A median cleft lip is a rare central midline deficiency of the upper lip. Multiple surgical techniques are described in the literature to address this defect, though there is little consensus on the preferred surgical...A median cleft lip is a rare central midline deficiency of the upper lip. Multiple surgical techniques are described in the literature to address this defect, though there is little consensus on the preferred surgical technique. We describe an intra-oral approach for repair of the median upper lip cleft using mucosal Z-plasty. This technique provides excellent access to the attenuated orbicularis oris muscle and the frenulum fibrosed to the labial margin. The tethered lip can be mobilized and the notch converted with appropriate mucosal length, lip height, and vermillion fullness. The contour of the free labial border immediately improves, all while avoiding a cutaneous scar. The midline cleft lip notch can be effectively treated by adhering to 3 major principles: 1) excision of the tight, constrictive labial band;2) achieving midline orbicularis oris muscle approximation;and 3) establishing mucosal lengthening using a Z-plasty.展开更多
Skin serves as the first-order protective barrier against the environment and any significant disruptions in skin integrity must be promptly restored.Despite significant advances in therapeutic strategies,effective ma...Skin serves as the first-order protective barrier against the environment and any significant disruptions in skin integrity must be promptly restored.Despite significant advances in therapeutic strategies,effective management of large chronic skin wounds remains a clinical challenge.Dermal fibroblasts are the primary cell type responsible for remodeling the extracellular matrix(ECM)in wound healing.Here,we investigated whether ECM derived from exogenous fibroblasts,in combination with keratinocytes,promoted scarless cutaneous wound healing.To overcome the limited lifespan of primary dermal fibroblasts,we established reversibly immortalized mouse dermal fibroblasts(imDFs),which were non-tumorigenic,expressed dermal fibroblast markers,and were responsive to TGF-β1 stimulation.The decellularized ECM prepared from both imDFs and primary dermal fi-broblasts shared similar expression profiles of extracellular matrix proteins and promoted the proliferation of keratinocyte(iKera)cells.The imDFs-derived ECM solicited no local immune response.While the ECM and to a lesser extent imDFs enhanced skin wound healing with excessive fibrosis,a combination of imDFs-derived ECM and iKera cells effectively promoted the re-epithelization and scarless healing of full-thickness skin wounds.These findings strongly suggest that dermal fibroblast-derived ECM,not fibroblasts themselves,may synergize with keratinocytes in regulating scarless healing and re-epithelialization of skin wounds.Given its low immu-nogenic nature,imDFs-derived ECM should be a valuable resource of skin-specific biomaterial for wound healing and skin tissue engineering.展开更多
With rapid advances in understanding molecular pathogenesis of human diseases in the era of genome sciences and systems biology,it is anticipated that increasing numbers of therapeutic genes or targets will become ava...With rapid advances in understanding molecular pathogenesis of human diseases in the era of genome sciences and systems biology,it is anticipated that increasing numbers of therapeutic genes or targets will become available for targeted therapies.Despite numerous setbacks,efficacious gene and/or cell-based therapies still hold the great promise to revolutionize the clinical management of human diseases.It is wildly recognized that poor gene delivery is the limiting factor for most in vivo gene therapies.There has been a long-lasting interest in using viral vectors,especially adenoviral vectors,to deliver therapeutic genes for the past two decades.Among all currently available viral vectors,adenovirus is the most efficient gene delivery system in a broad range of cell and tissue types.The applications of adenoviral vectors in gene delivery have greatly increased in number and efficiency since their initial development.In fact,among over 2000 gene therapy clinical trials approved worldwide since 1989,a significant portion of the trials have utilized adenoviral vectors.This review aims to provide a comprehensive overview on the characteristics of adenoviral vectors,including adenoviral biology,approaches to engineering adenoviral vectors,and their applications in clinical and preclinical studies with an emphasis in the areas of cancer treatment,vaccination and regenerative medicine.Current challenges and future directions regarding the use of adenoviral vectors are also discussed.It is expected that the continued improvements in adenoviral vectors should provide great opportunities for cell and gene therapies to live up to its enormous potential in personalized medicine.展开更多
Although bone morphogenetic proteins(BMPs)initially showed effective induction of ectopic bone growth in muscle,it has since been determined that these proteins,as members of the TGF-b superfamily,play a diverse and c...Although bone morphogenetic proteins(BMPs)initially showed effective induction of ectopic bone growth in muscle,it has since been determined that these proteins,as members of the TGF-b superfamily,play a diverse and critical array of biological roles.These roles include regulating skeletal and bone formation,angiogenesis,and development and homeostasis of multiple organ systems.Disruptions of the members of the TGF-b/BMP superfamily result in severe skeletal and extra-skeletal irregularities,suggesting high therapeutic potential from understanding this family of BMP proteins.Although it was once one of the least characterized BMPs,BMP9 has revealed itself to have the highest osteogenic potential across numerous experiments both in vitro and in vivo,with recent studies suggesting that the exceptional potency of BMP9 may result from unique signaling pathways that differentiate it from other BMPs.The effectiveness of BMP9 in inducing bone formation was recently revealed in promising experiments that demonstrated efficacy in the repair of critical sized cranial defects as well as compatibility with bone-inducing bio-implants,revealing the great translational promise of BMP9.Furthermore,emerging evidence indicates that,besides its osteogenic activity,BMP9 exerts a broad range of biological functions,including stem cell differentiation,angiogenesis,neurogenesis,tumorigenesis,and metabolism.This review aims to summarize our current understanding of BMP9 across biology and the body.展开更多
