ABSTRACT Musculoskeletal knee injuries are common and debilitating, with the most prevalent soft tissue injuries being anterior cruciate ligament (ACL) and meniscal tears. These tears do not heal well naturally, and biological therapies involving scaffolds are often unsuccessful, due in part to the synovial fluid environment of the joint. Viscous synovial fluid contains high concentrations of degradative enzymes, including plasmin, which prevents the stable formation of provisional fibrin scaffolds. Lack of provisional scaffold formation prevents bridging of torn tissue and subsequent remodeling for permanent tissue repair. Coagulation factors such as fibrinogen and thrombin, reinforced with synthetic platelet‐like particles (PLPs), can be introduced to synovial fluid to promote fibrin scaffold formation. PLPs bind to and retract fibrin fibers to enhance stiffness, density, and stability of fibrin scaffolds. Therefore, the objective of this work is to investigate the role of PLPs in enhancing fibrin scaffold formation and degradation capabilities within synovial fluid and to characterize the resulting scaffold structure, density, and mechanics. We investigated effects in synovial fluid with high or low viscosity, as viscosity can change with injury and can vary between individuals. Following the addition of clotting factors and PLPs to synovial fluid, we found an increase in fibrin scaffold density, structure, and maximum mechanics for low viscosity, but not high viscosity, synovial fluid groups. Furthermore, by lowering the viscosity of synovial fluid with hyaluronidase, the increase in scaffold density following PLP addition was restored, indicating the strong role of synovial fluid viscosity on stable scaffold formation. This technology contributes to the development of a more robust fibrin‐based therapy for intra‐articular musculoskeletal injuries. more »« less
Scull, Grant; Fisher, Matthew B.; Brown, Ashley C.
(, MEDICAL DEVICES & SENSORS)
null
(Ed.)
Anterior cruciate ligament (ACL) tears are a common and potentially career‐ending injury, particularly for athletes and soldiers. Partial and complete ruptures of this ligament cause instability in the knee, and the ACL does not have the capacity for healing due, in part, to its position within the highly thrombolytic synovial fluid environment of the knee joint. Traditional methods of ACL reconstruction, such as graft replacement, restore stability but do not prevent the development of post‐traumatic osteoarthritis. To enhance therapeutic treatment options, novel fibrin‐based technologies and repair techniques have been recently explored and show promise for improved patient outcomes. Through modification of existing surgical methods, such as the use of fibrin glues incorporating growth factors and cells and the implementation of scaffolds containing platelet‐rich plasma, platelet‐rich fibrin and other blood derivatives, surgeons are attempting to overcome the shortcomings of traditional treatments. This mini‐review will detail current efforts using fibrin‐based treatments and discuss opportunities to further enhance ACL healing.
Uncontrolled bleeding after trauma represents a substantial clinical problem. The current standard of care to treat bleeding after trauma is transfusion of blood products including platelets; however, donated platelets have a short shelf life, are in limited supply, and carry immunogenicity and contamination risks. Consequently, there is a critical need to develop hemostatic platelet alternatives. To this end, we developed synthetic platelet-like particles (PLPs), formulated by functionalizing highly deformable microgel particles composed of ultralow cross-linked poly (N-isopropylacrylamide) with fibrin-binding ligands. The fibrin-binding ligand was designed to target to wound sites, and the cross-linking of fibrin polymers was designed to enhance clot formation. The ultralow cross-linking of the microgels allows the particles to undergo large shape changes that mimic platelet shape change after activation; when coupled to fibrin-binding ligands, this shape change facilitates clot retraction, which in turn can enhance clot stability and contribute to healing. Given these features, we hypothesized that synthetic PLPs could enhance clotting in trauma models and promote healing after clotting. We first assessed PLP activity in vitro and found that PLPs selectively bound fibrin and enhanced clot formation. In murine and porcine models of traumatic injury, PLPs reduced bleeding and facilitated healing of injured tissue in both prophylactic and immediate treatment settings. We determined through biodistribution experiments that PLPs were renally cleared, possibly enabled by ultrasoft particle properties. The performance of synthetic PLPs in the preclinical studies shown here supports future translational investigation of these hemostatic therapeutics in a trauma setting.
