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Feng B, Liu Y, Zhang J, Qu S, Yang W. Miniature origami robot for various biological micromanipulations. Nat Commun 2025; 16:2633. [PMID: 40097451 PMCID: PMC11914047 DOI: 10.1038/s41467-025-57815-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2024] [Accepted: 02/27/2025] [Indexed: 03/19/2025] Open
Abstract
Robotic micromanipulation is widely applied in biological research and medical procedures, providing a level of operational precision and stability beyond human capability. Compared with traditional micromanipulators that require assembly from many parts, origami manipulators offer advantages such as small size, lightweight, cost-effectiveness, and scalability. However, there are still requirements in biological application to address regarding stiffness, precision, and dexterity. Achieving a compact and functional parallel mechanism through origami structures remains a challenging problem. Here, we present the Micro-X4, a 4-Degree-of-Freedom (4-DoF) origami micromanipulator, which offers a workspace of 756 mm3, with a precision of 346 nm and a stiffness of 2738 N/m. We conduct a series of micromanipulation tasks, ranging from the tissue scale to the subcellular scale, including pattern cutting, cell positioning and puncturing, as well as cell cutting and insertion. Contact force measurement is further integrated to demonstrate precise control over cell operations and puncturing. We envision the Micro-X4 as the foundation for the next generation of lightweight and compact micromanipulation devices.
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Affiliation(s)
- Bo Feng
- State Key Laboratory of Fluid Power & Mechatronic Systems, Zhejiang University, Hangzhou, China
- Key Laboratory of Soft Machines and Smart Devices of Zhejiang Province, Zhejiang University, Hangzhou, China
- Department of Engineering Mechanics, Zhejiang University, Hangzhou, China
- Center for X-Mechanics, Zhejiang University, Hangzhou, China
| | - Yide Liu
- State Key Laboratory of Fluid Power & Mechatronic Systems, Zhejiang University, Hangzhou, China.
- Key Laboratory of Soft Machines and Smart Devices of Zhejiang Province, Zhejiang University, Hangzhou, China.
- Department of Engineering Mechanics, Zhejiang University, Hangzhou, China.
- Center for X-Mechanics, Zhejiang University, Hangzhou, China.
| | - Jiahang Zhang
- State Key Laboratory of Fluid Power & Mechatronic Systems, Zhejiang University, Hangzhou, China
- Key Laboratory of Soft Machines and Smart Devices of Zhejiang Province, Zhejiang University, Hangzhou, China
- Department of Engineering Mechanics, Zhejiang University, Hangzhou, China
- Center for X-Mechanics, Zhejiang University, Hangzhou, China
| | - Shaoxing Qu
- State Key Laboratory of Fluid Power & Mechatronic Systems, Zhejiang University, Hangzhou, China.
- Key Laboratory of Soft Machines and Smart Devices of Zhejiang Province, Zhejiang University, Hangzhou, China.
- Department of Engineering Mechanics, Zhejiang University, Hangzhou, China.
- Center for X-Mechanics, Zhejiang University, Hangzhou, China.
- Eye Center of the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
| | - Wei Yang
- Department of Engineering Mechanics, Zhejiang University, Hangzhou, China
- Center for X-Mechanics, Zhejiang University, Hangzhou, China
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Czarnogórski MC, Koper K, Petrasz P, Vetterlein MW, Pokrywczyńska M, Juszczak K, Drewa T, Adamowicz J. Urinary bladder transplantation in humans - current status and future perspectives. Nat Rev Urol 2025; 22:175-186. [PMID: 39304780 DOI: 10.1038/s41585-024-00935-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/07/2024] [Indexed: 09/22/2024]
Abstract
Urinary bladder vascularized allograft transplantation in humans is currently extensively being investigated worldwide, owing to the theoretical potential of this approach as a therapeutic option for individuals with end-stage, non-oncological bladder conditions or congenital bladder pathologies. To date, a successful attempt at urinary bladder autotransplantation was carried out in a heart-beating brain-dead research human donor. The robot-assisted surgical technique was shown to be optimal for performing this procedure, achieving a good performance in terms of both bladder allograft collection as well as vascular, ureterovesical and vesicourethral anastomoses. The urinary bladder vascularized allograft would be an alternative to traditional urinary diversion methods that rely on the use of intestinal segments, potentially avoiding adverse effects associated with these approaches. However, different from ileal urinary diversion, bladder transplantation would require lifelong immune suppression. Clinical trials are in progress to assess the vascularized bladder allograft transplantation technique, as well as the safety of this procedure in oncological and non-oncological indications.
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Affiliation(s)
- Michał C Czarnogórski
- Department and Chair of Urology and Andrology, Ludwik Rydygier Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland.
| | - Krzysztof Koper
- Department of Oncology, Ludwik Rydygier Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
| | - Piotr Petrasz
- Department of Urology and Urological Oncology, Multidisciplinary Regional Hospital in Gorzów Wielkopolski, Gorzów Wielkopolski, Poland
| | - Malte W Vetterlein
- Department of Urology, University Medical Center Hamburg Eppendorf, Hamburg, Germany
| | - Marta Pokrywczyńska
- Chair of Urology, Department of Regenerative Medicine, Ludwik Rydygier Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
| | - Kajetan Juszczak
- Department and Chair of Urology and Andrology, Ludwik Rydygier Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
| | - Tomasz Drewa
- Department and Chair of Urology and Andrology, Ludwik Rydygier Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
| | - Jan Adamowicz
- Department and Chair of Urology and Andrology, Ludwik Rydygier Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
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Holguín-Ruíz JA, Rodríguez L, Ferreira-Galvao FH, Muñoz-Botina J, Bedoya Duque MA, Varela-Vásquez MDM, Rodríguez-Galviz H, Zambrano-Galeano R, Castaño-Valencia S, Gutiérrez-Montes JO. An innovative ear transplantation for vascularized composite allotransplantation research in porcine model. Sci Rep 2024; 14:30896. [PMID: 39730666 DOI: 10.1038/s41598-024-81908-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Accepted: 11/29/2024] [Indexed: 12/29/2024] Open
Abstract
Vascularized composite allotransplantation (VCA) represents a clinical challenge for transplant therapy, as it involves different tissues with unique immunogenicity. Even when receiving immunosuppressive therapy, they are more vulnerable to severe hypoxia, microvascular damage, and ultimately the rejection or chronic graft dysfunction after transplantation. This study aimed to develop a surgical protocol for VCA of the ear in a porcine biomodel in the absence of immunosuppression, maintaining the in vitro co-culture of the allograft and assessing their relationship with allograft survival. We employed four crossbred pigs and four outbred mini pig biomodels (Sus scrofa), as donors and recipients, to perform four VCAs. Blood samples were taken from each biomodel for crossmatch testing and SLA haplotype identification. Bone marrow samples were taken from each recipient for subsequent co-culture. In vitro culture and co-culture conditions were maintained and assessed. Histological analysis using hematoxylin and eosin staining was performed on the allograft that lasted the longest time showing the smallest macroscopic signs of rejection. A surgical protocol for Vascularized Composite Allograft (VCA) ear transplantation in a porcine biomodel was developed, including the skin. The presence of SLA-DRB1*01:02 and SLA-DRB1*06:01 haplotypes in the recipient and donor, respectively, showed concordance with positive crossmatch tests. In the allograft with the highest survival time, no histological signs of hyperacute rejection were found ten days after transplantation in the anastomosis area. The results obtained from this protocol can provide valuable recommendations for translational applications in face transplantation and regenerative medicine.
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Affiliation(s)
- Jorge A Holguín-Ruíz
- Pharmacology Research Group, Universidad del Valle, Colombia, Cali, 760043
- School of Basic Sciences Department of Physiological Sciences, Universidad del Valle, Cali, Colombia, 760043
| | - Laura Rodríguez
- Pharmacology Research Group, Universidad del Valle, Colombia, Cali, 760043.
- Department of Pharmaceutical and Chemical Sciences, Universidad Icesi, Calle 18 No. 122-135, Cali, Colombia, 760008.
| | | | - Jaime Muñoz-Botina
- Pharmacology Research Group, Universidad del Valle, Colombia, Cali, 760043
- School of Basic Sciences Department of Physiological Sciences, Universidad del Valle, Cali, Colombia, 760043
| | - Maria Alejandra Bedoya Duque
- Department of Pharmaceutical and Chemical Sciences, Universidad Icesi, Calle 18 No. 122-135, Cali, Colombia, 760008
| | - María Del Mar Varela-Vásquez
- Department of Pharmaceutical and Chemical Sciences, Universidad Icesi, Calle 18 No. 122-135, Cali, Colombia, 760008
| | | | | | - Santiago Castaño-Valencia
- Pharmacology Research Group, Universidad del Valle, Colombia, Cali, 760043
- School of Basic Sciences Department of Physiological Sciences, Universidad del Valle, Cali, Colombia, 760043
| | - José Oscar Gutiérrez-Montes
- Pharmacology Research Group, Universidad del Valle, Colombia, Cali, 760043
- School of Basic Sciences Department of Physiological Sciences, Universidad del Valle, Cali, Colombia, 760043
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4
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Kim M, Fisher DT, Bogner PN, Sharma U, Yu H, Skitzki JJ, Repasky EA. Manipulating adrenergic stress receptor signalling to enhance immunosuppression and prolong survival of vascularized composite tissue transplants. Clin Transl Med 2022; 12:e996. [PMID: 35994413 PMCID: PMC9394753 DOI: 10.1002/ctm2.996] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 07/05/2022] [Accepted: 07/11/2022] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND Vascularized composite tissue allotransplantation (VCA) to replace limbs or faces damaged beyond repair is now possible. The resulting clear benefit to quality of life is a compelling reason to attempt this complex procedure. Unfortunately, the high doses of immunosuppressive drugs required to protect this type of allograft result in significant morbidity and mortality giving rise to ethical concerns about performing this surgery in patients with non-life-threatening conditions. Here we tested whether we could suppress anti-graft immune activity by using a safe β2 -adrenergic receptor (AR) agonist, terbutaline, to mimic the natural immune suppression generated by nervous system-induced signalling through AR. METHODS A heterotopic hind limb transplantation model was used with C57BL/6 (H-2b) as recipients and BALB/c (H-2d) mice as donors. To test the modulation of the immune response, graft survival was investigated after daily intraperitoneal injection of β2 -AR agonist with and without tacrolimus. Analyses of immune compositions and quantification of pro-inflammatory cytokines were performed to gauge functional immunomodulation. The contributions to allograft survival of β2 -AR signalling in donor and recipient tissue were investigated with β2 -AR-/- strains. RESULTS Treatment with the β2 -AR agonist delayed VCA rejection, even with a subtherapeutic dose of tacrolimus. β2 -AR agonist decreased T-cell infiltration into the transplanted grafts and decreased memory T-cell populations in recipient's circulation. In addition, decreased levels of inflammatory cytokines (IFN-γ, IL-6, TNF-α, CXCL-1/10 and CCL3/4/5/7) were detected following β2 -AR agonist treatment, and there was a decreased expression of ICAM-1 and vascular cell adhesion molecule-1 in donor stromal cells. CONCLUSIONS β2 -AR agonist can be used safely to mimic the natural suppression of immune responses, which occurs during adrenergic stress-signalling and thereby can be used in combination regimens to reduce the dose needed of toxic immunosuppressive drugs such as tacrolimus. This strategy can be further evaluated for feasibility in the clinic.
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Affiliation(s)
- Minhyung Kim
- Department of Surgical OncologyRoswell Park Comprehensive Cancer CenterBuffaloNew YorkUSA
- Department of ImmunologyRoswell Park Comprehensive Cancer CenterBuffaloNew YorkUSA
| | - Daniel T. Fisher
- Department of Surgical OncologyRoswell Park Comprehensive Cancer CenterBuffaloNew YorkUSA
- Department of ImmunologyRoswell Park Comprehensive Cancer CenterBuffaloNew YorkUSA
| | - Paul N. Bogner
- Department of PathologyRoswell Park Comprehensive Cancer CenterBuffaloNew YorkUSA
| | - Umesh Sharma
- Department of Medicine, Division of CardiologyUniversity at BuffaloBuffaloNew YorkUSA
| | - Han Yu
- Department of Biostatistics and BioinformaticsRoswell Park Comprehensive Cancer CenterBuffaloNew YorkUSA
| | - Joseph J. Skitzki
- Department of Surgical OncologyRoswell Park Comprehensive Cancer CenterBuffaloNew YorkUSA
- Department of ImmunologyRoswell Park Comprehensive Cancer CenterBuffaloNew YorkUSA
| | - Elizabeth A. Repasky
- Department of ImmunologyRoswell Park Comprehensive Cancer CenterBuffaloNew YorkUSA
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5
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Walton K, Walker K, Riddle M, Koehn BH, Reff J, Sagatys EM, Linden MA, Pidala J, Kim J, Lee MC, Kiluk JV, Hui JYC, Yun SY, Xing Y, Stefanski H, Lawrence HR, Lawrence NJ, Tolar J, Anasetti C, Blazar BR, Sebti SM, Betts BC. Dual JAK2/Aurora kinase A inhibition prevents human skin graft rejection by allo-inactivation and ILC2-mediated tissue repair. Am J Transplant 2022; 22:717-730. [PMID: 34668635 PMCID: PMC8897228 DOI: 10.1111/ajt.16870] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 09/30/2021] [Accepted: 10/15/2021] [Indexed: 01/25/2023]
Abstract
Prevention of allograft rejection often requires lifelong immune suppression, risking broad impairment of host immunity. Nonselective inhibition of host T cell function increases recipient risk of opportunistic infections and secondary malignancies. Here we demonstrate that AJI-100, a dual inhibitor of JAK2 and Aurora kinase A, ameliorates skin graft rejection by human T cells and provides durable allo-inactivation. AJI-100 significantly reduces the frequency of skin-homing CLA+ donor T cells, limiting allograft invasion and tissue destruction by T effectors. AJI-100 also suppresses pathogenic Th1 and Th17 cells in the spleen yet spares beneficial regulatory T cells. We show dual JAK2/Aurora kinase A blockade enhances human type 2 innate lymphoid cell (ILC2) responses, which are capable of tissue repair. ILC2 differentiation mediated by GATA3 requires STAT5 phosphorylation (pSTAT5) but is opposed by STAT3. Further, we demonstrate that Aurora kinase A activation correlates with low pSTAT5 in ILC2s. Importantly, AJI-100 maintains pSTAT5 levels in ILC2s by blocking Aurora kinase A and reduces interference by STAT3. Therefore, combined JAK2/Aurora kinase A inhibition is an innovative strategy to merge immune suppression with tissue repair after transplantation.
