WO1990015636A1

WO1990015636A1 - Porous percutaneous access device

Info

Publication number: WO1990015636A1
Application number: PCT/AU1990/000242
Authority: WO
Inventors: Michael David Hallett; Peter Craig Farrell; John Moran; Laura Poole-Warren
Original assignee: Baxter International Inc.
Priority date: 1989-06-02
Filing date: 1990-06-01
Publication date: 1990-12-27
Also published as: EP0431102A1; EP0431102A4; CA2033336A1

Abstract

A tissue interface material in a particular form comprises a cuff (12) of generally cylindrical shape which encircles a tube (10). The cuff (12) is made from biocompatible material having a homogeneous, interconnected structure of the type which can be produced by the replamineform process. The cuff (12) is surgically placed subcutaneously whereby downgrowth of dermal and epidermal tissue is supported by the porous structure of the cuff (12) so as to form a seal which acts to prevent ingress of microorganisms which would elicit a pathological state. The structure is particularly suited to anchoring a conduit (10) within skin layers and promoting a biological seal at the same time.

Description

POROUS PERCUTANEOUS ACCESS DEVICE

Field of the Invention

This invention relates to devices for providing

percutaneous access to the body, and more particularly to materials and structures suitable to anchor such devices within the body for substantial periods of time.

Description of the Prior Art

Percutaneous access is often required for the delivery of therapeutic agents, the provision of electrical, pneumatic or similar impulses or the removal of endogenously or

exogenously manufactured material. The inability of known access devices (commonly referred to as catheters) to bond effectively to or to bind with contiguous tissue,

particularly at the dermal /epidermal interface or exit site, in a fashion analogous to non-transgressed or unbroken skin, facilitates egress of internal fluids and ingress of

biological pathogens.

Pathogenically mediated inflammation at the exit site leads to discomfort and, depending upon the severity, an aesthetically unpleasant appearance and odour. Such

infection if left unchecked, or if it progresses in an uncontrollable fashion, will track along the in vivo portion of the catheter and can lead to systemic infection or

infection of one or more of the recipients internal organs.

Continuous ambulatory peritoneal dialysis is an example of a therapy requiring chronic stable percutaneous access. Continuous ambulatory peritoneal dialysis requires

approximately 2 litres of hypertonic solution be instilled and be drained from the peritoneal cavity of the patient four times per day. Fluid access to the peritoneum is gained via a percutaneously positioned catheter. Patients will be maintained on this therapy until such time as they recover kidney function, are given a donor kidney, placed on

alternative therapies or they die. Typically, patients are maintained on continuous ambulatory peritoneal dialysis for three to four years although some patients have been on the therapy for as long as 10 years. Exit site and catheter tunnel infection and peritonitis associated with a poorly maintained exit site has been a cause of considerable

morbidity in these patients who number approximately 50,000 worldwide since 1990.

I n the prior art attention has, therefore, focussed upon the detailed construction and composition of that part of the percutaneous access device which remains in contact with the upper skin layers for extended periods of time when the percutaneous access device is in use.

Particularly the prior art discloses various forms of cuff which engage the periphery of tubing and the like at the point where the tubing enters the body in such a manner as to provide a physical buffer between the skin layers at the entry point and the tubing material itself.

A common form of cuff material, Dacron (Trade Mark), is disclosed in relation to a relatively complex "retainer" structure in US 4,278,092 (Borsanyi et al). US 3,663,965 (to Lee et al) discloses a relatively complex cuff which includes what might be termed a disc adapted to extend well away from the tubing which it

surrounds so as to help anchor the cuff and tube in place. The disc portion includes a plurality of holes adapted to aid the ingrowth of body material.

In current practice, certainly in Australia, surgeons have opted for simplicity with good cuff anchoring

characteristics at the expense of possible medium to long term soft-tissue complications. Specifically, access is via a silicon catheter with a Dacron (trade mark) felt cuff placed in the subcutanium at 5 to 30 millimetres from the skin exit site. This form of subcutaneous cuff is designed to anchor the catheter, provide immobilisation and,

theoretically, prevent epidermal downgrowth. An additional cuff is usually placed several centimetres deeper below the skin surface to prevent leakage of dialysate from the

peritoneum.

The major failure modes of these catheters relate to soft tissue complications such as exit site infection and cuff extrusion which is hypothesised to be primarily due to poor compatibility of the Dacron cuff and/or failure of the cuff to prevent sinus formation.

