Recent advances of biomaterials in stem cell therapies

Abstract

Stem cells have been utilized as ‘living drugs’ in clinics for decades. Their self-renewal, differentiation, and immunomodulating properties provide potential solutions for a variety of malignant diseases and disorders. However, the pathological environment may diminish the therapeutic functions and survival of the transplanted stem cells, causing failure in clinical translation. To overcome these challenges, researchers have developed biomaterial-based strategies that facilitate in vivo tracking, functional engineering, and protective delivery of stem cells, paving the way for next-generation stem cell therapies. In this perspective, we briefly overview different types of stem cells and the major clinical challenges and summarize recent progress of biomaterials applied to boost stem cell therapies.

1. Introduction

Empowered with prolonged self-renewal, differentiation, and immunomodulating properties, multipotent somatic stem cells, such as hematopoietic stem cells (HSCs) and mesenchymal stromal/stem cells (MSCs), have been extensively applied as ‘therapeutic cells’ in clinics for the treatments of various malignant diseases and disorders [1–5]. HSCs are a type of stem cell mainly located in bone marrow of human bodies and perform as the primary source of all mature blood cells such as lymphocytes and erythrocytes [1]. The unique functions and multipotent differentiation ability of HSCs have demonstrated great potential in curing multiple hematological cancers, thereby receiving immense attention from researchers for over half a century [2]. Later on, the identification of human leukocyte antigen, which could reduce graft-versus-host disease (GVHD) after transplantation, boosted the clinical success of allogeneic hematopoietic stem cell therapy in the treatments of multiple myeloma and leukemias [6]. MSCs represent another type of multipotent stem cells that can be easily isolated from various tissue sources, such as adipose tissue, bone marrow, and umbilical cord [7, 8]. Apart from serving as a source for cell replacement therapy, MSCs demonstrate unique paracrine signaling ability to potently elicit immunomodulatory or regenerative effects, which can efficiently reprogram the local pathological environments [9]. This paracrine mechanism is now regarded as the primary therapeutic pathway of MSCs, making them a promising cell therapy against inflammatory disorders and autoimmune diseases [10–12]. Compared with clinical success of HSCs, however, MSCs display limited clinical efficacy owning to low survival rate at the disease sites after transplantation, impeding their therapeutic paracrine activities [9]. Particularly, over 900 clinical trials of MSCs have been conducted in the past two decades, but only two of them got approved for clinical use: one is Prochymal for the treatment of GVHD and the other is Alofisel for the treatment of Crohn’s disease [11, 13]. Additional efforts are needed to improve clinical translation of MSC therapies. Recently, induced pluripotent stem cells (iPSCs) have been widely applied in disease modeling as they are able to be differentiated into a wide range of cell types [14–16]. Such broad differentiation ability also paves the way for clinical investigations of iPSC in disease treatments [15]. The clinical implementations of iPSCs, however, are hindered by the risk of teratoma formation in vivo. The promising iPSC-based cell replacement therapies are currently limited within the tissues with minimal proliferative phenotypes, such as retinal pigment epithelium and neuron [17, 18].

The current clinical-available stem cell-based therapies take advantage of the natural properties of cells, thereby restricting the broader applications of stem cell therapies in different diseases [6, 19]. Moreover, some issues regarding in vitro culture in stem cell manufacture, such as low differentiation efficiency and slow proliferation rate, hindered the quality and potency of the therapeutic cells [20]. More importantly, the desirable conditions of stem cell therapy highlight the sustainable responses towards the complicated local microenvironment, which requires the transplanted stem cells to migrate and retain in the target sites. The conventional administration approaches of stem cell therapies are limited to buffer fluids that are not able to protect the stem cells against a harsh physiological environment upon transplantation [21]. Recent efforts towards developing next-generation stem cell therapies have utilized biomaterials to improve the potency of stem cell therapies, especially for MSCs-based therapies [19, 22–26]. In this perspective, we concisely summarize the state-of-the-art approaches in designing various biomaterials-based strategies to boost stem cell therapies. Specifically, three essential functions of biomaterials are described, which include tracking transplanted stem cells, engineering stem cells with additional functional properties, and protective delivery of transplanted stem cells in situ.

