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Biochemistry: A Comprehensive Review

  1. A Comprehensive Review on Eryptosis
  2. 3rd Edition
  3. Publication details
  4. Biochemistry of Foods - 3rd Edition

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Your message has been successfully sent to your colleague. Save my selection. Herrmann, Jennifer L. Most contemporary biodegradable products are derived from hyaluronic acid, calcium hydroxylapatite, or poly-L-lactic acid. Achievement of desired cosmetic outcomes is largely dependent on selection of the optimal injectable product based on the chemical composition, the physiologic interactions with surrounding tissue, product longevity, and a thorough understanding of potential adverse reactions.

The underlying biochemical properties of each product and how they contribute to specific physiologic and adverse tissue reactions is described. Address correspondence and reprint requests to: Rachel K.

A Comprehensive Review on Eryptosis

The authors have indicated no significant interest with commercial supporters. As public awareness and acceptance of fillers has grown, so have the number of injections performed annually. In , 2. Of the 2. To fully appreciate the HA filler group, HA should be reviewed in its native form. Hyaluronic acid is a natural glycosaminoglycan composed of glucuronic acid and N-acetyl glucosamine disaccharide units Figure 1.

Up to 30, units can be linked together, forming structures with molecular weights reaching 10 7 Da. The hydroxyl groups participate in hydrogen bonding with water, stabilizing the solvated state. The salt group dissociates, resulting in a more favorable, lower energy state. Hyaluronic acid surrounds extracellular spaces, and is associated with proteins and cells.

An average human body contains about 15 g of HA, half of which is located in the skin. Enzymes such as hyaluronidase and free radicals continuously degrade free HA polymers. Cleaved fragments are cleared by the lymphatics and ultimately converted to carbon dioxide and water in the liver. The half-life of native HA is 1 to 2 days. Because the basic monomeric unit of HA does not show specificity for any organ or species, HA is considered immunologically inert.

Excellent host tolerance as well as its viscoelastic and hydrating properties make HA an ideal soft tissue filler.

In the exogenous form, HA is synthesized primarily from Streptococcus equi species of bacteria and purified by alcohol precipitation to remove reactive antigens. Hylaform fillers are composed of purified HA derived from rooster combs and are contraindicated in patients with known hypersensitivity to avian proteins.

Note that non—cross-linked HA is liquid. Cross-linking of fluid HA provides structure and adhesive stick, creating a gel. In Allergan's range of fillers, the remaining unreacted BDDE is reported at less than 2 parts per million. The degradation by-products of cross-linked HA, uncrosslinked HA, and unreacted BDDE have all been described as harmless at the concentrations found in fillers, or are already found in the skin.

Cross-linking is measured as the percentage of disaccharide units bound to a cross-linking molecule. Higher degrees of cross-linking translate to stiffer gel products resistant to deformation. Rarely, this can provoke a foreign body reaction by the host's immune system, which could be further compounded by increased longevity from cross-linking. Biphasic or particulate products consist of cross-linked particles with an average particle size proportional to the grade of sieve used.

Products with larger particle sizes are typically used for deeper injections, are stiffer to inject, and last longer in tissue. Rheology, the study of flow and deformation of materials between liquids and solids, is used to understand the mechanical properties of HA fillers and their implantation into soft tissue. The cohesivity of the gel refers to the tendency to hold form or shape under stress, proportional to the degree of attraction between the cross-linked HA units. It increases with both cross-linking degree and HA concentration. High-cohesivity fillers, however, are better suited for revolumizing larger areas of loss.

Molecular weight also determines the biologic and physicochemical properties of HA. There are low molecular-weight forms of HA, and high molecular-weight forms, greater than 1, kDa. Most cosmetic HA products contain high molecular-weight polymers and range from to 6, kDa.

3rd Edition

However, in reviewing this table, it is important to consider the inherent variations in the reported rheologic properties that are calculated at different times, under different conditions, yielding widely variable results. It is composed of CaHA microspheres suspended in an aqueous glycerin—sodium carboxymethylcellulose carrier gel Figure 2. It has been used in multiple medical applications with no reported toxicities.

