Damon Cooney - Academia.edu (original) (raw)
Papers by Damon Cooney
Plastic and Reconstructive Surgery, 2013
ABSTRACT PURPOSE: Vascularized Composite Allografts (VCA), such as hand and upper extremity trans... more ABSTRACT PURPOSE: Vascularized Composite Allografts (VCA), such as hand and upper extremity transplants, contain vascularized bone marrow (BM) and a BM niche representing a constant source of donor-derived stem cells and hence can favor chimerism and tolerance induction (1). This study investigates the immunological effects of vascularized BM within VCA under co-stimulation blockade-based regimen and its impact on allograft survival and tolerance induction. METHODS AND MATERIALS: Fully MHC- and gender mismatched MGH miniature swine (n=20) underwent heterotopic hind-limb transplantation containing intact vascularized BM component (Figure 1). Recipient animals received a short course (30 days) of tacrolimus monotherapy with or without donor BM infusion (60x106 cells/kg), and CTLA4Ig. Short course tacrolimus only and untreated animals served as controls. Chimerism was assessed by SRY-1 qRT-PCR analysis. Sequential skin and muscle biopsies were performed for histology. Alloreactivity against donor antigens was assessed in vitro using CFSE-based mixed lymphocyte reaction assays. Challenge with secondary skin grafts was utilized to demonstrate robust immune tolerance in vivo. RESULTS: The co-stimulation blockade based immunomodulatory protocol resulted in indefinite graft survival (>150 days) in 3 out of 5 animals whereas control and tacrolimus only groups rejected allografts at days 7+/-1 and 29+/-2 respectively (Figure 2). Combined costimulation blockade with augmented donor BM infusion resulted in indefinite graft survival in 2 out of 3 animals (>150 days). Long-term survivors demonstrated only transient peripheral but stable micro-chimerism in various graft and recipient tissues including skin, lymph node, bone marrow, and spleen. CFSE-MLR data showed unresponsiveness to donor but not to third party allogeneic controls. Secondary skin grafting demonstrated advanced rejection of third party grafts on day 7 while donor-matched grafts were accepted indicating donor-specific immune tolerance. There was no evidence of donor specific antibody formation in long-term survivors. Donor unresponsiveness in MLR was lost 5 weeks post-graftectomy, which demonstrated that persistent antigenic stimulation was required for operational tolerance. CONCLUSION: Combined costimulation blockade and donor BM cell infusion can induce robust immune tolerance in a fully MHC mismatched hind limb transplant model. Such targeted immunomodulatory protocols might eliminate the need for long-term multi-drug immunosuppression after reconstructive transplantation. Figure 1: Schematic diagram: Osteomyocutaneous flap is transplanted to a subcutaneous pocket with externalized skin component. Figure 2: Kaplan-Meier survival curve demonstrating rejection free survival of skin component of VCA
Eplasty, 2008
Knowledge of anatomic landmarks for the first dorsal compartment can assist clinicians with manag... more Knowledge of anatomic landmarks for the first dorsal compartment can assist clinicians with management of de Quervain's disease. The radial styloid, the scaphoid tubercle, and Lister's tubercle can be used as superficial landmarks for the first dorsal compartment. Thirty-two cadaveric wrists were dissected, and measurements were taken from the predetermined landmarks to the extensor retinaculum. The compartments were also inspected for variability of the abductor pollicis longus tendon and intracompartmental septations. The average length of the extensor retinaculum from its proximal to distal extent measured approximately 2.2 cm. The distal aspect of the radial styloid was 0.3 cm distal to the distal aspect of the extensor retinaculum, and the distance between the distal aspect of the extensor retinaculum and the APL-Lister's-Scaphoid juncture was approximately 0.5 cm. A separate compartment for the extensor pollicis brevis was noted in 35% of the specimens. The abducto...
