Hemocompatibility and Preangiogenic Attributes of SiBxCyNzOm Coatings for Biomedical Applications.

In current clinical practices related to orthopedics, dental, and cardiovascular surgeries, a number of biomaterial coatings, such as hydroxyapatite (HAp), diamond-like carbon (DLC), have been used in combination with metallic substrates (stainless steel, Ti6Al4V alloy, etc.). Although SiBCN coatings are widely explored in material science for diverse applications, their potential remains largely unexplored for biomedical applications. With this motivation, the present work reports the development of SiBxCyNzOm coatings on a Ti6Al4V substrate, employing a reactive radiofrequency (RF) magnetron sputtering technique. Three different coating compositions (Si0.27B0.10C0.31N0.07O0.24, Si0.23B0.06C0.21N0.22O0.27, and Si0.20B0.05C0.19N0.20O0.35) were obtained using a Si2BC2N target and varying nitrogen flow rates. The hydrophilic properties of the as-synthesized coatings were rationalized in terms of an increase in the number of oxygen-containing functional groups (OH and NO) on the surface, as probed using XPS and FTIR analyses. Furthermore, the cellular monoculture of SVEC4-10 endothelial cells and L929 fibroblasts established good cytocompatibility. More importantly, the coculture system of SVEC4-10 and L929, in the absence of growth factors, demonstrated clear cellular phenotypical changes, with extensive sprouting leading to tube-like morphologies on the coating surfaces, when stimulated using a customized cell stimulator (StimuCell) with 1.15 V/cm direct current (DC) electric field strength for 1 h. In addition, the hemocompatibility assessment using human blood samples revealed clinically acceptable hemolysis, less erythrocyte adhesion, shorter plasma recalcification, and reduced risk for thrombosis on the SiBxCyNzOm coatings, when compared to uncoated Ti6Al4V. Taken together, the present study unambiguously establishes excellent cytocompatibility, hemocompatibility, and defines the preangiogenic properties of SiBxCyNzOm bioceramic coatings for potential biomedical applications.

Low-Concentration Gelatin Methacryloyl Hydrogel with Tunable 3D Extrusion Printability and Cytocompatibility: Exploring Quantitative Process Science and Biophysical Properties.

Three-dimensional (3D) bioprinting of hydrogels with a wide spectrum of compositions has been widely investigated. Despite such efforts, a comprehensive understanding of the correlation among the process science, buildability, and biophysical properties of the hydrogels for a targeted clinical application has not been developed in the scientific community. In particular, the quantitative analysis across the entire developmental path for 3D extrusion bioprinting of such scaffolds is not widely reported. In the present work, we addressed this gap by using widely investigated biomaterials, such as gelatin methacryloyl (GelMA), as a model system. Using extensive experiments and quantitative analysis, we analyzed how the individual components of methacrylated carboxymethyl cellulose (mCMC), needle-shaped nanohydroxyapatite (nHAp), and poly(ethylene glycol)diacrylate (PEGDA) with GelMA as baseline matrix of the multifunctional bioink can influence the biophysical properties, printability, and cellular functionality. The complex interplay among the biomaterial ink formulations, viscoelastic properties, and printability toward the large structure buildability (structurally stable cube scaffolds with 15 mm edge) has been explored. Intriguingly, the incorporation of PEGDA into the GelMA/mCMC matrix offered improved compressive modulus (∼40-fold), reduced swelling ratio (∼2-fold), and degradation rates (∼30-fold) compared to pristine GelMA. The correlation among microstructural pore architecture, biophysical properties, and cytocompatibility is also established for the biomaterial inks. These photopolymerizable bio(material)inks served as the platform for the growth and development of bone and cartilage matrix when human mesenchymal stem cells (hMSCs) are either seeded on two-dimensional (2D) substrates or encapsulated on 3D scaffolds. Taken together, this present study unequivocally establishes a significant step forward in the development of a broad spectrum of shape-fidelity compliant bioink for the 3D bioprinting of multifunctional scaffolds and emphasizes the need for invoking more quantitative analysis in establishing process-microstructure-property correlation.

Implementing Machine Learning approaches for accelerated prediction of bone strain in acetabulum of a hip joint.

