Integration Of Biomaterials Research Articles

Evaluation of M2-like macrophage enrichment after diffuse traumatic brain injury through transient interleukin-4 expression from engineered mesenchymal stromal cells

BackgroundAppropriately modulating inflammation after traumatic brain injury (TBI) may prevent disabilities for the millions of those inflicted annually. In TBI, cellular mediators of inflammation, including macrophages and microglia, possess a range of phenotypes relevant for an immunomodulatory therapeutic approach. It is thought that early phenotypic modulation of these cells will have a cascading healing effect. In fact, an anti-inflammatory, “M2-like” macrophage phenotype after TBI has been associated with neurogenesis, axonal regeneration, and improved white matter integrity (WMI). There already exist clinical trials seeking an M2-like bias through mesenchymal stem/stromal cells (MSCs). However, MSCs do not endogenously synthesize key signals that induce robust M2-like phenotypes such as interleukin-4 (IL-4).MethodsTo enrich M2-like macrophages in a clinically relevant manner, we augmented MSCs with synthetic IL-4 mRNA to transiently express IL-4. These IL-4 expressing MSCs (IL-4 MSCs) were characterized for expression and functionality and then delivered in a modified mouse TBI model of closed head injury. Groups were assessed for functional deficits and MR imaging. Brain tissue was analyzed through flow cytometry, multi-plex ELISA, qPCR, histology, and RNA sequencing.ResultsWe observed that IL-4 MSCs indeed induce a robust M2-like macrophage phenotype and promote anti-inflammatory gene expression after TBI. However, here we demonstrate that acute enrichment of M2-like macrophages did not translate to improved functional or histological outcomes, or improvements in WMI on MR imaging. To further understand whether dysfunctional pathways underlie the lack of therapeutic effect, we report transcriptomic analysis of injured and treated brains. Through this, we discovered that inflammation persists despite acute enrichment of M2-like macrophages in the brain.ConclusionThe results demonstrate that MSCs can be engineered to induce a stronger M2-like macrophage response in vivo. However, they also suggest that acute enrichment of only M2-like macrophages after diffuse TBI cannot orchestrate neurogenesis, axonal regeneration, or improve WMI. Here, we also discuss our modified TBI model and methods to assess severity, behavioral studies, and propose that IL-4 expressing MSCs may also have relevance in other cavitary diseases or in improving biomaterial integration into tissues.

Neutrophils in Biomaterial-Guided Tissue Regeneration: Matrix Reprogramming for Angiogenesis.

Biomaterial-guided in situ tissue regeneration uses biomaterials to stimulate and guide the body's endogenous, regenerative processes to drive functional tissue repair and regeneration. To be successful, cell migration into the biomaterials is essential, which requires angiogenesis to maintain cell viability. Neutrophils, the first cells responding to an implanted biomaterial, are now known to play an integral part in angiogenesis in multiple tissues and exhibit considerable potential for driving angiogenesis in the context of tissue regeneration. In terms of biomaterial-guided in situ tissue regeneration, harnessing the proangiogenic potential of the neutrophil through its robust secretion of matrix metalloproteinase 9 (MMP-9) may provide a mechanism to improve biomaterial performance by initiating matrix reprogramming. This review will discuss neutrophils as matrix reprogrammers and what is currently known about their ability to create a microenvironment that is more conducive for angiogenesis and tissue regeneration through the secretion of MMP-9. It will first review a set of ground-breaking studies in tumor biology and then present an overview of what is currently known about neutrophils and MMP-9 in biomaterial vascularization. Finally, it will conclude with potential strategies and considerations to engage neutrophils in biomaterial-guided angiogenesis and in situ tissue regeneration. Impact statement This review draws attention to a highly neglected topic in tissue engineering, the role of neutrophils in biomaterial-guided tissue regeneration and angiogenesis. Moreover, it highlights their abundant secretion of matrix metalloproteinase 9 (MMP-9) for matrix reprogramming, a topic with great potential yet to be vetted in the literature. It presents strategies and considerations for designing the next generation of immunomodulatory biomaterials. While there is literature discussing the overall role of neutrophils in angiogenesis, there are a limited number of review articles focused on this highly relevant topic in the context of biomaterial integration and tissue regeneration, making this a necessary and impactful article.

