Long-term Biocompatibility Research Articles

Mechanically robust, biocompatible, and durable PHEMA-based hydrogels enabled by the synergic effect of strong intermolecular interaction and suppressed phase separation

Poly(2-hydroxyethyl methacrylate) (PHEMA) hydrogel is highly biocompatible and stable, but its actual application in soft-tissue replacement is limited by its poor mechanical properties. This study develops a facile strategy to construct PHEMA-based hydrogels with the highest strength and toughness ever reported. The strategy relies on introducing robust coordination interactions between the carboxylate groups of copolymerized maleic acid (MA) units and Fe 3+ to suppress the phase separation of PHEMA chains from aqueous solution, thereby inducing a homogeneous network. The homogeneous network can avoid stress concentrations, and dynamic coordination crosslinking can effectively dissipate energy and simultaneously maintain network elasticity. The synergistic effects of these two factors impart exceptionally high tensile strength (3.44 MPa), elastic modulus (14.22 MPa), and toughness (4.17 MJ/m 3 ) to the hydrogels, which are 22.7, 43.1, and 24.2 times higher than those of pure PHEMA hydrogels, respectively. Such mechanical properties are comparable to human nasal and auricular cartilage. The hydrogels manifest outstanding self-recovery properties and fatigue resistance, which are essential for long-term and sustainable use. In vitro cell and in vivo animal experiments show that this strategy does not sacrifice the excellent biocompatibility and stability of the PHEMA hydrogels. These PHEMA-based hydrogels, with excellent mechanical properties, fatigue resistance, and biocompatibility, are promising candidates for replacing diseased or damaged nasal and auricular cartilage. Mechanically robust, biocompatible, and durable PHEMA-based hydrogels with cartilage mimetic properties are prepared by designing a homogeneous network with strong ionic coordination interactions. The hydrogels possess excellent mechanical properties by modulating the MA content or FeCl 3 solution concentration, which is comparable to human nasal and auricular cartilage. Good fatigue resistance properties support the hydrogels for long-term and sustainable use. Combined with long-term biocompatibility and stability in vivo , the high-performance PHEMA-based hydrogels show great application prospects as a desirable candidate material for replacing diseased or damaged nasal and auricular cartilage. • Hydrogels are designed by a homogenous network with robust coordination interactions. • The homogeneous network is induced by suppressing phase separation. • The mechanical properties of hydrogels are significantly improved by such design. • Hydrogels also manifest good biocompatibility and stability. • Hydrogels are promising candidates in nasal and auricular cartilage replacement.

Nanocrystalline Yttria-Stabilized Zirconia Ceramics for Cranial Window Applications.

Transparent yttria-stabilized zirconia (YSZ) ceramics are promising for cranial window applications because of their good mechanical and optical properties as well as biocompatibility. YSZ discs with different yttria concentrations were either processed via current-activated pressure-assisted densification (CAPAD) using commercial nanoparticles or densified via spark plasma sintering (SPS) using pyrolysis-synthesized nanoparticles in-house. This study provided critical results to screen composition, processing, microstructure, and cytocompatibility of transparent YSZ discs for cranial window applications. CAPAD-processed YSZ discs with 6 or 8 mol % yttria (6YSZ and 8YSZ) and SPS-densified YSZ discs with 4 mol % yttria (4YSZ_P) showed 200-350 nm polycrystalline grains containing 20-30 nm crystallite domains. SPS-densified YSZ discs with 8 mol % yttria (8YSZ_P) showed larger polycrystalline grains of 819 ± 155 nm with 29 ± 5 nm crystallite domains. CAPAD-processed YSZ discs with 3 mol % yttria (3YSZ) showed 39 ± 9 nm grains. Bone-marrow-derived stem cells (BMSCs) on the polished YSZ discs showed statistically higher spreading areas than those on the unpolished YSZ discs of the same compositions. Generally, polished 8YSZ, 4YSZ_P, and 8YSZ_P discs and unpolished 8YSZ_R, 4YSZ_PR, and 8YSZ_PR discs had lower average cell adhesion densities than other YSZ discs under direct contact conditions. Under indirect contact conditions, all the YSZ disc groups showed similar average cell adhesion densities to the Cell-only control. The groups of polished 4YSZ_P and 8YSZ_P discs, unpolished 4YSZ_PR and 8YSZ_PR discs, and particle control of 8YSZ_Pnp showed higher Y3+ ion concentrations than other groups. No mineral deposition was detected on the polished YSZ discs after cell culture. Considering multiple factors such as cytocompatibility, cell adhesion density, Y3+ ion release, mineral deposition, and optical transparency collectively, 8YSZ may be the best candidate for the cranial window applications. Further studies are needed to evaluate the long-term transparency and biocompatibility of YSZ discs.

