Calcium Hydroxyapatite Filler With Integral Lidocaine CaHA (+) for Soft Tissue Augmentation: Results from an Open-Label Multicenter Clinical Study.

BACKGROUND: Soft tissue augmentation with calcium hydroxylapatite (CaHA) is a versatile technique for line filling, skin tightening, lifting, contouring, and volumizing. The present study was designed to confirm safety and effectiveness of the product with lidocaine (CaHA (+)) in a holistic treatment of nasolabial folds (NLFs), marionette lines, and/or cheeks. METHODS: A total of 207 subjects with moderate to severe facial volume deficit were treated with CaHA(+) in this open-label study. Effectiveness assessments included Merz Aesthetics Scales® (MAS), investigator- and subject-assessed Global Aesthetic Improvement Scales (iGAIS/sGAIS), and FACE-QTM questionnaires. Responder rates were defined as at least one-point improvement on MAS according to blinded rating. Safety was assessed through adverse event reporting. RESULTS: Primary endpoint was evaluated 12 weeks after last injection. Responder rates were 93.6%, 88.7%, and 81.9% in the NLFs, marionette lines, and cheeks, respectively, and were statistically significant above the pre-defined 60% threshold (P< 0.0001). Investigator- and subject-assessed GAIS were consistent and showed high rates of improvement throughout the study, with peak values of 98.0% at week 4 on iGAIS and 93.5% at 12 weeks after last injection on sGAIS. After 18 months, the majority of subjects (52.5%) still perceived improvement via sGAIS. Moreover, total FACE-Q scores demonstrated high subject satisfaction with treatment. All related treatment emergent adverse events were transient and expected injection-site reactions mostly of mild to moderate intensity. CONCLUSION: CaHA (+) has demonstrated safety and effectiveness in the treatment of NLFs, marionette lines, and cheek volume loss in real-life conditions up to 18 months. J Drugs Dermatol. 2022;21(5):481-487. doi:10.36849/JDD.6737.

Managing intravascular complications following treatment with calcium hydroxylapatite: An expert consensus.

BACKGROUND: Inadvertent intra-arterial injection of dermal fillers including calcium hydroxylapatite (CaHA) can result in serious adverse events including soft tissue necrosis, permanent scarring, visual impairment, and blindness. When intra-arterial injection occurs, immediate action is required for optimal outcomes, but the infrequency of this event means that many physicians may never have experienced this scenario. The aim of this document is to provide evidence-based and expert opinion recommendations for the recognition and management of vascular compromise following inadvertent injection of CaHA. METHODS: An international group of experts with experience in injection of CaHA and management of vascular complications was convened to develop a consensus on the optimal management of vascular compromise following intra-arterial CaHA injection. The consensus members were asked to provide preventative advice for the avoidance of intravascular injection and to produce a treatment protocol for acute and delayed presentation. To ensure all relevant treatment options were included, the recommendations were supplemented with a PubMed search of the literature. RESULTS: For prevention of intra-arterial CaHA injection, consensus members outlined the importance of a thorough knowledge of facial vascular anatomy and patient history, as well as highlighting potential risk zones and optimal injection techniques. Individual sections document how to recognize the symptoms of vascular occlusion leading to vision loss and tissue necrosis as well as detailed treatment protocols for the management of these events. For impending tissue necrosis, recommendations are provided for early and delayed presentations with treatment protocols for acute and follow-up treatment. A separate section details the treatment options for open and closed wounds. CONCLUSIONS: All physicians should be prepared for the eventuality of intra-arterial injection of a dermal filler, despite its rarity. These consensus recommendations combine advice from aesthetic experts with the latest reports from the published literature to provide an up-to-date office-based protocol for the prevention and treatment of complications arising from intra-arterial CaHA injection.

Light Perception Vision Recovery After Treatment for Calcium Hydroxylapatite Cosmetic Filler-Induced Blindness.