Hydrogel-Based Bioinks for 3D Bioprinting in Tissue Regeneration

Three-dimensional (3D) printing of biomaterials provides an interesting alternative for the production of allograft tissues and organs to circumvent the incidences of donor scarcity and organ shortages. With the current deficit of readily available and viable organs for transplantation, the medical sector is faced with an increasing demand for organs and the shortfall in supply. Over the past decades, tissue engineering and regenerative medicine continue to provide alternative strategies for artificial tissues and organs. Current research shows that employing hydrogels as a cell-laden bioinks for the fabrication of 3D tissue constructs enables a lack of immunogenicity, since the hydrogel-based bioink is patient-specific and derived from biopolymers that demonstrate excellent biocompatibility and biodegradability, decreased organ rejection, increased organ viability and enhanced the supply in accordance to the demand. While sufficient evidence directs researchers to conclude the safe and efficacious process of seeding cells, biomolecules and biomaterials using 3D bioprinting, there are multiple limitations, which requires significant attention, such as cost, volumetric bioprinting, integrity and strength of biomaterials as well as multi-cellular and multi-material bioprinting. In this review, the focus is on the applications of hydrogels as bioinks employed in 3D bioprinting, and where applicable, considerations of note and challenges encountered. This review proposes to highlight the progress forged in this area, but also the limitations of hydrogel-based bioink investigations to date and the need for further multidisciplinary investigation and progression to the stage of clinical testing of human-scale tissue constructs.

Advanced Strategies for Modulation of the Material–Macrophage Interface

AbstractBiomaterials are becoming increasingly crucial for healthcare solutions, with extensive use in the field of tissue engineering and drug delivery. After implantation, biomaterials trigger an immune response characterized by the recruitment of bone‐marrow‐derived proinflammatory macrophages that develop as the most abundant cell type surrounding the biomaterial. Chronic activation of this recruited macrophage population induces a foreign body reaction response and consequent biomaterial rejection. However, transition toward a proreparative phenotype is associated with biomaterial integration and tissue homeostasis restoration. In this review, the most relevant strategies that modulate biomaterial immune response are discussed, including mechanical properties, surface coatings, release of anti‐inflammatory molecules and cytokines, antibacterial features, origin and inner moieties of biomaterials, and cell crosstalk. Moreover, the role of tissue resident macrophages, an embryo‐derived macrophage population with a strong reparative potential, in promoting biomaterial tolerance will be reviewed. This provides new insights to better tune the reaction of the host immune system to implanted biomaterials in order to favor integration and increase the knowledge of macrophages as key players in tissue homeostasis.

Functionalization of PTFE Materials Using a Combination of Polydopamine and Platelet-Rich Fibrin

BackgroundThe diaphragm, which forms a physical barrier between the thoracic and the abdominal cavities, is also the major part of the respiratory system. Congenital diaphragmatic hernia (CDH) is a malformation of that partition muscle. Expanded polytetrafluoroethylene (e-PTFE), a synthetic nondegradable biomaterial, is currently used for the repair of diaphragm defects. Indeed, this hydrophobic biomaterial does not promote rapid and dense cell colonization. Surface modifications are needed to favor or even guide cellular responses. Materials and methodsIn this context, we present here a practical and effective way of functionalization of the e-PTFE material. We investigated, by using electron microscopy, the coating with PRF (Platelet-Rich Fibrin) of PDA (Polydopamine) treated e-PTFE implant material. ResultsWe demonstrate that this straightforward chemical functionalization with PDA increases the hydrophilicity of e-PTFE and thus improves tissue integration. Then, we demonstrated that whatever the contact time between PRF and e-PTFE and the centrifugation speed, the PDA coating on the e-PTFE biomaterial promotes further biological events like cell adhesion and spreading. ConclusionsOur findings clearly show that this composite coating (chemically by using PDA + biologically by using PRF) method of e-PTFE is a simple, interesting and promising way to favor tissular integration of such biomaterials.

