Lupeng Teng, Soichiro Fukushima, Makoto Koizumi, Hirotaka James Okano, Takao Ohki, Koji Matsuura, Ryosuke Iwai
Several studies have investigated the location of transplanted cells and tissue-engineered cell constructs in the body by incorporating contrast nanoparticles into cells by endocytosis; however, these have yet to be applied clinically because of the complexity of assessing the safety of nanoparticles. In this study, we proposed that our developed adherent cell self-aggregation technique (CAT) could be used to develop cell aggregates loaded with contrast particles of a size that would exclude the possibility of endocytosis, and aimed to prepare these aggregates followed by biological and computed tomography (CT) contrast evaluation under X-rays. Once human bone marrow-derived mesenchymal stem cells (HBMSCs) were seeded into culture dishes coated with CAT-inducing polymer to form gapless cell monolayer sheets, tungsten carbide (WC) particles smaller than 1 μm or titanium (Ti) particles larger than 10 μm were added, and thus each particle deposited on the surface of the cell monolayer sheet. During the subsequent overnight incubation, spontaneous detachment and aggregation of the cell monolayer sheets with deposited WC and Ti particles occurred, forming single spherical cell aggregates (spheroids) and loading these particles. Histological analysis confirmed that Ti particles with a diameter of at least 10 μm were not endocytosed and remained attached to the outside of cells forming spheroids, while WC particles were endocytosed into the cells. The CT images of the Ti-loaded spheroids were clearly visible along the spheroid shape under X-ray irradiation. Then, we confirmed that there was no toxicity to the cells forming the spheroids by loading Ti particles, and the cells could sprout and proliferate by culturing the spheroids. We successfully prepared Ti particle-loaded HBMSCs aggregates with long fiber shape (> 10 cm) by applying CAT to a culture dish with a ring-fiber-shaped culture groove and confirmed their clear visibility on CT images under X-ray irradiation, as well as their containment and ejection into a catheter, demonstrating their applicability to catheter-mediated regenerative therapy.
{"title":"Successful Preparation of Contrast Particle-Loaded Human Mesenchymal Stem Cell Aggregates Using Adherent Cell Self-Aggregation Technique","authors":"Lupeng Teng, Soichiro Fukushima, Makoto Koizumi, Hirotaka James Okano, Takao Ohki, Koji Matsuura, Ryosuke Iwai","doi":"10.1002/jbm.a.37964","DOIUrl":"https://doi.org/10.1002/jbm.a.37964","url":null,"abstract":"<div>\u0000 \u0000 <p>Several studies have investigated the location of transplanted cells and tissue-engineered cell constructs in the body by incorporating contrast nanoparticles into cells by endocytosis; however, these have yet to be applied clinically because of the complexity of assessing the safety of nanoparticles. In this study, we proposed that our developed adherent cell self-aggregation technique (CAT) could be used to develop cell aggregates loaded with contrast particles of a size that would exclude the possibility of endocytosis, and aimed to prepare these aggregates followed by biological and computed tomography (CT) contrast evaluation under X-rays. Once human bone marrow-derived mesenchymal stem cells (HBMSCs) were seeded into culture dishes coated with CAT-inducing polymer to form gapless cell monolayer sheets, tungsten carbide (WC) particles smaller than 1 μm or titanium (Ti) particles larger than 10 μm were added, and thus each particle deposited on the surface of the cell monolayer sheet. During the subsequent overnight incubation, spontaneous detachment and aggregation of the cell monolayer sheets with deposited WC and Ti particles occurred, forming single spherical cell aggregates (spheroids) and loading these particles. Histological analysis confirmed that Ti particles with a diameter of at least 10 μm were not endocytosed and remained attached to the outside of cells forming spheroids, while WC particles were endocytosed into the cells. The CT images of the Ti-loaded spheroids were clearly visible along the spheroid shape under X-ray irradiation. Then, we confirmed that there was no toxicity to the cells forming the spheroids by loading Ti particles, and the cells could sprout and proliferate by culturing the spheroids. We successfully prepared Ti particle-loaded HBMSCs aggregates with long fiber shape (> 10 cm) by applying CAT to a culture dish with a ring-fiber-shaped culture groove and confirmed their clear visibility on CT images under X-ray irradiation, as well as their containment and ejection into a catheter, demonstrating their applicability to catheter-mediated regenerative therapy.</p>\u0000 </div>","PeriodicalId":15142,"journal":{"name":"Journal of biomedical materials research. Part A","volume":"113 7","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144598404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The identification of materials that effectively promote mineralization and vascularization is crucial for advancing clinical applications in bone regeneration. Biomimetic silicified collagen scaffold (SCS) has emerged as a promising candidate, demonstrating significant potential to enhance both osteogenesis and angiogenesis. However, the mechanisms by which SCS directly influences angiogenesis to facilitate bone defect healing remain largely unexplored. In this study, we observed that the implantation of SCS in rabbit femoral defects resulted in extensive bone regeneration and angiogenesis at the wound sites. Notably, SCS outperformed commercial alternatives such as Bio-Oss in terms of degradation and angiogenic response. In vitro assays further demonstrated that SCS upregulates angiogenic protein expression and promotes endothelial cell angiogenesis through the activation of the HIF-1α/VEGF signaling pathway. Consequently, SCS modulates the phenotype of vascular endothelial cells, leading to the formation of CD31hiEmcnhi type H endothelial cells, which are critical for effective bone regeneration. This study offers valuable perspectives on the dual effects of silicified materials on osteogenesis and angiogenesis, advancing the understanding of their potential functions in regenerative medicine.
