Background/Basic Science of Calcium Hydroxyapatite Fillers

Introduction

Facial aging is a dynamic process that is etiologically multifactorial comprising of environmental factors (e.g., extrinsic aging and effects of gravity), dermal thinning, craniofacial skeletal remodeling (e.g., bone expansion and resorption)^1,2 and superficial and deep subcutaneous tissue atrophy,³ which altogether contribute to structural deficits and volume loss. Fat atrophy in the aging face is selective and is initially observed in the tear trough and cheeks, followed by the chin and mandible.⁴ Age-related morphological changes of the facial contour give rise to concavities and lines⁴ and may manifest as facial wrinkles, folds, laxity and an overall unbalanced profile. Since a youthful face has a more homogenous appearance due to more even superficial and deep fat distribution, one way to reestablish contour is through volume restoration via implantation/filling. Though the first collagen dermal filler became available over 30 years ago, the first injectable cosmetic filler dates back to 1899 when Robert Gersuny injected mineral oil (liquid paraffin) to create a testicular prosthetic.^3,5 He then experimented with small quantities of petrolatum due to its ability to liquefy upon heating but solidify and stabilize after injection. The success he experienced incited the medical community to use paraffin and petrolatum as soft-tissue fillers. However, serious complications ensued, which included inflammation, filler migration, infection/fistula, embolism, nodules and granulomatous foreign-body reactions. Hence, the search for more viable options continued and in 1965, a purified injectable silicone was introduced due to its inert properties and ease of injection.^3,6 However, complications echoed that of paraffin use such as migration, fistula formation as well as siliconomas. Consequently, the FDA denounced the use of silicone in 1979.^3,6 In 1981, the FDA approved the use of bovine collagen (Zyderm) as the first facial filler for cosmetic use followed by Zyderm II and Zyplast (Allergen, Inc., Irvine, CA, USA) in 1985, but these options also came with the associated risks of nodule formation.³ In 2003, Restylane (Medics Aesthetics, Inc., Scottsdale, AZ, USA) was FDA approved as the first non-animal derived hyaluronic acid. Finally, the FDA approved calcium hydroxyapatite (CaHA) in 2006 as a semi-permanent filler after it was approved for vocal fold augmentation, radiographic soft tissue marking and oral/maxillofacial defect correction in 2002.

Mechanism of action

Calcium hydroxyapatite (CaHA; Radiesse^TM; Merz North America, Greensboro, NC, USA) is a synthetic, biodegradable and bio-stimulatory/non-inflammatory semi-permanent filler. Since it is the major inorganic constituent of bones and teeth, it does not require a pretreatment allergy test as it rarely elicits a foreign body reaction. It is unique due to its ability to replace volume and induce collagen biostimulation secondary to fibroblast activation.⁷ The material consists of 30% synthetic CaHA microspheres (25-45μm diameter) suspended in a 70% gel carrier composed of 36.6% sterile water, 6.4% glycerin and 1.3% sodium carboxymethylcellulose.⁴ The gel carrier evenly distributes CaHA microspheres in a 1:1 corrective fashion and gradually dissipates within weeks to months of injection.⁷ The remaining CaHA microspheres serve as a scaffold for neocollagenesis through fibroblast activation and replacement of type I collagen by type III⁸ and are eventually degraded by phagocytes into calcium and phosphate ions within 12-18 months.⁷  Neocollagenesis with use of dilute CaHA (1:1 ratio of original CaHA reconstituted with lidocaine/saline) and hyperdilute CaHA (1:2 or higher reconstitution ratios) can occur as early as 4 weeks post injection and is observed at 3, 6 and 12 months follow-up.⁸ However, skin treated with dilution ratios greater than 1:1 (hyperdilute CaHA of 1:2, 1:4, and 1:6 ratios) are more effective for collagen biostimulation with histological evidence of  significant increases in type I and III collagen 4 months after treatment and stability by 9 months. ⁸ Further, CaHA’s rheological properties of a high elastic modulus (G’) and viscosity (η*) contribute to its ability to resist deformation under applied pressure and provides lifting capacity as well as resistance to high shearing forces,^7,9 which enable it to retain its structure with minimal migration into adjacent tissue. ^7,9

