Bio-Dermal Restoration With Rapidly Polymerizing Collagen: A Multicenter Clinical Study

Bio-Dermal Restoration With Rapidly Polymerizing Collagen: A Multicenter Clinical Study Abstract Background Despite the increasing popularity of facial contouring with hyaluronic acid, innovation has been limited to iterations that feature different particle sizes, concentrations, and degrees of crosslinking. Bio-dermal restoration is a new approach for correcting facial tissue defects by supplementing the natural dermal structure providing a scaffold for fibroblast adherence and proliferation. Objectives The purpose of the study was to evaluate the safety of RPC Pure-Collagen for the treatment of facial contours. Methods A prospective, multicenter, open-label study in 30 patients treated with RPC Pure-Collagen in the nasolabial fold and followed up to 12 weeks after injection. A subset of patients was further followed up to 9 months after treatment. RPC Pure-Collagen is a sterile, nonpyrogenic, viscous, clear solution composed of pure porcine collagen ethylenediamine tetraacetic acid (EDTA) and Mannitol that can be injected through a 30 gauge needle as a liquid and fibrilizes in situ forming a natural, open 3-dimensional collagen matrix for bio-dermal restoration. Results No treatment related adverse events were noted in addition to transient injection site reactions typical to injection procedures, which were mild or moderate in severity except for one case of severe bruising. There were no reports of hypersensitivity, supporting that RPC Pure Collagen does not require skin testing prior to treatment. Performance results showed a significant improvement from baseline upon treatment, and at the end of the study, on both the Merz Aesthetic Scale and the Global Aesthetic Improvement Scale assessments. Conclusions This initial study shows that RPC Pure-Collagen is safe for its use in facial contouring and provides good indication for long-term safety. Bio-dermal restoration with RPC Pure-Collagen holds promise as safe, lasting, and natural facial contouring treatment. Level of Evidence: 4 Facial contouring to regain a more youthful look, correct defects, and smooth facial folds and contours has gained popularity over the last decade. Facial contouring can be achieved in a number of ways including traditional cosmetic surgery and minimally invasive procedures through the use of dermal fillers. Since the introduction of hyaluronic acid dermal fillers now nearly two decades ago, innovation in the space to not only fill dermal defects but to also restore deficient dermal tissue has been limited. Primary advances have been concentrated on modifying the physical properties of hyaluronic acid compositions for application in different facial tissue locations and on developing more durable alternative compositions for correcting dermal deficiencies. A key focus for development of next generation filler technologies has been on making products that are less palpable and not detectable once injected, reflecting the consumer’s desire for natural-looking, natural-feeling results with natural dynamics. During natural or chronological aging of the skin, collagen, and elastin, major structural proteins in the dermis, are produced at a slower rate affecting the ability of the skin to resist mechanical stress and affecting its ability to repair itself. The reduction of collagen (particularly Type I and III procollagen) results in this thinner dermis.1-3 In fact, the dermis can lose from 20% to 80% of its thickness.4 The skin aging process starts with collagen scaffold loss leading to fibroblast and skin collapse and loss of elasticity, which in turn leads to the appearance of wrinkles, folds, and facial contour changes.5 An ideal Biodermal Restoration construct would: (1) promote fibroblast attachment to stimulate neocollagenesis; (2) be easy and precise to inject; (3) form a natural open 3-dimensional (3D) scaffold to not restrict cell migration; and (4) slowly break down stimulating growth factors and cytokines to promote neocollagenesis, elastic fiber production, neovascularization, and the wound healing response/repair.6,7 Such a construct can not only fill in a contour deficiency or wrinkle upon injection to provide immediate contour stable results, but also recreates extracellular matrix in the specific site for more natural, long-lasting effects and thus achieving bio-dermal restoration. Bio-dermal restoration includes a continuous process by which tissue-engineered scaffolds undergo complementary degradation and remodeling processes to become replaced by new, organized host tissue that is infiltrated with cells and new vasculature. Animal studies have demonstrated that RPC Pure-Collagen mode of action delivers bio-dermal restoration.8 RPC Pure-Collagen is injected as liquid that polymerizes through the natural fibrillization process in the skin to form an open natural 3D matrix which acts as a substrate/scaffold for host cell adherence and proliferation restoring tissue and replacing the native skin scaffold. RPC Pure-Collagen is a novel technology providing bio-dermal restoration as a new approach to correct facial defects, aiming at natural lasting results both in look, feel, and dynamics. Based on collagen, the structural and most prevalent component of the skin, and other well-known biocompatible materials to provide a good safety profile, RPC Pure-Collagen restores the dermal tissue structures and thickness lost during the ageing process with a lasting noncrosslinked collagen scaffold. Significantly differentiating RPC Pure-Collagen from other fillers is that fact that although it is not crosslinked, ethylenediamine tetraacetic acid (EDTA) shields it from degradation in vivo providing longer effects than previous noncrosslinked collagens. One of the limitations of the present filling approach to facial contouring is the appearance of areas that are hardened or look inflated. These limitations become more prominent in challenging indications, such as superficial skin rejuvenation and peri-oral and peri-orbital contouring. Facial contouring through bio-dermal restoration holds a potential to reduce or avoid areas that look inflated or are hardened because it restores the natural tissue structures rather than simply volumizing the depleted areas. Therefore, bio-dermal restoration has the potential of resolving some of the limitations of dermal fillers providing an alternative approach to facial contouring. METHODS This was a prospective, multicenter, open-label study in 30 patients seeking correction for contour deficiencies and soft tissue correction in the nasolabial folds. Patients were included at 2 clinical sites, one in London and one in Stockholm. The first patient was enrolled in November of 2014 and the study was closed in August of 2015. The purpose of the study was to evaluate the safety of RPC Pure-Collagen for the treatment of facial contours such as nasolabial folds. RPC Pure-Collagen is an advanced technology for bio-dermal restoration. RPC Pure-Collagen is a sterile, nonpyrogenic, clear solution composed of molecules of pure porcine collagen (nonfibrillar) and EDTA to provide an in situ polymerizable composition of neutral pH. The EDTA stabilizer also serves to bind (and deactivate) surrounding calcium ions providing integral protection against collagenase degradation, thereby prolonging duration. This degradation-resistance approach is crosslink free, thereby maximizing biocompatibility and optimizing rapid host cell infiltration. RPC Pure-Collagen is injected as a liquid allowing for precise placement and easy molding. The solution polymerizes in situ forming a contour-stable open 3D collagen to allow for bio-dermal restoration. Patients fulfilling the inclusion criteria and who had provided written informed consent were treated with RPC Pure-Collagen on the nasolabial folds. Patients seeking treatment for the nasolabial folds between