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Efficiency analysis of commercial polymeric membranes for bone regeneration in rat cranial defects

ABSTRACT

Purpose:

To evaluate the in vivo efficiency of commercial polymeric membranes for guided bone regeneration.

Methods:

Rat calvarial critical size defects was treated with LuminaCoat (LC), Surgitime PTFE (SP), GenDerm (GD), Pratix (PR), Techgraft (TG) or control (C-) and histomorphometric analysis determined the percentage of new bone, connective tissue and biomaterial at 1 or 3 months. Statistical analysis used ANOVA with Tukey’s post-test for means at same experimental time and the paired Student’s t test between the two periods, considering p < 0.05.

Results:

New bone at 1 month was higher for SP, TG and C-, at 3 months there were no differences, and between 1 and 3 months PR had greater increase growthing. Connective tissue at 1 month was higher for C-, at 3 months for PR, TG and C-, and between 1 and 3 months C- had sharp decline. Biomaterial at 1 month was higher for LC, in 3 months for SP and TG, and between 1 and 3 months, LC, GD and TG had more decreasing mean.

Conclusions:

SP had greater osteopromotive capacity and limitation of connective ingrowth, but did not exhibit degradation. PR and TG had favorable osteopromotion, LC less connective tissue and GD more accelerated biodegradation.

Key words
Biocompatible Materials; Bone Regeneration; Guided Tissue Regeneration; Collagen; Polymers; Materials Testing

Introduction

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,2323 Rothamel D, Schwarz F, Herten M, Becker J. Biodegradation of differently cross-linked collagen membranes: an experimental study in the rat. Clin Oral Impl Res. 2005;16(3):369-78. https://doi.org/10.1111/j.1600-0501.2005.01108.x
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. Degradation control can be related to microporosities < 3 μm, which mantain nutritional diffusion without impairing the mechanical stability2424 Loh QL, Choong C. Three-dimensional scaffolds for tissue engineering applications: role of porosity and pore size. Tissue Eng Part B Rev. 2013;19(6):485-502. https://doi.org/10.1089/ten.TEB.2012.0437
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, use of fibrillar matrix crosslinking techniques or its association with apatite2626 An YZ, Heo YK, Lee JS, Jung U-W, Choi S-H. Dehydrotermally cross-linked collagen membrane with a bone graft improves bone regeneration in a rat calvarial defect model. Materials (Basel). 2017;10(8):e927. https://doi.org/10.3390/ma10080927
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,2727 Araújo LK, Antunes GS, Melo MM, Castro-Silva II. Brazilian dentists’ perceptions of using bone grafts: an inland survey. Acta Odontol Latinoam. 2020;33(3):165-73. https://doi.org/10.54589/aol.33/3/165
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or thicknesses from 0.1 to 1 mm to achieve desirable osteopromotive efficacy2828 Pilger AD, Schneider LD, Silva GM , Schneider KCC , Smidt R. Membranes and barriers for guided bone regeneration. Rev Ciênc Méd Biol. 2020;19(3):441-8. https://doi.org/10.9771/cmbio.v19i3.36390
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, with greater densities delaying its total degradation2929 Lee YJ, An SJ, Bae EB, Gwon HJ, Park JS, Jeong SI, Jeon YC, Lee SH, Lim YM, Huh JB. The Effect of Thickness of Resorbable Bacterial Cellulose Membrane on Guided Bone Regeneration. Materials (Basel). 2017;10(3):e320. https://doi.org/10.3390/ma10030320
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.

Despite of multiple options for GBR membranes in the dental market, there is no scientific consensus to indicate a gold standard that align simultaneously osteopromotive efficiency, physical barrier action against soft tissue ingrowth and balanced resorption during tissue repair, as desirable properties3030 Bassi APF, Bizelli VF, Brasil LFM, Pereira JC, Al-Sharani HM, Momesso GAC, Faverani LP, Lucas FA. Is the bacterial cellulose membrane feasible for osteopromotive property? Membranes. 2020;10(9):e230. https://doi.org/10.3390/membranes10090230
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. This study compared the performance of different commercial membranes in an experimental in vivo model of a critical size defect in rat calvaria, evaluating bone and connective tissue formation and residual biomaterials.

Methods

Ethical aspects

This study adopted the international principles of Substitution, Reduction and Refinement in Animal Research: Reporting of In vivo Experiments (3R-ARRIVE guide). The protocol was approved by the Ethics Committee on the Use of Animals of the Federal University of Ceará, Sobral, Brazil, under protocol number 06/2020.

Commercial samples of GBR membranes

Five commercial products approved for clinical dental use in Brazil were selected as test groups3131 Criteria. LuminaCoat. [Web] 24 nov. 2022. Available in: https://www.loja.criteria.com.br/membrana-biologica-lumina-coat/p?skuId=8.
https://www.loja.criteria.com.br/membran...
3535 Baumer. Techgraft. [Web] 24 nov. 2022. Available in: https://www.baumer.com.br/produtos/techgraft.
https://www.baumer.com.br/produtos/techg...
and are described in Table 1. All GBR membranes had their commercial dimensions adapted to individual 10 mm2 square samples, necessary for the in vivo study. After customization, the materials were handled aseptically until the implantation procedure.

Table 1
Groups of commercial polymeric membranes for GBR used in this study.

Implants in rat critical size bone defects

Sixty animals were distributed according to different experimental conditions (6 groups, 2 times, 5 animals each). The animals were given intramuscular anesthesia with 10% ketamine solution (Dopalen, Sespo Indústria e Comércio Ltda, Brazil) at a dose of 100mg/kg and xylazine 2% (Anasedan, Sespo Indústria e Comércio Ltda, Brazil) at a dose of 10 mg/kg. Then, there was trichotomy of the upper part of the head and antisepsis with 0.5% aqueous chlorhexidine. A semilunar incision was made followed by a mucoperiosteal flap, reflected with Molt’s periosteal elevator, exposing the cortical bone in the frontoparietal region. A single, 8-mm diameter circular defect of critical size was created in each animal using a surgical trephine drill (Sistema de Implantes Nacionais, Brazil) attached to a contra-angle with 20:1 rotation reduction (Dentscler, Brazil) and a surgical micromotor (VK Driller Equipamentos Elétricos Ltda., Brazil) under irrigation conditions with cold and sterile 0.9% saline solution during the procedure. The osteotomized fragment was gently removed using an Ochsenbein #1 chisel. The test groups had the bone defect filled by one of the materials (G1, G2, G3, G4 or G5). As a negative control (C-), it was adopted a natural filling with blood clot after the bone defect. The operated regions had simple sutures with 4.0 mononylon thread. Subcutaneous anti-inflammatory/analgesic medication Meloxicam (2 mg/kg, Ourofino, Brazil) was applied every 12 h for 2 days. At 1 and 3 months after the surgeries, the animals were euthanized by an overdose of anesthetic solution and an immediate excisional necropsy of the area compatible with each surgery was performed.

Histotechnic, histological and histomorphometric analysis

The samples were fixed in 10% buffered formalin solution (v/v), pH 7.0, for 48 h. After fixation, all necropsies were decalcified with rapid acid decalcifying solution (Allkimia, Brazil) for 4 days, washed in running water for 1 h, cleaved with a razor in the center of the bone defect, dehydrated in increasing baths from 70 to 100% of ethanol, cleared in xylol baths, impregnated and embedded in paraffin, evidencing the central region of the bone defect. The paraffin blocks were microtomized in 4μm sections and stained in hematoxylin-eosin (HE).

Biological phenomena were analyzed in qualitative and quantitative perspectives. Five images of each sample were captured in adjacent, non-overlapping fields using the Cybershot DSC-W300 Super Steady Shoot camera (Sony, Japan) coupled with the FWL-1000 optical microscope (Feldman Wild Leitz, Brazil) using a 10x objective lens, 10x ocular lens and 4× digital zoom, making a final magnification of 400×. For qualitative analysis, slides from each test and control group were selected and morphologically described to represent the observed events. The following biological criteria were evaluated on the edge-to-edge extension of the bone defect, covering its entire diameter: newly formed bone, connective tissue and implanted biomaterial.

Quantitative histomorphometric analysis was performed using the ImageJ 1.52a version software (National Institutes of Health, USA), calibrated in micrometers/pixel. The biological criteria mentioned above were counted using a grid of 130 points superimposed on each photomicrograph and from the absolute number of points obtained, the percentage volume density (%i) of each parameter was determined according to the Eq. 1:

% i = ( p i p ) 100 % (1)

where pi represents the number of poins in each parameter and P the total number of points. Figure 1 summarizes the in vivo characterization procedures of this study.

Data for each parameter were tabulated in Excel software (Microsoft Office, USA), expressed graphically as mean±standard deviation and statistically analyzed using the Prism 7.0 software (GraphPad, USA) for comparisons of groups and experimental times. Analysis of variance (ANOVA) with Tukey’s post-test was applied to analyze the normal/parametric distribution of the means of each parameter between the five experimental groups and the control at each experimental time. Paired Student’s t test was applied to analyze the normal/parametric distribution of the means of each parameter between the five experimental groups and the control at each experimental time, as dependent samples. They were considered confidence level of 95% and significant differences if p < 0.05.