2. Applications of biomaterials in stem cell therapy

Fine-tuning of structures and components has facilitated the development of many biomaterials-based platforms in stem cell therapy, including nanoparticles, hydrogels, matrixes and microneedles. These biomaterials could warrant precise tracking of the transplanted stem cells, efficient reprogramming of stem cells’ properties and functions, and protective delivery of stem cells to the pathological environment (figure 1). In this section, we review recent advances in the applications of biomaterials in boosting stem cell therapies.

Figure 1.

Schematic illustration of biomaterials-based strategies for enhancing stem cell therapy. Created with BioRender.com.

2.1. Biomaterials for tracking stem cells

Although stem cells can migrate to disease sites by capturing the circulating or local signal cytokines, many cells are currently required for transplantation so as to generate a viable population in targets [19]. Other cells migrating to the wrong sites in the body may diminish the therapeutic efficacy and even disrupt the normal functions of surrounding tissue or cells. Therefore, in vivo real-time tracking plays an important role in illustrating the tissue distribution, retention and survival of the stem cells after transplantation, which are the essential factors to determine the administration routes, predict the efficacy and potential side effects, and explore new disease applications of different stem cell therapies [27–29]. A series of stem cell tracking approaches have been developed for decades, including fluorescent markers, stimulated emission depletion imaging, PET scan, and radiolabelling [25, 30, 31]. However, these conventional methods lack reliability for sustainable detection of stem cells in deep tissues due to weak signal penetration ability and fast self-degradation of the labelling materials. Biomaterials, including inorganic materials and synthetic organic materials, can form nanoparticles (NPs) that can be effectively internalized inside stem cells, thus achieving sustainable and efficient imaging [32]. Compared with conventional labelling reagents, imaging nanoparticles, especially metallic ones, have shown superior photostability, great emission ability and negligible toxicity [30]. Moreover, they can be easily conjugated with plenty of bio-functional molecules to enhance imaging intensity as well as deliver therapeutic agents to improve the efficacy of engineered stem cells.

As a representative example of inorganic materials, gold (Au) has been extensively utilized as stem cell tracking material, the design of which could be easily modified to be suitable for the labelling of different types of stem cells [33]. For example, Jokerst et al developed the silica-coated gold nanorods to significantly increase the cellular uptake of gold in hMSCs, which was facilitated by entrapment in the endosomes while barely affecting the normal properties and functions of the labelled cells [34]. The silica-coated gold nanorods served as a contrast agent for photoacoustic (PA) imaging of the intramuscularly-transplanted hMSCs in the rodent muscle tissues and provided an optimal detection limit of 9 × 10⁴ cells in vivo, indicating great clinical potential. Notably, the silica-coated gold nanorods were later developed for in vivo detection of the subcutaneouslyinjected hMSC by multispectral optoacoustic tomography (MSOT) imaging [35]. The silica coating offered plasmon broadening and increased the photoacoustic sensitivity, resulting in a long-term detection limit of 2 × 10⁴ cells in vivo. In addition, when used as the contrast agent for micro-computed tomography (CT) imaging of hMSCs, the AuNPs were conjugated with poly-L-lysine (PLL) and rhodamine B isothiocyanate (RITC), which enabled a low detection threshold for hMSC injected in striatum [36].

