Tissue Scaffolds Research Articles

Dynamic optimisation for graded tissue scaffolds using machine learning techniques

Tissue scaffolds have emerged as a promising solution for treatment of critical size bone defects, offering significant advantages over conventional strategies. One of the key functionalities of bone scaffolds is their ability to promote long-term bone ingrowth effectively. To enhance this functionality, we develop a novel dynamic optimisation framework to customise bone scaffolds for achieving maximum bone ingrowth outcomes over a certain period in this study. To improve the design efficiency, we extensively leverage machine learning (ML) techniques within our proposed dynamic optimisation framework. Specifically, two neural networks are integrated into a dynamic bone growth model, and another neural network is coupled with a genetic algorithm for dynamic optimisation process. To demonstrate the effectiveness and efficiency of the approach, we employ a sheep mandible reconstruction for treating a critical size bone defect as an illustraive example. To validate the finite element (FE) model established, we first conduct a mechanical test on the sheep mandible assembled with a tailored 3D printed scaffold made of Polyetherketone (PEK) material. Then, we compare three different optimisation schemes, namely uniform design, lateral gradient design, and vertical gradient design, with an empirical design under the same biomechanical conditions. A 18.5 % enhancement is found in the long-term bone ingrowth when the optimised scaffold is adopted in comparison with the empirical design, which is attributed to the fine-tuning of strut sizes within lattice scaffold structures for facilitating bone regeneration in the gradient regions. This study proposes a novel design framework by combining ML and time-dependent topology optimisation, which provides a new methodology for developing innovative tissue scaffolds with better clinical outcomes.

Porous Anisometric PNIPAM Microgels: Tailored Porous Structure and Thermal Response.

The porous structure of microgels significantly influences their properties and, thus, their suitability for various applications, in particular as building blocks for tissue scaffolds. Porosity is one of the crucial features for microgel-cell interactions and significantly increases the cells' accumulation and proliferation. Consequently, tailoring the porosity of microgels in an effortless way is important but still challenging, especially for nonspherical microgels. This work presents a straightforward procedure to fabricate complex-shaped poly(N-isopropyl acrylamide) (PNIPAM) microgels with tuned porous structures using the so-called cononsolvency effect during microgel polymerization. Therefore, the classical solvent in the reaction solution is exchanged from water to water-methanol mixtures in a stop-flow lithography process. For cylindrical microgels with a higher methanol content during fabrication, a greater degree of collapsing is observed, and their aspect ratio increases. Furthermore, the collapsing and swelling velocities change with the methanol content, indicating a modified porous structure, which is confirmed by electron microscopy micrographs. Furthermore, swelling patterns of the microgel variants occur during cooling, revealing their thermal response as a highly heterogeneous process. These results show a novel procedure to fabricate PNIPAM microgels of any elongated 2D shape with tailored porous structure and thermoresponsiveness by introducing the cononsolvency effect during stop-flow lithographypolymerization.

A Biodegradable Piezoelectric Sensor for Real‐Time Evaluation of the Motor Function Recovery After Nerve Injury

AbstractNerve injury can lead to defects in related motor functions. It is critical to achieve long‐term and convenient real‐time evaluation of motor function recovery status during nerve injury repair. In this study, an implantable PLLA/BTO piezoelectric sensor (PBPS) with good biodegradability and biocompatibility for real time evaluation of the motor function recovery after nerve injury is developed. PLLA fibers doped with BTO are employed as piezoelectric material in PBPS, which can convert the biomechanical signals generated by motion into electrical signals. PBPS can be implant simultaneously with commonly used tissue scaffolds for treatment in the rats with sciatic nerve injury. The linearity of the pressure and the output voltage of PBPS is ≈0.9445. For the evaluation effectiveness, as the treatment process progresses, the signals generated by PBPS exhibited good consistency with EMG signals, indicating effectively evaluation of the motor function. Moreover, the integration of PBPS and wireless module can break the limitations of time and space for sensing and realize wireless evaluation of motor function in rat. The implantable sensor based on PBPS may bring new ideas for the development of implantable bioelectronics.

