Twenty-five years have passed since the first clinical trial utilising mesenchymal stomal/stem cells (MSCs) in 1995. In this time academic research has grown our understanding of MSC biochemistry and our ability to manipulate these cells in vitro using chemical, biomaterial, and mechanical methods. Research has been emboldened by the promise that MSCs can treat illness and repair damaged tissues through their capacity for immunomodulation and differentiation. Since 1995, 31 therapeutic products containing MSCs and/or progenitors have reached the market with the level of in vitro manipulation varying significantly. In this review, we summarise existing therapeutic products containing MSCs or mesenchymal progenitor cells and examine the challenges faced when developing new therapeutic products. Successful progression to clinical trial, and ultimately market, requires a thorough understanding of these hurdles at the earliest stages of in vitro pre-clinical development. It is beneficial to understand the health economic benefit for a new product and the reimbursement potential within various healthcare systems. Pre-clinical studies should be selected to demonstrate efficacy and safety for the specific clinical indication in humans, to avoid duplication of effort and minimise animal usage. Early consideration should also be given to manufacturing: how cell manipulation methods will integrate into highly controlled workflows and how they will be scaled up to produce clinically relevant quantities of cells. Finally, we summarise the main regulatory pathways for these clinical products, which can help shape early therapeutic design and testing.

Introduction

As a multipotent cell type, mesenchymal stem (or stromal) cells (MSCs) have been a main source of focus within the field of regenerative medicine [1]. A set of criteria defining this cell population emerged in 2006 from the International Society for Cellular Therapy (ISCT) [2]. The ISCT criteria include: plastic adherence; tri-lineage differentiation potential (osteogenic, chondrogenic, and adipogenic); and a panel of surface markers which are expected (CD105, CD73, and CD90), and not expected (CD45, CD34, CD14, CD11b, CD79a, CD19, and HLA-DR) to be expressed. The ISCT criteria provide a highly beneficial benchmark to standardise studies, even when cell populations are sourced from different tissues. Distinct tissues such as bone marrow, peripheral blood, umbilical cord, and fat have all been shown to contain MSCs [3,4]. Comparative studies have demonstrated that tissue source can impact tri-lineage differentiation potential, along with other cell functions such as proliferation rate and cytokine expression [5,6]. Although cell source is important, there is therapeutic potential for all of these MSC populations, as demonstrated by comparative in vivo studies for osteogenic and chondrogenic repair where both were shown to have regenerative effect [7,8].

Even amongst MSC products, the therapeutic mode of action (MoA) will vary significantly based on clinical indication. From a European regulatory perspective, distinction is made between; somatic cell therapy medicinal products (sCTMPs), which illicit effect through pharmacological, immunological or metabolic means; and tissue-engineered products (TEPs), which aim to regenerate, repair or replace tissue [9]. In the field of regenerative medicine, MSCs are normally used due to their ability to differentiate into functional progenitor tissue types [1,10]. However, clinical efficacy may be determined by their longevity and ability to engraft. Typically MSCs have a transient and short engraftment duration which can limit their therapeutic efficacy [11]. Methods to increase the persistence of MSCs following implantation are, therefore, a key consideration for specific clinical applications. Biomaterial carriers can provide supportive environments for cells (e.g. injectable hydrogels and protein-based patches) and have shown the ability to retain 50–60% of implanted MSCs versus 10% of cells delivered via saline [12,13]. Pre-treatment of cells (with hypoxia or cytokines) can prepare them for ischemic environments [14] and pharmacological treatment can minimise lineage commitment (e.g. inhibition of the Wnt pathway to maintain MSC multipotency) [15] allowing improved persistence upon implantation. As well as increasing longevity, it has been demonstrated that biomaterials can support MSC viability and drive differentiation via cell–material interactions [16,17].

In terms of immunological MoAs, MSC can interact with immune cells, including T-lymphocytes and dendritic cells. This capacity increases opportunities for allogeneic transplant procedures [18,19] with MSCs acting as a suppressive ‘drug’. The mechanism involves cell-to-cell contact and also the MSC secretome, which includes key factors such as: transforming growth factor beta 1 (TGFb1), hepatocyte growth factor (HGF), C-X-C motif chemokine ligand (CXCL)-10, and CXCL-12 [20,21]. The paracrine impact of MSCs contrasts from the direct replacement of damaged tissue and allows treatment of conditions such as graft-versus-host disease (e.g. as a result of marrow transplantation) [22] or to support islet transplantation [23]. Indeed, such immunomodulatory and anti-inflammatory properties are helping MSCs to find applications in cardiac, hepatic, and even neuronal regenerative approaches [24–29]. As the use of therapeutic MSCs grows it has become important to consider how cell expansion will be achieved, and if a naïve phenotype can be maintained. For some therapeutic purposes, it may be desirable to manipulate MSC phenotype, or to even differentiate them during this process. To successfully provide a therapy or build a business, provision of billions, or even trillions (depending on dosage), of MSCs is required [30]. At the same time maintaining the desired phenotype is central to the reproducibility of the final therapy.

In this review, we will examine key considerations when seeking to translate MSC/progenitor therapies from the academic laboratory to clinic. We will discuss: control of MSC phenotype; scale-up of cell culture; and the impact on commercial, clinical, and regulatory viability.

In vitro manipulation of MSCs

To be specific, in this review, and in general clinical use, when we describe MSCs we are discussing the whole adherent population of the stroma that will include stem and progenitor cells. They are often described as mesenchymal stem cells, but, strictly, the stem cells are a clonogenic population of stromal cells able to recreate cartilage, bone, haematopoiesis-supporting stroma [31,32]. The stem cells are typically purified using CD markers and magnet-activated cell sorting/flow sorting. However, selection of CD purified populations significantly reduces cell number. The extent of this reduction is dependent on the specific markers, pre-purification steps and source tissue used [33,34]. Therefore, a pragmatic decision is typically made to use the whole unselected stromal population.

Although the ISCT criteria are beneficial in terms of quality control, they are not the only consideration from a commercial perspective. As the number of MSC products grow it will be crucial for new therapeutics to distinguish themselves from competitor products [30]. This could include targeted clinical functionality or novel product/process intellectual property. As a result, many products will seek to supplement the standard ISCT criteria with additional phenotypic markers relating to the intended clinical use. Some clinical indications will benefit from a naïve, immunomodulatory, MSC phenotype (e.g. graft-versus-host disease), whilst others may benefit from MSCs showing markers of early osteogenic differentiation (e.g. fracture repair) [35]. As an example, Stro-1 and CD271 have both been identified as MSC markers but are not expressed across all tissues [34]. Stro-1 positive MSCs have been linked with cardiac regeneration [36] whilst Stro-1 negative MSCs support haematopoietic stem cell engraftment [37]. Stro-1 expression can both increase or decrease throughout the culture, a key consideration for cell expansion [34]. CD271 can be co-expressed with other MSC markers and has been linked with improved cartilage repair when compared with CD271 negative MSCs [34,38]. Before reviewing current MSC therapies, we will briefly discuss materials and methods to manipulate MSC phenotype, including the maintenance of potency, a key consideration during cell expansion and other manufacturing processes.

Classically, chemical differentiation via soluble factors has been the go-to method of controlling MSC phenotype through use of specific growth factors or chemically defined media [39]. However, these methods can have their limitations of specificity with typical osteogenic reagents (e.g. dexamethasone, ascorbic acid, and β-glycerophosphate) also stimulating expression of adipogenic markers [40,41]. As an alternative, materials have proven useful tools in manipulating and understanding MSC growth and differentiation mechanisms. It is now understood that material chemistry, mechanical environment, and topography can each control MSC fate [17]. The ‘materials’ surrounding a cell, the extracellular matrix (ECM), are formed of proteins containing a rich milieu of biological factors such as adhesion peptide sequences (e.g. arg-gly-asp or RGD) and growth factors. The ECM also provides physical stimulus through varying stiffness, topography, and chemistry [35]. Cells more readily interact with this environment than the non-proteaceous man-made environments of culture plastics or inert biomaterials [42]. However, when synthetic materials are placed into culture media, or into the body, they absorb ECM proteins, and cells can then ligate via integrins to peptide motifs such as RGD [42]. This ligation is of central importance to MSC phenotype. As the cells adhere, integrins gather into focal adhesions and signalling proteins such as focal adhesion kinase (FAK) associate with the growing adhesion complex [43,44]. Stress fibres terminate at adhesions and signalling proteins drive actin contraction via biochemical mediators such as mitogen-activated proteins kinases (MAPKs) and extracellular signal-related kinase 1/2 (ERK 1/2) [35,45]. In fact, for MSCs, the size of the adhesions can be predictive of phenotype with adipocytes having very small adhesions (<1 µm length) and osteoblasts large, mature, adhesions (>5 µm length); fibroblasts and MSCs have intermediate-sized adhesions as will be discussed [35,46].

In considering MSC-material interactions, research first focussed on differentiation and key papers highlighted the role of intracellular tension in determining cell fate [17]. Use of cell containment in small, adhesion motif-rich fibronectin islands revealed that constraining MSCs so that they could not spread resulted in adipogenesis, while promoting spreading in larger islands drove an osteogenic response. Probing of mechanism revealed the roles of cytoskeletal tension mediated via RhoA kinase (ROCK) which controls actin-myosin interaction and cell contraction. This was illustrated by ROCK overexpressing cells in constrained morphologies developing into osteoblasts while inhibiting ROCK in well spread MSCs pushed differentiation towards adipogenesis [47]. A subsequent study used fibronectin patterns of similar size but differing shapes — stars and flowers. The rounded flower shapes were less amenable to cell adhesion and to the development of resultant intracellular tension than the sharp star shapes, which promoted adhesion and tension. Despite being the same size, MSCs differentiated preferentially to osteoblasts on the stars and adipocytes on the flowers and this, again, was seen to be ROCK dependant [45], helping to demonstrate that intracellular tension is important in MSC differentiation.

Stiffness has also been shown to direct adipogenesis and osteogenesis, with low stiffness environments directing adipogenesis while stiffer environments direct osteogenesis [48]. This is because MSCs in low stiffness niches share their intracellular tension with the material as they deform it resulting in a lower apparent cytoskeletal contraction. However, in stiff environments, MSCs experience all the cytoskeletal tension, hence driving osteogenesis [16]. Differentiation is morphology independent and tension dependant, as evidenced by stiffness driven osteogenesis not having concomitant enhanced cell spreading in 3D stiff matrices [49]. Nanoscale topographical patterns that drive osteogenic MSC differentiation also enhance adhesion and intracellular tension [50,51].

More recently, MSC interactions have been studied with materials incorporating controlled viscous, as well as elastic, properties [52]. These materials have again highlighted new methods to control MSC phenotype through modification of adhesive ligand mobility and introduction of time dependant material changes (e.g. controlled stress relaxation) [53]. Quicker stress relaxation aids material remodelling and supports the formation of relevant ECM to support differentiated tissues such as cartilage and bone [54,55].

The adipose and osteoblast differentiation mechanisms of MSCs have been the subject of intense study. However, the expansion of MSCs with maintained phenotype is much less well understood. Again, papers have emerged showing roles for topography [56], chemical patterning [57], and stiffness [58,59].

Using these material surfaces, various mechanisms have been revealed. MSCs appear similar to fibroblasts, indeed they were identified as fibroblast colony-forming units due to their fibroblastic morphology, clonogenic growth, and ability to differentiate [60]. However, it has been seen that while morphologically similar, MSCs have a slightly lower tension phenotype to fibroblasts; both being in the middle of adipocytes (low) and osteoblasts (high) in terms of intracellular tension [50]. Both fibroblasts and MSCs are fast-growing cells compared with adipocytes, where low adhesion results in low levels of ERK 1/2 activation, and osteoblasts, where very high levels of adhesion drive negative feedback on ERK 1/2 causing activation of bone-related transcription factors at the cost of proliferation [61,62]. While the growth rate is similar to fibroblasts, MSCs maintaining a naive phenotype appear to have subtle changes in cell cycle regulation. For example, cyclin dependant kinase 6 (CDK6), which is a positive regulator of cell cycle progression and linked with reduced sensitivity to the osteogenic growth factor bone morphogenetic protein 2 (BMP2) is up-regulated in MSC populations maintaining their phenotype on nanotopography [62]. These points are developed in Figure 1.