FDA-Cleared Indications

CaHA was FDA cleared in 2006 for the correction of moderate-to-severe facial wrinkles, nasolabial folds and HIV-associated facial lipoatrophy. It has also demonstrated efficacy in the treatment of marionette lines, acne scars, per-jowl sulcus, malar zone hollowing and flattening of the eminence.⁹ CaHA can be stored for up to three years at room temperature, does not require over correction for the appropriate volume, does not require a pretreatment allergy test due to its biocompatibility and has no risk of keloid formation or osteogenesis due to the lack of progenitor cells in soft tissue.⁹ In 2015, it was approved for volume restoration in the dorsal hands. CaHA has a duration of effect of 12 months or greater, but may be impacted by injector technique as well as host-related factors e.g., age, metabolism, immunologic state, medical history, current medications, severity of photodamage and chosen treatment area.⁹

Pre-procedure considerations

It is important to address and thoroughly discuss patient expectation on outcome prior to obtaining informed consent. Medications e.g., NSAIDs and herbal supplements e.g., ginkgo, ginseng associated with bleeding risk must be stopped at least one week prior to treatment in order to reduce hematoma formation. On the day of the procedure, standardized digital photographs should be taken under soft natural lighting. Patients should sit in an upright position (between 60 and 90 degrees) for proper facial assessment and injection. The treatment area must be cleansed with a neutral cleanser followed by an isopropropyl alcohol swab. The optional addition of chlorhexidine gluconate 4.0% solution can be used for enhanced antiseptic coverage. The injector may mark the area to be treated with a soft tip marker.

Anesthesia

Topical anesthesia for at least 10-15 minutes prior to procedure can decrease discomfort. There are a number of commercially available topical anesthetics such as lidocaine 4%, lidocaine 2.5%/prilocaine 2.5%, lidocaine 23%/tetracaine 7% and etc. Local infiltration with lidocaine should be avoided as it may lead to tissue distortion and increase the risk of overfilling and irregularities.⁹ However, the pretreatment addition of liquid lidocaine 2% to CaHA filler  (FDA approved in 2009) increases patient comfort without risk of tissue distortion associated with local infiltration. CaHA filler with 0.3% integral lidocaine (Radiesse+) is also commercially available as sterile prefilled syringes. The added liquid lidocaine not only lowers G’ and η* but also extrusion force of CaHA rendering it smoother and ideal for injection of the dorsal hand and thinner-skinned facial areas.⁹

Treatment regimen

Facial fillers correct the surface contour through the manipulation of the light-shadow interface as convexities reflect light and concavities create shadow. A 25-G to 27-G needle or a 25-G cannula are typically used for CaHA injection. When using a 27-G needle, careful placement into the subdermal region is needed and careful withdrawal of the needle is necessary to avoid superficial injection. Injections made into the subcutaneous tissue prevent inadvertent intravascular injection and surface irregularities. Manual massage is recommended to reduce risk of nodularity. Risk of inadvertent arterial occlusion in the lower and lateral midface is reduced with the use of a retrograde injection technique.⁹ Use of the 25-G cannula has been associated with less soft tissue trauma/ecchymosis and risk of intravascular occlusion. A 23-G pilot needle can be used to create an insertion site for the cannula, which is inserted in the same direction with lateral traction on the skin in order to widen the site.⁹ The cannula can be guided deep or superficial to the plane of insertion through transverse pinching anterior to the cannula while longitudinal stretching directs it superficially.⁹ Dermal injections of CaHA filler should be avoided due to high risk of nodularity and it should never be injected in highly mobile or anatomically thinned-skinned areas e.g., lips and tear trough because of its high resistance to deformation post-injection, which does not abate over time.

