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Received: 8 May 2019    Revised: 22 July 2019    Accepted: 8 September 2019

DOI: 10.1111/clr.13544

ORIGINAL RESEARCH

Acellular mineralized allogenic block bone graft does not

remodel during the 10 weeks following concurrent implant
placement in a rabbit femoral model

D. Joshua Cohen1 | Kayla M. Scott1 | Aniket N. Kulkarni1 | Jennifer S. Wayne1 |

Barbara D. Boyan1,2  | Zvi Schwartz1,3

1
College of Engineering, Virginia
Commonwealth University, Richmond, VA, Abstract
USA Objectives: Due to bone loss, endosseous implants often require addition of a bone
2
Wallace H. Coulter Department of
graft to support adequate primary fixation, bone regeneration, and osseointegration.
Biomedical Engineering, Georgia Institute of
Technology, Atlanta, GA, USA The aim of this study was to compare effectiveness of autogenic and allogenic bone
3
Department of Periodontics, University of grafts when used during simultaneous insertion of the implant.
Texas Health Science Center at San Antonio,
San Antonio, TX, USA
Materials and Methods: 4‐mm‐diameter rabbit diaphyseal bone autografts or allo‐
grafts (n = 16/group) with a 3.2‐mm pre‐drilled hole in the center were placed into
Correspondence
Zvi Schwartz, College of Engineering,
a 4  mm defect in the proximal femur of 3.5  kg male New Zealand White rabbits.
Virginia Commonwealth University, 601 Machined 3.2  ×  10  mm grit‐blasted, acid‐etched titanium–aluminum–vanadium
West Main Street, Room 397, Box 843068,
Richmond, VA 23284‐3068, USA.
(Ti6Al4V) implants were placed. Control implants were placed into progressively
Email: zschwartz@vcu.edu drilled 3.2‐mm holes in the contralateral limbs. Post‐insertion day 70, samples were

Funding information
analyzed by micro‐CT and calcified histology, or by mechanical torque and push‐out
AB Dental testing followed by decalcified histology.
Results: Both grafts were integrated with the native bone. Micro‐CT showed less
bone volume (BV) and bone volume/total volume (BV/TV) in the allograft group, but
histology showed no differences in BV or BV/TV between groups. Allograft lacked
living cells, whereas autograft was cellularized. No difference was found in maximum
removal torque between groups. Compressive loading at the graft‐to‐bone interface
was significantly lower in allograft compared with autograft groups.
Conclusions: There was less bone in contact with the implant and significantly less
maximum compressive load in the allograft group compared with autograft. The al‐
lograft remained acellular as demonstrated by empty lacunae. Taken together, block
allograft implanted simultaneously with an implant produces a poorer quality bone
compared with autograft.

KEYWORDS
animal experiments, bone implant interactions, bone substitutes, CT Imaging, guided tissue
regeneration/bone regeneration, histopathology/host mechanisms, morphometric analysis,
periodontology