{"title":"Enhancing Bone Regeneration: The Role of Biomimetic Silicified Collagen Scaffold in Osteogenesis and Angiogenesis","authors":"Ming-yuan Liu, Yu-xuan Ma, Lei Chen, Meng Wang, Zheng-long Zhang, Yu-xia Hou, Li-na Niu","doi":"10.1002/jbm.a.37954","DOIUrl":"https://doi.org/10.1002/jbm.a.37954","url":null,"abstract":"<div>\u0000 \u0000 <p>The identification of materials that effectively promote mineralization and vascularization is crucial for advancing clinical applications in bone regeneration. Biomimetic silicified collagen scaffold (SCS) has emerged as a promising candidate, demonstrating significant potential to enhance both osteogenesis and angiogenesis. However, the mechanisms by which SCS directly influences angiogenesis to facilitate bone defect healing remain largely unexplored. In this study, we observed that the implantation of SCS in rabbit femoral defects resulted in extensive bone regeneration and angiogenesis at the wound sites. Notably, SCS outperformed commercial alternatives such as Bio-Oss in terms of degradation and angiogenic response. In vitro assays further demonstrated that SCS upregulates angiogenic protein expression and promotes endothelial cell angiogenesis through the activation of the HIF-1α/VEGF signaling pathway. Consequently, SCS modulates the phenotype of vascular endothelial cells, leading to the formation of CD31<sup>hi</sup>Emcn<sup>hi</sup> type H endothelial cells, which are critical for effective bone regeneration. This study offers valuable perspectives on the dual effects of silicified materials on osteogenesis and angiogenesis, advancing the understanding of their potential functions in regenerative medicine.</p>\u0000 </div>","PeriodicalId":15142,"journal":{"name":"Journal of biomedical materials research. Part A","volume":"113 7","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144589633","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Arezoo Esrafili, Aleksandr Talitckii, Joshua Kupfer, Abhirami Thumsi, Madhan Mohan Chandra Sekhar Jaggarapu, Margaret Dugoni, Gregory Jensen, Matthew M. Peet, Julianne L. Holloway, Abhinav P. Acharya
Vaccine development requires innovative approaches to improve immune responses while reducing the number of immunizations. In this study, we explore the impact of controlled antigen release on immune activation and regulation using programmable infusion pumps and biodegradable biomaterials in OT-II and wild-type mice to understand the adaptive immune response through controlled antigen delivery in the absence of adjuvant. Ovalbumin (OVA) was delivered via an exponentially decreasing profile, mimicking clearance of infection, and an exponentially increasing profile, mimicking induction of infection. Exponentially decreasing OVA delivery through infusion pumps promoted regulatory T-cell (Treg) activation in secondary lymphoid organs and suppressed pro-inflammatory T-helper type 17 (Th17) responses in blood. An exponentially increasing OVA profile enhanced central memory T-cell (TCM) populations in submandibular blood and humoral immune responses in cardiac blood serum, demonstrating distinct immune modulation based on release kinetics. OVA was also delivered using a biodegradable PLGA-PEG-PLGA (PPP) depot, which provided controlled OVA release in an exponentially decreasing pattern. PPP-OVA treatment significantly reduced the frequency of pro-inflammatory T-helper type 1 (Th1) cells while increasing CD25+FOXP3+ Treg cells in the spleen. Moreover, to identify T-cell populations that most accurately characterize the divergence in Treg and T-helper response to OVA kinetics, a Sequential Feature Selection (SFS) algorithm with Machine Learning (ML) models was used. ML algorithms identified gMFI of RORγt+ as a key feature in submandibular blood and the ratio of gMFI of FOXP3+ to GATA3+ as the marker that was significantly changed by treatments in inguinal lymph nodes (iLN) when infusion pumps were used to deliver OVA. In addition, ML-based SFS identified CD25+FOXP3+ regulatory T cells as the most important feature, influencing the expression of other cell types in both inguinal lymph nodes (iLN) and spleen when PPP was used to deliver OVA. This finding suggests that the exponentially decreasing profile may generate anti-inflammatory responses. Overall, these findings suggest that controlled antigen delivery enhances immune regulation and memory T cells, providing new insights into immune responses mediated by the release kinetics.