Figure 1
Steps of the in vivo procedure. (a) Surgical creation of critical size bone efect (CSD) without coating in the control (C-); (b) Membranes for treatment: LuminaCoat (LC), Surgitime PTFE (SP), GenDerm (GD), Pratix (PR) or TechGraft (TG); (c) After cleavage of the samples and processing in paraffin, 5 fields were photocaptured per histological slide along the CSD; (d) Histomorphometric analysis by points using ImageJ software, with different biological criteria distinguished by colors.

Results

The histological analysis showed that all treatments and C- showed a small amount of newly formed bone closer to the edges of the bone defects, greater than the islets of bone in its most central region, with a progressive increase in centripetal osteogenesis between 1 and 3 months. The connective tissue was more abundant in C- compared to the other groups, evolving from a loose extracellular matrix in 1 month to a more fibrous tissue in 3 months. It was possible to observe the presence of material in up to 3 months in all groups except for C-, with no noticeable degradation for SP and PR, while LC and GD showed evident degradation of the material between 1 and 3 months (Fig. 2).

Figure 2
Histological analysis in critical size bone defects (CSD) in rat calvaria for the different experimental groups at one and three months. Qualitative data of control (C-), LuminaCoat (LC), Surgitime PTFE (SP), GenDerm (GD), Pratix (PR) and TechGraft (TG). All groups exhibited the most prominent presence of new bone (NB) at the edge of the CSD, adjacent to native old bone (OB), while at the center of the CSD there were varying amounts of connective tissue (CT) and/or residual membrane (M).

The histomorphometric analysis showed significant differences for the percentage of new bone at 1 month between the groups, with the mean of SP (12.26 ± 2.83%) being higher than the means of LC (5.64 ± 4.54%), PR (3.96 ± 2.19%) and GD (1.44 ± 1.31%) and the means of TG (10.38 ± 3.95%) and C- (9.81 ± 3.68%) being higher than the average of GD (1.44 ±1.31%). In the experimental period of 3 months, there was no significant difference between the groups (p = 0.074). In the evaluation between the experimental times, there was a significant difference for the mean of PR, increasing from 3.96 ± 2.19% in 1 month to 11.66 ± 5.94% in 3 months (Fig. 3a).

Figure 3
Histomorphometric analysis of volume density of (a) new bone, (b) connective tissue, and (c) biomaterial in critical size bone defects in rat calvaria for the different experimental groups at one and three months. Percentage data of control (C-), LuminaCoat (LC), Surgitime PTFE (SP), GenDerm (GD), Pratix (PR) and TechGraft (TG).

There were significant differences for the percentage of connective tissue at 1 month, with the mean of C- (48.43 ± 10.54%) surpassing the means of GD (32.51 ± 6.49%), TG (30.85 ± 3.29%), SP (28.46 ± 12.71%) and LC (25.79 ± 2.87%). In 3 months, the means of PR (31.01 ± 5.96%) and TG (27.65 ± 2.27%) exceeded those of LC (20.65 ± 4.88%) and SP (18.85 ± 5.75%), as well as C- (30.74 ± 9.15%) was higher than SP (18.85 ± 5.75%). In the evaluation between the experimental times, there was a significant difference for C-, decreasing from 48.43 ± 10.54% in 1 month to 30.74 ± 9.15% in 3 months (Fig. 3b).

There were significant differences for the percentage of biomaterial at 1 month, with the mean of LC (42.09 ± 4.28%) surpassing the mean of PR (21.25 ± 13.84%). In the period of 3 months, the average of SP (34.64 ± 1.42%) surpassed the averages of PR (18.80 ± 12.21%) and GD (7.70 ± 6.35%), while the mean of TG (23.57 ± 2.27%) was higher than the mean of GD. In the evaluation between the experimental times, there was a significant difference between 1 and 3 months, for LC (from 42.09 ± 4.28% to 20.91 ± 11.88%), GD (from 36, 37 ± 13.01% to 7.70 ± 6.35%) and TG (from 30.28 ± 3.84% to 23.57 ± 2.27%), which proves the presence of biodegradation in these groups (Fig. 3c).

Considering the results achieved over the 3 months of the experiment and the individual requirements for choosing an ideal regenerative membrane, the decreasing order of efficiency in terms of osteopromotive capacity would be: SP > PR > TG > LC > GD. As for the smallest tendency to formation of connective tissue, the decreasing order of efficiency would be: SP > LC > TG > GD > PR. Finally, regarding the presence of biodegradation, from the most accelerated modality to the non-resorption modality, the decreasing order of efficiency would be: GD > PR > LC > TG > SP. SP had greater osteopromotive capacity and limitation of connective tissue ingrowth, but did not exhibit degradation. PR and TG had favorable osteopromotion, LC less connective tissue and GD more accelerated biodegradation.

Discussion

Semiautomated histomorphometric analysis with manual point counting in software along the length of the critical defect is used for initial estimation of inflammation and neovascularization between 7 and 15 days post-surgery3636 Bassi APF, Bizelli VF, Francatti TM, Ferreira ACRM, Pereira JC, Al-Sharani HM, Lucas FA, Faverani LP. Bone Regeneration Assessment of Polycaprolactone Membrane on Critical-Size Defects in Rat Calvaria. Membranes. 2020;11(2):e124. https://doi.org/10.3390/membranes11020124
https://doi.org/10.3390/membranes1102012...
3838 Teixeira LJC, Balthazar MLB, de Deus G, Vidigal Jr. GM, Conz MB. Comparação de dois métodos histomorfométricos de análise na cicatrização de defeitos crticos na calvária de ratos, após tratamento com diferentes grânulos de hidroxiapatita. ImplantNews 2015;12(6a-PBA):197-202. or for its main objective of analyzing the percentage of bone formation and maturity, secondarily evaluating connective tissue and residual biomaterial, between 1 and 3 months after surgery44 International Organization for Standardization. ISO 22803. Dentistry - Membrane materials for guided tissue regeneration in oral and maxillofacial surgery - Contents of a technical file. Geneva: ISO; 2004.,1717 Meinig RP. Clinical use of resorbable polymeric membranes in the treatment of bone defects. Orthop Clin North Am. 2010;41:(1):39-47. https://doi.org/10.1016/j.ocl.2009.07.012
https://doi.org/10.1016/j.ocl.2009.07.01...
,3939 Ikumi R, Miyahara T, Akino N, Tachikawa N, Kasugai S. Guided bone regeneration using a hydrophilic membrane made of unsintered hydroxyapatite and poly(L-lactic acid) in a rat bone-defect model. Dent Mater J. 2018;37(6):912-18. https://doi.org/10.4012/dmj.2017-385
https://doi.org/10.4012/dmj.2017-385...
. Despite the automated counting in software by delimited area in pixels converted into mm2 is a fast resource and used with great popularity in thematic research1919 Yamatogi RS, Rahal SC, Granjeiro JM, Taga R, Cestari TM, Lima AFM. Microscopic evaluation of biologic membrane association from bovine origin implanted subcutaneously in rats. Cienc Rural. 2005;35(4):837-42. https://doi.org/10.1590/S0103-84782005000400014
https://doi.org/10.1590/S0103-8478200500...
,2727 Araújo LK, Antunes GS, Melo MM, Castro-Silva II. Brazilian dentists’ perceptions of using bone grafts: an inland survey. Acta Odontol Latinoam. 2020;33(3):165-73. https://doi.org/10.54589/aol.33/3/165
https://doi.org/10.54589/aol.33/3/165...
,3636 Bassi APF, Bizelli VF, Francatti TM, Ferreira ACRM, Pereira JC, Al-Sharani HM, Lucas FA, Faverani LP. Bone Regeneration Assessment of Polycaprolactone Membrane on Critical-Size Defects in Rat Calvaria. Membranes. 2020;11(2):e124. https://doi.org/10.3390/membranes11020124
https://doi.org/10.3390/membranes1102012...
3838 Teixeira LJC, Balthazar MLB, de Deus G, Vidigal Jr. GM, Conz MB. Comparação de dois métodos histomorfométricos de análise na cicatrização de defeitos crticos na calvária de ratos, após tratamento com diferentes grânulos de hidroxiapatita. ImplantNews 2015;12(6a-PBA):197-202.,4040 Jang YS, Moon SH, Nguyen TT, Lee MH, Oh TJ, Han AL, Bae TS. In vivo bone regeneration by differently designed titanium membrane with or without surface treatment: a study in rat calvarial defects. J Tissue Eng. 2019;10:2041731419831466. https://doi.org/10.1177/2041731419831466
https://doi.org/10.1177/2041731419831466...
4444 Hoornaert A, d’Arros C, Heymann MF, Layrolle P. Biocompatibility, resorption and biofunctionality of a new synthetic biodegradable membrane for guided bone regeneration. Biomed Mater. 2016;11(4):e045012. https://doi.org/10.1088/1748-6041/11/4/045012
https://doi.org/10.1088/1748-6041/11/4/0...
, the semiautomated counting values the histopathological diagnosis, allowing the optical distinction of new bone from old or native bone at the edges of the bone defect, as well as fragments of collagenous biomaterial against connective tissue fibers, making the calculation of these parameters more accurate44 International Organization for Standardization. ISO 22803. Dentistry - Membrane materials for guided tissue regeneration in oral and maxillofacial surgery - Contents of a technical file. Geneva: ISO; 2004.,1717 Meinig RP. Clinical use of resorbable polymeric membranes in the treatment of bone defects. Orthop Clin North Am. 2010;41:(1):39-47. https://doi.org/10.1016/j.ocl.2009.07.012
https://doi.org/10.1016/j.ocl.2009.07.01...
,3939 Ikumi R, Miyahara T, Akino N, Tachikawa N, Kasugai S. Guided bone regeneration using a hydrophilic membrane made of unsintered hydroxyapatite and poly(L-lactic acid) in a rat bone-defect model. Dent Mater J. 2018;37(6):912-18. https://doi.org/10.4012/dmj.2017-385
https://doi.org/10.4012/dmj.2017-385...
. Such scientific evidence makes this research robust, unbiased and accurate for the analysis of osteopromotive membranes for GBR.