Direct measurement of oxygen reduction reactions at neurostimulation electrodes

Objective. Electric stimulation delivered by implantable electrodes is a key component of neural engineering. While factors affecting long-term stability, safety, and biocompatibility are a topic of continuous investigation, a widely-accepted principle is that charge injection should be reversible, with no net electrochemical products forming. We want to evaluate oxygen reduction reactions (ORR) occurring at different electrode materials when using established materials and stimulation protocols. Approach. As stimulation electrodes, we have tested platinum, gold, tungsten, nichrome, iridium oxide, titanium, titanium nitride, and poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate). We use cyclic voltammetry and voltage-step amperometry in oxygenated versus inert conditions to establish at which potentials ORR occurs, and the magnitudes of diffusion-limited ORR currents. We also benchmark the areal capacitance of each electrode material. We use amperometric probes (Clark-type electrodes) to quantify the O2 and H2O2 concentrations in the vicinity of the electrode surface. O2 and H2O2 concentrations are measured while applying DC current, or various biphasic charge-balanced pulses of amplitude in the range 10–30 µC cm−2/phase. To corroborate experimental measurements, we employ finite element modelling to recreate 3D gradients of O2 and H2O2. Main results. All electrode materials support ORR and can create hypoxic conditions near the electrode surface. We find that electrode materials differ significantly in their onset potentials for ORR, and in the extent to which they produce H2O2 as a by-product. A key result is that typical charge-balanced biphasic pulse protocols do lead to irreversible ORR. Some electrodes induce severely hypoxic conditions, others additionally produce an accumulation of hydrogen peroxide into the mM range. Significance. Our findings highlight faradaic ORR as a critical consideration for neural interface devices and show that the established biphasic/charge-balanced approach does not prevent irreversible changes in O2 concentrations. Hypoxia and H2O2 can result in different (electro)physiological consequences.

Nanogenerator-Based Sensors for Energy Harvesting From Cardiac Contraction

Biomedical electric devices provide great assistance for health and life quality. However, their maintainable need remains a serious issue for the restricted duration of energy storage. Therefore, scientists are investigating alternative technologies such as nanogenerators that could harvest the mechanical energy of the human heart to act as the main source of energy for the pacemaker. Cardiac contraction is not a source for circulation; it utilizes body energy as an alternative energy source to recharge pacemaker devices. This is a key biomedical innovation to protect patients’ lives from possible risks resulting from repeated surgery. A batteryless pacemaker is possible via an implantable energy collecting tool, exchanging the restriction of the current batteries for a sustainable self-energy resource technique. In this context, the physiology of heart energy in the preservation of blood distribution pulse generation and the effects of cardiac hormones on the heart’s pacemaker shall be outlined. In this review, we summarized different technologies for the implantable energy harvesters and self-powered implantable medical devices with emphasis on nanogenerator-based sensors for energy harvesting from cardiac contraction. It could conclude that recent hybrid bio-nanogenerator systems of both piezoelectric and triboelectric devices based on biocompatible biomaterials and clean energy are promising biomedical devices for harvesting energy from cardiac and body movement. These implantable and wearable nanogenerators become self-powered biomedical tools with high efficacy, durability, thinness, flexibility, and low cost. Although many studies have proven their safety, there is a need for their long-term biosafety and biocompatibility. A further note on the biocompatibility of bio-generator sensors shall be addressed.

