Aspirin synergizes with mineral particle-coated macroporous scaffolds for bone regeneration through immunomodulation.
2023; 13 (13): 4512-4525
Rationale: Mineral particles have been widely used in bone tissue engineering scaffolds due to their osteoconductive and osteoinductive properties. Despite their benefits, mineral particles can induce undesirable inflammation and subsequent bone resorption. Aspirin (Asp) is an inexpensive and widely used anti-inflammatory drug. The goal of this study is to assess the synergistic effect of Asp and optimized mineral particle coating in macroporous scaffolds to accelerate endogenous bone regeneration and reduce bone resorption in a critical-sized bone defect model. Methods: Four commonly used mineral particles with varying composition (hydroxyapatite v.s. tricalcium phosphate) and size (nano v.s. micro) were used. Mineral particles were coated onto gelatin microribbon (µRB) scaffolds. Macrophages (Mφ) were cultured on gelatin µRB scaffolds containing various particles, and Mφ polarization was assessed using PCR and ELISA. The effect of conditioned medium from Mφ on mesenchymal stem cell (MSC) osteogenesis was also evaluated in vitro. Scaffolds containing optimized mineral particles were then combined with varying dosages of Asp to assess the effect in inducing endogenous bone regeneration using a critical-sized cranial bone defect model. In vivo characterization and in vitro cell studies were performed to elucidate the effect of tuning Asp dosage on Mφ polarization, osteoclast (OC) activity, and MSC osteogenesis. Results: Micro-sized tricalcium phosphate (mTCP) particles were identified as optimal in promoting M2 Mφ polarization and rescuing MSC-based bone formation in the presence of conditioned medium from Mφ. When implanted in vivo, incorporating Asp with mTCP-coated µRB scaffolds significantly accelerated endogenous bone formation in a dose-dependent manner. Impressively, mTCP-coated µRB scaffolds containing 20 µg Asp led to almost complete bone healing of a critical-sized cranial bone defect as early as week 2 with no subsequent bone resorption. Asp enhanced M2 Mφ polarization, decreased OC activity, and promoted MSC osteogenesis in a dosage-dependent manner in vivo. These results were further validated using in vitro cell studies. Conclusions: Here, we demonstrate Asp and mineral particle-coated microribbon scaffold provides a promising therapy for repairing critical-sized cranial bone defects via immunomodulation. The leading formulation supports rapid endogenous bone regeneration without the need for exogenous cells or growth factors, making it attractive for translation. Our results also highlight the importance of optimizing mineral particles and Asp dosage to achieve robust bone healing while avoiding bone resorption by targeting Mφ and OCs.
View details for DOI 10.7150/thno.85946
View details for PubMedID 37649612
View details for PubMedCentralID PMC10465219
Stem Cell Membrane-coated Microribbon Scaffolds Induce Regenerative Innate and Adaptive Immune Responses in a Critical-Size Cranial Bone Defect Model.
Advanced materials (Deerfield Beach, Fla.)
Naturally-derived cell membranes have shown great promise in functionalizing nanoparticles to enhance biointerfacing functions for drug delivery applications. However, its potential for functionalizing macroporous scaffolds to enhance tissue regeneration in vivo remains unexplored. Engineering scaffolds with immunomodulatory functions represents an exciting strategy for tissue regeneration but is largely limited to soft tissues. Critical sized bone defects cannot heal on its own, and the role of adaptive immune cells in scaffold-mediated healing of cranial bone defects remain largely unknown. Here we report mensenchymal stem cell membrane (MSCM)-coated microribbon (muRB) scaffolds for treating critical size cranial bone defects via targeting immunomodulation. Confocal imaging and proteomic analyses were used to confirm successful coating and characterize the compositions of cell membrane coating. We demonstrate MSCM coating promotes Mphi polarization towards regenerative phenotype, induces CD8+ T cell apoptosis, and enhances regulatory T cell differentiation in vitro and in vivo. MSCM primed with pro-inflammatory cytokines enhances regenerative immune response and promotes MSC osteogenesis. When combined with a low dosage of BMP-2, primed MSCM coating further accelerates bone regeneration and suppresses inflammation. These results establish cell membrane-coated microribbon scaffolds as a promising strategy for treating critical size bone defects via immunomodulation. The platform may be broadly used with different cell membranes and scaffolds to enhance regeneration of multiple tissue types. This article is protected by copyright. All rights reserved.
View details for DOI 10.1002/adma.202208781
View details for PubMedID 36560890
Differential dynamics of bone graft transplantation and mesenchymal stem cell therapy during bone defect healing in a murine critical size defect.
