A look into the existing bone graft portfolio and the pipeline proves that the goals in Regeneration at Straumann remain unchanged: to extend the boundaries and making implant therapy and oral regeneration faster, more predictable and more successful.

Toward a new-generation bone substitute material: a look into the existing bone  graft portfolio and  the pipeline proves that the goals in Regeneration at Straumann remain unchanged: to extend the boundaries and making implant therapy and oral regeneration faster, more predictable and  more successful.

Hidden potentials of Emdogain®: is the ability of Emdogain® to regenerate periodontal tissues based on a more general biological potential and, if so, can this potential be used in clinical applications beyond periodontal regeneration?

Toward a new-generation bone substitute material

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Straumann® BoneCeramic – a benchmark in synthetic bone grafting materials
Since our synthetic bone substitute Straumann® BoneCeramic was launched in 2005, more than 25 published studies in all major indications have earned the product wide recognition and acceptance by clinicians around the globe (see: www.straumann.com/science). Today, Straumann® BoneCeramic can be regarded as one of the reference products for dental synthetic bone grafting procedures. Excellent biocompatibility without any foreign body reaction combined with controlled, slow resorbability allows predictable volume maintenance and ensures mechanical stability over a long time period. The distribution of more than 320 000 units of Straumann® BoneCeramic has allowed for a significant insight on the needs and selection criteria of clinicians.

Successful allograft portfolio for the North American market
To meet local clinicians’ preferences, Straumann successfully introduced a range of allograft particulates in the North American market in 2009. This has led to an extended allograft portfolio of different types and granular sizes. The cooperation with LifeNet Health, one of the world’s most trusted providers of transplant solutions, and a clear focus on our customer’s requirements have lead to a significant market share in the allograft market within a very short period of time.

New possibilities with synthetic alloplastic bone substitutes
The possibilities to improve materials derived from nature, such as allografts and xenografts, by changing the composition and structure are rather limited. Thus, developments within this product group to increase regenerative potential are rare. In comparison, material composition and particle size and structure of synthetic materials can be reengineered to develop new and better solutions. In this way, synthetic alloplastic bone substitutes are able to provide new exciting possibilities since controlled production steps allow for the development of different product characteristics, leading to a new degree of precision down to a granular micro- and nano level.

Kick-starting the biologic process of new bone formation by using the surface structure
Within the group of biphasic calcium phosphates, the balance of the most clinically effective ratio of volume-preserving hydroxyapatite (HA) and vital bone-regenerating beta-tricalcium phosphate (β-TCP) has been an important research focus in the past.Actual findings at cellular level indicate that the surface structure can be used to trigger cell differentiation and thus initialize bone regeneration. Understanding of biological cell-to-cell communication and the corresponding influencing factors for bone regeneration combined with technical improvements in production made investigating a second-generation bone substitute evident.

The hypothesis of kick-starting the biological process of new bone formation by using the surface structure is already backed up by the results of several pre-clinical studies, which will be published in due time.2

VivOss® – accelerated bone regeneration
The extensive knowledge and experience of Straumann in surface textures on dental implants (SLA® and ZLA®) as well as input from research partners enabled the development of Straumann® VivOss, a second-generation bone substitute which is currently being tested in a clinical environment. Initial results indicate significantly higher bone regeneration activity within the early healing period, especially in contained defects.

Straumann® Osteogain – a new chapter in the clinical application of enamel matrix proteins

The history of Emdogain® dates back to the late 1980s when Prof. Lars Hammerström at Biora in Sweden suggested using enamel matrix derivative (EMD), the active principle of Emdogain®, to induce the regeneration of lost periodontal tissues. Soon after the Swedish market launch in 1995, Emdogain® was cleared for the US (1996) and Japan (1998). Today, after almost 20 years of market availability, Emdogain® is sold in nearly 50 countries around the globe, with its main markets in the US, Japan, Germany and Italy. Emdogain® is available in various sizes, allowing clinicians to offer the best treatment option to their patients in every treatment condition.

From a scientific point of view, enamel matrix derivative can certainly be considered as one of the best researched biologics in the dental field. Over 800 scientific publications, of which 200 have been published on the clinical (human) level, confirm the convincing biological rational of Emdogain®: enamel matrix derivative contains mainly amelogenin, which absorbs on the tooth root surface and is able to induce the processes involved in tooth formation by triggering new cementum formation and regeneration of the periodontium.1 Based on long-term data, Emdogain® promotes additional and more predictable gain of clinical attachment combined with better wound healing and fewer complications compared to procedures without Emdogain®, while patients treated with Emdogain® report less pain and swelling and hence an increased quality of life2, 3.

