Materiobiology-guided regulation of mesenchymal stromal cell fate for aging-related diseases: From basic parameter design to clinical application

Yuke Feng; Yuqian Qiu; Shaozhen Zhang; Kai Dai; Jing Wang; Changsheng Liu

doi:10.1016/j.bioactmat.2026.02.034

. 2026 Feb 26;61:577–600. doi: 10.1016/j.bioactmat.2026.02.034

Materiobiology-guided regulation of mesenchymal stromal cell fate for aging-related diseases: From basic parameter design to clinical application

Yuke Feng ^a,^b,¹, Yuqian Qiu ^a,^b,¹, Shaozhen Zhang ^a,^b, Kai Dai ^a,^b,^c,^⁎, Jing Wang ^a,^b,^c,^⁎⁎, Changsheng Liu ^b,^c,^d,^⁎⁎⁎

PMCID: PMC12963921 PMID: 41799951

Abstract

Mesenchymal stromal cells (MSCs) possess potent immunomodulatory, pro-angiogenic, and regenerative capacities, offering broad clinical promise in regenerative medicine. However, clinical application is constrained by low in vivo survival, poor targeting, variable efficacy, replicative senescence and insufficiently characterized in vivo cell fate. The accelerating global aging trend further complicates MSC therapy for age-associated diseases. Biomaterials have emerged as powerful tools to enhance MSC function and direct cell fate. This review adopts a materiobiology perspective to detail how biomaterial design—across physical (stiffness, topography), chemical (surface chemistry, ion release), and biological (growth factor release, gene delivery) parameters, can proactively steer MSC fate and function to amplify therapeutic efficacy. Subsequently, focusing on the characteristics of aging-related diseases from three perspectives—reactive oxygen species scavenging, epigenetic regulation, and telomere protection—this review summarizes the anti-aging functional design of biomaterials. To bridge biomaterial-driven MSC regulation with in vivo therapeutic outcomes, we systematically review post-transplant fate-tracking technologies, including imaging-based approaches (MRI, CT, fluorescent probes) and transcriptomic monitoring, which enable quantitative evaluation and causal understanding of MSC survival, biodistribution, functional states, and aging trajectories in vivo. Building on these methodological foundations, we summarize engineering solutions for MSC-biomaterial combination therapies in representative aging-related diseases, such as fibrosis, osteoarthritis, heart failure, and wound healing. Importantly, in vivo outcomes can in turn guide subsequent biomaterial design. Finally, we discuss policy and technical hurdles, current limitations, and future directions—including mitochondrial homeostasis control, microfluidics-based dynamic culture, and machine learning for structure-function prediction—to inform next-generation, intelligent MSC-biomaterial combination therapies.

Keywords: Mesenchymal stromal cell, Materiobiology, Cell fate regulation, Biomaterial design, Anti-aging

Graphical abstract

Materiobiology-Guided Regulation of Mesenchymal Stromal Cell (MSC) Fate This schematic summarizes a materiobiology-guided framework in which rational biomaterial design regulates MSC fate and therapeutic function. Basic material parameters-including stiffness, topography, surface chemistry, ion release, and bioactive factor or gene delivery-govern MSC sensing, adhesion, and early fate commitment. These foundational designs further enable anti-aging functionalization strategies, such as reactive oxygen species (ROS) scavenging, epigenetic regulation, and telomere protection, to restore or maintain MSC functionality in aged microenvironments. In vivo position tracking and cell fate tracking serve as a functional validation layer, providing critical insight into MSC biodistribution, persistence, and therapeutic outcomes. Biomaterial-modulated MSCs are subsequently applied to the treatment of aging-related diseases, including fibrosis, osteoarthritis, heart failure, and impaired wound healing, thereby forming a feedback loop that guides next-generation biomaterial design.

Highlights

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Parameter-to-function framing of physics, chemistry, biomolecules.
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Multimodal imaging-MRI/CT/fluorescence plus transcriptomics to map in vivo MSC fates.
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Aging diseases integrate Fibrosis, HF, OA, Wounds into a clinical engineering loop.
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Roadmap: mitochondrial tuning, microfluidic cell culture, machine learning-based inversion.

1. Introduction

Mesenchymal stromal cells (MSCs) are multifunctional cells with therapeutic potential in immune modulation, angiogenesis, and tissue regeneration [1], Over 2000 MSC trials are registered on ClinicalTrials.gov, with cells sourced from various adult and perinatal tissues, such as adipose(AD) tissue, bone marrow(BM), and umbilical cord(UC). The International Society for Cell & Gene Therapy (ISCT) recently updated MSC criteria, specifying CD73⁺, CD90⁺, CD105⁺, and CD45⁻ surface markers [2] The US Food and Drug Administration (FDA, December 2024) and the China National Medical Products Administration (NMPA, January 2025) approved the first MSC therapy products, following prior approvals in Canada, Japan, the UK, and South Korea, with graft-versus-host disease (GvHD) as a primary indication [3].

Table 1 lists MSC therapies approved by regulatory agencies worldwide. Despite these approvals, most MSC products remain minimally engineered and are largely confined to a limited set of indications, highlighting the persistent gap between broad biological potential and consistent therapeutic efficacy—particularly in aging-related diseases. Yet variability in cell source, culture conditions, delivery route, and dosing—and in vivo survival and homing efficiency—continues to impact clinical performance. Importantly, these limitations are further amplified in aging-related diseases, where chronic inflammation, oxidative stress, and senescent cell accumulation profoundly reshape the in vivo microenvironment and compromise MSC functionality. More fundamentally, the in vivo fate of transplanted MSCs—including their survival dynamics, spatial distribution, functional state transitions, and senescence trajectories—remains poorly defined.

Table 1.

MSC therapies approved by regulatory agencies worldwide.

Name/Year	Company (Country)	Indication	Cell source
Queencell/2010	Anterogen (Republic of Korea)	Connective tissue diseases	AD
Cellgram AMI/2011	Pharmicell (Republic of Korea)	Acute myocardial infarction	BM
Cupistem/2012	Anterogen (Republic of Korea)	Crohn's fistula	AD
Cartistem/2012	Medipost (Republic of Korea)	Knee Osteoarthritis	UC
NeuroNataR/2014	Corestem (Republic of Korea)	Amyotrophic lateral sclerosis	BM
RemestemcelL/2015	Mesoblast,Ltd. (Australia)	Pediatric acute and refractory Graft-versus-host disease (GvHD)	BM
Temcell HS/2015	JCR Pharmaceuticals (Japan)	Acute and refractory GvHD	BM
Stempeucel/2016	Stem-peutics Research Bangalore (India)	Critical limb ischemia	BM
Alofisel/2018	TiGenix (US) and Takeda (UK)	Complex perianal fistulas in Crohn's disease	AD
MesestroCell/2018	Cell Tech Pharmed (Iran)	Osteoarthritis	BM
Stemirac/2018	Nipro Corp (Japan)	Spinal cord injury	BM
AKUUGO/2024	SanBio(Japan)	Chronic motor deficits after traumatic brain injury	BM
Ryoncil/2025	Mesoblast(US)	Steroid-refractory acute GvHD	BM
Amimatoside/2025	BOSHENG EXCELLENCE(China)	Acute GvHD	UC

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Materiobiology is the study of how biomaterial properties elicit biological effects across different levels [4]. Prior studies show that biomaterial composition, mechanics, surface chemistry, and structural features modulate cell adhesion, migration, proliferation, and differentiation, guiding regeneration via direct and indirect cell-material interactions. Rather than acting as passive carriers, biomaterials need to be reconsidered as instructive platforms capable of actively programming MSC fate and functional trajectories across sourcing, expansion, and delivery stages. Accumulating evidence demonstrate that material composition, mechanical properties, surface chemistry, and structural features can modulate MSC adhesion, migration, proliferation, and differentiation through both direct and indirect cell-material interactions. However, most existing studies remain focused on isolated material parameters, providing limited insight into how multiple cues are integrated to regulate MSC fate in complex biological environments. Moreover, the lack of systematic in vivo evaluation—particularly with respect to cell fate dynamics and material-induced biological effects—has constrained the establishment of predictive and translatable design principles.

This review establishes an operational, scalable, and traceable materiobiology engineering framework that addresses key methodological bottlenecks in MSC-biomaterial research. Specifically, it organizes biomaterial regulation into a parameter-to-function paradigm encompassing mechanical and topological cues, surface chemistry and degradation products, and biological payloads, while explicitly recognizing limited quantitative datasets and insufficient in vivo readouts as major constraints on precision design. To overcome these challenges, the framework upgrades conventional outcome-based evaluation to a position-fate assessment strategy, integrating multimodal in vivo imaging with transcriptomic profiling to enable causal linkage between material cues, MSC states, and therapeutic function. Anchored in aging-related diseases, this approach further connects disease stratification, material customization, and cell empowerment within a clinically oriented engineering loop that supports iterative optimization and real-world validation. Collectively, this framework bridges basic material design and clinical translation, providing a coherent methodological foundation for advancing MSC-material combination therapies toward the next generation of intelligent, precise, and reproducible interventions (Fig. 1).

Fig. 1 — **Conceptual framework of materiobiology-guided regulation of mesenchymal stromal cell (MSC) fate for aging-related disease therapy.** Upstream: Biomaterials design across physical-chemical-biological axes, functionalize for aged microenvironments, and map “material properties-cell functions (proliferation, paracrine, differentiation)” relationships. Some images are reproduced with permission [[5], [6], [7], [8]], Copyright 2024, American Chemical Society; Midstream: post-transplant multimodal localization (MRI/CT/fluorescence) plus transcriptomic monitoring to assess “position and fate.” Downstream: staged clinical evaluation in aging-related diseases, feeding imaging and biomarker real-world data back into iterative, standardized, and traceable engineering pipelines. Created with BioRender.com. Some images are reproduced with permission [9], Copyright 2023,The American Association for the Advancement of Science.

2. Current landscape of MSC clinical trials

By 2025, MSC-based clinical applications have become widespread, with the majority of studies remaining in early-phase development (predominantly Phase I/II and a limited number of Phase III/IV trials). Overall, MSC therapies have demonstrated a favorable safety profile, as most trials report no significant mid-term adverse events, with only mild and transient infusion-related reactions observed in a small subset of patients.

This section outlines the general clinical landscape and translational status of MSC-based therapies by summarizing recent clinical trials that have reported preliminary efficacy across diverse disease indications. This overview provides contextual background for the subsequent, disease-oriented discussion in Section 6, which focuses on aging-related conditions and biomaterial-assisted strategies. Table 2 summarizes representative MSC clinical trials from the past five years, spanning respiratory, neurological, and musculoskeletal indications, and involving MSCs derived from adipose tissue, bone marrow, and umbilical cord sources. Both autologous and allogeneic products have been investigated using systemic or local administration routes, depending on the clinical context.

Table 2.

MSC trials with efficacy signals over the past five years.

