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. 2018 Jun 20;10(446):eaaq1802.
doi: 10.1126/scitranslmed.aaq1802.

Tissue engineering toward temporomandibular joint disc regeneration

Affiliations

Tissue engineering toward temporomandibular joint disc regeneration

Natalia Vapniarsky et al. Sci Transl Med. .

Abstract

Treatments for temporomandibular joint (TMJ) disc thinning and perforation, conditions prevalent in TMJ pathologies, are palliative but not reparative. To address this, scaffold-free tissue-engineered implants were created using allogeneic, passaged costal chondrocytes. A combination of compressive and bioactive stimulation regimens produced implants with mechanical properties akin to those of the native disc. Efficacy in repairing disc thinning was examined in minipigs. Compared to empty controls, treatment with tissue-engineered implants restored disc integrity by inducing 4.4 times more complete defect closure, formed 3.4-fold stiffer repair tissue, and promoted 3.2-fold stiffer intralaminar fusion. The osteoarthritis score (indicative of degenerative changes) of the untreated group was 3.0-fold of the implant-treated group. This tissue engineering strategy paves the way for developing tissue-engineered implants as clinical treatments for TMJ disc thinning.

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Conflict of interest statement

Competing interests: The authors have no conflicts of interest.

Figures

Fig. 1.
Fig. 1.. Formation of tissue engineered (TE) implants from costal chondrocytes and representative gross morphological and histological images.
(A) Diagram depicting the tissue engineering strategy and timeline from isolation of costal chondrocytes to the implants’ in vivo assessment. Costal cartilage from minipigs was harvested as an allogeneic donor chondrocyte source. The chondrocytes were then expanded in monolayer, redifferentiated in an aggregate culture, and self-assembled into 3D constructs using a scaffold-free approach. Upon construct maturation, the tissue engineered implants’ safety and efficacy were assessed via orthotopic implantation into TMJ discs. (B) Tissue engineered implants’ gross morphology. The tissue engineered implants’ dimensions shown are 8 mm × 8 mm × 0.4 mm (bar = 5 mm, n = 24). (C) Tissue engineered implants’ histology at time of implantation. Shown are hematoxylin and eosin (H&E), PicroSirius Red (PSR), and Safranin O/fast green (SafO/FG) stained sections (bar = 500 μm and 20 μm, respectively, n = 12).
Fig. 2:
Fig. 2:. Schematic and intraoperative images demonstrating the intra-laminar fenestration surgical technique.
This technique allowed modeling of TMJ disc thinning, orthotopic implantation, and the tissue engineered implant’s fixation in the TMJ disc of a minipig. (A, A’, B, B’) Posterolateral surgical approach to the TMJ disc is demonstrated. (C, C’) The disc is partially released from its posterolateral attachments, gently pulled caudally, and rotated superiorly. (D, D’, E, E’) Horizontal dissection is performed to create a bilaminar pouch. (F, F’, G, G’) A 3 mm fenestration defect is made in the pouch’s inferior lamina. (H, H’) The tissue engineered implant is inserted into the pouch. (J, J’, K, K’) The pouch is closed with sutures, and the disc attachments are reproduced with Quickanchor Plus and #0 suture. Bar = 5 mm.
Fig. 3.
Fig. 3.. Histological and immunohistochemical assessment of integration and safety of the tissue engineered implants.
(A, B) Gross morphology of the sections obtained from the minipig discs treated with tissue engineered implants, 2 and 8 weeks after implantation, respectively. (C, D) Low magnification H&E histology of the disc section containing a tissue engineered implant, which appears as a purple band at 2 weeks and as pale pink band at 8 weeks, respectively. (E, F, G, H) Higher magnification of the H&E sections containing implants at 2 and 8 weeks post-implantation, respectively. (I, J) Immunoreactivity for T cells (CD3) at 2 and 8 weeks, respectively. (K, L) Immunoreactivity for B cells (CD20) at 2 and 8 weeks, respectively. (M, N) Immunoreactivity for macrophages (CD68) at 2 and 8 weeks, respectively. Bar = 2 mm for A-H, bar = 200 μm for I-N.
Fig. 4.
Fig. 4.. Gross morphological and histological assessments of the TMJ disc and mandibular heads comparing the tissue engineered (TE) implant-treated to the untreated group at 8 weeks post-implantation (n = 6).
A = anterior, P = posterior, L = lateral, M = medial, S = superior, Inf = inferior. (A-F) Gross morphology and histology of the mandibular head articular surfaces in the treated versus untreated cases. (G) Gross morphology of the inferior surface of treated TMJ discs. (H) Gross morphology of sagittal (anteroposterior) sections of treated discs. The arrow marks the implant’s location and orientation. The square bracket indicates the location of the healed defect. (I, J) Low and high magnification H&E histology images of the mandibular heads in treated cases. The square bracket indicates the healed defect (I). (K) Gross morphology of the inferior surface of untreated TMJ discs. (L) Gross morphology of sagittal (anteroposterior) sections of untreated discs. The square bracket indicates the open defect’s location. (M, N) Low and high magnification H&E histology images of the mandibular heads in untreated cases. The square bracket indicates the open defect (M).
Fig. 5.
Fig. 5.. Quantitative assessment of the efficacy of the tissue engineered (TE) implant to heal the TMJ disc defect.
(A) Histological appearance of a defect treated with tissue engineered implant versus untreated discs. Square brackets indicate the defect location (bar = 2 mm). (B) Percent of the combined pouch and fenestration defect perimeter closure indicative of the extent of healing. (C) Young’s modulus values representing the tensile stiffness of the repair tissue that formed in the discs treated with tissue engineered implant versus untreated discs. (D) Osteoarthritis (OA) scores derived from evaluation of the mandibular heads in implant-treated versus untreated groups to measure TMJ degeneration. For all graphs, bars indicate means ± S.D., P < 0.05, Student’s t-test was used with n = 6, and all data were taken at 8 weeks after implantation.
Fig. 6.
Fig. 6.. Integration stiffness at the interface and changes in the biochemical content of the tissue engineered (TE) implants due to adaptive remodeling.
(A) Young’s modulus at the interface of the TE implant or untreated defect. Bars indicate means ± S.D., P < 0.05, Student’s t-test, n = 5–6, and all data were taken at 8 weeks after implantation. (B, C) Representative histology (H&E). Arrows show the native-to-native or native-to-implant interface, which is separated by space in the untreated defect. (D) GAG content in the tissue engineered implant at time zero (n = 6), after 5 weeks of in vitro culture (n = 6), and 8 weeks after implantation (n = 2). (E) Collagen content in the tissue engineered implant at time zero (n = 6), after 5 weeks of in vitro culture (n = 6), and 8 weeks after implantation (n = 2). (F, G, H) Representative Safranin O/fast green histochemical staining. (I, J, K) Representative PicroSirius Red histochemical staining.

Comment in

  • Jaw-dropping new surgical approach.
    McHugh J. McHugh J. Nat Rev Rheumatol. 2018 Aug;14(8):444. doi: 10.1038/s41584-018-0055-z. Nat Rev Rheumatol. 2018. PMID: 30002463 No abstract available.

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