A promising research direction in the field of biological engineering is the design and functional programming of three-dimensional (3D) biointerfaces designed to support living cell functionality and growth in vitro, offering a route to precisely regulate cellular behaviors and phenotypes for addressing therapeutic challenges. While traditional two-dimensional (2D) biointerfaces have provided valuable insights, incorporating specific signaling cues into a 3D biointeractive microenvironment at the right locations and time is now recognized as crucial for accurately programming cellular decision-making and communication processes. This approach aims to engineer cell-centric microenvironments with the potential to recapitulate complex biological functions into a finite set of growing cellular organizations. Additionally, they provide insights into the hierarchical logic governing the relationship between molecular components and higher-order multicellular functionality. The functional live cell-based microenvironment engineered through such innovative biointerfaces has the potential to be used as an in vitro model system for expanding our understanding of cellular behaviors or as a therapeutic habitat where cellular functions can be reprogrammed.

In vitro culture is a key and necessary step in the development of new therapeutics and tissue replacement/repair approaches. The recent decade has seen extensive efforts to improve in vitro culturing approaches for various mammalian cell types with advancements in single-cell and multicellular cultures, utilizing diverse substrates and spatial configurations.1 Important challenges remain including the selection and maintenance of appropriate cellular phenotypes, spatial organization of multiple cell types into relevant tissuelike mimics, and recapitulation of biological remodeling over time. Current and future developments within nano and molecular scale bioengineering have the potential to define precisely defined 3D microenvironments or niches with appropriate spatially and temporally programmed signaling cues for directed, sustained cell growth, and tissuelike organization.

Historically, 2D culture plates have been a mainstay for in vitro cell culture enabling basic cellular biology and efforts to address medical challenges.2 However, the limitation of these typically glass or plastic systems to poorly define relevant signaling environments and cellular phenotypes is well recognized and has led to significant research efforts to develop more sophisticated 2D biointerfaces capable of presenting complex signaling cues at microscale and nanoscale.3,4

These more advanced 2D format culture systems benefit from the relative ease of molecular placement and organization of the signaling cues, as well as compatibility with high-throughput and high-resolution imaging techniques allowing mechanistic understanding of cellular processes at the molecular scale and have demonstrated control of cellular function and cellular phenotypes.4,5 However, despite these improvements, it is not clear that these 2D biological signaling platforms can sufficiently replicate the more complex 3D in vivo biointerfaces and drive relevant tissuelike cellular organization and phenotypes.

In vivo cells reside in complex three-dimensional spaces interacting with neighboring cells, soluble signals, and the extracellular matrix (ECM).6 Various biochemical and biomechanical signaling cues locally influence cell functions, detectable from macro- to nanoscales and provide an intricate cellular microenvironment driving cellular phenotypes (Fig. 1).7,8 Designing a precise and personalized (or cell-specific) biointerface in vitro to accommodate cellular functions and program cell behaviors requires a mimic of each of these signaling factors and poses different challenges.

FIG. 1.

Dynamic in vivo cellular microenvironments. Complex and dynamic interplay between cells and their surrounding microenvironment, which consists of neighboring cells, an extracellular matrix, and various soluble and insoluble biochemical factors. Biomechanical cues such as matrix stiffness, degradability, and viscoelasticity, together with biochemical signals from matrix proteins, are critical at microscales, influencing cellular functions. At larger scales, external mechanical forces like compression, stretching, and curvature, as well as interactions with supporting cells such as immune, neuronal, and endothelial cells, modulate cellular responses. These dynamics occur across different spatial (nano to macroscales) and temporal (seconds to days) scales. Figure created with BioRender.com.

FIG. 1.

Dynamic in vivo cellular microenvironments. Complex and dynamic interplay between cells and their surrounding microenvironment, which consists of neighboring cells, an extracellular matrix, and various soluble and insoluble biochemical factors. Biomechanical cues such as matrix stiffness, degradability, and viscoelasticity, together with biochemical signals from matrix proteins, are critical at microscales, influencing cellular functions. At larger scales, external mechanical forces like compression, stretching, and curvature, as well as interactions with supporting cells such as immune, neuronal, and endothelial cells, modulate cellular responses. These dynamics occur across different spatial (nano to macroscales) and temporal (seconds to days) scales. Figure created with BioRender.com.

