A review of nonsurgical facial rejuvenation and the role of oxymetazoline hydrochloride ophthalmic solution, 0.1% in periorbital revitalization

The demand for nonsurgical facial rejuvenation options is growing, yet the periorbital region remains an area of relative unmet need. This review explores nonsurgical options for facial rejuvenation and the role of oxymetazoline hydrochloride ophthalmic solution, 0.1%, in treating age‐related blepharoptosis as part of periorbital rejuvenation.


| INTRODUC TI ON
Facial rejuvenation encompasses a variety of treatments that share the common aim of restoring a youthful appearance to the face.The eyes are typically a central feature to consider in the aging face.
These treatments can be surgical, such as facelifts and brow lifts, minimally invasive, such as dermal fillers and botulinum toxin injections, or noninvasive, such as skin resurfacing and oxymetazoline hydrochloride ophthalmic solution, 0.1%.
Aging is a complex process influenced by various factors, including genetics, lifestyle, and environmental variables.Intrinsic aging involves a decrease in the proliferation of cutaneous cells, particularly in the basal cell layer, which compromises the nutrient supply to the epidermis causing a further reduction in cell proliferation and thinning of the epidermis.Intrinsic aging also involves a reduction in components of the extracellular matrix, namely collagen, which provides tensile strength, elastin which maintains skin elasticity; and proteoglycans which provide hydration. 1Environmental factors such as sun exposure and pollution accelerate aging.Ultraviolet radiation damages the skin's collagen and elastin fibers leading to premature wrinkles, sagging skin, and age spots, which are particularly distressing in the facial area.Poor diet, chronic sleep deprivation, smoking, and other lifestyle factors contribute to premature aging.The skin loses elasticity and develops irregular pigmentation, soft tissues atrophy, bone reabsorption takes place, and fat is redistributed, all factors which affect the contour and general appearance of the face. 1,2gns of facial aging include glabellar lines, horizontal forehead creases, temporal and brow hollowing, crow's feet, volume loss and drooping of periorbital tissue, deepening of nasolabial folds, preauricular fat atrophy, vertical lip lines, and jaw irregularity. 2Ptosis of the eyelids is often a cardinal feature of an aged appearance.The features of an aging face are similar to the facial expression of negative emotions such as sadness, discontent, and anger. 3The face is the most invoked area of the body for self-perception and perception by others. 4Therefore, the impetus to appear young, healthy, and attractive extends beyond personal preferences to include the basic human need for connection.
All rejuvenation procedures, whether surgical, minimally invasive, or noninvasive, carry some risk of complications.Surgery can achieve impressive and long-lasting results and is the gold standard for facial rejuvenation; however, it is accompanied by a higher risk of side effects such as scarring, infection, and nerve damage, and unsatisfactory results need more surgical intervention to correct. 2,5nimally invasive and noninvasive facial rejuvenation procedures are increasingly used because of the lower risks, faster recovery time, and natural-appearing results. 2 A recent addition to the noninvasive options is oxymetazoline hydrochloride ophthalmic solution, 0.1%, to improve appearance and function for people with ptosis, both those who qualify for surgery and those who do not.This review aims to provide an overview of nonsurgical options for facial rejuvenation and discuss the role of oxymetazoline hydrochloride ophthalmic solution, 0.1%, in treating patients with periorbital concerns.

| Minimally invasive procedures for facial rejuvenation
The goals of nonsurgical facial rejuvenation include eliminating forehead wrinkles and eyebrow furrows, filling in under-eye hollows, restoring cheek volume, softening nasolabial folds, erasing smoker's lines, smoothing scarring, and plumping thinning lips.Several nonsurgical antiaging treatments have emerged to address these signs of aging in recent years.Minimally invasive and noninvasive procedures for facial rejuvenation include cosmetic neuromodulators, dermal fillers, and aestheticians' services such as laser treatments, chemical peels, and microdermabrasion (Table 1). 2