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Affiliation(s)
- Kelly Walton
- Division of Hematology, Oncology, and Transplantation, Department of Medicine, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
| | - Kirsti Walker
- Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
| | - Megan Riddle
- Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
| | - Brent H. Koehn
- Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
| | - Jordan Reff
- Department of Immunology, Moffitt Cancer Center, Tampa, FL, USA
| | - Elizabeth M. Sagatys
- Department of Immunology, Moffitt Cancer Center, Tampa, FL, USA,Department of Hematopathology and Laboratory Medicine, Moffitt Cancer Center, Tampa, FL, USA
| | - Michael A. Linden
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA
| | - Joseph Pidala
- Department of Immunology, Moffitt Cancer Center, Tampa, FL, USA,Department of Oncologic Sciences, Moffitt Cancer Center, Tampa, FL, USA,Department of Blood and Marrow Transplantation – Cellular Immunotherapy, Moffitt Cancer Center, Tampa, FL, USA
| | - Jongphil Kim
- Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL, USA
| | - Marie C Lee
- Department of Oncologic Sciences, Moffitt Cancer Center, Tampa, FL, USA,Department of Breast Oncology, Moffitt Cancer Center, Tampa, FL, USA
| | - John V. Kiluk
- Department of Oncologic Sciences, Moffitt Cancer Center, Tampa, FL, USA,Department of Breast Oncology, Moffitt Cancer Center, Tampa, FL, USA
| | | | - Sang Y. Yun
- Department of Oncologic Sciences, Moffitt Cancer Center, Tampa, FL, USA,Department of Drug Discovery, Moffitt Cancer Center, Tampa, FL, USA
| | - Yan Xing
- Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
| | - Heather Stefanski
- Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
| | - Harshani R. Lawrence
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA,Department of Drug Discovery, Moffitt Cancer Center, Tampa, FL, USA
| | - Nicholas J. Lawrence
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA,Department of Drug Discovery, Moffitt Cancer Center, Tampa, FL, USA
| | - Jakub Tolar
- Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
| | - Claudio Anasetti
- Department of Immunology, Moffitt Cancer Center, Tampa, FL, USA,Department of Oncologic Sciences, Moffitt Cancer Center, Tampa, FL, USA,Department of Blood and Marrow Transplantation – Cellular Immunotherapy, Moffitt Cancer Center, Tampa, FL, USA
| | - Bruce R. Blazar
- Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
| | - Said M. Sebti
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia USA
| | - Brian C. Betts
- Division of Hematology, Oncology, and Transplantation, Department of Medicine, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
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6
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Abstract
Composite tissue allotransplantation (CTA) is the culmination of progress in transplantation, allowing the reconstruction of the hand in amputees. Worldwide, more than 100 procedures have been performed. The aim of this work was to understand the hand allotransplantation approach, making known current aspects, risks, and benefits. A PubMed research was realized between October 2018 and March 2019, including terms like "Hand transplantation" AND "Composite tissue allotransplantation," "Hand transplantation" AND "Functional outcomes," "Hand transplantation" AND "Immunosuppression," "Hand prosthetics," "Hand Transplantation" AND "Ethics." There were included papers between 1995 and 2018, with English language, amputee human adults, systematic reviews, and clinical studies. Seventy-two papers were fully evaluated. There are technical aspects that influence the procedure like team coordination or surgical technique. It requires a long-life treatment, which has risks such as toxicity or infections. However, it allows the recovery of fine movements, and independence, to perform detailed tasks. The indications must be carefully considered, because some patients benefit from the use of prosthesis. CTA has become an option for amputees so it is important to do more research, to determine the benefits of this procedure. It is not considered a life-saving procedure, so there is an ethical debate because of the risks.
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Affiliation(s)
- Maria João Lúcio
- Department of Plastic and Reconstructive Surgery, and Burn Unity, Centro Hospitalar Universitário de São João, Porto Medical School, University of Porto, Porto, Portugal
| | - Ricardo Horta
- Department of Plastic and Reconstructive Surgery, and Burn Unity, Centro Hospitalar Universitário de São João, Porto Medical School, University of Porto, Porto, Portugal
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7
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Win TS, Crisler WJ, Dyring-Andersen B, Lopdrup R, Teague JE, Zhan Q, Barrera V, Ho Sui S, Tasigiorgos S, Murakami N, Chandraker A, Tullius SG, Pomahac B, Riella LV, Clark RA. Immunoregulatory and lipid presentation pathways are upregulated in human face transplant rejection. J Clin Invest 2021; 131:135166. [PMID: 33667197 PMCID: PMC8262560 DOI: 10.1172/jci135166] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Accepted: 02/25/2021] [Indexed: 01/04/2023] Open
Abstract
BACKGROUNDRejection is the primary barrier to broader implementation of vascularized composite allografts (VCAs), including face and limb transplants. The immunologic pathways activated in face transplant rejection have not been fully characterized.METHODSUsing skin biopsies prospectively collected over 9 years from 7 face transplant patients, we studied rejection by gene expression profiling, histology, immunostaining, and T cell receptor sequencing.RESULTSGrade 1 rejection did not differ significantly from nonrejection, suggesting that it does not represent a pathologic state. In grade 2, there was a balanced upregulation of both proinflammatory T cell activation pathways and antiinflammatory checkpoint and immunomodulatory pathways, with a net result of no tissue injury. In grade 3, IFN-γ-driven inflammation, antigen-presenting cell activation, and infiltration of the skin by proliferative T cells bearing markers of antigen-specific activation and cytotoxicity tipped the balance toward tissue injury. Rejection of VCAs and solid organ transplants had both distinct and common features. VCA rejection was uniquely associated with upregulation of immunoregulatory genes, including SOCS1; induction of lipid antigen-presenting CD1 proteins; and infiltration by T cells predicted to recognize CD1b and CD1c.CONCLUSIONOur findings suggest that the distinct features of VCA rejection reflect the unique immunobiology of skin and that enhancing cutaneous immunoregulatory networks may be a useful strategy in combatting rejection.Trial registrationClinicalTrials.gov NCT01281267.FUNDINGAssistant Secretary of Defense and Health Affairs, through Reconstructive Transplant Research (W81XWH-17-1-0278, W81XWH-16-1-0647, W81XWH-16-1-0689, W81XWH-18-1-0784, W81XWH-1-810798); American Society of Transplantation's Transplantation and Immunology Research Network Fellowship Research Grant; Plastic Surgery Foundation Fellowship from the American Society of Plastic Surgeons; Novo Nordisk Foundation (NNF15OC0014092); Lundbeck Foundation; Aage Bangs Foundation; A.P. Moller Foundation for the Advancement of Medical Science; NIH UL1 RR025758.
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Affiliation(s)
- Thet Su Win
- Department of Dermatology and
- Division of Plastic Surgery, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | | | | | - Rachel Lopdrup
- Division of Plastic Surgery, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | | | | | - Victor Barrera
- Bioinformatics Core, Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
| | - Shannan Ho Sui
- Bioinformatics Core, Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
| | - Sotirios Tasigiorgos
- Division of Plastic Surgery, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | | | | | - Stefan G. Tullius
- Division of Transplant Surgery, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Bohdan Pomahac
- Division of Plastic Surgery, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
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8
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Kohn TP, Peña V, Redett Iii RJ, Burnett AL. Penile allotransplantation: early outcomes from reported cases and survivorship considerations. Minerva Urol Nephrol 2021; 73:333-341. [PMID: 33781015 DOI: 10.23736/s2724-6051.21.04144-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Vascular composite allografts are at the forefront of medical and surgical innovation. With this new technique and the ability to transplant a face, hands, an abdominal wall, a uterus, or even a penis, patients can undergo operations that may drastically improve their quality of life. Although this process presents significant opportunities it is not always an easy road and requires significant upfront counseling and life-long immunosuppression. Often the recovery course is long, with functionality taking months to years to gain. Immunosuppression must be used to prevent rejection of the allograft although it has serious long-term side-effects. Only five patients have undergone penile allotransplantation but reported outcomes from these small numbers have nonetheless offered significant lessons with each patient. While the operation is still in its infancy, it is certain that shared experiences by surgical teams will yield improved outcomes in the future.
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Affiliation(s)
- Taylor P Kohn
- Johns Hopkins School of Medicine, Brady Urological Institute, Baltimore, MD, USA
| | - Vanessa Peña
- Johns Hopkins School of Medicine, Brady Urological Institute, Baltimore, MD, USA
| | - Richard J Redett Iii
- Vascularized Composite Allotransplantation (VCA) Laboratory, Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Arthur L Burnett
- Johns Hopkins School of Medicine, Brady Urological Institute, Baltimore, MD, USA -
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9
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Infectious complications of vascularized composite allograft transplantation. Curr Opin Organ Transplant 2021; 25:377-382. [PMID: 32487889 DOI: 10.1097/mot.0000000000000780] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
PURPOSE OF REVIEW Vascularized composite allograft (VCA) transplants constitute multiple tissues transplanted together as one functional unit. These procedures are increasing in frequency and complexity, yet data about graft survival, quality of life, and infection risk remain limited. RECENT FINDINGS Informative guidance for this patient population is often inferred from the solid organ transplantation literature. Yet, it is important to understand that VCA transplantation additionally carries its own significant and distinctive risk factors for infection. SUMMARY In this review, we give an overview of previously described infectious complications of VCA transplantation in the literature, discuss risk factors for future infection in these patients, and discuss how to manage such obstacles.
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10
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Vascularized Bone Marrow Cellular Depletion or Discontinuity Abrogates Protection of Vascularized Composite Allografts in Nonhuman Primates. Transplant Direct 2021; 7:e659. [PMID: 33521248 PMCID: PMC7837879 DOI: 10.1097/txd.0000000000001107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 09/28/2020] [Accepted: 10/13/2020] [Indexed: 11/29/2022] Open
Abstract
Background. Vascularized composite allografts (VCA) have demonstrated good clinical outcomes dependent on chronic immunosuppression. Previous work by our group and others supports that cotransplanted vascularized bone marrow (VBM) as a component of VCA offers immunologic protection to prolong graft survival. We aimed to characterize the requirements and potential mechanisms of VBM-mediated protection of VCA by modifying grafts through various strategies. Methods. Experimental groups of mismatched cynomolgus macaque recipients received VCA transplants modified by the following approaches: heterotopic separation of the VCA and VBM components; T-cell depletion of either donor or recipient; irradiation of donor VCA; and infusion of donor bone marrow. All groups received standard immunosuppression with tacrolimus and mycophenolate mofetil. Results. Experimental modifications to donor, recipient, or graft all demonstrated short-graft survivals (31 d). Chimerism levels without bone marrow infusion were transient and minimal when detected and were not associated with prolonged survival. Donor bone marrow infusion increased levels of chimerism but resulted in alloantibody production and did not improve graft survival. Conclusions. VCA graft survival is significantly reduced compared with previously reported VCA with VBM transplants (348 d; P = 0.01) when the hematopoietic niche is removed, altered, or destroyed via irradiation, depletion, or topographical rearrangement. These experimental manipulations resulted in similar outcomes to VCA grafts without cotransplanted VBM (25 d). These data support the presence of a radiosensitive, T-cell population within the VBM compartment not reconstituted by reinfusion of bone marrow cells.