This is too small to permit osseointegration, and to date, there have been no documented cases of Radiesse forming bone after injection into soft tissue. Poly-L-lactic acid is an immunologically inert polymer of L-enantiomeric lactic acid Figure 3. Lactic acid polymers have been used safely in medicine for 3 decades. They degrade into naturally occurring stereoisomers, which ultimately get excreted as carbon dioxide and water.

It must be left to hydrate at room temperature for at least 24 hours to ensure that a smooth hydrocolloid suspension of PLLA particles in the carrier gel is achieved. If inadequately hydrated and super-concentrated PLLA is injected, nodule formation can occur. Physiologic reactions when implanted into the skin are determined by the physical and biochemical properties of soft tissue fillers.

Ideally, an adverse reaction of the surrounding tissue should not occur. Inflammation must be limited to prolong product longevity, yet controlled such that stimulation of collagenesis is predictable with stimulatory fillers.

Publication details

The body's local reaction to foreign body through phagocytosis is arguably the most important factor in determining filler longevity. Particle size, shape, and hydrophilicity influence phagocytosis. With Radiesse, larger microspheres help prevent unwanted release of bone-resorptive cytokines by macrophages. Once injected into the skin, HA provokes a mild inflammatory reaction at the host-tissue border. Biphasic gels form large aggregates distributed regularly throughout the dermis and seem to push apart collagen bundles Figure 4A.

If injected too superficially, the larger aggregates of polyphasic gels may appear blue beneath the skin as longer-wavelength light is transmitted and shorter-wavelength blue light is refracted. This is known as the Tyndall effect. Because monophasic polydensified gels fill extracellular spaces most similarly to endogenous HA, these products are more suitable for superficial placement. Large aggregates of biphasic gels distort and push collagen bundles causing tissue swelling and pain. Conversely, such stretching of collagen fibers may stimulate fibroblasts to synthesize new collagen, a desired effect ultimately enhancing the performance of the filler.

At least one report has documented increased dermal production of collagen after injection of the biphasic NASHA filler, commercially available as Restylane Galderma Laboratories, L. Longevity of HA fillers is determined by particle size, manufacturing processes, volume, location of injection, and host metabolism. Suspension in a large amount of uncrosslinked HA can also shorten half-life. This can be demonstrated in vitro by adding hyaluronidase to HA products. Biphasic gels liquefy more quickly than monophasic gels.

By contrast, enzymes penetrate only the outermost gel surface of monophasic products; thus, more time is needed for their breakdown. They both stimulate fibroblasts and induce collagen synthesis. Although injection creates the appearance of immediate augmentation due to mechanical expansion of the surrounding tissue, this effect is transient. This ultimately creates gradual, naturally appearing volume that persists as filler particles degrade and inflammation fades. With cosmetic CaHA, fibrin has been shown to surround product microspheres at 1 month after injection. By 9 months, microspheres become deformed, irregular, and begin to disappear.

They are broken down into calcium and phosphate ions, which presumably get eliminated from the body, much like small pieces of bone. Visible correction in the appearance of the skin and rhytides typically ranges from 10 to 14 months, influenced by the amount of product injected and host metabolism. Poly-L-lactic acid generates a similar subclinical inflammatory response, ultimately resulting in collagen production. A capsule of macrophages, lymphocytes, mast cells, and fibroblasts surrounds these particles at 1 month after implantation.

By 18 months, the new collagen fibers persist, whereas the inflammatory response has largely resolved. This leads to more collagen synthesis and longer-lasting clinical results. On average, correction is visualized for 18 to 24 months. With all soft tissue filler injections, erythema, swelling, bruising, pain, and pruritus are common and occur almost immediately.


These reactions are caused by disruptions in the vasculature and dermal structures. With HA fillers, pain and swelling tend to increase with concentration of HA. The hydration level of HA products is below equilibrium; thus, they bind large amounts of water when injected into tissue. Lidocaine can be added to certain products through manufacturing or reconstitution to attenuate pain and pruritus. Although rare, inadvertent intra-arterial injection can lead to tissue necrosis, scarring, and blindness in the most severe cases. Some providers preferentially select HA products to mitigate these risks, as hyaluronidase injections can be done to breakdown the HA filler and potentially circumvent a complication.

