Calcium hydroxide: vai trò trong nội nha

A Comprehensive Review of Calcium Hydroxide Formulations in Modern Endodontics: A Market Analysis with a Special Focus on Calcipex II

Section 1: The Scientific and Biological Basis of Calcium Hydroxide Therapy

1.1. Physicochemical Properties and Ionic Dissociation

Calcium hydroxide, a white, odorless powder with the chemical formula $Ca(OH)_2$, has been a cornerstone of dental therapeutics for nearly a century.1 Its enduring relevance in endodontics is not due to a complex molecular structure but rather to a unique combination of simple yet potent physicochemical properties. The foundation of all its biological actions lies in its high alkalinity and its behavior in an aqueous environment.4 The most defining characteristic of calcium hydroxide is its high pH, which ranges from approximately 12.5 to 12.8, classifying it chemically as a strong base.2 This extreme alkalinity is the primary driver of its therapeutic effects, creating a local environment that is inhospitable to most microorganisms and capable of inducing profound changes in biological tissues.3 However, for this potential to be realized, the solid material must first interact with aqueous fluids, such as those present in the root canal system or periapical tissues. This interaction initiates the process of ionic dissociation, where the $Ca(OH)_2$ molecule separates into its constituent ions: calcium ($Ca^{2+}$) and hydroxyl ($OH^-$).1 It is these ions, not the parent molecule, that are the active agents responsible for the material's antimicrobial and tissue-inductive properties.1 A critical property governing this process is the low solubility of calcium hydroxide in water, which is approximately 1.2 g/L at 25°C.2 This characteristic is frequently cited as a significant clinical advantage.2 The low solubility ensures that the dissociation process is slow, controlled, and sustained over a prolonged period. This allows a single application of calcium hydroxide paste to act as a reservoir, continuously releasing $Ca^{2+}$ and $OH^-$ ions to maintain a high pH within the root canal for an extended duration, often for weeks.4 This sustained action is vital for its role as an inter-appointment intracanal medicament. This relationship between solubility and therapeutic action introduces a fundamental conflict in the design of calcium hydroxide-based materials, particularly root canal sealers. The very mechanism that makes the material biologically active—dissolution to release ions—is antithetical to the primary requirement of a root canal sealer, which is to be insoluble and provide a stable, long-term hermetic seal.10 For a calcium hydroxide sealer to be therapeutically effective, it is designed to dissolve, yet this dissolution inevitably leads to the formation of voids within the obturation mass over time, potentially compromising the integrity of the seal and allowing for microleakage.1 This inherent paradox explains the ongoing debate surrounding the long-term stability of these sealers and has driven the development of various vehicle formulations aimed at precisely modulating this rate of dissolution to balance therapeutic efficacy with structural longevity.

1.2. The Dual Mechanism: Antimicrobial Efficacy and Hard Tissue Induction

The therapeutic value of calcium hydroxide is derived from a dual mechanism of action, with each of its constituent ions playing a distinct but complementary role. The hydroxyl ions are responsible for its potent antimicrobial effects, while the calcium ions are central to its ability to induce hard tissue formation.1 The antimicrobial activity is a direct consequence of the release of hydroxyl ($OH^-$) ions.1 These ions are highly oxidant free radicals that exhibit extreme and indiscriminate reactivity with a wide range of biological molecules.3 The lethal effect on bacterial cells is not achieved through a single pathway but rather a multi-pronged assault on critical cellular structures and functions. The primary mechanisms include:

• Damage to the Bacterial Cytoplasmic Membrane: The high concentration of hydroxyl ions drastically alters the pH gradient across the bacterial membrane. This alkalinity causes chemical injury to the membrane's organic components, denatures structural and enzymatic proteins, and disrupts essential transport of nutrients.1 Furthermore, it induces lipid peroxidation, a process analogous to saponification, which destroys the phospholipid structure of the membrane.4
• Protein Denaturation: The extreme pH environment breaks down the delicate ionic bonds that maintain the tertiary structure of proteins, particularly enzymes. This irreversible denaturation leads to a loss of biological activity, disrupting cellular metabolism and vital functions.1
• Damage to DNA: The highly reactive hydroxyl ions can cause damage to bacterial genetic material, inducing the splitting of DNA strands and thereby inhibiting cellular replication and repair.1

While the hydroxyl ions are responsible for disinfection, the calcium ($Ca^{2+}$) ions are key players in tissue repair and regeneration. They function as important second messengers in cellular signaling pathways, promoting the differentiation of undifferentiated mesenchymal cells in the pulp into odontoblast-like cells.1 This cellular differentiation is the critical first step in the formation of a reparative hard tissue barrier, or tertiary dentin.5 When calcium hydroxide is applied directly to exposed pulp tissue, it initially causes a superficial zone of coagulation necrosis to a depth of up to 2 mm.1 Beneath this necrotic layer, at the interface with vital, inflamed pulp tissue, the release of calcium ions stimulates the biological cascade that results in the deposition of a dentinal bridge, effectively sealing the pulp from further injury.1 This mechanism extends beyond the confines of the root canal. The small and highly mobile hydroxyl ions can diffuse through the dentinal tubules to alter the pH of the external root surface and surrounding periodontal ligament.5 This phenomenon is particularly relevant in the treatment of inflammatory root resorption. The clastic cells (odontoclasts and osteoclasts) responsible for resorption are active in an acidic microenvironment created by the inflammatory process.10 By raising the pH on the external root surface, the diffused hydroxyl ions neutralize this acidic environment, directly inhibiting the enzymatic activity of these resorptive cells and arresting their destructive action.8 Therefore, the efficacy of calcium hydroxide in managing root resorption is not merely a secondary effect of its antimicrobial properties; it is a direct biochemical intervention that targets the cellular machinery of the resorptive process itself.