Critical defects in rat calvaria in control group without the use of membrane generally cause small percentages of newly formed bone, ranging from 0.4%4343 Bae EB, Kim HJ, Ahn JJ, Bae HY, Kim HJ, Huh JB. Comparison of Bone Regeneration between Porcine-Derived and Bovine-Derived Xenografts in Rat Calvarial Defects: A Non-Inferiority Study. Materials (Basel). 2019;12(20):3412. https://doi.org/10.3390/ma12203412
https://doi.org/10.3390/ma12203412...
to 4% at 1 month44 International Organization for Standardization. ISO 22803. Dentistry - Membrane materials for guided tissue regeneration in oral and maxillofacial surgery - Contents of a technical file. Geneva: ISO; 2004.,1717 Meinig RP. Clinical use of resorbable polymeric membranes in the treatment of bone defects. Orthop Clin North Am. 2010;41:(1):39-47. https://doi.org/10.1016/j.ocl.2009.07.012
https://doi.org/10.1016/j.ocl.2009.07.01...
,2727 Araújo LK, Antunes GS, Melo MM, Castro-Silva II. Brazilian dentists’ perceptions of using bone grafts: an inland survey. Acta Odontol Latinoam. 2020;33(3):165-73. https://doi.org/10.54589/aol.33/3/165
https://doi.org/10.54589/aol.33/3/165...
and from 0.9%4040 Jang YS, Moon SH, Nguyen TT, Lee MH, Oh TJ, Han AL, Bae TS. In vivo bone regeneration by differently designed titanium membrane with or without surface treatment: a study in rat calvarial defects. J Tissue Eng. 2019;10:2041731419831466. https://doi.org/10.1177/2041731419831466
https://doi.org/10.1177/2041731419831466...
to 5% in 3 months44 International Organization for Standardization. ISO 22803. Dentistry - Membrane materials for guided tissue regeneration in oral and maxillofacial surgery - Contents of a technical file. Geneva: ISO; 2004.,1717 Meinig RP. Clinical use of resorbable polymeric membranes in the treatment of bone defects. Orthop Clin North Am. 2010;41:(1):39-47. https://doi.org/10.1016/j.ocl.2009.07.012
https://doi.org/10.1016/j.ocl.2009.07.01...
or reaching up to 20%, considering the average of central regions with up to 2%, intermediate up to 8% and peripheral regions up to 40%3939 Ikumi R, Miyahara T, Akino N, Tachikawa N, Kasugai S. Guided bone regeneration using a hydrophilic membrane made of unsintered hydroxyapatite and poly(L-lactic acid) in a rat bone-defect model. Dent Mater J. 2018;37(6):912-18. https://doi.org/10.4012/dmj.2017-385
https://doi.org/10.4012/dmj.2017-385...
. The amount of connective tissue remains constant between 1 and 3 months, with about 23%44 International Organization for Standardization. ISO 22803. Dentistry - Membrane materials for guided tissue regeneration in oral and maxillofacial surgery - Contents of a technical file. Geneva: ISO; 2004. or can reach up to 40% in the aforementioned periods1717 Meinig RP. Clinical use of resorbable polymeric membranes in the treatment of bone defects. Orthop Clin North Am. 2010;41:(1):39-47. https://doi.org/10.1016/j.ocl.2009.07.012
https://doi.org/10.1016/j.ocl.2009.07.01...
.

In the experimental rat skull model, membranes for GBR alone can achieve different osteopromotive profiles. In the period of 1 and 2 months, the ratio of area of newly formed bone compared to control group can be two to ten times for Bio-Gide with collagens I and III from swine dermis1919 Yamatogi RS, Rahal SC, Granjeiro JM, Taga R, Cestari TM, Lima AFM. Microscopic evaluation of biologic membrane association from bovine origin implanted subcutaneously in rats. Cienc Rural. 2005;35(4):837-42. https://doi.org/10.1590/S0103-84782005000400014
https://doi.org/10.1590/S0103-8478200500...
,3636 Bassi APF, Bizelli VF, Francatti TM, Ferreira ACRM, Pereira JC, Al-Sharani HM, Lucas FA, Faverani LP. Bone Regeneration Assessment of Polycaprolactone Membrane on Critical-Size Defects in Rat Calvaria. Membranes. 2020;11(2):e124. https://doi.org/10.3390/membranes11020124
https://doi.org/10.3390/membranes1102012...
3838 Teixeira LJC, Balthazar MLB, de Deus G, Vidigal Jr. GM, Conz MB. Comparação de dois métodos histomorfométricos de análise na cicatrização de defeitos crticos na calvária de ratos, após tratamento com diferentes grânulos de hidroxiapatita. ImplantNews 2015;12(6a-PBA):197-202. or Jason with collagen III from porcine pericardium3838 Teixeira LJC, Balthazar MLB, de Deus G, Vidigal Jr. GM, Conz MB. Comparação de dois métodos histomorfométricos de análise na cicatrização de defeitos crticos na calvária de ratos, após tratamento com diferentes grânulos de hidroxiapatita. ImplantNews 2015;12(6a-PBA):197-202.,4242 Abou Fadel R, Samarani R, Chakar C. Guided bone regeneration in calvarial critical size bony defect using a double-layer resorbable collagen membrane covering a xenograft: a histological and histomorphometric study in rats. Oral Maxillofac Surg. 2018 Jun;22(2):203-13. https://doi.org/10.1007/s10006-018-0694-x
https://doi.org/10.1007/s10006-018-0694-...
, equal to five times for bovine GenDermFlex1919 Yamatogi RS, Rahal SC, Granjeiro JM, Taga R, Cestari TM, Lima AFM. Microscopic evaluation of biologic membrane association from bovine origin implanted subcutaneously in rats. Cienc Rural. 2005;35(4):837-42. https://doi.org/10.1590/S0103-84782005000400014
https://doi.org/10.1590/S0103-8478200500...
, two to four times for Collprotect with collagen from porcine dermis3838 Teixeira LJC, Balthazar MLB, de Deus G, Vidigal Jr. GM, Conz MB. Comparação de dois métodos histomorfométricos de análise na cicatrização de defeitos crticos na calvária de ratos, após tratamento com diferentes grânulos de hidroxiapatita. ImplantNews 2015;12(6a-PBA):197-202. or Super Fixorb with polylactic acid and hydroxyapatite (60:40)4040 Jang YS, Moon SH, Nguyen TT, Lee MH, Oh TJ, Han AL, Bae TS. In vivo bone regeneration by differently designed titanium membrane with or without surface treatment: a study in rat calvarial defects. J Tissue Eng. 2019;10:2041731419831466. https://doi.org/10.1177/2041731419831466
https://doi.org/10.1177/2041731419831466...
and two to three times for bovine GenDerm1919 Yamatogi RS, Rahal SC, Granjeiro JM, Taga R, Cestari TM, Lima AFM. Microscopic evaluation of biologic membrane association from bovine origin implanted subcutaneously in rats. Cienc Rural. 2005;35(4):837-42. https://doi.org/10.1590/S0103-84782005000400014
https://doi.org/10.1590/S0103-8478200500...
,4242 Abou Fadel R, Samarani R, Chakar C. Guided bone regeneration in calvarial critical size bony defect using a double-layer resorbable collagen membrane covering a xenograft: a histological and histomorphometric study in rats. Oral Maxillofac Surg. 2018 Jun;22(2):203-13. https://doi.org/10.1007/s10006-018-0694-x
https://doi.org/10.1007/s10006-018-0694-...
, and for synthetic membrane with policaprolactone and 5% hydroxyapatite3737 Bizelli VF, Ramos EU, Veras ASC, Teixeira GR, Faverani LP, Bassi APF. Calvaria critical size defects regeneration using collagen membranes to assess the osteopromotive principle: An animal study. Membranes. 2022;12(5):e461. https://doi.org/10.3390/membranes12050461
https://doi.org/10.3390/membranes1205046...
. There are cases such as the Biomend with collagen I that presents formation of new bone similar to control group4040 Jang YS, Moon SH, Nguyen TT, Lee MH, Oh TJ, Han AL, Bae TS. In vivo bone regeneration by differently designed titanium membrane with or without surface treatment: a study in rat calvarial defects. J Tissue Eng. 2019;10:2041731419831466. https://doi.org/10.1177/2041731419831466
https://doi.org/10.1177/2041731419831466...
, the bacterial cellulose membrane bellow of the control group in 1 month and above until five times its area in 2 months3636 Bassi APF, Bizelli VF, Francatti TM, Ferreira ACRM, Pereira JC, Al-Sharani HM, Lucas FA, Faverani LP. Bone Regeneration Assessment of Polycaprolactone Membrane on Critical-Size Defects in Rat Calvaria. Membranes. 2020;11(2):e124. https://doi.org/10.3390/membranes11020124
https://doi.org/10.3390/membranes1102012...
and the PLGA membrane, with no differences compared to control group at 2 months4545 Bernabé PF, Melo LG, Cintra LT, Gomes-Filho JE, Dezan E Jr, Nagata MJ. Bone healing in critical-size defects treated with either bone graft, membrane, or a combination of both materials: a histological and histometric study in rat tibiae. Clin Oral Implants Res. 2012;23:384-88. https://doi.org/10.1111/j.1600-0501.2011.02166.x
https://doi.org/10.1111/j.1600-0501.2011...
, showing that the performance of these implantable devices can vary greatly, depending on the type and duration of treatment.