the age of 30 and 65 and with a pretreatment Merz Aesthetic Score of at least 2 were considered for the study. Main exclusion criteria included previous treatment with a permanent filler or a resorbable filler in the last 6 months, allergy to product components, history of chronic debilitating systemic diseases, autoimmune diseases, malignancy and bleeding disorders, participants under immunosuppressive therapy, and participants with infectious, inflammatory, (pre-)cancerous lesions or unhealed wounds in the treatment area. Pregnant and breastfeeding females were also excluded from participation. A skin test was not required as part to the treatment. Participants were injected intradermally or subdermally using a thin needle or cannula (27-31Ga) with a maximum of 2 mL of RPC Pure-Collagen per side. Use of local anesthesia was at the discretion of the investigator, following the standard practice at the site. Patients who received treatment were followed at 1 week, where there was a possibility for a touch up, and at 4 weeks and 12 weeks after treatment. At each follow-up visit, patients were evaluated for safety, including adverse events and treatment site reactions. Both investigators and patients rated the presence and severity of the following injection site reactions, separately of other adverse events: bruising, redness, swelling, tenderness, itching, induration, and other injection site reactions. In addition, treatment areas were assessed for performance by the investigator and the patient with the Merz Aesthetic Scale,9 a 5-point scale from 0 to 4 where: 0) no wrinkles, 4) deeper wrinkles at rest and deeper furrows with facial expression; and the Global Aesthetic Improvement Scale (GAIS), a 7-point scale: 3) very much improved, 2) much improved, 1) improved, 0) no change, −1) worse, −2) much worse, −3) very much worse. Standardized photographs of the treated area were taken at pretreatment and at each follow-up visit and were used for an additional scoring of the Merz Aesthetic Scale and GAIS by a blinded evaluator. The assessments were linked to the individual via patient number such that a subset of patients could be pulled to track over time. This allowed the complete data sets to be generated at the conclusion of the study and patient dropouts could be removed if necessary. Participants at one of the investigational sites who achieved optimal correction, as evaluated by the investigator, were followed for an additional follow-up period 6 months and 9 months after treatment. All participants provided written informed consent pursuant to the Declaration of Helsinki requirements and local/country specific regulations. Prior to enrollment, the study was approved by the relevant ethics committees: the Health Research Authority NRES Committee in the United Kingdom and Regionala Etikprövningsnämnderna (Ethical Review Board) in Stockholm, Sweden. RESULTS A total of 30 patients were enrolled and treated in the study. One additional patient was enrolled and withdrawn before treatment due to mild severity of the nasolabial folds, while the study required moderate or severe severity. Of the 30 treated patients, one was lost to follow up before the last visit and one agreed to send the questionnaires for the last visit but did not attend the office visit. All enrolled patients were white and all but one (97%) were female, with a mean age of 49.3 years (range, 38-64 years). The majority of the participants (60%) had a Fitzpatrick skin type III (Table 1). Table 1. Demographic Characteristics (safety analysis set, n = 30) Age (years)   Mean ± SD  49.3 ± 7.7   Range  38-64  Gender, n (%)   Female  29 (96.7%)   Male  1 (3.3%)  Race, n (%)   White  30 (100.0%)  BMI (kg/m2)   Mean ± SD  23.81 ± 3.27   Range  19.1-32.0  Pretreatment Merz score, n (%)   2  20 (66.7%)   3  9 (30.0%)   4  1 (3.3%)  Fitzpatrick skin type, n (%)   Type I  1 (3.3%)   Type II  7 (23.3%)   Type III  18 (60.0%)   Type IV  4 (13.3%)  Age (years)   Mean ± SD  49.3 ± 7.7   Range  38-64  Gender, n (%)   Female  29 (96.7%)   Male  1 (3.3%)  Race, n (%)   White  30 (100.0%)  BMI (kg/m2)   Mean ± SD  23.81 ± 3.27   Range  19.1-32.0  Pretreatment Merz score, n (%)   2  20 (66.7%)   3  9 (30.0%)   4  1 (3.3%)  Fitzpatrick skin type, n (%)   Type I  1 (3.3%)   Type II  7 (23.3%)   Type III  18 (60.0%)   Type IV  4 (13.3%)  BMI, body mass index. View Large Table 1. Demographic Characteristics (safety analysis set, n = 30) Age (years)   Mean ± SD  49.3 ± 7.7   Range  38-64  Gender, n (%)   Female  29 (96.7%)   Male  1 (3.3%)  Race, n (%)   White  30 (100.0%)  BMI (kg/m2)   Mean ± SD  23.81 ± 3.27   Range  19.1-32.0  Pretreatment Merz score, n (%)   2  20 (66.7%)   3  9 (30.0%)   4  1 (3.3%)  Fitzpatrick skin type, n (%)   Type I  1 (3.3%)   Type II  7 (23.3%)   Type III  18 (60.0%)   Type IV  4 (13.3%)  Age (years)   Mean ± SD  49.3 ± 7.7   Range  38-64  Gender, n (%)   Female  29 (96.7%)   Male  1 (3.3%)  Race, n (%)   White  30 (100.0%)  BMI (kg/m2)   Mean ± SD  23.81 ± 3.27   Range  19.1-32.0  Pretreatment Merz score, n (%)   2  20 (66.7%)   3  9 (30.0%)   4  1 (3.3%)  Fitzpatrick skin type, n (%)   Type I  1 (3.3%)   Type II  7 (23.3%)   Type III  18 (60.0%)   Type IV  4 (13.3%)  BMI, body mass index. View Large All patients were treated bilaterally for the nasolabial fold. The investigators utilized standard clinical practices in administration of local anesthetic (ie, lidocaine), which consisted of mixing with RPC Pure-Collagen prior to injection. Mean injected volumes during the initial treatment were 1.69 (0.49) mL (mean [SD]). Fifty per cent (50%) of patients received a touch up at the first follow-up visit, one week after the initial treatment, while the rest did not receive any touch up. The decision to provide a touch up at the discretion of the physician after evaluation of the patient. The average injected volume among the touch ups was 0.86 (0.28) mL (mean [SD]) (Table 2). Participants rated the injections as mildly painful during the procedure with a median value of 4 in a 10-point scale. The pain was transient at injection, as it substantially reduced in 10 min, with participants reporting a median of 2 points on the pain scale. Figures 1 and 2 show representative images of participants before, directly after injection, 12 weeks after treatment, and 9 months after treatment (Figure 2). Table 2. Injection Volume Visit  Injection (mL)  Week 0 (visit 2)  No. of patients  30  Mean (SD)  1.69 (0.49)  Range  0.7-3.0  Week 1 (visit 3)  No. of patients  15  Mean (SD)  0.86 (0.28)  Range  0.4-1.3  Visit  Injection (mL)  Week 0 (visit 2)  No. of patients  30  Mean (SD)  1.69 (0.49)  Range  0.7-3.0  Week 1 (visit 3)  No. of patients  15  Mean (SD)  0.86 (0.28)  Range  0.4-1.3  View Large Table 2. Injection Volume Visit  Injection (mL)  Week 0 (visit 2)  No. of patients  30  Mean (SD)  1.69 (0.49)  Range  0.7-3.0  Week 1 (visit 3)  No. of patients  15  Mean (SD)  0.86 (0.28)  Range  0.4-1.3  Visit  Injection (mL)  Week 0 (visit 2)  No. of patients  30  Mean (SD)  1.69 (0.49)  Range  0.7-3.0  Week 1 (visit 3)  No. of patients  15  Mean (SD)  0.86 (0.28)  Range  0.4-1.3  View Large Figure 1. View largeDownload slide Representative photographs of a 41-year-old woman (A) before, (B) directly posttreatment, and (C) 12 weeks posttreatment. Figure 1. View largeDownload slide Representative photographs of a 41-year-old woman (A) before, (B) directly posttreatment, and (C) 12 weeks posttreatment. Figure 2. View largeDownload slide Representative photographs of a 48-year-old woman (A) before, (B) directly posttreatment, (C) 12 weeks posttreatment, and (D) 9 months posttreatment. Figure 2. View largeDownload slide Representative photographs of a 48-year-old woman (A) before, (B) directly posttreatment, (C) 12 weeks posttreatment, and (D) 9 months posttreatment. Evaluation of Safety The primary purpose of the study was to evaluate the safety of RPC Pure-Collagen over 12 weeks follow