Correlation between stem cell adhesion and growth.

Figure 1.
Correlation between stem cell adhesion and growth.

Low-adhesion phenotypes, such as adipocytes, have limited cell adhesion, low intracellular tension, low ERK 1/2 activation by FAK, and therefore, growth is very slow. High-adhesion phenotypes, such as osteoblasts, establish large adhesions driving increased intracellular tension. FAK activates ERK1/2 and a negative feedback loop limits growth in this phenotype. Fast-growing mesenchymal stem cells (MSCs) and fibroblasts represent intermediate adhesion-tension phenotypes, with integrin and FAK clustering, but with the subtle difference that MSCs have lower intracellular tension than fibroblasts. The thickness of the lines between the integrins and the nucleus represents the amount of cytoskeletal tension generated through adhesion. Image adapted from Dalby et al. [35].

Figure 1.
Correlation between stem cell adhesion and growth.

Low-adhesion phenotypes, such as adipocytes, have limited cell adhesion, low intracellular tension, low ERK 1/2 activation by FAK, and therefore, growth is very slow. High-adhesion phenotypes, such as osteoblasts, establish large adhesions driving increased intracellular tension. FAK activates ERK1/2 and a negative feedback loop limits growth in this phenotype. Fast-growing mesenchymal stem cells (MSCs) and fibroblasts represent intermediate adhesion-tension phenotypes, with integrin and FAK clustering, but with the subtle difference that MSCs have lower intracellular tension than fibroblasts. The thickness of the lines between the integrins and the nucleus represents the amount of cytoskeletal tension generated through adhesion. Image adapted from Dalby et al. [35].

The scale up to very large quantities of clinically useful MSCs, as will be discussed in this review, is an area of ongoing development. Methods to maintain cell phenotype during this process may be of significant value, whether MSC naivety or maturation is required. However, these methods and materials must be compatible with industrially relevant cell expansion systems.

Clinical application of MSCs

To understand the relevancy of in vitro MSC manipulation it is beneficial to examine the current level of clinical development and existing uses for MSCs in the treatment of disease. Although our understanding of in vitro MSC phenotype has grown rapidly in preceding decades, this has not directly led to widespread clinical application. Ever since the first clinical trial of MSCs in 1995 [63], their use to repair damaged tissues has been highly anticipated.

In 2018, the ISCT published a list of global tissue, gene, and cellular medicinal products, of which around 41 are cell based with marketing approval within one or more regulatory region [64]. However, this list does not include medical devices containing cells. Globally, as of 2019, 31 therapeutic products have reached market containing MSCs or mesenchymal progenitor cells (e.g. osteoblasts, chondrocytes) [65]. This is despite thousands of MSC focussed academic publications now being produced each year [66]. Several of these products are demineralised bone matrix which have retained their MSC and osteoprogenitor populations during processing [67], but these are regulated separately to biologic products.

The regulatory classification for these two types of MSC product varies between regions. These bone matrix products are largely marketed in the U.S.A. where cultured, manipulated, or processed cells, and cells used in a heterologous manner, are often classified as ‘351 products’ under human cells, tissues, and cellular and tissue-based product (HCT/P) regulation [68]. However, allogeneic tissue which is used in a homologous manner (e.g. demineralised bone matrix with cells used for bone grafting) is covered by section 361 of HCT/P regulation and subject to a lighter regulatory assessment. In the U.S.A., cell therapies which are covered by section 351 are classed as biologic products and subject to full premarket review, i.e. clinical trials and biologics licencing similar to devices or drugs [69]. A list of products which contain MSCs (previously and currently marketed) is shown in Table 1, including details of their clinical application, dosage and cost. Similarly, Table 2 lists previous and current products which use mesenchymal progenitor cells (e.g. osteoblasts or chondrocytes). It is notable that there are no products currently on the market which contain MSCs that have been pre-differentiated in vitro. Although, several, such as Bone Therapeutics’ Allob (osteogenically stimulated allogeneic bone marrow MSCs), are undergoing clinical trial [70].

Table 1.
Previous/currently marketed clinical products containing MSCs
Therapy nameProduct descriptionClinical indicationsReleaseMarket regionDoseCost/unit or dose
Osteocel Allogeneic Bone marrow MSCs Orthopaedic repair 2005 U.S.A. 3 m cells/cc [71$460/cc [71
AlloStem Allogeneic adipose MSCs Orthopaedic repair 2010 U.S.A. 66 255 cells/cc [71$540/cc [71
CardioRel Autologous MSCs Myocardial infarction 2010 India N/A N/A 
Queencell Autologous adipose cells Subcutaneous tissue defect 2010 South Korea 70 m cells [72N/A 
Cartistem Umbilical cord-blood MSCs Cartilage defects of the knee (osteoarthritis) 2011 South Korea 5 m cells/ml [73$19 000 [74
Cellgram- AMI Autologous bone marrow MSCs Acute myocardial infarction 2011 South Korea 50–90 m cells [75$15 000 [76
Grafix Allo. placental membrane, incl. MSCs Acute/chronic wounds 2011 U.S.A. N/A N/A 
Cellentra VCBM Allogeneic MSCs in bone matrix Orthopaedic repair 2012 U.S.A. >250 k cells/cc [71$620/cc [71
Cupistem Autologous adipose MSCs Crohn's fistula 2012 South Korea 160 m cells [77$3000–$5000 [74
Prochymal Allogeneic MSCs Acute graft vs host disease 2012 New Zealand/Canada 2 m cells/kg (10 doses) [78$200 000 [79
HiQCell Autologous adipose stromal vascular fraction Osteoarthritis/tendonitis 2013 Australia N/A AUD 1000 [80
Trinity ELITE Allogeneic MSCs in bone matrix Orthopaedic repair 2013 U.S.A. >500 k cells/cc [81N/A 
Map3 Allogeneic demineralised matrix and multipotent cells Orthopaedic repair 2014 U.S.A. N/A N/A 
Neuronata-R Autologous bone marrow MSCs Amyotrophic Lateral Sclerosis 2014 South Korea 1 m cells/kg (every 2 weeks) [82$55 136 p/a [83
OvationOS Allogeneic MSCs in bone matrix Orthopaedic repair 2014 U.S.A. >400 k cells/cc [71$2700/cc [71
Temcell HS Allogeneic marrow MSCs Acute graft vs host disease 2015 Japan 2 m cells/kg (12 doses) [84$113 000–$170 000 
Stempeucel Allogeneic MSCs Critical limb ischemia 2016 India 2 m cells/kg [85₹150 000 [86
Alofisel Allogeneic adipose MSCs Perianal fistulas in Crohn's disease 2018 Europe 120 m cells [87£54 000 [88
Stemirac Autologous bone marrow MSCs Spinal cord injury 2018 Japan 50–200 m cells [89$135 000 [90
Trinity Evolution Allogeneic MSCs/progenitors in bone matrix Orthopaedic repair 2019 U.S.A. >250 k cells/ cc [71$540/cc [71
Therapy nameProduct descriptionClinical indicationsReleaseMarket regionDoseCost/unit or dose
Osteocel Allogeneic Bone marrow MSCs Orthopaedic repair 2005 U.S.A. 3 m cells/cc [71$460/cc [71
AlloStem Allogeneic adipose MSCs Orthopaedic repair 2010 U.S.A. 66 255 cells/cc [71$540/cc [71
CardioRel Autologous MSCs Myocardial infarction 2010 India N/A N/A 
Queencell Autologous adipose cells Subcutaneous tissue defect 2010 South Korea 70 m cells [72N/A 
Cartistem Umbilical cord-blood MSCs Cartilage defects of the knee (osteoarthritis) 2011 South Korea 5 m cells/ml [73$19 000 [74
Cellgram- AMI Autologous bone marrow MSCs Acute myocardial infarction 2011 South Korea 50–90 m cells [75$15 000 [76
Grafix Allo. placental membrane, incl. MSCs Acute/chronic wounds 2011 U.S.A. N/A N/A 
Cellentra VCBM Allogeneic MSCs in bone matrix Orthopaedic repair 2012 U.S.A. >250 k cells/cc [71$620/cc [71
Cupistem Autologous adipose MSCs Crohn's fistula 2012 South Korea 160 m cells [77$3000–$5000 [74
Prochymal Allogeneic MSCs Acute graft vs host disease 2012 New Zealand/Canada 2 m cells/kg (10 doses) [78$200 000 [79
HiQCell Autologous adipose stromal vascular fraction Osteoarthritis/tendonitis 2013 Australia N/A AUD 1000 [80
Trinity ELITE Allogeneic MSCs in bone matrix Orthopaedic repair 2013 U.S.A. >500 k cells/cc [81N/A 
Map3 Allogeneic demineralised matrix and multipotent cells Orthopaedic repair 2014 U.S.A. N/A N/A 
Neuronata-R Autologous bone marrow MSCs Amyotrophic Lateral Sclerosis 2014 South Korea 1 m cells/kg (every 2 weeks) [82$55 136 p/a [83
OvationOS Allogeneic MSCs in bone matrix Orthopaedic repair 2014 U.S.A. >400 k cells/cc [71$2700/cc [71
Temcell HS Allogeneic marrow MSCs Acute graft vs host disease 2015 Japan 2 m cells/kg (12 doses) [84$113 000–$170 000 
Stempeucel Allogeneic MSCs Critical limb ischemia 2016 India 2 m cells/kg [85₹150 000 [86
Alofisel Allogeneic adipose MSCs Perianal fistulas in Crohn's disease 2018 Europe 120 m cells [87£54 000 [88
Stemirac Autologous bone marrow MSCs Spinal cord injury 2018 Japan 50–200 m cells [89$135 000 [90
Trinity Evolution Allogeneic MSCs/progenitors in bone matrix Orthopaedic repair 2019 U.S.A. >250 k cells/ cc [71$540/cc [71
Table 2.
Previous/currently marketed products containing MSC progenitors
Therapy nameProduct descriptionClinical indicationsReleaseMarket regionDoseCost
Carticel Autologous chondrocytes Articular Cartilage repair 1997 U.S.A./EU 0.6–3.3 m cells [91$13–15 k [91
Chondron Autologous chondrocytes Focal cartilage defect 2001 South Korea/India 12–72 m cells [92₹3–400 k [93
DeNovo NT Allogeneic cartilage with chondrocytes Articular Cartilage repair 2007 U.S.A. 2.5 cm2 fill [94$4–5 k [95
Chondro- celect Autologous chondrocytes Articular Cartilage repair 2009 EU 4 m cells [96£18 301 [96
Ossron Autologous osteoblasts Focal bone formation 2009 South Korea 12–72 m cells [92₹3–400 k [93
JACC Autologous chondrocytes in collagen gel Articular Cartilage repair 2012 Japan 45 k cells [97N/A 
MACI Autologous chondrocytes on porcine membrane Cartilage defects of the knee 2016 U.S.A./Europe 500 k cells/cm2 implant [96£16 226 [96
Ortho-ACI Autologous chondrocytes Cartilage lesion of the knee, patella and ankle 2017 Australia 4–10 m cells [98AUD 6500–10 000 [99
Spherox Autologous chondrocytes (spheroids) Cartilage defects of the knee (<10 cm22017 Europe Up to 100 spheroids [100£10 000 [101
Ossgrow Autologous osteoblasts Avascular necrosis of the hip 2017 India 48 m cells [102₹140 000 [103
Cartigrow Autologous chondrocytes Cartilage defects of the joints 2017 India 12 m cells [104₹140 000 [103
Therapy nameProduct descriptionClinical indicationsReleaseMarket regionDoseCost
Carticel Autologous chondrocytes Articular Cartilage repair 1997 U.S.A./EU 0.6–3.3 m cells [91$13–15 k [91
Chondron Autologous chondrocytes Focal cartilage defect 2001 South Korea/India 12–72 m cells [92₹3–400 k [93
DeNovo NT Allogeneic cartilage with chondrocytes Articular Cartilage repair 2007 U.S.A. 2.5 cm2 fill [94$4–5 k [95
Chondro- celect Autologous chondrocytes Articular Cartilage repair 2009 EU 4 m cells [96£18 301 [96
Ossron Autologous osteoblasts Focal bone formation 2009 South Korea 12–72 m cells [92₹3–400 k [93
JACC Autologous chondrocytes in collagen gel Articular Cartilage repair 2012 Japan 45 k cells [97N/A 
MACI Autologous chondrocytes on porcine membrane Cartilage defects of the knee 2016 U.S.A./Europe 500 k cells/cm2 implant [96£16 226 [96
Ortho-ACI Autologous chondrocytes Cartilage lesion of the knee, patella and ankle 2017 Australia 4–10 m cells [98AUD 6500–10 000 [99
Spherox Autologous chondrocytes (spheroids) Cartilage defects of the knee (<10 cm22017 Europe Up to 100 spheroids [100£10 000 [101
Ossgrow Autologous osteoblasts Avascular necrosis of the hip 2017 India 48 m cells [102₹140 000 [103
Cartigrow Autologous chondrocytes Cartilage defects of the joints 2017 India 12 m cells [104₹140 000 [103

As can be seen from Table 1, price varies by orders of magnitude between products, which is not readily explained by the variance in dosage. It is notable that products with lower costs, such as AlloStem, Cellentra, and Trinity Evolution, all fall under section 361 of HCT/P regulation where market access is easier to obtain. Another key factor to note is the lack of products incorporating differentiated MSCs. This is despite products existing which focus on repair of tissues such as cartilage and bone.