Molecular and cellular biology, 1997
Recently, we and others have demonstrated that negative signaling in B cells selectively induces ... more Recently, we and others have demonstrated that negative signaling in B cells selectively induces the tyrosine phosphorylation of a novel inositol polyphosphate phosphatase, p145SHIP. In this study, we present data indicating that p145SHIP binds directly a phosphorylated motif, immunoreceptor tyrosine-based inhibition motif (ITIM), present in the cytoplasmic domain of Fc gammaRIIB1. Using recombinant SH2 domains, we show that binding is mediated via the Src homology region 2 (SH2)-containing inositol phosphatase (SHIP) SH2 domain. SHIP also bound to a phosphopeptide derived from CD22, raising the possibility that SHIP contributes to negative signaling by this receptor as well as Fc gammaRIIB1. The association of SHIP with the ITIM phosphopeptide was activation independent, while coassociation with Shc was activation dependent. Furthermore, experiments with Fc gammaRIIB1-deficient B cells demonstrated a genetic requirement for expression of Fc gammaRIIB1 in the induction of SHIP phosp...
Journal of Transplantation Technologies & Research, 2012
Reconstructive transplantation, also referred to as vascularized composite allotransplantation (V... more Reconstructive transplantation, also referred to as vascularized composite allotransplantation (VCA), has rapidly emerged as a viable approach to repairing complex tissue defects. Over the past 20 years, major advances have been made in the field of VCA allowing for successful transplantation of over 150 hand/forearm/arm, larynx, trachea, abdominal wall, vascularized knee, and facial transplants with encouraging outcomes. These innovations have currently outpaced the scientific community's ability to fully address certain immunological and clinical challenges. The literature on ischemia-reperfusion injury (IRI) in VCA is limited and mechanistic questions remain. Specifically, the role IRI may play in acute rejection, the progression towards chronic rejection, or immune regulation and tolerance induction has only been partially or indirectly addressed. Hence, much of what we understand regarding IRI in VCA is extrapolated from research in solid organ transplantation (SOT). This review will address the role of IRI in VCA, first outlining its impact on SOT, it's effects on the immune system and allograft rejection, as well as the clinical implications that IRI has for VCA outcomes.
1 Background: Compromised perfusion in autologous breast reconstruction results in fat necrosis a... more 1 Background: Compromised perfusion in autologous breast reconstruction results in fat necrosis and flap loss. Increased flap weight with fewer perforator vessels may exacerbate imbalances in flap perfusion. We studied deep inferior epigastric perforator (DIEP) and muscle-sparing transverse rectus abdominis myocutaneous (MS-TRAM) flaps to assess this concept. Methods: Data from patients who underwent reconstruction with DIEP and/or MS-TRAM flaps between January 1, 2010 and December 31, 2011 (n = 123) were retrospectively reviewed. Patient demographics, comorbidities, intraoperative parameters, and postoperative outcomes were collected, including flap fat necrosis and donor/recipient site complications. Logistic regression analysis was used to examine effects of flap weight and perforator number on breast flap fat necrosis. Results: One hundred twenty-three patients who underwent 179 total flap reconstructions (166 DIEP, 13 MS-TRAM) were included. Mean flap weight was 658 ± 289 g; 132 (73.7%) were single perforator flaps. Thirteen flaps (7.5%) developed fat necrosis. African American patients had increased odds of fat necrosis (odds ratio, 11.58; P < 0.001). Odds of developing fat necrosis significantly increased with flap weight (odds ratio, 1.5 per 100 g increase; P < 0.001). In single perforator flaps weighing more than 1000 g, six (42.9%) developed fat necrosis, compared to 14.3% of large multiple perforator flaps. Conclusions: Flaps with increasing weight have increased risk of fat necrosis. These data suggest that inclusion of more than 1 perforator may decrease odds of fat necrosis in large flaps. Perforator flap breast reconstruction can be performed safely; however, considerations concerning race, body mass index, staging with tissue expanders, perforator number, and flap weight may optimize outcomes.
