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5 Future of Growth Factors in Implant Dentistry

5 Future of Growth Factors in Implant Dentistry

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6  Growth Factors for Site Preparation: Current Science, Indications, and Practice


with the existing bone in beagle dogs. They evaluated bone-implant interface at 4,

8, and 12 weeks and found that FGF-2 significantly promoted bone formation at

4 weeks and increased the ISQ value by about ten compared to control. However,

the increase in ISQ value peaked at 4 weeks and remained fairly constant even at

12  weeks for both the FGF-2-impregnated implants and control, suggesting that

FGF-2 accelerates bone formation but does not alter it over a longer timeframe.

Notably, FGF-2 was most remarkable in improving bone formation in areas delayed

by gaps between implant and bone [95]. Several studies demonstrated that the use

of FGF increased the amount of bone-to-implant contact, for improved osseointegration. In 2001, McCracken et al. found that addition of FGF in an activated fibrinogen matrix on titanium-aluminum-vanadium implants significantly increased the

amount of bone-to-implant contact (p < 0.05) compared to controls. This study also

demonstrated a greater percentage volume of bone deposition adjacent to the

implants, which supported the hypothesis that FGF could increase bone formation

around implants in a rat model [96].

6.5.2 Nell-1

NELL-1 is a potent pro-osteogenic protein, first discovered in locations of excessive

bone growth in calvarial sutures of patients with craniosynostosis [97]. To date,

NELL-1 has demonstrated induction of the bone in several preclinical models

including increased bone deposition in osteoporotic mice, distraction osteogenesis,

and increased rates of spinal fusion in various animal models. In 2006, Cowan et al.

studied NELL-1 in the craniofacial complex through administration on distracted

intermaxillary sutures in mice, demonstrating that NELL-1 induced bone formation

at rates similar to BMP-2 and accelerated chondrocyte hypertrophy and endochondral bone formation [98]. The ability of NELL-1 to induce bone formation in the

palatal suture demonstrates potential for usage in palatal defect healing. According

to a study by Cowan et al., NELL-1 has potential to synergistically enhance osteogenic differentiation of mesenchymal stem cells when used with BMP-2. This study

confirmed the osteochondral specificity of NELL-1 signaling, and potential for

enhanced therapeutic BMP-2 bone regeneration [99, 100]. NELL-1 is currently

being studied for clinical applications including vertebral compression fractures,

osteoporosis, as well as potential to promote development of cartilage. While there

is currently no existing literature on the application of NELL-1  in patients or to

implant dentistry, the characterization of NELL-1 as an osteogenic protein posits

NELL-1 as an important factor for consideration in future studies.


Allografts with Viable Cells

Alternative methods of enhancing bone regeneration include usage of mesenchymal

stem cells with bone allograft material. Autograft bone, harvested most commonly

from the patient’s iliac crest, is the gold standard for bone augmentation because it


T. Aghaloo and R. Lim

is histocompatible and non-immunogenic. Furthermore, autograft bone provides the

three pillars of bone growth: osteoconductive scaffold, osteoinductive factors, and

osteogenic cells [101]. However, the process of harvesting autogenous bone presents many clinical downfalls, such as donor site morbidity, increased surgical time,

risk of infection, and limited availability [102].

A new approach being investigated is the use of bone allograft combined with

bone marrow mesenchymal stem cells (BMSCs) to maintain osteoconductivity,

osteoinductivity, and osteogenicity. Since their discovery in 1966, mesenchymal

stem cells (MSCs) have been characterized with ability for self-renewal as well as

multipotential to differentiate into bone, cartilage, fat, nerve, muscle, and tendon,

depending on external cues in the local environment [103]. For MSC’s to be directed

to a particular lineage of differentiation, they require appropriate density, spatial

organization, and local factors [104]. Furthermore, MSCs are part of the bony repair

callus and differentiates into bone or cartilage based on stability. Vasculature and

angiogenesis are additional requirements for osteogenic differentiation. Current

growth factor systems rely on the body’s inherent local cells, including MSC’s and

osteoprogenitor cells, to help regenerate bone.

Several new products are now on the market that combine various formulations

of endogenous bone forming cells with osteoinductive growth factors (Trinity®

Evolution™, Osteocel® Plus, and Osiris BIO4™). Trinity® Evolution™ (TE) is a

cryopreserved allograft consisting of viable cancellous bone matrix and demineralized cortical bone matrix, with mesenchymal stem cells, osteoprogenitors, and

osteoinductive proteins, and osteoconductive matrix [105]. In 2016, a prospective

clinical study was performed, which observed the usage of TE in anterior cervical

discectomy and fusion. Degree of fusion was assessed based on radiographic

appearance, function, and residual pain, performed with a series of clinical tests by

examiners. This study reported fusion rates of 94% with TE, similar to previously

reported fusion rates of autografts in similar conditions. Overall, the study concluded that TE had a high rate of single-level cervical fusion with no serious adverse

events. Though inconclusive, current data of bone allografts with MSCs are favorable and offer an alternative to autografts, allografts, and growth factors. Clinical

trials are currently being conducted, with usage of MSCs with allograft in transforaminal lumbar body fusion, anterior cervical discectomy and fusion, and foot and

ankle fusion [101, 106, 107]. Favorable results of allograft and MSC usage include

new bone formation at site of implantation, with satisfactory clinical and radiographic success in situations of stable internal or external skeletal fixation. In

implant dentistry, although generally favorable, few case series are available to support the use of MSC/allograft technology [108].


