MSC-based clinical trials for OA management.
Abstract
Osteoarthritis (OA), a principal and challenging disorder of articular cartilage, has been regarded as the most frequent and prevalent chronic disease of degenerative joints, which is caused by multiple factors including aging, trauma, overweight, joint deformity and congenital abnormality, together with the increase in life expectancy. In spite of considerable improvements that have been obtained by conducting multidisciplinary therapies such as surgical procedures and anti-inflammatory drugs, the pathogenesis and efficacy of OA with functional losses and degeneration are still elusively complicated for ascertainment. Mesenchymal stem/stromal cells (MSCs), also termed as multipotent mesenchymal progenitor/precursor cells, skeletal stem cells, or medicinal signaling cells, are heterogeneous cell populations with hematopoietic-supporting and immunomodulatory properties, together with multilineage differentiation property. For decades, investigators have illuminated the application of the advantaged and promising sources with/without remarkable biomaterials for the treatment of recurrent and refractory disorders including OA. In this chapter, we mainly concentrate on the current progress of MSC-based cytotherapy in both preclinical study and clinical practice as well as the promising prospective and critical challenges in the field, which will conformably benefit the administration of OA in future.
Keywords
- osteoarthritis
- mesenchymal stem cells
- cytotherapy
- biomaterials
- tissue engineering
1. Introduction
Osteoarthritis (OA) is a whole organ disease characterized by the destruction or degeneration of articular cartilage, which is one of the most widespread and frequent chronic diseases and public health issues worldwide [1, 2]. During the course of OA, inflammatory response is a pivotal factor resulting in cartilage destruction or exacerbation of symptoms [2, 3, 4]. As satisfactory osteochondral repair, it’s of great importance for the zonal restoration of adjacent cartilage and the subchondral bone [5]. For the past decades, despite the significant number of progress have been achieved by multidisciplinary strategies such as surgeries (e.g., microfracture, mosaicplasty), autologous chondrocyte implantation (ACI), joint lubricants (e.g., hyaluronic acid), antiinflammatory drugs (e.g., NSAIDs) as well as cytotherapies (e.g., autologous chondrocyte implantation), the inherent limitations of regeneration and self-repair capacity in OA individuals still largely hinder the remission of the degeneration of articular cartilage [4, 6, 7, 8]. For example, even though joint replacement serves as an effective remedy for symptomatic end-stage disease including OA, most of the functional outcomes in patients are unsatisfactory and the lifespan of prosthesis is also largely limited [2, 9]. Distinguishing from the traditional remedies, cell-based strategies have emerged as an alternative with promising prospective in the treatment of OA and cartilage defects [10, 11].
State-of-the-art updates have turned to MSC-based cytotherapy for OA management both clinically and preclinically [5, 12]. The multifaceted superiorities of MSCs including multidirectional differentiation, high portability property, and low immunogenicity have made themselves ideal seed cells for OA treatment [3]. Meanwhile, MSCs or the derivatives are often encapsulated into natural or synthetic hydrogels, which can function by providing tunable biodegradability, and biocompatibility or enhancing cell vitality and functionality [10].
Herein, we mainly focus on the recent literatures relating to the application of MSCs for OA treatment based on the chondrogenic differentiation, and antiinflammatory and immunomodulatory effects of MSCs with or without biological scaffolds for cartilage regeneration. Meanwhile, we further discuss the promising prospective and formidable challenges of MSC-based cytotherapy in cartilage repair and regeneration as well.