{"title":"Exponentially Decreasing Antigen Release Reduces Inflammatory Markers in an Antigen-Specific Manner","authors":"Arezoo Esrafili, Aleksandr Talitckii, Joshua Kupfer, Abhirami Thumsi, Madhan Mohan Chandra Sekhar Jaggarapu, Margaret Dugoni, Gregory Jensen, Matthew M. Peet, Julianne L. Holloway, Abhinav P. Acharya","doi":"10.1002/jbm.a.37962","DOIUrl":"https://doi.org/10.1002/jbm.a.37962","url":null,"abstract":"<p>Vaccine development requires innovative approaches to improve immune responses while reducing the number of immunizations. In this study, we explore the impact of controlled antigen release on immune activation and regulation using programmable infusion pumps and biodegradable biomaterials in OT-II and wild-type mice to understand the adaptive immune response through controlled antigen delivery in the absence of adjuvant. Ovalbumin (OVA) was delivered via an exponentially decreasing profile, mimicking clearance of infection, and an exponentially increasing profile, mimicking induction of infection. Exponentially decreasing OVA delivery through infusion pumps promoted regulatory T-cell (Treg) activation in secondary lymphoid organs and suppressed pro-inflammatory T-helper type 17 (Th17) responses in blood. An exponentially increasing OVA profile enhanced central memory T-cell (TCM) populations in submandibular blood and humoral immune responses in cardiac blood serum, demonstrating distinct immune modulation based on release kinetics. OVA was also delivered using a biodegradable PLGA-PEG-PLGA (PPP) depot, which provided controlled OVA release in an exponentially decreasing pattern. PPP-OVA treatment significantly reduced the frequency of pro-inflammatory T-helper type 1 (Th1) cells while increasing CD25<sup>+</sup>FOXP3<sup>+</sup> Treg cells in the spleen. Moreover, to identify T-cell populations that most accurately characterize the divergence in Treg and T-helper response to OVA kinetics, a Sequential Feature Selection (SFS) algorithm with Machine Learning (ML) models was used. ML algorithms identified gMFI of RORγt<sup>+</sup> as a key feature in submandibular blood and the ratio of gMFI of FOXP3<sup>+</sup> to GATA3<sup>+</sup> as the marker that was significantly changed by treatments in inguinal lymph nodes (iLN) when infusion pumps were used to deliver OVA. In addition, ML-based SFS identified CD25<sup>+</sup>FOXP3<sup>+</sup> regulatory T cells as the most important feature, influencing the expression of other cell types in both inguinal lymph nodes (iLN) and spleen when PPP was used to deliver OVA. This finding suggests that the exponentially decreasing profile may generate anti-inflammatory responses. Overall, these findings suggest that controlled antigen delivery enhances immune regulation and memory T cells, providing new insights into immune responses mediated by the release kinetics.</p>","PeriodicalId":15142,"journal":{"name":"Journal of biomedical materials research. Part A","volume":"113 7","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jbm.a.37962","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144582064","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Maria Carolina Lanzino, Anika Höppel, Long-Quan R. V. Le, Stefania Morelli, Andreas Killinger, Wolfgang Rheinheimer, Hermann O. Mayr, Sofia Dembski, Ali Al-Ahmad, Moritz F. Mayr, Uwe Gbureck, Michael Seidenstuecker
This work highlights the potential of porous, bioactive coatings to advance implant technology and address critical clinical challenges. A key issue in implant coatings is to achieve the balance between infection prevention and successful osseointegration. Although titanium implants are widely used due to their mechanical strength and biocompatibility, their bioinert nature limits integration with bone tissue. To address these issues, porous calcium phosphate (CaP) coatings have been developed to enhance cell attachment and bone growth. However, CaP, especially in the widely used form of hydroxyapatite (HAp), has a low resorption rate, which often leads to prolonged coating stability and impairs natural bone remodeling. To overcome this limitation, magnesium phosphate (MgP), an underexplored but promising biomaterial with high biocompatibility and osteogenic potential, can be introduced. Another innovative strategy is the doping of biomaterials with antibacterial ions, among which copper (Cu) has attracted particular attention. The incorporation of Cu into the coating matrix can significantly reduce the risk of post-operative infection while promoting angiogenesis, a key factor for rapid and stable implant integration. This study presents bone implant coatings composed of tricalcium phosphate (TCP) and Cu-doped MgP clustered nanoparticles (supraparticles) fabricated via high-velocity suspension flame spraying (HVSFS). This particle system addresses current challenges in bone tissue regeneration by synergistically combining the high biodegradability of MgP, the bone-mimicking properties of CaP, and the antibacterial capabilities of Cu. In addition, the HVSFS process enables the creation of thin layers with porous microstructures. Biocompatibility of the prepared coatings was assessed using MG63 osteosarcoma cells, while the antibacterial efficacy was tested against Staphylococcus aureus and Escherichia coli. The incorporation of Cu-doped MgP supraparticles (MgPCu and MgPCu HT) into TCP coatings resulted in high Cu release and pronounced antibacterial efficacy compared to the TCP reference, while the addition of Cu-doped FT supraparticles (FTCu) led to high cell proliferation.