Microchannels Are an Architectural Cue That Promotes Integration and Vascularization of Silk Biomaterials in Vivo.

Functional integration of implanted biomaterials and bioengineered tissues in vivo requires effective and timely vascular ingrowth. While many vascularization strategies rely on delivery of angiogenic growth factors or endothelial cells to promote vascular ingrowth, the effect of physical and architectural features of biomaterials on the vascularization process is less well understood. Microchannels are a simple, accessible architectural feature frequently engineered into 3D biomaterials to promote mass transfer. In this study, the effect of microchannels on the integration and vascularization of 3D porous silk scaffolds was explored over a 14 week period. An array of 508 μm diameter microchannels spanning the length of critically sized, porous silk scaffolds significantly improved tissue ingrowth into the constructs. At week 6, all silk scaffolds (n = 8) with microchannels showed complete tissue infiltration throughout the construct, while only one of eight (12.5%) did so in the absence of microchannels. The presence of microchannels improved silk scaffold vascularization with significantly more vessels per unit area in the presence of microchannels. The vessel size distribution was similar in both scaffold types, but a shift in distribution toward smaller vessels was observed in the presence of microchannels. The blood vessels in silk scaffolds were perfused, functional and connected to the animal's cardiovascular system, as demonstrated by the presence of red blood cells in the vessel lumens, and effective delivery of a contrast agent the vessels inside the scaffold. This study demonstrates the utility of microchannels as a simple architectural feature that significantly improves vascularization and integration of implanted biomaterials.

RGD-functionalized supported lipid bilayers modulate pre-osteoblast adherence and promote osteogenic differentiation.

Biomaterial integration into bone requires optimal surface conditions to promote osteoprogenitor behavior, which is affected by integrin-binding via arginine-glycine-aspartate (RGD). RGD-functionalized supported lipid bilayers (SLBs) might be interesting as biomaterial coating in bone regeneration, because they allow integration of proteins, for example, growth factors, cytokines, and/or antibacterial agents. Since it is unknown whether and how they affect osteoprogenitor adhesion and differentiation, the aim was to investigate adhesion, focal adhesion formation, morphology, proliferation, and osteogenic potential of pre-osteoblasts cultured on RGD-functionalized SLBs compared to unfunctionalized SLBs and poly-l-lysine (PLL). After 17 hr, pre-osteoblast density on SLBs without or with RGD was similar, but lower than on PLL. Cell surface area, elongation, and number and size of phospho-paxillin clusters were also similar. Cells on SLBs without or with RGD were smaller, more elongated, and had less and smaller phospho-paxillin clusters than on PLL. OPN expression was increased on SLBs with RGD compared to PLL. Moreover, after 1 week, COL1a1 expression was increased on SLBs without or with RGD. In conclusion, pre-osteoblast adhesion and enhanced differentiation were realized for the first time on RGD-functionalized SLBs, pointing to a new horizon in the management of bone regeneration using biomaterials. Together with SLBs nonfouling nature and the possibility of adjusting SLB fluidity and peptide content make SLBs highly promising as substrate to develop innovative biomimetic coatings for biomaterials in bone regeneration.

Hydrophilic titanium surfaces reduce neutrophil inflammatory response and NETosis.

