Claudio Maldonado - Academia.edu (original) (raw)

Papers by Claudio Maldonado

Transplantation, 1998

Background. Low-dose cyclosporine (CsA)/mycophenolate mofetil (MMF) therapy has significantly red... more Background. Low-dose cyclosporine (CsA)/mycophenolate mofetil (MMF) therapy has significantly reduced the frequency of rejection and drug-induced side effects in rat hindlimb allograft recipients. With an eye toward direct clinical application, we developed a large-animal extremity composite tissue allograft model to assess the antirejection efficacy and systemic toxicity of combination CsA/MMF treatment.

Plastic and Reconstructive Surgery, 2007

Dynamic myoplasty has many clinical applications and has proven to be a versatile surgical proced... more Dynamic myoplasty has many clinical applications and has proven to be a versatile surgical procedure with great promise. This procedure has been used to achieve fecal/urinary continence, as in the dynamic graciloplasty, and to augment cardiac ventricular function, as is commonly seen with dynamic latissimus cardiomyoplasty. In the present study, the authors describe a functional innovative island flap sphincter created from the rectus abdominis muscle in a large-animal model to provide stomal continence for future clinical studies. The caudal region of the rectus abdominis muscle in eight mongrel canines (23 to 25 kg) was investigated through anatomical dissections during which the location of the neurovascular pedicles and the intersegmental muscle dimensions between the muscle inscriptions were noted. The rectus abdominis muscle was used to create functional dynamic stomal sphincters that were trained with subcutaneously implanted pulse stimulators. The neurovascular pedicles were consistently found in similar locations along the posterior medial aspect of the caudal portion of the canine's rectus abdominis muscle. The vertical height of the deep inferior epigastric pedicle and caudal intercostal nerve muscular mean entry points were 6.75 +/- 1.89 cm and 7.44 +/- 0.86 cm, respectively. The mean caudal intersegmental muscle length of the rectus abdominis muscle used to create the sphincter was 9.69 +/- 1.81 cm. The canine rectus abdominis muscle has reliable anatomical locations where the neurovascular pedicle may be found. This canine muscle may be used to create a continent island flap stomal sphincter. This large-animal sphincter model is versatile, durable, and easy to manipulate, with minimal morbidity to the animal.

Journal of Hand Surgery-american Volume, 2006

Twenty-four hands have been transplanted in 18 individuals and clinicians continue to debate whet... more Twenty-four hands have been transplanted in 18 individuals and clinicians continue to debate whether the risks justify the benefits in these procedures. To assess quantitatively the risks versus benefits in hand transplantation we used a validated instrument (Louisville Instrument for Transplantation) to measure the degree of risk individuals are willing to accept to receive different types of transplantation procedures.The Louisville Instrument for Transplantation contains 237 standardized questions that incorporate modified standard gamble and time trade-off outcome measures and questions that assess body image perception, depression, self-esteem, optimism, socially desirable responding, and demographics. Respondents were questioned on the extent to which they would trade off specific numbers of life-years or sustain other costs in exchange for receiving 7 different transplantation procedures. For this study we questioned 227 individuals in 4 study populations with differing life experiences: healthy individuals, organ transplant recipients, upper-extremity amputee patients, and lower-extremity amputee patients.All populations questioned perceived risk similarly despite their differing life experiences and would accept differing degrees of risk for the different transplantation procedures. Organ transplant recipients were the most risk-tolerant group whereas upper-extremity amputee patients were the most risk adverse, even when considering a single hand transplant. All groups that were questioned would accept a higher degree of risk to receive a double versus a single hand transplant.By questioning individuals who have experienced directly the risks of immunosuppression and those who could benefit from hand transplantation, this study presents an empiric basis for assessing risk versus benefit in this procedure.

Composite tissue allotransplantation (CTA) has recently emerged as a new therapeutic modality to ... more Composite tissue allotransplantation (CTA) has recently emerged as a new therapeutic modality to reconstruct major tissue defects of the face, larynx, and extremities. However, because the risk-versus-benefit ratio for CTA procedures has not yet been defined, the decision as to whether or not to perform these new reconstructive techniques is based on subjective opinions rather than objective data. To address this problem, the authors developed a reliable and valid instrument to objectively assess the relative risk that individuals are willing to accept in order to receive the benefits of various CTA procedures.

Clinics in Plastic Surgery, 2007

Facial transplantation has long captured the interest and imagination of scientists, the media, a... more Facial transplantation has long captured the interest and imagination of scientists, the media, and the lay public. Facial transplantation could provide an excellent alternative to current treatments for facial disfigurement caused by burns, trauma, cancer extirpation, or congenital birth defects. This article discusses the major technical, immunologic, psychosocial and ethical hurdles that have been overcome to bring facial transplantation from an idea to a clinical reality by providing the reader with a chronologic overview of the research and events that have led this exciting new treatment into the clinical arena.

