Genetically-associated chronic obstructive pulmonary disease treatment
09801637 · 2017-10-31
Assignee
Inventors
Cpc classification
A61B17/12131
HUMAN NECESSITIES
A61B90/37
HUMAN NECESSITIES
A61B17/1215
HUMAN NECESSITIES
A61B17/12163
HUMAN NECESSITIES
A61B17/12145
HUMAN NECESSITIES
A61B50/30
HUMAN NECESSITIES
International classification
A61B17/12
HUMAN NECESSITIES
A61B90/00
HUMAN NECESSITIES
Abstract
A method for treating a genetically associated chronic obstructive pulmonary disease. At least one implant is advanced into an airway of a lung having a genetically associated chronic obstructive pulmonary disease. The at least one implant is delivered into the lung to increase tension of the lung and thereby improve breathing function of the lung.
Claims
1. A method for treating a genetically associated chronic obstructive pulmonary disease, comprising: advancing at least one implant into an airway of a lung of a patient having alpha-1 antitrypsin deficiency; and delivering the at least one implant into the lung to increase tension of the lung and thereby improve breathing function of the lung.
2. The method of claim 1, wherein the genetically associated chronic obstructive pulmonary disease causes uniformly diseased alveolus tissue distributed throughout at least one lower lobe the lung, and wherein the advancing and the delivering of the at least one implant are performed so that the at least one implant locally compresses an associated at least one region of the uniformly diseased tissue.
3. The method of claim 1, wherein the genetically associated chronic obstructive pulmonary disease causes uniformly diseased alveolus distributed throughout a lower lobe of the lung, and wherein the advancing and the delivering of the at least one implant are performed so that the at least one implant locally compresses a region of another lobe of the lung outside the uniformly diseased tissue.
4. The method of claim 1, further comprising: determining the patient has a chronic obstructive pulmonary disease, wherein a plurality of alternative therapies are available for treatment of a plurality of alternative types of the chronic obstructive pulmonary disease; identifying that the chronic obstructive pulmonary disease of the patient comprises alpha-1 antitrypsin deficiency from among a plurality of alternative chronic obstructive pulmonary diseases; and selecting a treatment using the at least one implant from among the plurality of alternative therapies in response to the determination that the chronic obstructive pulmonary disease of the patient comprises alpha-1 antitrypsin deficiency.
5. The method of claim 1, wherein improving breathing function comprises reduced air-trapping within the alveolus.
6. The method of claim 1, wherein the at least one implant comprises a coil-shaped implant that folds at least one airway of the lung to increase tension.
7. The method of claim 1, wherein at least one implant comprises a plurality of implants.
8. A method for treating a genetically associated chronic obstructive pulmonary disease, comprising: advancing at least one implant into an airway of a lung having uniformly distributed diseased alveolus within the lung; and compressing a portion of the uniformly distributed diseased alveolus using the at least one implant to cause improved breathing function of the lung.
9. The method of claim 8, wherein the uniformly diseased alveolus is caused by alpha-1 antitrypsin deficiency.
10. The method of claim 8, wherein compressing the uniformly diseased alveolus comprises positioning the at least one implant within the lung to increase tension at at least one lobe of the lung.
11. The method of claim 8, wherein the at least one implant comprises a coil-shaped implant that folds at least one airway of at least one lobe of the lung to increase tension.
12. The method of claim 8, wherein the at least one implant comprises a plurality of implants.
13. A method for treating a genetically associated chronic obstructive pulmonary disease, comprising: implanting at least one implant into a lung having alveolar damage caused by alpha-1 antitrypsin deficiency to increase tension of the lung and thereby improve breathing function of the lung; and provide at least one augmentation therapy to boost circulating alpha-1 antitrypsin plasma levels within the lung and thereby slow or halt progression of the alveolar damage to the lung.
14. The method of claim 13, wherein at least one implant comprises a plurality of implants.
15. A method for treating a genetically associated chronic obstructive pulmonary disease, comprising: advancing at least one implant into an airway of a lung having intact and uniformly diseased alveolus within at least one lower lobe of the lung, the lung having non-diseased alveolus within upper lobes of the lung; and compressing the intact and uniformly diseased alveolus within the at least one lower lobe of the lung using the at least one implant to cause improved breathing function of the lung.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
(1) A better understanding of the features and advantages of the present invention will be obtained by reference to the attached documents that set forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:
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DETAILED DESCRIPTION OF THE INVENTION
I. Etiology and Description of AATD
(42) Alpha-1 antitrypsin deficiency was first reported in 1963 by Carl-Bertil Laurell and Sten Eriksson. They observed a link between low plasma serum levels of alpha-1-antitrypsin and symptoms of pulmonary emphysema.
(43) Alpha-1 antitrypsin is a 52 kD protein belonging to the serpin family of protease inhibitors. Though AAT inhibits multiple targets, it is now known that a major target of inhibition is the human neutrophil elastase (HNE) (Sandhaus, 2004). HNE, in the absence of adequate inhibition by AAT, is free to break down elastin, which creates a loss of the elasticity in the lung tissue, resulting in respiratory complications such as emphysema.
(44) The molecular structure of AAT includes 394 amino acids with 3 glycosylated side-chains. The AAT active site has a methionine molecule that is susceptible to conversion to methionine sulfoxide by oxidants from cigarette smoke, greatly reducing AAT's inhibitory activity on FINE. Thus, low serum levels of AAT can contribute to early onset of clinical symptoms (Russi 2008; ATSERS, 2003).
(45) AATD results when there is a mutation in the gene that directs the body to make the AAT protein. This SERPINA1 gene is carried by both males and females and thus can be inherited from either parent. Genetic AATD is associated with inheritance of one or two alleles with reduced AAT expression or activity (Kumar, 2005). Thus, levels of circulating alpha 1-antitrypsin in the blood depend on genotype. The most common
(46) AAT alleles are: M—Normal (associated with normal amounts of AAT protein) S (slightly deficient) and Z (strongly deficient)—Abnormal (associated with deficient amounts of AAT protein) Null—Abnormal (deficient; no AAT protein is detected)
(47) It is the combination of genes that an individual receives from the parents that determines whether he or she is “normal,” is an AATD “carrier” due to inheritance of one abnormal allele, or is severely deficient in AAT due to inheritance of two abnormal alleles. It is important to understand that the disorder can be inherited either from a parent who has AATD or from parents who are carriers but do not themselves display symptoms of AATD.
(48) Subjects who are identified as AAT deficient carry an increased risk of developing emphysema. This includes the most frequently observed variants such as Z and S genotypes. Subjects with the abnormal gene (Null) and no detectable plasma levels of AAT are also at high risk of developing lung disease. Such individuals with severe AATD are more likely to manifest clinical symptoms (De Serres, 2002; Luisetti, 2004).
(49) Embodiments of the invention include a genetic diagnostic sample delivery subsystem for transmitting a genetic specimen from the patient to a genetic diagnostic system configured for diagnosing AAT deficiency. The diagnostic system can detect low plasma serum levels of AAT to prompt use of another subsystem, such as at least one delivery catheter. It has been found that an AAT serum level of less than 35 mg/dl is associated with AAT deficiency (http://alpha-1foundation.org/testing-for-alpha-1/). The genetic diagnostic sample delivery subsystem can include a cartridge container for storing blood and a needle for collecting a blood sample.