The Finite Element (FE) methods for biomechanical analysis involving implant design and subject parameters for musculoskeletal applications are extensively reported in literature. Such an approach is manually intensive and computationally expensive with longer simulations times. Although Artificial Intelligence (AI) based approaches are implemented to a limited extent in biomechanics, such approaches to predict bone strain in acetabulum of a hip joint, are hardly explored. In this context, the primary objective of this paper is to evaluate machine learning (ML) models in tandem with high-fidelity FEA data for the accelerated prediction of the biomechanical response in the acetabulum of the human hip joint, during the walking gait. The parameters used in the FEA study included the subject weight, number and distribution of fins on the periphery of the acetabular shell, bone condition and phases of the gait cycle. The biomechanical response has also been evaluated using three different acetabular liners, including pre-clinically validated HDPE-20% HA-20% Al2O3, highly-crosslinked ultrahigh molecular weight polyethylene (HC-UHMWPE) and ZrO2-toughened Al2O3 (ZTA). Such parametric variation in FEA analysis, involving 26 variables and a full factorial design resulted in 10,752 datasets for spatially varying bone strains. The bone condition, as opposed to subject weight, was found to play a statistically significant role in determining the strain response in the periprosthetic bone of the acetabulum. While utilising hyperparameter tuning, K-fold cross validation and statistical learning approaches, a number of ML models were trained on the FEA dataset, and the Random Forest model performed the best with a coefficient of determination (R2) value of 0.99/0.97 and Root Mean Square Error (RMSE) of 0.02/0.01 on the training/test dataset. Taken together, this study establishes the potential of ML approach as a fast surrogate of FEA for implant biomechanics analysis, in less than a minute.

Gelatin Methacryloyl (GelMA)-Based Biomaterial Inks: Process Science for 3D/4D Printing and Current Status.

Tissue engineering for injured tissue replacement and regeneration has been a subject of investigation over the last 30 years, and there has been considerable interest in using additive manufacturing to achieve these goals. Despite such efforts, many key questions remain unanswered, particularly in the area of biomaterial selection for these applications as well as quantitative understanding of the process science. The strategic utilization of biological macromolecules provides a versatile approach to meet diverse requirements in 3D printing, such as printability, buildability, and biocompatibility. These molecules play a pivotal role in both physical and chemical cross-linking processes throughout the biofabrication, contributing significantly to the overall success of the 3D printing process. Among the several bioprintable materials, gelatin methacryloyl (GelMA) has been widely utilized for diverse tissue engineering applications, with some degree of success. In this context, this review will discuss the key bioengineering approaches to identify the gelation and cross-linking strategies that are appropriate to control the rheology, printability, and buildability of biomaterial inks. This review will focus on the GelMA as the structural (scaffold) biomaterial for different tissues and as a potential carrier vehicle for the transport of living cells as well as their maintenance and viability in the physiological system. Recognizing the importance of printability toward shape fidelity and biophysical properties, a major focus in this review has been to discuss the qualitative and quantitative impact of the key factors, including microrheological, viscoelastic, gelation, shear thinning properties of biomaterial inks, and printing parameters, in particular, reference to 3D extrusion printing of GelMA-based biomaterial inks. Specifically, we emphasize the different possibilities to regulate mechanical, swelling, biodegradation, and cellular functionalities of GelMA-based bio(material) inks, by hybridization techniques, including different synthetic and natural biopolymers, inorganic nanofillers, and microcarriers. At the close, the potential possibility of the integration of experimental data sets and artificial intelligence/machine learning approaches is emphasized to predict the printability, shape fidelity, or biophysical properties of GelMA bio(material) inks for clinically relevant tissues.

Comprehensive functional outcome analysis and importance of bone remodelling on personalized cranioplasty treatment using Poly(methyl methacrylate) bone flaps.

Cranioplasty involves the surgical reconstruction of cranial defects arising as a result of various factors, including decompressive craniectomy, cranial malformations, and brain injury due to road traffic accidents. Most of the modern decompressive craniectomies (DC) warrant a future cranioplasty surgery within 6-36 months. The conventional process of capturing the defect impression and polymethyl methacrylate (PMMA) flap fabrication results in a misfit or misalignment at the site of implantation. Equally, the intra-operative graft preparation is arduous and can result in a longer surgical time, which may compromise the functional and aesthetic outcomes. As part of a multicentric pilot clinical study, we recently conducted a cohort study on ten human subjects during 2019-2022, following the human ethics committee approvals from the participating institutes. In the current study, an important aspect of measuring the extent of bone remodelling during the time gap between decompressive craniectomy and cranioplasty was successfully evaluated. The sterilised PMMA bone flaps were implanted at the defect area during the cranioplasty surgery using titanium mini plates and screws. The mean surgery time was 90 ± 20 min, comparable to the other clinical studies on cranioplasty. No signs of intra-operative and post-operative complications, such as cerebrospinal fluid leakage, hematoma, or local and systemic infection, were clinically recorded. Importantly, aesthetic outcomes were excellent for all the patients, except in a few clinical cases, wherein the PMMA bone flap was to be carefully customized due to the remodelling of the native skull bone. The extent of physiological remodelling was evaluated by superimposing the pre-operative and post-operative CT scan data after converting the defect morphology into a 3D model. This study further establishes the safety and efficacy of a technologically better approach to fabricate patient-specific acrylic bone flaps with improved surgical outcomes. More importantly, the study outcome further demonstrates the strategy to address bone remodelling during the patient-specific implant design.