Disease	MSC Source	Engineered	NCT Number	Location(s)	Phase	Administration Route
Acute Respiratory Distress Syndrome (COVID-19 related)	Not specified	Unknown	NCT04524962	Iowa City, IA; Baltimore, MD, USA	1	Not specified
ALS (Amyotrophic Lateral Sclerosis)	Autologous bone marrow NurOwn (MSC-NTF)	Yes (NTF-induced)	NCT03280056	Irvine/Los Angeles/San Francisco, CA; Boston/Worcester, MA	3	Intrathecal
ALS (randomized multicenter)	Autologous bone marrow NurOwn (MSC-NTF)	Yes (NTF-induced)	NCT02017912	Boston, MA; Rochester, MN, USA	2	Intrathecal
Alzheimer's Disease	Not specified	Unknown	NCT03117738	California; Hawaii, USA	1/2	Intravenous
Acute Respiratory Distress Syndrome (Moderate or Severe)/COVID-19 Pneumonia	Not specified	No	NCT04466098	Minneapolis, MN; Pittsburgh, PA, USA	2	Intravenous
Cerebral Palsy (children)	Allogeneic cord blood and cord tissue MSCs	No	NCT03473301	Durham, NC, USA	1/2	Intravenous
Cystic Fibrosis	Allogeneic bone marrow MSCs	No	NCT02866721	Cleveland, OH, USA	1	Intravenous
Degenerative Disc Disease/Intervertebral Disc Disease/Low Back Pain	Allogeneic bone marrow MSCs	No	NCT01860417	Valladolid, Spain	1/2	Intradiscal injection
Diabetes Mellitus Type 2 (endothelial dysfunction)	Allogeneic bone marrow MSCs	No	NCT02886884	Miami, FL, USA	1/2	Intravenous
Endothelial Dysfunction/Metabolic Syndrome/Chronic Inflammation	Allogeneic UC-MSCs and BM-MSCs	No	NCT03059355	Miami, FL, USA	1/2	Intravenous
Ischemic Cardiomyopathy (CONCERT-HF)	Autologous bone marrow MSCs	No	NCT02501811	CA/FL/IN/KY/MN/TX, USA	2	Transendocardial injection
Knee Osteoarthritis (JointStem vs Synvisc-One)	Not specified	Unknown	NCT02674399	Santa Monica; Walnut Creek, CA, USA	2	Intra-articular injection
Knee Osteoarthritis (MILES)	Autologous bone marrow MSCs; allogeneic UCT-MSCs	No	NCT03818737	FL/GA/NC/ND/SD, USA	3	Intra-articular injection
Lateral Epicondylitis (Tennis Elbow)	Allogeneic adipose MSCs	No	NCT01856140	Seoul, South Korea	Early 1	Ultrasound-guided local injection
Multiple Sclerosis (chronic progressive; open-label repeat dosing)	Autologous bone marrow NurOwn	Yes (NTF-induced)	NCT03799718	Los Angeles, CA; Redwood City, CA; New York, NY; Cleveland, OH, USA	2	Intrathecal
Multiple Sclerosis (randomized DB vs placebo)	Autologous adipose MSCs	No	NCT05116540	Sugar Land, TX, USA	2	Intravenous
Parkinson's Disease (early & moderate)	Allogeneic adipose MSCs	No	NCT04928287	Sugar Land, TX, USA	2	Intravenous
Perinatal Arterial Ischemic Stroke (neonates)	Allogeneic bone marrow MSCs	No	NCT03356821	Utrecht, Netherlands	1/2	Intranasal
Post COVID-19 Syndrome (Long COVID)	Allogeneic adipose HB-adMSCs	No	NCT05126563	Sugar Land, TX, USA	2	Intravenous
Rheumatoid Arthritis	Autologous adipose MSCs	No	NCT03691909	Pasadena, TX, USA	1/2	Intravenous
Rotator Cuff Tear (partial thickness)	Allogeneic adipose MSCs	No	NCT02298023	Seoul, South Korea	2	Ultrasound-guided local injection
Salivary Gland Hypofunction/Xerostomia (post-radiation)	Autologous adipose MSCs	No	NCT02513238	Denmark	2	Local injection
COVID-19 (suspected; treatment)	Allogeneic adipose MSCs	No	NCT04362189	Houston, TX, USA	2	Intravenous
COVID-19 (severe ALI/ARDS)	Allogeneic UC-MSCs	No	NCT04355728	Miami, FL, USA	1/2	Intravenous
COVID-19 (immune support; no signs of infection)	Allogeneic adipose MSCs	No	NCT04348435	Sugar Land, TX, USA	2	Intravenous
COVID-19 ARDS (randomized pilot; Duke/Miami)	Allogeneic cord tissue MSCs	No	NCT04399889	Boca Raton & Miami, FL; Valhalla, NY; Durham, NC, USA	1/2	Intravenous

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Collectively, the current clinical evidence primarily supports the feasibility and tolerability of MSC-based therapies, while large-scale, reproducible efficacy data remain limited. Taken together, these clinical studies outline the current translational status of MSC-based therapies and provide a foundation for the following disease-specific discussions on biomaterial-assisted strategies.

Before detailing the physicochemical and biological cues of biomaterials and the underlying regulatory mechanisms, it is necessary to clarify the therapeutic context in which MSCs are being discussed. While early clinical strategies primarily relied on the exogenous administration of MSCs, accumulating evidence has revealed substantial translational challenges associated with direct MSC infusion, including poor in vivo survival, limited homing efficiency, phenotypic instability, and highly variable therapeutic outcomes. These limitations have prompted a paradigm shift from cell replacement-centered strategies toward approaches that modulate the regenerative microenvironment.

In this emerging framework, biomaterials are increasingly recognized not merely as delivery vehicles for exogenous MSCs, but as active regulators capable of reshaping local niches and dynamically modulating the behavior of endogenous MSCs in situ. Such material-mediated regulation of resident MSC populations offers a potentially more controllable, scalable, and clinically translatable strategy, particularly in complex disease settings where direct cell transplantation faces intrinsic barriers. Accordingly, Sections 3, 4 primarily focus on how material physicochemical and biological properties influence MSC fate and function within the in vivo microenvironment, laying a mechanistic foundation for understanding material-assisted MSC therapies beyond conventional cell infusion paradigms.

3. Basic design principles for biomaterial parameters

While biochemical factors (e.g., growth factors, hormones) regulate cellular and tissue functions, biophysical effects of materials are increasingly recognized as key modulators of biological activity [4]. As illustrated in Fig. 2, this section outlines three routes—physical parameter regulation, chemical composition control, and biomolecules loading—to modulate MSC functions such as adhesion, proliferation, migration, and differentiation. Notably, the lack of high-quality datasets linking material parameters to cell function—especially in vivo functional readouts—currently limits precision materiobiology-guided design.

Fig. 2 — **Basic parameter design strategies for materiobiology-guided regulation of MSC fate**. This schematic summarizes the major categories of biomaterial parameters that govern MSC behavior through physical, chemical, and biological cues. Physical parameters include matrix stiffness regulation and topographical structure, which modulate MSC adhesion, cytoskeletal organization, and mechanotransduction, thereby governing lineage commitment and differentiation outcomes, particularly through stiffness gradients and micro-/nano-structured microenvironments. Chemical parameters involve surface chemical modifications and regulation by material degradation products, enabling dynamic modulation of cellular metabolism, proliferation, and differentiation via changes in ion release, local chemical composition, and energy states. Biological parameters are represented by biomolecule-based strategies, including controlled growth factor release and gene delivery systems, which directly regulate MSC signaling pathways and transcriptional programs. Collectively, these basic parameter design strategies define the foundational materiobiology framework through which biomaterials interact with MSCs to orchestrate fate decisions. Created with BioRender.com. Some images are adapted with permission [5,10,11], Copyright 2022,American Chemical Society.

In Sections 3, 4, we focus on how biomaterial physicochemical and biological cues regulate MSC fate and functional states at the cellular and microenvironmental levels. These regulatory principles are discussed in a source-agnostic manner, as the core mechanotransduction and signaling responses to material cues are largely conserved across endogenous and exogenously delivered MSCs.

3.1. Physical parameter modulation

Physical parameters of biomaterials constitute a primary layer of instructive cues that govern MSC behavior through direct mechanical interactions. Unlike biochemical signals that rely on ligand-receptor binding, physical cues such as matrix stiffness and surface topography are continuously sensed by MSCs via integrin-mediated adhesion, cytoskeletal organization, and force transmission, thereby shaping cell morphology, migration, fate commitment, and functional output. Increasing evidence indicates that these parameters do not act as passive background properties but actively engage mechanotransduction pathways that translate extracellular mechanics into intracellular biochemical, transcriptional, and epigenetic responses. In this section, we focus on two representative and mechanistically distinct physical regulatory dimensions-matrix stiffness gradients and micro-nanoscale topographical architectures-to illustrate how materiobiology-guided physical parameter modulation directs MSC lineage specification and functional programming across multiple biological scales.

To facilitate visualization of how physical parameters are implemented in practice, Fig. 3 presents one representative example illustrating stiffness- and topography-based regulation of MSC behavior.

3.1.1. Mechanotransduction of lineage commitment under stiffness gradients

In recent years, increasing evidence has demonstrated that the extracellular matrix (ECM) plays a central role in regulating MSC fate. Among ECM properties, mechanical characteristics—particularly matrix stiffness—have been identified as critical biophysical cues that exert profound effects on MSC behavior.

Matrix stiffness orchestrates MSC function by simultaneously influencing cell morphology, migration, and proliferative behavior. On relatively soft substrates (<10 kPa), MSCs tend to maintain smaller, rounded, or elongated morphologies. In contrast, on substrates with intermediate stiffness (e.g. 17 kPa), MSCs more frequently adopt a spindle-shaped morphology. On stiff substrates (e.g. 28.9 kPa), MSCs exhibit extensive spreading and a polygonal morphology. These stiffness-dependent morphological changes arise from cytoskeletal reorganization, particularly alterations in F-actin and microtubule structures, enabling MSCs to sense mechanical cues and adapt their morphology accordingly. In addition to shaping cell morphology, matrix stiffness also regulates MSC migration. Notably, MSCs cultured on substrates with stiffness gradients exhibit pronounced durotaxis, preferentially migrating toward regions of higher stiffness.

The ability of matrix stiffness to direct MSC lineage commitment represents another critical aspect of its relevance in tissue engineering. Numerous studies have shown that substrate stiffness alone can independently guide MSC differentiation toward specific lineages. Soft substrates (<10 kPa) preferentially promote adipogenic differentiation, whereas stiffer substrates (e.g., ∼50 kPa) favor osteogenic differentiation. Substrates with intermediate stiffness (around 13 kPa) tend to support chondrogenic differentiation. These stiffness-dependent differentiation patterns are closely associated with intracellular mechanotransduction pathways. In particular, the nuclear localization of Yes-associated protein (YAP) is widely recognized as a key molecular mechanism underlying osteogenic differentiation induced by stiff substrates.

Beyond lineage specification, matrix stiffness further regulates MSC function by activating a series of intracellular signaling pathways. Mechanical cues transmitted through mechanotransduction pathways can modulate intracellular reactive oxygen species (ROS) levels, thereby influencing the MSC secretome and their role in tissue repair. For example, MSCs cultured on soft substrates (1.5 kPa) exhibit significantly elevated ROS levels. This mild oxidative stress can optimize MSC paracrine activity and enhance their reparative function. Moreover, low stiffness gradients (50 ± 3.2 Pa μm⁻¹) suppress MSC polarization, activate H4K16ac-mediated chromatin relaxation, promote TLR3 expression, and ultimately drive MSCs toward an anti-inflammatory phenotype.

Overall, matrix stiffness represents a fundamental biophysical regulator of MSC behavior across multiple levels, including morphology, migration, differentiation, and intracellular signaling. However, the stiffness thresholds associated with specific cellular outcomes remain highly context-dependent and are often influenced by additional microenvironmental cues. Addressing these limitations will be essential for translating stiffness-guided MSC regulation into rational biomaterial design and reliable therapeutic strategies.

3.1.2. Topographical regulation of MSC fate

Topography refers to microscale and nanoscale geometric features that are preserved under continuous deformation. Scaffold topographies regulate MSC behaviors including migration, adhesion, proliferation, and lineage differentiation. In tissue engineering, mimicking ECM physical features—particularly micro/nanoscale topographies—provides an optimal microenvironment for stem cells [14].

Synthetic polymer scaffolds offer a versatile platform for engineering diverse and precisely tunable topographical features, including surface roughness, fiber alignment, spatial periodicity, and pore geometry. These architectural parameters function as dominant physical cues that reorganize the MSC cytoskeleton and mechanosensing machinery, thereby shaping differentiation trajectories and paracrine activity, often accompanied by epigenetic and secretomic remodeling. Roughened polymeric surfaces, for example, have been shown to bias MSC fate toward osteogenesis through epigenetic reprogramming, characterized by reduced H3K27me3 and elevated H3K9ac enrichment at osteogenic gene loci, highlighting a direct link between topographical cues and chromatin accessibility [15]. Beyond uniform designs, gradient and spatially heterogeneous microarchitectures enable localized and position-dependent lineage specification. Gradient-sized diamond-pored microstructures fabricated via dual-stage temperature-controlled 3D printing induced region-specific fibrocartilage-like and hyaline-like MSC differentiation, effectively recapitulating the zonal biomechanics of native meniscal tissue [5]. Anisotropic fibrous topographies, particularly aligned fiber architectures, further modulate MSC secretory phenotypes. Compared with randomly oriented fibers, aligned topographies selectively activate MAPK-associated pathways, reshaping the ADSC secretome to favor tenogenic repair [16]. At the microscale, precise control of fiber spacing represents a critical determinant of MSC paracrine potency. Three-dimensional fibrous scaffolds with narrowly defined strand spacing (∼40 μm) activate the FAK-PI3K/Akt mechanotransduction axis, significantly enhancing immunomodulatory and pro-angiogenic factor secretion and accelerating cutaneous regeneration [17]. Similarly, fiber intersection angles serve as topographical regulators of transcriptional programs. Microfibrous architectures with orthogonal (90°) orientations preferentially promote osteogenic commitment via the miR-222-5p/cbfb/Runx2 regulatory axis, underscoring the sensitivity of MSC gene regulation to geometric constraints [18]. More complex three-dimensional spatial topographies, inspired by space-filling polyhedral geometries, mimic the trabecular meshwork of cancellous bone. Such architectures activate PI3K-Akt signaling to simultaneously promote osteogenesis, angiogenesis, and neurogenesis in situ, achieving functional regeneration without exogenous cells or growth factors [19] Collectively, polymer-based topographical strategies demonstrate the high sensitivity of MSC fate to architectural parameters; however, most designs remain empirically optimized, with limited parameter standardization and cross-study comparability, constraining their predictive value for translational scaffold design.

