Patent Publication Number: US-2022225975-A1

Title: Apparatus and methods for sealing a vascular puncture

Description:
RELATED APPLICATION DATA 
     The present application claims benefit of co-pending U.S. provisional application Ser. No. 61/434,412, filed Jan. 19, 2011, the entire disclosure of which is expressly incorporated by reference herein. 
    
    
     FIELD OF THE INVENTION 
     The present invention relates generally to sealants, apparatus, and methods for sealing punctures in a body, and more particularly, to apparatus and methods for sealing a vascular puncture extending through tissue to a blood vessel. 
     BACKGROUND 
     Apparatus and methods are known for accessing a patient&#39;s vasculature percutaneously, e.g., to perform a procedure within the vasculature, and for sealing the puncture that results after completing the procedure. For example, a hollow needle may be inserted through a patient&#39;s skin and overlying tissue into a blood vessel. A guide wire may be passed through the needle lumen into the blood vessel, whereupon the needle may be removed. An introducer, procedural, or femoral sheath may then be advanced over the guide wire into the vessel, e.g., in conjunction with or subsequent to one or more dilators. A catheter or other device may be advanced through the introducer sheath and over the guide wire into a position for performing a medical procedure. Thus, the introducer sheath may facilitate accessing and/or introducing various devices into the vessel, while minimizing trauma to the vessel wall and/or minimizing blood loss. 
     Upon completing the procedure, the device(s) and introducer sheath may be removed, leaving a puncture extending between the skin and the vessel wall. To seal the puncture, external pressure may be applied to the overlying tissue, e.g., manually and/or using sandbags, until hemostasis occurs. This procedure, however, may be time consuming and expensive, requiring as much as an hour of a medical professional&#39;s time. It is also uncomfortable for the patient, and may require the patient to remain immobilized in the operating room, catheter lab, or holding area. In addition, a risk of hematoma exists from bleeding before hemostasis occurs. 
     Various apparatus and methods have been suggested for sealing vascular punctures resulting from such procedures, such as those disclosed in U.S. Pat. Nos. 7,316,704, 7,331,979, 7,335,220, and 7,806,856, and U.S. Publication Nos. 2007/0231366, 2008/0082122, 2009/0088793, 2009/0254110, 2010/0168789, 2010/0274280, and 2010/0280546. The entire disclosures of these references are expressly incorporated by reference herein. 
     For example, the MATRIX™ product included two synthetic polyethylene glycol (“PEG”) polymer powders that were mixed with appropriate buffers and injected through a femoral sheath at an arteriotomy site, e.g., as disclosed in U.S. Pat. No. 7,316,704. The Mynx® Vascular Closure Device is another system for sealing vascular punctures, e.g., as disclosed in one or more of the references identified above, such as U.S. Pat. No. 7,335,220. 
     Accordingly, apparatus and methods for sealing a puncture through tissue would be useful. 
     SUMMARY 
     The present invention is directed to apparatus and methods for sealing a puncture in a body. More particularly, the present invention is directed to sealants for sealing a puncture through tissue, and to methods for making such sealants. In addition, the present invention is directed to apparatus and methods for providing temporary or permanent hemostasis within a puncture extending through tissue, and/or to apparatus and methods for delivering a sealant into a percutaneous puncture extending from a patient&#39;s skin to a blood vessel or other body lumen. 
     In accordance with one embodiment, a sealant is provided for sealing a puncture through tissue that includes a first section including a proximal end, a distal end, and a cross-section sized for delivery into a puncture through tissue, and a second section fused to and extending from the distal end of the first section. The first section may be formed from a freeze-dried hydrogel that expands when exposed to physiological fluid within a puncture. The second section may be formed from a solid mass of non-freeze-dried, non-crosslinked hydrogel precursors, the precursors remaining in an unreactive state until exposed to an aqueous physiological, whereupon the precursors undergo in-situ crosslinking with one another to provide an improved adhesion of the sealant to the arteriotomy. 
     In one embodiment, the first section may consist essentially of freeze-dried hydrogel, and the second section may consist essentially of the non-crosslinked precursors. Alternatively, the second section may include one or more reinforcement elements, e.g., a plurality of filaments or particles, mixed with, embedded in, or surrounding the precursors. In addition or alternatively, the second section may include one or more diluents to enhance one or more properties of the second section. 
     Optionally, the sealant may include one or more pH adjusting agents, e.g., impregnated into, coated over, or otherwise included in the first and/or section sections. For example, when the sealant is exposed within a puncture, the agent(s) may alter the localized pH on or around the sealant, e.g., to enhance cross-linking of the precursors and/or creation of a desired adhesive material. Alternatively, the materials for the precursors may be selected such that the pH and/or buffering capacity of interstitial body fluids and/or blood are effective to drive or facilitate cross-linking of the precursors and the pH adjusting agents may be omitted. 
     In accordance with another embodiment, a sealant is provided for sealing a puncture through tissue that includes an elongate first section including a proximal end, a distal end, and a cross-section sized for delivery into a puncture through tissue, the first section consisting essentially of a freeze-dried hydrogel that expands when exposed to physiological fluid within a puncture; and a second section fused to and extending from the distal end of the first section, the second section consisting essentially of a solid mass of non-freeze-dried, non-crosslinked hydrogel precursors, the precursors remaining in an unreactive state until exposed to an aqueous physiological environment, whereupon the precursors undergo in-situ crosslinking to provide an adhesive layer to bond the first section relative to adjacent tissue. 
     In accordance with still another embodiment, a sealant is provided for sealing a puncture through tissue that includes an elongate body including a proximal end, a distal end, and a cross-section extending between the proximal and distal ends sized for delivery into a puncture through tissue. The elongate body may consist essentially of a solid mass of non-freeze-dried, non-crosslinked hydrogel precursors, the precursors remaining in an unreactive state until exposed to an aqueous physiological environment, whereupon the precursors undergo in-situ crosslinking to provide an adhesive material that bonds to adjacent tissue within the puncture. Alternatively, the elongate body may also include one or more reinforcement members, one or more diluents, and/or one or more pH adjusting agents. 
     In accordance with yet another embodiment, a sealant is provided for sealing a puncture through tissue that includes a first section including a proximal end, a distal end, and a cross-section sized for delivery into a puncture through tissue, and a second section fused to and extending from the distal end of the first section. The first section may be formed from a freeze-dried hydrogel that expands when exposed to physiological fluid within a puncture. The second section may consisting essentially of a solid mass of non-freeze-dried, non-crosslinked hydrogel precursors and one or more pH adjusting agents, reinforcement elements, and/or diluents mixed with the precursors to enhance one or more mechanical properties of the second section. 
     In accordance with still another embodiment, a method is provided for making a sealant for sealing a puncture through tissue that includes forming an elongated first section including a proximal end, a distal end, and a cross-section sized for delivery into a puncture through tissue. The first section may be formed from a freeze-dried hydrogel or other biocompatible, bioabsorbable material that expands when exposed to physiological fluid within a puncture. A solid mass of non-crosslinked hydrogel precursors may be fused or otherwise attached onto the distal end, the precursors remaining in an unreactive state until exposed to an aqueous physiological environment, whereupon the precursors undergo in-situ crosslinking with one another to provide an improved adhesion to the arteriotomy. For example, the solid mass may be formed as a substantially uniform solid plug or may be formed as a sintered mass of powder. 
     In accordance with yet another embodiment, a method is provided for making a sealant for sealing a puncture through tissue that includes forming a sheet of the freeze-dried hydrogel that expands when exposed to physiological fluid within a puncture; rolling the sheet into a tubular roll including a lumen extending between the proximal and distal ends; and loading the tubular roll into a tubular member such the distal end of the tubular roll is offset inwardly from a first end of the tubular member. A plurality of non-crosslinked hydrogel precursors may be mixed and melted, optionally with one or more diluents, the precursors remaining in an unreactive state until exposed to an aqueous physiological, whereupon the precursors undergo in-situ crosslinking; The melted precursors may be applied to the distal end of the tubular roll within the tubular member, and allowed to solidify to create the solid mass fused to the distal end of the tubular roll. 