Biomaterial implantation triggers an immune response initially predominated by neutrophils, which activate an inflammatory cascade by producing cytokines, enzymes, immune cell recruitment chemokines, and DNA fiber networks called neutrophil extracellular traps (NETs). While the role of neutrophils has been studied extensively in infection, little is known of their role in the response to biomaterials, in this case titanium (Ti) implants. Furthermore, while implant surface modifications have been shown to attenuate pro-inflammatory polarization in other immune cells, their effects on neutrophil behavior is unknown. The aim of this study was to characterize the neutrophil response to Ti surface topography and hydrophilicity and understand how the products of biomaterial-induced neutrophil activation alters macrophage polarization. Murine neutrophils were isolated by density gradient centrifugation and plated on smooth, rough, and rough hydrophilic (rough-hydro) Ti surfaces. Neutrophils on rough-hydro Ti decreased pro-inflammatory cytokine and enzyme production as well as decreased NET formation compared to neutrophils on smooth and rough Ti. Conditioned media (CM) from neutrophils on smooth Ti enhanced pro-inflammatory macrophage polarization compared to CM from neutrophils on rough or rough-hydro Ti; pretreatment of neutrophils with a pharmacological NETosis inhibitor impaired this macrophage stimulation. Finally, co-culture of neutrophils and macrophages on Ti surfaces induced pro-inflammatory macrophage polarization compared to macrophages alone on surfaces, but this effect was ablated when neutrophils were pretreated with the NETosis inhibitor. These findings demonstrate that neutrophils are sensitive to changes in biomaterial surface properties and exhibit differential activation in response to Ti surface cues. Additionally, inhibition of NETosis enhanced anti-inflammatory macrophage polarization, suggesting NETosis as a possible therapeutic target for enhancing implant integration.

Immune responses towards bioengineered tissues and strategies to control them.

Research into development of artificial tissues and bioengineered organs to replace physiological functions of injured counterparts has highlighted a previously underestimated challenge for its clinical translatability: the immune response against biomaterials. Herein, we will provide an update and review current knowledge regarding this important barrier to regenerative medicine. Although a clear understanding of the immune reactivity against biomaterials remains elusive, accumulating evidence indicates that innate immune cells, primarily neutrophils and macrophages, play a key role in the initial phases of the immune response. More recently, data have shown that in later phases, T and B cells are also involved. The use of physicochemical modifications of biomaterials and cell-based strategies to modulate the host inflammatory response is being actively investigated for effective biomaterial integration. The immune response towards biomaterials and bioengineered organs plays a crucial role in determining their utility as transplantable grafts. Expanding our understanding of these responses is necessary for developing protolerogenic strategies and delivering on the ultimate promise of regenerative medicine.

Deferoxamine: An Angiogenic and Antioxidant Molecule for Tissue Regeneration.

Deferoxamine (DFO) has been in use for half a century as a Food and Drug Administration-approved iron chelator, but recent studies indicate a variety of properties that could expand this drug's application into the fields of tissue and regenerative engineering. DFO has been implicated as an angiogenic agent in studies on ischemia, wound healing, and bone regeneration because of its ability to upregulate hypoxia-inducible factor-1 alpha (HIF-1α) and other key downstream angiogenic factors. DFO has also demonstrated antioxidant capabilities unrelated to its iron-chelating properties, making it a potential modulator of the oxidative stress involved in the inflammation response. Together, these properties make DFO a potential bioactive molecule to promote wound healing and enhance tissue integration of biomaterials in vivo. Impact Statement Deferoxamine (DFO) is approved by the Food and Drug Administration as an iron chelator and is been used to treat iron overload. Recent studies indicate that DFO may have important applications in the growing field of tissue regeneration because of its unique properties of downregulating inflammation while promoting vascularization, thereby enhancing wound healing in vivo.

