- Email: [email protected]
Immediate fat grafting in primary cleft lip repair
Journal of Plastic, Reconstructive & Aesthetic Surgery (2014) 67, 1644e1650
Immediate fat grafting in primary cleft lip repair Daniel M. Balkin a,b, Salem Samra a,b, Derek M. Steinbacher a,b,* a b
Yale University School of Medicine, New Haven, CT, USA Plastic and Reconstructive Surgery, Yale University School of Medicine, New Haven, CT, USA
Received 4 March 2014; accepted 18 August 2014
KEYWORDS Cleft lip; Fat graft; Adipose-derived stem cells; Scar; Wound healing
Summary Background: Successful cleft lip repair creates symmetric nasolabial morphology with minimal scar. Fat grafting is used in cosmetic and reconstructive settings to provide contour, condition tissue and aid healing. This study employs immediate fat grafting concurrent with primary cleft nasolabial repair. We hypothesize that simultaneous fat transfer is safe and may optimize the result. Methods: This retrospective analysis included a series of consecutive infants who underwent primary cleft lip repair with immediate fat grafting. Demographic and peri-operative details were recorded. Post-operative photographs were analyzed by three blinded reviewers (AlOmari et al. and Asher-McDade et al.). Kappa statistics were employed to assess inter-rater reliability (Randolph and Watkins MW). Results: 30 children, 37 sides (13 left, 10 right, 7 bilateral; 62% complete, 38% incomplete) who underwent cleft lip repair at Yale were included. 20 underwent nasolabial repair with simultaneous fat grafting. Mean age of repair was 3.5 mo (range 1.5e6.4). Fat was hand suctioned from the thighs (15 left; 2 right; 3 both) with mean yield of 2.1 cc (range 1e5 cc). An average of 1.4 cc (range 0.5e2.5 cc) was injected to the philtrum, vermillion, piriform and ala. No complications were experienced with lip repair, fat harvest or graft injection. Mean follow-up was 24.7 months (range 12.4e60.2 months). Postoperative photographic assessment revealed minimal residual cleft stigmata with inter-rater reliability. Each ordinal score was statistically significant compared fat grafted repairs to those without fat grafting (p < 0.05). Conclusions: Simultaneous fat grafting and cleft lip repair can be performed safely. The augmentation and modulation of scar formation may optimize results. Prospective comparison is necessary to further corroborate our findings. Level of evidence: Therapeutic (Level IV). ª 2014 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.
* Corresponding author. Yale University School of Medicine, 330 Cedar Street, New Haven, CT 06510, USA. Tel.: þ1 (203) 785 4559. E-mail addresses: [email protected], [email protected] (D.M. Steinbacher). http://dx.doi.org/10.1016/j.bjps.2014.08.049 1748-6815/ª 2014 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.
Immediate fat grafting in primary cleft lip repair
Introduction Cleft lip with or without cleft palate is the most common congenital craniofacial anomaly.5 Embryologically, cleft lip results from a failed fusion of the maxillary and medial nasal processes. This defect results in a deformity of the nasolabial complex, with a complete cleft exhibiting the most significant structural displacement.6 A myriad of repair techniques and presurgical cleft protocols have been described with conserved goals to align the lip and nose in an “anatomically correct” fashion.7e18 While aligning lip landmarks is essential to performing a cleft lip nasolabial repair, the most natural result requires reestablishing the normal contours of the nasolabial region, blending the incision along subunits and minimizing scar caliber. Intrinsic to the anomaly, clefted tissues are displaced and nasolabial structures are hypoplastic.19,20 The described cleft lip repair techniques require tissue to be discarded and consequently do not convey nor supplement additional tissue to the nasolabial complex. Therefore, even in the best of repairs the contours of the reconstructed lip and nose may be blunted and not adequately supported. In addition to topographic differences, scar formation impacts the success of a repaired cleft lip. Scarring is a constant and unavoidable aspect of wound healing, and several factors likely contribute to scar caliber, including suture type, duration of suture placement, tissue tension and the child’s intrinsic healing capacity.21e24 Undue scarring following cleft lip repair may cede secondary deformities of the lip and nose, including wide or pigmented scars, lip landmark distortion, vermilion irregularities as well as nasal deformities. Taken together, the repaired cleft lip stigmata result from insufficient nasolabial support, improper landmark alignment and excessive scar formation. Such asymmetries draw attention and therefore lessen the overall success of the cleft lip repair. Fat transfer techniques have demonstrated utility in the correction of a host of deformities through soft tissue augmentation.25e31 More recently, there is evidence that fat grafts harbor stem cells,32e34 termed adipose-derived stem cells (ADSCs), and that these pluripotent cells produce factors beneficial for wound healing and regeneration.35e40 This autogenous tissue may also improve scar caliber and minimize scar burden.36,40 Research from our group has recently revealed that infant-derived ADSCs are more biologically robust than those obtained from adult tissue.37 The purpose of this study is to analyze immediate fat grafting in the primary cleft lip nasolabial repair. Given such favorable biophysical and biochemical properties, we postulate that the introduction of fat grafting will prove beneficial in the infant cleft lip population by recreating lip/nasal contours through tissue support and augmentation and that infant-derived ADSCs will assist the wound healing and regenerative process to minimize scar burden.
