Acta biomaterialia最新文献

Treatment of triple-negative breast cancer (TNBC) poses significant challenges due to its propensity for metastasis. A key impediment lies in the suppressive immune microenvironment, which fosters tumor progression. This study introduces an approach employing a dual immune-stimulatory CD73 antibody-polymeric cytotoxic drug complex (αCD73-PLG-MMAE). This complex is designed for targeted eradication of TNBC while modulating tumor immunity through mechanisms such as immunogenic cell death (ICD) and interference with the adenosine signaling pathway. By enhancing antitumor immune responses, this strategy offers a highly effective means of treating TNBC and mitigating metastasis. The complex is synthesized by combining αCD73 with poly(_L-glutamic acid) (PLG) grafted Fc binding peptides (Fc-III-4C) and Val-Cit-PAB-monomethyl auristatin E (MMAE), exploiting the affinity between αCD73 and Fc-III-4C. αCD73 selectively targets CD73 molecules on both tumor and immune suppressive cells, thereby inhibiting the adenosine pathway. Meanwhile, Val-Cit-PAB-MMAE, activated by cathepsin B, triggers selective release of MMAE, inducing ICD in tumor cells. In a 4T1 tumor model, αCD73-PLG-MMAE significantly enhances drug accumulation in tumors by 4.13-fold compared to IgG-PLG-MMAE, leading to suppression of tumor growth and metastasis. Furthermore, it synergistically augments the antitumor effects of αPD-1, resulting in a tumor inhibition rate of 92% as compared to 21% with αPD-1 alone. This study thus presents a pioneering therapeutic strategy for TNBC, emphasizing the potential of targeted immunomodulation in cancer treatment. STATEMENT OF SIGNIFICANCE: Antibody-drug conjugate (ADC) therapy holds promise for treating triple-negative breast cancer (TNBC). However, the current ADC, sacituzumab govitecan, fails to overcome the crucial role of adenosine in the suppressive immune microenvironment characteristic of this "cold tumor". Here, we present a dual immune-stimulatory complex, αCD73-PLG-MMAE, which targets TNBC specifically and modulates tumor immunity through mechanisms such as immunogenic cell death (ICD) and interference with the adenosine signaling pathway. Thus, it kills tumor cells with cytotoxic drugs, comprehensively regulates immunosuppression, and restores a durable immune response. This study proposes an antibody-polymeric drug complex with immunomodulatory and immunoagonist roles, offering new insights into TNBC treatment.

Tissue expansion (TE) is the primary method for breast reconstruction after mastectomy. In many cases, mastectomy patients undergo radiation treatment (XR). Radiation is known to induce skin fibrosis and is one of the main causes for complications during post-mastectomy breast reconstruction. TE, on the other hand, induces a pro-regenerative response that culminates in growth of new skin. However, the combined effect of XR and TE on skin mechanics is unknown. Here we used the porcine model of TE to study the effect of radiation on skin fibrosis through biaxial testing, histological analysis, and kinematic analysis of skin deformation over time. We found that XR leads to stiffening of skin compared to control based on a shift in the transition stretch (transition between a low stiffness and an exponential stress-strain region characteristic of collagenous tissue). The change in transition stretch can be explained by thicker, more aligned collagen fiber bundles measured in histology images. Skin subjected to both XR+TE showed similar micostructure to controls as well as similar biaxial response, suggesting that physiological remodeling of collagen induced by TE partially counteracts pro-fibrotic XR effects. Skin growth was indirectly assessed with a kinematic approach that quantified increase in permanent area changes without reduction in thickness, suggesting production of new tissue driven by TE even in the presence of radiation treatment. Future work will focus on the detailed biological mechanisms by which TE counteracts radiation induced fibrosis. STATEMENT OF SIGNIFICANCE: Breast cancer is the most prevalent in women and its treatment often results in total breast removal (mastectomy), followed by reconstruction using tissue expanders. Radiation, which is used in about a third of breast reconstruction cases, can lead to significant complications. The timing of radiation treatment remains controversial. Radiation is known to cause immediate skin damage and long-term fibrosis. Tissue expansion leads to a pro-regenerative response involving collagen remodeling. Here we show that tissue expansion immediately prior to radiation can reduce the level of radiation-induced fibrosis. Thus, we anticipate that this new evidence will open up new avenues of investigation into how the collagen remodeling and pro-regenerative effects of tissue expansion can be leverage to prevent radiation-induced fibrosis.

