Nasal septum-derived chondroprogenitor cells control mandibular condylar resorption consequent to orthognathic surgery: a clinical trial

Abstract

Condylar resorption is an aggressive and disability form of temporomandibular joint (TMJ) degenerative disease, usually non-respondent to conservative or minimally invasive therapies and often leading to surgical intervention and prostheses implantation. This condition is also one of the most dreaded postoperative complications of orthognathic surgery, with severe cartilage erosion and loss of subchondral bone volume and mineral density, associated with a painful or not inflammatory processes. Because regenerative medicine has emerged as an alternative for orthopedic cases with advanced degenerative joint disease, we conducted a phase I/IIa clinical trial (U1111-1194-6997) to evaluate the safety and efficacy of autologous nasal septal chondroprogenitor cells. Ten participants underwent biopsy of the nasal septum cartilage during their orthognathic surgery. The harvested cells were cultured in vitro and analyzed for viability, presence of phenotype markers for mesenchymal stem and/or chondroprogenitor cells, and the potential to differentiate into chondrocytes, adipocytes, and osteoblasts. After the intra-articular injection of the cell therapy, clinical follow-up was performed using the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) and computed tomography (CT) images. No serious adverse events related to the cell therapy injection were observed during the 12-month follow-up period. It was found that autologous chondroprogenitors reduced arthralgia, promoted stabilization of mandibular function and condylar volume, and regeneration of condylar tissues. This study demonstrates that chondroprogenitor cells from the nasal septum may be a promise strategy for the treatment of temporomandibular degenerative joint disease that do not respond to other conservative therapies.

Keywords: cellular therapy; clinical translational; progenitor cells; skeleton.

Graphical Abstract

Figure 1.

(A) In vitro chondrogenic differentiation. Cells were induced to chondrogenic differentiation (induced) or were not induced (control). Type II collagen immunohistological staining. (B) In vitro adipogenic differentiation. Cells were induced to adipogenic differentiation (induced) or were not induced (control). Oil Red O dye identifies the presence of lipid vacuoles inside the cells. (C) In vitro osteogenic differentiation. Cells were induced to osteogenic differentiation (induced) or were not induced (control). Brightfield and corresponding Alizarin Red stained identify calcium deposits produced by differentiated cells. (D) Percentage of type II collagen immunopositive cells. No significant difference between the control group and the cells induced to differentiation was observed. (E) Oil Red O quantification and (F) Alizarin Red S quantification. After differentiation, samples were submitted to the Oil Red O dye absorbance quantification assay to quantify the adipogenic differentiation and the Alizarin Red S dye absorbance quantification assay to quantify osteogenic differentiation. A statistical difference was observed for adipogenic and osteogenic differentiation (P < .01). Scale bar= 200 μm (A) and 50 μm (B and C).

Figure 2.

Relative expression analysis of genes related to chondrogenesis and osteogenesis after chondrogenic differentiation. The dotted line represents the expression at control (non-induced) condition. Statistical analysis was performed using the Mann-Whitney test. *P < .05.

Figure 3.

Image analysis by computed tomography of the TMJ joint and 3-dimensional remodeling images of condyles of participants before and after autologous chondroprogenitor cells joint injection. Right and left CT images from the patients before (upper line) and 8-15 months after (bottom line) the treatment: external lateral view (0^°), frontal view (90^°), and internal lateral view (180^°). Prior to the initiation of the treatment, specific regions were demarcated using arrowheads, with the color blue designating instances of discontinuous cortical structure, and rose indicating continuous cortical structure. Subsequent to the treatment, the designated areas were redefined with arrows, wherein blue represented bone apposition and recorticalization, red signified bone apposition, white denoted recorticalization, rose represented continuous cortical structure, and yellow was assigned to discontinuous cortical structure. Additionally, the presence of a blue star was used to highlight areas undergoing adaptive remodeling. The color map indicates condylar resorption (negative value) and apposition (positive value) on the superimposed condylar surfaces (before and after treatment models). The orange arrows establish a correlation between the pre-treatment and post-treatment regions in the computed tomography (CT) scans and their respective counterparts observed in the 3-dimensional superimposed images.