David A. Stoker

Perivascular Stem Cells: A Prospectively Purified Mesenchymal Stem Cell Population for Bone Tissue Engineering

Adipose tissue is an ideal source of mesenchymal stem cells for bone tissue engineering: it is largely dispensable and readily accessible with minimal morbidity. However, the stromal vascular fraction (SVF) of adipose tissue is a heterogeneous cell population, which leads to unreliable bone formation. In the present study, we prospectively purified human perivascular stem cells (PSCs) from adipose tissue and compared their bone‐forming capacity with that of traditionally derived SVF. PSCs are a population (sorted by fluorescence‐activated cell sorting) of pericytes (CD146+CD34−CD45−) and adventitial cells (CD146−CD34+CD45−), each of which we have previously reported to have properties of mesenchymal stem cells. Here, we found that PSCs underwent osteogenic differentiation in vitro and formed bone after intramuscular implantation without the need for predifferentiation. We next sought to optimize PSCs for in vivo bone formation, adopting a demineralized bone matrix for osteoinduction and tricalcium phosphate particle formulation for protein release. Patient‐matched, purified PSCs formed significantly more bone in comparison with traditionally derived SVF by all parameters. Recombinant bone morphogenetic protein 2 increased in vivo bone formation but with a massive adipogenic response. In contrast, recombinant Nel‐like molecule 1 (NELL‐1; a novel osteoinductive growth factor) selectively enhanced bone formation. These studies suggest that adipose‐derived human PSCs are a new cell source for future efforts in skeletal regenerative medicine. Moreover, PSCs are a stem cell‐based therapeutic that is readily approvable by the U.S. Food and Drug Administration, with potentially increased safety, purity, identity, potency, and efficacy. Finally, NELL‐1 is a candidate growth factor able to induce human PSC osteogenesis.

An Abundant Perivascular Source of Stem Cells for Bone Tissue Engineering

Adipose tissue is an ideal mesenchymal stem cell (MSC) source, as it is dispensable and accessible with minimal morbidity. However, the stromal vascular fraction (SVF) of adipose tissue is a heterogeneous cell population, which has disadvantages for tissue regeneration. In the present study, we prospectively purified human perivascular stem cells (PSCs) from n = 60 samples of human lipoaspirate and documented their frequency, viability, and variation with patient demographics. PSCs are a fluorescence‐activated cell sorting‐sorted population composed of pericytes (CD45−, CD146+, CD34−) and adventitial cells (CD45−, CD146−, CD34+), each of which we have previously reported to have properties of MSCs. Here, we found that PSCs make up, on average, 43.2% of SVF from human lipoaspirate (19.5% pericytes and 23.8% adventitial cells). These numbers were minimally changed by age, gender, or body mass index of the patient or by length of refrigerated storage time between liposuction and processing. In a previous publication, we observed that human PSCs (hPSCs) formed significantly more bone in vivo in comparison with unsorted human SVF (hSVF) in an intramuscular implantation model. We now extend this finding to a bone injury model, observing that purified hPSCs led to significantly greater healing of mouse critical‐size calvarial defects than hSVF (60.9% healing as opposed to 15.4% healing at 2 weeks postoperative by microcomputed tomography analysis). These studies suggest that adipose‐derived hPSCs are a new cell source for future efforts in skeletal regenerative medicine. Moreover, hPSCs are a stem cell‐based therapeutic that is readily approvable by the U.S. Food and Drug Administration, with potentially increased safety, purity, identity, potency, and efficacy.

One-stage mastopexy with breast augmentation : A review of 321 patients

Background: One-stage mastopexy with breast augmentation is an increasingly popular procedure among patients. In the past 9 years, there has been a 506 percent increase in mastopexy procedures alone. Although some recommend a staged mastopexy and breast augmentation, there are currently no large studies evaluating the safety and efficacy of a one-stage procedure. Methods: A retrospective chart review was conducted of 321 consecutive patients who underwent one-stage mastopexy and breast augmentation. Data collected included the following: patient characteristics, implant information, operative technique, and postoperative results. Complication and revision rates were calculated to evaluate the safety and efficacy of the one-stage procedure. Results: No severe complications were recorded over an average of 40 months’ follow-up. The most common complication was deflation of a saline implant (3.7 percent), followed by poor scarring (2.5 percent), recurrent ptosis (2.2 percent), and areola asymmetry (2.2 percent). Forty-seven patients (14.6 percent) underwent some form of revision surgery following the one-stage procedure. Thirty-five (10.9 percent) of these were for an implant-related issue, whereas 12 patients (3.7 percent) underwent a tissue-related revision. This 10.9 percent implant-related revision rate is less than a previously documented 13.2 percent 3-year reoperation rate for breast augmentation alone. The authors’ 3.7 percent tissue-related revision rate also compares favorably to an 8.6 percent revision surgery rate in patients who underwent mastopexy alone. Conclusions: Although it has been stated that the risks of a one-stage procedure are more than additive, the results of our review suggest otherwise. Although a revision rate of 14.6 percent is significant, it is far from the 100 percent reoperation rate required for a staged procedure.