Postoperative adhesions commonly form in various tissues, resulting in serious implications and an increased risk of secondary surgery. The application of anti-adhesion films as physical barriers has proven effective in reducing adhesion incidence and severity. However, existing anti-adhesion films require manual deployment during minimally invasive surgery, posing inconvenience and possibility of further injury. To address these limitations, we have developed an intelligent anti-adhesion film based on shape memory polyurethane. In this work, a linear shape memory polyurethane (ISO2-PU), incorporating hexamethylene isocyanate and isosorbitol as hard segments and poly(D, L-lactic acid) macrodiol as soft segments, was fabricated into an anti-adhesion film. The favorable shape memory effect of the ISO2-PU film ensures its convenient delivery and automatic unfolding, as revealed by a simulation experiment for endoscopic surgical implantation. Furthermore, the glass transition temperature (T_g) close to body temperature endows the ISO2-PU film with good mechanical compliance, thus ensuring a reliable fit with the wounded tissue to avoid undesired folding. Finally, in vivo experiments using a rat cecal abdominal wall injury model demonstrated that the combination of reliable fit, appropriate degradation rate, and good cytocompatibility promises the ISO2-PU film with high anti-adhesion efficacy. This work validates the concept of shape memory anti-adhesion barrier and expands future directions for advanced anti-adhesion biomaterials. STATEMENT OF SIGNIFICANCE: Postoperative adhesions are a common complication that occurs widely after various surgeries. This work developed an intelligent anti-adhesion film based on a linear shape memory polyurethane (ISO2-PU). This film is featured with remarkable shape memory effect and mechanical compliance at body temperature, appropriate degradability, and good cytocompatibility. These merits ensure convenient delivery and smart unfolding of ISO2-PU film during minimally invasive surgery and favorable postoperative anti-adhesion efficacy. The results validate the concept of shape memory anti-adhesion barrier and paves a way for designing next-generation anti-adhesion biomaterials.

The stress relaxation of the TZ region, located at the interface of the Annulus Fibrosus (AF) and Nucleus Pulposus (NP) of the disc, and how its stress is relaxed compared to the adjacent regions is unknown. The current study aimed to identify the TZ stress relaxation properties under different strain magnitudes (0.2, 0.4, and 0.6 mm/mm) and compared the TZ stress relaxation characteristics to the NP and inner AF (IAF) regions at a specific strain magnitude (0.6 mm/mm). The results of the current study revealed that the TZ region exhibited different stress relaxation properties under various strain magnitudes with significantly higher initial (p < 0.008) and reduced stresses (marginally; p = 0.06) at higher strains. Our experimental stress relaxation data revealed a significantly higher equilibrium stress for the IAF compared to the TZ and NP regions (p < 0.001) but not between the TZ and NP regions (p = 0.7). We found that NP radial stress relaxed significantly faster (p < 0.04) than the TZ and NP. Additionally, the current study proposed a simple mathematical model and identified that, consistent with experimental data, the overall effect of region on both the level of decayed stress and the rate at which stress is relaxed was significant (p < 0.006). The current study found a similar stress relaxation characteristic between the NP and TZ regions, while IAF exhibited different stress relaxation properties. It is possible that this mismatch in stress relaxation acts as a shape transformation mechanism triggered by viscoelastic behavior. STATEMENT OF SIGNIFICANCE: Our understanding of the biomechanical properties of the transition zone (TZ) in the IVD, a region at the interface of the Nucleus Pulposus (NP) and Annulus Fibrosus (AF), is sparse. Unfortunately, there are no current studies that investigate the TZ stress relaxation properties and how stress is relaxed in the TZ compared to the adjacent regions. For the first time, the current study characterized the stress relaxation properties of the TZ and described how the TZ stress is relaxed compared to its adjacent regions.