Treatment areas

Upper face

CaHA with integral lidocaine is typically recommended to correct temporal wasting due to lower G’ , η* and extrusion force. A cannula can be inserted in an entry point overlying the zygoma or in the temporal hairline to subdermally deliver small boluses (0.1-0.2 mL). Alternatively, a 27-G needle can be used for supraperiosteal injection.⁹ To safely correct forehead convexity and brow ptosis, caution to avoid intravascular injection is needed. A blunt-tipped cannula is used to subdermally deliver small volumes in a retrograde linear fashion and is either inserted medially to the supraorbital artery within 2 cm of the supraciliary ridge of the frontal bone (as the supraorbital and supratrochlear vessels run deep here) or supraperiosteally behind the galeal fat pad when injecting more superiorly (vessels course more superficially here).

Midface

A 27-G needle or 25-G blunt-tipped cannula can be used to restore the midface due to bone resorption and fat atrophy in the malar and zygomatic regions. Entry sites are placed in the submalar region and lateral zygoma, which enables fanning and crosshatching of the entire midface, while supraperiosteal injections followed by deep dermal layering can correct cheek flattening. ⁹ To treat nasolabial folds (NLF), a 25-G blunt-tipped cannula can be used at an entry point at the distal end of the NLF. Injection is best done with a linear threading technique starting at the base of the NLF. ⁹ CaHA can also be used for nasal augmentation e.g., convexities and concavities or post-rhinoplasty correction e.g., depressions and columellar retraction. A 25-G blunt-tipped cannula can be used to correct nasal convexities by lengthening the appearance of the nose and reducing dorsal hump prominence. CaHA should be supraperiosteally placed at the origin of the radix and feathered into the dorsal hump using a retrograde fanning or serial droplet technique.^9,10 Dorsal concavities can be corrected with injection into the bony cartilaginous skeleton.⁹ Avoid injection into the nasal supratip and alar region due to greater risk of vascular complications.⁸ Multiple smaller volume injections are advised to reduce the risk of overcorrection.

Lower face

Crosshatching linear threads of CaHA in a deep subdermal plane can add bulk to the lower face and elevate the corners of the mouth, thereby improving marionette lines. This is achieved through an entry point made slightly medial to the melolabial fold along the line.¹⁰ Supraperiosteal boluses and subdermal linear threading may be used to correct chin convexity, which contributes to the worsening appearance of marionette lines. To correct prejowl sulcus, supraperiosteal injection onto the mandible will restore the inferior border. Additionally, mandibular augmentation can be achieved with a blunt-tipped cannula. Entry points at the mandibular angle and lateral aspect of the prejowl sulcus enables for crosshatching of subdermal retrograde linear threads.⁹ Added definition of the lateral jaw can be accomplished with supraperiosteal injection at the mandibular angle.

Hands

Revolumization of the entire dorsal hand can be achieved through one single entry site in the dorsal wrist or two entry sites proximal to the 1^st and 5^th metacarpophalangeal. Depending on the patient hand size, a 22-G¹¹ to 25-G blunt-tipped cannula may be used to evenly place the product in a radial distribution, which mirrors the direction of the hand’s tendons. Further, the blunt tip reduces risk of  puncture as the dorsal veins can be safely pushed aside.¹¹ CaHA mixed with lidocaine 1%¹⁰ or 2%⁹ (diluted 1:1 or 2:1) is recommended due to lower G’, η* and extrusion force of the material.^9,11 Numerous small aliquots are placed in the areolar plane between the subcutaneous tissue and superficial fascia. Administration of one syringe (0.5-1.5 mL of diluted Radiesse for a total injection volume between 1 and 2.25 mL) per hand per treatment session¹¹  reduces post-treatment edema and risk of nodularity, but up to 3 mL per session has been shown to be safe.⁹ Post-injection massage will help ensure even product distribution and smoothen the appearance of depressions, veins and extensor tendons.¹¹

Contraindications, Side effects and Complications

Despite its high safety profile, a few absolute contraindications include cutaneous infection, foreign bodies at the treatment site, systemic collagen diseases, pregnancy and breastfeeding. ⁹  Relative contraindications include history of keloidal scarring, bleeding disorder or current oral retinoid use. ⁹ Side effects of erythema, edema, pain, tenderness, induration and ecchymosis are mild, transient and self-resolving. Pain and tenderness can be treated with NSAIDs or acetaminophen and use of blunt-tipped cannulas are associated with reduced post-treatment pain, erythema, edema and ecchymosis.

