天美传媒

Cell-free biomaterials; Immunomodulation; Regenerative medicine; Tissue engineering; Immune-instructive materials; Innate immunity; Adaptive immunity; Inflammation control; Biomimetic scaffolds; Extracellular vesicles; Exosome-functionalized materials

Introduction

In recent years, the field of regenerative medicine and tissue engineering has shifted toward developing advanced biomaterials that not only support tissue repair but also actively modulate the immune system [1]. Cell-free immunomodulatory biomaterials represent a novel class of therapeutic platforms engineered to engage with the host immune system in a controlled and purposeful manner without the direct use of living cells. Unlike traditional scaffolds that passively interact with biological environments, these materials are designed to influence key immune pathways, shaping both innate and adaptive immune responses to create a pro-regenerative microenvironment [2]. By modulating inflammation, recruiting reparative immune cells, and promoting the resolution of injury, immunomodulatory biomaterials can significantly enhance the healing of complex tissues such as skin, bone, nerve, and cardiac muscle [3].

Emerging strategies in this area include the integration of immunoactive molecules, cytokine-mimetic structures, and extracellular vesicles (such as exosomes) into biocompatible scaffolds [4]. These cell-free constructs reduce the challenges associated with live cell therapies such as storage, viability, immune rejection, and regulatory hurdles while maintaining or enhancing regenerative outcomes. This paper delves into the recent progress in the development and application of cell-free immunomodulatory biomaterials, highlighting their mechanisms of action, material design considerations, and therapeutic potential in diverse tissue engineering applications. By harnessing the immune system’s inherent role in healing, these biomaterials are paving the way for next-generation regenerative therapies that are both safe and clinically translatable [5].

Discussion

The concept of cell-free immunomodulatory biomaterials marks a paradigm shift in regenerative medicine, moving beyond passive structural support to active immune engagement. These biomaterials aim to fine-tune the host immune response to promote tissue healing, rather than suppressing or avoiding it entirely [6]. This shift reflects a deeper understanding of the immune system’s dual role in both initiating inflammation and guiding regeneration. At the core of these materials is the ability to interact with immune cells, particularly macrophages, dendritic cells, and T cells, to steer the healing process. For example, materials that promote M2 macrophage polarization a phenotype associated with tissue repair can suppress chronic inflammation and encourage constructive remodeling. This is achieved through surface topography, controlled degradation, and biochemical cues like immobilized cytokines or bioactive peptides [7].

In contrast to cell-based therapies, cell-free immunomodulatory systems offer numerous advantages: reduced immunogenicity, greater stability, off-the-shelf availability, and simplified regulatory approval. Biomaterials embedded with extracellular vesicles (EVs) or exosomes derived from mesenchymal stem cells (MSCs), for instance, have been shown to recapitulate many therapeutic benefits of live-cell delivery by modulating immune signaling and enhancing angiogenesis all without the challenges of cell survival and integration. Recent studies also emphasize the role of material chemistry, stiffness, and degradation kinetics in influencing immune responses. For example, hydrogels with defined viscoelastic properties can modulate dendritic cell activation, while the release of degradation byproducts such as lactic acid can indirectly influence T cell recruitment and activity. These findings underscore the need to design immune-instructive materials that integrate mechanical, chemical, and biological signals for optimal performance [8].

Despite significant progress, several challenges remain. One is the complexity and variability of the immune system itself, which can result in heterogeneous responses depending on the patient’s health status, age, and genetic background. Furthermore, long-term studies are needed to ensure that these materials do not elicit delayed immune responses or interfere with tissue homeostasis [9]. Moreover, while many preclinical studies report promising outcomes, clinical translation remains limited. This may be attributed to the difficulty in scaling up production, ensuring reproducibility, and defining clear biomarkers for immune modulation and therapeutic efficacy. Addressing these gaps will require a multidisciplinary effort involving biomaterials science, immunology, bioengineering, and regulatory sciences. In summary, cell-free immunomodulatory biomaterials offer a versatile and powerful platform for regenerative medicine, with the potential to replace or complement traditional cell therapies. Through intelligent design and a deeper understanding of host–material interactions, these biomaterials may unlock a new era of immune-guided healing strategies across a range of clinical applications [10].

Conclusion

Cell-free immunomodulatory biomaterials have emerged as a transformative strategy in regenerative medicine and tissue engineering, enabling precise modulation of the immune response without the complexities of live cell therapies. By harnessing the power of immune-instructive cues such as cytokine-mimetic molecules, extracellular vesicles, and tailored material properties these advanced biomaterials offer a unique approach to promoting tissue repair, reducing inflammation, and restoring function. Their versatility, scalability, and safety profile position them as highly attractive candidates for clinical translation across a range of applications, including skin regeneration, bone repair, neural healing, and cardiovascular tissue engineering. While challenges such as personalized immune responses and long-term biocompatibility remain, continued interdisciplinary research and technological innovation are rapidly advancing this field. As our understanding of immune–biomaterial interactions deepens, cell-free immunomodulatory scaffolds are poised to redefine the landscape of regenerative therapies—offering a smart, safe, and scalable path toward next-generation, immune-integrated healing solutions.

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