Topographical engineering on metallic biomaterials often extends beyond passive physical guidance, integrating chemical and biological functionalities to synergistically regulate MSC behavior. Fibrous microtopographies on titanium implants enhance MSC adhesion and migration while simultaneously increasing intracellular uptake of surface-bound plasmid DNA, enabling efficient gene delivery that cooperatively promotes osteogenesis and osseointegration alongside antibacterial activity [20]. At the nanoscale, bioactive nanostructures with intrinsic antioxidative properties further reinforce MSC mechanosensing under pathological conditions. Nanoceria-decorated topographies synergize integrin-mediated adhesion with TGF-β signaling, preserving MSC osteogenic capacity under diabetic oxidative stress and markedly improving early bone regeneration [21]. These studies illustrate that multifunctional metallic topographies can couple mechanical instruction with biochemical protection; nevertheless, their long-term biosafety, degradation behavior, and gene-delivery stability in vivo remain insufficiently characterized.

Nucleic acid nanomaterials elevate topographical regulation to the molecular and supramolecular scale, enabling programmable control over ligand density, spatial arrangement, and multivalent interactions. Precisely engineered three-dimensional nanotopographies based on tetrahedral framework nucleic acids, achieved by tuning the number and positioning of Apt19S moieties, optimize binding to MSC surface receptors such as CXCR4. This molecular-scale topography generates multivalent “stem cell catcher” effects, markedly enhancing early MSC [22]. While nucleic acid-based nnanotopographies offer unmatched precision, their scalability, manufacturing cost, and immunological safety warrant systematic evaluation before broader translational application.

Collectively, biomaterial topography regulates MSC fate not through isolated signaling pathways, but via a unified mechanotransduction process that converts physical cues into biochemical responses. Micro- and nanoscale architectural features reorganize integrin-mediated adhesion, focal adhesion assembly, and cytoskeletal tension, thereby reshaping intracellular force distribution. These biophysical perturbations are sensed by mechanosensitive hubs such as focal adhesion kinase (FAK), which in turn activate convergent downstream modules including PI3K/Akt and MAPK. Rather than acting independently, these pathways function as integrated executors that translate topographical inputs into transcriptional, epigenetic, and functional programs governing MSC differentiation and paracrine activity.

Despite substantial progress, several unresolved issues remain. First, although downstream pathways such as PI3K/Akt are frequently implicated, the initial molecular events linking specific topographical features to upstream mechanosensing remain incompletely defined. Second, there is no unified framework for optimizing key topographical parameters (e.g., angle, fiber spacing, roughness), with outcomes highly dependent on cell source, material system, and experimental context. Third, precise and scalable fabrication of hierarchically heterogeneous architectures remains technically challenging. Finally, long-term in vivo stability and biosafety data for complex topographical designs are still limited. Future efforts should prioritize systematic, high-quality datasets that map topographical parameters to MSC fate outcomes across biological scales, thereby strengthening the theoretical and translational foundations of materiobiology-guided topographical regulation.

3.2. Chemical parameter modulation

Beyond providing structural support, biomaterials establish a chemically active microenvironment that directly governs MSC sensing, metabolism, and fate decisions. Chemical parameter modulation represents a critical strategy for transforming biomaterials from passive substrates into instructive regulators of cell behavior. In this section, two complementary yet mechanistically distinct approaches are highlighted: surface chemical modification, which primarily operates at the cell-material interface to regulate adhesion, signaling, and early fate commitment; and material degradation products, which act at the microenvironmental and metabolic levels by releasing bioactive ions or metabolites that reshape immune responses and cellular energy pathways. Together, these strategies enable both immediate and sustained chemical cue delivery, forming a coherent framework for actively directing MSC function in complex regenerative settings.

As an illustrative example, Fig. 4 depicts one representative chemical parameter-based strategy for modulating MSC fate, encompassing surface modification and degradation product-mediated regulation.

3.2.1. Surface chemistry modification

Cell-material interactions are initiated at the material surface, rendering surface chemistry a primary determinant of early cell sensing and downstream fate decisions. By tailoring surface functional groups, biomaterials can actively regulate protein adsorption, integrin engagement, and intracellular signaling, thereby exerting sustained control over MSC behavior beyond initial adhesion events.

Surface functional groups critically shape MSC differentiation and lineage commitment by modulating interfacial chemical cues [25]. For instance, nanocellulose surfaces bearing distinct oxidation chemistries differentially regulate MSC responses. Aldehyde-rich TEMPO-oxidized nanocellulose exhibits limited effects on MSC adhesion, proliferation, and osteogenesis, whereas aldehyde-free, reduced surfaces significantly enhance cell spreading and osteogenic differentiation, underscoring the sensitivity of MSC fate to subtle chemical variations at the interface [26]. Beyond single-function modifications, multifunctional surface chemistries enable the simultaneous regulation of antibacterial performance, osteogenesis, and immune responses. Titanium implant surfaces decorated with spatially organized quaternary ammonium (antibacterial) and phosphate (osteogenic) groups achieve a balanced microenvironment that promotes MSC osteogenic differentiation while polarizing macrophages toward a pro-repair M2 phenotype, thereby enhancing osseointegration [27,28]. Similarly, metal-phenolic network coatings provide chemically active interfaces that enhance BMSC adhesion and osteogenic differentiation while concurrently modulating host immune responses. Such coatings promote M2 macrophage polarization, contributing to improved implant integration through coordinated osteo-immune regulation [29]. Functional group-based surface modifications highlight the potency of chemical cues in directing MSC fate; however, most current strategies rely on static surface chemistries, with limited consideration of temporal dynamics or in vivo chemical stability.

Surface modification and specialized coatings extend chemical control beyond lineage specification to encompass MSC migration, paracrine signaling, and microenvironmental remodeling. Plasma-treated polycaprolactone nanofibers with increased hydrophilicity and protein adsorption activate FAK-ERK1/2 signaling, thereby enhancing MSC migration and accelerating bone regeneration [30]. For three-dimensional porous scaffolds, uniform internal biofunctionalization remains a critical challenge. Packed-bed plasma immersion ion implantation enables homogeneous chemical modification throughout complex architectures, supporting robust MSC expansion while preserving multipotency—an essential prerequisite for translational scaffold design [31]. In material coatings, incorporating surface-immobilized bioactive ligands, rather than soluble factors, further refines chemical instruction at the cell-material interface. Disordered micro-nano patterned surfaces bearing covalently immobilized BMP-2 mimetic peptides in combination with RGD motifs significantly enhance MSC osteogenesis, demonstrating that spatial presentation of chemical cues is as critical as ligand identity [32]. Under pathological conditions, chemically functionalized surfaces can actively restore compromised MSC function. Metal-phenolic nanozyme coatings scavenge excessive reactive oxygen species, alleviate diabetic oxidative stress, and rescue MSC osteogenic capacity, thereby improving osseointegration in metabolically impaired environments [33]. Additional strategies, including therapeutic molecule-modified scaffolds and protein-functionalized interfaces, further modulate inflammatory and angiogenic microenvironments, facilitating vascularized bone regeneration and coordinated recruitment of MSCs and pro-regenerative immune cells [34,35]. These multifunctional surface chemistries demonstrate strong potential for microenvironmental modulation; nevertheless, disentangling the relative contributions of chemical cues versus secondary immune-mediated effects remains challenging.

Beyond static designs, dynamic surface chemistries introduce temporal control over MSC-material interactions. Thermoresponsive mixed polymer brushes that reversibly modulate surface cationic properties enable temperature-dependent control of cell adhesion and detachment, allowing selective MSC separation from heterogeneous cell populations [11].

Despite significant progress, several limitations constrain the translational impact of surface chemistry-based MSC regulation. Many studies remain confined to in vitro settings, with limited in vivo validation of chemical stability and biological durability. Moreover, a substantial proportion of reported effects are phenomenological, lacking mechanistic dissection of how specific functional groups are sensed and transduced by MSCs. Finally, the complexity and cost of advanced surface modification techniques pose challenges for large-scale manufacturing and clinical standardization.

Future research should prioritize high-throughput and modular surface chemistry platforms, coupled with real-time, noninvasive functional assessments, to establish robust structure-function relationships and accelerate clinical optimization.

3.2.2. Regulation via degradation products

Implanted biomaterials can release inorganic ions (e.g., Ca, Sr, Zn) and tricarboxylic acid (TCA) cycle intermediates (e.g., citrate, succinate) upon degradation, contributing to bone regeneration/mineralization and to immune regulation and tissue repair.

Controlled release of bioactive inorganic ions represents a major mechanism by which degradation products indirectly govern MSC fate through immune microenvironment remodeling. Calcium-, strontium-, and zinc-releasing ceramic or composite coatings have been shown to promote M2 macrophage polarization, establishing an anti-inflammatory milieu that favors MSC osteogenic differentiation [36,37]. Expanding beyond single-ion systems, multi-ion co-doped nanostructured coatings enable temporally coordinated immune regulation. Quadruple-ion-doped Na₂TiO₃ nanorod coatings release Ca²⁺, Mg²⁺, and other ions via ion exchange, sequentially regulating macrophage polarization while simultaneously promoting angiogenesis and osteogenesis [38]. Stimuli-responsive materials can smartly control ion release; for example, Stimuli-responsive materials further introduce on-demand ion delivery, enabling stage-specific regulation during tissue repair. Ultrasound-responsive hydrogels that release Ca²⁺ upon sonication enhance BMSC migration, rescue apoptosis, and promote osteogenic differentiation, thereby supporting multistage bone regeneration [39]. In addition to immune-mediated pathways, continuous release of mineral-associated elements can directly modulate calcium homeostasis and cellular metabolism. Black phosphorus-based three-dimensional nanofiber scaffolds releasing phosphorus, calcium, and silicon synergistically promote osteogenesis by combining nutrient supply with photothermal modulation of mineral metabolism [40]. Notably, coordinated release of antibacterial agents and osteogenic ions enables simultaneous infection control and tissue regeneration. Gentamicin-encapsulated chitosan-borosilicate glass implants achieve sustained release of both gentamicin and Ca²⁺, effectively treating osteomyelitis while enhancing BMSC osteogenic gene expression and protein secretion [41]. At the mitochondrial level, ion-releasing biomaterials can reprogram intracellular quality control and redox balance. Calcium silicate-based materials induce mitophagy, facilitating clearance of dysfunctional mitochondria, reducing reactive oxygen species, and shifting BMSC metabolism from glycolysis toward oxidative phosphorylation [42]. Collectively, ion-mediated degradation strategies highlight the central role of immune and metabolic coupling in MSC fate regulation; however, disentangling the direct effects of ions on MSCs from secondary immune-mediated mechanisms remains challenging.

A class of “bioenergetic-active materials” directly modulates cellular energy metabolism via degradation products that MSCs uptake and integrate into core metabolic pathways, effectively turning materials into energy sources. Citrate-based polymer/hydroxyapatite composites release citrate upon degradation, which is actively internalized by MSCs via SLC13A5 transporters and funneled into mitochondria to fuel the TCA cycle [43]. Beyond citrate delivery, metabolically instructive degradation products enhance mitochondrial function and cellular energy availability. Bioenergetic-active materials have been shown to elevate mitochondrial membrane potential(ΔΨm) and intracellular ATP levels, thereby promoting MSC osteogenesis and chondrogenesis [24,44]. This emerging strategy effectively “empowers” MSC regenerative capacity by directly targeting cellular energy metabolism, representing a conceptual shift from indirect microenvironmental modulation to intrinsic metabolic reprogramming.

Overall, degradation product-mediated regulation has evolved from passive ion leakage toward active, multifunctional, and stimuli-responsive control strategies, enabling tailored interventions for acute defects, chronic degenerative conditions, and infectious lesions. Nevertheless, several limitations persist. Long-term biosafety and in vivo material fate remain incompletely understood, particularly for complex multifunctional systems. Additionally, immunogenicity, chronic toxicity, and off-target metabolic effects are rarely evaluated systematically. From a translational perspective, reproducibility, scalability, and standardization pose major challenges, especially for responsive hydrogels and multifunctional nanoparticle-based platforms. Future research should prioritize mechanism-resolved studies, standardized degradation-function mapping frameworks, and long-term in vivo safety assessment to facilitate clinical translation of degradation product-mediated MSC regulation.

3.3. Spatiotemporal delivery of bioactive molecules

3.3.1. Growth factor controlled-release systems

Recently, strategies combining growth factors, stem cells, and smart biomaterials have been widely explored for tissue repair. Controlled release of growth factors via biomaterials is a key means to enhance MSC therapeutic efficacy—modulating cell behavior and playing critical roles in targeted tissue regeneration.

Sustained and localized release of growth factors enables prolonged activation of lineage-specific signaling pathways while minimizing systemic exposure. Peptide-based hydrogels crosslinked via phenylboronic acid-catechol chemistry allow efficient loading and twoweek sustained release of TGF-β1, markedly enhancing BMSC proliferation and chondrogenic differentiation [45]. Similarly, endocrine-mimetic and ECM-inspired protein platforms provide a biomimetic context for sustained delivery of fibroblast growth factor-2 (FGF-2), enabling continuous modulation of MSC behavior over extended culture periods [46].

