WO2008097890A2

WO2008097890A2 - Method and use of a bioreplaceable tissue material implant for treating snoring

Info

Publication number: WO2008097890A2
Application number: PCT/US2008/052892
Authority: WO
Inventors: Edmund A. Pribitkin
Original assignee: Thomas Jefferson University
Priority date: 2007-02-02
Filing date: 2008-02-04
Publication date: 2008-08-14
Also published as: WO2008097890A3

Abstract

The present invention generally relates to methods and compositions for treating conditions of the palatal area such as snoring and/or sleep apnea. More particularly, the invention pertains to a method and composition comprising implants which remodel the soft tissue of the palatal area, and more particularly to bioreplaceable implants which are replaced by host cells where the remodeled soft-palate has a reduced frequency of oscillation in response to airflow past the soft-palate and results in reduce snoring. In some embodiments, the bioreplaceable implants comprise processed tissue material to reduce the frequency of oscillation of the soft palate in response to airflow, and more particularly to submucosa tissue implants.

Description

METHOD AND USE OF A BIOREPLACEABLE TISSUE MATERIAL IMPLANT FOR

TREATING SNORING

FIELD OF THE INVENTION

[1] The present invention relates generally to methods for treating conditions of the palatal area such as snoring and sleep apnea. More particularly, the invention pertains to method and implants to reduce the frequency of oscillation of the soft palatal area to air flow.

CROSS REFERENCED APPLICATIONS

[2] This Application claims benefit under 35 U. S. C. 119(e) of U.S. Provisional Application Serial Number 60/899,154 filed on February 2, 2007 the consents of which are incorporated herein in their entirety by reference.

BACKGROUND

[3] Snoring is a common problem, with 81% of men aged 40-65 years snoring more than

10% of the night, and 22% snoring from more than 50% of the night (Bearpark et al, 1995; Am J Resp Critic Care Med, 151;1459-65). One publication estimates that up to 20% of the adult population snores habitually. The primary therapeutic aim of all available therapies is the reduction in duration and intensity of snoring to a tolerable degree without harming the patient.

[4] Huang, et al., "Biomechanics of Snoring", Endeavour, p. 96 - 100, Vol. 19, No. 3 (1995). Snoring can be a serious cause of marital discord. In addition, snoring can present a serious health risk to the snorer. In 10% of habitual snorers, collapse of the airway during sleep can lead to obstructive sleep apnea syndrome.

[5] The fundamental cause of snoring is a restriction or blockage of the air passage in the throat. This occurs when muscles relax during sleep allowing soft tissue in the back of the throat to sag. This soft tissue then blocks the flow of air needed for breathing. Most people that snore overcome this blockage by breathing harder, and the increased air pressure partially opens up the air passage. The snoring sound is the restricted airflow vibrating the soft tissue. Besides the obvious noise, the snoring person also has laborious breathing that decreases the quality of sleep. In extreme cases of air passage blockage, there is a medical condition called obstructive sleep apnea where the quality of sleep is severely degraded.

[6] There are hundreds of patents relating to anti-snoring devices. Almost all the mechanical devices that have been developed simply do not treat the fundamental cause of snoring because they do not open up the blocked air passage in the throat. There are two classes of mechanical anti-snoring devices that actually open up this blocked air passage. The first class opens the blocked air passage in the throat by forcing the lower jaw to jut forward to an unnatural position. However, these devices are very uncomfortable and can cause alignment problems with the teeth.

[7] Notwithstanding numerous efforts to address snoring, effective treatment of snoring has been elusive. Such treatment can include mouth guards or other appliances worn by the snorer during sleep. However, patients find such appliances uncomfortable and frequently discontinue use (presumably adding to marital stress).

[8] Apart from the conservative treatments that require patient compliance to be successful, various kinds of surgical procedures exist, with techniques for the soft palate being the most widespread. All these procedures aim to reduce palatal flutter, the major cause of snoring. Uvulopalatoparyngoplasty (UPPP) and laser-assisted uvulopalatoplasty (LAUP) are well known but associated with a significant morbidity (Haavisto et al, 1994; Clinotolaryngol 19;243-7 and Astor et al, Otolaryngol Head Neck Surg. 19978;118;478-480). Uvulopalatopharyngoplasty (UPPP) is also described in Harries, et al., "The Surgical treatment of snoring", Journal of Laryngology and Otology, pp. 1105 - 1106 (1996) which describes removal of up to 1.5 cm of the soft palate. Assessment of snoring treatment is discussed in Cole, et al., "Snoring: A Review and a Reassessment", Journal of Otolaryngology, pp. 303 - 306 (1995). However, these treatments are invasive, destructive and painful, and/or irreversible to a certain extent. Furthermore, in certain procedures, general anesthesia can be required.

[9] In laser-assisted uvulopalatoplasty (LAUP), laser ablation is used to remove about 2 cm of the trailing edge of the soft palate thereby reducing the soft palate's ability to flutter between the tongue and the pharyngeal wall of the throat. The procedure is frequently effective to ablate snoring but is painful and frequently results in undesirable side effects. Namely, removal of the soft palate trailing edge compromises the soft palate's ability to seal off nasal passages during swallowing and speech. In an estimated 25% of uvulopalatopharyugoplasty patients, fluid escapes from the mouth into the nose while drinking.

[10] Huang, et al., supra, describe the soft palate and palatal snoring as an oscillating system which responds to airflow over the soft palate. Resulting flutter of the soft palate (rapidly opening and closing air passages) is a dynamic response generating sounds associated with snoring. Huang, et al., propose an alternative to uvulopalatopharyngoplasty. The proposal includes using a surgical laser to create scar tissue on the surface of the soft palate. The scar is to reduce flexibility of the soft palate to reduce palatal flutter. Huang, et al., report initial results of complete or near-complete reduction in snoring and reduced side effects.

[11] Surgical procedures such as uvulopalatopharyngoplasty and LAUP and those proposed by Huang, et al., continue to have problems. The area of surgical treatment (i.e., removal of palatal tissue or scarring of palatal tissue) can be more than is necessary to treat the patient's condition. Surgical lasers are expensive. The proposed procedures are painful with drawn out and uncomfortable healing periods. The procedures have complications and side effects and variable efficacy (e.g., Huang, et al., report promising results in 75% of patients suggesting a full quarter of patients are not effectively treated after painful surgery). The procedures can involve lasting discomfort. For example, scar tissue on the soft palate can present a continuing irritant to the patient. Importantly, the procedures are not reversible in the event they happen to induce adverse side effects not justified by the benefits of the surgery.

[12] Many known prior art anti-snoring devices utilize an implant in the soft palate to alter the dynamic response and reduce snoring. Typical soft palate implant patents are: US Patent Nos. 6,848,447; 6,634,362; 6,601,585; 6,578,580; 6,523,543 to Conrad and US patent nos. 6,626,181 6,601,584; 6,523,542 to Knudson.

[13] In particular most of the implants use either permanent or bioresorbable or biodegradable implants. Many of the bioresorbable implants, particularly those described by Conrad et al, are specifically designed to induce fibrosis (also commonly known as scarring), thereby stiffening the soft palate and reducing snoring. The implants of Conrad et al. are modified to either structurally induce fibrosis, or to release an agent that induces fibrosis. For example, the implants comprise compositions of fibrosis-inducing agents that promote the formation of fibrosis or the process of fibrosis. Such implants are used to increase or accelerate the formation of fibrous tissue (i.e., by inducing or promoting one or more of the processes of angiogenesis, fibroblast migration or proliferation, ECM production, and/or remodeling).

[14] As mentioned above, scar tissue on the soft palate can present a continuing irritant to the subject. Further, the release of fibrosis-inducing agents and/or the presence of structures that induce fibrosis will certainly be irritating to the subject during the process of the fibrotic response. The fibrotic response is part of the wound healing process, which involves inflammation, and thus associated inflammatory mediators and inflammatory mediator associated pain. Inflammation followed by a process of proliferation, which involves angiogenesis and finally a maturation process, where extracellular matrix is deposited, adding strength of the scar tissue. Fibrosis or scarring of the soft palate as a chronic or permanent strategy of palatal stiffening, has associated side effects, and cannot be regulated for controlled palatal stiffening.

[15] Associated with a fibrotic response is the induction of angiogenesis which adds additional undesirable side effects, as angiogenesis has been associated with, for example, solid tumors, that can not justify the use of such fibrosis-inducing implants. Furthermore, excessive angiogenesis can impair function of the soft palate to close a nasal passage of the subject during swallowing.

[16] Additional problems also exist with use of conventional permanent and/or modified bioresorbable or biodegradable implants in the fact they are structurally rigid, and as a result one major complication from their use is protrusion from the site of implantation, which can happen at any point (short term or long-term) after surgery and could substantially impair function of the soft palate to close a nasal passage of the subject during swallowing.

[17] Thus the above-described approaches have failed to provide a satisfactory long-term solution to the problem of snoring without additional complications and poor cure rates. These failures lie in the inability of the implants to remain within the soft palate as well as undesirable side effects associated with fibrosis or scarring in the methods. Thus, it would be desirable to have a method for an effective long-lasting and biocompatible approach for the treatment of snoring.

SUMMARY

[18] The invention relates to an improved method for treating subjects with upper airway conditions such as snoring and sleep apnea. The invention relates to implantation of a processed tissue material comprising a submucosal tissue, where the processed tissue material is replaced in vivo with the subject's own cells and results in the remodeled soft palate tissue which has a reduced frequency of oscillation in response to air flow past it, as compared to the frequency of oscillation prior the placement of the implant. In some embodiments, the remodeled soft palate tissue has sufficient stiffness or an altered dynamic response following the implantation without substantially impairing a function of the soft palate.

[19] One aspect of the present invention relates to a method for treating snoring of a subject comprising implanting a processed tissue material, such as submucosa tissue into the soft palate of the subject, wherein the processed tissue material, when it is implanted into the subject undergoes biodegradation and is replaced by the subject's living cells, such that the frequency of oscillations of the soft palate in response to airflow past the soft palate are reduced which results in decreased snoring by the subject. [20] In some embodiments, the decreased or reduced frequency of oscillation of the soft palate is due to an increased stiffness of the soft palate. In some embodiments, the decreased frequency of oscillations of the soft palate in response to airflow is due to an alteration of the dynamic response of the soft palate to the airflow past the subject's soft palate, where such alteration is a reduced dynamic response to the airflow, which results in reduction of the frequency of oscillation of the soft palate and/or a decrease in snoring. In some embodiments, the decreased frequency of oscillations of the soft palate in response to airflow is due to an increased stiffness of the soft palate as a response to tissue remodeling of the soft palate. In some embodiments, the submucosal tissue is derived from the tunica submucosa or tunica muscularis or the luminal portion of the tunica mucosa of the small intestine of a mammal, or a digest thereof. In some embodiments, the tunica submucosa comprises substantially acellular telopeptide collagen. In some embodiments, the submucosal tissue useful in the methods and compositions as disclosed herein is small intestine submucosa (SIS).

[21] In some embodiments, the methods and compositions as disclosed herein are useful for treating a subject who suffers from snoring, such as, for example, snoring attributable to, at least in part, a snoring sound generated from an oscillation of the subject's soft palate in response to airflow past the subject's soft palate, and wherein a reduction in the frequency of oscillation of the soft palate in response to airflow past said soft palate reduces snoring by the subject.