Magnetic nanoparticles were also used in monitoring the distribution of stem cells in vivo [32]. For instance, the Tat peptide-functionalized superparamagnetic NPs were incorporated in the CD34⁺ hematopoietic and neural progenitor cells to precisely monitor their bone marrow homing using magnetic resonance imaging (MRI). The engineered stem cells retained their proliferation and differentiation ability [37]. Such labelling approach mediated by the magnetic nanoparticles also allowed the subsequent recovery of the labelled stem cells by magnetic separation columns after transplantation. Recently, Park et al constructed a multifunctional magnetic nanocluster consisting of iron oxide NPs, a fluorescent dye and PLGA polymer [38]. The formed nanocluster was consecutively functionalized with a cationic polymer, PEI, to load target therapeutic genes. The multifunctional nanocomplex-internalized hMSCs enabled efficient gene delivery, effective regulation of cell migration in vivo under a predefined magnetic field and real-time detection of the transplanted stem cells using both optical and MR imaging. Wang et al reported the effects of the shapes of iron oxide NPs (IONPs) on hMSCs tracking sensitivity by formulating cubic and spherical IONPs, respectively [39]. The cubic IONPs with an edge length of 22 nm demonstrated superior MRI sensitivity and resolution compared with those with larger edge length and also the spherical ones, indicating the importance of determining morphonology in IONP design.

Near-infrared long persistent luminescence nanoparticles (NIR-LPLNPs) were recently developed for stem cell tracking [40–42]. Notably, NIR-LPLNPs demonstrated deep tissue penetration and red LED light-renewable ability. For example, Wu et al constructed an LPLNPs-based dual-functional platform to facilitate stem cell tracking and engineering [40]. Particularly, LPLNPs were coated with a layer of PEI for sequential conjugation of the transactivator of transcription penetration peptide and the therapeutic plasmid encoding (EGFP)-TRAIL. The functionalized LPLNPs could effectively deliver the plasmid to BM-MSCs without influencing the normal properties of the cells, and induce substantial secretion of TRAIL protein. Intratumor injection of the engineered MSCs showed long-term retention in the in situ glioblastoma tissue using optical imaging and displayed potent anti-tumor efficacy compared with untreated cells.

2.2. Biomaterials for engineering stem cells

Current clinical stem cell therapies harness the natural differentiation or immunoregulating properties of therapeutic stem cells [43–46]. Although these properties have been thoroughly investigated and defined, sticking with them when designing stem cell therapies may limit the applications of stem cells in various disease treatments such as cancer immunotherapy and inherited diseases. Through the treatments of therapeutic agents including genes, proteins and small molecule drugs, stem cells can be reprogrammed to release certain disease-suppressing biofactors and drugs, express specific antigens and constantly generate functional proteins [6, 19]. Moreover, the inherent tissue or pathological microenvironment migratory properties of stem cells can be enhanced through precise engineering. But the reprogramming efficiency may be hindered by the low delivery efficiency of biomolecules in stem cells. The traditional physical techniques represented by electroporation can effectively transfect biomolecules to stem cells but may inflict significant toxicity [47]. Viral vectors like lentiviruses and adenoviruses have been utilized in stem cell functional engineering as well. The potential mutagenesis and immunogenicity of virus-based transfection, however, may cause unexpected alterations of stem cell properties and induce severe immune responses after transplantation, which consequently diminishes the therapeutic efficacy [24]. Therefore, biomaterials represented by polymers and lipids have been being explored as a promising stem cell engineering strategy owing to their biocompatibility, superior transfection efficiency and fine-tuning of structures and designs [9, 48–53].

Bio-nanoparticles can be formulated to deliver intracellular-acting molecules to stem cells and endow them with predetermined functions [48]. Lipid-based materials represent the most extensively-studied non-viral nucleic acid carriers, and have been utilized in stem cell engineering [54–57]. For example, Lipofectamine, a liposomal transfection reagent composed of cationic lipid DOPSA and helper lipid DOPE, could deliver synthetic mRNA to somatic cells and reprogram them into iPSCs with high efficiency. The RNA-induced iPSCs could be further precisely directed to myogenic cells using the same RNA delivery technique [58]. Moreover, lipofectamine was later used to deliver multiple mRNAs separately encoding IL-10, PSGL-1 and SLex to hMSCs [51]. In a murine experimental autoimmune encephalomyelitis (EAE) model, the surface expression of PSGL-1/SLex of the engineered hMSCs significantly increased the cell homing capacity to the inflamed spinal through systemic delivery. More importantly, the engineered hMSCs could further secrete the anti-inflammatory factor, IL-10, to hinder the proliferation of the CD4 + T lymphocytes at the inflammatory microenvironment, thereby attenuating the disease progression and improving myelination of the diseased spinal cord [51].