Form-finding mechanism derived from plant movement in response to environmental conditions for building envelopes

The paper provides a mechanism of an eco-friendly building envelope that adapts itself to environmental conditions and its design principles. In particular, the proposed envelope helps to reduce energy consumption in buildings due to the use of bio-inspired materials. Although several bio-inspired design approaches in architecture are currently available, the implementation of these principles in real life projects is still a challenge. A major challenge is a difference between their structural systems and their functional scales that creates several problems in the application of the main concept. A few research studies have been carried out in the response of plants to environmental stimuli and changes by botanical scientists. However, the application of the principles behind these changes into the field of engineering especially architecture is yet to be investigated and developed despite the existence of a few examples. Furthermore, the development of materials, fabrication and construction technology in conjunction with the advancement of computer and parametric design technology have made it possible to employ the underlying principles and mechanisms in real buildings. The paper considers issues associated with plants responsive to environmental stimulus, integration of bio-materials into building design, and structural analogies related to the most recent bio-inspired building. The paper is divided into two main parts. In the first part, an introduction to the design concept of building envelopes, and its strategies are presented. A design methodology is also provided. This is followed by the presentation of the fundamental concepts of bio-inspired building envelopes. In the second part, an innovative method for façade design is proposed based on the obtained information. As an outcome, a movement mechanism that is derived from a plant called Ice plant seed capsules is used in the design of a building façade. Then a dynamic strategy is proposed to obtain the form of these bio-inspired design concepts. This dynamic strategy is under the effect of two functions; hydro-actuated texture and deformability based on bending-active capability. In general, the presented envelope is created by arranging a basic module in a regular network of a building facade that reacts to changing dry/wet conditions.

Bioprinting of a Cell-Laden Conductive Hydrogel Composite.

Bioprinting has gained significant attention for creating biomimetic tissue constructs with potential to be used in biomedical applications such as drug screening or regenerative medicine. Ideally, biomaterials used for three-dimensional (3D) bioprinting should match the mechanical, hydrostatic, bioelectric, and physicochemical properties of the native tissues. However, many materials with these tissue-like properties are not compatible with printing techniques without modifying their compositions. In addition, integration of cell-laden biomaterials with bioprinting methodologies that preserve their physicochemical properties remains a challenge. In this work, a biocompatible conductive hydrogel composed of gelatin methacryloyl (GelMA) and poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) was synthesized and bioprinted to form complex, 3D cell-laden structures. The biofabricated conductive hydrogels were formed by an initial cross-linking step of the PEDOT:PSS with bivalent calcium ions and a secondary photopolymerization step with visible light to cross-link the GelMA component. These modifications enabled tuning the mechanical properties of the hydrogels, with Young's moduli ranging from ∼40-150 kPa, as well as tunable conductivity by varying the concentration of PEDOT:PSS. In addition, the hydrogels degraded in vivo with no substantial inflammatory responses as demonstrated by haematoxylin and eosin (H&E) and immunofluorescent staining of subcutaneously implanted samples in Wistar rats. The parameters for forming a slurry of microgel particles to support 3D bioprinting of the engineered cell-laden hydrogel were optimized to form constructs with improved resolution. High cytocompatibility and cell spreading were demonstrated in both wet-spinning and 3D bioprinting of cell-laden hydrogels with the new conductive hydrogel-based bioink and printing methodology. The synergy of an advanced fabrication method and conductive hydrogel presented here is promising for engineering complex conductive and cell-laden structures.

Interaction of a tripeptide with titania surfaces: RGD adsorption on rutile TiO2(110) and model dental implant surfaces.

The adsorption of peptides on metal oxides is an area of significant interest, both fundamentally and in a number of technologically important areas. These range from the integration of biomaterials in the body, to denaturation of protein therapeutics and the use of biomolecules and bioinspired materials in synthesis and stabilization of novel nanomaterials. Here we present a study of the tripeptide arginylglycylaspartic acid (RGD) on the surfaces of vacuum-prepared single crystalline TiO2(110), pyrocatechol-capped TiO2(110), and model SLA and SLActive dental implant samples. X-ray Photoelectron Spectroscopy and Scanning Tunneling Microscopy show that the RGD adsorption mode on the single crystal is consistent with bonding through the deprotonated carboxylate groups of the peptide to surface Ti atoms of the substrate. Despite the increased hydrophobicity of the pyrocatechol-capped TiO2(110) surface RGD adsorption from solution increases following this surface treatment. RGD adsorption on SLA and SLActive surfaces shows that the SLActive surface has a greater uptake of RGD. The RGD uptake on the pyrocatechol capped single crystal and the model implant surfaces suggest that the ease with which surface contaminant hydrocarbons are removed from the surface has a greater influence on peptide adsorption than hydrophobicity/hydrophilicity of the surface.