Clinical Impact of Computational Heart Valve Models.

This paper provides a review of engineering applications and computational methods used to analyze the dynamics of heart valve closures in healthy and diseased states. Computational methods are a cost-effective tool that can be used to evaluate the flow parameters of heart valves. Valve repair and replacement have long-term stability and biocompatibility issues, highlighting the need for a more robust method for resolving valvular disease. For example, while fluid–structure interaction analyses are still scarcely utilized to study aortic valves, computational fluid dynamics is used to assess the effect of different aortic valve morphologies on velocity profiles, flow patterns, helicity, wall shear stress, and oscillatory shear index in the thoracic aorta. It has been analyzed that computational flow dynamic analyses can be integrated with other methods to create a superior, more compatible method of understanding risk and compatibility.

Polysaccharide Layer-by-Layer Coating for Polyimide-Based Neural Interfaces.

Implantable flexible neural interfaces (IfNIs) are capable of directly modulating signals of the central and peripheral nervous system by stimulating or recording the action potential. Despite outstanding results in acute experiments on animals and humans, their long-term biocompatibility is hampered by the effects of foreign body reactions that worsen electrical performance and cause tissue damage. We report on the fabrication of a polysaccharide nanostructured thin film as a coating of polyimide (PI)-based IfNIs. The layer-by-layer technique was used to coat the PI surface due to its versatility and ease of manufacturing. Two different LbL deposition techniques were tested and compared: dip coating and spin coating. Morphological and physiochemical characterization showed the presence of a very smooth and nanostructured thin film coating on the PI surface that remarkably enhanced surface hydrophilicity with respect to the bare PI surface for both the deposition techniques. However, spin coating offered more control over the fabrication properties, with the possibility to tune the coating’s physiochemical and morphological properties. Overall, the proposed coating strategies allowed the deposition of a biocompatible nanostructured film onto the PI surface and could represent a valid tool to enhance long-term IfNI biocompatibility by improving tissue/electrode integration.

Coupling and maintaining link efficiency ultrasonics in transcutaneous energy transfer systems

We present on the development of a 12.8 mm diameter ultrasonic transcutaneous energy transfer system for powering implanted hearing devices. The system was based on two custom 8mm diameter PMN-PT 1-3 composite transducers operating at 1.25MHz and featured three significant innovations. First, to ensure long-term biocompatibility and reliability of the implanted portion of the link and to ensure robust attachment to bone, the implanted transducer was designed into a 12.8 mm diameter, 3.5 mm thick hermetically sealed titanium package in an easy-to-implant form factor. The transducer was designed to deliver sound efficiently through the casing walls using a mass-spring acoustic matching technique. Second, for the external unit a “dry” acoustic coupling system based on a silicone pressure sensitive adhesive was designed that combined efficient acoustic coupling, robust adhesion to skin and that was comfortable to wear. The external unit was aligned with the internal unit using a magnetic alignment system. Third, we developed and demonstrated an efficient Class E transmit amplifier and receive electronics that incorporated compensation for changes in acoustic separation between the transducer to maintain robust, high efficiency power transmission. The system achieved 33% DC-to-DC electrical conversion efficiency through 5mm of water and 19% DC-to-DC efficiency through 5mm of porcine tissue.

