Maximizing cartilage formation and integration via a trajectory-based tissue engineering approach

Abstract

Given the limitations of current surgical approaches to treat articular cartilage injuries, tissue engineering (TE) approaches have been aggressively pursued. Despite reproduction of key mechanical attributes of native tissue, the ability of TE cartilage constructs to integrate with native tissue must also be optimized for clinical success. In this paper, we propose a “trajectory-based” tissue engineering (TB-TE) approach, based on a hypothesis that time-dependent increases in construct maturation in-vitro prior to implantation (i.e. positive rates) may provide a reliable predictor of in-vivo success. As an example TE system, we utilized hyaluronic acid hydrogels laden with mesenchymal stem cells. We first modeled the maturation of these constructs in-vitro to capture time-dependent changes. We then performed a sensitivity analysis of the model to optimize the timing and amount of data collection. Finally, we showed that integration to cartilage in-vitro is not correlated to the maturation state of TE constructs, but rather their maturation rate, providing a proof-of-concept for the use of TB-TE to enhance treatment outcomes following cartilage injury. This new approach challenges the traditional TE paradigm of matching only native state parameters of maturity and emphasizes the importance of also establishing an in-vitro trajectory in constructs in order to improve the chance of in-vivo success.

Cartilage Repair and Subchondral Bone Remodeling in Response to Focal Lesions in a Mini-Pig Model: Implications for Tissue Engineering

“…[19][20][21] Two days before surgery, MeHA macromer was sterilized by exposure to a biocidal UV lamp for 15 min and dissolved in saline at 1% (mass/ volume) with 0.05% Irgacure-2959 photoinitiator (CibaGeigy). Hydrogels were polymerized within the defects via exposure to UV light (365 nm) for 10 min at an intensity of 1 mW/cm 2 (Omnicure S2000; Lumen Dynamics Group).…”

“…This is a base material that our group and others has used as a cell-delivery vehicle and scaffold for cartilage TE. 14,[19][20][21] It is important to note that the bioactivity of the HA hydrogel had no discernable impact on bony remodeling or the morphology of the tissue which formed in the cartilage defect. These results are similar to the in-vivo findings for other ''scaffold-only'' formulations in the literature.…”

“…6,[8][9][10][11][12] While not yet in clinical practice, many other tissue engineering (TE) and regenerative medicine approaches have also been pursued with some approaches achieving biomechanical and biochemical properties on the order of native cartilage. [13][14][15][16][17][18][19][20][21][22] When translating new TE technologies and surgical approaches to preclinical large animal models, it is important to note that the type of defect can vary substantially (e.g., partial-thickness chondral vs. full-thickness chondral vs. osteochondral). [23][24][25][26][27][28][29] Although full-thickness chondral defects are clinically relevant, the thin cartilage in most species ( < 1 mm) raises questions regarding the ability of an implanted construct to remain within the defect postoperatively.…”

Growth Factor-Mediated Migration of Bone Marrow Progenitor Cells for Accelerated Scaffold Recruitment

“…1A). 1,[7][8][9][10][11][12][13][14] One candidate class of scaffolds for augmenting microfracture is self-assembling peptide hydrogels. 15,16 These injectable hydrogels assemble upon exposure to physiological pH and ionic strength at concentrations less than 0.5%, allowing ample space for cells to deposit neotissue.…”

Anatomic Mesenchymal Stem Cell-Based Engineered Cartilage Constructs for Biologic Total Joint Replacement

“…28,29 Using these photopolymerizable HA networks (formed through ultraviolet (UV)-induced free radical generation), chondrocytes and MSCs can be encapsulated to generate neocartilage with biochemical and mechanical properties approaching that of native tissue. 24,[29][30][31][32] However, this UV-mediated crosslinking method is generally not compatible with rapid prototyping techniques in which cells suspended in liquid monomer are injected into opaque anatomic 3D molds made from metal or plastic. Recently, Temenoff et al developed a thermal radical initiation system that was used to encapsulate rat marrow stromal cells.…”