Advancing Peripheral Nerve Regeneration: 3D Bioprinting of GelMA-Based Cell-Laden Electroactive Bioinks for Nerve Conduits.

Peripheral nerve injuries often result in substantial impairment of the neurostimulatory organs. While the autograft is still largely used as the "gold standard" clinical treatment option, nerve guidance conduits (NGCs) are currently considered a promising approach for promoting peripheral nerve regeneration. While several attempts have been made to construct NGCs using various biomaterial combinations, a comprehensive exploration of the process science associated with three-dimensional (3D) extrusion printing of NGCs with clinically relevant sizes (length: 20 mm; diameter: 2-8 mm), while focusing on tunable buildability using electroactive biomaterial inks, remains unexplored. In addressing this gap, we present here the results of the viscoelastic properties of a range of a multifunctional gelatin methacrylate (GelMA)/poly(ethylene glycol) diacrylate (PEGDA)/carbon nanofiber (CNF)/gellan gum (GG) hydrogel bioink formulations and printability assessment using experiments and quantitative models. Our results clearly established the positive impact of the gellan gum on the enhancement of the rheological properties. Interestingly, the strategic incorporation of PEGDA as a secondary cross-linker led to a remarkable enhancement in the strength and modulus by 3 and 8-fold, respectively. Moreover, conductive CNF addition resulted in a 4-fold improvement in measured electrical conductivity. The use of four-component electroactive biomaterial ink allowed us to obtain high neural cell viability in 3D bioprinted constructs. While the conventionally cast scaffolds can support the differentiation of neuro-2a cells, the most important result has been the excellent cell viability of neural cells in 3D encapsulated structures. Taken together, our findings demonstrate the potential of 3D bioprinting and multimodal biophysical cues in developing functional yet critical-sized nerve conduits for peripheral nerve tissue regeneration.

Three-Dimensional Extrusion Printed Urinary Specific Grafts: Mechanistic Insights into Buildability and Biophysical Properties.

The compositional formulations and the optimization of process parameters to fabricate hydrogel scaffolds with urological tissue-mimicking biophysical properties are not yet extensively explored, including a comprehensive assessment of a spectrum of properties, such as mechanical strength, viscoelasticity, antimicrobial property, and cytocompatibility. While addressing this aspect, the present work provides mechanistic insights into process science, to produce shape-fidelity compliant alginate-based biomaterial ink blended with gelatin and synthetic nanocellulose. The composition-dependent pseudoplasticity, viscoelasticity, thixotropy, and gel stability over a longer duration in physiological context have been rationalized in terms of intermolecular hydrogen bonding interactions among the biomaterial ink constituents. By varying the hybrid hydrogel ink composition within a narrow compositional window, the resulting hydrogel closely mimics the natural urological tissue-like properties, including tensile stretchability, compressive strength, and biophysical properties. Based on the printability assessment using a critical analysis of gel strength, we have established the buildability of the acellular hydrogel ink and have been successful in fabricating shape-fidelity compliant urological patches or hollow cylindrical grafts using 3D extrusion printing. Importantly, the new hydrogel formulations with good hydrophilicity, support fibroblast cell proliferation and inhibit the growth of Gram-negative E. coli bacteria. These attributes were rationalized in terms of nanocellulose-induced physicochemical changes on the scaffold surface. Taken together, the present study uncovers the process-science-based understanding of the 3D extrudability of the newly formulated alginate-gelatin-nanocellulose-based hydrogels with urological tissue-specific biophysical, cytocompatibility, and antibacterial properties.

3D bioprinting of multifunctional alginate dialdehyde (ADA)-gelatin (GEL) (ADA-GEL) hydrogels incorporating ferulic acid.