Current reconstructive approaches to large craniofacial skeletal defects are often complicated and challenging.Critical-sized defects are unable to heal via natural regenerative processes and require surgical interven...Current reconstructive approaches to large craniofacial skeletal defects are often complicated and challenging.Critical-sized defects are unable to heal via natural regenerative processes and require surgical intervention,traditionally involving autologous bone(mainly in the form of nonvascularized grafts)or alloplasts.Autologous bone grafts remain the gold standard of care in spite of the associated risk of donor site morbidity.Tissue engineering approaches represent a promising alternative that would serve to facilitate bone regeneration even in large craniofacial skeletal defects.This strategy has been tested in a myriad of iterations by utilizing a variety of osteoconductive scaffold materials,osteoblastic stem cells,as well as osteoinductive growth factors and small molecules.One of the major challenges facing tissue engineers is creating a scaffold fulfilling the properties necessary for controlled bone regeneration.These properties include osteoconduction,osteoinduction,biocompatibility,biodegradability,vascularization,and progenitor cell retention.This review will provide an overview of how optimization of the aforementioned scaffold parameters facilitates bone regenerative capabilities as well as a discussion of common osteoconductive scaffold materials.展开更多
Notch is a cellecell signaling pathway that is involved in a host of activities including development,oncogenesis,skeletal homeostasis,and much more.More specifically,recent research has demonstrated the importance of...Notch is a cellecell signaling pathway that is involved in a host of activities including development,oncogenesis,skeletal homeostasis,and much more.More specifically,recent research has demonstrated the importance of Notch signaling in osteogenic differentiation,bone healing,and in the development of the skeleton.The craniofacial skeleton is complex and understanding its development has remained an important focus in biology.In this review we briefly summarize what recent research has revealed about Notch signaling and the current understanding of how the skeleton,skull,and face develop.We then discuss the crucial role that Notch plays in both craniofacial development and the skeletal system,and what importance it may play in the future.展开更多
Burn wound healing is a complex and dynamic process that involves the interaction between different cell types and mediators. Neovascularization is an imperative stage of wound healing and consists of not only angioge...Burn wound healing is a complex and dynamic process that involves the interaction between different cell types and mediators. Neovascularization is an imperative stage of wound healing and consists of not only angiogenesis but also adult vasculogenesis. A superficial partial-thickness burn (SPTB) heals within 2 weeks without scarring. A deep partial-thickness burn (DPTB), conversely, requires 2 weeks or longer to heal and requires an aggressive treatment to prevent hypertrophic scarring. Burn blisters on the skin are a hallmark of not only SPTB but also DPTB;however, the effect of burn blister fluids on the neovascularization in these types of burns has not been fully explored. To verify this effect, the role of different burn fluids and the angiogenic factors that modulate this process are currently under investigation.展开更多
Aim:Scar prevention and reduction is an area of therapeutic opportunity and unmet medical need.With no current effective scar therapy,patients are often disappointed in their appearance post surgery and re-present to ...Aim:Scar prevention and reduction is an area of therapeutic opportunity and unmet medical need.With no current effective scar therapy,patients are often disappointed in their appearance post surgery and re-present to surgeons,only to be turned away.The purpose of this study was to develop and test a device that produces intermittent parallel stretch on new scars and to analyze its potential to reduce scarring.Methods:Mice were randomized into 5 scar stretch treatment groups:1 control,1 sham,and 3 stretch models(0.5×,1×,or 2×device strength)and treated for 10 days.Scars were scored using the Vancouver Scar Scale.Scar tissue samples were compared by histology and transforming growth factor beta 1(TGF-β1)expression between control and treatment groups.Results:Scar scores of 0.5×and 1×groups were significantly lower than the control group(P<0.05).Scar scores from the 1×treatment group were also significantly lower than the 0.5×group(P<0.05).Sham,control scar and 2×groups showed more collagen deposition and a thicker dermal scar than the 0.5×and 1×groups.Unstretched scars had fewer fibroblasts with more collagen deposition than the 0.5×and 2×groups.TGF-β1 levels were significantly lower in the 0.5×(342.1±9.2)and 1×(254.1±3.1)groups than in the control group(P<0.05).TGF-β1 levels in the 1×treatment group were also significantly lower than the 0.5×treatment group(P<0.05).Conclusion:Intermittent cutaneous tissue stretch parallel to scars during the proliferative phase of wound healing decreases fibrosis on a macroscopic,microscopic and biochemical level.展开更多
Advances in three-dimensional(3D)printing have increased feasibility towards the synthesis of living tissues.Known as 3D bioprinting,this technology involves the precise layering of cells,biologic scaffolds,and growth...Advances in three-dimensional(3D)printing have increased feasibility towards the synthesis of living tissues.Known as 3D bioprinting,this technology involves the precise layering of cells,biologic scaffolds,and growth factors with the goal of creating bioidentical tissue for a variety of uses.Early successes have demonstrated distinct advantages over conventional tissue engineering strategies.Not surprisingly,there are current challenges to address before 3D bioprinting becomes clinically relevant.Here we provide an overview of 3D bioprinting technology and discuss key advances,clinical applications,and current limitations.While 3D bioprinting is a relatively novel tissue engineering strategy,it holds great potential to play a key role in personalized medicine.展开更多