Automated brightfield layerwise evaluation in three-dimensional micropatterning via two-photon polymerization.

Two-photon polymerization (TPP) is an advanced 3D fabrication technique capable of creating features with submicron precision. A primary challenge in TPP lies in the facile and accurate characterization of fabrication quality, particularly for structures possessing complex internal features. In this study, we introduce an automated brightfield layerwise evaluation technique that enables a simple-to-implement approach for in situ monitoring and quality assessment of TPP-fabricated structures. Our approach relies on sequentially acquired brightfield images during the TPP writing process and using background subtraction and image processing to extract layered spatial features. We experimentally validate our method by printing a fibrous tissue scaffold and successfully achieve an overall system-adjusted fidelity of 87.5% in situ. Our method is readily adaptable in most TPP systems and can potentially facilitate high-quality TPP manufacturing of sophisticated microstructures.

Injectable Nanocomposite Hydrogels with Strong Antibacterial, Osteoinductive, and ROS-Scavenging Capabilities for Periodontitis Treatment.

Injectable antibacterial and osteoinductive hydrogels have received considerable attention for promoting bone regeneration owing to their versatile functionalities. However, a current hydrogel with antibacterial, osteoinductive, and antioxidant properties by a facile method for periodontitis treatment is still missing. To overcome this issue, we designed an injectable hydrogel system (GPM) composed of gelatin, Ti3C2Tx MXene nanosheets, and poly-l-lysine using a simple enzymatic cross-linking technique. Physicochemical characterization demonstrated that the GPM hydrogel matrix exhibited excellent stability, moderate tissue adhesion ability, and good mechanical behavior. The GPM hydrogels significantly inhibited the growth of Porphyromonas gingivalis, scavenged reactive oxygen species, attenuated inflammatory responses, and enhanced bone tissue regeneration. Intriguingly, the arrangement of the junctional epithelium, alveolar bone volume, and alveolar bone height in the GPM-treated periodontal disease group recovered to that of the healthy group. Therefore, our injectable hydrogel system with versatile functions may serve as an excellent tissue scaffold for the treatment of periodontitis.

Fabrication and Characterization of Quad-Component Bioinspired Hydrogels to Model Elevated Fibrin Levels in Central Nervous Tissue Scaffolds.

Multicomponent interpenetrating polymer network (mIPN) hydrogels are promising tissue-engineering scaffolds that could closely resemble key characteristics of native tissues. The mechanical and biochemical properties of mIPNs can be finely controlled to mimic key features of target cellular microenvironments, regulating cell-matrix interactions. In this work, we fabricated hydrogels made of collagen type I (Col I), fibrin, hyaluronic acid (HA), and poly (ethylene glycol) diacrylate (PEGDA) using a network-by-network fabrication approach. With these mIPNs, we aimed to develop a biomaterial platform that supports the in vitro culture of human astrocytes and potentially serves to assess the effects of the abnormal deposition of fibrin in cortex tissue and simulate key aspects in the progression of neuroinflammation typically found in human pathologies such as Alzheimer's disease (AD), Parkinson's disease (PD), and tissue trauma. Our resulting hydrogels closely resembled the complex modulus of AD human brain cortex tissue (~7.35 kPa), promoting cell spreading while allowing for the modulation of fibrin and hyaluronic acid levels. The individual networks and their microarchitecture were evaluated using confocal laser scanning microscopy (CLSM) and scanning electron microscopy (SEM). Human astrocytes were encapsulated in mIPNs, and negligible cytotoxicity was observed 24 h after the cell encapsulation.