D. Joshua Cohen and Kayla M. Scott should be considered joint first author.

Clin Oral Impl Res. 2019;00:1–12. wileyonlinelibrary.com/journal/clr   © 2019 John Wiley & Sons A/S. |  1
Published by John Wiley & Sons Ltd
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2       COHEN et al.
1 |  I NTRO D U C TI O N
Resorption of underlying bone occurs most rapidly in the first year
following tooth loss, and 40%–60% of bone loss occurs in the first
3 years (Carlsson, Thilander, & Hedegård, 1967; Leong et al., 2014;
Tallgren, 2003). Due to the bone loss, endosseous implants often
require regeneration of new bone to achieve a functional implant
with adequate primary fixation and ultimate osseointegration with
the native bone. Bone graft substitutes are used to enhance osse‐
ointegration, in part by stimulating regeneration and in part by re‐
storing bone height and width (Heinemann, Hasan, Bourauel, Biffar,
& Mundt, 2015). However, the choice of bone graft is often based
on availability rather than on controlled evidence‐based studies
comparing technologies. Particulate bone graft substitutes, whether
synthetic, mineralized bone chips, or demineralized bone matrix, can
be used when implants are placed concurrently to restore missing
bone. However, solid mineralized bone grafts are more commonly
used because they provide better physical support for primary
fixation.
Autografts are the current gold standard as it is proposed that
the live osteoblasts in the autograft contribute to the osseointegra‐
tion process (Corinaldesi et al., 2007; Felice et al., 2009; Fontana
et al., 2008; Heinemann et al., 2015; Piattelli et al., 2002; Pistilli
et al., 2014; Shand, Heggie, Holmes, & Holmes, 2002; Spin‐Neto,
Landazuri Del Barrio, et al., 2013; Spin‐Neto et al., 2015). Most stud‐
ies comparing effectiveness of autografts and allografts have used
particulate bone fragments with and without bone marrow but do
not evaluate block grafts. The additional surgical site required to
obtain block autografts can lead to secondary infection, donor site
morbidity, increased operation time, scarring, and pain for patients,
making their use less common, particularly where larger drillable
grafts are desired (Clavero & Lundgren, 2003; Raghoebar, Meijndert,
Kalk, & Vissink, 2007; Schlee & Rothamel, 2013; Sindet‐Pedersen &
Enemark, 1990). The use of allografts has become more popular, with
approximately one third of bone grafts used in orthopedic proce‐
dures in the United States being allografts (Giannoudis, Dinopoulos,
& Tsiridis, 2005; Kao & Scott, 2007). Not only are allografts more
convenient, articles evaluating the success rates of implants found
no apparent differences in implant failure rate when using allografts
or autografts for augmentation of the vertical and horizontal alve‐
olar ridge (Chavda & Levin, 2017; Lyford, Mills, Knapp, Scheyer, &
Mellonig, 2003), of the maxillary ridge (Leonetti & Koup, 2003), or of
the atrophic maxillary ridge (Monje et al., 2014).
The question of the appropriate surgical procedure when con‐
ducting regeneration and implantation simultaneously remains
controversial, especially when block grafts are used. Some ad‐
vocates have found that single‐stage regeneration and implant
placement concurrently does not jeopardize the treatment result
(Glauser et al., 2001), while others have demonstrated better sta‐
bility and success rates using a two‐stage procedure (Fraguas et
al., 2013), and many researchers state there is no difference in
success rates between the two methods (Heinemann et al., 2015;
Peñarrocha‐Diago, Aloy‐Prósper, Peñarrocha‐Oltra, Guirado, &
Peñarrocha‐Diago, 2013; Ribeiro et al., 2018). A single‐stage sur‐
gery involving placement of the bone substitute and implant at the
same time has the benefit of a single surgical procedure for the
patient. In addition, the implant placement helps secure the bone
graft to the surrounding bone, maintains space needed for regen‐
eration, and yields high implant success rates (Peñarrocha‐Diago
et al., 2013).
The processing method of grafts is important for patient heal‐
ing. Particulate bone grafts may be mineralized or demineralized
and can vary in osteoconductive, osteogenic, and osteoinductive
properties depending on processing parameters as well as the age
and sex of the donor (Vail, Trotter, & Powers, 1994; Zhang, Powers,
& Wolfinbarger, 1997; Zhang et al., 1997). Less is known about the
variability in block autografts and allografts, although these types
of bone grafts are commonly used for single‐stage implant insertion
procedures, as well as ridge regeneration.
The purpose of the present study was to compare effectiveness
of block bone grafts used to support dental implant insertion in a
non‐weight bearing rabbit cortical bone model. We hypothesized
that autografts would perform better than allografts when evaluat‐
ing osseointegration with respect to bone‐to‐implant contact as well
as mechanical strength.
2 | M ATE R I A L S A N D M E TH O DS
2.1 | Implants
The titanium–aluminum–vanadium (Ti6Al4V) implants used in this
study were fabricated by AB Dental (Ashdod, Israel) and provided
to us as a gift. Implants were manufactured by CNC machining to
be 3.2  ×  10  mm and were grit‐blasted and acid‐etched with an Sa
value of 1.42  ±  0.10. These implants are used clinically for partial
edentulism and are available from the company (Catalog #: I55‐3,10).
The CNC implant surface properties have been previously described
(Hyzy et al., 2016).
2.2 | Bone graft preparation
Allograft bone was harvested from the tibias of two 3.2–3.5  kg
male New Zealand White rabbits (Robinson Services Inc.). Cellular
components were removed using high pressure hosing; bone was
then washed and bathed in gentamicin solution (80  mg/1  L 0.9%
NaCl) and frozen and stored at −80°C two months prior to surgery
to mimic the processing procedures implemented at human bone
banks for mineralized block allografts (Pelegrine, Da Costa, Sendyk,
& Gromatzky, 2011). Autografts were harvested from the right tibia
of each rabbit at the time of surgery. All grafts were harvested using
a 5 mm (external diameter)/4 mm (internal diameter) trephine to pro‐
duce a 4‐mm‐diameter bone graft (Figure 1). Immediately prior to
implant placement, a 3.2  mm osteotomy was progressively drilled
into the center of each graft to allow placement of an implant.
COHEN et al. |
      3