Despite the high delivery efficiency, cationic liposomes are associated with potential toxicity and immunogenicity, which may negatively impact the expansion and differentiation of stem cells. The predetermined structure and formulation of the lab-standard lipid-based transfection agents also limit broader applications in different types of stem cells. As a superior alternative to cationic lipids, ionizable lipids containing tertiary amines have been developed as optimal lipid-based stem cell engineering strategies owing to their low cytotoxicity as well as potent delivery capacity [59, 60]. For example, Takeda et al developed a series of biodegradable ionizable lipids consisting of various amine groups and various disulfide bond-contained acrylate tails to deliver miRNA to hMSC [49]. Screened through a fluorescence-based approach, 306-O16B-3 was identified as the leading material for cytosolic delivery and further used to deliver miR-9, a neuronal differentiation factor, to hMSCs. The expression of neuronal marker genes was significantly increased in the treated cells compared with control groups, and neuron-like morphology was also detected, demonstrating efficient cell engineering. In a following study, Zhao et al developed an ionizable lipidoid, 400-O16B-3, to substitute for 306-O16B-3 due to the relatively low viability of the 306-O16B-3-treated hMSCs [61]. This lipidoid could potently deliver both Cas9 mRNA and sgRNA to hMSCs with negligible toxicity, and effectively induce neural-like differentiation.

Polymer-based nanoparticles have also been utilized as a nanoscale delivery platform for stem cell engineering. For instance, Yang et al developed an end-modified biodegradable poly(beta-amino ester) (PBAE) polymer, C32–122, for efficient vascular endothelial growth factor (VEGF) DNA delivery to hMSCs [62]. In a murine model of ischemic hind-limb, intramuscular injection of PBAE-VEGF polyplex-modified hMSCs substantially increased angiogenesis and regeneration of the diseased limbs. Recently, the cationic poly(ethyleneimine) (PEI) polyplexes carrying plasmid and siRNA were mixed with PLGA, a negatively charged copolymer, to form a stable nanoparticulated delivery system for hMSCs reprogramming [63]. The co-delivery of coSOX9 plasmid and anti-Cbfa-1 siRNA mediated by the PLGA NPs induced the chondrogenesis of hMSCs with high efficiency. Polyglutamic acid (PGA) has been used to load Cas9 RNPs and HDR template for in vitro delivery [50]. The PGA/Cas9 nanoparticles significantly increased the HDR efficiency by two to six folds in multiple therapeutic primary cells including hematopoietic stem progenitor cells, highlighting the great translational potential of this delivery technique for boosting adoptive cell therapy. In another study, PGA could self-assemble on the polyplex surface and be easily anchored with stem cell-specific antibodies as targeting ligands. Efficient ex vivo mRNA delivery in HSCs was achieved by conjugating anti-CD105 antibodies on the PBAE polyplex surface [64]. In addition, a library of highly or lowly branched poly(β-amino ester)s (HPAEs) containing bioreducible disulfide groups was developed by Liu et al to deliver minicircle DNA encoding GFP to human AD-MSCs and primary astrocytes [56]. The optimal polymer, HPAESG-1, induced the highest level of GFP expression in both types of cells. Huang et al constructed a multifunctional nanocarrier by complexing biocompatible polymers, PBAE and PLGA, with a plasmid expressing anti-SOX9 siRNA, retinoic acid and Ag₂S quantum dots to synergistically regulate the Wnt/β-catenin and RA signaling pathways of neural stem cells (NSCs) as well as guide distribution of the transplanted cells in vivo using a second near-infrared window (NIR-II) [65]. The expression of neprilysin, an essential Aβ-degrading protease, was genetically introduced to the NSCs by lentivirus. The engineered neural stem cells demonstrated significantly enhanced neuronal differentiation efficiency, accumulation in the hippocampus and long-term (up to six months) efficient Aβ elimination, thereby substantially recovering the memory and learning ability of the mice with Alzheimer’s diseases [65].