Combining controlled growth-factor release with MSC-laden biomaterial scaffolds enables synergistic regulation of cell fate and tissue-specific regeneration. Ultrasound-triggered delivery of growth factors from lipid nanohybrid cerasomes integrated into three-dimensionally printed polycaprolactone scaffolds enhances tendon-to-bone interface regeneration by coordinating biochemical signaling with structural support [47]. Beyond musculoskeletal repair, multifunctional scaffolds that co-deliver growth factors and MSCs can simultaneously address structural, biological, and immunological demands. Coaxially printed scaffolds incorporating heparin-binding epidermal growth factor serve both as physical anti-adhesion barriers and as bioactive delivery systems that promote neovascularization-driven endometrial regeneration [48]. Notably, MSC-mediated immunomodulation further contributes to therapeutic outcomes, as MSCs within growth-factor-releasing scaffolds can polarize macrophages toward a pro-repair M2 phenotype, reinforcing regenerative microenvironments.

Beyond protein growth factors, controlled release of small-molecule drugs provides an alternative and complementary route for MSC fate control. Kartogenin-releasing composite hydrogels activate the Nrf2–TXNIP–NLRP3 signaling axis, directing ADSCs toward a nucleus pulposus-like phenotype while enhancing antioxidative capacity in intervertebral disc repair [49]. Similarly, sustained delivery of melatonin from highly porous nanofiber scaffolds reprograms MSC mitochondrial energy metabolism, promoting osteogenic differentiation while indirectly enhancing angiogenesis via upregulated VEGFA secretion, ultimately achieving vascularized bone regeneration [50]. Compared with growth factors, small-molecule drugs offer advantages in stability and cost; however, their pleiotropic signaling effects necessitate careful dose and release-kinetic optimization.

Single-factor release systems are increasingly being complemented by multi-factor, spatiotemporally programmed delivery strategies that better recapitulate native tissue repair cascades. Spatial positioning of microencapsulated BMP-2 and VEGF within bioprinted vascularized bone grafts enables region-specific osteogenic and angiogenic differentiation of MSCs [51]. In parallel, independently tunable release kinetics of multiple growth factors further refine MSC responses. Poly(lactic-co-glycolic acid) nanospheres enabling differential release of BMP-7 and FGF-2 synergistically enhance MSC proliferation, migration, and osteogenic mineralization, demonstrating the importance of temporal signal coordination [52]. These emerging strategies highlight that not only factor identity but also release sequence and spatial distribution critically determine MSC fate outcomes.

Despite substantial progress, biomaterial-enabled growth-factor delivery systems face several unresolved challenges. Growth-factor instability and loss of bioactivity in vivo, limited precision in release-kinetic control, and incomplete understanding of downstream mechanistic targets continue to constrain translational reliability. Moreover, the complexity of multi-factor delivery systems raises manufacturing and regulatory hurdles. Future research should focus on improving factor stabilization strategies, integrating real-time release monitoring, and establishing mechanism-aligned design principles that more faithfully mimic the dynamic signaling landscapes of native tissues.

3.3.2. Gene delivery

Beyond soluble growth factors, gene delivery systems based on MSC-derived exosomes and lipid nanoparticles (LNPs) have emerged as powerful alternatives for regulating MSC fate and regenerative function. These nanoscale carriers enable the transfer of nucleic acids and regulatory molecules with high biological specificity, offering sustained and programmable control over gene expression in regenerative microenvironments.

Exosomes are nanoscale vesicles released by cells through the extracellular secretory pathway that can carry and deliver diverse bioactive molecules, such as micro ribonucleic acids (miRNA), proteins, and lipids [53]. These vesicles facilitate intercellular signaling, regulate gene expression, and promote tissue repair and regeneration. Currently, exosome delivery systems fall into four main categories: hydrogel or microsphere systems, functionalized scaffolds or implants, microneedle arrays, and bioinspired or engineered exosomes.

Hydrogels and microspheres enable localized and sustained release of exosomes, thereby prolonging their bioactivity and enhancing regenerative outcomes. Site-directed delivery of exosomes co-loaded with osteoregulatory miRNAs within injectable hydrogels has been shown to synergistically promote angiogenesis while suppressing osteoclast-associated gene expression, resulting in accelerated bone regeneration [54]. Similarly, sustained release of preconditioned MSC-derived exosomes from hydrogel microspheres can reshape the inflammatory microenvironment, modulate miRNA profiles in recipient cells, and promote cartilage regeneration in osteoarthritic contexts [55]. These approaches highlight the importance of delivery kinetics and microenvironmental context; however, batch-to-batch variability in exosome composition remains a key challenge.

Immobilization of exosomes onto three-dimensional scaffolds or implant surfaces integrates structural support with localized gene regulation. Hierarchically porous scaffolds functionalized with exosomes enriched in neurovascular regulatory miRNAs can activate MAPK and PI3K-Akt signaling, thereby promoting coupled neurovascularization and innervated bone regeneration [56]. In cartilage repair, bioprinted or ECM-inspired scaffolds loaded with miRNA-enriched exosomes activate lineage-specific transcriptional programs, such as the Kdm2a/SOX2 axis, to stimulate endogenous cartilage regeneration [57]. Notably, scaffold architecture itself can modulate exosome cargo composition. Exosomes harvested from MSCs cultured within three-dimensional ECM-mimetic scaffolds exhibit distinct miRNA profiles and enhanced reparative capacity when reintroduced into osteochondral defect models [58]. These findings suggest that biomaterials not only deliver exosomes but can also precondition their genetic cargo, introducing an additional layer of regulatory complexity.

Microneedle arrays provide minimally invasive and spatially precise delivery of exosomes, particularly suited for skin and superficial tissues. Dissolvable microneedles loaded with engineered exosomes enable targeted modulation of fibrotic signaling pathways, such as TGF-β/Smad, thereby suppressing hypertrophic scar formation [59]. Beyond cutaneous applications, tissue-matched microneedle architectures loaded with miRNA-engineered exosomes can restore mitophagy and extracellular matrix homeostasis, effectively delaying intervertebral disc degeneration [60]. Although microneedle-based systems offer high delivery precision, their long-term efficacy and scalability across deep tissues remain to be established.

Importantly, biomaterials act beyond simple delivery vehicles, serving as active priming platforms that regulate MSC states prior to exosome secretion and thereby indirectly program the genetic cargo and downstream gene delivery performance of MSC-derived exosomes. Pan et al. (2024) [61] demonstrated that culturing BMSCs within a three-dimensional hydrogel microparticle system not only enabled sustained exosome delivery but also reshaped the exosomal miRNA profile. Specifically, the 3D hydrogel microenvironment promoted the enrichment of osteogenic and angiogenic miRNAs, such as miR-29a, in BMSC-derived exosomes, thereby enhancing their gene-regulatory capacity during bone regeneration. Consistent with this concept, biomaterial-mediated three-dimensional culture conditions have been shown to increase exosome secretion efficiency and facilitate the selective packaging of bioactive RNAs compared with conventional two-dimensional culture, improving their suitability for gene delivery applications [62]. Beyond dimensionality, extracellular matrix stiffness also acts as a critical biophysical cue regulating exosome secretion behavior, cargo sorting, and cellular uptake, ultimately determining delivery efficiency and downstream gene-regulatory effects [63]. In addition to biophysical signals, inflammatory microenvironment-mimicking preconditioning further modulates the miRNA composition of MSC-derived exosomes, enhancing their immunoregulatory and reparative relevance under pathological conditions [64]. Collectively, these studies highlight that biomaterial-mediated priming of MSCs represents an effective upstream strategy to tailor exosome cargo and optimize exosome-based gene delivery outcomes.

Lipid nanoparticles have gained prominence as gene delivery vehicles following their clinical success in mRNA therapeutics. In regenerative contexts, LNPs enable efficient in vivo delivery of nucleic acids to MSCs, facilitating direct genetic reprogramming. LNP-mediated delivery of small interfering RNA can selectively silence osteogenic suppressor genes in bone-resident MSCs, thereby redirecting lineage commitment toward osteoblast differentiation and opening new avenues for anabolic therapies in osteoporosis [65]. used LNP systems to deliver small interfering ribonucleic acid, effectively targeting MSCs in bone tissue in vivo and, by silencing osteogenic suppressor genes, successfully directing differentiation toward osteoblasts. This opens a new avenue for developing gene-silencing-based anabolic therapies for bone diseases such as osteoporosis. Beyond gene silencing, bioinspired and engineered LNP systems expand the functional scope of nucleic acid delivery. Artificial exosome-like nanoparticles efficiently delivering pro-angiogenic miRNAs enhance vascularization both in vitro and in vivo, while biodegradable glycerolipid-based LNPs enable circular mRNA delivery to engineer MSCs for cartilage repair [66,67] To achieve localized and minimally invasive gene delivery, LNP-mRNA systems are increasingly integrated with advanced biomaterial platforms. Dissolvable microneedle patches loaded with mRNA-LNPs enable uniform MSC transfection, long-term room-temperature storage, and localized gene expression, providing a practical route for translational deployment in skin and subcutaneous tissue regeneration [68]. Despite their efficiency, LNP-based systems raise important questions regarding cell-type specificity, off-target effects, and immune activation in repeated dosing scenarios.

In summary, recent studies demonstrate that MSC-derived exosomes and lipid nanoparticle-based systems, when integrated with rational biomaterial design, provide powerful platforms for efficient and targeted gene delivery in regenerative medicine. Beyond serving as passive carriers, biomaterials can actively regulate MSC states and exosomal cargo composition, thereby enhancing downstream gene-regulatory functions. However, challenges such as exosome heterogeneity, limited standardization of production and characterization, and insufficient long-term biosafety evaluation continue to impede clinical translation. Future efforts should focus on mechanistic elucidation of biomaterial-MSC-exosome interactions, standardized manufacturing strategies, and advanced in vivo tracking to enable precise and durable gene delivery therapies.

4. Anti-aging functionalized design

In MSC therapy, the challenges of aging-related diseases arise from systemic complexity and heterogeneity: inflammatory aging of the microenvironment, the senescence-associated secretory phenotype, and mitochondrial functional decline lead to low homing and survival rates and diluted therapeutic effects. Within the tissue microenvironment, cells face multiple stressors such as accumulation of oxidative stress and telomere shortening, which collectively weaken the survival, regeneration, and immunomodulatory capacities of MSCs. The biomaterials discussed in Section 3 are primarily designed based on fundamental physical, chemical, and biological properties, with limited functional modulation tailored to the complex symptomatology of aging-related diseases. As shown in Fig. 5, this section systematically elaborates the conceptual framework and technical roadmap for anti-aging functional design of the “MSC + biomaterials” therapy from three perspectives: reactive oxygen species scavenging, epigenetic regulation, and telomere protection.

Fig. 5 — **Functionalized biomaterial strategies for anti-aging regulation of MSCs.** This schematic illustrates representative functionalized biomaterial designs that mitigate MSC aging through complementary anti-aging mechanisms. ROS-scavenging strategies, including metal-phenolic nanocoatings and piezoelectric nanocomposites, reduce oxidative stress by neutralizing excessive reactive oxygen species, thereby preserving cellular redox homeostasis. Epigenetic regulation is achieved through bioactive and injectable material systems that modulate chromatin remodeling and histone modifications, enabling the restoration of youthful transcriptional programs. In parallel, piezoelectric films and wireless electronic stimulation platforms provide sustained biophysical cues that support telomere protection, prolong telomere length, and reverse cellular senescence. Collectively, these functionalized biomaterial approaches converge on MSC rejuvenation by stabilizing redox balance, epigenetic states, and genomic integrity. Created with BioRender.com. Some images are reproduced with permission [6,7,69] Copyright 2024,American Chemical Society [8],Copyright 2024,American Chemical Society.

4.1. ROS scavenging

Oxidative stress is a central pathological feature of aging-related tissue degeneration, impairing MSC survival, function, and regenerative capacity. Antioxidant coating strategies attach reactive oxygen species (ROS)-scavenging components to biomaterial surfaces to restore redox homeostasis, alleviate inflammatory damage, and enhance cell- and tissue-level repair. This section summarizes recent materiobiology-guided antioxidant strategies that integrate advanced biomaterials with MSC-based therapies to reprogram hostile microenvironments and improve regenerative outcomes.

Enzyme-mimetic catalytic materials emulate the activity of endogenous antioxidant enzymes, enabling sustained and recyclable ROS clearance. Unlike stoichiometric antioxidants, these systems rely on catalytic centers that are not consumed during redox reactions, providing long-term protection against oxidative stress. Metal–phenolic network coatings incorporating redox-active metal ions and polyphenols can mimic cascade enzymatic reactions. Such coatings catalytically convert superoxide anions into water, alleviate diabetic oxidative stress, and promote MSC proliferation and osteogenic differentiation [70]. Similarly, self-assembled nanocoatings based on polyphenol-metal coordination exhibit enzyme-mimetic activity, effectively clearing ROS while enhancing osteogenic differentiation of BMSCs [6]. Beyond static catalysis, stimuli-responsive enzyme-mimetic systems introduce dynamic antioxidant regulation. Piezoelectric nanocomposites functionalized with redox-active polymers generate electrical potentials under ultrasound stimulation, driving reversible quinone-phenol redox cycling and enabling “self-renewing” antioxidant capacity. This sustained ROS regulation significantly upregulates osteogenic gene and protein expression in MSCs, supporting long-term bone regeneration [71]. Enzyme-mimetic systems offer durable antioxidative protection; however, their catalytic efficiency and long-term stability in complex in vivo environments remain incompletely characterized.

