Tissue Deficiency Research Articles

THU301 Natural History Of Pregnancy And Pregnancy Outcomes In Subjects With Lipodystrophy

Abstract Disclosure: T.J. Neal: None. M.S. Startzell: None. E. Cochran: None. M. Lightbourne: None. R.J. Brown: None. Lipodystrophy syndromes are a group of rare heterogenous disorders characterized by deficiency of adipose tissue in a regional distribution (Partial Lipodystrophy, PL) or all of the body (Generalized Lipodystrophy, GL), leading to severe insulin resistance, diabetes, hypertriglyceridemia, non-alcoholic steatohepatitis, and polycystic ovarian syndrome. During pregnancy in patients with lipodystrophy, insulin resistance worsens during late gestation, leading to pregnancy complications that may threaten the lives of the fetus and mother. Case reports have suggested increased risk of pregnancy complications such as pre-eclampsia in patients with lipodystrophy. We sought to systematically examine pregnancy complications and offspring outcomes in lipodystrophy through a prospective study involving structured interviews with patients with known lipodystrophy and past pregnancy. Data were collected in 7 patients with PL (2 LMNA, PPARG, 4 unknown genetic cause) and 1 with GL (AGPAT2). These 7 patients had 21 pregnancies (mean 2.6), including 19 singleton and 2 twin gestations. 14 pregnancies (67%) were spontaneous and 7 (33%) required fertility treatment. 10 pregnancies (48%) in 6 patients resulted in 12 live births (7 term, 3 preterm; 3 vaginal and 8 C-section delivery) and 11 (52%) resulted in miscarriage (9 first trimester, 2 second trimester in 1 patient due to cervical insufficiency). There were no episodes of acute pancreatitis during pregnancy. Among the 10 pregnancies resulting in live birth, 100% were complicated by diabetes. 5 (50%) had pre-gestational diabetes and 5 (50%) had gestational diabetes that resolved after delivery. 8 (80%) required insulin during pregnancy (of whom none required insulin pre-pregnancy). 5 (50%) of these pregnancies were complicated by pre-eclampsia. Among all 21 pregnancies, metformin was used in 8 (38%), insulin in 8 (38%), metreleptin in 4 (19%) pregnancies (all 4 of which were in 1 patient with GL), and fenofibrate in 2 (9.5%). Among 12 offspring, 1 (8%) was small for gestational age (GA), 8 (67%) were appropriate for GA and 3 (25%) were large for GA. 6 (50%) had neonatal hypoglycemia. In summary, pregnancies in women with lipodystrophy showed high complication rates, including very high rates of miscarriage, diabetes, and pre-eclampsia. Larger studies are needed to determine how management of these patients during pregnancy, including with newer treatments such as metreleptin for GL, affects pregnancy and offspring outcomes. Presentation: Thursday, June 15, 2023

FRI057 Drug Concentrations And Dosing Considerations For Mibavademab, A Novel Leptin Receptor Agonist, In Individuals With Generalized Lipodystrophy

Abstract Disclosure: J. Mendell: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. Y. Wang: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. B.A. Olenchock: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. S. Podgrabinska: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. O.E. Pagovich: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. E.A. Oral: Advisory Board Member; Self; Regeneron Pharmaceuticals. Consulting Fee; Self; Third Rock Ventures, Rejuvenate Inc. Grant Recipient; Self; Amryt Pharamceuticals, Ionis Pharmaceuticals Inc., Gemphire Theraputics. Research Investigator; Self; Regeneron Pharmaceuticals, Novo Nordisk, Rhythm pharmaceuticals, Fractyl Laboratories, GI Dynamics. Other; Self; Has IP rights to Metreleptin manufactured by Amryt Pharmaceuticals and receives royalty payments. R.J. Brown: Research Investigator; Self; Regeneron Pharmaceuticals. J. Davis: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. Background: Generalized lipodystrophy (GLD) is characterized by deficiency of adipose tissue and, consequently, low levels of the adipose-derived hormone leptin. Leptin deficiency in GLD causes metabolic abnormalities and complications that are often refractory to treatment with usual glucose/lipid-lowering agents. Mibavademab is a first-in-class human leptin receptor (LEPR) agonist monoclonal antibody that activates LEPR. We investigated baseline serum leptin in patients with GLD, pharmacokinetics (PK) of mibavademab, and soluble LEPR (sLEPR) levels from a phase 2 study. Methods: In this phase 2 trial (NCT04159415), patients with GLD (≥12 yrs old) underwent a single-blind placebo run-in, followed by 1:1 randomization to one of two fixed sequence arms: Treatment A (placebo for 8 weeks, then mibavademab low dose for 8 weeks, then mibavademab high dose for 20 weeks) or Treatment B (mibavademab low dose for 8 weeks, then mibavademab high dose for 28 weeks). A loading dose of intravenous mibavademab was administered before low-dose treatment. Mibavademab and sLEPR concentrations in serum were serially measured during mibavademab treatment using validated bioanalytical methods. Results: Sixteen patients were enrolled with median body weight (BW) of 51 kg, corresponding to the approximate BW cut point for mibavademab. Baseline serum leptin was below the lower limit of quantitation (0.078 mg/L) in 5 patients with a median concentration of 0.345 mg/L (n=15). Baseline sLEPR concentrations with Treatments A and B were 30.6 and 33.9 μg/L, respectively. At Week 8, mean (SD) mibavademab trough concentrations (Ctrough) with Treatments A and B were 0 (0) and 1.61 (1.71) mg/L, respectively. Low-dose PK were less than predicted from a first in human study in healthy volunteers with higher leptin levels, reflecting higher target mediated clearance in patients with GLD. At Week 16, Ctrough for Treatments A and B increased to 2.31 and 43.0 mg/L, respectively, but were still below predicted. At Week 36, Ctrough for Treatments A and B were 60 (35.3) and 67.7 (44.2) mg/L, respectively. Clinically meaningful metabolic benefit (i.e reflected by reductions in fasting triglycerides and glycated hemoglobin) was observed at Week 36 with both Treatments A and B. Conclusions: Mibavademab concentrations by Week 36 were associated with clinically meaningful improvement in metabolic parameters. Presentation: Friday, June 16, 2023