Contribution of nascent cohesive fiber-fiber interactions to the non-linear elasticity of fibrin networks under tensile load

Fibrin is a viscoelastic proteinaceous polymer that determines the deformability and integrity of blood clots and fibrin-based biomaterials in response to biomechanical forces. Here, a previously unnoticed structural mechanism of fibrin clots' mechanical response to external tensile loads is tested using high-resolution confocal microscopy and recently developed three-dimensional computational model. This mechanism, underlying local strain-stiffening of individual fibers as well as global stiffening of the entire network, is based on previously neglected nascent cohesive pairwise interactions between individual fibers (crisscrossing) in fibrin networks formed under tensile load. Existence of fiber-fiber crisscrossings of reoriented fibers was confirmed using 3D imaging of experimentally obtained stretched fibrin clots. The computational model enabled us to study structural details and quantify mechanical effects of the fiber-fiber cohesive crisscrossing during stretching of fibrin gels at various spatial scales. The contribution of the fiber-fiber cohesive contacts to the elasticity of stretched fibrin networks was characterized by changes in individual fiber stiffness, the length, width, and alignment of fibers, as well as connectivity and density of the entire network. The results show that the nascent cohesive crisscrossing of fibers in stretched fibrin networks comprise an underappreciated important structural mechanism underlying the mechanical response of fibrin to (patho)physiological stresses that determine the course and outcomes of thrombotic and hemostatic disorders, such as heart attack and ischemic stroke. Statement of SignificanceFibrin is a viscoelastic proteinaceous polymer that determines the deformability and integrity of blood clots and fibrin-based biomaterials in response to biomechanical forces. In this paper, a novel structural mechanism of fibrin clots’ mechanical response to external tensile loads is tested using high-resolution confocal microscopy and newly developed computational model. This mechanism, underlying local strain-stiffening of individual fibers as well as global stiffening of the entire network, is based on previously neglected nascent cohesive pairwise interactions between individual fibers (crisscrossing) in fibrin networks formed under tensile load. Cohesive crisscrossing is an important structural mechanism that influences the mechanical response of blood clots and which can determine the outcomes of blood coagulation disorders, such as heart attacks and strokes.

Bone extracts immunomodulate and enhance the regenerative performance of dicalcium phosphates bioceramics

Immunomodulation strategies are believed to improve the integration and clinical performance of synthetic bone substitutes. One potential approach is the modification of biomaterial surface chemistry to mimic bone extracellular matrix (ECM). In this sense, we hypothesized that coating synthetic dicalcium phosphate (DCP) bioceramics with bone ECM proteins would modulate the host immune reactions and improve their regenerative performance. To test this, we evaluated the in vitro proteomic surface interactions and the in vivo performance of ECM-coated bioceramic scaffolds. Our results demonstrated that coating DCP scaffolds with bone extracts, specifically those containing calcium-binding proteins, dramatically modulated their interaction with plasma proteins in vitro, especially those relating to the innate immune response. In vivo, we observed an attenuated inflammatory response against the bioceramic scaffolds and enhanced peri-scaffold new bone formation supported by the increased osteoblastogenesis and reduced osteoclastogenesis. Furthermore, the bone extract rich in calcium-binding proteins can be 3D-printed to produce customized hydrogels with improved regeneration capabilities. In summary, bone extracts containing calcium-binding proteins can enhance the integration of synthetic biomaterials and improve their ability to regenerate bone probably by modulating the host immune reaction. This finding helps understand how bone allografts regenerate bone and opens the door for new advances in tissue engineering and bone regeneration. Statement of SignificanceForeign-body reaction is an important determinant of in vivo biomaterial integration, as an undesired host immune response can compromise the performance of an implanted biomaterial. For this reason, applying immunomodulation strategies to enhance biomaterial engraftment is of great interest in the field of regenerative medicine. In this article, we illustrated that coating dicalcium phosphate bioceramic scaffolds with bone-ECM extracts, especially those rich in calcium-binding proteins, is a promising approach to improve their surface proteomic interactions and modulate the immune responses towards such biomaterials in a way that improves their bone regeneration performance. Collectively, the results of this study may provide a conceivable explanation for the mechanisms involved in presenting the excellent regenerative efficacy of natural bone grafts.