Physical scavenging materials rely on specific chemical structures or physical properties to directly capture, adsorb, and neutralize reactive oxygen species. Nanoparticles with catechol-rich polydopamine shells exemplify this strategy, effectively protecting MSCs from oxidative damage by directly trapping reactive radicals [72]. While physical scavengers act rapidly and efficiently, their antioxidant capacity is finite and may diminish under prolonged oxidative challenge.

Controlled-release materials deliver antioxidant-active components on demand by using smart responsive carriers. Such systems allow precise modulation of oxidative stress within bone defects, significantly enhancing MSC proliferation and osteogenic differentiation [73]. Although controlled-release systems provide high precision, their responsiveness, release predictability, and safety under repeated stimulation require further validation.

Beyond material-centered approaches, cellular engineering strategies endow MSCs with intrinsic antioxidant and targeting capabilities. Chemical modification of MSC surfaces with adhesive and antioxidant moieties enhances targeted cell retention in ischemic tissues while directly conferring ROS-scavenging capacity, substantially improving therapeutic outcomes after transplantation [74]. Alternatively, indirect antioxidant modulation can be achieved by engineering the cell microenvironment. Biomimetic scaffolds coated with immune cell membranes modulate local immune signaling, alleviate oxidative stress, and create a supportive niche that enhances MSC survival and function during diabetic wound repair [75]. Cell-based and biomimetic strategies offer high biocompatibility but introduce added complexity in manufacturing, standardization, and regulatory assessment.

In summary, ROS-scavenging strategies operate through distinct yet complementary mechanisms. Enzyme-mimetic materials provide sustained catalytic protection, physical scavengers offer rapid radical neutralization, controlled-release systems enable precise spatiotemporal modulation, and cellular engineering approaches enhance biocompatibility and functional integration. Despite promising outcomes, several challenges remain. These include difficulties in large-scale manufacturing and quality control; uncertain biodistribution and potential toxicity associated with long-term nanoparticle retention; incomplete understanding of degradation products and their chronic effects; and persistent concerns regarding coating stability and durability, even in cyclic antioxidant designs. Addressing these limitations will be essential for translating antioxidant materiobiology strategies into clinically viable MSC-based therapies for aging-related diseases.

4.2. Epigenetic regulation strategies

Epigenetic regulation constitutes a central mechanism by which biomaterials exert durable control over MSC fate and function. By modulating chromatin organization, histone modifications, DNA methylation, and non-coding RNA activity, biomaterial cues can reprogram MSC transcriptional states beyond transient signaling, thereby influencing proliferation, lineage commitment, and long-term functional stability. This section synthesizes emerging materiobiology strategies that regulate MSC epigenetics through mechanical-structural cues, metabolic-epigenetic coupling, and epigenetic memory programming.

Mechanical and structural cues transmitted from biomaterials to MSCs directly reshape nuclear organization and chromatin accessibility. Senescent MSCs typically exhibit nuclear envelope instability, heterochromatin loss, and a bias toward adipogenic differentiation, rendering them particularly sensitive to mechanotransductive regulation. Material properties such as stiffness, topography, and dynamic mechanics are sensed through integrin-cytoskeleton-nucleoskeleton linkages, enabling force transmission to the nucleus and subsequent epigenetic remodeling. Dynamic mechanical environments exemplify this mode of regulation. Sliding hydrogels that induce continuous MSC “cell tumbling” generate cyclic stresses transmitted through the linker of nucleoskeleton and cytoskeleton complex, globally reducing chromatin accessibility while selectively enhancing chondrogenic differentiation programs [76]. Beyond bulk mechanics, mesoscopic ECM-like architectures function as independent epigenetic cues. Collagen hydrogels mimicking heterogeneous mesoscopic structures regulate MSC fate independent of bulk stiffness, underscoring the importance of spatial organization in chromatin regulation [77]. At the micro- and nanoscale, adhesion-regulated epigenetic modulation further refines lineage bias. Colloidal self-assembled crystal substrates alter MSC spreading and adhesion, reshaping histone modification landscapes—such as H3K4me3 and H3K27me3—to direct osteogenic or adipogenic differentiation [69]. Mechanistically, these diverse material systems converge on a shared pathway whereby cytoskeleton-mediated force transmission reshapes nuclear architecture, alters chromatin accessibility, and biases histone modification landscapes, thereby coupling mechanical inputs to stable lineage-specific transcriptional programs.

Beyond mechanics, biomaterials can regulate MSC epigenetics by reshaping intracellular and paracrine metabolic states. Degradation products or metabolite-functionalized materials serve as substrates or cofactors for epigenetic enzymes, directly linking cellular metabolism to chromatin modification. Metabolite-releasing scaffolds exemplify this strategy. Lactate-functionalized 3D-printed scaffolds release lactate that induces histone lactylation (e.g., H3K18la) and lactylation of transcriptional regulators such as STAT1, directly activating osteogenic gene programs in MSCs [78]. In parallel, ion-mediated neuro-epigenetic signaling provides an indirect metabolic route to chromatin regulation. Injectable bioactive ion composite microspheres activate sensory neurons to secrete calcitonin gene-related peptide, which in turn modulates histone methylation and enhances osteogenic gene transcription in BMSCs [7]. Collectively, these studies illustrate a unifying metabolic-epigenetic paradigm in which biomaterials reshape intracellular or paracrine metabolic states, thereby modulating the availability or activity of epigenetic substrates and cofactors to directly program chromatin modifications and downstream gene expression.

Emerging strategies extend epigenetic regulation beyond transient modulation toward the establishment of durable epigenetic memory. By stabilizing chromatin states through DNA methylation, histone modification, or non-coding RNA regulation, biomaterials can confer long-lasting functional reprogramming of MSCs. Developmentally inspired BMP-2-based materials not only guide MSC differentiation but also imprint stable DNA methylation patterns that preserve immunomodulatory functions over time [79]. Similarly, long non-coding RNA-targeted material systems lift epigenetic repression to unlock osteogenic potential. In situ MEG3-silencing ossification micro-units relieve Polycomb-mediated H3K27me3 suppression, enabling sustained activation of osteogenic transcriptional programs [80]. At a mechanistic level, these strategies extend epigenetic regulation beyond transient signaling by stabilizing chromatin states through DNA methylation, histone modification, or long non-coding RNA-mediated repression, thereby conferring long-term epigenetic memory and sustained functional reprogramming of MSCs.

Despite rapid progress, several challenges constrain the translational impact of biomaterial-mediated epigenetic regulation. Most studies focus primarily on MSC-intrinsic epigenetic changes, overlooking interactions with immune, endothelial, and neural cells that strongly shape epigenetic landscapes in vivo. Additionally, many materials provide sustained, global stimuli without precise spatiotemporal control, increasing the risk of over-activation or ectopic tissue formation. Finally, current work often targets a limited set of candidate genes or pathways, lacking unbiased, genome-wide epigenomic profiling. Future research should integrate multi-cellular epigenetic crosstalk, develop smart materials enabling multi-modal and temporally programmable epigenetic regulation, and establish predictive models linking epigenetic markers to MSC fate and therapeutic outcomes.

4.3. Telomere protection

Replicative senescence represents a fundamental bottleneck for the clinical-scale expansion and therapeutic efficacy of mesenchymal stromal cells, with progressive telomere shortening as a defining hallmark. Loss of telomere integrity compromises genomic stability, proliferative capacity, and regenerative potential, rendering telomere maintenance a critical target in anti-aging MSC therapies. Podoplanin has emerged as a key regulator linking cell-cycle progression to replicative lifespan. Sustained podoplanin expression restrains activation of the p16^Ink4a-retinoblastoma pathway, thereby maintaining proliferative competence, whereas its depletion induces G1 arrest, cellular senescence, and accelerated telomere shortening [81]. Extracellular vesicle–mediated delivery of proliferating cell nuclear antigen (PCNA) to senescent MSCs enhances DNA repair efficiency and significantly lengthens telomeres, demonstrating that reinforcing replication and repair machinery can directly address telomere attrition-the core driver of replicative aging [82]. Piezoelectric culture substrates that convert ambient mechanical vibrations into mild electrical signals improve mitochondrial function, suppress oxidative stress and advanced glycation end-product accumulation, and create a favorable intracellular milieu for telomere maintenance, significantly slowing telomere shortening during replicative senescence [8]. Compared with direct genetic interventions, materiobiology-based strategies offer a non-invasive route to telomere protection by modulating upstream cellular stress and metabolic states.

Telomeres function as central regulators of cellular lifespan and aging, and their preservation is essential for maintaining MSC therapeutic competence. Current evidence indicates that telomere length and stability can be supported through complementary strategies, including reinforcement of DNA repair machinery, inhibition of senescence-associated signaling pathways, and improvement of cellular homeostasis via exogenous physical or biochemical cues. Future research should integrate telomere-targeted interventions with materiobiology-guided design to develop adaptive stem cell-biomaterial systems that sense aging-associated stress and proactively preserve telomere integrity, thereby sustaining MSC function during expansion and after transplantation.

5. In vivo fate tracking of MSC transplantation

While most studies on biomaterial-MSC interactions focus on in vitro fate regulation and downstream therapeutic outcomes, the causal linkage between material-induced MSC modulation and in vivo efficacy remains insufficiently validated. In this context, in vivo fate tracking serves as a critical evaluative layer that connects biomaterial design with MSC state modulation and downstream therapeutic function. As shown in Fig. 6, this section reviews two angles of post-transplant analysis: position tracking and fate tracking of MSCs.

Fig. 6 — **In vivo tracking strategies for evaluating the fate and function of MSCs.** This schematic illustrates an integrated in vivo tracking framework for transplanted mesenchymal stromal cells (MSCs), comprising location tracking and cell fate tracking. Location tracking (left) visualizes the spatiotemporal distribution, retention, and migration of MSCs using representative imaging modalities such as MRI, CT, and fluorescence, enabling assessment of cell localization and persistence in vivo. Reproduced from Ref. [83]. under the Creative Commons Attribution Non-Commercial No Derivatives (CC BY-NC-ND) license. In parallel, cell fate tracking (right) captures the dynamic biological states of MSCs after engraftment through transcriptomic monitoring and signaling analysis, linking microenvironmental cues and immune modulation to MSC proliferation, differentiation, and lineage commitment. Together, these complementary tracking strategies provide a coordinated evaluation of MSC behavior in vivo, bridging spatial localization with functional fate outcomes. Created with BioRender.com.

By resolving where transplanted MSCs localize, how long they survive, and whether they undergo functional state transitions within complex host microenvironments, fate tracking provides indispensable evidence to verify whether biomaterial-mediated regulatory strategies are preserved, reprogrammed, or attenuated in vivo. Therefore, this section emphasizes the validation role of in vivo tracking in assessing material-regulated MSC behavior in vivo.

5.1. In vivo position tracking

In vivo position tracking provides a critical functional validation layer for materiobiology-guided MSC regulation. Rather than merely visualizing cell location, position tracking establishes spatial and temporal coordinates that link MSC biodistribution, residence time, survival, and paracrine activity to therapeutic outcomes. In this context, in vivo tracking enables assessment of whether biomaterial-mediated modulation translates into effective cell retention, targeted homing, and functionally meaningful tissue engagement.

Magnetic resonance imaging offers deep tissue penetration, high spatial resolution, and clinical translatability, making it a cornerstone modality for MSC tracking. Labeling strategies encompass intracellular and extracellular nanoparticle uptake as well as reporter gene approaches, enabling longitudinal monitoring across diverse disease models. Responsive contrast agents further extend MRI from passive localization to functional state assessment [84]. ROS-responsive T1-T2 switchable probes allow discrimination between viable and compromised transplanted MSCs, enabling real-time evaluation of cell survival under pathological oxidative stress. Nanoparticle-mediated magnetic labeling remains widely adopted, with extracellular labeling strategies reducing cytotoxicity while preserving tracking sensitivity [[85], [86], [87]]. In addition to nanoparticle labeling, reporter gene–based MRI strategies provide genetically encoded and potentially more stable contrast for long-term MSC tracking [88]. Comparative studies reveal that nanoparticle composition and magnetic properties critically influence signal strength and relaxation behavior, underscoring the need for rational probe selection. Beyond labeling, MRI-visible nanomaterials increasingly serve dual roles as therapeutic enhancers [[89], [90], [91]]. Magnetized MSC-nanoparticle systems improve targeted homing and therapeutic efficacy in glioblastoma and ischemic stroke models while enabling real-time visualization of cell migration and retention. Antioxidant nanozymes further protect MSCs from hostile microenvironments, illustrating how tracking agents can actively shape therapeutic outcomes.