Biocompatibility of a New Calcium Silicate-Based Root Canal Sealer Mediated via the Modulation of Macrophage Polarization in a Rat Model

(1) Background: The EndoSequence BC Sealer HiFlow (Brasseler, Savannah, GA, USA) has recently been introduced in clinical applications. Thus, the aims of the present study are to determine its biocompatibility in vivo and to examine its ability to drive macrophage polarization in vitro and in vivo. (2) Methods: HiFlow was implanted into rat connective tissue for 7, 30 and 150 days. The microstructures and elemental compositions were determined by scanning electron microscopy-energy-dispersive X-ray spectroscopy (SEM-EDX). Hematoxylin–eosin, immunofluorescence, RT–qPCR and flow cytometry were used to elucidate the effects on inflammatory responses and macrophage polarization. (3) Results: SEM-EDX revealed the formation of surface hydroxyapatite crystal layers. Histological evaluation showed that HiFlow exhibited long-term biocompatibility because it decreased inflammatory responses and reduced the number of macrophages over time; however, tissue necrosis was observed in all the groups. RT–qPCR verified that HiFlow regulated the expression of inflammatory factors to inhibit the inflammatory response. Immunofluorescence analysis performed on in vivo samples revealed that HiFlow promoted M2-like macrophage polarization, and these results were confirmed by flow cytometry in vitro. (4) Conclusion: After 150 days of investigation, HiFlow was considered biologically acceptable, and the formation of apatite crystal layers and the promotion of M2-like macrophage polarization may contribute to its favorable biocompatibility.

Long-Term Biocompatibility of a Highly Viscously Thiol-Modified Cross-Linked Hyaluronate as a Novel Vitreous Body Substitute.

Purpose: In surgical ophthalmology, the treatment of complicated retinal and vitreous diseases is one of the central challenges. For this purpose, the vitreous body is removed as part of the standard therapy and replaced by a temporary tamponade to stabilize the position of the retina. Since the tamponading properties of previous materials such as silicone oils, gases, or semi-fluorinated alkanes are a combination of their surface tension and their buoyancy vector, they cannot completely fill the vitreous cavity. The aim of this work was to test in vivo a novel vitreous body substitute (ViBos strong) based on cross-linked hyaluronic acid for its compatibility. Methods: A pars plana vitrectomy with posterior vitreous detachment was performed in the right eye of 18 pigmented rabbits, with subsequent injection of ViBos strong. Follow-up examination included slit-lamp examination, funduscopy, intraocular pressure measurements (IOP), optical coherence tomography (OCT), and electroretinogram (ERG) measurements. The rabbits were sacrificed at three different time points (1, 3, and 6 months; each 6 animals) and examined macroscopically and prepared for histological examination (HE staining) and immunohistochemistry (Brn3a and glial fibrillary acidic protein (GFAP)). Results: ViBos strong demonstrated good intraoperative handling and remained stable for at least 1 month and degraded slowly over 6 months. IOP was within clinical acceptable values at all follow-up examinations. Retinal function was well preserved after instillation of the hydrogel and comparable to the untreated eye after 6 months in OCT, ERG, and histological examinations. An increase in the GFAP expression was found in the surgery eyes, with a peak in the 3-month group. The Brn3a expression was not significantly affected by vitrectomy with ViBos strong. Conclusion: Highly viscously thiol-modified cross-linked hyaluronate showed a good biocompatibility in rabbit eyes over 6 months after vitrectomy, making it a promising potential as a vitreous substitute.

Development of polycarbonate urethane-based materials with controlled diclofenac release for cartilage replacement.