Additive Effects of Sonic Hedgehog and Nell-1 Signaling in Osteogenic Versus Adipogenic Differentiation of Human Adipose-Derived Stromal Cells

A theoretical inverse relationship exists between osteogenic (bone forming) and adipogenic (fat forming) mesenchymal stem cell (MSC) differentiation. This inverse relationship in theory partially underlies the clinical entity of osteoporosis, in which marrow MSCs have a preference for adipose differentiation that increases with age. Two pro-osteogenic cytokines have been recently studied that each also possesses antiadipogenic properties: Sonic Hedgehog (SHH) and NELL-1 proteins. In the present study, we assayed the potential additive effects of the biologically active N-terminus of SHH (SHH-N) and NELL-1 protein on osteogenic and adipogenic differentiation of human primary adipose-derived stromal cell (hASCs). We observed that both recombinant SHH-N and NELL-1 protein significantly enhanced osteogenic differentiation and reduced adipose differentiation across all markers examined (alkaline phosphatase, Alizarin red and Oil red O staining, and osteogenic gene expression). Moreover, SHH-N and NELL-1 directed signaling produced additive effects on the pro-osteogenic and antiadipogenic differentiation of hASCs. NELL-1 treatment increased Hedgehog signaling pathway expression; coapplication of the Smoothened antagonist Cyclopamine reversed the pro-osteogenic effect of NELL-1. In summary, Hedgehog and Nell-1 signaling exert additive effects on the pro-osteogenic and antiadipogenic differentiation of ASCs. These studies suggest that the combination cytokines SHH-N+NELL-1 may represent a viable future technique for inducing the osteogenic differentiation of MSCs.

Is one-stage breast augmentation with mastopexy safe and effective? a review of 186 primary cases

BACKGROUND Although some authors have reported that 1-stage breast augmentation with mastopexy does not increase the risks of surgery, recent literature has raised the question of whether better results might be achieved by staging the procedures. OBJECTIVE The authors evaluated the safety and efficacy of 1-stage breast augmentation with mastopexy in their own patients by analyzing long-term complication and revision rates. METHODS A retrospective chart review was performed of 186 consecutive patients who underwent primary 1-stage breast augmentation with mastopexy at a single outpatient facility. Patient data recorded included age, body mass index, smoking status, degree of breast ptosis, and any preoperative asymmetry. Operation-related data recorded included type of mastopexy performed, operating surgeon, length of surgery, American Society of Anesthesiologists level, and concomitant procedures. Data on implant type, volume, and position were also collected. Complication and revision rates were recorded and calculated. RESULTS Ninety-six patients (44%) received saline implants; 104 (56%) received silicone implants. In most cases, textured implants were placed in submuscular pockets. The mean implant volume was 320 cc. Inverted T mastopexy was performed in 60% of cases, circumareolar in 24% of cases, and vertical or crescent accounted for most of the remainder. No severe complications occurred, although 1 patient developed a late infection that required removal of the breast implant. The most common complication was saline implant deflation (5.9%), although saline implants were used in less than half of cases. Thirty-one patients (16.7%) underwent some form of revision surgery within the average 42-month follow-up period. CONCLUSIONS Our review of 1-stage breast augmentation with mastopexy procedures revealed no severe complications. Although the overall revision rate of 16.7% is significant, it is comparable to rates for breast augmentation alone and is significantly lower than the 100% reoperation rate required for a staged procedure. In our experience, it is a safe and effective procedure, although one that is not easy to perform. Patients should be advised of the possibility that a second procedure may be necessary.

Clinical experience with a fourth-generation textured silicone gel breast implant: a review of 1012 Mentor MemoryGel breast implants.