The Dacron felt cuff is a woven felt structure and, as such, is not a truly porous structure in the sense used in this specification. The prior art in the field of percutaneous and

subcutaneous cuff devices acknowledges that some attention needs to be paid to the porosity of the cuff material, at least at the cuff/skin interface. A paper entitled

"Permanent Percutaneous Devices" in the January, 1981 issue (Vol.5) of CRC Critical Reviews in Bioengineering provides a comprehensive summary, as at that date, of such devices and, at page 50 et seq, devotes itself particularly to the matter of percutaneous device-skin interactions. Porosity is specifically discussed here.

PCT/US85/01809 (W086/01729) to Yamamoto et al discloses a particular, distendable cuff structure and notes that the surface of the cuff structure must have tissue sealing properties "which can be conferred by (2) the attachment of porous, tissue ingrowth promoting material, such as woven felts, and velours, textured polymers, and foam or spongelike materials, (2) the surface texturing of the sleeve material by high energy bombardment or salting out methods; (3) the attachment or incorporation of tissue adhesive biomolecules such as lectins.". Yamamato uses the term "porous" in a loose, broad sense.

EP0164896 to Thermedics discloses a structure having cavities which are interconnected by a tortuous path. The "porosity" of such a structure is somewhat limited.

Generally, it can be said that the prior art indicates that the solutions to the problems of obtaining a

satisfactory anchoring system for a percutaneous access structure lie in increased complexity of geometrical

structure of cuffs used at the body entry point for such devices and increased complexity of chemical composition and chemical treatment of the skin contacting portions of those devices. In practice surgeons have settled for relatively simple structures which anchor reliably and are easy to install, but which still have tissue interaction and

infection problems and therefore requires stringent exit site care.

It is an object of this invention to provide an

improved yet simply constructed percutaneous access device which will bond to or bind with contiguous tissue to a sufficient degree and in such a way so as to overcome to at least some extent the problems associated with prior art catheters and their anchoring systems.

Summary of the Invention

According to the invention there is provided a

percutaneous access device comprising a conduit adapted to be passed through the skin to define a portal to and from the body and a porous cuff of biocompatible material around the conduit; said biocompatible material having a homogeneous interconnected porous structure of the type which can be produced by the replamineform technique; said cuff adapted to be surgically placed so as to anchor said conduit within the body as a result of tissue ingrowth into said cuff.

The pores of the cuff are interconnecting and an analogy between this porous structure may be made, for example with the structure of cancellous or spongy bone, the trabeculae-like structures in this situation being

constructed of the biocompatible material, forming a lattice on which tissue is directed, nurtured and supported.

The cuff of the invention may be manufactured by established techniques such as the replamineform process in which the skeletal structures of marine invertebrates are used as template molds.

The structure produced by the replamineform process has been described by its originator as a "periodic minimal surface" (White R.A. "Evaluation of Small Diameter Graft Perameters using Replamineform Vascular Prosthesis" at page 315 in Vascular Grafting, ed., John Wright, P.S.G., Inc., Massachusetts, 1983). Such a surface is stated in the same article to divide space into two interpenetrating networks, each having pores and interconnections between the pores of essentially the same dimension. The replamineform process uses the micro porous skeletal structure of selected marine species as a template to obtain the desired porous network by the process of filling the void spaces in the skeletal structure with the desired biocompatible material and then etching away the skeletal structure itself to leave only the biocompatible material. The process is characterised by its ability to produce porous structures of the above described "type. Throughout this specification the use of the term

"homogeneous, interconnected porous structure" will be used to denote a porous structure as described by White and capable of being produced by the replamineform process.

A photomicrograph of a section though a 200 micron pore size structure produced by the replamineform process is reproduced in Fig. 3 of this specification. The reader of this specification is also referred to other illustrations of such porous structures produced by the replamineform process as, for example, illustrated at page 175 of Biomaterials, Vol. 2, July 1981, where a 25 micron pore size structure of the precursor material is shown in section and also to Fig. 1 at page 146 of Biomaterials, Vol. 3, July 1982. The

structures are available commercially from Interpore

International Inc. in Irvine, California, United States of America.

Preferably, the porous cuff is made of medical grade silicone rubber and is positioned either subcutaneously

(under the skin) or percutaneously (through the skin) thereby allowing fibrous and epidermal tissue ingrowth into the pores facilitating implant ankylosis and tissue stability needed to prevent infection of the surrounding and underlying tissue and/or avulsion and exteriorisation of the cuff.

