Dimethyl sulfoxide (DMSO) is the cryoprotectant of choice for most animal cell systems since the early history of cryopreservation. It has been used for decades in many thousands of cell transplants. These treatments would not have taken place without suitable sources of DMSO that enabled stable and safe storage of bone marrow and blood cells until needed for transfusion. Nevertheless, its effects on cell biology and apparent toxicity in patients have been an ongoing topic of debate, driving the search for less cytotoxic cryoprotectants. This review seeks to place the toxicity of DMSO in context of its effectiveness. It will also consider means of reducing its toxic effects, the alternatives to its use and their readiness for active use in clinical settings.

pdf/dimethyl-sulfoxide-a-central-player-since-the-dawn-of-2z4iokt2x6.pdf

Dimethyl sulfoxide: a central player since the dawn of cryobiology, is efficacy balanced by toxicity?

The clinical translation of promising products, technologies and interventions from the disciplines of nanomedicine and cell therapy has been slow and inefficient. In part, translation has been hampered by suboptimal research practices that propagate biases and hinder reproducibility. These include the publication of small and underpowered preclinical studies, suboptimal study design (in particular, biased allocation of experimental groups, experimenter bias and lack of necessary controls), the use of uncharacterized or poorly characterized materials, poor understanding of the relevant biology and mechanisms, poor use of statistics, large between-model heterogeneity, absence of replication, lack of interdisciplinarity, poor scientific training in study design and methods, a culture that does not incentivize transparency and sharing, poor or selective reporting, misaligned incentives and rewards, high costs of materials and protocols, and complexity of the developed products, technologies and interventions. In this Perspective, we discuss special manifestations of these problems in nanomedicine and in cell therapy, and describe mitigating strategies. Progress on reducing bias and enhancing reproducibility early on ought to enhance the translational potential of biomedical findings and technologies.

/pdf/how-to-design-preclinical-studies-in-nanomedicine-and-cell-2pefrt6fu7.pdf

How to design preclinical studies in nanomedicine and cell therapy to maximize the prospects of clinical translation.

Introduction: Currently, promising outcomes from clinical trials of allogeneic cells, especially allogeneic mesenchymal stromal cells, fibroblasts, keratinocytes, and human cardiac stem cells, have encouraged research institutions, small and medium enterprises (SMEs), and big pharmaceutical companies to invest and focus on developing allogeneic cell therapy products. Commercial and large-scale production of allogeneic cell therapy products requires unique capabilities to develop technologies that generate safe and effective allogeneic cells/cell lines and their fully characterized master/working banks. In addition, it is necessary to design robust upstream and downstream manufacturing processes, and establish integrated, well-designed manufacturing facilities to produce high quality affordable products in accordance with current GMP regulations for the production of cell therapy products.Areas covered: The authors highlight: the recent advances in the development of allogeneic products, the availa...

Allogeneic cell therapy manufacturing: process development technologies and facility design options.

Although human induced pluripotent stem cell (hiPSC) lines are karyotypically normal, they retain the potential for mutation in the genome. Accordingly, intensive and relevant quality controls for clinical-grade hiPSCs remain imperative. As a conceptual approach, we performed RNA-seq-based broad-range genetic quality tests on GMP-compliant human leucocyte antigen (HLA)-homozygous hiPSCs and their derivatives under postdistribution conditions to investigate whether sequencing data could provide a basis for future quality control. We found differences in the degree of single-nucleotide polymorphism (SNP) occurring in cells cultured at three collaborating institutes. However, the cells cultured at each centre showed similar trends, in which more SNPs occurred in late-passage hiPSCs than in early-passage hiPSCs after differentiation. In eSNP karyotyping analysis, none of the predicted copy number variations (CNVs) were identified, which confirmed the results of SNP chip-based CNV analysis. HLA genotyping analysis revealed that each cell line was homozygous for HLA-A, HLA-B, and DRB1 and heterozygous for HLA-DPB type. Gene expression profiling showed a similar differentiation ability of early- and late-passage hiPSCs into cardiomyocyte-like, hepatic-like, and neuronal cell types. However, time-course analysis identified five clusters showing different patterns of gene expression, which were mainly related to the immune response. In conclusion, RNA-seq analysis appears to offer an informative genetic quality testing approach for such cell types and allows the early screening of candidate hiPSC seed stocks for clinical use by facilitating safety and potential risk evaluation.

/pdf/development-of-genetic-quality-tests-for-good-manufacturing-1f1p2qn917.pdf

Development of genetic quality tests for good manufacturing practice-compliant induced pluripotent stem cells and their derivatives.

The past few decades have produced a large number of proof-of-concept studies in regenerative medicine. However, the route to clinical adoption is fraught with technical and translational obstacles that frequently consign promising academic solutions to the so-called "valley of death." Here, we present a proposed blueprint for translational regenerative medicine. We offer principles to help guide the selection of cells and materials, present key in vivo imaging modalities, and argue that the host immune response should be considered throughout design and development. Last, we suggest a pathway to navigate the often complex regulatory and manufacturing landscape of translational regenerative medicine.

/pdf/a-blueprint-for-translational-regenerative-medicine-245o58irwz.pdf

A Blueprint for Translational Regenerative Medicine

To ensure the sustainability of tissue engineered products there is a need to consider the engineering and manufacturing
issues related to them particularly for the purposes of process optimization and product quality assurance. This work
describes the application of Raman spectroscopy for in process monitoring of a skin substitute and rotating orthogonal
polarization imaging to track collagen alignment in a tissue engineered tendon. The skin substitute studied is produced
from culturing fibroblasts in a fibrin matrix. Throughout the production process the fibroblasts secrete extracellular
matrix and in doing so deposit collagen in the matrix. Key to optimization of the skin substitute production process is
development of strategies to track the collagen and fibrin content. The work presented here discusses the feasibility of
Raman spectroscopy to resolve fibrin and collagen components in the skin substitutes. Collagen alignment is also
important in the engineering of many tissues, in particular tendons. Thus, this work will also investigate the ability of
rotating orthogonal polarization imaging to track collagen alignment in a tissue engineered tendon.

Raman spectroscopy and rotating orthogonal polarization imaging for non-destructive tracking of collagen deposition in tissue engineered skin and tendon

This paper summarizes the proceedings of a workshop held at Trinity Hall, Cambridge to discuss comparability and includes additional information and references to related information added subsequently to the workshop. Comparability is the need to demonstrate equivalence of product after a process change; a recent publication states that this 'may be difficult for cell-based medicinal products'. Therefore a well-managed change process is required which needs access to good science and regulatory advice and developers are encouraged to seek help early. The workshop shared current thinking and best practice and allowed the definition of key research questions. The intent of this report is to summarize the key issues and the consensus reached on each of these by the expert delegates.

/pdf/comparability-manufacturing-characterization-and-controls-1dxknwt074.pdf

Comparability: manufacturing, characterization and controls, report of a UK Regenerative Medicine Platform Pluripotent Stem Cell Platform Workshop, Trinity Hall, Cambridge, 14–15 September 2015

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Raman spectroscopy and rotating orthogonal polarization imaging for non-destructive tracking of collagen deposition in tissue engineered skin and tendon

Comparability: manufacturing, characterization and controls, report of a UK Regenerative Medicine Platform Pluripotent Stem Cell Platform Workshop, Trinity Hall, Cambridge, 14–15 September 2015