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11
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Petruzzo P, Luong S, Kanitakis J, Sardu C, Feugier P, Danjou F, Gazarian A, Badet L, Morelon E. Graft vasculopathy in upper extremity allotransplantation: Results of a retrospective high-resolution ultrasonographic study. Clin Transplant 2020; 35:e14130. [PMID: 33099801 DOI: 10.1111/ctr.14130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 08/14/2020] [Accepted: 10/17/2020] [Indexed: 11/29/2022]
Abstract
Graft vasculopathy (GV) is the most severe pathologic change of chronic rejection in vascularized composite allotransplantation. Since 2012, the intimal media thickness (IMT) of radial and ulnar arteries was annually monitored by high-resolution ultrasonography in seven bilateral upper extremity transplant (UET) patients. We also investigated the IMT of seven matched healthy subjects (controls). No significant difference between IMT values of controls and UET patients was found. The median IMT values of recipient radial and ulnar arteries were 0.23 mm and 0.25 mm, respectively, while the median IMT values of grafted radial and ulnar arteries were 0.27 mm and 0.30 mm, respectively. There was a statistically significant difference in the IMT values of the grafted and recipient ulnar arteries (p = .043), but this difference was no longer significant when patient #2 was excluded. He showed a significant difference between recipient and grafted arteries and significantly higher IMT values (p = .001) of his grafted arteries compared with those of all transplanted patients. This patient developed GV leading to graft loss 11 years after the transplantation. In conclusion, this study showed a significant IMT increase in an UET recipient who developed GV.
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Affiliation(s)
- Palmina Petruzzo
- Department of Transplantation, Hôpital Edouard Herriot, HCL, Lyon, France.,Department of Surgery, University of Cagliari, Cagliari, Italy
| | - Stephane Luong
- Department of Urinary and Vascular Imaging, Hôpital Edouard Herriot, HCL, Lyon, France
| | - Jean Kanitakis
- Department of Dermatology, Hôpital Edouard Herriot, HCL, Lyon, France
| | - Claudia Sardu
- Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy
| | - Patrick Feugier
- Vascular Surgery Unit, Groupement Hospitalo-Universitaire Lyon Sud, HCL, Lyon, France.,Université Claude Bernard, Lyon1, Lyon, France
| | - Fabrice Danjou
- Département d'Information Médicale, Hôpital Saint Camille, Bry-sur-Marne, France
| | - Aram Gazarian
- Chirurgie de la Main et du Membre Supérieur, Hôpital Edouard Herriot, HCL, Lyon, France.,Chirurgie de la Main et du Membre Supérieur, Polyclinique Orthopédique de Lyon, Lyon, France
| | - Lionel Badet
- Department of Transplantation, Hôpital Edouard Herriot, HCL, Lyon, France.,Université Claude Bernard, Lyon1, Lyon, France
| | - Emmanuel Morelon
- Department of Transplantation, Hôpital Edouard Herriot, HCL, Lyon, France.,Université Claude Bernard, Lyon1, Lyon, France
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Giannis D, Moris D, Cendales LC. Costimulation Blockade in Vascularized Composite Allotransplantation. Front Immunol 2020; 11:544186. [PMID: 33042138 PMCID: PMC7527523 DOI: 10.3389/fimmu.2020.544186] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 08/19/2020] [Indexed: 12/14/2022] Open
Abstract
Vascular composite allotransplantation (VCA) is a field under research and has emerged as an alternative option for the repair of severe disfiguring defects that result from infections or traumatic amputation in a selected group of patients. VCA is performed in centers with appropriate expertise, experience and adequate resources to effectively manage the complexity and complications of this treatment. Lifelong immunosuppressive therapy, immunosuppression associated complications, and the effects of the host immune response in the graft are major concerns in VCA. VCA is considered a quality of life transplant and the risk-benefit ratio is dissimilar to life saving transplants. Belatacept seems a promising drug that prolongs patient and graft survival in kidney transplantation and it could also be an alternative approach to VCA immunosuppression. In this review, we are summarizing current literature about the role of costimulation blockade, with a focus on belatacept in VCA.
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Affiliation(s)
- Dimitrios Giannis
- Institute of Health Innovations and Outcomes Research, Feinstein Institutes for Medical Research, Manhasset, NY, United States
| | - Dimitrios Moris
- Duke Surgery, Duke University Medical Center, Durham, NC, United States
| | - Linda C. Cendales
- Duke Surgery, Duke University Medical Center, Durham, NC, United States
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13
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Prosthetic Rehabilitation and Vascularized Composite Allotransplantation following Upper Limb Loss. Plast Reconstr Surg 2019; 143:1688-1701. [PMID: 31136485 DOI: 10.1097/prs.0000000000005638] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
BACKGROUND Upper limb loss is a devastating condition with dramatic physical, psychological, financial, and social consequences. Improvements in the fields of prosthetics and vascularized composite allotransplantation have opened exciting new frontiers for treatment and rehabilitation following upper limb loss. Each modality offers a unique set of advantages and limitations with regard to the restoration of hand function following amputation. METHODS Presented in this article is a discussion outlining the complex considerations and decisions encountered when determining patient appropriateness for either prosthetic rehabilitation or vascularized composite allotransplantation following upper limb loss. In this review, the authors examine how psychosocial factors, nature of injury, rehabilitation course, functional outcomes, and risks and benefits may affect overall patient selection for either rehabilitative approach. RESULTS This review summarizes the current state of the literature. Advancements in both prosthetic and biological strategies demonstrate promise with regard to facilitating rehabilitation following upper limb loss. However, there remains a dearth of research directly comparing outcomes in prosthetic rehabilitation to that following upper extremity transplantation. CONCLUSIONS Few studies have performed a direct comparison between patients undergoing vascularized composite allotransplantation and those undergoing prosthetic rehabilitation. Upper extremity transplantation and prosthetic reconstruction should not be viewed as competing options, but rather as two treatment modalities with different risk-to-benefit profiles and indications.
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14
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Cheng HY, Tay SKL, Wen CJ, Lin CF, Wang AYL, Shih LY, Liu SC, Kobayashi E, Lin CH, Wei FC. Bioimaging of alloantigen-stimulated regulatory T cells in rat vascularized composite allotransplantation. PLoS One 2018; 13:e0203624. [PMID: 30192879 PMCID: PMC6128578 DOI: 10.1371/journal.pone.0203624] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Accepted: 08/23/2018] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Tipping the balance toward regulatory T cells (Tregs) through adoptive cell therapy has shown promise to induce transplantation tolerance. Although such strategy has been explored in many mice organ transplantation studies, less knowledge was available in rat systems. Furthermore, the behaviors of the transferred cells have not been well studied in real-time fashion. METHODS Tregs from naïve LEW rats were purified in two steps with the autoMACS system. Immunosuppression potential of these cells was examined with mixed lymphocyte reaction. Following stimulation by the alloantigen in vitro, the purified Tregs were infused into the recipients of vascularized composite allotransplantation (VCA). Secondary allogeneic skin grafting challenge was performed on the recipients with long-term survived VCA. Live optical imaging was performed to track luciferase-expressing Tregs following infusion to the VCA recipients. Expression of relevant molecules was studied by flow cytometry or quantitative RT-PCR. RESULTS Rat Tregs were enriched following two-step cell sorting and showed immunosuppressive capacity. Upon infusion into the VCA recipients that have been treated with antilymphocyte serum and short-term Cyclosporin A, the antigen-stimulated Tregs significantly prolonged VCA survival and induced donor-specific tolerance. Tracking of the infused bioluminescent Tregs showed their specific homing to lymph nodes, and then to the VCAs. Following secondary skin grafting, Tregs specifically gathered at the donor-derived skin that was not rejected by the recipient. The in vivo migratory pattern coincided with the altered expression of cell surface molecules of CD62L, CD103, CD134, and CD278, following donor-antigen stimulation. Elevated expression of CCR4 and CCL22 in allograft may also participate in recruiting Tregs for maintenance of VCA survival and promoting donor-specific tolerance. CONCLUSION Sorted Tregs induced donor-specific tolerance to VCA in rats. Live cell tracking demonstrated that activated CD4+CD25+FoxP3+ Tregs targeted primarily to the lymph nodes and VCA. The Tregs migrated to the secondary grafted donor skin and contributed to the maintenance of donor-specific tolerance. These behaviors were associated with phenotypic changes induced by donor antigen stimulation. Increased expression of CCR4 and CCL22 in VCA skin may also be relevant.
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Affiliation(s)
- Hui-Yun Cheng
- Center for Vascularized Composite Allotransplantation, Linkou Chang Gung Memorial Hospital, Gueishan, Taoyuan, Taiwan
| | - Sheri K. L. Tay
- Department of Plastic and Reconstructive Surgery, Linkou Chang Gung Memorial Hospital, Gueishan, Taoyuan, Taiwan
- Canniesburn Plastic Surgery Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom
| | - Chih-Jen Wen
- Center for Vascularized Composite Allotransplantation, Linkou Chang Gung Memorial Hospital, Gueishan, Taoyuan, Taiwan
| | - Chih-Fan Lin
- Center for Vascularized Composite Allotransplantation, Linkou Chang Gung Memorial Hospital, Gueishan, Taoyuan, Taiwan
| | - Aline Yen-Ling Wang
- Center for Vascularized Composite Allotransplantation, Linkou Chang Gung Memorial Hospital, Gueishan, Taoyuan, Taiwan
| | - Ling-Yi Shih
- Department of Plastic and Reconstructive Surgery, Linkou Chang Gung Memorial Hospital, Gueishan, Taoyuan, Taiwan
| | - Shiao-Chin Liu
- Department of Plastic and Reconstructive Surgery, Linkou Chang Gung Memorial Hospital, Gueishan, Taoyuan, Taiwan
| | - Eiji Kobayashi
- Department of Organ Fabrication, Keio University School of Medicine, Tokyo, Japan
| | - Cheng-Hung Lin
- Center for Vascularized Composite Allotransplantation, Linkou Chang Gung Memorial Hospital, Gueishan, Taoyuan, Taiwan
- Department of Plastic and Reconstructive Surgery, Linkou Chang Gung Memorial Hospital, Gueishan, Taoyuan, Taiwan
| | - Fu-Chan Wei
- Center for Vascularized Composite Allotransplantation, Linkou Chang Gung Memorial Hospital, Gueishan, Taoyuan, Taiwan
- Department of Plastic and Reconstructive Surgery, Linkou Chang Gung Memorial Hospital, Gueishan, Taoyuan, Taiwan
- School of Medicine, Chang Gung University, Gueishan, Taoyuan, Taiwan
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15
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Enhanced Drug Delivery to the Skin Using Liposomes. PLASTIC AND RECONSTRUCTIVE SURGERY-GLOBAL OPEN 2018; 6:e1739. [PMID: 30175003 PMCID: PMC6110675 DOI: 10.1097/gox.0000000000001739] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Accepted: 02/07/2018] [Indexed: 12/02/2022]
Abstract
Background: Enhancing drug delivery to the skin has importance in many therapeutic strategies. In particular, the outcome in vascularized composite allotransplantation mainly depends on systemic immunosuppression to prevent and treat episodes of transplant rejection. However, the side effects of systemic immunosuppression may introduce substantial risk to the patient and are weighed against the expected benefits. Successful enhancement of delivery of immunosuppressive agents to the most immunogenic tissues would allow for a reduction in systemic doses, thereby minimizing side effects. Nanoparticle-assisted transport by low temperature–sensitive liposomes (LTSLs) has shown some benefit in anticancer therapy. Our goal was to test whether delivery of a marker agent to the skin could be selectively enhanced. Methods: In an in vivo model, LTSLs containing doxorubicin (dox) as a marker were administered intravenously to rats that were exposed locally to mild hyperthermia. Skin samples of the hyperthermia treated hind limb were compared with skin of the contralateral normothermia hind limb. Tissue content of dox was quantified both via high-performance liquid chromatography and via histology in skin and liver. Results: The concentration of dox in hyperthermia-treated skin was significantly elevated over both normothermic skin and liver. (P < 0.02). Conclusions: We show here that delivery of therapeutics to the skin can be targeted and enhanced using LTSLs. Targeting drug delivery with this method may reduce the systemic toxicity seen in a systemic free-drug administration. Development of more hydrophilic immunosuppressants in the future would increase the applicability of this system in the treatment of rejection reactions in vascularized composite allotransplantation. The treatment of other skin condition might be another potential application.