2. MSCs and derivatives
MSCs are cell populations with unique immune-privileged and hematopoietic properties, which are capable of differentiating into a variety of functional cells such as adipocytes, osteoblasts and chondrocytes, which thus have garnered increased interest for clinical translation in the last few decades [13, 14]. Therewith, MSCs have been considered as the uppermost components in the bone marrow microenvironment as well as splendid sources for regenerative medicine [15, 16]. Not until the year of 2006, International Society for Cellular Therapy (ISCT) released the basic criteria for MSC definition including spindle-shaped morphology, high expression of mesenchymal-associated biomarkers (CD73, CD90, CD105) whereas minimal expression of hematopoietic-associated biomarkers (CD31, CD34, CD45),
Since the 1970s, MSCs have been isolated from various adult tissues including bone marrow, adipose tissues, synovial fluid, periosteum and dental tissues (e.g., dental pulp, periodontium) [18, 19, 20]. After that, perinatal or fetal tissues including umbilical cord, placenta, amniotic member and amniotic fluid have also been reported for MSC isolation [21]. Distinguish from those derived from adult tissues, MSCs isolated from the “discarded” perinatal tissues have been considered with preferable immunoregulatory properties and long-term
For decades, the derivatives generated from MSCs such as exosomes and relative microvesicles have been extensively investigated and regarded as the dominating factor during pathogenesis and disease treatment [20, 33]. Exosomes, also known as small extracellular vesicles (sEVs) or biological spherical lipid bilayer vesicles, are nano-sized extracellular vesicles secreted by various types of cells (e.g., MSCs, natural killer cells, T or B lymphocytes, epithelial cells, macrophages, dendritic cells, tumor cells) with partial sizes ranging from 20 to 200 nm according to the Minimal Information for Studies of Extracellular Vesicles 2018 (MISEV 2018) guidelines [34, 35, 36]. The plasma membrane-derived vesicles contain lipids, proteins (e.g., CD9, CD63, CD81, GTPases, HSP70, HSP90, Tsg101, Alix), nucleic acids (e.g., microRNAs, LncRNAs, mRNAs), and other bioactive substances, which thus play an important role in various physiological and pathological processes, and in particular, serving as intermediators for material exchange and intercellular communication via delivering a variety of the aforementioned bioactive substances [37, 38]. Numerous preclinical and clinical investigations including the International Society for Extracellular Vesicles (ISEV) have shown that MSC-derived extracellular vesicles (EVs) including exosomes and microvesicles (MV) are rich in growth factors, cytokines, mRNAs, signaling lipids and regulatory miRNAs, which are adequate to influence intercellular neighbors and tissue responses to infections, injuries, and diseases [39, 40]. However, the concomitant shortcomings of exosomes such as low purity, low yield, stability for storage and weak targeting collectively limit their preclinical investigation and clinical application. Therefore, there’s still a long way to optimize the aforementioned problems and facilitate further exploration upon large-scale preparation (e.g., ultracentrifugation techniques, polymer precipitation, size-based isolation techniques, immunoaffinity chromatography, micro-vortex chips, commercial isolation kits) for translational purposes [41, 42, 43].
3. Biomaterials/MSC-based composites for osteoarthritis management
Biomaterials of different categories and characteristics have attracted great concerns of investigators in the field of MSC-based regenerative medicine, and thus allow the utilization of unique scaffolds to promote the expansion of MSCs and facilitate their differentiation into appropriate lineages [24, 44]. Biomaterials with highly biocompatible properties are adequate to act as splendid scaffolds for cell attachment and supply preferable microenvironment for the maintenance, differentiation, and biofunction of the encapsulated MSCs, which collectively benefit the
3.1 Hydrogel/MSC-based scaffolds for OA management
Hydrogels are splendid biomaterials with unique physical and chemical properties for both soft and hard tissue engineering and regenerative medicine, which largely attributes to the feasibility of orchestrating the critical properties (e.g., elasticity, water content, bioactivity, mechanical stiffness, degradation) rationally and conveniently [48, 49, 50]. For decades, hydrogels alone or in combination with appropriate biomaterials have been extensively investigated in various osteoarticular disorders such as OA and meniscus injury [51, 52, 53]. For example, our groups recently reported the reinforced efficacy upon OA rabbits by hyaluronic acid (HA) hydrogel and PSC-MSCs composite (HA/PSC-MSCs) compared to those with HA hydrogel or PSC-MSCs alone [24]. Instead, Chung and colleagues systematically compared the efficacy by implanting various hydrogels/UC-MSCs composites in rats such as alginate, chitosan, pluronic, hyaluronic acid (HA), and verified that HA/hUC-MSCs composites rather than relative hydrogels resulted in preferable cartilage repair and achieved collagen organization pattern and cellular arrangements much similar to the adjacent uninjured articular cartilage [54].