     In accordance with another embodiment, an apparatus is provided for sealing a puncture through tissue that includes a tubular member including a proximal end, a distal end sized for insertion into a puncture, a lumen extending between the proximal and distal ends, and a distal opening in communication with the lumen, a sealant within the lumen, and an advancer member within the lumen for deploying the sealant from the lumen out the distal opening, e.g., when the tubular member is retracted from a puncture relative to the advancer member. The sealant may include a first section including proximal and distal ends, and a second section fused to and extending from the distal end. The sealant may be disposed within the lumen such that the second section is disposed closer to the distal opening than the first section. In an exemplary embodiment, the first section may be formed from a freeze-dried hydrogel that expands when exposed to physiological fluid within a puncture, and/or the second section may be formed from non-crosslinked hydrogel precursors, the precursors remaining in an unreactive state until exposed to an aqueous physiological environment, whereupon the precursors undergo in-situ crosslinking with one another to provide improved adhesion to the arteriotomy. 
     In accordance with still another embodiment, a method is provided for sealing a puncture through tissue that includes providing sealant including a first section including proximal and distal ends, and a second section fused to and extending from the distal end. In an exemplary embodiment, the first section may be formed from a freeze-dried hydrogel, and/or the second section may be formed from non-crosslinked hydrogel precursors in an unreactive state. The sealant may be introduced into a puncture through tissue with the second section entering the puncture before the first section. The sealant may be exposed to fluid within the puncture, whereupon the precursors of the second section undergo in-situ crosslinking with one another to provide improved adhesion to the arteriotomy, and the freeze-dried hydrogel of the first section expands to fill space within the puncture to provide hemostasis. 
     Other aspects and features of the present invention will become apparent from consideration of the following description taken in conjunction with the accompanying drawings. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       It will be appreciated that the exemplary apparatus shown in the drawings are not necessarily drawn to scale, with emphasis instead being placed on illustrating the various aspects and features of the illustrated embodiments. 
         FIG. 1  is a perspective view of an exemplary embodiment of a sealant member including a main section, e.g., formed from freeze-dried hydrogel, and a distal tip section, e.g., formed from non-crosslinked precursors. 
         FIG. 1A  is a cross-sectional view of a transfer tube and mandrel, showing a method for making the sealant member of  FIG. 1 . 
         FIG. 2A  is a side view of an exemplary embodiment of an apparatus for delivering a sealant into a puncture through tissue, including a positioning member, and a cartridge movable over the positioning member that includes the sealant. 
         FIG. 2B  is an exploded perspective view of the apparatus of  FIG. 2A . 
         FIG. 2C  is a partial cross-sectional side view of the apparatus of  FIGS. 2A and 2B . 
         FIGS. 3A-3G  are cross-sections of a patient&#39;s body showing a method for sealing a puncture using the apparatus of  FIGS. 2A-2C . 
         FIGS. 4A and 4B  are side views of a first alternative embodiment of a sealant being compressed against an arteriotomy, e.g., using the apparatus and methods of  FIGS. 2A-3G . 
         FIGS. 5A and 5B  are side views of a second alternative embodiment of a sealant being compressed against an arteriotomy, e.g., using the apparatus and methods of  FIGS. 2A-3G . 
         FIGS. 6A-6C  are side views of a third alternative embodiment of a sealant being compressed against an arteriotomy, e.g., using the apparatus and methods of  FIGS. 2A-3G . 
         FIGS. 7A and 7B  are side views of a fourth alternative embodiment of a sealant being compressed against an arteriotomy, e.g., using the apparatus and methods of  FIGS. 2A-3G . 
         FIGS. 8A-8C  are side views of a fifth alternative embodiment of a sealant being compressed against an arteriotomy, e.g., using the apparatus and methods of  FIGS. 2A-3G . 
         FIG. 9  includes side views of additional alternative embodiments of sealants including a freeze-dried hydrogel section and one or more non-crosslinked precursor sections. 
         FIGS. 10A-10C  are perspective views of another embodiment of a sealant, showing a method for creating an adhesive coating on a base section of material to provide the sealant. 
         FIG. 10D  is a cross-sectional view of a patient&#39;s body showing a method for sealing a puncture using the sealant of  FIGS. 10A-10C . 
         FIG. 11A  is a perspective view of an exemplary embodiment of a patch for sealing a puncture in tissue. 
         FIG. 11B  is a cross-sectional view of the patch of  FIG. 11A  taken along line  11 B- 11 B. 
         FIGS. 12A and 12B  are side views of alternative embodiments of non-crosslinked precursor sections that may be provided on a sealant, such as that shown in  FIG. 1 . 
     
    
    
     DETAILED DESCRIPTION OF THE EXEMPLARY EMBODIMENTS 
     Turning to the drawings,  FIG. 1  shows an exemplary embodiment of a sealant  2  for sealing a puncture extending through tissue (not shown). Generally, the sealant  2  includes a first, proximal, or main section  4  including proximal and distal ends  4   a ,  4   b , and a second, distal, or tip section  6  formed from a plurality of non-freeze-dried and/or non-crosslinked precursors, e.g., formed as a solid mass or solid plug, fused or otherwise attached to and extending distally from the distal end  4   b  of the first section  4 . As described further below, the non-crosslinked precursors may remain in an unreactive state, e.g., before or until exposure to an aqueous physiological environment, e.g., when deployed or otherwise exposed within a puncture extending through tissue. 
     For example, this configuration of sealant  2  may combine crosslinking of the second section  6  to create an adhesive material in-situ with swell characteristics of a freeze-dried hydrogel or other expandable material of the first section  4 . By improving the adherence characteristics of the expandable hydrogel, the sealant  2  may provide enhanced extra-vascular closure, e.g., by providing expansion of the first section  4  in combination with improved adhesion of the sealant  2  to tissue surrounding an arteriotomy or other adjacent tissue structure, e.g., entirely extra-vascularly or extending partially into the arteriotomy and/or vessel, by virtue of the in-situ polymer crosslinking that occurs at the second section  6  of the sealant  2 . 
     As shown, the first section  4  may be formed generally into an elongate cylindrical shape, e.g., including proximal and distal ends  4   a ,  4   b , and an outer surface  4   c  extending therebetween. Optionally, as shown in phantom, the sealant  2  may include a lumen  5  extending between the proximal and distal ends  4   a ,  4   b  of the first section  4  and through the second section  6 , e.g., to facilitate delivery of the sealant  2 . For example, the lumen  5  may be dimensioned to accommodate receiving a balloon catheter or other positioning member  14  (not shown, see, e.g.,  FIGS. 2A-2C  and associated description below) therethrough, e.g., such that the sealant  2  may slide relative to or pass over the positioning member  14  and/or the positioning member  14  may be directed axially relative to the sealant  2 , as described further below. Alternatively, the sealant  2  may be a substantially continuous rod of material, e.g., such that the sealant  2  may be delivered into a puncture using a cartridge or shuttle without a positioning member (not shown). 
     In an exemplary embodiment, the first section  4  may be formed from a sheet of freeze-dried hydrogel rolled into a tubular shape, e.g., as disclosed in U.S. Publication No. 2007/0231336, the entire disclosure of which is expressly incorporated by reference herein. It will be appreciated that the first section  4  may have other tubular or solid rod cross-sections or shapes, as desired, such as elliptical, triangular, square, conical, disk, polygonic shapes, and the like (not shown). 
     In exemplary embodiments, the sealant  2  may have an overall length between about three and twenty millimeters (3-20 mm), e.g., between about five and ten millimeters (5-10 mm) or between about fifteen and twenty millimeters (15-20 mm), and an outer diameter or other cross-section between about one and eight millimeters (1-8 mm), e.g., between about one and three millimeters (1-3 mm), e.g., between about 1.5 and two millimeters (1.5-2.0 mm), e.g., about 0.069 inch (1.75 mm). In the embodiment shown in  FIG. 1 , the first section  4  is substantially longer than the second section  6 , although it will be appreciated that, alternatively, the sections  4 ,  6  may have similar lengths, or the second section  6  may be longer than the first section  4 . In a further alternative embodiment, the first section  4  may be omitted, and the second section  6  may provide the entire length of the sealant  2  (not shown), e.g., having a length between about three and twenty millimeters (3-20 mm). 
     For example, the first section  4  may have a length between about zero (if the sealant  2  is formed entirely from the second section  6 ) and twenty millimeters (0-20 mm), e.g., between about five and twenty millimeters (5-20 mm), e.g., about fifteen millimeters (15 mm). The second section  6  may have an outer diameter similar to the first section  4 , but may have a length that is substantially shorter, e.g., between about zero (if the sealant  2  is formed entirely from the first section  4 ) and eight millimeters (0-8 mm), e.g., between about half and five millimeters (0.5-5.0 mm), e.g., about 1.5 millimeters. 