Close modal

Encapsulating cells in 3D microenvironments can significantly enhance cellular functions if relevant signaling cues are present. Many 3D biointerfaces have been developed, aiming to incorporate specific biomimetic signals, typically constructed using naturally or synthetically derived polymeric structures with cutting-edge technologies, such as (wet) electrospinning,9,10 microfluidics,11 bioprinting,12 and other micro and nanofabrication approaches.13 Initially, research mainly focused on ensuring that scaffolds were exhibiting minimal biocompatibility; however, the importance of more biomimetic 3D platforms to anatomically and physiologically resemble the targeted tissues has become clear, e.g., incorporating branched nanofiber architectures or microscale tubular designs.14 These efforts have aided the understanding of cellular behavior and their organizations and informed the optimization of 3D biomaterials for particular applications.

Cells interact with the scaffold materials/biomaterial interfaces, reacting to biochemical and physical cues, which modulate phenotype or behavior. While three-dimensional structures provide a foundation, further modifications are necessary to induce more natural cellular functionality. One route is via surface modification, where specific biomimetic signaling cues can be incorporated into a preformed scaffold. One strategy is coating the structures with functional molecules, for example, ECM proteins fibronectin, laminins, collagens, or arginine-glycine-aspartic acid (RGD)15 oligopeptide motif to mimic in vivo cell-matrix interactions or cell-membrane proteins such as cadherins and selectins, to mimic cell-cell interactions.16 Another approach to biointerface modifications, particularly for 3D environments, involves using responsive materials17 where the activity of signaling or adhesion molecules can be modulated by factors such as temperature, electric fields, light,18 and pH. These changes can impact cell adhesion, detachment, migration, and other cellular activities.

The use of hydrogels adds a mechanical dimension by allowing tuning of stiffness, viscoelasticity, and/or compliance.19 Materials possessing tissue-mimicking mechanical characteristics, including stiffness, viscoelasticity, tensile strength, and topographical features, play an important role in promoting physiological cell behaviors and functions.20 These materials regulate both biochemical and biomechanical signaling events, thereby facilitating normal and corresponding cellular responses.21,22

Returning to the in vivo cellular microenvironments, we often find a support network of surrounding cells, insoluble ECM protein, and soluble signaling factors engaging in regulating signaling pathways, typically occurring in a specific spatial manner (Fig. 1). This phenomenon holds true for both physiological and pathological scenarios. Therefore, the spatial localization of signaling cues via 3D biointerfaces will likely be necessary to functionally mimic these environments. By leveraging advanced multidisciplinary approaches, innovative and smart 3D biointerfaces have been designed, paving the way for the steering of cells to function and organize themselves as they would in natural settings.

The transition from 2D biointerfaces to state-of-the-art 3D biointerfaces represents significant progress in the precise design of optimal cellular environments, enabling better programming and accommodation of cellular activities (Fig. 2).23 However, much remains to be done to incorporate nanoscale spatial organization demonstrated in 2D into a 3D biointerface design that supports cell functionality and organization during growth with a need for new approaches.

FIG. 2.

Spatial signaling cues in 2D and 3D biointerfaces. The schematic illustrates the potential for achieving various geometries, topographies, stiffness patterns, and cell-adhesive matrices, as well as cell-cell protein-ligand interactions and multicellular patterning on 2D biointerfaces. This makes it suitable for high-throughput and high-resolution microscopy with the ability for nanoresolution modulation. In contrast, 3D biointerfaces offer increased dimensionality, allowing for the design of more intricate geometries and the utilization of a wide range of biomaterials. This facilitates the spatial arrangement of biomechanical and biochemical cues, as well as multicellular organization within 3D microenvironments. Figure created with BioRender.com.

FIG. 2.

Spatial signaling cues in 2D and 3D biointerfaces. The schematic illustrates the potential for achieving various geometries, topographies, stiffness patterns, and cell-adhesive matrices, as well as cell-cell protein-ligand interactions and multicellular patterning on 2D biointerfaces. This makes it suitable for high-throughput and high-resolution microscopy with the ability for nanoresolution modulation. In contrast, 3D biointerfaces offer increased dimensionality, allowing for the design of more intricate geometries and the utilization of a wide range of biomaterials. This facilitates the spatial arrangement of biomechanical and biochemical cues, as well as multicellular organization within 3D microenvironments. Figure created with BioRender.com.