Recently, Yang and colleagues further reported the utilization of an injectable and biocompatible Diels-Alder crosslinked hyaluronic acid/PEG (DAHP) hydrogel for OA treatment, which was found with considerable improvement by controlling the release of MSC-derived small extracellular vesicles (MSC-sEVs) [55]. Similarly, Heirani-Tabasi et al. confirmed the enhanced chondrogenic differentiation capacity of adipose-derived MSCs (AD-MSCs) after incubation with an injectable chitosan-hyaluronic acid (CS-HA) hydrogel [56]. Additionally, Tang et al. demonstrated that sEVs derived from umbilical cord MSCs (UC-MSC-sEVs) revealed comparable therapeutic effects for OA but with upregulated proteins mostly involved in extracellular matrix (ECM) organization, immune effector process, PI3K-AKT and Rap1 signaling pathways [57]. Collectively, MSCs or derivatives (e.g., exosomes, sEVs) in combination with injectable hydrogels have attracted considerable attention in OA management for their advantaged chondrogenic differentiation capacity [51, 56, 58].
3.2 Hydroxyapatite (HAP)/MSCs scaffolds for OA management
State-of-the-art renewals have also highlighted the combination of HAP-based biomaterials with MSCs for OA administration and bone regeneration. For instance, Ji and colleagues recently took advantage of a novel hybrid scaffold composed of nano-hydroxyapatite (nHA)/poly ε-caprolactone (PCL) and thermosensitive hydroxypropyl chitin hydrogel (HPCH) for bone defect repair via a mechanism of enhancing vascularization and osteogenesis of encapsulated MSCs [59].
Instead, Shimomura et al. took advantage of a scaffold-free tissue-engineered construct (TEC) and a HAP artificial bone for the treatment of a rabbit osteochondral defect model, and found that osteochondral defects treated with the synovial MSC-derived TEC and HAP composite revealed more rapid and efficient subchondral bone repair coupled with cartilaginous tissues as well as good tissue integration to adjacent host cartilage. Moreover, the combined MSC-based implants significantly accelerated postoperative rehabilitation and sustained the longer-term durability of repaired osteochondral lesions in patients with OA [5]. Similarly, with the aid of bone marrow-derived MSCs (BM-MSCs) and an interconnected porous hydroxyapatite ceramic (IP-CHA), the large osteochondral defect of the knee in a 21-year-old man was effectively alleviated, and cartilage-like regeneration and bone formation were observed as well [12]. Additionally, we recently also reported the preferable outcomes of OA by conducting multidimensional optimization of MSC-based formulation in combination with the advantageous HA/PG biomaterials, which showed evaluated therapeutic efficacy over HA alone in ameliorating osteoarthritis progression [60, 61].
4. Molecular mechanism of MSC-based cytotherapy for OA management
Generally, MSCs function mainly via orchestrating a series of mode of action including compositional microenvironment, immunoregulation, autocrine, paracrine, and direct- or trans-differentiation into functional cells [15, 62, 63]. In particular, the unique immunomodulatory property and paracrine manner have prompted the enthusiasm for allogenic transplantation of the “off-the-shelf” MSC products in both preclinical and clinical practices in the field of regenerative medicine.
4.1 Compositional microenvironment
In the bone marrow microenvironment, MSCs function as dominating component and stromal cells for the homeostasis and regeneration of hematopoietic stem cells (HSCs) and the concomitant derived cells [30, 64, 65]. In the context of physiological hematogenesis, MSCs are competent for the maintenance or replenishment of the stem cell pool in damaged tissues, and thus help reconstruct the microenvironment for the subsequent hematopoietic reconstitution [22, 30]. As to OA, by conducting MSC infusion into the articular cavity, the hyperactivated inflammatory response caused by inflammatory cytokines is supposed to be effectively suppressed by the released anti-inflammatory factors, extracellular organelles, and vesicles in the microenvironment [24, 66]. As to OA, the roles of MSCs are to orchestrate the spatiotemporal balance between the inflammation and cartilage tissue reconstruction via providing the damaged tissues including bone tissue and cartilage tissue with a relatively desirable environment for tissue repair [24, 67].