The present work explores the 3D extrusion printing of ferulic acid (FA)-containing alginate dialdehyde (ADA)-gelatin (GEL) scaffolds with a wide spectrum of biophysical and pharmacological properties. The tailored addition of FA (≤0.2 %) increases the crosslinking between FA and GEL in the presence of calcium chloride (CaCl2) and microbial transglutaminase, as confirmed using trinitrobenzenesulfonic acid (TNBS) assay. In agreement with an increase in crosslinking density, a higher viscosity of ADA-GEL with FA incorporation was achieved, leading to better printability. Importantly, FA release, enzymatic degradation and swelling were progressively reduced with an increase in FA loading to ADA-GEL, over 28 days. Similar positive impact on antibacterial properties with S. epidermidis strains as well as antioxidant properties were recorded. Intriguingly, FA incorporated ADA-GEL supported murine pre-osteoblast proliferation with reduced osteosarcoma cell proliferation over 7 days in culture, implicating potential anticancer property. Most importantly, FA-incorporated and cell-encapsulated ADA-GEL can be extrusion printed to shape fidelity-compliant multilayer scaffolds, which also support pre-osteoblast cells over 7 days in culture. Taken together, the present study has confirmed the significant potential of 3D bioprinting of ADA-GEL-FA ink to obtain structurally stable scaffolds with a broad spectrum of biophysical and therapeutically significant properties, for bone tissue engineering applications.

Biomechanical analysis of peri-prosthetic bone response to hybrid threaded zirconia dental implants: An in silico model.

The biomechanical response of mandibular bone determines primary stability and concomitant osseointegration of dental implants. This study explores the impact of nature of loading and bone conditions on biomechanical response of hybrid threaded single-piece zirconia dental implants. To develop such understanding, three implants (SQ_V, V_BUT, and V_V), with different combinations of threads, square (SQ), buttress (BUT), and triangular (V), have been investigated. Finite Element Analysis (FEA) was carried out to simulate implantation at the molar position of mandible of varying densities under axial (≤500 N) and oblique (118.2 N) loadings. Patient-specific bone conditions (for a wider population) were considered by scaling the density and the elastic modulus of mandible to represent, 'weak', 'healthy', and 'strong' bone conditions. FEA results revealed that SQ_V and V_BUT implants exhibited a better biomechanical response without significant variation (<0.5%) in von Mises stress, regardless of bone density and axial loadings. These implants are predicted to perform with clinically acceptable factor of safety under investigated implantation scenarios, whereas V_BUT implant showed a larger variation (∼±12%). FEA simulation with oblique loading further validated such results. The 'weak' bone conditions resulted in maximum peri-implant microstrain, whereas 'strong and healthy' bone exhibited values close to the permissible range of physiological remodeling. The maximum micromotion (∼12.3 ± 6.2 µm for 'weak' bone) at bone-implant interface suggested that implant loosening and impaired osseointegration will not occur in any of selected virtual implantation cases. Both SQ_V and V_BUT implants will be considered further in implant development, involving manufacturing and product prototype validation. Taken together, the critical analysis of FEA results indicates a significant impact of bone density and distinct combinations of external threads on the biomechanical responses, in both the implant and the surrounding bone.

Computational nodal displacement analysis of acetabulum fossa for injection molded cemented polyethylene acetabular liner.

The acetabular liner (AL) is one of the key components that determine the functionality and durability of the total hip joint replacement (THR) device. The performance of Ultra high molecular weight polyethylene (UHMWPE)-based AL depends critically on the manufacturing route and its properties, which are evaluated pre-clinically using a host of experimental and computational analyses. The conventional manufacturing of an AL involves multiple stages, including extrusion/compression molding followed by machining, which is time/cost intensive and leads to material loss. In such a scenario, injection molding is a promising alternative, yet its feasbility remains unexplored for the manufacturing of AL for THA applications. Against this backdrop, the two-fold objectives of this work are to report our recent efforts to establish the efficacy of the injection molding of new generation UHMWPE biomaterial; HU (60 wt% HDPE- 40 wt% UHMWPE blend) for manufacturing AL prototype and to present the key biomechanical response analysis of this prototype, in silico. A range of manufacturing relevant material properties, as well as customized mold design to manufacture HU-based AL with external design features, are discussed. Such guidelines are particularly relevant to mold polymeric parts with a higher thickness (>8 mm). As part of the pre-clinical validation of AL with new design features, a less explored in silico approach to assess biomechanical micro-strain in the acetabulum fossa is presented, and the results are analysed in accordance with the mechanostat theory. The outcomes revealed that for a 100 kg subject weight, average micro-strain in the remodelling region was 1132, while it was determined as 723 for a 55 kg subject weight. Such results highlight the influence of subject weight on micro-strain generation and distribution in the acetabulum fossa. The von Mises stress in AL also increased with subject weight from 17 MPa in a subject weight of 55 kg to 28 MPa in a subject weight of 100 kg. Taken together, this work demonstrates the feasibility and competence of this new generation biomaterial in terms of implant manufacturing via injection molding with a clinically desired biomechanical response.