F I G U R E 1   In vivo experimental design. (Top) Autografts were obtained by creating a 4 mm defect in the tibia. For both autograft and
allograft groups, a 3.2‐mm hole was drilled into the center of the graft to create an outer ring with a hollow hole in the center for implant
placement. The autograft and implant were placed into a 4 mm defect created in the proximal left femur. (Bottom) Allografts were harvested,
cleaned, and frozen at −80°C for 2 months before surgery to mimic processing procedures used at human bone banks. Right femurs were
used as contralateral control legs and only received an implant, with no surrounding graft. Seventy day after surgery, femurs were collected
and micro‐CT, calcified histology, and mechanical testing were performed

further for destructive mechanical testing followed by decalcified

2.3 | Animal housing conditions
All animal procedures were performed according to the National
Research Council's Guide for the Care and Use of Laboratory
Animals guidelines and approved by Virginia Commonwealth
University's Institutional Animal Care and Use Committee under
protocol AD10000675. Male New Zealand White rabbits weigh‐
ing between 3.2 and 3.5  kg were single‐housed at a temperature
of 17–28°C with a humidity of 40%–70% and a 14‐/10‐hr light/dark
cycle. All rabbits were given ad libitum access to standard pellet and
water and received fresh food daily. As described in the Guide and
the Animal Welfare Act Regulations, the rabbits were housed in
caging constructed of stainless steel and elevated shelves that met
the standards for interior floor square surface area. The collection
pans underneath the cages were changed twice weekly. The entire
cage was changed and sanitized biweekly. The racks were situated
to allow visual, auditory, and olfactory stimulation for all rabbits in
the room, and all rabbits received toys as part of their environmental
enrichment.
Thirty‐two rabbits were divided into three treatment groups.
Group 1 received autograft with a pre‐drilled hole for a dental im‐
plant (n = 16); Group 2 received allograft with a pre‐drilled hole for
a dental implant (n = 16); and Group 3 was the contralateral control
receiving only the implant (n  =  32). These groups were subdivided
histology (16 animals, n  =  8 per treatment group). Sixteen animals
were designated for micro‐CT and calcified histology (n  =  8 per
treatment group); however, 2 animals were withdrawn from the
study due to fractures resulting in 14 animals with n = 7 per treat‐
ment group.
The animal number per group was chosen based on a power anal‐
ysis using an alpha of 0.05 and a power of 80% (delta = 5, sigma = 3,
m = 1) to reveal a minimum of n = 7 per group for the study to yield
statistical significance.
2.4 | Animal surgery
Rabbits were sedated with 20 mg/kg ketamine in combination with
3  mg/kg xylazine by intramuscular injection into the quadriceps.
Rabbits were intubated with a V‐gel pharyngeal airway (Jorgensen
Labs), and anesthesia was maintained using 0.5%–4% inhaled isoflu‐
rane in O2, to effect. Rabbits were randomly divided into the experi‐
mental groups. The greater trochanter of the femur was palpated,
and a 5‐cm incision was made overlying this anatomic landmark. The
muscles were separated, and the posterior surface of the both left
and right proximal femur was localized. To prepare the site of the im‐
plant, we used a physiodispenser connected to a high‐speed dental
handpiece with a maximum torque of 35 N. All parts of the surgery
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4       COHEN et al.
used this controller with irrigation in order to avoid heating of the
bone. Using a 4  mm (external diameter), 3  mm (internal diameter)
trephine attached to a high‐speed dental handpiece, a 4 mm diam‐
eter  ×  8  mm in depth defeat was created. Either fresh autografts
(n = 8 × 2) or frozen allografts (n = 8 × 2) were implanted into the
4 mm defect in the left proximal femur flush with the cortical bone.
Implants were placed through the osteotomy into the underlying
bone. Following primary fixation of the implant and graft, the mus‐
cles were re‐approximated and secured with 5‐0 vicryl suture, and
the skin was closed with 5‐0 nylon suture in a running technique.
In the contralateral femur, a progressively drilled 3.2 mm defect
was created and an identical implant was placed to serve as a con‐
trol (n  =  32). Animals were euthanized using an ear vein injection
of sodium pentobarbital at post‐surgical day 70. Femurs processed
for micro‐CT and calcified histology were fixed in 10% neutral buff‐
ered formalin for a minimum of 72 hr (16 animals, n = 8 per group
but two animals were withdrawn from the study due to fractures
resulting in n = 7 per group). Femurs processed for mechanical test‐
ing (16 animals, n  =  8 per group) were kept moist and cut to size,
and torque removal testing was conducted the same day as harvest.
After mechanical testing was performed, femurs were processed for
decalcified histology to examine the interface between the graft and