Methods A retrospective analysis was performed in accordance with the Yale University Human Investigation Committee
1645 (#1209010767). A consecutive series of infants who underwent primary cleft lip repair with simultaneous fat grafting were included. A group who underwent primary repair without fat grafting were included as comparison. Demographic information, perioperative, and post-operative details were recorded. Continuous variables were summarized using mean and range, and categorical variables using frequencies and percentages. Three blinded reviewers analyzed photographs to assess the residual cleft-related facial stigmata (overall appearance of the full face, upper lip, nose and midface) using the following five-point ordinal scale: 1 Z nonvisible stigmata (very good appearance); 2 Z barely visible (good appearance); 3 Z slightly visible (fair appearance); 4 Z moderately visible (poor appearance); 5 Z very visible (very poor appearance).1,2 The percent of overall agreement (Po) and the free-marginal kappa (kappa),3 a chance-adjusted measure of multi-rater agreement in which raters’ distributions of cases into categories are not restricted, were analyzed using the software package MacKappa.4
Results Demographics Children who underwent cleft lip repair at the Yale-New Haven Hospital. 30 infants, 37 sides, aged 1.5e6.4 months (mean 3.5 months), were included. 20 underwent repair with simultaneous primary fat grafting (Table 1). The cleft lip sidedness was 13 left, 10 right and 7 bilateral. 62% of the cleft lip anomalies were complete, while 38% were incomplete (Table 1).
Surgical procedure The cleft lip repair technique employed for unilateral cases was the modified inferior triangle technique or rotation advancement,10 while bilateral lips were repaired using a variation of the standard repair.13 In fat injection cases, fat was harvested from one or both thighs in all instances (15 left leg only; 2 right leg only; 3 both legs; operative time approximately 10 min) using manual suction as previously described (Table 2).38,39 An average of 1e3 cc of 1% lidocaine (1:100,000 epinephrine) was injected at the donor site. No tumescent was used. Aspirated fat was strained on Telfa and transferred to a 1 cc syringe. Fat was white and of dense consistency without significant heme (Figure 1). The graft harvest yield was 2.1 cc (mean) (range 1e5 cc) and
Table 1
þFG FG
Patient demographics. Subjects
Age at operation (months)
Gender
Diagnosis
N Z 20 N Z 10 N Z 30
3.9 3.2 3.5
12F:8M 5F:5M 17F:13M
7L:8R:5B 5L:2R:2B 13L:10R:7B
Gender: male (M) and female (F); Lip diagnosis: unilateral (U), bilateral (BL), complete (C) and incomplete (IN).
1646 Table 2
D.M. Balkin et al.
Perioperative care
Fat grafting.
Harvest site
Fat yield
Fat injected
15L:2R:3B
1e3 cc
0.5e2.5 cc
Fat harvest site from thighs: left (L), right (R) and bilateral (BL).
1.4 cc (mean) (range 0.5e2.5 cc) was injected into the cleft side philtril column(s), vermillion, piriform and ala using a 19 gauge needle on a 1 cc syringe in 0.10 cc aliquots (Figures 1 and 2, Table 2). The fat was deposited submucosally (at the vermillion/mucosal junction); subcutaneously and intra-muscular (along the phitrum); and preperiosteal at the piriform rim; as the final stage following all suture placement.
The mean operative time was 2.1 h (range 1.4e3.4 h) (Table 2). All patients were discharged one to two days postoperatively tolerating oral feeds (mean 1.2 days). Scar care included steristrips for two weeks, then vitamin E for two weeks, followed by silicone gel and gentle massage for subsequent months. Mean follow-up was 24.7 months (range 12.4e60.2 months).
Scar and nasolabial anatomical analyses Standardized post-operative photographs were analyzed by three blinded reviewers and the residual cleft-related deformity was scored independently using a described assessment (Figure 3).1,2 Presented examples represent a
Figure 1 Intraoperative use of fat grafting in primary cleft lip repair. (A) Syringe filled with infant fat graft; and (B) Representative example of 0.1 cc aliquot injections into ala, piriform, philtrum and vermillion border.
Figure 2 Sites of fat graft injection. Frontal (left) and submental (right) photographs of the nasolabial complex. Sites of fat graft injection indicated.
Immediate fat grafting in primary cleft lip repair
1647
Figure 3 Pre- and post-operative photographs. Four patients pre-operative (left) and post-operative (right), which represent various cleft severities and different ethnicities. Post-operative photographs of unilateral and bilateral cases were acquired at 6 and 12 months, respectively.
1648
D.M. Balkin et al.
variety of ethnic backgrounds, some of which may be more prone to wide or obvious scars (Figure 3). Statistical analyses revealed the following percent of overall agreement within fat grafted subjects (Po) and free-marginal kappa (kappa): overall appearance of the full face (Po Z 0.619; kappa Z 0.524); Upper lip (Po Z 0.619; kappa Z 0.524); Nose (Po Z 0.643; kappa Z 0.554); and Midface (Po Z 0.548; kappa Z 0.435) (Figure 3 and Table 3). The mean ordinal scale values were improved for the fat grafted subjects compared to those non-fat grafted (overall 3:2.1; upper lip 3.3:1.9; nose 3.5:2.4; midface 3:2.15, all p < 0.005) (Table 3).