Plastic and Reconstructive Surgery, 2012
Journal of the American College of Surgeons, 2014
Immunology Today, 1997
duces positive signaling events that result in pmliferation and sarehan of soluble antigen-specif... more duces positive signaling events that result in pmliferation and sarehan of soluble antigen-specific Ig. The activation pmclzss is regxdated at several IeveIs, in&ding the interaction of B 4s with helper T c&s, as well as the fornation and _cretion of lymphokines that promote B-cell pmIiferation and differentiation into Ig-secreting c&I or memory B &Is. Siirly, secreted, dntigen-specitic Ig plays a" important role Negotiue sigtznlr~~g irz B cells IS rrritinfed by/ cc-crosslinking of rlic mtrgtw receptor md the Fey receptor, resultrq in ces_dio,r of B-celi sipfiq tmfzfs ma?, ii1 twn, hrhibiting B-cell prolifemtim od mtibody secretion. Here, LI cornpeltfrve role 1s proposed for SHIP irr blocking the ivteructior; of She with the GrbZ-Sos complex of proteins thnt lend to Rm flctiitntiorz I)I B cells.
Plastic and Reconstructive Surgery, 2014
Le Fort-based, maxillofacial allotransplantation is a reconstructive alternative gaining clinical... more Le Fort-based, maxillofacial allotransplantation is a reconstructive alternative gaining clinical acceptance. However, the vast majority of single-jaw transplant recipients demonstrate less-than-ideal skeletal and dental relationships, with suboptimal aesthetic harmony. The purpose of this study was to investigate reproducible cephalometric landmarks in a large-animal model, where refinement of computer-assisted planning, intraoperative navigational guidance, translational bone osteotomies, and comparative surgical techniques could be performed. Cephalometric landmarks that could be translated into the human craniomaxillofacial skeleton, and that would remain reliable following maxillofacial osteotomies with midfacial alloflap inset, were sought on six miniature swine. Le Fort I- and Le Fort III-based alloflaps were harvested in swine with osteotomies, and all alloflaps were either autoreplanted or transplanted. Cephalometric analyses were performed on lateral cephalograms preoperatively and postoperatively. Critical cephalometric data sets were identified with the assistance of surgical planning and virtual prediction software and evaluated for reliability and translational predictability. Several pertinent landmarks and human analogues were identified, including pronasale, zygion, parietale, gonion, gnathion, lower incisor base, and alveolare. Parietale-pronasale-alveolare and parietale-pronasale-lower incisor base were found to be reliable correlates of sellion-nasion-A point angle and sellion-nasion-B point angle measurements in humans, respectively. There is a set of reliable cephalometric landmarks and measurement angles pertinent for use within a translational large-animal model. These craniomaxillofacial landmarks will enable development of novel navigational software technology, improve cutting guide designs, and facilitate exploration of new avenues for investigation and collaboration.
Plastic and Reconstructive Surgery, 2014
Computed tomographic angiography is often used for preoperative mapping. The authors aimed to sys... more Computed tomographic angiography is often used for preoperative mapping. The authors aimed to systematically assess breast reconstruction outcomes after abdominally based free flaps planned with preoperative computed tomographic angiography versus Doppler ultrasonography. A search of the PubMed, EMBASE, and Scopus databases and an additional hand-search of relevant articles until June of 2012 rendered 442 English-language citations. Three authors independently reviewed these citations and included all the studies comparing preoperative computed tomographic angiography versus Doppler ultrasonography with regard to short-term postoperative outcomes and operative times. A meta-analysis was performed to evaluate the incidence of flap-related complications (seven studies), donor-site morbidity (four studies), and operative times (five studies) between preoperative computed tomographic angiography and Doppler ultrasonography. A pooled relative risk was calculated using a random-effect model to compare complication rates between the computed tomographic angiography and Doppler ultrasonography groups. A total of 13 studies met inclusion criteria. Preoperative computed tomographic angiography was associated with significantly fewer flap-related complications (relative risk, 0.87; 95 percent CI, 0.78 to 0.97), reduced donor-site morbidity (relative risk, 0.84; 95 percent CI, 0.76 to 0.94), and shorter reconstruction operative time by 87.7 minutes (mean difference, 87.7 minutes; 95 percent CI, 78.3 to 97.1 minutes). The use of preoperative computed tomographic angiography reduces the operative time, postoperative flap-related complications, and donor-site morbidity compared with Doppler ultrasonography. Preoperative computed tomographic angiography has the potential to reduce operative cost and increase efficiency in the operating room. Thus, preoperative mapping by computed tomographic angiography should be strongly considered for abdominally based free flap breast reconstruction.