| Neuromodulators
Botulinum toxin is one of the most frequently used minimally invasive forms of facial rejuvenation.When injected locally, botulinum toxin type A binds to presynaptic nerve terminals, where it is internalized and undergoes activation by a host-specific protease.The activated toxin prevents muscle contraction by cleaving SNARE proteins essential for transmitting acetylcholine across the neuromuscular junction.With acetylcholine blocked, the affected muscles relax and become paralyzed.The resulting reduction in muscle activity causes a decrease in wrinkles.The effects typically last for 2 to 6 months, after which the nerve terminals regenerate the necessary SNARE proteins, and muscle function returns to baseline. 6,7imary targets for botulinum toxin in the upper face include the forehead and glabellar lines, periorbital lines, or crow's feet. 2 Side effects and complications are often due to overtreatment or the migration of the drug to unwanted areas and include asymmetry, impaired eyelid function, and the unmasking of preexisting ptosis. 8tulinum toxin is contraindicated in pregnancy and patients with neuromuscular disease.It is often combined with other minimally invasive facial rejuvenation forms, such as dermal fillers, for more comprehensive results. 2

| Dermal fillers
Dermal fillers are injectable materials that can improve the appearance of wrinkles, restore volume, and enhance the contours of the face to address signs of aging.The most frequently used fillers are hyaluronic acid, calcium hydroxylapatite, poly-L-lactic acid, and collagen. 2

Hyaluronic acid
Hyaluronic acid, a naturally occurring hydrophilic glycosaminoglycan, is used to replace age-associated volume loss, improve the appearance of wrinkles and scars, and correct asymmetry.Target areas include the temporal and orbital regions, the cheeks, and around the mouth.It is available in animal-or bacteria-derived formulations, which carry such a low risk of allergic reactions that allergy testing is unnecessary.Post-procedural edema can last for 3 to 5 days.Hyaluronic acid injections are generally safe in the hands of an expert practitioner.Side effects usually result from improper technique and can include local ischemia, gangrene, vascular embolism, nerve damage, bruising, erythema, and activation of herpes virus.It is contraindicated in patients with allergies to the ingredients and sites of infection. 2It is also contraindicated in patients undergoing rhinoplasty since they have an increased risk of skin necrosis due to post-operative vascular changes. 9Hyaluronic acid fillers' effects last 3 months to a year.There have been reports of delayed infections due to retained filler material. 10

Calcium hydroxylapatite
Calcium hydroxylapatite (CaHA) is a mineral that occurs naturally in human bone and teeth. 2 As a dermal filler, it is injected in microspheres carried in a suspension of aqueous carboxymethyl cellulose gel.The gel carrier provides instant volume replacement, and the CaHA provides a structure that activates fibroblasts, which induces collagen synthesis approximately 4 weeks after the procedure. 11This results in a greater modulus of elasticity than with hyaluronic acid. 2 The facial rejuvenation effects can last for 1 to 2 years; at this point, the CaHA is broken down into calcium and phosphate ions and reabsorbed.CaHA can correct the concavity of the forehead and temporal region in the upper face, smooth wrinkles, and lift the brow.Complications include nodule formation and accidental injection into a vessel which can cause embolization and necrosis or scarring.The use of proper techniques substantially reduces these risks.Common side effects include erythema, edema, bruising, and pruritis for the first 2 weeks following the procedure. 11CaHA is contraindicated in inflamed sites. 2

Poly-L-Lactic acid
Poly-L-lactic acid (PLLA) is a synthetic, biocompatible polymer used in absorbable suture material and was first used as a facial filler for patients with HIV-related lipodystrophy.Like CaHA, it stimulates collagen synthesis.PLLA microparticles are injected in a hydrocolloidal suspension and cause an immediate subclinical inflammatory response involving the local proliferation of fibroblasts and deposition of collagen type I in the extracellular matrix.As the inflammatory response subsides over about 6 months, PLLA microparticles are degraded by the same metabolic pathway as lactic acid (about 9 months), while collagen accumulates over 8 months to 2 years. 12Possible side effects include erythema, edema, ecchymosis, pain, surface irregularities, granuloma, scabbing, and peeling.One of the drawbacks of PLLA is that it can require multiple treatments to avoid overcorrection since dermal thickening is slow and progressive.Patients must also avoid direct sunlight for 2 weeks post-procedure.PLLA is contraindicated in patients with a collagen allergy, some autoimmune diseases, scar hyperplasia, coagulation disorders, and during pregnancy and lactation.