Fluorescence imaging complements MRI by offering high sensitivity and molecular-level visualization of MSC fate. Near-infrared and magneto-fluorescent probes enable real-time monitoring of cell viability and migration, particularly in metabolically active or superficial tissues [[92], [93], [94]]. Advanced fluorescence systems enable ratiometric and multimodal readouts, allowing discrimination of live versus compromised MSCs and visualization of guided homing under magnetic control [92,93]. Importantly, emerging strategies extend fluorescence tracking beyond localization toward visualization of intercellular communication and gene expression dynamics. Bioengineered “cytotransducer” probes enable spatiotemporally controlled visualization of MSC–immune cell interactions by reporting microenvironmental changes during programmed cell death [83]. In parallel, gene-delivery-based fluorescent reporters delivered via lipid nanoparticle microneedles enable long-term, gene-level tracking of MSC activity with high transfection efficiency and storage stability [68] Integration of fluorescence imaging with MRI further enhances tracking fidelity. Bimodal probes combining organic radicals or quantum dots with magnetic contrast agents achieve simultaneous high-resolution anatomical imaging and sensitive fluorescence readouts without compromising MSC viability [95,96].

Computed tomography offers excellent spatial resolution and clinical accessibility, making it suitable for tracking MSCs labeled with high-X-ray-attenuation materials. Gold nanoparticles (AuNPs) are particularly attractive due to efficient cellular labeling and strong contrast generation through either intracellular uptake or membrane anchoring strategies [[97], [98], [99]] Strategies that anchor AuNPs to the MSC membrane rather than intracellular compartments improve signal stability and reduce metabolic signal loss, supporting durable CT tracking. Composite nanoplatforms integrating AuNPs with magnetic components further amplify CT signals while enabling magnetic guidance [99,100] Beyond imaging, CT-visible nanomaterials increasingly function as protective and empowering platforms, serving as gene carriers, antioxidative shields, and homing enhancers that improve MSC survival and therapeutic persistence under hostile in vivo conditions [97,98,[100], [101], [102]]

Collectively, in vivo position tracking has evolved from a passive visualization tool into an active evaluative and enabling framework for MSC-based therapies. By integrating MRI, fluorescence imaging, and CT, researchers can achieve precise, multimodal fate mapping that links cell localization with survival, function, and therapeutic efficacy. Nevertheless, challenges remain. The long-term biosafety of many nanoprobe systems has not been fully validated, and scalable, standardized manufacturing remains limited. Future progress will depend on developing biocompatible, multifunctional probes that simultaneously report, protect, and potentiate MSC function, ensuring that tracking technologies faithfully reflect-and enhance-clinical translation.

5.2. Transcriptome monitoring

Transcriptome monitoring, particularly single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics, provides a critical molecular readout for decoding MSC fate regulation in materiobiology-guided systems. By capturing global gene expression states and cellular heterogeneity, transcriptomic analyses establish a functional bridge between biomaterial parameters and downstream differentiation, paracrine activity, and therapeutic performance, thereby supporting mechanism elucidation, optimization strategies, and standardization of MSC-based therapies.

Physical cues encoded in biomaterial microenvironments can reprogram MSC transcriptional states through multiscale genome organization. Transcriptome-integrated chromatin analyses reveal that stiff extracellular matrices not only alter gene expression profiles but also induce higher-order three-dimensional genome reconfiguration, including enhanced long-range chromatin interactions and fusion of topographically associated domains. This mechanically driven nuclear remodeling selectively upregulates osteogenic transcription factors such as SP1 and ETS1, providing direct transcriptomic evidence that physical forces can instruct lineage commitment at the genome-architecture level [103]. Beyond bulk stiffness, biomimetic mechanical microenvironments enable fine-tuned transcriptional control of MSC differentiation. Pericellular matrix-like systems that recapitulate native chondrocyte mechanics activate chondrogenic programs in MSCs through coordinated TRPV4-YAP/TAZ-PI3K-Akt signaling, as revealed by combined mRNA sequencing and spatial transcriptomic analyses, demonstrating that mechanical cues can be translated into spatially resolved transcriptional responses [104]. In addition to passive mechanics, electrical and conductive material cues reshape MSC transcriptomes by biasing signaling pathway activation. Conductive bio-inks coupled with electrical stimulation synergistically activate osteogenic signaling cascades (e.g., NOTCH, MAPK, and SMAD) while suppressing inhibitory pathways such as Wnt/β-catenin, thereby transcriptionally steering MSCs toward osteogenesis [105]. Chemical and biological components within biomaterials further refine transcriptional regulation. Bioactive small molecules, phytochemicals, and extracellular vesicle-modulated matrices create pro-regenerative transcriptional landscapes by coordinately regulating cytoskeletal organization, immune-associated signaling, and lineage-specific gene networks, ultimately enhancing osteogenic potential and therapeutic function [106].

Transcriptomics offers an unparalleled observational window into MSC state transitions and regulatory network activation, yet it primarily captures correlations rather than direct causal relationships. Dissecting causality within complex signaling and cell-cell interaction networks requires complementary perturbation-based or lineage-tracing approaches. Cellular heterogeneity presents an additional challenge. Although scRNA-seq reveals intrinsic diversity, MSCs derived from distinct tissue sources (e.g., bone marrow, adipose tissue) exhibit baseline transcriptional and functional differences, complicating cross-study comparison and integration. Moreover, many current studies infer in vivo MSC fate and mechanisms from in vitro transcriptomic datasets, limiting physiological relevance.

Direct transcriptomic monitoring of MSCs after transplantation remains technically challenging but uniquely informative. Low cell abundance, dynamic phenotypic transitions, and intermixing with host cells complicate cell recovery and high-quality library preparation, particularly in the presence of complex biomaterial matrices.

Despite these hurdles, single-cell and spatial transcriptomics have begun to reveal immune-driven transcriptional trajectories of MSC fate in vivo. In inflammatory microenvironments, quiescent MSCs can be transcriptionally mapped through proliferative intermediates toward chondrogenic or osteogenic lineages, with immune cells such as macrophages and neutrophils providing instructive cues via pathways including JAK/STAT and PI3K/AKT. These findings establish a transcriptomic basis for osteoimmunology and demonstrate how immune-MSC interactions dynamically govern fate decisions in pathological settings [107].

Advancing in vivo transcriptome monitoring of transplanted MSCs will be pivotal for linking biomaterial design to functional fate outcomes. Such approaches can define temporal windows of material-cell interaction, resolve how physical and chemical parameters shape transcriptional programs, and strengthen mechanistic causality across scales. Integrating transcriptomics with imaging-based tracking and functional assays represents a promising direction toward comprehensive, mechanism-resolved evaluation frameworks in materiobiology-guided MSC therapies.

6. Clinical applications in aging-related diseases and biomaterial solutions

This section builds a systematic framework linking clinical research on MSCs in aging-associated diseases with engineering materials strategies. Representative preclinical studies of MSC-based therapies are summarized in Table 3. Focusing on shared pathology and heterogeneous clinical phenotypes of representative age-related conditions-fibrosis (lung, liver), osteoarthritis (OA), heart failure and wound healing-it outlines MSC-centered therapeutic paradigms and engineering paths to enhance efficacy (Fig. 7).

Table 3.

Representative preclinical studies of MSC-based therapies.

Disease/Indication	Source	Animal	Administration Route	References
Chronic ischaemic cardiomyopathy	Bone marrow	Porcine	Intravenous infusion	[108]
Myocardial infarction	Bone marrow	Porcine	Intramyocardial injection	[109]
Myocardial infarction	Human umbilical cord	Porcine	Epicardial cell-sheet transplantation	[110]
Osteoarthritis	Adipose	Goat	Intra-articular injection	[111]
Acute cutaneous wound	Bone marrow	Porcine	Local intradermal injection	[112]
Full-thickness burn injury	Human iPSC	Porcine	Local delivery via dermal scaffold	[113]

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Fig. 7 — **Biomaterial-assisted MSC therapy in representative aging-related diseases.** This schematic outline major aging-related indications for MSC therapy, including fibrosis, osteoarthritis, heart failure, and wound healing, together with key translational limitations and corresponding biomaterial-enabled strategies. Across these diseases, challenges such as limited efficacy, poor long-term outcomes, and incomplete mechanistic understanding motivate the integration of biomaterials to enhance MSC delivery, retention, and functional regulation. Collectively, the figure highlights how biomaterial-assisted approaches aim to overcome current bottlenecks and improve the translational potential of MSC-based therapies. Created with BioRender.com. Some images are reproduced with permission [9,114] Copyright 2023,The American Association for the Advancement of Science.

While biomaterial-based strategies can, in principle, modulate both endogenous and transplanted MSCs, their therapeutic relevance is highly indication-dependent. Endogenous MSC modulation is most applicable to bone-related aging disorders, where resident MSC populations are abundant; however, these conditions are beyond the primary scope of this review. For the majority of aging-related diseases discussed below, including pulmonary and liver fibrosis, osteoarthritis, heart failure, and wound healing, therapeutic strategies predominantly rely on exogenous MSC administration, with biomaterials primarily serving to support and program transplanted cells.

6.1. Fibrotic diseases

With aging, fibrosis incidence rises markedly across organs (lung, heart, liver, kidney). Idiopathic pulmonary fibrosis (IPF) predominantly affects individuals over 60, with shorter survival in older patients [115]. Similarly, the incidence of cardiovascular fibrosis, hepatic fibrosis, and renal fibrosis increases sharply with advancing age [116].Aging promotes fibrosis via multiple molecular mechanisms-cellular senescence and telomere dysfunction, mitochondrial impairment and oxidative stress, dysregulated autophagy and proteostasis imbalance, and epigenetic alterations. Fibrosis, in turn, disrupts the microenvironment, inducing chronic inflammation and hypoxia that exacerbate senescence and stem cell exhaustion, forming a vicious “aging-fibrosis” cycle. Engineering-enhanced MSC therapies are increasingly applied clinically. This section reviews MSC-based approaches for pulmonary and liver fibrosis.

6.1.1. Pulmonary fibrosis (PF)

Treatment strategies have evolved beyond conventional pharmacotherapy to extensive use of biomaterials to augment MSC therapy, enable targeted delivery, improve local microenvironments, and allow imaging-based tracking.

In clinical research, efforts have primarily focused on the efficacy of direct infusion of MSCs for pulmonary fibrosis. Multiple Phase I clinical trials consistently confirmed the good safety and tolerability of MSCs for treating idiopathic pulmonary fibrosis [117,118](NCT01919827). However, current clinical studies face challenges: long-term follow-up by Ntolios et al. (2018) [119] showed that although cell therapy appeared safe initially, patients exhibited significant decline in pulmonary function at approximately two years, with median survival comparable to historical data, indicating that MSC therapy may require repeat dosing or combination therapeutic strategies.

Biomaterials-enabled MSC therapies are increasingly explored. Fundamentally, MSCs act via paracrine factors and mitochondrial transfer to exert antifibrotic, anti-inflammatory, and pro-regenerative effects [120],but poor lesion retention and survival are major bottlenecks. Engineering strategies—liposome or nanoparticle surface modification [9,121],microgel encapsulation [122], and magnetic nanoparticle tagging [123]-enhance collagen-degrading capacity, immune evasion, and lung targeting. Inorganic nanomaterials, leveraging optical/electrical/magnetic properties, support cell labeling, in vivo tracking, and microenvironment modulation. Gold-based nanomaterials offer biocompatibility and strong X-ray attenuation, serving as robust CT contrast agents; diverse Au-based systems enable long-term tracking of implanted MSCs [99,102,124],Additionally, Lv et al. (2023) [101] encapsulated CuxO nanozymes to scavenge ROS in fibrotic niches. Organic/polymeric systems and liposomes are pivotal for carriers, cell encapsulation, and stimuli-responsive drug release-including liposomes/LNPs [9,125,126], hydrogels/microcapsules [122,127] and polymeric nanoparticles [100,121]. These materials enhance MSC antioxidation, collagen degradation, lesion survival, and ROS-responsive smart release. PF biomaterial therapies are trending toward diversified, intelligent, and integrated designs, moving from simple cell infusion to precise engineering of cells and derivatives using inorganic, organic, and hybrid materials. Challenges persist: source heterogeneity, gene-editing safety, nanomaterial biocompatibility, and modeling of replicative aging.

6.1.2. Liver fibrosis

Biomaterials that potentiate MSC therapy are at the forefront of liver fibrosis research. By engineering MSCs, optimizing delivery, and providing protective microenvironments, these strategies markedly improve targeting, durability, and efficacy.

