Table 1.
Key translationally relevant studies in biomaterial-facilitated stem cell-based regenerative therapies
| Targets | Technologies/platforms | Engineered biomaterials and cells | Merits and outcomes | References |
|---|---|---|---|---|
| Cardiovascular system | four-dimensional (4D) cardiac patch | photocurable GelMA/PEGDA inks with tricultured hiPSC-CMs, hMSCs, and hECs | recapitulated the architectural and biological features of the native myocardial tissue and provided anisotropic mechanical adaption that improved cardiomyocyte maturation, vascularization, and engraftment in models of myocardial infarction | (Cui et al., 2020) |
| electronically stable conductive patch (CP)-based scaffold | polyaniline (PANI) doped with phytic acid chelated on the surface of a chitosan film tested on myocardium | provided a robust conductive system that could be interfaced with electroresponsive cardiac tissue without inducing proarrhythmogenic activities | (Mawad et al., 2016) | |
| myocardial extracellular matrix (ECM) | ventricular porcine myocardium-derived ECM and endogenous recruitment of stem cells | increased cardiac muscle, improved contractility, enhanced cardiac function, prevented negative left ventricular remodeling, and increased cardiac regeneration by recruiting stem cells after myocardial infarction | (Seif-Naraghi et al., 2013) | |
| cardiac cell-integrated microneedle patch | polyvinyl alcohol (PVA) with cardiac stromal cells | robustly reduced myocardial apoptosis, promoted angiomyogenesis in the peri-infarct area, and thus encouraged regeneration, improved retention, and enhanced engraftment, morphology, and cardiac output | (Tang et al., 2018) | |
| therapeutic replenishable epicardial reservoir (Therepi) | polyurethane (TPU) polymer device encapsulated with cardiac progenitors and macromolecules | ensured continuous and on-demand access to the bioactive molecules, improved retention, regeneration, and provided functional benefits in ejection fraction, stroke work, and fractional shortening | (Whyte et al., 2018) | |
| perfusable multifunctional epicardial device (PerMed) | poly(glycerol sebacate) and poly(ε-caprolactone) (PCL) for endogenous repair | improved ventricular function, displayed targeted and sustained release of growth factors, and enhanced efficacy of cardiac repair | (Huang et al., 2021) | |
| polypyrrole-loaded cardiogel | precardiogel (pCG–decellularized heart) cross-linked with polypyrrole for cardiac progenitor delivery | improved mechanical properties, enhanced electrical conductivity, decreased fibrotic tissue, increased retention, and enhanced vasculature and regeneration | (Parchehbaf-Kashani et al., 2021) | |
| multivascular network hydrogels | poly(ethylene glycol) diacrylate (PEGDA), GelMA | intravascular and multivascular design was achieved using photopolymerization of the hydrogel and demonstrated successful vessel generation, blood flow, and gas exchange | (Grigoryan et al., 2019) | |
| acellular, artificial cardiac patch | decellularized porcine myocardial extracellular matrix scaffold with synthetic cardiac stromal cells (PLGA microparticles loaded with cardiac stromal cell factors) | maintained potency after long-term cryopreservation and reduced scarring, encouraged angiomyogenesis, and improved cardiac function in rodent models of acute myocardial infarction | (Huang et al., 2020) | |
| injectable mesoporous silica nanoparticles (MSNs)/miRNA hydrogel | aldehyde-capped poly(ethylene glycol) (PEG) hydrogel matrix (Gel@MSN/miR-21-5p) | promoted anti-inflammatory and proangiogenic effects and effectively reduced infarct size in a porcine model of myocardial infarction | (Li et al., 2021b) | |
| Central nervous system | 3D microtopographic scaffolds | tyrosine-derived polycarbonate pDTEc with human-induced pluripotent stem cell (hiPSC)-derived neurons | enhanced subtype-specific neuronal reprogramming, transplantation, survival, and integration in a rodent model; potential to reprogram iPSCs to other specific subtypes | (Carlson et al., 2016) |