FRI055 LYNC-LD: Prospective Multicenter Natural History Study Of Lipodystrophy Syndromes To Determine Prevalence, Incidence And Predictors Of Diabetes And Severe Hypertriglyceridemia, And Their Complications

Abstract Disclosure: M.C. Foss de Freitas: Advisory Board Member; Self; PTC Therapeutics. D.S. Rosenberg: None. M. Celik Guler: None. M. Yosef: None. S. Khalatbari: None. R. Carman: None. A. DillGomes: None. M. Ashmus: None. C. Spino: None. B. Akinci: Advisory Board Member; Self; Aegerion Pharmaceuticals, Regeneron Pharmaceuticals. Consulting Fee; Self; Aegerion Pharmaceuticals, Regeneron Pharmaceuticals, AstraZeneca, Lilly USA, LLC, Merck & Co., Novartis Pharmaceuticals, Novo Nordisk, Boehringer Ingelheim, Sanofi, Servier. R.J. Brown: Grant Recipient; Self; Regeneron Pharmaceuticals. E.A. Oral: Consulting Fee; Self; Regeneron Pharmaceuticals, Aegerion Pharmaceuticals, Ionis Pharmaceuticals Inc., Third Rock Ventures, Rejuvenate Inc. Grant Recipient; Self; Regeneron Pharmaceuticals, Aegerion Pharmaceuticals, Ionis Pharmaceuticals Inc., Novo Nordisk, Rhythm pharmaceuticals, Fractyl Laboratories, GID Dynamics. Other; Self; Aegerion Pharmaceuticals. Background: Lipodystrophy syndromes are rare disorders characterized by selective deficiency of adipose tissue leading to insulin resistance, diabetes mellitus, dyslipidemia and hepatic steatosis. We are conducting a comprehensive, multicenter and international observational registry study to document the natural history and prevalence of lipodystrophy syndromes in the contemporary era. Methods: All participants clinically diagnosed with a lipodystrophy syndrome, excluding HIV-associated lipodystrophy, at the participating centers may be enrolled. Once enrolled, demographic information and detailed medical history are obtained by the study team and from the participant. Patients are followed with reevaluations every 12 months. Participant questionnaires include the Patient Health Questionnaire (PHQ-9), the generalized anxiety disorder 7-item scale (GAD-7), the RAND SF-36 quality of life questionnaire, and a brief pain inventory (BPI). Univariable and multivariable repeated measure analyses were performed. Results: 148 individuals were enrolled from March 2018 to March 2022 (data-cut) with baseline age: 42 ± 15 years, 82% female, and BMI: 27.6 ± 6.5 kg/m2. Familial partial lipodystrophy is the most prevalent diagnosis (n=93, 65%), followed by congenital generalized lipodystrophy (n=13, 9.1%). There was a high prevalence of diabetes mellitus (77%), hypertriglyceridemia (82%), and hepatic steatosis (69%). 25% had at least one pancreatitis episode reported, with first episode of pancreatitis reported at age 30 ± 13 years. Cirrhosis was observed in 10% of the participants, with age of onset 39 ± 13 years. We observed a high incidence of depression and anxiety (47 and 45%) from medical history evaluation. The pain severity score (PSS) calculated from the BPI was positively associated with depression (PHQ9; p<0.0001) and anxiety (GAD-7; p=0.0003) adjusted for follow-up time. Patients with mild/moderate pain (PSS ≤4) showed a significant positive association with several Quality of Life (QoL) scores, such as physical functioning, limitation to physical health, limitation with emotional problems, and lack of energy/fatigue, social functioning, and general health (p<0.001 for all associations). During follow-up, we observed a decrease in triglyceride levels (from 585 ± 802 at baseline to 480 ± 486 mg/dL at year 3 (n=28)), while HbA1c increased from 7.4 ± 1.9 at baseline to 8.2 ± 2.1 % at year 3 (n=28). We observed 6 (4%) deaths during the 4-year follow-up. Conclusion: Our data may help clinicians, scientists, and patients with medical evaluation and decision-making in the clinical environment and provide insight into natural history as regulators evaluate new drugs. Presentation: Friday, June 16, 2023