Hydrogels are very promising human cartilage replacement materials since they are able to mimic its structure and properties. Besides, they can be used as platforms for drug delivery to reduce inflammatory postsurgical reactions. Polycarbonate urethane (PCU) has been used in orthopedic applications due to its long-term biocompatibility and bio-durability. In this work, PCU-based hydrogels with the ability to release an anti-inflammatory (diclofenac) were developed, for the first time, for such purpose. The materials were reinforced with different amounts of cellulose acetate (CA, 10%, 15%, and 25% w/w) or carbon nanotubes (CNT, 1% and 2% w/w) in order to improve their mechanical properties. Samples were characterized in terms of compressive and tensile mechanical behavior. It was found that 15% CA and 2% CNT reinforcement led to the best mechanical properties. Thus, these materials were further characterized in terms of morphology, wettability, and friction coefficient (CoF). Contrarily to CNTs, the addition of CA significantly increased the material's porosity. Both materials became more hydrophilic, and the CoF slightly increased for PCU + 15%CA. The materials were loaded by soaking with diclofenac, and drug release experiments were conducted. PCU, PCU + 15%CA and PCU + 2%CNT presented similar release profiles, being able to ensure a controlled release of DFN for at least 4 days. Finally, in vitro cytotoxicity tests using human chondrocytes were also performed and confirmed a high biocompatibility for the three studied materials.

Functional Bioelectronic Materials for Long-Term Biocompatibility and Functionality

Wearable and implantable bioelectronics have received a great deal of interest since the need for personalized healthcare systems has arisen. Bioelectronics are designed to detect biological signals and apply medical treatments, thereby enabling patients to monitor and manage their health conditions. However, current bioelectronics lack long-term stability, biocompatibility, and functionality after implantation into the human body. In particular, the intrinsically different natures of the devices and human tissue result in low device–tissue compatibility. The obstacles for this can be defined as (1) physical, (2) biological, and (3) interfacial. The mechanical mismatch between rigid device materials and soft tissue results in physical incompatibility, which causes user discomfort and scar tissue formation. In addition, devices can show poor biocompatibility since the device materials are recognized as foreign bodies by the immune system. Accordingly, the applied devices can be toxic and/or induce an undesirable immune response and inflammation. Last, tissue environments are moist, irregular, and dynamic, which causes poor interfacial compatibility between the device and the human body. Herein, we describe various recent strategies to overcome limitations in the physical, biological, and interfacial compatibility of bioelectronics for long-term functionality in vivo. Moreover, in the last part of the review, we mention current limitations and future perspectives of bioelectronics for commercialization.

Early Clinical Outcomes of Polydioxanone Mesh for Prepectoral Prosthetic Breast Reconstruction.

Background:Many biologic matrices and synthetic meshes are available as adjuncts for prosthetic and autologous breast reconstructions to help control implant position and to reinforce abdominal flap donor sites. Absorbable synthetic meshes may have advantages over biologic matrices and permanent meshes, such as lower cost and better long-term biocompatibility. We present a prospective case series of patients undergoing two-stage, prepectoral breast reconstruction with polydioxanone (PDO) mesh.Methods:This prospective, consecutive single-surgeon series of patients who received PDO mesh during two-stage, prepectoral breast reconstruction involved incorporation of the PDO mesh at stage 1 as an anterior tarp over the tissue expander. A detailed description of surgical technique is provided herein. Surgical complications monitored included surgical site infection, wound dehiscence, mastectomy skin flap necrosis, hematoma or seroma requiring operative intervention, and reconstructive failure.Results:Seven patients with fourteen breast reconstructions were included in the study. All patients had unilateral cancer and underwent bilateral mastectomies with immediate reconstruction. The average age of patient was 50.0 (SD 7.4) and BMI was 29.3 (SD 2.7). Patients were followed for a median of 274 days, during which only one late infection (7.1%) occurred requiring expander removal.Conclusions:PDO mesh has an acceptable short-term complication rate in two-stage prepectoral prosthetic breast reconstruction. Future investigations should elucidate its comparative efficacy and safety against alternative products with respect to long-term outcomes.

Long-term safety and absorption assessment of a novel bioresorbable nitrided iron scaffold in porcine coronary artery.