II. Natural History and Progression of the Disease
(50) Severe clinical manifestations of AATD involve the lungs, liver and skin. The signs and symptoms of the condition and the age at which they appear vary among individuals. AATD is often first inappropriately or incompletely diagnosed as asthma or smoking-related COPD. The risk of emphysema increases proportionately to the magnitude of deficiency in AAT serum levels. Normal serum levels of AAT range from 150 to 350 mg/dL (Stoller, 1997). Individuals afflicted with AATD have had AAT serum levels as low as 35 mg/dL.
(51) Most individuals who suffer from advanced AATD experience hyperinflation. With hyperinflation, the most diseased regions of the lung have normal inspiration but trap air upon expiration. Less affected or undamaged regions of the lung can then become compressed by the hyperinflated portions. This compression effectively compromises the remaining tissue that is exchanging gas in the lung.
(52) Many features of emphysema due to AATD are similar to those of emphysema in individuals with normal levels of AAT. However, there are three distinctive features of emphysema associated with AATD described by various authors in the literature.
(53) First, although the onset of emphysema is accelerated by smoking, emphysema can occur in AATD patients who have never smoked or been exposed to other environmental factors, which is exceptionally rare otherwise. Thus this disease is independent of personal choice or environmental factors.
(54) Second, AATD patients often develop emphysema when they are in their 30s or 40s, in contrast to patients who are long time smokers but are not AAT deficient. Non-AAT deficient smokers usually do not develop symptoms until they are in their 50s or 60s. The mean age at diagnosis of AATD-associated emphysema was 46 years in the National Heart, Lung and Blood Institute (NHBLI) registry and 50 years in the British Thoracic Association series (Stoller, 1997).
(55) Third, the radiographic pattern of AATD emphysema patients differs significantly from that of AATD-independent emphysema patients (Kaplan, 2010). Conventional emphysema due to smoking usually causes emphysematous tissue in the upper parts of the lung. In contrast, AATD emphysema patients show a radiographic pattern of panacinar emphysema predominant in the lung bases rather than the apex (Holme, 2009).
(56) Additionally, AAT augmentation therapy is prescribed for AATD patients and pharmacotherapy regimes vary from the more widespread form of emphysema associated with smoking and/or asthma.
III. Prevalence and Incidence of AATD
(57) AATD is a rare genetic deficiency, with estimates of prevalence ranging from 26,000 to 155,000 total affected individuals in the US. See below for a summary of available citations and the estimates provided therein (Table 1), collected from scientific and medical peer-reviewed articles, reviews and textbooks; the websites of patient advocacy groups (e.g., Alpha-1 Foundation); and governmental agency statistics (e.g., Centers for Disease Control).
(58) Emphysema resulting from AATD generally occurs relatively early in life (in comparison to emphysema pursuant to smoking or occupational exposure). People develop symptoms in their 30s or 40s in smokers and in their 40s and 50s for non-smokers (Fregonese, 2008). Life expectancy from the time that symptoms appear is approximately 15 years (AllergyCases.org):
(59) “Adults with α1-antitrypsin deficiency present with emphysema in the third or fourth decade of life . . . . Smokers with α1-antitrypsin deficiency develop symptoms by 30 to 40 years, whereas nonsmokers do not become symptomatic until 50 years of age. Mean life expectancy for smokers is 50 years and 66 years for nonsmokers.”
(60) Thus, to provide the most conservative (i.e. the highest) estimate of yearly incidence, a life expectancy of 50 years is used in Table I below to calculate incidence from the cited prevalence values.
(61) TABLE-US-00001 TABLE 1 Summary of Prevalence and Incidence Values for AATD Estimate of Incidence Statistic Cited in Estimate of (individuals/ Reference Reference Prevalence.sup.a year) Kaplan, 2010 1 in 2,000 to 1 in 5,000 62,000 to 1,240 to 3,100 individuals 155,000 Alpha-1 Foundation 100,000 individuals 100,000 2,000 (www.alpha-1foundation.org) with AATD Alpha-1 Foundation 1 in 2,500 individuals 124,000 2,480 (www.alpha-1foundation.org) www.orpha.net 1 in 5,000 to 1 in 10,000 31,000 to 620 to 1,240 individuals 62,000 Luisetti, 2004 310,881 individuals 181,800 3,636 with AATD.sup.b CDC (Summary Health 2% of adults aged 18 47,000 to 940 to 2820 Statistics for U.S. Adults) and over diagnosed with 141,000 National Center for Health emphysema; 1-3% of Statistics (Akinbami, 2011) emphysema cases due to AATD.sup.c Alpha-1 Association 1 in 2,500 individuals 124,000 2,480 (www.alpha1.org) with AATD Fregonese, 2008 1 in 2,500 124,000 2,480 AAT Registry 100,000 individuals 100,000 2,000 (www.aatregistry.org) with AATD Stoller, 1997 60,000 to 100,000 60,000 to 1,200 to 2,000 individuals with AATD 100,000 .sup.aAll estimates assume a U.S. population of 310 million individuals. .sup.bCited statistic was 257,708 individuals with Pi*S/Pi*Z genotype and 53,173 individuals with Pi*Z/Pi*Z genotype in North America, who together make up the vast majority of the population with manifest AAT deficiency. Assuming a North American population of ~530 million and a U.S. population of 310 million, this suggests ~150,700 individuals with Pi*S/Pi*Z genotype and 31,100 individuals with Pi*Z/Pi*Z genotype in the U.S. .sup.cAssumes 235 million adults (aged 18 and over) in the U.S. 2% of this population yields 4.7 million people diagnosed with emphysema, and 1-3% (47,000 to 141,000) are due to AAT deficiency.
(62) The data summarized in Table 1 above suggests that the incidence of AATD ranges from 620 to 3,636 cases per year, with most estimates of incidence at approximately 2,000 new births per year. Importantly, however, it has been noted that only a small fraction of AATD individuals have been properly diagnosed. The clinical manifestations of AATD, including breathlessness, cough, phlegm, wheeze and fatigue, especially in individuals who are non-smokers or never-smokers, leads to frequent misdiagnosis of AATD as asthma. Kaplan (2010, reference therein), Sandhaus (2004), and the Alpha-1 Foundation estimate that only 5-10% of individuals with AATD have been properly diagnosed. Applied against the estimates of the true incidence rate from Table 1 above (620 to 3,636 per year), this suggests that only 31 to 364 cases (100 to 200 cases in most estimates) will be diagnosed yearly.
(63) Furthermore, the incidence rates noted above include some early diagnoses in individuals who still retain normal lung function and display only mild spirometric obstruction. COPD is rarely seen before the age of 30 in AATD, therefore, any proposed intervention that targets hyperinflation or an FEV1<50% predicted, such as the PneumRx AATD Treatment System, would be appropriate for the smaller fraction of patients showing these clinical symptoms.
IV. AATD is an Orphan Indication
(64) Consistent with the analysis in Section 3.3, both AATD and AATD-related emphysema have been assigned orphan indication status by the FDA. These determinations, obtained from the FDA Office of Orphan Products Development (OOPD) database, are listed in Table 2 below. Though the standards for demonstrating a rare disease population are different for drugs [prevalence of fewer than 200,000 individuals, as per 21 CFR 316.20(b)(8)(0] and devices [incidence of fewer than 4,000 individuals per year, as per 21 CFR 814.3(n)], designation of orphan status indicates that FDA accepts the total prevalence of AATD in the US to be fewer than 200,000 individuals. This is in substantial agreement with the prevalence estimates above (ranging from 26,000 to 181,800 individuals in the US), which were derived from scientific and medical literature, advocacy groups, and various registries/databases.