up after the initial treatment. Injection site reactions were reported systematically at each follow-up visit and separately from other adverse events. No adverse events that were not injection site reactions were reported as related to the device or procedure by the investigator. There were no serious adverse events and no unanticipated adverse device effects during the study. Injection site reactions were recorded for overall incidence, and incidence of bruising, redness, swelling, tenderness, itching, induration, and “other” by the investigator. Eighty per cent (80% [24/30]) of participants had at least 1 injection site reaction after the initial injection and 40.0% (6/15) of the participants having a touch up experienced at least one injection site reaction after the touch up. All injection site reactions were mild or moderate in severity except for one case of severe bruising reported at the 1-week follow-up visit for a participant not receiving a touch up. Injection site reactions had mainly resolved by the next follow-up visit, with only 31% of participants having any injection site reaction at week 1, prior to any touch up. At week 4, only 1 injection site reaction was reported. This was a case of mild induration that resolved before the last follow-up visit. At the last follow-up visit (week 12), no injection site reactions were reported by the investigator. Injection site reactions were also reported directly by the patients in parallel to the investigator reporting. Patients tended to report more injection site reactions, but the profile and resolution pattern were consistent with the reports from the investigator. All patients receiving treatment reported the presence of some injection site reaction after treatment, both for the initial injection and for the touch-up injections. Similar to the investigator reporting, the majority of injection site reactions had resolved before the next follow-up visit, with only 55% of participants reporting any injection site reaction at week 1 before any touch up. Table 3 presents all injection site reactions as reported by the investigator at follow-up visit. Table 3. Injection Site Reactions by Investigator (safety analysis set, n = 30) Adverse reaction  Posttreatment (N = 30)  Pretouch-up week 1 (N = 29)  Posttouch up (N = 15)  Week 4 (N = 29)  Week 12 (N = 28)  Overall incidence  24 (80.0%)  9 (31.0%)  6 (40.0%)  1 (3.4%)  0  Bruising  5 (16.7%)  7 (24.1%)  2 (13.3%)  0  0  Redness  24 (80.0%)  2 (6.9%)  5 (33.3%)  0  0  Swelling  10 (33.3%)  4 (13.8%)  0  0  0  Tenderness  13 (43.3%)  5 (17.2%)  3 (20.0%)  0  0  Itching  1 (3.3%)  1 (3.4%)  1 (6.7%)  0  0  Induration  12 (40.0%)  0  0  1 (3.4%)  0  Other  0  0  0  0  0  Adverse reaction  Posttreatment (N = 30)  Pretouch-up week 1 (N = 29)  Posttouch up (N = 15)  Week 4 (N = 29)  Week 12 (N = 28)  Overall incidence  24 (80.0%)  9 (31.0%)  6 (40.0%)  1 (3.4%)  0  Bruising  5 (16.7%)  7 (24.1%)  2 (13.3%)  0  0  Redness  24 (80.0%)  2 (6.9%)  5 (33.3%)  0  0  Swelling  10 (33.3%)  4 (13.8%)  0  0  0  Tenderness  13 (43.3%)  5 (17.2%)  3 (20.0%)  0  0  Itching  1 (3.3%)  1 (3.4%)  1 (6.7%)  0  0  Induration  12 (40.0%)  0  0  1 (3.4%)  0  Other  0  0  0  0  0  N, number of patients with nonmissing values. View Large Table 3. Injection Site Reactions by Investigator (safety analysis set, n = 30) Adverse reaction  Posttreatment (N = 30)  Pretouch-up week 1 (N = 29)  Posttouch up (N = 15)  Week 4 (N = 29)  Week 12 (N = 28)  Overall incidence  24 (80.0%)  9 (31.0%)  6 (40.0%)  1 (3.4%)  0  Bruising  5 (16.7%)  7 (24.1%)  2 (13.3%)  0  0  Redness  24 (80.0%)  2 (6.9%)  5 (33.3%)  0  0  Swelling  10 (33.3%)  4 (13.8%)  0  0  0  Tenderness  13 (43.3%)  5 (17.2%)  3 (20.0%)  0  0  Itching  1 (3.3%)  1 (3.4%)  1 (6.7%)  0  0  Induration  12 (40.0%)  0  0  1 (3.4%)  0  Other  0  0  0  0  0  Adverse reaction  Posttreatment (N = 30)  Pretouch-up week 1 (N = 29)  Posttouch up (N = 15)  Week 4 (N = 29)  Week 12 (N = 28)  Overall incidence  24 (80.0%)  9 (31.0%)  6 (40.0%)  1 (3.4%)  0  Bruising  5 (16.7%)  7 (24.1%)  2 (13.3%)  0  0  Redness  24 (80.0%)  2 (6.9%)  5 (33.3%)  0  0  Swelling  10 (33.3%)  4 (13.8%)  0  0  0  Tenderness  13 (43.3%)  5 (17.2%)  3 (20.0%)  0  0  Itching  1 (3.3%)  1 (3.4%)  1 (6.7%)  0  0  Induration  12 (40.0%)  0  0  1 (3.4%)  0  Other  0  0  0  0  0  N, number of patients with nonmissing values. View Large The case of severe bruising reported by the investigator was also reported as severe by the patient. There was one additional injection site reaction reported as severe by the patient. This was a case of redness at the week 1 visit which was rated as mild in severity by the investigator. The patient further reported redness of moderate and mild severity at pre- and posttouch up, respectively, and no redness as subsequent visits. The investigator reported no redness from the week 4 visit onwards. Patients evaluated the treatment area as smooth and not looking irritated over time. Consistently over 90% of the patients at all follow-up visits 1 week after treatment of later, “agreed” or “strongly agreed” with the statement that “The treatment area is smooth (no lumps).” And right after the injection treatment, at initial and touch-up treatments respectively, 77% and 87% “agreed” or “strongly agreed” with this statement. Consistent with the reported injection site reactions, most patients felt that the treated area looked irritated right after treatment, at 67% and 60% after initial treatment and after touch up, respectively, who “agree” or “strongly agree” with the statement “Facial area that was treated looks irritated.” However, the majority, 76% or more, of the patients disagreed with this statement at follow-up visits 1 week or later after treatment. Evaluation of Performance In addition to the safety evaluation, the study included performance measurements as an early indicator of the effectiveness of RPC Pure-Collagen for facial contouring. The Merz Aesthetic Scale and the GAIS were rated at each follow-up visit by the investigator, the participant, and the blinded evaluator, by using photographs. All three assessors presented a similar pattern of mean GAIS scores over time, with the investigator scores being numerically higher than for the other assessors. GAIS scores by all three assessors showed high improvement upon treatment and maintained a significant improvement at the end of the study. Statistically significant improvement from pretreatment to the end of the study (week 12) was shown for all assessors (Figure 3), confirmed by t test and Wilcoxon signed rank test (P < 0.001) at all time points (after, 1 week, 4 weeks, and 12 weeks) and for all assessors (physician, participant, and blinded evaluator), meaning that there has been an improvement according to GAIS. Consistent with the GAIS scores, Merz Aesthetic Scores by all three assessors showed a statistically significant improvement through the end of the study (week 12) with a mean improvement from pretreatment to end of study of between 0.7 and 1.1 points for the three assessors (Figure 4). Figure 3. View largeDownload slide Mean Merz Aesthetic Scale score over time, all assessors (safety analysis set, n = 30). Figure 3. View largeDownload slide Mean Merz Aesthetic Scale score over time, all assessors (safety analysis set, n = 30). Figure 4. View largeDownload slide Mean Global Aesthetic Improvement Scale Score over time, all assessors (safety analysis set, n = 30). Figure 4. View largeDownload slide Mean Global Aesthetic Improvement Scale Score over time, all assessors (safety analysis set, n = 30). Additional Follow Up Nine patients at one of the investigational sites who achieved optimal correction were followed up at 6 and 9 months after treatment. There were no late-onset adverse events or site reactions through the 9 months follow up and there were no injection site reactions reported by these cohort during this extension. The correction resulted