Different tissues exhibit distinct mechanical properties, including stiffness and viscoelasticity. Both static and dynamic mechanical cues modulate cellular behaviour and induce phenotypic changes. To leverage this regulatory mechanism, researchers have engineered dynamic hydrogels through physical interactions and dynamic covalent bonds (DCBs). Prior studies demonstrate that viscoelastic hydrogels effectively direct mesenchymal stem cell (MSC) behaviour, making them promising candidates for bone tissue engineering (BTE). This review systematically summarizes (i) dynamic hydrogel crosslinking strategies (ionic, hydrogen bonding, hydrazone, boronate ester, and imine), (ii) quantitative viscoelastic modulation methods (molecular weight, crosslinking chemistry, and network architecture), and (iii) mechanotransduction pathways governing MSC proliferation, spreading, migration, osteogenesis, and chondrogenesis. Several conclusions emerge from the above perspectives: viscoelastic effects are context-dependent, varying with the cell source, dimensionality, and matrix chemistry; YAP/TAZ serves as a convergent node integrating diverse mechanosensory inputs (integrin-FAK, TRPV4, and Piezo1) into lineage-specific programs; and clinical translation faces persistent challenges from non-standardized characterization protocols, limited long-term in vivo validation, and scalable manufacturing constraints. By integrating these perspectives, this review aims to develop the rational design of ECM-mimetic dynamic hydrogels for bone and cartilage regeneration.

Collagen/inorganic hydroxyapatite (HAp) composite materials prepared through biomimetic mineralization hold significant promise for bone repair. However, previous studies have encountered challenges such as low mineralization efficiency and concerns regarding the biosafety of collagen. Drawing inspiration from the structure of natural bone, we innovatively developed a model involving the encapsulation of cations within recombinant human collagen type I hydrogels and anions penetration to facilitate in situ biomimetic mineralization of HAp nanocrystals. Subsequently, recombinant human collagen type I/HAp composites (rC@HAp) were fabricated with varying HAp contents. Compared to alternative mineralization methods, our method efficiently generated numerous HAp crystals without agglomeration within one hour, suggesting superior spatial dispersion and uniformity. Importantly, the biocompatible rC@HAp could effectively promote osteogenic differentiation in vitro and induce bone formation in vivo. It was found that rC@HAp45 displayed comparable efficacy to existing commonly used bone repair products. This study provides a low-cost, eco-friendly, feasible, and scalable approach for manufacturing osteoconductive hydrogel composites for bone repair, tackling the shortage of humanized bone repair products and expediting the development of artificial bone repair products.

Effective management of inflammation is one of the promising strategies to prevent the formation of chronic wounds. Despite hydrogen being a prospective molecule for anti-inflammatory effects, the on-demand delivery of hydrogen that could synchronize with the dynamic inflammation stages has yet remained unaddressed. Moreover, its specific immunomodulatory mechanisms are still veiled. In this study, we introduced ISO-ZIF-8@AB, a hydrogen-generating nanoplatform that integrated visible-light photocatalysis and hydrolysis reactions to achieve controllable hydrogen release on demand, functioning with an initial peak release and following a sustained release. With ISO-ZIF-8@AB further loaded into an aligned ECM-like scaffold, the complex significantly alleviated inflammation and prevented protracted unhealing. The bulk-RNA sequencing combined with single-cell RNA sequencing revealed that hydrogen treatment effectively reduced the excessive aggregation and infiltration of innate immune cells. Specifically, hydrogen reduced the proportion of Ptgs2+Nos2+ pro-inflammatory macrophages (PIMs) by mitigating mitochondrial stress and suppressing HIF-1α-induced glycolysis, the immune-metabolic regulation of which reduced harmful crosstalk between PIMs and hypodermal fibroblasts and facilitated extracellular matrix production accompanied by the ultimate wound repair. Overall, this study presented a strategy for controllable hydrogen release in terms of timing and rate, with further discussions regarding the underlying immune-metabolic regulation mechanisms of hydrogen therapy.

