The use of bioactive proteins and peptides to promote osseointegration and success of dental implants: a narrative review

Introduction

The advent of dental implants has revolutionized the surgical and restorative aspects of dentistry, as they have become an excellent and more predictable alternative to fixed and removable prostheses. Although the success of dental implants has been shown to be rather high with survival rates of 93–97% (1), the placement of dental implants in clinical practice has unfortunately led to many post-operative complications, which include inadequate osseointegration and peri-implantitis (2). Although these conditions have led to implant failure, the literature has proposed ways to mitigate these mechanisms and/or slow their progression. These include promoting the quality of the bone-implant interface, accelerating bone formation surrounding implants, inhibiting bacterial adherence, etc. (3-6). The literature has demonstrated many ways that biological proteins and peptides can be used for the purposes mentioned above. The use of these molecules for promoting implant success is a very promising strategy due to high compatibility between proteins and the immune response, ease of synthesis, high antibacterial activity, and bone forming properties (7). However, data regarding the use of proteins and peptides in the field of implantology is relatively scattered. Concise results compiling the relevant molecules into one study would be of high value to the clinician or institution that practices surgical implant placement. Our objective for this study is to review the major biologic proteins and peptides that have been used to promote the success and osseointegration of medical and dental implants. By summarizing this information, we can provide researchers and clinicians valuable information regarding molecules that have been most heavily studied and show the most promising data for promoting implant success. We expect proteins and peptides to be key parts of the arsenal that clinicians use to treat patients needing dental implants, and can hopefully save many patients from experiencing implant failure. We present this article in accordance with the Narrative Review reporting checklist (available at https://fomm.amegroups.com/article/view/10.21037/fomm-24-25/rc).

Methods

The methodology of this literature review was inspired by Jurczak et al., 2020 (7) review of proteins, peptides, and peptidomimetics in implant surface functionalization. Analysis of this study revealed that three broad categories of proteins and peptides exist in the use of implant surfaces: (I) extracellular matrix (ECM) components; (II) growth factors; and (III) antimicrobial peptides (AMPs). Based on this, our search engine strategy involved 3 separate keyword searches into Google Scholar, PubMed, and MEDLINE searches. Each search contained the keywords “implant”, “osseointegration”, “peri-implantitis”, and the 3 different searches differed in the addition of “extracellular matrix and growth factors”, “antimicrobial peptides”, and “proteins and peptides” within the years 2012–2021. There were 9 total searches with the inclusion of Google Scholar, PubMed, and MEDLINE (Table 1). The search yielded 4,906 results total and relevant studies were analyzed that fit our inclusion criteria. Our inclusion criteria consisted of studies that tested the effects of biologic proteins and peptides on the biologic interactions between host cells and implant surfaces/materials in vitro and in vivo, including those belonging to both medical and dental implants. No language considerations were used for our inclusion and exclusion criteria. Host cells included mesenchymal stem cells, osteoblasts, epithelial cells, and other cells involved in promoting implant integration. Implant surfaces included those belonging to orthopedic and dental implants of either ceramic, metal, or polymeric. We excluded studies that did not fit this criteria. We also utilized backward citation searching to obtain 7 additional studies that were published earlier than 2012. The authors each reviewed the articles and analyzed the studies independently. The primary goal of our analysis was to extract data regarding what molecules have shown promising results regarding osseointegration of implants. These studies were highly relevant and provided additional insight into the protein/peptide of interest.

Our search engine strategy yielded a total of 106 studies to be reviewed. All 106 studies could be divided into four sections: (I) ECM components; (II) growth factors; (III) AMPs; and (IV) miscellaneous. The miscellaneous catergory involved a diverse array of proteins and peptides that did not quite fit into the above categories. The majority of molecules in this study belonged largely to the ECM category, with 32 studies investigating 14 different proteins/peptides. The following sections will summarize the functions of these categories of molecules as well as the findings associated with their effects on implant surfaces and cellular responses.