1.3. Tissue Dissolution and Interaction with the Pulpal Environment

In addition to its antimicrobial and hard-tissue-inducing properties, calcium hydroxide possesses a significant capacity to dissolve organic tissue remnants within the root canal system.13 This function is of paramount importance, as mechanical instrumentation alone is often insufficient to debride anatomically complex areas such as isthmuses, fins, and accessory canals, where pulp tissue and microorganisms can persist.15 In vitro studies have consistently demonstrated this tissue-dissolving capability. Research comparing different forms of calcium hydroxide found that a paste formulation is a significantly more effective solvent for necrotic tissue than a simple aqueous solution of the material.16 This suggests that a high concentration and sustained contact, as provided by a paste, are necessary for effective dissolution. The same study revealed a synergistic relationship with sodium hypochlorite (NaOCl), the most common endodontic irrigant. Pretreatment of necrotic tissue with calcium hydroxide paste was found to increase its subsequent solubility in a dilute (0.5%) NaOCl solution, indicating that the medicament can chemically alter the tissue to make it more susceptible to removal by irrigation.16 Further investigations using scanning electron microscopy have visualized this effect directly on uninstrumented root canal walls. An application of calcium hydroxide paste for a period of 7 days was shown to remarkably reduce the amount of attached pulpal tissue debris.17 This effect was comparable to irrigation with NaOCl for over 30 seconds. Notably, the combination of a calcium hydroxide dressing followed by NaOCl irrigation proved to be more effective at cleaning the canal walls than either treatment used in isolation.17 This body of evidence supports the clinical rationale for using calcium hydroxide not only as a disinfectant but also as a chemical debriding agent that complements and enhances the effects of mechanical preparation and irrigation, contributing to a more thoroughly cleaned root canal system.

Section 2: A Critical Evaluation of Calcium Hydroxide in Clinical Practice

2.1. Efficacy as an Intracanal Medicament: A Review of In Vitro and In Vivo Evidence

Calcium hydroxide is widely regarded as the first choice and standard material for an inter-appointment intracanal medicament (ICM).3 Its primary role in this context is to continue the disinfection process initiated by chemomechanical preparation, eliminating residual microorganisms and preventing reinfection between visits.3 The evidence supporting its efficacy comes from both animal and human studies. In vivo animal models provide valuable histological insights into the healing process. Studies conducted on dogs' teeth with induced periapical lesions have demonstrated that dressing the canals with calcium hydroxide for periods of 15 to 30 days results in more advanced and superior histological repair of periapical tissues compared to immediate obturation.21 Similarly, a one-week disinfection period with calcium hydroxide prior to obturation has been shown to lead to significantly less periapical inflammation.21 These findings suggest that the use of calcium hydroxide as an ICM creates a more favorable biological environment for periapical healing. Human clinical studies, which typically rely on microbial culturing techniques, corroborate its ability to reduce the bacterial load within the root canal. Application of a calcium hydroxide paste for one week or more has been shown to be sufficient to reduce canal bacteria to a level that results in a negative culture in many cases.4 Studies comparing single-session treatment with two-session treatment involving a calcium hydroxide dressing have found that the medicament significantly reduces the colony counts of aerobic and anaerobic bacteria.24 However, the clinical evidence is not unequivocal. While bacterial counts are consistently and significantly reduced, complete sterilization of the root canal system is rarely achieved.22 Microorganisms often persist, particularly in the anatomical complexities of the canal system, leading to a nuanced view of its clinical effectiveness.

2.2. Limitations and Controversies: Pathogen Resistance and Biofilm Ineffectiveness

Despite its widespread use and documented benefits, the antimicrobial efficacy of calcium hydroxide is a subject of considerable controversy, with significant limitations that can impact clinical outcomes.10 The most critical of these limitations is its reduced effectiveness against specific, highly resilient endodontic pathogens. Numerous studies have consistently identified Enterococcus faecalis and the fungus Candida albicans as being particularly resistant to the high pH environment created by calcium hydroxide.3 E. faecalis, a gram-positive facultative anaerobe, is frequently implicated in persistent and secondary endodontic infections and is a primary cause of treatment failure.4 Its resistance is attributed to its ability to form protective biofilms, survive in highly alkaline conditions, and penetrate deep into dentinal tubules where the buffering capacity of dentin can neutralize the pH of the medicament.18 Several in vitro and in vivo studies have shown that E. faecalis can survive in dentinal tubules even after extended periods of contact with a calcium hydroxide dressing.4 This issue of pathogen resistance contributes to the broader controversy surrounding its overall antimicrobial effect. While it is effective against a wide range of common endodontic pathogens, its failure to reliably eliminate key persistent species means that its application does not guarantee disinfection.10 This has led some clinical outcome studies to conclude that there is no significant improvement in the healing of periapical lesions when calcium hydroxide is applied between appointments compared to single-visit therapy, as the residual resistant bacteria may be sufficient to perpetuate the disease process.22 Furthermore, the effectiveness of calcium hydroxide against mature microbial biofilms is questionable.4 Biofilms are structured communities of bacteria encased in a self-produced extracellular polymeric substance (EPS) matrix. This matrix acts as a physical barrier, preventing the penetration of antimicrobial agents, and can also buffer the high pH of calcium hydroxide, protecting the bacteria residing within the deeper layers of the biofilm. This limited ability to disrupt and eliminate established biofilms is a significant shortcoming in the treatment of chronic endodontic infections.

