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Over eight million surgical procedures are conducted annually in the United Stats to address organ failure or tissue losses. In response to this pressing need, recent medical advancements have significantly improved patient outcomes, primarily through innovative reconstructive surgeries utilizing tissue grafting techniques. Despite tremendous efforts, repairing damaged tissues remains a major clinical challenge for bioengineers and clinicians. 3D bioprinting is an additive manufacturing technique that holds significant promise for creating intricately detailed constructs of tissues, thereby bridging the gap between engineered and actual tissue constructs. In contrast to non-biological printing, 3D bioprinting introduces added intricacies, including considerations for material selection, cell types, growth, and differentiation factors. However, technical challenges arise, particularly concerning the delicate nature of living cells in bioink for tissue construction and limited knowledge about the cell fate processes in such a complex biomechanical environment. A bioink must have appropriate viscoelastic and rheological properties to mimic the native tissue microenvironment and attain desired biomechanical properties. Hence, the properties of bioink play a vital role in the success of 3D bioprinted substitutes. This review comprehensively delves into the scientific aspects of tissue-centric or tissue-specific bioinks and sheds light on the current challenges of the translation of bioinks and bioprinting.

Musculoskeletal disorders are on the rise, and despite advances in alternative materials, treatment for orthopedic conditions still heavily relies on biometal-based implants and scaffolds due to their strength, durability, and biocompatibility in load-bearing applications. Bare metallic implants have been under scrutiny since their introduction, primarily due to their bioinert nature, which results in poor cell-material interaction. This challenge is further intensified by mechanical mismatches that accelerate failure, tribocorrosion-induced material degradation, and bacterial colonization, all contributing to long-term implant failure and posing a significant burden on patient populations. Recent efforts to improve orthopedic medical devices focus on surface engineering strategies that enhance the interaction between cells and materials, creating a biomimetic microenvironment and extending the service life of these implants. This review compiles various physical, chemical, and biological surface engineering approaches currently under research, providing insights into their potential and the challenges associated with their adoption from bench to bedside. Significant emphasis is placed on exploring the future of bioactive coatings, particularly the development of smart coatings like self-healing and drug-eluting coatings, the immunomodulatory effects of functional coatings and biomimetic surfaces to tackle secondary infections, representing the forefront of biomedical surface engineering. The article provides the reader with an overview of the engineering approaches to surface modification of metallic implants, covering both clinical and research perspectives and discussing limitations and future scope.

Scaffolds for bone tissue engineering require considerable mechanical strength to repair damaged bone defects. In this study, we designed and developed mechanically competent composite shape memory triphasic bone scaffolds using fused filament fabrication (FFF) three dimensional (3D) printing. Wollastonite particles (WP) were incorporated into the poly lactic acid (PLA)/polycaprolactone (PCL) matrix as a reinforcing agent (up to 40 wt%) to harness osteoconductive and load-bearing properties from the 3D printed scaffolds. PCL as a minor phase (20 wt%) was added to enhance the toughening effect and induce the shape memory effect in the triphasic composite scaffolds. The 3D-printed composite scaffolds were studied for morphological, thermal, and mechanical properties, in vitro degradation, biocompatibility, and shape memory behaviour. The composite scaffold had interconnected pores of 550 μm, porosity of more than 50%, and appreciable compressive strength (∼50 MPa), which was over 90% greater than that of the pristine PLA scaffolds. The flexural strength was improved by 140% for 40 wt% of WP loading. The inclusion of WP did not affect the thermal property of the scaffolds; however, the inclusion of PCL reduced the thermal stability. An accelerated in vitro degradation was observed for WP incorporated composite scaffolds compared to pristine PLA scaffolds. The inclusion of WP improved the hydrophilic property of the scaffolds, and the result was significant for 40 wt% WP incorporated composite scaffolds having a water contact angle of 49.61°. The triphasic scaffold exhibited excellent shape recovery properties with a shape recovery ratio of ∼84%. These scaffolds were studied for their protein adsorption, cell proliferation, and bone mineralization potential. The incorporation of WP reduced the protein adsorption capacity of the composite scaffolds. The scaffold did not leach any toxic substance and demonstrated good cell viability, indicating its biocompatibility and growth-promoting behavior. The osteogenic potential of the WP incorporated scaffolds was observed in MC3T3-E1 cells, revealing early mineralization in pre-osteoblast cells cultured in different WP incorporated composite scaffolds. These results suggest that 3D-printed WP reinforced PLA/PCL composite bioactive scaffolds are promising for load bearing bone defect repair.