Collagen membrane alone after 1 month of implantation in a bone defect can generate 8% of new bone and 0.3% of remnants, and when associated with bone graft, it reaches 15% of new bone and 0.03% of remnants2727 Araújo LK, Antunes GS, Melo MM, Castro-Silva II. Brazilian dentists’ perceptions of using bone grafts: an inland survey. Acta Odontol Latinoam. 2020;33(3):165-73. https://doi.org/10.54589/aol.33/3/165
https://doi.org/10.54589/aol.33/3/165...
. The combination of resorbable collagen membrane Cola-D and xenografts Bio-Oss (bovine; granulometry: 0.25–1 mm) or Bone-XP (porcine; granulometry: 0.2–1 mm) can generate new bone, 5.83% and 9.08% at 1 month and 21.68% and 25.22% at 2 months, respectively4444 Hoornaert A, d’Arros C, Heymann MF, Layrolle P. Biocompatibility, resorption and biofunctionality of a new synthetic biodegradable membrane for guided bone regeneration. Biomed Mater. 2016;11(4):e045012. https://doi.org/10.1088/1748-6041/11/4/045012
https://doi.org/10.1088/1748-6041/11/4/0...
. Another study with Bio-Oss (granulometry: 0.5–1 mm) coated with BioGide in 1 or 2 layers showed that the single coating generated in 1 and 2 months, respectively, more bone (22.7% and 37%) than the double (17.3% and 24.5%) or the graft without membrane (11.5% and 16.8%), although the amount of residual material was slightly higher in the double (30.2% and 25.5%) than in simple (32.5% and 28.5%) or with graft without membrane (15.3% and 9.4%)4343 Bae EB, Kim HJ, Ahn JJ, Bae HY, Kim HJ, Huh JB. Comparison of Bone Regeneration between Porcine-Derived and Bovine-Derived Xenografts in Rat Calvarial Defects: A Non-Inferiority Study. Materials (Basel). 2019;12(20):3412. https://doi.org/10.3390/ma12203412
https://doi.org/10.3390/ma12203412...
. In rat tibia defects, membrane GenDerm alone could favor new bone formation by 25.3% at 1 month and 32.2% at 3 months, and when associated with organic bovine graft GenOx, it increased bone formation to 45.5% and 52.4%, respectively4646 Al-Maawi S, Orlowska A, Sader R, James Kirkpatrick C, Ghanaati S. In vivo cellular reactions to different biomaterials-Physiological and pathological aspects and their consequences. Semin Immunol. 2017;29:49-61. https://doi.org/10.1016/j.smim.2017.06.001
https://doi.org/10.1016/j.smim.2017.06.0...
.

Regarding the formation of connective tissue, there was no variation between the membranes studied. However, the literature admits some microscopic distinctions in fibrogenesis, according to the type and duration of treatment. Metallic nonresorbable biomaterials (e.g., titanium) have more discrete fibrogenesis because they are bioinert4747 Neto AMD, Sartoretto SC, Duarte IM, Resende RFB, Alves ATNN, Mourão CFAB, Calasans-Maia J, Montemezzi P, Tristão GC, Calasans-Maia MD. In Vivo Comparative Evaluation of Biocompatibility and Biodegradation of Bovine and Porcine Collagen Membranes. Membranes (Basel). 2020;10(12):e423. https://doi.org/10.3390/membranes10120423
https://doi.org/10.3390/membranes1012042...
. Natural resorbable polymers (e.g., collagen) exhibit greater peripheral and internal cellularity, mild to moderate chronic inflammation (lymphocytes, macrophages and giant cells) and fibroblast proliferation, in addition to mild to moderate production of connective matrix in the spaces left by the degrading implant up to 60 days1111 Ronda M, Rebaudi A, Torelli L, Stacchi C. Expanded vs. dense polytetrafluoroethylene membranes in vertical ridge augmentation around dental implants: A prospective randomized controlled clinical trial. Clin Oral Implants Res. 2014;25(7):859-66. https://doi.org/10.1111/clr.12157
https://doi.org/10.1111/clr.12157...
,4646 Al-Maawi S, Orlowska A, Sader R, James Kirkpatrick C, Ghanaati S. In vivo cellular reactions to different biomaterials-Physiological and pathological aspects and their consequences. Semin Immunol. 2017;29:49-61. https://doi.org/10.1016/j.smim.2017.06.001
https://doi.org/10.1016/j.smim.2017.06.0...
5151 Sousa EM, Melo EF, Ribeiro HL, Feitosa JAP, Souza-Filho MSM, Melo MM, Castro-Silva II. Biocompatibility and biodegradation analysis of Nile tilapia gelatin and apatite membranes. Rev Ciênc Agron. 2022;53:e20218217.. Natural composite membranes with collagen and apatite also exhibit fibrogenesis similar to collagen biopolymers1717 Meinig RP. Clinical use of resorbable polymeric membranes in the treatment of bone defects. Orthop Clin North Am. 2010;41:(1):39-47. https://doi.org/10.1016/j.ocl.2009.07.012
https://doi.org/10.1016/j.ocl.2009.07.01...
,5050 Lindner C, Alkildani S, Stojanovic S, Najman S, Jung O, Barbeck M. In Vivo Biocompatibility Analysis of a Novel Barrier Membrane Based on Bovine Dermis-Derived Collagen for Guided Bone Regeneration (GBR). Membranes (Basel). 2022;12(4):e378. https://doi.org/10.3390/membranes12040378
https://doi.org/10.3390/membranes1204037...
,5252 Korzinskas T, Jung O, Smeets R, Stojanovic S, Najman S, Glenske K, et al. In vivo analysis of the biocompatibility and macrophage response of a non-resorbable PTFE membrane for guided bone regeneration. Int J Mol Sci. 2018;19(10):e2952. https://doi.org/10.3390/ijms19102952
https://doi.org/10.3390/ijms19102952...
. On the other hand, synthetic polymers present connective tissue formation dependent on the degradability pattern, in a lower fibrogenesis scale in non-resorbable biomaterials (e.g., PTFE)1111 Ronda M, Rebaudi A, Torelli L, Stacchi C. Expanded vs. dense polytetrafluoroethylene membranes in vertical ridge augmentation around dental implants: A prospective randomized controlled clinical trial. Clin Oral Implants Res. 2014;25(7):859-66. https://doi.org/10.1111/clr.12157
https://doi.org/10.1111/clr.12157...
,1212 Kim EV, Petronyuk YS, Guseynov NA, Tereshchuk SV, Popov AA, Volkov AV, Gorshenev VN, Olkhov AA, Levin VM, Dymnikov AB, Rodionov VE, Tumanyan GA, Ivashkevich SG, Bonartsev AP, Borozdkin LL. Biocompatibility and Bioresorption of 3D-Printed Polylactide and Polyglycolide Tissue Membranes. Bull Exp Biol Med. 2021;170(3):356-59. https://doi.org/10.1007/s10517-021-05066-x
https://doi.org/10.1007/s10517-021-05066...
,2424 Loh QL, Choong C. Three-dimensional scaffolds for tissue engineering applications: role of porosity and pore size. Tissue Eng Part B Rev. 2013;19(6):485-502. https://doi.org/10.1089/ten.TEB.2012.0437
https://doi.org/10.1089/ten.TEB.2012.043...
,4747 Neto AMD, Sartoretto SC, Duarte IM, Resende RFB, Alves ATNN, Mourão CFAB, Calasans-Maia J, Montemezzi P, Tristão GC, Calasans-Maia MD. In Vivo Comparative Evaluation of Biocompatibility and Biodegradation of Bovine and Porcine Collagen Membranes. Membranes (Basel). 2020;10(12):e423. https://doi.org/10.3390/membranes10120423
https://doi.org/10.3390/membranes1012042...
,5353 Geremias TC, Sartoretto SC, Batistella MA, Souza AAU, Alves ATNN, Uzeda MJP, Calasans-Maia J, Montemezzi P, Mourão CFAB, Calasans-Maia M. In Vivo Biological Evaluation of Biodegradable Nanofibrous Membranes Incorporated with Antibiofilm Compounds. Polymers (Basel). 2021;13(15):e2457. https://doi.org/10.3390/polym13152457
https://doi.org/10.3390/polym13152457...
and higher in resorbable ones (e.g., PLGA)1313 Radenković M, Alkildani S, Stoewe I, Bielenstein J, Sundag B, Bellmann O, Jung O, Najman S, Stojanovic S, Barbeck M. Comparative in vivo analysis of the integration behavior and immune response of collagen-based dental barrier membranes for guided bone regeneration (GBR). Membranes. 2021;11(9):e712. https://doi.org/10.3390/membranes11090712
https://doi.org/10.3390/membranes1109071...
,2424 Loh QL, Choong C. Three-dimensional scaffolds for tissue engineering applications: role of porosity and pore size. Tissue Eng Part B Rev. 2013;19(6):485-502. https://doi.org/10.1089/ten.TEB.2012.0437
https://doi.org/10.1089/ten.TEB.2012.043...
,4545 Bernabé PF, Melo LG, Cintra LT, Gomes-Filho JE, Dezan E Jr, Nagata MJ. Bone healing in critical-size defects treated with either bone graft, membrane, or a combination of both materials: a histological and histometric study in rat tibiae. Clin Oral Implants Res. 2012;23:384-88. https://doi.org/10.1111/j.1600-0501.2011.02166.x
https://doi.org/10.1111/j.1600-0501.2011...
,4747 Neto AMD, Sartoretto SC, Duarte IM, Resende RFB, Alves ATNN, Mourão CFAB, Calasans-Maia J, Montemezzi P, Tristão GC, Calasans-Maia MD. In Vivo Comparative Evaluation of Biocompatibility and Biodegradation of Bovine and Porcine Collagen Membranes. Membranes (Basel). 2020;10(12):e423. https://doi.org/10.3390/membranes10120423
https://doi.org/10.3390/membranes1012042...
,5454 Pereira LC, Mourão CFAB, Alves ATNN, Resende RFB, Uzeda MJPG, Granjeiro JM, Louro RS, Calasans-Maia MD. In vitro physico-chemical characterization and standardized in vivo evaluation of biocompatibility of a new synthetic membrane for guided bone regeneration. Materials (Basel). 2019;12(7):e1186. https://doi.org/10.3390/ma12071186
https://doi.org/10.3390/ma12071186...
,5555 Luz EPCG, Chagas BS, Almeida NT, Borges MF, Andrade FK, Muniz CR, Castro-Silva II, Teixeira EH, Popat K, Rosa MF, Vieira RS. Resorbable bacterial cellulose membranes with strontium release for guided bone regeneration. Mater Sci Eng C Mater Biol Appl. 2020;116:e111175. https://doi.org/10.1016/j.msec.2020.111175
https://doi.org/10.1016/j.msec.2020.1111...
. None of the experimental groups had a foreign body granuloma (nonimmunogenic) with a fibrous capsule, which is considered an unwanted implant rejection response1717 Meinig RP. Clinical use of resorbable polymeric membranes in the treatment of bone defects. Orthop Clin North Am. 2010;41:(1):39-47. https://doi.org/10.1016/j.ocl.2009.07.012
https://doi.org/10.1016/j.ocl.2009.07.01...
,1818 Danieletto-Zanna CF, Bizelli VF, Ramires GADA, Francatti TM, Carvalho PSP, Bassi APF. Osteopromotion capacity of bovine cortical membranes in critical defects of rat calvaria: Histological and immunohistochemical analysis. Int J Biomater. 2020;2020:e6426702. https://doi.org/10.1155/2020/6426702
https://doi.org/10.1155/2020/6426702...
,4747 Neto AMD, Sartoretto SC, Duarte IM, Resende RFB, Alves ATNN, Mourão CFAB, Calasans-Maia J, Montemezzi P, Tristão GC, Calasans-Maia MD. In Vivo Comparative Evaluation of Biocompatibility and Biodegradation of Bovine and Porcine Collagen Membranes. Membranes (Basel). 2020;10(12):e423. https://doi.org/10.3390/membranes10120423
https://doi.org/10.3390/membranes1012042...
.