Mechanisms of incorporation

According to the literature, it seems as though there are four main ways proteins and peptides are utilized for promoting implant integration: coating onto implant surface, release systems, local injection, and systemic administration. Out of the studies we analyzed, the most common technique was coating the molecule of interest onto the implant surface. Immobilization of a moeclue onto an implant surface involves chemical tethering procedures utilizing covalent bonding, including ultraviolet (UV)-mediated crosslinking, silanization, and polyethelyne glycol coating (7). Physical adsorption, which involves the use of non-covalent interactions between the molecule and surface, have also been used as an immobilization method (8). Release systems incorporate specific molecules onto the surface of implants, which allow for controlled and local delivery of the molecule into the surrounding tissues (9). Local injection and systemic administration involve delivery of the molecule without dependence of implant surface modification, as these molecules are injected locally around the implant or systemically via subcutaneous access. Each of these techniques are indicated depending on the molecule of interest and can be associated with certain negative outcomes.

ECM components

Glycoproteins

The ECM is present within all tissues and organs and is composed of non-cellular components such as protein, glycosaminoglycan, and glycoconjugate (10) (role of extracell, Frantz 2010). The importance of the ECM lies in its physical scaffolding for cellular elements and its role in initiating crucial biochemical processes that are required for tissue changes and homeostasis (10). Regarding the fibrous protein component of the ECM, the main molecules of this class are collagens, fibronectins, elastins, and laminins (10). Initial interaction of cells with the implant surface is accomplished through specific receptors such as integrins, which is important for promoting the adhesion of bone cells for osseointegration (11). Integrins mediate cellular binding to matrix proteins, which enables cell-ECM interactions to facilitate differentiation of osteoblasts (11). The molecular and cellular interactions between the ECM and osteoblasts are incredibly important for promoting osseointegration of dental implants, and various studies in the literature have confirmed positive effects of coating ECM proteins onto the surface of implants. A complete list of molecules we have reviewed can be found in Table 2.

Type I collagen is the most abundant protein in the ECM and is a mediator of osteoblastic functions (46). Many studies involving titanium implants have demonstrated the ability for type I collagen to regulate osteogenic activity, promote bone formation, and activate fibroblasts (12-15). Other than type I collagen, other glycoproteins such as fibronectin, laminins, and derivatives of elastin can influence implant dynamics. Fibronectin is a large glycoprotein that can be found in various tissues throughout the body and is crucial in cell-ECM interactions and can participate in platelet aggregation (47,48). Studies have shown fibronectin to enhance the cellular responses surrounding titanium implant surfaces in vitro and in vivo (20-22,49). Similar findings are seen in other matrix proteins such as laminins (26,27) and elastin-like polypepides (31-34). Laminins are glycoproteins that are present in the basal lamina of epithelia (50,51) and are capable of binding integrins, which promote adhesion, angiogenesis, and differentiation, which explains many of the positive responses seen in the literature. On the other hand, elastin, which is found in elastic tissue such as blood vessels and ligaments, has been shown function in anchoring AMPs to the titanium implant surface (31), as well as potentiate biomineralization and osteoblastic responses (33).

Although many of these matrix proteins have been shown to be quite successful in promoting bone formation and cell adhesion around implants, many studies have opted to use smaller peptides derived from these proteins in promoting implant success. There are a few reasons as to why peptides offer benefit to larger proteins. For one, full-length matrix proteins (i.e., type I collagen) are often limited by low specificity for particular integrins which can lower the control for cellular responses (16). Also, large matrix proteins often have binding sites for other ligands, which may trigger signaling cascades that can interfere with healing (16). Peptides derived from collagen, such as P-15 and GFOGER, are beneficial due to their smaller sequence that allows for inclusion of only the cell binding sequence of collagen, which limits immunogenicity (52). Peptides derived from type I collagen (P-15, GFOGER), fibronectin (GRGDSP, F20) and laminins (DLTIDDSYWRYI, RNIPPFEGCIWN, laminin 332) also have similar positive outcomes in titanium implant coatings (16-19,23-25,28-30).

SIBLING proteins

SIBLING proteins are a family of non-collagenous glycoproteins in the ECM consisting of osteopontin (OPN), bone sialoprotein (BSP), dentin matrix protein 1 (DMP1), dentin sialophosphoprotein (DSPP), and matrix extracellular phosphoglycoprotein (MEPE) (53). SIBLING proteins share many structural characteristics and are located primarily in dentin and bone. Evidence has shown that SIBLING proteins are involved in matrix mineralization (53), and the coating of SIBLING proteins to the surface of implants have shown promising results.