In a further preferred form, the porous cuff is made from hydroxyapatite or titanium.

In an alternative preferred form, the porous cuff is made from biocompatible material comprising one or more of silicone rubber, semi-rigid polyurethane or other soft, elastomeric material.

The size and design of the cuff will be dependent upon the size of the conduit transgressing the skin. However, the length will range usually from one to several times the external diameter of the conduit. The thickness of the cuff may be variable depending upon pore size and application.

Pore size is selected such that it will allow ingrowth and nurturing of fibroblasts which lay down collagen forming fibrous tissue to ankylose the conduit which the porous material surrounds.

Preferably, the pore size of the cuff (that is, the average diameter of the irregularly shaped intercommunicating pores within the cuff material) is in the range of 30 to 500 um. More preferably the pore size of the cuff material lies in the range 75 to 300 micrometres and yet more preferably in the range 100 to 220 micrometres. A particular preferred form of the invention has a pore size of approximately 200 micrometres.

It is also preferred that the porosity of the cuff (that is the fraction of bulk volume of the material

occupied by voids) is greater than 20%. More preferably it is desired that the porosity of the cuff material lies in the range 25% to 85%.

Preferably where elastomeric materials are used for the biocompatible material said compliance is in the range of 21 to 81 or more preferably 21 to 60 Shore A points based on standard ASTM tests, more preferably in the range 35 to 45 Shore A points and, yet more preferably, approximately 40 Shore A points. Substances (and their derivatives or active subunits) which promote the ingrowth of tissue and/or inhibit the growth of bacteria may be associated with the surfaces and interstices of the pores. Tissue growth promoters will include the chemotactic factors such as platelet derived growth factor.

The surface of the pores can be modified to improve their innate bioactivity such as by increasing surface hydrophillicity through treatment with polyglycolic acid. Labile substances such as growth factors can be placed within the pores in a supporting medium such as a collagen gel.

Robust biological active species and substances in terms of their ability to withstand subsequent chemical manipulation may be grafted to or within the polymer surface by a variety of chemical techniques such as plasma grafting or

incorporation in the polymer prior to cuff manufacture.

Grafting may encompass covalent or more labile intermolecular attractions such as those involving hydrogen bonding, dipole interactions and Van der Waals forces.

In a further broad form of the invention there is provided a method of forming a cuff from biocompatible material for enclosing a conduit for the purpose of anchoring said conduit within skin layers and promoting a biological seal) said method comprising forming said biocompatible material in such a manner that its structure includes a plurality of pores which are highly interconnected. Preferably said method includes use of the replamineform process to produce said biocompatible material.

In yet a further broad form of the invention there is provided a tissue interface wherein a tissue seal is formed between a conduit and skin interface, said tissue interface comprising biocompatible material made by the replamineform process whereby a structure having controlled porosity and a compliance in a preselected range is obtained.

Preferably said porosity (that is, the fraction of bulk volume of the material occupied by voids) is greater than 20% and more preferably in the range 25% to 85%. Preferably where elastomeric materials are used for the biocompatible material said compliance is in the range of 21 to 60 Shore A points based on standard ASTM tests, more preferably in the range 35 to 45 Shore A points and, yet more preferably, approximately 40 Shore A points.

Description of the Drawings

In order that the invention may be more readily

understood and put into practical effect, reference will now be made to the accompanying drawings in which:-

Fig 1 is a schematic view of a percutaneous access

device according to one embodiment of the

invention placed subcutaneously, and, Fig 2 is a view similar to Figure 1 with the

percutaneous access device placed percutaneously. Fig 3 is a photomicrograph of a 200 micron pore size structure of an embodiment of the structure utilized bv the invention. Description of the Preferred Embodiments

Fig. 1 shows a percutaneous access device comprising a conduit 10 of appropriate composition and length. For peritoneal dialysis, for example, the catheter is made from silicone silicone and has an outside diameter of between 5 and 7 millimetres. The conduit 10 passes through an incision 13 in the skin 11 into the body tissue 14. In the case of peritoneal dialysis it is desired to leave the tube 10 in place for as long as possible, for the order of weeks, months or even years.