To facilitate in vivo stem cell engineering, a lipid/polymer hybrid nanoparticle was designed by incorporating PEI600 to an epoxide-terminated lipid material and formulated with various PEG-lipid conjugates to encapsulate siRNA [66]. The top-performing formulation containing denser PEG-lipid, NichEC-15, was identified based on the highest gene silencing efficiency in bone marrow, which could specifically target hematopoietic stem cell niche and be uptaken by bone marrow endothelial cells. The systemic delivery of anti-Sdf1 or anti-Mcp1 siRNA assisted by NichEC-15 efficiently promoted or impeded the release of stem cells and leukocytes from bone marrow, respectively. In a mouse myocardial infarction model, NichEC-15-mediated anti-Mcp1 siRNA delivery significantly decreased leukocytes in the diseased hearts, and subsequently promoted heart recovery [66].

Biomaterials have also been utilized to enhance ex vivo expansion of stem cells. For example, Jia et al constructed a RGD peptide-functionalized poly (ethylene glycol) diacrylates (PEGDA) hydrogel microarray to support the growth of hiPSC-derived cardiomyocytes [67]. Recently, Xu et al reported a hyaluronic acid (HA) core–shell hydrogel microcapsule to encapsulate iPSCs for proliferation [68]. Such expansion platform could generate a large homogeneous population of iPSCs with high expression of pluripotency markers compared with conventional culture approaches. Bai et al developed a super-hydrophilic hydrogel matrix composed of star-shaped zwitterionic poly(carboxybetaine acrylamide) (pCBAA) polymers, biofunctional polypeptides and a metalloproteinase-degradable motif [69]. Compared with the HSCs cultured in the conventional hydrophobic hydrogels, those expanded in this zwitterionic hydrogel demonstrated reduced production of ROS and minimal undesired differentiation, leading to efficient long-term repopulating in vivo.

In addition to direct functional engineering, stem cells have also been applied as advanced delivery systems as they are able to actively migrate to the diseased sites [47, 70–73]. For example, Na et al reported a bioreducible copolymer, PCDP, to efficiently encapsulate oncolytic adenovirus (oAd) into nanoparticles, which could promote superior virus transfection and replicon in hMSCs compared with naked viral capsids [74]. The PCDP-oAd/RLX (relaxin) treated hMSCs were able to transport into tumor tissues after systemic administration and consistently release relaxin protein to the tumor microenvironment, thereby inducing potent anti-tumor efficacy in a pancreatic tumor model. Recently, the platelets functionalized with anti-PD-1 antibodies were conjugated with the membrane surface of haematopoietic stem cells (HSCs) through DBCO/azide-mediated click reactions [75]. In a murine model of acute myeloid leukaemia (AML), the natural homing ability of HSCs enabled sufficient accumulation of the cell complexes in bone marrow after systemic delivery, and the activation of platelets facilitated effective release of anti-PD-1 antibodies to the immunosuppressive microenvironment, which significantly provoked the proliferation of CD8⁺ effector and memory T cells against leukaemia cells compared with the discrete administrations of the involved therapeutics. Recently, Martinez et al developed a bone-marrow-derived MSC (BM-MSC)-based delivery system by incorporating a porous silicon multi-stage nanovectors (MSVs) loaded with anti-inflammatory cytokine IL-10 into the MSCs. Notably, the natural targeting and migration capacity of MSCs could effectively deliver MSVs to the inflamed tissues and facilitate the local delivery of IL-10 [76]. Compared with the free systemic delivery of MSV, BM-MSC-mediated delivery of MSV efficiently increased the accumulation of particles at the inflammatory microenvironment, and significantly prolonged the survival of mice with systemic inflammation.

