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Biomedical subjects

W C Breidenbach

Publications and source records attributed to W C Breidenbach.

At least 19 recordsLinked to original sources
PubMed2005

Ethical considerations in the early composite tissue allograft experience: a review of the Louisville Ethics Program.

This paper reviews the formulation and evolution of the ethical component in one of the earliest clinical composite tissue allograft (CTA) programs, the hand transplantation program in Louisville, Kentucky, USA. The purpose was to derive lessons and define principles to give guidance for future programs and introduction of new CTA. We reviewed the initial ethical considerations, including input from respected ethical scholars, guidelines for innovative procedures transparency in public and professional scrutiny, and compliance with human studies regulations (IRB approval). We found the initial focus on ethics, scholarly input, guidelines for innovative procedures, and human studies protection regulations to be valid. Moreover, we noted the effect of autonomy in subjective, quality-of-life benefits on equipoise and effective risk-benefit analysis in effective informed consent. We found that psychiatric screening and support to be exceptionally valuable in protecting autonomy, suitability for participation, assessing personality organization, and determining compliance ability. We conclude that the program ethical principles were validated. For future CTA programs and procedures, we recommend an ethical emphasis with adherence to high standards and transpire to independence to scrutiny and oversight. We recommend protection of autonomy judgments in equipoise judgment and informed consent. We recommend skilled psychiatric screening and support. We endorse scholarship, scientific accuracy, and data sharing.

Humans↗
PubMed2001

Different reference frames can lead to different hand transplantation decisions by patients and physicians.

Different frames of reference can affect one's assessment of the value of hand transplantation. This can result in different yet rational decisions by different groups of individuals, especially patients and physicians. In addition, factors other than frames of reference can affect one's evaluation of hand transplantation, which can result in different decisions.

Attitude of Health Personnel↗
PubMed2001

Hand transplantation.

The surgical techniques necessary to perform hand transplantation have been available for at least 25 years. In this article, the authors provide a review of hand transplantation, including its history, preoperative evaluation, and case reports. Data on transplant preparation, operation data, immunosuppression, rejection, immunologic assessment, and functional assessment are presented in easy-to-use table format.

Adult↗
PubMed2000

Successful hand transplantation. One-year follow-up. Louisville Hand Transplant Team.

BACKGROUND: On the basis of positive results in studies of the transplantation of pig extremities and the information exchanged at an international symposium on composite tissue transplantation, we developed a protocol for human hand transplantation. METHODS: After a comprehensive pretransplantation evaluation and informed-consent process, the left hand of a 58-year-old cadaveric donor, matched for size, sex, and skin tone, was transplanted to a 37-year-old man who had lost his dominant left hand 13 years earlier. Immunosuppression consisted of basiliximab for induction therapy and tacrolimus, mycophenolate mofetil, and prednisone for maintenance therapy. RESULTS: The cold-ischemia time of the donor hand was 310 minutes. There were no intraoperative or early postoperative complications. Moderate acute cellular rejection of the skin of the graft developed 6, 20, and 27 weeks after transplantation. All three episodes resolved completely after treatment with intravenous methylprednisolone and topical tacrolimus and clobetasol. Temperature, pain, and pressure sensation had developed in the hand and fingers by one year. At one year, the patient had regained the ability to perform many functional activities with his left hand that he had not been able to perform with his prosthesis, such as throwing a baseball, turning the pages of a newspaper, writing, and tying his shoelaces. CONCLUSIONS: Early success has been achieved in hand transplantation with the use of currently available immunosuppressive drugs.

Adult↗
PubMed2000

Osteomyocutaneous flap as a preclinical composite tissue allograft: swine model.

Composite tissue allotransplantation (CTA) constitutes one of the last frontiers of microsurgery. Prior to its clinical application, the long-term efficacy of modern immunotherapy must be tested in a pre-clinical CTA model. Based on the concept of osteomyocutaneous forearm flap, we developed a CTA flap model in swine. After identifying the vascular territory of the flaps in six pigs (vascular casting), flaps were transplanted from mismatched donor to recipient pigs (n = 6). Rejection was assessed daily by visual inspection and histopathology of biopsy specimens. Recipient pigs were able to ambulate immediately following surgery. There were no flap failures owing to technical or surgical complications. Rejection occurred over a period of 7 days as manifested by edema, cellular infiltration, epidermalysis, and thrombosis. This pre-clinical flap model is excellent for evaluating the effectiveness of modern immunotherapy because it is anatomically and immunologically relevant and because the minimal morbidity caused to the animal permits long-term studies.

Animals↗
PubMed2000

Hand transplantation: comparisons and observations of the first four clinical cases.