Additive Manufacturing of Biomaterials − The Evolution of Rapid Prototyping

Biomaterials rapid prototyping (RP), recently known as additive manufacturing (AM), has appeared as a revolutionary technology, promising to transform research into medical therapeutics. RP is a layer by layer manufacturing process which directly translates computer data such as Computer Aided Design (CAD), Computer Tomography (CT), and Magnetic Resonance Imaging (MRI) into three‐dimensional (3D) objects. RP technologies play a significant role in biomedical industry such as anatomical models for surgery training/planning, rehabilitation, dentistry, customized implants, drug delivery devices, tissue engineering, and organ printing. The integration of biomaterials and rapid prototyping technologies is an exciting route in developing biomaterial implants for the past decade. This review describes and classifies the RP systems into three categories of liquid‐based, solid‐based, and powder‐based according to the initial form of their feed materials. Then, discusses possible benefits, drawbacks, and applications of each process in the field of biomaterials science and engineering.

Macrophage behavior and interplay with gingival fibroblasts cultured on six commercially available titanium, zirconium, and titanium-zirconium dental implants.

The host-material interface has been a crucial relationship dictating the successful integration of biomaterials, including dental implants. The aim of the present study was to first investigate how macrophages behaved on various dental implant surfaces and thereafter to investigate their effect on soft tissue cells. Macrophage adhesion, proliferation, and polarization towards either an M1 or M2 phenotype were investigated on six implant surfaces fabricated from pure titanium (Ti), pure zirconium (ZLA), and a titanium-zirconium (Ti-Zi) alloy of various surface topographies/chemistries. Thereafter, conditioned media (CM) collected from macrophages seeded on these various implant surfaces was cultured with murine gingival fibroblasts and investigated for their ability to promote collagen synthesis. Macrophages attached and proliferated in similar levels on all implant surfaces; however, the modSLA hydrophilic surfaces tended to decrease the pro-inflammatory response by lowering the gene expression of TNF-alpha, IL-1, and IL-6 and promoting tissue resolution through the expression of an M2-macrophage cytokine IL-10. Thereafter, CM from macrophages were seeded with gingival fibroblasts on each implant surface. In general, CM from macrophages significantly promoted gingival fibroblast cell attachment on all implant surfaces at either 4 or 8h and, most notably, significantly promoted fibronectin and TGF-beta gene expression on both Ti and Ti-Zi hydrophilic surfaces. The present study found that implant surface topography and chemistry substantially impacted macrophage behavior. Most notably, modifications via hydrophilicity to both the pure Ti and Ti-Zi were shown to favor the secretion of macrophage pro-resolution markers and favored subsequent gingival fibroblast cell behavior when cultured with CM, whereas surface composition (Ti vs ZLA vs Ti-Zi) had little effect on macrophage polarization or gingival fibroblast behavior. This finding suggests that surface hydrophilicity would improve the soft tissue integration of dental implants, irrespective of material composition.