Ti6Al4V superalloy is recognized as a good candidate for bone implants owing to its biocompatibility, corrosion resistance, and high strength-to-weight ratio. While dense metal implants are associated with stress shielding issues due to the difference in densities, stiffness, and modulus of elasticity compared to bone tissues, the surface of the implant/scaffold should mimic the properties of the bone of interest to assure a good integration with a strong interface. In this study, we investigated the additive manufacturing of porous Ti6Al4V scaffolds and coating modification for enhanced osteoconduction using osteoblast cells. The results showed the successful fabrication of porous Ti6Al4V scaffolds with adequate strength. Additionally, the surface treatment with NaOH and Dopamine Hydrochloride (DOPA) promoted the formation of Dopamine Hydrochloride (DOPA) coating with an optimized coating process, providing an environment that supports higher cell viability and growth compared to the uncoated Ti6Al4V scaffolds, as demonstrated by the higher proliferation ratios observed from day 1 to day 29. These findings bring valuable insights into the surface modification of 3D-printed scaffolds for improved osteoconduction through the coating process in solutions.

An increasing number of novel biomaterials have been applied in wound healing therapy. Creating beneficial environments and containing various bioactive molecules, hydrogel- and extracellular vesicle (EV)-based therapies have respectively emerged as effective approaches for wound healing. Moreover, the synergistic combination of these two components demonstrates more favorable outcomes in both chronic and acute wound healing. This review provides a comprehensive discussion and summary of the combined application of EVs and hydrogels to address the intricate scenario of wounds. The wound healing process and related biological mechanisms are outlined in the first section. Subsequently, the utilization of EV-loaded hydrogels during the wound healing process is evaluated and discussed. The moist environment created by hydrogels is conducive to wound tissue regeneration. Additionally, the continuous and controlled release of EVs from various origins could be achieved by hydrogel encapsulation. Finally, recent in vitro and in vivo studies reported on hydrogel dressings loaded with EVs are summarized and challenges and opportunities for the future clinical application of this therapeutic approach are outlined.

The development of sensitive and specific exosome detection tools is essential because they are believed to provide specific information that is important for early detection, screening, diagnosis, and monitoring of cancer. Among the many detection tools, surface-plasmon resonance (SPR) biosensors are analytical devices that offer advantages in sensitivity and detection speed, thereby making the sample-analysis process faster and more accurate. In addition, the penetration depth of the SPR biosensor, which is <300 nm, is comparable to the size of the exosome, making the SPR biosensor ideal for use in exosome research. On the other hand, another type of nanoplasmonic sensor, namely a localized surface-plasmon resonance (LSPR) biosensor, has a shorter penetration depth of around 6 nm. Structural optimization through the addition of supporting layers and gap control between particles is needed to strengthen the surface-plasmon field. This paper summarizes the progress of the development of SPR and LSPR biosensors for detecting exosomes. Techniques in signal amplification from two sensors will be discussed. There are three main parts to this paper. The first two parts will focus on reviewing the working principles of each sensor and introducing several methods that can be used to isolate exosomes. This article will close by explaining the various sensor systems that have been developed and the optimizations carried out to obtain sensors with better performance. To illustrate the performance improvements in each sensor system discussed, the parameters highlighted include the detection limit, dynamic range, and sensitivity.