2.3. The Biomechanical Impact: Long-Term Application and Dentin Fracture Susceptibility

Beyond its biological and antimicrobial properties, the application of calcium hydroxide has a significant biomechanical impact on tooth structure, particularly when used for extended periods. A growing body of evidence indicates that long-term exposure of root dentin to the highly alkaline environment of calcium hydroxide can weaken the tooth, increasing its susceptibility to vertical root fracture.12 The proposed mechanism for this structural degradation involves the effect of the high pH on the organic component of dentin. Dentin is a composite material, consisting of an inorganic hydroxyapatite matrix reinforced by an organic collagen network. The strong alkalinity of calcium hydroxide is believed to denature this collagen matrix by breaking down key chemical bonds, such as carboxylate and phosphate groups, which act as bonding agents between the collagen fibrils and the hydroxyapatite crystals.27 This disruption of the organic framework compromises the structural integrity and resilience of the dentin, making it more brittle over time. This weakening effect is time-dependent. While short-term applications of a week or two may have a negligible impact, studies have demonstrated a measurable reduction in root fracture resistance after periods of 4 to 5 weeks or more.27 One study reported an 8.2% reduction in the fracture strength of teeth after a 4-week placement of calcium hydroxide.28 Other research has suggested a weakening of dentin by as much as 23% after 84 days, with one theory proposing a potential 50% reduction in strength over the course of a year.26 This presents a significant clinical dilemma, creating a trade-off between the duration of application needed for therapeutic effect and the risk of iatrogenic structural damage. While a longer dressing time may be desirable to combat persistent infections, particularly those involving resistant species that require extended contact, this very chronicity increases the risk of biomechanical weakening. This is especially critical in cases that traditionally required long-term therapy, such as apexification in immature teeth with thin, fragile root walls.27 The high risk of fracture in these already compromised teeth has been a major factor in the shift towards alternative materials like Mineral Trioxide Aggregate (MTA) for apexification, as MTA provides an apical barrier in a single visit, thereby avoiding the detrimental effects of long-term calcium hydroxide application.27 The clinician's decision on the duration of calcium hydroxide therapy is therefore not simply a matter of disinfection but a complex risk-benefit analysis that must weigh the antimicrobial goals against the imperative to preserve the tooth's long-term structural integrity.

2.4. Clinical Challenges: The Persistent Problem of Intracanal Removal and Its Consequences

One of the most significant and persistent challenges in the clinical use of calcium hydroxide is the difficulty of its complete removal from the root canal system prior to final obturation.30 Despite various techniques and protocols, studies consistently show that remnants of the medicament are often left adhering to the canal walls, particularly in the critical apical third and within anatomical complexities such as isthmuses, fins, and lateral canals.31 The presence of these residual medicament particles is not benign; it can have a direct and negative impact on the quality and long-term success of the endodontic treatment. The primary consequences of incomplete removal include:

• Interference with Sealer Properties: Residual calcium hydroxide has been shown to interfere with the chemical setting reaction of zinc oxide-eugenol (ZOE) based sealers, preventing a standard set and altering the physical properties of the sealer.34
• Compromised Seal: The remnants act as a physical barrier, preventing the intimate adaptation of the root canal sealer to the dentin walls. This inhibits the penetration of the sealer into the dentinal tubules, which is crucial for creating a three-dimensional, fluid-tight seal.33
• Increased Apical Leakage: The compromised seal resulting from sealer interference and poor adaptation can lead to increased apical microleakage, providing a pathway for bacteria and their byproducts to re-enter and re-contaminate the periapical tissues, ultimately leading to treatment failure.33

The traditional method for removal, which involves irrigation with NaOCl or saline using a conventional syringe and needle, often combined with recapitulation with the master apical file, has been proven to be largely inadequate.30 Its effectiveness is limited by the inability of the irrigant to reach and physically dislodge the paste from the full extent of the complex canal system. This well-documented clinical failure has been a powerful catalyst for technological innovation in the field of endodontic irrigation. The clear and present need to more effectively remove calcium hydroxide and other debris from the canal has directly driven the development and adoption of advanced irrigation and agitation systems. Technologies such as:

• Passive Ultrasonic Irrigation (PUI): Utilizes an ultrasonically oscillating file to generate acoustic streaming and cavitation, which creates powerful hydrodynamic forces that dislodge debris and medicament from the canal walls.31
• Sonic Activation: Employs sonic energy to activate a polymer tip (e.g., EndoActivator, EDDY), creating similar hydrodynamic effects to improve cleaning.35
• Negative Apical Pressure Systems (e.g., EndoVac): Uses a microcannula to deliver irrigant and simultaneously evacuate it from the apical third, safely drawing the solution to the full working length.31
• Laser-Assisted Irrigation: Uses laser energy to activate the irrigant, generating vapor bubbles that expand and collapse to create powerful cleaning forces.31

These technologies were developed, in large part, to overcome the specific shortcomings of conventional methods in debriding the canal and removing intracanal medicaments. Numerous studies have shown that these advanced systems significantly improve the removal of calcium hydroxide compared to syringe irrigation, although even they do not always guarantee complete removal.31 This demonstrates a clear and powerful feedback loop where the limitations of a century-old material have directly shaped the trajectory of 21st-century endodontic engineering.

Section 3: The Commercial Landscape of Calcium Hydroxide Products

3.1. The Decisive Role of the Vehicle: Aqueous, Viscous, and Oily Formulations

The clinical performance of a commercial calcium hydroxide product is determined not only by its active ingredient but, critically, by the vehicle in which it is suspended. The vehicle is not merely an inert carrier; it is a decisive component that governs the paste's physicochemical properties, including its rate of ionic dissociation, diffusion, solubility, and handling characteristics.5 Manufacturers deliberately select specific vehicles to tailor their products for different clinical applications, creating a diverse market where formulations are optimized for specific therapeutic goals. These vehicles can be broadly categorized into three main types: aqueous, viscous, and oily.5