| hybrid synthetic matrix-assisted and rapidly templated (SMART) neurospheres | manganese dioxide (MnO2) graphene oxide (GO) nanosheets with hiPSC-neural stem cells (NSCs) and laminin | supported high survival rates, controlled differentiation, and functional recovery in a SCI rodent model; represents a substantial development in material-facilitated 3D cell culture systems | (Rathnam et al., 2021) | |
| designer injectable gels | shear-thinning hydrogel for injectable encapsulation and long-term delivery (SHIELD) hydrogels made from C7 protein, 8-arm PEG polymer modified with proline-rich peptides, and PNIPAAm for Schwann cell transplants | increased Schwann cell survival and retention, significantly improved spatial distribution within endogenous tissue, reduced cystic cavitation and neuronal loss, and substantially increased forelimb strength and coordination | (Marquardt et al., 2020) | |
| glycomaterial implants | acellular-engineered chondroitin sulfate (eCS) matrix with brain-derived neurotrophic factor (BDNF) and fibroblast growth factor 2 (FGF-2) | accelerated cellular repair and gross motor function recovery, enhanced volumetric vascularization, activity-regulated cytoskeleton (Arc) protein expression, and perilesional sensorimotor connectivity in chronic severe TBI | (Latchoumane et al., 2021) | |
| Wharton’s Jelly | scaffolds derived from human platelet lysate and human plasma fibrinogen with thrombin as a cross-linker and encapsulated with human mesenchymal stem cells (hMSCs) | demonstrated high survivability, stable proliferation rate, migration out of the hydrogel, upregulated expression of neurotrophic factors, cytokines, and neural markers, and increased expression of neural differentiation markers | (Lech et al., 2020) | |
| Elastic ECM | thin polyacrylamide substrates (PA), ECM with myelinating glia | demonstrated inhibited branching and differentiation of oligodendrocytes (OLs) on rigid, lesion-like matrices whereas Schwann cells (SCs) developed normally in both soft and stiffer matrices to promote healing and regeneration in both CNS and PNS | (Urbanski et al., 2016) | |
| HYDROSAP hydrogels | self-assembling peptides (SAPs) hydrogels with human neural stem cell (hNSC) | decreased astrogliosis and immune response, increased neuronal markers, improved hNSC engraftment, enhanced behavioral recovery, and formation of 3D functional neuronal networks | (Marchini et al., 2019) | |
| brain stiffness-mimicking gel | tilapia collagen gel with hiPSCs-derived dorsal cortical neurons | demonstrated lineage commitment to the terminal neural subtype, improved neurogenesis and neural function, and enhanced production of dorsal cortical neurons | (Iwashita et al., 2019) | |
| thermosensitive hydrogels combined growth factors | acellular spinal cord scaffold with bFGF and heparin-poloxamer (HP) for endogenous regeneration | efficient inhibition of glial scars and improved functional recovery via regeneration of nerve axons and the differentiation of neural stem cells in the SCI | (Xu et al., 2016) | |
| photoresponsive neuroprotective protein hydrogel | His6-tagged recombinant protein, SpyTag-ELP-CarHC-ELP-SpyTag (ACA), metal ions, and adenosylco-balamin with hMSCs and leukemia inhibitory factors (LIFs) | showed excellent injectability, photodegradability, facile encapsulation and delivery of cells and proteins, prolonged cellular signaling, and enhanced axon regeneration | (Jiang et al., 2020) | |
| multichannel polymer scaffold | PLGA scaffolds with activated Schwann cells and MSCs | exhibited significant recovery of nerve function, enhanced differentiation into neuron-like cells, good colocalization with host neurons, and formation of robust bundles of regenerated fibers | (Yang et al., 2017) | |