[22] It is preferred that the processed tissue material does not induce a substantial fibrotic response in the subject. In some embodiments, the subject's cells which replace the implanted processed tissue are a cell population substantially free of fibroblast cells.

[23] Another aspect of the present invention relates to a composition comprising submucosal tissue for the treatment of snoring and/or sleep apnea. Another aspect of the present invention relates to a composition comprising submucosal tissue to decrease snoring and/or sleep apnea in a subject. In some embodiments, the compositions as disclosed herein comprise submucosal tissue which is small intestine submucosa (SIS).

[24] In some embodiments, the compositions as disclosed herein can be implanted or inserted into a subject in an effective amount into the soft palate of a subject to reduce the frequency of oscillation of the soft-palate. In some embodiments, the implant can be used to increase the stiffness of the subject's soft palate. In some embodiments, the composition is bioreplaceable with the subject's living cells, for example, living cells which are substantially not fibroblast cells. Stated another way, the population of living cells which replace the composition are substantially free of fibroblasts.

BRIEF DESCRIPTION OF FIGURES

[25] Figure 1 shows a cross-section view of a naso-pharyngeal area of a side sectional view of a portion of a human head showing a soft palate in a relaxed state and in relation to adjacent anatomical features.

[26] Figure 2 shows a portion of the view of Figure 1 showing the soft palate in a flexed state.

[27] Figure 3 shows a schematic representation of a spring-mass system model of the soft palate.

[28] Figure 4 shows a view of Figure 1 with the soft palate containing an implant according to a first embodiment of the present invention.

[29] Figure 5 shows a front view of the open mouth shown in Figure 1 prior to a surgical procedure.

[30] Figure 6 shows the view of Figure 5 showing the embodiment of Figure 4.

[31] Figure 7 shows a perspective view of the implant of Figure 4.

[32] Figure 8 shows a cross-sectional view from the side of the implant of Figure 4.

[33] Figure 9 shows a cross-sectional view from the side of the implant of Figure 4 with the implant pre-formed to assume the shape of a soft palate in a relaxed shape.

[34] Figure 10A-10E' shows perspective views of examples of basic different conformations of the implant in Fig.7. Figure 1OA shows a perspective view of layers of the material for the implant, aligned in the same direction. Figure 1OB shows a perspective view of layers of the material for the implant, aligned in different directions. Figure 1OC shows a perspective view of the implant material in a coil. Figure 1OD shows a perspective view of the implant material folded. Figure 1OE shows a perspective view of the implant material in a square coil.

[35] Figure 11 shows the end view of the implants in Figure 10. Figure HA shows the end view of Fig. 10a; Figure HB shows the end view of Fig. 10b; Figure IIC shows the end view of Fig. 10, and Fig. 11C shows an embodiment of the view of Fig 11C, where the coiled is multiple layers of the material of the invention (as a non-limiting example, 2 layers are shown). The layered material can be in the same orientation or different orientations. Figure 1 ID shows is the end view of Fig. 10D; and figure 1 ID' shows an embodiment of the view of Fig 1 ID, where multiple layers of the material of the invention are folded (as a non-limiting example, 2 layers are shown). Figure HW shows the end view of Fig. 1OE and figure HE' shows an embodiment of figure 1 IE, where multiple layers of material of the invention are coiled in a square coil. Figure 1 IE' ' shows a further embodiment of the conformation of

Figure HE, where the coil is any symmetrical coil, for example a hexagonal coil, pentagonal coil or octagonal coil etc. [36] Figure 12 shows a view of Figure 6, showing the positions of the implants in one embodiment. [37] Figure 13 shows a view of Figure 6, showing the locations of where the implants are inserted for the positions shown in Figure 12. [38] Figure 14 shows a view of Figure 5, showing an alternative embodiment for the position of the implants. [39] Figure 15 shows a view of Figure 5, showing another alternative embodiment for the position of the implants. [40] Figure 16 shows a view of Figure 5, showing another alternative embodiment for the position of the implants. [41] Figure 17 shows a side sectional view of the soft palate in Figure 1, showing palatal muscle in the soft palate. [42] Figure 18 shows the view of Figure 17, showing a delivery tool being advanced through an incision into the soft palate. [43] Figure 19 shows the view of Figure 18 following delivery of the implant and removal of the delivery tool.

[44] Figure 20 shows the view taken along line 32-32 in Figure 19. [45] Figure 21 shows a SURGISIS® strand (Cook Biotech Inc, West Lafayette, Indiana) with trocar prior to rehydration. [46] Figure 22 shows a submucosial tunneling of the SURGISIS® strand (Cook Biotech Inc,

West Lafayette, Indiana) in the lower lip. [47] Figures 23A-23B shows the placement of a single lower lip implant. Figure 23A shows the preoperative anterior view, and Figure 23B shows the postoperative anterior view. [48] Figures 24A-24B shows the placement of a single upper lip implant. Figure 24A shows the preoperative lateral view, and Figure 24B shows the postoperative lateral view.

DETAILED DESCRIPTION [49] The invention relates to an improved method for the treating subjects with upper airway conditions such as snoring and sleep apnea. The invention relates to use and implantation of a bioreplaceable material. In some embodiments, the bioreplaceable is processed tissue material comprising a submucosal tissue, where in vivo the processed tissue material is replaced with the subject's own cells and remodeled tissue reduces the frequency of oscillation of the soft palate and thus reduces snoring or sleep apnea by the subject. In some embodiments, the soft tissue in the soft palate is remodeled to have altered (i.e. increased or decreased) stiffness to alter the dynamic response following the implantation without substantially impairing a function of the soft palate to close a nasal passage of the subject during swallowing, such that the soft palate has reduced frequency of oscillation in response to airflow past the soft palate. In some embodiments, the soft tissue in the soft palate is remodeled to have altered increased stiffness to alter the dynamic response following the implantation such that the soft palate has reduced frequency of oscillation in response to airflow past the soft palate.

[50] While not wishing to be bound by theory, the processed tissue material of the invention functions as a biotrophic/biodegradable scaffold that induces endogenous tissues to invade and replace the bioreplaceable material with endogenous palate tissue.

[51] The methods and compositions as disclosed herein are much less traumatic than prior surgical procedures. Further the methods permit the use of reversible procedures as well as procedures which can be selectively tuned to the subjects needs both during surgery and postoperatively.

[52] The bioreplaceable material, for example, the submucosal tissue graft useful in the methods and compositions as disclosed herein is surgically implanted to promote the growth of endogenous palate tissue to result in a tissue remodeled soft palate which has reduced frequency of oscillation in response to airflow past it. In some embodiments, the surgically implanted bioreplacable material promotes the growth of endogenous palate tissue for soft palate tissue remodeling to result in a structural strength for palate stiffening. The tissue graft material serves as a scaffold and induces the proliferation of functional palate soft tissue formation which replaces the tissue graft without shrinking of the graft area and without the formation of "scar" tissue or a fibrotic response.

[53] The implant useful in the methods and compositions as disclosed herein is bioreplaceable, and will undergo controlled biodegradation occurring concomitantly with remodeling and replacement by host cells and tissue. The bioreplaceable material has dual properties: first it functions to reinforce the soft palate, and second, while still functioning to reinforce the soft palate, it functions as a remodeling template for the ingrowth of host cells. Accordingly, the present invention allows for immediate post-operative stiffening (and snoring abatement), followed by controlled palatal stiffening of the soft palate, substantially without the formation of chronic permanent fibrosis (scarring). Scarring of the soft palate is permanent, has associated side effects and also leads to uncontrolled palatal stiffening. [54] In one embodiment of the present invention, the bioreplaceable material is a processed tissue material developed from submucosal tissue, for example from layers of submucosal tissue that is able to be bonded to itself and other submucosal tissue layers to form an implant.

[55] The bioreplaceable material described herein is semi-permeable, even though in some embodiments it has been layered, and in some embodiments bonded. In the context of the present invention, semi-permeability refers to the ability of the implant to permit ingrowth of host cells for remodeling and for deposition of adherents and components that would affect remoldelability, cell ingrowth, adhesion prevention or promotion of blood flow.

Definitions

[56] The term "bioreplaceable" as used herein, and when used in the context of an implant, refers to a process where de novo growth of the endogenous tissue replaces the implant material. A bioreplacable material as disclosed herein does not provoke an immune or inflammatory response from the subject and does not induce fibrosis. A bioreplaceable material is distinguished from bioresorbable material in that bioresorbable material is not replaced by de novo growth by endogenous tissue.

[57] The terms "processed tissue matrix" and "processed tissue material" are used interchangeably herein, to refer to native, normally cellular tissue that as been procured from an animal source, for example a mammal, and mechanically cleaned of attendant tissues and chemically cleaned of cells and cellular debris, and rendered substantially free of non- collagenous extracellular matrix components. In some embodiments, the processed tissue matrix can further comprise non-cellular material naturally secreted by cells, such as intestinal submucosa cells, isolated in their native configuration with or without naturally associated cells.

[58] As used herein the term "submucosal tissue" refers to natural extracellular matrices, known to be effective for tissue remodelling, that have been isolated in their native configuration. The submucosal tissue can be from any animal, for example a mammal, such as but not limited to, bovine or porcine submucosal tissue. In some embodiments, the submucosal tissue is derived from a human, such as the subject into which it is subsequently implanted (i.e. autograft transplantation) or from a different human donor (i.e. allograft transplantation). The submucosa tissue can be derived from intestinal tissue (autograft, allograft, and xenograft), stomach tissue (autograft, allograft, and xenograft), bladder tissue (autograft, allograft, and xenograft), alimentary tissue (autograft, allograft, and xenograft), respiratory tissue (autograft, allograft, and xenograft) and genital tissue (autograft, allograft, and xenograft), and derivatives of liver tissue (autograft, allograft, and xenograft), including for example liver basement membrane and also including, but not limited to, dermal extracellular matrices (autograft, allograft, and xenograft) from skin tissue.

[59] The use of the term 'strip" herein is not intended to be limited to long, narrow implants but can also include plates and other geometries of implants to alter the dynamic model of the soft palate SP. Elongated strips are disclosed as one geometry as proof of principle due to the facilitated ease of implantation, although other geometries are also encompassed for use in the present invention.

[60] The term "reduced" or "reduce" as used herein generally means a decrease by at least 10% as compared to a reference or baseline level, for example a decrease by at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% decrease, or any integer decrease between 10-100% as compared to a reference or baseline level.

[61] The term "increased" or "increase" as used herein generally means an increase of at least 10% as compared to a reference or baseline level, for example an increase of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% increase or any integer increase between 10-100% as compared to a reference or baseline level, or about a 2-fold, or about a 3-fold, or about a 4-fold, or about a 5-fold or about a 10-fold increase, or any increase between 2-fold and 10-fold or greater as compared to a reference or baseline level.

