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Endogenous cell therapy improves bone healing

Layliev, John; Marchac, Alexander; Tanaka, Rica; Szapalski, Caroline; Henderson, Raven; Rubin, Marcie S; Saadeh, Pierre B; Warren, Stephen M
BACKGROUND: Although bone repair is often a relatively rapid and efficient process, many bone defects do not heal. Because an adequate blood supply is essential for new bone formation, we hypothesized that augmenting new blood vessel formation by increasing the number of circulating vasculogenic progenitor cells (PCs) with AMD3100 and enhancing their trafficking to the site of injury with recombinant human parathyroid hormone (rhPTH) will improve healing. METHODS: Critical-sized 3-mm cranial defects were trephined into the right parietal bone of C57BLKS/J 6 mice (N = 120). The mice were divided into 4 equal groups (n = 30 for each). The first group received daily subcutaneous injections of AMD3100 (5 mg/kg). The second group received daily subcutaneous injections of rhPTH (5 mg/kg). The third group received both AMD3100 and rhPTH. The fourth group received subcutaneous injections of saline. Circulating vasculogenic PC numbers, new blood vessel formation, and bony regeneration were assessed. Progenitor cell adhesion, migration, and tubule formation were assessed in the presence of rhPTH and AMD3100. RESULTS: Flow cytometry demonstrated that combination therapy significantly increased the number of circulating PCs compared with all other groups. In vitro, AMD3100-treated PCs had significantly increased adhesion migration, and tubule formation was assessed in the presence of rhPTH. Combination therapy significantly improved new blood vessel formation in those with cranial defect compared with all other groups. Finally, bony regeneration was significantly increased in the combination therapy group compared with all other groups. CONCLUSIONS: The combination of a PC-mobilizing and traffic-enhancing agent improved bony regeneration of calvarial defects in mice.
PMID: 25502704
ISSN: 1049-2275
CID: 1464772

Endogenous Cell Therapy Improves Bone Healing (vol 26, pg 300, 2015) [Correction]

Layliev, John; Marchac, Alexander; Tanaka, Rica; Szpalski, Caroline; Henderson, Raven; Rubin, Marcie S.; Saadeh, Pierre B.; Warren, Stephen M.
ISSN: 1049-2275
CID: 5390652

Factors affecting parental anxiety and postoperative pain in infants undergoing cleft lip or palate repair [Meeting Abstract]

Clark, R; Lou, Jiang X; Chibbaro, P; Mahajan, A; Staffenberg, D A; Warren, S; Mendelsohn, A; Rosenberg, R
Background/Purpose: Pediatric cleft lip and palate surgery can be stressful for both the child and the parents. Limited pain knowledge and certain parent psychological traits are associated with increased parental anxiety around surgery in older children. Increased parental anxiety has been associated with increased child pain, decreased ability of the child to cope with pain and worse outcomes in other surgical settings. Little is known about parental anxiety and child pain in preverbal children undergoing cleft lip and palate repair. The objectives of this study were to explore possible sociodemographic factors contributing to parental anxiety in the immediate postoperative period and to determine if there is a relationship between parental postoperative anxiety and infant postoperative pain. Methods/Description: Cross-sectional pilot study, semi-structured interview. Eight mothers of children under 18 months of age undergoing cleft lip/palate (CL/P) repair at an urban craniofacial center were recruited. Semi-structured interviews about their experience with their infant's surgery were conducted. Demographics were collected at a preoperative visit, while maternal anxiety scores, measured using the Hospital Anxiety and Depression Scale (HADS), and nurse-recorded child pain scores (Face, Legs, Activity, Cry, Consolability scale), were collected on postoperative day (POD) 1. Fisher's exact tests were used to compare demographics and Student's t-tests were used to analyze pain medication and doses given. Results: Mothers who were healthcare workers were more likely to have borderline/abnormal anxiety scores (HADS > 7) than mothers who were non-healthcare workers (p = .035) on POD1. Mothers of infants undergoing a bilateral CL/P repair tended to be more anxious than mothers of infants undergoing a unilateral CL/P repair (p=.090). Infants of anxious mothers tended to have more variation in pain scores, more pain scores recorded (95% CI -1.74, 4.0) (p = .19) and more pain medication given (95% CI 2.!
ISSN: 1055-6656
CID: 1361642