BACKGROUND Since the introduction of fourth- and fifth-generation silicone gel implants, manufacturers have conducted several prospective, multicenter trials to examine their safety and efficacy. However, these studies were not standardized with regard to surgeon skill, pocket placement, operative technique, adjunct therapies, or postoperative management. OBJECTIVE The purpose of this study was to examine the surgical outcomes of a single surgeon (WGS) in a consecutive series of breast augmentation cases using a fourth-generation cohesive silicone MemoryGel breast implant (Mentor, Santa Barbara, CA). METHODS A retrospective chart review was conducted to identify all patients who underwent silicone breast augmentation within the Mentor Adjunct Silicone MemoryGel breast implant by a single surgeon (WGS) within a single free-standing outpatient surgical center over a 13-year period (1992 to 2006). For each patient, demographic information, comorbidities, and surgical information (implant size and concomitant surgery) were recorded. In addition, outcomes were analyzed to identify complications and the need for surgical revision. RESULTS A total of 1012 fourth-generation, textured, cohesive silicone gel implants were placed in 511 patients during the 13-year study period. The overall complication rate per implant was 5.5% (n=56 implants in 43 patients). The most common complication was capsular contracture (n=26; 2.6 %) followed by abnormal scarring (n=11; 1.1%). The overall revision rates per patient and per implant were 8.0% (n = 41 patients) and 6.8% (n = 69 implants), respectively. The average time interval between initial implantation and revision was 18.5 months (range, 2 weeks to 26 months). The most common indication for surgical revision was patient desire for implant size change (n=15 patients) followed by Baker class III or IV capsular contracture (n=13 patients). The presence of previous surgery for capsular contracture was not statistically correlated to the need for revision (P= .326). Age (P= .568), previous history of breast surgery (P= .704), and history of smoking (P= .138) were also not statistically correlated to revision. Placement of the implant in the subglandular position (n=30 implants), however, was statistically correlated with need for revision (P< .01). CONCLUSIONS Mentor fourth-generation cohesive silicone gel implants possess a complication and revision profile that is superior to earlier-generation silicone gel implants. Implantation with MemoryGel implants, when standardized with regard to surgeon and operative technique, can have significantly reduced complication and revision rates compared to the Mentor Core Data.

Outpatient Reduction Mammaplasty: An Eleven-Year Experience

BACKGROUND In the last 15 years, reduction mammaplasty has been increasingly performed on an outpatient basis. Despite this evolution, few outcome studies have been published regarding outpatient breast reduction surgery. OBJECTIVE The authors documented clinical outcomes of reduction mammaplasty performed in an outpatient setting over an 11-year period and compared these results with published normative values in the plastic surgery literature. METHODS A retrospective review was undertaken of 884 reduction mammaplasties in 444 patients at a single outpatient surgical center performed by the senior author (W.G.S.) from 1995 through 2006. In all cases, a laser-assisted, inferior pedicle, Wise pattern, reduction mammaplasty was performed. In addition to demographic and surgical data, complication frequency and type were recorded. Complication data were further stratified into minor and major categories. Potential minor complications included seroma, hematoma, soft tissue infection, dog-ears requiring revision, and small incisional breakdowns or delayed healing of less than 2 cm. Potential major complications included large incisional breakdowns or delayed healing of greater than 2 cm, nipple/areolar necrosis, need for blood transfusion, deep vein thrombosis, pulmonary embolus, myocardial infarction, and death. RESULTS The mean patient age was 38 years (range, 16 to 73 years). Mean body-mass index was 27 (range 17 to 47). The reported preoperative brassiere cup sizes ranged from a 34 C to a 38 K, with a DD being the most common size. The mean preoperative sternal notch-to-nipple distance was 29 cm (range 22 to 54 cm). Forty patients smoked (9%). Mean clinical follow-up was 13 months. Mean total resection weight of breast tissue was 1228 g (range 100 to 5295 g). Mean operative time for reduction mammaplasty was 115 minutes (range 50 to 195 minutes). Nineteen percent of patients underwent multiple procedures, including abdominoplasty, lipoplasty, and facial procedures, with a mean operative time of 132 minutes (range 75 to 345 minutes). The overall complication rate was 14%, with 70 minor complications occurring in 62 patients. Specific minor complications included one seroma, four hematomas, eight soft tissue infections, two of which required a short course of intravenous antibiotics, one patient with dog-ears requiring surgical revision, and 56 small incisional wound breakdowns (< 2 cm). The small incisional breakdowns, which represented the largest group of complications, were further subdivided into 44 minor T-zone wounds, 3 nipple-areolar complex wounds, and 9 wounds of the vertical and horizontal incisions. Three major complications (0.67%) were recorded. Two patients had development of partial nipple/areolar necrosis. A third patient required anticoagulation for a pulmonary embolus diagnosed 10 days after surgery. Statistical analysis of the complication data revealed one significant relationship. Patients with a body mass index above the mean had a 21% complication rate as compared with a 12% rate for those below the mean. Of note, there was no increase in complication rate in the context of multiple procedures. CONCLUSIONS This retrospective series is the largest to date involving outpatient reduction mammaplasty. Complication data derived from this series are comparable to previously published studies and thus support the safety and efficacy of outpatient reduction mammaplasty performed in an accredited facility.

