R e g e n e R a t i o n RepoRtVolume 3 | Issue 3

this issue’s featuRed topic: Optimizing Long-Term Implant Success

In today’s esthetically driven world, adequate

bone volume and architecture in the anterior

maxilla are absolute prerequisites for successful

implant supported restorations. However, a

bone volume deficit in the esthetic zone of the

maxilla often occurs following tooth removal.

Guided Bone Regeneration, or GBR, remains

the most predictable technique for ensuring long

term implant survival and remains the standard

of care for regenerating bone in the maxillary

esthetic zone, as well as other areas of the oral

cavity.

GBR is primarily a procedure of exclusion,

in which unwanted nonosteogenic cells are

prevented from entering the grafted defect site,

thereby allowing angiogenic and osteogenic

cells from surrounding vascular and bony tis-

sues to repopulate and regenerate the area with

bone. Well-designed and effective membranes

are critical to successful GBR procedures.

As a technique, GBR was first described by

Hurley et al. in 1959 and studied extensively

by Boyne in the 1960s.1,2,3,4 Far ahead of their

time, these insightful men realized early on the

great potential of GBR and the pivotal role

membranes would play in providing successful

clinical results.

As a consequence of understanding the

importance of membranes to successful re-

generative outcomes, research into membrane

technology has continued unabated since the

inception of GBR. We now have a better

understanding of the underlying physiology of

GBR and those attributes membranes must have

to support nature’s requirements for successful

bone and tissue regeneration. In this edition of

The Regeneration Report we take a close look at

newly acquired information regarding resorbable

collagen membranes and how this information

expands our understanding of the important

role membranes play not only in bone regenera-

tion, but in mucosal soft tissue healing as well.

We hope that you enjoy receiving our publication. Are you interested in contributing your case reports? Have a topic you would be interested in for future issues? Please contact us by email at info@osteohealth.com with comments or suggestions!

P.O. BOX 9001 | ONE LUITPOLD DRIVE | SHIRLEY, NY 11967RegeneRation RepoRt

in this issue:Featured Topic: Optimizing Long-Term Implant Success •

Collagen Membranes - crosslinking vs. 100% natural collagen •

shaRe the RegeneRation RepoRt!We encourage you to share the Regeneration Report with your colleagues. If you have a study club or meeting coming up, call us! We’ll be happy to provide you with copies for distrubution.

to Request additional copies, contact us by phone at 1-800-874-2334 oR email at info@osteohealth.com

An early study by Zitzmann et al. compared lin-

ear bone gain and percent bone fill in 84 peri-im-

plant defects in 25 subjects grafted with Bio-Oss®

using either non-crosslinked Bio-Gide® or ePTFE

non-resorbable barrier membranes. At 6 months,

all defects were re-entered and measurements taken.

As noted in Table 2 (left), bone regeneration in both

groups were not statistically significantly different

(p = 0.94) with Bio-Gide® covered defects trending

toward a somewhat better result.5

In a more recent study, Wallace et al. examined

bone regeneration and implant survival in 64 sinus

augmentation procedures performed on 51 subjects

using either no membrane, Bio-Gide® or ePTFE

membranes to cover the lateral window.7 After

6 – 10 months, the percent of vital bone regenera-

tion was not significantly different between both

membrane groups (Fig. 9a, 9b, 10a, 10b). The no

membrane group produced the least amount of

new vital bone. Likewise, implant survival was not

Perc

ent B

one

Fill

100

90

80

70Bio-Gide® ePTFE

92%

78%

Results - Bone Fill

Table 2 — Bio-Gide®, a natural non-crosslinked membrane produced equivalent bone fill results to ePTFE nonresorbable membrane covered sites.5

significantly different between both the resorbable

Bio-Gide® and nonresorbable ePTFE groups.

In the above studies, nonresorbable ePTFE

membranes were used. Since ePTFE membranes

do not resorb, they represent the longest possible

intact barrier membrane durations, even longer

than crosslinked collagen membranes. Yet non-

crosslinked Bio-Gide® covered sites yielded bone

regeneration results equivalent to sites covered with

the longest possible surviving membrane. Current

evidence, therefore, seems to suggest that cross-

linking is not needed to produce effective clinical

results in GBR procedures.

Furthermore, Bio-Gide, a natural bilayer,

noncrosslinked collagen membrane is an effective

alternative to non-resorbable membranes.

Fig. 9a & 9b - Bio-Gide® covered lateral sinus window: 30% vital bone, 22% Bio-Oss®, 49% connective tissue.6

Fig. 10a & 10b - ePTFE covered lateral sinus window: 30% vital bone, 29% Bio-Oss®, 41% connective tissue.6

1. Hurley LA, Stinchfield FE, et al. The role of soft tissues in osteogenesis. J Bone Joint Surg 1959; 41:1243-1254. 2. Boyne PJ. Regeneration of alveolar bone beneath cel-lulose acetate filter implants. J Dent Res 1964; 43:827-832. 3. Boyne PJ, Mikels TE. Restoration of alveolar ridges by intramandibular transposition of osseous grafting. J Oral Surg 1968; 26(9):569-576. 4. Boyne PJ. Restoration of osseous defects in maxillofacial casualties. J Am Dent Assoc 1969; 78(4):767-776.