Although many of these marketed products involve in vitro expansion of the cells, few seem to involve structured carrier materials. By this we mean using cells and a scaffolding material such as a gel, microparticle, or polymer; an area of significant ongoing academic development [105,106]. Crucially, carrier materials may assist the efficacy and longevity of cells once implanted. In terms of marketed products the exceptions are MACI (matrix-induced autologous chondrocyte implantation), which includes a carrier membrane [107], and Spherox, which forms spheroids [100]. These strategies are designed to deliver and retain cells at the local site. In the case of Spherox (also named chondrospheres), the specific use of spheroids increases the cells’ ability to produce key constituents of cartilage (collagen II and glycosaminoglycans) over prolonged implantation durations (up to 24 weeks), when assessed in murine models. As a result, newly synthesised cartilage was produced and integrated with the surrounding native matrix [108].

Although relatively few structured (e.g. with biomaterials) MSC products have reached market it is apparent that there is a significant pipeline of therapeutic products currently progressing through clinical trial. Figure 2 shows the growth of MSC focussed clinical trials over the past 15 years and includes 909 studies from 1st January 2004 [109]. Figures include trials listed on clinicaltrials.gov which reference the use of mesenchymal stem cells or mesenchymal stromal cells. This includes studies using cultured MSCs and also MSCs as part of bulk tissues (e.g. bone marrow aspirate) but excludes observational studies (i.e. studies without a defined MSC-based intervention). As can be seen, there was a rapid growth in the number of experimental MSC therapies during this time frame which appears to have now stabilised at a level of roughly 50–70 new phase I studies per year. Also clear from this data are the high levels of attrition through each clinical trial phase, with drastically fewer experimental therapies being tested in phase III studies (less than 5 per year). Although, it is not apparent what the reason for attrition is as there are many factors which can contribute to failure to reach the market. Factors such as insufficient efficacy, inability to scale manufacturing, and high reimbursement prices can factor into the health economic assessment of product viability and ultimately cease therapeutic development.

Clinicaltrials.gov entries for interventional studies starting in the years 2004–2019.

Figure 2.
Clinicaltrials.gov entries for interventional studies starting in the years 2004–2019.

The data show the number of clinical trials using mesenchymal stem/stromal cells which started each year. The chart separates the trials each year by trial phase, where information is available in the database. Data collected November 2019.

Figure 2.
Clinicaltrials.gov entries for interventional studies starting in the years 2004–2019.

The data show the number of clinical trials using mesenchymal stem/stromal cells which started each year. The chart separates the trials each year by trial phase, where information is available in the database. Data collected November 2019.

Health economics of cell therapies

Although seemingly a commercial concern, health economics are a key factor dictating successful therapeutic translation and are ideally considered during product conceptualisation [110,111]. A clear clinical need must be established, ideally where current clinical solutions are limited or there is an opportunity to decrease the overall cost of treatment (e.g. reduced surgical time, hospital admission times, or increases in quality of life) [112]. An assessment of the innovation headroom is then required to demonstrate that the expected therapeutic benefits will exceed the expected cost of treatment. There are many frameworks used to decide on uptake of new therapies depending on region, including cost-benefit analysis, cost-consequence analysis, and budget impact analysis [112].

As example, in the U.K. the National Institute for Health and Care Excellence (NICE) assesses the cost effectiveness of new therapies and makes recommendations on their adoption within the NHS. Therapies are scored based on their ability to provide patients with increased quality-adjusted life years (QALYs). Although subject to many additional factors, NICE typically assumes that a cost lower than £20 000 per QALY gained is cost effective, a value determined by independent committee [113]. However, even if a new treatment is determined cost effective for an individual patient, the overall budgetary impact (based on the number of anticipated patients) may pose limitations dependant on overall national healthcare budgets [114].

Early understanding of target pricing can also be highly beneficial to shape product development at the earliest pre-clinical stages. Cellular products are typically highly engineered and manufacturing intensive, it is essential to ensure that healthcare payers will be willing to cover potentially high reimbursement costs for the target indication [115]. For this reason, new commercial models are being defined, including deferred/instalment payment for therapies, based on continued delivery of patient outcomes [116]. In these arrangements, it would be increasingly important for the therapy to establish long-lasting patient benefits.

As shown in Tables 1 and 2, products vary drastically in price. The South Korean autologous MSC therapy, Cellgram-AMI, costs in the region of $15 000 per treatment. The clinical target for this product is damage due to myocardial infarction and the clinical endpoint measured was left ventricular ejection fraction, 6 months after treatment. For one dose a 6% improvement in ejection fraction resulted [117].

In some cases, high reimbursement costs have not been matched by sufficient improvement in patient outcomes, with some of the first therapeutics to reach market subsequently failing commercially. Key examples include autologous chondrocyte implants (ACIs), e.g. ChondroCelect and MACI (matrix-induced ACI). Both achieved market approval in Europe but have since failed to secure national reimbursement from key countries. This has led to them being withdrawn from the market [118]. Although not an MSC therapy, Provenge illustrates this challenge. Provenge is an autologous immunotherapy for the treatment of prostate cancer which aimed to secure reimbursement of $93 000 per dose. However, the demonstrated patient benefit equated to between 2 and 4 months increase in survival, a level which could only expect to justify costs of $30 000 in the U.S.A. [110,118]. As such, the therapy has failed to achieve reimbursement in the U.S.A. or Europe.

The ability for new therapies to achieve reimbursement largely relates to the balance of efficacy and production/testing cost. At the earliest stages of development, a key focus should be to define the target clinical indication and relevant outcome measures via broad engagement with clinicians [119]. Once known this can be used to select appropriate in vivo models for efficacy testing. Regarding the product itself, it is crucial to lock a variety of product parameters early on in development (e.g. cell source, administration method, carrier materials) based on commercial and clinical appropriateness. This can reduce repetition when progressing through in vivo testing. Product parameters such as autologous vs allogeneic starting material, or the ability to cryopreserve cells can lead to drastic impacts on the subsequent commercial model and production cost [120,121].

Pre-clinical testing of cellular products

Beyond initial in vitro evidence of cell activity and phenotype, in vivo models should show both efficacy and safety of the final therapeutic. Animal models should reproduce, as closely as possible, the condition being targeted in humans for data to have maximum relevance [122]. However, the ability to do so is often determined by the availability of such models, either academically or through contract research organisations (CROs).

At the earliest stages, in vivo efficacy testing can often follow an iterative process whilst production parameters (e.g. culture conditions, administration methodology) are honed for the specific therapeutic target. As such, an early consideration of reagents and processes which can be carried over into good manufacturing practice (GMP) manufacture can minimise the need for later in vivo re-testing and minimise the potential for subsequent failure [123]. In addition, the levels of efficacy demonstrated in vivo should aim beyond simple statistical significance and should demonstrate clinical significance [124]. This is particularly relevant when comparing the new treatment to controls simulating the current standard of care. The study design is a key consideration and efforts should be made to ensure studies are sufficiently powered and follow protocols which maximise reproducibility [125].

If efficacy is demonstrated in small animal models, such as rodents, then many therapeutics progress onto larger animal models. This is often the route chosen where there is uncertainty over the ability to scale the therapy (e.g. in the repair of larger volumes of tissue) [126]. However, the necessity of large animal studies is a matter which will vary based on: clinical trial regulator, the condition being treated, and the prior clinical use of similar cellular products [127]. The importance of this type of study for human translation is still a matter of debate [128]. Indeed, when performing these models it is debatable if the best route is to test the human cell line with immunomodulation of the animal, or to produce an equivalent cell line derived from the species being tested. The relevancy of either scenario to final human use is questionable. For this reason, there is growing interest in humanised in vitro or ex vivo models [129–131].

Beyond efficacy, the safety of any new cellular product must be demonstrated in vivo as part of any application to perform clinical trials. Although it may be possible to collect indicators of safety during initial studies, a comprehensive safety assessment of the final therapy formulation will be required through pivotal safety testing [132]. This is usually carried out on GMP manufactured cells, or GMP-like cells to demonstrate equivalence with the final product [133].

The design of pivotal safety studies will be specific to the therapy and in the European Union guidance is provided that a risk-based approach should be adopted [134]. This aims to identify potential adverse outcomes and then design the pivotal studies to examine their likelihood. For MSCs there are number of common risks to consider including but not limited to: tumorgenicity, immunogenicity, chromosomal instability, and unsafe biodistribution profiles [22,135–137]. From a regulatory perspective, it will be required to justify the model's appropriateness, both in terms of simulated condition and duration. Furthermore, it is typical to carry out these studies to good laboratory practice (GLP) standard, including data analysis [133]. The availability of GLP models can be a barrier to progression and may require co-development of a new model with a commercial test house.

Transition to GMP manufacture

It is important not to underestimate the complexity of moving academic protocols into an industrial therapeutic manufacturing facility. This can include challenges related to reagents, specialised equipment, poorly defined user-dependant steps and finally, scalability [115]. Technically there can also be difficulties characterising the cells and linking this to their clinical potency. This requires a thorough understanding of their intended MoA. Finally, therapeutic cells need to be measurably consistent from batch to batch and upon delivery into clinic [138].

Manufacturing strategies vary depending on the specific product and clinical delivery route. Autologous products may require cellular manipulation close to clinic, whereas allogeneic products benefit from the ability to manufacture at a centralised facility. The number of manufacturing sites also becomes a consideration when looking to supply larger numbers of doses or supply across multiple regions [139]. However, for any steps considered ‘substantial manipulation’ there is the general requirement that these occur in a facility with GMP accreditation and within a cleanroom to ensure product safety. The specific grade of clean room will depend on the culture systems used, i.e. open (e.g. a culture flask requiring opening for media exchange within a flow cabinet) or closed (e.g. bag culture with automated media exchange on benchtop) [140,141].

With the growth of therapeutic candidates, the number of industrial cell manufacturing facilities has also increased [142]. Organisations such as the U.K.’s Cell and Gene Therapy Catapult provide quick connections and access to national GMP manufacturing hubs and guidance for the engagement with industrial manufacturing partners. Similar networks also exist at the European level including the European Society for Gene and Cell Therapy and the European Commission funded Restore initiative.

One of the major differences between therapeutic manufacture and academic development is the requirement to use GMP validated reagents and cultureware. For many in vitro cell manipulation protocols the use of novel reagents or biomaterials may pose a barrier to GMP manufacture, this is particularly true for cell culture media [143]. It is common for academic cell culture to use animal products such as porcine trypsin or basal media supplementation with foetal calf serum (FCS). However, this introduces potential for disease transmission, batch variability, and insufficient supply [144]. Efforts should be made to find xeno-free reagents and supplements which can support the desired levels of cell growth and end yields. Commonly this involves replacement of FCS with human serum (viral tested), other blood-derived supplements (e.g. human platelet lysate) or commercial serum-free formulations [143,145]. Alterations of culture conditions can lead to significant changes in cell phenotype and clinical functionality. For this reason, early introduction of GMP validated reagents can increase the relevance of pre-clinical test data.