Exosomes are small extracellular vesicles secreted by cells, ranging in size from 30 to 150 nm. They contain proteins, nucleic acids, lipids, and other bioactive molecules, which play a crucial role in intercellular communication and material transfer. In tumor immunity, exosomes present various functions while the following two are of great importance: regulating the immune response and serving as delivery carriers. This review starts with the introduction of the formation, compositions, functions, isolation, characterization, and applications of exosomes, and subsequently discusses the current status of exosomes in tumor immunotherapy, and the recent applications of exosome-based tumor immunity regulation and antitumor drug delivery. Finally, current challenge and future prospects are proposed and hope to demonstrate inspiration for targeted readers in the field., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Qiu, Liang, Yang, Xie, Wang, Wang, Zhang, Nanda, Zhou, Huang, Peng, Lu, Chen and Zhou.)

Scaffold is one of the key components for tissue engineering application. Three-dimensional (3D) printing has given a new avenue to the scaffolds design to closely mimic the real tissue. However, material selection has always been a challenge in adopting 3D printing for scaffolds fabrication, especially for hard tissue. The fused filament fabrication technique is one of the economical 3D printing technology available today, which can efficiently fabricate scaffolds with its key features. In the present study, a hybrid polymer-ceramic scaffold has been prepared by combining the benefit of synthetic biodegradable poly (lactic acid) (PLA) and osteoconductive calcium sulphate (CaS), to harness the advantage of both materials. Composite PLA filament with maximum ceramic loading of 40 wt% was investigated for its printability and subsequently scaffolds were 3D printed. The composite filament was extruded at a temperature of 160 °C at a constant speed with an average diameter of 1.66 ± 0.34 mm. PLA-CaS scaffold with ceramic content of 10%, 20%, and 40% was 3D printed with square pore geometry. The developed scaffolds were characterized for their thermal stability, mechanical, morphological, and geometrical accuracy. The mechanical strength was improved by 29% at 20 wt% of CaS. The porosity was found to be 50-60% with an average pore size of 550 µm with well-interconnected pores. The effect of CaS particles on the degradation behaviour of scaffolds was also assessed over an incubation period of 28 days. The CaS particles acted as porogen and improved the surface chemistry for future cellular activity, while accelerating the degradation rate.

Engineered human tissues created by three-dimensional cell culture of human cells in a hydrogel are becoming emerging model systems for cancer drug discovery and regenerative medicine. Complex functional engineered tissues can also assist in the regeneration, repair, or replacement of human tissues. However, one of the main hurdles for tissue engineering, three-dimensional cell culture, and regenerative medicine is the capability of delivering nutrients and oxygen to cells through the vasculatures. Several studies have investigated different strategies to create a functional vascular system in engineered tissues and organ-on-a-chips. Engineered vasculatures have been used for the studies of angiogenesis, vasculogenesis, as well as drug and cell transports across the endothelium. Moreover, vascular engineering allows the creation of large functional vascular conduits for regenerative medicine purposes. However, there are still many challenges in the creation of vascularized tissue constructs and their biological applications. This review will summarize the latest efforts to create vasculatures and vascularized tissues for cancer research and regenerative medicine.