Plastic and Reconstructive Surgery - PLAST RECONSTR SURG, 2008

A great deal of ethical debate has accompanied the introduction of facial tissue allotransplantat... more A great deal of ethical debate has accompanied the introduction of facial tissue allotransplantation into the clinical arena. Critics contend that the risks of lifelong immunosuppression do not justify the benefits of this new non-life-saving reconstructive procedure, whereas proponents argue that they do. Absent from this debate are the opinions of individuals with real-life experiences with the risks and benefits associated with this new treatment. In this study, the authors question facially disfigured individuals (n = 33) and the reconstructive surgeons who treat them (n = 45), organ transplant recipients (n = 42) and the professionals who manage their immunosuppression medication (n = 37), and healthy volunteer controls (n = 148) to determine the amount of risk they are willing to accept to receive facial tissue allotransplantation. A survey with psychometrically reliable and validated questions was administered to the above five groups, and appropriate statistical analysis was used to analyze and compare the data within and between groups. Of the five groups studied, reconstructive surgeons would accept the least amount of risk for a facial tissue allotransplant, followed by transplant specialists, then kidney transplant recipients, then facially disfigured individuals, and finally healthy control volunteers, who would accept the most amount of risk. The authors' data indicate that reconstructive surgeons are the least tolerant of risks compared with the other groups studied concerning facial tissue allotransplantation. This is particularly important because they are the primary caregivers to facially disfigured patients and, as such, will be the ones to lead the effort to move this new reconstructive treatment into the clinical arena.

Transplantation, 1998

Background. Low-dose cyclosporine (CsA)/mycophenolate mofetil (MMF) therapy has significantly red... more Background. Low-dose cyclosporine (CsA)/mycophenolate mofetil (MMF) therapy has significantly reduced the frequency of rejection and drug-induced side effects in rat hindlimb allograft recipients. With an eye toward direct clinical application, we developed a large-animal extremity composite tissue allograft model to assess the antirejection efficacy and systemic toxicity of combination CsA/MMF treatment.

Transplantation, 2003

We and others have shown that mixed allogeneic chimerism induces donor-specific tolerance to comp... more We and others have shown that mixed allogeneic chimerism induces donor-specific tolerance to composite tissue allografts across major histocompatibility complex barriers without the need for immunosuppression. However, a delay period between bone marrow transplantation and limb allotransplantation is required, making such protocols impractical for clinical application. This study eliminates this delay period in a rat hind limb allotransplantation model by performing mixed allogeneic chimerism induction and transplantation "simultaneously." Group 1 included controls in which naïve Wistar Furth (WF) hosts received ACI hind limbs. Group 2 included (ACI-->WF) chimeras that received limbs from third-party donors (Fisher), and group 3 included chimeras that received irradiated (1,050 cGy) ACI limbs. In group 4, WF hosts conditioned with 950 cGy received irradiated (1,050 cGy) ACI limbs followed by infusion of 100 x 10(6) ACI T-cell-depleted bone marrow cells and immunotherapy (tacrolimus and mycophenolate mofetil) for 28 days. Group 5 animals received the same treatment as group 4 animals without immunotherapy. The rats in groups 1 and 2 rejected their limbs within 10 days. Only one rat in group 4 survived to the end of the study. Groups 3 and 5 demonstrated long-term limb survival without rejection or graft-versus-host disease. High levels of donor chimerism (>80%) were achieved and maintained throughout the study. Mixed lymphocyte reaction assays in both groups revealed donor-specific hyporesponsiveness with vigorous third-party reactivity. This study demonstrated that infusion of donor bone marrow cells into conditioned hosts immediately after limb transplantation results in stable mixed chimerism, robust tolerance, and reliable limb allograft survival.

Transplantation, 2003

We and others have shown that mixed allogeneic chimerism induces donor-specific tolerance to comp... more We and others have shown that mixed allogeneic chimerism induces donor-specific tolerance to composite tissue allografts across major histocompatibility complex barriers without the need for immunosuppression. However, a delay period between bone marrow transplantation and limb allotransplantation is required, making such protocols impractical for clinical application. This study eliminates this delay period in a rat hind limb allotransplantation model by performing mixed allogeneic chimerism induction and transplantation "simultaneously." Group 1 included controls in which naïve Wistar Furth (WF) hosts received ACI hind limbs. Group 2 included (ACI-->WF) chimeras that received limbs from third-party donors (Fisher), and group 3 included chimeras that received irradiated (1,050 cGy) ACI limbs. In group 4, WF hosts conditioned with 950 cGy received irradiated (1,050 cGy) ACI limbs followed by infusion of 100 x 10(6) ACI T-cell-depleted bone marrow cells and immunotherapy (tacrolimus and mycophenolate mofetil) for 28 days. Group 5 animals received the same treatment as group 4 animals without immunotherapy. The rats in groups 1 and 2 rejected their limbs within 10 days. Only one rat in group 4 survived to the end of the study. Groups 3 and 5 demonstrated long-term limb survival without rejection or graft-versus-host disease. High levels of donor chimerism (>80%) were achieved and maintained throughout the study. Mixed lymphocyte reaction assays in both groups revealed donor-specific hyporesponsiveness with vigorous third-party reactivity. This study demonstrated that infusion of donor bone marrow cells into conditioned hosts immediately after limb transplantation results in stable mixed chimerism, robust tolerance, and reliable limb allograft survival.

Transplantation, 2002

Composite tissue allotransplantation (CTA) recently took its first steps in the clinical arena in... more Composite tissue allotransplantation (CTA) recently took its first steps in the clinical arena in 1998 with the successful hand transplant performed in Lyons, France. That single operation represented a culmination of many years of laboratory research in multiple fields involving integumentary/musculoskeletal transplantation. Here we review the prerequisite developments in the field of immunology, microsurgery, and pharmacotherapy that helped bring CTA to clinical reality. This new field still has many unanswered questions which are addressed below. Additionally, new evolving research in CTA is also discussed.