To remain in place, the tube 10 requires to be reliably anchored within the body tissue 14. For this purpose a porous cuff 12 is attached to the periphery of the tube at a location immediately below the skin surface. A non-porous sleeve 15 which is integrally connected to the inside surface of the porous cuff 12 is permanently connected to the outer surface of the tube 10 by glue. The step of gluing can be performed at the time of manufacture of tube 10 or it can be performed during the operation to insert the tube 10 into the body tissue 14. The non-porous sleeve 15 serves to isolate the porous structure of the cuff 12 from the glue.

Porous material from which the generally cylindrical cuff 12 is made is biocompatible material constructed by the replamineform process so as to provide the biocompatible material with a homogeneous, interconnected porous structure.

The process itself is described in, for example,

Science 176:922-924, 1972 in an article by White R.A. et al entitled "Replamineform: A New Process for Preparing Porous Ceramic. Metal, and Polymer Prosthetic Materials".

The technique is used for duplicating the

microstructure of carbonate skeletal components in ceramic, metal or polymer materials. The process allows control of pore size and the size of the interconnection between

adjacent pores. The process is particularly useful where "relatively uniform pore size and permeability are desired since carbonate skeletal structures having such

characteristics are common in nature.

For peritoneal dialysis, the height (dimension A in Fig. 1) of the generally cylindrical cuff structure is in the range of 0.5 to 2 centimetres. Dimension B in Fig. 1 (the thickness of the porous structure of the cuff) is in the range 0.5 millimetre to 3 millimetres. These dimensions vary according to the physical size of the patient or animal, the body location into which the tube 10 is to be inserted and the particular task which is to be performed by the tube 10.

For uses other than peritoneal dialysis, generally the dimension A will be in the range 1 to 5 times the outside diameter of the tublar element enclosed by the cuff.

Dimensions generally are selected according to the particular application.

In the subcutaneous arrangement of Fig. 1, the cuff 12 is ideally located within 1 centimetre of the surface of the skin 11. i.e. the top of the cuff 12 as illustrated is within 1 centimeter of the surface of the skin 11. The inside diameter of the cuff 12 is selected to match the outside diameter of the tube 10. This dimension will vary according to the task which the tube 10 is to perform.

The pore size within the porous structure of the cuff 12, when produced according to the replamineform process, is relatively consistent, usually with a standard diviation of 10% of the average pore size of the structure.

Average pore size can be selected from within the range 30 to 500 microns. Experimental results to date suggest 75 to 300 microns is a preferred pore size range from which to select whilst 100 to 220 microns is the most desired range from which to select. As indicated below, the experimental results show that the very small pore sizes do not allow good fibrous tissue ingrowth whilst very large pore sizes tend to produce structural characteristics which are mechanically not desirable.

The photomicrograph shown in Fig. 3 is a section through a 200 micron pore size cuff structure made according to the replamineform process from polysyloxane. That cross section is typical of cross sections to be expected in the porous cuff structure 12 of embodiments of the invention.

The replamineform process predominantly allows control over pore size and pore size consistency and pore

interconnectivity. In conjunction with this primary

characteristic, control is also exerted over the "porosity" (defined as the fraction of the bulk volume of the material occupied by voids) cf the biocompatible material and, by allowing a wide choice of biocompatible material also allows control over the compliance of the material.

In the embodiment of Fig. 1 the porosity should be greater than 20% and, ideally, should lie in the range 25 to 85%. Where the porous structure of the cuff is made from elastomeric material. the compliance should be in the range 21 to 60 Shore A points and ideally in the range 35 to 45 Shore A points. The structure made from silicone rubber previously described and illustrated in Fig. 3 has a

compliance of approximately 40 Shore A points and a porosity of around 30%.

Fig. 2 discloses a second embodiment of the invention where like parts have the same numbers as in Fig. 1. The structure and its composition is in all respects the same as that described with respect to Fig. 1, save that the cuff 12 is placed percutaneously so that it protrudes a few

millimetres above the surface of the skin layer 11. The experimental results to be described below indicate that this placement of the cuff is not as preferred as the arrangement of Fig. 1.

Results to date indicate that the structure of the first embodiment described with reference to Fig. 1 allows use of the simple, generally cylindrical cuff structure having approximately the same dimensions as the currently preferred Dacron fibre cuffs used for anchoring purposes. However the particular structure described here allows the possibility of placing the cuff even closer to the skin surface than is desirable with the Dacron cuff structures thereby making surgical insertion easier and lessening trauma. Additionally the structure shows promise of

providing an improved seal against the outside environment once ingrowth of body cells into the porous structure has taken place over a six week or so period.