| bioactive scaffolds with enhanced supramolecular motion | library of IKVAV peptide amphiphiles with different sequences of amino acids V, A, and G (IKVAV PA1 to PA8) for endogenous regeneration | intensified molecular motions within scaffold fibrils enhanced vascular growth, axonal regeneration, myelination, survival of motor neurons, and functional recovery with reduced gliosis | (Álvarez et al., 2021) | |
| growth facilitators | diblock copolypeptide hydrogel K180L20 with FGF-2, EGF, GNDF for endogenous regeneration | regrew full spinal segment beyond lesion centers into neural tissue with terminal-like contacts and displaying synaptic markers, improved electrophysiological conduction, and reinstated developmentally essential mechanisms to facilitate axon growth | (Anderson et al., 2018) | |
| 3D scalable culture system | PNIPAAm-PEG hydrogel with pluripotent stem cells from human oligodendrocyte precursors | generated oligodendrocyte precursor cells (OPCs) in 3D culture without enrichment that displayed excellent engraftment, migration, and maturation into myelinating oligodendrocytes in vivo | (Rodrigues et al., 2017) | |
| Ocular system | 3D micro and ultra-fine matrix | porcine urinary bladder matrix (UBM) with a complex mixture of intracellular and extracellular proteins | UBM particulate substantially reduced corneal haze and promoted proregenerative environments by stimulating type 2 immune response that led to improved wound healing and vision restoration | (Wang et al., 2021a) |
| retinal cell sheets | hESC-derived retinal pigment epithelial (RPE) cells sheets on human amniotic membrane | rescued photoreceptor cells and improved visual acuity in models of retinal degeneration | (M’Barek et al., 2017) | |
| biosynthetic cornea | recombinant human collagen type III (RHCIII) | successful integration of the biosynthetic cornea that remained avascular without the use of long-term immunosuppression, restoration of the tear film, regeneration of nerves, and improvement in vision | (Fagerholm et al., 2010) | |
| polarized RPE polymer matrix | adult human RPE stem cells on polyethylene terephthalate (PET) | human RPE monolayer remained polarized and survived on PET carriers in the subretinal space | (Stanzel et al., 2014) | |
| rotating-wall vessel bioreactors | retinal organoids derived from iPSC, ESCs cultured on a poly(2-hydroxyethyl methacrylate) (polyHEMA)-coated substrate | improved bioprocess for organoid growth and differentiation in the rotating-wall vessel (RWV) bioreactors was observed | (DiStefano et al., 2018) | |
| ultrathin micromolded 3D scaffolds | poly(glycerol sebacate) scaffold with retinal organoids generated from hPSCs | microfabricated scaffolds patterned with high-density photoreceptors produced a multicellular photoreceptor layer for outer retinal reconstruction | (Lee et al., 2021) | |
| retinal pigment epithelium patch | PLGA scaffolds with iPSC-derived RPE | improved integration and functionality of RPE; promising alternative autologous therapy for dry and wet AMD | (Sharma et al., 2019a) | |
| self-organizing human retinal tissue | hESC differentiation to neural retina (NR), GSK3, and FGFR inhibitors | NR-RPE boundary tissue self-organizes a niche for ciliary margin stem cells and expands NR peripherally via de novo progenitor generation | (Kuwahara et al., 2015) | |
| substrate with matching corneal biomechanics | type-I collagen substrates with limbal epithelial stem cell (LESC) | Collagenase-treated burned surface of the cornea restores its appropriate mechanical properties and supports growth of undifferentiated LESCs by YAP suppression | (Gouveia et al., 2019) | |
| rhodopsin genomic loci DNA nanoparticles | polyethylene glycol-substituted polylysine (CK30PEG) conjugated with TAT peptide, rhodopsin genomic loci DNA | gDNA vectors resulted in long-term increased levels of transgene expression and helped rescue retinal degeneration | (Zheng et al., 2020b) | |