INDIRECT REVASCULARIZATION OF THE DISTAL PARTS OF THE LOWER LIMB AT THE TERMINAL STAGES OF OCCLUSIVE-STENOTIC LESIONS OF ITS ARTERIES

Background. The terminal stages of occlusive-stenotic lesions of the limb arteries, especially in the distal areas, are characterized by critical ischemia, the development of gangrenous lesions of parts of the limb, and despite the use of a number of medical and surgical methods, there is a threat of limb loss. An effective remedy in this situation is the removal of dead tissue, reliable closure of the defect with revascularization of ischemic tissue.
 Aim: to improve the results of treatment of patients with distal occlusive lesions of the lower extremity arteries by combined revascularization using free soft tissue flaps.
 Materials and methods. We studied 45 patients with terminal stages of occlusive-stenotic lesions of the distal lower extremities (lower legs and feet). Preliminary graft sizes were established after clinical and instrumental assessment of the volume of tissue deficiency in the recipient area. The expected size of the flap tissue transformation, which occurred in the long term after surgery, was also taken into account.
 Results. The effectiveness of the method was studied in the transplantation of 48 flaps in 45 patients with terminal limb arterial lesions. The used method ensures 90.5% of limb survival after 3 years; 81.0% of good results - walking with a cane.
 Conclusion. 1. The used method of treatment of limbs with terminal stages of occlusive-stenotic arterial lesions by indirect revascularization with a thoraco-dorsal flap is effective, provides 90.5% survival of the limb after 3 years. Preliminary graft sizes should be established after clinical and instrumental assessment of the volume of tissue deficiency in the recipient area, taking into account the size of tissue transformation. Combined revascularization of the lower extremities significantly improves the hemodynamics of the ischemic limb.

Dynamics of changes in the velocity of ultrasound propagation in the bone tissue of premature children according to the data of ultrasound densitometry

All premature babies lack the intrauterine phase of active mineralization of the bones, osteogenesis changes, speed of ultrasound propagation in bone tissue changes. Aim. The purpose of the article was to determine osteopenia in premature babies (PB) based on ultrasound densitometry at birth and during the period of intensive care. Materials and methods. 70 premature babies and 20 full-term newborns were studied. The authors determined the bone ultrasound speed (SOS, m/s) and its comparative evaluation (Z-score) with the representative base of the ultrasound sonometer “Sunlight Omnisense 9000” (Israel). SOS was defined as average at Z ≥-1.0 SD, as low – at Z from -1.1 to -2.0 SD, and as significantly low – Z ≤- 2.0 SD. Results. 54.3 % of PB had osteopenia at birth: low indicators in 28.6 %, significantly low in 25.7 %. Postnatally, an increase in bone tissue deficiency of PB was observed – osteopenia with a low Z was diagnosed in 41.1 %, with a significantly low – in 37.5 % of PB. Conclusions. The number of PB with osteopenia increased 1.4 times, during the first 4 weeks of life. An increase in bone tissue deficiency was most often (p < 0.05) observed among children (52.0 %) with normal / average Z-score SOS indicators. Z-score SOS indicators in children with osteopenia were stable during the first month of life. The odds ratio of having osteopenia were 3.37 times higher for those born in GA of 33 weeks or less (OR = 3.37; CI 95 % [1.25, 9.09], p < 0.05), and 7.50 times higher odds of having significantly low Z-scores (OR = 7.50; CI 95 % [1.60, 34.59], p < 0.05), ), and 8.15 times higher odds of having significantly low Z-scores after 1 month of life (OR = 8.15; CI 95 % [2.23; 29.70], р < 0.05), than in children with greater GA. Indicators of physical development of premature newborns do not allow assessing the state of bone mineral velocity and require dynamic ultrasonic densitometry, despite the presence of correlations of SOS with indicators of the mass or length of infants depending on the gestational timing of birth.

