Functional Reconstruction of Turbinates with Growth Factors and Adipose Tissue in the Treatment of Empty Nose Syndrome

Lino Di Rienzo Businco, Alessia Di Mario*, Mario Tombolini*, Domenico Crescenzi**, Marco Radici**

Department of Otorhinolaryngology Santo Spirito Hospital, Rome, Italy

*Department of Otorhinolaryngology, Santo Volto Clinic, Rome, Italy

** Department of Otorhinolaryngology, S.Giovanni Calibita Hospital, Rome, Italy

Corresponding author: Dott. Lino Di Rienzo Businco,Via G.B.de Rossi 15A, 00161 Rome, Italy, Tel.+390644202269;

Email: ldirienzo@businco.net

Received: 11-25-2015

Accepted: 12-07-2015

Published: 12-28-2015

Copyright: © 2015

Abstract

Background:

Empty nose syndrome (ENS) is a devastating complication of turbinate surgery. The management of ENS is challenging

and the evidence base for most treatment modalities remains low. In the present study we propose a safe and effective

surgical reconstruction treatment based on the use of Platelet Rich Plasma mixed with Adipose tissue (PRL). The PRL is a

preparation rich in stem cells and growth factors, taken from the same patient, that has the potential capability to regenerate

the volume of the turbinate and to restore the functionality of the mucosa.

Methodology:

46 patients randomly divided in two groups: one group treated with PRL and the other one with medical treatment alone.

The aim of the study was to compare the safety and efficacy of the PRL for the treatment of ENS in comparison with medical

treatment alone.

Results:

Both procedures had no collateral effects but only patients treated with PRL showed a statistically significant improvement

(p<0.05) in the subjective nasal symptoms and the endoscopic nasal objectivity after surgery.

Conclusions:

Turbinate reconstruction with PRL is a safe, simple and effective procedure characterized by a very low invasiveness with

easy availability to autologous biological tissue and no collateral effects.

Keywords: Empty Nose Syndrome, Turbinate, Stem cells, Atrophic Rhinitis, PRP.

Introduction:

Surgery for turbinate hypertrophy is very common and

represents the eighth most frequent procedure employed in

the otolaryngological field [1]. Over years numerous surgery

techniques for the treatment of inferior turbinate hypertrophy

have been proposed, in which the principle problem was

to increase the nasal airflow preserving the functions of the

mucosal lining, location of important protective activity

and of pharmaceutical drug absorption useful in the long

term postoperative treatment of submucosal membrane

inflammation (turbinectomy, submucosal membrane

extraction with or without debrider, cryocoagulation,

receptors determines the perception of the passage of air

from the nose) [9,10]. Various world specialists have tried

to identify a reconstructive surgical technique capable of

improving the symptoms of ENS, with encouraging yet partial

results; Rice and Di Rienzo Businco with the use of hyaluronic

acid [11,12], Yong with inferolateral endonasal cartilage

implants [13], and Papay with his fibromuscular temporalis

graft implantation [14], but these techniques reveal problems

with the reabsorption of the substance used in reconstruction

over time. Those problems have been overcome by Jiang

with Medpor’s implants which is resolute regarding the

volume loss but with scarce effectiveness on the recovery of

mucosal functionality [15] and by Modrznski with submucosal

mono or bipolar electrocauterization, Laser CO and diode,

injections of hydroxyapatite on the turbinate and septum [16].

radiofrequencies, coblator, molecular quantum resonance)

[1,2]. Before the diffusion of turbinate shrinkage mini-invasive

techniques without thermic damage, many of the former

techniques (in particular those using high temperatures

with old generation radiofrequencies and those extremely

demolitive ones with scissors with partial or complete

amputations of the turbinate, though they guaranteed an

apparent increase of the nasal airflow and a reduction of air

resistance to rhinomanometry) were accompanied by a loss

of nasal sensitiveness and by the paradoxical reduction of the

perception of the air passage with the damage of the mucosal

nervous receptors of intranasal anatomy and of the mucosa

itself, and by the production of aerial vortices with secondary

atrophic rhinitis leading to real ‘Empty nose’ syndromes

(ENS) with crusting, bleeding and synechiae, with a strong

negative impact on the quality of the patient’s life [1,3,4] ENS,

described for the first time by Kern and Stenkvist in 1994, is

a rare and highly debilitating pathology, and fortunately not

all patients subjected to demolitive surgical intervention on

turbinates (inferior or middle) develop this syndrome [5,6].