A 51-year-old woman presented with no light perception vision of the right eye 12 hours after another provider injected calcium hydroxylapatite into the glabella and dorsum of the nose. Exam and fluorescein angiography demonstrated optic nerve edema and choroidal hypoperfusion consistent with ischemia of the posterior ciliary circulation. The central retinal circulation appeared intact. One thousand two hundred units of retrobulbar hyaluronidase were injected urgently in several boluses. Oral prednisone and aspirin also were administered. Ocular massage was also initiated. One day later, visual acuity improved to light perception that remained stable at 3 months. Retrobulbar hyaluronidase injection, ocular massage, prednisone, and aspirin were correlated to recovery of light perception vision in this case of calcium hydroxylapatite filler embolization to the choroidal circulation. The mechanism for the recovery of some vision and the role of hyaluronidase and other medications remain uncertain. Further research in treatments for ophthalmic complications of facial fillers is warranted.

Acute effects of calcium supplements on blood pressure and blood coagulation: secondary analysis of a randomised controlled trial in post-menopausal women.

Recent evidence suggests that Ca supplements increase the risk of cardiovascular events, but the mechanism(s) by which this occurs is uncertain. In a study primarily assessing the effects of various Ca supplements on blood Ca levels, we also investigated the effects of Ca supplements on blood pressure and their acute effects on blood coagulation. We randomised 100 post-menopausal women to 1 g/d of Ca or a placebo containing no Ca. Blood pressure was measured at baseline and every 2 h up to 8 h after their first dose and after 3 months of supplementation. Blood coagulation was measured by thromboelastography (TEG) in a subgroup of participants (n 40) up to 8 h only. Blood pressure declined over 8 h in both the groups, consistent with its normal diurnal rhythm. The reduction in systolic blood pressure was smaller in the Ca group compared with the control group by >5 mmHg between 2 and 6 h (P≤0·02), and the reduction in diastolic blood pressure was smaller at 2 h (between-groups difference 4·5 mmHg, P=0·004). Blood coagulability, assessed by TEG, increased from baseline over 8 h in the calcium citrate and control groups. At 4 h, the increase in the coagulation index was greater in the calcium citrate group compared with the control group (P=0·03), which appeared to be due to a greater reduction in the time to clot initiation. These data suggest that Ca supplements may acutely influence blood pressure and blood coagulation. Further investigation of this possibility is required.

Inflammatory response to nano- and microstructured hydroxyapatite.

The proliferation and activation of leukocytes upon contact with a biomaterial play a crucial role in the degree of inflammatory response, which may then determine the clinical failure or success of an implanted biomaterial. The aim of this study was to evaluate whether nano- and microstructured biomimetic hydroxyapatite substrates can influence the growth and activation of macrophage-like cells. Hydroxyapatite substrates with different crystal morphologies consisting of an entangled network of plate-like and needle-like crystals were evaluated. Macrophage proliferation was evaluated on the material surface (direct contact) and also in extracts i.e. media modified by the material (indirect contact). Additionally, the effect of supplementing the extracts with calcium ions and/or proteins was investigated. Macrophage activation on the substrates was evaluated by quantifying the release of reactive oxygen species and by morphological observations. The results showed that differences in the substrate's microstructure play a major role in the activation of macrophages as there was a higher release of reactive oxygen species after culturing the macrophages on plate-like crystals substrates compared to the almost non-existent release on needle-like substrates. However, the difference in macrophage proliferation was ascribed to different ionic exchanges and protein adsorption/retention from the substrates rather than to the texture of materials.

Partial vision recovery after iatrogenic retinal artery occlusion.

BACKGROUND: To describe the first case of partial vision recovery in a 32-year-old woman with iatrogenic retinal artery occlusion (RAO) following glabella calcium hydroxylapatite (CaHA) injection, and to explore appropriate diagnostic and therapeutic measures according to a literature review. CASE PRESENTATION: A 32-year-old woman had left eye RAO and a bilateral visual field defect after CaHA injection into the glabella region. Topical and systemic intraocular pressure lowering agents, isovolemic hemodilution, globe massage, and anticoagulation with acetylsalicylic acid were prescribed. Carbogen inhalation and oral corticosteroids were also given. In addition to the above therapies, hyperbaric oxygen therapy (HBOT) was implemented as adjuvant treatment. The final best corrected visual acuity (BCVA) of the left eye improved from hand motion at 15 cm to 0.1. Improved retinal circulation and decreased retinal vessel leakage were found in the follow-up fluorescein angiography. However, there were still multiple emboli in the conjunctival and retinal arteries. CONCLUSION: This is the first case report on partial recovery of BCVA after iatrogenic RAO following cosmetic CaHA injection. Because no reliable treatments have been reported for such complications, HBOT may be considered as an alternative adjuvant therapy.