Twenty, 15, and 8 months after the first four successful human hand transplant procedures were performed in Lyon (France), Louisville (U. S.), and Guangzhou (China), the transplant teams convened in Louisville, Kentucky, to share their experiences at the Second International Symposium on Composite Tissue Allotransplantation. This article presents reconstructive and immunological data from these landmark procedures in tabular format, in an attempt to answer some key questions about early outcomes of clinical hand transplantation. On the basis of these data, the initial outcomes of the first four hand transplants are encouraging and warrant proceeding with additional hand transplantations.

Adult↗
PubMed2000

Swine composite tissue allotransplant model for preclinical hand transplant studies.

Our laboratory previously developed and used an orthotopic radial forelimb osteomyocutaneous flap in the pig as a preclinical composite tissue allograft (CTA) model. To ensure that it mimicked the clinical situation as closely as possible we developed this model taking many immunologic and reconstructive considerations into account. While our original pig CTA model was ideal for studying the methods of preventing skin, muscle, bone, vessel and nerve rejection, and systemic toxicity, it did not include specialized tissues/structures of a joint and digit. Therefore, we were unable to evaluate rejection of these specialized tissues and their functional properties. Recognizing the importance of assessing joint rejection and function in hand transplantation research we developed a new swine forelimb CTA model that included the animal's medial digit. The present study describes the anatomy and the transplantation technique used in this new preclinical CTA model. We transplanted a radial osteomyocutaneous flap that included the medial digit between two size- (17-21 kg) and age- (6-8-week) matched farm pigs. We removed the digit from the recipient pig's forelimb in continuity with a section of the radial bone and replaced it with the same structure transplanted from a donor pig. After transplantation, a full-length cast was placed on the recipient pig's operated limb and changes in flap color, temperature and the presence of edema were monitored continuously for 6 h, and then regularly at predetermined intervals over 4 days. No weight bearing restrictions were placed on the animal's operated limb. After 4 days, the animal was euthanized. Direct visual monitoring of the allograft during 4 days revealed it was viable with no signs of graft failure due to technical complications associated with the transplant procedure. Upon waking from anesthesia, the animal stood and wandered freely about its cage with no apparent difficulty. Based on the animal's high level of activity at this time, we concluded that the procedure caused it minimal morbidity. At 4 days after the operation, early signs of rejection (skin erythema and edema) were observed. By incorporating a digit into our original CTA pig forelimb model we have made it a better model for performing preclinical hand transplant studies. The added advantage of being able to assess methods of preventing rejection in the specialized joint/digital tissues (articular cartilage, digital flexor and extensor systems, the nail complex) and assess long-term function of these structures is important. The fact that the procedure does not cause major morbidity to the animal makes it possible to conduct long-term graft survival and functional studies.

Animals↗
PubMed2000

A randomized prospective study of polyglycolic acid conduits for digital nerve reconstruction in humans.

This article reports the first randomized prospective multicenter evaluation of a bioabsorbable conduit for nerve repair. The study enrolled 98 subjects with 136 nerve transections in the hand and prospectively randomized the repair to two groups: standard repair, either end-to-end or with a nerve graft, or repair using a polyglycolic acid conduit. Two-point discrimination was measured by a blinded observer at 3, 6, 9, and 12 months after repair. There were 56 nerves repaired in the control group and 46 nerves repaired with a conduit available for follow-up. Three patients had a partial conduit extrusion as a result of loss of the initially crushed skin flap. The overall results showed no significant difference between the two groups as a whole. In the control group, excellent results were obtained in 43 percent of repairs, good results in 43 percent, and poor results in 14 percent. In those nerves repaired with a conduit, excellent results were obtained in 44 percent, good results in 30 percent, and poor results in 26 percent (p = 0.46). When the sensory recovery was examined with regard to length of nerve gap, however, nerves with gaps of 4 mm or less had better sensation when repaired with a conduit; the mean moving two-point discrimination was 3.7 +/- 1.4 mm for polyglycolic acid tube repair and 6.1 +/- 3.3 mm for end-to-end repairs (p = 0.03). All injured nerves with deficits of 8 mm or greater were reconstructed with either a nerve graft or a conduit. This subgroup also demonstrated a significant difference in favor of the polyglycolic acid tube. The mean moving two-point discrimination for the conduit was 6.8 +/- 3.8 mm, with excellent results obtained in 7 of 17 nerves, whereas the mean moving two-point discrimination for the graft repair was 12.9 +/- 2.4 mm, with excellent results obtained in none of the eight nerves (p < 0.001 and p = 0.06, respectively). This investigation demonstrates improved sensation when a conduit repair is used for nerve gaps of 4 mm or less, compared with end-to-end repair of digital nerves. Polyglycolic acid conduit repair also produces results superior to those of a nerve graft for larger nerve gaps and eliminates the donor-site morbidity associated with nerve-graft harvesting.

Absorbable Implants↗
PubMed1999

Blood flow in a chronic entrapment neuropathy model in the rabbit sciatic nerve.