An early discovery: the hidden potential of EMD
Besides these well-known facts, a very basic question remains, which is related to the unique and astonishing capability of EMD to regenerate and restore the original architecture of periodontal tissues: is the ability of EMD to regenerate periodontal tissues based on a more general biological potential and, if so, can this potential be used in clinical applications beyond periodontal regeneration? Very soon after its discovery, it became evident that EMD is a scaffold which has the capacity to modulate the wound healing processes that lead to regeneration instead of scar tissue formation4. This is an remarkable capacity. The majority of higher organisms, especially vertebrates, have mostly lost their capacity to regenerate injured or deteriorated tissues. Rapid repair and faster wound closure with non-functional fibrotic scar tissues instead of slower regenerative processes to restore original tissues apparently represented an evolutionary advantage, since the body was able to ward off pathogens from its environment more quickly. As a result, our genes have been programmed in a way that our wounds repair but do not regenerate5.

Fig. 3: Micrograph of the periodontal ligament (PL) with its perfect organization of collagen fiber bundles spanning the area between the root covered with cementum (C) and the alveolar bone (AB).  D: dentin.

Fig. 4: Axolotls belong to the few organisms that can regenerate lost body parts perfectly. The biological mechanisms for regeneration of salamanders like the Axolotl have been conserved in humans. The goal is to research those mechanisms and learn how to induce them for human benefit.

Literature reports that mainly appeared after 2000 have quickly pointed out that the ability of EMD to regenerate the periodontium is probably only a special case, which is related to a more general capacity of modulating the biological mechanisms involved in soft and hard tissue wound healing.6 If this is the case, then it might be speculated that periodontal regeneration is just a glimpse of the full potential of EMD and that more fields of application need to be established and documented.

A component of embryonic tissue: does EMD have intrinsic potential to stimulate and modulate the healing process?
The biological model and functions of EMD have been reviewed and postulated more extensively in the last five to six years7. Amelogenin is a hydrophobic protein that self assembles into nanospheres. Under physiological conditions, these nanospheres assemble and form an insoluble matrix on tooth root surfaces and bone graft materials. This matrix is able to stimulate cell adhesion and colonization on the root surface or on bone graft materials. More importantly, depending on the biological context, EMD seems to be able to provide a microenvironment to stimulate the differentiation of precursor cells into cementoblasts, periodontal ligament cells, fibroblasts or osteoblasts and to stimulate these cell types to proliferate and to express key factors that modulate the inflammatory cascade associated with soft and hard tissue wound healing.7 And that is not all: inflammation and pain are physiologically linked processes. According to a customer survey, more than 80 % of experienced Emdogain® users confirm improved wound healing of the soft tissue when using Emdogain®, while clinical studies indicate that patients treated with Emdogain® report less pain and swelling compared to alternative procedures without the use of Emdogain®3.

The standard of care in oral soft tissue wound healing?
Based on these evident properties, Straumann is focusing on two new development approaches for EMD. By generalizing the application of Emdogain® for mucoperiostal flaps, we are aiming to extend the use of Emdogain® for oral soft tissue procedures in general. Clinical needs for such an application have arisen from invasive procedures or procedures with high esthetic demand, where improved wound healing would clearly bring a benefit to the patient. With its hydrogel-like consistency, Emdogain® is today already well suited to serve as a wound dressing. Preclinical studies have shown that when exposed to Emdogain®, fibroblasts are stimulated to migrate, proliferate and express growth factors and extracellular matrix molecules that promote soft tissue healing and angiogenesis7. Further preclinical studies indicate that EMD can even prevent fibroblasts from apoptosis under challenging conditions. All these features support our efforts in establishing Emdogain® as the standard of care in oral soft tissue wound healing.

Using biological cues to challenge current implant treatment standards
With the development and introduction of the Straumann® SLActive surface, the development of implant surfaces seems to have culminated in a maximum level of performance that can be achieved by pure physicochemical implant surface modification. Further improvements in implant integration, secondary stability and ultimately reliability might, however, still be achievable. One possible route to achieving this goal is to use biological cues to enhance bone formation and maturation associated with bone grafting procedures around implants.

Hhypothetical effect of faster bone maturation around dental implants

Fig. 7: Schematic illustration of the hypothetical effect of faster bone maturation around dental implants leading to earlier secondary stability, as induced by biological enhancers (Osteogain®).