in an over one-point correction from the pretreatment on the Merz Aesthetic scale from pretreatment at 6 months as evaluated by the investigator. Both investigator and participant assessments on the Merz Aesthetic scale presented over a half point improvement from pretreatment to 9 months. On the GAIS scale at 9 months, the mean scores were 0.88 points and 1.22 points among participants and investigator, respectively, on a scale where 1 = improved (Table 4). Table 4. Extended Follow-Up (n = 9) Parameter  6 month (visit 6)  9 month (visit 7)  Injection site reaction  0  0  Other adverse events  0  0  Merz Aesthetic Scale, change from pre-treatment (mean ± SD)  Patients  NR  −1.33 ± 0.56  Investigator  −1.33 ± 0.56  −0.56 ± 0.53  Global Aesthetic Improvement Scale (mean ± SD)  Patient  0.75 ± 0.61  0.88 ± 0.64  Investigator  NR  1.22 ± 0.67  Parameter  6 month (visit 6)  9 month (visit 7)  Injection site reaction  0  0  Other adverse events  0  0  Merz Aesthetic Scale, change from pre-treatment (mean ± SD)  Patients  NR  −1.33 ± 0.56  Investigator  −1.33 ± 0.56  −0.56 ± 0.53  Global Aesthetic Improvement Scale (mean ± SD)  Patient  0.75 ± 0.61  0.88 ± 0.64  Investigator  NR  1.22 ± 0.67  NR, not recorded. View Large Table 4. Extended Follow-Up (n = 9) Parameter  6 month (visit 6)  9 month (visit 7)  Injection site reaction  0  0  Other adverse events  0  0  Merz Aesthetic Scale, change from pre-treatment (mean ± SD)  Patients  NR  −1.33 ± 0.56  Investigator  −1.33 ± 0.56  −0.56 ± 0.53  Global Aesthetic Improvement Scale (mean ± SD)  Patient  0.75 ± 0.61  0.88 ± 0.64  Investigator  NR  1.22 ± 0.67  Parameter  6 month (visit 6)  9 month (visit 7)  Injection site reaction  0  0  Other adverse events  0  0  Merz Aesthetic Scale, change from pre-treatment (mean ± SD)  Patients  NR  −1.33 ± 0.56  Investigator  −1.33 ± 0.56  −0.56 ± 0.53  Global Aesthetic Improvement Scale (mean ± SD)  Patient  0.75 ± 0.61  0.88 ± 0.64  Investigator  NR  1.22 ± 0.67  NR, not recorded. View Large DISCUSSION This study evaluated the safety of an advanced technology, based on bio-dermal restoration, for its use in facial contouring, by treating moderate-to-severe nasolabial folds. The study results show no device or procedure related adverse events other than transient and mild-to-moderate injection site reactions that are common to trans-dermal injection procedures. Thereby this study provides evidence that RPC Pure-Collagen is safe for its intended use. Of note, there were no reports of late-onset lumps or nodules, by either the investigator or the patient, which speaks to the potential for smooth and less palpable results that are expected with bio-dermal restoration mechanisms, as compared to filling approaches. This is further supported by the responses of patients regarding the appearance of the treated area, where over 90% of patients at each follow-up visit 1 week after treatment or later agreed that the treatment area “is smooth (no lumps).” RPC Pure-Collagen is injected as a liquid using thin 27-31 Ga cannulae or needles that allow for precise placement. The product is placed intradermally or subdermally, as with many other aesthetic products, and therefore will feel familiar to most physicians. Direct experience during the treatment injections, indicated no need to overcompensate or undercompensate the injected volume for the desired result, a desirable feature to obtain predictable results and facilitate achievement of optimal correction. Since the primary purpose of the study was the evaluation of safety, it has some limitations when evaluating performance. One limitation is on the sample size, as it was determined based on safety needs and therefore the study was not performed to show effectiveness. Illustrating this point, of the 16 patients that may have been followed up to 9 months, only nine were followed as the other patients had not achieved optimal correction. In addition, the investigators opted for limited touch up with only 50% of the patients receiving second injections. Long-term follow up for a larger sample size would also be desirable to confirm long-term results. Despite these limitations, the study showed a statistically significant duration of effects at 12 weeks, with significant improvement from pretreatment, both as evaluated by the investigator and the patients; and a potential for long-term duration through 9 months. These are encouraging results that hold great promise for this advanced technology. This study adds to the knowledge base by presenting a new technology, and thereby a new option, for the treatment of wrinkles and folds. Additional studies will be needed to confirm these results and the long-term effectiveness, appearance, and feel of bio-dermal restoration with RPC Pure-Collagen. CONCLUSIONS This first study shows that RPC Pure-Collagen is safe for its use in facial contouring and provides good indication for long-term safety showing no signs of hypersensitivity. Performance results are encouraging in the potential for bio-dermal restoration with RPC Pure-Collagen as an advanced and distinct tool for safe and lasting results in the aesthetic treatment of the face. Additional studies will be needed to confirm the long-term results and its use in other areas of the face, beyond the nasolabial folds. Disclosures Dr Inglefield is Lead Medical Advisor and Dr DeVore is Chief Scientific Officer for EternoGen Aesthetics, LLC. Drs Samuelson and Landau declared no potential conflicts of interest with respect to the research, authorship, and publication of this article. Funding The authors received no financial support for the research, authorship, and publication of this article. REFERENCES 1. Dayan S, Clark K, Ho AA. Altering first impressions after facial plastic surgery. Aesthetic Plast Surg . 2004; 28( 5): 301- 306. Google Scholar CrossRef Search ADS PubMed  2. Eppley BL, Dadvand B. Injectable soft-tissue fillers: clinical overview. Plast Reconstr Surg . 2006; 118( 4): 98e- 106e. Google Scholar CrossRef Search ADS PubMed  3. Murray CA, Zloty D, Warshawski L. The evolution of soft tissue fillers in clinical practice. Dermatol Clin . 2005; 23( 2): 343- 363. Google Scholar CrossRef Search ADS PubMed  4. Fisher GJ, Varani J, Voorhees JJ. Looking older: fibroblast collapse and therapeutic implications. Arch Dermatol . 2008; 144( 5): 666- 672. Google Scholar CrossRef Search ADS PubMed  5. Howard D. Structural Changes Associated with Aging Skin. http://www.dermalinstitute.com/us/library/11_article_Structural_Changes_Associated_with_Aging_Skin.html. Accessed January 25, 2018. 6. Turner NJ, Badylak SF. Biologic scaffolds for musculotendinous tissue repair. Eur Cell Mater . 2013; 25: 130- 143. Google Scholar CrossRef Search ADS PubMed  7. Badylak SF, Brown BN, Gilbert TW, Daly KA, Huber A, Turner NJ. Biologic scaffolds for constructive tissue remodeling. Biomaterials . 2011; 32( 1): 316- 319. Google Scholar CrossRef Search ADS PubMed  8. Devore D, Zhu J, Brooks R, McCrate RR, Grant DA, Grant SA. Development and characterization of a rapid polymerizing collagen for soft tissue augmentation. J Biomed Mater Res A . 2016; 104( 3): 758- 767. Google Scholar CrossRef Search ADS PubMed  9. Narins RS, Carruthers J, Flynn TC, et al.   Validated assessment scales for the lower face. Dermatol Surg . 2012; 38( 2 Spec No.): 333- 342. Google Scholar CrossRef Search ADS PubMed  © 2018 The American Society for Aesthetic Plastic Surgery, Inc. Reprints and permission: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Aesthetic Surgery Journal Oxford University Press

Bio-Dermal Restoration With Rapidly Polymerizing Collagen: A Multicenter Clinical Study

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Oxford University Press
Copyright
© 2018 The American Society for Aesthetic Plastic Surgery, Inc. Reprints and permission: journals.permissions@oup.com
ISSN
1090-820X
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1527-330X
D.O.I.