Close modal

Future technologies could utilize chemical patterns present with 3D nanomaterials (e.g., hydrophobic/hydrophilic surface domains) on phase-separated or block copolymer electrospun fibers24 to direct the deposition of specific protein ligands. Alternatives could develop 2D approaches such as colloidal lithography25 to pattern biomolecules onto surfaces of 3D porous or fibrous materials, however, with the need for all solution-based patterning. Hydrogels could be given nanoscale structures by inclusion of preclustered ligands as chemically linked bioconstructs or via immobilization of ligands at nanomaterials such as nanoparticles or DNA origami constructs.26 Via a combination of these nanoscale approaches together with micro-to-centimeter scale approaches (e.g., 3D printing), hierarchical materials will be possible.

The extracellular matrix (ECM) present in the native microenvironment comprises a variety of proteins in a complex three-dimensional network that provides cells with mechanical resilience against various forces, including tensile, shear, and compressive stresses.27 Adhesive proteins play a crucial role in facilitating cell attachment to the matrix through specific receptors such as integrins, selectins, and syndecan. Integrin-based complexes, such as focal adhesions or hemidesmosomes, are particularly important as they also serve as essential signaling complexes.28 Additionally, robust interactions among neighboring cells, such as tight junctions, adherence junctions, and desmosomes, represent additional mechanical signals.29 These interactions serve as essential mechanotransducers, enabling cells to perceive and react to mechanical signals originating from their surroundings. Emerging need lies not just in introducing cues at the appropriate location but also at the appropriate time within these 3D environments. Designing these dynamic or time-programmed 3D systems presents a challenging task that will require both novel synthetic bioengineering and better characterization of in vivo microenvironments (Fig. 3).

FIG. 3.

Spatiotemporal control of signaling cues in 3D biointerfaces. Achieving precise spatiotemporal modulation of signaling factors impacting cell behavior ex vivo is crucial for tailoring 3D microenvironments to specific tissues and applications. Strategies such as employing stimulus-responsive materials activated by external cues (like light, pH, and temperature), dynamic competitors, or ligand modulations offer potential ways for such modulation. Additionally, cell-mediated modifications of materials can facilitate spatiotemporal modulation of matrix properties, including local degradation and deposition. Considering the complexity of multicellular organization in natural environments, achieving controlled multicellular organization on 3D biointerfaces can involve synthetic cell-cell contact or ligand-driven cell assembly. Figure created with BioRender.com.

FIG. 3.

Spatiotemporal control of signaling cues in 3D biointerfaces. Achieving precise spatiotemporal modulation of signaling factors impacting cell behavior ex vivo is crucial for tailoring 3D microenvironments to specific tissues and applications. Strategies such as employing stimulus-responsive materials activated by external cues (like light, pH, and temperature), dynamic competitors, or ligand modulations offer potential ways for such modulation. Additionally, cell-mediated modifications of materials can facilitate spatiotemporal modulation of matrix properties, including local degradation and deposition. Considering the complexity of multicellular organization in natural environments, achieving controlled multicellular organization on 3D biointerfaces can involve synthetic cell-cell contact or ligand-driven cell assembly. Figure created with BioRender.com.

Close modal

Recent developments in hydrogel biomaterial design,30 featuring customizable physicochemical properties, and fabrication methodologies such as bioprinting, micropatterning, and microfluidics, have enabled 3D spatial biomechanical and biochemical microenvironments for better cell accommodation in vitro. The mechanical microenvironment of cells in vivo can undergo dynamic changes over time, exhibiting variations in softness or stiffness during processes such as tissue development, regeneration, and pathological conditions.31,32 Consequently, controlling the mechanical properties of 3D biointerfaces preprogrammed over time or in a responsive cell-driven process will be crucial for regulating mechanotransduction signaling and subsequent cellular behaviors.