Polymethyl methacrylate
Polymethyl methacrylate (PMMA) is a semi-permanent filler with a good safety profile.It is a biocompatible synthetic polymer that is used in bone cement and cranial plates.

| Laser therapy
Four types of laser therapy are used depending on the concerns being addressed. 15Non-fractionated ablative lasers are the most aggressive; they vaporize the epidermis and papillary dermis, stimulating collagen synthesis and tissue remodeling as the area is re-epithelialized. 15,16Ablative therapy is highly effective but has a prolonged recovery period of 1 to 2 weeks and is accompanied by scarring, infection, and hypo-or hyperpigmentation risks. 17It produces the most dramatic results of all forms of laser therapy and is used for wrinkles, acne scars, and atrophic scars and for correcting sun-damaged skin.The main risk of non-fractionated ablative laser therapy is hypopigmentation and occasionally hyperpigmentation, which is a consideration for patients of color. 16n-ablative lasers heat the dermis, avoiding the epidermis, and denature dermal proteins to stimulate collagen regeneration. 15Thermolysis of the dermis can help with wrinkle reduction, skin tightening, irregular pigmentation, and telangiectasias.Side effects include scarring, persistent edema, and changes in pigmentation. 18They are used for mild scarring, wrinkles, and dyspigmentation.Unlike ablative laser therapy, non-ablative lasers do not cause pigmentation changes.Recovery times are shorter, but serial treatments are often required to achieve the desired effect. 16actionation can be applied to ablative or non-ablative lasers and involves narrow columns of light to more accurately target a treatment zone, increase control and lower the risk of scarring, changes in pigmentation, and persistent erythema. 18Fractionation can create microthermal treatment zones rather than affecting a large area.Ablative fractionated laser therapy creates the same effects as non-fractionated, but the side effects are somewhat mitigated, although more treatments may be required to achieve the desired results. 16

| Microdermabrasion
Microdermabrasion is used to treat signs of photoaging, such as wrinkles and pigmentation abnormalities, acne, acne scars, and striae distensae.Inert crystals are accelerated over the skin, causing a mechanical erosion of the upper layer of the epidermis.This process is thought to provoke a temporary inflammatory response in the dermis and epidermis, stimulate dermal collagen production, and produce changes in the dermal matrix's constituents, which can smooth fine scars and wrinkles.Side effects include pain and erythema; multiple sessions may be needed to achieve acceptable results.

| Periorbital rejuvenation
The periorbital region is a predominant concern for people seeking facial rejuvenation.Some of the earliest signs of aging occur in the periorbital area and can be the most troublesome. 4This is evidenced by the fact that blepharoplasty is the most frequent cosmetic surgical procedure performed in the United States in people over 40. 19The attractiveness of the eyes is strongly correlated with the individual's perceived age.1][22] An unpublished online survey (N = 10 000) in 2021 reported that even those with "normal" eyelids were bothered by their lid position.Upper eyelids that drooped were more troublesome.
Blepharoptosis, or ptosis, is unilateral or bilateral drooping of the upper eyelid with the eye in primary gaze (Figure 2).The abnormal development of upper eyelid retractor muscles or nerves causes congenital blepharoptosis.Acquired blepharoptosis is typically caused by age-related weakening of the muscles (aponeurotic ptosis), but can also be caused by neurological disorders, injury, some drugs, complications of botulinum toxin injection, side effects of ocular surgery, and the long-term use of contact lenses. 23,24As well as being cosmetically undesirable, blepharoptosis can cause functional impairment as even mild ptosis can obstruct the pupil and cause superior visual field deficits. 23Both functional and cosmetic concerns are associated with increased levels of depression and anxiety and decreased health-related quality-of-life (HRQoL) measures. 25epharoptosis can be confused with, or masked by, brow pto- The incidence of ptosis is estimated to be between 4.7% and 13.5% in the adult population and becomes increasingly prevalent with age. 25Up to 60% of adult women in the United States selfidentify with ptosis.Many patients do not discuss their concerns with their clinicians until they become functionally impaired and are referred to surgery. 25om an anatomical standpoint, upper eyelid elevation is provided by the levator palpebrae superioris, a skeletal muscle that attaches to the superior tarsal plate, and the superior tarsal muscle (or Müller's muscle), a smooth muscle that originates from the levator muscle and inserts on the superior tarsal plate maintaining elevation and adding 2 to 3 mm of lift. 23,27Aponeurotic ptosis involves the stretching or dehiscence of the levator muscle complex. 25rrective surgery is usually performed on Müller's muscle.Since it contains adrenergic receptors, Müller's muscle is also an attractive target for pharmacological intervention.0.5%).Mild instillation site pain was experienced by 2.1% of the participants receiving the active drug. 27Alpha-adrenergic receptors are expressed in the aqueous outflow tract, the conjunctiva, the iris, and the ciliary body, which could account for these findings. 27,28There were no clinically significant changes in heart rate, blood pressure, visual acuity (Snellen VA), intraocular pressure, pupil diameter, or corneal fluorescein staining (Figure 5). 25 Patients with a larger lid platform had a more noticeable response with oxymetazoline hydrochloride ophthalmic solution, 0.1% than patients with a small lid platform.Tachyphylaxis and rebound effects are common with the chronic use of drugs targeting α-adrenergic receptors and occur with oxymetazoline 0.05% nasal spray; however, no tachyphylaxis or rebound effects were observed with oxymetazoline hydrochloride ophthalmic solution, 0.1% in any of the studies, including the 84-day safety study. 27Although there are no contraindications, some dermatologists will refer their patients with glaucoma to an ophthalmologist prior to initiating therapy.