2.3. Biomaterials for delivering stem cells

The therapeutic functions of stem cells are precisely regulated by the complicated biological signals in the pathological microenvironment, the process of which requires sufficient survival and retention of transplanted stem cells [4, 21, 22]. However, the current fluid-based administration approaches in clinically available stem cell therapies may not provide essential protection for the stem cells facing harsh local microenvironment stress in malignant diseases. Delicate designs of biomaterials have been explored to form innovative delivery systems capable of encapsulating stem cells, regulating cell fates, improving survival rates, and facilitating sustainable and local release. The delivery systems can be fabricated into minimally invasive injectable and implantable ones, commonly represented by hydrogels, scaffolds and microneedles [22].

Hydrogel is one of the most extensively-studied delivery systems in stem cell therapy. Particularly, hydrogels are three-dimensional networks formed by physically or chemically cross-linked oligomers, of which the tunable characteristics and versatile fabrication approaches show great potential in biomedical applications, especially in stem cell therapies [77–80]. More importantly, hydrogels can mimic the properties of natural extracellular matrices (ECM) for continuous stem cell proliferation and differentiation in vivo. For example, Lee et al constructed an injectable in situ cross-linkable gel by conjugating gelatin, a biocompatible and biodegradable material, with hydroxyphenyl propionic acid [81]. The BM-MSCs encapsulated in the gel demonstrated a higher differentiation ratio to endothelial cells and showed increased expression of multiple angiogenesis markers, which were driven by the material properties-based signal pathways. The hydrogels were also effective in protecting the transplanted stem cells against harsh pathological microenvironments. For instance, the infiltration of pro-inflammatory cytokines and T-Lymphocytes into the MSCs-loaded gold-standard hydrogels could induce the apoptosis of MSCs and diminish their bone regeneration ability through a CASPASE-3/CASPASE-8 proapoptotic cascade [82]. To maintain the viability and functions of MSCs after s.c. implantation, Moshaverinia et al constructed an alginate hydrogel platform to encapsulate BM-MSCs to efficiently reduce the penetration of pro-inflammatory T cells. The alginate hydrogel was incorporated with an anti-inflammatory drug, indomethacin, to increase the viability of the implanted MSCs and restore their bone regeneration ability [82]. Recently, Drzeniek et al developed a laminin-functionalized collagen I-hyaluronic acid hydrogel (COL-HA) to augment paracrine secretion of therapeutic cytokines or growth factors from MSCs. Notably, COL-HA provided a favorable spatial structure to allow the attachment and spreading of the encapsulated MSCs, leading to high cell viability and paracrine potency. Moreover, the intrinsic properties of COL-HA, including ligand types, motif adhesion, stiffness, elasticity and structure, could perform as bio-instructive cues to modulate secretome activity of MSCs, highlighting the importance of rational design of hydrogels in MSC applications [83].

Moreover, stimuli-responsive biomaterials have been utilized to generate environmental-sensitive hydrogels with the distinct capacities to improve the therapeutic efficacy of stem cells upon stimulation. Martin et al constructed a reactive oxygen species (ROS)-sensitive hydrogel by cross-linking PEG hydrogels with ROS-degradable poly(thioketal) (PTK) polymers [84]. The ROS-sensitive hydrogel could scavenge the free radicals that extensively distribute in the local inflammatory environment to minimize the exposure of hMSCs to the cytotoxic levels of ROS as well as facilitate gradual release of the loaded cells. Compared with conventional enzymatically-degradable hydrogels, the ROS-sensitive hydrogel profoundly increased the viability of the implantable hMSCs in situ for a long-term period, indicating great potential in clinical applications [84]. Recently, Wang et al developed a hyaluronic acid hydrogel consisting of thermoresponsive hydrazine-modified elastin-like protein (ELP) [85]. This novel hydrogel established the first network under room temperature to provide effective mechanical protection for hMSCs during syringe needle injection. The formation of the second network was provoked through a thermal phase transition to increase the structural strength, facilitating a long-term gradual release of the loaded hMSCs in situ.

