Table 2.
Summary of biomaterials and strategies of spheroid engineering according to the target applications
| Target | Cell type | Functional biomaterials | A method for spheroid formation | Strategy |
|---|---|---|---|---|
| Bone defect repair | hBMSC | RGD-modified alginate gels (31) | Microwells | Controlling MSC migration from spheroids to enhance spheroid osteogenic potential |
| hBMSC | Alginate hydrogel (36) | Microwells | Applying dynamic mechanical stimulation to spheroids for enhancing osteogenic potential of MSC | |
| hADSC | Adenosine and polydopamine coated PLLA fragmented fibers (38) | Centrifugation | Scaffolds-mediated adenosine delivery to improve osteogenic differentiation of MSCs | |
| rbBMSC | Silk fibroin microfiber (39) | Centrifugation | Creating gaps in spheroids, leading to enhanced transportation of oxygen and nutrients to the core region | |
| hADSC | Biomineral-coated PLLA fragmented fibers (41) | Centrifugation | Accelerating osteogenic differentiation by providing bone-like mineralized environments | |
| hADSC | PDGF/biomineral-coated PLLA fragmented fibers (42) | Centrifugation | Providing bone-mimicking multiple factors for vascularized bone regeneration | |
| Cartilage defect repair | rBMSC | Magnetic nanoparticles (54) | Magnetic condensation using magnetic devices | Controlling sizes and patterns of spheroids at the millimetric scale by using magnetic devices |
| rbADSC | PLGA/chitosan porous scaffold (55) | In situ aggregation in pores | Forming denser mass of spheroids in the scaffold, leading to enhanced chondrogenic differentiation capacity of stem cells | |
| hADSC | TGF-β3 and FN adsorbed graphene oxide sheet (58) | Hanging-drop | Providing a cell-adhesion substrate and simultaneously delivering chondrogenic growth factors for improving chondrogenic differentiation of stem cells | |
| UCB-MSC | hFDM and TGF-β1-coated PLGA/PLLA microfiber (59) | Non-adherent plates | ||
| Critical limb ischemia repair | UCB-MSC | Hyaluronic acid/alginate core-shell microcapsules (64) | Microencapsulation | Encapsulating spheroids to protect and retain the cells from harsh environments after transplantation |
| hADSC | Poly(L-glutamic acid)/PEG-based porous hydrogel (65) | In situ aggregation in pores | In situ spheroid formation via gel-sol transition in vivo, protecting spheroids from shear stress during injection | |
| RAW 264.7 | Chrysin-encapsulated fiber fragments (68) | Electrosprayed microcapsulation | Promoting vascular anastomosis via chronological shifting from M1 to M2 phenotypes, regulated by chrysin delivery | |
| Cardiac repair | hiPSC-CM | Silicon nanowires (70, 71) | Microwells | Incorporating electrically conductive biomaterials to achieve synchronized and enhanced contraction of cardiac spheroids |
| Used both exogenous and endogenous electrical stimuli for advanced structural and functional development of cardiac spheroids | ||||
| hBMSC | Reduced graphene oxide flake (72) | Hanging-drop | Incorporating electroconductive biomaterials to spheroids for enhancing paracrine factors and connexin 43 expression | |
| Islet transplantation | Human pancreatic islets | ECM hydrogels made of porcine decellularized tissues (83) | Encapsulation | Recapitulating the in vivo peri-islet niche to enhance cell survival and functions |
| Mouse pancreatic islets | Chondroitin sulfate incorporated starPEG (80) | Nanocoating | Nanocoating of islets to reduce blood coagulation, improve islet cells survival, and protect against disruption | |
| Fas ligand-conjugated PEG microgel (81) | Microencapsulation | Local immunomodulation to avoid acute rejection of islet allografts, avoiding the need for systemic chronic immunosuppression | ||
| Programmed cell death-1-conjugated PEG microgel (79) | Microencapsulation | |||
| TGF-β1-loaded PLG microporous scaffold (82) | In situ aggregation in pores | Localized TGF-β1 delivery to modulate the immunological environment of transplanted sites | ||
| Hair follicle regeneration | hDPC | Polyvinyl alcohol (PVA) (91) | PVA-coated plates | Developed a controllable spheroid formation technique |
| mDPC | Chitosan/PVA nanofiber sponge (92) | In situ aggregation in pores | Developed a technique for controllable and scalable spheroids formation | |
| Gelatin and alginate (93) | Layer-by-layer nanoencapsulation | Developed a tunable and scalable spheroid formation model by inducing aggregation of nanoencapsulated cells |
MSC, mesenchymal stem cell; hBMSC, human bone marrow-derived MSC; hADSC, human adipose-derived stem cell; rbBMSC, rabbit bone marrow-derived MSC; rbADSC, rabbit adipose-derived stem cell; UCB-MSC, human umbilical cord blood-derived MSC; hiPSC-CM, human induced pluripotent stem cell-derived cardiomyocytes; hDPC, human dermal papilla cells; mDPC, mouse DPC; RGD, Arg-Gly-Asp; PLLA, poly (L-lactic acid); PDGF, platelet-derived growth factor; PLGA, poly(lactic-co-glycolic acid); TGF, transforming growth factor; FN, fibronectin; hFDM, human lung fibroblast decellularized ECM; PEG, polyethylene glycol; PLG, poly(lactide-co-glycolide).