• Aqueous Vehicles: These formulations use water-soluble substances like distilled water, saline, or anesthetic solutions as their base.7 They promote the fastest and most complete ionic dissociation of calcium hydroxide, leading to a rapid onset of high pH and a potent, immediate antimicrobial effect.7 Because they are water-soluble, these pastes are also the easiest to remove from the root canal with standard irrigation. However, their high solubility means they are resorbed relatively quickly from the canal, which may necessitate more frequent reapplication in long-term cases.43 Products like Ultradent's UltraCal XS and Nishika's Calcipex II fall into this category.45
• Viscous Vehicles: These formulations utilize water-soluble but more viscous substances such as glycerine, polyethylene glycol (PEG), or propylene glycol.43 The higher viscosity slows down the rate of ionic dissociation and diffusion compared to aqueous vehicles. This results in a more gradual and sustained release of calcium and hydroxyl ions over a longer period.43 This prolonged action makes them well-suited for cases requiring longer inter-appointment intervals. Pulpdent's Multi-Cal, described as a smooth, creamy preparation, is an example of a product with a viscous consistency.48
• Oily Vehicles: These formulations are based on non-water-soluble substances like silicone oil, olive oil, or camphorated monochlorophenol (CMCP).5 They exhibit the slowest rate of ionic dissociation, providing maximum stability and longevity within the root canal.5 This makes them suitable for very long-term applications where frequent replacement is impractical. However, this stability comes with significant clinical trade-offs. The delayed ion release translates to a delayed onset of antimicrobial action, and their oily, non-water-soluble nature makes them extremely difficult to completely remove from the canal, posing a significant risk of interference with the final obturation seal.5 Commercially available products like Metapex and Vitapex are well-known examples of oil-based formulations.5

The choice of vehicle thus represents a strategic decision by the manufacturer to balance competing clinical demands: rapid action versus sustained effect, and ease of removal versus in-canal stability. There is no single "best" vehicle; rather, the appropriateness of a formulation is dictated by the specific clinical scenario. An aqueous paste is ideal for routine short-term disinfection, while an oily paste might be considered for a pulpectomy in a primary tooth where its slow resorption is an advantage. This formulation-driven market segmentation requires clinicians to understand the underlying material science to make an informed, evidence-based selection for each individual case.

3.2. A Comparative Survey of Commercially Available Products

The global dental market offers a wide array of calcium hydroxide products, reflecting its diverse applications in endodontics. These products range from pure powders for extemporaneous mixing to sophisticated, pre-mixed injectable pastes and root canal sealers. A multitude of manufacturers, including major international corporations and regional specialists, contribute to this landscape. Key players include Ultradent Products, Inc. (USA), Kerr Dental (USA), Pulpdent Corp. (USA), Directa Dental (Sweden), VOCO (Germany), Prevest Denpro (India), Meta Biomed (South Korea), and Nippon Yakushin / Nishika (Japan).45 The following table provides a comparative overview of a selection of prominent commercially available calcium hydroxide products, categorized by their formulation and key characteristics to aid in clinical decision-making.

Product Name Manufacturer Formulation Type Vehicle Base Key Additives Delivery System Radiopacity Calcipex II Nippon Yakushin (Nishika) Premixed Paste Aqueous (Water-based) Barium Sulfate Syringe with plastic needle Yes 47 UltraCal XS Ultradent Products, Inc. Premixed Paste Aqueous None specified Syringe with NaviTip Yes 45 Calcicur VOCO Premixed Paste Aqueous (Water-based) None specified Syringe Yes 48 Multi-Cal Pulpdent Corp. Premixed Paste Viscous (Creamy) None specified Syringe Yes 48 Metapex / Vitapex Meta Biomed / Neo Dental Premixed Paste Oily (Silicone oil) Iodoform Syringe Yes 5 Calasept Plus Directa Dental Premixed Paste Aqueous (Saline) None specified Syringe Yes 48 Sealapex Kerr Dental Root Canal Sealer Polymeric Resin None specified Two-paste system (tubes) Yes 52 Calcium Hydroxide Powder Various (e.g., Produits Dentaires) Powder N/A (Mixed by clinician) None Jar No (unless mixed with radiopacifier) 61

3.3. Analysis of Formulations with Additives

Many commercial calcium hydroxide products are not pure formulations but are compounded with additional substances to enhance their clinical properties, primarily their antimicrobial efficacy and radiopacity.

• Radiopacifying Agents: The most common additive is a radiopacifier, which is essential for visualizing the material on a radiograph to confirm its placement and distribution within the root canal.62 Barium sulfate ($BaSO_4$) is the most frequently used agent for this purpose and is found in products like Calcipex II and RCTcal.53 While necessary, these agents are not without potential drawbacks. If the paste is extruded beyond the apex, barium sulfate is not readily resorbed by the body and can persist in the periapical tissues for an extended period.26 This can obscure the radiographic assessment of healing at the apex and has been reported to potentially delay healing or enhance local inflammatory responses.26
• Iodoform: Iodoform is another common additive, prized for its potent, broad-spectrum antimicrobial properties, which can augment the antibacterial effect of the calcium hydroxide itself.50 It also serves as an effective radiopacifying agent. It is typically incorporated into oily-vehicle pastes, such as Metapex and Vitapex.5 The primary disadvantages of iodoform-containing products are the potential for inducing allergic reactions in patients with iodine hypersensitivity and the risk of causing discoloration of the tooth structure.57
• Chlorhexidine (CHX): To address the known resistance of E. faecalis to calcium hydroxide, some protocols advocate for mixing calcium hydroxide powder with a chlorhexidine solution or gel at the time of use.18 CHX is a potent, broad-spectrum antimicrobial agent with proven efficacy against E. faecalis. Studies have shown that this combination can produce a synergistic antimicrobial effect that is superior to that of either agent used alone, offering a clinical strategy to overcome one of the primary limitations of traditional calcium hydroxide therapy.14

Section 4: In-Depth Analysis: Calcipex II (Nippon Yakushin / Nishika)

4.1. Product Profile: Composition, Handling Characteristics, and Radiopacity

Calcipex II, manufactured by the Japanese company Nippon Yakushin (also known as Nishika), is a prominent example of a modern, premixed calcium hydroxide intracanal medicament.47 Its formulation and delivery system are designed to optimize clinical handling and efficacy for temporary root canal dressing.