Molting is a vital physiological process essential for the growth and development of Penaeus vannamei, with significant implications for aquaculture productivity. This study aimed to identify neuropeptide-related genes involved in molting through transcriptomic analysis. RNA sequencing of pre-molt and post-molt samples revealed 1203 differentially expressed genes (DEGs). Functional enrichment analysis indicated that these genes play significant roles in cuticle formation and molting regulation. Among the DEGs, 243 were predicted to be neuropeptides based on the presence of signal peptides and the absence of transmembrane domains. Five key neuropeptide genes—PvCHH, PvMIH, PvEH I, PvCDA I, and PvCDA II—were identified as critical regulators of molting. Their role was further validated through RT-qPCR analysis, confirming their close association with the molting process. These genes were highlighted in this study as pivotal factors driving molting in P. vannamei. The neuropeptides identified in this research are anticipated to offer valuable insights into the regulation of molting. Additionally, their synthetic products hold promise for improving molting consistency in shrimp aquaculture.

Excellent moisture resistance and high thermal conductivity are key characteristics of diamond/Al composites applied in electronic packaging. However, it is barely possible to achieve both by adjusting the initial thickness or the phase structure of the interface layer alone. In this study, the metallurgical behaviors of the diamond/Al interfaces were investigated to clarify the melting process and eventually prepare diamond/Al composites with both excellent moisture resistance and high thermal conductivity. Specifically, an Al film was deposited on tungsten-coated diamond plates with different phase compositions to explore diffusion and metallurgical behaviors of W, Al and C. W in the coatings exhibited significantly active diffusion behaviors and participated in interfacial metallurgical reactions in the Al matrix under optimized conditions. Regardless of the phase compositions of the coatings, W, W2C and WC were exposed to erosion by liquid Al during infiltration, resulting in varying interfacial metallurgical structures. When the interfacial metallurgical structure was Diamond/WC/ Al4C3/Al5W/Al, the thermal conductivity reached 658 W center dot m- 1 center dot K- 1. After water incubation for 680 h, the thermal conductivity decreased by 8.9 % only, indicating good moisture resistance. Additionally, theoretical calculations revealed that the thermal conductivity of diamond/Al composites can be improved by reducing the content of Al5W in the Al matrix, and the WC/Al4C3/Al5W interfacial interlayer plays a crucial role in inhibition of Al4C3 hydrolysis at the interface. This study facilitates understanding of interfacial metallurgical behaviors of W coating at the diamond/Al interface, as well as preparation of high-performance diamond/Al composites.

This study investigates the role of γδ T cells in wound healing facilitated by an EGCG (Epigallocatechin gallate)-releasing nanofibrous scaffold with aligned topography (APEMS). Incorporating core-shell microcapsules for sustained EGCG release over 11 days, the biocompatible scaffold enhances γδ T cell activity to promote advanced wound repair. In a splinted wound excisional model in 6-8 weeks-old male C57BL/6J mice, APEMS significantly improved re-epithelialization and wound closure compared to a control scaffold (APS). Single-cell RNA sequencing revealed a marked increase in γδ T cell in the APEMS group, where γδ T cells accounted for 66.2 % of the T cell population, compared to 33.8 % in the APS group. Cellchat analysis identified the AREG-EGFR signaling axis as pivotal to γδ T cell-mediated wound repair. APEMS-induced γδ T cells secreted amphiregulin (AREG), which acted on keratinocytes and fibroblasts to enhance keratinocyte proliferation, migration, and fibroblast-driven extracellular matrix remodeling. In immunodeficient mice lacking mature γδ T cells (TCRδ-/-), wound healing was significantly impaired, characterized by delayed re-epithelialization, reduced neo-dermal thickness, and increased inflammation. Inhibition of AREG and EGFR function via monoclonal antibodies against AREG and EGFR antagonist Gefitinib similarly delayed wound healing, the therapeutic advantage of APEMS over APS was abolished, emphasizing its critical role in the process. These findings provide a framework for developing advanced wound management materials and highlight the therapeutic potential of targeting γδ T cells and AREG-EGFR signaling to enhance tissue regeneration.