(65) TABLE-US-00002 TABLE 2 Summary of Orphan Drug Product Designations for AATD by FDA Desig- nation Generic Name Date Indication Alpha-1-Antitrypsin Jan. 1, As supplementation therapy for (Recombinant DNA 1984 alpha-1-antitrypsin deficiency in Origin) the ZZ genotypepopulation. Alpha1-Proteinase Dec. 7, For replacement therapy in the Inhibitor (Human) 1984 alpha-1-proteinase inhibitor congenital deficiency state. Hyaluronic Acid Mar. 19, Treatment of emphysema in 2002 patients due to alpha-1 antitrypsin deficiency. Recombinant Mar. 29, Treatment of congenital alpha-1 Secretory Leucocyte 1991 antitrypsin deficiency. Protease Inhibitor May 19, Treatment of emphysema Transgenic Human 1999 secondary to alpha 1 antitrypsin Alpha 1 Antitrypsin deficiency. Alpha1 Proteinase Jan. 29, Treatment of emphysema Inhibitor (Human) 2010 secondary to congenital alpha1- antitrypsin deficiency. Alpha1-Proteinase Nov. 24, For slowing the progression of Inhibitor (Human) 1999 emphysema in alpha1-antitrypsin deficient patients. Recombinant Adeno- Jan. 27, Treatment of alpha1-antitrypsin Associated Virus 2003 deficiency. Alpha 1-Antitrypsin Vector
(66) Of the four therapeutics approved as augmentation therapies for the treatment of AATD (discussed in more detail in Section 4 below), Prolastin was approved as an orphan drug.
V. Treatment Options for AATD-Induced Emphysema
(67) Symptomatic patients with AATD-associated emphysema are currently treated according to published guidelines for treatment of emphysema with the addition of augmentation therapy. If applicable, smoking cessation is the first line recommended treatment. Many of the medical treatments available for emphysema including medications, supplemental oxygen and pulmonary rehabilitation may be effective for the AATD population. However, there are no existing therapies for relieving or improving symptoms of AATD-associated emphysema involving the use of implants, namely lung volume reduction implants as disclosed herein. Atelectasis inducing implants for non-genetically induced emphysema would not be useful for AATD-associated emphysema, since empty cavities traversing diseased alveoli are not associated with AATD-associated emphysema to make use of such devices. Hence, there may be a substantial belief by those skilled in the art that, in general, an implantable device for lung volume reduction would not be effective for treating AATD-associated emphysema.
(68) AATD-associated emphysema can be treated medically with inhaled bronchodilators, inhaled corticosteroids, and supplemental oxygen. These patients are prone to respiratory infections and thus are often prescribed antibiotics as well. Pulmonary rehabilitation includes exercise, training, and education. Although lung transplant remains an option for some patients, this option is considered to be a last resort due to its high risks. LVRS, an uncommon option in COPD, has not been shown to be effective in AATD-induced emphysema (Stoller, 2007)).
(69) Because of the genetic deficiency inherent in AATD-associated disease, AATD patients are commonly treated with augmentation therapy (see Table 3 below). Augmentation therapy with intravenous administration of human AAT increases the levels of AAT in the bronchoalveolar lavage fluid of AATD individuals (ATSERS, 2003). This therapy maintains the serum AAT concentration at levels sufficient to inhibit most HNE. However, in contrast to the proven effectiveness of augmentation treatment, the clinical effect of supplemental AAT on pulmonary function, morbidity and survival has been demonstrated only in prospective observational studies, but not in randomized controlled trials. Finally, because these augmentation therapies (Table 3 below) seek to prevent progression of emphysema, approvals do not claim improvement in symptoms of emphysema in patients with existing disease.
(70) TABLE-US-00003 TABLE 3 Augmentation Therapies for Alpha-1-Antitrypsin Deficiency in the U.S. Treatment Prolastin-C ® Aralast ® Zemaira ® Glassia ® Manufacturer Talecris Alpha Aventis Kamada, Ltd. Biotherapeutics, Therapeutic Behring LLC (U.S. rights acquired Inc (now Corp. (now (now by Baxter) manufactured manufactured manufactured by Grifols) by Baxter) by CSL Behring) Orphan Status Prolastin has No orphan status No orphan status No orphan status orphan License BLA; Dec. 2, BLA; Dec. 23, BLA; Jul. 8, BLA; Jul. 1, 2010 1987 2002 2003 Indication Adults who have Indicated for Chronic GLASSIA is an alpha1- emphysema augmentation augmentation proteinase inhibitor that caused by therapy in and maintenance is indicated for chronic inherited alpha patients having therapy in augmentation and 1-antitrypsin congenital individuals with maintenance therapy in deficiency deficiency of alpha1- adults with emphysema alpha1- proteinase due to congenital proteinase inhibitor deficiency of alpha1- inhibitor with deficiency and proteinase inhibitor clinically evidence of (Alpha1-PI), also evident emphysema known as alpha1- emphysema antitrypsin deficiency Contraindications Not indicated Contraindicated in Individuals IgA deficient patients as therapy for individuals with with selective with antibodies against lung disease in selective IgA IgA IgA; history of severe patients in deficiencies (IgA deficiencies immediate whom severe level less than 15 who have hypersensitivity Alpha1- PI mg/dL) who have known reactions, including deficiency has known antibody antibodies anaphylaxis, to Alpha1- not been against IgA, since against IgA PI products established; they may (anti-IgA IgA deficient experience severe antibodies) patients with reactions, including should not antibodies anaphylaxis receive against IgA Zemaira should not receive Prolastin-C due to the risk of hypersensitivity Route of Admin Intravenous Intravenous Intravenous Intravenous infusion infusion infusion infusion Adverse Events Chills, a general Headache, Asthenia, The most common feeling of being musculoskeletal injection site product-related adverse unwell, headache, discomfort and pain, dizziness, reactions (>5%) in rash, hot flush, somnolence headache, clinical studies were and itching paresthesia and headache and dizziness pruritus
(71) Unlike augmentation therapy, the embodiments disclosed herein intended to improve lung function, exercise capacity and quality of life in patients who have emphysema due to deficiency of genetically related emphysema, such as alpha-1 antitrypsin, by achieving a lung volume reduction implant system using minimally invasive means. As noted above, the panacinar sub-type of emphysema is most commonly associated with AATD patients (Holme, 2009). Panacinar emphysema destroys the entire alveolus uniformly and predominantly affects the lower half of the lungs.
(72) Many embodiments include at least one implant that behaves as a spring element that, through compression of diseased tissue, creates tension in the surrounding healthy lung tissue and may result in restoration of radial suspension of the lung airway network. By compressing the diseased tissue and providing increased tension and outward radial support of airways in the healthy parts of the lung, the implant can reduce air-trapping and help regain diaphragm mobility and muscle activity, which also supports breathing function.