The SIBLING proteins that have been heavily studied in the literature regarding promoting implant success are OPN, BSP, and DMP1. These proteins have many functions including angiogenesis, cell adhesion, and matrix mineralization (54). OPN has been shown to promote osteogenesis around the implant surface (35-37). The success of OPN coatings is due to its various binding sites for integrins, hydroxyapatite (HA) crystals, collagen, and calcium ions (36), which allows for the deposition of bone following attachment to the implant surface and promotion of osseointegration. DMP1 is another SIBLING protein that has been studied regarding implant surface coatings. Although there are currently no in vivo studies with DMP1, studies have shown that DMP1 can induce osteoblast activity and increase bone mineral density around Ti discs (41-43). This ability of DMP1 can be explained by its multiple phosphorylation sequences and integrin bindings sites that allow it to promote nucleation of calcified matrices (55). BSP, on the other hand, has had some conflicting results in the literature. BSP can promote cellular attachment and differentiation of osteoblasts due to its ability to bind to vitronectin receptors of osteoblasts (56). Although some studies were able to show that BSP coatings increased osteoblast activity and mineral deposition surrounding titanium surfaces (38,57), other studies did not show this ability with other biomaterials such as in calcium phosphate cement (39) and polymer-based scaffolds (40).

Arg-Gly-Asp (RGD)

RGD is a principal integrin-binding domain that is found within matrix proteins such as fibronectin, fibrinogen, OPN, and BSP (58). RGD has been extensively studied in the literature and is highly effective at promoting cell attachment to a variety of biomaterials (58-60). Some advantages of using synthetic RGD are that it can bind to multiple integrin receptors, it can be maintained throughout the processing and sterilization steps needed for synthesis, there is minimal risk of immune reactivity, and it is a relatively inexpensive peptide (58). Interesting results have been noted for the use of RGD in implant coatings. Not only have RGD-immobilized Ti substrates been shown to increase cellular adhesion and proliferation, but can also increase the level of integrins, type I collagen, and sibling proteins around the implant to further enhance osteogenesis (44). Other studies have also shown that type I collagen rich in RGD led to higher fixation speed between the implant and surrounding bone, faster osseointegration and differentiation, and ECM secretion (45,61,62).

Growth factors

Growth factors are biological molecules that are secreted to affect cellular growth, including the promotion or inhibition of cellular division and differentiation (63). Growth factors are either peptides that bind to cell-surface receptors and initiate a downstream cascade of molecular events or are lipid-soluble and bind to intracellular receptors to regulate gene expression (63). They have many important roles in the body, such as in inflammation, wound healing, angiogenesis, and growth (63). Due to these important roles, various growth factors have been analyzed for the incorporation onto dental and medical implants to promote faster wound healing and osseointegration. A complete summary of growth factors can be found in Table 3.

Bone morphogenic proteins (BMPs)

BMPs are growth factors that are part of the transforming growth factor-beta (TGF-b) superfamily and play a role in promoting osteogenesis (82). BMPs regulate the bone forming process by binding to BMP receptors and activating the SMAD pathway, which in turn leads to differentiation of mesenchymal cells into cartilage and bone forming cells (83). BMPs are often utilized for bone graft material, which contributes to higher bone to implant contact (BIC) (84). The use of BMPs on the surface of implants have been reported to improve osteogenesis, osteoblast activity, chondroblast activity, and osseointegration (84). Out of the 15 total BMPs, the most effective for inducing bone morphogenesis following surgical implantation are BMP-2 and BMP-7, and to a lesser extent BMP-9 (84-86). BMP-2 is the peptide with the most evidence of promoting osseointegration. Studies have shown that administration of BMP-2 on the surface of Ti discs and implants leads to increased osteoblast activity, glycosaminoglycans, and bone remodeling (64-66). BMP-7 has also been reported to enhance osteogenic potential both in vitro and in vivo (67,68). Although it is worth noting that a study done by (87) did not find any effect of BMP7 on implant attachment. BMP-9 has been the least studied in the family, but has been shown to exhibit even higher osteogenic properties compared to BMP-2 and BMP-7 (85,86). A study done by Souza et al., 2018 (69) observed the effects of BMP-9 on osteoblast differentiation following administration to titanium surfaces. The results showed overall increases in osteoblastic markers, however more research is needed to confirm the effects of BMP-9 on implant surfaces.