This study aimed to investigate the long-term biocompatibility, safety, and degradation of the ultrathin nitrided iron bioresorbable scaffold (BRS) in vivo, encompassing the whole process of bioresorption in porcine coronary arteries. Fifty-two nitrided iron scaffolds (strut thickness of 70 μm) and 28 Vision Co–Cr stents were randomly implanted into coronary arteries of healthy mini-swine. The efficacy and safety of the nitrided iron scaffold were comparable with those of the Vision stentwithin 52 weeks after implantation. In addition, the long-term biocompatibility, safety, and bioresorption of the nitrided iron scaffold were evaluated by coronary angiography, optical coherence tomography, micro-computed tomography, scanning electron microscopy, energy dispersive spectrometry and histopathological evaluations at 4, 12, 26, 52 weeks and even at 7 years after implantation. In particular, a large number of struts were almost completely absorbed in situ at 7 years follow-up, which were first illustrated in this study. The lymphatic drainage pathway might serve as the potential clearance way of iron and its corrosion products.

Abstract 14093: Open Thoracic Surgical Implantation of Cardiac Pacemakers in Rodents

Introduction: Cardiovascular science has greatly benefited from bioelectronics and genetic engineering. However, combinations of these approaches have been hampered by challenges in genetic engineering of large animals and implantation of cardiac devices in rodents. New surgical approaches to reliably interface bioelectronics to the heart with minimal disruption to the native physiology are necessary for validation of novel bioelectronics therapies and bioelectronics-enabled in vivo studies of physiology. Objective: To develop an effective and reproducible surgical approach to implant epicardial devices in rodents. Methods: All rat surgeries (n = 138) were performed according to protocols approved by The George Washington University Institutional Animal Care and Use Committee. Inhaled isoflurane vapors provided general anesthesia. After orotracheal intubation, an intercostal incision was made and retracted in order to view the target cardiac implantation area (a). The electrode pad of a novel leadless battery-free pacemaker (b) was sutured or attached by bioadhesive to the epicardium with the device body placed subcutaneously. The ribs, muscle, and skin were subsequently closed. Post-operative care included injectable analgesics. Daily pacing trials confirmed device functionality. Results: Rats survive and quickly recover from the operation without complications. Electrocardiograms reveal that implanted miniature battery-free cardiac pacemakers pace the heart for up to 32 days after surgery (c). Echocardiography and assessment of biomarkers demonstrate no disruption to mechanical function (d) and no evidence of myocardial ischemia (e) or heart failure (f), respectively. Conclusions: This surgical technique reliably implants epicardial devices in rodents. It has broad applications to verify the long-term functionality and biocompatibility of innovative bioelectronics and to conduct in vivo studies of cardiovascular physiology.

Physically Crosslinked Chitosan/PVA Hydrogels Containing Honey and Allantoin with Long-Term Biocompatibility for Skin Wound Repair: An In Vitro and In Vivo Study.

Chitosan/PVA hydrogel films crosslinked by the freeze–thaw method and containing honey and allantoin were prepared for application as wound dressing materials. The effects of the freeze–thaw process and the addition of honey and allantoin on the swelling, the gel content and the mechanical properties of the samples were evaluated. The physicochemical properties of the samples, with and without the freeze–thaw process, were compared using FTIR, DSC and XRD. The results showed that the freeze–thaw process can increase the crystallinity and thermal stability of chitosan/PVA films. The freeze–thaw process increased the gel content but did not have a significant effect on the tensile strength. The presence of honey reduced the swelling and the tensile strength of the hydrogels due to hydrogen bonding interactions with PVA and chitosan chains. Long-term cell culture experiments using normal human dermal fibroblast (NHDF) cells showed that the hydrogels maintained their biocompatibility, and the cells showed extended morphology on the surface of the hydrogels for more than 30 days. The presence of honey significantly increased the biocompatibility of the hydrogels. The release of allantoin from the hydrogel was studied and, according to the Korsmeyer–Peppas and Weibull models, the mechanism was mainly diffusional. The results for the antimicrobial activity against E. coli and S. aureus bacteria showed that the allantoin-containing samples had a more remarkable antibacterial activity against S. aureus. According to the wound healing experiments, 98% of the wound area treated by the chitosan/PVA/honey hydrogel was closed, compared to 89% for the control. The results of this study suggest that the freeze–thaw process is a non-toxic crosslinking method for the preparation of chitosan/PVA hydrogels with long term biocompatibility that can be applied for wound healing and skin tissue engineering.