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16
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Iglesias M, Ramírez-Berumen M, Butrón P, Alberú-Gómez J, Salazar-Hernández F, Macias-Gallardo J, Leal-Villalpando RP, Zamudio-Bautista J, Acosta V, Jauregui L, Hernández-Campos A, Espinosa-Cruz V, Vázquez-Lamadrid J, González-Sánchez J, Cuellar-Rodriguez J, Sierra-Madero JG, Gaytan-Cervantes R, Contreras-Barbosa S, Navarro-Lara A, Guzman-Gonzalez J, Domínguez-Cherit J, Vilatoba M, Toussaint-Caire S, Vega-Boada F, Gómez-Pérez FJ, Mayorquin-Ruiz M. Functional Outcomes 18 Months After Total and Midarm Transplantation: A Case Report. Transplant Proc 2018; 50:950-958. [PMID: 29555246 DOI: 10.1016/j.transproceed.2017.12.027] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Revised: 11/22/2017] [Accepted: 12/12/2017] [Indexed: 10/17/2022]
Abstract
BACKGROUND The function reported after arm transplantation is deemed beneficial relative to the marked disability that upper arm amputation causes. OBJECTIVE We report a 51-year-old man with a Disabilities of the Arm, Shoulder and Hand (DASH) score of 75.83 who underwent bilateral arm transplantation in October 2015. PROCEDURE The right arm was transplanted at the glenohumeral joint level, including transplantation of the humeral head, joint capsule, and rotator cuff ligaments and tendons. Additionally, neurorrhaphies were performed at the origin of the terminal branches of the brachial plexus, including the axillary and musculocutaneous nerves. Therefore, this was considered a total arm transplantation. The left arm was transplanted at the transhumeral level, with complete transplantation of the biceps and triceps brachii, and terminolateral neurorrhaphy of the donor musculocutaneous nerve to the receptor radial nerve. A maintenance triple immunosuppression scheme was administered, with tacrolimus levels kept at 10 ng/mL. RESULTS At 18 months post-transplantation, the intrinsic musculature in the left hand showed electrical registry, DASH score was 67.5, Carroll test score was 28 in both extremities, Hand Transplant Score System was 67.5 in the right extremity and 77.5 in the left extremity, and Short Form-36 score was 96.1. The patient was healthy, with restored body integrity. He could lift medium-sized weightless objects, eat and go to the bathroom by himself, drink liquids with bimanual grasp, swim, dress almost independently, and drive. CONCLUSION The functional evolution of the patient was similar to previously reported transplanted arms, even though the right arm transplant involved the glenohumeral joint and axillary and musculocutaneous nerve repair.
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Affiliation(s)
- M Iglesias
- Plastic Surgery Service, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México.
| | - M Ramírez-Berumen
- Plastic Surgery Service, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México
| | - P Butrón
- Plastic Surgery Service, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México
| | - J Alberú-Gómez
- Transplant Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México
| | - F Salazar-Hernández
- Plastic Surgery Service, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México
| | - J Macias-Gallardo
- Laboratory of Clinical Neurophysiology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México
| | - R P Leal-Villalpando
- Anesthesiology Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México
| | - J Zamudio-Bautista
- Anesthesiology Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México
| | - V Acosta
- Anesthesiology Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México
| | - L Jauregui
- Anesthesiology Department, Hospital Gea Gonzalez, Secretaria de Salud, Ciudad de México, México
| | - A Hernández-Campos
- Plastic Surgery Service, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México
| | - V Espinosa-Cruz
- Radiology and Imaging Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México
| | - J Vázquez-Lamadrid
- Radiology and Imaging Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México
| | - J González-Sánchez
- Psychiatry Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México
| | - J Cuellar-Rodriguez
- Infectology Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México
| | - J G Sierra-Madero
- Infectology Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México
| | - R Gaytan-Cervantes
- Rehabilitation Service, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México
| | - S Contreras-Barbosa
- Rehabilitation Service, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México
| | - A Navarro-Lara
- Rehabilitation Service, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México
| | | | - J Domínguez-Cherit
- Dermatology Department, Instituto Nacional de Ciencias Médicas y Nutrición, México City, México
| | - M Vilatoba
- Transplant Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México
| | - S Toussaint-Caire
- Dermatology Department, Hospital Gea Gonzalez, Secretaria de Salud, Ciudad de México, México
| | - F Vega-Boada
- Neurology Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México
| | - F J Gómez-Pérez
- Endocrinology Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, México
| | - M Mayorquin-Ruiz
- Ocular Ultrasound Service, Asociación para Evitar la Ceguera en México, IAP, Ciudad de México, México
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17
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Huchon L, Badet L, Roy AC, Finos L, Gazarian A, Revol P, Bernardon L, Rossetti Y, Morelon E, Rode G, Farnè A. Grasping objects by former amputees: The visuo-motor control of allografted hands. Restor Neurol Neurosci 2018; 34:615-33. [PMID: 26890093 DOI: 10.3233/rnn-150502] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
PURPOSE Hand allograft has recently emerged as a therapeutic option for upper limb amputees. Functional neuroimaging studies have progressively revealed sensorimotor cortices plasticity following both amputation and transplantation. The purpose of our study was to assess and characterize the functional recovery of the visuo-motor control of prehension in bilateral hand transplanted patients. METHODS Using kinematics recordings, we characterized the performance of prehension with or without visual feed-back for object of different position and size, in five bilateral hand allograft recipients and age-matched control subjects. Both hands were assessed, separately. RESULTS Despite an overall slower execution, allografted patients succeeded in grasping for more than 90% of the trials. They exhibited a preserved hand grip scaling according to object size, and preserved prehension performances when tested without visual feedback. These findings highlight the allograft recipients' abilities to produce an effective motor program, and a good proprioceptive-dependent online control. Nevertheless, the maximum grip aperture was reduced and delayed, the coupling between Transport and Grasp components was altered, and the final phase of the movement was lengthened. CONCLUSION Hand allotransplantation can offer recipients a good recovery of the visuo-motor control of prehension, with slight impairments likely attributable to peripheral neuro-orthopedic limitations.
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Affiliation(s)
- Laure Huchon
- ImpAct Team, INSERM U1028, CNRS UMR5292, Lyon Neuroscience Research Center, Lyon, France.,Physical and Rehabilitation Medicine Department, Mouvement Handicap, Henry Gabrielle Hospital, Hospices Civils de Lyon, Lyon, France.,Claude Bernard Lyon 1 University, Lyon, France
| | - Lionel Badet
- Claude Bernard Lyon 1 University, Lyon, France.,Transplantation Surgery Department, Edouart Herriot Hospital, Hospices Civils de Lyon, Lyon, France
| | | | - Livio Finos
- Department of Statistical Sciences, University of Padova, Padova, Italy
| | - Aram Gazarian
- Orthopaedic Surgery Department, Clinique du Parc Lyon, Lyon, France
| | - Patrice Revol
- ImpAct Team, INSERM U1028, CNRS UMR5292, Lyon Neuroscience Research Center, Lyon, France.,Physical and Rehabilitation Medicine Department, Mouvement Handicap, Henry Gabrielle Hospital, Hospices Civils de Lyon, Lyon, France.,Claude Bernard Lyon 1 University, Lyon, France
| | | | - Yves Rossetti
- ImpAct Team, INSERM U1028, CNRS UMR5292, Lyon Neuroscience Research Center, Lyon, France.,Physical and Rehabilitation Medicine Department, Mouvement Handicap, Henry Gabrielle Hospital, Hospices Civils de Lyon, Lyon, France.,Claude Bernard Lyon 1 University, Lyon, France
| | - Emmanuel Morelon
- Claude Bernard Lyon 1 University, Lyon, France.,Nephrology and Immunology Department, Edouart Herriot Hospital, Hospices Civils de Lyon, Lyon, France
| | - Gilles Rode
- ImpAct Team, INSERM U1028, CNRS UMR5292, Lyon Neuroscience Research Center, Lyon, France.,Physical and Rehabilitation Medicine Department, Mouvement Handicap, Henry Gabrielle Hospital, Hospices Civils de Lyon, Lyon, France.,Claude Bernard Lyon 1 University, Lyon, France
| | - Alessandro Farnè
- ImpAct Team, INSERM U1028, CNRS UMR5292, Lyon Neuroscience Research Center, Lyon, France.,Claude Bernard Lyon 1 University, Lyon, France
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18
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Inhibition of Lymphatic Drainage With a Self-Designed Surgical Approach Prolongs the Vascularized Skin Allograft Survival in Rats. Ann Plast Surg 2018; 80:76-82. [DOI: 10.1097/sap.0000000000001210] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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19
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Friedman O, Carmel N, Sela M, Abu Jabal A, Inbal A, Ben Hamou M, Krelin Y, Gur E, Shani N. Immunological and inflammatory mapping of vascularized composite allograft rejection processes in a rat model. PLoS One 2017; 12:e0181507. [PMID: 28746417 PMCID: PMC5528841 DOI: 10.1371/journal.pone.0181507] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Accepted: 07/03/2017] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Hand and face vascularized composite allotransplantation (VCA) is an evolving and challenging field with great opportunities. During VCA, massive surgical damage is inflicted on both donor and recipient tissues, which may contribute to the high VCA rejection rates. To segregate between the damage-induced and rejection phase of post-VCA responses, we compared responses occurring up to 5 days following syngeneic versus allogeneic vascularized groin flap transplantations, culminating in transplant acceptance or rejection, respectively. METHODS The immune response elicited upon transplantation of a syngeneic versus allogeneic vascularized groin flap was compared at Post-operative days 2 or 5 by histology, immunohistochemistry and by broad-scope gene and protein analyses using quantitative real-time PCR and Multiplex respectively. RESULTS Immune cell infiltration began at the donor-recipient interface and paralleled expression of a large group of wound healing-associated genes in both allografts and syngrafts. By day 5 post-transplantation, cell infiltration spread over the entire allograft but remained confined to the wound site in the syngraft. This shift correlated with upregulation of IL-18, INFg, CXCL9, 10 and 11, CCL2, CCL5, CX3CL1 and IL-10 in the allograft only, suggesting their role in the induction of the anti-alloantigen adaptive immune response. CONCLUSIONS High resemblance between the cues governing VCA and solid organ rejection was observed. Despite this high resemblance we describe also, for the first time, a damage induced inflammatory component in VCA rejection as immune cell infiltration into the graft initiated at the surgical damage site spreading to the entire allograft only at late stage rejection. We speculate that the highly inflammatory setting created by the unique surgical damage during VCA may enhance acute allograft rejection.
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Affiliation(s)
- Or Friedman
- The Plastic Reconstructive Surgery Department, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Narin Carmel
- The Plastic Reconstructive Surgery Department, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Meirav Sela
- The Plastic Reconstructive Surgery Department, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ameen Abu Jabal
- The Plastic Reconstructive Surgery Department, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Amir Inbal
- The Plastic Reconstructive Surgery Department, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Moshe Ben Hamou
- The Plastic Reconstructive Surgery Department, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Yakov Krelin
- The Plastic Reconstructive Surgery Department, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Eyal Gur
- The Plastic Reconstructive Surgery Department, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Nir Shani
- The Plastic Reconstructive Surgery Department, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- * E-mail:
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20
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Shanmugarajah K, Powell H, Leonard DA, Mallard C, Albritton A, Harrington E, Randolph MA, Farkash E, Sachs DH, Kurtz JM, Cetrulo CL. The Effect of MHC Antigen Matching Between Donors and Recipients on Skin Tolerance of Vascularized Composite Allografts. Am J Transplant 2017; 17:1729-1741. [PMID: 28035752 DOI: 10.1111/ajt.14189] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2016] [Revised: 12/16/2016] [Accepted: 12/22/2016] [Indexed: 01/25/2023]
Abstract
The emergence of skin-containing vascularized composite allografts (VCAs) has provided impetus to understand factors affecting rejection and tolerance of skin. VCA tolerance can be established in miniature swine across haploidentical MHC barriers using mixed chimerism. Because the deceased donor pool for VCAs does not permit MHC antigen matching, clinical VCAs are transplanted across varying MHC disparities. We investigated whether sharing of MHC class I or II antigens between donors and recipients influences VCA skin tolerance. Miniature swine were conditioned nonmyeloablatively and received hematopoietic stem cell transplants and VCAs across MHC class I (n = 3) or class II (n = 3) barriers. In vitro immune responsiveness was assessed, and VCA skin-resident leukocytes were characterized by flow cytometry. Stable mixed chimerism was established in all animals. MHC class II-mismatched chimeras were tolerant of VCAs. MHC class I-mismatched animals, however, rejected VCA skin, characterized by infiltration of recipient-type CD8+ lymphocytes. Systemic donor-specific nonresponsiveness was maintained, including after VCA rejection. This study shows that MHC antigen matching influences VCA skin rejection and suggests that local regulation of immune tolerance is critical in long-term acceptance of all VCA components. These results help elucidate novel mechanisms underlying skin tolerance and identify clinically relevant VCA tolerance strategies.