     The first section  4  may be formed from a biocompatible and/or bioabsorbable material, for example, a porous and/or bioabsorbable hydrogel, that may have desired expansion characteristics when hydrated. In one embodiment, the first section  4  may be formed entirely from a freeze-dried and crosslinked hydrogel, e.g., polyethylene glycol (“PEG”), or other synthetic material, as disclosed in U.S. Publication No. 2007/0231336, incorporated by reference above, although optionally including a transition zone (not shown) where the material of the second section  6  has penetrated partially into the distal end  4   b  of the first section  4 , e.g., during fusion, as described further below. 
     For example, the PEG polymer for the hydrogel sealant may include two components of Polyethylene Glycol Hydrogel, e.g., PEG-Amine: 8A20K-NH2 and PEG-Ester: 4A10K-CM-HBA-NHS, e.g., as disclosed in the references incorporated by reference above. In an exemplary embodiment, the molar ratio of PEG-Amine/PEG-Ester may be between 1:9 (10% PEG-Amine: 90% PEG-Ester) and 9:1 (90% PEG-Amine:10% PEG-Ester), for example, about a 1:1 ratio. 
     In alternative embodiments, the first section  4  may be formed from other materials, such as pro-thrombotic material, e.g., including one or more biological pro-thrombotics, such as collagen, fibrin, carboxymethylcellulose, oxidized cellulose, alginates, gelatin, or other protein-based material, and/or synthetic materials, e.g., as polyglycolic acids (PGA&#39;s), polylactides (PLA&#39;s), polyvinyl alcohol (PVA), and the like. The material of the first section  4  may be at least partially absorbed by the body over time, e.g., over a period of days, weeks, or months. 
     Optionally, the first section  4  (and/or second section  6 ) may include therapeutic and/or pharmaceutical agents, e.g., to promote healing, prevent infection and/or other adverse medical events, and the like. Such agents may be embedded in the material and/or applied as one or more coatings or layers. In addition, the material of the first section  4  may have a substantially uniform composition or the composition may be varied, e.g., along its length and/or within underlying layers within the first section  4 . 
     In an exemplary embodiment, the first section  4  may be formed entirely from freeze-dried hydrogel, e.g., initially formed as a thin sheet of freeze-dried polymer. For example, to fabricate the first section  4  from a PEG hydrogel material, PEG-amine and PEG-ester powders intended to form the hydrogel may be filled into separate vials. Phosphate and borate buffers may be made, e.g., by dissolving the sodium borate and sodium phosphate in sterile water for injection (WFI) and adjusting the pH of each solution to meet pre-established requirements. The two PEG powders may then be dissolved in their respective buffer solutions. These precursor solutions may be mixed together, poured into trays, and freeze-dried. The freeze-dried material may be subjected to a series of heat and/or humidity conditioning cycles, e.g., to complete the polymerization reaction. 
     The freeze-dried and conditioned sheet of hydrogel sealant may then be trimmed according to size and mass requirements, e.g., cut to a desired length for the finished first section  4 . For example, as shown in  FIG. 1A , the trimmed hydrogel may be dried, rolled, and loaded into a transfer tube  8  for subsequent attachment to the second section  6 . Additional information on materials and methods for making the first section  4  may be found in U.S. Publication No. 2007/0231366, incorporated by reference above. 
     To fabricate the non-freeze-dried, non-crosslinked distal section  6  of the sealant  2 , PEG-amine and PEG-ester powders (or other crosslinkable polymer precursors) may be melted in a beaker, mixed, and heated at a pre-determined temperature and duration. For example, the precursors may be melted in a substantially dry air or inert gas environment, e.g., to minimize or prevent entrapment of moisture, which may otherwise cause premature crosslinking Using a vacuum generator, the melted PEG may then be applied onto the distal end  4   b  of the rolled freeze-dried first section  4 . 
     For example, as described above, the first section  4  may be formed from a rolled sheet and loaded into a transfer tube  8 , as shown in  FIG. 1A . The transfer tube  8  may have an inner diameter or other cross-section corresponding to the desired outer diameter or cross-section for the finished sealant  2 . The transfer tube  8  may be formed from any material sufficient to handle the processing parameters of the assembly process, such as polymers, metals, or composite materials, and may optionally include desired coatings, e.g., PTFE to facilitate insertion of the first section  4  and/or removal of the sealant  2 . 
     The first section  4  may be loaded into the transfer tube  8  such that the distal end  4   b  of the first section  4  is offset inwardly a predetermined distance L 6  from the end of the transfer tube  8 , e.g., corresponding to or greater than the desired length of the second section  6 . For example, for a desired finished length of the second section  6  of about 1.5 millimeters, the distal end  4   b  may be offset inwardly about two millimeters (2.0 mm) from the end of the transfer tube  8  (with any excess material may trimmed off later, as described below). Using the vacuum generator, the melted non-crosslinked PEG is then applied onto the distal end  4   b  of the rolled freeze-dried sealant, e.g., the vacuum directing the melted PEG into the transfer tube  8  and against the distal end  4   b  of the first section  4  (as represented by the arrow labeled “vacuum”). Thus, the transfer tube  8  may mold the melted PEG into the desired shape, e.g., diameter and/or length, for the second section  6 . 
     The vacuum may cause the melted precursors to nominally abut the distal end  4   b  of the first section  4 , and/or may partially draw the melted precursors into the pores and/or other open spaces within the first section  4 , e.g., due to capillary action and the like. In this situation, a transition zone  7  may be created within the distal end  4   b  of the first section  4  in which the melted precursors permeate the freeze-dried hydrogel or other material of the first section  4 , which may enhance fusing the second section  6  to the first section  4 . For example, the melted precursors may quickly cool under ambient conditions such that the penetration into the distal end  4   b  may be relatively short, e.g., resulting in a transition zone  7  of one millimeter (1 mm) or less. 
     The melted precursors may be dried under ambient conditions, e.g., simply allowed to cool and solidify, or alternatively, the melted and applied precursors may be exposed to desired conditions to accelerate or facilitate solidification of the melted precursors. The vacuum process effectively fuses the two sections together to provide a length of sealant  2 . 
     If desired, the resulting sealant  2  may then be trimmed to length, as desired, e.g., for loading into a delivery apparatus, e.g., a cartridge or shuttle, such as those described further below and in the references incorporated by reference herein. For example, any excess length of the second section  6  may be removed, e.g., by mechanical cutting, laser cutting, and the like, to provide the desired length for the final second section  6 . In addition or alternatively, the first section  4  may be trimmed to a desired length, e.g., by cutting the proximal end  4   a  before loading the first section  4  into the transfer tube  8  (as described above) and/or after fusing the second section  6  to the distal end  4   b.    
     In addition or alternatively, if the sealant  2  and/or first section  4  includes a lumen  5 , the lumen  5  may be created when the first section  4  is formed, e.g., if the first section  4  is rolled from one or more sheets or layers of material or formed by molding. Alternatively, the lumen  5  may be formed by boring into or otherwise removing material from an already formed and solid first section  4 , second section  6 , or through the entire sealant  2 . For example, if the first section  4  is formed from a rolled sheet, a rod or other mandrel  9  (which may be fabricated similar to the transfer tube  8 ) may be inserted through the lumen  5  before the second section  6  is applied to the distal end  4   b , e.g., that extends from the transfer tube  8 , as shown in  FIG. 1A . Thus, the second section  6  may be molded and fused to distal end  4   b  around the mandrel  9 , e.g., within the transfer tube  8 . The mandrel  8  may be removed once the melted precursors have solidified, resulting in a continuous lumen through the second section  6  and the first section  4 . Alternatively, the portion of the lumen  5  through the second section  6  may be bored, drilled, or otherwise created after the second section  6  is formed and fused to the first section  5 . 
