TISSUE EXPANSION METHOD

Abstract

The invention provides a method for skin expansion utilizing at least one polymer.

Claims

1. A method for skin expansion, the method comprising injecting an amount (or volume) of a filler formulation to a subject at a skin region, said amount being sufficient to cause expansion and growth of skin at said skin region over time, optionally repeating said injection one or more times, to thereby cause expansion and growth of said skin region.

2. A method for therapeutically or cosmetically treating or correcting a skin defect, the method comprising sequentially injecting a filler formulation under at a skin region of a subject, the skin region being optionally a skin region adjacent to the skin defect, to thereby expand and cause growth of a skin tissue at said skin region and manipulate the grown skin tissue to treat the skin defect.

3. The method of claim 1, wherein the method further comprises a step of manipulating said grown skin region to enable use of the skin region in a method of reconstructive treatment or surgery.

4. The method according to claim 1, wherein the filler formulation comprises at least one polymeric material.

5. The method according to claim 4, wherein the at least one polymeric material is selected from poly-L-lactic Acid, polymethylmethacrylate (PMMA), calcium hydroxyapatite (CaHA), chitosan, alginate and hyaluronic acid (HA).

6. The method according to claim 5, wherein the at least one polymeric material is HA.

7. The method according to claim 6, wherein the concentration of HA is at least 5 mg/ml, or is between 5 and 50, 5 and 100, 10 and 50, 10 and 100, 20 and 50, 20 and 100, 30 and 50, 30 and 100mg/ml.

8. The method according to claim 6, wherein the HA is selected from Macrolane, Hylaform, Hylaform Plus, Restylane, Perlane, Restylane Fine Lines, Hylaform Plus, Captique, Juvederm Ultra, Juvederm Ultra plus, Puragen Plus, HYAcorp MLF1 and Belotero.

9. The method according to claim 8, wherein the HA in the filler formulation is Macrolane.

10. The method according to claim 6, wherein the HA is cross-linked HA.

11. The method according to claim 4, wherein the at least one polymeric material is in the form of a phase transfer material.

12. The method according to claim 1, wherein the filler formulation is in a form of material particles.

13. The method according to claim 1, wherein the at least one polymeric material is provided in particulate form.

14. The method according to claim 12, wherein the filler formulation comprises between about 500 and 2,000, 800 to 1,500, or 900 to 1,200 material particles/ml.

15. The method according to claim 1, wherein the filler formulation is in the form of a gel material.

16. The method according to claim 1, wherein the filler formulation further comprises at least one carrier material and further optionally at least one excipient.

17. The method of claim 16, wherein the at least one excipient is selected from the group consisting of a vitamin, a degradation inhibitor, an antioxidant, a stabilizer, a steroid, a retinoid or salt/derivative thereof.

18. The method according to claim 1, wherein the filler formulation is delivered by a single injection or by sequential injections.

19. The method according to claim 1, wherein the volume of filler formulation injected per single injection is between about 20 and 250 cc or between 5 and 100 cc.

20. A method for preparing a skin graft to repair/treat/reconstruct a skin defect, the method comprising: sequentially injecting a filler formulation into a skin region to be used as a skin donor, to cause expansion and growth of said skin region to obtain grown skin; harvesting at least a part of the grown skin; and implanting the harvested skin in a recipient site to treat the skin defect.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0106] In order to better understand the subject matter that is disclosed herein and to exemplify how it may be carried out in practice, embodiments will now be described, by way of non-limiting example only, with reference to the accompanying drawings, in which:

[0107] FIG. 1 is a photo of a Macrolane injection using 18-gauge needle on a 24-year old woman. The needle entry is at the hair-bearing mastoid area with expansion of the non-hair-bearing skin.

[0108] FIG. 2 is an anterolateral view of the same 24-year old woman from FIG. 1 after completion of 20.00 mL Macrolane expansion prior to total right ear reconstruction. The endpoint blanching effect of expansion is noted.

[0109] FIGS. 3A-B depict (FIG. 3A) posterior view of a framework from a 33-year old man with the addition of a large cartilage support providing substantial elevation of 1.5 cm projection and (FIG. 3B) an additional view of the framework with the cartilage support.