native bone.
2.5 | Micro‐CT
Micro‐CT (SkyScan 1173, Bruker) was used to evaluate bone‐to‐im‐
plant contact (BIC) in the distal femur. Femurs used for micro‐CT
were fixed and stored in 10% neutral buffered formalin for at least
72  hr prior to imaging. The proximal femur of fixed samples was
scanned at a resolution of 1,120 × 1,120 pixels (image pixel size of
15.10 µm) over 360° using a 0.25 mm brass filter, scanning energies
of 130 kV and 60 μA, 385 ms exposure time, and 5 x‐ray projections
acquired every 0.2° averaged. A standard Feldkamp reconstruction
was done using NRecon Software (Kontich, Belgium) with a beam
hardening correction of 20% and a Gaussian smoothing kernel of 0.
Samples were analyzed using CTAn version 1.17.7.2. Bone volume
3
(mm ) was calculated by isolating all bone within 3 pixels of the outer
three‐dimensional surface of the implant, and bone volume over
total volume (BV/TV) reflects this value (BV) divided by the outer
three‐dimensional surface of the implant volume (TV). These data
are represented as mean ± standard error (n = 7).
2.6 | Calcified histology
Following micro‐CT, samples were commercially processed (Histion,
Everett, WA). Briefly, samples were embedded in methyl meth‐
acrylate and one section was taken from each specimen. Sections
were stained with Stevenel's Blue/Van Gieson and imaged using
Zen 2012 Blue Edition with an AxioCam MRc5 camera and Axio
Observer Z.1 microscope (Carl Zeiss Microscopy). Methods outlining
histomorphometric analysis measurements are included in Figure S1.
Bone‐to‐implant contact (BIC) was defined as the lack of discernable
space between the bone and the implant in the cortical region, the
bone marrow cavity, and the combination of the two, represented as
cortical + bone marrow. BIC was measured in units of μm and nor‐
malized to implant perimeter to account for variations in slice depth.
Graft characterization was performed, and BIC of the graft to
the native bone was analyzed. New bone area formed in the marrow
cavity was assessed by measuring new bone in a consistent region of
interest from the endosteal side of the cortical bone to the opposite
cortical bone and normalized to the region of interest. New bone
marrow cavities were observed in all samples adjacent to the defect.
Linear measurements (5 lines per side, a mean of 10 lines) from the
base of the previous cortical bone to the end of new bone marrow
region were measured (Cohen et al., 2016).
2.7 | Mechanical testing
Destructive mechanical testing was performed on a separate co‐
hort of animals (16 animals, n  =  8 per group). Torque testing was
performed on fresh, hydrated samples using 1x phosphate‐buffered
saline (PBS) using a previously established method (Felfel, Ahmed,
Parsons, & Rudd, 2012). Testing was performed at a rate of 1 RPM as
recommended by ASTM standard F543‐00 using a Bose Electroforce
3,200 series bi‐axial mechanical testing system equipped with a
445 N/5.7 N‐m load/torque transducer (Materials, Head, & Screws,
1989). A custom‐made clamping bracket was created to hold the rab‐
bit femur stationary after flattening the medial and lateral aspects of
the femur using a Dremel‐300 rotary sander to provide a flat grip‐
ping surface for the bracket. A dental driver was held securely in
the custom‐made top fixture and attached to the dental implant in
the femur, taking care to maintain a perpendicular plane to prevent
lateral translation of the driver. Max torque required to dislodge the
implant from the bone was reported (Figure 7a).
After the implant was removed, specimens were stored at −80 ̊C
for 2 months. Push‐out testing was performed according to a pre‐
viously established protocol (Li et al., 2018). Briefly, samples were
thawed and cut in half along the sagittal plane to create a flat surface
on which the specimen would rest. Each sample was approximately 5
inches in length, with the defect centered in the middle. Since push‐
out testing evaluates the interface of the native bone and the graft,
push‐out testing could only be performed on specimens containing
an implanted graft and not on control legs. Push‐out testing method‐
ology was adapted from a previously published protocol (Boschian
Pest, Cavalli, Bertani, & Gagliani, 2002). On the day of testing, spec‐
imens were thawed and an internal acrylic support was fashioned
inside the bone marrow cavity using acrylic repair powder (Henry
Schein Animal Health, Dublin, Ohio) cross‐linked using acrylic liquid
self‐cure (Henry Schein Animal Health), taking care to avoid the area
of the defect. Samples were allowed to cure for 1–2 hr and wrapped
in 1X PBS‐soaked gauze in 4 C
̊ for 1 hr prior to testing.
A washer (outer diameter  =  35mm, inner diameter  =  11.2  mm)
was placed on the flat‐topped mechanical testing mounts to provide
support to both sidewalls and reinforce the acrylic mold. A 5‐mm cir‐
cular rod was positioned directly above the defect site, and uniaxial
COHEN et al. |
      5

(a) (b) (c) (d)

(e) (f) (g) (h)

(i) (j) (k) (l)