     In exemplary embodiments, the precursors for the second section  6  may include one or more of the following: 
     a) Polyethylene glycol derivatives or polyethylene glycols with at least two end groups (2Arms) and having at least one crosslinkable end groups. The first functional groups may chemically react with the second functional groups in-situ to form covalent bonds and thereby form a crosslinkable gel. 
     b) The first functional groups or second functional groups may be chosen from groups that are strong electrophiles, e.g., epoxide, succinimide, N-hydroxysuccinimide, acrylate, methacrylate, maleimide, and N-hydroxysulfosuccinimide in addition to a group including amine, sulfhydryl, carboxyls, or hydroxyls. 
     c) The molecular weight of the polyethylene glycols may range from 5000 to 40,000 Da and may include at least about 2 to 8 functional groups. 
     d) Examples of the polyethylene glycols derivatives that may be used include but are not limited to the following formulations:
         i) Branched PEG Derivatives:   Y-Shape PEG NHS Ester, MW 40000   Y-Shape PEG Maleimide, MW 40000   Y-Shape PEG Acetaldehyde, MW 40000   Y-Shape PEG Propionaldehyde, MW 40000   ii) Heterofunctional PEG Derivatives:   Hydroxyl PEG Carboxyl, MW 3500   Hydroxyl PEG Amine, HCl Salt, MW 3500   Amine PEG Carboxyl, HCl Salt, MW 3500   Acrylate PEG NHS Ester, MW 3500   Maleimide PEG Amine, TFA Salt, MW 3500   Maleimide PEG NHS Ester, MW 3500   4 Arm PEG Succinimidyl Succinate (pentaerythritol), MW 10 KDa   8 Arms PEG Amine, MW 10-20 KDa   iii) Linear Monofunctional PEG Derivatives:   Methoxy PEG Succinimidyl Carboxymethyl Ester, MW 10-20K   Methoxy PEG Maleimide, MW 10-20K   Methoxy PEG Vinylsulfone, MW 10-20K   Methoxy PEG Thiol, MW 10-20K   Methoxy PEG Propionaldehyde, MW 10-20K   Methoxy PEG Amine, HCl Salt, MW 10-20K       

     Optionally, the second section may include one or more pH adjusting agents. For example, a pH adjusting agent, e.g., sodium borate, sodium phosphate, sodium bicarbonate, and/or other salts, such as Na 2 B 4 O 7 .10H 2 O in crystalline or powder form, may be melted with the precursors and then applied with the precursors to the distal end  4   b  of the first section  4 , as described above. Alternatively, the pH adjusting agent may be applied to the second section  6  after fusing the melted precursors to the first section  4 , e.g., by bonding or impregnating crystals of borate or other salts to the outer surface of the solid mass of non-crosslinked precursors and/or by melting and applying a coating of melted salts to the outer surface, e.g., similar to embodiments disclosed in the references incorporated by reference elsewhere herein. In addition or alternatively, one or more pH adjusting agents may be provided on the first section  4 , if desired. 
     In this manner, the pH adjusting agent may alter the localized pH on or around the sealant  2 , e.g., when deployed within a puncture to enhance cross-linking and/or creation of a desired adhesive material. Alternatively, the pH and/or buffering capacity of interstitial body fluids and/or blood may be effective to drive or facilitate cross-linking of the second section  6 . For example, the precursors of the second section  6  may be optimized to take into account all of these factors and/or form a robust attachment to tissue. 
     In addition or alternatively, diluents, such as low molecular PEG and/or glycerol, may be added to the formulation, i.e., the melted precursors before application to the first section  4 , e.g., to improve the mechanical strength and/or integrity of the first section  6  and/or to minimize the brittleness of the second section  6 . 
     In a further alternative, if desired, one or more reinforcement elements may be provided within the second section  6 . For example, as shown in  FIG. 12A , a bioabsorbable mesh  6   a ′ may be embedded within and/or surround the precursors  6   b ′ of a second section  6 .′ The mesh  6   a ′ of bioabsorbable material may have greater rigidity, elasticity, and/or other desired properties than the solidified precursors  6   b .′ Exemplary materials for the reinforcement elements may include any of the bioabsorbable materials described above for the first section  4 . 
     As shown, the mesh  6   a ′ may include one or more fibers or filaments having a helical configuration (one helical filament shown), or alternatively the mesh  6   a ′ may include a braid of filaments, a rolled porous mat, and the like (not shown). In an exemplary embodiment, the mesh  6   a ′ may be embedded in the precursors  6   b ′ of the second section  6 ,′ e.g., by inserting the reinforcement element(s) into the end of the transfer tube  8  (not shown, see  FIG. 1A ) before applying the melted precursors (not shown), as described above. Thus, as the applied precursors are drawn into the transfer tube  8  and cool (or are otherwise dried and/or solidified), the precursors  6   b ′ may permeate through and/or surround the mesh  6   a ,′ thereby embedding the element(s) in the second section  6 .′ 
     Alternatively, as shown in  FIG. 12B , reinforcing particles or fillers  6   a ″ may be provided in a second section  6 .″ For example, similar compositions of bioabsorbable material having greater rigidity, elasticity, and/or other desired properties than the precursors  6   b ,″ such as the materials described above, may be mixed into the melted precursor mixture, and then the reinforcing fillers  6   a ″ may be applied to the distal end  4   b  of the first section  4  (not shown) along with the precursors  6   b ,″ e.g., using the vacuum process described above. Thus, the filler material  6   a ″ may be distributed randomly, substantially uniformly, or in a desired pattern throughout the second section  6 ,″ thereby enhancing the rigidity, reducing the brittleness, and/or otherwise modifying the properties of the precursors  6   b ″ of the second section  6 ″ in a desired manner. 
     Once the sealant  2  is formed and/or trimmed, as described above, the sealant  2  may be loaded onto a delivery apparatus for use in sealing a puncture, e.g., using the methods described below. 
     Turning to  FIGS. 2A-2C , an exemplary embodiment of an apparatus  10  is shown for sealing a puncture through tissue, e.g., using the sealant  2  (or any of the other embodiments described elsewhere herein). Generally, the apparatus  10  includes a positioning member  14  and a cartridge or shuttle  16  carried on the positioning member  14  for delivering a sealant  2  therein into a puncture (not shown). Optionally, the apparatus  10  may be part of a system, e.g., which may also include a delivery, access, procedure, introducer, or other sheath  80  (not shown, see, e.g.,  FIGS. 3A-3F ). Optionally, the apparatus  10  and/or system may include one or more other components, e.g., a needle, guidewire, and/or other instrument for creating a puncture, a source of inflation media, and/or a source of additional sealing compound (not shown), for example, to provide a kit for a medical procedure. 
     As shown in  FIGS. 2A-2C , the cartridge  16  includes an elongate tubular member  20  carrying the sealant  2  therein, an advancer tube or member  30  adjacent the sealant  2  within the tubular member  20 , and a handle or hub  23  coupled to the tubular member  20 . Generally, as best seen in  FIG. 2C , the tubular member  20  includes a proximal end  22  coupled to the hub  23 , a distal end  24  sized for introduction into an introducer sheath and/or puncture (not shown), and a lumen  26  extending between proximal and distal ends  22 ,  24  of the tubular member  20 . The tubular member  20  may be substantially rigid, semi-rigid, or flexible, e.g., such that the tubular member  20  may be advanced through an introducer sheath or otherwise into a puncture through tissue. Optionally, the hub  23  may include one or more detents or other features (not shown) for releasably coupling the cartridge  16  to the positioning member  14 , e.g., as described in the references incorporated by reference herein. 
     With additional reference to  FIGS. 2C, 3E, and 3F , the advancer member  30  may be an elongate tubular body sized to be slidably received within the lumen  26  of the tubular member  20 , although the advancer member  30  may abut or otherwise interact with the hub  23  of the cartridge  16 , e.g., such that the advancer member  30  is advanced distally when the cartridge  16  is advanced. A distal end  34  of the advancer member  30  may terminate in a substantially blunt distal tip proximal to the tubular member distal end  24 , as best seen in  FIG. 2C , e.g., by simply cutting the end of the advancer member  30 , which may facilitate contacting and/or otherwise maintaining the sealant  2  within a puncture, e.g., when the tubular member  20  is refracted during use, as described further below. 
     The advancer member  30  may be substantially rigid, semi-rigid, and/or substantially flexible, e.g., having sufficient column strength to allow proximal movement of the tubular member  20  relative to the sealant  2  without buckling the advancer member  30  and/or to allow the distal end  34  of the advancer member  30  to be advanced to compress the sealant  2  within a puncture, e.g., by pushing from the proximal end  32 , as described further below. As best seen in  FIG. 2C , the advancer member  30  may also include a lumen  36  extending between the proximal and distal ends  32 ,  34 , e.g., to accommodate the positioning member  14 , a flowable sealing compound, and/or fluid (not shown). 
     Optionally, the advancer member  30  may include one or more elements (not shown) on the proximal end  32 , e.g., for interacting with one or more cooperating elements (also not shown) on the positioning member  14 , e.g., to limit movement of the advancer member  30  relative to the positioning member  14 , e.g., as described in the references incorporated by reference herein. As shown in phantom in  FIG. 2C , the sealant  2  (which, alternatively, may be any of the embodiments herein, e.g., sealant  102 - 502 ) may be disposed within the lumen  26  of the tubular member  20  proximate to the distal end  24 , e.g., immediately adjacent the distal tip. The lumen  26  may be sized such that the tubular member  20  and sealant  2  are slidable relative to one another, e.g., to allow the tubular member  20  to be retracted proximally relative to the sealant  2  and/or advancer member  30 , as described further below. 