Bone tissue regeneration holds the potential to solve both osteoporosis and large skeletal defects,two problems associated with significant morbidity.The differentiation of mesenchymal stem cells into the osteogenic l...Bone tissue regeneration holds the potential to solve both osteoporosis and large skeletal defects,two problems associated with significant morbidity.The differentiation of mesenchymal stem cells into the osteogenic lineage requires a specific microenvironment and certain osteogenic growth factors.Neural EGF Like-Like molecule 1(NELL-1)is a secreted glycoprotein that has proven,both in vitro and in vivo,to be a potent osteo-inductive factor.Furthermore,it has been shown to repress adipogenic differentiation and inflammation.NELL-1 can work synergistically with other osteogenic factors such as Bone Morphogenic Protein(BMP)2 and9,and has shown promise for use in tissue engineering and as a systemically administered drug for the treatment of osteoporosis.Here we provide a comprehensive up-to-date review on the molecular signaling cascade of NELL-1 in mesenchymal stem cells and potential applications in bone regenerative engineering.展开更多
Critical-sized craniofacial defect repair represents a significant challenge to reconstructive surgeons.Many strategies have been employed in an effort to achieve both a functionally and cosmetically acceptable outcom...Critical-sized craniofacial defect repair represents a significant challenge to reconstructive surgeons.Many strategies have been employed in an effort to achieve both a functionally and cosmetically acceptable outcome.Bone morphogenetic proteins(BMPs)provide a robust osteoinductive cue to stimulate bony growth and remodeling.Previous studies have suggested that the BMP-9 isoform is particularly effective in promoting osteogenic differentiation of mesenchymal progenitor cells.The aim of this study is to characterize the osteogenic capacity of BMP-9 on calvarial mesenchymal progenitor cell differentiation.Reversibly immortalized murine calvarial progenitor cells(iCALs)were infected with adenoviral vectors encoding BMP-9 or GFP and assessed for early and late stages of osteogenic differentiation in vitro and for osteogenic differentiation via in vivo stem cell implantation studies.Significant elevations in alkaline phosphatase(ALP)activity,osteocalcin(OCN)mRNA transcription,osteopontin(OPN)protein expression,and matrix mineralization were detected in BMP-treated cells compared to control.Specifically,ALP activity was elevated on days 3,7,9,11,and 13 post-infection and OCN mRNA expression was elevated on days 8,10,and 14 in treated cells.Additionally,treatment groups demonstrated increased OPN protein expression on day 10 and matrix mineralization on day 14 post-infection relative to control groups.BMP-9 also facilitated the formation of new bone in vivo as detailed by gross,microcomputed tomography,and histological analyses.Therefore,we concluded that BMP-9 significantly stimulates osteogenic differentiation in iCALs,and should be considered an effective agent for calvarial tissue regeneration.展开更多
Aim:Autologous tissue is considered the“gold standard”for breast reconstruction today.However,little is known about deep inferior epigastric perforator(DIEP)flap reconstruction in combination with tissue expander(TE...Aim:Autologous tissue is considered the“gold standard”for breast reconstruction today.However,little is known about deep inferior epigastric perforator(DIEP)flap reconstruction in combination with tissue expander(TE)/implant.The authors describe a series of combined DIEP flap/TE reconstruction,including its indications and technique to ensure protection of the pedicle during the expansion process.Methods:Between January 2009 and December 2012,patients undergoing immediate DIEP with TE reconstruction were retrospectively reviewed.Oncologic,comorbid conditions,intraoperative,postoperative expansion,complications,and technique data points were collected.Photographs were taken postoperatively and patient’s satisfaction surveys were obtained to assess overall satisfaction.Results:Five patients underwent immediate DIEP flap/TE reconstruction utilizing our alloderm sling technique.There were no complications to the pedicle,flap,expander,or mastectomy skin perioperatively or postoperatively.All patients describe being very satisfied,often with improved breast volume and projection as compared to their preoperative appearance.Conclusion:The results of this study suggest that DIEP flap/TE reconstruction is safe,in particular when utilizing the alloderm sling technique,and should be considered in patients who lack sufficient abdominal tissue,have existing breast asymmetries,or do not desire the scar deformity of latissimus dorsi.展开更多
Aim:The advent of 3D photoimaging and mammometrics has allowed for quantitative,volumetric breast analyses.This study uses 3D photoimaging and mammometrics to compare the postoperative morphometric outcomes of the mod...Aim:The advent of 3D photoimaging and mammometrics has allowed for quantitative,volumetric breast analyses.This study uses 3D photoimaging and mammometrics to compare the postoperative morphometric outcomes of the modified Robertson technique to the more traditional Wise pattern inferior pedicle technique.Methods:Inferior pedicle reduction mammoplasty was performed using either a Wise pattern or modified Robertson skin incision.3D photography and analysis were done at 1-3 months and 6-12 months postoperatively.Results:There were 14 breasts in the modified Robertson group(ROB)and 24 breasts in the Wise pattern group(WISE).There were no significant differences in demographic data or amount of tissue resected.At 6-12 months,the modified Robertson cohort demonstrated increased superior pole fullness(62.9%ROB vs.58.3%WISE,P=0.05).The Wise cohort,however,maintained greater maximum breast projection(5.52 cm ROB vs.6.54 cm WISE,P=0.01)and increased medial pole fullness(29.6%ROB vs.46.9%WISE,P<0.01).There was no difference in tissue shifting from the superior pole to the inferior pole over time(+3.36 superior pole%ROB vs.+1.42 superior pole%WISE,P=0.28).Areola surface area increased equally in both cohorts(+3.08 cm2 ROB vs.+2.59 cm2 WISE,P=0.77);however,the final size of the areola was greater in the modified Robertson cohort(26.9 cm2 ROB vs.21.6 cm2 WISE,P<0.01).Conclusion:Using 3D mammometrics,we found increased superior pole fullness in the modified Robertson group while the Wise pattern group demonstrated greater medial pole fullness and maximum breast projection.展开更多