Regarding the biodegradability of membranes in rats, Lumina-Coat confirmed the stability time of 4 to 6 weeks1111 Ronda M, Rebaudi A, Torelli L, Stacchi C. Expanded vs. dense polytetrafluoroethylene membranes in vertical ridge augmentation around dental implants: A prospective randomized controlled clinical trial. Clin Oral Implants Res. 2014;25(7):859-66. https://doi.org/10.1111/clr.12157
https://doi.org/10.1111/clr.12157...
,3131 Criteria. LuminaCoat. [Web] 24 nov. 2022. Available in: https://www.loja.criteria.com.br/membrana-biologica-lumina-coat/p?skuId=8.
https://www.loja.criteria.com.br/membran...
, falling short of the Lumina-Coat Double Time, stable up to 8 weeks5050 Lindner C, Alkildani S, Stojanovic S, Najman S, Jung O, Barbeck M. In Vivo Biocompatibility Analysis of a Novel Barrier Membrane Based on Bovine Dermis-Derived Collagen for Guided Bone Regeneration (GBR). Membranes (Basel). 2022;12(4):e378. https://doi.org/10.3390/membranes12040378
https://doi.org/10.3390/membranes1204037...
,5656 Sousa BGB, Pedrotti G, Sponchiado AP, Cunali RS, Aragones A, Sarot JR, Zielak JC, Ornaghi BP, Leão MP. Analysis of tensile strength of poly(lactic-co-glycolic acid) (PLGA) membranes used for guided tissue regeneration. RSBO. 2014;11(1):59-65.. Surgitime PTFE did not show resorption during the experiment, as expected for the synthetic polymer PTFE1111 Ronda M, Rebaudi A, Torelli L, Stacchi C. Expanded vs. dense polytetrafluoroethylene membranes in vertical ridge augmentation around dental implants: A prospective randomized controlled clinical trial. Clin Oral Implants Res. 2014;25(7):859-66. https://doi.org/10.1111/clr.12157
https://doi.org/10.1111/clr.12157...
,1212 Kim EV, Petronyuk YS, Guseynov NA, Tereshchuk SV, Popov AA, Volkov AV, Gorshenev VN, Olkhov AA, Levin VM, Dymnikov AB, Rodionov VE, Tumanyan GA, Ivashkevich SG, Bonartsev AP, Borozdkin LL. Biocompatibility and Bioresorption of 3D-Printed Polylactide and Polyglycolide Tissue Membranes. Bull Exp Biol Med. 2021;170(3):356-59. https://doi.org/10.1007/s10517-021-05066-x
https://doi.org/10.1007/s10517-021-05066...
,2424 Loh QL, Choong C. Three-dimensional scaffolds for tissue engineering applications: role of porosity and pore size. Tissue Eng Part B Rev. 2013;19(6):485-502. https://doi.org/10.1089/ten.TEB.2012.0437
https://doi.org/10.1089/ten.TEB.2012.043...
,3232 Bionnovation. Surgitime PTFE. [Web] 24 nov. 2022. Available in: https://portal.bionnovation.com.br/surgitime_ptfe/.
https://portal.bionnovation.com.br/surgi...
,5353 Geremias TC, Sartoretto SC, Batistella MA, Souza AAU, Alves ATNN, Uzeda MJP, Calasans-Maia J, Montemezzi P, Mourão CFAB, Calasans-Maia M. In Vivo Biological Evaluation of Biodegradable Nanofibrous Membranes Incorporated with Antibiofilm Compounds. Polymers (Basel). 2021;13(15):e2457. https://doi.org/10.3390/polym13152457
https://doi.org/10.3390/polym13152457...
. Despite GenDerm being well organized, with high tensile strength and less deformation compared to Lumina-Coat and Surgidry Dental F, internal cracks explain structural fragility and greater subcutaneous degradation, predicted for up to 45 days1111 Ronda M, Rebaudi A, Torelli L, Stacchi C. Expanded vs. dense polytetrafluoroethylene membranes in vertical ridge augmentation around dental implants: A prospective randomized controlled clinical trial. Clin Oral Implants Res. 2014;25(7):859-66. https://doi.org/10.1111/clr.12157
https://doi.org/10.1111/clr.12157...
,3333 Baumer. Genderm. [Web] 24 nov. 2022. Available in: https://www.baumer.com.br/produtos/genderm.
https://www.baumer.com.br/produtos/gende...
. GenDerm fragments disappear after 30 days in tibial defects2424 Loh QL, Choong C. Three-dimensional scaffolds for tissue engineering applications: role of porosity and pore size. Tissue Eng Part B Rev. 2013;19(6):485-502. https://doi.org/10.1089/ten.TEB.2012.0437
https://doi.org/10.1089/ten.TEB.2012.043...
,4646 Al-Maawi S, Orlowska A, Sader R, James Kirkpatrick C, Ghanaati S. In vivo cellular reactions to different biomaterials-Physiological and pathological aspects and their consequences. Semin Immunol. 2017;29:49-61. https://doi.org/10.1016/j.smim.2017.06.001
https://doi.org/10.1016/j.smim.2017.06.0...
, which resembles another demineralized bone cortical membrane, intact in the subcutaneous tissue at 15 days, degraded in 30 days and absent in 60 days2020 Romandini M, Fratini A, Americo LM, Panda S, Marchett E. Biomaterials for Periodontal and Peri-Implant Regeneration. Materials. 2022;(14):e3319. https://doi.org/10.3390/ma14123319
https://doi.org/10.3390/ma14123319...
and differs from BioGide, with subcutaneous residues present up to 63 days4848 Gasque KCS, Oliveira RC, Ceolin D, Cestari TM, Taga R, Taga EM, Corrêa A, Paiva KB, Takyia M, Granjeiro JM. Evaluation of the biocompatibility of an acellular bovine pericardium membrane and its potential as an osteoblast scaffold. Cienc Odontol Bras. 2008;11 (1):58-66. or mild degradation in swine mandibular bone defects up to 12 weeks and disappearing at 27 weeks2222 Costa NMF, Yassuda DH, Sader MS, Fernandes GVO, Soares GDA, Granjeiro JM. Osteogenic effect of tricalcium phosphate substituted by magnesium associated with Genderm® membrane in rat calvarial defect model. Mater Sci Eng C. 2016;61:63-71. https://doi.org/10.1016/j.msec.2015.12.003
https://doi.org/10.1016/j.msec.2015.12.0...
. The resorption time predicted between 90 and 120 days of Pratix3434 Baumer. Pratix. [Web] 24 nov. 2022. Available in: https://www.baumer.com.br/produtos/pratix.
https://www.baumer.com.br/produtos/prati...
becomes plausible, as it practically did not change, according to the pattern observed in subcutaneous tissue in 254 or 3 months5555 Luz EPCG, Chagas BS, Almeida NT, Borges MF, Andrade FK, Muniz CR, Castro-Silva II, Teixeira EH, Popat K, Rosa MF, Vieira RS. Resorbable bacterial cellulose membranes with strontium release for guided bone regeneration. Mater Sci Eng C Mater Biol Appl. 2020;116:e111175. https://doi.org/10.1016/j.msec.2020.111175
https://doi.org/10.1016/j.msec.2020.1111...
and already expected for PLGA, with high tensile strength5757 Conz MB, Campos CN, Serrão SD, Soares GA, Vidigal Jr GM. Physical and chemical characterizations of 12 biomaterials used as bone grafts in Implantology. ImplantNews 2010;7(4):541-6. and slower degradation1313 Radenković M, Alkildani S, Stoewe I, Bielenstein J, Sundag B, Bellmann O, Jung O, Najman S, Stojanovic S, Barbeck M. Comparative in vivo analysis of the integration behavior and immune response of collagen-based dental barrier membranes for guided bone regeneration (GBR). Membranes. 2021;11(9):e712. https://doi.org/10.3390/membranes11090712
https://doi.org/10.3390/membranes1109071...
,2424 Loh QL, Choong C. Three-dimensional scaffolds for tissue engineering applications: role of porosity and pore size. Tissue Eng Part B Rev. 2013;19(6):485-502. https://doi.org/10.1089/ten.TEB.2012.0437
https://doi.org/10.1089/ten.TEB.2012.043...
, demonstrated subcutaneously from 4 to 26 weeks4545 Bernabé PF, Melo LG, Cintra LT, Gomes-Filho JE, Dezan E Jr, Nagata MJ. Bone healing in critical-size defects treated with either bone graft, membrane, or a combination of both materials: a histological and histometric study in rat tibiae. Clin Oral Implants Res. 2012;23:384-88. https://doi.org/10.1111/j.1600-0501.2011.02166.x
https://doi.org/10.1111/j.1600-0501.2011...
. Techgraft outperformed subcutaneous bovine pericardium membranes, intact in 15 days and absent between 30 and 60 days2020 Romandini M, Fratini A, Americo LM, Panda S, Marchett E. Biomaterials for Periodontal and Peri-Implant Regeneration. Materials. 2022;(14):e3319. https://doi.org/10.3390/ma14123319
https://doi.org/10.3390/ma14123319...
,4949 Souza FFP, Cavalcante FL, Castro-Silva II, Silva ALC, Souza Filho MSM. Poultry by-products as source of collagen, nanokeratin and bioapatite for biomedical use. Rev Ciênc Agron. 2021;52(4):e20207565. https://doi.org/10.5935/1806-6690.20210049
https://doi.org/10.5935/1806-6690.202100...
. The biodegradation between 4 and 6 months suggested for Techgraft3535 Baumer. Techgraft. [Web] 24 nov. 2022. Available in: https://www.baumer.com.br/produtos/techgraft.
https://www.baumer.com.br/produtos/techg...
converges with the same time observed with Jason in subcutaneous tissue3838 Teixeira LJC, Balthazar MLB, de Deus G, Vidigal Jr. GM, Conz MB. Comparação de dois métodos histomorfométricos de análise na cicatrização de defeitos crticos na calvária de ratos, após tratamento com diferentes grânulos de hidroxiapatita. ImplantNews 2015;12(6a-PBA):197-202.,4242 Abou Fadel R, Samarani R, Chakar C. Guided bone regeneration in calvarial critical size bony defect using a double-layer resorbable collagen membrane covering a xenograft: a histological and histomorphometric study in rats. Oral Maxillofac Surg. 2018 Jun;22(2):203-13. https://doi.org/10.1007/s10006-018-0694-x
https://doi.org/10.1007/s10006-018-0694-...
and in swine mandibular defects, slightly degraded up to 12 weeks and absent at 27 weeks2222 Costa NMF, Yassuda DH, Sader MS, Fernandes GVO, Soares GDA, Granjeiro JM. Osteogenic effect of tricalcium phosphate substituted by magnesium associated with Genderm® membrane in rat calvarial defect model. Mater Sci Eng C. 2016;61:63-71. https://doi.org/10.1016/j.msec.2015.12.003
https://doi.org/10.1016/j.msec.2015.12.0...
.