Unilateral Cleft Lip Repair

Vyas, Raj M; Warren, Stephen M
Modern cleft surgery requires four-dimensional and functional anatomic understanding of the cleft (and noncleft) lip, nose, and alveolus. Some techniques for nasolabial repair rely more on precise anatomic geometry, whereas others afford the surgeon a more flexible design. Consistent anthropometry enables accurate assessment and reporting of long-term outcomes; such reports are needed to guide perioperative care, delineate optimal repair principles, and resolve ongoing controversies.
PMID: 24607186
ISSN: 0094-1298
CID: 853492

Disparities in initial presentation and treatment outcomes of diabetic foot ulcers in a public, private, and Veterans Administration hospital ()

Blumberg, Sheila N; Warren, Stephen M
BACKGROUND: Disparities in diabetic foot ulcer (DFU) treatment outcomes are well described, although few studies identify risk factors contributing to disparate healing and amputation rates. In a unique academic center serving urban public, private, and veteran patients, we investigated amputation and healing rates and specific risk factors for disparate treatment outcomes. METHODS: A retrospective chart review of diabetic patients with a new diagnosis of a foot ulcer at geographically adjacent, but independent public, private, and Veterans Administration (VA) hospitals was conducted. Healing and lower extremity amputation outcomes were assessed. RESULTS: Across the three hospitals, 234 patients met the inclusion criteria. Patients at the VA hospital were older (mean 72.5 years; P < 0.001) and had gangrenous ulcers (mean 14.1%; P < 0.001) compared with patients in the private and public hospitals. Public hospital patients were mostly Hispanic (mean 54%; P < 0.001) with a shorter duration of diabetes (mean 12.8 years; P = 0.02), but were more poorly controlled than VA and private hospital patients (P
PMID: 23551696
ISSN: 1753-0407
CID: 680882

Combination therapy accelerates diabetic wound closure

Allen, Robert J Jr; Soares, Marc A; Haberman, Ilyse D; Szpalski, Caroline; Schachar, Jeffrey; Lin, Clarence D; Nguyen, Phuong D; Saadeh, Pierre B; Warren, Stephen M
BACKGROUND: Non-healing foot ulcers are the most common cause of non-traumatic amputation and hospitalization amongst diabetics in the developed world. Impaired wound neovascularization perpetuates a cycle of dysfunctional tissue repair and regeneration. Evidence implicates defective mobilization of marrow-derived progenitor cells (PCs) as a fundamental cause of impaired diabetic neovascularization. Currently, there are no FDA-approved therapies to address this defect. Here we report an endogenous PC strategy to improve diabetic wound neovascularization and closure through a combination therapy of AMD3100, which mobilizes marrow-derived PCs by competitively binding to the cell surface CXCR4 receptor, and PDGF-BB, which is a protein known to enhance cell growth, progenitor cell migration and angiogenesis. METHODS AND RESULTS: Wounded mice were assigned to 1 of 5 experimental arms (n = 8/arm): saline treated wild-type, saline treated diabetic, AMD3100 treated diabetic, PDGF-BB treated diabetic, and AMD3100/PDGF-BB treated diabetic. Circulating PC number and wound vascularity were analyzed for each group (n = 8/group). Cellular function was assessed in the presence of AMD3100. Using a validated preclinical model of type II diabetic wound healing, we show that AMD3100 therapy (10 mg/kg; i.p. daily) alone can rescue diabetes-specific defects in PC mobilization, but cannot restore normal wound neovascularization. Through further investigation, we demonstrate an acquired trafficking-defect within AMD3100-treated diabetic PCs that can be rescued by PDGF-BB (2 mug; topical) supplementation within the wound environment. Finally, we determine that combination therapy restores diabetic wound neovascularization and accelerates time to wound closure by 40%. CONCLUSIONS: Combination AMD3100 and PDGF-BB therapy synergistically improves BM PC mobilization and trafficking, resulting in significantly improved diabetic wound closure and neovascularization. The success of this endogenous, cell-based strategy to improve diabetic wound healing using FDA-approved therapies is inherently translatable.
PMID: 24651576
ISSN: 1932-6203
CID: 936422