Aim:Incobotulinumtoxin A(xeomin)has been proposed as an alternative to abobotulinumtoxin A(dysport)and onabotulinumtoxin A(Botox)in the treatment of glabellar frown lines.A recent study is comparing abobotulinumtoxin ...Aim:Incobotulinumtoxin A(xeomin)has been proposed as an alternative to abobotulinumtoxin A(dysport)and onabotulinumtoxin A(Botox)in the treatment of glabellar frown lines.A recent study is comparing abobotulinumtoxin A and onabotulinumtoxin A revealed equivalent efficacy with a dose conversion ratio of 2.5:1.We sought to establish effectiveness and dosing equivalency of incobotulinumtoxin A vs.abobotulinumtoxin A.Methods:Inclusion criteria for this pilot study included patients of a single surgeon(LAC)who had previously received a constant dose of abobotulinumtoxin A over at least four consecutive treatment sessions for the previous 12 months to achieve an 85-90%elimination of dynamic glabellar frown lines.The primary outcome sought dose comparison between established maintenance abobotulinumtoxin A dosing and incobotulinumtoxin A first-time dosing.A 2:1 conversion(abobotulinumtoxin A:incobotulinumtoxin A)was chosen in most patients.Secondary outcomes were patient-reported onset of effect,physician-assessed effect at 10-12 weeks,pain associated with administration,and patient perceived need for re-treatment at 2 weeks.Results:A total of 32 subjects were included.The mean dose of incobotulinumtoxin A was 17.1 units(±6.1,the median dose 20 units).The mean dose of abobotulinumtoxin A was 27.6(±11.7,the median dose 27.5 units).The mean difference in treatment units was 10.5(95%confidence interval,P<0.001).Among 30 patients who reported effect onset,the median was 8.5 days,with a range of 1-14.At 10-12 weeks,muscle paralysis was assessed to be 69.2%(±27.3),vs.90.3%(±1.8)with abobotulinumtoxin A(P<0.001).The majority of patients rated pain of administration as equal or greater to that of abobotulinumtoxin A(63%and 22%,respectively).Three patients(9%)required re-treatment at 2 weeks with abobotulinumtoxin A due to lack of effective treatment with incobotulinumtoxin A.Abobotulinumtoxin A re-treatment was chosen by the patient.Conclusion:We found incobotulinumtoxin A at 17.1(±6.1)units to be less effective than abobotulinumtoxin A at 27.6(±11.7)units in the treatment of glabellar frown lines at 10-12 weeks postadministration.Dosing was less predictable than dosing associated with abobotulinumtoxin A treatment.Larger,randomized controlled trials are indicated to further delineate these differences and to clarify whether this difference from previously published incobotulinumtoxin A dosing may have been due to the small sample size.展开更多
Hypertrophic scar and keloid are a major medical problem,which may lead to disfigurement,growth restriction,and permanent loss of function,causing severe physical,psychological,and economic burdens.1 When skin injury ...Hypertrophic scar and keloid are a major medical problem,which may lead to disfigurement,growth restriction,and permanent loss of function,causing severe physical,psychological,and economic burdens.1 When skin injury occurs,the wound heals through a dynamic series of physiological events,including blood clotting,granulation tissue formation,re-epithelialization,and extracellular matrix remodeling.2 However,the newly formed extracellular matrix in a scar may never achieve the flexibility or strength of the original tissue.展开更多
Proximal nerve injury can lead to devastating functional impairment.Because axonal regeneration is slow,timely reinnervation of denervated muscle does not occur.These denervated muscles atrophy and lose function.Senso...Proximal nerve injury can lead to devastating functional impairment.Because axonal regeneration is slow,timely reinnervation of denervated muscle does not occur.These denervated muscles atrophy and lose function.Sensory protection is a surgical technique thought to prevent denervated muscle impairment using local sensory nerves to provide trophic support to the muscle until motor nerves can regenerate,and neuromuscular junctions are reestablished.We performed a comprehensive literature search using multiple databases to find primary articles reporting on the outcomes and treatment of sensory protection.This paper reviews the three main approaches to sensory protection:(1)end-to-end neurorrhaphy,(2)end-to-side neurorrhaphy,and(3)direct muscle neurotization.It discusses the evidence supporting each technique and outlines goals for future investigations.展开更多
Physiologic surgical options,including vascularized lymph node transplant and lymphovenous bypass are becoming increasingly popular interventions for the treatment of lymphedema of both the upper and lower extremities...Physiologic surgical options,including vascularized lymph node transplant and lymphovenous bypass are becoming increasingly popular interventions for the treatment of lymphedema of both the upper and lower extremities.Many different lymph node donor sites have been described,including submental,lateral thoracic,superficial groin,supraclavicular,and various intraabdominal sites.This paper describes a step-by-step approach to the harvest of vascularized lymph nodes from the supraclavicular area,which is the preferred donor site for most patients with both upper and lower extremity lymphedema.展开更多
文摘A median cleft lip is a rare central midline deficiency of the upper lip. Multiple surgical techniques are described in the literature to address this defect, though there is little consensus on the preferred surgical technique. We describe an intra-oral approach for repair of the median upper lip cleft using mucosal Z-plasty. This technique provides excellent access to the attenuated orbicularis oris muscle and the frenulum fibrosed to the labial margin. The tethered lip can be mobilized and the notch converted with appropriate mucosal length, lip height, and vermillion fullness. The contour of the free labial border immediately improves, all while avoiding a cutaneous scar. The midline cleft lip notch can be effectively treated by adhering to 3 major principles: 1) excision of the tight, constrictive labial band;2) achieving midline orbicularis oris muscle approximation;and 3) establishing mucosal lengthening using a Z-plasty.