• Composition: The core composition of Calcipex II is a water-based (aqueous) paste.47 The primary active ingredient is calcium hydroxide. To ensure visibility on radiographs, it incorporates barium sulfate as a radiopacifying agent.57 The vehicle consists of purified water and other unspecified components, likely including a humectant to maintain its paste consistency and flowability.57 A critically important feature of its composition is that it is iodoform-free, distinguishing it from another major category of commercial pastes.57 Its high concentration of calcium hydroxide in an aqueous medium results in a strongly alkaline paste with a pH of approximately 12.4.47
• Handling Characteristics: Calcipex II is supplied as a stable, premixed paste in a pre-loaded syringe, eliminating the need for chairside mixing and ensuring a consistent product.47 This delivery system, often paired with a flexible, tapered plastic needle (Nishika Spin), is designed for easy and direct application into the root canal.47 A key handling property derived from its water-based vehicle is its high flowability, which allows the paste to be filled into the canal system with relative ease.47 Rheological studies have confirmed that Calcipex II, like other injectable pastes, exhibits pseudoplastic behavior—its viscosity decreases under the pressure of injection, facilitating its flow through a narrow needle tip.68 This property is advantageous for placement but also necessitates careful control to prevent overfilling. Perhaps its most significant handling characteristic is its ease of removal. Being water-soluble, it can be readily flushed out of the root canal using standard irrigation techniques, a distinct advantage over more tenacious oily or viscous pastes.47
• Radiopacity: The inclusion of barium sulfate renders Calcipex II sufficiently radiopaque.47 This property is essential for clinicians to radiographically verify the depth and quality of the fill after placement and to ensure its complete removal before final obturation.62

4.2. The Clinical Advantages of a Water-Based, Iodoform-Free Formulation

The specific formulation of Calcipex II as a water-based, iodoform-free paste confers several distinct clinical advantages that align with the goals of modern endodontic disinfection. The primary advantage of the aqueous vehicle is the rapid and efficient dissociation of calcium hydroxide into its active calcium ($Ca^{2+}$) and hydroxyl ($OH^-$) ions.57 This immediate bioavailability of hydroxyl ions leads to a rapid elevation of the intracanal pH, allowing the paste to exert its antimicrobial and tissue-dissolving effects quickly upon placement. This is coupled with the material's high flowability, which theoretically allows for better penetration into the anatomical complexities of the root canal system, bringing the active ions into closer contact with residual pulp tissue and microorganisms.47 In vitro studies comparing the diffusion of different types of calcium hydroxide pastes through dentin have supported this concept, showing that hydrophilic (water-based) materials like Calcipex II achieve greater diffusion compared to hydrophobic (oil-based) materials, which tend to remain more localized.72 A second, and perhaps more significant, clinical advantage is the ease of removal. As discussed previously, residual calcium hydroxide can severely compromise the quality of the final root canal seal. The water-soluble nature of Calcipex II means it can be removed more thoroughly and predictably with standard irrigation protocols compared to oil-based pastes, which adhere tenaciously to the canal walls.47 This characteristic directly addresses one of the most persistent clinical challenges associated with calcium hydroxide use, reducing the risk of treatment failure due to sealer interference. Finally, the iodoform-free formulation enhances its biocompatibility and safety profile. While iodoform is an effective antimicrobial, it is a known potential allergen. By omitting iodoform, Calcipex II can be used safely in patients with iodine hypersensitivity, broadening its clinical applicability and avoiding the risk of adverse allergic reactions.57 This makes it a more universally suitable option for routine intracanal medication.

4.3. Review of Clinical Performance: Evidence from Case Reports and Comparative Studies

The clinical utility of Calcipex II has been documented in a series of case reports and evaluated in comparative studies, which provide insight into its performance in various clinical scenarios. A collection of clinical cases highlights its effectiveness in managing challenging endodontic conditions, particularly those characterized by persistent inflammation and exudation.65 In multiple reported cases of chronic apical periodontitis with persistent weeping canals, Calcipex II was successfully used to suppress the exudate and resolve clinical symptoms, often after previous medicaments (including iodoform-based ones) had failed.65 These cases demonstrate its ability to alter the periapical environment sufficiently to allow for healing and subsequent bone regeneration, which was observed radiographically in follow-up appointments.65 The reports suggest that for suppressing exudate, less frequent applications (e.g., every 2-4 weeks) are more effective.65 In terms of antimicrobial efficacy, the picture is more nuanced. Its high pH provides a strong theoretical basis for its antibacterial action.67 However, comparative in vitro studies have investigated its potency against the notoriously resistant Enterococcus faecalis. One such study found that the antibacterial effect of Calcipex II was less than that of standard irrigants like sodium hypochlorite and chlorhexidine.73 This finding is consistent with the known limitations of calcium hydroxide in general against this specific pathogen. Recognizing the clinical importance of this comparison, a randomized controlled trial was designed specifically to compare the in vivo antimicrobial efficacy of Calcipex (calcium hydroxide alone) with Metapex (calcium hydroxide with iodoform) in teeth with chronic apical periodontitis.59 The existence of such a trial underscores the ongoing clinical debate and the need for high-level evidence to clarify the relative benefits of different commercial formulations in eliminating intracanal bacteria.

