Novel Osteochondral Biotemplate Improves Long-term Cartilage Repair Compared With Microfracture in an Ovine Model.

BACKGROUND: Current cartilage repair therapies do not re-create the complex mechanical interface between cartilage and bone, which is critical for long-term repair durability. New biomaterial designs that include hard tissue-soft tissue interface structures offer promise to improve clinical outcomes. PURPOSE/HYPOTHESIS: The purpose of this study was to evaluate the efficacy and safety of a naturally derived osteochondral biotemplate with a novel contiguous hard tissue-soft tissue interface in an ovine model as a regenerative solution for articular cartilage defects. It was hypothesized that the osteochondral biotemplate would produce structurally superior repair tissue compared with microfracture over a 13-month period. STUDY DESIGN: Controlled laboratory study. METHODS: Osteochondral biotemplates were manufactured from porcine cancellous bone. Skeletally mature sheep (N = 30) were randomly allocated to 3 groups: early healing stage (euthanasia at 4 months), 6-month treatment, and 13-month treatment. In the early healing stage group, an 8 mm-diameter by 5 mm-deep osteochondral defect was created on the medial femoral condyle and treated at the time of iatrogenic injury with an osteochondral biotemplate. The contralateral limb received the same treatment 2 months later. In the 6- and 13-month treatment groups, 1 limb received the same osteochondral procedure as the early healing stage group. In the contralateral limb, an 8 mm-diameter, full-thickness cartilage defect (1-2 mm deep) was created and treated with microfracture. Cartilage repair and integration were quantitatively and qualitatively assessed with gross inspection, histological evaluation, and magnetic resonance imaging (MRI). Wilcoxon signed-rank and McNemar tests were used to compare the treatments. RESULTS: At 6 and 13 months after treatment, the biotemplate was not present histologically. At 13 months, the biotemplate treatment demonstrated statistically higher histological scores than microfracture for integration with surrounding cartilage (biotemplate: 74 ± 31; microfracture: 28 ± 39; P = .03), type 2 collagen (biotemplate: 72 ± 33; microfracture: 40 ± 38; P = .02), total cartilage (biotemplate: 71 ± 9; microfracture: 59 ± 9; P = .01), and total integration (biotemplate: 85 ± 15; microfracture: 66 ± 20; P = .04). The osteochondral biotemplate treatment produced a notable transient nonneutrophilic inflammatory response that appeared to approach resolution at 13 months. MRI results were not statistically different between the 2 treatments. CONCLUSION: Even with the inflammatory response, after 13 months, the osteochondral biotemplate outperformed microfracture in cartilage regeneration and demonstrated superiority in integration between the repair tissue and host tissue as well as integration between the newly formed cartilage and the underlying bone. CLINICAL RELEVANCE: This work has demonstrated the clinical potential of a novel biomaterial template to regenerate the complex mechanical interface between cartilage and the subchondral bone.

Advancing Engineered Heart Muscle Tissue Complexity with Hydrogel Composites.

A heart attack results in the permanent loss of heart muscle and can lead to heart disease, which kills more than 7 million people worldwide each year. To date, outside of heart transplantation, current clinical treatments cannot regenerate lost heart muscle or restore full function to the damaged heart. There is a critical need to create engineered heart tissues with structural complexity and functional capacity needed to replace damaged heart muscle. The inextricable link between structure and function suggests that hydrogel composites hold tremendous promise as a biomaterial-guided strategy to advance heart muscle tissue engineering. Such composites provide biophysical cues and functionality as a provisional extracellular matrix that hydrogels cannot on their own. This review describes the latest advances in the characterization of these biomaterial systems and using them for heart muscle tissue engineering. The review integrates results across the field to provide new insights on critical features within hydrogel composites and perspectives on the next steps to harnessing these promising biomaterials to faithfully reproduce the complex structure and function of native heart muscle.

Extrusion 3D Printing of Porous Silicone Architectures for Engineering Human Cardiomyocyte-Infused Patches Mimicking Adult Heart Stiffness.