[62] The term "reference" or "baseline" as used herein typically means a level at an earlier timepoint (i.e. prior to an implantation of a bioreplacable implant). The term "baseline" typically refers to a level in a naive subject, such as a subject without any prior insertions of a bioreplacable implant, whereas the term "reference" level typically refers to a level in a subject measured at a first timepoint which can be compared to a level taken at a second timepoint. For example and as a non-limiting illustration, a reference level can be the level in a subject after insertion of one implant (i.e. first timepoint) which can be compared to the level after insertion of one or more additional implants (i.e. second timepoint). Alternatively, a reference level can be a level after insertion of one implant (i.e. first timepoint), which can be compared to a level taken at a second timepoint, such as six months, or one year later (i.e. second timepoint) after no subsequent implant insertions. [63] The term "substantially" as used herein means a proportion of at least about 60%, or preferably at least about 70% or at least about 80%, or at least about 90%, at least about 95%, at least about 97% or at least about 99% or more, or any interger between 70% and 100%.

[64] The term "substantially" as used in the context of a cell population substantially free of fibroblasts, refers to a population of cells that is at least about 75%, preferably at least about 85%, more preferably at least about 90%, and most preferably at least about 95% free from fibrobasts with respect to the cells making up a total cell population. Recast, the phrase a cell population "substantially free of fibroblast cells", with regard to cells which replace the processed tissue material, refers to a population of cells that contain fewer than about 20%, more preferably fewer than about 15%, 10%, 8%, 7%, most preferably fewer than about 5%, 4%, 3%, 2%, 1%, or less than 1%, of cells that are fibroblast cells or cells derived from fibroblasts.

[65] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element. The term "comprising" means "including but not limited to", and that the word "comprises" has a corresponding meaning.

[66] It should be understood that this invention is not limited to the particular methodology, protocols, and reagents, etc., described herein and as such can vary. The terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention, which is defined solely by the claims.

[67] Other than in the operating examples, or where otherwise indicated, all numbers expressing quantities of ingredients or reaction conditions used herein should be understood as modified in all instances by the term "about." The term "about" when used in connection with percentages can mean +1%. The present invention is further explained in detail by the following examples, but the scope of the invention should not limit thereto.

General

[68] For ease of understanding the present invention, the dynamics of snoring are explained with reference to FIGS. 1-3. The hard palate HP overlies the tongue T and forms the roof of the mouth M. The hard palate HP includes a bone support B and does not materially deform during breathing. The soft palate SP is soft and is made up of mucous membrane, fibrous and muscle tissue extending rearward from the hard palate HP. A leading end LE of the soft palate SP is anchored to the trailing end of the hard palate HP. A trailing end TE of the soft palate SP is unattached. Since the soft palate "SP" is not structurally supported by bone or hard cartilage, the soft palate SP droops down from the plane of the hard palate "HP" in an accurate geometry of response.

[69] The pharyngeal airway passes air from the mouth M and the nasal passages N into the trachea TR. The portion of the pharyngeal airway defined between opposing surfaces of the upper surface of the soft palate SP and the wall of the throat is the nasopharynx NP.

[70] During normal breathing, the soft palate SP is in the relaxed state shown in FIG. 1 with the nasopharynx NP unobstructed and with air free to flow into the trachea TR from both the mouth M and the nostrils N.

[71] During swallowing, the soft palate SP flexes and extends (as shown in FIG. 2) to close the nasopharynx NP thereby preventing fluid flow from the mouth M to the nasal passages N. Simultaneously, the epiglottis EP closes the trachea TR so that food and drink pass only into the esophagus ES and not the trachea TR. The soft palate SP is a valve to prevent regurgitation of food into the nose N. The soft palate SP also regulates airflow through the nose N while talking. Since the soft palate SP performs such important functions, prior art techniques for surgically altering the soft palate SP can compromise these functions.

[72] The majority of snoring is caused by the soft palate SP flapping back and forth. If breathing is solely through the nose N with the mouth closed, the trailing edge TE of the soft palate SP is sucked into the nasopharyngeal space NP obstructing the airway and subsequently falls opening the airway in a repeating cycle. When the mouth is open, air flows over the upper and lower surfaces of the soft palate SP causing the soft palate SP to flap up and down (i.e. oscillate) alternating in obstructing the oral and nasal passageways M, N. The snoring sound is generated by impulses caused by rapid obstruction and opening of airways. Huang, et al., state the airway passage opening and closing occurs as much as 50 times per second during a snore. Huang, et al., utilize a spring-mass model (FIG. 3) to illustrate oscillation of the soft palate in response to airflow (where the soft palate is the ball "B" of mass depending by a spring "S" from a fixed anchor "A").

[73] Huang, et al., analogize the shortening of the soft palate SP in uvulopalatopharyngoplasty as effectively raising the critical air flow speed at which soft palate flutter will occur. In previous methods to reduce snoring, a significant portion of the trailing end TE of the soft palate SP was removed during a procedure called uvulopalatopharyngoplasty (UPPP) (not shown). The alternative procedure was developed by Huang, et al., which reduced the flexibility of the soft palate SP through surface scarring of the trailing end TE of the soft palate SP which is asserted as affecting the critical flow speed. [74] Referring to the spring-mass model of FIG. 3 as a convenient model of the soft palate SP, the methods described herein are directed to a surgical implant of the bioreplaceable implant material as disclosed herein into the soft palate SP to alter the elements of the model, thereby stiffening the soft palate SP and reducing the soft palate's SP oscillation's in response to airflow. Thus the bioreplacable implant or the tissue which replaces the bioreplacable implant alters the dynamic response of the soft palate SP to airflow. Accordingly, the bioreplacable implant results in increasing the stiffness of the soft palate which results in decreased snoring or sleep apnea in a subject. The implant can alter the mass of the model (the ball B of FIG. 3), the spring constant of the spring S, the dampening of the spring S or any combination of these elements. The implants that will be described are easy to insert in a small incision resulting in reduced patient discomfort and are not exposed to the interior of the mouth (such as the surface scarring of Huang, et al.) as a patient irritant. Also, as will be described, the degree of dynamic remodeling of the soft palate can be fine tuned using the methods as disclosed herein, avoiding the need for excessive anatomical modification and are reversible in the event of adverse consequences.

[75] In order to reduce snoring, the spring component, denoted S in FIG. 3 can be modified (alone or in combination with mass modification) to alter the dynamic response, i.e. to reduce oscillation of the soft palate. FIG. 4-16 illustrate an implant 20 in the form of a flexible strip for placement in the soft palate. The use of the term "strip" herein is not intended to be limited to long, narrow implants but can also include plates or other geometries implanted to alter the dynamic model of the soft palate SP. Elongated strips are presently a preferred geometry that facilitates ease of implant, although other geometries are also encompassed in the methods and composition as disclosed herein.

[76] In one embodiment, the strip 20 has a transverse dimension less than a longitudinal dimension. By way of non-limiting example, the strip can have a length Ls of about 20-30 mm, a thickness Ts of about 2-4 mm and a width Ws of 5-10 mm. As shown in FIG. 4, in this embodiment the strip 20 is embedded in the soft palate SP with the longitudinal dimension Ls extending from adjacent the hard palate HP toward the trailing end TE of the soft palate SP. As shown in FIG. 6, multiple strips 20 can be embedded in the soft palate SP extending either straight rearward or angled to the sides while extending rearward. The strips 20 can be formed straight (FIG. 8) or pre-shaped (FIG. 9) to have a rest shape approximate to the side- cross section shape of the soft palate in a relaxed state.

[77] The strips 20 comprise a bioreplaceable material, as discussed in more detail below. Such strips 20 of a bioreplaceable material are stiffer than the soft palate SP, to reinforce the soft palate SP and assist the soft palate SP in resisting deflection due to airflow. Such stiffening of the soft palate SP stiffens and dampens the spring S as referred to in the spring-mass system of FIG. 3 and alters the dynamic response of the soft palate SP. The strip 20 can have a spring constant to further resist deflection of the soft palate SP as well as urging the soft palate SP to the relaxed state of FIG. 3. The stiffness of the strip 20, a spring constant of the strip 20, and the number of strips 20, are selected to avoid preclusion of closure of the soft palate SP during swallowing. Examples of suitable bioreplaceable materials include submucosal tissue which is discussed in more detail below.

[78] As shown in the embodiment depicted in FIGS. 10 and 11, the implant strips 20 can comprise layers of bioreplaceable material, for example submucosal tissue in different conformations. In one embodiment and as illustrative examples only, the strip implant can be layers, one on top of another, (FIG 10a) where the layers of submucosal tissue are orientated in the same direction (FIG 10a and FIG lla) or in different orientations for added strength (FIGlOb, FIG lib). In alternative embodiments, the bioreplaceable material can be in a coil (FIG 10c), and again this can comprise a single layer of bioreplaceable material (FIG lie) or multiple layers prior to formation of a coiled configuration, for example as shown in example (FIG lie'). In an alternative embodiment, the bioreplaceable material can be folded as shown in example FIG 1Od, which can comprise a continuous layer of bioreplaceable material (FIG 1 Id) or multiple layers of the bioreplaceable material as shown in the example in FIG 1 Id. Another configuration of the bioreplaceable material that can be used is the bioreplaceable material in the form of a geometric coil, for example a square coil as shown in the example FIG 1Oe. The geometric coils and/or symmetrical coils can comprise a single continuous layer of bioreplaceable material (FIG lie), or as in previous embodiments, can comprise multiple layers prior to configuration into the coil structure, as shown in example FIG lie'. Furthermore, the coil can comprise any geometric coil, for example a hexagonal coil, octagonal coil, etc. as shown for example, in FIG lie". It is also encompassed that where the bioreplaceable material is not in the conformation of a coil, for example in FIGS 10a,b and 1Od, and FIGS 1 la,b and 1 Id and d' .

[79] In one embodiment, the strips can be structurally modified to control their flexibility. In some embodiments, the bottom of the strip 20 (facing the tongue after placement) is provided with transverse notches to enhance downward flexion of the strip 20 relative to upward flexion of the strip 20 following placement. By modifying the longitudinal (i.e., anterior to posterior) cross-sectional geometry of the soft palate SP, the aerodynamic response and, accordingly, the dynamic response are altered. [80] The placement of the strip implant can vary, as shown, for example, in FIGS 12-16. In some embodiments, the placement of the implants can be according to at least one or multiple arrangements as shown in FIGS 12-16, and in some embodiments, an implant located at each position can be implanted such that a cross hatched effect is achieved.

[81] In an alternative embodiment, the implant can exist as particles of the bioreplacable tissue material. In such embodiments, individual particles of bioreplacable tissue material increase the mass of the soft palate as well as being replaced with the subject's living cells to reduce the oscillations of the soft palate in response to air flow past it, and thus reduce snoring by the subject. In such embodiments, the bioreplacable particles (such as in the form of spheres or particle implants of other geometry, such as squares, ovals etc.) are imbedded in the soft palate SP in close proximity to the trailing end TE. With reference to the model of FIG. 3, the bioreplacable tissue material spheres add mass to the mass-spring system whereby, as well as remodeling the soft palate to reduce frequency of oscillation when air is passed by, the bioreplacable tissue material spheres also alter the dynamic response to airflow and add resistance to displacement and acceleration of oscillation. In some embodiments, such particles of the bioreplaceable tissue material will increase the soft palate stiffness.

[82] In some embodiments, the surgeon can progressively increase the number of implanted modules 20 until the altered dynamic response is such that snoring inducing oscillation is abated at normal airflow. The individual implants 20 can be placed into the soft palate SP through small individual incisions closed by sutures which is much less traumatic than the gross anatomical destruction of uvulopalatopharyngoplasty or the large surface area scarring proposed by Huang, et al.