Collagen, recognized as the primary structural component of human skin, is essential for preserving dermal integrity and function. Its progressive depletion has been closely associated with structural deterioration of the dermis and the visible signs of skin aging. Among current therapeutic strategies, the injection of exogenous collagen has been established as an effective method for alleviating aging-related skin changes. In the present study, a comprehensive evaluation was conducted to assess the injectability, cellular interactions, and photoaging repair efficacy of recombinant human collagen type III (RHC). The RHC solution was found to demonstrate favorable injectability and support the adhesion and chemotactic behavior of L929 cells, while also upregulating the expression of type I and type III collagen. In co-culture systems with lipopolysaccharide-stimulated macrophages, RHC treatment suppressed macrophage proliferation and reduced the production of proinflammatory cytokines, suggesting notable immunomodulatory properties. Upon intradermal injection of RHC into photoaged rat skin, an increased density of dermal collagen fibers was observed, accompanied by a more organized and uniform fiber arrangement. Additionally, hydroxyproline content and the expressions of collagen I and III were markedly elevated in the RHC group compared with the control and hyaluronic acid groups. Collectively, these findings suggest that RHC holds considerable promise as a therapeutic agent for both medical and cosmetic purposes targeting the restoration and maintenance of youthful skin characteristics.

Chronic nonhealing wounds represent significant complications of diabetes, bearing a substantial burden and posing risks of disability or mortality. In diabetic wounds, continuous tissue fluid exudation, inflammatory cell migration, fibrosis, and bacterial biofilm formation create a "barrier", which decreases the treating efficacy of therapeutics. To address these limitations, a recombinant human collagen type III microneedle patch (rhCol III-PRPM) loaded with platelet-rich plasma (PRP) was developed, in which methacrylated rhCol III (rhCol III-MA) loaded with PRP was utilized to form needle tips, while rhCol III-MA formed the base part of the patch. RhCol III-PRPM featured adequate mechanical qualities, swelling capacity, and sustained in vitro release of growth factors from the activation of PRP for over 7 days. Leveraging the synergistic effects of rhCol III and PRP, rhCol III-PRPM patches facilitated cell proliferation, migration, and angiogenesis, and reduced oxidative stress. In animal experiments, this microneedle patch effectively promoted the healing of diabetic wounds during a 20-day treatment, partially due to upregulating integrins and phosphorylated ERK protein levels. Diverging from other microneedle strategies, the rhCol III exhibited "dual functionality," serving as both the microneedle patch matrix and therapeutic agent, promoting wound healing upon patch dissolution while delivering PRP. The combination of rhCol III and PRP in the form of a microneedle patch offered a straightforward and efficacious way for effective diabetic wound management, and showed promise in bringing new possibilities in clinical practice.

The physiological response to feeding is important for production aspects that include feed utilization and growth, and the responses require the action of numerous secretory factors. However, as an important aquaculture animal, the secretory response of Pacific White Shrimp (Litopenaeus vannamei) after feeding has not been comprehensively characterized. In this study, transcriptome analysis showed that 3172 differentially expressed genes were involved in the post-feeding response, including 289 new genes not annotated in the L. vannamei reference genome. Subsequently, 715 differentially expressed secretory reference genes and 18 new differentially expressed secretory genes were obtained through the identification of signal peptides in secreted proteins. Functional classification revealed that differentially expressed secretory genes were enriched in pathways pertaining to lipid metabolism (20 genes), carbohydrate metabolism (21 genes), glycan biosynthesis and metabolism (27 genes), digestive system (40 genes), and transport and metabolism (43 genes). The 14 pathways most enriched by differentially expressed secretory genes involved 83 genes, 71 of which encoded enzymes involved in food digestion and metabolism. Specific enzymes such as lipase 3-like and NPC intracellular cholesterol transporter 1-like in lipid metabolism, alpha-amylase-like and glucosylceramidase-like in carbohydrate metabolism, and cysteine proteinase 4-like and trypsin-1-like in the digestive system were found to be differentially expressed. Furthermore, we discovered a new gene, MSTRG.2504, that participates in the digestive system and carbohydrate metabolism. The study provides valuable insights into the secretory response (especially metabolism-related enzymes) to feeding in L. vannamei, uncovering the significant roles of both known and new genes. Furthermore, this study will improve our understanding of the feeding physiology of L. vannamei and provide a reference basis for further feeding endocrine research in the future.