     With continued reference to  FIGS. 2A-2C , the positioning member  14  generally includes an elongate member  40  including a proximal end  42  (not shown, see, e.g.,  FIG. 2B ), a distal end  44 , and an occlusion or positioning element  46  on the distal end  44 . The positioning element  46  may be an expandable member, such as a balloon, a wire mesh structure, an expandable frame, and the like, e.g., as disclosed in the references incorporated by reference herein. The positioning element  46  may be selectively expandable, e.g., using a source of inflation media, such as syringe  148 , a pull wire, and/or other actuator (not shown), operable from the proximal end  42  of the positioning member  14 . 
     For example, as shown, the positioning element may be a balloon  46 , and the positioning member  14  may include a tubular body  40  including a lumen (not shown) extending between the proximal and distal ends  42 ,  44  and communicating with an interior of the balloon  46 . In this embodiment, the positioning member  14  may include a source of inflation media, such as syringe  148 , that may be coupled to a housing  48  on the proximal end  42  of the positioning member  14 . Optionally, the positioning member  14  may include an internal pull wire (not shown) that causes the balloon  46  to shorten during expansion and extend during collapse. Exemplary embodiments of positioning members  14  including balloons that may be used are disclosed in U.S. Publication Nos. 2004/0249342, 2004/0267308, 2006/0253072, and 2008/0009794. The entire disclosures of these references are expressly incorporated by reference herein. 
     Alternatively, the positioning element may be biased to an enlarged condition, but may be compressed to a contracted condition, e.g., by an overlying sleeve or other constraint (not shown). The constraint may be removed to expose the positioning element, allowing the expandable element to automatically expand to the enlarged condition. Additional information on expandable structures that may be provided on the positioning member  14  may be found in U.S. Pat. Nos. 6,238,412, 6,635,068, and 6,890.343, and in co-pending application Ser. No. 10/975,205, filed Oct. 27, 2004. The entire disclosures of these references are expressly incorporated herein by reference. 
     With additional reference to  FIGS. 3A-3G , the apparatus  10  may be used to position and deliver the sealant  2  within a puncture, e.g., extra-vascularly just above or otherwise adjacent to an arteriotomy in a blood vessel or other body lumen communicating with a puncture, as described further elsewhere herein. In one embodiment, as shown in  FIGS. 2A and 3A , the cartridge  16  (along with the advancer member  30  and sealant  2  within the tubular member  20 ) may be initially provided on the proximal end  42  of the positioning member  14 . For example, the housing  48  on the positioning member  14  and the hub  23  on the cartridge  16  may be initially connected to one another, e.g., using one or more releasable detents (not shown). Alternatively, the cartridge  16  may be initially provided such that the distal  24  of the tubular member  20  is disposed adjacent the balloon  46 , e.g., as disclosed in U.S. Pat. No. 7,335,220 and U.S. Publication No. 2008/0082122, incorporated by reference elsewhere herein. 
     As shown in  FIG. 3C , the cartridge  16  may be slidable distally along the positioning member  14 , e.g., by disconnecting the hub  23  from the housing  48 , and then advancing the cartridge  16 , e.g., until the distal end  24  of the tubular member  20  is disposed adjacent the positioning element  46 . For example, detents on the hub  23  and housing  48  may simply separate from one another when the hub  23  is advanced away from the housing  48  with sufficient force. Alternatively, one of the hub  23  and housing  48  may include an actuator or lock that may be activated (not shown) to separate the detents and/or otherwise allow the cartridge  16  to be advanced relative to the positioning member  14 . 
     Optionally, the cartridge  16  and/or positioning member  14  may include cooperating features that limit distal movement of the cartridge  16  relative to the positioning member  14 . For example, the hub  23  of the cartridge  16  may include a pocket and the positioning member  14  may include a detent or other feature (both not shown) that may be received within the pocket when the cartridge  16  is advanced to a distal position. In addition or alternatively, the positioning member  14  and/or advancer member  30  may include one or more elements that engage when the cartridge  16  reaches a predetermined location when advanced along the positioning member  14 , e.g., to limit subsequent proximal movement of the advancer member  30  relative to the positioning member  14  when the tubular member  20  is subsequently retracted, similar to embodiments disclosed in the references incorporated by reference herein. 
     In addition or alternatively, one or more markers may be provided on the apparatus  10 , e.g., to identify when components are located at one or more desired positions or otherwise to facilitate use of the apparatus  10 . For example, the positioning member  14  may include one or more markers at predetermined locations on the elongate member  40 . Such markers may provide visual confirmation when the cartridge  16  has been advanced to a desired distal position, e.g., when the marker(s) emerge from the hub  23  as the cartridge  16  is advanced over the positioning member  14 . In addition or alternatively, as shown in  FIGS. 3E and 3F , the advancer member  30  may include one or more markers  33  thereon, which may be visible when the cartridge  16  is advanced to a distal position and then the tubular member  20  is retracted to expose the sealant  2 . These markers  33  may also provide visual guides to inform the user when the advancer member  30  is manipulated, e.g., advanced into a puncture to compress the sealant  2  therein, as described further below. 
     The apparatus  10  may be assembled using conventional manufacturing methods and/or using methods disclosed in the references incorporated by reference herein. Although an exemplary process is described below as being performed in an exemplary order, it will be appreciated that the actual order of the assembly steps may be changed, as desired. 
     For example, the positioning member  14  may be formed by providing a length of tubing for the tubular body  40  and attaching a balloon  46  to the distal end  44 . To make the balloon, a section of tubing, e.g., LLDPE or other elastic material, may be cut to a predetermined length that is necked down to a smaller diameter, e.g., using a hot die or hot air necker. The tubing may then be placed into a balloon blower, which may use a split aluminum or other mold (not shown) to form the balloon  46 , e.g., at a desired temperature and blow pressure. The resulting balloon subassembly may then be trimmed as desired and attached to the distal end  44  of the tubular body  40 , which may also be necked down to facilitate attachment of the balloon  46 , e.g., by an interference fit, bonding with adhesive, fusing, and the like. 
     The components of the cartridge  16 , the tubular body  20 , advancer tube  30 , and hub  23  may be formed using conventional methods, e.g., extruding, molding, and the like. For example, the hub  23  may be formed from a plurality of molded shells that may be attached together and to which the proximal end  22  of the tubular body  20  may be attached. 
     In the exemplary embodiment shown, the cartridge  16  includes a single tubular body  20  attached to the hub  23 . In an alternative embodiment, the cartridge  16  may include inner and outer cartridge assemblies, including inner and outer tubular bodies (not shown) attached to the hub  23 , e.g., similar to embodiments disclosed in the references incorporated by reference herein. For example, an inner cartridge subassembly may include tubing bonded to a molded hub, and an outer cartridge subassembly may include tubing bonded to a molded slider. The inner and outer cartridges may then be captured within halves of a shuttle shell providing the hub  23 . 
     The advancer member  30  may include a section of tubing with a thermoformed tapered tip. Once the tubular body  20  (or bodies) is assembled to the hub  23 , the advancer member  30  may be inserted into the lumen  26  of the tubular body  20  (e.g., into the inner cartridge tubing if inner and outer cartridge tubular bodies are provided). 
     To provide the hub  48  of the positioning member  14 , a hub barrel  48   a , stopcock  48   b , and extension line  48   c  may be assembled, as shown in  FIG. 2B , similar to embodiments disclosed in the references incorporated by reference herein. One end of the extension line  48   c  may be bonded or otherwise attached to the stopcock  48   b , and the other end of the extension line  48   c  may be bonded or otherwise attached into the side port of the hub barrel  48   a.    
     To complete the positioning member  14 , locking features (not shown) may be bonded onto the tubular body  40 , e.g., spaced a predetermined distance from the proximal end  42 . The proximal leg of the balloon  46  may be bonded to the distal end  44  of the tubular body  40 . The cartridge  16 , hub barrel  48  and a core wire with tension plunger (not shown) are all then assembled with the tubular body  40 , e.g., similar to embodiments in the references incorporated by reference herein. The core wire may then be bonded into the distal leg of the balloon  46 . The hub barrel  48   a  is bonded to the proximal end  42  of the tubular body  40  and captured within the halves of the handle shell to provide the hub  48 , as shown in  FIG. 2 . 