A rare lipodystrophy syndrome with familial partial lipodystrophy 2 (FPLD2)

Background: Lipodystrophy (LD) syndromes are a diverse group of ultra-rare diseases characterized by adipose tissue deficiency, resulting in potentially severe metabolic disturbances. Due to their scarcity, diagnosis and management are often challenging for clinicians. This study aimed to report a rare case of LD syndromes, as well their diagnosis and possible management. Case Presentation: A 27-year-old female presented to Dr. Soetomo General Academic Hospital, Surabaya, Indonesia with a chief complaint of abdominal (epigastric) pain, accompanied by diarrhea, nausea, and vomiting. The patient had a history of uncontrolled type-2 diabetes mellitus (T2DM), dyslipidemia, severe hypertriglyceridemia (HTG), diabetic retinopathy, and glaucoma. Physical examination indicated subcutaneous fat loss, especially from the extremities, and excessive fat accumulation in the face. Hepatosplenomegaly and ascites were detected, further confirmed through abdominal ultrasonography (USG). Laboratory investigations revealed hyperglycemia, dyslipidemia, severe HTG, and renal dysfunction. All of the assessment findings led to the diagnosis of LD syndrome with familial partial lipodystrophy 2 (FPLD2) (Dunnigan syndromes). Therapies included insulin injections and pioglitazone for the treatment of hyperglycemia, simvastatin and fenofibrate to reduce HTG, and some symptomatic drugs to reduce symptoms of the disease. Lifestyle modification (diet and exercise) was recommended to ameliorate metabolic derangements. Conclusion: There is currently no cure for LD syndrome. Treatment modalities are limited to preventing or reducing severe comorbidities of these syndromes. Increasing knowledge and awareness of the symptoms indicative of LD at an early onset is important.

Management of the Congenital Cleft Earlobe with a Conchal Cartilage Graft.

Congenital earlobe clefts are the most common lower auricular malformations. They represent a unique reconstructive challenge. The goal of surgery includes restoration of a natural lobular contour and volume as well as a fine surgical scar. Several surgical techniques have been described, most of which only address the cleft deformity but not the soft tissue deficiency. We hereby describe a technique which addresses both the cleft and improves soft tissue deficiency through a conchal cartilage graft.

Elimination of soft tissue deficiency of the alveolar ridge in the experiment

To date, dental implantation is the most common routine way to restore the continuity of dentition. Additional bone augmentation surgery is required in 50-80% of patients. In order to improve the results and reduce the risks of osseointegration, denudation and rejection of bone autografts, various ways of correcting the deficiency of soft tissues of the alveolar ridge are proposed, which include the use of free soft-woven autografts, the low efficiency of which is due to a high shrinkage coefficient.The purpose of the study: to test an experimental model of a vascularized muco-periosteal flap to eliminate the volume deficit of the soft tissues of the alveolar ridge.Material and methods. On the basis of the vivarium of the Stavropol State Agrarian University (StSAU), 15 biological mannequins (heads of female dwarf pigs) were subjected to a pilot experimental study. The study was conducted in accordance with the decision of the local Ethics Committee of the StSAU, as well as the provision of the World Convention on the Protection of Animals and the Procedure for the Treatment of Experimental Animals adopted by the Helsinki Council in 2002.Results. In the course of the study, the technical stages of the tested intervention were clarified, the metric parameters of the elimination of defects of the alveolar ridge were determined.Conclusion. The results obtained will make it possible to eliminate extended soft tissue defects of the alveolar ridge by increasing the possibility of tissue sampling in the donor bed in a volume not less than 3 times greater than the intake of free palatine flaps.

MOLECULAR AND CELLULAR MECHANISMS OF HYPOXIC RESPONSE

Hypoxia is a typical pathological process characterized by oxygen tissue deficiency with the pathological and protective-compensatory reactions. The article briefly outlines the issues of hypoxia study and interval hypoxic training in clinical and rehabilitation practice while treating various diseases and pathological processes. The authors consider types of physiological and pathological responses to hypoxia, key aspects in the pathogenesis of normo- and hypobaric hypoxia under normal and reduced atmospheric pressure, and stages of hypoxia development. Physiological and biochemical responses to interval hypoxic training are associated with oxidative stress, which develops as a result of an imbalance between the pro- and antioxidant systems, and excessive production of reactive oxygen species. Interval hypoxic training is aimed at adequate activation of defense systems with the formation of stable adaptation to damaging factors. The authors prove the key role of HIF-1α biological effects in the mechanisms of cellular and tissue adaptation to oxygen deficiency. The authors also analyze the role of adenosine and adenosine receptors in acute and chronic inflammatory diseases associated with tissue hypoxia.