Complications Following surgical reconstruction, fat grafting was performed to various elements of the lip and nose without complications or delays in recovery. There was no evidence of bleeding, seroma or hematoma at the donor site. There were no reports of increased pain or increased pain medicine requirements during the patients’ hospital stay or readmission for infection, bleeding or wound breakdown. The only complication was difficulty fitting nasal stents.
Discussion The cleft lip nasolabial repair has undergone numerous revisions with preserved ambitions of accurately restoring structures to their proper anatomic position such that the functional and aesthetic outcomes are optimized and the burden of secondary deformities is minimized. While such efforts have lessened the frequency and severity of secondary deformities of the lip and nose, problems can persist. In nature, the eye is attracted to differences and asymmetries. Simple alignment of anatomic landmarks is necessary but not sufficient to achieve the most anatomically normal-appearing lip and nose. The nasolabial complex exhibits contours (concavities and convexities) that require construction and restitution. Inequalities within anatomic boundaries and sharp breaks between normally blended transitions may result from an improperly executed repair, complications in wound healing, alterations in growth and development of facial elements, and the formation of a wide or obvious scar. Residual deformities will appear conspicuous as cleft lip stigmata, and a host of techniques have been employed to revise secondary cleft lip abnormalities, such as scar manipulation, Table 3
Po Kappa p-value FG þFG p-value
Post operative assessment of repair. Overall
Upper lip
Nose
Midface
0.619 0.524 0.012 3 (2e4) 2.1 (1e3) 0.0013
0.619 0.524 0.001 3.3 (2e4) 1.9 (1e3) 0.0001
0.643 0.554 0.001 3.5 (3e4) 2.4 (1e3) 0.0003
0.548 0.435 0.022 3 (2e4) 2.15 (1e3) 0.0013
The overall appearance of the full face, upper lip, nose and midface were scored using a five-point ordinal scale described in methods. Po Z percent overall agreement; kappa Z freemarginal kappa; p Z p-value.
lip landmark reapproximation, rhinoplasty and tissue augmentation with dermal or fat grafting.13,38,39 While scarring is an important and unavoidable aspect of wound healing, patients scar in different and often unpredictable manners. Thus, even a properly performed cleft lip repair may result in scars that are obvious, unsightly and/or disfiguring. Although great advances have been achieved in decreasing the burden of scar formation through both technical21,22,24 and adjunctive21,40 measures, scar management remains a difficult problem worthy of intense investigative inquiry. Insight into the general principles underwriting wound healing and scar formation has been elucidated through unexpected observations. It was long assumed that inflammation was a critical feature of the healing process, that phagocytic cells were required to clear wound debris and that the inflammatory cell-mediated growth factor response was necessary to orchestrate downstream cell and tissue movements required for wound healing.35,36 However, unique experimental observations illustrate otherwise. Intriguingly, during a defined period of gestation the fetus heals wounds in a regenerative and scarless fashion, completely restoring the cutaneous anatomy as well as its strength.32e36 Research efforts have demonstrated that scarless fetal wound healing occurs during a period of gestation where wounds heal with a paucity of inflammatory cell infiltrate. Moreover, scarless wound healing ceases when inflammation becomes a natural component of the biological healing process.34e36 Thus, inflammation does not appear to impact wound healing but instead coincides with scar formation. Thus, a therapeutic strategy that targets inflammation at the site of wound healing might diminish scar burden without impairing the overall healing process. Critical to such a therapeutic approach would be the development of a sustainable source of antiinflammatory mediators capable of interacting with the surrounding wound environment. Growth factors are an essential element of the natural wound healing process. When compared to acute wounds, analysis of fluid collected from chronic wounds reveals depressed levels of growth factors as well as elevated proinflammatory cytokines.35,40 In theory, given the critical importance of growth factors and cytokines in orchestrating the molecular and cellular events required for proper wound healing and scar formation, the application of growth factors to sites of injury held great promise in clinically promoting the healing process.32e40 In practice, however, the benefits of such an approach were not fulfilled. Likely, the wound healing process requires a medley of growth factors applied in a strict and regulated spatiotemporal manner. Adipose tissue is a plentiful source of mesenchymal stems cells that promote wound healing and minimize scar burden by both reducing the inflammatory response to injury and providing growth factors in a physiological manner. Experimental evidence suggests that ADSCs tune down inflammation by impairing lymphocytic proliferation and by suppressing a variety of T-, B- NK- and perhaps dendritic-cell functions.32e37 Intriguingly, ADSCs also secrete a complement of growth factors that govern the wound healing process35e40 and, when applied to sites of wounds in vivo, ADSCs remain viable and secrete growth factors in a continuous regulated manner.35