Musculoskeletal injuries including bone defects continue to present a significant challenge in orthopedic surgery due to suboptimal healing. Bone reconstruction strategies focused on the use of biological grafts and bone graft substitutes in the form of biomaterials-based 3D structures in fracture repair. Recent advances in biomaterials science and engineering have resulted in the creation of intricate 3D bone-mimicking structures that are mechanically stable, biodegradable, and bioactive to support bone regeneration. Current efforts are focused on improving the biomaterial and implant physicochemical properties to promote interactions with the host tissue and osteogenesis. The "smart" biomaterials and their 3D structures are designed to actively interact with stem/progenitor cells and the extracellular matrix (ECM) to influence the local environment towards osteogenesis and de novo tissue formation. This article will summarize such smart biomaterials and the methodologies to apply either internal or external stimuli to control the tissue healing microenvironment. A particular emphasis is also made on the use of smart biomaterials and strategies to create functional bioactive implants for bone defect repair and regeneration., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Conventionally biometals were used for design and development of bioimplants. However, the Young's Modulus (YM) of these bioimplants is higher than that of a natural bone. Asymmetric load transfer from a bone to the bioimplant results in aseptic loosening and stress shielding. Here-in, the use of functionally graded materials (FGM) has been introduced to design the femoral stem prosthesis as a model bioimplant using computational biomechanics. The material properties variations in these FGMs in longitudinal and radial directions are explored to minimize the aseptic loosening and stress-shielding that plays a vital role in defining the performance and longevity of the prosthesis. Three groups of FGM (Ti-HA, SS316L-HA and CoCr alloy-HA) have been explored to design the stem prosthesis and the finite element analysis (FEA) was carried out using computational biomechanics. The stress distribution profile in the designed stem prosthesis demonstrated an increase in the stress values with an increase in the volume fraction exponent. The results corroborated with the stress distribution obtained from the simulation results of a cortico-cancellous bone. The stress distribution in the Ti-HA prosthesis is observed to be more uniform than CoCr-HA and SS316L-HA prosthesis. In addition, the reduced number of stress shielding points were observed for the Ti-HA prosthesis when compared with the CoCr-HA and SS 316 L-HA stem prostheses. Hence, the results suggested that the Ti-HA prosthesis could be considered as a mechanically stable prosthesis and the same could offer safe design for further development of a femoral bioimplant.

There are more than 2 million bone grafting procedures performed annually in the US alone. Despite significant efforts, the repair of large segmental bone defects is a substantial clinical challenge which requires bone substitute materials or a bone graft. The available biomaterials lack the adequate mechanical strength to withstand the static and dynamic loads while maintaining sufficient porosity to facilitate cell in-growth and vascularization during bone tissue regeneration. A wide range of advanced biomaterials are being currently designed to mimic the physical as well as the chemical composition of a bone by forming polymer blends, polymer-ceramic and polymer-degradable metal composites. Transforming these novel biomaterials into porous and load-bearing structures via three-dimensional printing (3DP) has emerged as a popular manufacturing technique to develop engineered bone grafts. 3DP has been adopted as a versatile tool to design and develop bone grafts that satisfy porosity and mechanical requirements while having the ability to form grafts of varied shapes and sizes to meet the physiological requirements. In addition to providing surfaces for cell attachment and eventual bone formation, these bone grafts also have to provide physical support during the repair process. Hence, the mechanical competence of the 3D-printed scaffold plays a key role in the success of the implant. In this review, we present various recent strategies that have been utilized to design and develop robust biomaterials that can be deployed for 3D-printing bone substitutes. The article also reviews some of the practical, theoretical and biological considerations adopted in the 3D-structure design and development for bone tissue engineering.

The need for a wound dressing material that can accelerate wound healing is increasing and will last for a long time. In this study, cerium oxide nanoparticle (CeNP) incorporated poly-L-lactic acid (PLLA)-gelatin composite fiber membranes were fabricated using established electrospinning techniques for use as a low-cost sustainable wound dressing material. The obtained membranes were characterized for their morphology, and physical, mechanical and biological properties. The results showed that the membranes maintained an integrated morphology, and demonstrated water absorption and improved mechanical propert i es. An in vitro cell proliferation test confirmed that the cells presented better activities over the composite fiber membranes. In the rat scalding model, rapid wound recombination was observed. All these data suggested that electrospun CeNP incorporated PLLA-gelatin composite fiber membranes can be an ideal dressing substitute that can be used for wound healing applications. Furthermore, the use of biodegradable polymers and environmentally sustainable production technologies presented better sustainability for the commercial production of these composite membranes promoting tissue regeneration and scar remodeling.