Journal of orthopaedic translation
2022; 36: 64-74
Background: A critical size bone defect is a clinical scenario in which bone is lost or excised due to trauma, infection, tumor, or other causes, and cannot completely heal spontaneously. The most common treatment for this condition is autologous bone grafting to the defect site. However, autologous bone graft is often insufficient in quantity or quality for transplantation to these large defects. Recently, tissue engineering methods using mesenchymal stem cells (MSCs) have been proposed as an alternative treatment. However, the underlying biological principles and optimal techniques for tissue regeneration of bone using stem cell therapy have not been completely elucidated.Methods: In this study, we compare the early cellular dynamics of healing between bone graft transplantation and MSC therapy in a murine chronic femoral critical-size bone defect. We employ high-dimensional mass cytometry to provide a comprehensive view of the differences in cell composition, stem cell functionality, and immunomodulatory activity between these two treatment methods one week after transplantation.Results: We reveal distinct cell compositions among tissues from bone defect sites compared with original bone graft, show active recruitment of MSCs to the bone defect sites, and demonstrate the phenotypic diversity of macrophages and T cells in each group that may affect the clinical outcome.Conclusion: Our results provide critical data and future directions on the use of MSCs for treating critical size defects to regenerate bone.Translational Potential of this article: This study showed systematic comparisons of the cellular and immunomodulatory profiles among different interventions to improve the healing of the critical-size bone defect. The results provided potential strategies for designing robust therapeutic interventions for the unmet clinical need of treating critical-size bone defects.
View details for DOI 10.1016/j.jot.2022.05.010
View details for PubMedID 35979174
Immunomodulatory strategies for bone regeneration: A review from the perspective of disease types.
2022; 286: 121604
Tissue engineering strategies for treating bone loss to date have largely focused on targeting stem cells or vascularization. Immune cells, including macrophages and T cells, can also indirectly enhance bone healing via cytokine secretion to interact with other bone niche cells. Bone niche cues and local immune environment vary depending on anatomical location, size of defects and disease types. As such, it is critical to evaluate the role of the immune system in the context of specific bone niche and different disease types. This review focuses on immunomodulation research for bone applications using biomaterials and cell-based strategies, with a unique perspective from different disease types. We first reviewed applications for prolonging orthopaedic implant lifetime and enhancing fracture healing, two clinical challenges where immunomodulatory strategies were initially developed for orthopedic applications. We then reviewed recent research progress in harnessing immunomodulatory strategies for regenerating critical-sized, long bone or cranial bone defects, and treating osteolytic bone diseases. Remaining gaps in knowledge, future directions and opportunities were also discussed.
View details for DOI 10.1016/j.biomaterials.2022.121604
View details for PubMedID 35667249
Endothelial cell membrane-based biosurface for targeted delivery to acute injury: analysis of leukocyte-mediated nanoparticle transportation
2021; 13 (35): 14636-14643
Mimicking and leveraging biological structures and materials provide important approaches to develop functional vehicles for drug delivery. Taking advantage of the affinity and adhesion between the activated endothelial cells and innate immune cells during inflammatory responses, hybrid polyester nanoparticles coated with endothelial cell membranes (EM-P) containing adhesion molecules were fabricated and their capability as vehicles to travel to the acute injury sites through leukocyte-mediated processes was investigated. The in vivo studies and quantitative analyses performed through the lung-inflammation mouse models demonstrated that the EM-Ps preferentially interacted with the neutrophils and monocytes in the circulation and the cellular membrane-based biosurface improved the nanoparticle transportation to the inflamed lung possibly via the motility of neutrophils. Utilizing the transgenic zebrafish model, the leukocyte-mediated transportation and biodistribution of EM-Ps were further visualized in real time at the whole-organism level. Endothelial membranes provided a new biosurface for developing biomimetic vehicles to allow the immune cell-mediated transportation and may enable advanced systems for active and highly efficient drug delivery.
View details for DOI 10.1039/d1nr04181a
View details for Web of Science ID 000692360800001
View details for PubMedID 34558568
Mesenchymal stromal exosome-functionalized scaffolds induce innate and adaptive immunomodulatory responses toward tissue repair.
2021; 7 (20)
Designing scaffolds capable of inducing and guiding appropriate immune responses holds promise for tissue repair/regeneration. Biofunctional scaffolds were here prepared by immobilizing mesenchymal stromal exosomes onto fibrous polyester materials and allowed cell-mediated delivery of membrane-bound vesicles. Quantitative cell-level analyses revealed that immune cells dominated the uptake of exosomes from scaffolds in vivo, with materials and exosomes acting as the recruiter and trainer for immune cells, respectively, to synergistically promote beneficial macrophage and regulatory T cell responses in skin wounds in mice. Adaptive T helper cell responses were found active in remote immune organs, and exosome-laden scaffolds facilitated tissue repair in large skin injury models. This study demonstrated important mechanisms involved in local and systemic immune responses to biological implants, and understanding tissue-reparative immunomodulation may guide the design of new biofunctional scaffolds.