4.4. A Nuanced Assessment of Risks: Complications Associated with Overfilling and Material Composition

While Calcipex II offers significant clinical advantages, its use is not without risks, primarily related to accidental overfilling and the biological response to its specific components. Like any injectable paste system, particularly one with high flowability, there is an inherent risk of extruding the material beyond the apical foramen during application.13 The consequences of such extrusion have been the subject of several detailed case reports, which reveal a specific and significant complication associated with Calcipex II. Multiple reports have documented that when overfilled into the periapical tissues, Calcipex II can induce a chronic foreign body granulomatous reaction.64 This is a critical finding, as it points to a risk that goes beyond the simple chemical irritation expected from a highly alkaline material. Histological analysis of biopsy specimens from these lesions has revealed that the inflammatory response is not primarily directed at the calcium hydroxide component, which is largely resorbable. Instead, the reaction is targeted at fine, non-resorbable polymer resin micro-beads that are part of the Calcipex II formulation.76 These micro-beads, approximately 1 µm in diameter, are engulfed by macrophages but are not degraded. This frustrated phagocytosis leads to macrophage apoptosis and a persistent, chronic inflammatory state, which in some severe cases has led to complications such as chronic maxillary sinusitis.66 This highlights a crucial point: the primary risk associated with Calcipex II extrusion stems not from its well-known active ingredient ($Ca(OH)_2$) but from a less-publicized, inert component of its proprietary formulation. The biocompatibility of pure calcium hydroxide is well-established, but the biological inertness of these polymer additives is not absolute. This creates a risk profile for Calcipex II that is fundamentally different from that of a simple, extemporaneously mixed paste of calcium hydroxide and water. It underscores the principle that clinicians must consider the biological impact of the entire formulation of a commercial product, not just its active ingredient, when assessing potential risks. Fortunately, this research has also yielded a valuable diagnostic tool. It was discovered that the polymer resin granules of Calcipex II exhibit a distinct, bright birefringence when viewed under a polarizing light microscope.76 This characteristic allows for their definitive identification in histological specimens, providing a clear method for diagnosing a Calcipex II-induced foreign body reaction and differentiating it from other periapical pathologies.

Section 5: Clinical Recommendations and Future Perspectives

5.1. Evidence-Based Protocols for Application and Removal

The extensive body of research on calcium hydroxide provides a foundation for evidence-based clinical protocols aimed at maximizing its therapeutic benefits while minimizing its known risks. For application, the primary goal is to deliver the medicament densely throughout the canal system without extruding it into the periapical tissues. This is particularly critical for injectable, high-flowability pastes like Calcipex II. Best practices include:

• Confirming apical patency and accurately determining the working length.
• Selecting a delivery needle (e.g., NaviTip, Nishika Spin) that fits passively in the canal and does not bind against the walls.13
• Placing the needle tip 2-3 mm short of the working length.
• Injecting the paste with slow, steady pressure while simultaneously withdrawing the needle from the canal. This back-filling technique reduces the buildup of apical pressure.13
• Taking a postoperative radiograph to confirm the placement and check for any extrusion.67

For removal, a hierarchical approach is recommended, as no single technique has been proven to be 100% effective in all cases.30 The protocol should be adapted to the complexity of the canal and the type of paste used.

• Baseline Protocol: The process should begin with copious irrigation using sodium hypochlorite, combined with mechanical agitation by recapitulating with the master apical file or a similar-sized instrument to break up the bulk of the paste.31
• Chemical Adjuncts: A final rinse with a chelating agent, such as 17% ethylenediaminetetraacetic acid (EDTA), is crucial. EDTA is effective at dissolving the inorganic calcium hydroxide particles and helps to remove the smear layer, exposing any medicament trapped within dentinal tubules.31
• Advanced Agitation: For anatomically complex canals, or when removing more tenacious viscous or oily pastes, the use of advanced irrigant agitation systems is strongly indicated. Passive ultrasonic irrigation (PUI) and sonic activation systems (e.g., EDDY, EndoActivator) have consistently been shown to be significantly more effective at removing calcium hydroxide remnants than conventional syringe irrigation alone.31

5.2. Selecting the Appropriate Calcium Hydroxide Formulation for Specific Clinical Scenarios

The diverse range of commercially available calcium hydroxide products allows the clinician to select a formulation whose properties are best matched to the specific demands of the clinical situation.

• Routine Inter-appointment Disinfection (1-4 weeks): For standard cases of necrotic teeth with apical periodontitis requiring disinfection between appointments, an aqueous, water-based paste (e.g., Calcipex II, UltraCal XS) is often the preferred choice. Its rapid ion release provides a potent antimicrobial effect, and its ease of removal minimizes the risk of residual material compromising the final obturation.47
• Long-Term Apexification (>1 month): While calcium hydroxide has historically been the material of choice for apexification, its tendency to weaken dentin with long-term use warrants significant caution.27 If it is to be used, a more stable, slow-releasing viscous or oily paste might be considered to reduce the number of retreatments needed to replace the medicament. However, the clinician must accept the significant trade-off of increased difficulty in final removal. For most cases today, single-visit apexification with an apical plug of MTA is considered the superior alternative.27
• Persistent Exudation (Weeping Canals): In cases with persistent periapical exudate, the goal is to create a significant and rapid shift in the periapical pH to an alkaline state to control inflammation and cauterize inflamed tissue.10 A highly alkaline, fast-acting aqueous paste is well-suited for this purpose, as demonstrated by the successful use of Calcipex II in such cases.65
• Suspected E. faecalis Infection (Retreatment Cases): Given the known resistance of E. faecalis to calcium hydroxide alone, its use as a monotherapy in retreatment cases is questionable. Consideration should be given to extemporaneously mixing calcium hydroxide powder with an agent like 2% chlorhexidine to create a synergistic combination with a broader antimicrobial spectrum.18

5.3. Emerging Frontiers: Nano-formulations and Synergistic Therapies

While calcium hydroxide has been in use for a century, research and development continue in an effort to overcome its inherent limitations. The future of this therapeutic agent likely lies not in its traditional form but in advanced formulations and combination therapies.