10.1093/asj/sjy061
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Abstract

Abstract Background Despite the increasing popularity of facial contouring with hyaluronic acid, innovation has been limited to iterations that feature different particle sizes, concentrations, and degrees of crosslinking. Bio-dermal restoration is a new approach for correcting facial tissue defects by supplementing the natural dermal structure providing a scaffold for fibroblast adherence and proliferation. Objectives The purpose of the study was to evaluate the safety of RPC Pure-Collagen for the treatment of facial contours. Methods A prospective, multicenter, open-label study in 30 patients treated with RPC Pure-Collagen in the nasolabial fold and followed up to 12 weeks after injection. A subset of patients was further followed up to 9 months after treatment. RPC Pure-Collagen is a sterile, nonpyrogenic, viscous, clear solution composed of pure porcine collagen ethylenediamine tetraacetic acid (EDTA) and Mannitol that can be injected through a 30 gauge needle as a liquid and fibrilizes in situ forming a natural, open 3-dimensional collagen matrix for bio-dermal restoration. Results No treatment related adverse events were noted in addition to transient injection site reactions typical to injection procedures, which were mild or moderate in severity except for one case of severe bruising. There were no reports of hypersensitivity, supporting that RPC Pure Collagen does not require skin testing prior to treatment. Performance results showed a significant improvement from baseline upon treatment, and at the end of the study, on both the Merz Aesthetic Scale and the Global Aesthetic Improvement Scale assessments. Conclusions This initial study shows that RPC Pure-Collagen is safe for its use in facial contouring and provides good indication for long-term safety. Bio-dermal restoration with RPC Pure-Collagen holds promise as safe, lasting, and natural facial contouring treatment. Level of Evidence: 4 Facial contouring to regain a more youthful look, correct defects, and smooth facial folds and contours has gained popularity over the last decade. Facial contouring can be achieved in a number of ways including traditional cosmetic surgery and minimally invasive procedures through the use of dermal fillers. Since the introduction of hyaluronic acid dermal fillers now nearly two decades ago, innovation in the space to not only fill dermal defects but to also restore deficient dermal tissue has been limited. Primary advances have been concentrated on modifying the physical properties of hyaluronic acid compositions for application in different facial tissue locations and on developing more durable alternative compositions for correcting dermal deficiencies. A key focus for development of next generation filler technologies has been on making products that are less palpable and not detectable once injected, reflecting the consumer’s desire for natural-looking, natural-feeling results with natural dynamics. During natural or chronological aging of the skin, collagen, and elastin, major structural proteins in the dermis, are produced at a slower rate affecting the ability of the skin to resist mechanical stress and affecting its ability to repair itself. The reduction of collagen (particularly Type I and III procollagen) results in this thinner dermis.1-3 In fact, the dermis can lose from 20% to 80% of its thickness.4 The skin aging process starts with collagen scaffold loss leading to fibroblast and skin collapse and loss of elasticity, which in turn leads to the appearance of wrinkles, folds, and facial contour changes.5 An ideal Biodermal Restoration construct would: (1) promote fibroblast attachment to stimulate neocollagenesis; (2) be easy and precise to inject; (3) form a natural open 3-dimensional (3D) scaffold to not restrict cell migration; and (4) slowly break down stimulating growth factors and cytokines to promote neocollagenesis, elastic fiber production, neovascularization, and the wound healing response/repair.6,7 Such a construct can not only fill in a contour deficiency or wrinkle upon injection to provide immediate contour stable results, but also recreates extracellular matrix in the specific site for more natural, long-lasting effects and thus achieving bio-dermal restoration. Bio-dermal restoration includes a continuous process by which tissue-engineered scaffolds undergo complementary degradation and remodeling processes to become replaced by new, organized host tissue that is infiltrated with cells and new vasculature. Animal studies have demonstrated that RPC Pure-Collagen mode of action delivers bio-dermal restoration.8 RPC Pure-Collagen is injected as liquid that polymerizes through the natural fibrillization process in the skin to form an open natural 3D matrix which acts as a substrate/scaffold for host cell adherence and proliferation restoring tissue and replacing the native skin scaffold. RPC Pure-Collagen is a novel technology providing bio-dermal restoration as a new approach to correct facial defects, aiming at natural lasting results both in look, feel, and dynamics. Based on collagen, the structural and most prevalent component of the skin, and other well-known biocompatible materials to provide a good safety profile, RPC Pure-Collagen restores the dermal tissue structures and thickness lost during the ageing process with a lasting noncrosslinked collagen scaffold. Significantly differentiating RPC Pure-Collagen from other fillers is that fact that although it is not crosslinked, ethylenediamine tetraacetic acid (EDTA) shields it from degradation in vivo providing longer effects than previous noncrosslinked collagens. One of the limitations of the present filling approach to facial contouring is the appearance of areas that are hardened or look inflated. These limitations become more prominent in challenging indications, such as superficial skin rejuvenation and peri-oral and peri-orbital contouring. Facial contouring through bio-dermal restoration holds a potential to reduce or avoid areas that look inflated or are hardened because it restores the natural tissue structures rather than simply volumizing the depleted areas. Therefore, bio-dermal restoration has the potential of resolving some of the limitations of dermal fillers providing an alternative approach to facial contouring. METHODS This was a prospective, multicenter, open-label study in 30 patients seeking correction for contour deficiencies and soft tissue correction in the nasolabial folds. Patients were included at 2 clinical sites, one in London and one in Stockholm. The first patient was enrolled in November of 2014 and the study was closed in August of 2015. The purpose of the study was to evaluate the safety of RPC Pure-Collagen for the treatment of facial contours such as nasolabial folds. RPC Pure-Collagen is an advanced technology for bio-dermal restoration. RPC Pure-Collagen is a sterile, nonpyrogenic, clear solution composed of molecules of pure porcine collagen (nonfibrillar) and EDTA to provide an in situ polymerizable composition of neutral pH. The EDTA stabilizer also serves to bind (and deactivate) surrounding calcium ions providing integral protection against collagenase degradation, thereby prolonging duration. This degradation-resistance approach is crosslink free, thereby maximizing biocompatibility and optimizing rapid host cell infiltration. RPC Pure-Collagen is injected as a liquid allowing for precise placement and easy molding. The solution polymerizes in situ forming a contour-stable open 3D collagen to allow for bio-dermal restoration. Patients fulfilling the inclusion criteria and who had provided written informed consent were treated with RPC Pure-Collagen on the nasolabial folds. Patients seeking treatment for the nasolabial folds between