F I G U R E 2   μCT representation and quantification of implant site. (a, b) Autograft, (c, d) allograft, (e, f) contralateral control leg of
autograft, and (g, h) contralateral control leg of allograft group. (b, d, f, h) Implant was removed to allow visualization of new bone growth
around implant. Implant was pseudo‐colored red to allow for easy visualization. (i) Micro‐CT quantification of bone volume around implant.
(j) Quantified bone volume normalized to contralateral leg. (k) Quantified bone volume over total volume (BV/TV) and (l) BV/TV normalized
to contralateral control. (a–d) Blue box indicates graft area placement for groups that received a graft. Groups not sharing a letter are
statistically significant using an alpha equal to 0.05. An * denotes significance using the Wilcoxon signed‐rank test with an alpha equal to
0.05 in treatment group versus its contralateral control (data not shown, no significance was found)

compression testing was performed at a rate of 10 mm/min until fail‐
ure (Figure 7b). Method was adapted from a previously established
protocol (Saksø et al., 2013). Specimens that did not fail at the graft
interface were excluded. The acrylic mold was removed by soaking
samples in acetone (VWR, Radnor, PA) for 5 hr. Samples were then
rinsed in running deionized water for 15 min and placed in 30 ml of
10% neutral buffered formalin (VWR) until processing for decalci‐
fied histology.
2.8 | Decalcified histology
Following removal torque and push‐out testing, the remaining auto‐
graft and allograft samples were decalcified for 7 days using Decal™
Decalcifier (StatLab), rinsed in running deionized water for 15 min,
dehydrated in a series of 70%, 95%, and 100% ethanol and xylene
washes, and embedded with Richard‐Allan Scientific Histoplast
Paraffin (Thermo Scientific). Sections of 5 µm were collected using
a manual microtome (Shandon Finesse 325, Thermo Scientific) and
stained using hematoxylin (VWR) and eosin‐Y (Thermo Scientific)
(H&E). Samples were imaged using Zen 2012 Blue Edition software
with an AxioCam MRc5 camera and Axio Observer Z.1 microscope
(Carl Zeiss Microscopy).
2.9 | Statistical analysis
Data are represented as mean ± standard error. Results were ana‐
lyzed using an unpaired t test (autograft vs. allograft) or a paired t
test (contralateral control vs. graft). Groups with different letters are
statistically significant using an α  =  0.05. When graphs were ana‐
lyzed as treatment over control, a Shapiro–Wilk test was performed
to ensure normality followed by a paired t test on the contralateral
control and treatment group. Significance to its contralateral control
is denoted with an * using an α = 0.05 using the Wilcoxon's signed‐
rank test.
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6       COHEN et al.

(a) (b) (c) (d)

(e) (f) (g) (h)

F I G U R E 3   Calcified histology stained using Stevenel's blue. (b) Autograft, (d) allograft, (f) contralateral control leg for autograft, and (h)
contralateral control leg for allograft. Magnified images showing the interaction of the native bone and the graft for (a) autograft and (c)
allograft and the same locations in the contralateral controls for (e) autograft and (g) allograft, which did not receive grafts. Im, implant; Gf,
graft; Nb, native bone; BM, bone marrow cavity; scale bars, 1,000 μm