Piezoelectric nanogenerators for self-powered wearable and implantable bioelectronic devices.

One of the recent innovations in the field of personalized healthcare is the piezoelectric nanogenerators (PENGs) for various clinical applications, including self-powered sensors, drug delivery, tissue regeneration etc. Such innovations are perceived to potentially address some of the unmet clinical needs, e.g., limited life-span of implantable biomedical devices (e.g., pacemaker) and replacement related complications. To this end, the generation of green energy from biomechanical sources for wearable and implantable bioelectronic devices gained considerable attention in the scientific community. In this perspective, this article provides a comprehensive state-of-the-art review on the recent developments in the processing, applications and associated concerns of piezoelectric materials (synthetic/biological) for personalized healthcare applications. In particular, this review briefly discusses the concepts of piezoelectric energy harvesting, piezoelectric materials (ceramics, polymers, nature-inspired), and the various applications of piezoelectric nanogenerators, such as, self-powered sensors, self-powered pacemakers, deep brain stimulators etc. Important distinction has been made in terms of the potential clinical applications of PENGs, either as wearable or implantable bioelectronic devices. While discussing the potential applications as implantable devices, the biocompatibility of the several hybrid devices using large animal models is summarized. This review closes with the futuristic vision of integrating data science approaches in developmental pipeline of PENGs as well as clinical translation of the next generation PENGs. STATEMENT OF SIGNIFICANCE: Piezoelectric nanogenerators (PENGs) hold great promise for transforming personalized healthcare through self-powered sensors, drug delivery systems, and tissue regeneration. The limited battery life of implantable devices like pacemakers presents a significant challenge, leading to complications from repititive surgeries. To address such a critical issue, researchers are focusing on generating green energy from biomechanical sources to power wearable and implantable bioelectronic devices. This comprehensive review critically examines the latest advancements in synthetic and nature-inspired piezoelectric materials for PENGs in personalized healthcare. Moreover, it discusses the potential of piezoelectric materials and data science approaches to enhance the efficiency and reliability of personalized healthcare devices for clinical applications.

Design and development of a patient-specific temporomandibular joint implant: Probing the influence of bone condition on biomechanical response.

Total temporomandibular joint (TMJ) replacement is widely recognized as an effective treatment for TMJ disorders. The long-term stability of TMJ implants depends on two important factors which are design concepts for fixation to anatomical locations in the mandible and bone conditions. Other factors include stress distribution, microstrain in the peri-implant, bone attributes like bone conditions leading to the clinical complications and failures. This study addresses these limitations by examining the influence of patient-specific design concepts and bone conditions on TMJ implant performance. Clinical evidences support the importance of implant design on healing ability. Previous studies have focused on achieving precise implant fit based on geometric considerations, however those published studies did not explore the impact of such. Against this perspective, the present study reports the extensive finite element analysis (FEA) results, while analyzing the impact of a newly designed patient-specific TMJ implant to address clinical complications associated with various bone conditions, particularly osteoporotic bone. In validating the FEA results, the performance of additively manufactured patient-specific TMJ implants was compared with designs resembling two commonly used clinically approved implant designs. By addressing the limitations of previous research and emphasizing the importance of bone conditions, the study provides valuable guidelines for the development of next-generation TMJ implants. These findings contribute to enhanced clinical outcomes and long-term success in the treatment of TMJ disorders.

Regenerative bioelectronics: A strategic roadmap for precision medicine.