Another raw material which is crucial to secure are the cells themselves. For allogeneic MSC supply it will be necessary to establish a procurement strategy which encompasses donor consent and confidentiality, along with a banking strategy involving a master donor cell bank and working bank of therapeutic doses [138,146]. Quality control of the donor material is required, both in terms of safety, identity, and expected potency. This could include testing for MSC surface markers, infectious agents, and genetic abnormalities [147]. In terms of in vitro manipulation of MSCs, it may be advantageous to pre-screen cells for their differentiation potential or immunomodulatory capacity to ensure higher yields of the desired cell population at the end of production.

At the end of production, assessment of the final product will be required to demonstrate comparability with set release criteria. Both product safety (e.g. no increases in tumorgenicity) and correct cellular identity will need to be demonstrated [147]. The cellular identity will be highly individualised to the specific therapy and assessment may involve flow cytometry for specific surface markers or assessment of secreted proteins. It can also be these release criteria which form the central claims for intellectual property protection. For example, Bone Therapeutics’ MSC derived products are defined by MSC surface markers, CD105, CD90, CD73, and CD34, and this identity, along with specified growth factors used during production, are central to their patent protection [148].

In terms of long-term potential, scalability can be a major barrier if phenotype is likely to change during culture. Scalability involves in vitro MSC expansion to produce clinically relevant quantities of cells to perform trials and then to support a company selling a product into multiple centres. As discussed previously, the cost is a major factor in therapeutic adoption and cell yield during manufacturing is a critical factor driving the end cost [149]. For this reason, there is a balance to be struck between higher cell yields and maintenance of the cell identity at the end of manufacture [150].

There already exists many reviews exploring the scaling of cell manufacture [151–153]. However, the first step for smaller clinical trials typically involves transition to multi-layer cell stacks. These have capacities in the region of 10 million cells per layer and are regularly used in GMP culture conditions. These planar cell culture methods are suitable for small clinical trials but become increasingly labour intensive when moving to larger trials where billions of cells may be required [151]. Larger scale culture strategies include bioreactors which can provide increased culture area through the use of hollow fibres or microcarriers [154,155]. Significant work has already been carried out by groups such as the Cell Technologies Research Group at Aston University to understand how microcarrier culture differs from, and could replace, planar, flask-based, culture. This has included studies to examine: serum-free/human serum culture media, optimum rotation speed of spinner flasks, metabolite production, and the choice of microcarriers [30,156–159]. For MSC expansion these types of vessel have been validated up to culture volumes of 2 l; equivalent to 760 million MSCs per batch [160]. In most of these studies, it has been demonstrated that the ISCT criteria for MSCs are met, even following expansion [157,161]. This crucial translational research increases confidence that MSC therapies can continue to be scaled and gain further industrial relevance.

Many commercial systems are being developed, including with built in automation (Figure 3). The Cell and Gene Therapy Catapult have carried out systematic comparisons of planar and automated hollow fibre culture systems which demonstrate the labour and cost benefits of these commercial hollow fibre systems [162]. Beyond the supply of clinical trials, where tens of billions of cells are required, there will be need to go further than these existing technologies, either finding ways to multiplex multiple bioreactors, or to develop even larger culture vessels [91,163,164]. For many academic cell manipulation techniques, particularly those involving physical or material stimulus, it will be difficult to implement them at these sorts of scales unless they can be incorporated into hollow fibres or microcarriers [165–167]. Early consideration of the steps required to move sequentially along this pathway of scale will help to avoid pauses during later clinical trials, as has been the case with some commercial products [168].

Potential culture technologies for cell manufacture.

Figure 3.
Potential culture technologies for cell manufacture.

Monolayer cell culture methods start at the scale of standard tissue culture flasks with yields of several million cells per flask. To supply clinical trials it is necessary to consider the expansion of cells in larger culture vessels, such as multi-layer cell stacks or hollow fibre systems providing increased surface area for growth. Beyond this, microcarrier based culture via small and industrial scale stirred tank systems may present a route to supplying billions of cells per batch.

Figure 3.
Potential culture technologies for cell manufacture.

Monolayer cell culture methods start at the scale of standard tissue culture flasks with yields of several million cells per flask. To supply clinical trials it is necessary to consider the expansion of cells in larger culture vessels, such as multi-layer cell stacks or hollow fibre systems providing increased surface area for growth. Beyond this, microcarrier based culture via small and industrial scale stirred tank systems may present a route to supplying billions of cells per batch.

Regulatory considerations

The regulatory pathway is also a major factor determining the speed of progress towards clinic [115]. Every cellular product is unique and determining the correct therapeutic classification is a key first step [112]. However, the distinction between transplant and cell therapy is largely determined by the level of manipulation that the cells undergo, and whether this classes as ‘substantial’, and therefore a manufacturing step. Within Europe, this is described through the 2001/83/EC Directive defining advanced therapy medicinal products (ATMPs) which includes: gene therapies, sCTMPs, and TEPs [169]. As discussed the distinction between sCTMPs and TEPs is largely down to the product's MoA [9]. Subsequent updates via the 1394/2007 ATMP regulation have amended this definition to include combination-ATMPs, where a medical device (e.g. a biomaterial) is an integral component [170]. As discussed, the FDA in the U.S.A. regulates cell therapies through their HCT/P regulations depending on the level of manipulation and intended use of the implanted material [68].

In both jurisdictions there are regulatory routes which can ease the requirements for new products and speed their passage through clinical trial. Orphan status, relating to medical conditions with small patient populations, can drastically reduce the clinical trial requirements before attaining market authorisation [171,172]. In 2017, the FDA also introduced a new regenerative medicine advanced therapy designation (RMAT) which allows for expedited trialling of new therapies which tackle life threatening conditions or meet serious unmet needs [173]. Since 2017 several MSC products have been awarded RMAT status [64].

Of course, the variety of ATMPs pose a challenge to regulators, and in many cases there are overlaps with medical device regulation if a carrier material is used. This is particularly relevant in the case of 3D bioprinted implants. Currently, the existing regulation fails to define a clear path for the manufacturing and quality control of these patient-specific treatments. In some jurisdictions (e.g. Australia) they may be completely unregulated if using autologous cells [174]. As a result, clinical trials of 3D printed ATMPs are even more scarce. Hourd et al. [175] reported the example of a 3D printed nasal implant which could also contain a cellular component . In this study, they examine the regulatory challenges of delivering this type of therapy into clinic. Central to this is the requirement to demonstrate GMP quality control of the implant, which by nature will be personalised to each patient.

Conclusions

The rapid expansion of MSC research is driving an increased rate of early phase clinical trials which utilise MSCs for therapeutic purposes. However, there appears to be a bottleneck with significant attrition when moving beyond Phase II studies as relatively few treatments have reached market. In addition, it is apparent that very few current MSC therapies are utilising biomaterials or methods for manipulating cell phenotype, instead relying on the patient's body as the bioreactor to differentiate the cells. This review has taken an academic perspective, highlighting some of the key challenges when taking new MSC culture techniques towards clinical use and has highlighted many key papers which offer guidance for new researchers planning their own translational activities.

The importance of understanding therapy reimbursement has been highlighted, as cellular products can be costly to produce when considering the time and manual cell culture operations. Many high-profile commercial failures indicate that insufficient attention is being given to clinical benefit when developing these therapies. The price difference between minimally manipulated tissue products and cultured ATMPs has also been noted. However, cultured therapies appear to offer far greater control over the final product composition, offering opportunity to precisely define cell phenotype and potency.

Linked with patient benefit are the importance of in vivo models to demonstrate efficacy, safety and the potential for clinical benefit. Without strong in vivo evidence, it will be difficult to secure investment or funding for further technical development. Sub-optimal predictive capabilities of in vivo models are a key barrier to market which can lead to attrition for new therapeutics at later stages of development. For cellular products, it can be increasingly hard to identify suitable models for efficacy and safety testing since specific facilities and training are required for cellular products. This does, however, signal a developmental opportunity for non-animal technologies, such as humanised in vitro and ex vivo models.

In terms of manufacturing, there is the potential for the largest impact on end cost and product success. The use of allogeneic cells does offer benefits of scale but cell expansion technologies must also continue to develop. The use of novel cell manipulation technologies will only work if they can be readily up taken into GMP manufacturing and if they are compatible with promising processes such as microcarrier culture.

Although last on this list, the regulatory path has the ability to determine how long, and how much it will cost for a therapeutic to reach market. As with the other aspects of this review, early engagement with the regulatory body of interest can help to avoid a false start in terms of pre-clinical development and the manufacturing process.

Competing Interests

The authors declare that there are no competing interests associated with the manuscript.

Funding

The authors would like to recognise funding received from EPSRC (EP/P001114/1, EP/S02347X/1), BBSRC (BB/N018419/1, BB/S018808/1), and the Sir Bobby Charlton Foundation.

Author Contribution

P.G.C., M.J.D., S.R., and M.S.S. contributed to the writing of the review.

Acknowledgements

The authors would like to acknowledge Dr. Aleixandre Rodrigo-Navarro for his design of Figure 1.