However, when ENS occurs (this may happen after months or

years from demolitive surgery), its symptoms strongly reduce

the quality of life, and they can be summarized in: intranasal

mucosal dryness, paradoxical nasal breathing obstruction

(notwithstanding the large intranasal airspace), facial

pains, cephalea, crusting and altered nasal discharge, with a

variability of clinical manifestations which differ according to

In these cases of iatrogenic damage with ENS and secondary

atrophic rhinitis, the medical therapy (antihistamines, steroids,

specific nasal immunotherapy, nasal wash solutions.) prove

themselves invariably insufficient to resolve the symptoms of

nasal obstruction and inflammations of the patient, with the

quality of life considerably reduced and with few possibilities

on the doctor’s part to improve the local nasal clinical history

casefile [8,9]. Even the usual examination tools employed for

the evaluation of nasal patency (rhinomanometry, acoustic

rhinometry, peak nasal inspiratory flow) are unable to

correlate with the clinical symptoms of patients as they do

not investigate the physiological mechanisms of the subjective

perception of the intranasal airflow (the activation of TRPM8

Also, the studies of AlloDerm (acellular dermal matrix) was

proposed by Saafan as having a greater efficacy with respect to

silastic implants, yet with partial results when compared with

a relatively invasive surgical technique [17]. For some years,

plasma enriched with platelets, Platelet Rich Plasma (PRP)

have been extensively employed in medicine and surgery

for their properties to stimulate an efficient regeneration of

both soft tissue and bone tissue (better scar healing and with

a reduction in postoperative infections, pain and blood loss)

leading these blood components to be routinely used in various

branches of surgery and medicine [18,19]. The widespread

use of platelet derivatives has certainly proved favourable in

their efficacy, combined with an extreme easiness of use and

not least in the absence of adverse reactions. Adipose tissue

has likewise been the object of great attention these years,

for its regenerative potential (above all Stromal Vascular

Fraction SVF, Adipose Stem Cells ASC), developed to return

volume and functionality, especially in plastic surgery [20-

23]. Based on these assumptions, our aim was to verify the

efficacy and safety of a new and simple endoscopic infiltrative

technique for the reconstruction in patients affected with ENS,

of atrophic turbinates and partially amputated, in that they

had been coagulated or resected by previous nasal surgery,

in addition to a topical medical treatment based on thermal

water cleansing and a humidifying vitamin unguent. Such a

reconstructive endoscopic surgical technique, different from

other methodologies as described in previously published

literature which entail intranasal cutting and more invasive

implants, is based on the simple injective proceedings in

locations of resected turbinates, of PRP mixed with autologous

fat [21] taken from a periumbilical extraction (PRL). The fat was

purified utilizing Coleman’s technique [24,25], and the mixture

of PRL thus attained was injected endoscopically into a group

of ENS affected patients, comparing the functional results with

a group checked with ENS undergoing sole medical therapy.

Our aim was to compare the variations of clinical-instrumental

parameters and symptoms from the beginning to the end of

the treatments – dividing patients into two groups of study, the

first (group A), with sole medical pharmaceutical therapy and

the second (group B) with the same medical therapy to which

was added an endoscopic treatment with PRL on inferior

turbinate regions previously amputated.

Materials and Methods:

For the study, 46 patients (39 male) with an age of above

18 years were enrolled consecutively (table 1), following a

complete ORL evaluation with physical clinical examination,

endoscopy, ConeBeam CT scan of paranasal sinuses, allergy

evaluation and SNOT-22 questionnaire, undergoing more

than 3 years of treatment in other centers, to turbinectomy

or electrocauterization operations of the inferior turbinates

owing to their hypertrophy with consequent ENS results

(ENS-IT according to the Houser classification) [5]. The ENS

diagnosis was supported by the Houser test, which consisted

in positioning a pledget soaked in a saline solution in the

nasal cavity of patients for 20-30 minutes, revealing their

subjective improvement from obstructive symptoms [5].

The criteria for patient inclusion in the study were: failure in

every precedent medical test carried out, obstructive nasal

symptoms to the VAS greater than 5 (min. 0 – max. 10), and

documented resection of the inferior turbinates for a surface

equal to or greater than 50% of the endoscopic examination

and CT. For the evaluation of damage from inferior turbinate

resections our compartmental turbinate classification

was utilized so as to objectively quantify the location and

the amputated section (Figure 1 and 2) [1].

(Figure 1. Compartmental classification of the inferior turbinate. On

the right: 1 Superior, 2: Middle, 3: Inferior, 4: Infero-lateral On the left:

1: Anterior, 2: Posterior.)