Immediate fat grafting in primary cleft lip repair The benefits of ADSCs on wound healing and scar formation are not merely theoretical. In experimental models, ADSCs bolster wound healing by nurturing angiogenesis, promoting granulation and triggering reepithelization.37 Moreover, ADSCs appear to benefit overall wound cosmesis by decreasing scar size, enhancing color quality and improving scar pliability.36 Recent evidence from our group revealed that infant adipose tissue, as opposed to older cell donor tissue, contains robust ADSC populations with enhanced angiogenic and osteogenic capabilities. Similar to older donor cells, infant ADSCs also possess paracrine osteogenic activity.37 Our experimental evidence suggests that infant adipose tissue might represent an ideal substrate from which to extract ADSCs with regenerative capabilities. The purpose of our analysis is to investigate the use of fat grafting concurrent with the primary cleft lip repair, hypothesizing that fat graft ADSCs modulate wound healing to improve scar cosmesis and that fat grafts lessen the degree of secondary deformities through tissue augmentation at the piriform, philtrum and nasal tip. We performed fat grafting at the time of cleft repair in a cohort of 20 patients. No complications were experienced with cleft lip repair, fat harvest or graft injection in the operative or post-operative follow-up period, and postoperative photographic assessment revealed minimal residual cleft stigmata. To fully gauge the safety and success of this intervention, a longer and continued follow-up period time period will certainly be necessary. Inherent to the care and treatment of the cleft population is the necessity for longterm follow-up, and we look forward to continuing our assessment of the safety of this intervention in this series of patients. However, we suppose that fat grating is safe in the setting of the primary cleft lip repair given our described analysis as well as the favorable safety profile and acceptance of fat grating in other clinical scenarios, such as breast cancer reconstruction, irradiated tissue rejuvenation and reconstructive and/or cosmetic augmentation. While this data is compelling and demonstrates a proof of concept, given the difficulty of determining the value of one intervention amongst other determinants of outcome, a prospective analysis with two treatment options (intervention versus lack of intervention) will be required to impart scientific clarity on whether fat grafting simultaneous with cleft lip repair is beneficial. In future investigations, it will be important to work to elucidate the precise effect ADSCs confer on the immediate cleft lip via inflammation, growth factors and/or tissue augmentation, to identify whether infant fat is truly superior to older fat and whether ADSCs without fat are alone sufficient. It will also be important to evaluate the quantity of graft and ADSCs that persist in the cleft lip repair as well as in the surrounding tissues employing safe and reliable techniques in the infant population.
Conclusion Fat grafting can be safely performed in the primary cleft lip repair. Moreover, fat grafting may optimize results through
1649 both soft tissue augmentation as well as the modulation of scar formation. Prospective comparison is necessary to further corroborate our findings.
Ethical approval N/A.
Funding None.
Financial disclosures None of the authors has a financial interest in any of the products, devices or drugs mentioned in this manuscript.
Conflict of interest None.
References 1. Al-Omari I, Millett DT, Ayoub A, et al. An appraisal of three methods of rating facial deformity in patients with repaired complete unilateral cleft lip and palate. Cleft Palate Craniofac J 2003;40:530e7. 2. Asher-McDade C, Roberts C, Shaw WC, Gallager C. Development of a method for rating nasolabial appearance in patients with clefts of the lip and palate. Cleft Palate Craniofac J 1991; 28:385e90. discussion 90e1. 3. Randolph JJ. Free-marginal multirater kappa (multirater k free): an alternative to fleiss fixed-marginal multirater kappa. In: Joensuu learning and instruction symposium. Citeseer; 2005. 4. Watkins MW. MacKappa. In. Phoenix, AZ(ed) Psych Associates. 2002. 5. Dixon MJ, Marazita ML, Beaty TH, Murray JC. Cleft lip and palate: understanding genetic and environmental influences. Nat Rev Genet 2011;12:167e78. 6. Marazita ML, Mooney MP. Current concepts in the embryology and genetics of cleft lip and cleft palate. Clin Plast Surg 2004; 31:125e40. 7. Blair V, Brown J. Mirault operation for single harelip. Surg Gynecol Obstet 1930;51:81e98. 8. Brown J, McDowell F. Simplified design for repair of single cleft lip. Surg Gynecol Obstet 1945;80:12e26. 9. Davies D. The one-stage repair of unilateral cleft lip and palate: a preliminary report. Plast Reconstr Surg 1966;38:129e36. 10. Fisher DM. Unilateral cleft lip repair: an anatomical subunit approximation technique. Plast Reconstr Surg 2005;116: 61e71. 11. Le MA. A method of cutting and suturing the lip in the treatment of complete unilateral clefts. Plast Reconstr Surg 1946; 1949(4):1e12. 12. Millard D. A primary camouflage of the unilateral harelook. Transactions of the first international congress of plastic surgery. Stockholm. Baltimore: Williams & Wilkins; 1957. 13. Mulliken JB. Primary repair of bilateral cleft lip and nasal deformity. Plast Reconstr Surg 2001;108:181e94. examination 95e6. 14. Mulliken JB, LaBrie RA. Fourth-dimensional changes in nasolabial dimensions following rotation-advancement repair of unilateral cleft lip. Plast Reconstr Surg 2012;129:491e8.
