Modern biological fillers

, medical expert
Last reviewed: 25.06.2018

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Currently in the US, biological materials derived from human or animal tissues are used more often than synthetic biomaterials. The most popular materials for increasing soft tissues are auto-fat and bovine collagen. With the development of laboratory methods of cultivation, the choice was supplemented by the possibility of injections of a mixture of human collagen and cultured fibroblasts.

trusted-source[1], [2], [3], [4], [5]

Materials derived from human tissue

Injection of auto-fat

The unpredictability of the results of the use of fat autografts was realized quite quickly, it was associated, mainly, with local resorption of transplanted fat. Two decades after Neuber reported the successful transplantation of free fat transplants, Bruning first described the technique of fat injection. He put small pieces of fat in a syringe and used it to correct deformities after rhinoplasty. In 1950 Peer pointed out that the mass of freely transplanted fat decreases by an average of 45% after 1 year. He proposed the theory of cell survival, postulating that live fat after istage is ischemic, some fat cells die, and the tissue dissolves and is replaced by cystic structures and fibrous tissue. Other authors have shown that fatty grafts taken surgically retain volume better than those obtained by suction. With the introduction of liposuction, described by Illouz in the late 70s of the last century, large volumes of adipose tissue became available for implantation.

The method of microlipoinjection consists of sampling, storage and reimplantation of fat. Fat is taken in aseptic conditions, under local anesthesia, using the technique of hypotonic infiltration, blunt microcannons or a syringe in a sterile container. The withdrawn fat can also be frozen in liquid nitrogen for future use. Potential donor sites can serve as lateral surfaces of the hips, buttocks and abdomen. Serum and blood are separated from the fat, then it is washed with a sterile saline solution. Transplantable fat is injected into the subcutaneous tissue with a wide perforating needle. After the injection, the tissues are massaged to distribute the introduced fat evenly. Indications for microlipoinjection are the correction of nasolabial and buccal-labial folds, furrows on the bridge of the nose, lips, and hemifacial atrophy. Since resorption of the introduced fat is expected, hypercorrection is recommended for 30-50%. In more mobile areas, resorption is accelerated, so repeated injections may be required to achieve a lasting result.

In addition to complications in the donor site, potential complications of microlipoinjection are mild edema and ecchymosis in the area of administration, which are usually resolved within 72 hours. There is one report on the development of unilateral blindness after injection of an autogyro in the nadtriperosye. The resorption of fatty grafts requires repeated injections, and the replacement of the graft with a fibrous tissue is the main problem of this technique.

Lipocyte correction of the dermis

In 1989, Fournier developed a modification of the auto-injection. He suggested that if adipocytes break and triglyceride contents are removed, the remaining cell walls and intercellular fibrous septa can be used as a connective tissue filler to correct dermal changes. He called this tissue an autologous collagen, believing that it is rich in these fibers.

Coleman and his colleagues reported excellent clinical results with good tolerability. The durability of this material, according to their data, is comparable to that for Zyplast (derived from bovine collagen) or Fibrel (porcine collagen), especially if the filling procedure is repeated after 2-4 weeks. Early biopsies revealed not intact adipocytes, but significant inflammatory infiltration. Subsequent biopsies showed an expansion of the dermis and the replacement of inflammatory cells with cellular fibrosis. Interestingly, biopsies showed a very low collagen content in the most transplanted material. Instead, the injection causes collagen deposition by the host organism.

Although this method is technically more difficult and requires more time than using Zyplast or Fibrel, it appears to be safe and yields acceptable clinical results. It can be useful for correction of perioral atrophy and skin scars. It can also be combined with other techniques, such as microlipoinjection, laser exposure or the administration of botulinum exotoxin A (botox). The procedure often requires repetition. However, due to the excess of the donor material, it can be cost-effective, especially for large defects.

Fat is taken in the same way as for microlipoinjection. He is given a few minutes to settle in the syringe, so that it is possible to separate the fat from the liquid part of the aspirate. Then the resulting fat is dialed into small syringes, with 1 cm3 of sterile distilled water added to each 2 cc of fat, and then frozen in liquid nitrogen. After that syringes quickly defrost in warm water. As a result, the supernatant is separated from the fat residues, which are removed. The remaining triglycerides are separated from the injectable material by centrifuging the syringes for 1 minute at 1000 rpm. The treated tissue can be injected intradermally via a 23 G or 25 G needle.