A model of chronic entrapment neuropathy in the rabbit sciatic nerve was developed to try to elucidate the pathogenesis of chronic nerve entrapment. A non-compressive Silastic cuff was wrapped around the nerve at the mid-thigh level in eight rabbits. A sham operation that only elevated the sciatic nerve was performed in seven control rabbits. Six months later, the blood flow in the cuffed and the control sciatic nerves was determined with intra-arterially injected microspheres. Blood flow was significantly reduced in the entrapped nerve, compared to control nerves, but only in the segment proximal to the cuff. After surgical release of the cuff, the blood flow significantly increased in the proximal segment. This suggested that decreased blood flow may occur, but not necessarily at the site of nerve entrapment. Nerve conduction velocity changes were also consistent with an entrapment neuropathy. However, there were no significant quantitative morphometric changes at the nerve entrapment site, that is, in myelin thickness/nerve diameter ratio, distribution of axon sizes, and mean nerve fiber diameter. This indicates that only a mild entrapment was created.

Animals↗
PubMed1999

Pharmacokinetic advantage of intra-arterial cyclosporin A delivery to vascularly isolated rabbit forelimb. I. Model development.

Effective antirejection therapy with minimal systemic morbidity is required if limb transplantation is to become a clinical reality. We investigated whether i.a. infusion of cyclosporin A (CSA) into the vascularly isolated rabbit forelimb will distribute drug homogeneously to the tissues and produce higher local drug levels than same-dose i.v. treatment, thereby improving the therapeutic index. CSA 4.0 mg/kg/day was infused continuously via osmotic minipump into either the right brachial artery (i.a. group) or jugular vein (i.v. group) of New Zealand rabbits. Ligation of all muscles at the right mid-arm level was performed in the i.a. group to eliminate collateral circulation and simulate allografting, while leaving bone and neurovasculature intact. On day 6, CSA concentrations were measured in skin, muscle, bone, and bone marrow samples taken from different compartments of the right and left forearms in the i.a. group and right forearm only in the i.v. group. There were no significant differences between compartmental CSA levels in all tissues examined on the locally treated, right side during i.a. infusion, indicating that drug streaming from the catheter tip is not occurring in our model. During i.a. infusion, mean CSA concentrations were 4- to 7-fold higher in the right limb than in the left limb in all four tissues examined. Tissue CSA levels in the left limb were equivalent to those achieved during i.v. infusion, but CSA concentrations in blood, kidney, and liver were higher during i.a. infusion. These favorable, preliminary, single-dose pharmacokinetic results warrant further investigation in our novel rabbit model.

Animals↗
PubMed1999

Pharmacokinetic advantage of intra-arterial cyclosporin A delivery to vascularly isolated rabbit forelimb. II. Dose dependence.

A vascularly isolated rabbit forelimb model simulating conditions of composite tissue allografting was used to determine the regional pharmacokinetic advantage achievable in extremity tissue components during i.a. cyclosporin A (CSA) administration. CSA was infused continuously via osmotic minipump into the right brachial artery of New Zealand rabbits at multiple doses ranging from 1.0 to 8.0 mg/kg/day. On day 6, CSA concentrations were measured in aortic whole blood, as well as in skin, muscle, bone, and bone marrow samples from both right and left forelimbs. The variation of right-sided mean CSA concentrations with dose was tissue dependent and saturable in the case of skin and bone, whereas left-sided tissue concentrations correlated significantly with systemic blood levels. At 1.0 mg/kg/day, there were no significant differences between right and left mean CSA concentrations for all four tissues examined. However, with a doubling of the i.a. dose, huge increases in local tissue CSA concentrations were produced with only very modest increases in systemic whole-blood and tissue drug levels, resulting in a 4-fold regional advantage (right/left ratio of CSA concentrations) in bone and bone marrow, 7-fold in muscle, and 14-fold in skin. With further dose increases to 8.0 mg/kg/day, the regional advantage decreased to 4-fold in skin, increased to 9-fold in bone marrow, remained relatively constant in bone, and initially decreased and then increased to 9-fold in muscle. These favorable pharmacokinetic results suggest that reduced, local doses of CSA might be useful in preventing extremity composite tissue allograft rejection with decreased systemic drug exposure.

Animals↗
PubMed1999

Pharmacokinetics of intra-arterial delivery of tacrolimus to vascularly isolated rabbit forelimb.