The additional encapsulation of functional biomolecules in hydrogels could provoke stem cell engineering along with local delivery. For example, Garcia et al reported a PEG hydrogel tethered with recombinant IFN- γ to realize sustainable activation of the encapsulated hMSCs in vivo, which showed significantly increased paracrine release of immunosuppressive cytokines and potently hindered the proliferation of antigen-presenting cells and T cells relative to the cells treated with IFN- γ ex vivo [86]. In a murine model of colonic wounds, the hMSC encapsulated in the IFN- γ modified hydrogel substantially accelerated the healing of wounds in both immunocompromised and immunocompetent mice. In a following study, the PEG hydrogel loading hBM-MSCs was conjugated with a cell-specific peptide, GFOGER, to increase the survival and retention of the implanted hMSCs as well as their bone repair capacity after transplantation[87]. Tang et al reported an injectable and intrecrosslinkable gelatin microribbon hydrogel for in situ formation of adipose-derived MSCs-loading depot [88]. Such platform significantly increased the proliferation of MSCs in vivo and enhanced bone regeneration of mice with cranial defects. Additional incorporation of BMP2 to the hydrogel solution substantially accelerated and improved the therapeutic efficacy of adipose-derived MSCs.

Apart from hydrogels, a variety of biomaterial-based delivery systems have been used for stem cell delivery. Tang et al developed a microneedle (MN) patch with a biocompatible polymer, poly(vinyl alcohol)(PVA), via a micromolding approach and integrated the cardiac stromal cells (CSCs)-loaded gels on the MN patch surface [89]. In both murine and porcine models of acute myocardial infarction (MI), the MN patch carrying CSCs was placed onto the diseased area of heart, where the microneedle could absorb growth factors from heart to support the survival of the CSCs as well as facilitate the release of the paracrine factors secreted by the CSCs to host myocardium, thus generating a loop for efficient cardiac tissue repair. Notably, the implantation of the MN on the heart did not augment the inflammation, indicating excellent biocompatibility. Recently, a detachable hybrid microneedle (d-HMND) consisting of a PLGA-formed outer shell and an inner mixture of gelatin methacryloyl (GelMA) and hMSCs was designed for local and sustainable release of the loaded cells [90]. Once implanted onto the wounded skin sites, the microneedle’s PLGA shell was gradually degraded, facilitating the release of the encapsulated hMSCs to the pathological microenvironment at the disease’s sites. Compared with direct s.c. injection of the hMSCs, the d-HMND-mediated delivery of hMSCs demonstrated significantly enhanced viability and wound healing efficacy.

Vegas et al constructed a triazole–thiomorpholine dioxide (TMTD) alginate microcapsule to protect insulin-secreting human stem cell-derived beta (SC-β) cells post intraperitoneal injection. In a murine model of type 1 diabetes, the microcapsule mitigates foreign-body immune responses against the transplanted SC-β cells, enabling long-term glycemic control [91]. Recently, Lee et al developed a collagen-dendrimer scaffold functionalized with multiple pro-survival peptides via cross-linking [92]. The scaffold could adhere to the ECMs in heart after the intramyocardial administration together with cardiac progenitor cells (CPCs) and enable long-term gradual release of the peptides to the local diseased sites. In a murine model of myocardial infarction, the peptide-loaded collagen/dendrimer matrix significantly increased the survival of the implanted CPSs (up to six weeks) by activating the AKT and ERK pathways via the release of pro-survival peptides and substantially restored the functions of the left ventricle. Similarly, the matrix promoted the survival of the transplanted bone marrow mononuclear cells (BMMNCs) in a hind-limb ischemia model [92].