| DISCUSS ION
The demand for cosmetic procedures sharply increased during the pandemic and continues to rise.A survey conducted by the American Society of Plastic Surgeons in 2022 found that the desire to correct aging caused by the stress of the pandemic, the ease of scheduling and aesthetics, and the position of injectables and fillers must be patient-specific.Gender differences must also be considered, as men typically request more subtle and conservative treatments than women. 31A literature review regarding the composition of male and female skin found that skin thickness, hydration, transepidermal water loss, microcirculation, sebum, and pigmentation are greater in men compared to women, while skin pH is higher for women in general. 32The longevity of the results is another consideration.Invasive surgical procedures generally produce results that last a long time, while most minimally invasive and noninvasive facial rejuvenation treatments are temporary and require maintenance or touch-ups to sustain their effects.However, the longevity of results varies depending on factors such as the patient's age, skin quality, and lifestyle habits. 2 In addition to alteration in the skin, eyelid appearance, and especially eyelid ptosis, is central for consideration of the aging face.Decreased eyelid opening is recognized as a sign of aging but can be reversed in a noninvasive fashion.Oxymetazoline hydrochloride ophthalmic solution, 0.1%, can be used as the daily administration can be continued consistently or stopped and used as needed to correct blepharoptosis.As the demand for safe and effective options for facial rejuvenation continues to rise, the trend toward noninvasive facial rejuvenation will likely continue to grow.
Advisors experienced in facial rejuvenation met to discuss existing literature on the upper face and periorbital rejuvenation, focusing on minimally invasive procedures, including facial injections, dermal fillers, and other methods.They discussed the role of oxymetazoline hydrochloride ophthalmic solution, 0.1%, in treating facial aging.The current literature was reviewed in the context of the authors' expertise and clinical experience.

14 2 3. 2 |
As a dermal filler, it is injected in the form of microspheres mixed with collagen.The collagen is absorbed within 1 to 3 months, and the microspheres remain, providing a semi-permanent or permanent scaffold for the host's connective tissue.It improves acne scarring and deep wrinkles, including forehead lines.Immediate side effects can include temporary edema and bruising in patients who have consumed alcohol or taken antiplatelet drugs or NSAIDS.Complications can include beading around the eyes and forming granulomas that must be removed surgically.If infection occurs, it is usually due to overtreatment and the resultant compression of local vasculature.Since it is long-lasting, delayed foreign body reactions can occur, and the material can eventually migrate, leading to nodule formation or sclerosis.Noninvasive procedures for facial rejuvenation: skin resurfacing The three main methods for skin resurfacing include laser therapy, microdermabrasion, and chemical peels.All three are designed to promote cell turnover and collagen production.

3. 2 . 3 |
photoaging such as roughness, keratoses, solar lentigines, melasma, post-inflammatory dyspigmentation, and scarring.Side effects include transient or persistent erythema, edema, pigmentary changes, infection (in particular, herpes infection), and scarring.The depth of the peel positively correlates with the degree of efficacy, the severity of side effects, and the length of healing time.Superficial peels may require multiple treatments.16

26 F I G U R E 1
sis.Brow ptosis can also occur due to age-related changes such as decreased skin elasticity and weakening of the frontalis muscle and can also cause impairment of the superior visual field.In some cases, surgical brow ptosis repair will correct the problem; in others, it can reveal an underlying blepharoptosis.Ptosis of the upper eyelid.Adapted with permission from Finsterer J. Ptosis: causes, presentation, and management.Aesthetic Plast Surg.2003;27 (3):193-204.Doi: 10.1007/s00266-003-0127-5.