1650 15. Skoog T. A design for the repair of unilateral cleft lips. Am J Surg 1958;95:223e6. 16. Tennison CW. The repair of the unilateral cleft lip by the stencil method. Plast Reconstr Surg e 1946 1952;9:115e20. 17. Trauner R, Trauner M. Results of cleft lip operations. Plast Reconstr Surg 1967;40:209e19. 18. Wynn SK. Lateral flap cleft lip surgery technique. Plast Reconstr Surg Transpl Bull 1960;26:509e20. 19. Mulliken JB. Primary repair of bilateral cleft lip and nasal deformity. In: Georgiade GS, Riefkohl R, Levin LS, editors. Georgiade plastic, maxillofacial, and reconstructive surgery. 3rd ed. Baltimore: Williams & Wilkins; 1997. p. 230e8. 20. Mulliken JB, Pensler JM, Kozakewich HP. The anatomy of Cupid’s bow in normal and cleft lip. Plast Reconstr Surg 1993;92: 395e403. discussion 4. 21. Broughton G, Rohrich RJ, Dallas TUoTSMCa, Center BUM. Wounds and scars. Sel Read Plast Surg 2005:10. 22. Crikelair GF. Surgical approach to facial scarring. J Am Med Assoc 1960;172:160e2. 23. Gurtner GC. Wound healing: normal and abnormal. In: Thorne C, Beasley RW, Aston SJ, Bartlett SP, Gurtner GC, Spear SL, editors. Grabb and Smith’s plastic surgery. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2007. 24. Thorne C. Techniques and principles in plastic surgery. In: Thorne C, Beasley RW, Aston SJ, Bartlett SP, Gurtner GC, Spear SL, editors. Grabb and Smith’s plastic surgery. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2007. 25. Billings Jr E, May Jr JW. Historical review and present status of free fat graft autotransplantation in plastic and reconstructive surgery. Plast Reconstr Surg 1989;83:368e81. 26. Ducic Y. Fat grafting in trauma and reconstructive surgery. Facial Plast Surg Clin North Am 2008;16:409e16. 27. Guerrerosantos J, Chicas M, Rivera H. Palatopharyngeal lipoinjection: an advantageous method in velopharyngeal incompetence. Plast Reconstr Surg 2004;113:776e7.
D.M. Balkin et al. 28. Guijarro-Martinez R, Miragall Alba L, Marques Mateo M, Puche Torres M, Pascual Gil JV. Autologous fat transfer to the craniomaxillofacial region: updates and controversies. J Craniomaxillofac Surg 2011;39:359e63. 29. Khouri R, Del Vecchio D. Breast reconstruction and augmentation using pre-expansion and autologous fat transplantation. Clin Plast Surg 2009;36:269e80. 30. La Rusca I, Schonauer F, Molea G. Core fat graft transplantation for depressed scar. Plast Reconstr Surg 2009;123: 1394e5. author reply 5. 31. Toledo LS, Mauad R. Fat injection: a 20-year revision. Clin Plast Surg 2006;33:47e53. 32. Schaffler A, Buchler C. Concise review: adipose tissue-derived stromal cellsebasic and clinical implications for novel cellbased therapies. Stem Cells 2007;25:818e27. 33. Zuk PA, Zhu M, Ashjian P, et al. Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell 2002;13:4279e95. 34. Zuk PA, Zhu M, Mizuno H, et al. Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng 2001;7:211e28. 35. Kim WS, Park BS, Sung JH. The wound-healing and antioxidant effects of adipose-derived stem cells. Expert Opin Biol Ther 2009;9:879e87. 36. Yun IS, Jeon YR, Lee WJ, et al. Effect of human adipose derived stem cells on scar formation and remodeling in a pig model: a pilot study. Dermatol Surg 2012 Oct;38(10):1678e88. 37. Wu W, Niklason L, Steinbacher DM. The effect of age on human adipose derived stem cells. Plast Reconstr Surg 2013 Jan; 131(1):27e37. 38. Coleman SR. Hand rejuvenation with structural fat grafting. Plast Reconstr Surg 2002;110:1731e44. discussion 45e7. 39. Gatti JE. Permanent lip augmentation with serial fat grafting. Ann Plast Surg 1999;42:376e80. 40. Martin P. Wound healingeaiming for perfect skin regeneration. Science 1997;276:75e81.
Immediate fat grafting in primary cleft lip repair Daniel M. Balkin a,b, Salem Samra a,b, Derek M. Steinbacher a,b,* a b
Yale University School of Medicine, New Haven, CT, USA Plastic and Reconstructive Surgery, Yale University School of Medicine, New Haven, CT, USA
Received 4 March 2014; accepted 18 August 2014
KEYWORDS Cleft lip; Fat graft; Adipose-derived stem cells; Scar; Wound healing
Summary Background: Successful cleft lip repair creates symmetric nasolabial morphology with minimal scar. Fat grafting is used in cosmetic and reconstructive settings to provide contour, condition tissue and aid healing. This study employs immediate fat grafting concurrent with primary cleft nasolabial repair. We hypothesize that simultaneous fat transfer is safe and may optimize the result. Methods: This retrospective analysis included a series of consecutive infants who underwent primary cleft lip repair with immediate fat grafting. Demographic and peri-operative details were recorded. Post-operative photographs were analyzed by three blinded reviewers (AlOmari et al. and Asher-McDade et al.). Kappa statistics were employed to assess inter-rater reliability (Randolph and Watkins MW). Results: 30 children, 37 sides (13 left, 10 right, 7 bilateral; 62% complete, 38% incomplete) who underwent cleft lip repair at Yale were included. 20 underwent nasolabial repair with simultaneous fat grafting. Mean age of repair was 3.5 mo (range 1.5e6.4). Fat was hand suctioned from the thighs (15 left; 2 right; 3 both) with mean yield of 2.1 cc (range 1e5 cc). An average of 1.4 cc (range 0.5e2.5 cc) was injected to the philtrum, vermillion, piriform and ala. No complications were experienced with lip repair, fat harvest or graft injection. Mean follow-up was 24.7 months (range 12.4e60.2 months). Postoperative photographic assessment revealed minimal residual cleft stigmata with inter-rater reliability. Each ordinal score was statistically significant compared fat grafted repairs to those without fat grafting (p < 0.05). Conclusions: Simultaneous fat grafting and cleft lip repair can be performed safely. The augmentation and modulation of scar formation may optimize results. Prospective comparison is necessary to further corroborate our findings. Level of evidence: Therapeutic (Level IV). ª 2014 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.