Abbreviations

     
  • ACI

    autologous chondrocyte implantation

  •  
  • ATMP

    advanced therapy medicinal products

  •  
  • BMP

    bone morphogenetic protein

  •  
  • CDK

    cyclin dependant kinase

  •  
  • CRO

    contract research organisation

  •  
  • CXCL

    C-X-C motif chemokine ligand

  •  
  • ECM

    extracellular matrix

  •  
  • ERK

    extracellular signal-related kinase

  •  
  • FAK

    focal adhesion kinase

  •  
  • FCS

    foetal calf serum

  •  
  • GLP

    good laboratory practice

  •  
  • GMP

    good manufacturing practice

  •  
  • HCT/P

    human cells, tissues, and cellular and tissue-based product

  •  
  • HGF

    hepatocyte growth factor

  •  
  • HLA-DR

    human leukocyte antigen-DR isotype

  •  
  • ISCT

    International Society for Cellular Therapy

  •  
  • MACI

    matrix-induced autologous chondrocyte implantation

  •  
  • MoA

    mode of action

  •  
  • MSC

    mesenchymal stem/stromal cell

  •  
  • QALY

    quality-adjusted life years

  •  
  • RGD

    arginylglycylaspartic acid

  •  
  • RMAT

    regenerative medicine advanced therapy designation

  •  
  • sCTMP

    somatic cell therapy medicinal product

  •  
  • TEP

    tissue-engineered product

  •  
  • TGFb1

    transforming growth factor beta 1

References

References
1
Samsonraj
,
R.M.
,
Raghunath
,
M.
,
Nurcombe
,
V.
,
Hui
,
J.H.
,
van Wijnen
,
A.J.
and
Cool
,
S.M.
(
2017
)
Concise review: multifaceted characterization of human mesenchymal stem cells for use in regenerative medicine
.
Stem Cells Transl. Med.
6
,
2173
2185
2
Dominici
,
M.
,
Le Blanc
,
K.
,
Mueller
,
I.
,
Slaper-Cortenbach
,
I.
,
Marini
,
F.
,
Krause
,
D.
et al (
2006
)
Minimal criteria for defining multipotent mesenchymal stromal cells. The international society for cellular therapy position statement
.
Cytotherapy
8
,
315
317
3
Bianco
,
P.
,
Robey
,
P.G.
and
Simmons
,
P.J.
(
2008
)
Mesenchymal stem cells: revisiting history, concepts, and assays
.
Cell Stem Cell
2
,
313
319
4
Phinney
,
D.G.
and
Prockop
,
D.J.
(
2007
)
Concise review: mesenchymal stem/multipotent stromal cells: the state of transdifferentiation and modes of tissue repair—current views
.
Stem Cells
25
,
2896
2902
5
Toupadakis
,
C.A.
,
Wong
,
A.
,
Genetos
,
D.C.
,
Cheung
,
W.K.
,
Borjesson
,
D.L.
,
Ferraro
,
G.L.
et al (
2010
)
Comparison of the osteogenic potential of equine mesenchymal stem cells from bone marrow, adipose tissue, umbilical cord blood, and umbilical cord tissue
.
Am. J. Vet. Res.
71
,
1237
1245
6
Im
,
G.-I.
,
Shin
,
Y.-W.
and
Lee
,
K.-B.
(
2005
)
Do adipose tissue-derived mesenchymal stem cells have the same osteogenic and chondrogenic potential as bone marrow-derived cells?
Osteoarthr. Cartil.
13
,
845
853
7
Kang
,
B.-J.
,
Ryu
,
H.-H.
,
Park
,
S.S.
,
Koyama
,
Y.
,
Kikuchi
,
M.
,
Woo
,
H.-M.
et al (
2012
)
Comparing the osteogenic potential of canine mesenchymal stem cells derived from adipose tissues, bone marrow, umbilical cord blood, and Wharton's jelly for treating bone defects
.
J. Vet. Sci.
13
,
299
310
8
Koga
,
H.
,
Muneta
,
T.
,
Nagase
,
T.
,
Nimura
,
A.
,
Ju
,
Y.-J.
,
Mochizuki
,
T.
et al (
2008
)
Comparison of mesenchymal tissues-derived stem cells for in vivo chondrogenesis: suitable conditions for cell therapy of cartilage defects in rabbit
.
Cell Tissue Res.
333
,
207
215
9
Committee for Advanced Therapies. (2012) EMA/CAT/600280/2010 - Reflection paper on classification of advanced therapy medicinal products, European Medicines Agency. Available from: https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/reflection-paper-classification-advanced-therapy-medicinal-products_en.pdf
10
Anderson
,
H.J.
,
Sahoo
,
J.K.
,
Ulijn
,
R.V.
and
Dalby
,
M.J.
(
2016
)
Mesenchymal stem cell fate: applying biomaterials for control of stem cell behavior
.
Front. Bioeng. Biotechnol.
4
,
38
11
Kean
,
T.J.
,
Lin
,
P.
,
Caplan
,
A.I.
and
Dennis
,
J.E.
(
2013
)
MSCs: delivery routes and engraftment, cell- targeting strategies, and immune modulation
.
Stem Cells Int.
2013
,
732742
12
Suuronen
,
E.J.
,
Veinot
,
J.P.
,
Wong
,
S.
,
Kapila
,
V.
,
Price
,
J.
,
Griffith
,
M.
et al (
2006
)
Tissue-engineered injectable collagen-based matrices for improved cell delivery and vascularization of ischemic tissue using CD133+ progenitors expanded from the peripheral blood
.
Circulation
114
,
I-138
II-44
13
Roche
,
E.T.
,
Hastings
,
C.L.
,
Lewin
,
S.A.
,
Shvartsman
,
D.E.
,
Brudno
,
Y.
,
Vasilyev
,
N.V.
et al (
2014
)
Comparison of biomaterial delivery vehicles for improving acute retention of stem cells in the infarcted heart
.
Biomaterials
35
,
6850
6858
14
Li
,
X.
,
Tamama
,
K.
,
Xie
,
X.
and
Guan
,
J.
(
2016
)
Improving cell engraftment in cardiac stem cell therapy
.
Stem Cells Int.
2016
,
7168797
15
Saraswati
,
S.
,
Deskins
,
D.L.
,
Holt
,
G.E.
and
Young
,
P.P.
(
2012
)
Pyrvinium, a potent small molecule Wnt inhibitor, increases engraftment and inhibits lineage commitment of mesenchymal stem cells (MSCs)
.
Wound Repair Regen.
20
,
185
193
16
Dalby
,
M.J.
,
Gadegaard
,
N.
and
Oreffo
,
R.O.
(
2014
)
Harnessing nanotopography and integrin–matrix interactions to influence stem cell fate
.
Nat. Mater.
13
,
558
569
17
Discher
,
D.E.
,
Mooney
,
D.J.
and
Zandstra
,
P.W.
(
2009
)
Growth factors, matrices, and forces combine and control stem cells
.
Science
324
,
1673
1677
18
Wang
,
M.
,
Yuan
,
Q.
and
Xie
,
L.
(
2018
)
Mesenchymal stem cell-based immunomodulation: properties and clinical application
.
Stem Cells Int.
2018
,
3057624
19
Hare
,
J.M.
,
Fishman
,
J.E.
,
Gerstenblith
,
G.
,
Velazquez
,
D.L.D.
,
Zambrano
,
J.P.
,
Suncion
,
V.Y.
et al (
2012
)
Comparison of allogeneic vs autologous bone marrow–derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial
.
JAMA
308
,
2369
2379
20
Di Nicola
,
M.
,
Carlo-Stella
,
C.
,
Magni
,
M.
,
Milanesi
,
M.
,
Longoni
,
P.D.
,
Matteucci
,
P.
et al (
2002
)
Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli
.
Blood
99
,
3838
3843
21
Roemeling-van Rhijn
,
M.
,
Khairoun
,
M.
,
Korevaar
,
S.S.
,
Lievers
,
E.
,
Leuning
,
D.G.
and
IJzermans
,
J.N.
et al (
2013
)
Human bone marrow-and adipose tissue-derived mesenchymal stromal cells are immunosuppressive in vitro and in a humanized allograft rejection model
.
J. Stem Cell Res. Ther.
56
,
20780
22
Tolar
,
J.
,
Le Blanc
,
K.
,
Keating
,
A.
and
Blazar
,
B.R.
(
2010
)
Concise review: hitting the right spot with mesenchymal stromal cells
.
Stem Cells
28
,
1446
1455
23
Ito
,
T.
,
Itakura
,
S.
,
Todorov
,
I.
,
Rawson
,
J.
,
Asari
,
S.
,
Shintaku
,
J.
et al (
2010
)
Mesenchymal stem cell and islet co-transplantation promotes graft revascularization and function
.
Transplantation
89
,
1438
1445
24
Tsimbouri
,
P.M.
,
Childs
,
P.G.
,
Pemberton
,
G.D.
,
Yang
,
J.
,
Jayawarna
,
V.
,
Orapiriyakul
,
W.
et al (
2017
)
Stimulation of 3D osteogenesis by mesenchymal stem cells using a nanovibrational bioreactor
.
Nat. Biomed. Eng.
1
,
758
25
Somoza
,
R.A.
,
Welter
,
J.F.
,
Correa
,
D.
and
Caplan
,
A.I.
(
2014
)
Chondrogenic differentiation of mesenchymal stem cells: challenges and unfulfilled expectations
.
Tissue Eng. B Rev.
20
,
596
608
26
Maharam
,
E.
,
Yaport
,
M.
,
Villanueva
,
N.L.
,
Akinyibi
,
T.
,
Laudier
,
D.
,
He
,
Z.
et al (
2015
)
Rho/Rock signal transduction pathway is required for MSC tenogenic differentiation
.
Bone Res.
3
,
15015
27
Guan
,
J.
,
Wang
,
F.
,
Li
,
Z.
,
Chen
,
J.
,
Guo
,
X.
,
Liao
,
J.
et al (
2011
)
The stimulation of the cardiac differentiation of mesenchymal stem cells in tissue constructs that mimic myocardium structure and biomechanics
.
Biomaterials
32
,
5568
5580
28
Anghileri
,
E.
,
Marconi
,
S.
,
Pignatelli
,
A.
,
Cifelli
,
P.
,
Galié
,
M.
,
Sbarbati
,
A.
et al (
2008
)
Neuronal differentiation potential of human adipose-derived mesenchymal stem cells
.
Stem Cells Dev.
17
,
909
916
29
Lee
,
K.D.
,
Kuo
,
T.K.C.
,
Whang-Peng
,
J.
,
Chung
,
Y.F.
,
Lin
,
C.T.
,
Chou
,
S.H.
et al (
2004
)
In vitro hepatic differentiation of human mesenchymal stem cells
.
Hepatology
40
,
1275
1284
30
Heathman
,
T.R.
,
Nienow
,
A.W.
,
McCall
,
M.J.
,
Coopman
,
K.
,
Kara
,
B.
and
Hewitt
,
C.J.
(
2015
)
The translation of cell-based therapies: clinical landscape and manufacturing challenges
.
Regen. Med.
10
,
49
64
31
Kanczler
,
J.
,
Tare
,
R.S.
,
Stumpf
,
P.
,
Noble
,
T.J.
,
Black
,
C.
and
Oreffo
,
R.O.
(
2019
)
Isolation, differentiation, and characterization of human bone marrow stem cells In vitro and In vivo
.
Methods Mol. Biol.
1914
,
53
70
32
Bianco
,
P.
,
Cao
,
X.
,
Frenette
,
P.S.
,
Mao
,
J.J.
,
Robey
,
P.G.
,
Simmons
,
P.J.
et al (
2013
)
The meaning, the sense and the significance: translating the science of mesenchymal stem cells into medicine
.
Nat. Med.
19
,
35
42
33
Arufe
,
M.C.
,
De la Fuente
,
A.
,
Fuentes-Boquete
,
I.
,
De Toro
,
F.J.
and
Blanco
,
F.J.
(
2009
)
Differentiation of synovial CD-105+ human mesenchymal stem cells into chondrocyte-like cells through spheroid formation
.
J. Cell. Biochem.
108
,
145
155
34
Lv
,
F.-J.
,
Tuan
,
R.S.
,
Cheung
,
K.M.
and
Leung
,
V.Y.
(
2014
)
Concise review: the surface markers and identity of human mesenchymal stem cells
.
Stem Cells
32
,
1408
1419
35
Dalby
,
M.J.
,
García
,
A.J.
and
Salmeron-Sanchez
,
M.
(
2018
)
Receptor control in mesenchymal stem cell engineering
.
Nat. Rev. Mat.
3
,
1
14
36
Martens
,
T.P.
,
See
,
F.
,
Schuster
,
M.D.
,
Sondermeijer
,
H.P.
,
Hefti
,
M.M.
,
Zannettino
,
A.
et al (
2006
)
Mesenchymal lineage precursor cells induce vascular network formation in ischemic myocardium
.
Nat. Clin. Pract. Cardiovasc. Med.
3
,
S18
S22
37
Bensidhoum
,
M.
,
Chapel
,
A.
,
Francois
,
S.
,
Demarquay
,
C.
,
Mazurier
,
C.
,
Fouillard
,
L.
et al (
2004
)
Homing of in vitro expanded Stro-1-or Stro-1+ human mesenchymal stem cells into the NOD/SCID mouse and their role in supporting human CD34 cell engraftment
.
Blood
103
,
3313
3319