Transplant International, 2004

In previous rat studies, the use of mixed allogeneic chimerism (MAC) to induce host tolerance to ... more In previous rat studies, the use of mixed allogeneic chimerism (MAC) to induce host tolerance to hind limb allografts has resulted in severe graft-versus-host disease (GVHD). The purpose of this study was to determine if immunocompetent cells in bone marrow (BM) and/ or lymph nodes (LNs) of transplanted limbs were responsible for inducing GVHD in mixed chimeric hosts. [ACI + Wistar Furth] chimeric rats received ACI hind limbs that were non-irradiated, irradiated (1050 cGy) or lymphadenectomized. Rejection. GVHD and donor chimerism was assessed. Chimeric hosts rejected none of their limbs. However, hosts of non-irradiated hind limbs succumbed to GVHD 22.4 f 0.8 days after transplantation. In contrast. chimeras that received irradiated or lymphadenectomized ACI hind limbs showed no clinical or histological signs of GVHD at 5 months. We conclude that mixed chimeric hosts are susceptible to GVHD due to the immunocompetent cell load provided by the LNs, not the BM, of hind limb allografts.

The American Journal of Bioethics, 2004

Plastic and Reconstructive Surgery, 2006

Plastic and Reconstructive Surgery, 2002

Although the mechanism by which vascular delay benefits skin flaps is not completely understood, ... more Although the mechanism by which vascular delay benefits skin flaps is not completely understood, this topic has been extensively studied and reported on in the literature. In contrast, little has been documented about the effects of vascular delay in skeletal muscle flaps. Recent animal studies tested the effectiveness of vascular delay to enhance latissimus dorsi muscle flap viability for use in cardiomyoplasty and found that it prevented distal flap necrosis. However, these studies did not define the optimal time period necessary to achieve this beneficial effect. The purpose of this study was to determine how many days of "delay" can elicit the beneficial effects of vascular delay on latissimus dorsi muscle flaps. To accomplish this, 90 latissimus dorsi muscles of 45 male Sprague-Dawley rats were randomly subjected to vascular delay on one side or a sham procedure on the other. After predetermined delay periods (0, 3, 7, 10, and 14 days) or a sham procedure, all latissimus dorsi muscles were elevated as single pedicled flaps based only on their thoracodorsal neurovascular pedicle. Latissimus dorsi muscle perfusion was measured using a Laser Doppler Perfusion Imager just before and immediately after flap elevation. The muscles were then returned to their original vascular beds, isolated from adjacent tissue with Silastic film, sutured into place to maintain their original size and shape, and left there for 5 days. After 5 days, the latissimus dorsi muscle flaps were dissected free, scanned again (Laser Doppler Perfusion Imager-perfusion measurements), and the area of distal necrosis was measured using digitized planimetry of magnified images. The authors' results showed that delay periods of 3, 7, 10, and 14 days significantly increased (p < 0.05) blood perfusion and decreased (p < 0.05) distal flap necrosis when compared with sham controls. On the basis of these findings, the authors conclude that in their rat latissimus dorsi muscle flap model the beneficial effects of vascular delay are present as early as 3 days. If these findings also hold true in humans, they could be useful in cardiomyoplasty by allowing surgeons to shorten the amount of time between the vascular delay procedure and the cardiomyoplasty procedure in these very sick patients.

Plastic and Reconstructive Surgery, 2003

The use of dynamic myoplasty to restore function to failing organs is an exciting new application... more The use of dynamic myoplasty to restore function to failing organs is an exciting new application of skeletal muscle flaps. A complication of large flap elevation that can compromise flap function is ischemia-induced necrosis; one approach to minimizing this is to pretreat tissues with ischemic preconditioning. The purpose of this study was to determine whether systemic administration of monophosphoryl lipid A, a drug known to mimic late-phase ischemic preconditioning in the heart, could reduce ischemia-induced necrosis in latissimus dorsi muscle flaps. Forty latissimus dorsi muscle flaps from 20 Sprague-Dawley rats were allocated into four groups. In group I (n = 10), flaps were not preconditioned and served as controls. In group II (n = 10), flaps received ischemic preconditioning with two 30-minute periods of ischemia interspersed by 10 minutes of reperfusion. In group III (n = 10), rats received an intravenous bolus of approximately 0.3 ml of monophosphoryl lipid A vehicle only. In group IV (n = 10), rats received an intravenous bolus of 450 microg/kg of monophosphoryl lipid A and vehicle. Twenty-four hours after treatment, all latissimus dorsi muscle flaps were elevated on a single neurovascular pedicle and subjected to 4 hours of ischemia. After 72 hours of reperfusion, latissimus dorsi muscles were harvested, weighed, stained with nitroblue tetrazolium, and assessed for percent necrosis using digitized images of muscle sections and computerized planimetry. The percent necrosis in ischemic preconditioning-treated flaps (group II) was significantly reduced by 57 percent (p < 0.05) compared with control flaps (group I). The percent necrosis in flaps treated with monophosphoryl lipid A (group IV) was significantly reduced by 58 percent (p < 0.05) compared with vehicle-control flaps (group III). There was no difference in mean percent necrosis between ischemic preconditioning (group II) and monophosphoryl lipid A-treated (group IV) flaps or between ischemic preconditioning-control (group I) and monophosphoryl lipid A vehicle-control (group III) flaps. Intravenous administration of systemic monophosphoryl lipid A mimics the late-phase protective effect of ischemic preconditioning in the authors' rat latissimus dorsi muscle flap model.