Cyanophycin modifications for applications in tissue scaffolding

Cyanophycin (CGP) is a polypeptide consisting of amino acids—aspartic acid in the backbone and arginine in the side chain. Owing to its resemblance to cell adhesive motifs in the body, it can be considered suitable for use in biomedical applications as a novel component to facilitate cell attachment and tissue regeneration. Although it has vast potential applications, starting with nutrition, through drug delivery and tissue engineering to the production of value-added chemicals and biomaterials, CGP has not been brought to the industry yet. To develop scaffolds using CGP powder produced by bacteria, its properties (e.g., biocompatibility, morphology, biodegradability, and mechanical strength) should be tailored in terms of the requirements of the targeted tissue. Crosslinking commonly stands for a primary modification method for renovating biomaterial features to these extents. Herein, we aimed to crosslink CGP for the first time and present a comparative study of different methods of CGP crosslinking including chemical, physical, and enzymatic methods by utilizing glutaraldehyde (GTA), UV exposure, genipin, 1-ethyl-3-[3-dimethylaminopropyl] carbodiimide hydrochloride/N-hydroxysuccinimide (EDC/NHS), and monoamine oxidase (MAO). Crosslinking efficacy varied among the samples crosslinked via the different crosslinking methods. All crosslinked CGP were non-cytotoxic to L929 cells, except for the groups with higher GTA concentrations. We conclude that CGP is a promising candidate for scaffolding purposes to be used as part of a composite with other biomaterials to maintain the integrity of scaffolds. The initiative study demonstrated the unknown characteristics of crosslinked CGP, even though its feasibility for biomedical applications should be confirmed by further examinations.Key points• Cyanophycin was crosslinked by 5 different methods• Crosslinked cyanophycin is non-cytotoxic to L929 cells• Crosslinked cyanophycin is a promising new material for scaffolding purposesGraphical

Application of biomimetic three-dimensional scaffolds in bone tissue repairing

Application of biomimetic three-dimensional scaffolds in bone tissue repairing

Carbon black silicone composite in surgical simulation—A detailed electromechanical characterization

The integration of advanced materials into surgical simulators has revolutionized medical training. In this study, a detailed characterization of carbon black silicone composites specifically designed as soft sensor material in hybrid surgical simulators including a hyper visco plasto elastic model is performed. Carbon black-silicone composites offer unique properties such as flexibility, softness and electrical conductivity, making them ideal for integration into synthetic tissue imitations in simulators. These sensors provide real-time feedback on tissue deformation, improving the realism and evaluation capability of surgical simulations. The comprehensive, closed-form material model enables detailed analysis of the composite’s mechanical and electrical behavior, accounting for viscoelasticity, plasticity and hyperelasticity. The application of this model provides insights into the behavior of the conductive composite in different sensory scenarios, which facilitates the development of more realistic simulators.

Precise, low-intensity triggered release in biological systems using ultrasound-responsive antibubbles

Antibubbles are an emerging carrier for low-intensity, ultrasound-triggered release that can carry large payloads in their liquid cores. As we have previously shown, antibubbles can release their payloads at adjustable pressures, ranging from as low as a few kPa (MI < 0.01) to above a few hundred kPa (MI > 0.2). The specific release threshold and behavior can be determined during fabrication, making it possible to realize either single-shot release or multi-stage dosing of a payload. These characteristics make antibubbles an attractive alternative to conventional microbubble delivery agents particularly in sensitive tissues where risks of ultrasound need to be kept to a minimum. In this talk, we discuss recent experiments in which we demonstrate triggered release from antibubbles in in vitro biological systems. We show that payload release can be controlled using patterned or focused ultrasound fields, and we characterize the distribution and cellular uptake of payloads inside cell-laden matrices. These results not only demonstrate the potential of antibubbles for therapeutic applications but also open the door to targeted delivery in complex tissue scaffolds for tissue engineering.