had significantly less BV/TV compared with the autograft group

3 |   R E S U LT S
3.1 | Micro‐CT
Micro‐CT was conducted on autograft (Figure 2a,b), allograft
(Figure 2c,d), and the respective contralateral controls for autograft
samples (Figure 2e,f) and allograft samples (Figure 2g,h). New bone
growth was observed around the implant in the bone marrow cavity
and around the base of the implant fixing it to the opposing bone cor‐
tices in all treatment groups when the implant was in close approxima‐
tion with the cortical bone, as is shown in micro‐CT images with the
implant removed (Figure 2b,d,f,h). Bone growth was seen at the graft‐
to‐implant interface as well as at the graft‐to‐native bone interface in
both the autograft and allograft groups (Figure 2a‐d). As expected,
contralateral legs receiving the implant only displayed significant
bone growth around the implant and at both cortical interfaces.
Quantification of new bone volume in contact with the im‐
plant (BIC) revealed no difference between autograft and allograft
groups (Figure 2i). When new bone adjacent to the implant was nor‐
malized to new peri‐implant bone in the contralateral control limb,
allografted sites had less bone than autografted sites (Figure 2j).
No differences were observed in BV/TV between the autograft
versus allograft groups or their contralateral controls (Figure 2k).
However, when values were normalized to contralateral control
legs to account for differences between animals, the allograft group
(Figure 2l). Additionally, the use of allograft produced less bone
around the implant compared with autograft.
3.2 | Calcified histology
Bone formation occurred regardless of graft type, and a secure fixa‐
tion of the native bone with the implant was seen (Figure 3). Native
bone growth (Nb) was observed tightly formed around the graft
(Figure 3a,c), and fixing the implant in place (Figure 3a,c,e,g). Calcified
histologic sections showed that an extra‐cortical bone marrow cav‐
ity (Bm) formed to the left and or right of the top of the implant (Im)
in all samples, regardless of graft placement (Figure 3b,d,f,h).
3.3 | Decalcified histology
Magnified images outlining the graft placement for autograft and al‐
lograft can be seen in Figure 4a,b, respectively. Decalcified histology
showed that living cells were present in the autografts (Figure 4c).
The non‐uniform demarcation of the autograft border suggests pos‐
sible remodeling of the autograft by the native bone (Figure 4c, black
arrows). Border remodeling in the non‐vital allograft samples was
nearly non‐existent compared with autograft samples, and empty
lacunae were observed in the graft indicating the lack of re‐popula‐
tion by osteocytes as well as minimal remodeling (Figure 4d).
COHEN et al.
F I G U R E 4   Representative images
displaying interactions of grafts with
(a)
surrounding native bone for (a, b) calcified
histology stained using Stevenel's blue
(2.5x magnification; scale bar, 1,000 μm),
and (c, d) decalcified histology stained
using H&E examining the graft‐to‐native‐
bone interface following max torque
removal and push‐out testing (63x
magnification; scale bar, 100 μm). (a, c)
Autograft, (b, d) allograft. Gf, graft; Gf‐v,
graft‐vital; Bm, bone marrow cavity; Gf‐
nv, graft‐non‐vital; Nb, native bone; Im,
implant; dotted yellow line, outlines graft; (c)
black arrows, highlighting graft border
3.4 | BIC histomorphometrics
Histomorphometric analysis revealed no differences in bone‐to‐
implant contact between autograft and allograft in cortical region
(Figure 5a), the bone marrow cavity (Figure 5b), or the combination
of the two (Figure 5c). No differences were observed when analyzed
as treatment over control (Figure 5d‐f), respectively. Measurements
of new bone formed in the marrow cavity and normalized to the re‐
gion of interest (ROI) revealed no differences (Figure 5g). All sam‐
ples, regardless of treatment group, had a new cortical bone marrow
cavity form to the left and or right of the defect (top of implant).
No differences were found in the average thickness of this region
(Figure 5h).
3.5 | Graft histomorphometrics
No differences were found due to graft type based on graft‐to‐im‐
plant contact and graft‐to‐bone contact or new bone growth sur‐
rounding the entire graft (Figure 6a,c). Graft area was measured and
no differences were observed, indicating similar volumes of grafts
were placed in both the autograft and allograft groups (Figure 6b).
3.6 | Mechanical testing
Removal torque was performed to determine osseointegration be‐
tween the graft and implant, and no differences were found be‐
tween autograft and allograft groups (Figure 7c) or when samples
were normalized to their contralateral control (Figure 7d). Push‐out
testing was performed on treatment legs to determine the strength
of the native bone and graft interface. Autograft groups displayed a
|
      7
(b)
(d)
significantly higher ability to resist compressive loading compared
with allograft groups (Figure 7e).
4 | D I S CU S S I O N
Insufficient bone for implant placement requires an additional re‐
generative procedure in order to gain new bone. These procedures
include the addition of a bone graft particulate or block grafting in
order to produce a greater volume of new bone in which the implant
will be placed. This process was initially done in two stages; however,
the need for a faster, simultaneous insertion of both the implant and
graft at the same time was desired. In this method, primary fixation
is achieved by fixing the graft to the surrounding bone using the im‐
plant. It is still debated whether the quality of bone and healing is
the same using this method (Peñarrocha‐Diago et al., 2013; Tosun
et al., 2018).
The goal of this study was to understand the long‐term outcomes
of using an implant and graft in a simultaneous procedure, as well
as how graft type affects these biological interactions. Our results
indicate that using an autograft bone in conjunction with an implant
provides the same level of bone volume as an implant without any
regeneration as measured by micro‐CT and removal torque. Calcified
histology clearly shows new bone formation around implant in the
bone marrow cavity and surrounding the graft. Interestingly, the BIC
in the cortical space of autograft groups was statistically higher than
their contralateral control groups, but not in the allograft groups and
their respective contralateral control.
These data indicate that the live cells in the autograft groups may
signal to increase new bone formation in the cortical region. This
 |
8       COHEN et al.