The regeneration of articular cartilage posed a formidable challenge due to the restricted treatment efficacy of existing therapies. Scaffold-based tissue engineering emerges as a promising avenue for cartilage reconstitution. However, most scaffolds exhibit inadequate mechanical characteristics, poor biocompatibility, or absent cell adhesion sites. In this study, cartilage-like protein-polysaccharide hybrid hydrogel based on DOPA-modified hyaluronic acid, bovine type I collagen (Col I), and recombinant humanized type II collagen (rhCol II), denoted as HDCR. HDCR hydrogels possessed the advantage of injectability and in situ crosslinking through pH adjustment. Moreover, HDCR hydrogels exhibited a manipulable degradation rate and favorable biocompatibility. Notably, HDCR hydrogels significantly induced chondrogenic differentiation of rabbit bone marrow mesenchymal stem cells in vitro, as demonstrated by the upregulation of crucial chondrogenic genes (type II collagen, aggrecan) and the abundant accumulation of glycosaminoglycan. This approach presented a strategy to manufacture injectable, biodegradable scaffolds based on cartilage-like protein-polysaccharide polymers, offering a minimally invasive solution for cartilage repair. Graphical abstract

BACKGROUND:Alcohol withdrawal-induced hyperalgesia (AWH) is characterized as an increased pain sensitivity observed after cessation of chronic alcohol use. Alcohol withdrawal-induced hyperalgesia can contribute to the negative affective state associated with abstinence and can increase susceptibility to relapse. We aimed to characterize pain sensitivity in mice during withdrawal from two different models of alcohol exposure: chronic drinking in the dark (DID) and the Lieber-DeCarli liquid diet. We also investigated whether treatment with a histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid (SAHA), could ameliorate AWH in mice treated with the Lieber-DeCarli diet. METHODS:Male and female C57BL/6J mice were used for these studies. In the DID model, mice received bottles of 20% ethanol or water during the dark cycle for 4 h per day on four consecutive days per week for 6 weeks. Peripheral mechanical sensitivity was measured weekly the morning of Day 5 using von Frey filaments. In the Lieber-DeCarli model, mice received ethanol (5% v/v) or control liquid diet for 10 days, along with a single binge ethanol gavage (5 g/kg) or control gavage, respectively, on Day 10. Peripheral mechanical sensitivity was measured during the liquid diet administration and at 24 and 72 h into ethanol withdrawal. An independent group of mice that received the Lieber-DeCarli diet were administered SAHA (50 mg/kg, i.p.) during withdrawal. RESULTS:Male mice exhibited mechanical hypersensitivity after consuming ethanol for 5 weeks in the DID procedure. In the Lieber-DeCarli model, ethanol withdrawal led to hyperalgesia in both sexes. Suberoylanilide hydroxamic acid treatment during withdrawal from the ethanol liquid diet alleviated AWH. CONCLUSIONS:These results demonstrate AWH in mice after chronic binge drinking in males and after Lieber-DeCarli liquid diet administration in both sexes. Like previous findings in rats, HDAC inhibition reduced AWH in mice, suggesting that epigenetic mechanisms are involved in AWH.

The objective of regenerative wound healing dressings is to accelerate skin tissue regeneration and restore normal physiological function at wound sites. Achieving this goal requires biomaterials capable of repairing distinct phases of wound healing in a way that balances material function, degradation, safety, and tissue growth. In this study, we introduced a novel dual-stage wound dressing system comprising methacrylic anhydride-modified recombinant humanized type III collagen (rhCol III-MA) and methacrylic anhydride-modified dopamine (DMA) (RMDM), which was synthesized through free radical polymerization and π-π stacking. Within this system, RMDM was formulated into two forms with identical compositions: hydrogel and sponge, tailored for application across various stages of wound repair. These materials displayed favorable hemocompatibility, biocompatibility, antioxidant properties, and angiogenic potential in vitro. Moreover, the in vivo experiments also demonstrated that sponges could rapidly stop the bleeding of wounds in mouse tail amputation and liver incision models. Notably, the sponge/gel (S/G) system accelerated wound healing compared to individual sponge and gel treatments in a rat full-thickness skin wound model, underscoring the synergistic benefits of combining sponge and gel materials for wound repair at different stages. Therefore, this research provides valuable insights into designing advanced biomaterials that can be tailored to specific stages of wound healing, which may have significant potential for biomedical applications. Graphical Abstract