(73) The implant is available in different lengths. Longer lengths of the implant to facilitate access to diseased tissue through longer airways, and sufficiently treat the lower lobes, for example 100-150 mm. Thus, an implant may be placed within a middle and/or upper lobe to affect treatment of a lower lobe. Since AATD emphysema patients show panacinar emphysema predominant in the lung bases, such lengths are anticipated to facilitate access to the diseased tissue in the lower zones of the lung. Generally, at least one implant is required to affect treatment of a lower lobe, however, a plurality of implants can be used. For example, in some cases 8-12 implants can be used. Regardless, it should be understood that the number of implants used depends on the particular type of implant(s), the state of disease in the recipient lung, and implant location(s). For example, stronger coils can be used within upper lobes of a lung to affect a diseased lower lobe and/or relatively weaker coils can be used directly within the lower lobe.
(74) Currently there is no other device or drug available, specifically for this population, that helps treat the symptoms of AATD-induced emphysema and improve quality of life for these patients. The augmentation therapies treat the underlying cause of the disease but do not claim to improve the clinical symptoms or treat/mitigate lung tissue damage that has already occurred. Because the implant system is designed to restore lung recoil and improve clinical symptoms, it is expected to improve quality of life for AATD emphysema patients. The two therapies have different mechanisms of action in targeting AATD-dependent emphysema, and it is suggested that the disclosed implant system may be used concurrently with augmentation therapy to provide both immediate improvement in disease symptoms and a delay in progression of the disease itself (augmentation therapy).
(75) TABLE-US-00004 TABLE 4 Potential advantages and benefits of the implant system as a treatment for emphysema due to AATD. Aspect of Currently Approved Therapies Therapy (Prolastin-C, Aralast, Zemaira, Glassia) Implant system Nature of All are drugs within the same therapeutic Device. Unique therapeutic therapy class (augmentation therapy with purified modality with a novel, alpha-1 antitrypsin). mechanical Mechanism of Action (MOA). May be useful in patients who do not respond to augmentation therapy or for whom augmentation therapy is contraindicated. Risk of disease Purified from pooled human plasma No risk of disease transmission. transmission (possible risk of disease transmission, including HIV, hepatitis, Parvovirus, or Creutzfeldt- Jakob disease transmission). Immune Prolonged treatment may promote No expectation of immune response development of antibodies to the protein response; can be used for therapy. prolonged treatment. All drugs are contraindicated in patients IgA sensitivity would not with IgA sensitivity due to the possibility restrict implantation of the presence of IgA in the product (severe coils. hypersensitivity/anaphylaxis may result). Mechanism of Disease-modifying therapy Symptom-modifying therapy Action (MOA) (replacement of natural alpha-1 (mechanically compresses antitrypsin inhibits neutrophil damaged parenchyma and elastase activity in the lung). tenses the surrounding Late diagnosis of AATD is common due healthy tissue, thereby to similarity of symptoms to asthma and increasing elastic recoil, the lack of association with smoking; gap reducing hyperinflation, and between symptom onset and diagnosis is redirecting air to healthier frequently 7 years or more (Needhan, portions of the lung). 2004; Kaplan, 2010). Thus most Effective in ameliorating diagnoses occur in patients with emphysema symptoms, but significant existing lung damage and not predicted to be effective significant emphysema in slowing progression of symptoms. emphysema. Effective in slowing development or PneumRx System MOA is progression of emphysema due to predicted to complement unrestrained elastase activity, but not augmentation therapies effective in ameliorating existing rather than replace them. emphysema symptoms. Safety Though generally safe, associated adverse Not predicted to share an AE events (AEs) include asthenia, injection profile with available site pain, dizziness, headache, paresthesia, augmentation therapies. AEs pruritus, chills, malaise, rash, hot flush, associated with the treatment and somnolence. system placement are similar in type and frequency to those seen with bronchoscopy alone(required for deployment of the implants).
(76) TABLE-US-00005 TABLE 5 Comparison with Known Therapies Trade Name Prolastin-C ® Aralast ® Zemaira ® Glassia ® Implant System Mechanism Because Augmentation Zemaira ® GLASSIA ® The implant system of PROLASTIN ® therapy has been serves as A1-PI is an is intended to Action “augments” or shown to maintain augmentation augmentation improve lung (MOA) replaces missing serum levels of therapy in this therapy that function in patients AAT, it is AAT above the patient serves to with emphysema by referred to as ATS/ERS- population, maintain introducing nitinol “augmentation recommended acting to serum levels spring coil(s) therapy” or protective increase of AAT implant(s) into the “replacement threshold of and maintain lungs to compress therapy.” 11 μM. serum levels damaged tissue and lung (lung volume epithelial lining reduction) and fluid (ELF) restore elastic recoil levels of A1- to the remaining PI. undamaged lung tissue via minimally invasive means. Adverse chills, a general headache, asthenia, The most Bronchoscopy Events feeling of being musculosk injection site common procedure related unwell, eletal pain, dizziness, product-related adverse events headache, discomfort headache, adverse such as rash, hot and paresthesia and reactions (>5%) pneumothorax and flush, and somnolence. pruritus. in clinical infection; immune itching. studies were reaction to the headache and implant is rare. dizziness. Pros Effective in slowing progression of emphysema. Effective in treating the symptoms of emphysema. Cons Because this product is made from human plasma, it may carry a risk MOA predicts no of transmitting infectious agents. slowing in The effect of therapy with any ATT on pulmonary exacerbations and progression of on the progression of emphysema in ATT deficiency has not been emphysema. demonstrated in randomized, controlled clinical trials.
(77) Per the FDA OOPD database, augmentation therapies that boost circulating AAT plasma levels have been classified under orphan drugs, indicating that the FDA has previously determined that the AATD patient population in the United States is fewer than 200,000 individuals. There are approximately 100 to 200 new AATD emphysema diagnoses in the U.S. each year. The combined estimated incidence of diagnosed and undiagnosed AATD emphysema is 620 to 3636 cases per year. These numbers qualify the disclosed implant system for a Humanitarian Use Device designation in this indication.
(78) As shown above, there are several medical treatments available for AATD emphysema patients including augmentation therapy and surgery. Augmentation therapy slows the progression of the underlying damage to the lung, but is not intended to improve current clinical symptoms of emphysema. Surgical options, including LVRS and lung transplant surgery, are highly invasive and carry significant safety risks. The disclosed implant system and the method for use can also have their own related adverse events, but the benefits of the implant system outweigh the risks involved, and the device offers unique benefits that are not currently available with pharmacotherapy. The implant system can be used concomitantly with augmentation therapy or alone in the treatment of symptoms from emphysema associated with AATD. The implant system is anticipated to be safe for its intended use using a minimally invasive procedure, and, unlike augmentation therapy, the implant system may provide relief from emphysema symptoms, unlike augmentation therapy, with a minimally invasive procedure.