Chan, Deva D; Guilak, Farshid; Sah, Robert L; Calve, Sarah
(, Annual Review of Biomedical Engineering)
Toner, Mehmet; Yarmush, Martin L
(Ed.)
Hyaluronan (HA) plays well-recognized mechanical and biological roles in articular cartilage and synovial fluid, where it contributes to tissue structure and lubrication. An understanding of how HA contributes to the structure of other musculoskeletal tissues, including muscle, bone, tendon, and intervertebral discs, is growing. In addition, the use of HA-based therapies to restore damaged tissue is becoming more prevalent. Nevertheless, the relationship between biomechanical stimuli and HA synthesis, degradation, and signaling in musculoskeletal tissues remains understudied, limiting the utility of HA in regenerative medicine. In this review, we discuss the various roles and significance of endogenous HA in musculoskeletal tissues. We use what is known and unknown to motivate new lines of inquiry into HA biology within musculoskeletal tissues and in the mechanobiology governing HA metabolism by suggesting questions that remain regarding the relationship and interaction between biological and mechanical roles of HA in musculoskeletal health and disease.
Coburn, Brandon; Salary, Roozbeh “Ross”
(, American Society of Mechanical Engineers (ASME))
Abstract Cell-laden, scaffold-based tissue engineering methods have been successfully utilized for the treatment of bone fractures and diseases, caused by factors such as trauma, tumors, congenital anomalies, and aging. In such methods, the rate of scaffold biodegradation, transport of nutrients and growth factors, as well as removal of cell metabolic wastes at the site of injury are critical fluid-dynamics factors, affecting cell proliferation and ultimately tissue regeneration. Therefore, there is a critical need to identify the underlying material transport mechanisms and factors associated with cell-seeded, scaffold-based bone tissue engineering. The overarching goal of this study is to contribute to patient-specific, clinical treatment of bone pathology. The overall objective of the work is to establish computational fluid dynamics (CFD) models to identify: (i) the consequential mechanisms behind internal and external material transport through/over porous bone scaffolds and (ii) optimal triply periodic minimal surface (TPMS) scaffold designs toward cell-laden bone fracture treatment. In this study, 10 internal-flow and 10 external-flow CFD models were established using ANSYS, correspondingly based on 10 single-unit TPMS bone scaffold designs, where the geometry of each design was parametrically created using Rhinoceros 3D software. The influence of several design parameters, such as surface representation iteration, merged toggle iso value, and wall thickness, on geometry accuracy as well as computational time, was investigated in order to obtain computationally efficient and accurate CFD models. The fluid properties (such as density and dynamic viscosity) as well as the boundary conditions (such as no-slip condition, inlet flow velocity, and pressure outlet) of the CFD models were set based on clinical/research values reported in the literature as well as according to the fundamentals of internal/external Newtonian flow modeling. Several fluid characteristics, including flow velocity, flow pressure, and wall shear stress, were analyzed to observe material transport internally through and externally over the TPMS scaffold designs. Regarding the internal flow CFD modeling, it was observed that “P.W. Hybrid” (i.e., Design #7) had the highest-pressure output, with “Neovius” (i.e., Design #1) following second to it. These two designs have a relatively flatter surface area. In addition, “Schwarz P” (i.e., Design #2) was the lowest pressure output of all 10 TPMS designs. “Neovius” and “Schwarz P” had the highest and lowest values of wall shear stress. Besides, the velocity streamlines analysis showed an increase in velocity along the curved sections of the scaffolds’ geometry. Regarding the external flow CFD modeling, it was observed that “Neovius” yielded the highest-pressure output within the inlet section, which contains the area of the highest-pressure location. Furthermore, “Diamond” (i.e., Design #8) displayed having the highest values of wall shear stress due to the results of fluid interaction that accrues with complex curved structures. Also, when we look at designs like “Schwarz G”, the depiction of turbulent motion can be seen along the internal curved sections of the structure. As the external velocity streamlines decrease within the inner channels of the designs, this will lead to an increased pressure buildup due to the intrinsic interactions between the fluid with the walls. Overall, the outcomes of this study pave the way for optimal design and fabrication of complex, bone-like tissues with desired material transport properties for cell-laden, scaffold-based treatment of bone fractures.