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Affiliation(s)
- K Shanmugarajah
- Transplantation Biology Research Center, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA.,Department of Plastic Surgery, Massachusetts General Hospital, Boston, MA
| | - H Powell
- Transplantation Biology Research Center, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA
| | - D A Leonard
- Transplantation Biology Research Center, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA.,Department of Plastic Surgery, Massachusetts General Hospital, Boston, MA
| | - C Mallard
- Transplantation Biology Research Center, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA
| | - A Albritton
- Transplantation Biology Research Center, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA
| | - E Harrington
- Transplantation Biology Research Center, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA
| | - M A Randolph
- Department of Plastic Surgery, Massachusetts General Hospital, Boston, MA
| | - E Farkash
- Transplantation Biology Research Center, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA
| | - D H Sachs
- Transplantation Biology Research Center, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA
| | - J M Kurtz
- Transplantation Biology Research Center, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA.,Department of Biology, Emmanuel College, Boston, MA
| | - C L Cetrulo
- Transplantation Biology Research Center, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA.,Department of Plastic Surgery, Massachusetts General Hospital, Boston, MA
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Özkan Ö, Özkan Ö, Doğan U, Yılmaz VT, Uysal H, Ündar L, Doğan EA, Salim O, Çinpolat A, Ramazanoglu A. Consideration of difficulties and exit strategies in a case of face allotransplantation resulting in failure. Microsurgery 2017; 37:661-668. [DOI: 10.1002/micr.30137] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2015] [Revised: 11/14/2016] [Accepted: 11/23/2016] [Indexed: 12/19/2022]
Affiliation(s)
- Özlenen Özkan
- Department of Plastic and Reconstructive Surgery; Akdeniz University Faculty of Medicine; Antalya Turkey
| | - Ömer Özkan
- Department of Plastic and Reconstructive Surgery; Akdeniz University Faculty of Medicine; Antalya Turkey
| | - Umuttan Doğan
- Department of Cardiology; Akdeniz University Faculty of Medicine; Antalya Turkey
| | - Vural Taner Yılmaz
- Department of Nephrology; Akdeniz University Faculty of Medicine; Antalya Turkey
| | - Hilmi Uysal
- Department of Neurology; Akdeniz University Faculty of Medicine; Antalya Turkey
| | - Levent Ündar
- Department of Hematology; Akdeniz University Faculty of Medicine; Antalya Turkey
| | - Ebru Apaydın Doğan
- Department of Neurology; Akdeniz University Faculty of Medicine; Antalya Turkey
| | - Ozan Salim
- Department of Hematology; Akdeniz University Faculty of Medicine; Antalya Turkey
| | - Anı Çinpolat
- Department of Plastic and Reconstructive Surgery; Akdeniz University Faculty of Medicine; Antalya Turkey
| | - Atilla Ramazanoglu
- Department of Anaesthesiology and Reanimation; Akdeniz University Faculty of Medicine; Antalya Turkey
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Shores JT, Malek V, Lee WPA, Brandacher G. Outcomes after hand and upper extremity transplantation. JOURNAL OF MATERIALS SCIENCE. MATERIALS IN MEDICINE 2017; 28:72. [PMID: 28361279 DOI: 10.1007/s10856-017-5880-0] [Citation(s) in RCA: 89] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Accepted: 03/06/2017] [Indexed: 06/07/2023]
Abstract
Hand and upper extremity transplantation (HUET) has emerged as the most frequently performed reconstructive procedure in the burgeoning field of vascularized composite allotransplantation (VCA). VCA refers to a form of transplant with multiple tissue types that represents a viable treatment option for devastating injuries where conventional reconstruction would be unable to restore form and function. As hand transplantation becomes increasingly more common, discussions on advantages and disadvantages of the procedure seem to intensify. Despite encouraging functional outcomes, current immunosuppressive regimens with their deleterious side-effect profile remain a major concern for a life-changing but not life-saving type of transplant. In addition, a growing number of recipients with progressively longer follow-up prompt the need to investigate potential long-term sequelae, such as chronic rejection. This review will discuss the current state of HUET, summarizing outcome data on graft survival, motor and sensory function, as well as immunosuppressive treatment. The implications of these findings for VCA in terms of achievements and challenges ahead will then be discussed.
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Affiliation(s)
- Jaimie T Shores
- Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Veronika Malek
- Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Ruprecht-Karls University Heidelberg Medical Faculty, Heidelberg, Germany
| | - W P Andrew Lee
- Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Gerald Brandacher
- Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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23
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Gacto-Sanchez P. Surgical treatment and management of the severely burn patient: Review and update. Med Intensiva 2017; 41:356-364. [PMID: 28456441 DOI: 10.1016/j.medin.2017.02.008] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2016] [Revised: 02/08/2017] [Accepted: 02/18/2017] [Indexed: 01/20/2023]
Abstract
Since one of the main challenges in treating acute burn injuries is preventing infection, early excising of the eschar and covering of the wound becomes critical. Non-viable tissue is removed by initial aggressive surgical debridement. Many surgical options for covering the wound bed have been described, although split-thickness skin grafts remain the standard for the rapid and permanent closure of full-thickness burns. Significant advances made in the past decades have greatly improved burns patient care, as such that major future improvements in survival rates seem to be more difficult. Research into stem cells, grafting, biomarkers, inflammation control, and rehabilitation will continue to improve individualized care and create new treatment options for these patients.
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Affiliation(s)
- P Gacto-Sanchez
- Plastic Surgeon, Plastic and Reconstructive Department, Burns Unit, Virgen del Rocio University Hospital, Sevilla, Spain.
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24
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Salminger S, Sturma A, Roche AD, Hruby LA, Paternostro-Sluga T, Kumnig M, Ninkovic M, Pierer G, Schneeberger S, Gabl M, Chelmonski A, Jablecki J, Aszmann OC. Functional and Psychosocial Outcomes of Hand Transplantation Compared with Prosthetic Fitting in Below-Elbow Amputees: A Multicenter Cohort Study. PLoS One 2016; 11:e0162507. [PMID: 27589057 PMCID: PMC5010226 DOI: 10.1371/journal.pone.0162507] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Accepted: 08/01/2016] [Indexed: 01/10/2023] Open
Abstract
Background Hand-transplantation and improvements in the field of prostheses opened new frontiers in restoring hand function in below-elbow amputees. Both concepts aim at restoring reliable hand function, however, the indications, advantages and limitations for each treatment must be carefully considered depending on level and extent of amputation. Here we report our findings of a multi-center cohort study comparing hand function and quality-of-life of people with transplanted versus prosthetic hands. Methods Hand function in amputees with either transplant or prostheses was tested with Action Research Arm Test (ARAT), Southampton Hand Assessment Procedure (SHAP) and the Disabilities of the Arm, Shoulder and Hand measure (DASH). Quality-of-life was compared with the Short-Form 36 (SF-36). Results Transplanted patients (n = 5) achieved a mean ARAT score of 40.86 ± 8.07 and an average SHAP score of 75.00 ± 11.06. Prosthetic patients (n = 7) achieved a mean ARAT score of 39.00 ± 3.61 and an average SHAP score of 75.43 ± 10.81. There was no significant difference between transplanted and prosthetic hands in ARAT, SHAP or DASH. While quality-of-life metrics were equivocal for four scales of the SF-36, transplanted patients reported significantly higher scores in “role-physical” (p = 0.006), “vitality” (p = 0.008), “role-emotional” (p = 0.035) and “mental-health” (p = 0.003). Conclusions The indications for hand transplantation or prosthetic fitting in below-elbow amputees require careful consideration. As functional outcomes were not significantly different between groups, patient’s best interests and the route of least harm should guide treatment. Due to the immunosuppressive side-effects, the indication for allotransplantation must still be restrictive, the best being bilateral amputees.
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Affiliation(s)
- Stefan Salminger
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria
- Christian Doppler Laboratory for Restoration of Extremity Function, Division of Plastic and Reconstructive Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - Agnes Sturma
- Christian Doppler Laboratory for Restoration of Extremity Function, Division of Plastic and Reconstructive Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria
- Department of Physical Medicine and Rehabilitation, Medical University of Vienna, Vienna, Austria
| | - Aidan D. Roche
- Christian Doppler Laboratory for Restoration of Extremity Function, Division of Plastic and Reconstructive Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria
| | - Laura A. Hruby
- Christian Doppler Laboratory for Restoration of Extremity Function, Division of Plastic and Reconstructive Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria
- Department of Physical Medicine and Rehabilitation, Medical University of Vienna, Vienna, Austria
| | - Tatjana Paternostro-Sluga
- Department of Physical Medicine and Rehabilitation, Medical University of Vienna, Vienna, Austria
- Department of Physical Medicine and Rehabilitation, Danube Hospital Vienna, Vienna, Austria
| | - Martin Kumnig
- Center for Advanced Psychology in Plastic and Transplant Surgery, Department of Medical Psychology, Medical University of Innsbruck, Innsbruck, Austria
| | - Marina Ninkovic
- Department of Physical Medicine and Rehabilitation, Medical University of Innsbruck, Innsbruck, Austria
| | - Gerhard Pierer
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Stefan Schneeberger
- Departments of General and Transplant Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Markus Gabl
- Department of Traumatology, Medical University of Innsbruck, Innsbruck, Austria
| | - Adam Chelmonski
- Hand Trauma Center, St. Hedwigs’s Hospital, Trzebnica, Subdepartment of Replantation of Limbs, Trzebnica, Poland
| | - Jerzy Jablecki
- Hand Trauma Center, St. Hedwigs’s Hospital, Trzebnica, Subdepartment of Replantation of Limbs, Trzebnica, Poland
- State Higher Medical Professional School, Opole, Poland
| | - Oskar C. Aszmann
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria
- Christian Doppler Laboratory for Restoration of Extremity Function, Division of Plastic and Reconstructive Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria
- * E-mail:
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Kumnig M, Jowsey-Gregoire SG. Key psychosocial challenges in vascularized composite allotransplantation. World J Transplant 2016; 6:91-102. [PMID: 27011907 PMCID: PMC4801807 DOI: 10.5500/wjt.v6.i1.91] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2015] [Revised: 12/16/2015] [Accepted: 01/08/2016] [Indexed: 02/05/2023] Open
Abstract
Psychosocial factors are important elements in the assessment and follow-up care for vascularized composite allotransplantation (VCA) and require multidisciplinary evaluation protocols. This review will highlight differences between VCA with solid organ transplantation (SOT), provide information on the psychosocial selection of VCA candidates, ethical issues, psychological outcomes, and on the need for multicenter research. VCA is primarily a life-enhancing procedure to improve recipients' quality of life and psychological well-being and it represents a potential option to provide reproduction in case of penile or uterine transplantation. The risk benefit ratio is distinctly different than SOT with candidates desiring life enhancing outcomes including improved body image, return to occupations, restored touch, and for uterine transplant, pregnancy. The Chauvet Workgroup has been convened with membership from a number of transplant centers to address these issues and to call for multicenter research. A multicenter research network would share similar evaluation approaches so that meaningful research on psychosocial variables could inform the transplant community and patients about factors that increase risk of non-adherence and other adverse psychosocial and medical outcomes.
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Immunopathology of rejection: do the rules of solid organ apply to vascularized composite allotransplantation? Curr Opin Organ Transplant 2016; 20:596-601. [PMID: 26536419 DOI: 10.1097/mot.0000000000000242] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
PURPOSE OF REVIEW As both the number of vascularized composite allotransplants (VCAs) recipients and the duration of their follow-up are limited, immunopathology of VCA rejection remains incompletely understood. VCAs have several immunological peculiarities, which make inaccurate a direct extrapolation of all rules established for solid organs. RECENT FINDINGS Despite their bone marrow content, VCA do not induce chimerism in recipient and are therefore not spontaneously tolerated. Skin compartment of VCA contains a high density of antigen-presenting cells (APCs), some with self-renewal capacity. Donor APCs are responsible for continuous direct allosensitization of recipient's T cells that explains the high incidence of skin T-cell-mediated rejection and their occurrence beyond 1 year.Regenerative capability of the skin prevents the development of chronic rejection of this compartment as long as immunosuppression is maintained. In contrast, VCA can develop graft arteriosclerosis, which could be because of T cell and/or chronic antibody-mediated rejection (AMR). VCA recipients can indeed develop donor-specific antibodies (DSA). Whether DSA can also trigger acute AMR of VCA remains to be clarified. SUMMARY A better understanding of the specificities of the immunopathology of VCA rejection should pave the way for the rationalization of immunosuppressive strategies aiming at optimizing long-term outcome.
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Chuback J, Yarascavitch B, Yarascavitch A, Kaur MN, Martin S, Thoma A. Measuring utilities of severe facial disfigurement and composite tissue allotransplantation of the face in patients with severe face and neck burns from the perspectives of the general public, medical experts and patients. Burns 2015; 41:1524-31. [DOI: 10.1016/j.burns.2015.05.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2014] [Revised: 04/21/2015] [Accepted: 05/12/2015] [Indexed: 12/22/2022]
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Freitas AM, Samy KP, Farris AB, Leopardi FV, Song M, Stempora L, Strobert EA, Jenkins JA, Kirk AD, Cendales LC. Studies Introducing Costimulation Blockade for Vascularized Composite Allografts in Nonhuman Primates. Am J Transplant 2015; 15:2240-9. [PMID: 26139552 PMCID: PMC4918096 DOI: 10.1111/ajt.13379] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2014] [Revised: 04/28/2015] [Accepted: 05/04/2015] [Indexed: 01/25/2023]
Abstract
Vascularized composite allografts (VCAs) are technically feasible. Similar to other organ transplants, VCAs are hampered by the toxicity and incomplete efficacy associated with conventional immunosuppression. Complications attributable to calcineurin inhibitors remain prevalent in the clinical cases reported to date, and these loom particularly large given the nonlifesaving nature of VCAs. Additionally, acute rejection remains almost ubiquitous, albeit controllable with current agents. Costimulation blockade offers the potential to provide prophylaxis from rejection without the adverse consequences of calcineurin-based regimens. In this study, we used a nonhuman-primate model of VCA in conjunction with immunosuppressive regimens containing combinations of B7-specific costimulation blockade with and without adhesion blockade with LFA3-Ig to determine what adjunctive role these agents could play in VCA transplantation when combined with more conventional agents. Compared to tacrolimus, the addition of belatacept improved rejection free allograft survival. The combination with LFA3-Ig reduced CD2(hi) memory T cells, however did not provide additional protection against allograft rejection and hindered protective immunity. Histology paralleled clinical histopathology and Banff grading. These data provide the basis for the study of costimulation blockade in VCA in a relevant preclinical model.
