Mesenchymal Stem Cells, Bioactive Factors, and Scaffolds in Bone Repair: From Research Perspectives to Clinical Practice
Abstract
:1. Introduction
2. The Role of MSCs in Bone Formation and Healing
2.1. Bone Ossification
2.2. Bone Repair
3. MSC-Based Tissue Engineering Therapies in Bone Repair from a Research Perspective
3.1. Sources and Biological Properties of MSCs for Bone Regeneration
Safety and Limitation of MSC Therapy
3.2. Cytokines, Growth Factors and Signaling Pathways Enhancing Osteogenesis
3.3. Bone Scaffolds in Tissue Engineering
3.3.1. Scaffold Properties
3.3.2. Scaffold Types
- 1.
- Bioceramics
- 2.
- Biodegradable polymers
- 3.
- Composite biomaterials
3.3.3. 3D Printing of Bone Scaffolds
3.4. Animal Models for In Vivo Studies
3.5. Preclinical Studies
4. Clinical Trials
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Animal | Cells (Suspension) | Scaffold | Treated Side | Results | References |
---|---|---|---|---|---|
Rat | Human BM-MSCs (2 × 106 cells/mL) | PLLA | Cranial bone defect | Pre-seeding an MSCs-scaffold construct leads to a higher osteogenic capacity than for MSCs injected into a scaffold during surgery. | [129] |
Rat | BM-MSCs | PEG/PLA | Thigh muscle pouches | An MSCs-scaffold construct had an excellent osteogenic potential in vitro and a good biocompatibility in vivo. | [130] |
Rabbit | BM-MSCs | PGA | Defect of infraspinatus tendons | 16 weeks after implantation, mechanical analysis and the tendon maturing score showed higher values in the MSC-scaffold treated group than in the PGA-only treated rabbits. | [131] |
Rat | AT-MSCs (104 cells per scaffold) | PLGA | Vertebral body of the spine defect | Between 2 and 4 weeks after MSC-scaffold construct implantation, bone formation occurred. However, in the group treated with osteogenic-induced AT-MSCs and a scaffold, a second bone formation occurred, contrary to the non-induced group. | [132] |
Rat | Human BM-MSCs (2 × 104 cells/cm2 or 2 × 105 cells/cm2 of scaffold) | nano-fiber PLGA | Collagen-induced arthritis | An MSCs-scaffold construct suppressed bone destruction and arthritis in rats. | [133] |
Sheep | BM-MSCs (100 × 106 cells) | PCL-HA + CaP | Segmental tibial bone defect | For a delayed injection of BM-MSCs into a scaffold, 4 weeks after biomaterial implantation biomechanical testing and micro-CT analysis showed improved bone regeneration compared to previously-seeded PCL-HA-cell construct or scaffold-only group. | [134] |
Canine | AT-MSCs (1 × 106 cells/50 µL PBS) | (1) autologous serum-derived albumin (ASA) scaffold, (2) ASA + β-TCP | Segmental ulna bone defect | 16 weeks post-implantation, radiograph and histomorphometric analysis showed the most extensive new bone formation in ASA with AT-MSCs compared to untreated, ASA-only, and ASA+β-TCP with or without AT-MSCs. | [135] |
Monkey | BM-MSCs (1.3–4.1 × 106/mL) | β-TCP | Segmental femoral bone defect | 12 weeks after transplantation, β-TCP + AT-MSCs treatment led to a higher success rate of bone regeneration compared to β-TCP treatment alone. | [136] |
Sheep | BM-MSCs (107 cells) | coral scaffold | Long metatarsal bone defect | 4 months post implantation, micro-CT and histological analysis showed better bone formation in the group treated with the construct scaffold + BMP-2 + BM-MSCs compared to scaffold + BMP-2 or scaffold + BM-MSCs. | [137] |
Sheep | BM-MSCs (107 cells) | PLLA-PCL | Segmental tibial bone defect | 12 weeks after implantation, significant bone regeneration was confirmed with micro-CT, mechanical testing and histological analysis in the group treated with PLLA-PCL + BM-MSCs compared to PLLA-PCL-only and untreated group. | [138] |
Rat | BM-MSCs, osteogenic and endothelial differentiated BM-MSCs (5 × 104 cells/cm2 BM-MSCs sheet)—biomimetic periosteum (BP) | β-TCP | Calvarial defect | 8 weeks post-surgery, micro-CT and histological analysis showed better new bone formation in β-TCP + BP and β-TCP + autologous periosteum groups than in the control groups. | [139] |
Goat | BM-MSCs | β-TCP | Critical size bone defects in tibia | 6 months after operation X-ray, micro-CT and histological analysis showed that the defect treatment using β-TCP + BM-MSCs was significantly superior to that using β-TCP alone. | [140] |
Pig | Human AT-MSCs | TCP | Segmental long bone defect | 8 and 12 weeks after reconstruction, radiographic images and pathological sections analysis showed that TCP + human AT-MSCs promoted bone healing. | [141] |