Maxillary Mucocele With Proptosis and Visual Impairment: A Late Complication of Le Fort III Distraction

Patel, Parit A; Warren, Stephen M; McCarthy, Joseph G
Maxillary mucoceles are a relatively rare entity especially following surgical procedures involving osteotomies of the maxilla. The etiology of maxillary mucoceles has been ascribed to facial trauma (fractures), sinus surgery, and chronic inflammatory diseases or infections. Mucoceles can follow injury to the sinus mucosa and/or sinus outflow tract with a resulting expansile cystic mass. The clinical presentation ranges from swelling, pain, a palpable mass, proptosis, enophthalmos, and diplopia. The treatment involves either open or endoscopic incision and drainage of the cyst, mucosal resection, and an antrostomy for drainage.We report the case of a patient with Pfeiffer syndrome who underwent Le Fort III distraction osteogenesis and developed a symptomatic mucocele 15 years postoperatively.
PMID: 24220390
ISSN: 1049-2275
CID: 626992

Lacunocanalicular fluid flow transduces mechanical tension stress during distraction osteogenesis

Davidson, Edward H; Sultan, Steven M; Butalala, Parag; Knobel, Denis; Warren, Stephen M
The mechanotransduction mechanisms linking distraction device activation to new bone formation remain unknown. We hypothesize that the tension stress of activation during distraction osteogenesis is transmitted through lacunocanalicular fluid flow to initiate the osteogenic signaling cascade. Adult Sprague-Dawley rats (N = 24) were subjected to mandibular osteotomy and application of an external distraction device. After a 3-day latency period, half the animals (n = 12) underwent device activation at 0.25 mm twice daily for 6 days (total activation, 3 mm), and the other half (n = 12) had no activation. On day 10, the animals were injected with fluorescent reactive red lacunocanalicular tracer before killing. Mandibles were harvested, embedded, and sectioned, and reactive red epifluorescence lacunocanalicular flow was measured. Protein was harvested for focal adhesion kinase 1 (FAK1), NESPRIN1, SUN1, LAMIN A/C, and SMAD1 Western blotting as well as for bone morphogenetic protein (BMP)-2 enzyme-linked immunosorbent assay and alkaline phosphatase assay. Lacunocanalicular fluid flow was significantly greater in the distracted samples (60.5 +/- 14 vs 10.3 +/- 4 molecules of equivalent soluble fluorochrome per megapixel, P = 0.01). Flow distribution demonstrated the highest lacunocanalicular flow near the center of the distraction gap. Increased lacunocanalicular flow resulted in increased FAK1 (P = 0.009), NESPRIN1 (P = 0.01), SUN1 (P = 0.01), and LAMIN A/C (P = 0.008) expression. Focal adhesion kinase 1 activation in the presence of BMP-2 protein expression (P = 0.001) resulted in increased intranuclear SMAD1 phosphorylation (P = 0.04) and alkaline phosphatase activity (P < 0.0001). These findings suggest that activation of the distraction osteogenesis device affects cellular response through changes in lacunocanalicular fluid flow.
PMID: 24036726
ISSN: 1049-2275
CID: 541842