A vascularly isolated rabbit forelimb model simulating conditions of composite tissue allografting was used to determine the regional pharmacokinetic advantage achievable in extremity tissue components during i.a. tacrolimus (FK506) administration. FK506 was infused continuously via osmotic minipump into the right brachial artery of New Zealand rabbits at 0.05, 0.1, and 0.2 mg/kg/day. On day 6, FK506 concentrations were measured in aortic whole blood, heart, lung, liver, kidney, spleen, and fat, as well as in skin, muscle, bone, and bone marrow samples from both right and left forelimbs. The relative tissue concentrations of FK506 in descending order were [spleen approximately lung approximately kidney] > [heart approximately skin approximately muscle] > [fat approximately bone marrow] > [liver approximately bone approximately blood]. In marked contrast to previous results with i.a. cyclosporin A infusion, only a minimal regional advantage of local FK506 delivery (mean right/left concentration ratios 1.0-1.4) was obtained in all forearm tissues over the dose range studied. For each limb tissue, left-sided FK506 concentrations significantly correlated with systemic blood levels, and the left-sided tissue-to-whole-blood concentration ratio did not vary significantly with dose. We conclude that FK506 is pharmacokinetically inferior to cyclosporin A for continuous i.a. administration to the vascularly isolated rabbit forelimb, and hypothesize that this difference is the result of differences in the distribution of each drug within whole blood. Our findings suggest that, despite its demonstrated efficacy in experimental and clinical transplantation, FK506 would not be an appropriate immunosuppressant to deliver via the i.a. route for prevention of limb allograft rejection.

Animals↗
PubMed1999

The role of emergency free flaps for hand trauma.

Primary closure of a wound with free flap requires minimizing the risk of infection in an effort to cover vital exposed structures. Careful patient selection, radical débridement of the wound, and an experienced microsurgical team are important for the routine application of this technique. Primary reconstruction of all injured structures is an extension of this technique that enables efficient management of severe upper extremity problems in a single setting.

Adult↗
PubMed1999

Long-term survival of an extremity composite tissue allograft with FK506-mycophenolate mofetil therapy.

BACKGROUND: High-dose tacrolimus (FK506) monotherapy has significantly prolonged rat hindlimb allograft survival. With an eye toward direct clinical application, we used a large-animal extremity composite tissue allograft model to assess the antirejection efficacy and systemic toxicity of combination FK506-mycophenolate mofetil (MMF) treatment. METHODS: Radial forelimb osteomyocutaneous flap transplants were performed between size-matched outbred pigs assigned to one of two groups: 5 control pigs received no immunosuppression and 9 animals received a once-daily oral FK506-MMF-prednisone regimen. Rejection was assessed by visual inspection of flap skin and was correlated with serial histopathologic examination of skin biopsy specimens. RESULTS: In all control pigs the flap was completely rejected on day 7. Of the 9 pigs receiving treatment, 3 died from pneumonia on days 29, 30, and 83 without signs of rejection and another died from gastric rupture on day 42 with persistent mild rejection. The remaining 5 animals were free of rejection at the end of the 90-day follow-up period (P < 0.005 vs controls). Overall, 5 pigs had pneumonia, 4 septic arthritis, 3 toe abscesses, and 5 diarrhea and decreased weight gain. CONCLUSIONS: Combination oral FK506-MMF treatment provided a superior antirejection effect but more produced more toxicity than that previously demonstrated with cyclosporin A-MMF therapy in our model. Our results suggest that reduction of FK506 or MMF doses might decrease both infectious and drug-specific side effects while still providing adequate prophylaxis against rejection.

Animals↗
PubMed1998

Long-term composite tissue allograft survival in a porcine model with cyclosporine/mycophenolate mofetil therapy.

BACKGROUND: Low-dose cyclosporine (CsA)/mycophenolate mofetil (MMF) therapy has significantly reduced the frequency of rejection and drug-induced side effects in rat hindlimb allograft recipients. With an eye toward direct clinical application, we developed a large-animal extremity composite tissue allograft model to assess the antirejection efficacy and systemic toxicity of combination CsA/MMF treatment. METHODS: Radial forelimb osteomyocutaneous flap transplants were performed between size-matched, outbred pigs assigned to one of two groups: 5 control pigs received no immunosuppression, and 10 pigs received a once-daily oral CsA/MMF/prednisone regimen. Rejection was assessed by visual inspection of flap skin and correlated with serial histopathologic examination of skin biopsies. RESULTS: In all control pigs, the flap was completely rejected on day 7. Of the 10 pigs receiving treatment, one died from pneumonia and an another from an anesthetic complication on days 19 and 30, respectively, without signs of rejection. Two flaps were lost on days 25 and 29 from severe rejection. Three pigs were free of rejection at the end of the 90-day follow-up period, and three had stable mild-to-moderate rejection at 90 days (P= 0.0007 vs. controls). White blood cell and platelet counts, serum creatinine values, and liver function tests remained normal in all animals receiving immunosuppressive therapy. CONCLUSIONS: Our results, to our knowledge, demonstrate for the first time that rejection can be significantly delayed in a large-animal composite tissue allograft model including skin using only orally administered agents dosed according to clinically relevant strategies without significant drug-specific systemic side effects.

Animals↗