基金supported in part by research grants from the Natural Science Foundation of China(82102696,JF)Chongqing Nat-ural Science Foundation(2024NSCQ-MSX0073,JF)+3 种基金the National Institutes of Health(CA226303 to TCH,and DE030480 to RRR)supported in part by The University of Chicago Comprehensive Cancer Center Support Grant(P30CA014599)the National Center for Advancing Translational Sciences of the National Institutes of Health through Grant Number UL1 TR000430supported by the Mabel Green Myers Research Endowment Fund and The University of Chicago Orthopaedics Alumni Fund.
文摘Skin serves as the first-order protective barrier against the environment and any significant disruptions in skin integrity must be promptly restored.Despite significant advances in therapeutic strategies,effective management of large chronic skin wounds remains a clinical challenge.Dermal fibroblasts are the primary cell type responsible for remodeling the extracellular matrix(ECM)in wound healing.Here,we investigated whether ECM derived from exogenous fibroblasts,in combination with keratinocytes,promoted scarless cutaneous wound healing.To overcome the limited lifespan of primary dermal fibroblasts,we established reversibly immortalized mouse dermal fibroblasts(imDFs),which were non-tumorigenic,expressed dermal fibroblast markers,and were responsive to TGF-β1 stimulation.The decellularized ECM prepared from both imDFs and primary dermal fi-broblasts shared similar expression profiles of extracellular matrix proteins and promoted the proliferation of keratinocyte(iKera)cells.The imDFs-derived ECM solicited no local immune response.While the ECM and to a lesser extent imDFs enhanced skin wound healing with excessive fibrosis,a combination of imDFs-derived ECM and iKera cells effectively promoted the re-epithelization and scarless healing of full-thickness skin wounds.These findings strongly suggest that dermal fibroblast-derived ECM,not fibroblasts themselves,may synergize with keratinocytes in regulating scarless healing and re-epithelialization of skin wounds.Given its low immu-nogenic nature,imDFs-derived ECM should be a valuable resource of skin-specific biomaterial for wound healing and skin tissue engineering.
基金Research in the authors’laboratories was supported in part by research grants from the National Institutes of Health(AT004418,DE020140 to TCH and RRR)the US Department of Defense(OR130096 to JMW)+3 种基金the Scoliosis Research Society(TCH and MJL)the 973 Program of the Ministry of Science and Technology(MOST)of China(#2011CB707906 to TCH)The reported work was also supported in part by The University of Chicago Cancer Center Support Grant(P30CA014599)the National Center for Advancing Translational Sciences of the National Institutes of Health through Grant Number UL1 TR000430.
文摘With rapid advances in understanding molecular pathogenesis of human diseases in the era of genome sciences and systems biology,it is anticipated that increasing numbers of therapeutic genes or targets will become available for targeted therapies.Despite numerous setbacks,efficacious gene and/or cell-based therapies still hold the great promise to revolutionize the clinical management of human diseases.It is wildly recognized that poor gene delivery is the limiting factor for most in vivo gene therapies.There has been a long-lasting interest in using viral vectors,especially adenoviral vectors,to deliver therapeutic genes for the past two decades.Among all currently available viral vectors,adenovirus is the most efficient gene delivery system in a broad range of cell and tissue types.The applications of adenoviral vectors in gene delivery have greatly increased in number and efficiency since their initial development.In fact,among over 2000 gene therapy clinical trials approved worldwide since 1989,a significant portion of the trials have utilized adenoviral vectors.This review aims to provide a comprehensive overview on the characteristics of adenoviral vectors,including adenoviral biology,approaches to engineering adenoviral vectors,and their applications in clinical and preclinical studies with an emphasis in the areas of cancer treatment,vaccination and regenerative medicine.Current challenges and future directions regarding the use of adenoviral vectors are also discussed.It is expected that the continued improvements in adenoviral vectors should provide great opportunities for cell and gene therapies to live up to its enormous potential in personalized medicine.
基金The reported work was supported in part by research grants from the National Institutes of Health(CA226303,DE020140 to TCH and RRR)the U.S.Department of Defense(OR130096 to JMW)+5 种基金the Scoliosis Research Society(TCH and MJL)the Scoliosis Research Society(TCH and MJL)the National Key Research and Development Program of China(2016YFC1000803 and 2011CB707906).This project was also supported in part by The University of Chicago Cancer Center Support Grant(P30CA014599)and the National Center for Advancing Translational Sciences of the National Institutes of Health through Grant Number UL1 TR000430.SM and MP were supported by the Summer Research Program of The University of Chicago Pritzker School of Medicine.TCH was also supported by the Mabel Green Myers Research Endowment Fund and The University of Chicago Orthopaedic Alumni Fund.Funding sources were not involved in the study designin the collection,analysis and interpretation of datain the writing of the reportand in the decision to submit the paper for publication.
文摘Although bone morphogenetic proteins(BMPs)initially showed effective induction of ectopic bone growth in muscle,it has since been determined that these proteins,as members of the TGF-b superfamily,play a diverse and critical array of biological roles.These roles include regulating skeletal and bone formation,angiogenesis,and development and homeostasis of multiple organ systems.Disruptions of the members of the TGF-b/BMP superfamily result in severe skeletal and extra-skeletal irregularities,suggesting high therapeutic potential from understanding this family of BMP proteins.Although it was once one of the least characterized BMPs,BMP9 has revealed itself to have the highest osteogenic potential across numerous experiments both in vitro and in vivo,with recent studies suggesting that the exceptional potency of BMP9 may result from unique signaling pathways that differentiate it from other BMPs.The effectiveness of BMP9 in inducing bone formation was recently revealed in promising experiments that demonstrated efficacy in the repair of critical sized cranial defects as well as compatibility with bone-inducing bio-implants,revealing the great translational promise of BMP9.Furthermore,emerging evidence indicates that,besides its osteogenic activity,BMP9 exerts a broad range of biological functions,including stem cell differentiation,angiogenesis,neurogenesis,tumorigenesis,and metabolism.This review aims to summarize our current understanding of BMP9 across biology and the body.