Outcomes of Shoulder Instability Repair - Latarjet vs Arthroscopic Bankart Repair: A Retrospective Study

This retrospective study aimed to compare the outcomes of two surgical procedures, Latarjet repair and arthroscopic Bankart repair, for the treatment of anterior shoulder instability. The study included 31 patients between the ages of 16 and 40 years who underwent either Latarjet repair or arthroscopic Bankart repair. The patients were evaluated using the Constant Murley Shoulder Score (CMS) and the American Shoulder and Elbow Surgeons Score (ASES) at 3, 6, and 12 months postoperatively. The results showed a gradual improvement in functional outcomes for both groups during the follow-up period. At one year postoperative, the Bankart repair group exhibited a CMS score of 89.3 and an ASES score of 94.1, while the Latarjet repair group showed a CMS score of 87.8 and an ASES score of 91.3. Statistical analysis revealed no significant differences in the CMS scores at any follow-up time point. However, the ASES score at 12 months postoperative was significantly higher in the Bankart repair group compared to the Latarjet repair group. The findings of this study suggest that both Latarjet repair and arthroscopic Bankart repair yield favorable clinical outcomes in terms of functional improvement for patients with anterior shoulder instability. Although arthroscopic techniques are minimally invasive and preferred by surgeons, the Latarjet procedure offers comparable results with less expenditure. The choice of surgical approach should be based on factors such as the patient's age, level of activity, and the presence of significant bone defects or soft tissue deficiencies. Further comparative studies with long-term follow-ups are recommended to validate these findings and provide more comprehensive insights into the outcomes of these procedures.

The use of abdominal wall tissue expansion prior to herniorrhaphy in massive ventral hernia defects

Massive ventral hernias pose a challenging reconstructive problem. In comparison to bridging mesh repair, the primary fascial repair is associated with significantly reduced rates of hernia recurrence. This study will review our experience with massive ventral hernia repairs using tissue expansion and anterior component separation as well as present the largest case series to date. A retrospective review was conducted of 61 patients who underwent abdominal wall tissue expansion prior to herniorrhaphy at a single institution between 2011 and 2017. Demographics, perioperative co-variates, and outcomes were recorded. Univariate and subgroup analysis was performed. Kaplan-Meier survival analysis was used to assess the time to recurrence. Sixty-one patients underwent abdominal wall expansion via tissue expanders (TE). Of these, 56 subsequently underwent staged anterior component separation for attempted closure of large ventral hernia. Major complications of TE placement included TE replacement (4,6.6%), TE leak (2,3.3%), and unplanned readmission (3,4.9%). Higher BMI groups were significantly associated with comorbid hypertension (BMI<30kg/m2, 22.7%; BMI 30-35kg/m2, 68.7%; BMI>35kg/m2, 64.7%; P= 0.004). 15 patients (32.6%) had hernia recurrence and 21 patients (34.4%) still required bridging mesh during herniorrhaphy after tissue expansion. The use of tissue expansion prior to herniorrhaphy can be effective in achieving durable closure for most massive abdominal wall defects - especially those associated with musculofascial, soft tissue, or skin deficiencies. In this proof-of-concept analysis, we found that the efficacy and safety profile of this technique compares favorably to other methods for massive hernia repair in the literature.

Repair of Scars and Tissue Deficiency With Free Grafts of Full-thickness Scalp in Secondary Unilateral Cleft Lip Deformity.

Although surgical techniques have developed, the incidence of secondary cleft lip deformities after the primary repair is still high. Asymmetry of Cupid's bow and philtrum is a common presentation and a technical challenge to reconstruct the upper lip. The authors introduce a technique to use the free grafts of the full-thickness scalp for the correction of scars and tissue deficiency in secondary unilateral cleft lip deformity. Thirty-seven patients with a prominent scar, tight upper lip, deformed Cupid's bow and philtrum, and irregular vermillion border were included in this study. The specific points of interest were assessed before and after surgery by independent examiners with both subjective and objective methods. All surgeries were successfully completed, and the assessment results were satisfactory. The rating scores of philtrum improvement was 1.6±0.4, the POSAS result of patient scales was 13.48±3.21, and the observer scale result was 11.98±3.88. The asymmetry of Cupid's bow was corrected ( P =0.004), the central tubercle of vermilion was more natural ( P =0.001), and the irregular vermillion border was improved ( P =0.015). The results presented significant differences before and after surgery. This method could be an optional treatment for repairing scars and tissue deficiency in secondary unilateral cleft lip deformity.