F I G U R E 5   Histomorphometrics from calcified histology examining bone‐to‐implant contact in (a, d) the cortical space, (b, e) the bone
marrow cavity, and (c, f) bone‐to‐implant contact in both the cortical space and the bone marrow cavity. An * denotes significance using the
Wilcoxon signed‐rank test with an alpha equal to 0.05 in treatment group versus its contralateral control (data not shown)

phenomenon is only seen in the cortical space and not in the mar‐
row cavity. Since our experiment separated the regions of BIC into
categories of cortical region, bone marrow cavity, and total BIC, we
were able to observe this finding where other studies have not. This
difference is lost when you look at the total BIC, most likely due to
the cortical region making up the largest portion of the BIC. These
date further reinforce the supporting role of live cells in the cortical
region in aiding in bone growth. This was not seen in the cortical BIC
of allograft groups compared with their contralateral controls.
We found no differences between allograft groups and their con‐
tralateral controls as measured by micro‐CT BIC in the marrow region,
and removal torque as compared to the implant control. Calcified his‐
tology revealed new bone formation in both the marrow cavity and
the cortical region. Decalcified histology after removal of the implant
showed a clear demarcation between surrounding vital bone and the
non‐vital allograft. This border shows the allograft was not remodeled
70 days after implantation which is in agreement with other studies
(Deluiz et al., 2016; Petrungaro & Amar, 2005; Spin‐Neto et al., 2014).
There were no differences in osseointegration between auto‐
graft and allograft groups to the implant as measured by BIC, by
bone volume, or by max removal torque. This is corroborated by nu‐
merous clinical studies that have found little difference in success
rates of autografts and allografts for dental and orthopedic appli‐
cations (Al‐Abedalla et al., 2015; Chavda & Levin, 2017; Hollawell,
2012; Leonetti & Koup, 2003; Lyford et al., 2003; Monje et al.,
2014; Roudbari, Haji Aliloo Sami, & Roudbari, 2015; Yercan, Ozalp,
Coşkunol, & Ozdemir, 2004), as well as no difference in max removal
torques between allograft and autograft bone grafts (Ribeiro et al.,
2018). Interestingly, when the variations between animals were re‐
moved as displayed in the treatment over control graphs for micro‐
CT, more bone volume and a higher BV/TV were seen in autograft
groups compared with allograft groups.
Push‐out testing of the graft after the implant was removed
demonstrated that autograft groups were able to resist the com‐
pressive forces better than allograft samples. This is in part due to
the lack of remodeling in the  allograft group. The minimal remod‐
eling of allograft samples has been well documented in the litera‐
ture (Deluiz et al., 2016; Petrungaro & Amar, 2005; Spin‐Neto et al.,
2014). Spin‐Neto et al. found no difference between BIC of autoge‐
nous bone and fresh‐frozen allogenic bone in humans but noted the
COHEN et al. |
      9

F I G U R E 6   Histomorphometric analysis
of graft characteristics. (a) graft‐to‐implant
contact, (b) graft area normalized to the
contralateral control, and (c) graft‐to‐bone
contact. Groups not sharing a letter are
statistically significant using an alpha
equal to 0.05

F I G U R E 7   Schematic diagrams representing the mechanical testing setups for evaluating the graft‐to‐implant interface and the graft‐
to‐native‐bone interface. (a) Max removal torque of the implant and (b) push‐out testing of the graft after the implant was removed. Max
removal torque of both (c) block graft groups and (d) normalized to their respective contralateral controls. (e) Push‐out testing representing
max compressive load of the graft from the surrounding native bone. Groups not sharing a letter are statistically significant using an alpha
equal to 0.05

lack of remodeling in the allogenic bone and concluded the clinical Despite evidence of minimal remodeling, no study has yet to
impact and long‐term performance due to poor graft incorporation demonstrate complete incorporation or remodeling of allogenic
remain unknown (Spin‐Neto et al., 2014). bone grafts. Carini and colleagues showed while short‐term success
 |
10       COHEN et al.