[83] In some embodiments, such modules 20 of mass are solid modules such as spheres of bioreplaceable material as discussed below. By way of non-limiting example, the modules 20 of mass can be about 2-4 mm in diameter.

[84] In the embodiments where the implant exists as particles of the bioreplacable tissue material, the amount of particles used is selected on the amount to stiffen the soft palate and reduce the dynamic response but not preclude the soft palate SP being moved to close off nasal passages N during swallowing. Through the replacement of the bioreplacable tissue material particles with the subject's living cells, the spring S of the model is stiffened.

[85] The foregoing describes numerous embodiments of implants for insertion into the soft palate to increase its stiffness and thus alter a dynamic response of the soft palate and thereby reduce the frequency of oscillation or fluttering of the soft palate with air flow, which reduces the occurrence of snoring in the subject. The present invention is much less traumatic than prior surgical treatments for the treatment of snoring or sleep apnea. Further, the present invention permits use of reversible procedures as well as procedures which can be selectively tuned both during surgery and post-operatively. Having described the present invention herein, alternative embodiments can be made by one of ordinary skill in the art. For example, the strips of FIG. 7 can be encased in bioreplaceable material which can be tightened to further stiffen the strips. Such strips can also be hinged segments. It is intended that such modifications and equivalents shall be included within the scope of the following claims.

Submucosa tissue

[86] The present invention relates to the use of an implant comprising a bioreplaceable material or materials suitable for the placement in the soft palate, which are effective to firstly stiffen, reinforce and/or strengthen the soft palate and secondly are replaced by the hosts own tissue. The bioreplaceable material useful in the methods as described herein has the resiliency and flexibility to provide appropriate amounts of support and reinforcement to the soft palate, for example, such remodeling of the soft palate reduces the fluttering and frequency of oscillation of the soft palate to air flow, thus the occurrence level of snoring in a subject. In one embodiment, the bioreplaceable material is submucosal tissue. In one embodiment, the submucosa tissue suitable for use in accordance with the invention comprises natural collagenous matrices that include highly conserved collagens, matrix proteins, glycoproteins, proteoglycans, and glycosaminoglycans in their natural configuration and natural concentrations, and other factors. In some embodiments, the submucosal tissue is from the intestine of a warm-blooded vertebrate. In some embodiments, the submucosal tissue is from the small intestine. In some embodiments, the vertebrate is a mammal. In some embodiments, the submucosal tissue is a commercially available material, such as SURGISIS® which is available from Cook Biotech Incorporated (Bloomington, Ind.).

[87] In one embodiment the bioreplaceable material comprises small intestinal submucosa of a warm blooded vertebrate. In one embodiment, the material comprises the tunica submucosa along with the lamina muscularis mucosa and the stratum compactum of a segment of intestine, said layers being delaminated from the tunica muscularis and the luminal portion of the tunica mucosa of said segment. Such a material is referred to herein as small intestinal submucosa (SIS). In accordance with one embodiment of the present invention the intestinal submucosa comprises the tunica submucosa along with basilar portions of the tunica mucosa of a segment of intestinal tissue of a warm-blooded vertebrate. While porcine SIS is widely used, it will be appreciated that intestinal submucosa can be obtained from other animal sources, including cattle, sheep, and other warm-blooded mammals.

[88] The preparation of SIS from a segment of small intestine is disclosed in US-4902508. A segment of intestine is first subjected to abrasion using a longitudinal wiping motion to remove both the outer layers (particularly the tunica serosa and the tunica muscularis) and the inner layers (the luminal portions of the tunica mucosa). Typically the SIS is rinsed with saline and optionally stored in a hydrated or dehydrated state until use. Details of the characteristics and properties of intestinal submucosa (SIS) which one can use in the methods and compositions as disclosed herein are described in US-4352463, US-4902508, US- 4956178, US-5281422, US-5372821, US-5445833, US-5516533, US-5573784, US- 5641518, US-5645860, US-5668288, US-5695998, US-5711969, US-5730933, US- 5733868, US-5753267, US-5755791, US-5762966, US-5788625, US-5866414, US- 5885619, US-5922028, US-6056777 and WO-97/37613, which are incorporated herein in their entirety by reference. SIS, in various forms, is commercially available from Cook Biotech Incorporated (Bloomington, Ind.). In some embodiments, the submucosal tissue is a commercially available, such as SURGISIS® which is available from Cook Biotech Incorporated (Bloomington, Ind.).

[89] In one embodiment an intestinal submucosa matrix is used as the starting material, and the material is comminuted by tearing, cutting, grinding, shearing and the like in the presence of an acidic reagent selected from the group consisting of acetic acid, citric acid, and formic acid. In one embodiment the acidic reagent is acetic acid. In one embodiment, the intestinal submucosa is ground in a frozen or freeze- dried state to prepare a comminuted form of SIS. Alternatively, comminuted SIS can also be obtained by subjecting a suspension of pieces of the submucosa to treatment in a high speed (high shear) blender, and dewatering, if necessary, by centrifuging and decanting excess water. In some embodiments, the bioreplaceable material is a material extracted from SIS, named SISH.

[90] Preparations of the submucosa tissue compatible with the methods and compositions as described herein are described in U.S. Pat. Nos. 4,902,508; 4,956,178 and 5,281,422 and 6,893,666 the disclosures of which are expressly incorporated herein in their entirety by reference in its entirety. In some embodiments, submucosal tissue is harvested from various warm blooded vertebrate sources, for example small intestine harvested from animals raised for meat production, including but not limited to, porcine, ovine or bovine species, but not excluding other warm-blooded vertebrate species. This tissue can be used in either its natural configuration or in a comminuted or partially enzymatically digested fluid form. Vertebrate submucosa tissue is a plentiful by-product of commercial meat production operations and is thus a low cost graft material, especially when the submucosal tissue is in its native layer sheet configuration.

[91] Suitable submucosal intestinal-derived submucosal tissue for use in the methods and compositions as disclosed herein typically comprises the tunica submucosa delaminated from both the tunica muscularis and at least the luminal portion of the tunica mucosa. In one embodiment of the present invention, the intestinal submucosa tissue comprises the tunica mucosa and a basilar portion of the tunica mucosa, which can include the lamina muscularis mucosa and the stratum compactum, which layers are known to vary in thickness and in composition definition and dependent on the vertebrate species.

[92] In some embodiments, the preparation of the submucosa tissue for use in accordance with this invention is as described in U.S. Patent No, 4,902,508, the disclosure of which is expressly incorporated herein in its entirety by reference. A segment of vertebrate intestine, preferably harvested from porcine, ovine or bovine species, but not excluding other species, is subjected to abrasion using a longitudinal wiping motion to remove outer layers, comprising smooth muscle tissue and the innermost layer, i.e. the luminal portion of the tunica mucosa. The submucosal tissue is rinsed with saline and optionally sterilized; it can be stored in a hydrated or dehydrated state. Lyophilized or air-dried submucosa tissue can be rehydrated optionally stretched and used in accordance with this invention without significant loss of its cell proliferation-inducing activity.

[93] Submucosal tissue prepared from warm-blooded vertebrate organs typically has an abluminal and a luminal surface. The luminal surface is the submucosal surface facing the lumen of the organ source and is typically adjacent to the inner mucosal layer in the organ source, whereas the abluminal surface is the submucosal surface facing away from the lumen of the organ source and typically is in contact with the smooth muscle tissue of the organ source.

[94] The submucosal tissue material of the present invention can be preconditioned by stretching the material in a longitudinal or lateral direction as described in U. S Pat. No. 5,275,826, the disclosure of which is incorporated herein it its entirety by reference.

[95] In some embodiments, strips or pieces of the submucosa tissue can be fused together to form a unitary multi-layered submucosal tissue construct having a surface area greater than any individual strips or pieces of submucosal tissue. The process of forming a larger area/multi-layer submucosal tissue construct is described in U.S. Pat. 2002/0103542, the disclosure of which is incorporated herein in its entirety by reference. In summary, the process of forming large area sheets of a portion of submucosal tissue comprises overlapping at least a portion of another strip of submucosal tissue and applying pressure at least to the overlapped portions under condition allowing dehydration of the submucosal tissue. Under these conditions, the overlapped portions will become "fused" to form a large unitary sheet of tissue.

[96] The large area constructs consist essentially of submucosal tissue, substantially free of potentially compromising adhesives and chemical pretreatments, and they have a greater surface area and greater mechanical strength than individual strips used to form tissue implant material. The multi-layered submucosal tissue can optionally be perforated as described in U.S. Patent. Application 08/418, 515, the disclosure of which is expressly incorporated herein by reference. The perforations of the submucosal tissue construct allow extracellular fluids to pass through the tissue graft material, decreasing fluid retention within the graft and enhancing the remodeling properties of the tissue grafts. The perforation of the submucosal tissue is especially beneficial for multi-laminate tissue graft constructs wherein the perforations also enhance the adhesive force between adjacent layers.

[97] In some embodiments, the submucosal tissue useful in the methods and compositions as disclosed herein can also be in a fluidized form. Submucosal tissue can be fluidized by comminuting the tissue and optionally subjecting it to enzymatic digestion to form a substantially homogenous solution. The preparation of fluidized forms of submucosa tissue is described in U.S. Patent No. 5,275,826, the disclosure of which is expressly incorporated herein in its entirety by reference. Fluidized forms of submucosal tissue are prepared by comminuting submucosa tissue by tearing, cutting, grinding, or shearing the harvested submucosal tissue. Thus pieces of submucosal tissue can be comminuted by shearing in a high speed blender, or by grinding the submucosa in a frozen or freeze-dried state to produce a powder that can thereafter be hydrated with water or a buffered saline solution to form a submucosal fluid of liquid, gel-like or paste-like consistency. The fluidized submucosa formulation can further be treated with enzymes such as protease, including trypsin or pepsin at an acidic pH, for a period of time sufficient to solubilize all or a major portion of the submucosal tissue components and optionally filtered to provide a homogenous solution of partially solubilized submucosa.

[98] The graft compositions for the methods described herein can be sterilized using conventional disinfection/sterilization techniques including glutaraldehyde tanning, formaldehyde tanning at acidic pH, propylene oxide treatment, ethylene oxide treatment, gas plasma sterilization, gamma irradiation or electron beam treatment, and peracetic acid (PAA) disinfection. Sterilization techniques which do not adversely affect the mechanical strength, structure, and biotropic properties of the submucosal tissue are preferred. For instance, strong gamma irradiation can cause loss of strength of the sheets of submucosal tissue. Preferred sterilization techniques include exposing the graft to peracetic acid, 1-4 Mrads gamma irradiation (more preferably 1-2.5 Mrads of gamma irradiation) or gas plasma sterilization. Typically, the submucosal tissue is subjected to two or more sterilization processes. After the submucosal tissue is treated in an initial disinfection step, for example by treatment with peracetic acid, the tissue can be wrapped in a plastic or foil wrap and sterilized again using electron beam or gamma irradiation sterilization techniques.

[99] As discussed above, submucosal tissue constructs applicable to the methods described herein can comprise intestinal submucosal tissue delaminated from both the tunica muscularis and at least the luminal portion of the tunica mucosa of warm-blooded vertebrate intestine, or a digest thereof. Such compositions or other implant compositions described herein can be combined with an added growth factor such as vascular endothelial growth factor, nerve growth factor or fibroblast growth factor or growth factor-containing extracts of submucosal tissue.