* Corresponding author. Yale University School of Medicine, 330 Cedar Street, New Haven, CT 06510, USA. Tel.: þ1 (203) 785 4559. E-mail addresses: [email protected], [email protected] (D.M. Steinbacher). http://dx.doi.org/10.1016/j.bjps.2014.08.049 1748-6815/ª 2014 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.
Immediate fat grafting in primary cleft lip repair
Introduction Cleft lip with or without cleft palate is the most common congenital craniofacial anomaly.5 Embryologically, cleft lip results from a failed fusion of the maxillary and medial nasal processes. This defect results in a deformity of the nasolabial complex, with a complete cleft exhibiting the most significant structural displacement.6 A myriad of repair techniques and presurgical cleft protocols have been described with conserved goals to align the lip and nose in an “anatomically correct” fashion.7e18 While aligning lip landmarks is essential to performing a cleft lip nasolabial repair, the most natural result requires reestablishing the normal contours of the nasolabial region, blending the incision along subunits and minimizing scar caliber. Intrinsic to the anomaly, clefted tissues are displaced and nasolabial structures are hypoplastic.19,20 The described cleft lip repair techniques require tissue to be discarded and consequently do not convey nor supplement additional tissue to the nasolabial complex. Therefore, even in the best of repairs the contours of the reconstructed lip and nose may be blunted and not adequately supported. In addition to topographic differences, scar formation impacts the success of a repaired cleft lip. Scarring is a constant and unavoidable aspect of wound healing, and several factors likely contribute to scar caliber, including suture type, duration of suture placement, tissue tension and the child’s intrinsic healing capacity.21e24 Undue scarring following cleft lip repair may cede secondary deformities of the lip and nose, including wide or pigmented scars, lip landmark distortion, vermilion irregularities as well as nasal deformities. Taken together, the repaired cleft lip stigmata result from insufficient nasolabial support, improper landmark alignment and excessive scar formation. Such asymmetries draw attention and therefore lessen the overall success of the cleft lip repair. Fat transfer techniques have demonstrated utility in the correction of a host of deformities through soft tissue augmentation.25e31 More recently, there is evidence that fat grafts harbor stem cells,32e34 termed adipose-derived stem cells (ADSCs), and that these pluripotent cells produce factors beneficial for wound healing and regeneration.35e40 This autogenous tissue may also improve scar caliber and minimize scar burden.36,40 Research from our group has recently revealed that infant-derived ADSCs are more biologically robust than those obtained from adult tissue.37 The purpose of this study is to analyze immediate fat grafting in the primary cleft lip nasolabial repair. Given such favorable biophysical and biochemical properties, we postulate that the introduction of fat grafting will prove beneficial in the infant cleft lip population by recreating lip/nasal contours through tissue support and augmentation and that infant-derived ADSCs will assist the wound healing and regenerative process to minimize scar burden.
Methods A retrospective analysis was performed in accordance with the Yale University Human Investigation Committee
1645 (#1209010767). A consecutive series of infants who underwent primary cleft lip repair with simultaneous fat grafting were included. A group who underwent primary repair without fat grafting were included as comparison. Demographic information, perioperative, and post-operative details were recorded. Continuous variables were summarized using mean and range, and categorical variables using frequencies and percentages. Three blinded reviewers analyzed photographs to assess the residual cleft-related facial stigmata (overall appearance of the full face, upper lip, nose and midface) using the following five-point ordinal scale: 1 Z nonvisible stigmata (very good appearance); 2 Z barely visible (good appearance); 3 Z slightly visible (fair appearance); 4 Z moderately visible (poor appearance); 5 Z very visible (very poor appearance).1,2 The percent of overall agreement (Po) and the free-marginal kappa (kappa),3 a chance-adjusted measure of multi-rater agreement in which raters’ distributions of cases into categories are not restricted, were analyzed using the software package MacKappa.4
Results Demographics Children who underwent cleft lip repair at the Yale-New Haven Hospital. 30 infants, 37 sides, aged 1.5e6.4 months (mean 3.5 months), were included. 20 underwent repair with simultaneous primary fat grafting (Table 1). The cleft lip sidedness was 13 left, 10 right and 7 bilateral. 62% of the cleft lip anomalies were complete, while 38% were incomplete (Table 1).
Surgical procedure The cleft lip repair technique employed for unilateral cases was the modified inferior triangle technique or rotation advancement,10 while bilateral lips were repaired using a variation of the standard repair.13 In fat injection cases, fat was harvested from one or both thighs in all instances (15 left leg only; 2 right leg only; 3 both legs; operative time approximately 10 min) using manual suction as previously described (Table 2).38,39 An average of 1e3 cc of 1% lidocaine (1:100,000 epinephrine) was injected at the donor site. No tumescent was used. Aspirated fat was strained on Telfa and transferred to a 1 cc syringe. Fat was white and of dense consistency without significant heme (Figure 1). The graft harvest yield was 2.1 cc (mean) (range 1e5 cc) and
Table 1
þFG FG
Patient demographics. Subjects
Age at operation (months)
Gender
Diagnosis
N Z 20 N Z 10 N Z 30
3.9 3.2 3.5
12F:8M 5F:5M 17F:13M
7L:8R:5B 5L:2R:2B 13L:10R:7B
Gender: male (M) and female (F); Lip diagnosis: unilateral (U), bilateral (BL), complete (C) and incomplete (IN).
