Piezoelectric dressings for advanced wound healing.

The treatment of chronic refractory wounds poses significant challenges and threats to both human society and the economy. Existing research studies demonstrate that electrical stimulation fosters cell proliferation and migration and promotes the production of cytokines that expedites the wound healing process. Presently, clinical settings utilize electrical stimulation devices for wound treatment, but these devices often present issues such as limited portability and the necessity for frequent recharging. A cutting-edge wound dressing employing the piezoelectric effect could transform mechanical energy into electrical energy, thereby providing continuous electrical stimulation and accelerating wound healing, effectively addressing these concerns. This review primarily reviews the selection of piezoelectric materials and their application in wound dressing design, offering a succinct overview of these materials and their underlying mechanisms. This study also provides a perspective on the current limitations of piezoelectric wound dressings and the future development of multifunctional dressings harnessing the piezoelectric effect.

Impact of surface biofunctionalization strategies on key effector cells response in polyacrylamide hydrogels for bone regeneration.

Despite the clinical prevalence of various bone defect repair materials, a full understanding of their influence on bone repair and regeneration remains elusive. This study focuses on poly(acrylamide) (PAAm) hydrogels, popular 2D model substrates, which have regulable mechanical properties within physiological. However, their bio-inert nature requires surface biofunctionalization to enhance cell-material interactions and facilitate the study of bone repair mechanisms. We utilized PAAm hydrogels of varying stiffness (18, 76 and 295 kPa), employed sulfosuccinimidyl-6-(4'-azido-2'-nitropheny-lamino) hexanoate (sulfo-SANPAH) and N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride/N-hydroxysuccinimidyl acrylate (EDC/NHS) as crosslinkers, and cultured macrophages, endothelial cells, and bone mesenchymal stem cells on these hydrogels. Our findings indicated that sulfo-SANPAH's crosslinking efficiency surpassed that of EDC/NHS, irrespective of pore size and stiffness. Importantly, we observed that the stiffness and surface biofunctionalization method of hydrogels significantly impacted cell adhesion and proliferation. The collagen-modified hydrogels by EDC/NHS strategy failed to support the normal biological behavior of bone mesenchymal stem cells and hindered endothelial cell spreading. In contrast, these modified hydrogels by the sulfo-SANPAH method showed good cytocompatibility with the three types of cells. This study underscores the critical role of appropriate conjugation strategies for PAAm hydrogels, providing valuable insights for hydrogel surface modification in bone repair and regeneration research.

The role of nanopores constructed on the micropitted titanium surface in the immune responses of macrophages and the potential mechanisms.

The delayed transition of macrophages (MΦs) from pro-inflammatory M1 to the pro-healing M2 state on implant surfaces is one of the most important reasons for poor osseointegration. This work reports the construction of closely packed nanopores with a small diameter on the micropitted titanium (Ti) surface by two-step acid etching to promote the M1-to-M2 transition of MΦs and pays special attention to the potential mechanisms by which the nanopores decorating the micropits exert immunomodulatory effects. The results show that the structure composed of hybrid nanopores (10-25 nm) and micropits (5-15 µm) can be produced on the Ti surface by a two-step acid etching process. Compared with the unitary micropits, the micropit/nanopore surface could facilitate the switch of MΦs from the pro-inflammatory M1 to the pro-healing M2 phenotype. RNA sequencing reveals that the MAPK, PI3K-AKT and C-type lectin signaling pathways play key roles in the micro/nano-structure-mediated transition. In addition, the micro/nano-structured surface down-regulated CYP1A2 expression, reducing the generation of mitochondrial ROS, in turn restraining the oxidative stress and further attenuating inflammation. This work provides novel insights into the underlying mechanisms of immunomodulation by the nano-structure-decorated micro-structures on the Ti surface, which is significant for designing the surface of orthopedic implants from the perspective of immunomodulation.

Multifunctional exosomes derived from bone marrow stem cells for fulfilled osseointegration.