{"title":"Biodegradable, Antibacterial TCP Implant Coatings With Magnesium Phosphate-Based Supraparticles","authors":"Maria Carolina Lanzino, Anika Höppel, Long-Quan R. V. Le, Stefania Morelli, Andreas Killinger, Wolfgang Rheinheimer, Hermann O. Mayr, Sofia Dembski, Ali Al-Ahmad, Moritz F. Mayr, Uwe Gbureck, Michael Seidenstuecker","doi":"10.1002/jbm.a.37963","DOIUrl":"https://doi.org/10.1002/jbm.a.37963","url":null,"abstract":"<p>This work highlights the potential of porous, bioactive coatings to advance implant technology and address critical clinical challenges. A key issue in implant coatings is to achieve the balance between infection prevention and successful osseointegration. Although titanium implants are widely used due to their mechanical strength and biocompatibility, their bioinert nature limits integration with bone tissue. To address these issues, porous calcium phosphate (CaP) coatings have been developed to enhance cell attachment and bone growth. However, CaP, especially in the widely used form of hydroxyapatite (HAp), has a low resorption rate, which often leads to prolonged coating stability and impairs natural bone remodeling. To overcome this limitation, magnesium phosphate (MgP), an underexplored but promising biomaterial with high biocompatibility and osteogenic potential, can be introduced. Another innovative strategy is the doping of biomaterials with antibacterial ions, among which copper (Cu) has attracted particular attention. The incorporation of Cu into the coating matrix can significantly reduce the risk of post-operative infection while promoting angiogenesis, a key factor for rapid and stable implant integration. This study presents bone implant coatings composed of tricalcium phosphate (TCP) and Cu-doped MgP clustered nanoparticles (supraparticles) fabricated via high-velocity suspension flame spraying (HVSFS). This particle system addresses current challenges in bone tissue regeneration by synergistically combining the high biodegradability of MgP, the bone-mimicking properties of CaP, and the antibacterial capabilities of Cu. In addition, the HVSFS process enables the creation of thin layers with porous microstructures. Biocompatibility of the prepared coatings was assessed using MG63 osteosarcoma cells, while the antibacterial efficacy was tested against <i>Staphylococcus aureus</i> and <i>Escherichia coli</i>. The incorporation of Cu-doped MgP supraparticles (MgPCu and MgPCu HT) into TCP coatings resulted in high Cu release and pronounced antibacterial efficacy compared to the TCP reference, while the addition of Cu-doped FT supraparticles (FTCu) led to high cell proliferation.</p>","PeriodicalId":15142,"journal":{"name":"Journal of biomedical materials research. Part A","volume":"113 7","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jbm.a.37963","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144573153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bioprinting is a growing area in the field of tissue engineering that offers a potential solution to the global shortage of organ transplants. Ensuring high printability is crucial for bioprinting. To better understand printability, a design of experiment model that examines printing speed and pressure in extrusion-based printing was developed. Two biomaterials, hyaluronic acid and sodium alginate, were selected as surrogate biomaterials to understand how rheological properties play a role in printability. Various rheological aspects such as shear-thinning behavior, viscosity, and recovery were investigated. To further evaluate printability, a new method was used that includes deep learning image similarity. The information obtained with the surrogate bioinks was then applied to another biomaterial, methacrylated hyaluronic acid, in combination with corneal keratocytes to demonstrate the successful implementation of the outcome of this design of experiment. As a result of this study, a better understanding of the rheological properties for bioprinting was achieved, leading to a next step towards improving extrusion-based bioprinting, which can be used for a wide range of applications.