Fibroblast growth factor-2 (FGF-2)

FGF-2 has been shown to regulate many cellular processes involving cell proliferation and angiogenesis. The FGF family of proteins are signaling proteins that bind heparin and have high mitogenic and angiogenic activities in tissues including epithelial, connective, bone, and nervous tissue (88). The growth enhancing effects of FGF-2 have led to many studies in the literature testing its effects on titanium surfaces in vivo and in vitro. Positive outcomes have been shown for FGF-2, as studies have shown increases in bone apposition, wound healing, osteogenesis, infection resistance, and bone fixation strength (70-73). It is important to note that heparin can be used to enhance the biological effects of FGF-2, as heparin binds to FGF-2 and can stabilize its action in in vitro (70).

Vascular endothelial growth factor (VEGF)

VEGF is an important growth factor in angiogenesis as it increases vascular permeability and increases endothelial cell migration through chemotaxis (77). Being that blood vessels play an essential role in promoting regeneration and bone repair, insufficient blood supply to areas after bone injury can lead to poor healing (77). Therefore, VEGF is widely used to promote vascular remodeling, and several studies have shown that VEGF is essential for regeneration and bone formation (77,89,90).

Studies have demonstrated promising results with the use of VEGF around the surface of Ti implants (74-77). VEGF has been shown to promote enhanced alkaline phosphatase (ALP) activity and calcium deposition when coated to Ti implants (74). Increased endothelial cell markers such as CD31, FIK-1, and von Willebrand factor (vWF) have been demonstrated in in vivo when VEGF is coated to porous hydroxyapatite scaffolds (75).

Osteogenic growth peptide (OGP)

OGP is a short tetra decapeptide that is identical to the C-terminal amino acid sequence 89–102 of histone H4 (80). OPG has been shown to promote density of newly formed bone and stimulate bone healing (91). Studies have demonstrated the use of OGP on titanium and found osteogenic capabilities (79-81,92). These included enhanced cellular attachment and osteogenesis (80,92), as well as inhibited secretion of inflammatory markers (79). It is worthy to note that these studies utilized OGP as a bifunctional coating, and some of the results can be attributed to the other peptide used in the coating.

AMPs

Biomaterial-associated infection (BAI) can be caused due to the accumulation of biofilm and the presence of antibiotic resistant bacteria (9,93). In order to combat this, the use of AMPs is extremely efficient due to their antimicrobial activity against antibiotic resistant bacteria and bacteria within biofilms. AMPs are part of the innate immune defense or multicellular and microorganisms, and display antimicrobial activity against bacteria, fungi, and enveloped viruses (9,94). The mechanism of action of AMPs is very broad depending on the family of AMP as well as the specific microbe being targeted. In Riool et al’s review of the use of AMPs in biomedical device manufacturing, they subdivided AMPs based on their method of incorporation onto the surface of implants: (I) AMPs used as contact killing surfaces; and (II) AMPs used as release systems. For contact killing surfaces, AMPs are immobilized on the surfaces of medical devices through chemical techniques, whereas AMPs utilized for release systems dissociate from the implant surface and reach the peri-implant tissues (9). Each technique comes with both advantages and disadvantages. Using AMPs through immobilization on the implant surface is highly dependent on the orientation of the covalently linked AMPs as well as the chemical tethering procedure, meaning that using AMP coatings may have significant reduced bactericidal compacity compared to the peptide in the free form (9,95). Another disadvantage also implicated is the inability for the AMP coatings to extend further out into the peri-implant tissues, as these coating are localized to the implant surface (9). On the other hand, utilizing AMPs through releasing mechanism can cause a selection for resistant bacteria and are also potentially ineffective against intracellular bacteria (9). It is therefore suggested that the best use of AMPs on medical devices involves synthesizing peptides with broad spectrum activity with no development of resistance, and tethering these AMPs to biomaterial surfaces along with mechanisms to control its release into the environment (9).