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Affiliation(s)
- AM Freitas
- Emory Transplant Center, Emory University School of Medicine, 101 Woodruff Circle, Atlanta, GA 30322
| | - KP Samy
- Department of Surgery, Duke University Medical Center, 200 Trent Drive, Baker House #129, DUMC 3098, Durham, NC 27710
| | - AB Farris
- Department of Pathology & Laboratory Medicine, Emory University, 1364 Clifton Road NE, Atlanta, GA 30322
| | - FV Leopardi
- Department of Surgery, Duke University Medical Center, 200 Trent Drive, Baker House #129, DUMC 3098, Durham, NC 27710
| | - M Song
- Department of Surgery, Duke University Medical Center, 200 Trent Drive, Baker House #129, DUMC 3098, Durham, NC 27710
| | - L Stempora
- Department of Surgery, Duke University Medical Center, 200 Trent Drive, Baker House #129, DUMC 3098, Durham, NC 27710
| | - EA Strobert
- Yerkes National Primate Research Center, 954 Gatewood Road NE, Atlanta, GA 30329
| | - JA Jenkins
- Yerkes National Primate Research Center, 954 Gatewood Road NE, Atlanta, GA 30329
| | - AD Kirk
- Emory Transplant Center, Emory University School of Medicine, 101 Woodruff Circle, Atlanta, GA 30322
,Department of Surgery, Duke University Medical Center, 200 Trent Drive, Baker House #129, DUMC 3098, Durham, NC 27710
| | - LC Cendales
- Department of Surgery, Duke University Medical Center, 200 Trent Drive, Baker House #129, DUMC 3098, Durham, NC 27710
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Jank BJ, Xiong L, Moser PT, Guyette JP, Ren X, Cetrulo CL, Leonard DA, Fernandez L, Fagan SP, Ott HC. Engineered composite tissue as a bioartificial limb graft. Biomaterials 2015; 61:246-56. [PMID: 26004237 DOI: 10.1016/j.biomaterials.2015.04.051] [Citation(s) in RCA: 86] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2015] [Revised: 04/22/2015] [Accepted: 04/30/2015] [Indexed: 12/18/2022]
Abstract
The loss of an extremity is a disastrous injury with tremendous impact on a patient's life. Current mechanical prostheses are technically highly sophisticated, but only partially replace physiologic function and aesthetic appearance. As a biologic alternative, approximately 70 patients have undergone allogeneic hand transplantation to date worldwide. While outcomes are favorable, risks and side effects of transplantation and long-term immunosuppression pose a significant ethical dilemma. An autologous, bio-artificial graft based on native extracellular matrix and patient derived cells could be produced on demand and would not require immunosuppression after transplantation. To create such a graft, we decellularized rat and primate forearms by detergent perfusion and yielded acellular scaffolds with preserved composite architecture. We then repopulated muscle and vasculature with cells of appropriate phenotypes, and matured the composite tissue in a perfusion bioreactor under electrical stimulation in vitro. After confirmation of composite tissue formation, we transplanted the resulting bio-composite grafts to confirm perfusion in vivo.
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Affiliation(s)
- Bernhard J Jank
- Center for Regenerative Medicine, Massachusetts General Hospital, USA; Harvard Medical School, Boston, MA, USA
| | - Linjie Xiong
- Center for Regenerative Medicine, Massachusetts General Hospital, USA
| | - Philipp T Moser
- Center for Regenerative Medicine, Massachusetts General Hospital, USA; Harvard Medical School, Boston, MA, USA
| | - Jacques P Guyette
- Center for Regenerative Medicine, Massachusetts General Hospital, USA; Harvard Medical School, Boston, MA, USA
| | - Xi Ren
- Center for Regenerative Medicine, Massachusetts General Hospital, USA; Harvard Medical School, Boston, MA, USA
| | - Curtis L Cetrulo
- Harvard Medical School, Boston, MA, USA; Transplantation Biology Research Center, Department of Surgery, Massachusetts General Hospital, USA
| | - David A Leonard
- Harvard Medical School, Boston, MA, USA; Transplantation Biology Research Center, Department of Surgery, Massachusetts General Hospital, USA
| | | | - Shawn P Fagan
- Massachusetts General Hospital, Division of Burn Surgery, Harvard Medical School, USA
| | - Harald C Ott
- Division of Thoracic Surgery, Department of Surgery, Massachusetts General Hospital, USA; Harvard Medical School, Boston, MA, USA.
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Leto Barone AA, Kurtz JM, Albritton A, Mallard CA, Shanmugarajah K, Torabi R, Leonard DA, Randolph MA, Huang CA, Sachs DH, Cetrulo CL. Effects of Transient Donor Chimerism on Rejection of MHC-Mismatched Vascularized Composite Allografts in Swine. ACTA ACUST UNITED AC 2015. [DOI: 10.1080/23723505.2015.1039692] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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Abstract
PURPOSE OF REVIEW Vascularized composite tissue allografts (CTAs) provide excellent restorative options for patients with limb loss and other deformities. Acute rejection remains common with CTA and immunosuppression is used in an attempt to prevent rejection. This has created ethical debates regarding the use of intensive immunosuppression for a nonlife-saving procedure. This highlights the need for newer immunosuppressive strategies for CTA, which are described in this review. RECENT FINDINGS Recent studies have looked into immunomodulation and tolerance to decrease toxicity of immunosuppression. Both strategies have had some success but have their own limitations. Although immunomodulation and decrease in immunosuppression decreases toxicity, it has been associated with higher rates of rejection. Induction of tolerance has achieved some initial success, but the initial conditioning regimens are associated with significant morbidity. SUMMARY Although recent advancements have been made in the immunosuppressive strategies in CTA, the ideal immunosuppression strategy with low toxicity and infection risk but with the ability to prevent acute and chronic rejection is yet to be discovered.
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The unique immunobiology of the skin: implications for tolerance of vascularized composite allografts. Curr Opin Organ Transplant 2015; 19:566-72. [PMID: 25333830 DOI: 10.1097/mot.0000000000000136] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
PURPOSE OF REVIEW Vascularized composite allograft (VCA) transplantation restores function and form following major soft tissue and musculoskeletal injury. Lifelong immunosuppression is necessary for graft function and survival but acute skin-targeted rejection episodes remain common. We review recent advances in skin immunobiology, emphasizing findings in clinical and experimental VCAs. We also highlight advances in immunotherapy and tolerance protocols with implications for the prevention of VCA rejection, and ultimately, induction of clinically applicable strategies for VCA tolerance. RECENT FINDINGS There is now an increasing appreciation for the role of skin-specific mechanisms, including lymphoid neogenesis, in VCA rejection. In contrast, expression of the regulatory master-switch FOXP3 was demonstrated to be significantly upregulated in the skin of tolerant VCAs in large animal models compared with normal skin and rejecting controls. SUMMARY Most VCA transplant centers continue to utilize antibody-mediated induction therapy and triple agent maintenance immunosuppression. Skin remains the primary target of rejection in VCAs, and current multicenter studies hope to elucidate the mechanisms involved. Proposed standardized procedures for skin biopsies, and diligent reporting of clinical data to the international registry, will be important to maximize the strength of these studies.
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Hand and upper extremity transplantation: an update of outcomes in the worldwide experience. Plast Reconstr Surg 2015; 135:351e-360e. [PMID: 25401735 DOI: 10.1097/prs.0000000000000892] [Citation(s) in RCA: 180] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Hand/upper extremity transplantation is the most common form of vascularized composite allotransplantation performed to date. An Update of worldwide outcomes is reported. METHODS The authors summarize the international experience with 107 known transplanted hand/upper extremities in 72 patients. Data from published medical literature, national and international meetings, lay press reports, and personal communications were utilized to provide the most up-to-date summary. RESULTS Although 24 losses (including four mortalities) are known, three of the four reported mortalities and eight of 24 limb losses were caused by multiple type vascularized composite allotransplantations (combined upper and lower limb or upper limb and face). Seven more losses were attributable to 15 patients in the early experience in China. In the United States and Western Europe, only three other non-acute graft losses have been reported, resulting in a patient survival rate for unilateral or bilateral hand transplantation in isolation of 98.5 percent and an overall graft survival rate of 83.1 percent. CONCLUSIONS Published functional outcomes continue to demonstrate improvement in function and quality of life. The international experience supports the idea that, for properly selected individuals, hand and upper extremity transplantation should be considered an important treatment option.
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Changing attitudes toward hand allotransplantation among North American hand surgeons. Ann Plast Surg 2014; 72 Suppl 1:S56-60. [PMID: 24740026 DOI: 10.1097/sap.0000000000000147] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
OBJECTIVES Although more than 70 hand transplants have been performed worldwide, the appropriate clinical indications for this operation are still being determined. Cost and patient exposure to the challenges of lifelong immunosuppression for what is a quality of life-improving (but not life-saving) operation are the focus of the ongoing discussion. A study performed in 2007 showed that surgeons' opinions on the issue varied widely. Recently, more information has been made available regarding long-term patient outcomes, and significant improvements in immunotherapy protocols have been reported. In light of this, we sought to examine changing attitudes regarding hand allotransplantation and its indications by surveying hand surgeons. METHODS An email-based survey was sent to members of the American Society for Surgery of the Hand. Demographic information and practice profiles were identified, followed by their risk assessment of hand allotransplants and endorsement of performing the operation in different clinical scenarios. Additional questions focused on the appropriate indications for hand allotransplantation, as well as the procedure's associated ethical and financial implications. RESULTS A total of 385 surgeons responded to the survey (14% response rate). The majority (82%) considered hand transplantation to be a high-risk operation (as opposed to 27% in hand replantation), with 78% citing lifelong immunosuppression as the primary factor impacting their overall risk assessment. The most commonly accepted indication for hand vascularized composite allotransplantation was loss of bilateral hands (80% in favor). Dominant hand loss (with an intact contralateral hand) was a far less frequently accepted indication (36% in favor). Patient adherence to immunosuppressive regimens (51%) and expectations of functional/aesthetic outcome (38%) were the most frequently chosen top psychosocial issues that must be addressed by the surgical/medical teams involved in the operation. CONCLUSIONS Our study's results demonstrate increasing overall support for hand allotransplantation and increasing acceptance of today's immunosuppressive regimens compared to prior literature. Bilateral hand loss remains the primary agreed-upon indication for transplantation. Despite increasing acceptance in the surgical community, the dangers of chronic immunosuppression, cost and patient adherence continue to be the primary concerns hindering its broader acceptance.
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Khalifian S, Brazio PS, Mohan R, Shaffer C, Brandacher G, Barth RN, Rodriguez ED. Facial transplantation: the first 9 years. Lancet 2014; 384:2153-63. [PMID: 24783986 DOI: 10.1016/s0140-6736(13)62632-x] [Citation(s) in RCA: 194] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Since the first facial transplantation in 2005, 28 have been done worldwide with encouraging immunological, functional, psychological, and aesthetic outcomes. Unlike solid organ transplantation, which is potentially life-saving, facial transplantation is life-changing. This difference has generated ethical concerns about the exposure of otherwise young and healthy individuals to the sequelae of lifelong, high-dose, multidrug immunosuppression. Nevertheless, advances in immunomodulatory and immunosuppressive protocols, microsurgical techniques, and computer-aided surgical planning have enabled broader clinical application of this procedure to patients. Although episodes of acute skin rejection continue to pose a serious threat to face transplant recipients, all cases have been controlled with conventional immunosuppressive regimens, and no cases of chronic rejection have been reported.
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Affiliation(s)
- Saami Khalifian
- Division of Plastic and Reconstructive Surgery, R Adams Cowley Shock Trauma Center, University of Maryland Medical Center, Baltimore, MD, USA; Department of Plastic and Reconstructive Surgery, Reconstructive Transplantation Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Philip S Brazio
- Division of Plastic and Reconstructive Surgery, R Adams Cowley Shock Trauma Center, University of Maryland Medical Center, Baltimore, MD, USA
| | - Raja Mohan
- Division of Plastic and Reconstructive Surgery, R Adams Cowley Shock Trauma Center, University of Maryland Medical Center, Baltimore, MD, USA
| | - Cynthia Shaffer
- Division of Plastic and Reconstructive Surgery, R Adams Cowley Shock Trauma Center, University of Maryland Medical Center, Baltimore, MD, USA
| | - Gerald Brandacher
- Department of Plastic and Reconstructive Surgery, Reconstructive Transplantation Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Rolf N Barth
- Division of Transplant Surgery, University of Maryland Medical Center, Baltimore, MD, USA
| | - Eduardo D Rodriguez
- Department of Plastic Surgery, Institute of Reconstructive Plastic Surgery, NYU Langone Medical Center, New York, NY, USA.