Percutaneous gene therapy heals cranial defects

Layliev, J; Sagebin, F; Weinstein, A; Marchac, A; Szpalski, C; Saadeh, P B; Warren, S M
Nonhealing bone defects are difficult to treat. As the bone morphogenic protein and transforming growth factor beta pathways have been implicated in bone healing, we hypothesized that percutaneous Smad7 silencing would enhance signaling through both pathways and improve bone formation. Critical sized parietal trephine defects were created and animals received percutaneous injection of: agarose alone or agarose containing nonsense or Smad7 small interfering RNA (siRNA). At 12 weeks, SMADs1, 2, 3, 5, 7 and 8 levels were assessed. Smad1/5/8 osteogenic target, Dlx5, and SMAD2/3 angiogenic target, plasminogen activator inhibitor-1 (Pai1), transcription levels were measured. Noncanonical signaling through TGFbeta activated kinase-1 (Tak1) and target, runt-related transcription factor 2 (Runx2) and collagen1alpha1 (Col1alpha1), transcription were also measured. Micro-computed tomography and Gomori trichome staining were used to assess healing. Percutaneous injection of Smad7 siRNA significantly knocked down Smad7 mRNA (86.3+/-2.5%) and protein levels (46.3+/-3.1%). The SMAD7 knockdown resulted in a significant increase in receptor-regulated SMADs (R-SMAD) (Smad 1/5/8 and Smad2/3) nuclear translocation. R-SMAD nuclear translocation increased Dlx5 and Pai1 transcription. Additionally, noncanonical signaling through Tak1 increased Runx2 and Col1alpha1 target transcription. Compared with animals treated with agarose alone (33.9+/-2.8% healing) and nonsense siRNA (31.5+/-11.8% healing), animals treated Smad7 siRNA had significantly great (91.2+/-3.8%) healing. Percutaneous Smad7 silencing increases signal transduction through canonical and noncanonical pathways resulting in significant bone formation. Minimally invasive gene therapies may prove effective in the treatment of nonhealing bone defects.
PMID: 23594990
ISSN: 0969-7128
CID: 519362

Quality-control culture system restores diabetic endothelial progenitor cell vasculogenesis and accelerates wound closure

Tanaka, Rica; Vaynrub, Max; Masuda, Haruchika; Ito, Rie; Kobori, Michiru; Miyasaka, Muneo; Mizuno, Hiroshi; Warren, Stephen M; Asahara, Takayuki
Delayed diabetic wound healing is, in part, the result of inadequate endothelial progenitor cell (EPC) proliferation, mobilization, and trafficking. Recently, we developed a serum-free functional culture system called the quality and quantity culture (QQc) system that enhances the number and vasculogenic potential of EPCs. We hypothesize that QQc restoration of diabetic EPC function will improve wound closure. To test this hypothesis, we measured diabetic c-kit(+)Sca-1(+)lin(-) (KSL) cell activity in vitro as well as the effect of KSL cell-adoptive transfer on the rate of euglycemic wound closure before and after QQc. KSL cells were magnetically sorted from control and streptozotocin-induced type I diabetic C57BL6J bone marrow. Freshly isolated control and diabetic KSL cells were cultured in QQc for 7 days and pre-QQc and post-QQc KSL function testing. The number of KSL cells significantly increased after QQc for both diabetic subjects and controls, and diabetic KSL increased vasculogenic potential above the fresh control KSL level. Similarly, fresh diabetic cells form fewer tubules, but QQc increases diabetic tubule formation to levels greater than that of fresh control cells (P < 0.05). Adoptive transfer of post-QQc diabetic KSL cells significantly enhances wound closure compared with fresh diabetic KSL cells and equaled wound closure of post-QQc control KSL cells. Post-QQc diabetic KSL enhancement of wound closure is mediated, in part, via a vasculogenic mechanism. This study demonstrates that QQc can reverse diabetic EPC dysfunction and achieve control levels of EPC function. Finally, post-QQc diabetic EPC therapy effectively improved euglycemic wound closure and may improve diabetic wound healing.
PMID: 23670975
ISSN: 0012-1797
CID: 540182