Biofabrication and Signaling Strategies for Tendon/Ligament Interfacial Tissue Engineering

Tendons and ligaments (TL) have poor healing capability, and for serious injuries like tears or ruptures, surgical intervention employing autografts or allografts is usually required. Current tissue replacements are nonideal and can lead to future problems such as high retear rates, poor tissue integration, or heterotopic ossification. Alternatively, tissue engineering strategies are being pursued using biodegradable scaffolds. As tendons connect muscle and bone and ligaments attach bones, the interface of TL with other tissues represent complex structures, and this intricacy must be considered in tissue engineered approaches. In this paper, we review recent biofabrication and signaling strategies for biodegradable polymeric scaffolds for TL interfacial tissue engineering. First, we discuss biodegradable polymeric scaffolds based on the fabrication techniques as well as the target tissue application. Next, we consider the effect of signaling factors, including cell culture, growth factors, and biophysical stimulation. Then, we discuss human clinical studies on TL tissue healing using commercial synthetic scaffolds that have occurred over the past decade. Finally, we highlight the challenges and future directions for biodegradable scaffolds in the field of TL and interface tissue engineering.</p

Natural, synthetic and commercially-available biopolymers used to regenerate tendons and ligaments

Tendon and ligament (TL) injuries affect millions of people annually. Biopolymers play a significant role in TL tissue repair, whether the treatment relies on tissue engineering strategies or using artificial tendon grafts. The biopolymer governs the mechanical properties, biocompatibility, degradation, and fabrication method of the TL scaffold. Many natural, synthetic and hybrid biopolymers have been studied in TL regeneration, often combined with therapeutic agents and minerals to engineer novel scaffold systems. However, most of the advanced biopolymers have not advanced to clinical use yet. Here, we aim to review recent biopolymers and discuss their features for TL tissue engineering. After introducing the properties of the native tissue, we discuss different types of natural, synthetic and hybrid biopolymers used in TL tissue engineering. Then, we review biopolymers used in commercial absorbable and non-absorbable TL grafts. Finally, we explain the challenges and future directions for the development of novel biopolymers in TL regenerative treatment.</p

A novel biocompatible polymeric blend for applications requiring high toughness and tailored degradation rate

Finding the right balance in mechanical properties and degradation rate of biodegradable materials for biomedical applications is challenging, not only at the time of implantation but also during biodegradation. For instance, high elongation at break and toughness with a mid-term degradation rate are required for tendon scaffold or suture application, which cannot be found in each alpha polyester individually. Here, we hypothesise that blending semi-crystalline poly(p-dioxanone) (PDO) and poly(lactide-co-caprolactone) (LCL) in a specific composition will enhance the toughness while also enabling tailored degradation times. Hence, blends of PDO and LCL (PDO/LCL) were prepared in varying concentrations and formed into films by solvent casting. We thoroughly characterised the chemical, thermal, morphological, and mechanical properties of the new blends before and during hydrolytic degradation. Cellular performance was determined by seeding mouse fibroblasts onto the samples and culturing for 72 hours, before using proliferation assays and confocal imaging. We found that an increase in LCL content causes a decrease in hydrolytic degradation rate, as indicated by induced crystallinity, surface and bulk erosions, and tensile properties. Interestingly, the noncytotoxic blend containing 30% PDO and 70% LCL (PDO3LCL7) resulted in small PDO droplets uniformly dispersed within the LCL matrix and demonstrated a tailored degradation rate and toughening behaviour with a notable strain-hardening effect reaching 320% elongation at break; over 3 times the elongation of neat LCL. In summary, this work highlights the potential of PDO3LCL7 as a biomaterial for biomedical applications like tendon tissue engineering or high-performance absorbable sutures.</p

The Technological Advancement to Engineer Next-Generation Stent-Grafts: Design, Material, and Fabrication Techniques

Endovascular treatment of aortic disorders has gained wide acceptance due to reduced physiological burden to the patient compared to open surgery, and ongoing stent-graft evolution has made aortic repair an option for patients with more complex anatomies. To date, commercial stent-grafts are typically developed from established production techniques with simple design structures and limited material ranges. Despite the numerous updated versions of stent-grafts by manufacturers, the reoccurrence of device-related complications raises questions about whether the current manfacturing methods are technically able to eliminate these problems. The technology trend to produce efficient medical devices, including stent-grafts and all similar implants, should eventually change direction to advanced manufacturing techniques. It is expected that through recent advancements, especially the emergence of 4D-printing and smart materials, unprecedented features can be defined for cardiovascular medical implants, like shape change and remote battery-free self-monitoring. 4D-printing technology promises adaptive functionality, a highly desirable feature enabling printed cardiovascular implants to physically transform with time to perform a programmed task. This review provides a thorough assessment of the established technologies for existing stent-grafts and provides technical commentaries on known failure modes. They then discuss the future of advanced technologies and the efforts needed to produce next-generation endovascular implants.</p

In Situ Characterization of Melt–Electrowritten Scaffolds in 3D Using Optical Coherence Tomography