[0110] FIG. 4 is an intraoperative view of left ear partial reconstruction in a 33-year old man demonstrating the Macrolane HA particles within the expanded pocket marked with *. (**) shows the expanded skin surface.

[0111] FIG. 5 is an intraoperative view of a total right ear reconstruction in a 24-year old woman showing tensionless redraping of the expanded skin over the projected framework.

[0112] FIGS. 6A-H provide preoperative photographs of a 21-year old woman scheduled for total right ear reconstruction using the Marcolane expansion method (A, C, E, G). The new ear had to be set low around the preexisting low set remnant (B, D, F, H). Postoperative view of the patient at 12 month are shown.

[0113] FIGS. 7A-H provide preoperative photographs of a 35-year old man scheduled for total right ear reconstruction using the Macrolane expansion method (A, C, E, G). A postoperative view of the patient at 12 month is shown in B, D, F and H.

[0114] FIG. 8 is an intraoperative view of a partial right ear reconstruction in a 33-year old man, demonstrating the Macrolane HA particles within the expanded pocket (*) as well as the pliable capsule formed around the HA (**).

[0115] FIG. 9 depicts low power (40) magnification; H&E histology slide of a capsule specimen after 12-week expansion demonstrating an inner layer early capsule with band condensation of collagen (*) surrounding HA filler material (**) associated with a focal inflammatory reaction (***).

[0116] FIG. 10 depicts high power (400) magnification; H&E histology slide of a capsule specimen after 10-week expansion demonstrating fibroblasts (*), macrophages (**), giant histocytes and eosinophils (***) in the vicinity of the HA particles (h).

DETAILED DESCRIPTION OF EMBODIMENTS

[0117] Patients and Methods: A retrospective chart review was performed to identify patients who underwent mastoid skin expansion with Macrolane, followed by total ear reconstruction. Ten patients underwent a one-stage, total or partial ear reconstruction using a rib cartilage framework as described in the modified Nagata technique. Tissue expansion was used in all ear reconstruction cases, either with HA injections or osmotic tissue expanders. Patients were offered both methods. The patients selected for this method were those consecutive cases that were mature enough to tolerate the filler injections and chose the technique. The board of Australian Therapeutic Goods Administration granted approval for the off-label use of Macrolane as an injectable tissue expander for each patient. The Melbourne Institute of Plastic Surgery's ethics board committee approved the study and informed consents were obtained. All data and demographics were collected from patients' charts (Table 1).

TABLE-US-00001 TABLE 1 Patients' demographics, expansion data and outcome; Rt (right), Lt (left), F (female), M (male). Mean injection Last volume Lowest Highest Total Ear follow Expansion Injection in one Volume volume volume Ear recons. up duration session session Injected Injected Injected pathology (total/ visit, Age Gender (weeks) number (ml) (ml) (ml) (ml) and side partial) month Complication 21 F 15 8 1.94 1 3 15.5 Rt total 24 Exposed Microtia wire on antihelix 10 M 14 7 2.07 1.5 3 14.5 Rt total 15 none Microtia 35 M 10 9 1.94 1 2.5 17.45 Lt total 12 none Microtia 33 M 11 10 2.35 1.5 3 23.5 Acquired partial 3 none upper LT ear loss 24 F 19 13 2.3 1.5 3 30 Rt total 6 none Microtia 21 F 12 10 2.13 1 3 21.3 Rt total 12 none microtia 18 M 12 10 1.90 1 2.5 19 Rt total 12 none microtia 14 M 10 10 1.7 1 3.5 17 Lt total 12 none microtia 19 F 12 10 2.00 1 3 20 Rt total 9 none microtia 17 M 14 10 1.94 1 2.5 19.5 Lt total 9 none microtia

[0118] The data was analyzed for complications, revisions and failure rate. In addition, apparent capsule tissue from the expanded pocket of a male patient after 12 weeks of expansion was sent for histological analysis using Hematoxylin and eosin stain (H&E stain).