VI. Literature References
(79) 1. AAT Registry. http://www.aatregistry.org/. 2. Akinbami L J, Liu X. Chronic Obstructive Pulmonary Disease Among Adults Aged 18 and Over in the United States, 1998-2009. National Center for Health Statistics Data Brief; June 2011. 3. AllergyCases.org. http://allergycases.org/2008/02/alpha-1-antitrypsin-deficiency.html. 4. Alpha-1 Association. http://www.alpha1.org/. 5. Alpha-1 Foundation. http://alpha-1foundation.org/. 6. Alpha-1-antitrypsin-deficiency. http://ghr.nlm.nih.gov/condition/alpha-1-antitrypsin-deficiency. 7. American Thoracic Society; European Respiratory Society (ATSERS). American Thoracic Society/European Respiratory Society statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med Vol 168. pp 818-900, 2003. http://www.thoracic.org/statements/resources/respiratory-disease-adults/alpha1.pdf. 8. Bronchoscopy. Johns Hopkins Medicine: Health Library. http://www.hopkinsmedicine.org/healthlibrary/test_procedures/pulmonary/bronchoscopy_92, P07743/. 9. Bronchoscopy. Medline Plus. http://www.nlm.nih.gov/medlineplus/ency/article/003857.htm. 10. de Serres F J. Worldwide racial and ethnic distribution of alpha1-antitrypsin deficiency: summary of an analysis of published genetic epidemiologic surveys. Chest. 2002. 122(5): 1818-29. 11. Fregonese L, Stalk J. Hereditary alpha 1 antitrypsin deficiency and its clinical consequences. Orphanet Journal of Rare Diseases 2008, 3:16. 12. Genetic and Rare Diseases website. http://rarediseases.info.nih.gov/GARD/Default.aspx?PageID=4. 13. Holme J, Stockley R A. C T scan appearance, densitometry, and health status in protease inhibitor S Z alpha1-antitrypsin deficiency. Chest. 2009 Nove; 136(5):1284-1290. 14. Kaplan A, Cosentino L. Alpha1-antitrypsin deficiency: forgotten etiology. Can Fam Physician. 2010 January; 56(1):19-24. 15. Kumar V, Abbas A K, Fausto N, ed. (2005). Robbin and Cotran Pathological Basis of Disease (7th ed.). Elsevier/Saunders: 911-2. 16. Luisetti M, Seersholm N. Alpha1-antitrypsin deficiency. 1: epidemiology of alpha1-antitrypsin deficiency. Thorax. 2004 February; 59(2):164-9. 17. National Center for Health Statistics Data Brief. Chronic Obstructive Pulmonary Disease Among Adults Aged 18 and Over in the United States, 1998-2009; June 2011. 18. National Heart, Lung and Blood Institute, U.S. Department of Health and Human Services. http://www.nhlbi.nih.gov/heatth/health-topics/topics/bron/risks.html. Feb. 8, 2012. 19. Needham M, Stockley R A. Alpha 1-antitrypsin deficiency. 3: Clinical manifestations and natural history. Thorax. 2004 May; 59(5):441-5. Review. 20. Office of Orphan Products Development (OOPD). http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm. Feb. 8, 2012 21. Orphanet. http://www.orpha.net/consor/cgi-bin/index.php. 22. Piitulainen E, Eriksson S. Decline in FEV1 related to smoking status in individuals with severe alpha1-antitrypsin deficiency (PiZZ). Eur Respir J. 1999 February; 13(2):247-251. 23. Russi E W. Alpha-1 antitrypsin: now available, but do we need it? Swiss Med Weekly. 2008 Apr. 5; 138(13-14):191-6. 24. Sandhaus R A. α1-Antitrypsin deficiency? 6: New and emerging treatments for a 1-antitrypsin deficiency. Thorax 2004; 59(10):904-909. 25. Sotller, J K, Gildea, T R, Ries, A L, Meli, Y M, Karafa, M T, Lung Volume Reduction Surgery in Patients with Emphysema and alpha-1 Antitrypsin Deficiency, Ann. Thoracic Surg. 2007; 83:241-251. 26. Summary Health Statistics for U.S. Adults: National Health Interview Survey, 2010; Vital and Health Statistics, CDC series 10 #252, January 2012; 30-36.
(80) By way of background and to provide context for embodiments herein,
(81) As shown in more detail in
(82) The lungs 19 are described in current literature as an elastic structure that floats within the thoracic cavity 11. The thin layer of pleural fluid that surrounds the lungs 19 lubricates the movement of the lungs within the thoracic cavity 11. Suction of excess fluid from the pleural space 46 into the lymphatic channels maintains a slight suction between the visceral pleural surface of the lung pleura 42 and the parietal pleural surface of the thoracic cavity 44. This slight suction creates a negative pressure that keeps the lungs 19 inflated and floating within the thoracic cavity 11. Without the negative pressure, the lungs 19 collapse like a balloon and expel air through the trachea 12. Thus, the natural process of breathing out is almost entirely passive because of the elastic recoil of the lungs 19 and chest cage structures. As a result of this physiological arrangement, when the pleura 42, 44 is breached, the negative pressure that keeps the lungs 19 in a suspended condition disappears and the lungs 19 collapse from the elastic recoil effect.
(83) When fully expanded, the lungs 19 completely fill the pleural cavity 38 and the parietal pleurae 44 and visceral pleurae 42 come into contact. During the process of expansion and contraction with the inhaling and exhaling of air, the lungs 19 slide back and forth within the pleural cavity 38. The movement within the pleural cavity 38 is facilitated by the thin layer of mucoid fluid that lies in the pleural space 46 between the parietal pleurae 44 and visceral pleurae 42. As discussed above, when the air sacs in the lungs are damaged 32, such as is the case with emphysema, it is hard to breathe. Thus, isolating the damaged air sacs to improve the elastic structure of the lung improves breathing. Similarly, locally compressing regions of the lung tissue while maintaining an overall volume of the lung increases tension in other portions of the lung tissue, which can increase the overall lung function.
(84) A conventional flexible bronchoscope is described in U.S. Pat. No. 4,880,015 to Nierman for Biopsy Forceps. As shown in
(85)
(86)
(87) Positioned within a lumen 113 of the tubular member 112, is an actuation element 116 or pull-wire. The actuation element can have a circular circumference in cross-section, as depicted, or can have any other suitable cross-section. The actuation element 116 may be anchored at one end of the device 110, e.g. the distal end, by a cap 119. The cap 119 can be bonded to the device and a distal crimp can be provided to crimp the cap 119 into the pull-wire 116. The cap 119 may be rounded as depicted to make the dip of the device atraumatic. Alternatively, cap 119 may be configured to include an anchor configured to grasp the adjacent airway during the device deployment within the airway. The anchor may increase the amount of tissue compression by a deployed device and thereby increase the amount of beneficial tension in the lung. Such optional anchors are discussed further below. The opposing end, e.g. proximal end, may be adapted and configured to engage a mechanism 120. The mechanism 120 may be adapted deploy the device. Further mechanism 120 may be configured to lock the device into a deployed configuration once the device 110 is deployed or to unlock the device to facilitate retrieval of the device from an airway. The device 110 may be configured to be detachable from a delivery catheter adapted to deliver the lung volume reduction device. The delivery catheter and delivery of the device are discussed further below.
(88) Mechanism 120, at the proximal end of the device may be adapted to include a retainer ring 122 that engages a ratchet 124 that can be used to lock the device in place. The coupler 126 retains the ratchet 124 such that the ratchet locks the device in place once deployed. At the proximal end, a retrieval adapter 130 is provided, such as a pull-wire eyelid. The retrieval adapter 130 may be adapted and configured to enable the device to be retrieved at a later point during the procedure or during a subsequent procedure. The ratchet device may include flanges that extend away from a central axis when deployed to lock the device in place.