CERAMENT treatment of fracture defects (CERTiFy): protocol for a prospective, multicenter, randomized study investigating the use of CERAMENT™ BONE VOID FILLER in tibial plateau fractures.

BACKGROUND: Bone graft substitutes are widely used for reconstruction of posttraumatic bone defects. However, their clinical significance in comparison to autologous bone grafting, the gold-standard in reconstruction of larger bone defects, still remains under debate. This prospective, randomized, controlled clinical study investigates the differences in pain, quality of life, and cost of care in the treatment of tibia plateau fractures-associated bone defects using either autologous bone grafting or bioresorbable hydroxyapatite/calcium sulphate cement (CERAMENT™|BONE VOID FILLER (CBVF)). METHODS/DESIGN: CERTiFy (CERament™ Treatment of Fracture defects) is a prospective, multicenter, controlled, randomized trial. We plan to enroll 136 patients with fresh traumatic depression fractures of the proximal tibia (types AO 41-B2 and AO 41-B3) in 13 participating centers in Germany. Patients will be randomized to receive either autologous iliac crest bone graft or CBVF after reduction and osteosynthesis of the fracture to reconstruct the subchondral bone defect and prevent the subsidence of the articular surface. The primary outcome is the SF-12 Physical Component Summary at week 26. The co-primary endpoint is the pain level 26 weeks after surgery measured by a visual analog scale. The SF-12 Mental Component Summary after 26 weeks and costs of care will serve as key secondary endpoints. The study is designed to show non-inferiority of the CBVF treatment to the autologous iliac crest bone graft with respect to the physical component of quality of life. The pain level at 26 weeks after surgery is expected to be lower in the CERAMENT bone void filler treatment group. DISCUSSION: CERTiFy is the first randomized multicenter clinical trial designed to compare quality of life, pain, and cost of care in the use of the CBVF and the autologous iliac crest bone graft in the treatment of tibia plateau fractures. The results are expected to influence future treatment recommendations. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT01828905.

Aesthetic applications of calcium hydroxylapatite volumizing filler: an evidence-based review and discussion of current concepts: (part 1 of 2).

BACKGROUND: Calcium hydroxylapatite filler (CaHA; Radiesse) is a synthetic, non-animal derived product composed of minerals that occur naturally in bone and teeth. Following its development in the US, initial approval by the US FDA for non-aesthetic indications and CE marking in Europe, it was used off FDA-labeling for aesthetic purposes. Its use has grown further since its FDA approval in 2006 for long-lasting correction of moderate to severe wrinkles and folds. It is a popular filler for volume restoration to the face, and also to nonfacial areas such as the dorsum of the hands. METHODS: The first article of this two-part series provides an evidence-based review of study data pertaining to the mechanism of action and biocompatibility of CaHA filler, and its safety, efficacy and tolerability when used for aesthetic purposes. The review includes data from a number of prospective, controlled comparative studies, from several retrospective studies, and from a meta-analysis of reported complications from alloplastic filler procedures over a 20-year period. The study methodology and number of study subjects are sufficiently robust to provide a high Evidence Level for much of the data. RESULTS: CaHA has good safety, efficacy and tolerability profiles that are comparable to those of hyaluronic acid (HA) fillers. It provides an initial, immediate volume replacement for up to 12 months followed by longer term correction due to biostimulation, resulting in collagenesis. Evidence Level II studies show longevity of 30 months or more after nasolabial fold implantation. Other studies demonstrate the appropriateness of CaHA filler for volume restoration to areas including the mid face, lower face and hands. CaHA is classified as an adjustable filler, whereas HA is fully reversible by hyaluronidase digestion. For this reason, and also because of CaHA's high viscosity and elasticity, evidence-based and experiential consensus suggests its avoidance in highly mobile areas (e.g. lips) or in anatomically unforgiving areas (e.g. the periocular region), where there may be increased incidence of nodules. CONCLUSION: CaHA filler is safe, efficacious and well-tolerated when used appropriately. It is increasingly recognized that many patients require pan-facial volume restoration, and that many can benefit from combined treatments. Therefore, CaHA and HA fillers may be considered complementary rather than competitive to each other. The second article of this series offers a discussion of product characteristics, scientific principles and injection techniques to optimize treatment with CaHA filler, including special considerations for avoidance and management of complications.