Preclinical studies look for membranes with adequate biocompatibility for application to GBR55 Elgali I, Omar O, Dahlin C, Thomsen P. Guided bone regeneration: materials and biological mechanisms revisited. Eur J Oral Sci. 2017;125(5):315-37. https://doi.org/10.1111/eos.12364
https://doi.org/10.1111/eos.12364...
,5151 Sousa EM, Melo EF, Ribeiro HL, Feitosa JAP, Souza-Filho MSM, Melo MM, Castro-Silva II. Biocompatibility and biodegradation analysis of Nile tilapia gelatin and apatite membranes. Rev Ciênc Agron. 2022;53:e20218217.. In general, Bio-Gide and Jason are membranes that present a good pattern of non-irritation, considering the inflammatory and repair response5151 Sousa EM, Melo EF, Ribeiro HL, Feitosa JAP, Souza-Filho MSM, Melo MM, Castro-Silva II. Biocompatibility and biodegradation analysis of Nile tilapia gelatin and apatite membranes. Rev Ciênc Agron. 2022;53:e20218217.. Regarding the tissue dynamics involved, the lower presence of inflammatory cells and twice the number of blood vessels in the first fifteen days after implant of Bio-Gide can explain its better performance in comparison to bacterial cellulose membranes, polycaprolactone with 5% hydroxyapatite, Jason and Collprotect3636 Bassi APF, Bizelli VF, Francatti TM, Ferreira ACRM, Pereira JC, Al-Sharani HM, Lucas FA, Faverani LP. Bone Regeneration Assessment of Polycaprolactone Membrane on Critical-Size Defects in Rat Calvaria. Membranes. 2020;11(2):e124. https://doi.org/10.3390/membranes11020124
https://doi.org/10.3390/membranes1102012...
3838 Teixeira LJC, Balthazar MLB, de Deus G, Vidigal Jr. GM, Conz MB. Comparação de dois métodos histomorfométricos de análise na cicatrização de defeitos crticos na calvária de ratos, após tratamento com diferentes grânulos de hidroxiapatita. ImplantNews 2015;12(6a-PBA):197-202.. Bio-Gide also outnumbered blood vessels up to 21 days in relation to bovine membrane Lyostypt4848 Gasque KCS, Oliveira RC, Ceolin D, Cestari TM, Taga R, Taga EM, Corrêa A, Paiva KB, Takyia M, Granjeiro JM. Evaluation of the biocompatibility of an acellular bovine pericardium membrane and its potential as an osteoblast scaffold. Cienc Odontol Bras. 2008;11 (1):58-66.. This behavior could be associated with the pro-angiogenic effect of collagens I and III, which would favor osteogenesis1616 Souza FFP, Pérez-Guerrero JA, Gomes M, Cavalcante FL, Souza Filho MSM, Castro-Silva II. Development and characterization of poultry collagen-based hybrid hydrogels for bone regeneration. Acta Cir Bras. 2022;37(3):e370302. https://doi.org/10.1590/acb370302
https://doi.org/10.1590/acb370302...
,3030 Bassi APF, Bizelli VF, Brasil LFM, Pereira JC, Al-Sharani HM, Momesso GAC, Faverani LP, Lucas FA. Is the bacterial cellulose membrane feasible for osteopromotive property? Membranes. 2020;10(9):e230. https://doi.org/10.3390/membranes10090230
https://doi.org/10.3390/membranes1009023...
.