In clinical research, multiple early studies investigating MSCs from different sources (umbilical cord [128], adipose tissue [129], bone marrow [130]) have provided solid evidence for the safety and efficacy of MSC therapy. Regarding long-term prognosis, the randomized controlled trial conducted by Shi et al. (2021) [131](NCT01220492) showed that patients receiving umbilical cord MSC infusion had significantly higher overall survival than the control group. The Phase Ia/Ib trial by Shi et al. (2025) [132](NCT05227846 and NCT05984303) found that higher doses or multiple administrations of MSCs elicited stronger immunomodulatory effects and showed a trend toward greater improvement in clinical metrics. In summary, although MSC therapy faces challenges such as standardization of cell preparation and uncertainties in long-term safety (for example, tumorigenesis), it still demonstrates substantial potential for clinical application.

Recently, combined biomaterial + MSC strategies have advanced notably. Targeting ligands/functional moieties(lactobionic acid [133], WKYMVm peptide [134], pPB peptide [135], nitric oxide donors [136]) are conjugated onto MSC membranes to modulate behavior, especially antifibrotic activity and homing to lesions. Another class encapsulates MSCs or exosomes for physical protection and controlled release, addressing short cell persistence and rapid clearance. Platforms include porous microspheres [137], MC-catechol/Fe(III) hydrogels [138], GelMA hydrogels [139] and HA-based 3D-printed hepatic patches [140], They act via TGF-β inhibition, multi-pathway metabolic reprogramming in NAFLD-associated fibrosis, oxidative stress reduction, and enhanced liver targeting to achieve durable antifibrotic effects. Notably, Dai et al. (2023) [114] designed a BMP-2 loaded scaffold implanted in vivo to create an “osteo-organoid” niche that yields therapeutically functional MSCs. MSCs harvested from this in vivo organoid effectively treated chronic liver fibrosis, offering a novel cell sourcing strategy.

Despite the growing sophistication of biomaterial-assisted MSC strategies for fibrotic diseases, clinical translation remains constrained by the highly hostile and dynamically evolving fibrotic microenvironment, which limits long-term MSC survival and functional persistence. Future research should prioritize the development of microenvironment-responsive biomaterials capable of adapting to disease stage-specific cues such as oxidative stress, hypoxia, and excessive matrix stiffness. In parallel, systematic evaluation of repeat dosing strategies, material biodegradation, and long-term safety in aged and fibrosis-relevant models will be essential to enable durable and clinically applicable antifibrotic therapies.

6.2. Osteoarthritis

Osteoarthritis(OA)is a prevalent degenerative joint disease affecting 595 million people worldwide (7.6% of the population) [141]. With aging, joint cells (e.g., chondrocytes) undergo senescence characterized by telomere dysfunction, accumulated DNA damage, and mitochondrial decline. Mitochondrial dysfunction and ROS accumulation exacerbate oxidative stress, impairing autophagy and energy metabolism. MSCs act via chondrogenic repair, immunomodulation/anti-inflammation, and trophic paracrine effects. This section reviews clinical status and emerging biomaterial-based strategies.

In clinical research, numerous studies have consistently demonstrated that intra-articular injection of MSCs, whether autologous or allogeneic, for osteoarthritis has good safety and tolerability, with serious adverse events being rare [[142], [143], [144], [145], [146]] (NCT02123368, NCT02784964, NCT03955497). Zhang et al. (2025) [147] (ChiCTR2300069677) revealed that adipose-derived stromal cell-enriched extracts exert effects by inhibiting chondrocyte senescence, providing a mechanistic explanation for their efficacy. Overall, the safety of MSC therapy for osteoarthritis has been widely confirmed. A large Phase III randomized controlled trial by Mautner et al. (2023) [148] (NCT03818737) showed that three cell therapies did not outperform corticosteroid injection on the primary endpoint at twelve months, indicating that for short-term pain control, MSCs may not be the absolute superior option.

Biomaterial-enabled MSC therapies offer effective solutions. Hydrogels-HA-based [149,150], gelatin-based [151,152], and smart stimuli-responsive systems [153] —enhance MSC chondrogenesis and homing by providing permissive niches and capturing endogenous TGF-β, among other mechanisms. Microspheres/nanoparticles are key to precise delivery and targeting. Yang et al. (2024) [154] used magnetic polysaccharide microcarriers to co-deliver MSC exosomes and an anti-inflammatory drug, boosting cartilage repair. Fontana et al. (2025) [155] employed mineral-coated microparticles to deliver TGF-β1 mRNA to MSCs, significantly enhancing chondrogenesis. Further design strategies include piezoelectric microspheres (Han et al. (2025) [152]) that trigger Ca²⁺/p38 MAPK to precisely drive MSC chondrogenesis, and M-Sec-engineered MSCs (Che et al. (2025) [156]) forming tunneling nanotubes to deliver mitochondria and nanozymes, markedly enhancing therapeutic effect.

The translation of biomaterial-enabled MSC therapies for osteoarthritis is hindered by a mismatch between mechanistic tissue regeneration and clinically adopted endpoints such as pain relief and functional improvement. Future studies should integrate biomaterial design with clinically meaningful outcome measures, including long-term structural preservation and disease modification rather than short-term symptom control. Additionally, simplifying material architectures and establishing standardized manufacturing and quality control pipelines will be critical to improve reproducibility and facilitate large-scale clinical translation.

6.3. Heart failure (HF)

HF is a leading cause of mortality and morbidity, imposing heavy personal and societal burdens [157]. To restore cardiac function, multiple novel strategies are under investigation; among them, stem cell therapy shows strong promise. MSCs are particularly attractive due to low immunogenicity, differentiation potential, and paracrine-mediated repair/regeneration [158,159]. Clinical development and novel strategies based on MSCs have advanced substantially.

In clinical research, numerous early trials have provided robust evidence for the safety of MSC therapy [[160], [161], [162]]. However, larger and more rigorously designed clinical trials have not consistently reproduced the early positive findings. Bolli et al. (2021) [163] found that autologous MSCs, either in combination with cardiac progenitor cells or alone, did not significantly improve left ventricular structure or function. Recent studies have begun to reveal that the same cell product exhibits divergent effects in patients with heart failure of different etiologies. The SCIENCE trial designed by Qayyum et al. (2023) [164] and its Phase II study in Denmark [165] clearly showed that intramyocardial injection of allogeneic adipose-derived MSCs in patients with chronic ischemic heart failure did not significantly improve key clinical indicators such as left ventricular end-systolic volume (LVESV) and left ventricular ejection fraction (LVEF), whereas in non-ischemic heart failure, adipose-derived stromal cells significantly improved LVESV, LVEF, and functional class [166].

In the realm of biomaterial-assisted MSC transplantation, researchers have developed novel functional materials to improve the cardiac microenvironment and protect MSCs. Yue et al. (2024) [167] constructed an injectable hydrogel based on Schiff base cross-linking and loaded it with monascus pigment nanoparticles. This system not only scavenges ROS and modulates macrophage phenotypes but also markedly enhances the survival and activity of BMSCs in the HF microenvironment, thereby effectively improving cardiac function in rats. Wang et al. (2025) [168] designed ultrasound-responsive biomimetic phase-change nanoparticles that integrate MSC membranes and macrophage membranes and carry therapeutic microRNA-125b. Using ultrasound-targeted microbubble destruction, this approach achieves precise delivery, aiming to promote cardiac functional recovery after acute myocardial infarction. In mechanistic exploration, Makkaoui et al. (2024) [169] elucidated the mechanisms of cell therapy from a proteomics perspective. They found that mesenchymal stromal cell treatment most effectively reversed right ventricular proteomic abnormalities induced by pressure overload, restoring the proteome toward a pre-disease state.

Clinical translation of biomaterial-assisted MSC therapy for heart failure is complicated by pronounced disease heterogeneity and etiology-dependent therapeutic responses. Future research should emphasize etiology-guided patient stratification and mechanism-informed biomaterial design tailored to ischemic versus non-ischemic cardiac remodeling. Moreover, combining biomaterial-enhanced cell delivery with longitudinal functional, molecular, and safety assessments will be necessary to determine whether improved cell retention can be translated into sustained cardiac repair and functional recovery.

6.4. Wound healing

The treatment of hard-to-heal wounds (chronic wounds) is closely linked biologically to aging. Aging affects wound healing through multiple mechanisms [170], such as the accumulation of senescent cells in chronic wounds leading to persistent inflammation, functional decline of immune cells in older individuals, and impaired angiogenesis. Multiple aging-related diseases (for example, diabetes, radiation ulcers, and infections by pathogenic microorganisms) are directly associated with non-healing wounds. MSC-based therapies, due to their strong regenerative and reparative capacity, have become a research frontier in this field.

In clinical research, direct transplantation of MSCs was the earliest strategy to enter clinical practice [[171], [172], [173], [174], [175]] (NCT124174455522). Recently, biomaterials and engineering strategies have become key avenues for enhancing therapeutic efficacy. Hashemi et al. (2019) [176] seeded MSCs onto amniotic scaffolds and significantly accelerated healing of diabetic wounds. A Phase II clinical trial by Tian et al. (2025) [177] (ChiCTR2400094739) showed that a placental MSC hydrogel effectively repaired radiation-induced skin injury. Meamar et al. (2021) [178] developed a therapy combining placental MSCs with a gelatin nanofiber scaffold and platelet-rich plasma, achieving favorable outcomes in the treatment of diabetic foot ulcers. Current clinical trials focus on the application of MSCs in refractory wounds, emphasizing safety and efficacy assessment. The main limitations include: a lack of long-term follow-up, precluding evaluation of long-term safety and durability of effect; and insufficient standardization of cell/product sourcing and manufacturing, which hampers reproducibility and comparability of efficacy across studies and even between batches.

In assisting MSC-mediated wound healing, suitable biomaterials not only protect cells and active substances but also provide appropriate microenvironments, control release behavior, and actively participate in regulating tissue repair. Natural polymer hydrogels, owing to excellent biocompatibility, degradability, and ECM-mimicking properties, have become the mainstream delivery vehicles. Multiple studies have confirmed that hydrogels enhance mesenchymal stromal cell retention, survival, and therapeutic effects at wound sites [179,180]. Specifically, Zhang et al. (2023) [181] designed a biomimetic peptide hydrogel that actively induces MSCs to form spheroids, thereby significantly enhancing their paracrine function. Synthetic and biomimetic materials, through chemical synthesis or biomimetic design, offer clear structures and precisely tunable properties. Li et al. (2024) [179] constructed a DNA network on the surface of MSCs that greatly enhanced adhesion at wound sites and may suppress anoikis by providing adhesion signals, thereby improving survival in hostile environments. Yuan et al. (2023) [182] designed flower-like porous microspheres loaded with BMSCs and curcumin, enabling drug-cell synergy to improve the wound microenvironment. Specifically, Zhang et al. (2025) [183] designed a protective scaffold composed of platelet-rich fibrin. Its fibrin network provides physical protection for mesenchymal stromal cell spheroids, while growth factors released during degradation activate key pro-repair pathways such as integrin-β1-vascular endothelial growth factor and Wnt/β-catenin. This generates strong synergy with mesenchymal stromal cell spheroids and shows promising clinical translational potential.

Despite substantial progress in biomaterial-supported MSC therapies for wound healing, several translational challenges remain. Current clinical studies predominantly focus on short-term closure and safety, with limited long-term follow-up to assess durability, recurrence, and functional restoration of regenerated tissue. In addition, variability in MSC sources, biomaterial compositions, and manufacturing processes hampers cross-study comparability and reproducibility. Given that most wound-healing strategies involve combination products, clearer standardization and regulatory pathways will be essential to facilitate consistent clinical translation in aging-related and chronic wound settings.

7. Challenges and prospects

7.1. Current policies and challenges

Over the past two decades, MSC therapy has achieved substantial progress, transitioning from early experimental clinical applications to commercial products. In June 2025, the International Society for Cell & Gene Therapy released updated identification criteria for MSCs, explicitly recommending the term “Mesenchymal stromal cells” to replace the traditional “Mesenchymal Stem Cells.” [2] This signifies that the field is moving beyond early conceptual hype, returning to scientific fundamentals, and entering a more rational, rigorous, and mechanism-focused mature phase. Globally, more than ten stem cell medicines have been approved for the market, most of which are based on MSCs and cover multiple indications including osteoarthritis, graft-versus-host disease, and Crohn's disease. The United States Food and Drug Administration and the National Medical Products Administration of China approved the first MSC therapy for the market in December 2024 and January 2025, respectively. Co-hosted by the China Association for Anti-Aging Promotion and Hainan University to promote clinical application, industrial development, and standardization in stem cell technology, the Second Boao Lecheng Stem Cell Conference announced three stem cell-related clinical technologies: umbilical cord mesenchymal stromal cell therapy for knee osteoarthritis (36,000 yuan per treatment), airway basal stem cell therapy for chronic obstructive pulmonary disease (150,000 yuan per treatment), and umbilical cord mesenchymal stromal cell therapy for heart failure (60,000 yuan per treatment). Although detailed clinical trial data disclosure is limited, the innovative application cases presented at the conference clearly depict broad clinical prospects.