| bioprinted construct | gelatin methacryloyl with conjunctival stem cells (CjSCs) | demonstrated injectable delivery of CjSC microtissue to treat of ocular surface diseases | (Zhong et al., 2021) | |
| Scaffold for thick sheet of retinal cells | Scaffold composed of gelatin type A, chondroitin sulfate, and hyaluronic acid with hESCs | successfully simulated the extracellular matrix of the neurosensory retina and supported differentiation into retinal cell types | (Singh et al., 2018) | |
| dual synthetic corneal tissue | synthetic Bowman’s membrane (sBM) and synthetic stromal layer (sSL) for endogenous repair | supported rapid re-epithelialization, maintained corneal transparency, improved mechanical strength, and enabled host/implant integration | (Wang et al., 2020) | |
| full-thickness artificial cornea | acellular porcine cornea matrix (APCM) with limbal epithelial cell-like (LEC-like) cells and corneal endothelial cell-like (CEC-like) cells | successful construction of a full-thickness cornea substitute with good host integration and transparency | (Zhang et al., 2017) | |
| pancreatic tissues | organoid microphysiological system | machined fluidic chips from optically clear PMMA and PFA membrane with islets isolated from rodents | demonstrated dynamic in vitro microenvironment for the preservation of primary organoid function | (Patel et al., 2021) |
| electrogenetic macro-encapsulation device | bioelectronic encapsulation device with electrosensitive designer cells (Electroβ cells) | demonstrated wireless electrical stimulation of vesicular insulin release to attenuate postprandial hyperglycemia | (Krawczyk et al., 2021), | |
| rapid oxygenation of cell encapsulation SONIC scaffold | poly(vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP) with islets isolated from rodents | biomimetic scaffold with internal continuous air channels enhanced O2 diffusivity by 10,000-fold and thus survival of transplanted graft | (Wang et al., 2021b) | |
| convection-enhanced macro-encapsulation device (ceMED) | poly(methyl methacrylate) (PMMA), PTFE membranes, and HF modified polyethersulfone with stem cell-derived beta-cells | 3D geometry of ceMED maximized cell loading, improved GSIS and nutrient exchange due to convection, enhanced cell viability, and rapid reduction of hyperglycemia | (Yang et al., 2021) | |
| fluorocapsules | 19F MRI detectable perfluoro-15-crown-5-ether (PFC) and Ba2+-gelled alginate microcapsules with luciferase-expressing mouse βTC6 insulinoma cells | demonstrated the use of 19F MRI signal as a predictive imaging surrogate biomarker for monitoring failure of encapsulated islet cell therapy | (Arifin et al., 2019) | |
| cell-particle hybrids polymeric microspheres | PLGA and FK506 (Tacrolimus) immune suppressant with islets isolated from rodents | demonstrated a method for local immunomodulation with higher efficacy and safety; the platform can be applied for cell tracking and combinatorial deliveries of therapeutic entities | (Nguyen et al., 2019) | |
| exosome loaded immunomodulatory biomaterials (AlgXO) | UPLVG alginate and exosomes with umbilical cord-derived mesenchymal stem cells (UC-MSCs) and rodent islets | successfully attenuated the local immune microenvironment by suppressing proinflammatory macrophages partly by interfering with NF-κB pathway | (Mohammadi et al., 2021) | |
| amino acid augmented macro-encapsulation device | polycaprolactone, alanine, and glutamine with stem cell-derived beta-cells | enhanced viability of encapsulated beta-cells in nutrient-limited conditions | (Chendke et al., 2019) | |
| ready-to-use cryopreserved pancreatic islets | trehalose, MitoQ, and DMSO with rodent islets | demonstrated an improved cryopreservation method to increase the on-demand availability of islets for transplantation | (Dolezalova et al., 2021) | |