Plastic and Reconstructive Surgery, 2013
ABSTRACT PURPOSE: Vascularized Composite Allografts (VCA), such as hand and upper extremity trans... more ABSTRACT PURPOSE: Vascularized Composite Allografts (VCA), such as hand and upper extremity transplants, contain vascularized bone marrow (BM) and a BM niche representing a constant source of donor-derived stem cells and hence can favor chimerism and tolerance induction (1). This study investigates the immunological effects of vascularized BM within VCA under co-stimulation blockade-based regimen and its impact on allograft survival and tolerance induction. METHODS AND MATERIALS: Fully MHC- and gender mismatched MGH miniature swine (n=20) underwent heterotopic hind-limb transplantation containing intact vascularized BM component (Figure 1). Recipient animals received a short course (30 days) of tacrolimus monotherapy with or without donor BM infusion (60x106 cells/kg), and CTLA4Ig. Short course tacrolimus only and untreated animals served as controls. Chimerism was assessed by SRY-1 qRT-PCR analysis. Sequential skin and muscle biopsies were performed for histology. Alloreactivity against donor antigens was assessed in vitro using CFSE-based mixed lymphocyte reaction assays. Challenge with secondary skin grafts was utilized to demonstrate robust immune tolerance in vivo. RESULTS: The co-stimulation blockade based immunomodulatory protocol resulted in indefinite graft survival (>150 days) in 3 out of 5 animals whereas control and tacrolimus only groups rejected allografts at days 7+/-1 and 29+/-2 respectively (Figure 2). Combined costimulation blockade with augmented donor BM infusion resulted in indefinite graft survival in 2 out of 3 animals (>150 days). Long-term survivors demonstrated only transient peripheral but stable micro-chimerism in various graft and recipient tissues including skin, lymph node, bone marrow, and spleen. CFSE-MLR data showed unresponsiveness to donor but not to third party allogeneic controls. Secondary skin grafting demonstrated advanced rejection of third party grafts on day 7 while donor-matched grafts were accepted indicating donor-specific immune tolerance. There was no evidence of donor specific antibody formation in long-term survivors. Donor unresponsiveness in MLR was lost 5 weeks post-graftectomy, which demonstrated that persistent antigenic stimulation was required for operational tolerance. CONCLUSION: Combined costimulation blockade and donor BM cell infusion can induce robust immune tolerance in a fully MHC mismatched hind limb transplant model. Such targeted immunomodulatory protocols might eliminate the need for long-term multi-drug immunosuppression after reconstructive transplantation. Figure 1: Schematic diagram: Osteomyocutaneous flap is transplanted to a subcutaneous pocket with externalized skin component. Figure 2: Kaplan-Meier survival curve demonstrating rejection free survival of skin component of VCA
Eplasty, 2008
Knowledge of anatomic landmarks for the first dorsal compartment can assist clinicians with manag... more Knowledge of anatomic landmarks for the first dorsal compartment can assist clinicians with management of de Quervain's disease. The radial styloid, the scaphoid tubercle, and Lister's tubercle can be used as superficial landmarks for the first dorsal compartment. Thirty-two cadaveric wrists were dissected, and measurements were taken from the predetermined landmarks to the extensor retinaculum. The compartments were also inspected for variability of the abductor pollicis longus tendon and intracompartmental septations. The average length of the extensor retinaculum from its proximal to distal extent measured approximately 2.2 cm. The distal aspect of the radial styloid was 0.3 cm distal to the distal aspect of the extensor retinaculum, and the distance between the distal aspect of the extensor retinaculum and the APL-Lister's-Scaphoid juncture was approximately 0.5 cm. A separate compartment for the extensor pollicis brevis was noted in 35% of the specimens. The abducto...