Plastic and Reconstructive Surgery, 2003

Dynamic skeletal muscle flaps are designed to perform a specific functional task through contract... more Dynamic skeletal muscle flaps are designed to perform a specific functional task through contraction and relaxation of their muscle fibers. The most commonly used dynamic skeletal flaps today are for cardiomyoplasty and anal or urinary myoplasty. Low-frequency chronic stimulation of these flaps enables them to use their intrinsic energy stores in a more efficient manner through aerobic metabolic pathways for increased endurance and improved work capacity. The purpose of this study was to (1) determine whether fiber type transformation from fatigue-prone (type II) muscle fibers to fatigue-resistant (type I) muscle fibers could be demonstrated in the authors' chronic canine stomal sphincter model where the rectus abdominis muscle was used to create a functional stomal sphincter, (2) assess whether there is any correlation between the degree of muscle fiber type transformation and the continence times, and (3) examine the long-term effects of the training regimens on the skeletal muscle fibers through histologic and volumetric analysis. Eight dynamic island-flap sphincters were created from a part of the rectus abdominis muscle in mongrel dogs by preserving the deep inferior epigastric vascular pedicle and the most caudal investing intercostal nerve. The muscular sphincters were wrapped around a blind loop of distal ileum and trained with pacing electrodes. Two different training protocols were used. In group A (n = 4), a preexisting anal dynamic graciloplasty training protocol was used. A revised protocol was used in group B (n = 4). Muscle biopsy specimens were obtained before and after training from the rectus abdominis muscle sphincter. Fiber type transformation was assessed using a monoclonal antibody directed against the fatigue-prone type II fibers. Pretraining and posttraining skeletal muscle specimens were examined histologically. A significant fiber type conversion was achieved in both group A and group B animals, with each group achieving greater than 50 percent conversion from fatigue-prone (type II) muscle fibers to fatigue-resistant (type I) muscle fibers. The continence time was different for both groups. Biopsy specimens 1 cm from the electrodes revealed that fiber type transformation was uniform throughout this region of the sphincters. Skeletal muscle fibers within both groups demonstrated a reduction in their fiber diameter and volume. Fiber type transformation is possible in this unique canine island-flap rectus abdominis sphincter model. The relative design of the flap with preservation of the skeletal muscle resting length and neuronal and vascular supply are important characteristics when designing a functional dynamic flap for stomal continence.

Plastic and Reconstructive Surgery, 2001

Pacing and Clinical Electrophysiology, 1995

The conventional electrode configuration of current internal defibrillation systems most commonly... more The conventional electrode configuration of current internal defibrillation systems most commonly use superior vena caval (SVC) or combined SVC and subcutaneous (SC) electrodes as anode, and right ventricular apex (RVA) electrode as cathode. We have demonstrated earlier that the septal mass is important for defibrillation. The purpose of the present study was to compare a transseptal to a conventional electrode arrangement in the canine model. Three endocardial electrodes, 5 French EnGuard were positioned in RVA, SVC, and the right ventricular outflow (RVO) in eight dogs. A 5 French SC electrode was positioned in the fifth left intercostal space. RVA-RVO-/SC+ (configuration 2) was compared to SVC-SC+/RVA- (configuration 1). Defibrillation threshold testing was performed using asymmetrical biphasic shock, 6 msec+/2 msec-. Probit fit was used to compare the results at 40%, 50%, 60%, and 90% probabilities, and the logistic regression analysis to estimate the impact of variables. Electrode configuration had the strongest predictive value. Configuration 2 was superior to configuration 1 (P = 0.0016). At any voltage settings the probability of success for configuration 2 was greater, and current less (P < 0.00005). The energy requirements were reduced by approximately 33% for configuration 2. There were no significant differences in impedance between the two configurations. We conclude that transseptal defibrillation is more effective because of the improved lead geometry and voltage gradient.

Pacing and Clinical Electrophysiology, 1995

Previous studies have established efficacy of transseptal defibrillation. The purpose of the pres... more Previous studies have established efficacy of transseptal defibrillation. The purpose of the present study was to evaluate the role of transvenous electrode surface area for defibrillation. Sixteen dogs were randomized to 8 French and 5 French EnGuard electrodes; 8 dogs in each group. The length of the defibrillation coils was identical for both, but the surface area was different due to differences in the electrode diameters. Defibrillation threshold (DFT) testing was performed using a biphasic shock waveform, 6 msec+/2msec-. Logistic regression analysis was used to determine if the probability of defibrillation adjusted for voltage, current, and energy was different for 8 French electrodes. Logistic regression analysis found significant differences between 8 French and 5 French electrodes, with less voltage (P < 0.005), current (P < 0.03), and energy (P < 0.001) required at any level of probability to defibrillate for 8 French electrodes. These results support the conclusion that the surface area for endocardial electrodes is a significant factor for defibrillation. Therefore, when designing endocardial electrodes a desirable objective of reducing the electrode size should be weighed against the need to minimize DFTs.

Pacing and Clinical Electrophysiology, 1991

and from 'Research and Development, Telectronics Pacing Systems, Englewood, Coiorado SINGER, I.. ... more and from 'Research and Development, Telectronics Pacing Systems, Englewood, Coiorado SINGER, I.. ET AL.: Effects of Stress and Beta; Blockade on the Ventricular Depolarization Gradient of the Rate Modulating Pacemaker.