The role of poly(3‐hydroxybutyrate)‐based derivatives in skin, nerve, cartilage, and bone tissue engineering applications—An updated review

AbstractPoly(3‐hydroxybutyrate) (PHB) has gained significant attention in the realm of medical applications in recent years. This acceptability is rooted in its bioactive properties and remarkable biocompatibility, as the degradation products exhibit negligible cytotoxicity. PHB boasts commendable mechanical resilience, distinguishing it from other polymers commonly used in tissue engineering. Using PHB in fabricating 3D scaffolds serves various objectives, often involving a combination with other polymers, ceramics, fibers, or regenerative factors. This distinctive approach sets it apart, leading to the creation of composite biomaterials. These incorporated materials enhance characteristics such as brittleness, hydrophobicity, degradation rate, and biocompatibility, within the composite. This review delves into the diverse roles that PHB, its alloys, and its compounds play in the engineering of skin, nerve, cartilage, and bone tissues. We explain these roles by highlighting key methodologies for crafting 3D tissue scaffolds with widely adopted techniques, including polymeric sponges, electrospinning, and salt leaching.

Optimization of Polydimethylsiloxane-Modified Composite Synthesis and Its Impact on Collagen Interactions: Perspectives for Biomedical Applications.

This research explores how silica composites modified with polydimethylsiloxane interact with collagen, aiming to enhance their application in the biomedical field. By adjusting the amount of polydimethylsiloxane in these composites, we evaluated their capacity to bind with collagen, an essential feature for biomaterials used in tissue engineering and drug delivery. Our findings reveal that incorporating polydimethylsiloxane into silica composites significantly boosts collagen attachment, indicating strong binding interactions. Notably, the collagen adhered to the composites maintains its natural structure, ensuring its functionality and compatibility with living tissues. This aspect is critical for biomaterials that support cell growth and regeneration in tissue scaffolds. Additionally, this study investigates how the viscosity of polydimethylsiloxane influences collagen binding, offering insights into the tailoring of composite properties for better biological performance. This work highlights the potential of polydimethylsiloxane-modified silica composites in creating innovative biomaterials for regenerative medicine and targeted therapeutic delivery.

Chitosan Poly(vinyl alcohol) Methacrylate Hydrogels for Tissue Engineering Scaffolds.

A major challenge in tissue engineering scaffolds is controlling scaffold degradation rates during healing while maintaining mechanical properties to support tissue formation. Hydrogels are three-dimensional matrices that are widely applied as tissue scaffolds based on their unique properties that can mimic the extracellular matrix. In this study, we develop a hybrid natural/synthetic hydrogel platform to tune the properties for tissue engineering scaffold applications. We modified chitosan and poly(vinyl alcohol) (PVA) with photo-cross-linkable methacrylate functional groups and then synthesized a library of chitosan PVA methacrylate hydrogels (ChiPVAMA) with two different photoinitiators, Irgacure 2959 (I2959) and lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP). ChiPVAMA hydrogels showed tunability in degradation rates and mechanical properties based on both the polymer content and photoinitiator type. This tunability could enable their application in a range of tissue scaffold applications. In a 2D scratch wound healing assay, all hydrogel samples induced faster wound closure compared to a gauze clinical wound dressing control. NIH/3T3 cells encapsulated in hydrogels showed a high viability (∼92%) over 14 days, demonstrating the capacity of this system as a supportive cell scaffold. In addition, hydrogels containing a higher chitosan content demonstrated a high antibacterial capacity. Overall, ChiPVAMA hydrogels provide a potential tissue engineering scaffold that is tunable, degradable, and suitable for cell growth.