Molecular and cellular biology, 1997
Recently, we and others have demonstrated that negative signaling in B cells selectively induces ... more Recently, we and others have demonstrated that negative signaling in B cells selectively induces the tyrosine phosphorylation of a novel inositol polyphosphate phosphatase, p145SHIP. In this study, we present data indicating that p145SHIP binds directly a phosphorylated motif, immunoreceptor tyrosine-based inhibition motif (ITIM), present in the cytoplasmic domain of Fc gammaRIIB1. Using recombinant SH2 domains, we show that binding is mediated via the Src homology region 2 (SH2)-containing inositol phosphatase (SHIP) SH2 domain. SHIP also bound to a phosphopeptide derived from CD22, raising the possibility that SHIP contributes to negative signaling by this receptor as well as Fc gammaRIIB1. The association of SHIP with the ITIM phosphopeptide was activation independent, while coassociation with Shc was activation dependent. Furthermore, experiments with Fc gammaRIIB1-deficient B cells demonstrated a genetic requirement for expression of Fc gammaRIIB1 in the induction of SHIP phosp...
Journal of Transplantation Technologies & Research, 2012
Reconstructive transplantation, also referred to as vascularized composite allotransplantation (V... more Reconstructive transplantation, also referred to as vascularized composite allotransplantation (VCA), has rapidly emerged as a viable approach to repairing complex tissue defects. Over the past 20 years, major advances have been made in the field of VCA allowing for successful transplantation of over 150 hand/forearm/arm, larynx, trachea, abdominal wall, vascularized knee, and facial transplants with encouraging outcomes. These innovations have currently outpaced the scientific community's ability to fully address certain immunological and clinical challenges. The literature on ischemia-reperfusion injury (IRI) in VCA is limited and mechanistic questions remain. Specifically, the role IRI may play in acute rejection, the progression towards chronic rejection, or immune regulation and tolerance induction has only been partially or indirectly addressed. Hence, much of what we understand regarding IRI in VCA is extrapolated from research in solid organ transplantation (SOT). This review will address the role of IRI in VCA, first outlining its impact on SOT, it's effects on the immune system and allograft rejection, as well as the clinical implications that IRI has for VCA outcomes.
1 Background: Compromised perfusion in autologous breast reconstruction results in fat necrosis a... more 1 Background: Compromised perfusion in autologous breast reconstruction results in fat necrosis and flap loss. Increased flap weight with fewer perforator vessels may exacerbate imbalances in flap perfusion. We studied deep inferior epigastric perforator (DIEP) and muscle-sparing transverse rectus abdominis myocutaneous (MS-TRAM) flaps to assess this concept. Methods: Data from patients who underwent reconstruction with DIEP and/or MS-TRAM flaps between January 1, 2010 and December 31, 2011 (n = 123) were retrospectively reviewed. Patient demographics, comorbidities, intraoperative parameters, and postoperative outcomes were collected, including flap fat necrosis and donor/recipient site complications. Logistic regression analysis was used to examine effects of flap weight and perforator number on breast flap fat necrosis. Results: One hundred twenty-three patients who underwent 179 total flap reconstructions (166 DIEP, 13 MS-TRAM) were included. Mean flap weight was 658 ± 289 g; 132 (73.7%) were single perforator flaps. Thirteen flaps (7.5%) developed fat necrosis. African American patients had increased odds of fat necrosis (odds ratio, 11.58; P < 0.001). Odds of developing fat necrosis significantly increased with flap weight (odds ratio, 1.5 per 100 g increase; P < 0.001). In single perforator flaps weighing more than 1000 g, six (42.9%) developed fat necrosis, compared to 14.3% of large multiple perforator flaps. Conclusions: Flaps with increasing weight have increased risk of fat necrosis. These data suggest that inclusion of more than 1 perforator may decrease odds of fat necrosis in large flaps. Perforator flap breast reconstruction can be performed safely; however, considerations concerning race, body mass index, staging with tissue expanders, perforator number, and flap weight may optimize outcomes.