Transplantation, 1998

Background. Low-dose cyclosporine (CsA)/mycophenolate mofetil (MMF) therapy has significantly red... more Background. Low-dose cyclosporine (CsA)/mycophenolate mofetil (MMF) therapy has significantly reduced the frequency of rejection and drug-induced side effects in rat hindlimb allograft recipients. With an eye toward direct clinical application, we developed a large-animal extremity composite tissue allograft model to assess the antirejection efficacy and systemic toxicity of combination CsA/MMF treatment.

Plastic and Reconstructive Surgery, 2007

Dynamic myoplasty has many clinical applications and has proven to be a versatile surgical proced... more Dynamic myoplasty has many clinical applications and has proven to be a versatile surgical procedure with great promise. This procedure has been used to achieve fecal/urinary continence, as in the dynamic graciloplasty, and to augment cardiac ventricular function, as is commonly seen with dynamic latissimus cardiomyoplasty. In the present study, the authors describe a functional innovative island flap sphincter created from the rectus abdominis muscle in a large-animal model to provide stomal continence for future clinical studies. The caudal region of the rectus abdominis muscle in eight mongrel canines (23 to 25 kg) was investigated through anatomical dissections during which the location of the neurovascular pedicles and the intersegmental muscle dimensions between the muscle inscriptions were noted. The rectus abdominis muscle was used to create functional dynamic stomal sphincters that were trained with subcutaneously implanted pulse stimulators. The neurovascular pedicles were consistently found in similar locations along the posterior medial aspect of the caudal portion of the canine's rectus abdominis muscle. The vertical height of the deep inferior epigastric pedicle and caudal intercostal nerve muscular mean entry points were 6.75 +/- 1.89 cm and 7.44 +/- 0.86 cm, respectively. The mean caudal intersegmental muscle length of the rectus abdominis muscle used to create the sphincter was 9.69 +/- 1.81 cm. The canine rectus abdominis muscle has reliable anatomical locations where the neurovascular pedicle may be found. This canine muscle may be used to create a continent island flap stomal sphincter. This large-animal sphincter model is versatile, durable, and easy to manipulate, with minimal morbidity to the animal.

Journal of Hand Surgery-american Volume, 2006

Twenty-four hands have been transplanted in 18 individuals and clinicians continue to debate whet... more Twenty-four hands have been transplanted in 18 individuals and clinicians continue to debate whether the risks justify the benefits in these procedures. To assess quantitatively the risks versus benefits in hand transplantation we used a validated instrument (Louisville Instrument for Transplantation) to measure the degree of risk individuals are willing to accept to receive different types of transplantation procedures.The Louisville Instrument for Transplantation contains 237 standardized questions that incorporate modified standard gamble and time trade-off outcome measures and questions that assess body image perception, depression, self-esteem, optimism, socially desirable responding, and demographics. Respondents were questioned on the extent to which they would trade off specific numbers of life-years or sustain other costs in exchange for receiving 7 different transplantation procedures. For this study we questioned 227 individuals in 4 study populations with differing life experiences: healthy individuals, organ transplant recipients, upper-extremity amputee patients, and lower-extremity amputee patients.All populations questioned perceived risk similarly despite their differing life experiences and would accept differing degrees of risk for the different transplantation procedures. Organ transplant recipients were the most risk-tolerant group whereas upper-extremity amputee patients were the most risk adverse, even when considering a single hand transplant. All groups that were questioned would accept a higher degree of risk to receive a double versus a single hand transplant.By questioning individuals who have experienced directly the risks of immunosuppression and those who could benefit from hand transplantation, this study presents an empiric basis for assessing risk versus benefit in this procedure.

Composite tissue allotransplantation (CTA) has recently emerged as a new therapeutic modality to ... more Composite tissue allotransplantation (CTA) has recently emerged as a new therapeutic modality to reconstruct major tissue defects of the face, larynx, and extremities. However, because the risk-versus-benefit ratio for CTA procedures has not yet been defined, the decision as to whether or not to perform these new reconstructive techniques is based on subjective opinions rather than objective data. To address this problem, the authors developed a reliable and valid instrument to objectively assess the relative risk that individuals are willing to accept in order to receive the benefits of various CTA procedures.

Clinics in Plastic Surgery, 2007

Facial transplantation has long captured the interest and imagination of scientists, the media, a... more Facial transplantation has long captured the interest and imagination of scientists, the media, and the lay public. Facial transplantation could provide an excellent alternative to current treatments for facial disfigurement caused by burns, trauma, cancer extirpation, or congenital birth defects. This article discusses the major technical, immunologic, psychosocial and ethical hurdles that have been overcome to bring facial transplantation from an idea to a clinical reality by providing the reader with a chronologic overview of the research and events that have led this exciting new treatment into the clinical arena.