Recent developments in melt electrowriting (MEW), a high-resolution additive manufacturing technology, have led to increases in scaffold complexity. However, MEW scaffolds are currently characterized ex situ, which causes time–consuming iterations of characterization and fabrication that limit scaffold throughput and more widespread use of the technology. For the first time, an in situ method to characterize the 3D microstructure of MEW scaffolds using optical coherence tomography (OCT) is described. Calculations of microstructural features are performed on OCT data using a custom algorithm, demonstrating close correspondence with scanning electron microscopy (SEM). For example, OCT calculations of fiber diameter and scaffold thickness are within an average of 0.31 and 1.79 μm, respectively, of corresponding SEM–derived calculations. Additionally, the 3D capabilities of OCT enable the nondestructive characterization of scaffolds with depth–varying microstructures, overcoming some main limitations of SEM. Finally, in situ characterization is achieved by integrating the OCT scanner within an MEW printer, enabling the scaffold microstructure to be evaluated and optimized during manufacture. This new capability represents an important step toward achieving an efficient fabrication–characterization cycle with the guaranteed scaffold quality and reproducibility required to validate the manufacturing process.<br/

Novel hybrid biocomposites for tendon grafts: The addition of silk to polydioxanone and poly(lactide-co-caprolactone) enhances material properties, in vitro and in vivo biocompatibility

Biopolymers play a critical role as scaffolds used in tendon and ligament (TL) regeneration. Although advanced biopolymer materials have been proposed with optimised mechanical properties, biocompatibility, degradation, and processability, it is still challenging to find the right balance between these properties. Here, we aim to develop novel hybrid biocomposites based on poly(p-dioxanone) (PDO), poly(lactide-co-caprolactone) (LCL) and silk to produce high-performance grafts suitable for TL tissue repair. Biocomposites containing 1–15% of silk were studied through a range of characterisation techniques. We then explored biocompatibility through in vitro and in vivo studies using a mouse model. We found that adding up to 5% silk increases the tensile properties, degradation rate and miscibility between PDO and LCL phases without agglomeration of silk inside the composites. Furthermore, addition of silk increases surface roughness and hydrophilicity. In vitro experiments show that the silk improved attachment of tendon-derived stem cells and proliferation over 72 h, while in vivo studies indicate that the silk can reduce the expression of pro-inflammatory cytokines after six weeks of implantation. Finally, we selected a promising biocomposite and created a prototype TL graft based on extruded fibres. We found that the tensile properties of both individual fibres and braided grafts could be suitable for anterior cruciate ligament (ACL) repair applications

Emerging materials and technologies for advancing bioresorbable surgical meshes

Surgical meshes play a significant role in the treatment of various medical conditions, such as hernias, pelvic floor issues, guided bone regeneration, and wound healing. To date, commercial surgical meshes are typically made of non-absorbable synthetic polymers, notably polypropylene and polytetrafluoroethylene, which are associated with postoperative complications, such as infections. Biological meshes, based on native tissues, have been employed to overcome such complications, though mechanical strength has been a main disadvantage. The right balance in mechanical and biological performances has been achieved by the advent of bioresorbable meshes. Despite improvements, recurrence of clinical complications associated with surgical meshes raises significant concerns regarding the technical adequacy of current materials and designs, pointing to a crucial need for further development. To this end, current research focuses on the design of meshes capable of biomimicking native tissue and facilitating the healing process without post-operative complications. Researchers are actively investigating advanced bioresorbable materials, both synthetic and natural biopolymers, while also exploring the performance of therapeutic agents, surface modification methods and advanced manufacturing technologies such as 4D printing. This review seeks to evaluate emerging biomaterials and technologies for enhancing the performance and clinical applicability of the next-generation of surgical meshes

Spatially heterogeneous tubular scaffolds for In situ heart valve tissue engineering using melt electrowriting

Producción CientíficaHeart valve tissue engineering (HVTE) aims to provide living autologous heart valve implants endowed with regenerative capabilities and life-long durability. However, fabrication of biomimetic scaffolds capable of providing the required functionality in terms of mechanical performance and tunable porosity to enable cellular infiltration remains a major challenge. Here, the additive manufacturing of bioinspired, spatially heterogeneous, tubular scaffolds enclosing the leaflets, inter-leaflet triangles, and their interface for in situ HVTE using melt electrowriting (MEW) is demonstrated. The innovative platform enables the digital fabrication of scaffolds with ad hoc architecture (e.g., tunable location, specific fiber pattern, and orientation) and customizable geometry via a custom-made control software. The user-friendly interface allows for the definition of areas of the scaffold with specific patterns to obtain properties such as tunable J-shaped stress–stain curve and anisotropy typical of the heart valve leaflet, compliant inter-leaflet triangles, and reinforced curvilinear boundary between them. Heterogeneous, tubular, heart valve MEW scaffolds are then embedded with a microporous elastin-like recombinamer (ELR) hydrogel to develop a soft-network composite favoring cell infiltration and ensuring hemocompatibility. The acute systolic hemodynamic functionality of the MEW/ELR composite satisfies the ISO 5840 requirements, under aortic and pulmonary conditions.Australian Research Council (ARC ITTC in Additive Biomanufacturing, IC160100026)German Research Foundation (DFG – Project number: 403170227 ArchiTissue)The START-Program of the Medical Faculty of RWTH Aachen University (60/17)Gobierno de España (PID2019-110709RB-100, RED2018-102417-T)Junta de Castilla y León (VA317P18, Infrared2018-UVA06)Interreg V España-Portugal POCTEP (0624_2IQBIONEURO_6_E