rates of allografts are comparable to autografts at around 96% or mandible, and our model was a non‐load bearing implant model.
for the first year, success rates fall to 40% after four years due to Future studies will use a larger animal for implant placement into
marginal bone loss around the allogenic bone (Carinci et al., 2010). the jaw.
These results are easily explained by our histological results indi‐
cating that the vital bone in allogenic groups is primarily confined
around the peri‐implant. Loading on non‐vital bone more read‐ 5 | CO N C LU S I O N
ily develops micro‐cracks (Akkus & Rimnac, 2001; Gouin, Passuti,
Verriele, Delecrin, & Bainvel, 1996; Presbítero et al., 2017; Wheeler The present study demonstrates that while there is no difference
& Enneking, 2005), and with a lack of resident osteoblasts adding in in the osseointegration of the implant to the allograft or autograft
the repair, it is reasonable that this bone would resorb more readily based on μCT and calcified histology, there is a difference in the in‐
leading to marginal bone loss (Spin‐Neto et al., 2014). A comparative tegration of the allogenic graft to the native bone as demonstrated
literature search for micro‐cracks in vitalized autograft did not yield by push‐out mechanical testing when both the implant and bone
any reports in the literature to‐date, indicating that this is not a clini‐ graft are inserted simultaneously. After ten weeks, the allogenic
cal issue that has warranted investigation. Therefore, the short‐term bone graft remains largely acellular compared with autograft, in‐
comparable success rates between autograft and allograft bone dicating the allograft did not undergo remodeling. The body in‐
grafts in recent publications need to be considered with caution tegrates the exterior of the graft to the native bone, much like it
(Al‐Abedalla et al., 2015; Chavda & Levin, 2017; Hollawell, 2012; integrates a metal implant to the bone. This may have implications
Leonetti & Koup, 2003; Lyford et al., 2003; Monje et al., 2014; in the overall quality and strength of the bone to the graft during
Roudbari et al.., 2015; Yercan et al., 2004). regeneration. It brings into question the long‐term success of the
Most metrics for determining success are through implant fixa‐ implant and the bone regeneration process when using allogenic
tion, but there are biological changes in bone that are not reflected in bone grafts, especially when they are inserted simultaneously with
these success rate metrics (Deluiz et al., 2016). Several studies have the implant.
shown that allograft bone material persists long after implantation
in both cortical and cortico‐cancellous implant models (Deluiz et al.,
2016; Spin‐Neto et al., 2015; Spin‐Neto, Stavropoulos, Dias Pereira, AC K N OW L E D G E M E N T S
Marcantonio, & Wenzel, 2013). More long‐term outcomes may need
This research was supported in part by AB Dental (Ashdod, Israel),
to be evaluated to ensure the lack of allograft remodeling does not
which also generously manufactured the implants for this study.
cause unintended consequences. A better quality of bone is seen in
Research reported in this publication was also supported by
the autograft through an increased bone volume and due to the live
the National Institute of Arthritis and Musculoskeletal and Skin
cells present in the graft, with obvious signs of remodeling present.
Diseases of the National Institutes of Health under Award Number
The empty lacunae in the allograft sample with minimal signs of re‐
1R01AR052102 and 1R01AR072500. The content is solely the re‐
modeling reduced its ability to resist compressive forces, as seen in
sponsibility of the authors and does not necessarily represent the
the push‐out testing. These data suggest that while the graft type
official views of the National Institutes of Health. BDB is a paid con‐
does not influence osseointegration of new bone to the implant, the
sultant for Titan Spine LLC (Mequon, Wisconsin, USA) and unpaid
live cells in the autograft are able to communicate with native bone
consultant for Institut Straumann AG (Basel, Switzerland). ZS is a
and strengthen the interface between the two. The push‐out testing
consultant for AB Dental.
allowed us to evaluate the native bone–graft interface, which to our
knowledge has been overlooked until this study. The results indicate
that the live cells present in the autograft and the superior resistance AU T H O R C O N T R I B U T I O N S
to compressive forces make it a better choice for some patients in
David J. Cohen planned the experiment, executed animal surgery,
clinical applications.
and prepared manuscript and figures. Kayla M. Scott developed
Interestingly, an extra‐cortical bone marrow cavity consistently
mechanical testing and prepared manuscript and figures. Aniket
formed above the site of graft implantation regardless of graft type.
Kulkarni performed imaging and morphometric analysis. Jennifer
A similar phenomenon has been reported in the orthopedic litera‐
Wayne advised and helped perform mechanical testing. Barbara
ture in connection with periosteal disruption due to chondrosarco‐
D. Boyan contributed to manuscript preparation and editing. Zvi
mas (Steiner, Schweitzer, Kenan, & Abdelwahab, 2011). This has not
Schwartz contributed to experimental planning, figure preparation,
been noted when implants are placed in the mandible or maxilla.
and manuscript editing.
Our model allows us to examine simultaneous insertion of the
block graft with the implant in a controlled manner and to conduct
mechanical testing on both the interface between the native bone ORCID
and the graft and to the graft‐to‐implant. However, there were lim‐
itations to our study. We assessed type 1 bone rather than type 3 Barbara D. Boyan  https://orcid.org/0000-0002-9642-0311

bone, our implant was placed in long bone rather than the maxilla Zvi Schwartz  https://orcid.org/0000-0003-1612-9223
COHEN et al.
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S U P P O R T I N G I N FO R M AT I O N
Additional supporting information may be found online in the
Supporting Information section at the end of the article. 
How to cite this article: Cohen DJ, Scott KM, Kulkarni AN,
Wayne JS, Boyan BD, Schwartz Z. Acellular mineralized
allogenic block bone graft does not remodel during the 10
weeks following concurrent implant placement in a rabbit
femoral model. Clin Oral Impl Res. 2019;00:1–12. https​://doi.
org/10.1111/clr.13544​