(Figure 2. On the right: Turbinate mucosa after turbinectomy

(Ematossilina-Eosina); On the left: Turbinate mucosa after PRL

(Ematossilina-Eosina).

Patients with a previous history of cocaine abuse, coagulopathy,

grave systemic or infective diseases and neoplastic pathologies

were excluded from the study. All patients signed the informed

consent and the study received approval from the local ethics

committee.

Study Design:

The patients were assigned alternately to two groups, A and

B (A: checkup, medical therapy only; B: medical therapy and

surgical reconstruction treatment) with each containing 23

patients. The assigning of patients to be subjected to treatment

A or B was obtained by a random sequence of computer

generated numbers. The medical treatment was based on

the administration of an intranasal spray with a solution of

salt-bromine-iodine thermal water (3 spurts per nostril 3

times daily) together with the nightly application of a nasal

unguent based on vitamins (vitamins E, A, D-panthenol).

Group B patients, before medical therapy, were subjected to

an endoscopic reconstruction of inferior turbinates with PRP

mixed with autologous fat (PRL). Both groups were requested

to note every and any collateral effect that presented itself

during the course of the study.

Preparation of Prp:

The preparation process consisted of 3 phases: hemal

extraction, centrifugation to obtain a concentrated platelet and

activation [26]. Following hemal extraction from a peripheral

vein, some sodium citrate as an anticoagulant was added

to the blood (system of RegenLab, Le Mon-sur-Lausanne,

Switzerland). The method of manual PRP preparation consists

in a centrifugation of 1500 rpm for a total of 10 minutes

which allowed the platelet to remain in suspension with the

plasma while the leucocytes and erythrocytes settled on the

bottom of the test tube. After the centrifugation the platelet

and leucocyte buffy coat were extracted with 9ml of plasma

[21]. Calcium chloride was added to the PRP as thus obtained

to activate the platelet and stimulate the secretions of growth

factors with emiocytosis of alpha granules.

Preparation of Fat:

The purified fat was obtained after the transumbilical

extraction with lipoaspiration microtubes (1.5mm in diameter)

via centrifugation for 3 minutes at 3000 rpm (Coleman’s

technique) and inserted aseptically into a syringe of 1ml mixed

with PRP. This procedure allowed a purified fat preserving the

adipocytes in their entirety to be obtained, while separating

the fluid components from those serosanguineous [24,25].

Procedure:

Group B patients undergoing treatment were prepared 15

minutes before the reconstruction of turbinates with local

anesthesia for mucosal contact with a cotton substance soaked

in Lidocaine located along the full length of the inferior meatus.

A nasal endoscope of 3mm 0° (Karl Storz, Tuttlingen, Germany)

was used for a selective infiltration of turbinate compartments

under endoscopic guidance. The PRL solution was injected,

after their endoscopic identification, in the sites of previous

cauterization regions or amputations of the previously tested

turbinates with the positioning of pledgets soaked in a saline

solution (Houser’s test), via a syringe of 5ml with a spinal

needle of 22G of 90mm. The procedure did not determine

significant bleeding, with exceptions made for a modest

quantity from the injection site (drops), which never required

either nasal tamponing or suspension of the procedure.

Clinical Evaluation:

At the beginning of the study (T0), every patient was requested

to indicate the seriousness of subjective nasal symptoms

on a VAS scale (0 min. -10 max.) (nasal obstruction, nasal

discharge, sneezing, itching, pain). All patients were required

to complete the SNOT-22 questionnaire before and after the

treatment and the results were confirmed with regards the

five most important questions. All patients underwent a

basal anterior rhinomanometry (AAR) to evaluate their nasal

resistance (Rhinomanometer Labat srl, Treviso, Italy) during

the day. In accordance with the International Committee

on Standardization of Rhinomanometry, the nasal airflow

resistance was measured using a standard pressure (150 Pa) and

the total nasal resistance was calculated by rhinomanometric

monolateral registrations [27]. The AAR measuring was not

carried out in the case the patient was affected by a common

acute cold or a nasal allergy crisis, postponing the measuring

to the end of the acute phase. The AAR measuring was

performed on a seated patient after a 15-minute period of

room acclimatization, in standard conditions of temperature

and humidity. Each patient was assigned a rhinoendoscopic

score with a 1-4 increasing gravity after at least one month of

abstinence from medical therapy, carried out at the beginning

and at the end of the study based on the evaluation (performed

by the same examiner) of the volume of the nasal crusting in

relation to the respiratory obstacle (from 1: flat crusting on the

mucosal surface, minimally obstructing the respiratory lumen,

to 4: bridge crusting between the nasal wall and completely

obstructing septum). In order to obtain a functional piece of

data on the nasal mucosal state in both groups under study, the

Mucociliary Transport Time (MCTt) was calculated, before and

after the treatment. All patients were subjected to MCTt nasal

evaluation, using a vegetable carbon powder and saccharin

mixture of 3%. The MCTt was calculated as the time interval

between the moment in which the powder was positioned on

the head of the inferior turbinate (anterior compartment) up to

when a stripe of the same powder appeared in the oropharynx

during the direct pharyngoscopic examination [28]. The

clearance time for saccharin was instead calculated taking the

end of the test into consideration when the patient detected

a sweet taste in the mouth. All evaluations and tests were

repeated and compared with those basal ones after 12 months

of treatment for both groups in the study. It was possible after

more than 1 year of treatment in 3 patients from group B, to

carry out a biopsy for histologic examinations of the region of

the turbinate reconstructed with PRL in the course of other

operations carried out for different reasons other than those

of the nose. The sections of the turbinate mucosa of 5μm were

prepared according to standard procedure after the inclusion

of paraffin and after being stained with hematoxylin-eosin.

Statistical Analysis:

The value P (Student test, with statistical significance for p

‹0.05) was utilized for all subjective and objective parameters.

The statistical analysis was undertaken with SPSS (software

package for statistical analysis) version 17.0 (Chicago, IL, USA).

Results

The study included 46 patients aged between 32-67 (table 1,

2). The medical therapy did not determine any collateral effects

in any of the patients from either group in the study. Patients

from group B did not report pain during or after the procedure,

with the exception made for few sporadic cases of nasal burns

and minimal discharge mixed with blood after nose-blowing,

for which paracetamol when required (500mg tablets) was

prescribed in the postoperative period without any adverse

consequences reported. In particular, no cases of epistaxis, nor

any general or local complications in the nasal sites treated

with PRL (synechiae, crusting formation) were found. The area

of umbilical fat removal was healed without residue and the

stitching (nylon 5-0) was removed in 5-7 postoperative days.

With regards the subjective nasal symptoms and the endoscopic

nasal objectivity, when compared with the after treatment, a

statistically significant improvement in group B (p<0.05) was

noted (table 3). Concerning the objective rhinomanometric

evaluation when compared to post-treatment, a trend similar

to what had been observed in subjective nasal symptoms was

noted, with an improvement in favour of group B that had

been treated with PRL (p<0.05) (table 4). The comparative

results between the two groups A and B of MCTt have shown

a statistically notable variation revealing a greater efficacy

of the treatment with PRL compared with that sole medical

one in the improvement in the mucociliary function (table

4). The comparison between groups A and B before and after

treatment according to the SNOT-22 questionnaire with regard

to the most important 5 questions, showed an improvement

for both groups under study but with more favourable efficacy.

Histologic Evaluations:

According to the results of previous histologic experiences of

the efficacy of PRP in animal and human studies, in the samples

of our examined patients we have observed a satisfactory

reconstruction of the mucosa and submucosa of the turbinate

after 12 months from the treatment with PRL compared with

the preoperative checkup (Figure 3) [29,30]. Particularly the

almost complete reepithelialization of the mucosal surface of

the turbinate and the reduction of the inflammatory part of

the submucosa have been observed in the areas subjected to a

reconstruction with PRL.

(Figure 3. Turbinates pre and after treatment with PRL.)

Discussion:

The results allow us to conclude a greater efficacy of both

medical therapy and infiltrative treatment with PRL, compared

to the sole medical therapy in order to check the signs and

symptoms of ENS-IT with the subtotal amputation of the

inferior turbinates. With regards the nasal symptoms VAS

evaluated, a greater efficacy has been shown in the checkup

of the group of patients following treatment B. In particular

the patients who received the treatment with PRL showed

better objective parameters (RAA, endoscopic score) and

with the SNOT-22, when compared to the group following the

sole medical therapy. The improvement (at RAA) of group B,

appears to be due to the smaller quantity of intranasal crusting

and consequently better air canalization in the patients treated

with PRL. The results of the evaluation of MCTt document

an improvement of the function of the mucosal surfaces of

the turbinate after the reconstruction with PRL, which is

very notable in a category of patients affected by ENS where

the damage of the mucociliary clearance together with the

mucosal atrophy represents the main invalidating pathogenic

moment of the quality of life owing to the continuous formation

and crusting stasis in the nasal cavity. In our experience, the

association of PRP with adipose cells (PRL) has resulted in

being one of the key points to the efficacy of the reconstructive

treatment in terms of restoring functionality, since both the

mixed components together contributed to the recovery both of

the volume and the specific-site functionalities of the damaged

or amputated nasal regions. It is possible to hypothesize

that on the basis of the favourable results obtained there is

a restoration of regional neovascularization where there has

been a volumetric site-specific increase, which together with

the regenerative powers of platelet GF have led to an objective

and symptomatological improvement [31-33]. The surgical

technique also showed itself to be extremely simple both

rhinosurgically and for the extraction of the periumbilical

fat, but above all, in accordance with previously published

literature, without the collateral effects [34] and discomfort

for the patient. The surgical approach we have described,

with endoscopic technique and compartmental evaluation

of the treated turbinate undersurface, allows a greater

homogeneity of the classification of ENS-IT damage, together

with a better evaluation of the obtained results after a certain

period, with the presupposed essential sharing of clinical

data among different centers and in order to guarantee the

reproducibility of the methodology. Such a repair operation

has been characterized by a very low invasiveness with a

rapid postoperative period (day surgery) with easy availability

to autologous biological tissue without the necessity of

using other tissue from other anatomic sites as reported by

other authors using different methodologies (nasal mucosa,

muscular band, osteo-cartilaginous flaps, etc), and, above all,

with no collateral effects. The basis of this regenerative surgery

is represented by 3 elements: growth factors contained in a

platelet gel, stem cells taken from adipose tissue (mixed with

the PRP to obtain the PRL) and the biomaterials of synthesis

(hyaluronic acid, collagen). The hematostatic capacity of

platelets and their complex action mechanism (more than

300 proteins) is well-known, but only recently, owing to the

progress of molecular biology could we minutely understand

the different mechanisms which induced growth factors. Once

activated, platelets release the growth factors contained in the

alpha granules which are able to perform specific functions

in the cell regeneration and in the development of the tissue

where they have been liberated. In fact, the GF (growth

factors) proteins are contained inside the platelets, factors

of growth implicated in the regeneration of the tissue which

have suffered damage. The PRP contains different typologies

of GF (isomers of the platelet GF transforming GF β1 and β2, GF

insulin α and β, vascular endothelial GF) able to promote bone

regeneration and to induce the differentiation of pluripotent

cells. The GFs act as activation signals to attract clones of stem

cells to the damage site and are contemporarily able to induce

their proliferation. The action of GF on the osteoblasts is, for

example, able to induce mitosis and to stimulate the migration

of the mesenchymal cell progenitors. A notable aspect for its

practical implication, is how the chemotactic and mitogenic

stimulus of PRP on mesenchymal stem cells is able to determine

the best reconstitution and regeneration of the damaged tissue

in a directly proportional way with the platelet concentration

(dose-dependent efficacy) [18,29,30,23]. The clinical effects of

the PRP [35,36] on the implanted tissue can be summarized in

a biostimulation with:

• cellular proliferation

• bioreparative and regenerative processes

• angiogenesis and revascularization of tissue

• proliferation of mesenchymal cells

• production of fibroblasts

• production of collagen

The clinical experience in the field of regenerative nasal surgery

has shown a greater efficacy in the processes of the mucosal

regeneration and its functionality with the activation of cellular

proliferation and gain of volume. In conclusion, regenerative

surgery in the nasal districts aims towards the more promising

possibility of mini-invasive solutions of many problems linked

to the defective functionality of the nose, particularly after

previous demolitive operations (ENS or atrophic rhinitis), but

also for the excessive use of inhaled stupefacient substances

(cocaine) thanks to the capacity of the new mixture to help

in rebuilding both the shape and the function of damaged

anatomic areas. Our studies are evaluating possible further

functional improvements in ENS after repeated sittings of

infiltrations of PRL in the same treated undersurface areas

from 6 and 12 months from the first infiltration [37] and the

stability during the time of the results obtained.

Conclusions:

The reconstruction with PRL of the inferior turbinates,

associated with the topical medical therapies of washing and

of using an emollient, has proved better able in a statistically

notable way to improve the subjective nasal symptoms and

objective rhinoendoscopic observations in a group of patients

affected by ENS, particularly noting an improvement in the

quality of the patient’s life concerning the nasal complaints

measured by using SNOT-22.

Disclosure Information:

The authors state to have no actual or potential conflict of interest

in relation to this paper. They didn’t receive funds(grants,

consulted fees,honorarium, travel remboursements,

medecines, equipment, or administrative support) from a

third party to support the work (such as government granting

agency,charitable foundation or commercial sponsor).

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