the age of 30 and 65 and with a pretreatment Merz Aesthetic Score of at least 2 were considered for the study. Main exclusion criteria included previous treatment with a permanent filler or a resorbable filler in the last 6 months, allergy to product components, history of chronic debilitating systemic diseases, autoimmune diseases, malignancy and bleeding disorders, participants under immunosuppressive therapy, and participants with infectious, inflammatory, (pre-)cancerous lesions or unhealed wounds in the treatment area. Pregnant and breastfeeding females were also excluded from participation. A skin test was not required as part to the treatment. Participants were injected intradermally or subdermally using a thin needle or cannula (27-31Ga) with a maximum of 2 mL of RPC Pure-Collagen per side. Use of local anesthesia was at the discretion of the investigator, following the standard practice at the site. Patients who received treatment were followed at 1 week, where there was a possibility for a touch up, and at 4 weeks and 12 weeks after treatment. At each follow-up visit, patients were evaluated for safety, including adverse events and treatment site reactions. Both investigators and patients rated the presence and severity of the following injection site reactions, separately of other adverse events: bruising, redness, swelling, tenderness, itching, induration, and other injection site reactions. In addition, treatment areas were assessed for performance by the investigator and the patient with the Merz Aesthetic Scale,9 a 5-point scale from 0 to 4 where: 0) no wrinkles, 4) deeper wrinkles at rest and deeper furrows with facial expression; and the Global Aesthetic Improvement Scale (GAIS), a 7-point scale: 3) very much improved, 2) much improved, 1) improved, 0) no change, −1) worse, −2) much worse, −3) very much worse. Standardized photographs of the treated area were taken at pretreatment and at each follow-up visit and were used for an additional scoring of the Merz Aesthetic Scale and GAIS by a blinded evaluator. The assessments were linked to the individual via patient number such that a subset of patients could be pulled to track over time. This allowed the complete data sets to be generated at the conclusion of the study and patient dropouts could be removed if necessary. Participants at one of the investigational sites who achieved optimal correction, as evaluated by the investigator, were followed for an additional follow-up period 6 months and 9 months after treatment. All participants provided written informed consent pursuant to the Declaration of Helsinki requirements and local/country specific regulations. Prior to enrollment, the study was approved by the relevant ethics committees: the Health Research Authority NRES Committee in the United Kingdom and Regionala Etikprövningsnämnderna (Ethical Review Board) in Stockholm, Sweden. RESULTS A total of 30 patients were enrolled and treated in the study. One additional patient was enrolled and withdrawn before treatment due to mild severity of the nasolabial folds, while the study required moderate or severe severity. Of the 30 treated patients, one was lost to follow up before the last visit and one agreed to send the questionnaires for the last visit but did not attend the office visit. All enrolled patients were white and all but one (97%) were female, with a mean age of 49.3 years (range, 38-64 years). The majority of the participants (60%) had a Fitzpatrick skin type III (Table 1). Table 1. Demographic Characteristics (safety analysis set, n = 30) Age (years)   Mean ± SD  49.3 ± 7.7   Range  38-64  Gender, n (%)   Female  29 (96.7%)   Male  1 (3.3%)  Race, n (%)   White  30 (100.0%)  BMI (kg/m2)   Mean ± SD  23.81 ± 3.27   Range  19.1-32.0  Pretreatment Merz score, n (%)   2  20 (66.7%)   3  9 (30.0%)   4  1 (3.3%)  Fitzpatrick skin type, n (%)   Type I  1 (3.3%)   Type II  7 (23.3%)   Type III  18 (60.0%)   Type IV  4 (13.3%)  Age (years)   Mean ± SD  49.3 ± 7.7   Range  38-64  Gender, n (%)   Female  29 (96.7%)   Male  1 (3.3%)  Race, n (%)   White  30 (100.0%)  BMI (kg/m2)   Mean ± SD  23.81 ± 3.27   Range  19.1-32.0  Pretreatment Merz score, n (%)   2  20 (66.7%)   3  9 (30.0%)   4  1 (3.3%)  Fitzpatrick skin type, n (%)   Type I  1 (3.3%)   Type II  7 (23.3%)   Type III  18 (60.0%)   Type IV  4 (13.3%)  BMI, body mass index. View Large Table 1. Demographic Characteristics (safety analysis set, n = 30) Age (years)   Mean ± SD  49.3 ± 7.7   Range  38-64  Gender, n (%)   Female  29 (96.7%)   Male  1 (3.3%)  Race, n (%)   White  30 (100.0%)  BMI (kg/m2)   Mean ± SD  23.81 ± 3.27   Range  19.1-32.0  Pretreatment Merz score, n (%)   2  20 (66.7%)   3  9 (30.0%)   4  1 (3.3%)  Fitzpatrick skin type, n (%)   Type I  1 (3.3%)   Type II  7 (23.3%)   Type III  18 (60.0%)   Type IV  4 (13.3%)  Age (years)   Mean ± SD  49.3 ± 7.7   Range  38-64  Gender, n (%)   Female  29 (96.7%)   Male  1 (3.3%)  Race, n (%)   White  30 (100.0%)  BMI (kg/m2)   Mean ± SD  23.81 ± 3.27   Range  19.1-32.0  Pretreatment Merz score, n (%)   2  20 (66.7%)   3  9 (30.0%)   4  1 (3.3%)  Fitzpatrick skin type, n (%)   Type I  1 (3.3%)   Type II  7 (23.3%)   Type III  18 (60.0%)   Type IV  4 (13.3%)  BMI, body mass index. View Large All patients were treated bilaterally for the nasolabial fold. The investigators utilized standard clinical practices in administration of local anesthetic (ie, lidocaine), which consisted of mixing with RPC Pure-Collagen prior to injection. Mean injected volumes during the initial treatment were 1.69 (0.49) mL (mean [SD]). Fifty per cent (50%) of patients received a touch up at the first follow-up visit, one week after the initial treatment, while the rest did not receive any touch up. The decision to provide a touch up at the discretion of the physician after evaluation of the patient. The average injected volume among the touch ups was 0.86 (0.28) mL (mean [SD]) (Table 2). Participants rated the injections as mildly painful during the procedure with a median value of 4 in a 10-point scale. The pain was transient at injection, as it substantially reduced in 10 min, with participants reporting a median of 2 points on the pain scale. Figures 1 and 2 show representative images of participants before, directly after injection, 12 weeks after treatment, and 9 months after treatment (Figure 2). Table 2. Injection Volume Visit  Injection (mL)  Week 0 (visit 2)  No. of patients  30  Mean (SD)  1.69 (0.49)  Range  0.7-3.0  Week 1 (visit 3)  No. of patients  15  Mean (SD)  0.86 (0.28)  Range  0.4-1.3  Visit  Injection (mL)  Week 0 (visit 2)  No. of patients  30  Mean (SD)  1.69 (0.49)  Range  0.7-3.0  Week 1 (visit 3)  No. of patients  15  Mean (SD)  0.86 (0.28)  Range  0.4-1.3  View Large Table 2. Injection Volume Visit  Injection (mL)  Week 0 (visit 2)  No. of patients  30  Mean (SD)  1.69 (0.49)  Range  0.7-3.0  Week 1 (visit 3)  No. of patients  15  Mean (SD)  0.86 (0.28)  Range  0.4-1.3  Visit  Injection (mL)  Week 0 (visit 2)  No. of patients  30  Mean (SD)  1.69 (0.49)  Range  0.7-3.0  Week 1 (visit 3)  No. of patients  15  Mean (SD)  0.86 (0.28)  Range  0.4-1.3  View Large Figure 1. View largeDownload slide Representative photographs of a 41-year-old woman (A) before, (B) directly posttreatment, and (C) 12 weeks posttreatment. Figure 1. View largeDownload slide Representative photographs of a 41-year-old woman (A) before, (B) directly posttreatment, and (C) 12 weeks posttreatment. Figure 2. View largeDownload slide Representative photographs of a 48-year-old woman (A) before, (B) directly posttreatment, (C) 12 weeks posttreatment, and (D) 9 months posttreatment. Figure 2. View largeDownload slide Representative photographs of a 48-year-old woman (A) before, (B) directly posttreatment, (C) 12 weeks posttreatment, and (D) 9 months posttreatment. Evaluation of Safety