The osteopromotive “side effect” of enamel matrix proteins
Despite the fact that Emdogain® gel has been designed for application on tooth root surfaces and not for mixing with bone graft materials, more than 30 clinical publications demonstrate the advantages of the combined use of Emdogain® with various bone graft materials for the treatment of bony periodontal defects. The clinical use of this combination is not only supported by the reported ability of EMD to stimulate periodontal regeneration, but also by the recent literature reporting on the ability of EMD to enhance bone healing and bone maturation when combined with bone graft materials. It is this osteopromotive effect of EMD, i.e. the ability to speed up bone formation and maturation, that could make it a clear game changer when it comes to bone grafting procedures.

Osteogain® – pushing the limits of current implant therapy associated with GBR
With Osteogain®, a new liquid formulation of EMD that has been optimized for application with porous bone substitutes, Straumann intends to push the limits of current implant therapy associated with GBR procedures: improving the overall outcome, allowing new and faster treatment options and, at the same time, improving safety and predictability in clinically challenging situations11.

The bottom line is that even after 20 years of Emdogain® market availability, the full clinical potential still remains to be unlocked.

SBC 1 Jensen SS, Bornstein MM, Dard M, Bosshardt DD, Buser D. Comparative study of biphasic calcium phosphates with different HA/TCP ratios in mandibular bone defects. A long-term histomorphometric study in minipigs. J Biomed Mater Res B Appl Biomater. 2009 Jul;90(1):171-81. doi: 10.1002/jbm.b.31271. PMID:19085941 2 Jensen SS, Yeo A, Dard M, Hunziker E, Schenk R, Buser D. Evaluation of a novel biphasic calcium phosphate in standardized bone defects: a histologic and histomorphometric study in the mandibles of minipigs. Clin Oral Implants Res. 2007 Dec;18(6):752-60. Epub 2007 Sep 20. PMID: 17888014 EMD 1 Sculean A, Alessandri R, Miron R, Salvi GE, Bosshardt DD, Enamel Matrix Proteins and Periodontal Wound healing and Regeneration, Clin Adv Periodontics 2011; 1:101-117 2 Sculean A, Kiss A, Miliauskaite A, Schwarz F, Arweiler NB, Hannig M. Ten-year results following treatment of intra-bony defects with enamel matrix proteins and guided tissue regeneration J Clin Periodontol. 2008 Sep;35(9):817-24. 3 Ozcelik O, Haytac MC, Seydaoglu G. Immediate post-operative effects of different periodontal treatment modalities on oral health-related quality of life: a randomized clinical trial. J Clin Periodontol. 2007 Sep;34(9):788-96. 4 Heijl L. Periodontal regeneration with enamel matrix derivative in one human experimental defect. A case report. J Clin Periodontol. 1997 Sep;24(9 Pt 2):693-6. 5 Gurtner GC, Werner S, Barrandon Y, Longaker MT. Wound repair and regeneration. Nature. 2008 May 15;453(7193):314-21. doi: 10.1038/nature07039. 6 Al-Hezaimi K, Al-Askar M, Al-Fahad H, Al-Rasheed A, Al-Sourani N, Griffin T, O’Neill R, Javed F. Effect of enamel matrix derivative protein on the healing of standardized epithelial wounds: a histomorphometric analysis in vivo. Int Wound J. 2012 Aug;9(4):436-41. 7 Grandin HM, Gemperli AC, Dard M. Enamel matrix derivative: a review of cellular effects in vitro and a model of molecular arrangement and functioning. Tissue Eng Part B Rev. 2012 Jun;18(3):181-202 8 Aspriello SD, Zizzi A, Spazzafumo L, Rubini C, Lorenzi T, Marzioni D, Bullon P, Piemontese M. Effects of enamel matrix derivative on vascular endothelial growth factor expression and microvessel density in gingival tissues of periodontal pocket: a comparative study. J Periodontol. 2011 Apr;82(4):606-12. 9 Zeldich E, Koren R, Dard M, Nemcovsky C, Weinreb M. Enamel matrix derivative protects human gingival fibroblasts from TNF-induced apoptosis by inhibiting caspase activation. J Cell Physiol. 2007 Dec;213(3):750-8. 10 Straumann Brochure “Make a difference in more indications” 11 Lyngstadaas SP, Wohlfahrt JC, Brookes SJ, Paine ML, Snead ML, Reseland JE., Enamel matrix proteins; old molecules for new applications. Orthod Craniofac Res. 2009 Aug;12(3):243-53. 12 Almqvist S, Kleinman HK, Werthén M, Thomsen P, Agren MS, Effects of amelogenins on angiogenesisassociated processes of endothelial cells. J Wound Care. 2011 Feb;20(2):68, 70-5.