Developing multifunctional nanoplatforms to comprehensively modulate the tumor microenvironment and enhance diagnostic and therapeutic outcomes still remains a great challenge. Here, we report the facile construction of a multivariate nanoplatform based on cancer cell membrane (CM)-encapsulated redox-responsive poly(N-vinylcaprolactam) (PVCL) nanogels (NGs) co-loaded with Cu(II) and chemotherapeutic drug toyocamycin (Toy) for magnetic resonance (MR) imaging-guided combination tumor chemodynamic therapy/chemoimmunotherapy. We show that redox-responsive PVCL NGs formed through precipitation polymerization can be aminated, conjugated with 3,4-dihydroxyhydrocinnamic acid for Cu(II) complexation, physically loaded with Toy, and finally camouflaged with CMs. The created ADCT@CM NGs with an average size of 113.0 nm are stable under physiological conditions and can efficiently release Cu(II) and Toy under tumor microenvironment with a high level of glutathione. Meanwhile, the developed NGs are able to enhance cancer cell oxidative stress and endoplasmic reticulum stress by synergizing the effects of chemodynamic therapy mediated by Cu-based Fenton-like reaction and Toy-mediated chemotherapy, thereby triggering significant immunogenic cell death (ICD). In a melanoma mouse model, the NGs show potent immune activation effects to reinforce tumor therapeutic efficacy through ICD induction and immune modulation including high levels of immune cytokine secretion, increased tumor infiltration of CD8⁺ cytotoxic T cells, and reduced tumor infiltration of regulatory T cells. With the CM coating and Cu(II) loading, the developed NG platform demonstrates homologous tumor targeting and T₁-weighted MR imaging, hence providing a general biomimetic NG platform for ICD-facilitated tumor theranostic nanoplatform. STATEMENT OF SIGNIFICANCE: Developing multifunctional nanoplatforms to comprehensively modulate the tumor microenvironment (TME) and enhance theranostic outcomes remains a challenge. Here, a cancer cell membrane (CM)-camouflaged nanoplatform based on aminated poly(N-vinylcaprolactam) nanogels (NGs) co-loaded with Cu(II) and toyocamycin (Toy) was prepared for magnetic resonance (MR) imaging-guided combination tumor chemodynamic therapy/chemoimmunotherapy. The tumor targeting specificity and efficient TME-triggered release of Cu(II) and Toy could enhance tumor cell oxidative stress and endoplasmic reticulum stress by synergizing the effects of chemodynamic therapy mediated by Cu-based Fenton-like reaction and Toy-mediated chemotherapy, respectively, thereby leading to significant immunogenic cell death (ICD) and immune response. With the CM coating and Cu(II) loading, the developed NG platform also demonstrates good T₁-weighted tumor MR imaging performance. Hence, this study provides a general biomimetic NG platform for ICD-facilitated tumor theranostics.

Osteoarthritis (OA) is a prevalent chronic degenerative disease affecting millions worldwide, with current treatment measures lacking efficacy in slowing disease progression. The synovial lymphatic system (SLS) has emerged as a crucial player in OA pathogenesis, with compromised drainage function contributing to disease advancement. Lymphatic endothelial cells (LECs) within the SLS are influenced by synovial macrophages, whose precise impact on LEC function remains unclear. Exosomes released by macrophages may serve as mediators of this interaction, with potential implications for OA progression. Here, we propose that polarized macrophages modulate LEC activity via exosome release in synovial tissue, with M2 macrophage-derived exosomes (M2^Exo) promoting LEC proliferation, migration, and lymphangiogenesis, potentially offering a therapeutic avenue for OA. Moreover, we developed an injectable thermosensitive hydrogel with the characteristic of sustained release of M2^Exo for alleviating OA. The hydrogel was prepared by dynamically linking hyaluronic acid (HA) and Pluronic F-127 and loading M2^Exo, termed as M2^Exo loaded HP hydrogel. The in vitro and in vivo experiments showed that M2^Exo loaded HP hydrogel exhibits a controlled release profile of exosomes, thereby efficaciously fostering synovial lymphangiogenesis and enhancing synovial lymphatic drainage functionality under OA conditions, thus alleviating OA progression, and providing promising insights into OA therapeutic strategies. STATEMENT OF SIGNIFICANCE: Osteoarthritis (OA) is a widespread degenerative disease with limited effective treatments to halt its progression. This research highlights the critical role of the synovial lymphatic system (SLS) in OA, focusing on how macrophage-derived exosomes influence lymphatic endothelial cell (LEC) function. We propose that M2 macrophage-derived exosomes (M2^Exo) enhance LEC activity, promoting lymphangiogenesis, and offering a therapeutic approach for OA. Furthermore, we developed an injectable thermosensitive hydrogel (M2^Exo loaded HP hydrogel) for sustained M2^Exo release. Our in vitro and in vivo experiments demonstrate that this hydrogel supports synovial lymphangiogenesis and improves lymphatic drainage, effectively alleviating OA progression. This study presents significant advancements in OA therapy, offering new insights into its management.