The longevity of the material for lipocyte correction is similar to that of Zyplast collagen. Due to the expected resorption, it is necessary to resort to some hypercorrection or to repeated injections. Side effects and complications of this procedure are the same as with microlipoinjection.

Autoderm Transplantation

Taking dermal grafts involves dissection, excision and reimplantation of small, monolithic pieces of autoderm as a means of increasing the volume of soft tissues. Originally used in ophthalmology and to restore voice, dermal transplants are used to treat retracted scars, skin folds and wrinkles, as well as deep, wide defects of soft tissues. In the treatment of fine wrinkles or small post-acne scars, they are not as effective. Large postagrevyye scars, at least 4 - 5 cm in diameter, this effect is treated better.

It has been shown that scar scarting as the only effect improves the appearance of these defects by separating the fixing fibrous strands from the skin, forming a new collagen and fibrous tissue and thereby raising the defect area. However, after such an impact, the scars, in a large number of cases, eventually reattach to the underlying fibrous tissue. The introduction of dermal grafts after an incision theoretically can prevent re-attachment to fibrous tissue and give longer results. First, a NoKor caliber 18 G needle (manufactured by Beckton-Dickinson, USA) is cut in the middle plane of the dermis. When dissecting fibrous strands, viscous resistance is noted. The introduction of dermal transplants is carried out 2-6 weeks after the initial cut.

A good donor place can serve as a behind-the-scenes area. The advantages of this area are that it has relatively little blood supply, contains few hair follicles and other appendages of the skin, and that the scar after tissue removal will be hidden. Under local anesthesia, the skin is dermabrasion with a rough diamond disc to the level of the deep dermis. The technique of dermabrasion provides speed and accuracy in depth; However, the epidermis can also be removed with a scalpel or laser. Then, the dermis can be taken up with a scalpel to the level of the bovine fascia and immediately put in a cold sterile physiological solution. The donor site is closed with absorbable suture material. Dermal graft with adipose tissue is divided into suitable fragments. Smaller grafts, 4-6 mm, can be used for smaller post-acne scars, whereas large dermal strips can be used to lift large defects, and also for correction of sweetness over the bridge of nose and nasolabial folds. Recipient zones are cut by a 18K NoKor needle at the level of the middle part of the dermis, and then a transplant is inserted and positioned through the needle hole. In larger recipient sites, such as nasolabial folds or lips, the graft can be stretched under the undercutting area for the thread attached to one of its ends. Both ends of the subcutaneous tunnel are then closed with thin absorbable sutures, including a graft in the stitches.

Side effects and complications of this procedure are local bruise, bruising, discoloration, swelling, crusting and pain. Wound infection is infrequent, but possible. The formation of inclusions in the form of epidermal cysts occurs if the epidermis is not completely removed from the graft. Cysts formed recently can be painful, but can be treated by dissection and drainage. Displacement of the graft occurs rarely; it may require the introduction of an additional graft. There may be scarring in the region of the incision, but the scars are amenable to correction by grinding.

There are reports of successful correction in 40-70% of cases after one procedure and in 50-100% of cases after two procedures. Within 1-6 months after treatment, there is some shrinkage; therefore, when transplanting a transplant, some hyper correction is recommended.

trusted-source[6], [7], [8], [9]

Cultured human fibroblasts (Isolagen)

With the introduction of new techniques for tissue culture, it became possible to easily grow large amounts of fibroblasts]. Fibroblasts from tissue cultures can serve as a potential dynamic, living filler for correction of scarring. Isolagen (producer of Isolagen Technologies, USA) is the product of this process. The company by processing biopsy specimens of autologous behind-the-ear skin and for 4-6 weeks prepares syringes containing 1-1.5 cm3 of injected autologous fibroblasts in a biocompatible medium. Isolagen is injected into the superficial, middle and deep layers of the dermis with a tuberculin syringe with a 30 gauge needle. To obtain 95% of the viability of fibroblasts, the material must be injected within 24 hours of delivery. Viability is reduced to 85% and 65% after 48 hours and 72 hours, respectively. This technique is proposed for the correction of wrinkles, nasolabial folds, furrows over the bridge of the nose, scars and hypoplastic lips. The recommended treatment consists of three to four injections for 3-6 months. When examining more than 100 patients in a 18-30 month follow-up, the number of good and acceptable results was approximately 80%, with no significant complications and hypersensitivity reactions. To improve the effect, Isolagen can be combined with other procedures for reconstructing the skin surface or injecting bovine collagen. Although the product itself and the concept of its application are promising, long-term results have not yet been studied. Isolagen is still being studied for approval by the Food and Drug Administration (USA).