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Davis TA, Anam K, Lazdun Y, Gimble JM, Elster EA. Adipose-derived stromal cells promote allograft tolerance induction. Stem Cells Transl Med 2014; 3:1444-50. [PMID: 25411475 DOI: 10.5966/sctm.2014-0131] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Amputations and unsalvageable injuries with devastating tissue loss are common in the combat wounded. Reconstructive transplantation in the civilian setting using vascular composite allotransplants (VCAs) with multiple tissues (skin, muscle, nerve, bone) combined with long-term multidrug immunosuppression has been encouraging. However, skin rejection remains a critical complication. Adipose-derived stromal/stem cells (ASCs) are easily obtained from normal individuals in high numbers, precluding ex vivo expansion. The reparative function and paracrine immunomodulatory capacity of ASCs has gained considerable attention. The present study investigated whether ASCs facilitate long-term skin allograft survival. ASCs were isolated from fresh human subcutaneous adipose lipoaspirate. Full-thickness skin grafts from BALB/c mice were transplanted onto the dorsal flanks of C57BL/6 mice treated with five doses of anti-CD4/CD8 monoclonal antibodies (10 mg/kg) on days 0, +2, +5, +7, and +14 relative to skin grafting. A single nonmyeloablative low dose of busulfan (5 mg/kg) was given on day +5. Seven days after skin transplantation, ASCs (3×10(6)) were infused i.v. with or without donor bone marrow cells (BMCs; 5×10(5)). ASC+BMC coinfusion with minimal conditioning led to stable lymphoid and myeloid macrochimerism, deletion of alloreactive T cells, expansion of regulatory T cells, and long-term allograft survival (>200 days). ASCs constitutively produced high levels of anti-inflammatory/immunoregulatory factors such as prostaglandin E2, indoleamine 2,3-dioxygenase, APO-1/Fas (CD95), and programmed cell death-1 ligand-2. These findings serve as a foundation for developing a translational advanced VCA protocol, embodying both ASCs and low-dose donor BMCs, in nonhuman primates, with the goal of enhancing functional outcomes and eliminating the complications associated with long-term immunosuppression.
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Affiliation(s)
- Thomas A Davis
- Regenerative Medicine Department, Operational and Undersea Medicine Directorate, Naval Medical Research Center, Silver Spring, Maryland, USA; Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA; Department of Medicine and Surgery Center for Stem Cell Research & Regenerative Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA; LaCell, LLC, New Orleans, Louisiana, USA
| | - Khairul Anam
- Regenerative Medicine Department, Operational and Undersea Medicine Directorate, Naval Medical Research Center, Silver Spring, Maryland, USA; Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA; Department of Medicine and Surgery Center for Stem Cell Research & Regenerative Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA; LaCell, LLC, New Orleans, Louisiana, USA
| | - Yelena Lazdun
- Regenerative Medicine Department, Operational and Undersea Medicine Directorate, Naval Medical Research Center, Silver Spring, Maryland, USA; Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA; Department of Medicine and Surgery Center for Stem Cell Research & Regenerative Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA; LaCell, LLC, New Orleans, Louisiana, USA
| | - Jeffrey M Gimble
- Regenerative Medicine Department, Operational and Undersea Medicine Directorate, Naval Medical Research Center, Silver Spring, Maryland, USA; Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA; Department of Medicine and Surgery Center for Stem Cell Research & Regenerative Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA; LaCell, LLC, New Orleans, Louisiana, USA
| | - Eric A Elster
- Regenerative Medicine Department, Operational and Undersea Medicine Directorate, Naval Medical Research Center, Silver Spring, Maryland, USA; Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA; Department of Medicine and Surgery Center for Stem Cell Research & Regenerative Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA; LaCell, LLC, New Orleans, Louisiana, USA
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Butkus J, Dennison C, Orr A, Laurent MS. Occupational Therapy with the Military Upper Extremity Amputee: Advances and Research Implications. CURRENT PHYSICAL MEDICINE AND REHABILITATION REPORTS 2014. [DOI: 10.1007/s40141-014-0065-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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Jablecki J, Kaczmarzyk L, Kaczmarzyk J, Chelmonski A. Unilateral arm transplant 28 years after amputation: fourteen-month result. Transplant Proc 2014; 43:3563-5. [PMID: 22099843 DOI: 10.1016/j.transproceed.2011.10.013] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
Abstract
Hand transplantation now represents a therapeutic alternative for amputees. Arm transplantation poses a serious challenge regarding many respects of the reconstructive procedure. To the end of 2010, only seven such procedures had been performed in four patients. The goal of this article was to present the preliminary results of an arm transplant in a 30-year-old male patient at 14 months. The patient sustained an amputation at the elbow-joint level as a 2-year-old child. The procedure was performed in October 2010. His postoperative course was complicated by one rejection episode (BANFF grade II), and a de novo cytomegalovirus infection. At this early stage, the patient is doing well regaining function. He can flex at the elbow joint, move his fingers, and experience protective sensitivity reaching the palm. The patient is satisfied with his transplantation.
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Affiliation(s)
- J Jablecki
- Subdepartment of Limb Replantation, General Surgery Ward, St Hedwig of Silesia Hospital, Trzebnica, Poland.
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Ramirez AE, Cheng HY, Lao WW, Wang YL, Wen CJ, Wallace CG, Lin CF, Shih LY, Chuang SH, Wei FC. A novel rat full-thickness hemi-abdominal wall/hindlimb osteomyocutaneous combined flap: influence of allograft mass and vascularized bone marrow content on vascularized composite allograft survival. Transpl Int 2014; 27:977-986. [PMID: 24861714 DOI: 10.1111/tri.12364] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2013] [Revised: 11/10/2013] [Accepted: 05/19/2014] [Indexed: 11/26/2022]
Abstract
Vascularized bone marrow transplantation (VBMT) appears to promote tolerance for vascularized composite allotransplantation (VCA). However, it is unclear whether VBMT is critical for tolerance induction and, if so, whether there is a finite amount of VCA that VBMT can support. We investigated this with a novel VCA combined flap model incorporating full-thickness hemiabdominal wall and hindlimb osteomyocutaneous (HAW/HLOMC) flaps. Effects of allograft mass (AM) and VBMT on VCA outcome were studied by comparing HAW/HLOMC VCAs with fully MHC-mismatched BN donors and Lewis recipients. Control groups did not receive treatments following transplantation. Treatment groups received a short course of cyclosporine A (CsA), antilymphocyte serum, and three doses of adipocyte-derived stem cells (POD 1, 8, and 15). The results showed that all flaps in control allogeneic groups rejected soon after VCAs. Treatment significantly prolonged allograft survival. Three of eight recipients in HLOMC treatment group had allografts survive long-term and developed donor-specific tolerance. Significantly higher peripheral chimerism was observed in HLOMC than other groups. It is concluded that the relative amount of AM to VBMT is a critical factor influencing long-term allograft survival. Accordingly, VBMT content compared with VCA mass may be an important consideration for VCA in humans.
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Affiliation(s)
- Alejandro E Ramirez
- Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Pontifical Catholic University of Chile, Santiago, Chile
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Abstract
Vascularized composite allotransplantation is a continuously evolving area of modern transplant medicine. Recently, vascularized composite allografts (VCAs) have been formally classified as 'organs'. In this review, key aspects of VCA procurement are discussed, with a special focus on interaction with the procurement of classical solid organs. In addition, options for a matching and allocation system that ensures VCA donor organs are allocated to the best-suited recipients are looked at. Finally, the different steps needed to promote VCA transplantation in society in general and in the medical community in particular are highlighted.
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Affiliation(s)
- Axel Rahmel
- Deutsche Stiftung Organtransplantation, Deutschherrnufer 52, Frankfurt am Main, 60594 Frankfurt, Germany
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Hautz T, Zelger BG, Nasr IW, Mundinger GS, Barth RN, Rodriguez ED, Brandacher G, Weissenbacher A, Zelger B, Cavadas P, Margreiter R, Lee WPA, Pratschke J, Lakkis FG, Schneeberger S. Lymphoid neogenesis in skin of human hand, nonhuman primate, and rat vascularized composite allografts. Transpl Int 2014; 27:966-76. [DOI: 10.1111/tri.12358] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2013] [Revised: 12/28/2013] [Accepted: 05/12/2014] [Indexed: 12/31/2022]
Affiliation(s)
- Theresa Hautz
- Department of Visceral, Transplant and Thoracic Surgery; Center of Operative Medicine; Innsbruck Medical University; Innsbruck Austria
| | - Bettina G. Zelger
- Department of Pathology; Innsbruck Medical University; Innsbruck Austria
| | - Isam W. Nasr
- Thomas E. Starzl Transplantation Institute; University of Pittsburgh School of Medicine; Pittsburgh PA USA
| | - Gerhard S. Mundinger
- Division of Plastic and Reconstructive Surgery; R Adams Cowley Shock Trauma Center; University of Maryland; Baltimore MD USA
- Department of Plastic Surgery; Johns Hopkins Medical University; Baltimore MD USA
| | - Rolf N. Barth
- Department of Surgery; University of Maryland School of Medicine; Baltimore MD USA
| | - Eduardo D. Rodriguez
- Division of Plastic and Reconstructive Surgery; R Adams Cowley Shock Trauma Center; University of Maryland; Baltimore MD USA
| | - Gerald Brandacher
- Department of Visceral, Transplant and Thoracic Surgery; Center of Operative Medicine; Innsbruck Medical University; Innsbruck Austria
- Department of Plastic Surgery; Johns Hopkins Medical University; Baltimore MD USA
| | - Annemarie Weissenbacher
- Department of Visceral, Transplant and Thoracic Surgery; Center of Operative Medicine; Innsbruck Medical University; Innsbruck Austria
| | - Bernhard Zelger
- Department of Dermatology; Innsbruck Medical University; Innsbruck Austria
| | | | - Raimund Margreiter
- Department of Visceral, Transplant and Thoracic Surgery; Center of Operative Medicine; Innsbruck Medical University; Innsbruck Austria
| | - W. P. Andrew Lee
- Department of Plastic Surgery; Johns Hopkins Medical University; Baltimore MD USA
| | - Johann Pratschke
- Department of Visceral, Transplant and Thoracic Surgery; Center of Operative Medicine; Innsbruck Medical University; Innsbruck Austria
| | - Fadi G. Lakkis
- Thomas E. Starzl Transplantation Institute; University of Pittsburgh School of Medicine; Pittsburgh PA USA
| | - Stefan Schneeberger
- Department of Visceral, Transplant and Thoracic Surgery; Center of Operative Medicine; Innsbruck Medical University; Innsbruck Austria
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Characterization, prophylaxis, and treatment of infectious complications in craniomaxillofacial and upper extremity allotransplantation: a multicenter perspective. Plast Reconstr Surg 2014; 133:543e-551e. [PMID: 24675206 DOI: 10.1097/prs.0000000000000015] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Vascularized composite allotransplants consist of heterogeneous tissues from different germ layers, which include skin, muscle, bone, fat, nerves, and lymph nodes. The antigenic diversity of these tissues, particularly of the highly immunogenic skin component, necessitates potent immunosuppressive regimens similar to that of some solid organ transplants. Indeed, the lifelong, high-dose, multidrug immunosuppressive protocols expose vascularized composite allotransplant recipients to considerable risk of infectious, metabolic, and neoplastic sequelae. In this article, the authors review the infectious risk to patients after vascularized composite allotransplantation, with special attention to the somewhat limited experience with the prophylaxis and treatment of infections after this innovative reconstructive surgery. METHODS A review of the literature was undertaken to elucidate the characterization, prophylaxis, and treatment of all documented infectious complications. RESULTS Infections in face and hand vascularized composite allotransplants follow a course similar to that of solid organ transplants. Several differences exist, including the unique flora of craniomaxillofacial transplants, the increased risk of donor-derived infections, and the alteration of the risk-to-benefit ratio for cytomegalovirus infections. CONCLUSIONS The patient with a face or limb transplant has many of the same infectious risks as a lung transplant recipient, which include bacterial, viral, and fungal infections. Because of the anatomy, mucosal exposure, and differing donor flora, however, the face or limb transplant is susceptible to invasive diseases from a variety of microbes.