Post-traumatic tendon adhesions significantly affect patient prognosis and quality of life, primarily stemming from the absence of effective preventive and curative measures in clinical practice. Current treatment modalities, including surgical excision and non-steroidal anti-inflammatory drugs, frequently exhibit limited efficacy or result in severe side effects. Consequently, the use of anti-adhesive barriers for drug delivery and implantation at the injury site to address peritendinous adhesion (PA) has attracted considerable attention. Electrospun nanofiber membranes (ENMs) have been extensively employed as drug-delivery platforms. In this study, we fabricated a polylactic acid (PLA)-dipyridamole (DP)-graft copolymer ENM called PLC-DP. This membrane exhibits enzyme-sensitive features, allowing more controlled and sustained drug release compared with conventional drug-loaded ENMs. In experiments, PLC-DP implantation reduced tissue adhesion by 47 % relative to the control group while not adversely affecting tendon healing. Mechanistically, PLC-DP effectively activates the FXYD domain containing ion-transport regulator 2 (FXYD2) protein, thereby downregulating the fibroblast-transforming growth factor beta (TGF-β)/Smad3 signaling pathway. PLC-DP leverages the anti-adhesive properties of DP and the enzyme-sensitive characteristics of graft copolymers, providing a promising approach for the future clinical treatment and prevention of PA. STATEMENT OF SIGNIFICANCE: Peritendinous adhesions (PA) are a common and disabling condition that seriously affects the prognosis and quality of life of post-trauma patients. Current treatments often have limited efficacy or severe side effects, leaving a serious gap in clinical practice. We developed a significant biomaterial, poly(lactic acid)-dipyridamole graft copolymer electrospun nanofibrous membrane (PLC-DP), specifically for PA inhibition. In addition, this study uniquely combines dipyridamole, an anti-adhesive agent, and enzyme-sensitive copolymers in electrospun nanofibrous membrane. Unlike conventional drug-loaded electrospun nanofibrous membranes, PLC-DPs have enzyme-sensitive drug properties that allow for sustained drug release on demand. Our experiments showed that implantation of PLC-DP was effective in reducing tissue adhesions by 47 % without affecting tendon healing. We elucidated the mechanism behind this phenomenon, suggesting that PCD activates FXYD2 to inhibit TGF-β-induced expression of Col III, which is a key factor in PA development.

Sonodynamic therapy (SDT) has garnered significant attention in cancer treatment, however, the low-yield reactive oxygen species (ROS) generation from sonosensitizers remains a major challenge. In this study, titanium boride nanosheets (TiB₂ NSs) with photo-enhanced sonodynamic efficiency was fabricated for SDT of glioblastoma (GBM). Compared with commonly-used TiO₂ nanoparticles, the obtained TiB₂ NSs exhibited much higher ROS generation efficiency under ultrasound (US) irradiation due to their narrower band gap (2.50 eV). Importantly, TiB₂ NSs displayed strong localized surface plasmon resonance (LSPR) effect in the second near-infrared (NIR II) window, which facilitated charge transfer rate and improved the separation efficiency of US-triggered electron-hole pairs, leading to photo-enhanced ROS generation efficiency. Furthermore, TiB₂ NSs were encapsulated with macrophage cell membranes (CM) and then modified with RGD peptide to construct biomimetic nanoagents (TiB₂@CM-RGD) for efficient blood-brain barrier (BBB) penetrating and GBM targeting. After intravenous injection into the tumor-bearing mouse, TiB₂@CM-RGD can efficiently cross BBB and accumulate in the tumor sites. The tumor growth was significantly inhibited under simultaneous NIR II laser and US irradiation without causing appreciable long-term toxicity. Our work highlighted a new type of multifunctional titanium-based sonosensitizer with photo-enhanced sonodynamic efficiency for GBM treatment. STATEMENT OF SIGNIFICANCE: Titanium boride nanosheets (TiB₂ NSs) with photo-enhanced sonodynamic efficiency was fabricated for SDT of glioblastoma (GBM). The obtained TiB₂ NSs displayed strong localized surface plasmon resonance (LSPR) effect in the second near-infrared (NIR II) window, which facilitated charge transfer rate and improved the separation efficiency of US-triggered electron-hole pairs, leading to photo-enhanced ROS generation efficiency. Furthermore, TiB₂ NSs were encapsulated with macrophage cell membranes (CM) and then modified with RGD peptide to construct biomimetic nanoagents (TiB₂@CM-RGD) for efficient blood-brain barrier (BBB) penetrating and GBM targeting. After intravenous injection into the tumor-bearing mouse, TiB₂@CM-RGD can efficiently cross BBB and accumulate in the tumor sites. The tumor growth was significantly inhibited under simultaneous NIR II laser and US irradiation without causing appreciable long-term toxicity.