{"title":"A Design of Experiment to Evaluate the Printability for Bioprinting by Using Deep Learning Image Similarity","authors":"Leon Balters, Stephan Reichl","doi":"10.1002/jbm.a.37961","DOIUrl":"https://doi.org/10.1002/jbm.a.37961","url":null,"abstract":"<p>Bioprinting is a growing area in the field of tissue engineering that offers a potential solution to the global shortage of organ transplants. Ensuring high printability is crucial for bioprinting. To better understand printability, a design of experiment model that examines printing speed and pressure in extrusion-based printing was developed. Two biomaterials, hyaluronic acid and sodium alginate, were selected as surrogate biomaterials to understand how rheological properties play a role in printability. Various rheological aspects such as shear-thinning behavior, viscosity, and recovery were investigated. To further evaluate printability, a new method was used that includes deep learning image similarity. The information obtained with the surrogate bioinks was then applied to another biomaterial, methacrylated hyaluronic acid, in combination with corneal keratocytes to demonstrate the successful implementation of the outcome of this design of experiment. As a result of this study, a better understanding of the rheological properties for bioprinting was achieved, leading to a next step towards improving extrusion-based bioprinting, which can be used for a wide range of applications.</p>","PeriodicalId":15142,"journal":{"name":"Journal of biomedical materials research. Part A","volume":"113 7","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jbm.a.37961","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144558004","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Stefanie Ficht, Lukas Schübel, Diana M. Rojas-González, Juliana Dos Santos Solheid, Stefan Leonhardt, Magdalena Kleybolte, Cécile Boudot, Markus Eblenkamp, Jana Steger, Dirk Wilhelm, Petra Mela
Additive manufacturing of patient specific implants made of biodegradable polymers is receiving increasing attention in the medical sector, including the trend towards manufacturing at the point-of-care. Despite this, the changes of the polymer structure and their effects on mechanical properties and degradation behavior caused by the additive manufacturing process and subsequent sterilization are still insufficiently investigated, although of key relevance for the implant's functionality. In this study, poly(p-dioxanone) (PPDO) was processed by fused filament fabrication (FFF). The effects of manufacturing as well as two different low-temperature sterilization techniques, namely H2O2 plasma and gamma irradiation, on the polymer structure were evaluated. Additionally, PPDO degradation was investigated by immersing the processed samples in Sorensen's phosphate buffer (PB) with pH = 6.47 for 28 days to mimic implantation in intestinal milieu and evaluated at regular time intervals. Results showed that we were able to successfully print PPDO without influencing the polymer structure or cytocompatibility. No significant changes were detected for plasma-sterilized samples (PS) while gamma-sterilized (GS) ones significantly decreased molecular weight (Mw and Mn) and showed significant lower inherent viscosity (IV) compared with the (non-sterilized) control group after processing. During immersion in PB, a decrease in Mw, Mn, and mechanical strength occurred for all samples. However, GS samples were affected to a much higher extent compared with the other groups both in final values and timeline. A degradation plateau was seen for the tensile strength of NS and PS samples over the first 21 and 17 days, respectively, followed by a steady decrease. In contrast, for the GS samples, a drastic decrease in tensile strength occurred already during the first 14 days. There was no notable mass loss detected within the first 28 days of degradation for any of the sample groups. Based on these results, we conclude that FFF with subsequent plasma sterilization is a reliable process for manufacturing PPDO devices for short-term applications that require stable mechanical conditions within the first weeks of implantation to guarantee the time needed for tissue healing before degrading, as for example, in the case of intestinal compression anastomoses. Such requirement could not be met with gamma sterilization with the dose used, because of the too fast decrease in mechanical properties.
{"title":"Effects of Additive Manufacturing and Sterilization on Poly(p-Dioxanone) for Short-Term Application in the Intestinal Environment","authors":"Stefanie Ficht, Lukas Schübel, Diana M. Rojas-González, Juliana Dos Santos Solheid, Stefan Leonhardt, Magdalena Kleybolte, Cécile Boudot, Markus Eblenkamp, Jana Steger, Dirk Wilhelm, Petra Mela","doi":"10.1002/jbm.a.37957","DOIUrl":"https://doi.org/10.1002/jbm.a.37957","url":null,"abstract":"<p>Additive manufacturing of patient specific implants made of biodegradable polymers is receiving increasing attention in the medical sector, including the trend towards manufacturing at the point-of-care. Despite this, the changes of the polymer structure and their effects on mechanical properties and degradation behavior caused by the additive manufacturing process and subsequent sterilization are still insufficiently investigated, although of key relevance for the implant's functionality. In this study, poly(p-dioxanone) (PPDO) was processed by fused filament fabrication (FFF). The effects of manufacturing as well as two different low-temperature sterilization techniques, namely H<sub>2</sub>O<sub>2</sub> plasma and gamma irradiation, on the polymer structure were evaluated. Additionally, PPDO degradation was investigated by immersing the processed samples in Sorensen's phosphate buffer (PB) with pH = 6.47 for 28 days to mimic implantation