[0119] Non-Surgical Expansion

[0120] Complete anterior and posterior three-dimensional framework coverage requires more skin than can be provided by simply utilizing the retroauricular non-hair-bearing skin alone. Nagata has extended the retroauricular mastoid skin flap surface area by including the skin on the posterior aspect of the lobule in most cases. To push the limits further, tissue expanders are placed during a separate surgery, to gain the extra skin necessary for retroauricular definition. In the present study practice Macrolane (VRF 20; NASHA gel; Q-Med, Uppsala, Sweden) was used in order to expand the retroauricular mastoid non-hair-bearing skin. The injection technique described herein is consistent with the product's instructions for use.

[0121] In the first visit, it is ensures that the patient is prepared to tolerate some discomfort over the course of multiple injections due to the expansion planned. Then the future expansion zone is marked according to the (1) size and measurements of the defect, and (2) location of available non-hair-bearing skin donor site.

[0122] On an outpatient basis, serial expansions are performed weekly or every other week. An hour prior to the scheduled procedure, topical local anesthetic cream (23% Lignocaine, 7% Tetracaine) is applied to the mastoid area and is covered with a clean plastic wrap for increased anesthetic efficacy. The procedure then begins with marking of the injection site at the temporal hair bearing area. After prepping the skin and planned injection sites with 70% alcohol, local anesthetic (Xylocaine 1%) is given subcutaneously along the planned injection sites and their tracks. Next, prior to each expansion, several features are examined and recorded. The skin is inspected and gently palpated for assessment of its color, thickness, pliability, capillary refill, blanching upon pressure, and tightness. These evaluations are repeated during the injection procedure several times and serve as the endpoint for an injection session, as traditionally done with tissue expanders.

[0123] Using an 18-gauge needle, the Macrolane is gradually injected from the marked hair bearing temporal area into the central mastoid area. When an endpoint such as skin tension, blanching or pain is reached, the injection halts, the needle is withdrawn and mild finger pressure with a gauze dressing is applied for a few minutes. One week before the reconstructive surgery, the final session of serial expansions is completed in the office, and a final evaluation of the skin is performed as described above (FIGS. 1-2).

[0124] Surgical Technique and Pocket Preparation

[0125] Subsequently, the patient undergoes a costochondral reconstruction per the Nagata method, but with the addition of a large cartilage support providing substantial elevation (FIGS. 3A-B). This technique takes advantage of both the expanded skin pocket and the additional cartilage support to create adequate projection in a single stage. Framework planned location is marked as well as the planned incisions. A rounded W-shaped flap is marked at the mastoid skin that extends onto the posterior surface of the lobule as described by Nagata. The Nagata method is otherwise followed, with preservation of a subcutaneous pedicle and bolster sutures without drains.

[0126] Using suction, the Macrolane HA particles are drawn away from the pocket with ease (FIG. 4). Prior to framework insertion, after saline irrigation of the pocket, further undermining is performed beyond the size of the planned reconstructed auricle. Remarkably, in all filler expanded pockets the observed capsule found was thin and pliable and did not require capsulotomy or capsulectomy. This allows preservation of the delayed subdermal plexus, and thus keeps skin vascularity robust.

[0127] Due to the substantial amount of excess skin generated by expansion, the framework is easily inserted into the skin pocket and rotated into place. The framework is then anchored to the mastoid fascia with 3-0 Prolene sutures (Ethicon, Inc., Somerville, N.J.) superiorly and inferiorly, at the anterior convexity of the helix and the lobule, respectively. A suction drain is placed in vacuum to allow the skin to drape and contour over the framework and then immediately withdrawn at the conclusion of surgery after the dressing is completed. This allows the skin to redrape in a tensionless fashion over the contours of the high relief framework (FIG. 5). Following inset, the incisions are closed with 6-0 nylon interrupted sutures. Betadine soaked Kaltostat (Convatec, Brandon Park, Victoria, Australia) is rolled and placed as bolsters with a covering gauze dressing and a foam ring held with a head net.

[0128] Results:

[0129] Demographics, data regarding expansion volume, expansion sessions and complications are listed in Table 1. Patients' age ranged from 10 to 35 years (mean age 21.2). Mean follow-up time was 11.1 months (range 3 to 24 months). Nine patients underwent total auricular reconstruction, and one underwent partial reconstruction due to a traumatic upper two-thirds auricular loss. Six cases were right-sided, and four were left-sided. Six were male and four female.