文摘Current reconstructive approaches to large craniofacial skeletal defects are often complicated and challenging.Critical-sized defects are unable to heal via natural regenerative processes and require surgical intervention,traditionally involving autologous bone(mainly in the form of nonvascularized grafts)or alloplasts.Autologous bone grafts remain the gold standard of care in spite of the associated risk of donor site morbidity.Tissue engineering approaches represent a promising alternative that would serve to facilitate bone regeneration even in large craniofacial skeletal defects.This strategy has been tested in a myriad of iterations by utilizing a variety of osteoconductive scaffold materials,osteoblastic stem cells,as well as osteoinductive growth factors and small molecules.One of the major challenges facing tissue engineers is creating a scaffold fulfilling the properties necessary for controlled bone regeneration.These properties include osteoconduction,osteoinduction,biocompatibility,biodegradability,vascularization,and progenitor cell retention.This review will provide an overview of how optimization of the aforementioned scaffold parameters facilitates bone regenerative capabilities as well as a discussion of common osteoconductive scaffold materials.
基金the National Institutes of Health(CA226303to TCH)the U.S.Department of Defense(OR130096 to JMW)+5 种基金the Scoliosis Research Society(TCH and MJL)the Pritzker-Northshore Fellowship at The University of Chicagothe Medical Scientist Training Program of the National Institutes of Health(T32 GM007281)The University of Chicago Cancer Center Support Grant(P30CA014599)the National Center for Advancing Translational Sciences of the National Institutes of Health through Grant Number UL1 TR000430the Mabel Green Myers Research Endowment Fund and The University of Chicago Orthopaedics Alumni Fund。
文摘Notch is a cellecell signaling pathway that is involved in a host of activities including development,oncogenesis,skeletal homeostasis,and much more.More specifically,recent research has demonstrated the importance of Notch signaling in osteogenic differentiation,bone healing,and in the development of the skeleton.The craniofacial skeleton is complex and understanding its development has remained an important focus in biology.In this review we briefly summarize what recent research has revealed about Notch signaling and the current understanding of how the skeleton,skull,and face develop.We then discuss the crucial role that Notch plays in both craniofacial development and the skeletal system,and what importance it may play in the future.
文摘Burn wound healing is a complex and dynamic process that involves the interaction between different cell types and mediators. Neovascularization is an imperative stage of wound healing and consists of not only angiogenesis but also adult vasculogenesis. A superficial partial-thickness burn (SPTB) heals within 2 weeks without scarring. A deep partial-thickness burn (DPTB), conversely, requires 2 weeks or longer to heal and requires an aggressive treatment to prevent hypertrophic scarring. Burn blisters on the skin are a hallmark of not only SPTB but also DPTB;however, the effect of burn blister fluids on the neovascularization in these types of burns has not been fully explored. To verify this effect, the role of different burn fluids and the angiogenic factors that modulate this process are currently under investigation.
文摘Aim:Scar prevention and reduction is an area of therapeutic opportunity and unmet medical need.With no current effective scar therapy,patients are often disappointed in their appearance post surgery and re-present to surgeons,only to be turned away.The purpose of this study was to develop and test a device that produces intermittent parallel stretch on new scars and to analyze its potential to reduce scarring.Methods:Mice were randomized into 5 scar stretch treatment groups:1 control,1 sham,and 3 stretch models(0.5×,1×,or 2×device strength)and treated for 10 days.Scars were scored using the Vancouver Scar Scale.Scar tissue samples were compared by histology and transforming growth factor beta 1(TGF-β1)expression between control and treatment groups.Results:Scar scores of 0.5×and 1×groups were significantly lower than the control group(P<0.05).Scar scores from the 1×treatment group were also significantly lower than the 0.5×group(P<0.05).Sham,control scar and 2×groups showed more collagen deposition and a thicker dermal scar than the 0.5×and 1×groups.Unstretched scars had fewer fibroblasts with more collagen deposition than the 0.5×and 2×groups.TGF-β1 levels were significantly lower in the 0.5×(342.1±9.2)and 1×(254.1±3.1)groups than in the control group(P<0.05).TGF-β1 levels in the 1×treatment group were also significantly lower than the 0.5×treatment group(P<0.05).Conclusion:Intermittent cutaneous tissue stretch parallel to scars during the proliferative phase of wound healing decreases fibrosis on a macroscopic,microscopic and biochemical level.
基金Research in the authors’laboratories was supported in part by research grants from the National Institutes of Health(AT004418,DE020140 to TCH and RRR)the US Department of Defense(OR130096 to JMW)+3 种基金the Chicago Biomedical Consortium with support from the Searle Funds at The Chicago Community Trust(RRR,GAA and TCH)the Scoliosis Research Society(TCH and MJL)a Cleft Palate Foundation Research Support Grant(RRR)the National Key Research and Development Program of China(2016YFC1000803 and 2011CB707906 to TCH).