Evaluation of the heel external rotation test in soft tissue deficiencies associated with adult acquired flatfoot deformity (AAFD). A cadaver sectioning analysis.

To date, evaluation of the heel external rotation test has not been taken with respect to AAFD. Traditional 'gold standard' tests do not account for the contribution of the midfoot ligaments towards instability. These tests would be flawed as any midfoot instability may produce a false positive result. To evaluate the differential contribution of the spring, deltoid and other local ligaments in external rotation generated at the heel. Serial ligament sectioning was performed on 16 cadaveric specimens, with a 40N-external rotation force applied to the heel. These were divided into four groups with different sequences of ligament sectioning. Measurements of the total amount/range of external, tibiotalar and subtalar rotation were made. The deep component of the deltoid ligament (DD) was the main ligament influencing heel external rotation (P<0.05, in all cases), and acted primarily at the tibiotalar joint (87.9 %). The spring ligament (SL) influenced heel external rotation predominantly (91.2 %) at the subtalar joint (STJ). Greater than 20 degrees external rotation could only be achieved with DD sectioning. The interosseous (IO) and cervical (CL) ligaments did not significantly contribute to external rotation at either joint (P>0.05). Clinically relevant external rotation (>20 degrees) is solely attributable to DD failure in the presence of intact lateral ligaments (LL). This test may improve detection of DD instability and allow clinicians to subclassify patients with Stage 2 AAFD into those where DD may or may not be compromised.

Treatment of Progressive Hemifacial Atrophy by Cartilage Graft and Free Adipofascial Flap Combined with Three-Dimensional Planning.

Progressive hemifacial atrophy (PHA) is a rare disease characterized by progressive atrophy of skin, soft tissue, muscles, and underlying bone structures. For severe PHA patients with obvious bone deformities, skeletal framework reconstruction is needed in addition to soft-tissue augmentation. The authors propose a new combinatorial surgical method using rib cartilage graft and free adipofascial flap for restoring facial symmetry. To improve the surgical accuracy, preoperative three-dimensional planning and printing was used. Twelve patients with severe facial atrophy were included in the authors' study. Three-dimensional facial image analyses were performed preoperatively to quantify the facial asymmetry. Rib cartilages were harvested and sculptured to the appropriate shape created by three-dimensional planning and fixed to the atrophic bone. The circumflex scapular artery-based adipofascial flap was transplanted to repair soft-tissue deficiency. A residual small monitor flap was left with the adipofascial flap. A revision surgery was performed to perfect the repair if the contour was suboptimal 6 months postoperatively. The adipofascial flaps survived in all 12 patients. All patients achieved good healing without complications. At 1 more year after surgery, the rib cartilage was still in position and rarely absorbed. The morphologic and volumetric difference between the affected side and the unaffected side was improved significantly postoperatively. All patients were satisfied with the results, and no more additional operations were required. The combinatorial surgery of rib cartilage graft and free adipofascial flap in the setting of three-dimensional planning and printing can be a good choice in restoring facial symmetry in severe cases of PHA. Therapeutic, IV.

Transcriptome sequencing of facial adipose tissue reveals alterations in mRNAs of hemifacial microsomia.

Hemifacial microsomia (HFM) is a common congenital malformation of the craniofacial region, including mandibular hypoplasia, microtia, facial palsy and soft tissue deficiencies. However, it remains unclear which specific genes are involved in the pathogenesis of HFM. By identifying differentially expressed genes (DEGs) in deficient facial adipose tissue from HFM patients, we hope to provide a new insight into disease mechanisms from the transcriptome perspective. RNA sequencing (RNA-Seq) was performed with 10 facial adipose tissues from patients of HFM and healthy controls. Differentially expressed genes in HFM were validated by quantitative real-time PCR (qPCR). Functional annotations of the DEGs were analyzed with DESeq2 R package (1.20.0). A total of 1,244 genes were identified as DEGs between HFM patients and matched controls. Bioinformatic analysis predicted that the increased expression of HOXB2 and HAND2 were associated with facial deformity of HFM. Knockdown and overexpression of HOXB2 were achieved with lentiviral vectors. Cell proliferation, migration, and invasion assay was performed with adipose-derived stem cells (ADSC) to confirm the phenotype of HOXB2. We also found that PI3K-Akt signaling pathway and human papillomavirus infection were activated in HFM. In conclusion, we discovered potential genes, pathways and networks in HFM facial adipose tissue, which contributes to a better understanding of the pathogenesis of HFM.