[100] In one embodiment, solid forms of submucosal tissue are combined with one or more growth factors by soaking the tissue in a buffered solution containing the growth factor. For example the submucosal tissue is soaked for 7-14 days at 4°C in a PBS buffered solution containing about 5 to about 500 mg/ml, or more preferably 25 to about 100 mg/ml of the growth factor. Submucosal tissue readily bonds to proteins and will retain an association with a bioactive agent for several days. However, to enhance the uptake of the growth factors into the submucosal tissue, the tissue can be partially dehydrated before contacting the growth factor solution. For compositions comprising fluidized, solubilized or guanidine extracts of submucosal tissue, lyophilized powder or solutions of growth factors can be directly mixed with the submucosal tissue. For example, fluidized or solubilized submucosal tissue can be mixed with a growth factor and then packed within a tube of submucosal tissue (or other biodegradable tissue). The open end of the tube can then be sealed shut after filling the tube with the fluidized or solubilized submucosal tissue.

Different geometries and conformations of the implant [101] The implants used in the methods described herein are sized and structured to allow substantially normal functioning of the soft palate and the epiglottis when the implant is located in the given position of the soft palate of the subject.

[102] It will become apparent that various configurations of the replaceable implant are possible to achieve one or more benefits of the present invention, for example in treating and/or reducing snoring and sleep apnea.

[103] Sizes and shapes for the implants will vary depending on the need of a particular subject. In one embodiment, the bioreplaceable implant is about 20-30 mm in length (Ls), about 2-4 mm thick (T_s) and about 5-10 mm wide (Ws); for example see FIG 7. In some embodiments, the implant is about 10-40 mm in length (Ls), and in some embodiments the length (Ls) is longer than 4cm, and about 1-10 mm thick (Ts) and about 5-15 mm wide (Ws).

[104] In some embodiments, variations in configurations, for example, the herein disclosed various configurations and modifications thereof, are considered to be within the scope of the present invention. Such configurations include, but are not limited to, an implant having a cross section of a substantially square configuration, substantially rectangular configuration, substantially circular configuration, substantially elliptical configuration, substantially hexagonal, or octagonal or heptagonal configuration etc. In some embodiments, the overall shape is a substantially rectangular configuration, a substantially cylindrical configuration, a substantially linear configuration, a substantially C-shaped configuration, a substantially cross-shaped configuration, or a substantially coil shaped configuration and the like and combinations thereof.

[105] In some embodiments, the implant is formed from submucosal tissue wherein the submucosal tissue is layered on top of a previous layer to form a multi-layered implant, for example, see FIG 10a and 11a. In some embodiments, the layers can be layered on top of each other in the same direction (i.e. the submucosal tissue is layered so the orientation of the lower sheet is the same as the orientation of the one placed above it) (see FIG 10a), and in other embodiments, the submucosal tissue is layered in different orientations, for example perpendicular to each other for additional strength, see FIG 10b and lib and U.S. Pat. 2002/0103542 which is specifically incorporated herein by reference in its entirety, for examples.

[106] In some embodiments, the implant is the implant is formed from submucosal tissue wherein the submucosal tissue is layered on top of a previous layer, form a multi-layered implant, where the multi-layered implant is formed by folding the submucosal tissue. For example, see FIG 1Od and FIG Hd. [107] In alternative embodiments, the implant is formed from submucosal tissue wherein the submucosal tissue is manipulated in a coil. In some embodiments, the coil is a circular coil (for example, FIG 10c and FIG lie) , in some embodiments the coil is a rectangular coil, in some embodiments, the coil is a square coil, for example see FIGS 1Oe and lie, and in some embodiments the coil is a hexagonal, (e.g. FIG lie") or a pentagonal coil etc. In some embodiments, the coil can comprise a single layer of submucosal tissue to form the coil, or can comprise a plurality of layers of submucosal tissue, for example at least two or three, or more than three layers of submucosal tissue. In the embodiments where the coil comprises multiple-layers of submucosal tissue, the layers can be in the same orientation or in different orientations as discussed above.

[108] In some embodiments, the implant is formed from submucosal tissue wherein the submucosal tissue is layered on top of a previous layer to form a multi-layered implant by folding a layer of submucosal tissue, for example see FIGlOd and FIGlIe. In particular embodiments, the implant comprises one or multiple layers of submucosal tissue, for example see FIG 1 Id' which is folded to form an implant of the present invention. The described conformations of implants described herein are not intended to limit the scope of the invention, but rather are intended to be exemplary of certain embodiments. Other conformations are within the scope of the described invention.

[109] In some embodiments, one or both ends of the implant are substantially flat, or substantially rounded, or substantially pointed, or substantially shaped, for example, one or both ends can be scored or otherwise provided with an anchor. In some embodiments, one end flairs outwardly following placement of the implant in the soft palate, which aids the retention of the implant in place while tissue ingrowth matures.

[110] In one embodiment, the implant is formed from submucosal tissue wherein the submucosal tissue is manipulated to define a cylinder having a diameter of the preferred size. In one embodiment, the submucosal tissue is prepared directly from intestinal tissue and in some embodiments, the implant has a generally cylindrical shape. The tissue can be manipulated to define a cylinder having the preferred diameter by suturing or otherwise securing the graft longitudinally and removing the excess tissue. For example, the graft construct can be prepared by selecting a sterile glass rod having an outer diameter equal to the desired diameter of the lumen of the formed graft construct. The glass rod is introduced into the graft lumen, redundant tissues is then gathered, and the desired lumen diameter is achieved by suturing along the length of the graft or by using other art recognized tissue securing techniques. [111] Alternatively, a tube of submucosal tissue can be formed by wrapping strips of submucosal tissue onto a mandrel wherein the wrapped submucosal tissue is overlapped leaving no portion of the underlying mandrel exposed. See U.S. Provisional Application Serial No. 60/032,679, the disclosure of which is expressly incorporated herein. The submucosal tissue can be spirally wrapped onto a mandrel as a continuous piece of submucosal tissue, and/or multiple strips of submucosal tissue can be used to form the tubular constructs. The wrapped submucosal tissue is then compressed under dehydrating conditions and the tubular construct is removed from the mandrel. The amount of overlap in a spirally wrapped construct in accordance with this embodiment ranges between 10 to 60% of the width of the previous strip and in some embodiments the overlapped portion is a 50%, or 100% overlap. In alternative embodiments, when viewing the implant from the cross- sectional view, the implant can comprise multiple cylindrical or hexagonal tubes, for example, a honey-comb effect. In some such embodiments, the honey comb or multiple cylindrical tubes are further encased in at least one layer of submucosal tissue.

[112] Upon formation of the bioreplaceable tube, the tube is filled with fluidized or solubilized submucosal tissue and the tube is sealed at one or both ends of the tube using art recognized methods (including clamping, suturing, binding pastes, and compression under dehydrating conditions). Alternatively the tube can be sealed at one or both ends of the tube before being filled with fluidized/solubilized tissue. The tube can then be filled by injecting fluidized/solubilized tissue into the lumen through the use of a syringe.

[113] In one embodiment, a bioreplacable implant as disclosed herein comprising submucosal tissue of a warm-blooded vertebrate is administered to a warm-blooded vertebrate at a site in need of palatal stiffening in an amount effective to induce endogenous soft palate related tissue growth at the site the composition is administered, in an amount effective to result in stiffening of the soft palate. The biotropic properties of submucosal tissue promote the growth of soft palate along the implant "strips" as defined by the path of the implanted submucosal tissue. Accordingly, as the bioreplacable implant degrades, it is replaced by the subject's own soft palate cells. Accordingly the growth of soft tissue can be directed to a site in need of palatal stiffening. In one embodiment the growth of soft tissue is "directed" through the use of an implant construct comprising a strip of submucosal tissue. In some embodiments, the strip is a cylinder of submucosal tissue filled with fluidized submucosal tissue.

[114] Each of the forgoing methods can be used in conjunction with the implant constructs of the present invention to provide a conduit for directed de novo growth of soft palate. In one embodiment submucosal tissue is prepared in the shape of a strip. In some embodiments, the strip has two open ends, the tube of submucosal tissue is directly implanted into the host organism. A syringe is then used to fill the tube with comminuted or solubilized submucosal tissue. Alternatively, submucosal tissue can be formed in the shape of a tube, filled with fluidized/solubilized submucosal tissue and sealed at each end. The sealed tube of submucosal tissue can then be stored until needed. In one embodiment the sealed tube of submucosal tissue is inserted into the host organism and fixed in place using techniques known to those skilled in the art. The inserted implant construct provides a conduit for new soft palate growth.

[115] In some embodiments, additional components can be added to the implant compositions as described herein to provide the compositions with additional structural support, for example hydroxyapatite and/or other biocompatible calcium containing minerals can be combined with the implant to give additional structural support for the replacement tissue.

Modification of the implants

[116] In some embodiments, the implant material can be coated with material that can be detected by an imaging system, for example but not limited to, coated with radioplaque or radiomarked for imaging by MRI, as an example of such material is a metal.

[117] The implants as described herein are comprised of, or encased in a bioreplacable material and/or a bioreplaceable material. In some embodiments the bioreplacable material that encases or constitutes the implants of the present invention is submucosal tissue, wherein submucosal tissue is the most outside layer of the implant, and as such encases the submucosal tissue in any configuration or conformation discussed above, for example, implants comprising submucosal tissue in a coiled conformation, folded configuration, in layers or a honey-comb configuration etc. In some embodiments, such an outer layer of submucosal tissue can be tight for added strength to the implant. Alternatively, other structures can be used, for example a strip or coil of submucosal tissue wrapped around the implant for additional strength to the implant. Variations on the use of additional submucosal tissue to encase the implants of the present invention comprising submucosal tissue are also encompassed for use in the methods described herein. In alternative embodiments, any biodegradable or bioreplacable material can be used to encase the bioreplaceable implants.

[118] As described above, in some embodiments, the implants can be coated in, or comprise bioactive agents. In some embodiments, the bioactive agents can facilitate tissue ingrowth. As used herein the term "bioactive agents" includes one or more of the following: chemotactic agents; therapeutic agents (e.g. antibiotics, steroidal and non-steroidal analgesics and antiinflammatories, anti-rejection agents such as immunosuppressants and anti-cancer drugs); various proteins (e.g. short chain peptides, bone morphogenic proteins, glycoprotein and lipoprotein); cell attachment mediators; biologically active ligands; integrin binding sequence; various growth and/or differentiation agents (e.g. epidermal growth factor, IGF-I, IGF-II, TGF-β I-III, growth and differentiation factors, vascular endothelial growth factors, fibroblast growth factors, platelet derived growth factors, insulin derived growth factor and transforming growth factors, parathyroid hormone, parathyroid hormone related peptide, bFGF; TGF superfamily factors; BMP-2; BMP-4; BMP-6; BMP-12; sonic hedgehog; GDF5; GDF6; GDF8; PDGF); small molecules that affect the upregulation of specific growth factors; tenascin-C; hyaluronic acid; chondroitin sulphate; fibronectin; decorin; thromboelastin; thrombin-derived peptides; heparin-binding domains; heparin; heparan sulphate; DNA fragments and DNA plasmids, steroidal and non-steroidal hormones such as vitamin D, ecosanoinds, immuno modulators such as ILlO, IL4 and IL12, and synthetic antiinflammatory and immunomodulating agents such as analgesics, p38 regulators, and other regulators of TNFβ upstream and downstream signaling.