文摘Advances in three-dimensional(3D)printing have increased feasibility towards the synthesis of living tissues.Known as 3D bioprinting,this technology involves the precise layering of cells,biologic scaffolds,and growth factors with the goal of creating bioidentical tissue for a variety of uses.Early successes have demonstrated distinct advantages over conventional tissue engineering strategies.Not surprisingly,there are current challenges to address before 3D bioprinting becomes clinically relevant.Here we provide an overview of 3D bioprinting technology and discuss key advances,clinical applications,and current limitations.While 3D bioprinting is a relatively novel tissue engineering strategy,it holds great potential to play a key role in personalized medicine.
基金Research in the authors’laboratories was supported in part by research grants from the National Institutes of Health(AT004418,DE020140 to TCH and RRR)the US Department of Defense(OR130096 to JMW)+4 种基金the Scoliosis Research Society(TCH and MJL)the 973 Program of the Ministry of Science and Technology(MOST)of China(#2011CB707906 to TCH)MP and SM were recipients of the Pritzker Summer Research Fellowship funded through the National Institute of Health(NIH)T-35 training grant(NIDDK)#T35DK062719-30The reported work was also supported in part by The University of Chicago Cancer Center Support Grant(P30CA014599)the National Center for Advancing Translational Sciences of the National Institutes of Health through Grant Number UL1 TR000430。
文摘Bone tissue regeneration holds the potential to solve both osteoporosis and large skeletal defects,two problems associated with significant morbidity.The differentiation of mesenchymal stem cells into the osteogenic lineage requires a specific microenvironment and certain osteogenic growth factors.Neural EGF Like-Like molecule 1(NELL-1)is a secreted glycoprotein that has proven,both in vitro and in vivo,to be a potent osteo-inductive factor.Furthermore,it has been shown to repress adipogenic differentiation and inflammation.NELL-1 can work synergistically with other osteogenic factors such as Bone Morphogenic Protein(BMP)2 and9,and has shown promise for use in tissue engineering and as a systemically administered drug for the treatment of osteoporosis.Here we provide a comprehensive up-to-date review on the molecular signaling cascade of NELL-1 in mesenchymal stem cells and potential applications in bone regenerative engineering.
基金This work was funded by the Chicago Biomedical Consortium with support from the Searle Funds at The Chicago Community TrustThe reported work was also supported in part by an NIH/NIDCK K08 Career Development Award(#1K08DE020140-01,RRR)This work was also supported in part by The University of Chicago Core Facility Subsidy grant from the National Center for Advancing Translational Sciences(NCATS)of the National Institutes of Health through Grant UL1 TR000430(RRR).
文摘Critical-sized craniofacial defect repair represents a significant challenge to reconstructive surgeons.Many strategies have been employed in an effort to achieve both a functionally and cosmetically acceptable outcome.Bone morphogenetic proteins(BMPs)provide a robust osteoinductive cue to stimulate bony growth and remodeling.Previous studies have suggested that the BMP-9 isoform is particularly effective in promoting osteogenic differentiation of mesenchymal progenitor cells.The aim of this study is to characterize the osteogenic capacity of BMP-9 on calvarial mesenchymal progenitor cell differentiation.Reversibly immortalized murine calvarial progenitor cells(iCALs)were infected with adenoviral vectors encoding BMP-9 or GFP and assessed for early and late stages of osteogenic differentiation in vitro and for osteogenic differentiation via in vivo stem cell implantation studies.Significant elevations in alkaline phosphatase(ALP)activity,osteocalcin(OCN)mRNA transcription,osteopontin(OPN)protein expression,and matrix mineralization were detected in BMP-treated cells compared to control.Specifically,ALP activity was elevated on days 3,7,9,11,and 13 post-infection and OCN mRNA expression was elevated on days 8,10,and 14 in treated cells.Additionally,treatment groups demonstrated increased OPN protein expression on day 10 and matrix mineralization on day 14 post-infection relative to control groups.BMP-9 also facilitated the formation of new bone in vivo as detailed by gross,microcomputed tomography,and histological analyses.Therefore,we concluded that BMP-9 significantly stimulates osteogenic differentiation in iCALs,and should be considered an effective agent for calvarial tissue regeneration.
文摘Aim:Autologous tissue is considered the“gold standard”for breast reconstruction today.However,little is known about deep inferior epigastric perforator(DIEP)flap reconstruction in combination with tissue expander(TE)/implant.The authors describe a series of combined DIEP flap/TE reconstruction,including its indications and technique to ensure protection of the pedicle during the expansion process.Methods:Between January 2009 and December 2012,patients undergoing immediate DIEP with TE reconstruction were retrospectively reviewed.Oncologic,comorbid conditions,intraoperative,postoperative expansion,complications,and technique data points were collected.Photographs were taken postoperatively and patient’s satisfaction surveys were obtained to assess overall satisfaction.Results:Five patients underwent immediate DIEP flap/TE reconstruction utilizing our alloderm sling technique.There were no complications to the pedicle,flap,expander,or mastectomy skin perioperatively or postoperatively.All patients describe being very satisfied,often with improved breast volume and projection as compared to their preoperative appearance.Conclusion:The results of this study suggest that DIEP flap/TE reconstruction is safe,in particular when utilizing the alloderm sling technique,and should be considered in patients who lack sufficient abdominal tissue,have existing breast asymmetries,or do not desire the scar deformity of latissimus dorsi.