Hard and soft tissue regeneration of severe peri-implantitis defects with the laser-assisted peri-implant defect regeneration technique: 3-year results

PurposeThis retrospective cohort study evaluates the regeneration of severe peri-implantitis deficiencies treated with the laser-assisted peri-implant defect regeneration (LAPIDER) approach within a 3-year follow-up.MethodsTwenty-four implants with severe peri-implantitis in 18 patients were treated according to the LAPIDER technique. In contrast to classic techniques for reconstructive peri-implantitis surgery with a marginal incision, a buccal split-flap preparation avoiding papillae separation was used. After a coronal flap elevation and a laser-assisted peri-implant defect cleaning, connective tissue and autogenous bone grafting was performed. Primary outcomes were the changes of the marginal bone levels (MBL) and the buccal bone thickness. Secondary outcomes included implant survival, peri-implant probing depths (PPD), bleeding on probing (BOP), recession, width of keratinized mucosa (KMW), thickness of keratinized mucosa (KMT), soft tissue esthetics (PES), and implant success.ResultsMBL improved interproximal by 3.10 ± 2.02 mm (p < 0.001), buccal by 3.49 ± 2.89 mm (p < 0.001), and lingual by 1.46 ± 1.98 mm (p = 0.003); buccal bone thickness by 0.55 ± 0.60 mm (p = 0.005), and 1.01 ± 1.25 mm (p = 0.001) at 1 and 3 mm below reference level. Two implants were removed; 22 implants were still in function at a mean follow-up of 36 months. PPD changed from 5.05 ± 1.39 to 3.08 ± 0.71 mm (p < 0.001); recession was reduced from 2.07 ± 1.70 to 0.91 ± 1.13 mm (p = 0.001); KMW increased from 2.91 ± 1.81 to 4.18 ± 1.67 mm (p = 0.006); KMT improved from 1.73 ± 0.50 to 2.44 ± 0.43 mm (p < 0.001); PES changed from 7.7 ± 2.8 to 10.7 ± 1.9 (p < 0.001). 45.8% to 54.2% of the implants met the criteria of implant success.ConclusionsThe favorable results document the proof of principle for the regeneration of severe peri-implant hard and soft tissue deficiencies by the LAPIDER treatment approach.

Stem Cell-Enriched Hybrid Breast Reconstruction Reduces Risk for Capsular Contracture in a Hybrid Breast Model.

Hybrid breast reconstruction (HBR) combines silicone implants with fat grafting to improve implant coverage, treating local tissue deficiencies and leading to a more natural breast appearance. Recent data also indicated less capsular contracture after HBR. The authors developed a novel technique and animal model of cell-assisted (CA) HBR to illuminate its effects on capsular contracture. Animals received silicone implants in a dorsal submuscular pocket. Although animals of the HBR group received fat grafting around the implant without stem cell enrichment, rats of the CA-HBR1 and the CA-HBR2 groups received stem cell-enriched fat grafting with 2 × 10 6 and 4 × 10 6 adipose-derived stem cells immediately after implant insertion. On day 60, animals underwent sonography and elastography imaging and were euthanized, and outcome analysis was performed by means of histology, immunohistochemistry, chemical collagen quantification, and gene expression analysis. With this novel technique, long-term survival of adipose-derived stem cells within the implant pocket was demonstrated after 60 days after implant insertion. CA-HBR led to significantly reduced thickness and collagen density of capsular contractures. In addition, CA-HBR resulted in reduced fibrotic responses with less occurrence of collagen type I and transforming growth factor-β in capsule tissue. Moreover, the addition of stem cells suppressed fibrotic and inflammatory responses on a genetic level with significant underexpression of collagen type I and transforming growth factor-β1. With this new technique and animal model, the authors observed a preventive effect on capsular contracture substantiating the basis of clinical outcomes of HBR. The authors propose that the addition of stem cells to HBR might booster its beneficial results. Stem cell-enriched fat grafting around silicone implants may reduce the risk for capsular contracture after silicone breast implantation. While fat grafting alone already shows beneficial effects, the addition of stem cells to the fat graft can potentiate this effect.

Biophotonic Effects of Low-Level Laser Therapy on Adipose-Derived Stem Cells for Soft Tissue Deficiency.