Regarding the osseodifferentiation process, the higher immunoexpression of osteocalcin and lower of osteopontin between 1 and 2 months of implantation in the calvaria could be interpreted as favorable bioindicators of greater bone maturation for membrane Bio-Gide, both when compared to cellulosic membrane3636 Bassi APF, Bizelli VF, Francatti TM, Ferreira ACRM, Pereira JC, Al-Sharani HM, Lucas FA, Faverani LP. Bone Regeneration Assessment of Polycaprolactone Membrane on Critical-Size Defects in Rat Calvaria. Membranes. 2020;11(2):e124. https://doi.org/10.3390/membranes11020124
https://doi.org/10.3390/membranes1102012...
and to collagen swine membranes Jason and Collprotect3838 Teixeira LJC, Balthazar MLB, de Deus G, Vidigal Jr. GM, Conz MB. Comparação de dois métodos histomorfométricos de análise na cicatrização de defeitos crticos na calvária de ratos, após tratamento com diferentes grânulos de hidroxiapatita. ImplantNews 2015;12(6a-PBA):197-202.. Similar results were found when comparing the porcine membrane Bio-Gide with the bovine membranes GenDerm and GenDermFlex, with higher expression of ostecalcin with porcine origin and of osteopontin with bovine origin at 1 and 2 months of implantation, showing a potential correlation between animal source and performance of GBR membranes1919 Yamatogi RS, Rahal SC, Granjeiro JM, Taga R, Cestari TM, Lima AFM. Microscopic evaluation of biologic membrane association from bovine origin implanted subcutaneously in rats. Cienc Rural. 2005;35(4):837-42. https://doi.org/10.1590/S0103-84782005000400014
https://doi.org/10.1590/S0103-8478200500...
,4242 Abou Fadel R, Samarani R, Chakar C. Guided bone regeneration in calvarial critical size bony defect using a double-layer resorbable collagen membrane covering a xenograft: a histological and histomorphometric study in rats. Oral Maxillofac Surg. 2018 Jun;22(2):203-13. https://doi.org/10.1007/s10006-018-0694-x
https://doi.org/10.1007/s10006-018-0694-...
. Fibrous organization of natural collagenic matrices from different sources may explain differences in osteopromotion and degradation time5858 Lima CJ, Silva IIC, Bittencourt RC, Takamori ER, Lenharo A, Granjeiro JM. Análise histológica de uma membrana colágena de submucosa intestinal suína. ImplantNews. 2010;7(4):515-20.,5959 Tumedei M, Mourão CF, D'Agostino S, Dolci M, Di Cosola M, Piattelli A, Lucchese A. Histological and Histomorphometric Effectiveness of the Barrier Membranes for Jawbone Regeneration: An Overview of More Than 30 Years- Experience of Research Results of the Italian Implant Retrieval Center (1988-2020). Appl Sciences. 2021;11(5):2438. https://doi.org/10.3390/app11052438
https://doi.org/10.3390/app11052438...
.

Porosity is a very sensitive characteristic of GBR membranes, as nanometric porosities (pores of 0.004 μm) into collagen membrane are associated with the same amount of newly formed bone as the control group4040 Jang YS, Moon SH, Nguyen TT, Lee MH, Oh TJ, Han AL, Bae TS. In vivo bone regeneration by differently designed titanium membrane with or without surface treatment: a study in rat calvarial defects. J Tissue Eng. 2019;10:2041731419831466. https://doi.org/10.1177/2041731419831466
https://doi.org/10.1177/2041731419831466...
. On the other hand, a greater porosity reduces the osteopromotive capacity, as in the case of a titanium membrane without pores, which reached a greater area of neoformed bone compared to both anodized membranes with pores of 0.4 and 1.5 mm, in the ratio 1.6:1, as well as increased immunoexpression of calcein for up to 7 weeks4141 Ramires GAD, Helena JT, Oliveira JCS, Faverani LP, Bassi APF. Evaluation of Guided Bone Regeneration in Critical Defects Using Bovine and Porcine Collagen Membranes: Histomorphometric and Immunohistochemical Analyses. Int J Biomater. 2021;2021:e8828194. https://doi.org/10.1155/2021/8828194
https://doi.org/10.1155/2021/8828194...
. Surgitime PTFE features more interconnected synthetic polymer fibers, providing less permeability and greater mechanical resistance compared to GenDerm and Lumina-Coat, natural polymers with a heterogeneous distribution of collagen fibers, which gives them highly porous surfaces with varied diameters4242 Abou Fadel R, Samarani R, Chakar C. Guided bone regeneration in calvarial critical size bony defect using a double-layer resorbable collagen membrane covering a xenograft: a histological and histomorphometric study in rats. Oral Maxillofac Surg. 2018 Jun;22(2):203-13. https://doi.org/10.1007/s10006-018-0694-x
https://doi.org/10.1007/s10006-018-0694-...
, justifying the present results of biodegradation in natural membranes.