In the past few decades, stem cell-based regenerative engineering has demonstrated its significant potential to repair damaged tissues and to restore their functionalities. Despite such advancement in regenerative engineering, the clinical translation remains a major challenge. In the stance of personalized treatment, the recent progress in bioelectronic medicine likewise evolved as another important research domain of larger significance for human healthcare. Over the last several years, our research group has adopted biomaterials-based regenerative engineering strategies using innovative bioelectronic stimulation protocols based on either electric or magnetic stimuli to direct cellular differentiation on engineered biomaterials with a range of elastic stiffness or functional properties (electroactivity/magnetoactivity). In this article, the role of bioelectronics in stem cell-based regenerative engineering has been critically analyzed to stimulate futuristic research in the treatment of degenerative diseases as well as to address some fundamental questions in stem cell biology. Built on the concepts from two independent biomedical research domains (regenerative engineering and bioelectronic medicine), we propose a converging research theme, 'Regenerative Bioelectronics'. Further, a series of recommendations have been put forward to address the current challenges in bridging the gap in stem cell therapy and bioelectronic medicine. Enacting the strategic blueprint of bioelectronic-based regenerative engineering can potentially deliver the unmet clinical needs for treating incurable degenerative diseases.

Osteogenesis, hemocompatibility, and foreign body response of polyvinylidene difluoride-based composite reinforced with carbonaceous filler and higher volume of piezoelectric ceramic phase.

Hybrid polymer-ceramic composites have been widely investigated for bone tissue engineering applications. The incorporation of a large amount of inorganic phase, like barium titanate (BaTiO3) with good dispersion, in a polymeric matrix using a conventional processing approach has always been challenging. Also, the comprehensive study encompassing the interactions of key components of living organisms (cell, blood, tissue) with such hybrid composites is not well explored in many published studies. Built on our earlier studies and recognizing the importance of poly(vinylidene fluoride) (PVDF) as a widely used polymer for a wide spectrum of biomedical applications, the present study reports the qualitative and quantitative analysis of the biocompatibility of PVDF composite (PVDF/30BT/3MWCNT) reinforced with large amounts of BaTiO3 (30 wt %) and tailored addition of multiwalled carbon nanotubes (MWCNT; 3 wt %). The melt mixing-extrusion-compression moulding-based processing approach resulted in an enhancement of ß-phase content, thermal stability, and wettability in the semi-crystalline PVDF composite. The enhanced hemocompatibility of PVDF/30BT/3MWCNT has been established conclusively by a series of in vitro blood-material interaction assays, including haemolysi, analysis of platelets attachment and activation, dynamic blood coagulation, and plasma recalcification time. The cytocompatibility study confirms an improved adhesion, proliferation, and migration of osteoprogenitor cells (preosteoblasts; MC3T3-E1) on PVDF/30BT/3MWCNT, in a manner better than neat PVDF, in vitro. When these cells were cultured in osteogenic differentiating media, the modulated osteogenesis, in terms of alkaline phosphatase activity, intracellular Ca2+ concentration, and calcium deposition on the PVDF/30BT/3MWCNT, was recorded. Following subcutaneous implantation of PVDF/30BT/3MWCNT in rat model, no apparent variation was recorded in the complete hemogram (blood hematology analysis) or serum biochemistry, post 30-, 60-, and 90-days surgery. Importantly, 90-days post-implantation, the fibrous capsule thickness was significantly reduced in the composites w.r.t PVDF alone, together with better blood vessel formation, indicating improved neovascularization around the composite. This study establishes the efficacy of inorganic fillers in enhancing the biocompatibility of PVDF, which could open up a wide range of biomedical applications.

Electrical field stimulated modulation of cell fate of pre-osteoblasts on PVDF/BT/MWCNT based electroactive biomaterials.

The present study reports the impact of the interplay between electroactive properties of the biomaterials and electrical stimulation (ES) toward the cell proliferation, migration and maturation of osteoprogenitors (preosteoblasts; MC3T3-E1) on the electroactive poly (vinylidene difluoride) (PVDF)-based composites. The barium titanate (BaTiO3; BT; 30 wt%) and multiwalled carbon nanotubes (MWCNT; 3 wt%) were introduced into the PVDF via melt mixing, which led to an enhancement of the dielectric permittivity, electrical conductivity, and surface roughness. We also present the design and development of an in-house customized 12-well plate-based device for providing different types (DC, square, biphasic) of ES to cells in culture in a programmable manner. In the presence of ES of 1 V cm-1 , biophysical stimulation experiments performed using 12-well plate-based device revealed that PVDF composite (PVDF/30BT/3MWCNT) can facilitate the enhanced adhesion and proliferation of the MC3T3-E1 in non-osteogenic media, with respect to non-stimulated conditions. Importantly, MC3T3-E1 cells demonstrated significantly better migration and differentiation on the PVDF/30BT/3MWCNT under ES when compared to ES-free culture conditions. Similar enhancement with respect to alkaline phosphatase activity, intracellular Ca2+ concentration, and calcium deposition in MC3T3-E1 cells was recorded, when pre-osteoblasts were grown for 21 days on electroactive substrates. All these observations supported the activation of osteo-differentiation fates, which were further promoted in the osteogenic medium. The present study demonstrates that the synergistic interactions of ES with piezoelectric PVDF-based polymer composite can potentially enhance the proliferation, migration, and osteogenesis of the pre-osteoblast cells, rendering it a promising bioengineering strategy for bone tissue engineering.