Understanding the viscoelastic properties of atherosclerotic plaques at rupture-prone scales is crucial for assessing their vulnerability. Here, we develop a Hybrid Hierarchical theory-Microrheology (HHM) approach, enabling the analysis of multiscale mechanical variations and distribution changes in regional tissue viscoelasticity within plaques across different spatial scales. We disclose a universal two-stage power-law rheology in plaques, characterized by distinct power-law exponents (α_short and α_long), which serve as mechanical indexes for plaque components and assessing mechanical gradients. We further propose a self-similar hierarchical theory that effectively delineates plaque heterogeneity from the cytoplasm, cell, to tissue levels. Moreover, our proposed multi-layer perceptron model addresses the viscoelastic heterogeneity and gradients within plaques, offering a promising diagnostic strategy for identifying unstable plaques. These findings not only advance our understanding of plaque mechanics but also pave the way for innovative diagnostic approaches in cardiovascular disease management. STATEMENT OF SIGNIFICANCE: Our study pioneers a Hybrid Hierarchical theory-Microrheology (HHM) approach to dissect the intricate viscoelasticity of atherosclerotic plaques, focusing on distinct components including cap fibrosis, lipid pools, and intimal fibrosis. We unveil a universal two-stage power-law rheology capturing mechanical variations across plaque structures. The proposed hierarchical model adeptly captures viscoelasticity changes from cytoplasm, cell to tissue levels. Based on the newly proposed markers, we further develop a machine learning (ML) diagnostic model that sets precise criteria for evaluating plaque components and heterogeneity. This work not only reveals the comprehensive mechanical heterogeneity within plaques but also introduces a mechanical marker-based ML strategy for assessing plaque conditions, offering a significant leap towards understanding and diagnosing atherosclerotic risks.

Decellularized adipose matrix (DAM) is considered to be the most potential biological scaffold for soft tissue repair and reconstruction, as it is able to induce the regeneration of adipose tissue in situ in adulthood. But how does this adipose tissue regeneration happen and develop in vivo? Is it the same as the original autologous one? Temporary existence or long-term survival? These are the key questions that will determine the future applications of DAM. In this study, we investigated the composition, structure and biomechanical properties of DAM before implanting it into the subcutaneous back of immunodeficient mice. The entire regeneration process in vivo was closely monitored histologically from 3 days to 1 year after implantation, including fat regeneration, vascular growth, inflammatory responses, and matrix degradation and remodeling. Transcriptome sequencing was used to analyze the difference in gene expression between regenerated fat and autologous fat at different periods. The results showed that the DAM-induced regenerated fat first appeared at 1w and remained stable over 6m, indicating remarkable similarity to autologous fat at the later stages of implantation. And about (18.3 ± 29.3) % of the regenerated adipocytes were still viable after one year. The process of adipogenesis was enhanced by the decrease in inflammatory infiltration and proceeded in parallel with angiogenesis. STATEMENT OF SIGNIFICANCE: : The decellularized adipose matrix (DAM) is the only biological scaffold that can spontaneously generate adipocytes in vivo without the need to add exogenous cells. However, in the previous studies, the longest DAM-related animal experiments were about 3 months. The different stages and characteristics of DAM implantation cannot be fully captured. Comprehensive preclinical researches on the initiation, characteristics, and long-term outcomes of DAM-induced adipose tissue regeneration in adulthood is crucial. In this study, we closely observed various aspects of the entire process in vivo from 3 days to 1 year after implantation including fat regeneration, vascular growth, inflammatory reactions as well as matrix degradation and remodeling. The thorough research will contribute to the understanding of stability and dynamic remodeling of DAM regeneration models.