38
Hermida-Gómez
,
T.
,
Fuentes-Boquete
,
I.
,
Gimeno-Longas
,
M.J.
,
Muiños-López
,
E.
,
Díaz- Prado
,
S.
,
de Toro
,
F.J.
et al (
2011
)
Bone marrow cells immunomagnetically selected for CD271+antigen promote in vitro the repair of articular cartilage defects
.
Tissue Eng. A
17
,
1169
1179
39
Russell
,
K.C.
,
Phinney
,
D.G.
,
Lacey
,
M.R.
,
Barrilleaux
,
B.L.
,
Meyertholen
,
K.E.
and
O'Connor
,
K.C.
(
2010
)
In vitro high-capacity assay to quantify the clonal heterogeneity in trilineage potential of mesenchymal stem cells reveals a complex hierarchy of lineage commitment
.
Stem Cells
28
,
788
798
40
Köllmer
,
M.
,
Buhrman
,
J.S.
,
Zhang
,
Y.
and
Gemeinhart
,
R.A.
(
2013
)
Markers are shared between adipogenic and osteogenic differentiated mesenchymal stem cells
.
J. Dev. Biol. Tissue Eng.
5
,
18
41
Mikami
,
Y.
,
Lee
,
M.
,
Irie
,
S.
and
Honda
,
M.J.
(
2011
)
Dexamethasone modulates osteogenesis and adipogenesis with regulation of osterix expression in rat calvaria-derived cells
.
J. Cell Physiol.
226
,
739
748
42
Kasemo
,
B.
and
Lausmaa
,
J.
(
1994
)
Material-tissue interfaces: the role of surface properties and processes
.
Environ. Health Perspect.
102
,
41
45
43
Kilian
,
K.A.
and
Mrksich
,
M.
(
2012
)
Directing stem cell fate by controlling the affinity and density of ligand–receptor interactions at the biomaterials interface
.
Angew. Chem. Int. Ed.
51
,
4891
4895
44
Kanchanawong
,
P.
,
Shtengel
,
G.
,
Pasapera
,
A.M.
,
Ramko
,
E.B.
,
Davidson
,
M.W.
,
Hess
,
H.F.
et al (
2010
)
Nanoscale architecture of integrin-based cell adhesions
.
Nature
468
,
580
584
45
Kilian
,
K.A.
,
Bugarija
,
B.
,
Lahn
,
B.T.
and
Mrksich
,
M.
(
2010
)
Geometric cues for directing the differentiation of mesenchymal stem cells
.
Proc. Natl. Acad. Sci. U.S.A.
107
,
4872
4877
46
Biggs
,
M.J.
,
Richards
,
R.G.
,
Gadegaard
,
N.
,
Wilkinson
,
C.D.
,
Oreffo
,
R.O.
and
Dalby
,
M.J.
(
2009
)
The use of nanoscale topography to modulate the dynamics of adhesion formation in primary osteoblasts and ERK/MAPK signalling in STRO-1+ enriched skeletal stem cells
.
Biomaterials
30
,
5094
5103
47
McBeath
,
R.
,
Pirone
,
D.M.
,
Nelson
,
C.M.
,
Bhadriraju
,
K.
and
Chen
,
C.S.
(
2004
)
Cell shape, cytoskeletal tension, and rhoA regulate stem cell lineage commitment
.
Dev. Cell
6
,
483
495
48
Mao
,
A.S.
,
Shin
,
J.-W.
and
Mooney
,
D.J.
(
2016
)
Effects of substrate stiffness and cell-cell contact on mesenchymal stem cell differentiation
.
Biomaterials
98
,
184
191
49
Huebsch
,
N.
,
Arany
,
P.R.
,
Mao
,
A.S.
,
Shvartsman
,
D.
,
Ali
,
O.A.
,
Bencherif
,
S.A.
et al (
2010
)
Harnessing traction-mediated manipulation of the cell/matrix interface to control stem-cell fate
.
Nat. Mater.
9
,
518
526
50
Tsimbouri
,
P.M.
,
McMurray
,
R.J.
,
Burgess
,
K.V.
,
Alakpa
,
E.V.
,
Reynolds
,
P.M.
,
Murawski
,
K.
et al (
2012
)
Using nanotopography and metabolomics to identify biochemical effectors of multipotency
.
ACS Nano
6
,
10239
10249
51
Dalby
,
M.J.
,
Gadegaard
,
N.
,
Tare
,
R.
,
Andar
,
A.
,
Riehle
,
M.O.
,
Herzyk
,
P.
et al (
2007
)
The control of human mesenchymal cell differentiation using nanoscale symmetry and disorder
.
Nat. Mater.
6
,
997
1003
52
Cantini
,
M.
,
Donnelly
,
H.
,
Dalby
,
M.J.
and
Salmeron-Sanchez
,
M.
(
2020
)
The plot thickens:the emerging role of matrix viscosity in cell mechanotransduction
.
Adv. Healthcare Mater.
9
,
1901259
53
Chaudhuri
,
O.
,
Gu
,
L.
,
Klumpers
,
D.
,
Darnell
,
M.
,
Bencherif
,
S.A.
,
Weaver
,
J.C.
et al (
2016
)
Hydrogels with tunable stress relaxation regulate stem cell fate and activity
.
Nat. Mater.
15
,
326
334
54
Lee
,
H.-P.
,
Gu
,
L.
,
Mooney
,
D.J.
,
Levenston
,
M.E.
and
Chaudhuri
,
O.
(
2017
)
Mechanical confinement regulates cartilage matrix formation by chondrocytes
.
Nat. Mater.
16
,
1243
1251
55
Darnell
,
M.
,
Young
,
S.
,
Gu
,
L.
,
Shah
,
N.
,
Lippens
,
E.
,
Weaver
,
J.
et al (
2017
)
Substrate stress- relaxation regulates scaffold remodeling and bone formation in vivo
.
Adv. Healthcare Mater.
6
,
1601185
56
McMurray
,
R.J.
,
Gadegaard
,
N.
,
Tsimbouri
,
P.M.
,
Burgess
,
K.V.
,
McNamara
,
L.E.
,
Tare
,
R.
et al (
2011
)
Nanoscale surfaces for the long-term maintenance of mesenchymal stem cell phenotype and multipotency
.
Nat. Mater.
10
,
637
644
57
Curran
,
J.M.
,
Stokes
,
R.
,
Irvine
,
E.
,
Graham
,
D.
,
Amro
,
N.
,
Sanedrin
,
R.
et al (
2010
)
Introducing dip pen nanolithography as a tool for controlling stem cell behaviour: unlocking the potential of the next generation of smart materials in regenerative medicine
.
Lab Chip
10
,
1662
1670
58
Kureel
,
S.K.
,
Mogha
,
P.
,
Khadpekar
,
A.
,
Kumar
,
V.
,
Joshi
,
R.
,
Das
,
S.
et al (
2019
)
Soft substrate maintains proliferative and adipogenic differentiation potential of human mesenchymal stem cells on long-term expansion by delaying senescence
.
Biol. Open
8
,
bio039453
59
Gilbert
,
P.M.
,
Havenstrite
,
K.L.
,
Magnusson
,
K.E.
,
Sacco
,
A.
,
Leonardi
,
N.A.
,
Kraft
,
P.
et al (
2010
)
Substrate elasticity regulates skeletal muscle stem cell self-renewal in culture
.
Science
329
,
1078
1081
60
Friedenstein
,
A.J.
(
1976
)
Precursor cells of mechanocytes
.
Int. Rev. Cytol.
47
,
327
359
61
Ge
,
C.
,
Cawthorn
,
W.P.
,
Li
,
Y.
,
Zhao
,
G.
,
MacDougald
,
O.A.
and
Franceschi
,
R.T.
(
2016
)
Reciprocal control of osteogenic and adipogenic differentiation by ERK/MAP kinase phosphorylation of Runx2 and PPARγ transcription factors
.
J. Cell. Physiol.
231
,
587
596
62
Lee
,
L.C.
,
Gadegaard
,
N.
,
De Andrés
,
M.C.
,
Turner
,
L.-A.
,
Burgess
,
K.V.
,
Yarwood
,
S.J.
et al (
2017
)
Nanotopography controls cell cycle changes involved with skeletal stem cell self-renewal and multipotency
.
Biomaterials
116
,
10
20
63
Lazarus
,
H.
,
Haynesworth
,
S.
,
Gerson
,
S.
,
Rosenthal
,
N.
and
Caplan
,
A.
(
1995
)
Ex vivo expansion and subsequent infusion of human bone marrow-derived stromal progenitor cells (mesenchymal progenitor cells): implications for therapeutic use
.
Bone Marrow Transplant.
16
,
557
564
PMID:
[PubMed]
64
Cuende
,
N.
,
Rasko
,
J.E.
,
Koh
,
M.B.
,
Dominici
,
M.
and
Ikonomou
,
L.
(
2018
)
Cell, tissue and gene products with marketing authorization in 2018 worldwide
.
Cytotherapy
20
,
1401
1413
65
Available Products: Alliance for Regenerative Medicine; 2019 Available from:
http://alliancerm.org/available-products/
66
Sipp
,
D.
,
Robey
,
P.G.
and
Turner
,
L.
(
2018
)
Clear up This Stem-Cell Mess
,
Nature Publishing Group
,
London
.
67
Baboolal
,
T.G.
,
Boxall
,
S.A.
,
El-Sherbiny
,
Y.M.
,
Moseley
,
T.A.
,
Cuthbert
,
R.J.
,
Giannoudis
,
P.V.
et al (
2014
)
Multipotential stromal cell abundance in cellular bone allograft: comparison with fresh age- matched iliac crest bone and bone marrow aspirate
.
Regen. Med.
9
,
593
607
68
US Food and Drug Administration. (2018) FDA regulation of human cells, tissues, and cellular and tissue-based products (HCT/P's) product list. Available from: https://www.fda.gov/vaccines-blood-biologics/tissue-tissue-products/fda-regulation-human-cells-tissues-and-cellular-and-tissue-based-products-hctps-product-list
69
Shapiro
,
J.K.
and
Wesoloski
,
B.J.
(
2007
)
FDA's regulatory scheme for human tissue
. Food And Drug Law Institute. Available from: https://hpm.com/wp-content/uploads/2007/12/00396737-1.pdf
70
Laruelle
,
P.
,
Jenicot
,
J.
and
Pietri
,
S.
(
2020
)
ALLOB, an off-the-shelf allogeneic bone-forming cell therapy product derived from BMSC displays bone regenerative property and improves bone healing
.
Cytotherapy
22
,
S193
71
Skovrlj
,
B.
,
Guzman
,
J.Z.
,
Al Maaieh
,
M.
,
Cho
,
S.K.
,
Iatridis
,
J.C.
and
Qureshi
,
S.A.
(
2014
)
Cellular bone matrices: viable stem cell-containing bone graft substitutes
.
Spine J.
14
,
2763
2772
72
Barekzai
,
J.
,
Petry
,
F.
,
Zitzmann
,
J.
,
Czermak
,
P.
, and
Salzig
,
D.
(
2019
)
Bioprocess Development for Human Mesenchymal Stem Cell Therapy Products. New Advances on Fermentation Processes: IntechOpen
;
73
Cartistem: Medipost, 2019 Available from
: http://www.medi-post.com/front/eng/stemcell/cartistem.do
74
Hildreth
,
C
.
Pricing of Approved Cell Therapy Products2018 2018-10-23. Available from
: https://bioinformant.com/price-of-cell-therapy-products/
75
Cell therapy products, Pharmicell Co., Ltd: Ministry of Food and Drug Safety; 2016 Available from
: https://www.mfds.go.kr/eng/brd/m_30/view.do?seq=70957
76
Doo-hyun
,
N
.
Will Korea's first stem cell therapy pass reexamination? 2018. Available from
: http://www.koreabiomed.com/news/articleView.html?idxno=585
77
Cho
,
Y.B.
,
Park
,
K.J.
,
Yoon
,
S.N.
,
Song
,
K.H.
,
Kim
,
D.S.
,
Jung
,
S.H.
et al (
2015
)
Long-term results of adipose-derived stem cell therapy for the treatment of Crohn's fistula
.
Stem Cells Transl. Med.
4
,
532
537
78
Remestemcel-L (Prochymal) for steroid refractory acute graft versus host disease – second line: NIHR 2015. Available from
: http://www.io.nihr.ac.uk/wp-content/uploads/migrated/Remestemcel-L-July2015.pdf
79
Shukla
,
V.
,
Seoane-Vazquez
,
E.
,
Fawaz
,
S.
,
Brown
,
L.
and
Rodriguez-Monguio
,
R.
(
2019
)
The landscape of cellular and gene therapy products: authorization, discontinuations, and cost
.
Hum. Gene Ther. Clin. Dev.
30
,
102
113
80
Regeneus - Moving to human clinical trials for key products. (2015) Edison Investment Research. Available from: https://www.edisoninvestmentresearch.com/?ACT=18&ID=14178
81
Trinity ELITE Brochure: Orthofix; 2016. Available from
: http://web.orthofix.com/Products/Products/Trinity%20ELITE/Trinity-ELITE-Brochure.pdf
82
ALS (NeuroNata-R®): Corestem; 2018. Available from
: http://corestem.com/en/m21.php
83
Han-soo,
L.
Corestem applies for FDA meet on Lou Gehrig's drug 2019. Available from
: http://www.koreabiomed.com/news/articleView.html?idxno=5832
84
Mesoblast's Japan Licensee Receives Pricing for TEMCELL® HS Inj. for Treatment of Acute Graft Versus Host Disease [press release]. Globalnewswire. Available from: https://www.globenewswire.com/news-release/2015/11/27/790909/0/en/Mesoblast-s-Japan-Licensee-Receives-Pricing-for-TEMCELL-HS-Inj-for-Treatment-of-Acute-Graft-Versus-Host-Disease.html