Bone marrow mesenchymal stem cells (BMSCs) have self-renewal, multi-directional differentiation potential, and immune regulation function and are widely used for de novo bone formation. However, the wide variation in individual amplification, the potential risk of cancer cell contamination, and the need for culture time significantly limit their widespread use clinically. Alternatively, numerous studies have shown that exosomes secreted by BMSCs in the nanoscale can also affect the functionality of endothelial cells (angiogenesis), macrophages (immunomodulation), and osteoblasts/osteoclasts (osteogenesis), which is a highly promising therapy for osseointegration with pronounced advantages (e.g., safety, high efficiency, and no ethical restrictions). The review aims to summarize the multifaceted effect of BMSCs-derived exosomes on osseointegration and provide reference and basis for rapid and qualified osseointegration.

Type I collagen decorated nanoporous network on titanium implant surface promotes osseointegration through mediating immunomodulation, angiogenesis, and osteogenesis.

Osseointegration of implants is a complex physiological process that requires temporal and spatial regulation of immune responses, angiogenesis, and osteogenesis. To achieve efficient and long-term osseointegration, type I collagen (COL1) decorated nanoporous network was developed on titanium substrates via alkali treatment, polydopamine coating, and layer-by-layer (LBL) self-assembly. It was noted that the simple physisorbed COL1 could be easily desorbed from the nanostructured surface, however, multilayer COL1 constructed by polydopamine and LBL self-assembly obscured the nanoporous network of the alkali-treated titanium surfaces. Interestingly, the nanostructured surface covalently immobilized with COL1 (T-ADC) could timely convert macrophages (MΦs) from pro-inflammatory M1 to pro-healing M2 phenotype, generating a beneficial osteoimmune microenvironment and promoting angio/osteo-genesis. RNA sequencing revealed that the nanostructure and COL1 could synergistically activate RhoA/ROCK, PI3K-AKT, and classical MAPK signaling pathways in MΦs to sustain the cell cycle, and trigger autocrine feedback-mediated JAK-STAT and FoxO signaling pathways, which in turn motivated autophagy and oxidative stress resistance and attenuated lipopolysaccharide-induced Toll-like receptor signaling pathway and its downstream NF-κB and JNK/p38 MAPK signaling cascades, leading to the inhibition of inflammation and osteoclastic-related gene expression of MΦs. Simultaneously, T-ADC prominently facilitated angiogenesis of endothelial cells and osteogenesis of osteoblasts as well as their cross-talks, further highlighting synergistically positive effects of the nanostructure and COL1 on osseointegration. In vivo experiments revealed that T-ADC could induce abundant new bone mass and ameliorative osseointegration, corroborating the in vitro results. The study elucidated that the COL1 decorated nanoporous network on titanium surfaces could significantly regulate early inflammatory reaction and subsequent angio/osteo-genesis processes, resulting in favorable osseointegration.

Biocompatible silane adhesion layer on titanium implants improves angiogenesis and osteogenesis.

Silane adhesion layer strategy has been widely used to covalently graft biomolecules to the titanium implant surface, thereby conferring the implant bioactivity to ameliorate osseointegration. However, few researchers pay attention to the effects of silanization parameters on biocompatibility and biofunctionality of the silane adhesion layers. Accordingly, the present study successfully fabricated the silane adhesion layers with different thickness, intactness, and surface morphologies by introducing 3-aminopropyltriethoxysilane on the alkali-treated titanium surface in time-varied processing of silanization. The regulatory effects of the silane adhesion layers on angiogenesis and osteogenesis were assessed in vitro. Results showed that the prolonged silanization processing time increased the thickness and intactness of the silane adhesion layer and significantly improved its biocompatibility. Notably, the silane adhesion layer prepared after 12 h of silanization exhibited a brain-like surface morphology and benefited the adhesion and proliferation of endothelial cells (ECs) and osteoblasts (OBs). Moreover, the layer promoted angiogenesis via stimulating vascular endothelial growth factor (VEGF) secretion and nitric oxide (NO) production of ECs. Simultaneously, it improved osteogenesis by enhancing alkaline phosphatase (ALP) activity, collagen secretion, and extracellular matrix mineralization of OBs. This work systematically investigated the biocompatibility and biofunctionality of the modified silane adhesion layers, thus providing valuable references for their application in covalently grafting biomolecules on the titanium implant surface.