Cardiac patches, three-dimensional (3D) constructs of polymer scaffold and heart muscle cells, have received widespread attention for regenerative therapy to repair damaged heart tissue. The implanted patches should mimic the micromechanical environment of native myocardium for effective integration and optimum mechanical function. In this study, we engineered compliant silicone scaffolds infused with cardiomyocytes (CMs) differentiated from human-induced pluripotent stem cells. Porous scaffolds are fabricated by extrusion 3D printing of room-temperature-vulcanized (RTV) silicone rubber. The stiffness and strength of scaffolds are tailored by designing a polymer strand arrangement during 3D printing. Single-strand scaffold design is found to display a tensile Young's modulus of ∼280 kPa, which is optimum for supporting CMs without impairing their contractility. Uniform distribution of cells in the scaffold is observed, ascribed to 3D migration facilitated by interconnected porous architecture. The patches demonstrated synchronized contraction 10 days after seeding scaffolds with CMs. Indentation measurements reveal that the contracting cell-scaffold patches display local moduli varying from ∼270 to 530 kPa, which covers the upper spectrum of the stiffness range displayed by the human heart. This study demonstrates the effectiveness of a porous 3D scaffold composed of flexible silicone rubber for CMs percolation, supporting a contractile activity, and mimicking native heart stiffness.

Functional MRI can detect changes in intratissue strains in a full thickness and critical sized ovine cartilage defect model.

Functional imaging of tissue biomechanics can reveal subtle changes in local softening and stiffening associated with disease or repair, but noninvasive and nondestructive methods to acquire intratissue measures in well-defined animal models are largely lacking. We utilized displacement encoded MRI to measure changes in cartilage deformation following creation of a critical-sized defect in the medial femoral condyle of ovine (sheep) knees, a common in situ and large animal model of tissue damage and repair. We prioritized visualization of local, site-specific variation and changes in displacements and strains following defect placement by measuring spatial maps of intratissue deformation. Custom data smoothing algorithms were developed to minimize propagation of noise in the acquired MRI phase data toward calculated displacement or strain, and to improve strain measures in high aspect ratio tissue regions. Strain magnitudes in the femoral, but not tibial, cartilage dramatically increased in load-bearing and contact regions especially near the defect locations, with an average 6.7% ±â€¯6.3%, 13.4% ±â€¯10.0%, and 10.0% ±â€¯4.9% increase in first and second principal strains, and shear strain, respectively. Strain heterogeneity reflected the complexity of the in situ mechanical environment within the joint, with multiple tissue contacts defining the deformation behavior. This study demonstrates the utility of displacement encoded MRI to detect increased deformation patterns and strain following disruption to the cartilage structure in a clinically-relevant, large animal defect model. It also defines imaging biomarkers based on biomechanical measures, in particular shear strain, that are potentially most sensitive to evaluate damage and repair, and that may additionally translate to humans in future studies.

In vitro and in vivo evaluation of orthopedic interface repair using a tissue scaffold with a continuous hard tissue-soft tissue transition.

Tendon tears produce pain and decrease joint stability; each year, over 1.1 million rotator cuff tendon surgical procedures are performed worldwide. However, surgical success is highly variable, and the inability of the procedure to drive the regeneration of the normal tendon-bone interface has been identified as a key factor in surgical failure. This study focuses on the development, in vitro evaluation, and in vivo assessment of a tissue scaffold derived from bovine cancellous bone with the potential to direct regeneration of a bone-soft tissue interface. The scaffold is a highly porous scaffold with a continuous hard tissue-soft tissue transition that facilitates load transfer across the interface and contains all of the extracellular matrix components of the orthopedic interface. This study demonstrated the in vitro characterization of the mechanical properties and successful in vivo assessment using an ovine model.

Mechanical characterization of collagen fibers and scaffolds for tissue engineering.

Engineered tissues must utilize scaffolding biomaterials that support desired cellular functions and possess or can develop appropriate mechanical characteristics. This study assessed properties of collagen as a scaffolding biomaterial for ligament replacements. Mechanical properties of extruded bovine achilles tendon collagen fibers were significantly affected by fiber diameter, with smaller fibers displaying higher tangent moduli and peak stresses. Mechanical properties of 125 micrometer-diameter extruded fibers (tangent modulus of 359.6+/-28.4MPa; peak stress of 36.0+/-5.4MPa) were similar to properties reported for human ligaments. Scaffolds of extruded fibers did not exhibit viscoelastic creep properties similar to natural ligaments. Collagen fibers from rat tail tendon (a well-studied comparison material) displayed characteristic strain-softening behavior, and scaffolds of rat tail fibers demonstrated a non-intuitive relationship between tangent modulus and specimen length. Composite scaffolds (extruded collagen fibers cast within a gel of Type I rat tail tendon collagen) were maintained with and without fibroblasts under standard culture conditions for 25 days; cell-incorporated scaffolds displayed significantly higher tangent moduli and peak stresses than those without cells. Because tissue-engineered products must possess appropriate mechanical as well as biological/chemical properties, data from this study should help enable the development of improved tissue analogues.