View details for DOI 10.1126/sciadv.abf7207
View details for PubMedID 33980490
Membrane-Binding Adhesive Particulates Enhance the Viability and Paracrine Function of Mesenchymal Cells for Cell-Based Therapy
2019; 20 (2): 1007-1017
Understanding the fundamental cell-material interactions is essential to designing functional materials for biomedical applications. Although mesenchymal stromal cells (MSCs) are known to secrete cytokines and exosomes that are effective to treat degenerative diseases, the inherent property of biomaterials to modulate the therapeutic function of MSCs remains to be investigated. Here, a multivalent cell-membrane adhesive conjugate was generated through polyamindoamine (PAMAM) and an oligopeptide, IKVAV, and the conjugate was further complexed with hyaluronic acid (HA). The adhesive particulates were used to coat the surface of adipose-derived mesenchymal stromal cells (Ad-MSCs) and studied in the MSC spheroid culture. The analysis showed that the adhesive complexes formed via PAMAM conjugates and HA significantly promoted the proliferation and the gene expression of pro-angiogenesis cytokines in MSCs; the production of anti-inflammatory miRNAs in exosomes could also be elevated. The transplantation of the Ad-MSCs primed with PAMAM-IKVAV/HA composite particulates in a rat myocardial infarction model further demonstrated the beneficial effects of membrane-binding materials on improving the cell retention and tissue angiogenesis. The new function of membrane-binding adhesive materials potentially provides useful ways to improve cell-based therapy.
View details for DOI 10.1021/acs.biomac.8b01624
View details for Web of Science ID 000458937200042
View details for PubMedID 30616345
Fibrous scaffolds potentiate the paracrine function of mesenchymal stem cells: A new dimension in cell-material interaction
2017; 141: 74-85
While the studies on the material interaction with mesenchymal stem cells (MSCs) have been mainly focused on the ability of materials to provide environment to regulate cell viability, proliferation or differentiation, the therapeutic effects of MSC-material constructs may result from the secretion of immunomodulatory and angiogenic cytokines from MSCs. Here, electrospun scaffolds composed of fibers in random, aligned and mesh-like patterns were fabricated, and the paracrine behavior of adipose-derived MSCs (Ad-MSCs) on the scaffolds were investigated in comparison to the cell culture via conventional microplates. It was found that the Ad-MSCs on the electrospun fibers produced significantly higher levels of anti-inflammatory and pro-angiogenic cytokines compared to those cultured on microplates. The enhanced modulatory effects of the secreted products of Ad-MSCs on fibrous electrospun scaffolds were also proven in the cultures of endothelial cells and the LPS-stimulated macrophages, with three types of scaffolds showing distinct influences on the paracrine function of Ad-MSCs. In a skin excisional wound-healing model in rat, the conditioned medium collected from the MSC-scaffold system accelerated the wound closure, promoted the macrophage recruitment and enhanced the polarization of macrophages toward the pro-healing phenotype in the wound bed. Our study demonstrates that the fibrous topography of scaffolds is a key material property that modulates the paracrine function of cells. The discovery elucidates a new aspect of material functions, laying the foundation for developing scaffold materials to promote tissue regeneration/repair through guiding the paracrine signaling network.
View details for DOI 10.1016/j.biomaterials.2017.06.028
View details for Web of Science ID 000406731500007
View details for PubMedID 28667901
Overcoming foreign-body reaction through nanotopography: Biocompatibility and immunoisolation properties of a nanofibrous membrane
2016; 102: 249-258
Implantable immunoisolation membranes need to possess superior biocompatibility to prohibit the fibrotic deposition that would reduce the nutrient supply and impair the viability/function of the encapsulated cells. Here, electrospun membranes based on thermoplastic polyurethane (TPU) were fabricated to contain microfibers (PU-micro) or nanofibers (PU-nano). The two types of membranes were compared in terms of their interaction with macrophage cells and the host tissues. It was found that the fibrous membranes of different topographies possess distinct material properties: PU-nano caused minimal macrophage responses in vitro and in vivo and induced only mild foreign body reactions compared to PU-micro membranes. A flat macroencapsulation device was fabricated using PU-nano membranes and its immunoisolation function investigated in subcutaneous transplantation models. The nanofibrous device demonstrated the capability to effectively shield the allografts from the immune attack of the host. Nanotopography may confer biocompatibility to materials and nanofibrous materials warrant further study for development of "invisible" immunoisolation devices for cell transplantation.
View details for DOI 10.1016/j.biomaterials.2016.06.028
View details for Web of Science ID 000380625700022
View details for PubMedID 27344368