The regeneration of oral tissues is a challenging clinical problem because of the complex microbial and biological stress environments. Electrospun fibrous scaffolds have attracted significant interest as effective barrier membranes for guided bone regeneration (GBR); however, no mature strategy yet exists for the surface modification of fibers to provide versatility to satisfy clinical requirements. This study demonstrated a practical biosafety strategy: the combined use of plant polyphenols and LL-37 peptides to modify the fiber surface to endow the fibrous scaffold with antimicrobial activity, immunoregulation, and vascularized bone regeneration. We confirmed that the LL-37 peptides interacted with tannic acid (TA) through noncovalent bonds through experiments and molecular docking simulation analysis. In vitro experiments showed that the TA coating imparted strong antibacterial properties to the fibrous scaffold, but it also caused cytotoxicity. The grafting of LL-37 peptide promoted the spreading, migration, and osteogenic differentiation of mesenchymal stem cells and was also conducive to the M2 polarization of RAW264.7 cells. In vivo experiments further verified that the LL-37 peptide-grafted fibrous scaffold significantly enhanced angiogenesis, antiinflammatory effects, and type-H vascularized bone regeneration. Overall, the fibrous scaffold modified by the LL-37 peptide through TA grafting has significant potential for GBR applications.

We previously discovered using transcriptomics that rats undergoing withdrawal after chronic ethanol exposure had increased expression of several genes encoding RNA splicing factors in the hippocampus. Here, we examined RNA splicing in the rat hippocampus during withdrawal from chronic ethanol exposure and in postmortem hippocampus of human subjects diagnosed with alcohol use disorder (AUD). We found that expression of the gene encoding the splicing factor, poly r(C) binding protein 1 ( PCBP1 ), was elevated in the hippocampus of rats during withdrawal after chronic ethanol exposure and AUD subjects. We next analyzed the rat RNA-Seq data for differentially expressed (DE) exon junctions. One gene, Hapln2 , had increased usage of a novel 3′ splice site in exon 4 during withdrawal. This splice site was conserved in human HAPLN2 and was used more frequently in the hippocampus of AUD compared to control subjects. To establish a functional role for PCBP1 in HAPLN2 splicing, we performed RNA immunoprecipitation (RIP) with a PCBP1 antibody in rat and human hippocampus, which showed enriched PCBP1 association near the HAPLN2 exon 4 3′ splice site in the hippocampus of rats during ethanol withdrawal and AUD subjects. Our results indicate a conserved role for the splicing factor PCBP1 in aberrant splicing of HAPLN2 after chronic ethanol exposure. As the HAPLN2 gene encodes an extracellular matrix protein involved in nerve conduction velocity, use of this alternative splice site is predicted to result in loss of protein function that could negatively impact hippocampal function in AUD.

Cutaneous wound healing is a complex process that strives to re-establish the original structure and functions of the skin. With the development of electrospinning technology, nanofibrous membrane biomaterials have emerged as promising pro-regenerative strategies for recapitulating the structure and composition of the natural extracellular matrix (ECM). Herein, a nanofibrous membrane wound dressing material based on recombinant human collagen type III (rhCol III) crosslinked by EDC/NHS (rhCol III (EN) NF), which incorporated multiple Gly-Glu-Lys (GEK) and Gly-Leu-Ser-Gly-Glu-Arg (GLSGER) integrin receptors, has been developed utilizing green electrospinning technology. The rhCol III (EN) NF exhibited excellent flexibility, mechanical properties and water absorption. Amino acid analysis showed that rhCol III (EN) NF retained integrin receptor-associated amino acids to mediate cell activities and then expedite wound healing. Subsequent in vitro experiments confirmed that the rhCol III (EN) NF effectively promotes cell adhesion, proliferation and migration. On a mouse full-thickness wound model, rhCol III (EN) NF dressings expedited wound closure and greatly improved collagen deposition, recovering dermal and epidermal structures as well as skin appendages. Altogether, our research demonstrated that rhCol III (EN) NF prepared by electrospinning technology could efficiently heal wounds and regenerate skin.