trusted-source[10], [11], [12], [13], [14]

Injection autocollagen (Autologen)

Autologen (manufactured by Collagenesis Inc, USA) consists of dispersed into the injectable form of intact autocollagen fibers obtained from the autoderm. The collagen fibers are in the form of a suspension in sterile phosphate buffer with a neutral pH. This product is usually offered in a standard 4% solution (Autologen) or a 6% crosslinked fiber (Autologen XL), but may also have a concentration ordered for a particular patient. Since the material is made from the patient's own skin, in theory, allergic and immunological reactions should not develop on him and he can not be a carrier of diseases.

Autologen is offered for the treatment of wrinkles on the face, contour defects of the dermis and scars. It is injected into the middle layer of the dermis with a needle of caliber 27-30 G. Injection at the desired depth causes a mild whitening of the covering skin. The suspension does not contain a local anesthetic, so the injection can be painful. A retrospective analysis of the procedure in 25 patients demonstrated correction of the folds on the face for up to 3 months after a single injection in 50-75% of cases and for up to 6 months in 50%. These results were not repeated by other users.

The main drawback of Autologen is that the skin needs to be taken from the recipient himself. Previously, the skin remaining after blepharoplasty, facelift, eyebrows, abdominoplasty, revision of scars and other cosmetic operations was used before. After receiving the tissue, it can be frozen for up to 2 weeks or immediately sent to the company's laboratory. The yield is about 1 ml per 5 cm2. Limited histopathological studies have not revealed a significant inflammatory response to the administration of Autologen. To evaluate long-term results, additional clinical trials are required.

Materials derived from homologous human tissue

The cell-free matrix of human skin (AlloDerm)

The increase in the volume of soft tissues with the help of homotypes produced various results. Although, in general, autografts are preferable, their use is limited to complications from the donor bed. AlloDerm (manufactured by LifeCell Corp, USA) is a cell-free dermal matrix derived from human allot skin obtained in US tissue banks. The graft is frozen-dried without damaging the intercellular matrix, and the structural and biochemical integrity of the dermis and basal membrane is preserved in it. Cells are removed by disengaging their bonds with the matrix and changes in calcium concentrations, ionic strength and acidity, combined with the use of low molecular weight buffered detergents. As a result of this process, a non-immunogenic graft is obtained. It remains stable in the frozen state for 2 years, and restores the water content for 10-20 min in physiological saline or Ringer-lactate solution immediately before use.

In clinical conditions, AlloDerm was first used in the treatment of deep burns. Since then, it has been used in a variety of cosmetic and reconstructive operations as a material to increase the volume of soft tissues. The experience of applying AlloDerm for lip augmentation, correction of nasolabial and buccal-labial folds, as well as folds above the bridge of the nose, was satisfactory. The ground preparation was also used as an implant for the alignment of retracted scars.

To correct nasolabial folds, a piece of AlloDerm 3 x 7 cm is diagonally dissected into two triangles. Each segment, after rehydration, is twisted along the long axis. Some surgeons fix the free edges of the graft with absorbable fibers. However, in such situations, a minimum amount of suture material should be used to prevent inflammation. The incisions are made in the corners of the lip in the furrow at the base of the nostrils; an elevator creates a subcutaneous tunnel. Then a graft is pulled through it and a careful massage is performed to properly place the transplant along the tunnel. The incisions are sewn up. For several days locally and orally administered antibiotics.

Atrophic perioral folds can be corrected by enlarging the lips using AlloDerm. A 3 x 7 cm piece of the transplant is usually used, which is folded after rehydration, as described above. Excess transplant can be cut to obtain the desired shape and thickness. The use of sutures to retain the shape of the graft should be minimized as much as possible. Some surgeons install the transplant without any seams, allowing it to take the form of a tunnel. Small sections of the oral mucosa are made, a little lateral than the mouth commissure, and a submucous tunnel is created bluntly below the border of the red border of the lip. It is necessary to act cautiously, so as not to damage the circular muscle of the mouth. Then the graft is carried out in a tunnel and placed evenly by massaging the lips. The excess material is cut off, and the incisions are sewn. The maximum edema in the area of the transplant develops 3 days after the operation. For several days, local and systemic antibiotic therapy is performed. Patients with a viral infection in the anamnesis are recommended a preventive reception of acyclovir.