The objectives of this study are to use diode lasers for low-level laser therapy (LLLT) and to assess its applicability and effects in adipose-derived stem cell (ADSC) growth processes. Studies were conducted on the diode laser with wavelengths of 622.7, 527.1, and 467.3 nm. The mechanism of action of LLL illumination was studied on ADSCs, isolated from human tissue, and then cultured by examining different wavelengths to determine the relevant light parameters for optimal responses. We used enzyme-linked immunosorbent assay and real-time polymerase chain to determine the percentages of fibroblast-mediated procollagen type 1 and matrix metallopeptidase 1 (MMP-1), MMP-2, and MMP-9 production at different wavelengths. The levels of lactate dehydrogenase produced by ADSCs after LLL illumination were assessed as well. Clinical results from 20 patients treated for soft tissue deficiency were collected for assessment of ADSC-assisted lipotransfer. Low-level laser (622.7 nm) illumination on cell cultures in vitro increased ADSCs proliferation, type 1 procollagen expression, collagen production, as well as MMP-1, MMP-2, and MMP-9 relative expression. Statistical analysis demonstrated a significant difference in red light (622.7 nm) versus green light (527.1 nm) and blue light (467.3 nm, P < 0.05). No significant differences were noted between the effects of green and blue lights. In clinical application, all patients attained significant improvement with treatment in the final outcome assessment after 6 months. Low-level laser illumination may affect ADSCs growth processes and ADSC-assisted lipotransfer for soft tissue deformity, scar treatment, wound healing, and other reconstructive surgery.

Fabrication and Properties of a Hybrid Biocompatible Nanofiber Mesh Constituted of Polycaprolactone and Self-Assembly Peptide

Conventional therapeutic methods for organ and tissue deficiencies include surgical reconstruction, organ transplantation, medical devices treatment, synthetic prosthesis and so on, of which the application is limited when donors exhibit a low availability and impaired organs and tissues cannot well perform their functions. Tissue Engineering (TE) can harmonize with regional organs or tissues, ensure optimal degradation time for novel structure rebirth, facilitate cell adhesiveness, contribute to cell procreation and differentiation in tissue scaffolds, etc., making it an alternative option for treating pathological obstacles. Artificial polymers such as polycaprolactone (PCL) and nature materials such as peptides are adopted for the fabrication of nanofiber scaffolds. The study first engineered porous PCL scaffolds for examining the fiber morphology and the diameter alternations considering the change of single variable condition of the solution concentration, voltage and electrode distance, etc., thereby finding the basic conditions for producing nanofiber scaffolds with good formation. With the increase in solution concentration, the more obvious molecule entanglement can limit the jet stretching, thereby enlarging the fiber diameters. Voltage negatively impacts the fiber diameters, and elevated voltage can strengthen the electric intensity, thereby leading to a complete stretching of cone jets and making fiber diameters thinner. Besides, increased electrode distance is followed by expanded flight distance and decreased electrode intensity (constant voltage), as a result, fibers become narrower. Nanofiber substance exhibits the optimal performance under the condition of solution concentration: 6%, voltage: 50kV, and electrode distance: 150mm. Subsequently, nanofiber scaffolds were fabricated based on the respective preparation of PCL/P11-4 and PCL/P11-8 polymer solutions. Both P11-4 and P11-8 presented uneven distribution in PCL scaffolds, which involved various PCL nanofiber substances with abundant peptides. PCL nanofiber scaffolds saw the breakage of P11-4 and P11-8 fibers.

Three-dimensional evaluation of the dental arch in cleft lip and palate after prosthetic treatment.

This study aimed to evaluate the stability of the surface of the maxillary teeth and mucosa in cleft lip and palate (CLP) patients with a maxilla defect or tissue deficiency according to the duration of observation and cleft type. Pairs of maxillary casts taken from 18 patients at different time points after prosthodontic treatment were investigated in this study. All 36 casts were scanned with an intraoral scanner, and the acquired images were saved in standard tesselation language (STL) files. The two STL files for each patient were then superimposed using three-dimensional (3D) evaluation software, with 3D deviations shown as a color map. Areas with a 3D deviation within ±0.100 mm were defined as stable. The influence of cleft type and duration of observation on the ratio of stable areas to the entire maxillary surface comprising the teeth and mucosa was investigated using multiple regression analysis. Statistical significance was set at p <0.05. Multiple regression analysis showed that the duration of observation was significantly associated with the stable area ratio (B = -23.463, P<.001), whereas cleft type was not (β = 0.13, P = 0.301). The maxillary teeth and mucosa of CLP patients changed over time, with stable areas showing a negative correlation with the observation period. However, the stability of the dental arch was not significantly affected by the cleft type. 3D analysis of the casts of CLP patients allowed for measurements and to accurately assess relapse of the maxillary arch after prosthetic treatment.