Compulsive alcohol drinking is a key symptom of alcohol use disorder (AUD) that is particularly resistant to treatment. An understanding of the biological factors that underly compulsive drinking will allow for the development of new therapeutic targets for AUD. One animal model of compulsive alcohol drinking involves the addition of bitter-tasting quinine to an ethanol solution and measuring the willingness of the animal to consume ethanol despite the aversive taste. Previous studies have demonstrated that this type of aversion-resistant drinking is modulated in the insular cortex of male mice by specialized condensed extracellular matrix known as perineuronal nets (PNNs), which form a lattice-like structure around parvalbumin-expressing neurons in the cortex. Several laboratories have shown that female mice exhibit higher levels of aversion-resistant ethanol intake but the role of PNNs in females in this behavior has not been examined. Here we compared PNNs in the insula of male and female mice and determined if disrupting PNNs in female mice would alter aversion-resistant ethanol intake. PNNs were visualized in the insula by fluorescent labeling with Wisteria floribunda agglutinin (WFA) and disrupted in the insula by microinjecting chondroitinase ABC, an enzyme that digests the chondroitin sulfate glycosaminoglycan component of PNNs. Mice were tested for aversion-resistant ethanol consumption by the addition of sequentially increasing concentrations of quinine to the ethanol in a two-bottle choice drinking in the dark procedure. PNN staining intensity was higher in the insula of female compared to male mice, suggesting that PNNs in females might contribute to elevated aversion-resistant drinking. However, disruption of PNNs had limited effect on aversion-resistant drinking in females. In addition, activation of the insula during aversion-resistant drinking, as measured by c-fos immunohistochemistry, was lower in female mice than in males. Taken together, these results suggest that neural mechanisms underlying aversion-resistant ethanol consumption differ in males and females.

Delaying aging is an eternal goal for humanity. Collagen-based materials, employed as dermal fillers to smoothen wrinkles, have attained extensive utilization. Nevertheless, traditional animal-derived collagen protein primarily presents concerns pertaining to disease risks, potential immunological reactions, and batch instability. In this investigation, the filler composed of recombinant human collagen type III (rhCol III) with excellent injectability was fabricated using synthetic biology. The in vitro examination of cell interaction with rhCol III revealed commendable biocompatibility, with concentration-dependent impacts on cell proliferation, migration and collagen secretion. Subsequently, we established a skin damage animal model through UV-photoaging and introduced rhCol III as a bioactive material for in vivo implantation, systematically comparing its biological effect with pCollagen, hyaluronic acid (HA) and saline thorough histological observation, immunofluorescence staining, hydroxyproline quantification and analysis of specific gene expression. Outcomes indicated rhCol III prompted augmented production of collagen I (Col I), collagen III (Col III) and elastic fibers, thereby contributing to the remodeling of the extracellular matrix (ECM). In summary, our investigation contributed robust biosafety and proficient attenuation of UV-induced skin photoaging by rhCol III under single injection. Despite the imperative ongoing efforts required for the successful translation from bench to clinic, the discernibly superior safety and efficacy profile of rhCol III positioned it as a promising candidate within the domain of dermal fillers.

Bone substitute material implantation has become an important treatment strategy for the repair of oral and maxillofacial bone defects. Recent studies have shown that appropriate inflammatory and immune cells are essential factors in the process of osteoinduction of bone substitute materials. Previous studies have mainly focused on innate immune cells such as macrophages. In our previous work, we found that T lymphocytes, as adaptive immune cells, are also essential in the osteoinduction procedure. As the most important antigen-presenting cell, whether dendritic cells (DCs) can recognize non-antigen biomaterials and participate in osteoinduction was still unclear. In this study, we found that surgical trauma associated with materials implantation induces necrocytosis, and this causes the release of high mobility group protein-1 (HMGB1), which is adsorbed on the surface of bone substitute materials. Subsequently, HMGB1-adsorbed materials were recognized by the TLR4-MYD88-NFκB signal axis of dendritic cells, and the inflammatory response was activated. Finally, activated DCs release regeneration-related chemokines, recruit mesenchymal stem cells, and initiate the osteoinduction process. This study sheds light on the immune-regeneration process after bone substitute materials implantation, points out a potential direction for the development of bone substitute materials, and provides guidance for the development of clinical surgical methods.

After implantation of a biomaterial, both the host immune system and properties of the material determine the local immune response. In a scaffold-induced immune micro-environment, immune cells like macrophages present functional heterogeneity and plasticity. With the advancement of technology, emerging techniques such as single-cell RNA sequencing (scRNA-seq) enable high-resolution characterization of immune cell populations. In-depth understanding of the interaction between scaffolds and the host immune system helps to provide clues for the design of biomaterials to optimize regeneration and promote a pro-regenerative local immune micro-environment. In this review, we discuss the procedures of foreign body reaction in brief, present recent advances in elucidating mechanisms of foreign body response, and discuss the application of scRNA-seq in probing the scaffold immune micro-environment. With regard to biomaterial design, we summarize the influences that physical and chemical properties of biomaterials have on cell behaviors in the micro-environment and provide some reference to designing immunomodulatory biomaterials.