Clinical validation of a nanodiamond-embedded thermoplastic biomaterial

Abstract

Detonation nanodiamonds (NDs) are promising drug delivery and imaging agents due to their uniquely faceted surfaces with diverse chemical groups, electrostatic properties, and biocompatibility. Based on the potential to harness ND properties to clinically address a broad range of disease indications, this work reports the in-human administration of NDs through the development of ND-embedded gutta percha (NDGP), a thermoplastic biomaterial that addresses reinfection and bone loss following root canal therapy (RCT). RCT served as the first clinical indication for NDs since the procedure sites involved nearby circulation, localized administration, and image-guided treatment progress monitoring, which are analogous to many clinical indications. This randomized, single-blind interventional treatment study evaluated NDGP equivalence with unmodified GP. This progress report assessed one control-arm and three treatment-arm patients. At 3-mo and 6-mo follow-up appointments, no adverse events were observed, and lesion healing was confirmed in the NDGP-treated patients. Therefore, this study is a foundation for the continued clinical translation of NDs and other nanomaterials for a broad spectrum of applications.

Keywords: biomaterial; clinical trial; infection; nanodiamonds; nanomedicine.

Conflict of interest statement

Conflict of interest statement: E.O. is an inventor on US Patent No. 7300958 entitled “Ultra-dispersed nanocarbon and method for preparing the same.” E.K.-H.C. and D. Ho are inventors on US Patent No. 20150238639 entitled “Contrast agent and applications thereof.” D. Ho is an inventor on US Patent No. 20100305309 entitled “Nanodiamond particle complexes” and US Patent No. 9125942 entitled “Paramagnetic metal–nanodiamond conjugates.” The other authors declare no conflict of interest.

Published under the PNAS license.

Figures

Fig. 1.

NDGP clinical presentation. (A) Top–down view and side view of NDGP in the middle third of the root canal and unmodified GP in the apical and coronal thirds of the root canal-treated tooth. (B) Top–down view of unmodified GP in the dispensing unit. (C) Top–down view of NDGP in the dispensing unit. (D) Extruded unmodified GP (top) and NDGP (bottom).

Fig. 2.

Thermogravimetric analysis and mechanical properties comparisons between the unmodified GP product and the 5% NDGP. (A) Thermodiagram of the GP and NDGP. (A, i) Decrease in wt% of GP and NDGP is attributed to the polymer decomposition and organic moiety. (A, ii) The amount of decomposed ND is equal to the amount of ND incorporated into the NDGP. (A, iii and iv) BaSO4 and ZnO residues left after the thermal decompositions. (B, Left) Image of GP (top) and NDGP (bottom) pellets. (B, Right) Digital X-ray image of GP (top) and NDGP (bottom) pellets. (C) Stress–strain curves from the measurement of tensile strength of GP and NDGP (5 wt% ND). (D) Elastic moduli of GP (167 ± 23.6 MPa) and NDGP with 5 wt% of ND (120 ± 28.3 MPa). Elastic moduli were calculated from the elastic region, the initial linear part of the stress–strain curves. Data are described as mean ± SD (n = 3), P value = 0.15. (E) Tensile strengths, the highest stress point of the stress–strain curve, for GP (4.9 ± 0.38 MPa) and NDGP with 5 wt% of ND (5.8 ± 0.20 MPa). Data are described as mean ± SD; *P value = 0.049 (n = 3). (F) The 0.2% offset yield strength of GP (2.5 ± 0.27 MPa) and NDGP with 5 wt% of ND (2.3 ± 0.57 MPa) measured from stress testing were correlated to the intersections of a stress–strain curve and projected straight lines, which were parallel to the initial straight portion of the stress–strain curve. The correlations explain the elastic limits of GP and NDGP. Data are described as mean ± SD (n = 3), P value = 0.63. (G) Percentages of elongation of GP (18.6 ± 1.18%) and NDGP with 5 wt% of ND (15.7 ± 0.660%) were calculated from comparing the change in length with the length of the original material. Data are described as mean ± SD; *P value = 0.04 (n = 3).

Fig. 3.

Control and NDGP obturation process. (A) Master GP cone placed with zinc-eugenol sealer. (B) Removal of excess GP with heated plugger. (C) Condensing master GP to apical 5 mm. (D) Canal space filled with GP, using extruder starting from apical end. (E) Canal space filled with unmodified GP up to cervical third. (F) Fully condensed and completed obturation with unmodified GP. (G) Middle third of the canal space was filled with NDGP, using extruder that started from the apical end. (H) Cervical third of the canal space was filled with unmodified GP. (I) Fully condensed and completed obturation with NDGP in the middle third of the canal.

Fig. 4.

Control patient (C1). (A) Pretreatment radiograph of tooth 13 with existing apical lesion (white arrow). (B) Completed backfill (white arrow) and apical seal with unmodified GP. (C) Six-month follow-up radiograph shows the apical lesion with increased bone density (white arrow). (D) Lesion diameter at pretreatment (red) and 6-mo follow-up (blue) appointments. (E) A 5.07-mm apical lesion diameter was visible on the pretreatment radiograph. (F) A 4.19-mm apical lesion diameter was visible on the 6-mo follow-up radiograph.

Fig. 5.

NDGP-treated patient 1 (ND1). (A) Pretreatment clinical image of tooth 27 taken after rubber dam placement. (B) Clinical image of access cavity (white arrow) before obturation. (C) Clinical image of completed obturation visible through access cavity (white arrow). (D) Clinical image of coronal restoration sealing access cavity (white arrow). (E) Pretreatment radiograph with periapical lesion (white arrow). (F) Completed obturation with unmodified GP apical seal, NDGP backfill, and unmodified GP coronal seal. (G) Three-month follow-up radiograph with healing periapical lesion (white arrow). (H) Six-month follow-up radiograph with healing periapical lesion. (I) Lesion diameter at pretreatment, 3-mo, and 6-mo follow-up appointments. (J) A 3.56-mm lesion was visible on pretreatment radiograph. (K) A 2.81-mm lesion diameter was visible on the 3-mo follow-up appointment. (L) A 2.48-mm lesion diameter was visible on the 6-mo follow-up appointment.

Fig. 6.

NDGP-treated patient 2 (ND2). (A) Pretreatment clinical image of tooth 6. (B) Clinical image of access cavity (white arrow). (C) Pretreatment radiograph with existing periapical lesion (white arrow). (D) Completed obturation with unmodified GP apical seal, NDGP backfill, and unmodified GP coronal seal (white arrow). (E) Three-month follow-up radiograph with healing periapical lesion (white arrow). (F) Lesion diameter at pretreatment (red) and 3-mo follow-up (blue) appointments. (G) The 3.45-mm lesion diameter was visible on the pretreatment radiograph. (H) The 2.63-mm lesion diameter was visible on the 3-mo follow-up radiograph.

Fig. 7.

NDGP-treated patient 3 (ND3). (A) Pretreatment clinical image of tooth 23. (B) Clinical image of access cavity (white arrow). (C) Clinical image of completed obturation (white arrow). (D) Pretreatment radiograph with existing periapical lesion (white arrow). (E) Completed obturation with unmodified GP apical seal, NDGP backfill, and unmodified GP coronal seal (white arrow). (F) The 3.53-mm pretreatment lesion diameter.