The primary purpose of the study was to evaluate the safety of RPC Pure-Collagen over 12 weeks follow up after the initial treatment. Injection site reactions were reported systematically at each follow-up visit and separately from other adverse events. No adverse events that were not injection site reactions were reported as related to the device or procedure by the investigator. There were no serious adverse events and no unanticipated adverse device effects during the study. Injection site reactions were recorded for overall incidence, and incidence of bruising, redness, swelling, tenderness, itching, induration, and “other” by the investigator. Eighty per cent (80% [24/30]) of participants had at least 1 injection site reaction after the initial injection and 40.0% (6/15) of the participants having a touch up experienced at least one injection site reaction after the touch up. All injection site reactions were mild or moderate in severity except for one case of severe bruising reported at the 1-week follow-up visit for a participant not receiving a touch up. Injection site reactions had mainly resolved by the next follow-up visit, with only 31% of participants having any injection site reaction at week 1, prior to any touch up. At week 4, only 1 injection site reaction was reported. This was a case of mild induration that resolved before the last follow-up visit. At the last follow-up visit (week 12), no injection site reactions were reported by the investigator. Injection site reactions were also reported directly by the patients in parallel to the investigator reporting. Patients tended to report more injection site reactions, but the profile and resolution pattern were consistent with the reports from the investigator. All patients receiving treatment reported the presence of some injection site reaction after treatment, both for the initial injection and for the touch-up injections. Similar to the investigator reporting, the majority of injection site reactions had resolved before the next follow-up visit, with only 55% of participants reporting any injection site reaction at week 1 before any touch up. Table 3 presents all injection site reactions as reported by the investigator at follow-up visit. Table 3. Injection Site Reactions by Investigator (safety analysis set, n = 30) Adverse reaction  Posttreatment (N = 30)  Pretouch-up week 1 (N = 29)  Posttouch up (N = 15)  Week 4 (N = 29)  Week 12 (N = 28)  Overall incidence  24 (80.0%)  9 (31.0%)  6 (40.0%)  1 (3.4%)  0  Bruising  5 (16.7%)  7 (24.1%)  2 (13.3%)  0  0  Redness  24 (80.0%)  2 (6.9%)  5 (33.3%)  0  0  Swelling  10 (33.3%)  4 (13.8%)  0  0  0  Tenderness  13 (43.3%)  5 (17.2%)  3 (20.0%)  0  0  Itching  1 (3.3%)  1 (3.4%)  1 (6.7%)  0  0  Induration  12 (40.0%)  0  0  1 (3.4%)  0  Other  0  0  0  0  0  Adverse reaction  Posttreatment (N = 30)  Pretouch-up week 1 (N = 29)  Posttouch up (N = 15)  Week 4 (N = 29)  Week 12 (N = 28)  Overall incidence  24 (80.0%)  9 (31.0%)  6 (40.0%)  1 (3.4%)  0  Bruising  5 (16.7%)  7 (24.1%)  2 (13.3%)  0  0  Redness  24 (80.0%)  2 (6.9%)  5 (33.3%)  0  0  Swelling  10 (33.3%)  4 (13.8%)  0  0  0  Tenderness  13 (43.3%)  5 (17.2%)  3 (20.0%)  0  0  Itching  1 (3.3%)  1 (3.4%)  1 (6.7%)  0  0  Induration  12 (40.0%)  0  0  1 (3.4%)  0  Other  0  0  0  0  0  N, number of patients with nonmissing values. View Large Table 3. Injection Site Reactions by Investigator (safety analysis set, n = 30) Adverse reaction  Posttreatment (N = 30)  Pretouch-up week 1 (N = 29)  Posttouch up (N = 15)  Week 4 (N = 29)  Week 12 (N = 28)  Overall incidence  24 (80.0%)  9 (31.0%)  6 (40.0%)  1 (3.4%)  0  Bruising  5 (16.7%)  7 (24.1%)  2 (13.3%)  0  0  Redness  24 (80.0%)  2 (6.9%)  5 (33.3%)  0  0  Swelling  10 (33.3%)  4 (13.8%)  0  0  0  Tenderness  13 (43.3%)  5 (17.2%)  3 (20.0%)  0  0  Itching  1 (3.3%)  1 (3.4%)  1 (6.7%)  0  0  Induration  12 (40.0%)  0  0  1 (3.4%)  0  Other  0  0  0  0  0  Adverse reaction  Posttreatment (N = 30)  Pretouch-up week 1 (N = 29)  Posttouch up (N = 15)  Week 4 (N = 29)  Week 12 (N = 28)  Overall incidence  24 (80.0%)  9 (31.0%)  6 (40.0%)  1 (3.4%)  0  Bruising  5 (16.7%)  7 (24.1%)  2 (13.3%)  0  0  Redness  24 (80.0%)  2 (6.9%)  5 (33.3%)  0  0  Swelling  10 (33.3%)  4 (13.8%)  0  0  0  Tenderness  13 (43.3%)  5 (17.2%)  3 (20.0%)  0  0  Itching  1 (3.3%)  1 (3.4%)  1 (6.7%)  0  0  Induration  12 (40.0%)  0  0  1 (3.4%)  0  Other  0  0  0  0  0  N, number of patients with nonmissing values. View Large The case of severe bruising reported by the investigator was also reported as severe by the patient. There was one additional injection site reaction reported as severe by the patient. This was a case of redness at the week 1 visit which was rated as mild in severity by the investigator. The patient further reported redness of moderate and mild severity at pre- and posttouch up, respectively, and no redness as subsequent visits. The investigator reported no redness from the week 4 visit onwards. Patients evaluated the treatment area as smooth and not looking irritated over time. Consistently over 90% of the patients at all follow-up visits 1 week after treatment of later, “agreed” or “strongly agreed” with the statement that “The treatment area is smooth (no lumps).” And right after the injection treatment, at initial and touch-up treatments respectively, 77% and 87% “agreed” or “strongly agreed” with this statement. Consistent with the reported injection site reactions, most patients felt that the treated area looked irritated right after treatment, at 67% and 60% after initial treatment and after touch up, respectively, who “agree” or “strongly agree” with the statement “Facial area that was treated looks irritated.” However, the majority, 76% or more, of the patients disagreed with this statement at follow-up visits 1 week or later after treatment. Evaluation of Performance In addition to the safety evaluation, the study included performance measurements as an early indicator of the effectiveness of RPC Pure-Collagen for facial contouring. The Merz Aesthetic Scale and the GAIS were rated at each follow-up visit by the investigator, the participant, and the blinded evaluator, by using photographs. All three assessors presented a similar pattern of mean GAIS scores over time, with the investigator scores being numerically higher than for the other assessors. GAIS scores by all three assessors showed high improvement upon treatment and maintained a significant improvement at the end of the study. Statistically significant improvement from pretreatment to the end of the study (week 12) was shown for all assessors (Figure 3), confirmed by t test and Wilcoxon signed rank test (P < 0.001) at all time points (after, 1 week, 4 weeks, and 12 weeks) and for all assessors (physician, participant, and blinded evaluator), meaning that there has been an improvement according to GAIS. Consistent with the GAIS scores, Merz Aesthetic Scores by all three assessors showed a statistically significant improvement through the end of the study (week 12) with a mean improvement from pretreatment to end of study of between 0.7 and 1.1 points for the three assessors (Figure 4). Figure 3. View largeDownload slide Mean Merz Aesthetic Scale score over time, all assessors (safety analysis set, n = 30). Figure 3. View largeDownload slide Mean Merz Aesthetic Scale score over time, all assessors (safety analysis set, n = 30). Figure 4. View largeDownload slide Mean Global Aesthetic Improvement Scale Score over time, all assessors (safety analysis set, n = 30). Figure 4. View largeDownload slide Mean Global Aesthetic Improvement Scale Score over time, all assessors (safety analysis set, n = 30). Additional Follow Up Nine patients at one of the investigational sites who achieved optimal correction were followed up at 6 and 9 months after treatment. There