[119] In some embodiments, the bioreplaceable implant as disclosed herein can be perforated to encourage tissue ingrowth. The perforations of a bioreplaceable implant allow extracellular fluids to pass through the bioreplaceable implant material, decreasing fluid retention within the implant and enhancing the remodeling properties of the implant. The perforation of the bioreplaceable material is especially beneficial for multi-laminate or multi-layered implants comprising submucosal tissue wherein the perforations also enhance the adhesive force between adjacent layers.

Administration of the bioreplaceable implants

[120] Any means to implant the bioreplaceable implant is encompassed for use in the present invention, for example a hollow bore needle. In some embodiments, the hollow bore needle is about 4cm long, and in some embodiments, the hollow bore needle is flexible and bendable, in which the implant is located in the bore of the needle device. In some embodiments, the needle is a flexible needle such as, but not limited to, a flexible 18G needle.

[121] In alternative embodiments, the implant is placed in the subject by forming a small incision 70 into the soft palate. In FIG 17 and FIG 18 an incision is made on the lower surface of the soft palate. The procedure could also be performed through the upper surface of the soft palate. The incision is sized to pass the distal tip 62 of tool 60. Any suitable blunt dissecting tool can be inserted into the incision for placement of the bioreplaceable implant of the present invention. In some embodiments, the implant is implanted into the soft tissue using a specific tool, for example the tool 60 which is disclosed in U.S. Patent 7,036,515 which is specifically incorporated herein in its entirety by reference.

[122] Also, any suitable blunt dissecting tool can be inserted into an incision 70 to separate the soft tissue ST from the palatal muscle PM by an amount sufficient to receive the implant. The distal tip 62 is placed though an incision 70 and advanced through the soft palate SP with the distal tip 62 separating the soft tissue ST and the palatal muscle PM (FIG 18). The tool 60 can be advanced by the physician tactilely noting position of tool 60 or through any visualization technique, for example an endoscope on the distal tip 62). When the distal tip 62 is fully advanced, the outer tube 66 of tool 60 is retracted while holding rod 64 in place causing implant 20 to be expelled through the distal tip 62. After full expulsion of the implant 20, the tool 60 is removed through the incision 70. The released implant 20 resides between the palatal muscle PM and the soft tissue ST (FIGS 18 and 19).

[123] In some embodiments, the bioreplaceable implants are implanted into the soft palate as shown in FIG 6. In alternative embodiments, more than three bioreplaceable implants can be implanted in alternative positions, as shown in FIGS 12-16. In some embodiments, the implants are positioned parallel to the front of the mouth, for example see FIG 14. In alternative embodiments, the implants are implanted at an angle to the front of the mouth, for example see FIGS 15 and 16. In some embodiments, the implants can be positioned according to one or more of the positions shown in FIGS 12-16. For example, one implant can be positioned according to FIG 12, at least one implant positioned according to FIG 14, or at least one positioned according to FIG 15, and/or at least one implant positioned according to FIG 16. In such an embodiment, the implants can form a cross-hatched arrangement in the soft palate. In alternative embodiments, the implants can be implanted at any time after a previous set of implants were inserted. Furthermore, any position of the implants is encompassed for use in the present invention.

[124] In an alternative embodiment, the implant is a bioreplaceable material that are particles, such as beads. In such an embodiment and as discussed above, the bioreplaceable material is solid modules, such as spheres, of bioreplaceable material, for example of submucosa tissue as discussed above. By way of non-limiting example, the modules can be about 2-4 mm in diameter of submucosa tissue. Measurement of efficacy of the implant for the treatment of snoring.

[125] In some embodiments, a bioreplacable implant as disclosed herein is administered to a subject in need of palatal remodeling to decrease the frequency of oscillation of the soft palate, where an effective amount of the implant is selected for the treatment of snoring in the subject, where effective treatment is a reduction of snoring by the subject. In some embodiments, the implant is inserted into the soft palate of the subject in an effective amount to induce endogenous soft palate related tissue ingrowth at the site the implant or composition is administered, and in some embodiments the composition is administered in an amount effective to result in stiffening of the soft palate. Accordingly, as the bioreplacable implant degrades, it is replaced by the subjects own soft palate cells. Accordingly the ingrowth of soft tissue can be directed to a site in need of soft palatal remodeling to decrease the frequency of soft palate oscillations in response to air flow. In some embodiments, the ingrowth of soft tissue can result in increased stiffening of the soft-palate.

[126] The terms "treat" or "treatment" refer to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow the occurrence of snoring and/or sleep apnea in the subject. Treatment is generally "effective" if one or more symptoms or clinical markers of snoring or sleep apnea are reduced as that term is defined herein. Alternatively, treatment is "effective" if the progression or development of a snoring condition and/or sleep apnea is reduced or halted. That is, "treatment" includes not just the improvement of at least one symptom of snoring or sleep apnea, but also a cessation or at least slowing of worsening of a symptom that might be expected in the absence of treatment. Beneficial or desired clinical results include, but are not limited to, a decrease in one or more symptom(s), stabilized snoring (i.e., not worsening), amelioration or palliation of the snoring, and remission (whether partial or total). Those in need of treatment include those who snore and/or have sleep apnea or have been diagnosed with obstructive sleep apnea (OSAS), or in some embodiments, those already diagnosed with sleep apnea as well as those likely to develop cardiovascular complications (Partinen and Guillemina et al 1990; Javaheri, 1996), physiological problems (Haraldsson et al. 1992; Jennum et al. 1993), social dysfunction, daytime tiredness, hypertension, morning headaches due to the lack of, or disturbances in sleep as a consequence of sleep apnea or snoring. Without wishing to be bound by theory, obstructive sleep apnea (OSAS) is characterized by habitual snoring together with episodic mixed or obstructive apnea and daytime somnolence (Roffwarg et al. 1979). Numerous studies have shown that OSAS is accompanied by cardiovascular complications (Partinen and Guillemina et al 1990; Javaheri, 1996) and social disorders (Haraldsson et al. 1992; Jennum et al. 1993).

[127] The term "effective amount" as used herein refers to the amount of the composition as disclosed herein to reduce at least one or more symptom of snoring and/or sleep apnea. The phrase "therapeutically effective amount" as used herein, e.g., the use of the bioreplacable implant as disclosed herein means implantation of at least one bioreplacable implant of sufficient size and quantity to treat (i.e. reduce the level of) snoring and/or sleep apnea at a reasonable benefit/risk ratio applicable to any medical treatment. The term "therapeutically effective amount" therefore refers to the quantity (i.e. the number and/or the thickness and length) of the bioreplacable implants of the composition as disclosed herein that is sufficient to effect a therapeutically or prophylactically significant reduction in a symptom of snoring and/or sleep apnea.

[128] A therapeutically or prophylatically significant reduction in snoring a symptom is, e.g. at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100% or more in a reduction in a measured parameter as compared to a reference or baseline level, or non-treated subject. Measured or measurable parameters of symptoms include, but not limited to, reduced frequency of snoring (i.e. in terms of number of snores per hour), reduced volume of snoring, reduced duration of snoring, increased sleep, a change in the wavelength frequency of snoring such that it is inaudible or less audible to other humans, reduced size and/or frequency oscillation of the soft palate SP per second, as well as parameters related to a clinically accepted scale of snoring and/or sleep apnea. Such measurable parameters can be determined in a sleep lab and/or by asking the spouse or sleeping partner of the subject affected with snoring. As an illustrative example, snoring can result from the frequency of oscillation of the subject's soft palate of about 50 oscillations per second in response to air flow past the soft palate, so an example of a significant reduction in a symptom of snoring would be a reduction or decrease in oscillations of the soft palate to about 40 oscillations per second or less, or preferably about 35 oscillations per second or less, or about 30 oscillations per second or less, or about 25 oscillations per second or less, or about 20 oscillations per second or less, or about 15 oscillations per second or less, or about 10 oscillations per second or less, or about 5 oscillations per second or less, or more preferably a reduction in oscillation of the soft palate to between 0 and 5 oscillations per second in response to airflow past the soft palate. [129] The efficacy of treatment can be judged by an ordinarily skilled practitioner. For any given case, an appropriate "effective amount" can be determined by one of ordinary skill in the art, and can determined in stages or increments, such as to measuring the efficacy of treatment after one implant and if one implant does not result in effective treatment, the subject can have at least one, or at least 2, or at least 3, or at least 4, or at least 5 or more additional implants. The exact effective amount, i.e. the quantity of the implants (i.e. the thickness and number of implants) as disclosed herein can be decided by the attending physician within the scope of sound medical judgment. The exact effective amount required will vary depending on a variety of factors such as, the age, gender and general health of the subject, prior treatment for snoring, and the severity of symptoms of snoring and/or sleep apnea in the subject. A therapeutically effective amount as the term is used herein need not totally eradicate snoring and/or sleep apnea in the subject, it need only result in a significant reduction in a symptom, as the term defines herein, of snoring and/or sleep apnea.

[130] Methods to measure the biomedical properties of the soft palate are known by person of ordinary skill in the art, and include methods such as use of a computerized endopharyngeal myotonometry (CEM) which can be used to measure the oscillations of the soft palate in response to air flow past it, as well as to measure stiffness and elasticity of a subject's soft palate, as described in Veldi et al. Computerized endopharyngeal myotonometry (CEM): a new method to evaluate the tissue tone of the soft palate in patients with obstructive sleep apnea syndrome, J. Sleep Res. 9 (2000) 279-284, which is specifically incorporated herein in its entirety by reference. Computerized endopharyngeal myotonometry (CEM) is further discussed and has been used to measure changes in soft-palate tone and soft-palate tone sleep-related breathing disorders as well as the stiffness of soft palate and genioglossal (Veldi et al, Clin. Physiol. 21 (2001) 358-364, Veldi, et al., Eur. Arch. Otorhinolaryngol. 259 (2002) 108-112; Veldi et al Sleep Med. (2003) S49, and Veldi et al., Pathophysiology. 2004 Dec;ll(3):159-165, which are incorporated herein in their entirety by reference).

[131] Briefly, computerized endopharyngeal myotonometry (CEM) is a method of analyzing the tissue tone of the soft palate during wakefulness and enables a comparison of the stiffness and tissue-tone parameters of the soft palate in subject prior to implantation with a tissue processed material as disclosed herein with stiffness and tissue-tone parameters of the soft palate in the subject following implantation. Vibration of the soft palate, and negative intrapharyngeal pressure during sleep, bring about changes in the soft palate tissues (Friberg 1997). [132] CEM, which is described in Veldi et al, (J. Sleep Res. 9 (2000) 279-284) which is incorporated herein by reference, is based on computerized myotonometric technology (Vain et al. 1992; Vain 1995; Hein and Vain 1998) and is a noninvasive method. In order to evaluate the tissue tone of the soft palate, one can use a hand-held myotonometer which was customized for endopharyngeal procedures. The testing arm of the device with a contact area and the elective weight is placed on the skin surface or, on the surface of the soft palate over the muscles. As a result, the tissues above the muscular area are in a compressed state. The CEM device is fired in response to a fixed pressure on the testing arm. The testing-arm driver produces a short impulse (a few ms, t^), which is forwarded by means of the testing arm to the contact area. Typically, the optimum duration of the impact on the soft palate tissue is 8 msec. The impulse terminates, with a quick release, at moment t₂.