F I G U R E 4 23 F I G U R E 5
Oxymetazoline significantly increased upper eyelid lift in two clinical studies.Pooled data from two 6-week, randomized, double-masked, placebo-controlled clinical trials; p < 0.0001 versus vehicle, from an ANCOVA model with study and treatment as fixed factors and baseline score as a covariate.Patients with congenital ptosis, Horner syndrome, myasthenia gravis, mechanical ptosis, pseudoptosis or substantial dermatochalasis (redundant eyelid skin occurring within 3 mm of the upper eyelid margin), or visual field loss from any cause other than ptosis were excluded from both trials.Oxymetazoline provided a rapid and sustained effect over 42 days.Data from 6-week, randomized, double-masked, placebocontrolled clinical trial (RVL-1201-202); p < 0.05 versus vehicle, from an ANCOVA model with treatment as a fixed factor and baseline score as a covariate. 25Mean (SD) change from baseline in MRD-1 (mm).recoverytime while working from home, and the "zoom effect" of increased awareness of facial appearance are all contributing factors to this growth in demand.29In 2021, facial procedures increased by 55%, with dermal fillers and botulinum toxin injections accounting for 65% of nonsurgical interventions.30The primary goal of facial rejuvenation is to restore a youthful appearance while preserving natural facial movements and maintaining or improving function.Current challenges in facial rejuvenation include addressing the signs of aging comprehensively, minimizing side effects and complications, addressing ethnic and gender differences, and balancing the procedure's invasiveness with the results' longevity.Age is a multifactorial process; correcting one area but neglecting others can result in an undesirable outcome.Facial rejuvenation can comprehensively address the signs of aging by using nonsurgical techniques or combining surgical and nonsurgical techniques.Periorbital rejuvenation focuses on the signs of aging of the eyelids.Botulinum toxin is often combined with dermal fillers; for instance, oxymetazoline can be used with other corrective measures. 2Clinician technique and expertise are essential for minimizing the risk of complications such as the migration of filler material, embolization, and distant necrosis, or the overtreatment or under-treatment of an area causing an unnatural appearance.Too much botulinum toxin or dermal filler, for example, can result in asymmetry or a frozen appearance.Facial rejuvenation treatments must account for the unique characteristics of different ethnicities and genders.Classical ideals of beauty in the Western hemisphere mainly derive from a White aesthetic, but this approach does not serve our increasingly diverse population.Patients of African, Asian, and Hispanic descent have different goals, skin parameters, Minimally invasive and noninvasive procedures for facial rejuvenation.
2,13 L E 1Suborbital and supranasal areas are at higher risk of intravascular injections, overcorrection, and nodule formation.2CollagenWhenusedasadermalfiller, human, porcine, or bovine collagen can restore skin structure, strength, and elasticity.Human-derived collagen can be bioengineered, cadaveric, or autologous.Porcine collagen is not used in the United States.Collagen dermal fillers act in two ways: They replace lost collagen and stimulate new collagen growth as capillaries migrate into the injected area, bringing oxygen and nutrients to stimulate the host's fibroblasts.After 1 to 2 weeks, injected collagen mixes with that of the host, and the skin becomes smoother and more natural in feel and appearance.As a filler, collagen produces less edema than other materials, rarely diffuses or embolizes, and is safe in the periorbital area.Collagen fillers work well for superficial wrinkles, scars, and crow's feet but are less effective for deeper wrinkles such as forehead lines.Drawbacks include a short duration of effect of only 3 to 6 months and the need for serial treatments to stimulate fibroblasts to produce new collagen.It is contraindicated in patients with a collagen allergy, and human collagen is contraindicated in patients with a gentamycin allergy.One option for patients with allergies is autologous collagen which has a low risk of hypersensitivity but is costly and has uncertain long-term efficacy.Sensitivity testing is essential before porcine or bovine collagen treatment since hypersensitivity to those materials is difficult to treat as collagen filler cannot be removed.Other rare complications and side effects include overtreatment, irregularities, sclerosis, bruising, infection, and reactivation of herpes virus.2AutologousfatAnautologousfat transplant has the advantage of being a biocompatible filler that can be removed if necessary.Fat is harvested from areas with a high concentration of stromal vascular cells, such as the inner thigh or the lower abdomen.Because fat can cause inflammation, it must be processed before use.This can be done by filtration, centrifuge, or gravity separation.Once processed, it must be placed near a blood supply to improve the viability of the graft.In the upper face, autologous fat grafting is effective for facial contouring and eliminating scars, wrinkles, and other age-related changes.Possible side effects and complications include transient erythema, asymmetry, and fat necrosis.2,13