There are a few significant AMP families that have been studied in the literature regarding its use on medical devices. These include human defensins, histatins, and LL-37. There are also many other AMPs that do not fit these categories but have also been studied for similar purposes. A full list of AMPs included in this review can be found in Table 4. Human beta defensins (HBDs) have many roles in the immune system such as bacterial, fungal, and viral killing (120) as well as keratinocyte differentiation (121) and tissue remodeling (122,123). HBDs are highly expressed and rapidly induced at epithelial surfaces in response to infection (112,124,125), and these peptides have been incorporated onto implant surfaces to prevent bacterial accumulation (99,111). Results from these studies show that HBDs (HBD-2) coated onto implants have highly efficient antimicrobial activity and can prevent the colonization of both gram-positive and negative bacteria (111,113), and can also increase the survival of keratinocytes and osteoblasts (112). LL-37 and histatins have also shown to promote osteogenic differentiation, adhesion, and antibacterial activity upon incorporation to the implant surface (114-119). LL-37 is a member of the cathelicidin family, and its function involves the promotion of wound healing and neutralization of lipopolysaccharide (LPS) (126), whereas histatins are found in saliva and are shown to exhibit potent antiungal, antibacterial, and antiviral capabilities (127).

Other proteins and peptides

Animal-inspired peptides

The utilization of peptides derived from animals have been widely used for biomedical applications, as they are often beneficial due to their mechanical properties, biocompatibility, and chemical interactions (128,129). Mainly, for the application of medical implants, peptides have been obtained or derived from arthropods such as Bombyx mori, Anthrea pernyi and spiders Nephila claveips and Araneus diadematus as well as marine mussels. Notably, silk fibroin (SF) and peptides derived from mussels have shown the most evidence of promoting implant success in the literature. The benefits of SF are due to its flexibility, self-assembling ability, biocompatibility, and mechanical properties (130). It is also a low-cost protein extracted from the cocoons of silkworms, making it a widely accessible option. It has also been reported to regulate several pathways responsible for bone remodeling and development (131,132). SF has been extensively tested in the literature as a drug-loaded coating for medical implants, notably in orthopedics (133). Many of the results indicate that the use of SF can promote mineralization, osteoblast adhesion, and osteoblast differentiation at the implant surface, all while minimizing an inflammatory response (134-136).

Peptides derived from the blue mussel Mytilus edulis have been utilized for the coating onto medical devices (137). The power of these peptides lie in the ability of Mytilus edulis to form strong bonding interfaces with various substrates (137), which can be attributed to mussel foot proteins that contain various amounts of lysine and 3,4-Dihydroxy-L-phenylalanine (DOPA) (138). The DOPA component of these peptides are highly important to their ability to self-polymerize and form surface-adherent films onto various materials (139). These peptides shine in their ability to form adherent surfaces that can link various bioactive molecules to the metal surface, such as AMPs, BMPs and RGD (109,140,141). The result is a stable and well controlled utilization of bioactive molecules that can promote antimicrobial and osteogenic activity (109,140). Not only are mussel-inspired peptides useful in forming dual coatings, but they have also been shown to induce osteogenesis on their own when coated onto polymer, metal, and ceramic implant coatings (142).

Titanium-binding peptides (TiBPs)

TiBPs are a group of inorganic peptides that bind to titanium with high affinity and can be conjugated to other molecules to enhance bioactivity (143). Immobilization of bioactive molecules on the implant surface along with TiBPs has been extensively studied, including ECM proteins, RGD, polyethylene glycol (PEG), and BMP (143-146). However, the usefulness of TiBPs stems from its ability to target inorganic substrates (Ti) with high affinity and specificity while interacting with other bioactive molecules, hence serving as an anchor for these molecules to the implant surface. The literature has shown that when TiBPs are incorporated onto the implant surface along with RGD or AMPs, significant osteogenesis and prevention of bacterial colonization were observed (143,147).