As for thickness, most commercial membranes tested are close to the range of 0.10 to 0.25 mm, most commonly reported in polymeric materials for GBR1111 Ronda M, Rebaudi A, Torelli L, Stacchi C. Expanded vs. dense polytetrafluoroethylene membranes in vertical ridge augmentation around dental implants: A prospective randomized controlled clinical trial. Clin Oral Implants Res. 2014;25(7):859-66. https://doi.org/10.1111/clr.12157
https://doi.org/10.1111/clr.12157...
,1818 Danieletto-Zanna CF, Bizelli VF, Ramires GADA, Francatti TM, Carvalho PSP, Bassi APF. Osteopromotion capacity of bovine cortical membranes in critical defects of rat calvaria: Histological and immunohistochemical analysis. Int J Biomater. 2020;2020:e6426702. https://doi.org/10.1155/2020/6426702
https://doi.org/10.1155/2020/6426702...
,2424 Loh QL, Choong C. Three-dimensional scaffolds for tissue engineering applications: role of porosity and pore size. Tissue Eng Part B Rev. 2013;19(6):485-502. https://doi.org/10.1089/ten.TEB.2012.0437
https://doi.org/10.1089/ten.TEB.2012.043...
,2828 Pilger AD, Schneider LD, Silva GM , Schneider KCC , Smidt R. Membranes and barriers for guided bone regeneration. Rev Ciênc Méd Biol. 2020;19(3):441-8. https://doi.org/10.9771/cmbio.v19i3.36390
https://doi.org/10.9771/cmbio.v19i3.3639...
,3838 Teixeira LJC, Balthazar MLB, de Deus G, Vidigal Jr. GM, Conz MB. Comparação de dois métodos histomorfométricos de análise na cicatrização de defeitos crticos na calvária de ratos, após tratamento com diferentes grânulos de hidroxiapatita. ImplantNews 2015;12(6a-PBA):197-202.,4040 Jang YS, Moon SH, Nguyen TT, Lee MH, Oh TJ, Han AL, Bae TS. In vivo bone regeneration by differently designed titanium membrane with or without surface treatment: a study in rat calvarial defects. J Tissue Eng. 2019;10:2041731419831466. https://doi.org/10.1177/2041731419831466
https://doi.org/10.1177/2041731419831466...
,4545 Bernabé PF, Melo LG, Cintra LT, Gomes-Filho JE, Dezan E Jr, Nagata MJ. Bone healing in critical-size defects treated with either bone graft, membrane, or a combination of both materials: a histological and histometric study in rat tibiae. Clin Oral Implants Res. 2012;23:384-88. https://doi.org/10.1111/j.1600-0501.2011.02166.x
https://doi.org/10.1111/j.1600-0501.2011...
,4646 Al-Maawi S, Orlowska A, Sader R, James Kirkpatrick C, Ghanaati S. In vivo cellular reactions to different biomaterials-Physiological and pathological aspects and their consequences. Semin Immunol. 2017;29:49-61. https://doi.org/10.1016/j.smim.2017.06.001
https://doi.org/10.1016/j.smim.2017.06.0...
,5757 Conz MB, Campos CN, Serrão SD, Soares GA, Vidigal Jr GM. Physical and chemical characterizations of 12 biomaterials used as bone grafts in Implantology. ImplantNews 2010;7(4):541-6.. Membranes beyond this range include Collprotect at 0.4 mm thickness3838 Teixeira LJC, Balthazar MLB, de Deus G, Vidigal Jr. GM, Conz MB. Comparação de dois métodos histomorfométricos de análise na cicatrização de defeitos crticos na calvária de ratos, após tratamento com diferentes grânulos de hidroxiapatita. ImplantNews 2015;12(6a-PBA):197-202., Lumina-Coat at 1 mm1111 Ronda M, Rebaudi A, Torelli L, Stacchi C. Expanded vs. dense polytetrafluoroethylene membranes in vertical ridge augmentation around dental implants: A prospective randomized controlled clinical trial. Clin Oral Implants Res. 2014;25(7):859-66. https://doi.org/10.1111/clr.12157
https://doi.org/10.1111/clr.12157...
or Lumina-Coat Double Time at 2 mm5050 Lindner C, Alkildani S, Stojanovic S, Najman S, Jung O, Barbeck M. In Vivo Biocompatibility Analysis of a Novel Barrier Membrane Based on Bovine Dermis-Derived Collagen for Guided Bone Regeneration (GBR). Membranes (Basel). 2022;12(4):e378. https://doi.org/10.3390/membranes12040378
https://doi.org/10.3390/membranes1204037...
,5656 Sousa BGB, Pedrotti G, Sponchiado AP, Cunali RS, Aragones A, Sarot JR, Zielak JC, Ornaghi BP, Leão MP. Analysis of tensile strength of poly(lactic-co-glycolic acid) (PLGA) membranes used for guided tissue regeneration. RSBO. 2014;11(1):59-65.. The thicker membrane design attempts to mechanically ensure its tissue barrier function, but contributes to a slower and more persistent inflammatory response, which can increase the pattern of irritation to the biomaterial1616 Souza FFP, Pérez-Guerrero JA, Gomes M, Cavalcante FL, Souza Filho MSM, Castro-Silva II. Development and characterization of poultry collagen-based hybrid hydrogels for bone regeneration. Acta Cir Bras. 2022;37(3):e370302. https://doi.org/10.1590/acb370302
https://doi.org/10.1590/acb370302...
,1717 Meinig RP. Clinical use of resorbable polymeric membranes in the treatment of bone defects. Orthop Clin North Am. 2010;41:(1):39-47. https://doi.org/10.1016/j.ocl.2009.07.012
https://doi.org/10.1016/j.ocl.2009.07.01...
,5050 Lindner C, Alkildani S, Stojanovic S, Najman S, Jung O, Barbeck M. In Vivo Biocompatibility Analysis of a Novel Barrier Membrane Based on Bovine Dermis-Derived Collagen for Guided Bone Regeneration (GBR). Membranes (Basel). 2022;12(4):e378. https://doi.org/10.3390/membranes12040378
https://doi.org/10.3390/membranes1204037...
,5656 Sousa BGB, Pedrotti G, Sponchiado AP, Cunali RS, Aragones A, Sarot JR, Zielak JC, Ornaghi BP, Leão MP. Analysis of tensile strength of poly(lactic-co-glycolic acid) (PLGA) membranes used for guided tissue regeneration. RSBO. 2014;11(1):59-65.. When comparing Lumina-Coat and Lumina-Coat Double Time, the degradation time doubles in the same proportion as its thickness, but it becomes more rigid and less attractive to surgical manipulation in small intraoral bone defects1111 Ronda M, Rebaudi A, Torelli L, Stacchi C. Expanded vs. dense polytetrafluoroethylene membranes in vertical ridge augmentation around dental implants: A prospective randomized controlled clinical trial. Clin Oral Implants Res. 2014;25(7):859-66. https://doi.org/10.1111/clr.12157
https://doi.org/10.1111/clr.12157...
,5050 Lindner C, Alkildani S, Stojanovic S, Najman S, Jung O, Barbeck M. In Vivo Biocompatibility Analysis of a Novel Barrier Membrane Based on Bovine Dermis-Derived Collagen for Guided Bone Regeneration (GBR). Membranes (Basel). 2022;12(4):e378. https://doi.org/10.3390/membranes12040378
https://doi.org/10.3390/membranes1204037...
,5656 Sousa BGB, Pedrotti G, Sponchiado AP, Cunali RS, Aragones A, Sarot JR, Zielak JC, Ornaghi BP, Leão MP. Analysis of tensile strength of poly(lactic-co-glycolic acid) (PLGA) membranes used for guided tissue regeneration. RSBO. 2014;11(1):59-65.. In composite membranes of PLGA, HA and βTCP, the thickness of 0.2 mm maintained the integrity of the material for up to 30 days, while thicknesses of 0.5 and 0.7 mm reached 90 days5555 Luz EPCG, Chagas BS, Almeida NT, Borges MF, Andrade FK, Muniz CR, Castro-Silva II, Teixeira EH, Popat K, Rosa MF, Vieira RS. Resorbable bacterial cellulose membranes with strontium release for guided bone regeneration. Mater Sci Eng C Mater Biol Appl. 2020;116:e111175. https://doi.org/10.1016/j.msec.2020.111175
https://doi.org/10.1016/j.msec.2020.1111...
. This logic does not always work, as the membrane Jason is half as thick and three times less dense than Bio-Gide, but both have similar biodegradation times2222 Costa NMF, Yassuda DH, Sader MS, Fernandes GVO, Soares GDA, Granjeiro JM. Osteogenic effect of tricalcium phosphate substituted by magnesium associated with Genderm® membrane in rat calvarial defect model. Mater Sci Eng C. 2016;61:63-71. https://doi.org/10.1016/j.msec.2015.12.003
https://doi.org/10.1016/j.msec.2015.12.0...
,3838 Teixeira LJC, Balthazar MLB, de Deus G, Vidigal Jr. GM, Conz MB. Comparação de dois métodos histomorfométricos de análise na cicatrização de defeitos crticos na calvária de ratos, após tratamento com diferentes grânulos de hidroxiapatita. ImplantNews 2015;12(6a-PBA):197-202.. To overcome these limitations, microstructural reinforcement has been more used, with chemical processes involving crosslinking, in order to keep the membrane thinning, its good adaptability to the bone defect and, at the same time, cohesion for a longer time to favor osteopromotion1616 Souza FFP, Pérez-Guerrero JA, Gomes M, Cavalcante FL, Souza Filho MSM, Castro-Silva II. Development and characterization of poultry collagen-based hybrid hydrogels for bone regeneration. Acta Cir Bras. 2022;37(3):e370302. https://doi.org/10.1590/acb370302
https://doi.org/10.1590/acb370302...
,1717 Meinig RP. Clinical use of resorbable polymeric membranes in the treatment of bone defects. Orthop Clin North Am. 2010;41:(1):39-47. https://doi.org/10.1016/j.ocl.2009.07.012
https://doi.org/10.1016/j.ocl.2009.07.01...
,3030 Bassi APF, Bizelli VF, Brasil LFM, Pereira JC, Al-Sharani HM, Momesso GAC, Faverani LP, Lucas FA. Is the bacterial cellulose membrane feasible for osteopromotive property? Membranes. 2020;10(9):e230. https://doi.org/10.3390/membranes10090230
https://doi.org/10.3390/membranes1009023...
.

The detailed description of a biomaterial is essential and should avoid scenarios with technical unconformities, as observed in a study with commercial grafts in Brazil, where erroneous information in the product package insert on physical-chemical characteristics was revealed in an independent test5757 Conz MB, Campos CN, Serrão SD, Soares GA, Vidigal Jr GM. Physical and chemical characterizations of 12 biomaterials used as bone grafts in Implantology. ImplantNews 2010;7(4):541-6.. The explicit biological data regarding osteogenesis, fibrogenesis and degradation of the tested regenerative membranes can contribute to decision making, good clinical planning and predictability of results in GBR.

Conclusion

The commercial membranes LuminaCoat, Surgitime PTFE, GenDerm, Pratix and Techgraft showed heterogeneous behavior in rat calvarial defects. Although Surgitime PTFE had greater osteopromotive capacity and limitation of connective tissue invagination, the biomaterial did not exhibit degradation. Pratix and Techgraft had favorable osteopromotion, LuminaCoat less connective tissue and GenDerm more accelerated biodegradation.

However, the most effective GBR membrane that simultaneously contemplates all the studied criteria remains undefined. The difficulty in meeting the set of specificities for choosing an ideal regenerative membrane raises future studies about the intrinsic factors of each biomaterial.

Acknowledgments

To undergraduate students at the Biomaterials Laboratory at the Universidade Federal do Ceará, Yasmin Alves Teles de Menezes, Abrahão Lincoln Alves Cunha, Ana Carolina de Oliveira Portela and Andresa Pereira Santiago, for their technical assistance during the surgical experimental phase.

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Publication Dates

  • Publication in this collection
    06 Mar 2023
  • Date of issue
    2023

History

  • Received
    30 Nov 2022
  • Accepted
    06 Jan 2023
Sociedade Brasileira para o Desenvolvimento da Pesquisa em Cirurgia https://actacirbras.com.br/ - São Paulo - SP - Brazil
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