were no late-onset adverse events or site reactions through the 9 months follow up and there were no injection site reactions reported by these cohort during this extension. The correction resulted in an over one-point correction from the pretreatment on the Merz Aesthetic scale from pretreatment at 6 months as evaluated by the investigator. Both investigator and participant assessments on the Merz Aesthetic scale presented over a half point improvement from pretreatment to 9 months. On the GAIS scale at 9 months, the mean scores were 0.88 points and 1.22 points among participants and investigator, respectively, on a scale where 1 = improved (Table 4). Table 4. Extended Follow-Up (n = 9) Parameter  6 month (visit 6)  9 month (visit 7)  Injection site reaction  0  0  Other adverse events  0  0  Merz Aesthetic Scale, change from pre-treatment (mean ± SD)  Patients  NR  −1.33 ± 0.56  Investigator  −1.33 ± 0.56  −0.56 ± 0.53  Global Aesthetic Improvement Scale (mean ± SD)  Patient  0.75 ± 0.61  0.88 ± 0.64  Investigator  NR  1.22 ± 0.67  Parameter  6 month (visit 6)  9 month (visit 7)  Injection site reaction  0  0  Other adverse events  0  0  Merz Aesthetic Scale, change from pre-treatment (mean ± SD)  Patients  NR  −1.33 ± 0.56  Investigator  −1.33 ± 0.56  −0.56 ± 0.53  Global Aesthetic Improvement Scale (mean ± SD)  Patient  0.75 ± 0.61  0.88 ± 0.64  Investigator  NR  1.22 ± 0.67  NR, not recorded. View Large Table 4. Extended Follow-Up (n = 9) Parameter  6 month (visit 6)  9 month (visit 7)  Injection site reaction  0  0  Other adverse events  0  0  Merz Aesthetic Scale, change from pre-treatment (mean ± SD)  Patients  NR  −1.33 ± 0.56  Investigator  −1.33 ± 0.56  −0.56 ± 0.53  Global Aesthetic Improvement Scale (mean ± SD)  Patient  0.75 ± 0.61  0.88 ± 0.64  Investigator  NR  1.22 ± 0.67  Parameter  6 month (visit 6)  9 month (visit 7)  Injection site reaction  0  0  Other adverse events  0  0  Merz Aesthetic Scale, change from pre-treatment (mean ± SD)  Patients  NR  −1.33 ± 0.56  Investigator  −1.33 ± 0.56  −0.56 ± 0.53  Global Aesthetic Improvement Scale (mean ± SD)  Patient  0.75 ± 0.61  0.88 ± 0.64  Investigator  NR  1.22 ± 0.67  NR, not recorded. View Large DISCUSSION This study evaluated the safety of an advanced technology, based on bio-dermal restoration, for its use in facial contouring, by treating moderate-to-severe nasolabial folds. The study results show no device or procedure related adverse events other than transient and mild-to-moderate injection site reactions that are common to trans-dermal injection procedures. Thereby this study provides evidence that RPC Pure-Collagen is safe for its intended use. Of note, there were no reports of late-onset lumps or nodules, by either the investigator or the patient, which speaks to the potential for smooth and less palpable results that are expected with bio-dermal restoration mechanisms, as compared to filling approaches. This is further supported by the responses of patients regarding the appearance of the treated area, where over 90% of patients at each follow-up visit 1 week after treatment or later agreed that the treatment area “is smooth (no lumps).” RPC Pure-Collagen is injected as a liquid using thin 27-31 Ga cannulae or needles that allow for precise placement. The product is placed intradermally or subdermally, as with many other aesthetic products, and therefore will feel familiar to most physicians. Direct experience during the treatment injections, indicated no need to overcompensate or undercompensate the injected volume for the desired result, a desirable feature to obtain predictable results and facilitate achievement of optimal correction. Since the primary purpose of the study was the evaluation of safety, it has some limitations when evaluating performance. One limitation is on the sample size, as it was determined based on safety needs and therefore the study was not performed to show effectiveness. Illustrating this point, of the 16 patients that may have been followed up to 9 months, only nine were followed as the other patients had not achieved optimal correction. In addition, the investigators opted for limited touch up with only 50% of the patients receiving second injections. Long-term follow up for a larger sample size would also be desirable to confirm long-term results. Despite these limitations, the study showed a statistically significant duration of effects at 12 weeks, with significant improvement from pretreatment, both as evaluated by the investigator and the patients; and a potential for long-term duration through 9 months. These are encouraging results that hold great promise for this advanced technology. This study adds to the knowledge base by presenting a new technology, and thereby a new option, for the treatment of wrinkles and folds. Additional studies will be needed to confirm these results and the long-term effectiveness, appearance, and feel of bio-dermal restoration with RPC Pure-Collagen. CONCLUSIONS This first study shows that RPC Pure-Collagen is safe for its use in facial contouring and provides good indication for long-term safety showing no signs of hypersensitivity. Performance results are encouraging in the potential for bio-dermal restoration with RPC Pure-Collagen as an advanced and distinct tool for safe and lasting results in the aesthetic treatment of the face. Additional studies will be needed to confirm the long-term results and its use in other areas of the face, beyond the nasolabial folds. Disclosures Dr Inglefield is Lead Medical Advisor and Dr DeVore is Chief Scientific Officer for EternoGen Aesthetics, LLC. Drs Samuelson and Landau declared no potential conflicts of interest with respect to the research, authorship, and publication of this article. Funding The authors received no financial support for the research, authorship, and publication of this article. REFERENCES 1. Dayan S, Clark K, Ho AA. Altering first impressions after facial plastic surgery. Aesthetic Plast Surg . 2004; 28( 5): 301- 306. Google Scholar CrossRef Search ADS PubMed  2. Eppley BL, Dadvand B. Injectable soft-tissue fillers: clinical overview. Plast Reconstr Surg . 2006; 118( 4): 98e- 106e. Google Scholar CrossRef Search ADS PubMed  3. Murray CA, Zloty D, Warshawski L. The evolution of soft tissue fillers in clinical practice. Dermatol Clin . 2005; 23( 2): 343- 363. Google Scholar CrossRef Search ADS PubMed  4. Fisher GJ, Varani J, Voorhees JJ. Looking older: fibroblast collapse and therapeutic implications. Arch Dermatol . 2008; 144( 5): 666- 672. Google Scholar CrossRef Search ADS PubMed  5. Howard D. Structural Changes Associated with Aging Skin. http://www.dermalinstitute.com/us/library/11_article_Structural_Changes_Associated_with_Aging_Skin.html. Accessed January 25, 2018. 6. Turner NJ, Badylak SF. Biologic scaffolds for musculotendinous tissue repair. Eur Cell Mater . 2013; 25: 130- 143. Google Scholar CrossRef Search ADS PubMed  7. Badylak SF, Brown BN, Gilbert TW, Daly KA, Huber A, Turner NJ. Biologic scaffolds for constructive tissue remodeling. Biomaterials . 2011; 32( 1): 316- 319. Google Scholar CrossRef Search ADS PubMed  8. Devore D, Zhu J, Brooks R, McCrate RR, Grant DA, Grant SA. Development and characterization of a rapid polymerizing collagen for soft tissue augmentation. J Biomed Mater Res A . 2016; 104( 3): 758- 767. Google Scholar CrossRef Search ADS PubMed  9. Narins RS, Carruthers J, Flynn TC, et al.   Validated assessment scales for the lower face. Dermatol Surg . 2012; 38( 2 Spec No.): 333- 342. Google Scholar CrossRef Search ADS PubMed  © 2018 The American Society for Aesthetic Plastic Surgery, Inc. Reprints and permission: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

Aesthetic Surgery JournalOxford University Press

Published: Mar 2, 2018

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