| graphene-Dex bioscaffolds | graphene, nickel foam, and PMMA with AD-MSCs and rodent islets | graphene bioscaffold functionalized for local immunomodulation by Dex together with AD-MSC significantly improved the survival and function of transplanted islets | (Razavi et al., 2021) | |
| zwitterionic polyurethane (ZPU) nanoporous device | 3-(Butylbis(2-hydroxyethyl) ammonio) propane-1-sulfonate (SB-Diol) and Polyurethanes with rodent islets | electrospun ZPU device lowered FBR when implanted in immunocompetent animals and showed better scalability and retrievability | (Liu et al., 2021) | |
| lotus-root-shaped cell-encapsulated constructs (LENCON) | microfluidic multicoaxial encapsulation device, laminin, and sodium hyaluronate with human stem cell-derived pancreatic beta-cells (hSC-βs) | demonstrated scalability, retrievability, and maintained the functionality of beta-cells in immunocompetent animals | (Ozawa et al., 2021) | |
| cellulose-based scaffolds | carboxymethyl cellulose (CMC) cryogels with INS1E beta-cells | prompted beta-cells to generate clusters and create specific ranges of pseudoislets; these scaffolds can control the organization and function of insulin-producing beta-cells | (Velasco-Mallorquí et al., 2021) | |
| extracellular matrix/alginate hydrogels | pancreatic acellular matrix and pECM/alginate hydrogel with iPSC-derived beta-cells | provided an ideal biomimetic microenvironment, improved differentiation efficiency, promoted insulin secretion, and increased expression of insulin-related genes | (Wang et al., 2021c) | |
| retrievable macro-encapsulation device | PCTE membrane and PDMS chips and zwitterionic monomers (CBMA and SBMA) with rodent islets | synthetic polymer coating prevented fibrosis for improved long-term function of the device in the absence of immunosuppression and demonstrated retrievability | (Bose et al., 2020) | |
| theranostic silencing nanoparticles | double-stranded siRNAs targeting baboon caspase-3, dextran-coated iron-oxide magnetic nanoparticles | reduced insulin requirements in animals transplanted with a marginal number of labeled islets and demonstrated a novel strategy to minimize the number of donor islets required | (Pomposelli et al., 2020) | |
| gene modification and microscaffold encapsulation | gelatin with MSCs engineered with Exendin-4 (MSC-Ex-4), a glucagon-like peptide-1 (GLP-1) | augmented insulin sensitivity and suppressed senescence and apoptosis of pancreatic beta-cells | (Zhang et al., 2021b) |
GelMA/PEGDA, gelatin methacrylamine (GelMA)-poly(ethylene glycol) diacrylate (PEGDA); hiPSC-CMs, human-induced pluripotent stem cell-derived cardiomyocytes; hMSCs, human mesenchymal stem cells; hECs, human endothelial cells; ECM, extracellular matrix; PLGA, poly(lactic-co-glycolic acid); miRNA, microRNA; hiPSCs, human-induced pluripotent stem cells; bFGF, basic fibroblast growth factor; MSCs, mesenchymal stem cells; IKVAV, laminin-derived functional peptide; FGF-2, fibroblast growth factor 2; EGF, epidermal growth factor; GDNF, glial cell line-derived neurotrophic factor; PNIPAAm-PEG, poly(N-isopropylacrylamide)-co-poly(ethylene glycol); hESCs, human embryonic stem cells; iPSC, induced pluripotent stem cells; ESCs, embryonic stem cells; GSK3, glycogen synthase kinase 3; FGFRs, fibroblast growth factor receptors; TAT, transactivator of transcription; PMMA, poly(methyl methacrylate); PFAs, perfluoroalkoxy alkanes; SONIC, speedy oxygenation network for islet constructs; PTFE, polytetrafluoroethylene; UPLVG, high guluronate low viscosity alginate; MitoQ, mitochondria-targeted ubiquinone; DMSO, dimethylsulfoxide; AD-MSCs, adipose-derived mesenchymal stem cells; PCTE, polycarbonate track etched; PDMS, polydimethylsiloxane; CBMA, 3-[[2-(methacryloyloxy)ethyl]dimethylammonio]propionate; and SBMA, sulfobetaine methacrylate.