[133] The soft-palate responds to such a mechanical impact with damped oscillations. The oscillations of the soft palate are recorded using the acceleration transducer, which is located on the testing arm. The acceleration value of the first period of oscillations, calculated from the oscillation graph, characterizes the deformation of the tissue that was caused by the testing arm. The data of the next oscillation period provide the basis for calculating the oscillation frequency and logarithmic decrement of damping, which are calculated by means of the following formulas;

[134] Oscillation frequency (J) of tissue, where T is oscillation period in second.

W

[135] Oscillation logarithmic decrement (T) of tissue, where a is oscillation amplitude.

[136] The frequency of the damped oscillation characterizes the soft palate tissue stiffness. Stiffness is the property of a tissue that resists the force that changes its shape.

[137] The logarithmic decrement of the damped oscillation characterizes tissue elasticity, whereas the decrement is inversely proportional to elasticity. Elasticity is the property of a tissue that restores its initial shape.

[138] Methods to use CEM are described in Veldi et al, (J. Sleep Res. 9 (2000) 279-284) which is incorporated herein it entirety by reference. CEM can be operated by a person of ordinary skill in the art to measure the frequency of oscillation and stiffness of a subject's soft-palate while they are awake. Accordingly, the neuromuscular factors of the soft palate relate to wakefulness and not sleep. The pharyngeal area can be anesthetized with a single dose of a 10% solution of lidocaine spray. The myotonometric test can begin as soon as the anesthetic takes effect, typically about 10 min after, for example lidocaine had been administered. CEM is typically performed on a subject lying in the supine position in a relaxed manner, with special attention paid to the degree of mouth opening and the tongue position to ensure the practitioner places the subject in a position to enable similar conditions of oropharyngeal tissues for each subjects during each and every measurements taken. Typically, the subject's mouth is open but not to a maximum degree. The practitioner applies even pressure to suppress the subject's tongue with a spatula without the subject offering resistance. The practitioner observes the subject's breathing. When the latter has stabilized, during an inspiration phase the practitioner places the testing arm of the myotonometer on the surface of the soft palate with the myotonometer turned on in readiness. The practitioner's hand pressure does not affect the pressure of the testing arm on the contact area because the testing arm is fixed to the freely moving pivotal two-armed lever. The testing arm affects the contact area only by its own weight. While lowering the myotonometer, at a particular pressure on the testing arm, the electromagnet is switched on and the testing arm makes a mechanical impact on the soft palate. The tissue response of the soft palate after this brief mechanical impact is expressed as a damped oscillation. The parameters of the damped oscillation are calculated using a computer program, and the myotonometer is then ready for the next measurement. All measurements were made in the central part of the soft palate, where the following muscles are located: m. uvulae, m. palatoglossus, m. palatopharyngeus and m. levator veli palatini. Typically three measurements are taken on each subject at one time, and the mean value of frequency of oscillation of the soft-palate is calculated. Two identical measurements indicated that the data is reliable.

EXAMPLES

[139] The forgoing describes numerous embodiments of an invention presented herein relating to the use of an implant comprising of bioreplaceable material for the treatment and reduction of snoring.

[140] In particular the present invention relates to the use of implants as disclosed herein comprising bioreplacable material into the soft palate for the treatment of snoring and/or sleep apnea. In some embodiments, the bioreplacable material implant in the soft palate remodels the soft-palate tissue to reduce the flapping or reduce the frequency of oscillation as a result of air flow over the soft palate, which can result in an alteration (i.e. decrease) of the dynamic response of the soft palate. In some embodiments, the remodeling increases the stiffness of the soft palate. The present invention has numerous advantages over prior materials for palatal implants. For example, the present invention permits tissue remodeling of the soft palate in a fully regulatable and controlled manner, without the formation of fibrosis (scarring) or without uncontrolled palatal stiffening. The methods and compositions as disclosed herein can be tuned to the particular needs of the subject, both by the effective amount of the implant used, as well as surgical placement of the implants and post-operative analysis to determine if subsequent implants are necessary for a further reduction in the frequency of oscillation of the soft palate in response to air flow, and/or increased stiffening of the soft palate.

[141] The embodiments of the conformation of implants as described herein are not intended to limit the scope of the invention, but rather are intended to be exemplary of certain embodiments. Variations in the exemplified methods and conformations which occur to persons of ordinary skill in the art are intended to fall within the scope of the present invention. Accordingly, having described the invention, alternatives and embodiments can occur to one of skill in the art. For example but not limited to, strips can also have hinged sections, or alternatively, be comprised of a spring like configuration, or be enclosed or encased in a coiled spring of bioreplaceable material which can be tightened to further alter the properties of the implants, such as to increase the flexibility of the implants while maintaining their ability to decrease the frequency of soft palate oscillation, or for example to increase the stiffness of the implants.

[142] Throughout this application, various publications are referenced. The disclosures of all of the publications and those references cited within those publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains. The forgoing figures are some examples of the present invention, and are not intended by any means to limit the scope of the claims to the invention, but rather, they are intended to be exemplary of certain embodiments. It will be appreciated that the bioreplacable implant of the present invention, its composition, shape and thickness is to be selected depending on the ultimate properties and indication desired of the replaceable implant. Those skilled in the art will recognize that various modifications can be made to methods described herein without departing from the spirit of the invention, and any such variations in the exemplified methods are intended to fall within the scope of the present invention. EXAMPLE 1: Submucosa tissue implants for treatment of snoring or sleep apnea

[143] The present invention relates to an improved method for treating subjects with upper airway conditions such as snoring and sleep apnea. The invention relates to use and implantation of a bioreplaceable material, such as a processed tissue material comprising a submucosal tissue, where the implanted tissue material is replaced with the subjects own cells and tissues in vivo, and the remodeled tissue decreases the frequency of oscillation of the soft palate in response to air flow, thus altering the dynamic response following the implantation without substantially impairing a function of the soft palate to close a nasal passage of the subject during swallowing. In some embodiments, the remodeled soft-palate has increased stiffness. In some embodiments, the submucosal material is intestinal submucosa (SIS), or the bioreplaceable material is a material extracted from SIS, named SISH. SIS, in various forms, is commercially available from Cook Biotech Incorporated (Bloomington, Ind.) and commercially known as SURGISIS®.

[144] As an exemplary embodiment of the methods and compositions as disclosed herein, an implant comprising submucosa tissue, such as for examplea strip of SURGISIS® can be used, as shown in figure 22. As an exemplary embodiment, a SURGISIS® strip of dimensions of about 2.5cm long x about 10mm width x about 5mm thick can be placed into the subject by forming a small incision in the lower surface of the soft palate as shown in figures 17 and figures 18, and inserting the implant by using an appropriate delivery tool, such as a blunt ended 18G flexible needle. Alternatively, the implant can be inserted into through the upper surface of the soft palate. Typically, a blunt dissecting tool can also be used to separate the soft tissue from the palatal muscle to assist in inserting the implant through an 18G flexible needle delivery tool. Once a physician has determined the location of the desired insertion site for the implant, the tool for delivering the implant is advanced through the incision and into the soft palate to the approximate delivery location where the implant is to be delivered, where the appropriate delivery location is an area between the soft tissue and the palatal muscle of the soft palate, as illustrated in Figure 18. Typically, this is done by, a delivery tool loaded with the implant, slowly inserted through the incision and into the soft plate to an appropriate distance where the implant is to be left in the soft palate of the subject. The appropriate distance that the delivery tool is inserted is based on the experience of the physician, or the physician tactilely noting the position and/or distance the tool has been inserted, or alternatively by visual indicators, such as obstruction of a measurement mark at the appropriate length on the tool, such as a mark on the 18G flexible needle, which indicates the delivery tool has traveled the appropriate distance inside the soft palate for the correct placement of the implant in the soft palate.

[145] Once the tool for delivering the implant has been advanced the appropriate distance for the proper placement of the implant into the desired location in the soft palate, the implant is expelled from the delivery tool into the soft palate at the same time the delivery tool is retracted and removed from the insert site, leaving the implant between the palatal muscle and the soft tissue of the soft palate as shown in figures 4, and figures 18 and 19. Once the tool used to deliver the implant is completely removed from the incision site, the incision site can be closed if necessary, for example by using sutures or liquid sutures (i.e. tissue glue). This process can be repeated numerous times to insert multiple implants, typically at least 1 or at least 2 or at least 3 implants into the soft palate of the subject. The subject is then analyzed for snoring and snoring symptoms as compared to snoring symptoms measured prior to the implantation of the processed tissue material implant. The treatment will effect a reduction in snoring by altering the dynamic response of the soft palate, and decreased frequency of oscillation of the soft palate to airflow past the soft palate.

EXAMPLE 2: Submucosa tissue implants for lip augmentation

[146] To illustrate the capacity that a bioreplaceable material such as SURGISIS® can be safely implanted into a subject and can be replaced by the subjects own cells to remodel the tissue, for example to remodel the tissue for altered tissue tone, such as but not limited to, an increased tissue stiffness, and does not substantially impair function, the inventors used strips of SURGISIS® for lip augmentation to improve the firmness and stiffness of subjects lips without impacting the function of the lips. This is an illustrative example of the ability to use of bioreplaceable material such as SURGISIS® to remodel a subjects own tissue with the desired sufficient stiffness.

[147] The lips are a vital feature of an attractive and youthful face. Full, well defined lips impart a sense of beauty and have been a desirable trait for centuries. Over time, cumulative forces act to thin and flatten the lips. Factors affecting the shape and contour of the lips include atrophy of the subcutaneous tissues, laxity in the perioral musculature, and demineralization of the mandible and maxilla.¹ This alteration in the appearance of the lips is an integral component of the aging face. Discontent with these labial aging signs has spawned the development of numerous techniques to augment lip volume and form. A myriad of injectable fillers and implantable materials, both biologic and synthetic, have been used to correct or enhance lip shape. This wide variety of treatment materials attests to the notion that to date, no ideal therapy exists. While many of these substances have produced excellent results, potential problems include donor site morbidity, transmission of cell-borne pathogens, allergic reactions, lack of durability, inconsistent results, implant migration and extrusion, and infectious complications.

[148] SURGISIS® (Cook Biotech Inc, West Lafayette, Indiana) is an acellular, freezedried, soft tissue graft derived from porcine small intestinal submucosa that can serve as an alternative to these fillers. SURGISIS® has been safely and effectively used in various colorectal, urologic, and otolaryngologic procedures. Small intestinal submucosa has been shown to support and maintain cell migration and spatial organization in vitro.²

[149] The graft provides a prosthetic scaffold into which adjacent cells migrate to create replacement tissue.³ These properties make SURGISIS® a viable option for lip augmentation and for implant to treat snoring and sleep apnea. The present study addresses the initial use of SURGISIS® for upper- and lower-lip enhancement.