Albumin

Albumin accounts for more than 50% of the proteinaceous component of blood and plays a key role as a protein carrier for transportation of various ligands (148). Albumin has been shown to promote adsorption of biomolecules (149-152) as well as hydroxyapatite nucleation (153), which are very important mechanisms for the osseointegration of implants. Likewise, serum albumin has been shown to increase corrosion resistance of Ti6Al4V (154). These features make albumin an attractive candidate for implant coatings to promote successful osseointegration. There have been studies in the literature that have tested these characteristics on titanium and polyetheretherketone (PEEK) implants. These studies have shown that albumin coatings can prevent bacterial adhesion, resist corrosion, and promote osseointegration (149,155-157).

Antibodies

The WNT/β-catenin pathway is involved in the growth and development of many organs and tissue types, particularly in bone and teeth (158). Negative regulators of this pathway, including sclerostin and dickkopf-1 (DKK-1), contribute to marked bone resorption and osteoclast activity. Therefore, inhibiting the action of these negative regulators can inhibit bone loss and enhance bone formation (159). Recent therapeutics to prevent alveolar bone loss following implant surgery involve antibodies to both sclerostin and DKK-1.

Sclerostin is a small glycoprotein that is a potent inhibitor of the WNT/β-catenin signaling pathway, leading to decreased bone formation (160-162). This protein is predominantly expressed by osteoblast lineage cells, and its expression leads to inhibition of bone formation and increased osteoclast activity (163). The hypothesis is that sclerostin antibodies can lead to increased bone formation and decreased bone resorption by blocking the binding of sclerostin to WNT co-receptors, which leads to elevated osteoblastic activity (160). Systemic administration of sclerostin antibodies has been shown to improve bone-implant contact, bone mineral density, and cementogenesis (160,164,165). It is worth to note that local administration of sclerostin antibodies has not been shown to heal periodontal osseous defects (165), which indicates that systemic administration of antibodies should be considered over local to promote osseointegration.

DKK-1 is another inhibitor of bone formation through downregulating the Wnt signaling pathway. It has been reported that mice overexpressing DKK-1 have reduced bone formation and low bone mineral density (166) and DKK-1 upregulation can lead to alveolar bone loss (167) Contrastingly, humans with mutations associated with lowered DKK-1 and sclerostin levels have systemically increased bone mineral density (168). Because of the action of DKK-1, the blockage of DKK-1 activity along with sclerostin has promising results. It has been reported that sclerostin antibody (Scl-Ab) therapy may be limited by reactive increase in DKK-1 expression, which makes DKK-1 antibodies a very attractive strategy to promote bone formation around implants. Results from several studies show that DKK-1 antibodies along with sclerostin antibodies can augment peri-implant bone formation in rodents and non-human primates (159,169).

Hormones

There are three main hormones that have been extensively studied in the literature for the promotion of implant integration: parathyroid hormone (PTH), growth hormone (GH), and melatonin. PTH is produced by the parathyroid glands and plays a role in controlling extracellular calcium and phosphate metabolism (170). PTH can induce bone formation through the downregulation of sclerostin (171). It has been shown that low, intermittent doses of PTH can result in osteoanabolic effects (172) and that PTH may enhance bone formation through the promotion of osteoblast maturation and decreasing osteoblast apoptosis (173-175). Results from various studies show that intermittent administration of PTH is effective at promoting new bone formation around implants (173,176-179). A summary of these hormones can be found in Table 5.

GH is an anterior pituitary hormone that stimulates the liver to release a variety of bone-derived growth factors (190). GH can have a significant impact on both osteoblast and osteoclast activity (191,192) and it has been suggested that GH enhances new bone formation and increases cortical bone mass (193). Furthermore, GH has also been suggested to stimulate synthesis of collagen, osteocalcin, ALP, and hard tissue mineralization (194,195). In regard to medical implants, it has been shown that GH can increase bone formation and accelerate bone repair in dogs (181-183). However, some limitations have been suggested for the use of GH. Many studies fail to acknowledge the long-term effects of GH administration, which can potentially involve increases in bone resorption (196,197), and there are also inconsistencies among studies regarding the design of the study. It is likely that GH induces bone formation surrounding implants, however studies need to focus on applying GH in a clinical setting as to minimize the conflicting factors that may have influenced the outcomes of other studies (190).