Patterning of stiffness within 3D biointerfaces such as hydrogels is possible across macro to micro and subcellular levels, by incorporating regions of different materials cross-linking or by modulating the physical microstructure, for example, via altered porosity or fiber diameter.33 Temporally programmed matrix stiffness, spanning from seconds to hours, can be achieved by carefully selecting optimal biomaterials via biodegradation or cross-linking.34 The importance of temporal regulation of stiffness levels in biological microenvironments is illustrated by embryoid bodies (EBs) formation from embryonic stem cells (ESCs), where spatial and temporal variations in mechanical forces impact ESC function and differentiation.35,36 As EBs grow, the cytoskeletal traction force escalates, potentially playing a role alongside gene regulation in triggering additional differentiation pathways with low anisotropy of cytoskeletal traction force favoring the differentiation of ESCs into endoderm and mesoderm, versus ectodermal.

Within programmable 3D biointerfaces featuring spatiotemporal mechanical forces, the inclusion of responsive materials will permit dynamic alterations in stiffness properties. These responsive materials, when strategically integrated at particular locations, provide stiffness patterning and gradient stiffness within hydrogels, facilitating stiffness modulation in response to relevant stimuli over specified timeframes. A key need is to extend the range of materials available to lower stiffness and viscoelastic37 hydrogels to better match the range of cellular microenvironments.19 Biodegradable hydrogels allow dynamic 3D mechanical biointerfaces where cells can modulate the degradation of the surrounding matrix as they grow. One approach to achieve better control of matrix remodeling over time involves modifying polymer chains within hydrogels with enzymatically degradable units. This modification, when paired with a sequential cross-linking approach, has been utilized to temporally regulate hydrogel stiffness by adjusting degradability. Mechanical stress and strain, compression, or shear stress as extrinsic factors play crucial roles in regulating cell functions alongside ECM stiffness, particularly for cells residing in tissues such as cartilage, bone, muscles, and heart. Stretching plays a significant role in physiological processes, such as muscle contraction and heart beating, and a straightforward approach to creating a controlled stress/strain 3D microenvironment might involve applying mechanical stretch to cell-laden hydrogels. However, it is crucial to recognize that the application of compressive or shear stress to 3D hydrogels must be done in a spatiotemporal manner, considering the targeted tissue and intended applications. In addition, care must be taken to balance the viscosity and elasticity of the matrix as time-varying viscoelastic properties of the ECM are believed to play a vital role in regulating cell functions and morphogenesis.32 These behaviors range from an elastic solidlike to a liquidlike viscous response varying from seconds to a few minutes on the relaxation time-scale. Recent strategies to address this have utilized reversible chemical bonds and other functional groups to create viscoelastic hydrogels that exhibit stress-relaxation properties19 which can be patterned to engineer programmable 3D biointerfaces with spatiotemporal mechanical properties.

The incorporation of appropriate biochemical signals is equally important as controlling the mechanical properties. These signaling cues should mimic those originating from both the adjacent cells and the matrix and can be integrated into artificial 3D environments by introducing correctly oriented and specific functional biomolecules or peptides into the backbone of biomaterials or through chemical modifications. Such cues need to go beyond the ECM matrix and include cell adhesion molecule signals (e.g., through integrins, selectins, and cadherins), growth factors (e.g., EGF, FGF, and GDNF), and other membrane-associated signaling pathways (e.g., Notch, Wnt, and Hedgehog).38 Engineering patterned environments that integrate these signals must be carried out precisely, selecting relevant biomolecules in specific patterns at the nano or microscales, and optimal cellular responses likely depend on ligand affinities and ligand spacing/densities also through multivalent signaling. In the complex in vivo environment, these biochemical signaling cascades function over time, requiring temporal patterning in vitro.

Emerging advanced technologies, such as nucleic acid nanotechnology (e.g., DNA origami, aptamers) and click chemistry, will facilitate submicrometer spatial organization of biomolecules over time, wherein signaling components can be selectively removed, shielded, or added by strand displacement or conformationally switched constructs (Fig. 3).37,39 Leveraging these innovative tools also allows cell-membrane engineering, thereby enabling the precise organization of cells in appropriate spatial and temporal contexts to promote the formation of multicellular arrangements enhancing overall functionality.40,41 A critical challenge for the control or steering of cellular function will be to define materials that can maintain the designed signal presentation over time in the background of cells’ own efforts to condition their surroundings. Cells release a plethora of soluble and insoluble proteins in a phenotype-specific manner which have the potential to decorate any introduced matrices/hydrogels as a protein corona.42 One approach can be to limit these proteins’ ability to bind [e.g., polyethylene glycol (PEG) backbones] or to engineer protein-based matrices lacking binding domains for unwanted proteins and deliberately recruiting other specific cell-released proteins.43 An alternative strategy can be implementing specific antibodies or nanobodies in a spatially organized manner within biointerfaces. This approach allows for the selective capturing of certain proteins secreted by cells in a controlled spatiotemporal fashion.