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Wang Z, He B, Duan Y, Shen Y, Zhu L, Zhu X, Zhu Z. Cryopreservation and replantation of amputated rat hind limbs. Eur J Med Res 2014; 19:28. [PMID: 24886622 PMCID: PMC4048362 DOI: 10.1186/2047-783x-19-28] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2014] [Accepted: 05/15/2014] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND In spite of the relatively high success rate of limb replantation, many patients cannot undergo replantation surgery because the preservation time of an amputated limb is only about six hours. In addition, although allotransplantation of composite tissues is being performed more commonly with increasingly greater success rates, the shortage of donors limits the number of patients that can be treated. So the purpose of this study is to examine the feasibility of cryopreservation and replantation of limbs in a rat model. METHODS Twelve five-month-old Sprague-Dawley rats were divided evenly into group A (above-knee amputation) and group B (Syme's amputation). One hind limb was amputated from each rat. The limbs were irrigated with cryoprotectant, cooled in a controlled manner to -140°C, and placed in liquid nitrogen. Thawing and replantation were performed 14 days later. RESULTS In group A, the limbs became swollen after restoration of blood flow resulting in blood vessel compression and all replantations failed. In group B, restoration of blood flow was noted in all limbs after replantation. In one case, the rat chewed the replanted limb and replantation failed. The other five rats were followed for three months with no abnormalities noted in the replanted limbs. CONCLUSIONS Limbs with a minimal amount of muscle tissue can be successfully cryopreserved and replanted.
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Affiliation(s)
- Zengtao Wang
- Department of Hand and Foot Surgery, Provincial Hospital Affiliated to Shandong University, Jinan 250021, China
| | - Bo He
- Department of Orthopaedic and Microsurgery, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Road 2, Guangzhou 510080, China
- Department of Hand and Foot Surgery, Provincial Hospital Affiliated to Shandong University, Jinan 250021, China
| | - Yongzhuang Duan
- Department of Orthopaedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Yun Shen
- The Science and Technology Research Institute of the National Population and Family Planning Commission, 12, Dahuishi Road, Haidian District, Beijing, China
| | - Lei Zhu
- Department of Hand and Foot Surgery, Qilu Hospital of Shandong University, Jinan 250012, China
| | - Xiaolei Zhu
- Department of Hand and Foot Surgery, Provincial Hospital Affiliated to Shandong University, Jinan 250021, China
| | - Zhaowei Zhu
- Department of Orthopaedic and Microsurgery, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan Road 2, Guangzhou 510080, China
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Abstract
PURPOSE OF REVIEW Psychosocial aspects are important indicators for reconstructive hand transplantation (RHT). They warrant further research attention given the influence of psychosocial factors on the success of RHT. This review will contrast RHT with solid organ transplantation, provide information to guide selection of RHT candidates and ethical implications, share information on psychological outcomes, and address the importance of a multicenter research approach. RECENT FINDINGS Previously published RHT reports have tried to identify psychosocial factors that are essential to guide selection of RHT candidates and that predict psychosocial outcomes. These issues in RHT are receiving increased attention, but standardized psychosocial evaluation and follow-up protocols are still needed. Recent study highlights the potential for a multicenter research approach that uses standardized assessment strategies and also emphasizes the need for a shared assessment approach to understand psychosocial outcomes. SUMMARY RHT combines the technical rigors of hand surgery and microsurgery with the complex multidisciplinary care that defines modern transplantation medicine. As recent work has provided a more complete picture of the complexities of the psychosocial factors in RHT, a psychosocial assessment protocol developed with input across the centers currently performing this procedure would capitalize on the collective diverse clinical experiences and standardize the assessment and follow-up protocol. With such standardized procedures in place, psychosocial risk factors for both poor psychosocial and medical/surgical outcomes can be identified which can inform the selection or preparation of future candidates.
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Vascularized composite allotransplantation: towards tolerance and the importance of skin-specific immunobiology. Curr Opin Organ Transplant 2014; 18:645-51. [PMID: 24126805 DOI: 10.1097/mot.0000000000000022] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE OF REVIEW Vascularized composite allotransplantation (VCA) is increasingly utilized in the restoration of complex injuries and tissue loss. Acute skin-targeted rejection episodes are common and concerns remain regarding the risks of conventional immunosuppression. We review current immunosuppressive regimens for VCA, progress with immunomodulatory and tolerance protocols, and highlight recent advances in cutaneous immunobiology which will have significant implications for future development in the field. RECENT FINDINGS Advances in induction protocols have demonstrated effective prevention of early graft loss in hand transplantation, although long-term outcomes are still pending. Furthermore, recent findings in leukocyte populations within the skin and their mechanisms of communication reveal that considerable numbers of resident T-effector memory cells, including a T-regulatory subset, exist, and that epidermal Langerhans' cells communicate with these cells, mediating both immunity and tolerance to maintain skin homeostasis. SUMMARY The majority of VCA centers utilize antibody-mediated induction, followed by double or triple-agent maintenance immunosuppression. A clinical trial of a minimal-immunosuppression protocol based on bone marrow infusion reports encouraging interim results, but long-term follow-up will be required. Skin remains the primary target of rejection in VCA. New data demonstrate extensive T-cell memory resident in skin, and complex interactions between these cells and epidermal Langerhans' cells will have implications for VCA rejection and tolerance, and warrant further investigation in the allogeneic setting.
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Cheng HY, Ghetu N, Huang WC, Wang YL, Wallace CG, Wen CJ, Chen HC, Shih LY, Lin CF, Hwang SM, Liao SK, Wei FC. Syngeneic adipose-derived stem cells with short-term immunosuppression induce vascularized composite allotransplantation tolerance in rats. Cytotherapy 2014; 16:369-380. [PMID: 24119648 DOI: 10.1016/j.jcyt.2013.06.020] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2013] [Revised: 06/23/2013] [Accepted: 06/27/2013] [Indexed: 12/29/2022]
Abstract
BACKGROUND AIMS A clinically applicable tolerance induction regimen that removes the requirement for lifelong immunosuppression would benefit recipients of vascularized composite allotransplantation (VCA). We characterized the immunomodulatory properties of syngeneic (derived from the recipient strain) adipocyte-derived stem cells (ADSCs) and investigated their potential to induce VCA tolerance in rats. METHODS ADSCs were isolated from Lewis (LEW, RT1A(l)) rats; their immunomodulatory properties were evaluated by means of mixed lymphocyte reactions in vitro and VCAs in vivo across a full major histocompatibility complex mismatch with the use of Brown-Norway (BN, RT1A(n)) donor rats. Two control and four experimental groups were designed to evaluate treatment effects of ADSCs and transient immunosuppressants (anti-lymphocyte globulin, cyclosporine) with or without low-dose (200 cGy) total body irradiation. Flow cytometry was performed to quantify levels of circulating CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs). RESULTS Cultured syngeneic ADSCs exhibited CD90.1(+)CD29(+)CD73(+)CD45(-)CD79a(-)CD11b/c(-) phenotype and the plasticity to differentiate to adipocytes and osteocytes. ADSCs dramatically suppressed proliferation of LEW splenocytes against BN antigen and mitogen, respectively, in a dose-dependent fashion, culminating in abrogation of allo- and mitogen-stimulated proliferation at the highest concentration tested. Accordingly, one infusion of syngeneic ADSCs markedly prolonged VCA survival in LEW recipients treated with transient immunosuppression; of these, 66% developed tolerance. Total body irradiation provided no additional VCA survival benefit. An important role for Tregs in tolerance induction/maintenance was suggested in vivo and in vitro. CONCLUSIONS Treatment comprising syngeneic ADSCs and transient immunosuppression (i) increased levels of circulating Tregs and (ii) induced tolerance in 66% of recipients of major histocompatibility complex-mismatched VCAs.
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Affiliation(s)
- Hui-Yun Cheng
- Center for Vascularized Composite Allotransplantation, Chang Gung Memorial Hospital, Gueishan, Taiwan; Department of Medical Research and Development Linkou Branch, Chang Gung Medical Foundation, Taoyuan, Gueishan, Taiwan
| | - Nicolae Ghetu
- Former Microsurgery Fellow, Chang Gung Memorial Hospital; Regional Oncological Institute, University of Medicine and Pharmacy. "Grigore T. Popa," Iasi, România
| | - Wei-Chao Huang
- Division of Plastic and Reconstructive Surgery, Tzu Chi General Hospital at Taipei, New Taipei, Taiwan
| | - Yen-Ling Wang
- Center for Vascularized Composite Allotransplantation, Chang Gung Memorial Hospital, Gueishan, Taiwan
| | | | - Chih-Jen Wen
- School of Medicine, Chang Gung University, Gueishan, Taiwan
| | - Hung-Chang Chen
- Graduate Institute of Biomedical Sciences, Chang Gung University, Gueishan, Taiwan
| | - Ling-Yi Shih
- Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, Gueishan, Taiwan
| | - Chih-Fan Lin
- School of Medicine, Chang Gung University, Gueishan, Taiwan
| | - Shiaw-Min Hwang
- Bioresource Collection and Research Center, Food Industry Research and Development Institute, Hsinchu, Taiwan
| | - Shuen-Kuei Liao
- Graduate Institute of Cancer Biology and Drug Discovery and Center of Excellence for Cancer Research, Taipei Medical University, Taipei, Taiwan; R&D Division, Vectorite Biomedica Inc, Taipei, Taiwan.
| | - Fu-Chan Wei
- Center for Vascularized Composite Allotransplantation, Chang Gung Memorial Hospital, Gueishan, Taiwan; Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, Gueishan, Taiwan; School of Medicine, Chang Gung University, Gueishan, Taiwan.
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Abstract
Vascularized composite allotransplantation (VCA) is a novel therapeutic option for treatment of patients suffering from limb loss or severe facial disfigurement. To date, 72 hand and 19 facial transplantations have been performed worldwide. VCA in hand and facial transplantation is a complex procedure requiring a multidisciplinary team approach and extensive surgical planning. Despite good functional outcome, courses after hand and facial transplantation have been complicated by skin rejection. Long-term immunosuppression remains a necessity in VCA for allograft survival. To widen the scope of these quality-of-life-improving procedures, minimization of immunosuppression to limit risks and side effects is needed.
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50
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Nguyen GK, Hwang BH, Zhang Y, Monahan JFW, Davis GB, Lee YS, Ragina NP, Wang C, Zhou ZY, Hong YK, Spivak RM, Wong AK. Novel biomarkers of arterial and venous ischemia in microvascular flaps. PLoS One 2013; 8:e71628. [PMID: 23977093 PMCID: PMC3743756 DOI: 10.1371/journal.pone.0071628] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2013] [Accepted: 06/29/2013] [Indexed: 01/09/2023] Open
Abstract
The field of reconstructive microsurgery is experiencing tremendous growth, as evidenced by recent advances in face and hand transplantation, lower limb salvage after trauma, and breast reconstruction. Common to all of these procedures is the creation of a nutrient vascular supply by microsurgical anastomosis between a single artery and vein. Complications related to occluded arterial inflow and obstructed venous outflow are not uncommon, and can result in irreversible tissue injury, necrosis, and flap loss. At times, these complications are challenging to clinically determine. Since early intervention with return to the operating room to re-establish arterial inflow or venous outflow is key to flap salvage, the accurate diagnosis of early stage complications is essential. To date, there are no biochemical markers or serum assays that can predict these complications. In this study, we utilized a rat model of flap ischemia in order to identify the transcriptional signatures of venous congestion and arterial ischemia. We found that the critical ischemia time for the superficial inferior epigastric fasciocutaneus flap was four hours and therefore performed detailed analyses at this time point. Histolgical analysis confirmed significant differences between arterial and venous ischemia. The transcriptome of ischemic, congested, and control flap tissues was deciphered by performing Affymetrix microarray analysis and verified by qRT-PCR. Principal component analysis revealed that arterial ischemia and venous congestion were characterized by distinct transcriptomes. Arterial ischemia and venous congestion was characterized by 408 and 1536>2-fold differentially expressed genes, respectively. qRT-PCR was used to identify five candidate genes Prol1, Muc1, Fcnb, Il1b, and Vcsa1 to serve as biomarkers for flap failure in both arterial ischemia and venous congestion. Our data suggests that Prol1 and Vcsa1 may be specific indicators of venous congestion and allow clinicians to both diagnose and successfully treat microvascular complications before irreversible tissue damage and flap loss occurs.
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Affiliation(s)
- Gerard K. Nguyen
- Division of Plastic & Reconstructive Surgery, Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
| | - Brian H. Hwang
- Division of Plastic & Reconstructive Surgery, Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
| | - Yiqiang Zhang
- City of Hope, Functional Genomics Core, Duarte, California, United States of America
- Division of Cardiology, Department of Medicine, University of Washington, Seattle, Washington, United States of America
| | - John F. W. Monahan
- Division of Plastic & Reconstructive Surgery, Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
| | - Gabrielle B. Davis
- Division of Plastic & Reconstructive Surgery, Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
| | - Yong Suk Lee
- Division of Plastic & Reconstructive Surgery, Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
| | - Neli P. Ragina
- Division of Colorectal Surgery, Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
| | - Charles Wang
- City of Hope, Functional Genomics Core, Duarte, California, United States of America
| | - Zhao Y. Zhou
- Division of Plastic & Reconstructive Surgery, Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
| | - Young Kwon Hong
- Department of Surgery and Biochemistry & Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
| | - Ryan M. Spivak
- Division of Plastic & Reconstructive Surgery, Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
| | - Alex K. Wong
- Division of Plastic & Reconstructive Surgery, Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
- * E-mail:
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