Empty nose syndrome pathogenesis and cell-based biotechnology products as a new option for treatment

Table 1 Comparative analysis of existing empty nose syndrome treatment approaches, clinical results

No.	No. of patients	Type of study	Material used for transplantation (implant material?)	Treatment details	ENS score before surgical intervention	ENS score after surgical intervention	Other effects	Complications, undesired effects	Follow-up time	Ref.
1	19	Prospective self-controlled study	Porous polyethylene (Medpor)	Submucosal implantation into the inferior turbinate and (or) lateral nasal wall and (or) nasal septum opposite the nasal concha	50.1 ± 18.7 (SNOT-20)	22.6 ± 15.8 (3 mo; P = 0.037); 20.4 ± 18.9 (6 mo; P = 0.007); 37.7 ± 7.6 (12 mo; P = 0.736) (SNOT-20)	Improvements of nasal resistance, nasal volume, and minimum cross-sectional area (P < 0.05) (CT, acoustic rhinometry); mucociliary clearance improved non-significantly	Partial implant extrusion in one patient at 6 mo follow-up	3-18 mo	[24]
2	16	Retrospective clinical study	Porous polyethylene (Medpor)	Submucosal implantation mainly in septum and nasal floor, unilaterally or bilaterally	39.25 ± 21.44 (SNOT-22)	19.81 ± 16.17 (3 mo, P < 0.05); 16.19 ± 13.98 (1 yr, P < 0.05) (SNOT-22)	Not evaluated	Chronic hypertrophic rhinitis in 1 patient 4 yr after implantation. Implant protrusion in 1 patient 6 mo after surgery	3 mo-1 yr	[25]
3	13	Prospective cohort study in a tertiary medical center	Porous polyethylene (Medpor)	Submucosal implantation into nasal floor	19 (BAI); 24.4 (BDI-II)	6.8 (BAI); 6.25 (BDI-II)	Mucosa covering the graft was smooth and intact on the lateral nasal wall (endoscopy)	Not reported	1 yr	[26]
4	14	Retrospective study in a tertiary medical center	Porous polyethylene (Medpor)	Inferior nasal wall submucosal implantation	40.7 ± 23.4 (SNOT-22); 22.6 ± 27.0 (BDI-II); 13.8 ± 19.5(BAI)	21.1 (P = 0.002) (SNOT-22); BDI-II decrease (P = 0.031)BAI decrease (P = 0.004)	Not evaluated	Not reported	1 yr	[27]
5	18 (16 followed-up)	Retrospective study in a tertiary medical center	Porous polyethylene (Medpor)	Lateral nasal wall submucosal implantation	49.3 ± 20.5 (SNOT-22); 20.5 ± 15.1 (BDI-II); 20.1 ± 15.2 (BAI)	11.8 (P < 0.001) (SNOT-22); BDI-II decrease (P < 0.001); BAI decrease (P < 0.001)	Not evaluated	Not reported	1 yr	[27]
6	68 (39 followed-up)	Prospective clinical study	Porous polyethylene (Medpor)	Submucosal implantation into the nasal floor or lateral wall	62.9 ± 25.3 (SNOT-25); 19.3 ± 15.0 (BDI-II); 17.7 ± 12.9 (BAI)	35.5 ± 24.4 (P < 0.001) (SNOT-25); 8.4 ± 10.1 (P < 0.001) (BDI-II); 10.5 ± 11.5 (P < 0.001) (BAI)	Not evaluated	Not improved nasal crusting and facial pain/pressure	6 mo	[28]
7	54 (46-38 followed-up)	Prospective case series in a tertiary medical center	Porous polyethylene (Medpor)	Submucosal implantation into the nasal floor or lateral wall	64.9 ± 24.7 (SNOT-25); 20.7 ± 15.3 (BDI-II); 19.8 ± 13.3(BAI)	32.9 ± 20.7 (3 mo); 30.2 ± 22.9 (6 mo); 29.1 ± 23.8 (12 mo); (P < 0.01) (SNOT-25); 8.2 ± 11.2 (3 mo); 8.0 ± 9.8 (6 mo); 7.8 ± 10.7 (12 mo); (P < 0.01) (BDI-II); 8.5 ± 9.8 (3 mo); 9.6 ± 11.0 (6 mo); 8.7 ± 10.1 (12 mo); (P < 0.01) (BAI)	Not evaluated	Not reported	3-12 mo	[14]
8	1	Case report	Hydroxyapatite cement	Implantation into subperiosteal tunnel on the lateral nasal wall	Not evaluated	Not evaluated	Not evaluated	Not reported	1 yr	[60]
9	3	Clinical study	Hyaluronic acid	Submucosal injections into the inferior nasal concha and under the mucous membrane of the septum	Not evaluated	Not evaluated	Subjective symptoms improvement, improved acoustic rhinometry results (3-6 mo)	After 1 yr the implant was absorbed in 2 patients, symptoms restored	1 yr	[61]
10	5	Prospective observational study in a tertiary medical center	β-tricalcium phosphate	Implantation into submucoperiosteal pocket along the lateral nasal wall, at the site of the former inferior turbinate head between the nasal floor and the ostium of the nasolacrimal duct	90 (90-95) (NOSE); 18.7 (18.7-43.7) (RhinoQoL frequency); 30 (20-43.3) (RhinoQoL bothersomeness); 62.5 (57.6-68.7) (RhinoQoL impact)	5 (5-25) (P = 0.01) (NOSE); 81.2 (75-81.2) (P = 0.01) (RhinoQoL frequency); 81 (76.7-90) (P = 0.05) (RhinoQoL bothersomeness); 8.3 (5.5-11) (P = 0.01) (RhinoQoL impact)	Median nasolacrimal duct aperture (DNLI) 4.2 mm (1.8-6.6) (CT)	One case of partial implant extrusion 6 d after surgery	13.5 mo (8.2-21)	[20]