The development of prosthetic bioimplants for fracture fixation using curved bone plates has been used as an established procedure for treatment in orthopedic. Here-in, we propose a novel curved bone plate fixation strategy to fix the designed biocompatible plates in different fracture models. Various biocompatible metallic biomaterials such as Ti-alloy (Ti-6Al-4V), stainless steel (SS 316L), and Co-alloy (Co-Cr) were created in SOLID works and used for the design of the bone plates. The typical fracture models (transverse and oblique) were created over a standard femur bone (models created using Materialize MIMIC/MAGIC) and two bone plates of similar materials were fixed side-by-side over the fractured femur using the screws made from Ti-6Al-4V. The finite element analysis (FEA) was carried out to evaluate the interface deformation, stress, and strain generated at the bone-bioimplant interface. The results from FEA demonstrated that the interface deformation and stress for a bone-bioimplant assembly are significantly reduced when natural anisotropic condition (functionally graded materials properties) of the human femur was well considered. Based on the analysis, Ti-6AL-4V and SS 316L were found as the best fit metallic biomaterials for the design and development of bone plate prosthetic bioimplants for fixation of an oblique fracture and transverse fracture respectively.

Exosomes are cell-secreted nanoparticles (generally with a size of 30-150 nm) bearing numerous biological molecules including nucleic acids, proteins and lipids, which are thought to play important roles in intercellular communication. As carriers, exosomes hold promise as advanced platforms for targeted drug/gene delivery, owing to their unique properties, such as innate stability, low immunogenicity and excellent tissue/cell penetration capacity. However, their practical applications can be limited due to insufficient targeting ability or low efficacy in some cases. In order to overcome these existing challenges, various approaches have been applied to engineer cell-derived exosomes for a higher selectivity and effectiveness. This review presents the state-of-the-art designs and applications of advanced exosome-based systems for targeted cargo delivery. By discussing experts' opinions, we hope this review will inspire the researchers in this field to develop more practical exosomal delivery systems for clinical applications., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Chen, Wang, Zeng, Schwarz, Nanda, Peng and Zhou.)

Driven by the clinical need for a strong tissue adhesive with elastomeric material properties, a departure from legacy crosslinking chemistries was sought as a multipurpose platform for tissue mending. A fresh approach to bonding wet substrates has yielded a synthetic biomaterial that overcomes the drawbacks of free-radical and nature-inspired bioadhesives. A food-grade liquid polycaprolactone grafted with carbene precursors yields CaproGlu. The first-of-its-kind low-viscosity prepolymer is VOC-free and requires no photoinitiators. Grafted diazirine end-groups form carbene diradicals upon low energy UVA (365 nm) activation that immediately crosslink tissue surfaces; no pre-heating or animal-derived components are required. The hydrophobic polymeric environment enables metastable functional groups not possible in formulations requiring solvents or water. Activated diazirine within CaproGlu is uniquely capable of crosslinking all amino acids, even on wet tissue substrates. CaproGlu undergoes rapid liquid-to-biorubber transition within seconds of UVA exposure-features not found in any other bioadhesive. The exceptional shelf stability of CaproGlu allows gamma sterilization with no change in material properties. CaproGlu wet adhesiveness is challenged against current unmet clinical needs: anastomosis of spliced blood vessels, anesthetic muscle patches, and human platelet-mediating coatings. The versatility of CaproGlu enables both organic and inorganic composites for future bioadhesive platforms., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Closure of wounds with tissue adhesives has many advantages over sutures, but existing synthetic adhesives are toxic and have poor workability. Blood-derived adhesives display complete resorption but have adhesion too weak for reliable wound dressings. We propose a semi-synthetic design that combines the positive attributes of synthetic and blood-derived tissue adhesives. PAMAM-g-diazirine (PDz) is a rapidly gelling bioadhesive miscible in both aqueous and organic solvents. PDz blended with platelet-rich plasma (PRP) forms PDz/PRP composite, a semi-synthetic formulation that combines PDz's wet tissue adhesion with PRP's potent wound healing properties. Light-activated PDz/PRP bioadhesive composite has similar elasticity to soft tissues and behaves as an induced hemostat-an unmet clinical need for rapid wound dressings. PDz/PRP composite applied to in-vivo full-thickness wounds observed a 25% reduction in inflammation, as assessed by the host-cell response., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: TWJS has a patent pending concerning aspects of the carbene bioadhesive technology., (Copyright © 2020. Published by Elsevier Ltd.)