4.2 Immunomodulatory effect
To date, extensive literatures have demonstrated the therapeutic or ameliorative effects of MSCs on refractory and recurrent diseases via a bidirectional immunomodulatory approach [14, 25]. Notably, a variety of antiinflammatory factors and cytokines have been reported to play a pivotal role during inflammatory reactions such as interleukins (e.g., IL-6, IL-8, IL-10), transforming growth factor (TGF), stromal cell-derived factor 1 (SDF-1), and vascular endothelial growth factor (VEGF) [22, 68, 69]. The underlying molecular mechanism lies in the sensitive response of MSCs toward the concentration gradient of inflammatory cytokines and chemokines [70]. As to OA, low-grade inflammation has been demonstrated critically in the pathogenesis, which therefore hinders the deposition of cartilage matrix at the damaged sites, delays the proliferation of osteoblast and chondrocytes, and thus resulting in low efficiency of articular cartilage repair [71, 72]. Currently, various kinds of immune cells have been observed in the synovium of OA, including the classically activated and proinflammatory macrophages (M1Mφ), antiinflammatory macrophages (M2Mφ), and T cells. For example, as the major counterparts of immune cells in the joints, Mφ can be hyperactivated by proinflammatory factors in OA patients such as tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and even the pathogen-associated molecular patterns [73]. Therefore, the efficient treatment of OA should also pay close attention to the regulation of the local inflammatory microenvironment. As mentioned above, MSC with multilineage differentiation potential and effective immunomodulatory properties have been supposed as an alternative remedy in the administration of cartilage degradation [74]. In detail, MSCs are purposefully recruited to the site of the damaged cartilage and initiate the therapeutic effects upon osteochondral defects, and thus accelerating the reconstruction of articular surface in OA patients [70]. MSCs have been demonstrated involved in the regulation of M1Mφ towards M2Mφ via releasing growth and angiogenic factors as well as down-regulating inflammation and accelerating the remodeling of damaged tissue in OA. Additionally, the immunoregulatory effect of MSCs or MSC-derived EVs upon T cell subsets has also been extensively and in-detail described during the Th1/Th2 cell transformation, Th17 cell and Treg cell generation, and the apoptosis of hyperactivated T cells [75, 76, 77, 78, 79]. Similarly, state-of-the-art renewal has also indicated the immunomodulatory effect of MSCs upon CD24+CD38+ B cells partially via soluble secreted factors. Interestingly, the role of MSC-derived EVs in mediating B-cell immunoregulation merit seems contradictory and still needs further investigation [67, 80].
4.3 Autocrine and paracrine
Autocrine and paracrine play a critical role in intercellular communications among MSCs and the adjacent osteochondral defects, which are at the cornerstone of regenerative medicine for MSC-based cytotherapy [81, 82]. The secreted substances such as cytokines and anti-inflammatory factors are responsible for the majority of the ascribed bioremediation via promoting the survival and proliferation of adjacent damaged cells and tissues. For example, mediators (e.g., VEGF, bFGF, IL-6, IL-8) in the conditioned media have been considered to play an important role in influencing the differentiation capacity of MSCs or cocultured cells through an autocrine loop [22, 23, 83]. Interestingly, Lee and colleagues have demonstrated that MSC-secreted PGE-2 plays a key role in the maintenance of self-renewal via EP2 receptor [84].
Of the indicated mode of action, the paracrine phenomenon has been widely recognized as the main benefit of MSC therapy based on the secreted factors acting on MSCs and the neighboring cells. Up to now, a variety of key factors have been isolated and verified including SDF-1, TGF, VEGF, prostaglandin E2 (PGE2), hepatocyte growth factor (HGF), and granulocyte-macrophage colony-stimulating factor (GM-CSF), and the diversity in the constitutive secretome has also been put forward by pioneering investigators in the field [23, 84, 85, 86]. As to OA, MSC-derived exosomes or sEVs are supposed to effectively avoid the inherent risks of MSCs and thus hold rosy prospects in clinical applications [87, 88]. However, the inherent disadvantages such as low efficacy in preparations, rapid degradation and clearance still need sustained efforts for further improvement [33, 80].
4.4 Direct- or trans-differentiation
For the past decades, the differentiation potential including direct-differentiation and tans-differentiation has been recognized as the key avenue for MSC-based repair [81]. Of note, the differentiation of MSCs into osteoblasts and chondrocytes has been extensively reported as achievable according to the ISCT guidelines [17]. However, current updates in the field indicate that it is likely that paracrine rather than the direct-differentiation or trans-differentiation play a core role in cartilage repair of OA after MSC delivery because intrathecal injection has presented limited MSC retention and engraftment. For example, aw we previously reviewed, initial attempts upon the molecular mechanisms for disease treatment with MSC transplantation focused on seeking direct evidence for generating functional cells during the rehabilitation of damaged tissues, whereas it was found to be difficult by most investigators when considering the insufficiency of effective retention rate (<5%) [89]. Instead, based on the unique homing property, MSCs mainly migrate to the damaged tissues and perform the restorative function through an orchestration of modulation, which is further verified with the aid of fluorescence
5. Clinical trials of MSC-based cytotherapy for OA management
In recent years, MSC-based cytotherapy has also aroused the intense interest of clinicians in OA treatment. According to the Clinicaltrials.gov database, a total number of 128 clinical trials have been registered worldwide to explore the safety and effectiveness of MSC-based remedies for OA treatment, and in particular, for knee OA and hip OA (Figure 1). Of the aforementioned clinical trials, 22 were respectively registered in China and the United States (USA) and followed by 10 in Korea and 9 in Iran (Table 1). Meanwhile, we noticed that most of the registered clinical trials were in Phase 1 and/or Phase 2 stage(s), and a total number 13 trials were in the Phase 3 stage instead (Table 1). For instance, by conducting a two-year follow-up visit (NCT number: NCT01183728), Orozco and colleagues reported a significant improvement in cartilage quality in 11 of the 12 enrolled knee OA patients with autologous MSC intervention according to the Visual Analogue Scale (VAS) measurements and the pain relief–versus–initial pain score plot [91, 92]. Furthermore, the pain improvement was maintained without significant modifications during the 2-year follow-up, and no serious adverse effects were observed in the aforementioned patients as they previously reported [93].
Rank | NCT No. | Age | Phases | Enrollment | Location |
---|---|---|---|---|---|
1 | NCT05160831 | 18–70 | Not Applicable | 50 | |
2 | NCT03956719 | 15–65 | Not Applicable | 8 | China |
3 | NCT01504464 | 18–65 | Phase 2 | 40 | Iran |
4 | NCT03383081 | ≤70 | Phase 2 | 60 | China |
5 | NCT04351932 | 18–70 | Phase 3 | 54 | Ecuador |
6 | NCT01459640 | 18–70 | Phase 2 | 50 | Malaysia |
7 | NCT03164083 | 25–65 | Phase 2 | 0 | Iran |
8 | NCT04130100 | 40–70 | Early Phase 1 | 60 | China |
9 | NCT03800810 | 30–80 | Early Phase 1 | 9 | Indonesia |
10 | NCT01809769 | 40–70 | Phase 1, Phase 2 | 18 | China |
11 | NCT01207661 | 18–65 | Phase 1 | 6 | Iran |
12 | NCT01499056 | 18–65 | Phase 1 | 6 | Iran |
13 | NCT02544802 | 50–70 | Phase 1 | 4 | China |
14 | NCT03357575 | 18–75 | Not Applicable | 14 | |
15 | NCT02237846 | 18–80 | Phase 1, Phase 2 | 0 | Panama |
16 | NCT03166865 | 30–70 | Phase 1, Phase 2 | 60 | China |
17 | NCT04208646 | 40–75 | Phase 2 | 108 | China |
18 | NCT02963727 | 42–75 | Phase 1 | 10 | Jordan |
19 | NCT03869229 | 30–75 | Phase 1, Phase 2 | 100 | Poland |
20 | NCT02966951 | 42–75 | Phase 1 | 10 | Jordan |
21 | NCT01586312 | 18–75 | Phase 1, Phase 2 | 30 | Spain |
22 | NCT01985633 | 40–75 | Phase 1, Phase 2 | 24 | India |
23 | NCT02641860 | 18–70 | Phase 1 | 22 | China |
24 | NCT01183728 | 18–76 | Phase 1, Phase 2 | 12 | Spain |
25 | NCT03969680 | 40–70 | Not Applicable | 60 | China |
26 | NCT04212728 | 40–70 | Not Applicable | 60 | China |
27 | NCT04326985 | 18–65 | Early Phase 1 | 20 | China |
28 | NCT01453738 | 40–70 | Phase 2 | 60 | India |
29 | NCT02123368 | 50–80 | Phase 1, Phase 2 | 30 | Spain |
30 | NCT03602872 | 35–65 | Phase 1 | 0 | Mexico |
31 | NCT02365142 | 40–80 | Phase 1, Phase 2 | 38 | Spain |
32 | NCT03358654 | 18–75 | Not Applicable | 9 | |
33 | NCT01448434 | 20–70 | Phase 2 | 72 | Malaysia |
34 | NCT01895413 | 25–65 | Phase 1, Phase 2 | 10 | Brazil |
35 | NCT01436058 | 18–65 | Phase 1 | 6 | Iran |
36 | NCT02162693 | 18–70 | Phase 2 | 53 | China |
37 | NCT03866330 | 30–75 | Phase 1, Phase 2 | 100 | Poland |
38 | NCT03477942 | 18–60 | Phase 1 | 16 | USA |
39 | NCT02003131 | 18–80 | Phase 1, Phase 2 | 0 | Panama |
40 | NCT04368806 | ≥18 | Phase 2, Phase 3 | 140 | USA |
41 | NCT04448106 | ≥18 | Phase 2 | 300 | USA |
42 | NCT02958267 | 40–70 | Phase 2 | 32 | USA |
43 | NCT05288725 | 18–80 | Phase 1, Phase 2 | 120 | USA |
44 | NCT04863183 | 30–75 | Phase 1, Phase 2 | 30 | |
45 | NCT05147675 | Phase 1 | 20 | Antigua and Barbuda | |
46 | NCT04893174 | 40–90 | Phase 1 | 6 | China |
47 | NCT00850187 | 45–60 | Phase 1 | 6 | Iran |
48 | NCT04520945 | 30–70 | Phase 2 | 100 | Malaysia |
49 | NCT04314661 | 55–70 | Phase 1, Phase 2 | 15 | Indonesia |
50 | NCT01300598 | 18–75 | Phase 1, Phase 2 | 18 | Korea |
51 | NCT02776943 | 18–70 | Phase 1, Phase 2 | 20 | |
52 | NCT05016011 | 18–65 | Phase 2 | 50 | Malaysia |
53 | NCT03357770 | 18–75 | Not Applicable | 9 | |
54 | NCT03589287 | ≥40 | Phase 1, Phase 2 | 18 | China |
55 | NCT05349565 | 41–70 | Not Applicable | 26 | Pakistan |
56 | NCT01873625 | 10–65 | Phase 2, Phase 3 | 60 | Iran |
57 | NCT05086939 | 18–75 | Phase 3 | 120 | Spain |
58 | NCT04240873 | 20–80 | Phase 1, Phase 2 | 24 | Korea |
59 | NCT02291926 | 18–75 | Phase 1 | 20 | China |
60 | NCT03818737 | 40–70 | Phase 3 | 480 | USA |
61 | NCT05027581 | 40–80 | Phase 2 | 70 | China |
62 | NCT02118519 | 40–68 | Phase 2 | 13 | Jordan |
63 | NCT03955497 | 18–70 | Phase 1, Phase 2 | 30 | China |
64 | NCT01879046 | ≥18 | Not Applicable | 35 | France |
65 | NCT03990805 | 20–100 | Phase 3 | 260 | Korea |
66 | NCT03000712 | 20–80 | Not Applicable | 26 | Korea |
67 | NCT03509025 | ≥18 | Phase 2 | 11 | Korea |
68 | NCT03014037 | 18–70 | Not Applicable | 35 | USA |
69 | NCT03337243 | 50–85 | Not Applicable | 60 | USA |
70 | NCT02855073 | 18–70 | Phase 2 | 28 | China |
71 | NCT04037345 | ≥19 | Phase 1 | 12 | Korea |
72 | NCT05344157 | 40–75 | Phase 1, Phase 2 | 54 | Australia |
73 | NCT05182034 | ≥19 | Phase 2 | 90 | |
74 | NCT02674399 | 22–60 | Phase 2 | 28 | USA |
75 | NCT00891501 | 15–55 | Phase 2, Phase 3 | 25 | Egypt |
76 | NCT03028428 | 40–75 | Phase 2 | 1 | |
77 | NCT03943576 | 40–80 | Phase 1, Phase 2 | 30 | China |
78 | NCT04339504 | ≥19 | Phase 1 | 12 | Korea |
79 | NCT03648463 | Not Applicable | 20 | ||
80 | NCT01159899 | 30–75 | Early Phase 1 | 50 | France |
81 | NCT04427930 | ≥20 | Phase 3 | 260 | Korea |
82 | NCT04825730 | ≥20 | Not Applicable | 14 | |
83 | NCT02468492 | ≥40 | Early Phase 1 | 18 | USA |
84 | NCT05280002 | 40–80 | Phase 2 | 30 | Bangladesh |
85 | NCT00557635 | 18–65 | Phase 2 | 50 | |
86 | NCT01931007 | 18–99 | Phase 1 | 25 | USA |
87 | NCT01041001 | ≥18 | Phase 3 | 104 | Korea |
88 | NCT03308006 | 45–65 | Phase 2 | 18 | Saudi Arabia |
89 | NCT02658344 | ≥18 | Phase 2 | 24 | Korea |
90 | NCT03379168 | ≥18 | Not Applicable | 100 | USA |
91 | NCT02696876 | 16–55 | Not Applicable | 20 | United Kingdom |
92 | NCT04230902 | ≥45 | Phase 3 | 48 | Lebanon |
93 | NCT05000593 | 30–75 | Not Applicable | 60 | China |
94 | NCT04604288 | USA | |||
95 | NCT02580695 | 18–70 | Phase 1, Phase 2 | 30 | Chile |
96 | NCT03790189 | 35–75 | Not Applicable | 25 | Italy |
97 | NCT03067870 | 17–75 | Phase 1 | 100 | |
98 | NCT01626677 | ≥18 | Phase 3 | 103 | Korea |
99 | NCT04821102 | ≥20 | Not Applicable | 21 | |
100 | NCT04716803 | 45–75 | Not Applicable | 10 | USA |
101 | NCT01926327 | 18–65 | Phase 3 | 150 | Iran |
102 | NCT04234412 | 30–65 | Not Applicable | 10 | |
103 | NCT03788265 | ≥18 | Not Applicable | 60 | China |
104 | NCT02351011 | 40–65 | Phase 1, Phase 2 | 12 | Canada |
105 | NCT02582489 | ≥18 | Not Applicable | 100 | USA |
106 | NCT01227694 | 18–65 | Phase 1, Phase 2 | 15 | Spain |
107 | NCT04990128 | 18–65 | Phase 3 | 100 | USA |
108 | NCT05276895 | 40–80 | Phase 1, Phase 2 | 60 | |
109 | NCT03048773 | ≥20 | Not Applicable | 40 | China |
110 | NCT02964143 | 50–80 | Not Applicable | 306 | |
111 | NCT04749758 | ≥18 | Not Applicable | 77 | Andorra |
112 | NCT04310852 | 40–70 | 25 | Italy | |
113 | NCT05193877 | 55–85 | Not Applicable | 60 | Iraq |
114 | NCT03410355 | 16–60 | Not Applicable | 6 | Canada |
115 | NCT04453111 | 18–75 | Phase 1, Phase 2 | 45 | Ukraine |
116 | NCT04308213 | 35–75 | Not Applicable | 30 | Italy |
117 | NCT05305833 | 18–65 | Phase 1, Phase 2 | 20 | Turkey |
118 | NCT04043819 | 18–80 | Phase 1 | 125 | USA |
119 | NCT05081921 | 40–70 | Phase 1, Phase 2 | 200 | Poland |
120 | NCT01739504 | 18–80 | Not Applicable | 10 | USA |
121 | NCT01413061 | 18–80 | Not Applicable | 140 | USA |
122 | NCT04222140 | 25–60 | Not Applicable | 40 | USA |
123 | NCT04223622 | ≥18 | 24 | Italy | |
124 | NCT01585857 | 50–75 | Phase 1 | 18 | Germany |
125 | NCT03608579 | 18–65 | Phase 1 | 24 | USA |
126 | NCT02838069 | 45–75 | Phase 2 | 153 | France |
127 | NCT01038596 | 50–90 | 30 | Germany | |
128 | NCT01733186 | ≥18 | Phase 1, Phase 2 | 12 | USA |
6. Conclusions
MSCs and concomitant derivatives have emerged as advantaged and alternative sources for OA administration and cartilage repair. MSC- or MSC-exo/sEVs- laden biomaterial systems have supplied overwhelming new tissue-engineering platforms to sequentially improve the osteochondral interface and alleviate the full-thickness articular cartilage defects, which collectively accelerates the reestablishment of osteochondral and cartilage tissues (Table 2). Of note, injecting MSCs into joints with an inflammatory environment may elevate the risk of ectopic calcification and osteoproliferation in patients with OA. Therefore, systematic and detailed investigations are urgently needed to ensure the maintenance of the intra-articular environment for cartilage repair before large-scale application in clinical practice. In spite of the tremendous progresses in the field of OA management and MSC-based regenerative medicine, it still remains challenging and there’s a long way to go to efficiently and cost-effectively repair the full-thickness articular cartilage defects and osteochondral interface via achieving efficient osteogenesis and chondrogenesis.