1646 Table 2
D.M. Balkin et al.
Perioperative care
Fat grafting.
Harvest site
Fat yield
Fat injected
15L:2R:3B
1e3 cc
0.5e2.5 cc
Fat harvest site from thighs: left (L), right (R) and bilateral (BL).
1.4 cc (mean) (range 0.5e2.5 cc) was injected into the cleft side philtril column(s), vermillion, piriform and ala using a 19 gauge needle on a 1 cc syringe in 0.10 cc aliquots (Figures 1 and 2, Table 2). The fat was deposited submucosally (at the vermillion/mucosal junction); subcutaneously and intra-muscular (along the phitrum); and preperiosteal at the piriform rim; as the final stage following all suture placement.
The mean operative time was 2.1 h (range 1.4e3.4 h) (Table 2). All patients were discharged one to two days postoperatively tolerating oral feeds (mean 1.2 days). Scar care included steristrips for two weeks, then vitamin E for two weeks, followed by silicone gel and gentle massage for subsequent months. Mean follow-up was 24.7 months (range 12.4e60.2 months).
Scar and nasolabial anatomical analyses Standardized post-operative photographs were analyzed by three blinded reviewers and the residual cleft-related deformity was scored independently using a described assessment (Figure 3).1,2 Presented examples represent a
Figure 1 Intraoperative use of fat grafting in primary cleft lip repair. (A) Syringe filled with infant fat graft; and (B) Representative example of 0.1 cc aliquot injections into ala, piriform, philtrum and vermillion border.
Figure 2 Sites of fat graft injection. Frontal (left) and submental (right) photographs of the nasolabial complex. Sites of fat graft injection indicated.
Immediate fat grafting in primary cleft lip repair
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Figure 3 Pre- and post-operative photographs. Four patients pre-operative (left) and post-operative (right), which represent various cleft severities and different ethnicities. Post-operative photographs of unilateral and bilateral cases were acquired at 6 and 12 months, respectively.
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D.M. Balkin et al.
variety of ethnic backgrounds, some of which may be more prone to wide or obvious scars (Figure 3). Statistical analyses revealed the following percent of overall agreement within fat grafted subjects (Po) and free-marginal kappa (kappa): overall appearance of the full face (Po Z 0.619; kappa Z 0.524); Upper lip (Po Z 0.619; kappa Z 0.524); Nose (Po Z 0.643; kappa Z 0.554); and Midface (Po Z 0.548; kappa Z 0.435) (Figure 3 and Table 3). The mean ordinal scale values were improved for the fat grafted subjects compared to those non-fat grafted (overall 3:2.1; upper lip 3.3:1.9; nose 3.5:2.4; midface 3:2.15, all p < 0.005) (Table 3).
Complications Following surgical reconstruction, fat grafting was performed to various elements of the lip and nose without complications or delays in recovery. There was no evidence of bleeding, seroma or hematoma at the donor site. There were no reports of increased pain or increased pain medicine requirements during the patients’ hospital stay or readmission for infection, bleeding or wound breakdown. The only complication was difficulty fitting nasal stents.
Discussion The cleft lip nasolabial repair has undergone numerous revisions with preserved ambitions of accurately restoring structures to their proper anatomic position such that the functional and aesthetic outcomes are optimized and the burden of secondary deformities is minimized. While such efforts have lessened the frequency and severity of secondary deformities of the lip and nose, problems can persist. In nature, the eye is attracted to differences and asymmetries. Simple alignment of anatomic landmarks is necessary but not sufficient to achieve the most anatomically normal-appearing lip and nose. The nasolabial complex exhibits contours (concavities and convexities) that require construction and restitution. Inequalities within anatomic boundaries and sharp breaks between normally blended transitions may result from an improperly executed repair, complications in wound healing, alterations in growth and development of facial elements, and the formation of a wide or obvious scar. Residual deformities will appear conspicuous as cleft lip stigmata, and a host of techniques have been employed to revise secondary cleft lip abnormalities, such as scar manipulation, Table 3
Po Kappa p-value FG þFG p-value
Post operative assessment of repair. Overall
Upper lip
Nose
Midface
0.619 0.524 0.012 3 (2e4) 2.1 (1e3) 0.0013
0.619 0.524 0.001 3.3 (2e4) 1.9 (1e3) 0.0001
0.643 0.554 0.001 3.5 (3e4) 2.4 (1e3) 0.0003
0.548 0.435 0.022 3 (2e4) 2.15 (1e3) 0.0013
The overall appearance of the full face, upper lip, nose and midface were scored using a five-point ordinal scale described in methods. Po Z percent overall agreement; kappa Z freemarginal kappa; p Z p-value.