Calcium hydroxylapatite nodule resolution after fractional carbon dioxide laser therapy.

BACKGROUND: Injection of calcium hydroxylapatite filler may result in nodule formation owing to superficial placement of the filler. Calcium hydroxylapatite nodules are difficult to reverse. Previously reported therapeutic options are limited and include intralesional triamcinolone, massage, needling, and excision, each with inconsistent results or potential for scarring. OBSERVATION: We have observed complete resolution of calcium hydroxylapatite nodules after a single treatment with fractional carbon dioxide laser. CONCLUSIONS: A single session of fractional carbon dioxide laser treatment may resolve selected cases of calcium hydroxylapatite nodules. The mechanism of action may involve conversion of the product into tricalcium phosphates which dissolve readily. This novel therapeutic technique may enhance treatment options for a difficult clinical problem.

A systematic review of dermal fillers for age-related lines and wrinkles.

BACKGROUND: Dermal fillers are gaining popularity for rapid aesthetic improvement. Long-term efficacy and safety have not been well documented. The aim of this systematic review was to assess the safety and efficacy of injectable dermal fillers compared with other facial augmentation techniques for the management of age-related lines and wrinkles. METHODS: Studies including patients receiving injectable semi-permanent or permanent dermal fillers for age-related lines and wrinkles were included in this review. Efficacy outcomes (including changes in skin thickness and patient satisfaction) and safety outcomes (including mortality, lumps and infections) were examined. RESULTS: Three randomized control trials and six case series were included. Permanent and semi-permanent dermal fillers improved subjective ratings of appearance and resulted in higher patient satisfaction than temporary fillers. Long-term efficacy appeared good in the few studies that reported it. Short-term safety appeared favourable. Lumps were reported in all but one study but received little follow-up. Long-term safety data were limited. CONCLUSIONS: The treatment of age-related lines and wrinkles with permanent and semi-permanent dermal fillers is more efficacious compared with temporary fillers in those studies that compared them. Case series evidence suggests that these fillers achieve their objective, which is to decrease the visible effects of age-related changes. These fillers appear at least as safe as temporary fillers in the short term in those studies that compared them. Long-term safety could not be determined.

Femur bone repair in ovariectomized rats under the local action of alendronate, hydroxyapatite and the association of alendronate and hydroxyapatite.

Summary An evaluation was made of the local action of alendronate sodium (A), hydroxyapatite (HA) and the association of both substances (A + HA), in different molar concentrations, on the femur bone repair of ovariectomized rats. Ninety-eight animals were divided into seven groups: control (C), starch (S), alendronate 1 mol (A1), alendronate 2 mols (A2), hydroxyapatite 1 mol (HA1), hydroxyapatite 2 mols (HA2) and the association of alendronate + hydroxyapatite (A + HA). Rats weighing about 250 g were ovariectomized and 2.5-mm diameter bone defects were made on the left femur 30 days later. Each experimental group had defects filled with appropriate material, except for group C (control). The animals were killed 7 and 21 days after surgery. Histological, histomorphometric and statistical analyses of bone neoformation in the bone defect site were performed. From the histological standpoint, the major differences occurred after 21 days. All specimens in groups C, S, HA1 and HA2 presented linear closure of the bone defect, and most animals in groups A1, A2 and A + HA showed no bone neoformation in the central area of the defect. No statistically significant difference was found among the experimental groups after 7 days; after 21 days, group HA2 presented the highest amount of neoformed bone. There was no significant difference among groups A1, A2 and A + HA in the two study periods. It was concluded that alendronate, either isolated or in association with hydroxyapatite, had an adverse effect on bone repair in this experimental model. Moreover, the hydroxyapatite used here proved to be biocompatible and osteoconductive, with group HA2 showing the best results.

Successful transpedicular lumbar interbody fusion by means of a composite of osteogenic protein-1 (rhBMP-7) and hydroxyapatite carrier: a comparison with autograft and hydroxyapatite in the sheep spine.