Melatonin is a hormone produced by the pineal gland and other organs including the retina, bone marrow, and intestines (198). The functions of melatonin include control of circadian rhythm and body temperature, regulation of sexual development, and activation of the immune system (199-201). Melatonin has been shown to act as an anti-inflammatory agent, and within the oral cavity can enhance bone formation and reduce bone resorption (198). The literature has shown that melatonin, whether applied topically to the surface of implants or administered systemically, can promote implant success due to its osteogenic, anti-inflammatory, and angiogenic properties in vitro and in vivo (184-186).

7ND

Peri-implant tissue expresses high levels of motif chemokine ligand 2 (CCL2) [monocyte chemoattractant protein-1 (MCP-1)], which plays a key role in the recruitment of macrophages to the site of particle-induced inflammation (189). Blockade of CCL2 signaling can therefore reduce inflammation-induced osteolysis (202), which is another emerging approach to prevent bone loss surrounding implants. 7ND, a mutant version of CCL2, has been shown to inhibit CCL2 signaling (203) and reduce particle-induced inflammation and osteolysis (204,205). Some studies have found that 7ND coatings to titanium rods and orthopedic implants lead to decreased macrophage and osteoclast recruitment (187,188), whereas a study done by Sato 2016 (189) did not observe any effects of the coating. It seems that 7ND has potential to lower inflammation and reduce bone loss around implants, but more studies regarding this protein are needed.

Discussion

To the best of our knowledge, this narrative review is the most comprehensive overview of proteins and peptides that have been studied for promoting osseointegration of dental and medical implants. A previous study written by Jurczak et al., 2020 (7) provides a similar overview of proteins and peptides for the use of implant surface functionalization. However, our study aimed at providing an overview for the clinician and offers a larger list of proteins and peptides that are not limited to surface immobilization. Some strengths of our study are that it includes proteins and peptides utilized via multiple delivery systems. Our study includes molecules used as release systems, immobilized substrates, and as injections, which allows us to evaluate and observe differences in outcomes and discuss pros and cons of each system. Our study also categorizes an overwhelming number of molecules by their mechanisms of action and chemical class, which makes it easier for the reader to comprehend and understand the principles behind this field of study. Limitations of our study included a lack of statistical analysis, as this work is meant to be a narrative review and cannot answer definitive questions regarding the optimal molecule or dispute any controversies that may have arisen in this field. It is also possible that since this study has been conducted, new outcomes of proteins and peptides may have been published but cannot be included in this work due to the dates used in the search criteria. We are well aware that although this is a comprehensive overview, there may be other molecules that have not been discussed which is reasonable due to the rapid advancement of this field and the new studies that are constantly being published.

Based off the studies that have been presented in the literature regarding the use of proteins and peptides to promote implant success, it seems that these molecules can assist in integration through numerous mechanisms, many of which overlap. These include bone formation, mineralization, matrix formation, epithelial proliferation, vascularization, antimicrobial activity, inflammatory inhibition, and anchorage to the implant surface. The overall majority of molecules used as implant coatings consisted of matrix proteins. Matrix proteins such as type I collagen, elastin, and fibronectin are highly beneficial due to their ability to bind integrins and promote osteoblast adhesion to the implant surface, which will lead to their differentiation and bone formation. However, it seems that using smaller peptides derived from these larger proteins is superior because they are faster and cheaper to synthesize, more specific to particular integrins, and have less immunogenicity, and are also easier to incorporate into multifunctional coatings.

Growth factors, on the other hand, have been shown to have benefit over these small peptides (RGD) because these peptides have only led to marginal increases in osseointegration (76) (Zavan). Growth factors are also essential for new tissue production, can be used in regenerative procedures, and can perform feedback controls on inflammatory processes (76). BMPs can directly stimulate osteoblast differentiation and FGF-2 can stimulate not only bone formation but soft tissue formation as well (88). Although growth factors have many positive effects, one limitation of growth factors is their short half-life, particularly limited to a few hours (135). Particularly some growth factors, such as BMP, can lead to long-term adverse effects such as inflammation and bone resorption (206). The aim of using peptides derived from animals (SF) are for their extremely good mechanical properties that can strongly increase implant fixation to bone. They have also been shown to increase osteogenesis and aid in wound healing (133,207).