     Finally, the sealant  2  is loaded onto the assembled apparatus  10 . For example, the rolled sealant  2  may be coaxially mounted over the tubular body  40  from the distal end  44  and positioned inside the tubular member  20  of the cartridge  16 , e.g., adjacent the distal end  24  and the advancer member  30  therein. For example, the sealant  2  stored within a transfer tube  8  (not shown, see  FIG. 1A ) may be aligned with the balloon  46  and distal end  44  of the tubular body  40  such that the proximal end  4   a  of the first section  4  is oriented towards the proximal end  42  of the tubular body  40 . The sealant  2  may then be transferred from the transfer tube  8  over the tubular body  40  into the cartridge  20  such that the distal section  6  is located closest to the distal end  24  within the tubular member  20 . 
     Optionally, a thin silicone coating may be applied to the tubular body  40 , the tubular member  20 , and the balloon  46 . A protective sheath (not shown) may then be placed over the balloon  46  and at least partially over the tubular body  40 . 
     The apparatus  10  and syringe  148  may then be placed with appropriate packaging, e.g., into respective cavities within a thermoformed clamshell tray (not shown), and the clamshell tray snaps may be closed. The closed tray may be inserted into a foil pouch or other packaging as desired. Additional processing, such as product labeling, sterilization, and the like, may be completed before the apparatus  10  is provided to a user. 
     Turning to  FIGS. 3A-3G , an exemplary method is shown for sealing a puncture  90 , e.g., using the apparatus  10  to deliver a sealant  2  (which again may be any of the exemplary embodiments herein), e.g., to achieve hemostasis within the puncture  90 . Generally, the puncture  90  extends from a patient&#39;s skin  92  through intervening tissue, e.g., to a body lumen  94 . In an exemplary embodiment, the puncture  90  may be a percutaneous puncture communicating with a blood vessel  94 , such as a femoral artery, carotid artery, and the like. 
     In an exemplary method, the puncture  90  may be created using known procedures, e.g., using a needle, guidewire, one or more dilators, and the like (not shown). An introducer sheath  80  may be advanced through the puncture  90  into the vessel  94 , e.g., over a guidewire (not shown) placed through the puncture  90  into the vessel  94 . The introducer sheath  80  may provide access into the vessel  92  for one or more instruments (not shown), e.g., to allow one or more diagnostic and/or interventional procedures to be performed via the vessel  94 . Upon completing the procedure(s) via the vessel  94 , any such instrument(s) may be removed from the puncture  90 , leaving the introducer sheath  80  extending through the puncture  90  into the vessel  94 . 
     With reference to  FIG. 3A , the positioning member  14  may be introduced into and/or through the lumen of the introducer sheath  80 , e.g., with the expandable positioning element  46  in a collapsed condition. The cartridge  16 , along with the sealant  2  and advancer member  30 , may be provided initially on the proximal end  42  of the positioning member  40 , e.g., as shown in  FIGS. 2A and 3A . Thus, the distal end  24  of the tubular member  20  may initially be located outside the puncture  90  when the positioning member  40  is advanced into the puncture  90 . 
     Still referring to  FIG. 3A , the distal end  44  of the positioning member  14  may be inserted through the puncture  90  (via the introducer sheath  80 ) and into the vessel  94 . Once the positioning element  46  is disposed within the vessel  94 , i.e., beyond a distal end  84  of the introducer sheath  80 , the positioning element  46  may be expanded to an enlarged condition, as shown. 
     After expanding the positioning element  46 , the positioning member  40  may be at least partially withdrawn until the positioning element  46  contacts the wall of the vessel  94 , e.g., to substantially seal the vessel  94  from the puncture  90 . In an exemplary method, shown in  FIGS. 3A and 3B , this may involve a two-step process (although it may be completed in a single substantially continuous action). First, with the positioning element  46  expanded within the vessel  94 , the positioning member  14  may be withdrawn until the positioning element  46  contacts the distal end  84  of the introducer sheath  80 , which may provide a first tactile feedback to the user (i.e., that the positioning element  46  has contacted the introducer sheath  80 , e.g., based upon the increased weight and/or resistance to proximal movement). The positioning member  14  may be withdrawn further until the positioning element  46  contacts the wall of the vessel  94  and resists further withdrawal, thereby providing a second tactile feedback. The introducer sheath  80  may be pulled proximally by the positioning element  46  as the positioning member  14  is withdrawn, e.g., until the distal end  84  of the introducer sheath  80  is withdrawn from the vessel  94  into the puncture  90 , as shown in  FIG. 3B . 
     Proximal tension may be applied and/or maintained on the positioning member  14  to hold the positioning element  46  against the wall of the vessel  94 , e.g., to seal the puncture  90  from the vessel  94  and/or prevent further removal of the positioning member  14 . The proximal tension may be maintained manually or using a tensioner device (not shown) to provide temporary hemostasis, e.g., during the subsequent steps. Exemplary tension devices are disclosed in U.S. Publication No. 2004/0267308, incorporated by reference elsewhere herein. 
     Turning to  FIG. 3C , the cartridge  16  (carrying the sealant  2 ) may then be advanced distally over the positioning member  14  into the puncture  90 . As shown, the distal end  24  of the tubular member  20  may enter the introducer sheath  80  and be advanced towards the positioning element  46 . The cartridge  16  may be advanced until a component of the cartridge  16  encounters a stop on the positioning member  14 , thereby preventing further advancement of the cartridge  16  and/or spacing the sealant  2  a predetermined distance from the positioning element  46 . Alternatively, the cartridge  16  may be advanced into the introducer sheath  80  until the distal end  24  contacts the expanded positioning element  46 , which may provide tactile feedback that the cartridge  16  has been advanced sufficiently, or the sealant  2  is otherwise positioned within the puncture  90 . 
     Thereafter, as shown in  FIG. 3D , the tubular member  20  of the cartridge  16  and introducer sheath  80  may be refracted, e.g., by pulling proximally on a hub  83  of the introducer sheath  80 , to withdrawn the introducer sheath  80  and tubular member  20  from the puncture  90  and expose the sealant  2  within the puncture  90  beyond the introducer sheath distal end  84 . Optionally, a sleeve or locking device (not shown) may be provided on the cartridge  16  that may couple the introducer sheath  80  to the tubular member, similar to embodiments disclosed in U.S. Publication No. 2009/0088793, the entire disclosure of which is expressly incorporated by reference herein. Thus, in this alternative, if the user pulls proximally on the hub  23  or tubular member  20  rather than the hub  83  of the introducer sheath  80 , the introducer sheath  80  and tubular member  20  may still be withdrawn together from the puncture  90 . 
     As the tubular member  20  is retracted, the advancer member  30  may prevent substantial proximal movement of the sealant  2 , thereby exposing the sealant  2  within the puncture  90 , as shown in  FIGS. 3D and 3E . For example, as described above, as the cartridge  16  is advanced, one or more features (not shown) on the proximal end  32  of the advancer member  30  may pass over a reduced region or other feature (also not shown) on the positioning member  14 , thereby preventing subsequent proximal withdrawal of the advancer member  30  relative to the positioning member  14 . Thus, when the cartridge  16  is then retracted, the features may prevent substantial proximal movement of the advancer member  30 , and the sealant  2  adjacent the distal end  34  of the advancer member  30 . 
     When the sealant  2  is exposed within the puncture  90 , the sealant  2  may be exposed to blood and/or other body fluids within the puncture  90 . This exposure may cause the sealant  2  to absorb fluid and activate to provide hemostasis, as described further elsewhere herein. Optionally, as shown in  FIG. 3E , once the sealant  2  is exposed within the puncture  90 , the advancer member  30  may be advanced to compress or tamp the sealant  2 , e.g., against the positioning element  46 . Optionally, the advancer member  30  may include one or more markers  33 , e.g., on or adjacent the proximal end  32 , and the advancer member  30  may be advanced into the puncture  90  a desired distance, which may be confirmed by monitoring the markers  33 . In addition or alternatively, the positioning member  14  may include a second feature (not shown) over which the advancer member  30  may pass when advanced a predetermined distance. The second feature may provide an audible confirmation that the advancer member  30  has been advanced the predetermined distance (in addition or instead of the visible confirmation provided by the markers  33 ). In addition, the second detent  41   b  may ensure that the advancer member  30  is not subsequently withdrawn once advanced the predetermined distance. 
     Once the sealant  2  has been exposed for sufficient time and/or tamped by the advancer member  30 , the positioning element  46  may be collapsed, and the positioning member  14  withdrawn from the vessel  94  and puncture  90 , e.g., pulling the collapsed positioning element  46  through the sealant  2  and advancer member  30 , as shown in  FIG. 3F . The advancer member  30  may be maintained substantially stationary during withdrawal of the positioning member  14 , e.g., to prevent migration and/or dislodgment of the sealant  2  within the puncture  90 . Once the positioning member  14  is completely removed, the advancer member  30  may be removed from the puncture  90 , leaving the sealant  2  within the puncture  90 , as shown in  FIG. 3G . 