lip landmark reapproximation, rhinoplasty and tissue augmentation with dermal or fat grafting.13,38,39 While scarring is an important and unavoidable aspect of wound healing, patients scar in different and often unpredictable manners. Thus, even a properly performed cleft lip repair may result in scars that are obvious, unsightly and/or disfiguring. Although great advances have been achieved in decreasing the burden of scar formation through both technical21,22,24 and adjunctive21,40 measures, scar management remains a difficult problem worthy of intense investigative inquiry. Insight into the general principles underwriting wound healing and scar formation has been elucidated through unexpected observations. It was long assumed that inflammation was a critical feature of the healing process, that phagocytic cells were required to clear wound debris and that the inflammatory cell-mediated growth factor response was necessary to orchestrate downstream cell and tissue movements required for wound healing.35,36 However, unique experimental observations illustrate otherwise. Intriguingly, during a defined period of gestation the fetus heals wounds in a regenerative and scarless fashion, completely restoring the cutaneous anatomy as well as its strength.32e36 Research efforts have demonstrated that scarless fetal wound healing occurs during a period of gestation where wounds heal with a paucity of inflammatory cell infiltrate. Moreover, scarless wound healing ceases when inflammation becomes a natural component of the biological healing process.34e36 Thus, inflammation does not appear to impact wound healing but instead coincides with scar formation. Thus, a therapeutic strategy that targets inflammation at the site of wound healing might diminish scar burden without impairing the overall healing process. Critical to such a therapeutic approach would be the development of a sustainable source of antiinflammatory mediators capable of interacting with the surrounding wound environment. Growth factors are an essential element of the natural wound healing process. When compared to acute wounds, analysis of fluid collected from chronic wounds reveals depressed levels of growth factors as well as elevated proinflammatory cytokines.35,40 In theory, given the critical importance of growth factors and cytokines in orchestrating the molecular and cellular events required for proper wound healing and scar formation, the application of growth factors to sites of injury held great promise in clinically promoting the healing process.32e40 In practice, however, the benefits of such an approach were not fulfilled. Likely, the wound healing process requires a medley of growth factors applied in a strict and regulated spatiotemporal manner. Adipose tissue is a plentiful source of mesenchymal stems cells that promote wound healing and minimize scar burden by both reducing the inflammatory response to injury and providing growth factors in a physiological manner. Experimental evidence suggests that ADSCs tune down inflammation by impairing lymphocytic proliferation and by suppressing a variety of T-, B- NK- and perhaps dendritic-cell functions.32e37 Intriguingly, ADSCs also secrete a complement of growth factors that govern the wound healing process35e40 and, when applied to sites of wounds in vivo, ADSCs remain viable and secrete growth factors in a continuous regulated manner.35
Immediate fat grafting in primary cleft lip repair The benefits of ADSCs on wound healing and scar formation are not merely theoretical. In experimental models, ADSCs bolster wound healing by nurturing angiogenesis, promoting granulation and triggering reepithelization.37 Moreover, ADSCs appear to benefit overall wound cosmesis by decreasing scar size, enhancing color quality and improving scar pliability.36 Recent evidence from our group revealed that infant adipose tissue, as opposed to older cell donor tissue, contains robust ADSC populations with enhanced angiogenic and osteogenic capabilities. Similar to older donor cells, infant ADSCs also possess paracrine osteogenic activity.37 Our experimental evidence suggests that infant adipose tissue might represent an ideal substrate from which to extract ADSCs with regenerative capabilities. The purpose of our analysis is to investigate the use of fat grafting concurrent with the primary cleft lip repair, hypothesizing that fat graft ADSCs modulate wound healing to improve scar cosmesis and that fat grafts lessen the degree of secondary deformities through tissue augmentation at the piriform, philtrum and nasal tip. We performed fat grafting at the time of cleft repair in a cohort of 20 patients. No complications were experienced with cleft lip repair, fat harvest or graft injection in the operative or post-operative follow-up period, and postoperative photographic assessment revealed minimal residual cleft stigmata. To fully gauge the safety and success of this intervention, a longer and continued follow-up period time period will certainly be necessary. Inherent to the care and treatment of the cleft population is the necessity for longterm follow-up, and we look forward to continuing our assessment of the safety of this intervention in this series of patients. However, we suppose that fat grating is safe in the setting of the primary cleft lip repair given our described analysis as well as the favorable safety profile and acceptance of fat grating in other clinical scenarios, such as breast cancer reconstruction, irradiated tissue rejuvenation and reconstructive and/or cosmetic augmentation. While this data is compelling and demonstrates a proof of concept, given the difficulty of determining the value of one intervention amongst other determinants of outcome, a prospective analysis with two treatment options (intervention versus lack of intervention) will be required to impart scientific clarity on whether fat grafting simultaneous with cleft lip repair is beneficial. In future investigations, it will be important to work to elucidate the precise effect ADSCs confer on the immediate cleft lip via inflammation, growth factors and/or tissue augmentation, to identify whether infant fat is truly superior to older fat and whether ADSCs without fat are alone sufficient. It will also be important to evaluate the quantity of graft and ADSCs that persist in the cleft lip repair as well as in the surrounding tissues employing safe and reliable techniques in the infant population.
Conclusion Fat grafting can be safely performed in the primary cleft lip repair. Moreover, fat grafting may optimize results through
1649 both soft tissue augmentation as well as the modulation of scar formation. Prospective comparison is necessary to further corroborate our findings.
Ethical approval N/A.
Funding None.
Financial disclosures None of the authors has a financial interest in any of the products, devices or drugs mentioned in this manuscript.
Conflict of interest None.
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