Bio-Oss® is registered trademark of Ed. Geistlich Söhne Ag Fur Chemische Industrie and is marketed under license by Osteohealth, a Division of Luitpold Pharmaceuticals, Inc.

Bio-Mend and BioMend Extend are registered trademarks of Integra Life Sciences Corp.

Ossix is a registered trademark of ColBar LifeScience Ltd.

R e g e n e R a t i o n R e p o R t

The probablity of successful Guided Bone and

Tissue Regeneration (GBR and GTR) procedures

is directly related to the efficacy of the membrane.

Although associated primarily with barrier function

and cell-occlusivity, membranes, to be truly effec-

tive, must provide for a high level of biocompatibil-

ity, tissue integration, nutrient transfer, and early

vascular in-growth while at the same time diminish

the incidence of overlying mucosal dehiscence

defects. In an attempt to prolong barrier function,

different types of crosslinking agents have been

introduced into a number of collagen membranes.

While crosslinking of collagen membranes prolongs

barrier function, it also diminishes tissue integra-

tion, nutrient transfer, and early vascular in-growth

when compared to non-crosslinked collagen

membranes.

Furthermore, crosslinked membranes exhibit

decreased ability to support osteoblastic and fibro-

blastic cellular migration and attachment, thereby

diminishing mucosal soft tissue healing and bone

regeneration. According to Rothamel et al., in

their in vitro study to evaluate the biocompatibility

of crosslinked versus non-crosslinked membranes,

BioMend, a crosslinked membrane, “inhibited

the attachment and proliferation of human PDL

fibroblasts and human SaOs-2 osteoblasts.” In the

same study, a non-crosslinked collagen membrane,

Bio-Gide, promoted fibroblastic and osteoblastic

cellular attachment (fig. 1 and 2).1

The ability of membranes to support the attach-

ment and proliferation of specific cell types is criti-

cal to successful bone and soft tissue regeneration.

However, the healing cascade is quite complex and

multifaceted and defect sites must be adequately

vascularized. GBR and GTR procedures will

special featuRe: Collagen Membranes - Crosslinking vs. 100% Natural Collagen

undoubtedly fail regardless of the effectiveness of

cellular attachment to membrane surfaces without

adequate vascularization. The ability of collagen

membranes to permit early ingrowth of blood ves-

sels into a grafted defect site is in part determined

by the presence or absence of crosslinking.

Bio-Gide®, a natural, non-crosslinked collagen

membrane permits early and rapid vasculariza-

tion in GBR and GTR procedures. An extensive

interconnected porous system allows for the early

transmembrane ingrowth of blood vessels so critical

to initial bone regeneration, while at the same time

excludes unwanted cell types from entering the

grafted area. (Fig. 3).2

Crosslinking of collagen membranes, how-

ever, appears to both delay and diminish vascular

ingrowth (Fig. 4, 5). In addition, as noted in two-

week post-grafting photomicrographs, tissue inte-

gration between surround-

ing connective tissue and

crosslinked membranes is

reduced, evidenced by splits

separating the membrane

from adjacent connective

tissue.3 Such splits may al-

low epithelial migration, i.e.

the development of a long

junctional epithelium, along

the root surface in GTR

procedures, preventing true

periodontal regeneration

from occurring (Fig. 4, 5).

The ability to support osteoblastic and fibroblas-

tic cellular attachment along with the favoring of

an adequate and early blood supply are parameters

that define membrane biocompatibility. Further,

utilization of membranes that are highly biocom-

patible decreases the risk that membrane related

complications will occur. Crosslinking of collagen

membranes tends to reduce membrane biocompat-

ibility. As a consequence, membrane induced soft

tissue dehiscences appear

to occur more frequently

with crosslinked than with

non-crosslinked mem-

branes.3 As Bornstein et al.

note in their recent study

comparing crosslinked to

non-crosslinked (Bio-Gide®)

membranes, “the premature

exposure in crosslinked

membrane sites represents a

complication rate of 33.3%

for the 8-week healing

period. This high complica-

tion rate is unacceptable from a clinician’s point of

view and is reminiscent of the high complication

rate experienced with bioinert ePTFE membranes

in clinical applications”3 (Fig. 6, 7, 8).