in intestinal milieu and evaluated at regular time intervals. Results showed that we were able to successfully print PPDO without influencing the polymer structure or cytocompatibility. No significant changes were detected for plasma-sterilized samples (PS) while gamma-sterilized (GS) ones significantly decreased molecular weight (M<sub>w</sub> and M<sub>n</sub>) and showed significant lower inherent viscosity (IV) compared with the (non-sterilized) control group after processing. During immersion in PB, a decrease in M<sub>w</sub>, M<sub>n</sub>, and mechanical strength occurred for all samples. However, GS samples were affected to a much higher extent compared with the other groups both in final values and timeline. A degradation plateau was seen for the tensile strength of NS and PS samples over the first 21 and 17 days, respectively, followed by a steady decrease. In contrast, for the GS samples, a drastic decrease in tensile strength occurred already during the first 14 days. There was no notable mass loss detected within the first 28 days of degradation for any of the sample groups. Based on these results, we conclude that FFF with subsequent plasma sterilization is a reliable process for manufacturing PPDO devices for short-term applications that require stable mechanical conditions within the first weeks of implantation to guarantee the time needed for tissue healing before degrading, as for example, in the case of intestinal compression anastomoses. Such requirement could not be met with gamma sterilization with the dose used, because of the too fast decrease in mechanical properties.</p>","PeriodicalId":15142,"journal":{"name":"Journal of biomedical materials research. Part A","volume":"113 7","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jbm.a.37957","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144558107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
This study aimed to develop an innovative (S-flurbiprofen)-diethylamine (SFP-DEA) emulgel formulation via incorporating SFP as the active pharmaceutical ingredient within a carbomer 940 gel matrix. SFP-DEA emulgel was synthesized by dissolving SFP-DEA in the aqueous phase of an oil-in-water (O/W) emulsion, followed by dispersion into a carbomer 940 gel matrix. The physicochemical stability of SFP-DEA emulgel was evaluated via centrifuge, temperature swing test, high temperature, and long-term storage at ambient conditions. Ex vivo SFP transdermal delivery of SFP-DEA emulgel was evaluated using a Franz diffusion cell combined with excised rat skin. The in vivo analgesic activity and skin irritation test of SFP-DEA emulgel were evaluated using a mouse knee osteoarthritis model and healthy rats, respectively. Results demonstrated that SFP-DEA emulgel showed robust physicochemical stability and retain a final SFP content of 1.5% (w/w). Ex vivo transdermal study demonstrated that EMG5 (the emulgel optimized with laurocapram and menthol as penetration enhancers) achieved an 8-h cumulative SFP transdermal flux of 741.28 μg/cm2 (44.23% of the administered dose), which is 27.94-fold higher than that of Loqoa (SFP tapes). In addition, SFP-DEA emulgel demonstrated rapid analgesic efficacy, with an 84.36% pain inhibition rate within 30 min in the osteoarthritis model, and elicited no signs of skin irritation in rats. In conclusion, the SFP-DEA emulgel developed herein exhibits high stability, enhanced transdermal delivery, preliminary analgesic activity, and favorable safety profiles, positioning it as a promising topical therapeutic candidate.
{"title":"Development and Evaluation of an Innovative S-Flurbiprofen-Diethylamine Emulgel With Superior Transdermal Delivery and Analgesic Activity","authors":"Jian Zhang, Jinmeng Han, Anqi Zhu, Xiaoqian Zhu, Yuyu Zeng, Mingyue Yin, Yang Xiao, Chenchen Wang, Chaoyang Yin, Xingyin Wang, Guisen Zhang, Chao Hao","doi":"10.1002/jbm.a.37936","DOIUrl":"https://doi.org/10.1002/jbm.a.37936","url":null,"abstract":"<div>\u0000 \u0000 <p>This study aimed to develop an innovative (S-flurbiprofen)-diethylamine (SFP-DEA) emulgel formulation via incorporating SFP as the active pharmaceutical ingredient within a carbomer 940 gel matrix. SFP-DEA emulgel was synthesized by dissolving SFP-DEA in the aqueous phase of an oil-in-water (O/W) emulsion, followed by dispersion into a carbomer 940 gel matrix. The physicochemical stability of SFP-DEA emulgel was evaluated via centrifuge, temperature swing test, high temperature, and long-term storage at ambient conditions. Ex vivo SFP transdermal delivery of SFP-DEA emulgel was evaluated using a Franz diffusion cell combined with excised rat skin. The in vivo analgesic activity and skin irritation test of SFP-DEA emulgel were evaluated using a mouse knee osteoarthritis model and healthy rats, respectively. Results demonstrated that SFP-DEA emulgel showed robust physicochemical stability and retain a final SFP content of 1.5% (w/w). Ex vivo transdermal study demonstrated that EMG5 (the emulgel optimized with laurocapram and menthol as penetration enhancers) achieved an 8-h cumulative SFP transdermal flux of 741.28 μg/cm<sup>2</sup> (44.23% of the administered dose), which is 27.94-fold higher than that of Loqoa (SFP tapes). In addition, SFP-DEA emulgel demonstrated rapid analgesic efficacy, with an 84.36% pain inhibition rate within 30 min in the osteoarthritis model, and elicited no signs of skin irritation in rats. In conclusion, the SFP-DEA emulgel developed herein exhibits high stability, enhanced transdermal delivery, preliminary analgesic activity, and favorable safety profiles, positioning it as a promising topical therapeutic candidate.