[0130] Expansion duration was defined as the time from the first expansion session to the last session, consistently ending one week before surgery. Expansion duration ranged between 10 to 19 weeks (mean 12.9 weeks). Macrolane injection sessions were performed every one to two weeks in accordance with patient and surgeons' timetable and clinical assessment, as previously described for traditional tissue expansion (23). Injection sessions ranged from 7 to 13 meetings (mean 9.7 sessions). The lowest volume of Macrolane injected in one session was 1.0 ml and the highest was 3.5 ml (Table 1). The mean injected volume in one injection session for all patients combined was 2.03 ml (range between 1.70 ml to 2.35 ml). Mean total injected volume per patient was 19.8 ml (range between 14.5 ml to 30.0 ml). No major complications occurred. In 10 patients, only one minor complication was encountered at a 12-month follow up (Table 1). This patient had an exposed wire that was easily removed from the antihelix in the office. At the 6-month clinic follow up visit, patients were interviewed by the senior author. All patients, excluding one that was lost to follow up at 3-month visit, were pleased with their result and expressed their satisfaction with the expansion process regarding pain and comfort, stating that they would do it again (FIGS. 5A-B, 6A-B).

[0131] Surrounding tissues from one expanded pocket were sent for Hematoxylin and eosin histological analysis (Melbourne Pathology, Collingwood, VIC, 3066 AUSTRALIA) to better define the capsule that clinically appeared present in all patients. We noticed the capsules were clinically thinner and more pliable than those formed around traditional expanders (FIG. 7). Additionally, no bathtub deformity was encountered on the underside or edges. The thin capsule could easily be manipulated without the need for capsular excision.

[0132] Capsules generally form with an inner layer adjacent to the expander. This layer consists of dense connective tissue (also known as band condensation), fibroblasts, macrophages and eosinophils. An outer capsule layer also develops and is made up of loose connective tissue and abundant vascularization. Histological analysis revealed a capsule surrounding HA filler material associated with a focal inflammatory reaction consisting of fibroblasts, macrophages, giant histiocytes and eosinophils. A thin band condensation was present along the capsule inner layer after 12 weeks of expansion (FIGS. 8-9).

[0133] Following Macrolane filler expansion adequate skin was gained for coverage of a fully elevated framework to a height between 1.0 to 1.5 cm. Using this novel non-surgical expansion technique, a fully reconstructed, well-projected, color-matched ear was provided in a single operation without the use of additional skin or fascial flaps.

[0134] Auricular reconstruction is both controversial and challenging. Since its introduction by Tanzer in 1959 the costal cartilage framework for autologous reconstruction has become the gold standard for total and some partial auricular reconstruction. Nagata's refinements are well documented and have been adopted by many surgeons. His technique demonstrates exceptional results with fewer complications. Nagata describes a two-stage procedure with incision modifications to allow for increased skin surface area and improved flap vascularity. His description involves framework inset in the first stage, and a second stage surgery with a fascial flap, skin graft and additional rib cartilage for increased projection. Even though Nagatas' two-stage procedure may produce symmetric auricular projection if the contralateral ear is not exceedingly protruded, it does not achieve a deep enough retroauricular sulcus; though, a shadow is created giving the impression of a sulcus. A one-stage, successful elevation of the ear framework with creation of a well-defined retroauricular sulcus continues to be a challenge.

[0135] Traditional tissue expansion in auricular reconstruction has been proposed as it may provide more skin coverage of a framework. A thin, color-matching skin pocket can be generated with use of tissue expanders, and the expanded skin can be used alone or with skin or fascial flaps to improve projection. Although some advocate it's use and believe that expansion results in superior outcomes others point out to the adverse effects on the thin skin needed to demonstrate the details of the microtic ear. Some of the major concerns are the added surgical stage for expander insertion and potential complications. For these reasons, tissue expanders have not been widely adopted in ear reconstruction.