Customizing the spatiotemporal biochemical and biomechanical architecture of 3D microenvironments will allow steering of the functionality and phenotype of cells, controlling growth, migration, differentiation, and senescence in single and multicellular constructs. Leveraging spatiotemporal-driven signaling cues offers a “personalized” approach applicable to various biomedical applications, including cell therapy, tissue engineering, and supporting organoid formation for precise in vitro disease models.

By creating 3D spatiotemporal microenvironments with appropriate signaling cues, it will become possible to engineer tissues or design implantable devices that enhance regeneration in situ. Moreover, designing innovative microenvironments capable of supporting cellular functionality in vitro enables the replication of native physiological or pathological conditions for single-cell types or multicellular organizations. This approach can deepen our understanding of cellular behavior and crosstalk, offering insights into complex biological processes, e.g., understanding cancer invasiveness and immune cell function within models of tumor-immune microenvironments.

Another key application will be overcoming inadequate signaling cues and cell organization within organoids44,45 by supporting their development within spatiotemporally designed 3D biointerfaces. These biointerfaces provide appropriate signaling cues to cells at the right time and location, potentially enabling the development of relevant organoids or fully functional organs. As an example, enhancing crypt-villus regionalization in in vitro intestinal organoid development may be enabled by appropriate biomolecules and mechanical properties of the 3D microenvironment patterned in a spatiotemporal manner. The next generation of 3D biointerfaces could extend support to other organoids, which frequently demonstrate diverse shapes and unpredictable variations in their developmental stage and functional capabilities.

Through numerous lessons learned, it is clear that the development of programmable 3D biointerfaces marks a significant advancement in tissue engineering and regenerative medicine. By precisely designing these microenvironments to mimic the mechanical and biochemical landscapes of the native extracellular matrix, significant strides have been made toward understanding and controlling cellular behavior in vitro. The incorporation of advanced biomaterials, capable of responding to cellular cues and environmental changes, offers unique opportunities for directing cell functions and organization. Emerging innovations will focus on refining these interfaces to precisely regulate the cellular microenvironment, accommodating dynamic interactions between cells and their surroundings over time. Leveraging interdisciplinary approaches spanning bioengineering, materials science, nanoscience, chemical engineering, and cellular biology will be essential to fully harness the potential of programmable 3D biointerfaces for therapeutic purposes.

S.G. acknowledges funding from the Novo Nordisk Foundation, Denmark (Grant No. NNF22OC0073507) and D.S.S. acknowledges from DNRF 135 Excellence Center, Denmark.

The authors have no conflicts to disclose.

Ethics approval is not required.

Sadegh Ghorbani: Conceptualization (equal); Project administration (equal); Resources (lead); Visualization (lead); Writing – original draft (lead); Writing – review & editing (equal). Duncan S. Sutherland: Conceptualization (equal); Project administration (equal); Writing – review & editing (equal).

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

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Sadegh Ghorbani has been a postdoctoral researcher in the Department of Materials Science and Engineering at Stanford University, USA, and the Department of Health Technology at DTU University, Denmark, since 2023, following his receipt of a Novo Nordisk Foundation-sponsored Visiting Scholar Fellowship. He obtained his Ph.D. in nanoscience from the Interdisciplinary Nano Center (iNANO) at Aarhus University, Denmark, under the guidance of Prof. Duncan S. Sutherland, where he focused on engineering nanopatterned biointerfaces for mimicking cellular interactions.

His current research, under the guidance of Prof. Sarah Heilshorn, focuses on fabrication of 3D biointerfaces with tunable mechanical and biochemical properties in a spatial and temporal manner. This innovative approach aims to better control cellular signaling cues in multicellular and multimaterial tissue models.

Through his expertise at the intersection of nanotechnology, materials science, biology, and bioengineering, Dr. Ghorbani aims to develop sophisticated models that closely replicate the complexities of human tissues with tunable properties in a spatiotemporal fashion for research and clinical applications.