文摘Aim:The advent of 3D photoimaging and mammometrics has allowed for quantitative,volumetric breast analyses.This study uses 3D photoimaging and mammometrics to compare the postoperative morphometric outcomes of the modified Robertson technique to the more traditional Wise pattern inferior pedicle technique.Methods:Inferior pedicle reduction mammoplasty was performed using either a Wise pattern or modified Robertson skin incision.3D photography and analysis were done at 1-3 months and 6-12 months postoperatively.Results:There were 14 breasts in the modified Robertson group(ROB)and 24 breasts in the Wise pattern group(WISE).There were no significant differences in demographic data or amount of tissue resected.At 6-12 months,the modified Robertson cohort demonstrated increased superior pole fullness(62.9%ROB vs.58.3%WISE,P=0.05).The Wise cohort,however,maintained greater maximum breast projection(5.52 cm ROB vs.6.54 cm WISE,P=0.01)and increased medial pole fullness(29.6%ROB vs.46.9%WISE,P<0.01).There was no difference in tissue shifting from the superior pole to the inferior pole over time(+3.36 superior pole%ROB vs.+1.42 superior pole%WISE,P=0.28).Areola surface area increased equally in both cohorts(+3.08 cm2 ROB vs.+2.59 cm2 WISE,P=0.77);however,the final size of the areola was greater in the modified Robertson cohort(26.9 cm2 ROB vs.21.6 cm2 WISE,P<0.01).Conclusion:Using 3D mammometrics,we found increased superior pole fullness in the modified Robertson group while the Wise pattern group demonstrated greater medial pole fullness and maximum breast projection.
文摘Aim:Incobotulinumtoxin A(xeomin)has been proposed as an alternative to abobotulinumtoxin A(dysport)and onabotulinumtoxin A(Botox)in the treatment of glabellar frown lines.A recent study is comparing abobotulinumtoxin A and onabotulinumtoxin A revealed equivalent efficacy with a dose conversion ratio of 2.5:1.We sought to establish effectiveness and dosing equivalency of incobotulinumtoxin A vs.abobotulinumtoxin A.Methods:Inclusion criteria for this pilot study included patients of a single surgeon(LAC)who had previously received a constant dose of abobotulinumtoxin A over at least four consecutive treatment sessions for the previous 12 months to achieve an 85-90%elimination of dynamic glabellar frown lines.The primary outcome sought dose comparison between established maintenance abobotulinumtoxin A dosing and incobotulinumtoxin A first-time dosing.A 2:1 conversion(abobotulinumtoxin A:incobotulinumtoxin A)was chosen in most patients.Secondary outcomes were patient-reported onset of effect,physician-assessed effect at 10-12 weeks,pain associated with administration,and patient perceived need for re-treatment at 2 weeks.Results:A total of 32 subjects were included.The mean dose of incobotulinumtoxin A was 17.1 units(±6.1,the median dose 20 units).The mean dose of abobotulinumtoxin A was 27.6(±11.7,the median dose 27.5 units).The mean difference in treatment units was 10.5(95%confidence interval,P<0.001).Among 30 patients who reported effect onset,the median was 8.5 days,with a range of 1-14.At 10-12 weeks,muscle paralysis was assessed to be 69.2%(±27.3),vs.90.3%(±1.8)with abobotulinumtoxin A(P<0.001).The majority of patients rated pain of administration as equal or greater to that of abobotulinumtoxin A(63%and 22%,respectively).Three patients(9%)required re-treatment at 2 weeks with abobotulinumtoxin A due to lack of effective treatment with incobotulinumtoxin A.Abobotulinumtoxin A re-treatment was chosen by the patient.Conclusion:We found incobotulinumtoxin A at 17.1(±6.1)units to be less effective than abobotulinumtoxin A at 27.6(±11.7)units in the treatment of glabellar frown lines at 10-12 weeks postadministration.Dosing was less predictable than dosing associated with abobotulinumtoxin A treatment.Larger,randomized controlled trials are indicated to further delineate these differences and to clarify whether this difference from previously published incobotulinumtoxin A dosing may have been due to the small sample size.
基金supported in part by research grants from the Natural Science Foundation of China(No.82102696 to J.F.)the Chongqing Natural Science Foundation of China(No.2024NSCQ-MSX0073 to J.F.)+1 种基金the US National Institutes of Health(No.CA226303 to T.C.H.DE030480 to R.R.R.).
文摘Hypertrophic scar and keloid are a major medical problem,which may lead to disfigurement,growth restriction,and permanent loss of function,causing severe physical,psychological,and economic burdens.1 When skin injury occurs,the wound heals through a dynamic series of physiological events,including blood clotting,granulation tissue formation,re-epithelialization,and extracellular matrix remodeling.2 However,the newly formed extracellular matrix in a scar may never achieve the flexibility or strength of the original tissue.
文摘Proximal nerve injury can lead to devastating functional impairment.Because axonal regeneration is slow,timely reinnervation of denervated muscle does not occur.These denervated muscles atrophy and lose function.Sensory protection is a surgical technique thought to prevent denervated muscle impairment using local sensory nerves to provide trophic support to the muscle until motor nerves can regenerate,and neuromuscular junctions are reestablished.We performed a comprehensive literature search using multiple databases to find primary articles reporting on the outcomes and treatment of sensory protection.This paper reviews the three main approaches to sensory protection:(1)end-to-end neurorrhaphy,(2)end-to-side neurorrhaphy,and(3)direct muscle neurotization.It discusses the evidence supporting each technique and outlines goals for future investigations.
文摘Physiologic surgical options,including vascularized lymph node transplant and lymphovenous bypass are becoming increasingly popular interventions for the treatment of lymphedema of both the upper and lower extremities.Many different lymph node donor sites have been described,including submental,lateral thoracic,superficial groin,supraclavicular,and various intraabdominal sites.This paper describes a step-by-step approach to the harvest of vascularized lymph nodes from the supraclavicular area,which is the preferred donor site for most patients with both upper and lower extremity lymphedema.