11	12	Prospective randomized blind clinical study	Silastic sheet	Implantation into submucoperichondrial and/or submucoperiosteal pockets fashioned along the septum, nasal floor, and lateral nasal wall	61.4 ± 16.3 (SNOT-25)	33.6 ± 17.1 (SNOT-25)	Decreased crustling (anterior rhinoscopy and endoscopic examination)	Partial implant extrusion in 4 patients	9-24 mo	[32]
12	14	Clinical study	Carboxymethylcellulose/glycerin gel (Prolaryn)	Submucosal injection into the inferior meatuses	20.8 ± 4.9 (ENS6Q); 50.3 ± 15.2 (SNOT-22); 8.6 (GAD-7)11.6 (PHQ-9)	ENS6Q: 10.5 (1 wk; P < 0.0001); 13.7 (1 mo, P = 0.002); 15.5 (3 mo; P > 0.05); SNOT-22: 29.3 (1 wk; P = 0.01); 35.5 (1 mo, P = 0.04); 39.3 (3 mo, P > 0.05); GAD-7: 5.4 (1 wk, P > 0.05); 4.9 (1 mo, P = 0.02); 5 (3 mo, P = 0.02); PHQ-9: 6.6 (1 wk; P = 0.01); 7 (1 mo, P = 0.004); 7.4 (3 mo, P > 0.05)	Not evaluated	Not reported	1 wk – 3 mo	[62]
13	3	Observational prospective cohort study	Porcine small intestine submucosal xenograft	Inferior turbinate reconstruction, implantation into submucosal pocket in the lateral nasal wall	77.6 (SNOT-25)	65 (1 wk); 57 (4 wk, P < 0.01); 55 (12 wk, P < 0.01) (SNOT-25)	Not evaluated	Mild partial implant reabsorption	1-12 wk	[63]
14	12	Retrospective clinical chart review	Autologous septal or conchal cartilage; nautologous or homologous costal cartilage	Submucosal implantation into lateral nasal wall	Not evaluated	Not evaluated	75% were satisfied with outcome; significantly decreased excessive airflow, nasal obstruction, and nasal or facial pain (P < 0.05) (VAS)	Under correction in 3 patients	11.8 mo (6-27 mo)	[64]
15	17	Case series with chart review	Conchal cartilage (autologous)	Submucoperiosteal implantation into lateral nasal wall	54.0 (27.0-57.8) (SNOT-25)	35.9 (24.0-51.5) (P = 0.007) (SNOT-25)	Good mucosal healing (endoscopy)	Not reported	6-12 mo	[30]
16	14	Case series with chart review	Costal cartilage (autologous or homologous)	Submucoperiosteal implantation into lateral nasal wall	46.6 (45-67.5) (SNOT-25)	21.9 (9.0-40.8) (P = 0.002) (SNOT-25)	Good mucosal healing (endoscopy)	Not reported	6-12 mo	[30]
17	7	Prospective cohort study in a tertiary medical center	Autologous bone graft from septal bone	Submucosal implantation into nasal floor	19 (BAI); 24.4 (BDI-II)	6.8 (BAI); 6.25 (BDI-II)	Mucosa covering the graft was smooth and intact on the lateral nasal wall (endoscopy)	Not reported	1 yr	[26]
18	1	Case report	Acellular dermis (Alloderm) + Cymetra (injectable acellular dermis)	Submucoperiosteal implantation	Not evaluated	Not evaluated	40% better (subjective)	Not reported	3 mo	[31]
19	8	Case series	Acellular dermis (Alloderm)	Submucoperichondrial and submucoperiosteal implantation into the former inferior turbinate; or into nasal septum and/or floor	58.3 (SNOT-20)	38.3 (P ≤ 0.02) (SNOT-20)	Subjective improvement in smell threshold	The initial graft shrinks, and then the graft appears to maintain stable size for years	6 mo – 4 yr	[5]
20	12	Prospective randomized blind clinical study	Acellular dermis (Alloderm)	Implantation into submucoperichondrialand/or submucoperiosteal pockets fashioned along the septum, nasal floor, and lateral nasal wall	63.7 ± 15.4 (SNOT-25)	34.2 ± 15.2 (SNOT-25)	Decreased crustling (anterior rhinoscopy and endoscopic examination)	Partial implant extrusion in 3 patients during the first 2 wk, but all healed with no sequelae. Partial graft shrinkage in 2 cases 2 mo postoperatively	9-24 mo	[32]
21	9	Prospective observational clinical study	Autologous stromal vascular fraction (SVF)	Injection into medial surface of inferior turbinates	70.1 ± 24.7 (SNOT-25)	62.4 ± 35.8 (P > 0.05) (SNOT-25)	Decreased IL-1β and IL-8 (P < 0.005) (ELISA)	Seroma in 1 patient	6 mo	[47]
22	30	Clinical study	Autologous ADSCs combined with autologous fat granules	Injections into the areas of mucosal damage (every 10 d, 3 in total)	Not evaluated	Not evaluated	Inflammation significantly reduced, collagenous fibers became aligned, fewer deposits observed, and the mucosal proteins increased 1 mo post-op (H&E, Masson’s, and AB-PAS stainings). Nasal resistance, nasal volume, minimum crosssectional area, and mucociliary clearance improved (acoustic rhinometry)	Not reported	3-9 mo	[49]