3. Conclusion

The development of stem cell therapies, favored by HSCs and mesenchymal stromal cells, in the past half-century paved the way for the treatments of certain malignant diseases. The inherent properties and functions of stem cells, however, may not be able to fulfill the requirements in the exploration of next-generation stem cell therapy, which aims to elicit broader therapeutic applications in various diseases. Recent advances in biomaterials have provided sophisticated toolkits to revolutionize current stem cell therapies by facilitating real-time stem cell tracking, functional engineering of stem cells and microenvironment-targeted delivery. Particularly, many biomaterials-based platforms focus on maintaining viability and paracrine secretion ability of MSCs in vivo since low survival rate of the transplanted MSCs in diseased sites is the main roadblock in eliciting their promising therapeutic efficacy in clinics. Some biomaterial-involved stem cell therapies are under clinical investigation (Summarized in table 1). For example, allogeneic adipose-derived MSCs were encapsulated in a hydrogel sheet to treat patients suffering from diabetic foot ulcers, which generated a 73% total wound recovery rate, significantly higher than the control group (47%) [93].

Table 1.

Representative biomaterial-involved stem cell therapies under clinical investigation.

Stem cell type	Biomaterial-constructed platforms	Function	Disease	Clinicaltrials.gov identifier	Phase
NSCs	Iron oxide nanoparticles	Tracking	Brain trauma	PMID: 17135597	Pilota
HSCs	Iron oxide nanoparticles	Tracking	Chronic spinal cord injury	PMID: 17610376	Pilota
hBM-MSCs	Iron oxide nanoparticles	Tracking	Osteoarthritis, Multiple sclerosis	NCT03648463, NCT00781872	I, II
hBM-MSCs	Biphasic calcium phosphate granules scaffold	Delivery	Severely atrophied mandibular bone	NCT02751125	I
hUCB-MSCs	Collagen scaffold	Delivery	Chronic spinal cord injury repair, chronic ischemic cardiomyopathy, diabetes	NCT02352077, NCT02635464, NCT02745808	I, I, I
hBM-MSCs	Collagen I scaffold	Delivery	Osteoarthritis	NCT00850187	I
hBM-MSCs	Protein matrix in collagen hydroxyapatite scaffold	Engineering; Delivery	Osteoarthritis	NCT01159899	I
hBM-MSCs	HYAFF® scaffold	Delivery	Osteoarthritis	NCT02659215	I
hUCB-MSCs	Hyaluronic acid hydrogel	Delivery	Osteoarthritic	NCT01733186, NCT02776943	II, II
hAD-MSCs	Hydrogel sheet	Delivery	Diabetic foot ulcers	NCT03183804	II
hAD-MSCs	Sodium hyaluronate hydrogel	Delivery	Osteoarthritis	NCT02162693	II

NSC: neural stem cell; HSC: hematopoietic stem cell, MSC: mesenchymal stem cell, BM: bone marrow, UCB: umbilical cord blood, AD: adipose.

^aIndicates no Clinicaltrials.gov identifier is available for the marked study, so PMID of the corresponding peer-reviewed research article is included.

Despite encouraging results in many preclinical studies and some early clinical trials, certain challenges of the involvement of biomaterials in stem cell therapy need to be addressed. The long-term effects of synthetic biomaterials, especially when used as stem cell delivery systems or expansion platforms, on differentiation and proliferation of the transfected stem cells should be carefully monitored as the cell loading approaches may cause constant biochemical or mechanical communications between materials and cells. Although some preclinical studies illustrated a safety profile lasting several weeks or months, clinical transplantation of stem cells usually requires a more extended evaluation period. The utilization of cell-derived materials to construct the biomaterials-based platforms will be helpful to minimize undesired effects on stem cells. Moreover, the current design of biomaterial-based platforms mainly focuses on single functional application, which may not be sufficient for a multifunctional stem cell therapy and may increase additional engineering. It would be essential for the future fabrications of biomaterials to pursue multivalent strategies. With growing demands for specialized usage and personalized medicine, the future design of biomaterials may rely on the distinct properties of stem cells from different sources or types, and the thorough evaluation of the pathological microenvironment of individual patients. In all, the continuous optimization of biomaterials will provide new opportunities for clinical translation and broader applications of stem cell therapies.

Data availability statement

No new data were created or analyzed in this study.