[0136] Macrolane was used for expansion due to its very large particle size of 1000 gel particles/ml, compared to 100,000 gel particles/mL in Restylane, and 8000-10,000 gel particles/ml in Perlane. The Large particle gels have significant lifting capacity and were therefore thought off as good temporary expansion modality that can substitute traditional tissue expanders. Since the expansion duration typically takes only several months to complete, the substance long term duration of action, efficacy and absorption rate are irrelevant to the expansion modality. Macrolane has been used in Europe and other countries for filling skin contour deformities and buttock enhancement. Previously, it had been used in Europe for breast enhancement, but the absence of controlled clinical trials raised questions regarding its use in the breast. In 2012, after conferring with European authorities, Q-Med stopped marketing Macrolane for breast enhancement. This arose from radiologists' concerns that it makes reading mammograms more difficult, and that HA degradation stimulates neovascularization masking cancer surveillance. Many studies have shown that Macrolane and HA is safe for use in humans, and the concerns regarding its use for breast enhancement did not relate to the safety of the product itself. Due to similar FDA restrictions regarding Macrolane in Australia, we were required to apply individually for each patients' expansion treatment, and receive a distinctive approval. Taking the many advantages of this modality, the Australian Therapeutic Goods Administration authorized the off-label use of Macrolane on an individual basis for tissue expansion in autologous ear reconstruction. As more and more HA products are being FDA approved and added to the U.S market, it can be quite confusing as to which product can give a good lifting capacity and thus an expansion modality. Overall, any product with large particle HA and good lifting capacity such as Juvederm Voluma (Allergan; 2525 Dupont Dr. Irvine, Calif. 92612) and Belotero Balance (Merz Pharmaceuticals, LLC; 4215 Tudor Lane Greensboro, N.C. 27410) would make sense for use.

[0137] In the past decade, HA based dermal fillers have provided an attractive and safe nonsurgical alternative to reduce skin wrinkles and folds. Multiple reports show that HA based fillers actually have positive secondary effects on the dermis. Our novel, minimally invasive, off-label use of Macrolane has enabled us to avoid the extra surgical stage required with traditional tissue expanders, while reaping the benefits of expanded skin.

[0138] Expansion using HA has many advantages when compared to using traditional tissue expanders. Injections of Macrolane are minimally invasive and performed in the office. This avoids the need for the initial 1.sup.st stage surgery and the morbidity associated with additional incisions, including: potential vascular compromise, port problems, expander extrusion, and deflation issues. The repeated Macrolane injections are analogues to the repeated and tolerable injections required to fill a tissue expander, even in the younger age. Filler expansion is performed with a needle entering along the periphery of the proposed area of expansion, unlike traditional expanders where the needle pricks are localized to the port area. This is advantageous as repeated injections in the same area can lead to more scarring and pain. Injection of Macrolane allows the surgeon to adjust the expansion process to each individual patient. The surgeon is not confined to the shapes and boundaries of a traditional expander, or even to a custom made expander. By not being limited to the borders of a traditional expander, the surgeon can better tailor the patient's tissue expansion throughout the entire process. Furthermore, following filler removal, secondary expansion of the expanded skin can be performed in a tailored manner as well. The end point to filler expansion is the skin give only and not the expander device's inherent predetermined volume and shape. The complete course of expansion with Macrolane costs substantially less than that of traditional expansion and the added surgical stage fees.

[0139] The study of capsule thickness in expanded skin is important and has previously been examined comparing smooth to textured surfaces. Histologic examination of the capsule formed around the Macrolane corroborated our clinical observation of a thin, pliable capsule. While traditional capsules may require surgical manipulation, the capsule found around HA in the herein described study did not require any surgical release or excision, allowing preservation of the vascularity. Capsule thickness in Macrolane expanded skin is an area for further research.

[0140] The patient's ages ranged from 10 to 35 years (mean age 21.2). The protocol traditionally has been to wait until 10 years of age or older in all patients as recommended by leaders of modern ear reconstruction. The later age was used in the herein described study for reasons such as minimum chest diameter for sufficient donor material, to avoid a chest deformity, making sure the patient is more emotionally mature, cooperative and involved in the decision to operate. In a study of 10 consecutive patients undergoing single stage autologous ear reconstruction, it was shown that the herein described expansion method was both safe and feasible.