[150] All patients undergoing lip augmentation tolerated the procedure under local anesthesia in an outpatient setting without any substantial local or systemic complications. All patients reported procedural pain as mild. Total procedure time was less than 1 hour in all cases. No procedure was terminated owing to pain or technical problems. One strand did tear from the trocar during implantation but was easily removed, and a new implant was used to complete the treatment. Preoperative and postoperative photography was used to document results (Figures 23 and Figure 24).

[151] Patient satisfaction determined by questionnaires found that at 2 weeks after the procedure, all 8 patients were satisfied with the results. The average score was 5.8 on a 10- point scale. Following the initial procedure, 4 patients requested additional augmentation. Of the 4 patients who underwent further implantation, 1 was lost to follow-up. The remaining 3 patients had an average satisfaction score of 7.0 two weeks after the second implant was placed. Of the 4 patients treated with only 1 implant, 1 was lost to follow-up, and the resulting average satisfaction score was 6.3 at both 12 and 24 weeks. One patient received a third implant and following this had a satisfaction score of 10. The procedure was well tolerated in all the patients, and the average pain score was 0.5. Six patients experienced no pain, and 2 patients each rated the pain a 2.0. In these 2 patients, the pain lasted less than 48 hours. Adverse reactions were limited to mild transient erythema in 2 patients that resolved spontaneously and 1 case of cellulitis of the upper lip following placement of the third implant. This condition was successfully treated with a 10-day course of cefdinir. No patients had a fibrotic response or scarring as a result of the implants. All patients denied bleeding or hematoma formation, allergic reactions, and implant extrusion. Furthermore, implants were neither noticeable nor palpable, and all patients denied changes in sensation or interference in lip function.

[152] SURGISIS® serves as a prosthetic scaffold derived from porcine small intestinal submucosa. It is composed primarily of type 1 porcine collagen. In addition, 5 glycosaminoglycans are present in the matrix: hyaluronic acid, heparin, heparin sulfate, chondroitin sulfate A, and dermatan sulfate.⁴ These glycosaminoglycans have been shown to provide structural integrity to the extracellular matrix. They also modulate the healing of tissues through the deposition of collagen fibers, stimulation of angiogenesis, inhibition of coagulation, and initiation of cell proliferation and differentiation.⁵ The amount of glycosaminoglycans in SURGISIS® corresponds well to the amounts reported in other basement membrane-containing tissue sites and is significantly more than that seen in skin, from which AlloDerm (LifeCell Corporation, Branchburg, New Jersey) is derived.⁶

[153] SURGISIS® is terminally sterilized to eliminate cell-borne pathogens and has been shown to elicit no immunologic response from host tissue.⁷ No skin testing is required prior to use. Use in various other sites and applications have demonstrated an excellent safety profile. In this series of 8 patients (19 implants), 1 postoperative infection occurred, and this only in the patient following placement of the third implant. The procedure was performed in a sterile fashion, and this infectious complication can have been owing to the multiple instrumentations rather than the implant material itself.

[154] The operative procedure was well tolerated in all cases under local anesthesia in an outpatient setting. All 8 patients reported minimal intraoperative and postoperative pain. Minimal bruising and swelling occurred following implantation, with all patients reporting a return to normal activity the following day. While all patients tolerated the procedure well with few adverse reactions, the aesthetic outcome was not universally acceptable. No patient reported asymmetry or palpable implants, but the degree of lip projection and fullness was often inadequate. Godin et al⁸ evaluated patient satisfaction based on a 10-point grading scale after using Radiesse (BioForm Inc, Franksville, Wisconsin) and Restylane (Q-Medical, Uppsala, Sweden) for facial augmentation.

[155] With Radiesse alone in the upper and lower vermilion borders, the satisfaction scores were 7.0 and 7.3, respectively. The combination of Radiesse and Restylane into the upper and lower vermilion borders yielded satisfaction scores of 7.7 and 6.5, respectively.⁸ In this study herein, the inventors used a similar satisfaction scale but did not distinguish between upper- and lower-lip implants. The inventors' scores from this study were comparable: 6.3 for 1 implant, 7.0 for 2 implants, and 10 for 3 implants. In the inventor's series, all 8 patients reported satisfaction with the procedure at 2 weeks; however, 4 patients requested greater augmentation on subsequent follow-up. One implant provided minimal augmentation in most cases, which was often insufficient in this patient population.

[156] Placing a second, and in one case a third, implant provided the more full appearance desired by our patients. An alternative to this, one can use a thicker implant to give a more pronounced augmentation. Wall et al⁹ assessed patient satisfaction with expanded polytetrafluoroethylene (Softform; Collagen Corporation, Palo Alto, California) lip implants and also reported that patients were more pleased in the immediate postoperative period than on subsequent visits. Furthermore, 67% of patients were willing to receive an additional implant, and 37% would replace the existing implant with a larger size.⁹ The thickness and configuration of lip implants can need to be modified to enhance patient satisfaction.

[157] The inventors demonstrate herein the ease of placement and moderate short-term efficacy of lip augmentation with SURGISIS®, a novel soft tissue filler. The inventors demonstrate that SURGISIS® can serve as scaffolding for ingrowth of striated muscle of the lip, providing increased stiffness of the lip tissue and lip augmentation. The degree of stiffness and augmentation was dependent on the number of implants, with lip augmentation with 1 implant increased and improved with placement of additional implants. The inventors demonstrate that SURGISIS® implantation is safe, well tolerated procedure which can be used for patients seeking lip augmentation from a biologic implant.

[158] The effect of a bioreplaceable material such as SURGISIS® to improve tissue stiffness and for tissue augmentation as disclosed herein in the Examples is expected to be a general effect of such a bioreplaceable material such as SURGISIS® on facial muscle tissue. That is, where a bioreplaceable material such as SURGISIS® is implanted into any facial tissue of any type, one would expect the approach as disclosed herein for using SURGISIS® to increase tissue stiffness and firmness for lip augmentation to work in other tissues to increase tissue stiffness. In particular, the methods and compositions as disclosed herein are likely to work to increase tissue stiffness in a subject where the bioreplaceable material has been implanted into the soft palate. One can use such a bioreplaceable material implant, such as SURGISIS® to increase tissue stiffness of the soft palate as compared to the subject without bioreplacable material implants, such that the increased tissue stiffness has a dampening sufficient to alter the dynamic response following the implantation without substantially impairing a function of the soft palate or closing a nasal passage of the subject during swallowing. Thus, such a bioreplaceable material implant, such as SURGISIS® which increases tissue stiffness at the site of implantation can be used to increase soft palate stiffness for the treatment and/or prevention of snoring and sleep apnea. Methods of insertion of submucosa tissue implants for Up augmentation [159] Patients presenting to the otolaryngology/ facial plastic surgery clinic seeking lip augmentation or treatment of previously acquired lip defects were offered a novel therapy using SURGISIS® as a soft tissue filler. Patients were excluded from participation if they had an active infectious or inflammatory condition of the implant site or a history of adverse reactions to porcine products, lidocaine, or epinephrine. Previous lip augmentation was not considered an exclusion criterion, and 1 study patient underwent a prior expanded polytetrafluoroethylene (GORE- TEX®; W. L. Gore and Associates, Flagstaff, Arizona) upper-lip implantation. Eight patients ranging in age from 35 to 70 years old signed informed consent forms for the procedure and were then photographed preoperatively, using standard techniques. Six patients were seeking cosmetic lip augmentation, and 2 patients desired treatment of previously acquired partial lip defects. Six women and 2 men were treated. In total, 19 implants were placed. Ten implants were used for cosmetic augmentation of either the upper or lower lip or both. Two implants were placed to fill partial lower-lip defects, and 7 implants were placed in patients requesting additional augmentation after the initial procedure.

[160] Seven upper lips and 12 lower lips were treated. Prior to surgical intervention, the SURGISIS® strand (Figure 23) was placed in an antibiotic and isotonic sodium chloride solution for a minimum of 5 minutes to rehydrate the implant. An antibiotic with gram- positive coverage was administered, and the facial region being treated was cleansed with alcohol. Approximately 3mLof lidocaine hydrochloride, 1%, with 1:100 000 epinephrine was injected into the treatment area. Stab incisions were created for the entrance and exit sites of the trocar on the mucosal surface of the lip approximately 1 mm from the vermilion border. The trocar was then inserted into the submucosa through the incision and passed through the full length of the area being treated (Figure 24). The SURGISIS® strand was trimmed and the overlying tissue was manipulated to ensure proper positioning and prevent bunching of the implant. The incisions were closed with a single 6-0 absorbable suture. Bacitracin was applied to the incisions, and ice was placed on the lips. Patients were seen in clinic 2 to 3 weeks postoperatively and then at approximately 4- week intervals thereafter. Questionnaires administered after the procedure were used to assess patient satisfaction, presence and level of pain, duration of pain, and complications. Patient satisfaction was graded on a 10- point scale at 2, 12, and 24 weeks after the procedure. Satisfaction was further evaluated in patients who received multiple implants 2 weeks after each successive implant was placed. Procedural pain was measured on a 10-point scale. Preoperative and postoperative photography was used in all cases.

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Claims

Claims:

1. A method for treating snoring of a subject, the method comprising implanting a processed tissue material into the soft palate of the subject, wherein the processed tissue material when implanted into the subject undergoes biodegradation concurrent with its replacement by the subject's living cells, such that the frequency of oscillation of the soft palate in response to airflow past said soft palate is reduced, and whereby snoring is reduced in said subject.

2. The method of claim 1, wherein the processed tissue material comprises submucosal tissue.

3. The method of claims 1 or 2, wherein the submucosal tissue is derived from the tunica submucosa or tunica muscularis or the luminal portion of the tunica mucosa of the small intestine, or a digest thereof.

4. The method of claim 3, wherein the tunica submucosa comprises substantially acellular telopeptide collagen.

5. The method of claim 1, wherein the subject suffers from snoring attributable to, at least in part, a snoring sound generated from an oscillation of the subject's soft palate in response to airflow past the subject's soft palate.

6. The method of claim 1, wherein the reduction in the frequency of oscillation of the soft palate in response to airflow past said soft palate is due to an alteration of the dynamic response of the soft palate to the airflow past the subject's soft palate.

7. The method of claim 6, wherein the altered dynamic response of the soft palate to the airflow results in a reduction in snoring by the subject.

8. The method of claims 1 or 2, wherein the processed tissue material does not induce a substantial fibrotic response in the subject.

9. The method of claims 1, 2 or 3, wherein the submucosal tissue is small intestine submucosa (SIS).

10. The method of claim 1, wherein the subject's cells which replace the implanted processed tissue are a cell population substantially free of fibroblast cells.

11. A composition comprising submucosal tissue for the treatment of snoring and/or sleep apnea.

12. A composition comprising submucosal tissue to decrease snoring and/or sleep apnea in a subject.

13. The composition of claims 11 or 12, wherein the submucosal tissue is small intestine submucosa (SIS).

14. The composition of claims 11, 12 or 13, wherein the composition is implanted in an effective amount into the soft palate of the subject to decrease the frequency of oscillations of the subject's soft palate to airflow past the soft palate.

15. The composition of any of claims 11 to 14, wherein the composition is bioreplaceable with the subject's living cells.

16. The composition of any of claims 11 to 15, wherein the living cells are substantially not fibroblast cells.