Vitronectin promotes the vascularization of porous polyethylene biomaterials

Rapid implant vascularization is a prerequisite for successful biomaterial engraftment. Vitronectin (VN) is a matricellular glycoprotein well known for its capability to interact with growth factors, proteases, and protease inhibitors/receptors. Since such proteins are highly relevant for angiogenic processes, we hypothesized that VN contributes to the tissue integration of biomaterials. Employing different in vivo and ex vivo microscopy techniques, engraftment of porous polyethylene (PPE) implants was analyzed in the dorsal skinfold chamber model in wild-type (WT) and VN−/− mice. Upon PPE implantation, vascularization of this biomaterial was severely compromised in animals lacking this matricellular protein. Proteome profiling revealed that VN deficiency does not cause major changes in angiogenic protein composition in the implants suggesting that VN promotes PPE vascularization via mechanisms modulating the activity of angiogenic factors rather than by directly enriching them in the implant. Consequently, surface coating with recombinant VN (embedded in Matrigel®) accelerated implant vascularization in WT mice by enhancing the maturation of a vascular network. Thus, VN contributes to the engraftment of PPE implants by promoting the vascularization of this biomaterial. Surface coating with VN might provide a promising strategy to improve the vascularization of PPE implants without affecting the host’s integrity. Statement of SignificancePorous polyethylene (PPE) is a biomaterial frequently used in reconstructive surgery. The proper vascularization of PPE implants is a fundamental prerequisite for its successful engraftment in host tissue. Although the overall biocompatibility of PPE is good, there are less favorable application sites for its use in tissue reconstruction mostly characterized by low blood supply. Employing advanced in vivo microscopy methods and proteomic analyses in genetically engineered mice, we here describe a previously unrecognized function of vitronectin (VN) that enables this abundantly present glycoprotein to particularly promote the vascularization of PPE biomaterial. These properties of VN specifically facilitate the formation of a dense vessel network within the implant which relies on modulating the activity of angiogenic mediators rather than on the enrichment of these factors in the implant. Consequently, surface coating with this matricellular protein effectively accelerated and intensified implant vascularization which might be beneficial for its implementation at unfavorable sites for implantation without affecting the host’s integrity.

Design Principles and Multifunctionality in Cell Encapsulation Systems for Tissue Regeneration.

Cell encapsulation systems are being increasingly applied as multifunctional strategies to regenerate tissues. Lessons afforded with encapsulation systems aiming to treat endocrine diseases seem to be highly valuable for the tissue engineering and regenerative medicine (TERM) systems of today, in which tissue regeneration and biomaterial integration are key components. Innumerous multifunctional systems for cell compartmentalization are being proposed to meet the specific needs required in the TERM field. Herein is reviewed the variable geometries proposed to produce cell encapsulation strategies toward tissue regeneration, including spherical and fiber-shaped systems, and other complex shapes and arrangements that better mimic the highly hierarchical organization of native tissues. The application of such principles in the TERM field brings new possibilities for the development of highly complex systems, which holds tremendous promise for tissue regeneration. The complex systems aim to recreate adequate environmental signals found in native tissue (in particular during the regenerative process) to control the cellular outcome, and conferring multifunctional properties, namely the incorporation of bioactive molecules and the ability to create smart and adaptative systems in response to different stimuli. The new multifunctional properties of such systems that are being employed to fulfill the requirements of the TERM field are also discussed.

Integration of Biomaterials into Sensors Based on Organic Thin-Film Transistors.

Sensors based on organic thin-film transistors (OTFTs) present various advantages, including high sensitivity and mechanical flexibility, thus possessing potential applications such as wearable devices and biomedical electronics for health monitoring, etc. However, such applications are partially limited by the biocompatibility, biodegradability, and sensitivity to target analytes of OTFT-based sensors, which can be improved by the incorporation of diverse biomaterials. This article presents a brief review from the viewpoint of the type of the integrated biomaterials, including naturally occurring biomacromolecules such as proteins, enzymes, and deoxyribonucleic acid, as well as biocompatible polymers such as polylactide, poly(lactide-co-glycolide), poly(ethylene glycol), cellulose, polydimethylsiloxane, parylene, etc. It is believed that future work in this field should be devoted to the selectivity, sensitivity, and stability improvement as well as the high-level integration and sophistication on the basis of the OTFT-based sensors for physical, chemical, and biological sensing applications.