     Optionally, after removing the positioning member  14 , liquid hydrogel or other sealing compound, or other material may be delivered into the puncture  90 , e.g., above and/or around the sealant  2 , to assist in achieving hemostasis. For example, such material may be delivered via the lumen  36  of the advancer member  30  and/or by introducing another delivery device (not shown) into the puncture  90 , e.g., after removing the advancer member  30 . 
     With additional reference to  FIG. 1 , with the freeze-dried hydrogel proximal section  4  of the sealant  2  delivered into the puncture  90  adjacent vessel  94 , hydration may occur substantially immediately as the sealant  2  is exposed from the tubular member  20  and begins to uptake local fluids (blood or interstitial fluids). For example, the proximal section  4  of the sealant  2  may begin to swell rapidly such that the swelling and the increase in the radial dimension of the proximal section  4  substantially fills a portion of the available space in the puncture  90  above the vessel  94 , e.g., above the arteriotomy in the vessel wall. The end result is a discrete, optimally targeted deposition of hydrogel sealant  2  that provides a seal over the arteriotomy. 
     In addition, the non-freeze-dried distal section  6  of non-crosslinked precursors absorbs local fluids, which initiates crosslinking in-situ and results in a more secure mechanical hold on the surrounding tissue as the freeze-dried hydrogel conforms to the spaces in the tissue tract. Optionally, if the sealant  2  includes salts or other pH adjusting agents, exposure of the sealant  2  may dissolve the agent(s) in the local fluids, which may enhance or facilitate crosslinking of the precursors. 
     In an exemplary, if the sealant  2  is compressed against the arteriotomy over the vessel  94 , the distal section  6  may bond to the outer surface of the vessel wall  96  and/or other tissue adjacent the arteriotomy, or may fill or otherwise penetrate into the arteriotomy, e.g., optionally extending into the interior of the vessel  94 , which may enhance the resulting seal and/or prevent migration of the proximal section  4  of the sealant  2 , e.g., away from the arteriotomy and vessel wall  96 . Thus, the end result may be a discrete, optimally targeted deposition of hydrogel sealant that provides a durable seal over or within the arteriotomy, as shown in  FIG. 3G . 
     Several alternative embodiments of sealants are shown in  FIGS. 4-11  and described below that may be delivered, e.g., using the apparatus and methods described elsewhere herein and/or in the references incorporated by reference herein. The sealants described below may be formed from any of the materials and methods described above for sealant  2 . 
     For example, turning to  FIGS. 4A and 4B , an exemplary embodiment of a sealant  102  is shown that includes a proximal section  104  of freeze-dried hydrogel and a distal section  106  of non-crosslinked precursors, generally similar to other embodiments herein. In an exemplary embodiment, uncoated biomaterial, e.g., freeze-dried hydrogel, may be rolled or otherwise formed, similar to other embodiments described herein, for the proximal section  104 . Thus, the sealant  102  may include a lumen (not shown) extending longitudinally between the proximal and distal sections  104 ,  106 , e.g., to allow delivery of the sealant  102  over a positioning member  40 , similar to other embodiments herein. 
     As shown in  FIG. 4A , a cylindrical plug or bolus  106  of substantially dry non-crosslinked hydrogel precursors may be fused or otherwise provided on or adjacent the distal end of the proximal section  104 . For example, the distal section  106  may be a solid mass or plug, e.g., a melted and solidified form attached to the proximal section  104 , similar to the processes described above. Alternatively, the distal section  106  may be a bolus of powder provided adjacent but separate from the proximal section  104 , e.g., sintered or otherwise compressed together, while remaining in a powder form, or simply loaded into a delivery cartridge distal to the proximal section  104  such that the powder is released when the sealant  102  is delivered from the cartridge. For example, if the precursor powder is sintered into a desired shape, the powder particles may behave as a solid mass yet may easily separate from one another, e.g., when delivered within a puncture, which may increase surface contact between the powder and physiologic fluids, which may accelerate and/or otherwise enhance crosslinking of the precursors. 
     Optionally, the non-crosslinked precursors of the distal section  106  and/or the uncoated biomaterial of the proximal section  104  may have salts or other pH adjusting agents impregnated therein or applied thereto such that, when physiological fluids wet the biomaterial and/or unreacted hydrogel precursors, a favorable pH may be obtained for cross-linking the distal section  106 . The ratio of the lengths of unreacted hydrogel precursors to uncoated biomaterial, i.e., distal to proximal sections  106 ,  104 , may range from 0-100% for the respective materials, and the length of the overall sealant  102  may vary, similar to other embodiments herein. During use, the sealant  102  may be advanced into position, e.g., over a positioning member  40  and/or towards a positioning element  46 , in apposition to the surface  96  of an artery at the arteriotomy within a puncture (not shown), e.g., using apparatus and methods similar to those described elsewhere herein. The local fluids within the puncture may initiate crosslinking of the precursors of the distal section  106 , which may cause the crosslinking precursors to soften, flow into available space within the puncture, e.g., into the arteriotomy and/or into the vessel itself, and begin to crosslink to form a hydrogel. The “setting” action of the non-crosslinked precursors as the in-situ crosslink occurs may act as a glue to substantially fix the sealant  102  in position over the arteriotomy. 
     The distal section  106  may also form a patch over the arteriotomy, e.g., against or into the vessel wall  96 , e.g., with the sealant  102  acting as a sponge to absorb any blood in the immediate area, e.g., to minimize subsequent oozing. For example, as shown in  FIG. 4B , the distal section  106  may be compressed against the vessel wall  96 , e.g., using a tamping member (not shown), similar to other embodiments herein, which may cause deformation of the crosslinking precursors, potentially enhancing the coverage area of the adherent material and/or increasing the surface area for the cross-linking reaction. 
     Turning to  FIGS. 5A and 5B , an alternative embodiment of a sealant  102 ′ is shown that includes a proximal section  104 ′ and a distal section  106 ′ generally similar to the sealant  102  of  FIGS. 4A and 4B . However, as shown in  FIG. 5A , unlike the previous embodiment, the proximal section  104 ′ may include a pocket  104   d ′ formed in the distal end of the uncoated biomaterial within which the non-crosslinked precursors of the distal section  106 ′ may be formed or deposited. For example, a solid mass of non-crosslinked precursors or a bolus of precursor powders may be loaded into the pocket  104   d ,′ e.g., loosely or fused to the distal end of the first section  104   a ,′ similar to previous embodiments. 
     As shown in  FIG. 5B , the sealant  102 ′ may be compressed within a puncture and/or against an arteriotomy in the vessel wall  96 , similar to other embodiments herein, which may cause an annular wall of the first section  104 ′ defining the pocket  104   d ′ to splay out over the flattened distal section  106 ,′ e.g., providing improved adhesion between the uncoated biomaterial of the proximal section  104 ′ and the adherent material of the distal section  106 .′ 
     Turning to  FIGS. 6A-6C , another alternative embodiment of a sealant  102 ″ is shown, similar to the sealant  102 ′ of  FIGS. 5A and 5B  (or the sealant  102  of  FIGS. 4A and 4B ) including a proximal section  104 ″ of freeze-dried hydrogel and a distal section  106 ″ of non-crosslinked polymers. Similar to the sealant  102 ,′ the proximal section  104 ″ includes a pocket  104   d ″ for receiving the non-crosslinked precursors of the distal section  106 .″ Unlike the previous embodiments, the proximal section  104 ″ may include one or more longitudinal slits  104   e ″ formed laterally through the uncoated biomaterial and extending only partially between and spaced apart from the proximal and distal ends of the proximal section  104 .″ Such a slit  104   e ″ through the side of the proximal section  104 ″ may facilitate collapsing the sealant  102 ″ during compression, e.g., into a “lantern” shaped body, as shown in  FIGS. 6B and 6C . For example, these drawings show how compression may result in a substantially flattened low profile for the delivered sealant  102 ,″ which may provide maximum surface area coverage against the vessel wall  96 . 
     Turning to  FIGS. 7A and 7B , still another embodiment of a sealant  202  is shown that includes two distinct sections of sealant material. The distal section  204  may be formed from a relatively softer, rapidly swelling composition, e.g., freeze-dried hydrogel, while the proximal section  206  may be formed from a relatively harder, slower swelling composition. As shown, the proximal section  206  may be nested to some degree into the distal section  204 , e.g, including a tapered distal tip  206   f  that is initially provided within a similar shaped pocket  204  in the proximal end of the distal section  204 , as shown in  FIG. 7A . 