Plastic and Reconstructive Surgery - PLAST RECONSTR SURG, 2008

A great deal of ethical debate has accompanied the introduction of facial tissue allotransplantat... more A great deal of ethical debate has accompanied the introduction of facial tissue allotransplantation into the clinical arena. Critics contend that the risks of lifelong immunosuppression do not justify the benefits of this new non-life-saving reconstructive procedure, whereas proponents argue that they do. Absent from this debate are the opinions of individuals with real-life experiences with the risks and benefits associated with this new treatment. In this study, the authors question facially disfigured individuals (n = 33) and the reconstructive surgeons who treat them (n = 45), organ transplant recipients (n = 42) and the professionals who manage their immunosuppression medication (n = 37), and healthy volunteer controls (n = 148) to determine the amount of risk they are willing to accept to receive facial tissue allotransplantation. A survey with psychometrically reliable and validated questions was administered to the above five groups, and appropriate statistical analysis was used to analyze and compare the data within and between groups. Of the five groups studied, reconstructive surgeons would accept the least amount of risk for a facial tissue allotransplant, followed by transplant specialists, then kidney transplant recipients, then facially disfigured individuals, and finally healthy control volunteers, who would accept the most amount of risk. The authors' data indicate that reconstructive surgeons are the least tolerant of risks compared with the other groups studied concerning facial tissue allotransplantation. This is particularly important because they are the primary caregivers to facially disfigured patients and, as such, will be the ones to lead the effort to move this new reconstructive treatment into the clinical arena.

Transplantation, 1998

Background. Low-dose cyclosporine (CsA)/mycophenolate mofetil (MMF) therapy has significantly red... more Background. Low-dose cyclosporine (CsA)/mycophenolate mofetil (MMF) therapy has significantly reduced the frequency of rejection and drug-induced side effects in rat hindlimb allograft recipients. With an eye toward direct clinical application, we developed a large-animal extremity composite tissue allograft model to assess the antirejection efficacy and systemic toxicity of combination CsA/MMF treatment.

Transplantation, 2003

We and others have shown that mixed allogeneic chimerism induces donor-specific tolerance to comp... more We and others have shown that mixed allogeneic chimerism induces donor-specific tolerance to composite tissue allografts across major histocompatibility complex barriers without the need for immunosuppression. However, a delay period between bone marrow transplantation and limb allotransplantation is required, making such protocols impractical for clinical application. This study eliminates this delay period in a rat hind limb allotransplantation model by performing mixed allogeneic chimerism induction and transplantation "simultaneously." Group 1 included controls in which naïve Wistar Furth (WF) hosts received ACI hind limbs. Group 2 included (ACI-->WF) chimeras that received limbs from third-party donors (Fisher), and group 3 included chimeras that received irradiated (1,050 cGy) ACI limbs. In group 4, WF hosts conditioned with 950 cGy received irradiated (1,050 cGy) ACI limbs followed by infusion of 100 x 10(6) ACI T-cell-depleted bone marrow cells and immunotherapy (tacrolimus and mycophenolate mofetil) for 28 days. Group 5 animals received the same treatment as group 4 animals without immunotherapy. The rats in groups 1 and 2 rejected their limbs within 10 days. Only one rat in group 4 survived to the end of the study. Groups 3 and 5 demonstrated long-term limb survival without rejection or graft-versus-host disease. High levels of donor chimerism (>80%) were achieved and maintained throughout the study. Mixed lymphocyte reaction assays in both groups revealed donor-specific hyporesponsiveness with vigorous third-party reactivity. This study demonstrated that infusion of donor bone marrow cells into conditioned hosts immediately after limb transplantation results in stable mixed chimerism, robust tolerance, and reliable limb allograft survival.

Transplantation, 2003

We and others have shown that mixed allogeneic chimerism induces donor-specific tolerance to comp... more We and others have shown that mixed allogeneic chimerism induces donor-specific tolerance to composite tissue allografts across major histocompatibility complex barriers without the need for immunosuppression. However, a delay period between bone marrow transplantation and limb allotransplantation is required, making such protocols impractical for clinical application. This study eliminates this delay period in a rat hind limb allotransplantation model by performing mixed allogeneic chimerism induction and transplantation "simultaneously." Group 1 included controls in which naïve Wistar Furth (WF) hosts received ACI hind limbs. Group 2 included (ACI-->WF) chimeras that received limbs from third-party donors (Fisher), and group 3 included chimeras that received irradiated (1,050 cGy) ACI limbs. In group 4, WF hosts conditioned with 950 cGy received irradiated (1,050 cGy) ACI limbs followed by infusion of 100 x 10(6) ACI T-cell-depleted bone marrow cells and immunotherapy (tacrolimus and mycophenolate mofetil) for 28 days. Group 5 animals received the same treatment as group 4 animals without immunotherapy. The rats in groups 1 and 2 rejected their limbs within 10 days. Only one rat in group 4 survived to the end of the study. Groups 3 and 5 demonstrated long-term limb survival without rejection or graft-versus-host disease. High levels of donor chimerism (>80%) were achieved and maintained throughout the study. Mixed lymphocyte reaction assays in both groups revealed donor-specific hyporesponsiveness with vigorous third-party reactivity. This study demonstrated that infusion of donor bone marrow cells into conditioned hosts immediately after limb transplantation results in stable mixed chimerism, robust tolerance, and reliable limb allograft survival.

Transplantation, 2002

Composite tissue allotransplantation (CTA) recently took its first steps in the clinical arena in... more Composite tissue allotransplantation (CTA) recently took its first steps in the clinical arena in 1998 with the successful hand transplant performed in Lyons, France. That single operation represented a culmination of many years of laboratory research in multiple fields involving integumentary/musculoskeletal transplantation. Here we review the prerequisite developments in the field of immunology, microsurgery, and pharmacotherapy that helped bring CTA to clinical reality. This new field still has many unanswered questions which are addressed below. Additionally, new evolving research in CTA is also discussed.