85
Gupta
,
P.K.
,
Krishna
,
M.
,
Chullikana
,
A.
,
Desai
,
S.
,
Murugesan
,
R.
,
Dutta
,
S.
et al (
2017
)
Administration of adult human bone marrow-derived, cultured, pooled, allogeneic mesenchymal stromal cells in critical limb ischemia due to buerger's disease: phase II study report suggests clinical efficacy
.
Stem Cells Transl. Med.
6
,
689
699
86
Jayaramam,
K.S.
(
2016
)
India's first stem cell based drug. Nature India. https://doi.org/10.1038/nindia.2016.61
87
Darvadstrocel for treating complex perianal fistulas in Crohn's disease NICE: NICE; 2018 Available from:
https://www.nice.org.uk/guidance/ta556/documents/appraisal-consultation-document
88
Darvadstrocel NHS Specialist Pharmacy Service: NHS Specialist Pharmacy Service; 2019 Available from:
https://www.sps.nhs.uk/medicines/darvadstrocel/
89
Pharmaceutical Safety and Environmental Health Bureau. (2018) Report on the Deliberation Results - Stemirac for Injection, Ministry of Health, Labour and Welfare. [cited 2020 Sept 3] Available from: https://www.pmda.go.jp/files/000231946.pdf
90
Horie,
H.
2019
Controversial New Stem Cell Therapy Targets Spinal-Cord Injuries. Available from:
https://news.bloomberglaw.com/pharma-and-life-sciences/controversial-new-stem-cell-therapy-targets-spinal-cord-injuries
91
Chilima
,
T.D.P.
,
Moncaubeig
,
F.
and
Farid
,
S.S.
(
2018
)
Impact of allogeneic stem cell manufacturing decisions on cost of goods, process robustness and reimbursement
.
Biochem. Eng. J.
137
,
132
151
92
Cell therapy products - Sewon Cellontech Co., LTD: Ministry of Food and Drug Safety; 2019 Available from:
https://www.mfds.go.kr/eng/brd/m_30/view.do?seq=70954
93
Apollo Hospitals ties up with cell therapy firm. (2017) The Hindu Business Line. Available from: https://www.thehindubusinessline.com/companies/apollo-hospitals-ties-up-with-cell-therapy-firm/article9730607.ece
95
Buckwalter
,
J.
,
Bowman
,
G.
,
Albright
,
J.
,
Wolf
,
B.
and
Bollier
,
M.
(
2014
)
Clinical outcomes of patellar chondral lesions treated with juvenile particulated cartilage allografts
.
Iowa Orthop. J.
34
,
44
49
PMID:
[PubMed]
96
Appraisal consultation document: Autologous chondrocyte implantation for repairing symptomatic articular cartilage defects of the knee. (2015) NICE. Available from: https://www.nice.org.uk/guidance/TA477/documents/knee-cartilage-defects-autologous-chondrocyte-implantation-id686-appraisal-consultation-document2
97
Ikawa
,
T.
,
Yano
,
K.
,
Watanabe
,
N.
,
Masamune
,
K.
and
Yamato
,
M.
(
2015
)
Non-clinical assessment design of autologous chondrocyte implantation products
.
Regen. Ther.
1
,
98
108
99
Orthocell: Pioneering Regenerative Medicines for Soft Tissue Injuries and Musculoskeletal Disorders: Cedrus Investments; 2018 Available from
: https://static1.squarespace.com/static/55d2ae4ce4b0e20eb51007ce/t/5ac42967562fa70b5edd4b12/1522805166018/Orthocell±Limited±Report±April±3±2018.pdf
100
Spherox CHMP assessment report: European Medicines Agency; 2017 Available from
: https://www.ema.europa.eu/en/documents/assessment-report/spherox-epar-public-assessment-report_en.pdf
101
Autologous chondrocyte implantation using chondrosphere for treating symptomatic articular cartilage defects of the knee: NICE; 2017 Available from
: https://www.nice.org.uk/guidance/ta508/documents/final-appraisal-determination-document
102
Ossgrow FAQs: Regrow; 2019 Available from
: https://www.regrow.in/pdf/Ossgrow-FAQs.pdf
103
Das,
S
. (
2018
)
Mumbai's Regrow Biosciences develops cell therapy for bone joint disorders, Business Standard. [cited 2020 Sept 3] Available from: https://www.business-standard.com/article/companies/mumbai-s-regrow-biosciences-develops-cell-therapy-for-bone-joint-disorders-118091000783_1.html
.
104
Foldager
,
C.B.
,
Gomoll
,
A.H.
,
Lind
,
M.
and
Spector
,
M.
(
2012
)
Cell seeding densities in autologous chondrocyte implantation techniques for cartilage repair
.
Cartilage
3
,
108
117
105
Luan
,
C.
,
Liu
,
P.
,
Chen
,
R.
and
Chen
,
B.
(
2017
)
Hydrogel based 3D carriers in the application of stem cell therapy by direct injection
.
Nanotechnol. Rev.
6
,
435
448
106
Vissers
,
C.
,
Ming
,
G.-L.
and
Song
,
H.
(
2019
)
Nanoparticle technology and stem cell therapy team up against neurodegenerative disorders
.
Adv. Drug Deliv. Rev.
148
,
239
251
107
Bartlett
,
W.
,
Gooding
,
C.
,
Carrington
,
R.
,
Skinner
,
J.
,
Briggs
,
T.
and
Bentley
,
G.
(
2005
)
Autologous chondrocyte implantation at the knee using a bilayer collagen membrane with bone graft: a preliminary report
.
J. Bone Jt. Surg. Br. Vol.
87
,
330
332
108
Schubert
,
T.
,
Anders
,
S.
,
Neumann
,
E.
,
Schölmerich
,
J.
,
Hofstädter
,
F.
,
Grifka
,
J.
et al (
2009
)
Long- term effects of chondrospheres on cartilage lesions in an autologous chondrocyte implantation model as investigated in the SCID mouse model
.
Int. J. Mol. Med.
23
,
455
460
109
ClinicalTrials.gov: U.S. National Institutes of Health; 2020 Available from
: https://www.clinicaltrials.gov/.
110
Bubela
,
T.
,
McCabe
,
C.
,
Archibald
,
P.
,
Atkins
,
H.
,
Bradshaw
,
S.E.
,
Kefalas
,
P.
et al (
2015
)
Bringing regenerative medicines to the clinic: the future for regulation and reimbursement
.
Regen. Med.
10
,
897
911
111
Driscoll
,
D.
,
Farnia
,
S.
,
Kefalas
,
P.
and
Maziarz
,
R.T.
(
2017
)
Concise review: the high cost of high tech medicine: planning ahead for market access
.
Stem Cells Transl. Med.
6
,
1723
1729
112
Mount
,
N.M.
,
Ward
,
S.J.
,
Kefalas
,
P.
and
Hyllner
,
J.
(
2015
)
Cell-based therapy technology classifications and translational challenges
.
Philos. Trans. R. Soc. B Biol. Sci.
370
,
20150017
113
The guidelines manual: process and methods [PMG6]. (2012) National Institute for Health and Care Excellence. Available from: https://www.nice.org.uk/process/pmg6/resources/the-guidelines-manual-pdf-2007970804933
114
Ogden
,
J.
(
2017
)
How will NICE's budget impact test affect new drug availability?
Prescriber
28
,
9
12
115
Dodson
,
B.P.
and
Levine
,
A.D.
(
2015
)
Challenges in the translation and commercialization of cell therapies
.
BMC Biotechnol.
15
,
70
116
Abou-El-Enein
,
M.
,
Bauer
,
G.
and
Reinke
,
P.
(
2014
)
The business case for cell and gene therapies
.
Nat. Biotechnol.
32
,
1192
117
Yang
,
H.
(
2011
)
South Korea's Stem Cell Approval
,
Nature Publishing Group
,
London
.
118
Abou-El-Enein
,
M.
,
Elsanhoury
,
A.
and
Reinke
,
P.
(
2016
)
Overcoming challenges facing advanced therapies in the EU market
.
Cell Stem Cell
19
,
293
297
119
Davies
,
B.M.
,
Rikabi
,
S.
,
French
,
A.
,
Pinedo-Villanueva
,
R.
,
Morrey
,
M.E.
,
Wartolowska
,
K.
et al (
2014
)
Quantitative assessment of barriers to the clinical development and adoption of cellular therapies: a pilot study
.
J. Tissue Eng.
5
,
2041731414551764
120
Smith
,
D.M.
(
2012
)
Assessing commercial opportunities for autologous and allogeneic cell- based products
.
Regen. Med.
7
,
721
732
121
Harel
,
A.
(
2013
)
Cryopreservation and cell banking for autologous mesenchymal stem cell- based therapies
.
Cell Tissue Transpl. Ther.
5
,
1
122
Liebschner
,
M.A.
(
2004
)
Biomechanical considerations of animal models used in tissue engineering of bone
.
Biomaterials
25
,
1697
1714
123
Louët
,
S.
(
2004
)
Reagent Safety Issues Surface for Cell/Tissue Therapies
,
Nature Publishing Group
,
London
.
124
Archambault
,
J.
,
Moreira
,
A.
,
McDaniel
,
D.
,
Winter
,
L.
,
Sun
,
L.
and
Hornsby
,
P.
(
2017
)
Therapeutic potential of mesenchymal stromal cells for hypoxic ischemic encephalopathy: A systematic review and meta-analysis of preclinical studies
.
PLoS One
12
,
e0189895
125
Ioannidis
,
J.P.A.
,
Kim
,
B.Y.S.
and
Trounson
,
A.
(
2018
)
Design preclinical studies for reproducibility
.
Nat. Biomed. Eng.
2
,
789
790
126
Harding
,
J.
,
Roberts
,
R.M.
and
Mirochnitchenko
,
O.
(
2013
)
Large animal models for stem cell therapy
.
Stem Cell Res. Ther.
4
,
23
127
Turner
,
C.G.
,
Klein
,
J.D.
,
Steigman
,
S.A.
,
Armant
,
M.
,
Nicksa
,
G.A.
,
Zurakowski
,
D.
et al (
2011
)
Preclinical regulatory validation of an engineered diaphragmatic tendon made with amniotic mesenchymal stem cells
.
J. Pediatr. Surg.
46
,
57
61
128
Epstein
,
S.E.
,
Luger
,
D.
and
Lipinski
,
M.J.
(
2017
)
Large animal model efficacy testing Is needed prior to launch of a stem cell clinical trial: An evidence-Lacking conclusion based on conjecture
.
Circ. Res.
121
,
496
498
129
Ud-Din
,
S.
and
Bayat
,
A.
(
2017
)
Non-animal models of wound healing in cutaneous repair: In silico, in vitro, ex vivo, and in vivo models of wounds and scars in human skin
.
Wound Repair Regen.
25
,
164
176
130
Petrovova
,
E.
,
Giretova
,
M.
,
Kvasilova
,
A.
,
Benada
,
O.
,
Danko
,
J.
,
Medvecky
,
L.
et al (
2019
)
Preclinical alternative model for analysis of porous scaffold biocompatibility in bone tissue engineering
.
ALTEX
36
,
121
130
131
Liguori
,
G.R.
,
Jeronimus
,
B.F.
,
de Aquinas Liguori
,
T.T.
,
Moreira
,
L.F.P.
and
Harmsen
,
M.C.
(
2017
)
Ethical issues in the Use of animal models for tissue engineering: Reflections on legal aspects, moral theory. three Rs strategies, and harm–Benefit analysis
.
Tissue Eng. Part C Methods
23
,
850
862
132
Frey-Vasconcells
,
J.
,
Whittlesey
,
K.J.
,
Baum
,
E.
and
Feigal
,
E.G.
(
2012
)
Translation of stem cell research: points to consider in designing preclinical animal studies
.
Stem cells Transl. Med.
1
,
353
358
133
Brennan
,
F.R.
,
Shaw
,
L.
,
Wing
,
M.G.
and
Robinson
,
C.
(
2004
)
Preclinical safety testing of biotechnology- derived pharmaceuticals
.
Mol. Biotechnol.
27
,
59
74
134
Kooijman
,
M.
,
van Meer
,
P.
,
Gispen-de Wied
,
C.
,
Moors
,
E.
,
Hekkert
,
M.
and
Schellekens
,
H.
(
2013
)
The risk-based approach to ATMP development–generally accepted by regulators but infrequently used by companies
.
Regul. Toxicol. Pharmacol.