Hypersensitivity and infections requiring removal of the transplant are rare. There is a report of a reduction in volume in the field of operation by 30-50% after 1 year. There are also two reports on the preservation of grafts in 65-70% of cases after 18 months in mobile areas and about 100% preservation of volume in fixed areas in 2 years. These early reports of longevity were, in general, disproved by clinical practice. Most surgeons using this material report on its preservation for 6-18 months.

Homologous injectable collagen (Dermalogen)

Dermalogen (manufactured by Collagenesis Inc, USA) is an injectable fiber of human collagen in suspension; it is prepared in aseptic conditions from human donor tissue obtained in tissue banks of the United States. The use of the drug is regulated by the Office for Control and Quality of Food and Drugs, as a transplant of human tissue. Like Autologen, the Dermalogen suspension is acellular with preservation of intact collagen fibers. Donor material is selected and intensively processed to prevent the possibility of carrying infectious agents. The indications and methods of application of Dermalogen are identical to those for Autologen, but without the need for sampling of the skin. It is released at a concentration of 3%, 4% and 5% and is injected with a 30 gauge needle. The product is supplied with a dose for the skin test, which must be done 72 hours before the operation. Preliminary data indicate the preservation of the shape of the correction area within 6-12 weeks. However, data on the long-term results of the use of Dermalogen have not yet been obtained.

Materials received not from a person

Injectable bovine collagen

In 1977, Kparr et al. The first to report on the development of a highly purified collagen preparation from bovine dermis. They injected purified human and bovine collagen into 42 patients for 20 months. The preparation was purified, filtered and dialyzed in physiological saline buffered with phosphate buffer with 0.5% lidocaine. In all cases, preliminary testing was carried out by introducing 0.1 ml of material. Complications were phlegmon, pemphigus and hyperpigmentation of the skin. Differences between human and bovine collagen were not revealed.

As a result of joint efforts in 1981, Zyderm I Collagen Implant, an injectable collagen (manufactured by Collagen Corp., USA) received permission from the Food and Drug Administration for market distribution. It was the first nonautological product to increase the volume of soft tissues legally authorized in the United States. Collagen Zyderm is made of bovine skin and is a purified suspension of collagen derived from bovine dermis. Its manufacture includes purification, enzymatic cleavage and sterilization. After purification, bovine collagen is digested with pepsin and reconstituted in physiological saline containing 0.3% lidocaine to a final concentration of 35 mg / ml. During this process, most of the antigenic determinants are removed from the telopeptide regions of the molecule without disturbing the natural spiral structure, which makes bovine collagen more compatible with human tissues. Intact and almost non-specific spiral part of the product on 95-98% consists of type I collagen and 2-5% of type III collagen.

The main limitation of Zyderm application is short-term corrective effect as a result of rapid resorption of the implant. To overcome this problem, more concentrated preparations, Zyderm II and Zyplast, were introduced. Zyplast is collagen, cross-linked with glutaraldehyde, which increases the duration of its life and reduces antigenicity. Unlike Zyderm I and Zyderm II, Zyplast is designed primarily for injections deep into the dermis. In a comparative study, Zyplast and Zyderm Kligman and Armstrong found Zyplast more stable. However, it causes a greater inflammatory response with fibroblast infiltration and collagen deposition, whereas the bulk of Zyderm dissolves after 3 months without fibroblast reaction. Even Zyplast, despite its relatively high durability, requires repeated injections.

Patients are tested by subcutaneous injection of 0.1 ml of material into the palmar part of the forearm. Place of administration is examined after 48-72 hours and after 1 month. Development of redness, densification, or both of these signs after 6 hours is a positive test result and contraindication to the use of the implant. It is reported about 3-3.5% of the frequency of positive skin tests and 1.3-6.2% of false negative results. Therefore, it is recommended to conduct a repeat test after 2-4 weeks. Therapeutic injections can be started 2 to 4 weeks after the negative result of a repeated skin test.