Probing the Influence of Hybrid Thread Design on Biomechanical Response of Dental Implants: Finite Element Study and Experimental Validation.

This study aimed to perform quantitative biomechanical analysis for probing the effect of varying thread shapes in an implant for improved primary stability in prosthodontics surgery. Dental implants were designed with square (SQR), buttress (BUT), and triangular (TRI) thread shapes or their combinations. Cone-beam computed tomography images of mandible molar zones in human subjects belonging to three age groups were used for virtual implantation of the designed implants, to quantify patient-specific peri-implant bone microstrain, using finite element analyses. The in silico analyses were carried out considering frictional contact to simulate immediate loading with a static masticatory force of 200 N. To validate computational biomechanics results, compression tests were performed on three-dimensional printed implants having the investigated thread architectures. Bone/implant contact areas were also quantitatively assessed. It was observed that, bone/implant contact was maximum for SQR implants followed by BUT and TRI implants. For all the cases, peak microstrain was recorded in the cervical cortical bone. The combination of different thread shapes in the middle or in the apical part (or both) was demonstrated to improve peri-implant microstrain, particularly for BUT and TRI. Considering 1500-2000 microstrain generates in the peri-implant bone during regular physiological functioning, BUT-SQR, BUT-TRI-SQR, TRI-SQR-BUT, SQR, and SQR-BUT-TRI design concepts were suitable for younger; BUT-TRI-SQR, BUT-SQR-TRI, TRI-SQR-BUT, SQR-BUT, SQR-TRI for middle-aged, and BUT-TRI-SQR, BUT-SQR-TRI, TRI-BUT-SQR, SQR, and SQR-TRI for the older group of human patients.

In silico study on probing atomistic insights into structural stability and tensile properties of Fe-doped hydroxyapatite single crystals.

Hydroxyapatite (HA, Ca10PO4(OH)2) is a widely explored material in the experimental domain of biomaterials science, because of its resemblance with natural bone minerals. Specifically, in the bioceramic community, HA doped with multivalent cations (e.g., Mg2+, Fe2+, Sr2+, etc.) has been extensively investigated in the last few decades. Experimental research largely established the critical role of dopant content on mechanical and biocompatibility properties. The plethora of experimental measurements of mechanical response on doped HA is based on compression or indentation testing of polycrystalline materials. Such measurements, and more importantly the computational predictions of mechanical properties of single crystalline (doped) HA are scarce. On that premise, the present study aims to build atomistic models of Fe2+-doped HA with varying Fe content (10, 20, 30, and 40 mol%) and to explore their uniaxial tensile response, by means of molecular dynamics (MD) simulation. In the equilibrated unit cell structures, Ca(1) sites were found to be energetically favourable for Fe2+ substitution. The local distribution of Fe2+ ions significantly affects the atomic partial charge distribution and chemical symmetry surrounding the functional groups, and such signatures are found in the MD analyzed IR spectra. The significant decrease in the intensity of the IR bands found in the Fe-doped HA together with band splitting, because of the symmetry changes in the crystal structure. Another important objective of this work is to computationally predict the mechanical response of doped HA in their single crystal format. An interesting observation is that the elastic anisotropy of undoped HA was not compromised with Fe-doping. Tensile strength (TS) is systematically reduced in doped HA with Fe2+ dopant content and a decrease in TS with temperature can be attributed to the increased thermal agitation of atoms at elevated temperatures. The physics of the tensile response was rationalized in terms of the strain dependent changes in covalent/ionic bond framework (Ca-P distance, P-O bond strain, O-P-O angular strain, O-H bond distance). Further, the dynamic changes in covalent bond network were energetically analyzed by calculating the changes in O-H and P-O bond vibrational energy. Summarizing, the current work establishes our foundational understanding of the atomistic phenomena involved in the structural stability and tensile response of Fe-doped HA single crystals.