Hierarchical porous PLLA/ACP fibrous membrane towards bone tissue scaffold

Electrospun fibres have emerged as vital components in developing tissue engineering scaffolds. Calcium phosphate-based materials, renowned for their bioactivity and biocompatibility, have garnered considerable attention in biomedical applications. This study focuses on the incorporation of amorphous calcium phosphate (ACP) nanoparticles into poly(L-lactic acid) (PLLA) to produce electrospun PLLA/ACP fibrous membranes. Subsequent treatment with acetone yielded a hierarchical porous structure, boasting an ultra-high surface area of 94.7753 ± 0.3884 m2/g. The ACP nanoparticles, initially encapsulated by PLLA, were exposed on the fibre surface after acetone treatment. Furthermore, the porous PLLA/ACP fibrous membrane exhibited superior mechanical properties (Young's modulus = 0.148 GPa, tensile strength = 3.05 MPa) and enhanced wettability. In a 7-day in vitro cell culture with human osteoblast-like cells, the porous PLLA/ACP fibrous membrane demonstrated a significant improvement in osteoblast adhesion and proliferation, with a proliferation rate increase of 252.0% and 298.7% at day 4 and day 7, respectively. These findings underscore the potential of the porous PLLA/ACP fibrous membrane as a promising candidate for bone tissue scaffolds.

Anti-Inflammatory Peptide-Conjugated Silk Fibroin/Cryogel Hybrid Dual Fiber Scaffold with Hierarchical Structure Promotes Healing of Chronic Wounds.

Chronic wounds resulting from diabetes, pressure, radiation therapy, and other factors continue to pose significant challenges in wound healing. To address this, this study introduces a novel hybrid fibroin fibrous scaffold (FFS) comprising randomly arranged fibroin fibers and vertically aligned cryogel fibers (CFs). The fibroin scaffold is efficiently degummed at room temperature and simultaneously formed a porous structure. The aligned CFs are produced via directional freeze-drying, achieved by controlling solution concentration and freezing polymerization temperature. The incorporation of aligned CFs into the expanded fibroin fiber scaffold leads to enhanced cell infiltration both in vitro and in vivo, further elevating the hybrid scaffold's tissue compatibility. The anti-inflammatory peptide 1 (AP-1) is also conjugated to the hybrid fibrous scaffold, effectively transforming the inflammatory status of chronic wounds from pro-inflammatory to pro-reparative. Consequently, the FFS-AP1+CF group demonstrates superior granulation tissue formation, angiogenesis, collagen deposition, and re-epithelialization during the proliferative phase compared to the commercial product PELNAC. Moreover, the FFS-AP1+CF group displays epidermis thickness, number of regenerated hair follicles, and collagen density closer to normal skin tissue. These findings highlight the potential of random fibroin fibers/aligned CFs hybrid fibrous scaffold as a promising approach for skin tissue filling and tissue regeneration.

Assessment of Selected Surface and Electrochemical Properties of Boron and Strontium-Substituted Hydroxyapatites.

Tissue engineering is an interdisciplinary field of science that has been developing very intensively over the last dozen or so years. New ways of treating damaged tissues and organs are constantly being sought. A variety of porous structures are currently being investigated to support cell adhesion, differentiation, and proliferation. The selection of an appropriate biomaterial on which a patient's new tissue will develop is one of the key issues when designing a modern tissue scaffold and the associated treatment process. Among the numerous groups of biomaterials used to produce three-dimensional structures, hydroxyapatite (HA) deserves special attention. The aim of this paper was to discuss changes in the double electrical layer in hydroxyapatite with an incorporated boron and strontium/electrolyte solution interface. The adsorbents were prepared via dry and wet precipitation and low-temperature nitrogen adsorption and desorption methods. The specific surface area was characterized, and the surface charge density and zeta potential were discussed.

Controlled pore anisotropy in chitosan-gelatin cryogels for use in bone tissue engineering.