With the introduction of collagen associated adverse reactions such as temporary erythema, edema, ecchymosis, local cutaneous necrosis, local granulomatous reaction and the formation of an abscess. Easy transient erythema can be expected soon after the administration of the drug. It was shown that the incidence of skin flap necrosis secondary to the violation of arterial blood supply after injection of Zyplast deep into the dermis is 0.09%. The formation of abscesses is associated with hypersensitivity. Treatment of painful, strained cysts consists in their dissection and drainage. This complication is rare (4: 10000) and can last more than 2 years. In several studies, circulating antibodies to Zyderm were detected in a number of patients after single or multiple injections. It was found that these circulating antibodies to bovine collagen cross-react with human collagen. Sensitization can be associated with either previous injections or with beef eaten. People with HLA antigen DR4 may be genetically more prone to hypersensitivity.

Implant with gelatinous base

Spangler in the 50s of last century reported the first application of fibrin foam, as an injectable filler for scars and folds on the face. Fibrin foam was a product of plasma fractionation containing fibrinogen and prothrombin. After the introduction of retracted scars, deposition of fibrin, fibroblast infiltration and the formation of a new collagen occurred. Based on this concept, Gottlieb made an improvement by developing a technique using gelatin, aminocaproic acid and plasma. Gelatin served to raise the retracted scar and promoted clot formation; aminocaproic acid stabilized fibrin, suppressing fibrinolysis, and the patient's plasma supplied coagulation factors. The implant with the gelatinous base Fibrel (manufactured by Mentor Corp., USA), which is the development of this technique, was authorized for sale by the Office of Control and Quality of Food and Drugs in 1987. It is sold as a kit consisting of a lyophilized mixture of 100 mg of a resorbable powder of gelatin and 125 mg of e-aminocaproic acid. Pork gelatin is used, therefore it is necessary to perform a skin test, which is evaluated after a month. In some patients with allergic reactions to Zyderm, the use of Fibrel does not cause hypersensitivity. Fibrel received recognition, mainly for intradermal administration with the purpose of correction of retracted scars. Significantly fibrous scarring can not be lifted well with Fibrel. Thin folds on the eyelids, lips and wrinkles from photodamage also respond poorly to Fibrel injections due to implant viscosity and inflammatory response.

A study of correction of scars and folds in 321 patients for 5 years showed the preservation of the result in 2 years in 80% of cases and in 50% after 5 years. Such adverse reactions as local erythema, edema, pruritus, bruise and pain have been found. With the introduction of Fibrel 288 patients, no major systemic adverse reactions were identified. Although there is a report that Fibrel is less allergenic and immunogenic than bovine collagen, its use requires more time to prepare and receive plasma. In combination with greater discomfort than with collagen injections, these factors limited the use of Fibrel.

Gel Hylan B (Hylaform)

The biocompatibility of the hyaluronic acid molecule, in combination with its insolubility in water and the stability to decomposition and migration, made this substance an attractive means for increasing the volume of the dermis.

The molecule does not have any specific or tissue specificity, since the chemical structure of this polysaccharide is the same in all animal species. Hylaform (manufacturer Biomatrix Inc., USA) is a purified preparation of hyaluronic acid of animal origin, derived from the cock's comb. This drug is used to treat retracted skin scars, wrinkles and wrinkles. Gel Hylaform is produced in a concentration of 5.5%. For maximum correction, a series of injections is usually required. Complications are temporary local erythema, hematoma and nodule formation. Hylaform is available in Europe, Canada and other countries, but has not yet been authorized by the Office of Control and Quality of Food and Drugs.


Restylane (producer Q-Med, Sweden) is a cross-linked, stabilized non-animal, third generation, hyaluronic acid non-animal gel with a large molecular weight (20 mg / ml) obtained from bacteria by fermentation. It is sold in sterile syringes containing 0.7 ml of material. The drug is introduced into the dermis at an average depth with needles of caliber of 27 G or 30 G. In Europe it is used to correct wrinkles above the bridge of nose, nasolabial folds, oral adhesions, retracted post-acne scars, and also to increase the lips. Up to 50-80% of the volume of correction remains after 6 months. The main complications are erythema and edema at the injection site. Like Hylaform, this drug dissolves over time. In the United States Restylane is not for sale.


Resoplast (manufactured by Rofil Medical International BV, the Netherlands) is the first injectable collagen implant in Europe. Consisting of monomolecular bovine collagen, Resoplast is available in 3.5% and 6.5% solution and requires skin testing. The indications, technique of introduction and results are similar to those for Zyderm or Zyplast. This drug is currently not available in the United States.

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