     The act of placing a compressive load on the proximal section  206  of the sealant  202  while holding the distal face of the distal section  204  substantially fixed (e.g., in this case using a balloon  46  as a backstop), may drive the proximal section  206  into the distal section  204 . As shown in  FIG. 7B , this action may expand the distal section  204  into a shape that is wider than its original configuration. For example, as shown in  FIG. 7B , the distal section  204  may be designed to split during compression, bulge, or otherwise deform under the compressive load. 
     Turning to  FIGS. 8A-8C , still another embodiment of a sealant  304  is shown that includes a proximal end  304   a , a distal end  304   b  and a longitudinal slit  304   e  extending partially between the proximal and distal ends  304   a ,  304   b , e.g., similar to the proximal section  104 ″ of the sealant  102 ″ of  FIGS. 6A-6C . In this embodiment, the freeze-dried hydrogel or other sealant may include one or more slits to enable a controlled deformation of the sealant  304  under a compressive load. For example, the sealant  304  may include two longitudinal slits  304   e  (only one visible in the side view shown in  FIG. 8A ), e.g., offset one hundred eighty degrees (180°) apart from one another around the circumference of the sealant  304 . Alternatively, the number and/or orientation of the slits  304   e  may be modified, e.g., to attain a desired morphology after compression. 
     It will be appreciated that the shape of any of the sealants herein may be modified to have a shape that is conducive to controlled deformation. Examples include an inverted golf tee, an hourglass, swept or wavy surfaces, and the like. 
     Turning to  FIG. 9 , additional alternative embodiments of sealants are shown that include non-crosslinked precursor sections  406   a - 406   g  and freeze-dried hydrogel main sections  404   a - 404   g . The location of the non-crosslinked precursors  406   a - 406   g  may be proximal to, distal to, or both proximal and distal to the hydrogel main sections  404   a - 404   g . The precursors  406   a - 406   g  may be provided as a solid mass fused or otherwise attached to the main section  404   a - 404   g  or as a bolus of powder, similar to other embodiments herein. For example, a sealant  402   a  may be provided that includes precursor sections  406   a  within pockets in both proximal and distal ends of the main section  404   a , while the sealant  402   b  may include a precursor section  406   b  within a pocket on the proximal end of the main section  404   b.    
     Sealants  402   c  and  402   d  include a main section  404   c ,  404   d , e.g., formed from freeze-dried hydrogel, and non-crosslinked precursor sections on either both ends  406   c  or one end  406   d  of the main section  404   c ,  404   d . In these embodiments, the non-crosslinked sections  406   c ,  406   d  may be a solid mass fused to the main sections  404   c ,  404   d  or a bolus or sintered mass of precursor powders. 
     Sealants  402   e - 402   g  include main sections  404   e - 404   g , e.g., formed from freeze-dried hydrogel, and distal sections  406   e - 406   g , e.g., solid masses of non-crosslinked precursors fused or otherwise attached to the main sections  404   a - 404   g . For example, in sealant  402   e , the main section  404   e  may include a recess, e.g., a conical recess in one end for receiving the distal section  406   e  substantially flush with the end of the main section  404   e . Alternatively, the distal section  406   f  may extend from the recess in the main section  404   f , as shown for the sealant  402   f . In a further alternative, the sealant  402   g  includes a smaller tab or other feature extending from the main section  404   g  around which the distal section  406   g  may be formed and/or extend. 
     Turning to  FIGS. 10A-10D , another embodiment of a sealant  502  is shown, which may include a section of rolled hydrogel or other base material  504 , such as any of the materials described above, including proximal and distal ends  504   a ,  504   b . A plurality of slits  504   h  may be formed in the distal end  504   b , e.g., by mechanical cutting, laser cutting, stamping, and the like, as shown in  FIG. 10A . The distal end  504   b  may then be coated, e.g., with non-crosslinked precursors, as shown in  FIG. 10C , similar to other embodiments herein and in the references incorporated by reference herein. Optionally, pH controlling salts and the like may be embedded in the coating or in the non-coated biomaterial, e.g., as shown in  FIG. 10B . The slits  504   h  may facilitate collapsing the coated end  504   b  of the sealant  502 , e.g., resulting in a wider footprint to cover an arteriotomy or other vessel puncture, as shown in  FIG. 10D . The sealant  502  may be delivered using apparatus and methods similar to those described elsewhere herein. 
     Turning to  FIGS. 11A and 11B , an exemplary embodiment of a pliable patch-like material  602  is shown, e.g., having lateral dimensions (from the perspective of  FIG. 11A ), e.g., a width, height, diameter, and the like depending on the desired shape for the patch, formed from material with minimal stretch in the lateral directions. The patch  602  may include a weave or other arrangement  605  of synthetic biocompatible and/or bioresorbable fibers, such as PLG, PLA or PGA, e.g., defining a first or base layer, as shown in  FIG. 11B . Alternatively, the patch  602  may also be formed from naturally occurring proteins, such as collagen, or other bioabsorbable materials, such as those described above. 
     As shown in  FIG. 11B , the patch  602  may be covered on one or both sides with non-crosslinked precursors, similar to other embodiments herein, e.g., to provide an adhesive layer  606  for the patch  602 . As shown, the coating  606  has been provided on only the bottom side of the base layer  605  of the patch  602 . In the case of coating  606  on only one side, a layer  604  of freeze-dried hydrogel or other expandable, bioabsorbable material may be provided on the top side of the base layer  605 , e.g., to absorb excess fluid and/or expand to fill a space above the delivery site. Optionally, salts to control the pH (not shown) may be blended with the coating  606 , embedded in the base material  605 , embedded in the freeze-dried hydrogel  604 , and/or dissolved in a buffer solution that is used to saturate the assembly immediately before or after the patch  602  is applied to a arteriotomy or other tissue surface. 
     The patch  602  may be delivered using the apparatus and methods described elsewhere herein, e.g., where the patch  602  is small enough to be loaded into a cartridge. Alternatively, the patch  602  may be applied manually, e.g., if the tissue surface is sufficiently exposed. 
     For example, upon application to a vessel or other tissue surface or structure, e.g., over an arteriotomy or other puncture (not shown), adhesion to the vessel may occur due to the coating  606 , but the non-stretch nature of the base layer  605  of the substrate patch  602  may prevent the expanding pressurized vessel from substantially opening or enlarging the arteriotomy because of the lateral resistance of the patch  602  to expansion. The dense weave of the base layer  605  and the cross-linking of the coating  606  may prevent blood or other fluid from the vessel from leaking though the patch  602 . The size of the patch  602  may vary from being large enough to surround all or a portion of vessel having a puncture therethrough, e.g., adhering the patch all around the puncture to only pulling together the mid-point of the vessel puncture for achieving substantial hemostasis. Optionally, after applying the patch, another hemostatic material, such as freeze-dried hydrogel (or any other sealant, such as those described elsewhere herein) may be applied over the top to achieve complete hemostasis. 
     In still another embodiment, a plurality of coated sealant pellets (not shown) may be provided for sealing a puncture through tissue. For example, freeze-dried hydrogel sealant may be used as a carrier for non-crosslinked PEGs or other precursors in a solid (i.e., melted, mixed, and solidified) form, e.g., a solid shell surrounding the underlying freeze-dried hydrogel. For example, freeze-dried hydrogel sealant may be punched, ground, or other formed into particles, e.g., having one or more diameters between about 0.5-10 millimeters. The particles may then be spray-coated with a hot liquid mass, e.g., including the melted PEG amine and PEG ester. The resulting pellets may then be delivered over an arteriotomy, into a puncture, or applied to a tissue surface, e.g., as a bolus through a sheath or other delivery device, and the non-crosslinked precursors may reconstitute and bind to form a slurry of adhesive gel and rapidly-absorbing hydrogel sealant over the arteriotomy, within the puncture, and/or onto the tissue surface. 
     It will be appreciated that elements or components shown with any embodiment herein are merely exemplary for the specific embodiment and may be used on or in combination with other embodiments disclosed herein. 
     While the invention is susceptible to various modifications, and alternative forms, specific examples thereof have been shown in the drawings and are herein described in detail. It should be understood, however, that the invention is not to be limited to the particular forms or methods disclosed, but to the contrary, the invention is to cover all modifications, equivalents and alternatives falling within the scope of the appended claims.