Functionalized cerium oxide nanoparticle (CeNP)-loaded fibro-porous poly-l-lactic acid (PLLA)/gelatin composite membranes were prepared via an electrospinning technology. Considering the importance of such membrane scaffolds for promoting angiogenesis in tissue engineering and drug screening, a series of PLLA/gelatin composite fiber membranes loaded with different doses of CeNPs was prepared. The prepared composite membranes demonstrated hydrophilicity, water absorption, and improved mechanical properties compared to a PLLA and PLLA/gelatin membrane. Also, cell viability assay using somatic hybrid endothelial cells (EA.hy926) proved the biocompatible nature of the scaffolds. The biocompatibility was further supported by in vivo chick embryo angiogenesis assay using fertilized eggs. Our initial results support that these membrane scaffolds could be useful for angiogenesis-related disease treatment after further investigations.

The worldwide, extraordinary outbreak of coronavirus pandemic (i.e., COVID-19) and other emerging viral expansions have drawn particular interest to the design and development of novel antiviral, and viricidal, agents, with a broad-spectrum of antiviral activity. The current indispensable challenge lies in the development of universal virus repudiation systems that are reusable, and capable of inactivating pathogens, thus reducing risk of infection and transmission. In this review, science-based methods, mechanisms, and procedures, which are implemented in obtaining resultant antiviral coated substrates, used in the destruction of the strains of the different viruses, are reviewed. The constituent antiviral members are classified into a few broad groups, such as polymeric materials, metal ions/metal oxides, and functional nanomaterials, based on the type of materials used at the virus contamination sites. The action mode against enveloped viruses was depicted to vindicate the antiviral mechanism. We also disclose hypothesized strategies for development of a universal and reusable virus deactivation system against the emerging COVID-19. In the surge of the current, alarming scenario of SARS-CoV-2 infections, there is a great necessity for developing highly-innovative antiviral agents to work against the viruses. We hypothesize that some of the antiviral coatings discussed here could exert an inhibitive effect on COVID-19, indicated by the results that the coatings succeeded in obtaining against other enveloped viruses. Consequently, the coatings need to be tested and authenticated, to fabricate a wide range of coated antiviral products such as masks, gowns, surgical drapes, textiles, high-touch surfaces, and other personal protective equipment, aimed at extrication from the COVID-19 pandemic.