67
,
221
225
135
Wallenborn
,
M.
,
Petters
,
O.
,
Rudolf
,
D.
,
Hantmann
,
H.
,
Richter
,
M.
,
Ahnert
,
P.
et al (
2018
)
Comprehensive high-resolution genomic profiling and cytogenetics of human chondrocyte cultures by GTG-banding, locus-specific FISH, SKY and SNP array
.
Eur. Cell Mater.
35
,
225
241
136
Ankrum
,
J.
and
Karp
,
J.M.
(
2010
)
Mesenchymal stem cell therapy: Two steps forward, one step back
.
Trends Mol. Med.
16
,
203
209
137
Barkholt
,
L.
,
Flory
,
E.
,
Jekerle
,
V.
,
Lucas-Samuel
,
S.
,
Ahnert
,
P.
,
Bisset
,
L.
et al (
2013
)
Risk of tumorigenicity in mesenchymal stromal cell–based therapies—bridging scientific observations and regulatory viewpoints
.
Cytotherapy
15
,
753
759
138
Kolkundkar
,
U.
,
Gottipamula
,
S.
and
Majumdar
,
A.
(
2014
)
Cell therapy manufacturing and quality control: current process and regulatory challenges
.
J. Stem Cell Res. Ther.
4
,
2
139
Hourd
,
P.
,
Ginty
,
P.
,
Chandra
,
A.
and
Williams
,
D.J.
(
2014
)
Manufacturing models permitting roll out/scale out of clinically led autologous cell therapies: regulatory and scientific challenges for comparability
.
Cytotherapy
16
,
1033
1047
140
Dietz
,
A.B.
,
Padley
,
D.
and
Gastineau
,
D.
(
2007
)
Infrastructure development for human cell therapy translation
.
Clin. Pharmacol. Ther.
82
,
320
324
141
Fekete
,
N.
,
Béland
,
A.V.
,
Campbell
,
K.
,
Clark
,
S.L.
and
Hoesli
,
C.A.
(
2018
)
Bags versus flasks: a comparison of cell culture systems for the production of dendritic cell–based immunotherapies
.
Transfusion
58
,
1800
1813
142
Cell and gene therapy GMP manufacturing in the UK: Capability and capacity analysis. (2019) Cell and Gene Therapy Catapult. Available from: https://ct.catapult.org.uk/sites/default/files/publication/2019%20GMP%20Manufacturing%20Report_v6_0.pdf
143
Sensebé
,
L.
,
Gadelorge
,
M.
and
Fleury-Cappellesso
,
S.
(
2013
)
Production of mesenchymal stromal/stem cells according to good manufacturing practices: a review
.
Stem Cell Res. Ther.
4
,
66
144
Karnieli
,
O.
,
Friedner
,
O.M.
,
Allickson
,
J.G.
,
Zhang
,
N.
,
Jung
,
S.
,
Fiorentini
,
D.
et al (
2017
)
A consensus introduction to serum replacements and serum-free media for cellular therapies
.
Cytotherapy
19
,
155
169
145
Heathman
,
T.R.
,
Stolzing
,
A.
,
Fabian
,
C.
,
Rafiq
,
Q.A.
,
Coopman
,
K.
,
Nienow
,
A.W.
et al (
2015
)
Serum- free process development: improving the yield and consistency of human mesenchymal stromal cell production
.
Cytotherapy
17
,
1524
1535
146
Ährlund-Richter
,
L.
,
De Luca
,
M.
,
Marshak
,
D.R.
,
Munsie
,
M.
,
Veiga
,
A.
and
Rao
,
M.
(
2009
)
Isolation and production of cells suitable for human therapy: challenges ahead
.
Cell Stem Cell
4
,
20
26
147
Kirouac
,
D.C.
and
Zandstra
,
P.W.
(
2008
)
The systematic production of cells for cell therapies
.
Cell Stem Cell
3
,
369
381
148
Badoer,
C.
,
Bastianelli,
E.
and
Pesesse,
X.
(
2016
)
Mesenchymal stem cells and bone-forming cells: U.S. Patent No. 9,371,515, U.S. Patent and Trademark Office, Washington, DC, USA, Available from: https://patents.google.com/patent/US9371515B2/en
149
Bandeiras
,
C.
,
Cabral
,
J.M.S.
,
Gabbay
,
R.A.
,
Finkelstein
,
S.N.
and
Ferreira
,
F.C.
(
2019
)
Bringing stem cell- based therapies for type 1 diabetes to the clinic: early insights from bioprocess economics and cost-effectiveness analysis
.
Biotechnol. J.
14
,
1800563
150
Marinkovic
,
M.
,
Dean
,
D.D.
and
Chen
,
X.-D.
(
2019
) Maintenance and culture of MSCs. In
A Roadmap to Non-Hematopoietic Stem Cell-Based Therapeutics
, (Chen, X.-D., ed.), pp.
39
61
,
Academic Press
,
Massachusetts, USA
.
151
Robb
,
K.P.
,
Fitzgerald
,
J.C.
,
Barry
,
F.
and
Viswanathan
,
S.
(
2019
)
Mesenchymal stromal cell therapy: progress in manufacturing and assessments of potency
.
Cytotherapy
21
,
289
306
152
Couto
,
P.S.
,
Bersenev
,
A.
and
Rafiq
,
Q.A.
(
2020
)
Process development and manufacturing approaches for mesenchymal stem cell therapies
. In
Engineering Strategies for Regenerative Medicine
, (Fernandes, T.G., Diogo, M.M. and Cabral, J.M.S., eds) pp.
33
-
71
,
Academic Press
,
Massachusetts, USA
.
153
Moutsatsou
,
P.
,
Ochs
,
J.
,
Schmitt
,
R.
,
Hewitt
,
C.
and
Hanga
,
M.
(
2019
)
Automation in cell and gene therapy manufacturing: from past to future
.
Biotechnol. Lett.
41
,
1245
1253
154
Mennan
,
C.
,
Garcia
,
J.
,
Roberts
,
S.
,
Hulme
,
C.
and
Wright
,
K.
(
2019
)
A comprehensive characterisation of large-scale expanded human bone marrow and umbilical cord mesenchymal stem cells
.
Stem Cell Res. Ther.
10
,
99
155
Kalra
,
K.
,
Banerjee
,
B.
,
Weiss
,
K.
and
Morgan
,
C.
(
2019
)
Developing efficient bioreactor microcarrier cell culture system for large scale production of mesenchymal stem cells (MSCs)
.
Cytotherapy
21
,
S73
156
Rafiq
,
Q.A.
,
Coopman
,
K.
and
Hewitt
,
C.J.
(
2013
)
Scale-up of human mesenchymal stem cell culture: current technologies and future challenges
.
Curr. Opin. Chem. Eng.
2
,
8
16
157
Heathman
,
T.R.
,
Nienow
,
A.W.
,
Rafiq
,
Q.A.
,
Coopman
,
K.
,
Kara
,
B.
and
Hewitt
,
C.J.
(
2018
)
Agitation and aeration of stirred-bioreactors for the microcarrier culture of human mesenchymal stem cells and potential implications for large-scale bioprocess development
.
Biochem. Eng. J.
136
,
9
17
158
Heathman
,
T.R.
,
Nienow
,
A.W.
,
Rafiq
,
Q.A.
,
Coopman
,
K.
,
Kara
,
B.
and
Hewitt
,
C.J.
(
2019
)
Development of a process control strategy for the serum-free microcarrier expansion of human mesenchymal stem cells towards cost-effective and commercially viable manufacturing
.
Biochem. Eng. J.
141
,
200
209
159
Moreira
,
F.
,
Mizukami
,
A.
,
de Souza
,
L.E.B.
,
Cabral
,
J.
,
da Silva
,
C.L.
,
Covas
,
D.T.
et al (
2020
)
Successful Use of human AB serum to support the expansion of adipose tissue-Derived mesenchymal stem/Stromal cell in a microcarrier-Based platform
.
Front. Bioeng. Biotechnol.
8
,
307
160
Hewitt,
C.J
,
P. Hanga
,
M.P.
,
Moutsatsou
,
P.
,
Ratnayake
,
S.
,
Nienow
,
A.W
and
Rafiq
,
Q.A
. (
2019
)
Isolation and expansion of human bone marrow-derived mesenchymal stem cells (hMSCs) directly on microcarriers in a stirred tank bioreactor. In Advancing Manufacture of Cell and Gene Therapies VI (Baksh, D., Rietze, R. and Wall, I., eds) ECI Symposium Series, UK. https://dc.engconfintl.org/cell_gene_therapies_vi/43
161
Cunha
,
B.
,
Aguiar
,
T.
,
Carvalho
,
S.B.
,
Silva
,
M.M.
,
Gomes
,
R.A.
,
Carrondo
,
M.J.
et al (
2017
)
Bioprocess integration for human mesenchymal stem cells: from up to downstream processing scale-up to cell proteome characterization
.
J. Biotechnol.
248
,
87
98
162
Hasan
,
J.
,
Bell
,
M.
,
Kushinga
,
G.
,
Nicholas
,
N.
,
Delahaye
,
M.
,
Kerby
,
J.
et al (
2017
)
A semi-automated cost-efficient process for the closed expansion and harvest of pluripotent stem cells using a hollow fibre bioreactor and continuous centrifugation
.
Cytotherapy
19
,
S158
163
Jones,
N.
and
Hsiao,
T.
(
2016
)
Single-step flask to 250 L cell culture with a hybrid mixing single-use bioreactor. In Cell Culture Engineering XV (Kiss, R., Harcum, S. and Chalmers, J., eds) ECI Symposium Series, California, USA. http://dc.engconfintl.org/cellculture_xv/151
164
Junne
,
S.
and
Neubauer
,
P.
(
2018
)
How scalable and suitable are single-use bioreactors?
Curr. Opin. Biotechnol.
53
,
240
247
165
Luciani
,
N.
,
Du
,
V.
,
Gazeau
,
F.
,
Richert
,
A.
,
Letourneur
,
D.
,
Le Visage
,
C.
et al (
2016
)
Successful chondrogenesis within scaffolds, using magnetic stem cell confinement and bioreactor maturation
.
Acta Biomater.
37
,
101
110
166
Doolin
,
M.T.
,
Ornstein
,
T.S.
and
Stroka
,
K.M.
(
2019
)
Nuclear deformation in response to mechanical confinement is cell type dependent
.
Cells
8
,
427
167
Au-yeung
,
K.L.
,
Sze
,
K.Y.
,
Sham
,
M.H.
and
Chan
,
B.P.
(
2010
)
Development of a micromanipulator-based loading device for mechanoregulation study of human mesenchymal stem cells in three- dimensional collagen constructs
.
Tissue Eng. Part C Methods
16
,
93
107
168
Taylor
,
N.P.
(
2018
)
Bone Therapeutics’ cell therapy hits goal in phase 1/2a, but manufacturing changes slow progress, Fierce Biotech, Massachusetts, USA. Available from: https://www.fiercebiotech.com/biotech/bone-therapeutics-cell-therapy-hits-goal-phase-1-2a-but-manufacturing-changes-slow-progress
169
Fontaine
,
N.
and
Reynders
,
D.
(
2001
)
Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the community code relating to medicinal products for human use
.
Off. J. Eur. Communities
2001
,
67
128
170
REGULATION (EC) No 1394/2007 OF THE EUROPEAN PARLIAMENT: Official Journal of the European Union; 2007 Available from:
https://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2007:324:0121:0137:en:PDF
171
Pariser
,
A.R.
,
Xu
,
K.
,
Milto
,
J.
and
Cote
,
T.R.
(
2011
)
Regulatory considerations for developing drugs for rare diseases: orphan designations and early phase clinical trials
.
Discov. Med.
11
,
367
375
172
Farkas
,
A.M.
,
Mariz
,
S.
,
Stoyanova-Beninska
,
V.
,
Celis
,
P.
,
Vamvakas
,
S.
,
Larsson
,
K.
et al (
2017
)
Advanced therapy medicinal products for rare diseases: state of play of incentives supporting development in Europe
.
Front. Med.
4
,
53
173
Vaggelas
,
A.
and
Seimetz
,
D.
(
2019
)
Expediting drug development: FDA's New regenerative medicine advanced therapy designation
.
Ther. Innov. Regul. Sci.
53
,
364
373
174
Gilbert
,
F.
,
O'Connell
,
C.D.
,
Mladenovska
,
T.
and
Dodds
,
S.
(
2018
)
Print me an organ? Ethical and regulatory issues emerging from 3D bioprinting in medicine
.
Sci. Eng. Ethics
24
,
73
91
175
Hourd
,
P.
,
Medcalf
,
N.
,
Segal
,
J.
and
Williams
,
D.J.
(
2015
)
A 3D bioprinting exemplar of the consequences of the regulatory requirements on customized processes
.
Regen. Med.
10
,
863
883

Author notes

*

Matthew Dalby is the recipient of the Biochemical Society's 2020 Industry and Academic Collaboration Award.

This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY).