MSC-exo-based clinical trials.
Abstract
Mesenchymal stem cells (MSCs), also known as mesenchymal stromal cells or medicinal signaling cells or multipotent stem cells, are heterogeneous cell populations with unique immunomodulatory feature and hematopoietic-supporting capacity. MSCs function through a variety of approaches including paracrine and autocrine, direct- or trans-differentiation, bidirectional immunomodulation, and serving as constitutive microenvironment. Of them, exosomes and microvesicles function as the pivotal vehicle for mediating the ameliorative and therapeutic effect of MSCs toward various recurrent and refractory diseases, such as xerophthalmia, radioactive nasal mucosa injury, acute-on-chronic liver failure (ACLF), dermal chronic ulcers, and intrauterine adhesions. State-of-the-art renewal has also highlighted the promising prospective of MSC-derived exosomes (MSC-exo) and diverse biomaterial composites in regenerative medicine. In this book chapter, we mainly focus on the concept, biological phenotypes, preclinical research, and clinical practice of MSC-derived exosomes (MSC-Exos) and/or biomaterials, which will collectively supply overwhelming new references for the further development of MSC-Exos-based biotherapy and disease diagnosis in future.
Keywords
- exosomes
- tissue engineering
- mesenchymal stem cells
- disease intervention
- immunomodulation
1. Introduction
Exosomes have been considered as cell-derived nanovesicles, which are indicated in disease diagnosis and treatment via the intercellular transportation of cellular constituents, such as proteins, mRNAs, microRNAs, lipids, and cytokines [1, 2, 3]. Longitudinal studies have indicated the secretion of exosome by mammalian cells and the wide distribution in cellular systems [1]. For instance, Heo et al. reported the effect of exosomes upon atherosclerosis by inducing or inhibiting progression of disease through cell-to-cell communication, which suggested the application in disease diagnosis and treatment [4]. State-of-the-art literatures also highlighted the marked technological advances of exosome-based nanotechnology to bloom the further exploitation of exosome-associated biology, pathology, chemistry, and therapeutics [5]. Despite the small membrane vesicles can be released and generated by a variety of eukaryotic cells, yet one of the major obstacles for potential application of exosomes is the strategies for high-efficient and robust enrichment of large-scale preparation with high quantity [1, 6].
Of the numerous parental cells for exosome enrichment, mesenchymal stem/stromal cells (MSCs) are considered with robust immunomodulatory property and therapeutic potential [7, 8, 9]. Differ from the relative cell types, MSCs are advantaged stem cells with high percentage of mesenchymal-associated biomarker expression (e.g., CD44, CD73, CD90, CD105), whereas with minimal expression of type II major histocompatibility complex (MHC-II) or hematopoietic-related surface marker expression (e.g., CD31, CD34, CD43, CD45) [10, 11, 12]. In this chapter, we summarize the basic and clinical research of MSC-derived exosomes (MSC-exo), including the definition, biological phenotypes and significance, preclinical and clinical investigations, and the concomitant molecular mechanism. Taken together, the contents in this chapter will benefit the further development of MSC-exo-based therapeutic regimens for refractory and recurrent disorder administration in future.
2. MSCs and exosomes
Mesenchymal stem/stromal cells (MSCs), also known as medicinal signaling cells, are unique multipotent stem cells with multi-lineage differentiation capacity and bidirectional immunomodulatory property [13]. Meanwhile, enormous literatures have demonstrated the hematopoietic-supporting effect of MSCs upon the self-renewal and lineage differentiation potential of hematopoietic stem cells (HSCs), which thus play a critical role in physiologic hematopoiesis and hematologic malignancies [14]. Since the first identification from clinical samples in 1968 [15], MSCs of different origins have been consecutively isolated from adult tissues (e.g., bone marrow, adipose tissue, dental pulp) and perinatal tissues (e.g., placenta tissue, amniotic membrane, umbilical cord, amniotic fluid) [16, 17]. Of them, bone marrow-derived MSCs (BM-MSCs) have been considered with the widest range of application, while umbilical cord-derived MSCs (UC-MSCs) have been recognized with the most robust long-term proliferation and immunoregulatory capacity, respectively [13, 18]. As shown by the ClinicalTrials.gov website, over 1400 trials have been registered for a variety of refractory and recurrent disease administration (Figure 1).
To date, MSCs have been considered with various origins, including mesoderm, endoderm, ectoderm, trophoblasts, and neural crest cells (NCCs) [19, 20]. Therewith, MSCs have been recognized as heterogeneous stem cells and show variations in multitudinous biofunctions. Since the year of 2005, pioneering investigators in the field have employed pluripotent stem cells (PSCs) including induced PSCs (iPSCs) and embryonic stem cells (ESCs) for the preparation of MSCs for large-scale application. For instance, Zhang et al. reported the high-efficiency MSC generation from human PSCs (hPSCs) within two weeks by a cell programming strategy, which was accomplished by the combination of a master transcription factor named MSX2 (Msh Homeobox 2) and small molecule cocktails (TGF-β, bFGF, decitabine) [19]. Subsequently, Wei et al. took advantage of two chemical compounds including OICR-9429 (a JAK signal and histone methyltransferase inhibitor) and decitabine (DAC) for the enhanced induction of MSCs from hESCs [21]. Very recently, we reported the high-efficiency MSC induction from hESCs within two weeks via the non-gene-editing cell programming with LLY-507 (a JAK/STAT or BRD4 inhibitor) and AZD5153 (an epigenetic reader domain inhibitor) [10]. Similar to UC-MSCs, hPSC-MSCs revealed superiority in ex vivo proliferation and immunomodulation over the counterparts from diverse adult tissues.
MSCs function via diverse modes of action, including differentiation, immunomodulation, and secretion. Of them, exosomes and small extracellular vesicles (sEVs) are considered as the two major forms of derivatives of MSCs, which thus play a pivotal role in mediating disease diagnosis and treatment [22, 23]. Exosomes are nano-sized sEVs secreted by the parent cells and play a pivotal role in diverse physiological and pathological processes [24]. To date, a variety of components have been identified from exosomes, such as nucleic acids (e.g., mRNAs, microRNAs, tRNAs, circRNAs), proteins (e.g., cytokines, peptides, amino acids, anti-inflammatory factors), lipids, metabolites, and relative bioactive substances [25].
Distinguish from liposomes and nanoparticles, exosomes with endogeneity and heterogeneity reveal unique and extensive advantages in the field of pathologic diagnosis and disease treatment [26]. Exosomes are nanoparticles with a diameter ranging from 50 nm to 200 nm, which are adequate to interact with organelles and relative intracellular vesicles [27, 28]. As a unique nanoscale spherical lipid bilayer vesicles, exosomes exhibit a density of 1.13–1.19 g • mL−1 according to the sucrose density gradient solution [29]. The conception of “exosomes” is firstly proposed by Trams et al. and referred to the vesicles derived from plasma membrane, which is also regarded as the membrane vesicles with 5′-nucleotide enzyme activity. Currently, exosomes are recognized as nano-particles with multitudinous physiological functions, which can be isolated from the exudation and supernatant of various cells and breezily cross the extracellular matrix and blood vessel wall [7, 30]. For instance, a category of exosomal microRNAs have been involved in the pathogenesis and diagnosis of tumors and immune disorders, which are adequate to mediate exosome-inflammasome crosstalk and epithelial mesenchymal transition (EMT), together with chemoresistance and metastasis of tumor cells [27, 30]. In 2021, Patil et al. reported the novel mechanisms of MSC-exo-mediated phagocytosis and opsonization of dying cardiomyocytes during myocardial ischemic injury both in vitro and in vivo [31].
As reviewed by Zhang et al., the ubiquitous exosomes are advantaged cell-free therapeutic products, which are small in size and thus breezily cross the extracellular matrix and blood vessel wall [7]. For instance, MSC-exo have shown considerable safety and therapeutic effects upon various diseases such as atherosclerosis, and acute and chronic wound model [4, 26]. Govindappa and the colleagues found that diabetic milieu were adequate to stimulate RNA-binding proteins like human antigen R (HuR) expression via increasing pro-fibrogenic and inflammatory responses in fibroblasts and cardiac fibrosis mediated by macrophages-derived exosomes [32]. Meanwhile, the chitosan hydrogel has been proved effective in boosting the stability and retention of exosomes enriched from placenta-derived mesenchymal stem cells (P-MSC-exo) and the contents (e.g., proteins, lipid, microRNAs), together with the resultant enhanced efficacy for hindlimb ischemia treatment and remission [12]. As mentioned above, MSC-derived exosomes (MSC-exo) and the relative sEVs have been reported with diverse application prospects in a variety of refractory and recurrent disease administration, yet the large-scale application for disease management is far from satisfaction, which largely attributes to the inherent disadvantages of exosomes, including the low yield, storage stability, low purity, and weak targeting [27].
3. Biomaterials/MSC-exo composites
Biomaterials with tissue compatibility and inflammatory response mainly function via in contact with biological tissue, which are mainly applied in the medical field for tissue engineering or developing artificial organs for regenerative purposes. Generally, biomaterials can be divided into synthetic polymer biomaterials (silicone rubber, polyurethane, polyester, polyacrylonitrile), natural polymer biomaterials (regenerated fibers, chitin, collagen, hyaluronic acid), medical metal materials (titanium and titanium alloys, stainless steel, titanium-nickel memory alloys), inorganic biomedical materials (bioactive ceramics, carbon materials, glass materials), hybrid biomaterials (e.g., cross-linked hybridization of collagen, polyvinyl alcohol), and composite biomaterials (e.g., bioceramics, glass reinforced with glass fibers).
Current progress in materials and cell biology has extensively indicated the superiority of multiple biomaterials for preclinical and clinical application upon diverse relapse and recurrent diseases, and in particular, the composites of biomaterials and MSC-exo for tissue engineering and regenerative purposes attribute to the unique biocompatibility. In details, biomaterials with biocompatible and biodegradable properties are capable of facilitating the efficacy of MSCs or MSC-exo and enhancing their manifestations during anti-tumor immunity by endowing the therapeutic ability of these encapsulated constituents [33, 34, 35]. To date, a variety of biomaterials have been introduced for MSC-exo-based regimens in biomedicine, such as hydrogel acid (HA) (e.g., ε-caprolactone (PCL)/nano-hydroxyapatite (nHA) scaffold, chitosan hydrogel, PCL/nHA + HPCH hybrid scaffolds), gelatin, and nanomaterials [12, 36]. These biomaterials with promising prospective have been proved with the ability to reinforce the biological properties or functions of the encapsulated objectives including MSC-exo [37]. Of them HA and gelatin are considered as the two major forms of extracellular matrix, which are widely distributed in tissues of the body and benefiting the preparation of the compatible hybrid hydrogels by orchestrating the specific composition, scaffold structure, immune microenvironment, and the concomitant physico-chemical property [38, 39]. For example, as reviewed by Celikkin et al. and Xiao et al., Gelatin methacrylate-based hydrogels exhibit preferable properties over other counterparts in tissue engineering and disease administration on the basis of their biofunctionality as well as unique mechanical tenability (e.g., chemical properties, porosity, physical strength, and conductivity) [40, 41]. Similarly, a number of investigators in the field have also observed the hydrogel encapsulation, exosome-loaded thermosensitive hydorgels, and MSC-exo/hydrogel hybrid patch in controlling the release of paracrine factors, enhancing the maintenance of the biological activity, enhancing corneal epithelium regeneration from MSCs and MSC-exos [42, 43, 44].
Longitudinal studies have also suggested the application of multifarious collagens with high biocompatibility is applied as natural scaffolds for tissue engineering, including extracellular matrix (ECM), elastin, proteoglycans, and glycoproteins [45, 46]. For example, the implantation of engineered collagen matrices or resorbable collagen scaffolds has been reported effectively for the remission of meniscus defects by Warth et al. and Patil et al. [47, 48]. Of note, the latest progress has also highlighted the bioprinting of pure collagen or in combination with MSCs and/or MSC-exo for regenerative purposes as well [49]. On the basis of the immunomodulatory properties, MSC-exo have been used as a dermatological nano-therapeutic agent for the administration of oxidative stress-induced skin injury by modulating the NRF2 defense system and H2O2-stimulated epidermal keratinocytes [50].
Nanomaterials are defined by their diameters ranging from 1 nm to 100 nm, together with the facilitating effect upon the permeability and retention of the encapsulated cells or cellular components including MSCs and the derivatives (e.g., exosomes, sEVs) [51]. Nanomaterials, together with the nanostructure-mediated physical signals, have been recognized as splendid sources for mimicking ECM and enhancing the therapeutic effect of MSC-exo, which are tightly orchestrated by activating specific signals [52, 53, 54, 55, 56, 57]. For example, Luo and the colleagues verified the feasibility of MSC-exo for amelioration of the inflammation-induced astrocyte alterations via the Nrf2-NF-κB signaling pathway [58]. Instead, Zhang et al. verified BM-MSC-derived exosomes (BM-MSC-exo) for promoting remyelination and reducing neuroinflammation via inhibiting the TLR2/IRAK1/NF-κB signaling pathway and increasing polarization of M2 phenotype in the demyelinating central nervous system [59]. Additionally, DiStefano et al. took advantage of Lactic-co-Glycolic Acid and the resultant hydrogel-embedded poly microspheres for the efficient delivery of hMSC-derived exosomes and the promotion of bioactive annulus fibrosus repair [60]. Very recently, Geng et al. reported the generation of the multifunctional antibacterial MSC-Exos@CEC-DCMC HG hydrogel (carboxyethyl chitosan-dialdehyde carboxymethyl cellulose) and BM-MSC-exo composite for accelerating diabetic wound healing [61]. Additionally, with the aid of optimized BM-MSC-exo and unique hierarchical scaffolds, Liu et al. demonstrated the application for bone regeneration by modulating the Smad pathway activated by Bmpr2/Acvr2b competitive receptor [62]. As to the underlying molecular mechanism of various biomaterials in MSC-exo-based regimens, various biomaterials function mainly via orchestrating a series of mode of action, including integrating or incorporating with the encapsulated MSC-exo, benefiting the secretion and maintenance of MSC-exo, serving as substrates or scaffolds, and reinforcing the antioxidant property as well [63, 64, 65]. Collectively, biomaterials of different kinds with high biocompatibility have been recognized as momentous components of the formulations for tissue engineering and regenerative medicine [66, 67, 68, 69, 70].
4. MSC-exo-based clinical trials
Attributes to the advantaged property, MSC-exo have been extensively explored in clinical trials. According to the ClinicalTrials.gov website (https://www.clinicaltrials.gov/) of National Institute of Health (NIH), a total number of 164 interventional trials have been registered up to February 4th, 2023 (Figure 2). Of them, most are in the phase 1 and phase 2 stages, together with the recruiting status (Table 1). To date, MSC-exo have been involved in numerous disease administration, including respiratory diseases (e.g., COVID-19, acute respiratory distress syndrome), digestive diseases (e.g., perianal fistula with Crohn’s disease, familial hypercholesterolemia, irritable bowel disease, non-alcoholic fatty liver disease), cutaneous diseases (e.g., alopecia, psoriasis, endothelial dysfunction, wounds and injuries, oral mucositis, diabetic foot), vascular diseases (e.g., cerebrovascular disorders, myocardial infarction, myocardial ischemia, myocardial stunning), reproductive diseases (e.g., extreme prematurity, preterm, polycystic ovary syndrome), neurodevelopmental disorders (e.g., neuralgia, refractory depression, anxiety disorders, post-stroke dementia, Alzheimer disease, major depressive disorder, bipolar disorder, mild cognitive impairment, stroke, acute ischemic stroke, Parkinson disease), movement disorders (e.g., knee osteoarthritis, meniscus tear, tibial and knee injuries, arthralgia), endocrine system diseases (e.g., type 1 diabetes mellitus, type 2 diabetes mellitus), immunological disorders (e.g., allergic asthma, severe eosinophilic asthma), and urinary diseases (e.g., chronic kidney failure, bladder cancer, polycystic kidney disease), and even tumors (e.g., metastatic melanoma, colon cancer, non-Hodgkin’s lymphoma, lung cancer, non-small cell lung cancer, metastatic pancreatic adenocarcinoma, squamous cell carcinoma of the head and neck, advanced breast cancer, triple negative breast cancer, gynecologic cancer, prostate cancer, intraductal papillary mucinous neoplasm, malignant glioma, advanced hepatocellular carcinoma, acute myeloid leukemia, T-cell lymphoma, squamous cell carcinoma, advanced gastric cancer, colorectal cancer).
Status | Phases | Cases | Diseases |
---|---|---|---|
Recruiting | Not Applicable | 20 | Hair Loss, Alopecia |
Completed | Phase 1 | 10 | Psoriasis |
Active | Phase 1, 2 | 80 | Perianal Fistula with Crohn’s Disease |
Recruiting | Phase 1, 2 | 80 | Fistula Perianal |
Unknown | Not Applicable | 15 | Metastatic Melanoma |
Unknown | Phase 1, 2 | 5 | Cerebrovascular Disorders |
Completed | Phase 1 | 24 | Coronavirus |
Not Recruiting | Not Applicable | 10 | Extreme Prematurity, Preterm Intraventricular Hemorrhage, Hypoxia-Ischemia, Neurodevelopmental Disorders |
Active | Phase 2 | 155 | COVID-19 Disease |
Unknown | Early Phase 1 | 10 | Periodontitis |
Not recruiting | Phase 1, 2 | 55 | Covid19, Novel Coronavirus Pneumonia, Acute Respiratory Distress Syndrome |
Unknown | Early Phase 1 | 5 | Ulcer |
Suspended | Not Applicable | 100 | Neuralgia |
Recruiting | Phase 1, 2 | 20 | Myocardial Infarction, Myocardial Ischemia, Myocardial Stunning |
Suspended | Not Applicable | 300 | Refractory Depression, Anxiety Disorders, Neurodegenerative Diseases |
Recruiting | Phase 2, 3 | 60 | SARS-CoV-2 Infection |
Not recruiting | Phase 1 | 10 | Knee Osteoarthritis |
Not recruiting | Not Applicable | 60 | Multiple Organ Failure |
Recruiting | Phase 1, 2 | 60 | Drug-resistant |
Recruiting | Phase 1 | 35 | Colon Cancer |
Completed | Phase 1 | 30 | Chronic Low Back Pain, Degenerative Disc Disease |
Recruiting | Phase 1 | 35 | SARS-CoV-2 |
Not Recruiting | Phase 1 | 30 | Familial Hypercholesterolemia |
Recruiting | Phase 2 | 30 | Knee injury, Meniscus Tear, Tibial and Knee Injuries, Arthralgia |
Recruiting | Not Applicable | 12 | Connective Tissue, Exercise |
Recruiting | Phase 2, 3 | 135 | Retinitis Pigmentosa |
Recruiting | Not Applicable | 90 | Non-Hodgkin (B-NHL) |
Recruiting | Not Applicable | 30 | Lung Cancer, Non-Small Cell Lung Cancer |
Withdrawn | Not Applicable | 0 | Polycystic Ovary Syndrome |
Unknown | Phase 2, 3 | 20 | Type 1 Diabetes Mellitus |
Unknown | Phase 1 | 60 | Corona Virus Infection, Pneumonia |
Recruiting | Phase 1, 2 | 27 | Dry Eye |
Recruiting | Not Applicable | 35 | Atrial Fibrillation |
Unknown | Not Applicable | 100 | Endothelial Dysfunction |
Recruiting | Not Applicable | 30 | Post-stroke Dementia, Acupuncture |
Recruiting | Phase 1 | 28 | Metastatic Pancreatic Adenocarcinoma, Pancreatic Ductal Adenocarcinoma, Stage IV Pancreatic Cancer |
Recruiting | Not Applicable | 40 | Insulin Resistance |
Not recruiting | Not Applicable | 5 | Wounds and Injuries |
Unknown | Phase 2 | 90 | Covid19, SARS-CoV-2 Pneumonia |
Completed | Phase 1, 2 | 30 | Covid19, SARS-CoV-2 Pneumonia |
Recruiting | Phase 2 | 90 | Covid19 |
Completed | Not Applicable | 10 | Healthy |
Completed | Phase 1 | 24 | Healthy |
Unknown | Phase 1, 2 | 169 | Acute Respiratory Distress Syndrome |
Active | Early Phase 1 | 44 | Macular Holes |
Not recruiting | Not Applicable | 30 | Non-Small Cell Lung Cancer |
Completed | Not Applicable | 4 | Irritable Bowel Disease |
Recruiting | Not Applicable | 60 | HIV Infections |
Completed | Not Applicable | 18 | Blood Coagulation, Platelet Function |
Completed | Early Phase 1 | 9 | Larynx, Lip, Oral Cavity, Pharynx |
Unknown | Not Applicable | 72 | Healthy |
Completed | Phase 1 | 60 | Head and Neck Cancer, Oral Mucositis |
Recruiting | Not Applicable | 120 | Type 2 Diabetes Mellitus |
Terminated | Not Applicable | 2 | Squamous Cell Carcinoma of the Head and Neck |
Unknown | Not Applicable | 200 | NSCLC Patients |
Unknown | Not Applicable | 60 | NSCLC |
Unknown | Not Applicable | 60 | NSCLC |
Recruiting | Phase 1 | 20 | COVID-19 Acute Respiratory Distress Syndrome, Respiratory Distress Syndrome |
Recruiting | Not Applicable | 80 | Metabolism |
Completed | Phase 2 | 41 | Non-Small Cell Lung Cancer |
Not recruiting | Not Applicable | 30 | Breast Cancer |
Withdrawn | Not Applicable | 0 | Breast Cancer, Leptomeningeal Metastasis |
Completed | Not Applicable | 9 | Prehypertension |
Recruiting | Not Applicable | 25 | Advanced Breast Cancer |
Not recruiting | Not Applicable | 30 | Diabetic Foot |
Unknown | Phase 1, 2 | 9 | Alzheimer Disease |
Recruiting | Not Applicable | 300 | Metastatic Breast Cancer |
Recruiting | Not Applicable | 1000 | Breast Cancer, Digestive Cancer, Gynecologic Cancer, Circulating Tumor DNA |
Not recruiting | Phase 1, 2 | 10 | Dystrophic Epidermolysis Bullosa |
Completed | Not Applicable | 84 | Overweight Children with Type 2 Diabetes Risk |
Recruiting | Not Applicable | 320 | Prostate Cancer |
Completed | Not Applicable | 71 | Cancer |
Recruiting | Not Applicable | 80 | Allergic Asthma, Severe Eosinophilic Asthma |
Not recruiting | Not Applicable | 1000 | Postoperative Delirium, General Anesthesia, Circadian Rhythm Disorders |
Active | Not Applicable | 48 | Sports Drug Abuse |
Active | Not Applicable | 367 | Breast Cancer |
Completed | Phase 1 | 17 | Normal Cellular Metabolism |
Active | Not Applicable | 1000 | Cancer of the Prostate |
Completed | Phase 1, 2 | 30 | Chronic Kidney Failure, Dialysis-Related Complication |
Recruiting | Early Phase 1 | 9 | Recurrent or Metastatic Bladder Cancer |
Active | Phase 2, 3 | 129 | Prostatic Neoplasms |
Recruiting | Not Applicable | 75 | Pancreatic Carcinoma, Pancreatic Intraductal Papillary Mucinous Neoplasm |
Completed | Not Applicable | 19 | Port-Wine Stain |
Recruiting | Not Applicable | 10,000 | Major Depressive Disorder, Bipolar Disorder |
Not recruiting | Phase 1 | 20 | Alveolar Bone Loss, Alveolar Bone Atrophy, Bone Grafting |
Completed | Phase 1 | 13 | Malignant Glioma of Brain |
Completed | Phase 1 | 33 | Malignant Glioma, Neoplasms |
Completed | Not Applicable | 28 | Type 1 Diabetes, Diabetes Complications |
Recruiting | Phase 1 | 15 | Triple Negative Breast Cancer |
Recruiting | Not Applicable | 60 | Treatment-resistant Depression |
Not recruiting | Phase 1 | 20 | Long COVID |
Recruiting | Phase 2 | 20 | Mild Cognitive Impairment |
Completed | Not Applicable | 90 | Obesity |
Completed | Not Applicable | 60 | Non-Small Cell Lung Cancer |
Recruiting | Phase 1 | 30 | Advanced Hepatocellular Carcinoma, Gastric Cancer Metastatic to Liver, Colorectal Cancer Metastatic to Liver |
Not recruiting | Not Applicable | 10 | Glioma |
Recruiting | Not Applicable | 72 | Acute Myeloid Leukemia |
Completed | Phase 1 | 38 | Chronic Ulcer |
Terminated | Phase 1, 2 | 17 | T-Cell Lymphoma |
Completed | Not Applicable | 10 | Hypertension |
Active | Phase 1, 2 | 20 | COVID-19, Acute Respiratory Distress Syndrome |
Completed | Not Applicable | 75 | Drug Resistant Epilepsy |
Recruiting | Not Applicable | 80 | Panic Disorder |
Completed | Phase 1 | 19 | Polycystic Kidney Disease |
Terminated | Not Applicable | 28 | Carcinoma, Hepatocellular, Colorectal Neoplasms, Melanoma, Kidney Neoplasms |
Completed | Phase 2 | 13 | Thyroid |
Completed | Not Applicable | 13 | Insulin Resistance |
Terminated | Phase 4 | 15 | Type 2 Diabetes Mellitus, Cardiovascular Diseases |
Unknown | Not Applicable | 90 | Childhood Obesity, Adolescent Obesity |
Unknown | Not Applicable | 40 | Fasting |
Not recruiting | Phase 2 | 78 | Esophageal Adenocarcinoma, Esophageal Squamous Cell Carcinoma, Gastroesophageal Junction Carcinoma |
Not recruiting | Not Applicable | 144 | Brugada Syndrome 1 |
Not recruiting | Phase 1, 2 | 12 | Obstructive Sleep Apnea, Brain Hypoxia, Stroke, Endothelial Dysfunction, Oxidative Stress |
Unknown | Not Applicable | 102 | Pancreas Adenocarcinoma |
Recruiting | Phase 3 | 68 | Muscular Dystrophies, Duchenne Muscular Dystrophy, Muscular Disorders, Neuromuscular Diseases, Genetic Diseases, Nervous System Diseases |
Completed | Phase 2 | 63 | Covid19 |
Completed | Phase 2 | 102 | COVID-19, ARDS |
Completed | Phase 2 | 18 | Duchenne Muscular Dystrophies, Atrophic Muscular Diseases, Neuromuscular Diseases, Genetic Diseases |
Completed | Early Phase 1 | 14 | Heart Failure with Preserved Ejection Fraction |
Recruiting | Early Phase 1 | 6 | Recessive Dystrophic Epidermolysis Bullosa |
Unknown | Not Applicable | 60 | Sleep Apnea, Inflammation, Atherosclerosis |
Recruiting | Not Applicable | 144 | Non-alcoholic Fatty Liver Disease, Metabolic Syndrome, Obesity |
Recruiting | Not Applicable | 300 | Obesity, Insulin Resistance |
Unknown | Not Applicable | 96 | Thoracic Surgery, Video-Assisted |
Recruiting | Phase 1, 2 | 30 | COVID-19 |
Terminated | Not Applicable | 1 | COVID-19 |
Recruiting | Not Applicable | 40 | Prostate Cancer |
Recruiting | Not Applicable | 180 | Obesity, Insulin Resistance |
Unknown | Not Applicable | 260 | Body Weight Changes |
Not recruiting | Phase 2 | 203 | Locally Advanced Gastric Cancer |
Unknown | Not Applicable | 180 | Rhinitis, Allergic, Perennial |
Active | Phase 2 | 45 | Lip, Oral Cavity Squamous Cell Carcinoma, Pharynx, Larynx, Squamous Cell Carcinoma |
Not recruiting | Phase 2 | 60 | Brain Metastases, Non-small Cell Lung Cancer Stage III |
Completed | Phase 1 | 12 | Drug–drug Interaction |
Recruiting | Not Applicable | 120 | Heart Failure |
Not recruiting | Phase 3 | 216 | Locally Advanced Gastric Cancer |
Not recruiting | Phase 1 | 18 | Glioma, Anaplastic Astrocytoma, Anaplastic Oligodendroglioma, Glioblastoma |
Unknown | Phase 2 | 40 | Metastatic Colorectal Cancer |
Completed | Not Applicable | 8 | Obesity, Insulin Resistance |
Withdrawn | Phase 2 | 0 | Prostate Carcinoma |
Not recruiting | Not Applicable | 200 | Alzheimer Disease |
Unknown | Not Applicable | 108 | Cancer |
Completed | Phase 2 | 25 | Non-Small Cell Lung Cancer |
Unknown | Phase 2 | 80 | Mild Cognitive Impairment |
Recruiting | Phase 2 | 18 | Cutaneous Squamous Cell Carcinoma of the Head and Neck |
Terminated | Phase 2 | 3 | Breast Cancer |
Unknown | Phase 1 | 60 | Advanced/Metastatic Colorectal Cancer |
Completed | Phase 4 | 40 | Non-alcoholic Fatty Liver Disease |
Not recruiting | Not Applicable | 100 | Myocardial Reperfusion Injury, Prognosis, ST Elevation Myocardial Infarction |
Active | Phase 2 | 43 | Chordoma |
Completed | Not Applicable | 45 | Stroke, Acute Ischemic Stroke, Cerebrovascular Disorders, Central Nervous System Diseases |
Completed | Phase 2 | 69 | Hypothyroidism, Endocrine System Diseases |
Completed | Phase 2 | 26 | Prostate Cancer |
Recruiting | Not Applicable | 124 | Multiple System Atrophy |
Active | Not Applicable | 69 | Cardiovascular System, Respiratory System |
Recruiting | Phase 2 | 53 | MSS, pMMR, Metastatic Colorectal Adenocarcinoma |
Active | Phase 1 | 46 | Resectable Soft Tissue Sarcoma, Soft Tissue Sarcoma |
Recruiting | Phase 1, 2 | 100 | Lung Non-Small Cell Carcinoma |
Recruiting | Phase 1 | 30 | Lung Non-Small Cell Carcinoma |
Completed | Phase 1, 2 | 4 | Minimal Residual Disease, AML |
Terminated | Phase 1 | 10 | Neoplasms, Refractory and Recurrent Solid Tumors |
Completed | Phase 1, 2 | 27 | Pancreatic Cancer, Pancreatic Ductal Adenocarcinoma |
Active | Phase 1 | 101 | Healthy Elderly, Parkinson Disease |
Recruiting | Not Applicable | 480 | Overweight and Obesity, Weight Loss, Pregnancy Related |
5. Conclusions
Biomaterials and MSC-exo composites are advantaged sources for tissue engineering and regenerative medicine, which hold superiority over other therapeutic regimens attributes to the unique characteristics. In this chapter, we detailed and introduced the basic conception and latest updates of biomaterials and MSC-exo composites for biomedicine, which will collectively facilitate the further development of MSC-exo-based cell-free regimens in future. Of the multitudinous biomaterials, those with preferable tissue compatibility and minimal inflammatory response would reveal more robust application prospect with MSC-exo in future.
Acknowledgments
The authors would like to thank the members in 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 Chinese Academy of Sciences Hefei Institute of Physical Science for their kind suggestions. This study was supported by grants from, National Natural Science Foundation of China (82260031, 82160534), Gansu Provincial Hospital Intra-Hospital Research Fund Project (22GSSYB-6, 21GSSYB-8, 20GSSY5-2), The 2022 Master/Doctor/Postdoctoral program of NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor (NHCDP2022004, NHCDP2022008, NHCDP2022014), the project Youth Fund funded by Shandong Provincial Natural Science Foundation (ZR2020QC097), Science and technology projects of Guizhou Province (QKH-J-ZK[2021]-107), Natural Science Foundation of Jiangxi Province (20224BAB206077, 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), the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2019PT320005), The 2021 Central-Guided Local Science and Technology Development Fund (ZYYDDFFZZJ-1), Guiding plan for scientific and technological development of Lanzhou (2019-ZD-102), Gansu Key Laboratory of molecular diagnosis and precision treatment of surgical tumors (18JR2RA033), Key talent project of Gansu Province of the Organization Department of Gansu provincial Party committee (2020RCXM076), Young Science and Technology Talent Support Project of Gansu Association for Science and Technology (GXH202220530-17), Natural Science Foundation of Gansu Province (21JR11RA186, 20JR10RA415).
Appendices and nomenclature
Nomenclature
Mesenchymal stem/stromal cells
Osteoarthritis
MSC-derived exosomes
Type II major histocompatibility complex
Acute-on-chronic liver failure
Placental-derived MSCs
Extracellular matrix
Umbilical cord-derived MSCs
ε-Caprolactone
Small extracellular vesicles
Pluripotent stem cell-derived MSCs
Embryonic stem cells
Induced pluripotent stem cells
Extracellular matrix
Neural crest cells
Poly ε-caprolactone
Hyaluronic acid
Nano-hydroxyapatite
Hydroxyapatite
Placenta-derived mesenchymal stem cells-derived exosomes
Hydroxypropyl chitin hydrogel
Msh Homeobox 2
Alzheimer disease
Corona virus disease 2019
Non-small cell lung cancer
Acute respiratory distress syndrome
Triple negative breast cancer
Acute myeloid leukemia
Bone marrow-derived MSCs
Non-alcoholic fatty liver disease
Hematopoietic stem cells
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