Transplant International, 2004

In previous rat studies, the use of mixed allogeneic chimerism (MAC) to induce host tolerance to ... more In previous rat studies, the use of mixed allogeneic chimerism (MAC) to induce host tolerance to hind limb allografts has resulted in severe graft-versus-host disease (GVHD). The purpose of this study was to determine if immunocompetent cells in bone marrow (BM) and/ or lymph nodes (LNs) of transplanted limbs were responsible for inducing GVHD in mixed chimeric hosts. [ACI + Wistar Furth] chimeric rats received ACI hind limbs that were non-irradiated, irradiated (1050 cGy) or lymphadenectomized. Rejection. GVHD and donor chimerism was assessed. Chimeric hosts rejected none of their limbs. However, hosts of non-irradiated hind limbs succumbed to GVHD 22.4 f 0.8 days after transplantation. In contrast. chimeras that received irradiated or lymphadenectomized ACI hind limbs showed no clinical or histological signs of GVHD at 5 months. We conclude that mixed chimeric hosts are susceptible to GVHD due to the immunocompetent cell load provided by the LNs, not the BM, of hind limb allografts.

The American Journal of Bioethics, 2004

Plastic and Reconstructive Surgery, 2006

Plastic and Reconstructive Surgery, 2002

Although the mechanism by which vascular delay benefits skin flaps is not completely understood, ... more Although the mechanism by which vascular delay benefits skin flaps is not completely understood, this topic has been extensively studied and reported on in the literature. In contrast, little has been documented about the effects of vascular delay in skeletal muscle flaps. Recent animal studies tested the effectiveness of vascular delay to enhance latissimus dorsi muscle flap viability for use in cardiomyoplasty and found that it prevented distal flap necrosis. However, these studies did not define the optimal time period necessary to achieve this beneficial effect. The purpose of this study was to determine how many days of "delay" can elicit the beneficial effects of vascular delay on latissimus dorsi muscle flaps. To accomplish this, 90 latissimus dorsi muscles of 45 male Sprague-Dawley rats were randomly subjected to vascular delay on one side or a sham procedure on the other. After predetermined delay periods (0, 3, 7, 10, and 14 days) or a sham procedure, all latissimus dorsi muscles were elevated as single pedicled flaps based only on their thoracodorsal neurovascular pedicle. Latissimus dorsi muscle perfusion was measured using a Laser Doppler Perfusion Imager just before and immediately after flap elevation. The muscles were then returned to their original vascular beds, isolated from adjacent tissue with Silastic film, sutured into place to maintain their original size and shape, and left there for 5 days. After 5 days, the latissimus dorsi muscle flaps were dissected free, scanned again (Laser Doppler Perfusion Imager-perfusion measurements), and the area of distal necrosis was measured using digitized planimetry of magnified images. The authors' results showed that delay periods of 3, 7, 10, and 14 days significantly increased (p < 0.05) blood perfusion and decreased (p < 0.05) distal flap necrosis when compared with sham controls. On the basis of these findings, the authors conclude that in their rat latissimus dorsi muscle flap model the beneficial effects of vascular delay are present as early as 3 days. If these findings also hold true in humans, they could be useful in cardiomyoplasty by allowing surgeons to shorten the amount of time between the vascular delay procedure and the cardiomyoplasty procedure in these very sick patients.

Plastic and Reconstructive Surgery, 2003

The use of dynamic myoplasty to restore function to failing organs is an exciting new application... more The use of dynamic myoplasty to restore function to failing organs is an exciting new application of skeletal muscle flaps. A complication of large flap elevation that can compromise flap function is ischemia-induced necrosis; one approach to minimizing this is to pretreat tissues with ischemic preconditioning. The purpose of this study was to determine whether systemic administration of monophosphoryl lipid A, a drug known to mimic late-phase ischemic preconditioning in the heart, could reduce ischemia-induced necrosis in latissimus dorsi muscle flaps. Forty latissimus dorsi muscle flaps from 20 Sprague-Dawley rats were allocated into four groups. In group I (n = 10), flaps were not preconditioned and served as controls. In group II (n = 10), flaps received ischemic preconditioning with two 30-minute periods of ischemia interspersed by 10 minutes of reperfusion. In group III (n = 10), rats received an intravenous bolus of approximately 0.3 ml of monophosphoryl lipid A vehicle only. In group IV (n = 10), rats received an intravenous bolus of 450 microg/kg of monophosphoryl lipid A and vehicle. Twenty-four hours after treatment, all latissimus dorsi muscle flaps were elevated on a single neurovascular pedicle and subjected to 4 hours of ischemia. After 72 hours of reperfusion, latissimus dorsi muscles were harvested, weighed, stained with nitroblue tetrazolium, and assessed for percent necrosis using digitized images of muscle sections and computerized planimetry. The percent necrosis in ischemic preconditioning-treated flaps (group II) was significantly reduced by 57 percent (p < 0.05) compared with control flaps (group I). The percent necrosis in flaps treated with monophosphoryl lipid A (group IV) was significantly reduced by 58 percent (p < 0.05) compared with vehicle-control flaps (group III). There was no difference in mean percent necrosis between ischemic preconditioning (group II) and monophosphoryl lipid A-treated (group IV) flaps or between ischemic preconditioning-control (group I) and monophosphoryl lipid A vehicle-control (group III) flaps. Intravenous administration of systemic monophosphoryl lipid A mimics the late-phase protective effect of ischemic preconditioning in the authors' rat latissimus dorsi muscle flap model.