• Nano-formulations: A promising area of research is the development of nano-formulated calcium hydroxide. By reducing the particle size of the material to the nanometer scale, it is theorized that its penetration into the dentinal tubules and its interaction with microbial biofilms can be significantly enhanced.18 Early research suggests that nano-Ca(OH)₂ may lead to improved pain control and fewer inter-appointment flare-ups compared to conventional micro-particle formulations.18
• Synergistic Therapies: The recognition that calcium hydroxide has a limited antimicrobial spectrum has spurred research into combination therapies. The goal is to pair calcium hydroxide with other antimicrobial agents to create a synergistic effect that is more potent and broader in spectrum than either component alone. The combination with chlorhexidine to target E. faecalis is the most well-studied example.14 Other agents, such as N-acetylcysteine (NAC), which has anti-biofilm properties, are also being explored as potential adjuncts.25

Ultimately, the long history of calcium hydroxide in endodontics is a compelling narrative of scientific evolution. Often referred to as a "gold standard," it is more accurately described as a deeply flawed but foundational material. Its clear benefits—high alkalinity, bactericidal action, and hard tissue induction—established it as a clinical staple.2 However, its significant and well-documented weaknesses—resistance from key pathogens, biomechanical weakening of dentin, the persistent challenge of removal, and risks associated with extrusion—have prevented it from being an ideal solution.3 Rather than leading to its obsolescence, these very flaws have become a primary engine for progress and innovation within endodontics. The development of different vehicles was an attempt to modulate its ion release. The addition of other antimicrobials was a direct response to its limited spectrum. The invention of sophisticated sonic and ultrasonic irrigation technologies was driven in large part by the imperative to remove it effectively. The current exploration of nano-formulations is the latest chapter in this ongoing effort to refine and enhance a century-old therapy. The story of calcium hydroxide is therefore not one of a static standard, but of a foundational catalyst whose imperfections have continually pushed the boundaries of endodontic science and technology. Nguồn trích dẫn 1. (PDF) Calcium hydroxide in dentistry: A Review. – ResearchGate, truy cập vào tháng 10 26, 2025, https://www.researchgate.net/publication/309634075_Calcium_hydroxide_in_dentistry_A_Review 2. Antimicrobial effect of calcium hydroxide as an intracanal medicament in root canal treatment: a literature review – Part I. In vitro studies – Restorative Dentistry & Endodontics, truy cập vào tháng 10 26, 2025, https://rde.ac/journal/view.php?doi=10.5395/rde.2014.39.4.241 3. Antimicrobial effect of calcium hydroxide as an intracanal medicament in root canal treatment: a literature review – Part I. In vitro studies – PMC – NIH, truy cập vào tháng 10 26, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4223092/ 4. Antimicrobial Activity of Calcium Hydroxide in Endodontics: A Review – PMC – NIH, truy cập vào tháng 10 26, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC3539092/ 5. Calcium Hydroxide in Endodontics- Properties, Clinical Applications and Recent Advances: A Review – MIDSR Journal, truy cập vào tháng 10 26, 2025, http://journal.mitmidsr.edu.in/public/pdf/volume_7_issue_1/Calcium-Hydroxide-in-Endodontics-Properties-Clinical-Applications-and-Recent-Advances-A-Review.pdf 6. Calcium Hydroxide as an Intracanal Medicament –A Review – IOSR Journal, truy cập vào tháng 10 26, 2025, https://www.iosrjournals.org/iosr-jdms/papers/Vol19-issue10/Series-10/C1910100913.pdf 7. View of Clinical application of calcium hydroxide in dental pathology and endodontics, truy cập vào tháng 10 26, 2025, https://www.bjbms.org/ojs/index.php/bjbms/article/view/3488/1031 8. Role Of Calcium Hydroxide In Endodontics – Global Journal of Medicine & Public Health, truy cập vào tháng 10 26, 2025, https://gjmedph.com/Uploads/Role%20Of%20Calcium%20Hydroxide.pdf 9. (PDF) The Use of Calcium Hydroxide as an Intracanal Medicament in the Treatment of Large Periapical Lesions. A Review – ResearchGate, truy cập vào tháng 10 26, 2025, https://www.researchgate.net/publication/343957085_The_Use_of_Calcium_Hydroxide_as_an_Intracanal_Medicament_in_the_Treatment_of_Large_Periapical_Lesions_A_Review 10. (PDF) Calcium Hydroxide in Endodontics: An Overview – ResearchGate, truy cập vào tháng 10 26, 2025, https://www.researchgate.net/publication/311915954_Calcium_Hydroxide_in_Endodontics_An_Overview 11. (PDF) Calcium Hydroxide-Based Root Canal Sealers: A Review, truy cập vào tháng 10 26, 2025, https://www.researchgate.net/publication/24257161_Calcium_Hydroxide-Based_Root_Canal_Sealers_A_Review 12. Calcium Hydroxide In Dental – Properties & Application – Medikabazaar, truy cập vào tháng 10 26, 2025, https://www.medikabazaar.com/blogs/calcium-hyroxide-dental 13. Overview and Management Of Endodontic Iatrogenic Extrusions …, truy cập vào tháng 10 26, 2025, https://decisionsindentistry.com/article/overview-and-management-of-endodontic-iatrogenic-extrusions/ 14. Tissue-dissolution capacity and dentin-disinfecting potential of calcium hydroxide mixed with irrigating solution | Request PDF – ResearchGate, truy cập vào tháng 10 26, 2025, https://www.researchgate.net/publication/9023264_Tissue-dissolution_capacity_and_dentin-disinfecting_potential_of_calcium_hydroxide_mixed_with_irrigating_solution 15. Pulp tissue dissolution in endodontics- A