STUDY DESIGN: Transpedicular lumbar interbody fusion (TLIF) was performed in a sheep model comparing three treatment groups: a composite of osteogenic protein (OP)-1 and hydroxyapatite carrier (HA), HA without OP-1, and autograft. OBJECTIVE: To evaluate the efficacy of the composite of OP-1 and HA (HA-OP-1) in achieving reliable TLIF. SUMMARY OF BACKGROUND DATA: Anterior fusion techniques directly address disc-related problems and achieve primary axial stability. However, they are characterized by high morbidity. Alternatively, the theoretically advantageous posterior TLIF technique using autograft fails clinically because it lacks compressive stability. METHODS: In 36 sheep, lumbar vertebrae L4 to L6 were instrumented posteriorly. Endoscopically assisted TLIF of L4 to L5 was performed. In 12 sheep, the defect was filled with injectable HA-OP-1. Another 12 sheep were treated with HA and another 12 with autograft. Animals were killed at 8 weeks and evaluated by radiologic, histologic, and histomorphometric analysis and by fluorochrome labeling. RESULTS: Only 10 autograft sheep were available for evaluation. Radiologically and histologically, TLIF with HA-OP-1 led to a fusion rate of 10 in 12 compared with autograft (one in 10 fused) and HA (two in 12 fused) ( = 0.0016). Semiquantitative radiologic and histologic scoring also revealed significant differences with superiority of HA-OP-1 ( = 0.0011). Compared with HA, HA-OP-1 presented significantly more ossification at the bone-cement interface ( = 0.0003) and less cement resorption ( = 0.0209). In four of 12 HA sheep, excessive resorption was responsible for local aseptic inflammation. CONCLUSIONS: Biointegration of the osteoconductive HA does not occur, because shear forces cause early HA fracture, subsequent fragmentation, and gross resorption (initiating severe inflammation in four of 12 sheep). In contrast, osteoinductive effects of HA-OP-1 enable bio-integration, resulting in full osseous composite sheathing and solid fusion. By use of this composite, TLIF is successfully applied in sheep. Harvesting autograft and the anterior approach are avoided.

Severe osteolysis after third-body wear due to hydroxyapatite particles from acetabular cup coating.

One concern about the fixation of HA-coated implants is the possible disintegration of the surface, with the migration of HA granules into the joint space, producing third-body wear. We report a study of six revisions of HA-coated polyethylene RM cups at 9 to 14 years after successful primary arthroplasty. In all six hips, we found HA granules embedded in the articulating surface of the polyethylene, with abrasive wear of the cup and the metal femoral head. The cup had loosened in four hips and three showed severe osteolysis of the proximal femur. Third-body wear due to HA particles from implant coating may produce severe clinical problems with few early warning signs. Further clinical, radiological and histological observations are needed to determine the possible incidence of this late complication in the various types of coating of a variety of substrates.

Osteoblast reaction at the interface between surface-active materials and bone in vivo: a study using in situ hybridization.

Osteoblast activation after implantation of two kinds of surface-active material in bone was investigated chronologically using in situ hybridization with digoxygenin-labeled procollagen alpha 1(I) complementary RNA probe. The bioactive materials used were hydroxyapatite (HA) and apatite- and wollastonite-containing glass-ceramic (A-W GC). A hole was drilled bilaterally in the distal epiphysis of rabbit femurs with subsequent implantation of HA or A-W GC cylinders in a press-fit manner. Specimens were collected at 3, 7, 14, and 28 days after operation and decalcified. Then the undecalcified implant cores were pushed out of the hole without causing damage to the bony side of the interface. In situ hybridization documented no qualitative differences in the expression of procollagen alpha 1(I) RNA between HA and A-W GC. Few osteoblasts at the bone-material interface showed a specific signal at day 3, whereas many osteoblasts were positive around the materials at days 7 and 14, indicative of active new bone formation. The positive osteoblasts seemed to originate from preexisting trabeculae and lined the trabeculae, newly formed bone, and material surface. At day 28, many osteoblasts lining material-surrounding bone were negative, whereas those in remodeling canals were positive, suggesting that the bone was in the remodeling stage after bone formation. These findings were comparable to those with beta-tricalcium phosphate in a previous study, thus suggesting osteoconductive bone formation on HA and A-W GC.