursement policies across six key Asian markets: Singapore, Japan, South Korea, China, India and Thailand. Drawing upon updated data from 2023 to 2025, we examine differences in regulatory maturity, access pathways, affordability and local manufacturing capabilities. The review highlights how certain countries, such as Japan and South Korea, have successfully implemented fast-track regulatory pathways, while others, like India and China, have emphasized domestic innovation to drive down costs. Despite progress, affordability, scalability and sustainable reimbursement remain persistent challenges. By presenting an up-to-date comparative analysis and synthesizing emerging policy innovations, this article offers insights into opportunities for harmonization, equitable access and future policy planning in Asia’s rapidly evolving CGT sector.

细胞和基因疗法（cgt）正在彻底改变一系列危及生命和罕见疾病的治疗模式，在传统疗法不足的地方提供治疗潜力。在亚洲，近年来，在监管改革、当地发展加快和产品审批数量不断增加的推动下，CGT格局已显著成熟。这份最新报告全面分析了六个主要亚洲市场（新加坡、日本、韩国、中国、印度和泰国）的CGT监管框架、产品批准、定价趋势和报销政策。根据2023年至2025年的最新数据，我们研究了监管成熟度、准入途径、可负担性和当地制造能力的差异。报告强调，日本和韩国等一些国家成功实施了快速监管途径，而印度和中国等其他国家则强调通过国内创新来降低成本。尽管取得了进展，但可负担性、可扩展性和可持续报销仍然是持续的挑战。通过提供最新的比较分析和综合新兴的政策创新，本文提供了对亚洲快速发展的CGT部门协调、公平获取和未来政策规划的机会的见解。

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引用次数: 0

Development and qualification of a sensitive method for residual feeder cell detection in NK cell therapy products NK细胞治疗产品中残余饲养细胞检测灵敏方法的建立与鉴定。

IF 3.2 3区医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Cytotherapy

Pub Date : 2025-08-20 DOI: 10.1016/j.jcyt.2025.08.002

Elizabeth Castro-Rivera , Alexandra Aquino-Acevedo , Li Chen , Myraida Toledo-Rojas , Kevin Avilés-Padilla , Daphne Ayala-Torres , Eliezer Romeu-Bonilla , Lei Zhang , Tania Rodriguez , Ivone Bruno

Cellular therapies must meet stringent regulatory standards for safety and quality. These requirements include the thorough evaluation of all manufacturing components, particularly residual cellular materials, and the potential impact of their presence in the final product. In this study we describe the development and qualification of a safety test method that supports the release of a Natural Killer (NK) cells drug product that is expanded by activation through a combination of cytokines and interaction with feeder cells, derived from a monoclonal K-562 cell line, modified to express 4-1BBL and mbIL-21 genes. In response to the safety and regulatory requirements with the use of feeder cells in NK cell manufacturing for clinical applications, and the limitation of current methodologies, we developed a residual test method enhanced by whole-genome sequencing and copy number analysis via droplet digital PCR (ddPCR). The method guarantees accurate identification of target cells via copy number with high specificity and precision with a coefficient of variation of <10%, linearity (R² = 0.999), and accuracy (72-115% recovery). The linear range reached a lower limit of quantification (LLOQ) of 0.1% and a lower limit of detection (LLOD) of 0.02%. These results support the applicability of this method for residual cell detection and release testing of cellular immunotherapies. Importantly, the methodological framework described here is broadly applicable and can be adapted for other cell therapy products where residual unwanted cells pose a risk of contamination in the final product, offering an adaptable, sensitive, and regulatory-compliant solution for safety testing.

细胞疗法必须符合严格的安全和质量监管标准。这些要求包括对所有制造部件，特别是残留细胞材料的彻底评估，以及它们在最终产品中存在的潜在影响。在这项研究中，我们描述了一种安全测试方法的开发和鉴定，该方法支持自然杀伤（NK）细胞药物产品的释放，该药物产品通过细胞因子的组合激活和与饲养细胞的相互作用而扩增，来源于单克隆K-562细胞系，修饰为表达4-1BBL和mbIL-21基因。针对临床NK细胞制造中使用饲养细胞的安全性和监管要求，以及现有方法的局限性，我们开发了一种通过全基因组测序和通过液滴数字PCR （ddPCR）进行拷贝数分析来增强的残留测试方法。该方法通过拷贝数准确鉴定靶细胞，特异性和精密度高，变异系数为2 = 0.999，准确度为72 ~ 115%。定量下限（LLOQ）为0.1%，检测下限为0.02%。这些结果支持了该方法在细胞免疫疗法残留细胞检测和释放测试中的适用性。重要的是，这里描述的方法框架是广泛适用的，可以适用于其他细胞治疗产品，其中残余的不需要的细胞在最终产品中构成污染风险，为安全性测试提供适应性强、敏感且符合法规的解决方案。

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引用次数: 0