These regulatory milestones also highlight unresolved challenges in MSC regulatory science. Key hurdles include substantial product heterogeneity across tissue sources and manufacturing platforms, limited product comparability, the absence of potency assays aligned with underlying mechanisms of action, and inconsistencies in chemistry, manufacturing, and controls as well as release criteria, all of which constrain cross-trial interpretability. At the same time, announcements of emerging clinical technologies and associated pricing signals, while reflecting translational momentum, cannot substitute for trial-grade evidence, given the limited transparency in study design, endpoint definition, and long-term follow-up.

Looking ahead, a constructive regulatory pathway may involve the integration of (i) standardized minimal reporting and characterization frameworks, (ii) mechanism-of-action–aligned critical quality attributes and potency assays linked to clinically measurable biomarkers, and (iii) strengthened post-marketing surveillance and registry-based real-world evidence to support conditional approvals and refine benefit–risk assessment over time.

Beyond regulatory science considerations, the translation of biomaterial-based MSC therapies—particularly for aging-related diseases—faces additional scientific and engineering challenges. First, many preclinical disease models insufficiently recapitulate human pathophysiology, limiting clinical translation. Second, most studies focus primarily on MSC responses and underexplore interactions with other cell types, thereby overlooking multicellular dynamics. Third, for many biomaterials, post-transplant MSC fate tracking remains limited to in vitro transcriptomics, and real-time in vivo monitoring is technically challenging. Fourth, complex manufacturing hinders scale-up and quality control. Fifth, long-term biosafety and the fate of degradation products are insufficiently characterized. Finally, heterogeneity in MSC sources (bone marrow, umbilical cord, adipose tissue, etc.) reduces reproducibility across studies. Future research should therefore prioritize the development of more predictive disease models, integrative multicellular analysis frameworks, advanced in vivo fate-tracking technologies, and scalable manufacturing strategies to improve reproducibility, safety, and clinical translatability.

7.2. Future research directions

Over the past decade and more, the integration of MSC therapy and materiobiology has progressed from “support and carrier” to “active regulation and intelligent response,” accumulating inspiring results in functional design and clinical trials targeting aging-related diseases. However, turning these scattered highlights into truly “reproducible, controllable, and deployable” therapeutic products require further research. Importantly, a fundamental bottleneck in current progress is the lack of systematic, low-cost, and high-throughput frameworks to map biomaterial parameters to MSC functions across both in vitro and in vivo settings. Most studies remain confined to low-dimensional, single-parameter modulation (e.g., stiffness or surface chemistry), whereas MSC fate in vivo arises from the integration of multiple, dynamically coupled cues, compounded by limited longitudinal fate-tracking. Overcoming these limitations requires a paradigm shift from isolated parameter optimization toward multidimensional, data-driven mapping strategies, which underpins the emerging directions discussed below.

To improve the combined efficacy of biomaterials and MSCs, we outline three promising directions: (1) enhancing cellular therapeutic efficacy, (2) deploying scalable, emerging cell-expansion technologies, and (3) leveraging machine learning to map the intrinsic links between cell fate and materials design.

7.2.1. Regulation by mitochondrial factors

Mitochondrial factors are signaling molecules that convey local mitochondrial stress to other mitochondria in distant cells and tissues. In clinical practice and research, mitochondrial factors serve as tools for mechanistic elucidation, diagnostic markers, and therapeutic targets, spanning exercise physiology, aging, metabolic diseases, neurological disorders, and tumor biology. Recent studies have proposed innovative approaches for MSC therapy from the perspectives of biological agents and nanomedicines. Do et al. (2024) [184] developed MSCs overexpressing fibroblast growth factor twenty-one and demonstrated in an ischemic brain model that they exert neuroprotective effects by preserving blood-brain barrier integrity. The specific mechanisms include upregulation of tight junction proteins, suppression of the expression of the edema-inducing factor aquaporin 4, and reduction of matrix metalloproteinase 9 activity, thereby significantly improving neurological deficits. Chen et al. (2025) [185] proposed a novel solution from the perspective of nanomaterials by developing an energy metabolism-engaged nanomedicine. This nanomedicine is fabricated via contact electrocatalysis and features highly exposed phosphate groups. It can specifically target the mitochondria of aged stem cells, bind directly to the beta subunit of ATP synthase, induce mitochondrial fission and autophagy, and achieve metabolic reprogramming with a shift from oxidative phosphorylation to glycolysis. In aged osteoporosis models, the nanomedicine specifically accumulates in bone tissue, reverses bone density loss, and restores the stemness and differentiation potential of endogenous BMSCs, providing a new therapeutic avenue for age-related bone diseases. Future work may emphasize (1) mitochondrial-targeted delivery systems for genetic modulation and (2) biomimetic mitochondria-inspired nanomaterials.

7.2.2. Microfluidic dynamic cultivation technologies

Microfluidic single-cell cultivation is an emerging field in fundamental and applied biology. Traditional cell culture methods, such as shake flasks and bioreactors, suffer from heterogeneous environmental conditions and averaged measurements, failing to reveal cellular heterogeneity. Single-cell cultivation enables real-time monitoring of individual-cell dynamics (e.g., proliferation, differentiation). Traditional platforms (e.g., microplates) suffer from low capture efficiency, cross-contamination, and limited microenvironmental control. Microfluidic systems provide tightly controlled culture environments with high throughput, precise and real-time manipulation, accurate microenvironmental control, low sample consumption with high sensitivity, and seamless integration with downstream analyses. [186]. Another review introduced the concept of dynamic environmental control [187], proposing technical schemes such as hydrostatic pressure methods and pressure pump methods to achieve step or pulse functions and modulation of pulse frequency, width, amplitude, as well as combinatorial modulation approaches. Dynamic environmental control can regulate expression of tetracycline-inducible promoters in Chinese hamster ovary cells and analyze Ca²⁺ dynamics in HEK-293 cells, demonstrating technical feasibility and biological value in single-cell research. Applying microfluidic single-cell cultivation to MSC culture can provide innovative tools from single-cell behavior studies to tissue engineering applications. Future work may focus on developing reproducibly manufactured commercial microfluidic platforms, integrating artificial intelligence algorithms to optimize predictions of culture parameters, and advancing applications of microfluidic MSC culture in regenerative medicine and personalized therapy.

7.2.3. Machine learning to predict structure-function relationships

Traditional research and development of biomaterials mainly relies on trial-and-error, that is, optimizing material performance through extensive experimental screening. This process is time-consuming and labor-intensive, inefficient, and ill-suited to revealing complex intrinsic associations between material structure and cellular responses. Introducing machine learning into research on MSC-related biomaterials can build interpretable predictive and optimization frameworks with small samples, rapidly screen formulations, accurately anticipate cellular responses, achieve multi-objective trade-offs, and reduce experimental costs and translational risks.

A study in 2023 employed deep learning models including VGG-19 and ResNet to analyze microscopic images of human mesenchymal stromal cells and successfully predict their differentiation direction [188]. Another study in twenty twenty-four developed a machine learning pipeline that uses convolutional neural networks to classify cell images to predict and characterize the timing of MSC differentiation [189]. Data scarcity is currently the greatest bottleneck constraining development in this field. There is an acute lack of publicly available, high-quality benchmark datasets that systematically link material physicochemical descriptors with quantitative response metrics of MSCs. Although high-throughput screening is considered an effective avenue to address data issues, public high-throughput datasets that include multidimensional material surface descriptors (such as roughness, chemistry, stiffness) alongside quantitative MSC functional outcomes (adhesion, proliferation, differentiation) are exceedingly rare. Future research may proceed in three directions: (1) building data-sharing ecosystems; (2) developing advanced and interpretable models, for example further exploring the potential of graph neural networks to predict cellular responses directly from material molecular or microstructural information, and applying transfer learning and self-supervised learning to alleviate dependence on large labeled datasets; (3) integrating automated experimental platforms by combining machine learning models with automated robotic platforms for high-throughput synthesis, characterization, and cell screening to form an autonomous “predict-synthesize-test-learn” research and development loop.

8. Conclusions

This review systematically maps and integrates the latest advances across the full pipeline—from basic design to clinical application—on mesenchymal stromal cell fate regulation through the lens of materiobiology. Biomaterials have evolved from simple cell carriers into intelligent microenvironments capable of actively and precisely regulating MSC behavior and fate. This article demonstrates in detail that material physical parameters (stiffness gradients, topography), chemical parameters (surface chemistry, degradation products), and the spatiotemporal delivery of bioactive molecules (growth factors, gene delivery) constitute three key dimensions for regulating MSC fate. By simulating or modulating in physiological or pathological microenvironments, these material strategies effectively guide MSCs toward desired therapeutic phenotypes and enhance their survival and function. In light of bottlenecks in clinical applications of MSCs for aging-related diseases, the review particularly emphasizes the importance of anti-aging material design. By introducing strategies such as ROS scavenging, epigenetic regulation, and telomere protection, materiobiology provides innovative solutions to maintain long-term MSC function and reverse aging microenvironments. Advanced in vivo tracing technologies, such as multimodal imaging and single-cell transcriptomics, provide unprecedented insights into the true fate of MSCs after transplantation and their interactions with the host environment. In clinical scenarios of typical aging-related diseases, including pulmonary or liver fibrosis, osteoarthritis, heart failure, and wound healing, biomaterials-based engineered MSC therapies show therapeutic potential that may exceed conventional cell infusion.

Despite broad prospects, the field still faces challenges such as limitations of disease models, cellular heterogeneity, the long-term biosafety of materials, and scalable manufacturing and standardization. Future research should focus on deeply exploring regulatory mechanisms at the organelle level, such as mitochondria, developing more biomimetic dynamic culture systems such as microfluidics, and leveraging machine learning to accelerate material design, ultimately advancing MSC therapy from proof-of-concept to safe, effective, and controllable clinical products.

CRediT authorship contribution statement

Yuke Feng: Writing – review & editing, Writing – original draft, Visualization, Project administration, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Yuqian Qiu: Writing – review & editing, Writing – original draft, Visualization, Project administration, Investigation, Formal analysis, Data curation, Conceptualization. Shaozhen Zhang: Writing – review & editing, Visualization. Kai Dai: Writing – review & editing, Visualization, Supervision, Investigation, Funding acquisition, Conceptualization. Jing Wang: Writing – review & editing, Supervision, Funding acquisition. Changsheng Liu: Writing – review & editing, Supervision, Funding acquisition.

Ethics approval and consent to participate

Not applicable.

Declaration of competing interest

The authors declare no competing interests.

Funding and Acknowledgment

This work was supported by the Excellence Research Group Program (no. T2288102), the Key Program of the National Natural Science Foundation of China (no. 32230059), the National Natural Science Foundation of China (no. 32301123 and 32571564), the Foundation of Frontiers Science Center for Materiobiology and Dynamic Chemistry (no. JKVD1211002).

Footnotes

Peer review under the responsibility of editorial board of Bioactive Materials.

Contributor Information

Kai Dai, Email: daikai233@ecust.edu.cn.

Jing Wang, Email: wangjing08@ecust.edu.cn.

Changsheng Liu, Email: liucs@ecust.edu.cn.

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PERMALINK

Materiobiology-guided regulation of mesenchymal stromal cell fate for aging-related diseases: From basic parameter design to clinical application

Yuke Feng

Yuqian Qiu

Shaozhen Zhang

Kai Dai

Jing Wang

Changsheng Liu

Abstract

Graphical abstract

Highlights

1. Introduction

Table 1.

Fig. 1.

2. Current landscape of MSC clinical trials

Table 2.

3. Basic design principles for biomaterial parameters

Fig. 2.

3.1. Physical parameter modulation

Fig. 3.

3.1.1. Mechanotransduction of lineage commitment under stiffness gradients

3.1.2. Topographical regulation of MSC fate

3.2. Chemical parameter modulation

Fig. 4.

3.2.1. Surface chemistry modification

3.2.2. Regulation via degradation products

3.3. Spatiotemporal delivery of bioactive molecules

3.3.1. Growth factor controlled-release systems

3.3.2. Gene delivery

4. Anti-aging functionalized design

Fig. 5.

4.1. ROS scavenging

4.2. Epigenetic regulation strategies

4.3. Telomere protection

5. In vivo fate tracking of MSC transplantation

Fig. 6.

5.1. In vivo position tracking

5.2. Transcriptome monitoring

6. Clinical applications in aging-related diseases and biomaterial solutions

Table 3.

Fig. 7.

6.1. Fibrotic diseases

6.1.1. Pulmonary fibrosis (PF)

6.1.2. Liver fibrosis

6.2. Osteoarthritis

6.3. Heart failure (HF)

6.4. Wound healing

7. Challenges and prospects

7.1. Current policies and challenges

7.2. Future research directions

7.2.1. Regulation by mitochondrial factors

7.2.2. Microfluidic dynamic cultivation technologies

7.2.3. Machine learning to predict structure-function relationships

8. Conclusions

CRediT authorship contribution statement

Ethics approval and consent to participate

Declaration of competing interest

Funding and Acknowledgment

Footnotes

Contributor Information

References

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