Plastic and Reconstructive Surgery, 2012
Journal of the American College of Surgeons, 2014
Immunology Today, 1997
duces positive signaling events that result in pmliferation and sarehan of soluble antigen-specif... more duces positive signaling events that result in pmliferation and sarehan of soluble antigen-specific Ig. The activation pmclzss is regxdated at several IeveIs, in&ding the interaction of B 4s with helper T c&s, as well as the fornation and _cretion of lymphokines that promote B-cell pmIiferation and differentiation into Ig-secreting c&I or memory B &Is. Siirly, secreted, dntigen-specitic Ig plays a" important role Negotiue sigtznlr~~g irz B cells IS rrritinfed by/ cc-crosslinking of rlic mtrgtw receptor md the Fey receptor, resultrq in ces_dio,r of B-celi sipfiq tmfzfs ma?, ii1 twn, hrhibiting B-cell prolifemtim od mtibody secretion. Here, LI cornpeltfrve role 1s proposed for SHIP irr blocking the ivteructior; of She with the GrbZ-Sos complex of proteins thnt lend to Rm flctiitntiorz I)I B cells.
Plastic and Reconstructive Surgery, 2014
Le Fort-based, maxillofacial allotransplantation is a reconstructive alternative gaining clinical... more Le Fort-based, maxillofacial allotransplantation is a reconstructive alternative gaining clinical acceptance. However, the vast majority of single-jaw transplant recipients demonstrate less-than-ideal skeletal and dental relationships, with suboptimal aesthetic harmony. The purpose of this study was to investigate reproducible cephalometric landmarks in a large-animal model, where refinement of computer-assisted planning, intraoperative navigational guidance, translational bone osteotomies, and comparative surgical techniques could be performed. Cephalometric landmarks that could be translated into the human craniomaxillofacial skeleton, and that would remain reliable following maxillofacial osteotomies with midfacial alloflap inset, were sought on six miniature swine. Le Fort I- and Le Fort III-based alloflaps were harvested in swine with osteotomies, and all alloflaps were either autoreplanted or transplanted. Cephalometric analyses were performed on lateral cephalograms preoperatively and postoperatively. Critical cephalometric data sets were identified with the assistance of surgical planning and virtual prediction software and evaluated for reliability and translational predictability. Several pertinent landmarks and human analogues were identified, including pronasale, zygion, parietale, gonion, gnathion, lower incisor base, and alveolare. Parietale-pronasale-alveolare and parietale-pronasale-lower incisor base were found to be reliable correlates of sellion-nasion-A point angle and sellion-nasion-B point angle measurements in humans, respectively. There is a set of reliable cephalometric landmarks and measurement angles pertinent for use within a translational large-animal model. These craniomaxillofacial landmarks will enable development of novel navigational software technology, improve cutting guide designs, and facilitate exploration of new avenues for investigation and collaboration.
Plastic and Reconstructive Surgery, 2014
Computed tomographic angiography is often used for preoperative mapping. The authors aimed to sys... more Computed tomographic angiography is often used for preoperative mapping. The authors aimed to systematically assess breast reconstruction outcomes after abdominally based free flaps planned with preoperative computed tomographic angiography versus Doppler ultrasonography. A search of the PubMed, EMBASE, and Scopus databases and an additional hand-search of relevant articles until June of 2012 rendered 442 English-language citations. Three authors independently reviewed these citations and included all the studies comparing preoperative computed tomographic angiography versus Doppler ultrasonography with regard to short-term postoperative outcomes and operative times. A meta-analysis was performed to evaluate the incidence of flap-related complications (seven studies), donor-site morbidity (four studies), and operative times (five studies) between preoperative computed tomographic angiography and Doppler ultrasonography. A pooled relative risk was calculated using a random-effect model to compare complication rates between the computed tomographic angiography and Doppler ultrasonography groups. A total of 13 studies met inclusion criteria. Preoperative computed tomographic angiography was associated with significantly fewer flap-related complications (relative risk, 0.87; 95 percent CI, 0.78 to 0.97), reduced donor-site morbidity (relative risk, 0.84; 95 percent CI, 0.76 to 0.94), and shorter reconstruction operative time by 87.7 minutes (mean difference, 87.7 minutes; 95 percent CI, 78.3 to 97.1 minutes). The use of preoperative computed tomographic angiography reduces the operative time, postoperative flap-related complications, and donor-site morbidity compared with Doppler ultrasonography. Preoperative computed tomographic angiography has the potential to reduce operative cost and increase efficiency in the operating room. Thus, preoperative mapping by computed tomographic angiography should be strongly considered for abdominally based free flap breast reconstruction.