Surgical adhesives are an attractive alternative to traditional mechanical tissue fixation methods of sutures and staples. Ease of application, biocompatibility, enhanced functionality (drug delivery) are known advantages but weak adhesion strength in the wet environment and lack of tissue compliant behavior still pose a challenge. In order to address these issues, non-aqueous bioadhesive based on blends of polyamidoamine (PAMAM) dendrimer, conjugated with 4-[3-(trifluoromethyl)-3H-diazirin-3-yl] benzyl bromide (PAMAM-g-diazirine) and liquid polyethylene glycol (PEG 400) has been developed. PEG 400 biocompatible solvent reduces the viscosity of PAMAM-g-diazirine dendrimer without incorporating aqueous solvents or plasticizers, allowing application by syringe or spray. Upon UV activation, diazirine-generated reactive intermediates lead to intermolecular dendrimer crosslinking. The properties of the crosslinked matrix are tissue compliant, with anisotropic material properties dependent on the PEG 400 wt%, UV dose, pressure and uncured adhesive thickness. The hygroscopic PAMAM-g-diazirine/PEG 400 blend was hypothesized to absorb water at the tissue interface, leading to high interfacial adhesion, however porous matrices led to cohesive failure. The hydrophilic nature of the polyether backbone (PEG 400) shielded cationic PAMAM dendrimers with cured bioadhesive film displaying significantly less platelet activation than neat PAMAM-g-diazirine or PLGA thin films., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Soft tissue fixation of implant and bioelectrodes relies on mechanical means (e.g., sutures, staples, and screws), with associated complications of tissue perforation, scarring, and interfacial stress concentrations. Adhesive bioelectrodes address these shortcomings with voltage cured carbene-based bioadhesives, locally energized through graphene interdigitated electrodes. Electrorheometry and adhesion structure activity relationships are explored with respect to voltage and electrolyte on bioelectrodes synthesized from graphene 3D-printed onto resorbable polyester substrates. Adhesive leachates effects on in vitro metabolism and human-derived platelet-rich plasma response serves to qualitatively assess biological response. The voltage activated bioadhesives are found to have gelation times of 60 s or less with maximum shear storage modulus (G') of 3 kPa. Shear modulus mimics reported values for human soft tissues (0.1-10 kPa). The maximum adhesion strength achieved for the ≈50 mg bioelectrode films is 170 g cm -2 (17 kPa), which exceeds the force required for tethering of electrodes on dynamic soft tissues. The method provides the groundwork for implantable bio/electrodes that may be permanently incorporated into soft tissues, vis-à-vis graphene backscattering wireless electronics since all components are bioresorbable., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Bioadhesives are a current unmet clinical need for mending of blood contacting soft tissues without inducing thrombosis. Recent development of carbene precursor bioadhesives with the advantages of on-demand curing, tuneable modulus, and wet adhesion have been synthesized by grafting diazirine onto poly (amidoamine) (PAMAM-G5) dendrimers. Herein, the structure activity relationships of platelet adhesion and activation is evaluated for the first time on the cured PAMAM-g-diazirine bioadhesives. Three strategies were employed to prevent healthy human donor platelets from adhering and activating on light-cured bioadhesive surfaces: (1) Attenuation of cationic surface charge, (2) antifouling composites by incorporating heparin and alginate in uncured formulation, and (3) heparin wash of cured bioadhesive surface. Topographical imaging of cured and ethanol dehydrated bioadhesive surfaces was used to quantify the adhered and activated platelets with scanning electron microscopy, whose resolution allowed identification of round senescent, short dendritic, and long dendritic platelets. Cured surfaces of PAMAM-g-diazirine (15%) had 10300 ± 500 adhered platelets mm -2 with 99.7% activation into short/long dendritic cells. Reduction of primary amines by higher degree of diazirine grafting or capping of free amines by acetylation reduces platelet adherence (2400 ± 200 vs 3000 ± 300, respectively). Physical incorporation of heparin and alginate in the formulations reduced the activated platelet; 1300 ± 300 and 300 ± 50, activated platelets mm -2 , in comparison with additive free adhesive formulation. Similarly, heparin rinse of the surface of additive free bioadhesive reduced the activated platelet to platelets of heparin composites at 600 ± 100 platelets mm -2 . PAMAM-g-diazirine (15%) bioadhesive retained the photocured mechanical properties and lap shear adhesion despite the addition of heparin and alginate additives.

The growth of new blood vessels from the pre-existing vasculature known as angiogenesis has a vital role in various physiological and pathological processes. In the present study, we demonstrate the pro-angiogenic properties of functional nanoconjugates of organosilane functionalized cerium oxide (CeO 2 ) nanoparticles (nanoceria). Aqueous dispersible CeO 2 and trivalent metal (samarium) ion-doped CeO 2 (SmCeO 2 ) nanoparticles conjugated with hydrophilic biocompatible and antifouling (6-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-hexyl)triethoxysilane moieties were prepared. These functional nanoconjugates were prepared via an in situ synthesis and functionalization procedure using an ammonia-induced ethylene glycol-assisted precipitation method. The prepared nanoconjugates were thoroughly characterized using various physico-chemical techniques such as transmission electron microscopy (TEM), X-ray diffraction (XRD) analysis, dynamic light scattering (DLS), Fourier-transform infrared (FTIR) spectroscopy, 13 C high-resolution solid-state nuclear magnetic resonance (NMR) spectroscopy, and X-ray photoelectron spectroscopy (XPS). The pro-angiogenic properties of the prepared nanoconjugates were evaluated by employing various angiogenesis assays (in vitro and in vivo). The results of the present study illustrate that the functional nanoconjugates of SmCeO 2 triggered endothelial cell proliferation and induced the growth of blood vessels in a chick embryo. The enhanced expression of pro-angiogenic markers (p38 MAPK/HIF-1α) by these functional nanoconjugates might be a plausible signaling mechanism underlying their pro-angiogenic properties. Considering all the observations, we believe that (6-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-hexyl)triethoxysilane conjugated SmCeO 2 nanoparticles could be developed as potential candidates for the treatment of cardiovascular, ischemic and ocular diseases where angiogenesis is the principal phenomenon.