Plastic and Reconstructive Surgery, 2003

Dynamic skeletal muscle flaps are designed to perform a specific functional task through contract... more Dynamic skeletal muscle flaps are designed to perform a specific functional task through contraction and relaxation of their muscle fibers. The most commonly used dynamic skeletal flaps today are for cardiomyoplasty and anal or urinary myoplasty. Low-frequency chronic stimulation of these flaps enables them to use their intrinsic energy stores in a more efficient manner through aerobic metabolic pathways for increased endurance and improved work capacity. The purpose of this study was to (1) determine whether fiber type transformation from fatigue-prone (type II) muscle fibers to fatigue-resistant (type I) muscle fibers could be demonstrated in the authors' chronic canine stomal sphincter model where the rectus abdominis muscle was used to create a functional stomal sphincter, (2) assess whether there is any correlation between the degree of muscle fiber type transformation and the continence times, and (3) examine the long-term effects of the training regimens on the skeletal muscle fibers through histologic and volumetric analysis. Eight dynamic island-flap sphincters were created from a part of the rectus abdominis muscle in mongrel dogs by preserving the deep inferior epigastric vascular pedicle and the most caudal investing intercostal nerve. The muscular sphincters were wrapped around a blind loop of distal ileum and trained with pacing electrodes. Two different training protocols were used. In group A (n = 4), a preexisting anal dynamic graciloplasty training protocol was used. A revised protocol was used in group B (n = 4). Muscle biopsy specimens were obtained before and after training from the rectus abdominis muscle sphincter. Fiber type transformation was assessed using a monoclonal antibody directed against the fatigue-prone type II fibers. Pretraining and posttraining skeletal muscle specimens were examined histologically. A significant fiber type conversion was achieved in both group A and group B animals, with each group achieving greater than 50 percent conversion from fatigue-prone (type II) muscle fibers to fatigue-resistant (type I) muscle fibers. The continence time was different for both groups. Biopsy specimens 1 cm from the electrodes revealed that fiber type transformation was uniform throughout this region of the sphincters. Skeletal muscle fibers within both groups demonstrated a reduction in their fiber diameter and volume. Fiber type transformation is possible in this unique canine island-flap rectus abdominis sphincter model. The relative design of the flap with preservation of the skeletal muscle resting length and neuronal and vascular supply are important characteristics when designing a functional dynamic flap for stomal continence.

Plastic and Reconstructive Surgery, 2001

Pacing and Clinical Electrophysiology, 1995

The conventional electrode configuration of current internal defibrillation systems most commonly... more The conventional electrode configuration of current internal defibrillation systems most commonly use superior vena caval (SVC) or combined SVC and subcutaneous (SC) electrodes as anode, and right ventricular apex (RVA) electrode as cathode. We have demonstrated earlier that the septal mass is important for defibrillation. The purpose of the present study was to compare a transseptal to a conventional electrode arrangement in the canine model. Three endocardial electrodes, 5 French EnGuard were positioned in RVA, SVC, and the right ventricular outflow (RVO) in eight dogs. A 5 French SC electrode was positioned in the fifth left intercostal space. RVA-RVO-/SC+ (configuration 2) was compared to SVC-SC+/RVA- (configuration 1). Defibrillation threshold testing was performed using asymmetrical biphasic shock, 6 msec+/2 msec-. Probit fit was used to compare the results at 40%, 50%, 60%, and 90% probabilities, and the logistic regression analysis to estimate the impact of variables. Electrode configuration had the strongest predictive value. Configuration 2 was superior to configuration 1 (P = 0.0016). At any voltage settings the probability of success for configuration 2 was greater, and current less (P < 0.00005). The energy requirements were reduced by approximately 33% for configuration 2. There were no significant differences in impedance between the two configurations. We conclude that transseptal defibrillation is more effective because of the improved lead geometry and voltage gradient.

Pacing and Clinical Electrophysiology, 1995

Previous studies have established efficacy of transseptal defibrillation. The purpose of the pres... more Previous studies have established efficacy of transseptal defibrillation. The purpose of the present study was to evaluate the role of transvenous electrode surface area for defibrillation. Sixteen dogs were randomized to 8 French and 5 French EnGuard electrodes; 8 dogs in each group. The length of the defibrillation coils was identical for both, but the surface area was different due to differences in the electrode diameters. Defibrillation threshold (DFT) testing was performed using a biphasic shock waveform, 6 msec+/2msec-. Logistic regression analysis was used to determine if the probability of defibrillation adjusted for voltage, current, and energy was different for 8 French electrodes. Logistic regression analysis found significant differences between 8 French and 5 French electrodes, with less voltage (P < 0.005), current (P < 0.03), and energy (P < 0.001) required at any level of probability to defibrillate for 8 French electrodes. These results support the conclusion that the surface area for endocardial electrodes is a significant factor for defibrillation. Therefore, when designing endocardial electrodes a desirable objective of reducing the electrode size should be weighed against the need to minimize DFTs.

Pacing and Clinical Electrophysiology, 1991

and from 'Research and Development, Telectronics Pacing Systems, Englewood, Coiorado SINGER, I.. ... more and from 'Research and Development, Telectronics Pacing Systems, Englewood, Coiorado SINGER, I.. ET AL.: Effects of Stress and Beta; Blockade on the Ventricular Depolarization Gradient of the Rate Modulating Pacemaker.