A computational study on strontium ion modified hydroxyapatite-fibronectin interactions.

Protein adsorption is the first key step in cell-material interactions. The initial phase of such an adsorption process can only be probed using modelling approaches like molecular dynamics (MD) simulations. Despite a large number of studies on the adsorption behaviour of proteins on different biomaterials including calcium phosphates (CaP), little attention has been paid towards the quantitative assessment of the effects of various physicochemical influencers like surface modification, pH, and ionic strength. In the case of doped CaPs, surface modification through isomorphic substitution of foreign ions inside the apatite structure is of particular interest in the context of protein-HA interactions, as it is widely used to tailor the biological response of HA. Given this background, we present here the molecular-level understanding of the fibronectin (FN) adsorption mechanism and kinetics on a Sr2+-doped hydroxyapatite, HA, (001) surface at 300 K by means of all-atom molecular dynamics simulations. Electrostatic interactions involved in the adsorption of FN on HA were found to be significantly modified due to Sr2+ doping into the apatite lattice. In harmony with the published experimental observations, the Sr-doped surfaces were found to better support FN adhesion compared to pure HA, with 10 mol% Sr-doped HA exhibiting the best FN adsorption. The observed altered adsorption behaviour of FN on Sr-doped HA was correlated with the Hofmeister effect. Moreover, the non-monotonous trend of the FN-material interaction energy can be attributed to the spatial rearrangement of the functional groups (PO43-, OH-) in the apatite crystal. Sr2+ ions also influence the stability of the secondary structure of FN, as observed from the root mean square deviation (RMSD) and root mean square fluctuation (RMSF) analysis. The presence of Sr2+ enhances the flexibility of specific residues (residue nos. 20-44, 74-88) of the FN module. Rupture forces to disentangle FN from the biomaterial surface, obtained from steered molecular dynamics (SMD) simulations, were found to corroborate well with the results of equilibrium MD simulations. One particular observation is that the availability of an RGD motif (Arginine-Glycine-aspartate sequence, which interacts with cell surface receptor integrin to form a focal adhesion complex) for the interaction with cell surface receptor integrin is not significantly influenced by Sr2+ substitution.

Next-generation personalized cranioplasty treatment.

Decompressive craniectomy (DC) is a surgical procedure, that is followed by cranioplasty surgery. DC is usually performed to treat patients with traumatic brain injury, intracranial hemorrhage, cerebral infarction, brain edema, skull fractures, etc. In many published clinical case studies and systematic reviews, cranioplasty surgery is reported to restore cranial symmetry with good cosmetic outcomes and neurophysiologically relevant functional outcomes in hundreds of patients. In this review article, we present a number of key issues related to the manufacturing of patient-specific implants, clinical complications, cosmetic outcomes, and newer alternative therapies. While discussing alternative therapeutic treatments for cranioplasty, biomolecules and cellular-based approaches have been emphasized. The current clinical practices in the restoration of cranial defects involve 3D printing to produce patient-specific prefabricated cranial implants, that provide better cosmetic outcomes. Regardless of the advancements in image processing and 3D printing, the complete clinical procedure is time-consuming and requires significant costs. To reduce manual intervention and to address unmet clinical demands, it has been highlighted that automated implant fabrication by data-driven methods can accelerate the design and manufacturing of patient-specific cranial implants. The data-driven approaches, encompassing artificial intelligence (machine learning/deep learning) and E-platforms, such as publicly accessible clinical databases will lead to the development of the next generation of patient-specific cranial implants, which can provide predictable clinical outcomes. STATEMENT OF SIGNIFICANCE: Cranioplasty is performed to reconstruct cranial defects of patients who have undergone decompressive craniectomy. Cranioplasty surgery improves the aesthetic and functional outcomes of those patients. To meet the clinical demands of cranioplasty surgery, accelerated designing and manufacturing of 3D cranial implants are required. This review provides an overview of biomaterial implants and bone flap manufacturing methods for cranioplasty surgery. In addition, tissue engineering and regenerative medicine-based approaches to reduce clinical complications are also highlighted. The potential use of data-driven computer applications and data-driven artificial intelligence-based approaches are emphasized to accelerate the clinical protocols of cranioplasty treatment with less manual intervention and shorter intraoperative time.