The biocompatible surface modification of metal oxide nanoparticles via surface functionalization technique has been used as an important tool in nanotechnology and medicine. In this report, we have prepared aqueous dispersible, trivalent metal ion (samarium)-doped cerium oxide nanoparticles (SmCNPs) as model redox altered CNPs of biological relevance. SmCNP surface modified with hydrophilic biocompatible (6-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-hexyl) triethoxysilane (MEEETES) were prepared using ammonia-induced ethylene glycol-assisted precipitation method and were characterized using a variety of complementary characterization techniques. The chemical interaction of functional moieties with the surface of doped nanoparticle was studied using powerful 13 C cross polarization magic angle sample spinning nuclear magnetic resonance spectroscopy. The results demonstrated the production of the extremely small size MEEETES surface modified doped nanoparticles with significant reduction in aggregation compared to their unmodified state. Moreover, the functional moieties had strong chemical interaction with the surface of the doped nanoparticles. The biocompatible surface modification using MEEETES should also be extended to several other transition metal ion doped and co-doped CNPs for the production of aqueous dispersible redox altered CNPs that are promising for nanobiology and medicine.

Directed stem cell differentiation over three-dimensional porous scaffolds capable of releasing bioactive instructive cues is an important tool in tissue engineering. In this research, we have prepared dexamethasone (Dex)-releasing collagen microbead-functionalized poly(L-Lactide)-collagen hybrid scaffolds as an osteoinductive platform for human bone marrow-derived mesenchymal stem cells (MSCs). The scaffolds were prepared by a combined method of emulsion freeze-drying and porogen-leaching using pre-prepared ice collagen particulates as a porogen material. Dex release from the hybrid scaffolds was studied at 37 °C under shaking condition and the impact of released Dex towards osteogenic lineage differentiation was investigated by 3 week in vitro culture of MSCs. The results showed that hybrid scaffolds had controlled pore structure and interconnected pores deposited with collagen fibers. The hybrid scaffold facilitated cell seeding and the spatial localization of Dex/collagen microbeads facilitated a microgel-assisted spatio-temporal control of Dex release. The released Dex was useful for osteogenic differentiation of MSCs, which was confirmed from the elevated expression of osteogenic-specific gene-encoded proteins. The hybrid scaffolds should be useful for regeneration of a functional bone tissue.

Controlled and local release of growth factors and nutrients from porous scaffolds is important for maintenance of cell survival, proliferation, and promotion of tissue regeneration. The purpose of the present research was to design a controlled release porous collagen-microbead hybrid scaffold with controlled pore structure capable of releasing insulin for application to cartilage tissue regeneration. Collagen-microbead hybrid scaffold was prepared by hybridization of insulin loaded PLGA microbeads with collagen using a freeze-drying technique. The pore structure of the hybrid scaffold was controlled by using preprepared ice particulates having a diameter range of 150-250 μ m. Hybrid scaffold had a controlled pore structure with pore size equivalent to ice particulates and good interconnection. The microbeads showed an even spatial distribution throughout the pore walls. In vitro insulin release profile from the hybrid scaffold exhibited a zero order release kinetics up to a period of 4 weeks without initial burst release. Culture of bovine articular chondrocytes in the hybrid scaffold demonstrated high bioactivity of the released insulin. The hybrid scaffold facilitated cell seeding and spatial cell distribution and promoted cell proliferation.