In tissue engineering, the development of an appropriate scaffold is crucial to provide a framework for new tissue growth. The use of cryogels as scaffolds shows promise due to their macroporous structure, but the pore size, distribution, and interconnectivity is highly variable depending on the fabrication process. The objective of the current research is to provide a technique for controlled anisotropy in chitosan-gelatin cryogels to develop scaffolds for bone tissue engineering application. A mold was developed using additive manufacturing to be used during the freezing process in order to fabricate cryogels with a more interconnected pore structure. The scaffolds were tested to evaluate their porosity, mechanical strength, and to observe cell infiltration through the cryogel. It was found that the use of the mold allowed for the creation of designated pores within the cryogel structure which facilitated cell infiltration to the center of the scaffold without sacrificing mechanical integrity of the structure.

Design and optimization of 3D-bioprinted cell-laden scaffolds in dynamic culture

Light-based 3D printing enables the fabrication of biological scaffolds with high precision, versatility and biocompatibility, particularly the cell-laden scaffolds with architecturally complex geometric features. However, many bioprinted tissue scaffolds suffer from low cell viability due to insufficient oxygen and nutrient supply, which is heavily influenced by scaffold structure and cultivation conditions. Current practice relies mainly on resource-intensive trial-and-error methods to optimize scaffolds’ structures and cultivation parameters. In this study, we developed a comprehensive multi-physics model integrating fluid dynamics, oxygen mass transfer, cell oxygen consumption, and cell growth processes to capture cell growth behaviors in scaffolds, establishing a robust theoretical foundation for scaffold structure optimization. The modeling results showed that a large number of parameters, such as system inlet flow rate, geometric feature size, cell parameters, and material properties, significantly impact oxygen concentration and cell growth within the scaffold. A two-step optimization strategy is proposed in this paper and was applied to obtain optimal geometric parameters of channeled scaffolds to demonstrate the model’s effectiveness for scaffold optimization. The model can be employed for scaffolds with arbitrary shapes and various materials, facilitating the optimal design of sophisticated scaffolds for more advanced tissue engineering.

Multi-objective optimization for designing porous scaffolds with controllable mechanics and permeability: A case study on triply periodic minimal surface scaffolds

Design of tissue scaffolds in terms of multiple objectives such as mechanical and biological performances simultaneously remains challenging. In this paper, we present the development of a topology optimization approach that enables to design porous scaffolds with consideration of both mechanical and fluid properties simultaneously. The relationship between structural parameters, mechanical and mass transport properties was investigated, and then the scaffolds were optimized under the constraint of given pore size, porosity and specific surface area. Case studies on the optimized design of triply periodic minimal surface (TPMS) scaffolds were performed to illustrate the effective of our approach. Simulation and experimental results demonstrated that the proposed optimization approach fully decouples the mechanical and mass transport properties, specifically, under given porosities, the elastic modulus and permeability of optimized scaffolds ranged from 1.33 GPa to 16.7 GPa and 0.07 × 10−8 m2 to 1.62 × 10−8 m2, respectively. Three types of optimized gradient scaffolds were designed and they all exhibited significant functional gradients and high adjustability. The proposed approach decouples synergy and enables individual customization of multi-physics properties, providing practical guidance for gradient scaffolds with desired performance.

Induction of macrophage polarization by electrospun nano-yarn containing naproxen sodium to promote tendon repair

Excessive inflammatory response can lead to failure of the tendon repair surgery. Tendon substitutes that can effectively balance inflammatory responses and have sufficient mechanical properties are one of the key factors in promoting repair. In this study, the nanofibers containing the naproxen sodium were attached to polylactic acid micron yarn by electrospinning to obtain double-layer core-spun yarn (DY). The DY was knitted into a tendon tissue engineering scaffold with sufficient mechanical properties. This study confirmed the optimal loading concentration of naproxen sodium. The results in vitro and in vivo indicated that sustained-release naproxen sodium in scaffolds could effectively inhibit the rapid proliferation of foreign fibroblasts, accelerate the polarization of macrophages, reduce the inflammatory response, and promote tendon tissue repair. This study provides a new scaffold for tendon tissue engineering that not only serves as a substitute for tendon repair, but also serves as an anti-inflammatory agent to better promote the repair process.