Engineering Multi-scale Structure of the Knee Meniscus using Advanced 3D Nonwovens Fabrication

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Abstract Meniscal tears are the most commonly reported knee injuries, and approximately 1 million surgeries involving the meniscus are performed annually in the US. Tissue engineering and regenerative medicine approaches are being actively pursued as potential alternatives to overcome limitations of current clinical treatments. Yet, the translation of these approaches to clinical application has been hampered by their limited ability to efficiently and reproducibly create physiologic-sized, patient-specific scaffolds featuring anisotropic structural and mechanical properties on the order of native meniscus. 3D printing can create scaffolds that replicate physiologic size and patient-specific geometry in a highly repeatable manner and with good handling characteristics for surgical implantation, yet, these fiber sizes are typically on the order of hundreds of microns, several orders of magnitude higher than the native tissue. On the other hand, nonwoven textiles approaches allow the fabrication of fibers on the scale of native collagen fibrils, but it is infeasible to create complex anatomical 3D geometries, such as that of the knee meniscus. The overall goal of this proposal is to investigate the ability of a new 3D nonwoven scaffold fabrication approach that synergistically integrates attributes of traditional nonwoven melt blowing and 3D printing to overcome these limitations and recapitulate complex anisotropic structural characteristics of the meniscus at multiple scales as a means to provide superior outcomes, in-vitro and in-vivo. We hypothesize that this 3D Melt Blowing (3DMB) approach can allow physiological fiber morphology (similar to other nonwovens such as electrospinning), while also enabling the creation of patient-specific meniscus 3D geometry via the customized rotating mandrel (similar to 3D printing). We further hypothesize that the resulting scaffold features will permit superior in-vivo outcomes, particularly, cell infiltration, new matrix production, and the prevention of cartilage degeneration via control of porosity and fiber size. Aim 1 is to determine the effect of the 3DMB process variables on polycaprolactone scaffold fibrous morphology and resulting ECM organization and biomechanical function using in-vitro, ex-vivo and sub- cutaneous in-vivo models. Additionally within this aim, a response surface function will be developed and validated to correlate cellular infiltration, collagen content, matrix alignment, and mechanics as a function of fiber diameter and scaffold porosity. Aim 2 is to assess the distribution of cellular infiltration and viability, aligned ECM formation and biomechanical function over 26 weeks in a sheep model for patient-specific 3D melt blown meniscus scaffolds of the leading-group determined from Aim 1 outcomes. This Aim will also provide the first one-on-one comparison between the characteristics of the 3DMB nonwoven and traditional 3D printed scaffolds, wherein there is an order of magnitude difference in the fiber morphologies. On completion, this project will provide fundamental knowledge about the micro- and macro-level process-structure-function relationships in meniscus-relevant scaffolds fabricated using our new 3DMB nonwovens approach, and will serve as a base technology of great significance allowing advances in the treatment of orthopaedic fibrous soft tissue injuries.