Jimenez, Julian M.; Tuttle, Tyler; Guo, Yifan; Miles, Dalton; Buganza-Tepole, Adrian; Calve, Sarah
(, Acta Biomaterialia)
Fibrin is a naturally occurring protein network that forms a temporary structure to enable remodeling during wound healing. It is also a common tissue engineering scaffold because the structural properties can be controlled. However, to fully characterize the wound healing process and improve the design of regenerative scaffolds, understanding fibrin mechanics at multiple scales is necessary. Here, we present a strategy to quantify both the macroscale (1–10 mm) stress-strain response and the deformation of the mesoscale (10–1000 µm) network structure during unidirectional tensile tests. The experimental data were then used to inform a computational model to accurately capture the mechanical response of fibrin gels. Simultaneous mechanical testing and confocal microscopy imaging of fluorophore-conjugated fibrin gels revealed up to an 88% decrease in volume coupled with increase in volume fraction in deformed gels, and non-affine fiber alignment in the direction of deformation. Combination of the computational model with finite element analysis enabled us to predict the strain fields that were observed experimentally within heterogenous fibrin gels with spatial variations in material properties. These strategies can be expanded to characterize and predict the macroscale mechanics and mesoscale network organization of other heterogeneous biological tissues and matrices.
@article{osti_10579831,
place = {Country unknown/Code not available},
title = {Noninvasive Fibrin Targeting Colloid‐Mediated Intra‐Articular Repair},
url = {https://par.nsf.gov/biblio/10579831},
DOI = {10.1002/jbm.a.37901},
abstractNote = {ABSTRACT Musculoskeletal knee injuries are common and debilitating, with the most prevalent soft tissue injuries being anterior cruciate ligament (ACL) and meniscal tears. These tears do not heal well naturally, and biological therapies involving scaffolds are often unsuccessful, due in part to the synovial fluid environment of the joint. Viscous synovial fluid contains high concentrations of degradative enzymes, including plasmin, which prevents the stable formation of provisional fibrin scaffolds. Lack of provisional scaffold formation prevents bridging of torn tissue and subsequent remodeling for permanent tissue repair. Coagulation factors such as fibrinogen and thrombin, reinforced with synthetic platelet‐like particles (PLPs), can be introduced to synovial fluid to promote fibrin scaffold formation. PLPs bind to and retract fibrin fibers to enhance stiffness, density, and stability of fibrin scaffolds. Therefore, the objective of this work is to investigate the role of PLPs in enhancing fibrin scaffold formation and degradation capabilities within synovial fluid and to characterize the resulting scaffold structure, density, and mechanics. We investigated effects in synovial fluid with high or low viscosity, as viscosity can change with injury and can vary between individuals. Following the addition of clotting factors and PLPs to synovial fluid, we found an increase in fibrin scaffold density, structure, and maximum mechanics for low viscosity, but not high viscosity, synovial fluid groups. Furthermore, by lowering the viscosity of synovial fluid with hyaluronidase, the increase in scaffold density following PLP addition was restored, indicating the strong role of synovial fluid viscosity on stable scaffold formation. This technology contributes to the development of a more robust fibrin‐based therapy for intra‐articular musculoskeletal injuries.},
journal = {Journal of Biomedical Materials Research Part A},
volume = {113},
number = {4},
publisher = {Wiley Blackwell (John Wiley & Sons)},
author = {Scull, Grant and Thompson, Jacob_D and Osareh, Melika and Rey, Ysabel and Aligwekwe, Adrian and Finkelstein, Sofie and Schnabel, Lauren_V and Fisher, Matthew_B and Brown, Ashley},
}
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