Cell type | Stage | Outcome | Ref. |
---|---|---|---|
UC-MSCs | Clinical trials | Safe and superior to active comparator in knee OA | Matas, et al. [94] |
AD-MSC/BM-MSC/UC-MSC/AD-MSCs | Clinical trials | Subjective improvements in knee function and pain reduction | Buzaboon, et al. [95] |
BM-MSCs/S-MSCs/AD-MSCs | Clinical trials | Pain relief and functional improvement | Cui, et al. [96] |
HA hydrogel/ hPSC-MSCs | Preclinical study | Preferable restorative and ameliorative function on OA rabbits | Zhang, et al. [24] |
HA hydrogel/UC-MSCs | Preclinical study | Significant gross and histological improvements in hyaline cartilage regeneration | Wu, et al. [97] |
Hydrogel/MSCs | Preclinical study | The defects significantly better histologic scores with morphologic characteristics of hyaline cartilage | Zscharnack, et al. [98] |
DAHP hydrogel/MSC-sEVs | Preclinical study | Enhanced efficacy for OA improvement | Yang, et al. [55] |
Acknowledgments
The authors would like to thank the members of the Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province & NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu Provincial Hospital, and the Institute of Biology & Hefei Institute of Physical Science, Chinese Academy of Sciences for their kind suggestions. This study was supported by grants from the National Natural Science Foundation of China (82260031), the project Youth Fund funded by Shandong Provincial Natural Science Foundation (ZR2020QC097), the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2019PT320005), Science and technology projects of Guizhou Province (QKH-J-ZK[2021]-107), The 2021 Central-Guided Local Science and Technology Development Fund (ZYYDDFFZZJ-1), Gansu Key Laboratory of molecular diagnosis and precision treatment of surgical tumors (18JR2RA033), Natural Science Foundation of Jiangxi Province (20212BAB216073), Key project funded by Department of Science and Technology of Shangrao City (2020AB002, 2020 K003, 2021F013, 2022AB003), Jiangxi Provincial Key New Product Incubation Program Funded by Technical Innovation Guidance Program of Shangrao (2020G002), Natural Science Foundation of Gansu Province (21JR11RA186, 20JR10RA415), Key talent project of Gansu Province of the Organization Department of Gansu provincial Party committee (2020RCXM076).
Nomenclature
mesenchymal stem/stromal cells
osteoarthritis
premature ovarian failure
acute myocardial infarction
acute-on-chronic liver failure
placental-derived MSCs
dental pulp-derived stem cells
umbilical cord-derived MSCs
adipose-derived MSCs
small extracellular vesicles
pluripotent stem cell-derived MSCs
embryonic stem cells
induced pluripotent stem cells
extracellular matrix
tissue-engineered construct
poly ε-caprolactone
hyaluronic acid
nano-hydroxyapatite
hydroxyapatite
bone marrow-derived MSCs
hydroxypropyl chitin hydrogel
microvesicles
Minimal Information for Studies of Extracellular Vesicles
corona virus disease 2019
critical limb ischemia
acute lung injury and acute respiratory distress syndrome
autologous chondrocyte implantation
International Society for Cellular Therapy
chitosan-hyaluronic acid
bone marrow-derived MSCs
interconnected porous hydroxyapatite ceramic
stromal cell-derived factor 1
transforming growth factor
hematopoietic stem cells
vascular endothelial growth factor
granulocyte-macrophage colony-stimulating factor
macrophages
prostaglandin E2
hepatocyte growth factor
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