Rabbit | BM-MSCs | PLA-HA | Radius long bone defect | 8, 12, and 16 weeks post transplantation, micro-CT, X-ray and histological analysis showed enhanced bone reconstruction in PLA-HA + BM-MSCs combined with induced membrane group compared to the other groups. | [142] |
Rat | Human UC-MSCs (2 × 105 cells) | HA-G | Tendon-to-bone interface | After 8 weeks, histological and biomechanical evaluation showed that the total regeneration score was significantly higher in the HA-G + UC MSC group compared to the other groups. | [143] |
Study Number | Disease | Cells (Suspension) | Scaffold | Patients (Groups) | Results | References |
---|---|---|---|---|---|---|
Not reported | Osteonecrosis of the femoral head | BMMNCs (1 × 109 cells in 40 mL) | IP-CHA | 30 patients: 8 patients treated with cell-free IP-CHA (control group) and 22 patients with IP-CHA + BMMNCs | 29 weeks after surgery in the IP-CHA- and BMMNC-treated group, the osteonecrotic lesion decreased in size. In the control group, a severe collapse of the femoral head occurred in 6 patients. | [147] |
Study #3096 Ethics Committee of the Heinrich Heine University Duesseldorf | Local bone defects larger than 1 cm × 1 cm | BMAC (8 mL) | Col or HA | 39 patients: 12 patients treated with Col + BMAC and 27 patients with HA + BMAC | New bone formation was observed in all treated patients; however, it appeared earlier in the HA group (6.8 weeks) compared to Col (13.6 weeks). | [148] |
Not reported | Critical size bone defects | IM as a complex cellular scaffold (rich source of MSCs) | 8 patients | Cellular composition and molecular profile of IM-promoted large defect repair. | [149] | |
3766/2012 Comitato Etico Sperimentazione Farmaco CESF, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy | Upper limb atrophic pseudarthrosis | BM-MSCs (0.5 × 106 –2.0 × 106 cells in 2 mL of autologous plasma) | Autologous fibrin clots | 8 patients | In all patients, recovery of limb functions was observed. | [144] |
EudraCT number 2012-005599-33 EU Clinical Trials Register | Femoral defects | BM-MSCs (15 ± 4.5 × 106 cells in 1.5 mL) | β-TCP | 18 patients: 9 patients treated with β-TCP alone (control group) and 9 patients with β-TCP + BM-MSCs | 12 months after surgery, in all 9 patients treated with β-TCP and BM-MSCs, trabecular remodeling was detected, and in the control group, only in one patient. | [150] |
ChiCTR-ONC-17011448 Chinese Clinical Trial Registry | Non-unions and others | BM-MSCs | β-TCP | 42 patients | In all patients, radiography showed full bone healing after 9 months. | [151] |
2017-385-T282 Shanghai Jiao Tong University Affiliated Ninth People’s Hospital Medical Ethics Committee | Depressed tibial plateaus fractures | BM-MSCs | β-TCP | 39 patients: 23 patients treated only with β-TCP (control group) and 16 patients with β-TCP + BM-MSCs | Excellent or good recovery was observed 2 years post transplantation in 15 of 16 patients treated with MSCs/β-TCP and in 14 of 23 treated with β-TCP alone. | [152] |
EC2012/047 Royal Perth Hospital Ethics Committee | Cranial defects | BM-MSCs (min. 0.5 × 106 cells per ml of scaffold granules) | β-TCP | 3 patients | Between 3 and 6 months post transplantation, good cranial contour restoration was maintained in all three patients. However, between 6 and 12 months, there was evidence of construct resorption. | [153] |
EudraCT, 2012-003139-50 EU Clinical Trials Register | Severely atrophied mandibular bone | BM-MSCs (20 × 106 cells/1 cm3 of scaffold) | BCP | 11 patients | In all patients, successful ridge augmentation and new bone formation of a dental implant were observed. | [154] |
EudraCT, 2011-005441-13 EU Clinical Trials Register | Long bone delayed and non-unions | BM-MSCs | BCP | 28 patients | 3 months after surgery, radiological consolidation amounted to 25.0% (7/28 cases), after 6 months, 67.8% (19/28 cases), and after 12 months, 92.8% (26/28 cases). | [155] |
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Stamnitz, S.; Klimczak, A. Mesenchymal Stem Cells, Bioactive Factors, and Scaffolds in Bone Repair: From Research Perspectives to Clinical Practice. Cells 2021, 10, 1925. https://doi.org/10.3390/cells10081925
Stamnitz S, Klimczak A. Mesenchymal Stem Cells, Bioactive Factors, and Scaffolds in Bone Repair: From Research Perspectives to Clinical Practice. Cells. 2021; 10(8):1925. https://doi.org/10.3390/cells10081925
Chicago/Turabian StyleStamnitz, Sandra, and Aleksandra Klimczak. 2021. "Mesenchymal Stem Cells, Bioactive Factors, and Scaffolds in Bone Repair: From Research Perspectives to Clinical Practice" Cells 10, no. 8: 1925. https://doi.org/10.3390/cells10081925