(89)
(90)
(91)
(92)
(93)
(94)
(95)
(96) In another embodiment of the invention, as illustrated in
(97)
(98) A Nitinol metallic implant, such as the one illustrated in
(99)
(100)
(101)
(102)
(103)
(104)
(105)
(106)
(107)
(108)
(109) In this particular embodiment, device 900 comprises a shape-memory material, however a person of ordinary skill would recognize that many of the methods described above may be used to configure a device such that it may be mechanically actuated and locked into a similar configuration. Device 900 as shown in the figures includes a right-handed helical section and a left-handed helical section and the transition section 910 between the two helical sections comprises a switchback transition section when the device is in the pre-implantation or post-implantation configuration. The switchback transition section may reduce the recoil forces during device 900 deployment thereby providing greater control of device 900 during deployment. Additionally, the switchback transition may reduce migration of the implant after deployment and thus maintain the device's tissue compression advantages. As shown in
(110)
(111) The proximal end 912 and distal end 914 of device 900 may be configured to be atraumatic. In the depicted embodiment, proximal end 912 and distal end 914 comprises a ball with a diameter of about 0.055±0.005 in which may be made by melting back a portion of the wire or may be additional components that are welded, pressed or glued onto the ends of the wire. The atraumatic ball may have a smaller surface area to allow a low catheter friendly profile or a larger ball which reduces the tissue stress with the larger surface area. In other embodiments, an anchor may be used to couple the proximal end or distal end of device 900 to an airway wall during the deployment of the device.
(112) Proximal end 912 is also configured as a stand-off proximal tail which may be defined by an outer cylindrical boundary defined by the distal coil. For example, as shown in
(113)
(114)
(115)
(116)
(117)
(118) The implant can be placed in pathologic regions in the lung that provide limited or no exchange of gas to and from the blood stream because the alveolar walls used to do so have been degraded by disease due to degeneration of elastin. These are typically the most degraded regions that have lost mechanical strength and elasticity. In an inhaling COPD patient these degraded areas fill with air first, at the expense of gas filling in regions that could better help the patient, because the weakened tissue presents little to no resistance to gas filling. By implanting the devices in these areas, resistance is provided so the gas is filled in regions that still can effectively exchange elements to and from the blood stream. Viable regions have structure remaining so resistance to gas filling is present as this is a normal physiologic property. The implant advantageously provides more gas filling resistance in the destroyed regions than the normal physiologic resistance in the viable regions so gas flows to viable tissue. This eliminates or reduces the counterproductive “preferential filling” phenomenon of the most diseased lung tissue prior to treatment. However, as mentioned above, the implant can be placed in non-diseased regions in the lung to affect diseased portions of the lung. Thus, the implant may be placed within a middle and/or upper lobe to affect treatment of a lower lobe.
(119) The implantable device may also delay collapse of airways during a breathing cycle thereby limiting the amount of air trapping in a lung. Accordingly, patients with small airway disease or with alpha 1-antitrypsin deficiency may also be treated with such a device. Additionally, the implantable device may be configured to provide enhanced breathing efficacy immediately after implantation while still allowing gas exchange distal to the deployed implant thereby reducing the chance of atelectasis of lung tissue distal to the implant.
(120) As with previous embodiments, the embodiments depicted in
(121) The devices can have any suitable length for treating target tissue. However, the length typically range from, for example, 1 to 20 cm. The diameter of the device can range from 1.00 mm to 1.5 mm, 1.00 to 3.0 mm, and in some embodiments 2.4 mm. The device is used with a catheter which has a working length of 60 cm to 200 cm, preferably 90 cm.
(122) In operation the devices shown in
(123) Each of the devices depicted in
(124) Embodiments of the lung volume reduction system can be adapted to provide an implant that is constrained in a first configuration to a relatively straighter delivery configuration and allowed to recover in situ to a second configuration that is less straight configuration. Devices and implants can be made, at least partially, of spring material that will fully recover after having been strained at least 1%, suitable material includes a metal, such as metals comprising Nickel and Titanium. In some embodiments, the implant of the lung volume reduction system is cooled below body temperature in the delivered configuration. In such an embodiment, the cooling system can be controlled by a temperature sensing feedback loop and a feedback signal can be provided by a temperature transducer in the system. The device can be configured to have an Af temperature adjusted to 37 degrees Celsius or colder. Additionally, at least a portion of the metal of the device can be transformed to the martensite phase in the delivery configuration and/or can be in an austenite phase condition in the deployed configuration.
(125) Lung volume reduction systems, such as those depicted in
(126) As will be appreciated by those skilled in the art, the devices illustrated in
(127)
(128) A variety of steps for performing a method according to the invention would be appreciated by those skilled in the art upon review of this disclosure. However, for purposes of illustration,
(129) In one embodiment, the device operation includes the step of inserting a bronchoscope into a patient's lungs and then inserting an intra-bronchial device or lung volume reduction device into the bronchoscope. The intrabronchial device is then allowed to exit the distal end of the bronchoscope where it is pushed into the airway. A variety of methods can then be used to verify the positioning of the device to determine if the device is in the desired location. Suitable methods of verification include, for example, visualization via visualization equipment, such as fluoroscopy, CT scanning, etc. Thereafter the device is activated by pulling the pull wire proximally (i.e., toward the user and toward the exterior of the patient's body). At this point, another visual check can be made to determine whether the device has been positioned and deployed desirably. Thereafter, the device can be fully actuated and the ratchet can be allowed to lock and hold the device in place. Thereafter, the implant is decoupled from the delivery catheter and the delivery catheter is removed.
(130) Another method of tensioning the lung is shown in
(131)
(132)
(133)
(134)
(135) Guidewire 5203 is threaded through bronchoscope 4902 and through the airway system to (and through) airway 5002. As described above, guidewire 5203 may optionally have a cross-section significantly smaller than that of the scope and/or the delivery catheter. Alternative embodiments may use a relatively large diameter guidewire. For example, rather than relying on a tapering dilator between the guidewire and the delivery catheter, the guidewire may instead be large enough to mostly or substantially fill the lumen of the delivery catheter, while still allowing sliding motion of the guidewire through the lumen. Suitable guidewires may have cross-section in a range from about 5 Fr to about 7 Fr, ideally being about 5½ Fr, while the delivery catheter may be between about 5 Fr and 9 Fr, ideally being about 7 Fr. A distal end 5209 of the guidewire 5203 may be angled as described above to facilitate steering. Still further variations are also possible, including delivery of the implant directly thru a working lumen of an endoscope (with use of a separate delivery catheter). In particular, where a cross-sectional size of a bronchoscope allows the scope to be advanced to a distal end of the target airway region, the bronchoscope itself may then be used as a delivery catheter, optionally without remote imaging.
(136) A fluoroscopic system, an ultrasound imaging system, an MRI system, a computed tomography (CT) system, or some other remote imaging modality having a remote image capture device 5211 allows guidance of the guidewire so that the guidewire and/or delivery catheter 5201 can be advanced beyond the viewing field of bronchoscope 4902. In some embodiments, the guidewire may be advanced under remote image guidance without the use of a scope. Regardless, the guidewire can generally be advanced well beyond the near lung, with the distal end of the guidewire often being advanced to and/or through the mid-lung, optionally toward or to the small airways of the far lung. When a relatively large guidewire is used (typically being over 5 Fr., such as a 5½ Fr guidewire), the cross-section of the guidewire may limit advancement to a region of the airway having a lumen size appropriate for receiving the implants described above. The guidewire may have an atraumatic end, with exemplary embodiments having a guidewire structure which includes a corewire affixed to a surrounding coil with a resilient or low-column strength bumper extending from the coil, the bumper ideally formed by additional loops of the coil with separation between adjacent loops so as to allow the bumper to flex axially and inhibit tissue damage. A rounded surface or ball at the distal end of the bumper also inhibits tissue injury. A distal end 5244 of laterally flexible delivery catheter 5201 can then be advanced through the lumen within bronchoscope 4902 and over guidewire 5203 under guidance of the imaging system, ideally till the distal end of the delivery catheter is substantially aligned with the distal end of the guidewire.