Potential complications include surface irregularities (“lumps and bumps”), discoloration, vascular compromise and blindness. Acute nodules that develop within 48 hours are typically due to technical errors such as uncontrolled injection technique or high extrusion force (injecting a high viscosity filler through an inappropriately small needle or cannula).⁹ They are typically treated with an ice pack and massage to fragment the particulate filler and stimulate its phagocytosis.¹² Subacute nodules may develop weeks after implantation and are due to intradermal or intramuscular injection. Highly mobile areas such as lips and tear trough should be avoided due to high risk of nodularity. Resolution of nodules may take weeks to months, but intralesional fluid (lidocaine and saline) combined with massage, intralesional 5-fluoruracil, dexamethasone and triamcinolone, as well as ablative and non-ablative fractional lasers have been shown to completely resolve persistent non-inflammatory dermal nodules.⁹ Rarely, inflammatory nodules due to poor sterile technique may occur in over a year after CaHA implantation. It is extremely important that injectors not only have a comprehensive understanding of surface landmarks and vascular anatomy, but practice with a safe and efficacious technique. Safety may be increased with use of blunt-tipped cannulas to slowly deliver small volumes of filler. However, very small cannulas have greater risk of arterial penetration and should be avoided. Further, certain anatomic regions carry greater risk of vascular occlusion i.e., glabella region has been associated with local tissue necrosis, embolization and blindness (retrograde embolization of CaHA and occlusion of ophthalmic and central retinal arteries). Aspiration prior to injection may reveal intravascular placement.

The management of vascular compromise with CaHA is more complicated than hyaluronic acid fillers as hyaluronidase is not effective in reversing the occlusion. General management consists of restoring blood flow (325 mg aspirin po, 50 mg sildenafil, 2% nitroglycerin paste) and increasing oxygen content (hyperbaric oxygen) to the affected area while decreasing pressure in the anatomic compartment (corticosteroid taper, hyaluronidase, warm compress).^12,13 However, a potential solution for the lack of a reversal agent is the use of intralesionally injected sodium thiosulfate (STS)¹⁴ as it is a known chelating agent for the treatment of calciphylaxis and calcinosis cutis. STS acts as a dispersion agent and creates a dilution effect, thereby effectively reducing CaHA volume. ¹⁴

Post-procedure care

On the first day post-treatment, an external ice pack should be gently applied to the treated area 15 minutes three times per day. The treated areas should not be massaged. Patients may take acetaminophen for mild tenderness and discomfort. Moderate edema, erythema and ecchymosis typically resolve in 7 days. Patients must avoid UV exposure until edema/erythema subside and regularly apply broad spectrum SPF. Strenuous exercise should be avoided for 24 hours in order to reduce bruising. Patients should avoid dental work for two weeks after treatment in order to avoid potential infections or irregularities. Patients are instructed to monitor and immediately notify staff of emergent symptoms i.e., extreme pain, blanching or marked bruising of the area, headache, constitutional symptoms or visual disturbances.

Conclusion

The practice of soft-tissue augmentation has progressed from the use of paraffin to permanent fillers. Since 2000, tissue filler procedures have increased 298%⁴ as there is more demand for non-invasive methods to treat the aging face. The current fillers are safe, biocompatible, relatively long lasting and predictable in their outcome. However, CaHA remains a staple as it is one of the most well-studied dermal fillers worldwide and because of its high safety profile, efficacy, longevity and ability for neocollagenesis. Complications include minor surface irregularities, discolorations, vascular compromise and blindness. Nonetheless, strong knowledge of surface landmarks and soft tissue and vascular anatomy coupled with a refined and safe strategy is pivotal in the safety and outcome of any soft-tissue augmentation. Additionally, the use of sodium thiosulfate as a CaHA reversal agent is a potential solution for the reduction of CaHA volume which may be useful for overcorrection, product misplacement and nodule reduction.¹⁴

References

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