review – International Journal of Applied Dental Sciences, truy cập vào tháng 10 26, 2025, https://www.oraljournal.com/archives/2017/vol3issue2/PartD/3-2-17-750.pdf 16. The effects of sodium hypochlorite and calcium hydroxide on tissue dissolution and root canal cleanliness – PubMed, truy cập vào tháng 10 26, 2025, https://pubmed.ncbi.nlm.nih.gov/9477824/ 17. Effect of calcium hydroxide on the dissolution of soft tissue on the root canal wall – PubMed, truy cập vào tháng 10 26, 2025, https://pubmed.ncbi.nlm.nih.gov/9641107/ 18. Effectiveness of calcium hydroxide as an intracanal medicament in …, truy cập vào tháng 10 26, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC12440338/ 19. pmc.ncbi.nlm.nih.gov, truy cập vào tháng 10 26, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC12440338/#:~:text=Intracanal%20medicaments%20(ICMs)%2C%20especially,flare%2Dups%20in%20retreatment%20cases. 20. The use of calcium hydroxide, antibiotics and biocides as antimicrobial medicaments in endodontics – ResearchGate, truy cập vào tháng 10 26, 2025, https://www.researchgate.net/publication/6289436_The_use_of_calcium_hydroxide_antibiotics_and_biocides_as_antimicrobial_medicaments_in_endodontics 21. Antimicrobial effect of calcium hydroxide as an intracanal medicament in root canal treatment: a literature review – Part II. in vivo studies – Restorative Dentistry & Endodontics, truy cập vào tháng 10 26, 2025, https://rde.ac/DOIx.php?id=10.5395/rde.2015.40.2.97 22. (PDF) Antimicrobial effect of calcium hydroxide as an intracanal medicament in root canal treatment: a literature review – Part II. in vivo studies – ResearchGate, truy cập vào tháng 10 26, 2025, https://www.researchgate.net/publication/308785726_Antimicrobial_effect_of_calcium_hydroxide_as_an_intracanal_medicament_in_root_canal_treatment_a_literature_review_-_Part_II_in_vivo_studies 23. 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Removal Efficiency of Calcium Hydroxide Dressing from the Root Canal without Chemically Active Adjuvant – The Journal of Contemporary Dental Practice, truy cập vào tháng 10 26, 2025, https://www.thejcdp.com/doi/10.5005/jp-journals-10024-1298 35. removal of calcium hydroxide intracanal medicament with four different techniques: a cone beam – Alexandria Dental Journal, truy cập vào tháng 10 26, 2025, https://adjalexu.journals.ekb.eg/article_250637_dde51550a8bdec457e9b378ef10f59b5.pdf 36. Removal efficacy and cytotoxicity of a calcium hydroxide paste using N-2- methyl-pyrrolidone as a vehicle – Semantic Scholar, truy cập vào tháng 10 26, 2025, https://pdfs.semanticscholar.org/9d46/1dc5c823e85e572af0999196f587bae626fe.pdf 37. The Comparison of Different Irrigation Systems to … – SciELO Brasil, truy cập vào tháng 10 26, 2025, https://www.scielo.br/j/pboci/a/6x4kQkZcFhS3bv4DPh496yr/ 38. 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Efficacy of five techniques for the removal of calcium hydroxide from straight and curved root canals – micro-CT study – Journal of IMAB, truy cập vào tháng 10 26, 2025, https://www.journal-imab-bg.org/issues-2025/issue1/vol31issue1p6054-6060.html 41. pmc.ncbi.nlm.nih.gov, truy cập vào tháng 10 26, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10593373/#:~:text=%5B27%5D%20conducted%20a%20study%20to,the%20root%20canal%20was%20better. 42. Evaluation of Intracanal Calcium Hydroxide Removal with Different Techniques: A Scanning Electron Microscope Study – The Journal of Contemporary Dental Practice, truy cập vào tháng 10 26, 2025, https://www.thejcdp.com/doi/10.5005/jp-journals-10024-2450 43. Influence of vehicle for calcium hydroxide on postoperative pain: a scoping review – NIH, truy cập vào tháng 10 26, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8995678/ 44. (PDF) Role of vehicles on antimicrobial efficacy of calcium hydroxide – ResearchGate, truy cập vào tháng 10 26, 2025, https://www.researchgate.net/publication/376997506_Role_of_vehicles_on_antimicrobial_efficacy_of_calcium_hydroxide 45. UltraCal™ XS – 35% Calcium Hydroxide Paste – Ultradent Products, truy cập vào tháng 10 26, 2025, https://www.ultradent.com/products/categories/endodontics/irrigants-lubricants-medicaments/ultracal-xs 46. Biocompatibility of Intracanal Medications Based on Calcium Hydroxide – PMC – NIH, truy cập vào tháng 10 26, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC3535743/ 47. Ca(OH)2 water-based paste CALCIPEXⅡ < radiopaque >, truy cập vào tháng 10 26, 2025, https://www.nishika.co.jp/english/product.php?mode=item&p_id=40 48. Calcium hydroxide | Net32, truy cập vào tháng 10 26, 2025, https://www.net32.com/ec/calcium-hydroxide-medicaments-endodontic-products-l-528-772-480 49. 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J Morita calcipex II Water Based Calcium Hydroxide Paste Online at Best Price – Dentalkart, truy cập vào tháng 10 26, 2025, https://www.dentalkart.com/j-morita-calcipex-ii-water-based-calcium-hydroxide-paste.html 68. Rheological properties and handling characteristics of four injectable calcium hydroxide pastes – ResearchGate, truy cập vào tháng 10 26, 2025, https://www.researchgate.net/publication/385250986_Rheological_properties_and_handling_characteristics_of_four_injectable_calcium_hydroxide_pastes 69. Rheological properties and handling characteristics of four … – J-Stage, truy cập vào tháng 10 26, 2025, https://www.jstage.jst.go.jp/article/dmj/advpub/0/advpub_2024-086/_article/-char/en 70. Rheological properties and handling characteristics of four injectable calcium hydroxide pastes – PubMed, truy cập vào tháng 10 26, 2025, https://pubmed.ncbi.nlm.nih.gov/39462608/ 71. 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