Preparation of long-lasting antibacterial wound dressing through diffusion of cationic-liposome-encapsulated polyhexamethylene biguanide

Polyhexamethylene biguanide (PHMB) has been used increasingly in various applications because of antibacterial properties; however, its cytotoxicity hampers application. On the other hand, there is a high affinity between the cell membrane complexes (CMCs) in wool structure and phospholipids of cationic nanoliposomes, leading to the transmission of cationic nanoliposomes into the wool. In this research, a novel method for PHMB controlled release is introduced by combining these facts. Firstly, PHMB was encapsulated into cationic liposome and then permeated into the wool to establish a highly controlled release then characterized through diverse methods. SEM images revealed successful transmission of cationic-liposome-encapsulated PHMB into the wool. The prepared wound dressings demonstrated highly sustained release for days and subsequently, long-term perfect antibacterial activity and biocompatibility.

Immunosuppressed Miniswine as a Model for Testing Cell Therapy Success: Experience With Implants of Human Salivary Stem/Progenitor Cell Constructs.

An urgent need exists to develop large animal models for preclinical testing of new cell therapies designed to replace lost or damaged tissues. Patients receiving irradiation for treatment of head and neck cancers frequently develop xerostomia/dry mouth, a condition that could one day be treated by cell therapy to repopulate functional saliva-producing cells. Using immunosuppression protocols developed for patients receiving whole face transplants, we successfully used immunosuppressed miniswine as a suitable host animal to evaluate the long-term stability, biocompatibility, and fate of matrix-modified hyaluronate (HA) hydrogel/bioscaffold materials containing encapsulated salivary human stem/progenitor cells (hS/PCs). An initial biocompatibility test was conducted in parotids of untreated miniswine. Subsequent experiments using hS/PC-laden hydrogels were performed in animals, beginning an immunosuppression regimen on the day of surgery. Implant sites included the kidney capsule for viability testing and the parotid gland for biointegration time periods up to eight weeks. No transplant rejection was seen in any animal assessed by analysis of the tissues near the site of the implants. First-generation implants containing only cells in hydrogel proved difficult to handle in the surgical suite and were modified to adhere to a porcine small intestinal submucosa (SIS) membrane for improved handling and could be delivered through the da Vinci surgical system. Several different surgical techniques were assessed using the second-generation 3D-salivary tissue (3D-ST) for ease and stability both on the kidney capsule and in the capsule-less parotid gland. For the kidney, sliding the implant under the capsule membrane and quick stitching proved superior to other methods. For the parotid gland, creation of a tissue “pocket” for placement and immediate multilayer tissue closure were well tolerated with minimal tissue damage. Surgical clips were placed as fiduciary markers for tissue harvest. Some implant experiments were conducted with miniswine 90 days post-irradiation when salivation decreased significantly. Sufficient parotid tissue remained to allow implant placement, and animals tolerated immunosuppression. In all experiments, viability of implanted hS/PCs was high with clear signs of both vascular and nervous system integration in the parotid implants. We thus conclude that the immunosuppressed miniswine is a high-value emerging model for testing human implants prior to first-in-human trials.

Long-Term Stability and Biocompatibility of Pericardial Bioprosthetic Heart Valves.