What is the future of growth factors in implant dentistry? This is a question that

is posed by patients, clinicians, researchers, and industry. Much work has been

done in the last few decades, but in many situations, the clinical relevance, predictability, and protocols have not been fully understood. It is unclear whether all

patients will require or benefit from growth factors to assist with wound healing

6  Growth Factors for Site Preparation: Current Science, Indications, and Practice

Table 6.4  Growth factor



Growth factor uses

All patients

Compromised wounds

Complex hard/soft tissue defects

Previously failed surgeries

Medically compromised patients

and augmentation or if they are only relevant in medically compromised patients

and those with previously failed procedures (Table 6.4). What is clear is that the

field is looking for materials and methods to enhance bone and soft tissue healing, allowing treatment of more complex patients and wounds. Growth factors,

and possibly stem cells, are a plausible answer to current limitations. However,

much more research, both basic and clinical, needs to be done to improve current

technologies, develop predictable protocols, and evaluate long-term results.


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Part III

Immediate Implant Placement and Immediate

Provisional Restoration


Advanced Grafting Techniques

for Implant Placement in Compromised


Bach Le and Joan Pi-Anfruns


The loss of teeth can result in up to 50% of alveolar ridge width shrinkage within

the first 1–3 years [1]. This bone loss is exacerbated if there are preexisting endodontic pathologies and/or periodontal disease or if the tooth is loss due to

trauma. Since prosthetically driven implant placement is only possible when

there is an adequate amount of the bone, the presence of significant resorption

can pose a considerable clinical challenge. Bone augmentation is often required

to create ideal gingival contours and aesthetics.



The loss of teeth can result in up to 50% of alveolar ridge width shrinkage within

the first 1–3 years [1]. This bone loss is exacerbated if there are preexisting endodontic pathologies and/or periodontal disease or if the tooth is loss due to trauma.

Since prosthetically driven implant placement is only possible when there is an

adequate amount of the bone, the presence of significant resorption can pose a considerable clinical challenge. Bone augmentation is often required to create ideal

gingival contours and aesthetics.

B. Le (*)

Department of Oral and Maxillofacial Surgery,

Herman Ostrow School of Dentistry at USC, Los Angeles, CA, USA

Private Practice, Whittier, CA, USA

J. Pi-Anfruns

Division of Diagnostic and Surgical Sciences, Division of Regenerative and Constitutive

Sciences, Dental Implant Center, UCLA School of Dentistry, Los Angeles, CA, USA

© Springer International Publishing AG, part of Springer Nature 2019

Todd R. Schoenbaum (ed.), Implants in the Aesthetic Zone,




B. Le and J. Pi-Anfruns

The high predictability and success of osseointegration have led to a shift in the

focus toward achieving ideal long-term aesthetics with peri-implant bone and tissue

architecture. Increasing patient demand for natural aesthetic outcomes has redefined

the definition of success. Implant success is no longer solely equated with implant

survival, yet most studies on implants fail to include criteria for aesthetic success. It

is reported that up to 16% of single implant restorations in the aesthetic zone fail for

aesthetic reasons [2–4] due to tissue loss or a failure to adequately restore this lost

volume [5]. Achieving an ideal aesthetic result in the compromised site is often

elusive and, in many cases, not yet possible [6]. The potential for unexpected complications which can compromise the final result always exists with any surgical

procedure and should be a part of the initial discussion on expectations. With proper

treatment planning and execution, poor outcomes can be avoided.

7.1.1 A

 esthetic Risk Assessment in Compromised Sites: FATTT


Even procedures with a high level of predictability will have aesthetic failures

defined by significant tissue recession, long clinical crowns, open gingival embrasures, and/or exposure of the abutment margin. Given the complexity of hard and

soft tissue reconstruction, the authors recommend using the following five simple

guidelines (FATTT) to help clinicians decrease the risk of an unaesthetic outcome

with hard and soft tissue reconstruction (Table 7.1).

7.1.2 Favorable Gingival Level (F)

Because gingival recession is common after prosthetic delivery [7–9], it is critical to

assess the preoperative gingival margin height of the tooth or implant site. This

margin is usually dictated by the underlying facial bone level. A free gingival margin that lies coronal to the planned restorative margin offers some insurance against

recession and is considered more favorable (Fig. 7.1). Ideally, the implant platform

should be placed 3 mm below the planned gingival margin with an abundance of

soft tissue height for prosthetic sculpting to achieve a harmonious gingival margin

with the adjacent teeth (Fig. 7.2a–d). In clinical cases where the gingival margin is

Table 7.1  Aesthetic risk assessment (FATTT)

FATTT criteria

Favorable gingival


Attachment on

adjacent tooth

Thick/thin biotype

Thick/thin labial


Tooth shape


Free gingival margin >1 mm coronal

to anticipated level

<5 mm from anticipated contact


No translucency on probing

>2 mm of residual labial bone


Free gingival margin at or apical

to anticipated level

>5 mm from anticipated contact


Probe visible through gingiva

<1 mm of residual labial bone



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5 Future of Growth Factors in Implant Dentistry

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