The use of antibodies to sclerostin and DKK-1 have shown very promising results. By inhibiting a negative regulator of bone formation through the use of antibodies, we can expect to see higher trabecular bone density and osteogenesis surrounding the implant. However, these antibodies have exclusively been shown to work when administered systemically, and adverse effects of using sclerostin antibodies in clinical trials have shown side effects such as cardiovascular incidents (208). Therefore, depending on the duration of treatment, potential adverse effects may be expected as a result of this therapy. Albumin is unique as it can prevent corrosion of titanium implants as well as improve bioactivity of other molecules to the implant surface, and TiBP serve as good anchors for other bioactive molecules. AMPs, although do not possess natural abilities to directly promote bone formation, are very effective at preventing bacterial colonization and infection of medical devices, including orthopedic and dental implants.

Taking all of this into consideration, one can see the many diverse options that exist for using bioactive molecules, particularly proteins and peptides, for the promotion of implant success. An illustration of the mechanisms reviewed can be found in Figure 1. However, based on the literature, it seems the most plausible and logical solution for deciding on the optimal molecule revolves around a coating and/or injection that can utilize all of the elements described above. These include peptides that have high affinity to the titanium surface, can induce differentiation of osteoblasts and promote bone formation, and can prevent bacterial colonization. To the best of our knowledge, no studies have combined molecules that can carry out all of the mechanisms mentioned above. To say that this combination of molecules would be the optimal solution for promoting implant success would require in vivo and in vitro studies to confirm the benefits of such a large combination, followed by clinical trials for mainstream implementation. In relation to clinical practice, many of these molecules differ in chemical structure, interaction with host cells, and potential side effects. Therefore, it may be dependent on the clinician to determine the optimal molecule to incorporate into treatment depending on both the clinical indication and the patient’s medical history, as even though it seems that all of these molecules are efficient in promoting osseointegration in laboratory studies, more clinical trials in humans are needed in order to determine important factors such as adverse effects, optimal dosage, duration of treatment, and drug interferences. Therefore, until large volumes of these studies are carried out, it is not reasonable to conclude what the optimal molecule is for promoting implant osseointegration and preventing peri-implantitis. Recommendations for future studies include in vivo and in vitro studies that test the effects of a combination of molecules that can promote bone formation, exhibit high antibacterial activity, and attach to the implant surface with high affinity. Also, randomized controlled clinical trials testing the effects of any of the molecules discussed in this review are indicated for further investigation.

Figure 1 Illustration of mechanisms that proteins and peptides utilize to promote successful integration of dental implants. Figure created using BioRender software.

Conclusions

Many studies seem to indicate that the utilization of proteins and peptides, either through immobilization to implant surfaces or systemic administration, is a promising strategy for preventing implant failure. The mechanisms in which they work is by promoting bone formation, fighting against bacterial infection, and enhancing cellular adhesion to implant surfaces. At this point in time, it is highly likely that the use bioactive molecules under the category of proteins and peptides are efficient at promoting implant success, but more research is needed in humans and randomized clinical trials in order to determine the optimal molecule, combination of molecules, and practical application in order for clinicians to utilize them in practice.

Acknowledgments

This work was presented at the 2024 Academy of Osseointegration Annual Meeting in Charlotte, North Carolina in the form of an eposter.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://fomm.amegroups.com/article/view/10.21037/fomm-24-25/rc

Peer Review File: Available at https://fomm.amegroups.com/article/view/10.21037/fomm-24-25/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://fomm.amegroups.com/article/view/10.21037/fomm-24-25/coif). G.E.R. serves as an unpaid editorial board member of Frontiers of Oral and Maxillofacial Medicine from October 2023 to September 2025. Both authors report that Stony Brook School of Dental Medicine funded the travel and meeting cost for this work to be presented at the Academy of Osseointegration 2024 Annual Meeting in Charlotte, NC. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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