An apparent consequence of premature

membrane exposure is significantly reduced bone

regeneration in GBR procedures. In a 2001 meta-

analysis examining the influence of premature

membrane exposure in GBR procedures related to

bone augmentation around implants, Machtei con-

cludes the following: “New bone formation around

dental implants treated with membrane barriers

that became exposed was reduced compared to sites

where the membrane remained submerged. These

differences between the groups were both statistically

References: 1. Rothamel D, Schwarz F, et al. Biocompatibility of various collagen membranes in cultures of human PDL fibroblasts and human osteoblast-like cells. Clin Oral Impl Res. 2004; 15:443-449.2. Rothamel, Schwarz F, at al. Biodegradation of differently cross-linked collagen membranes: an experimental study in the rat. Clin Oral Impl Res. 2004; 16:369-378. 3. Bornstein MM, Bosshardt D, Buser D. Effect of Two Different Bioabsorbable Membranes on Guided Bone Regeneration: A Comparative Histomorphometric Study in the Dog Mandible. J Periodontol. 2007; 78:1943-1953. 4. Machtei EE. The effect of membrane exposure on the outcome of regenerative procedures in humans: A meta-analysis. J Periodontol. 2001; 72:512-516. 5. Zitzmann NU, Naef R, et al. Resorbable versus nonresorbable membranes in combination with Bio-Oss for guided bone regeneration. Int J Oral maxillofac Implants. 1997; 6:844-852. 6. Wallace S, Froum S, et al. Sinus Augmentation Utilizing Anorganic Bovine Bone (Bio-Oss) with Absorbable and Nonabsorble Membranes Placed of the Lateral Window: Histomorphometric and Clinical Analyses. Int J Periodontics Restorative Dent. 2005; 25:551-559.

Bio-Oss® and Bio-Gide® are registered trademarks of Ed. Geistlich Söhne Ag Fur Chemische Industrie and are marketed under license by Osteohealth, a Division of Luitpold Pharmaceuticals, Inc. ©2008 Luitpold Pharmaceuticals, Inc. OHD218f Iss. 9/2008

Fig. 2 — Osteoblasts adhere to the rough porous surface of Bio-Gide allowing increased mineralization.1

Fig. 4 — At 2 weeks, crosslinked BioMend (MB) exhibits little vasculariztion and a split (S) separating the membrane from the surrounding connective tissue (AT).2

Fig. 3 — At 2 weeks Bio-Gide (MB) is completely vascularized.2

Fig. 1 — PDL fibroblasts adhere to the smooth, finely textured layer of Bio-Gide promoting soft tissue healing.1

Fig. 5 — At 2 weeks, crosslinked Ossix (MB) exhibits no vascu-larization through the membrane and a large split (S) separating the membrane from the surrounding connective tissue (AT).2

“...premature exposure in crosslinked membrane

sites represents a complication rate of 33.3%... This high complication rate

is unacceptable from a clinician’s point of view...”

Bio-Gide - the bilayer matrix: Scanning EM of the smooth side of the bilayer matrix, which acts as a guide for the soft tissue healing (Left). Scanning EM of the rough side of the bilayer matrix, which acts as a guide for osteoblasts (Right) (Source Dr. M Bufler).

and clinically significant (0.56 mm vs. 3.01 mm,

p =0.0019) (Table 1).”4

Crosslinking, whether with ultraviolet light,

glutaraldehyde, or enzyme induced, prolongs

membrane biodegradation.2 The question remains,

however, whether prolonged membrane biodegra-

dation is necessary for successful bone regeneration

to occur in GBR procedures. Unfortunately, cur-

rent knowledge does not allow a definitive answer.

However, where does the evidence point?

Fig. 6 — Premature crosslinked membrane exposure associated with soft tissue dehiscence.3

Fig. 8 — Premature crosslinked membrane exposure (*) leads to less bone regeneration in GBR procedures.3

Fig. 7 — In the same test group, another soft tissue dehiscence with associated inflammation following placement of a cross-linked membrane.3

Table 1 — Premature membrane exposure leads to reduced bone formation in GBR procedures.

Change in Alveolar Bone Height (ABH) Adjacent to Implants Treated With GBR Procedure — Meta-Analysis of Exposed Versus Submerged Sites

Exposed Sites (E)

Mean ∆ ABH (mm ± SE)

-0.21 ± 0.56

2.00 ± 0.77

0.56 ± 0.45

N

27

9

36

Reference

Gher

Nowzari

Wmean

Submerged Sites (S)

Mean ∆ ABH (mm ± SE)

1.95 ± 0.55

4.04 ± 0.53

3.01 ± 0.38

N

16

8

24

P Value*

0.0079

0.0249

0.0019†

* 1-tailed Student t test† Fisher’s combined P statistics

Figures 1 - 5 reprinted from Clin Oral Implants Res 2004; 15: 443-449 and Clin Oral Implants Res 2005; 16: 369-379 with the permission of the Author, Dr. Daniel Rothamel and the publisher, Blackwell Publish-ing. Figures 6 - 8 reprinted from the Journal of Periodontology 2007; 78:1943-1953 with the permission of the Author, Dr. M. Bornstein and the publisher.

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