(137) The distal portion of guidewire 5203 is provided with indicia of length 5206, the indicia indicating distances along the guidewire from distal end 5209. The indicia may comprise scale numbers or simple scale markings, and distal end 5244 of catheter 5201 may have one or more corresponding high contrast markers, with the indicia of the guidewire and the marker of the catheter typically visible using the remote imaging system. Hence, remote imaging camera 5211 can identify, track or image indicia 5206 and thus provide the length of the guidewire portion extending between (and the relative position of) the distal end of the bronchoscope and the distal end 5209 of guidewire 5203. Indicia of length 5206 may, for example, comprise radiopaque or sonographic markers and the remote imaging modality may comprise, for example, an x-ray or fluoroscopic guidance system, a computed tomography (CT) system, an MRI system, or the like. Exemplary indicia comprise markers in the form of bands of high-contrast metal crimped at regular axial intervals to the corewire with the coil disposed over the bands, the metal typically comprising gold, platinum, tantalum, iridium, tungsten, and/or the like. Note that some of the indicia of the guidewire are schematically shown through the distal portion of the catheter in
(138) Remote imaging modality 5221 is coupled to imaging processor 5224 via cable 5215. Imaging processor 5224 is coupled to a monitor 5226 which displays an image 5228 on screen 5227. Image 5228 shows the indicia of lengths 5205 and 5206 of delivery catheter 5201 and guidewire 5203, respectively. As described above, when a small-diameter guidewire is used a dilator 5217 may be advanced through the lumen of the catheter so that the distal end of the dilator extends from the distal end of delivery catheter 5201 when the catheter is being advanced. Dilator 5217 atraumatically expands openings of the airway system as delivery catheter 5201 advances distally. Dilator 5217 tapers radially outwardly proximal of the distal tip of guidewire 5203, facilitating advancement of the catheter distally to or through the mid-lung toward the far lung. Once the catheter has been advanced to the distal end of airway portion 5002 targeted for delivery (optionally being advanced over the guidewire to the distal end of the guidewire when a large diameter guidewire is used to identify a distal end of a target region for an implant, or as far as the cross-section of the catheter allows the catheter to be safely extended over a smaller diameter guidewire), the length of the airway (optionally between the distal end of the guidewire and the distal end of the bronchoscope) is measured. The dilator 5217 (if used) and guidewire 5203 are typically withdrawn proximally from deliver catheter 5201 so as to provide an open lumen of the delivery catheter from which a lung volume reduction device or implant can be deployed.
(139)
(140)
(141) In exemplary embodiments, the pusher grasper 5009 moves distally while the catheter 5201 is retracted proximally from over the implant during deployment. The selected implant may have a length greater than the measured distance between the distal end of the guidewire (and hence the end of the delivery catheter) and the distal end of the scope. This can help accommodate recoil or movement of the ends of the implant toward each during delivery so as to avoid imposing excessive axial loads between the implant and tissue. Distal movement of the pusher grasper 5009 and proximal end of the implant during deployment also helps keep the proximal end of the implant within the field of view of the bronchoscope, and enhances the volume of tissue compressed by the implant. Exemplary implants may be more than 10% longer than the measured target airway axial region length, typically being from 10% to about 30% longer, and ideally being about 20% longer. Suitable implants may, for example, have total arc lengths of 125, 150, 175, and 200 mm.
(142) Related U.S. patent application Ser. No. 12/558,206 describes exemplary methods for treating a patient and evaluating the treatment, each of which may be used with aspects of the present invention. For example, the treatment method may comprise delivering an implant within the lung and then evaluating the patient's breathing thereafter to determine whether more implants are needed. Alternatively, a plurality of implants may be delivered within the patient's lungs before an evaluation. The patient's lungs may be evaluated by measuring a forced expiratory volume (FEV) of the patient, measuring/visualizing a change in tissue density at the implantation region, measuring/visualizing displacement of the diaphragm or of the lung fissures, etc.
(143) In some embodiments, an implant is deployed in a straight configuration with the use of a catheter, e.g., catheter 5201, to contain it in a generally straight shape. Alternative embodiments may use the working lumen of the bronchoscope directly so that the bronchoscope is used as a delivery catheter. Upon removal of the constraining catheter, the implant recoils to a deployed shape that can be easily identified by the fact that the distance from one end to the second is reduced. The proximal end of the implant may be grasped, e.g., with pusher grasper device 5009, and held so that the distal end of the implant remains engaged against the desired airway tissue as the length of the implant is progressively unsheathed (by withdrawing the catheter proximally). High tensile forces might be generated between the distal portion of the implant and the airway tissue if the proximal end of the implant is held at a fixed location throughout deployment, as the implant is biased to recoil or bring the ends together when released. Hence, it can be advantageous to allow the proximal end of the implant to advance distally during release, rather than holding the implant from recoiling, as these forces may be deleterious. For example, the distance and tissue thickness between the distal end of the implant and the lung surface is short, there may be little strain relief on the tissue and the risk of rupture may be excessive. Additionally, the implant might otherwise tend to foreshortened after it is released by the grasper. When foreshortening occurs, the proximal end of the implant may travel distally beyond the viewing field of the bronchoscope and the user can have difficulty retrieving the implant reliably.
(144) Thus, as schematically shown in
(145)
(146) By using a longer implant 5300, the proximal end of implant 5300 can also be fed into the airway while the potential energy of the implant is being freed to apply work on the lung tissue (while the catheter is being pulled off of the implant). The lung airways can be distorted so the airway cross section is pushed to a more oval shape. Longer implants can tend to zigzag back and forth across the airway lumen so that implants that are significantly longer than the measured airway length can be introduced. For example, a 150 mm long (arc length) implant can be deployed into a 100 mm long airway. The greater length of the implant may minimize the uncontrolled recoil that may cause the proximal end to be lost in the patient upon release. Greater implant length can also allow the user to feed the implant into the patient while the catheter is removed without over stressing the lung tissue. Additionally, should foreshortening of the longer implant occur, the proximal end of the implant can still remain within the viewing field of the bronchoscope and the user can thus retain the ability to retrieve the implant reliably. It should be understood that the length of the implant relative to the diameter of the airway may be much greater than the schematic illustration of
(147) As will be appreciated by those skilled in the art, the device can be manufactured and deployed such that it is deliverable through a bronchoscope. When actuated, the device can be adapted and configured to bend or curl which then distorts lung tissue with which the device comes in contact. Lung tissues that may be beneficially distorted by the device are airways, blood vessels, faces of tissue that have been dissected for introduction of the device or a combination of any of these. By compressing the lung tissue, the device can result in an increase in elastic recoil and tension in the lung in at least some cases. Additionally, in some instances, lung function can be at least partially restored regardless of the amount of collateral ventilation. Further, the diaphragm may, in some instances, move up once greater tension is created which enables the lung cavity to operate more effectively.