Animal-derived hyaluronidase products from ovine and bovine testicular hyaluronidase are commercially available as Vitrase Vitrase; ISTA Pharmaceuticals Inc. It is considered less immunogenic, and is often used in cosmetic practice. Noninflammatory reactions include the appearance of papules and nodules. Noninflammatory nodule formation early on may be related to injection technique, excessive filler use, superficial placement, the use of an inappropriate product for a given indication, subsequent muscular activity, product impurities, or irregularities of filler surfaces.

Massage, hyaluronidase, or simple incision and product expression is often curative. Rarely, if a large amount of product is deposited after depot injection, formation of a surrounding fibrous capsule occurs. Insertion of a large bore needle to break through the capsule and aspiration of product may be necessary for correction. In addition to proper dilution and reconstitution, deep placement is critical with CaHA.

Nodules from CaHA usually result from injections that are either too superficial or from placement of product within the muscle fibers. Intramuscular placement is particularly common around the mouth as CaHA traverses the orbicularis oris muscle to form deposits under the submucosa of the inner lip.

Shaking the product immediately after adding water, suboptimal crystal hydration leading to in vivo hydration, and a poor suspension at the time of injection can all result in an uneven distribution of the product in the tissue, giving it a lumpy appearance. Similarly, superficial injection of product and placement into muscles should be avoided because complications like those seen with CaHA can occur. Adverse reactions after filler injection can be inflammatory in nature. Although uncommon, infection after filler treatment can occur.

Infections can be caused by bacteria, viruses, fungi, including Candida , or can be polymicrobial. If multiple abscesses occur, the cause is most often from product contamination. Early on single facial abscess is generally due to Staphylococcus aureus or Streptococcus pyogenes. The risk of infection can be mitigated by skin cleansing, working in a clean space, and by following product handling and storage guidelines. In some cases, the development of biofilms can complicate filler injections.

This allows for up to 1,fold improved resistance to antibiotics. Biofilms may cause abscesses, granulomatous inflammation, and recurrent infections. Because biofilms are difficult to detect and eradicate, effort should be focused on their prevention. Antimicrobial skin preparation and limited needle insertion through mucosal surfaces with high proximity to oral flora are advisable. A study using a porcine skin model demonstrated no significant difference between alcohol, povidone iodine, and chlorhexidine in reducing the biofilm bacterial burden of S.

The bacterial burden was reduced 3 logs during the wiping process. In the same study, using an in vitro injection model with artificial silicone skin, the fanning technique was found to increase the risk of transferring skin flora compared with serial puncture and linear threading. The risk of transferring viable bacteria was also increased with lower-gauge wider bore needles and superficial injections. Granulomatous inflammation after injection has been reported with nearly all soft tissue fillers.

Biochemistry of Foods - 3rd Edition

Granulomatous inflammation is most accurately defined as a systemic, adverse, type IV hypersensitivity reaction. The presence of only a few foreign body giant cells on histopathology does not constitute a granulomatous reaction. In the case of PLLA, histologic examination can help distinguish between nodules and granulomatous inflammation.

A nodule appears as a mass of product surrounded by scattered foreign body giant cells, whereas a true granuloma appears as product fragments surrounded by a palisaded wall of multinucleated giant cells, attempting to isolate the foreign body from surrounding tissue Figure 6. The occurrence of true granulomas is difficult to predict; however, they may occur more often in patients with known granulomatous disease. There have been reports of filler inducing granulomatous plaques in sarcoidosis patients, with development of sarcoidal granulomas around filler particles Figure 7.

Treatment of granulomas is challenging.

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Intralesional steroids, 5-fluorouracil, or a combinational approach are frequently used. Since its inception, soft tissue augmentation has progressed from filling lines to more comprehensively sculpting faces and rejuvenating nonfacial sites. A better understanding of product differences in composition, physical properties, and their associated tissue reactions allows clinicians to more thoughtfully select and correctly inject products to achieve specific clinical goals.

With better anticipation of tissue reactions, complications and undesired outcomes can be minimized. You may be trying to access this site from a secured browser on the server. Please enable scripts and reload this page. Wolters Kluwer Health may email you for journal alerts and information, but is committed to maintaining your privacy and will not share your personal information without your express consent. For more information, please refer to our Privacy Policy. Subscribe to eTOC. Journal Logo. Advanced Search. Toggle navigation. Subscribe Register Login.

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