Safe and consistent outcomes of successfully combining breast surgery and abdominoplasty: an update.

BACKGROUND Combined cosmetic procedures have become increasingly popular. One of the most common combinations of cosmetic procedures includes abdominoplasty and cosmetic breast surgery. The shortened recovery and financial savings associated with combined surgery contribute to the increased demand for these combined surgeries. OBJECTIVE The goal of this study was to evaluate the safety and efficacy of combined abdominoplasty and breast surgery at a single plastic surgery practice that performs a large volume of these cases. This is an update to a study published in 2006. METHODS A retrospective review was performed for patients who underwent combined abdominoplasty and cosmetic breast surgery during the last 10 years at a single outpatient surgery center. Abdominoplasty inclusion criteria were defined as lower, mini, full, reverse, or circumferential abdominoplasty. Cosmetic breast surgery inclusion criteria were defined as augmentation, mastopexy, augmentation-mastopexy, reduction, or removal and replacement of implants. Pertinent preoperative and intraoperative data were recorded along with complications and revisions. RESULTS There were 268 patients during the 10-year period between 1997 and 2007. There were no cases of death, pulmonary embolism, deep venous thrombosis, or other life-threatening complications. The overall complication rate was 34%. Abdominoplasty seroma and scars requiring revision comprised 68% (n = 74) of the complications. The total revision rate was 13%. CONCLUSIONS Combined abdominoplasty and cosmetic breast surgery was safe and effective in this large series of cases performed at a single plastic surgery practice. The complication and revision rates of the combined surgery were similar to those reported for individually staged procedures.

“Extreme” Cosmetic Surgery: A Retrospective Study of Morbidity in Patients Undergoing Combined Procedures

BACKGROUND It is increasingly common for patients to request that multiple cosmetic procedures be performed during a single operation. The advantages of combined procedures include a single recovery period, reduced surgery costs, and faster patient gratification. Traditional surgical thinking, however, has favored the performance of some procedures individually in an effort to decrease complications associated with prolonged anesthesia. OBJECTIVE The goal of this study was to determine whether performance of combined cosmetic surgery procedures results in increased morbidity. METHODS Two hundred forty-eight abdominoplasties performed by the same surgeon over a 10-year period were reviewed retrospectively. Four groups of procedures were compared: abdominoplasty alone, abdominoplasty combined with breast surgery, abdominoplasty combined with facial surgery, and abdominoplasty combined with both breast and facial surgery. RESULTS No statistically significant differences in complication rates were found among the four groups. The prevalence of morbidity in all groups compared favorably to the parameters established in previous reviews. CONCLUSIONS The results of this retrospective review do not indicate that the combination of cosmetic surgical procedures increases morbidity. The potential benefits of combined procedures may be considered with the expectation of comparably low complication rates.

Human Perivascular Stem Cell-Based Bone Graft Substitute Induces Rat Spinal Fusion

Adipose tissue is an attractive source of mesenchymal stem cells (MSCs) because of its abundance and accessibility. We have previously defined a population of native MSCs termed perivascular stem cells (PSCs), purified from diverse human tissues, including adipose tissue. Human PSCs (hPSCs) are a bipartite cell population composed of pericytes (CD146+CD34−CD45−) and adventitial cells (CD146−CD34+CD45−), isolated by fluorescence‐activated cell sorting and with properties identical to those of culture identified MSCs. Our previous studies showed that hPSCs exhibit improved bone formation compared with a sample‐matched unpurified population (termed stromal vascular fraction); however, it is not known whether hPSCs would be efficacious in a spinal fusion model. To investigate, we evaluated the osteogenic potential of freshly sorted hPSCs without culture expansion and differentiation in a rat model of posterolateral lumbar spinal fusion. We compared increasing dosages of implanted hPSCs to assess for dose‐dependent efficacy. All hPSC treatment groups induced successful spinal fusion, assessed by manual palpation and microcomputed tomography. Computerized biomechanical simulation (finite element analysis) further demonstrated bone fusion with hPSC treatment. Histological analyses showed robust endochondral ossification in hPSC‐treated samples. Finally, we confirmed that implanted hPSCs indeed differentiated into osteoblasts and osteocytes; however, the majority of the new bone formation was of host origin. These results suggest that implanted hPSCs positively regulate bone formation via direct and paracrine mechanisms. In summary, hPSCs are a readily available MSC population that effectively forms bone without requirements for culture or predifferentiation. Thus, hPSC‐based products show promise for future efforts in clinical bone regeneration and repair.