</p>\u0000 </div>","PeriodicalId":15142,"journal":{"name":"Journal of biomedical materials research. Part A","volume":"113 7","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144558290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Plasma electrolytic oxidation (PEO) considerably affects controlling the degradation rate of magnesium-based implants to approach the healing period. However, the biological properties still require further improvement, particularly for blood-contact applications, such as cardiovascular stents. This research aims to study in vitro biological properties of the duplex diamond-like carbon (DLC)/plasma electrolytic oxidation (PEO) coatings as a function of various PEO middle layers for potential cardiovascular stent applications. To this aim, two different PEO coatings including silicate and phosphate compounds were applied on AZ31 substrate as middle-layers, and a top DLC layer with 1 μm thickness was successfully synthesized on them. Moreover, the role of different PEO interlayers on the degradation behavior, biocompatibility, hemocompatibility, and its mechanism are studied. Results showed a considerable decrease in degradation rate after applying the PEO process and the PEO-Ph revealed the optimized degradation performance in just PEO-coated samples. On the other side, the best degradation performance between duplex-coated samples was obtained for DLC/PEO-Si according to its higher diamond-like structure. Moreover, the viability of human umbilical vein endothelial cells on DLC/PEO-Ph was higher than that of the DLC/PEO-Si, which might be attributed to higher protein adsorption on its surface. In the case of hemocompatibility, a considerable decrease in hemolysis ratio along with remarkable improvement in clotting behavior was observed by applying the PEO process. However, the hemolysis ratio was reduced as being safe for blood-contact applications just for duplex-coated samples. In conclusion, a promising coating for blood-contact applications based on DLC/PEO in particular in the case of DLC/PEO-Si has been provided in this study.
{"title":"Biological Responses and Hemocompatibility of Diamond-Like Carbon Thin Films on Different PEO Interlayers for Potential Cardiovascular Stent Applications","authors":"Nasir Shahin, Morteza Shamanian, Mahshid Kharaziha","doi":"10.1002/jbm.a.37953","DOIUrl":"https://doi.org/10.1002/jbm.a.37953","url":null,"abstract":"<div>\u0000 \u0000 <p>Plasma electrolytic oxidation (PEO) considerably affects controlling the degradation rate of magnesium-based implants to approach the healing period. However, the biological properties still require further improvement, particularly for blood-contact applications, such as cardiovascular stents. This research aims to study in vitro biological properties of the duplex diamond-like carbon (DLC)/plasma electrolytic oxidation (PEO) coatings as a function of various PEO middle layers for potential cardiovascular stent applications. To this aim, two different PEO coatings including silicate and phosphate compounds were applied on AZ31 substrate as middle-layers, and a top DLC layer with 1 μm thickness was successfully synthesized on them. Moreover, the role of different PEO interlayers on the degradation behavior, biocompatibility, hemocompatibility, and its mechanism are studied. Results showed a considerable decrease in degradation rate after applying the PEO process and the PEO-Ph revealed the optimized degradation performance in just PEO-coated samples. On the other side, the best degradation performance between duplex-coated samples was obtained for DLC/PEO-Si according to its higher diamond-like structure. Moreover, the viability of human umbilical vein endothelial cells on DLC/PEO-Ph was higher than that of the DLC/PEO-Si, which might be attributed to higher protein adsorption on its surface. In the case of hemocompatibility, a considerable decrease in hemolysis ratio along with remarkable improvement in clotting behavior was observed by applying the PEO process. However, the hemolysis ratio was reduced as being safe for blood-contact applications just for duplex-coated samples. In conclusion, a promising coating for blood-contact applications based on DLC/PEO in particular in the case of DLC/PEO-Si has been provided in this study.</p>\u0000 </div>","PeriodicalId":15142,"journal":{"name":"Journal of biomedical materials research. Part A","volume":"113 7","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144536962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Poor osseointegration of Titanium (Ti) implants in osteoporotic bone can lead to early construct failure in clinical settings. This study investigated whether combining Strontium (Sr) surface loading (modified alkali and heat treatment) with systemic teriparatide administration could enhance implant osseointegration in osteoporotic conditions. Mouse osteoblast-like cells (MC3T3-E1) were cultured on Sr-loaded Ti surfaces with and without teriparatide administration to evaluate cell adhesion, proliferation, differentiation, and mineralization capacity. This in vivo study utilized an osteoporotic rabbit femur through ovariectomy and steroid administration. The combined treatment (Sr-loaded Ti and teriparatide) enhanced osteoblast differentiation and mineralization in vitro, with an increase in alkaline phosphatase activity and alizarin red staining. Six and twelve weeks after in vivo implantation, the combination therapy demonstrated superior outcomes compared to the single treatments (Sr-loaded Ti or teriparatide), including enhanced bone–implant interfacial strength, improved bone morphology parameters, higher mineral apposition rates, and greater bone–implant contact. These findings demonstrate that the synergistic approach of Sr-loaded Ti implants combined with systemic teriparatide administration considerably improves implant osseointegration in osteoporotic bone, suggesting a promising strategy for enhancing implant outcomes in patients with osteoporotic bone quality.