(148) Devices according to the invention have a small cross-section, typically less than 10 F. The flexibility of the device prior to deployment facilitates advancement of the device through the tortuous lung anatomy. Once deployed, the device can remain rigid to hold and maintain a tissue deforming effect. Further, the device design facilitates recapture, de-activation and removal as well as adjustment in place.
(149) Candidate materials for the devices and components described herein would be known by persons skilled in the art and include, for example, suitable biocompatible materials such as metals (e.g. stainless steel, shape memory alloys, such a nickel titanium alloy (nitinol), titanium, and cobalt) and engineering plastics (e.g. polycarbonate). See, for example U.S. Pat. No. 5,190,546 to Jervis for Medical Devices Incorporating SIM Memory Alloy Elements and U.S. Pat. No. 5,964,770 to Flomenblit for High Strength Medical Devices of Shape Memory Alloy. In some embodiments, other materials may be appropriate for some or all of the components, such as biocompatible polymers, including polyetheretherketone (PEEK), polyarylamide, polyethylene, and polysulphone.
(150) Polymers and metals used to make the implant and delivery system may be coated with materials to prevent the formation and growth of granular tissue, scar tissue and mucus. Many of the drugs used with stent products to arrest hyperplasia of smooth muscle cells in blood vessels after deploying metallic stents will work very well for these devices. Slow release drug eluting polymers or solvents may be used to regulate the release of drugs that include any substance capable of exerting a therapeutic or prophylactic effect for a patient. For example, the drug could be designed to inhibit the activity of smooth muscle cells. It can be directed at inhibiting abnormal or inappropriate migration and/or proliferation of smooth muscle cells to inhibit tissue mass buildup. The drug may include small molecule drugs, peptides or proteins. Examples of drugs include antiproliferative substances such as actinomycin D, or derivatives and analogs thereof (manufactured by Sigma-Aldrich of Milwaukee, Wis., or COSMEGEN available from Merck). Synonyms of actinomycin D include dactinomycin, actinomycin IV, actinomycin.sub.1, actinomycin X.sub.1, and actinomycin C.sub.1. The active agent can also fall under the genus of antineoplastic, anti-inflammatory, antiplatelet, anticoagulant, antifibrin, antithrombin, antimitotic, antibiotic, antiallergic and antioxidant substances. Examples of such antineoplastics and/or antimitotics include paclitaxel (e.g. TAXOL® by Bristol-Myers Squibb Co. of Stamford, Conn.), docetaxel (e.g. Taxotere®, from Aventis S. A. of Frankfurt, Germany) methotrexate, azathioprine, vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride (e.g. Adriamycin® from Pharmacia & Upjohn of Peapack N.J.), and mitomycin (e.g. Mutamycin® from Bristol-Myers Squibb). Examples of such antiplatelets, anticoagulants, antifibrin, and antithrombins include sodium heparin, low molecular weight heparins, heparinoids, hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclin analogues, dextran, D-phe-pro-arg-chloromethylketone (synthetic antithrombin), dipyridamole, glycoprotein Hh/IIIa platelet membrane receptor antagonist antibody, recombinant hirudin, and thrombin inhibitors such as Angiomax™ (Biogen, Inc. of Cambridge, Mass.). Examples of such cytostatic or antiproliferative agents include angiopeptin, angiotensin converting enzyme inhibitors such as captopril (e.g. Capoten® and Capozide® from Bristol-Myers Squibb), cilazapril or Hsinopril (e.g. Prinivil® and Prinzide® from Merck & Co., Inc. of Whitehouse Station, N.J.); calcium channel blockers (such as nifedipine), colchicine, fibroblast growth factor (FGF) antagonists, fish oil (omega 3-fatty acid), histamine antagonists, lovastatin (an inhibitor of HMG-CoA reductase, a cholesterol lowering drug, brand name Mevacor® from Merck & Co.), monoclonal antibodies (such as those specific for Platelet-Derived Growth Factor (PDGF) receptors), nitroprusside, phosphodiesterase inhibitors, prostaglandin inhibitors, suramin, serotonin blockers, steroids, thioprotease inhibitors, triazolopyrimidine (a PDGF antagonist), and nitric oxide. An example of an antiallergic agent is permirolast potassium. Other therapeutic substances or agents which jtnay be appropriate include alpha-interferon, genetically engineered epithelial cells, tacrolimus, dexamethasone, and rapamycin and structural derivatives or functional analogs thereof, such as 40-O-(2-hydroxy)ethyl-rapamycin (known by the trade name of EVEROLIMUS available from Novartis of New York, N.Y.), 40-O-(3-hydroxyl)propyl-rapamycin, 40-O-[2-(2-hydroxyl)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin.
(151) Other polymers that may be suitable for use in some embodiments, for example other grades of PEEK, such as 30% glass-filled or 30% carbon filled, provided such materials are cleared for use in implantable devices by the FDA, or other regulatory body. The use of glass filled PEEK would be desirable where there was a need to reduce the expansion rate and increase the flexural modulus of PEEK for the instrument Glass-filled PEEK is known to be ideal for improved strength, stiffness, or stability while carbon filled PEEK is known to enhance the compressive strength and stiffness of PEEK and lower its expansion rate. Still other suitable biocompatible thermoplastic or thermoplastic polycondensate materials may be suitable, including materials that have good memory, are flexible, and/or deflectable have very low moisture absorption, and good wear and/or abrasion resistance, can be used without departing from the scope of the invention. These include polyetherketoneketone (PEKK), polyetherketone (PEK), polyetherketoneetherketoneketone (PEKEKK), and polyetheretherketoneketone (PEEKK), and generally a polyaryletheretherketone. Further other polyketones can be used as well as other thermoplastics. Reference to appropriate polymers that can be used in the tools or tool components can be made to the following documents, all of which are incorporated herein by reference. These documents include: PCT Publication WO 02/02158 A1, to Victrex Manufacturing Ltd. entitled Bio-Compatible Polymeric Materials; PCT Publication WO 02/00275 A1, to Victrex Manufacturing Ltd. entitled Bio-Compatible Polymeric Materials; and PCT Publication WO 02/00270 A1, to Victrex Manufacturing Ltd. entitled Bio-Compatible Polymeric Materials. Still other materials such as Bionate®, polycarbonate urethane, available from the Polymer Technology Group, Berkeley, Calif., may also be appropriate because of the good oxidative stability, biocompatibility, mechanical strength and abrasion resistance. Other thermoplastic materials and other high molecular weight polymers can be used as well for portions of the instrument that are desired to be radiolucent.
(152) Any implant described herein can be made of a metallic material or an alloy such as, but not limited to, cobalt-chromium alloys (e.g., ELGILOY), stainless steel (316L), “MP3SN,” “MP2ON,” ELASTINITE (Nitinol), tantalum, tantalum-based alloys, nickel-titanium alloy, platinum, platinum-based alloys such as, e.g., platinum-iridium alloy, iridium, gold, magnesium, titanium, titanium-based alloys, zirconium-based alloys, or combinations thereof. Devices made from bioabsorbable or biostable polymers can also be used with the embodiments of the present invention. “MP35N” and “MP2ON” are trade names for alloys of cobalt, nickel, chromium and molybdenum available from Standard Press Steel Co. of Tenkintown, Pa. “MP35N” consists of 35% cobalt, 35% nickel, 20% chromium, and 10% molybdenum. “MP2ON” consists of 50% cobalt, 20% nickel, 20% chromium, and 10% molybdenum.
(153) While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims presented will define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.