Resveratrol promotes osteogenesis and angiogenesis through mediating immunology of senescent macrophages.

Orthopedic implants have been used clinically to restore the functions of the compromised bone tissues, but there is still a relatively high risk of failure for elderly people. A critical reason is pro-inflammatory immune microenvironment created by senescent macrophages with homeostasis imbalance impairs osteogenesis and angiogenesis, two major processes involved in implant osseointegration. The present work proposes to use resveratrol as an autophagy inducing agent to upregulate the autophagy level of senescent macrophages to restore homeostasis, consequently generating a favorable immune microenvironment. The results show 0.1-1 µM of resveratrol can induce autophagy of senescent macrophages, promote cell viability and proliferation, reduce intracellular reactive oxygen species level, and polarize the cells to pro-healing M2 phenotype. The immune microenvironment created by senescent macrophages upon resveratrol stimulation can promote osteogenesis and angiogenesis, as manifested by upregulated proliferation, alkaline phosphatase activity, type I collagen secretion, and extracellular matrix mineralization of senescent osteoblasts as well as nitric oxide production, migration, andin vitroangiogenesis of senescent endothelial cells. In addition, resveratrol-loaded silk fibroin coatings can be fabricated on titanium surface through electrophoretic co-deposition and the coatings show beneficial effects on the functions of senescent macrophages. Our results suggest resveratrol can be used as surface additive of titanium implants to promote osseointegration of elderly people though regulating immunology of senescent macrophages.

A micro/nano-biomimetic coating on titanium orchestrates osteo/angio-genesis and osteoimmunomodulation for advanced osseointegration.

Osseointegration is a sophisticated bone and implant healing process comprising of initial hematoma formation, immediate osteoimmunomodulation, angiogenesis, and osteogenesis. To fulfill rapid and satisfying osseointegration, this study developed a biomimetic implant coating that could confer the intraosseous implants a systematical regulation of the participatory processes. Herein, we shaped dissimilar nano-scale (NS) to form highly biomimetic structures of natural extracellular matrix (ECM) of the host bone and bone healing hematoma with micro/nano-scale (MNS) titania fiber-like network on the surface of titanium (Ti) implants. In vitro experiments revealed that the MNS not only facilitated osteogenic and angiogenic differentiation of bone marrow stromal cells (BMSCs) and endothelial cells, respectively, but also suppressed M1 macrophages (MΦs), whereas, stimulated pro-healing M2 phenotype. Notably, BMSCs on MNS surfaces enabled a significant immunomodulatory effect on MΦs resulting in the downregulation of inflammation-related cell signaling pathways. The favorable osteoimmune microenvironment manipulated by MNS further facilitated osteo-/angio-genesis via the crosstalk of multi-signaling pathways. In vivo evaluation mirrored the aforementioned results, and depicted that MNS induced ameliorative osseointegration when compared with the NS as well as the pristine Ti implant. The study demonstrated the modulatory effect of the multifaceted biomimetic structure on spatiotemporal regulation of the participatory processes during osseointegration.

Exosomes derived from macrophages upon cobalt ion stimulation promote angiogenesis.

Angiogenesis is critical for tissue repair and regeneration, including implant osseointegration. It is well known that macrophages exert immunomodulatory functions in angiogenesis. However, whether macrophage-derived exosomes participate in the process is still unclear. Cobalt (Co) ions are frequently used as implant additives to mimic hypoxic microenvironment, which can induce angiogenesis through stabilizing hypoxia inducible factor-1α (HIF-1α) of macrophages and endothelial cells (ECs). The present work attempts to investigate whether exosomes derived from macrophages upon Co ion stimulation can mediate angiogenesis and the possible mechanism. The results show that the exosomes promote endothelial migration and angiogenesis in vitro and in vivo, particularly when Co ion concentration is 200 µM. Further studies reveal that the exosomes upregulating nitric oxide (NO), vascular endothelial growth factor (VEGF), and integrin ß1 expression may be the underlying mechanism of the observations. Our findings provide new insights for Co ion mediated macrophage-EC communication and surface design of biomaterials from the perspective of pro-angiogenesis.