The use of bioprostheses for heart valve therapy has gradually evolved over several decades and both surgical and transcatheter devices are now highly successful. The rapid expansion of the transcatheter concept has clearly placed a significant onus on the need for improved production methods, particularly the pre-treatment of bovine pericardium. Two of the difficulties associated with the biocompatibility of bioprosthetic valves are the possibilities of immune responses and calcification, which have led to either catastrophic failure or slow dystrophic changes. These have been addressed by evolutionary trends in cross-linking and decellularization techniques and, over the last two decades, the improvements have resulted in somewhat greater durability. However, as the need to consider the use of bioprosthetic valves in younger patients has become an important clinical and sociological issue, the requirement for even greater longevity and safety is now paramount. This is especially true with respect to potential therapies for young people who are afflicted by rheumatic heart disease, mostly in low- to middle-income countries, for whom no clinically acceptable and cost-effective treatments currently exist. To extend longevity to this new level, it has been necessary to evaluate the mechanisms of pericardium biocompatibility, with special emphasis on the interplay between cross-linking, decellularization and anti-immunogenicity processes. These mechanisms are reviewed in this paper. On the basis of a better understanding of these mechanisms, a few alternative treatment protocols have been developed in the last few years. The most promising protocol here is based on a carefully designed combination of phases of tissue-protective decellularization with a finely-titrated cross-linking sequence. Such refined protocols offer considerable potential in the progress toward superior longevity of pericardial heart valves and introduce a scientific dimension beyond the largely disappointing ‘anti-calcification’ treatments of past decades.

A biodegradable, mechanically tunable micro-arc oxidation AZ91D-based composite implant with calcium phosphate/chitosan coating promotes long-term bone tissue regeneration.

To reduce the biodegradable rate and develop the long-term osteogenic ability of magnesium (Mg) alloy, we prepared a new biodegradable micro arc oxidation AZ91D-based composite implant with calcium phosphate/chitosan coating (CaP-CS/MAO/AZ91D) and investigated its mechanical property and long-term bone tissue regeneration ability. The results showed that the binding force and bioactivity of CaP-CS/MAO/AZ91D was better when the ratio of water to ethanol was 4:6 and MAO constant current was 0.1 A cm-2 . Compressive strengths of 4:6 sample were more than 1300 N when the soaking time was increased to 21 days. CaP-CS/MAO/AZ91D extracts promoted differentiation and proliferation of rat mesenchymal stem cells (RMSC), which achieved higher proliferation rates over 16 days of culture and exhibited early alkaline phosphatase activity and late bone sialoprotein markers. CaP-CS/MAO/AZ91D was established to promote RMSC osteogenic differentiation within a proper range for at least 90 days through Wnt/β-catenin pathway activation, which would allow sufficient time for bone healing. Collectively, our findings suggest that the CaP-CS/MAO/AZ91D coating could not only reduce the corrosion rate and lead to better long-term biocompatibility but also promote osteogenic mineralization.

A grade 1 titanium capacitive microsensor for continuous pressure monitoring of intracorporal pressures

Long-term implantable pressure monitoring is a key clinical parameter bringing a lot to clinicians by helping them treating many chronical diseases (e.g. glaucoma, hydrocephalus or heart failure). However for decades and up to now, most of the implantable sensors exhibited poor technological and clinical success due to the long-term biocompatibility constraints of the transducing part. The prime novelty of this paper is to propose a functional implantable MEMS pressure sensor with a bulk-micromachined titanium (Ti) transducer. Thanks to its small size, the active part of the sensor is thought versatile enough to be integrated in an active implantable device for measuring various intracorporal pressures. The transducer is made out of grade 1 Ti, which is one of the metalic materials of choice to insure long-term biocompatibility and has been proved to be a reliable material in the implantable industry. The uniqueness of the proposed sensor comes from its micromachining. The transducer, including a bulk titanium membrane, has been obtained through subtractive machining techniques benefiting from the extensive research experience on silicon MEMS. This Ti-based technology avoids the use of additionnal costly, complex and bulky encapsulation step to get a biocompatible device, thus enabling higher miniaturization level of implantable devices and lower rate of long term drift risks thanks to its monolithic architecture. The presented Ti MEMS sensor exhibits 1 fF mmHg−1 sensitivity within a clinically relevant pressure range of 0–300 mmHg, which is compatible with off the shelf low-power readout electronics.