{"title":"Strontium-Loaded Titanium and Systemic Teriparatide Synergistically Enhance Osteogenesis and Osseointegration in an Osteoporotic Rabbit Model","authors":"Koichiro Shima, Takayoshi Shimizu, Seiji Yamaguchi, Bungo Otsuki, Toshiyuki Kawai, Yaichiro Okuzu, Yusuke Takaoka, Norimasa Ikeda, Shuichi Matsuda","doi":"10.1002/jbm.a.37960","DOIUrl":"https://doi.org/10.1002/jbm.a.37960","url":null,"abstract":"<div>\u0000 \u0000 <p>Poor osseointegration of Titanium (Ti) implants in osteoporotic bone can lead to early construct failure in clinical settings. This study investigated whether combining Strontium (Sr) surface loading (modified alkali and heat treatment) with systemic teriparatide administration could enhance implant osseointegration in osteoporotic conditions. Mouse osteoblast-like cells (MC3T3-E1) were cultured on Sr-loaded Ti surfaces with and without teriparatide administration to evaluate cell adhesion, proliferation, differentiation, and mineralization capacity. This in vivo study utilized an osteoporotic rabbit femur through ovariectomy and steroid administration. The combined treatment (Sr-loaded Ti and teriparatide) enhanced osteoblast differentiation and mineralization in vitro, with an increase in alkaline phosphatase activity and alizarin red staining. Six and twelve weeks after in vivo implantation, the combination therapy demonstrated superior outcomes compared to the single treatments (Sr-loaded Ti or teriparatide), including enhanced bone–implant interfacial strength, improved bone morphology parameters, higher mineral apposition rates, and greater bone–implant contact. These findings demonstrate that the synergistic approach of Sr-loaded Ti implants combined with systemic teriparatide administration considerably improves implant osseointegration in osteoporotic bone, suggesting a promising strategy for enhancing implant outcomes in patients with osteoporotic bone quality.</p>\u0000 </div>","PeriodicalId":15142,"journal":{"name":"Journal of biomedical materials research. Part A","volume":"113 7","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144550945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Metal–organic frameworks (MOFs) are porous materials composed of metal ions or clusters and organic ligands connected through coordination bonds, exhibiting high specific surface areas, tunable pore structures, and excellent chemical stability. These unique features have enabled MOFs to be widely applied in catalysis, gas separation, and environmental purification. In recent years, the potential of MOFs in the biomedicine field has garnered significant attention. MOFs offer efficient drug loading and controlled release capabilities, particularly for targeted therapies in oncology and other diseases. Furthermore, their structural versatility positions them as promising candidates for antitumor and antibacterial treatments. However, challenges related to biocompatibility, in vivo degradation, and potential toxicity need further investigation. This review explores the latest advancements in MOF applications in biomedicine, focusing on drug delivery, targeted therapy, and modification strategies, as well as toxicity assessment and mechanisms. Finally, future research directions are proposed, including the development of intelligent drug delivery systems, multimodal diagnostic platforms, and optimized MOF designs for clinical translation.
{"title":"Multidimensional Applications and Challenges of Metal–Organic Frameworks (MOFs) in Biomedicine: From Drug Safety Evaluation to Drug Delivery","authors":"Zhe Liu, Yuanye Gao, Wenyuan Shao, Xuhui Guo, Danqing Zhao, Rui Yang, Siwei Li","doi":"10.1002/jbm.a.37952","DOIUrl":"https://doi.org/10.1002/jbm.a.37952","url":null,"abstract":"<div>\u0000 \u0000 <p>Metal–organic frameworks (MOFs) are porous materials composed of metal ions or clusters and organic ligands connected through coordination bonds, exhibiting high specific surface areas, tunable pore structures, and excellent chemical stability. These unique features have enabled MOFs to be widely applied in catalysis, gas separation, and environmental purification. In recent years, the potential of MOFs in the biomedicine field has garnered significant attention. MOFs offer efficient drug loading and controlled release capabilities, particularly for targeted therapies in oncology and other diseases. Furthermore, their structural versatility positions them as promising candidates for antitumor and antibacterial treatments. However, challenges related to biocompatibility, in vivo degradation, and potential toxicity need further investigation. This review explores the latest advancements in MOF applications in biomedicine, focusing on drug delivery, targeted therapy, and modification strategies, as well as toxicity assessment and mechanisms. Finally, future research directions are proposed, including the development of intelligent drug delivery systems, multimodal diagnostic platforms, and optimized MOF designs for clinical translation.</p>\u0000 </div>","PeriodicalId":15142,"journal":{"name":"Journal of biomedical materials research. Part A","volume":"113 7","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144492953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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