Example 1

Subcutaneously positioned discs were placed in rabbits above the superficial fascia to study the importance of pore structure and pore size on tissue growth.

The trial sample cuff structures were made from silicone rubber, polyurethane and hydroxyapatite using the replamineform process so as to produce sample structures having respectively 20 micron average pore size, 100 micron average pore size, 200 micron average pore size and 500 micron average pore size.

The 20 micron pore size samples made from each of the materials showed little fibrous tissue ingrowth into the pores after four weeks implantation. It appeared that the pore size was simply too small to be effective.

The 100 micron structures performed well giving mature collagen and good ingrowth after four weeks with the majority of pores filled. The hydroxyapatite caused the least

inflammation whilst polyurethane caused the most.

The 200 micron samples performed much the same as the 100 micron samples but with quality of ingrowth being a little better and the amount of inflammation being a little less. These samples produced the optimum results.

Only hydroxyapatite samples were made with a 500 micron pore size. The results of this structure were generally the same as for the 100 and 200 micron pore size hydroxyapatite samples. However, hydroxyapatite is bioactive and dissolves in the tissues over time. The 500 micron hydroxyapatite sample showed a greater predeliction to this behaviour than the smaller pore size hydroxyapatite samples.

Generally silicone rubber was found to have better inflammation behaviour than poiyurethane. Hydroxyapatite probably performed the best as far as inflammation results are concerned but is an inherently brittle material which does not have the desirable compliance characteristics of silicone rubber or poiyurethane.

Example 2

Trials were also conducted using sheep. The cuffs used included an integral bottom flange made from the same material as the rest of the porous structure of the cuff and extending approximately 4 millimetres radially away from the cuff cylindrical surface. The flanges were incorporated merely as a substitute for the stabilising effect normally provided by the tube 10 to which the cuff 12 is attached in normal usage. Cuff structures of Dow Corning Q7-4840 silicone rubber and poiyurethane, both of 100 micron average pore size and 200 micron average pore size were made

according to the replamineform process and installed both subcutaneously and percutaneously in sheep. The cuff structures were flanged as in the previous examples for the reasons given in the previous examples. The progress of the implants over a twelve week and twenty six week period was observed.

Ultimately there appeared to be little difference in epidermal behaviour between the 100 micron and the 200 micron pore size implants. Ingrowth tissue was generally stable having fibroblasts and low levels of chronic inflammatory cells. Tissue vascularisation was advanced within the pores by twelve weeks. Peri-implant inflammatory response was mild with some focal collections of lymphocytes. Subcutaneous cuff placement allowed formation of a more stable tissue interface at the exit site than percutaneous cuff placement. Example 3

A cylindrical cuff, as generally illustrated and described in respect of Fig. 1 or Fig. 2 and having a cuff porous structure as illustrated in section in Fig. 3 was prepared from Dow Corning Q7-4840 silicone rubber porous material made using the replamineform process. The

replamineform process was carried out so as to produce a cuff having a homogeneous, interconnected porous structure having a compliance of approximately 40 Shore A points, a porosity of approximately 30% and a pore size of approximately 200 micrometers.

Various modifications may be made in details of design and construction without departing from the scope and ambit cf the invention.

Claims

1. A percutaneous access device comprising a conduit adapted to be passed through the skin to define a portal to and from the body and a porous cuff of biocompatible material having pores formed into a porous structure therein placed around the conduit; said biocompatible material having a homogeneous, interconnected structure of the type which can be produced by the replamineform process: said cuff adapted to be surgically placed so as to anchor said conduit within the body as a result of tissue ingrowth into said cuff.

2. The device of claim 1 wherein said cuff is generally cylindrical in shape and adapted to fit over and retain said conduit at a preselected location where said conduit passes through the skin.

3. The device of claim 2 wherein said cuff includes a nonporous internal sleeve.

4. The device of claim 1 or 2 or 3 wherein said porous cuff is made of medical grade silicone rubber, semi-rigid polyurethane or other soft, biocompatible elastomeric material.

5. The device of any one of claims 1 to 4 wherein said biocompatible material comprising said cuff has a compliance specified by a durometer reading in the range 21 to 81 Shore A or in the range 21 to 60 Shore A.

6. The device of claim 5 wherein said compliance is specified by a durometer reading in the range of 35 to 45.

7. The device of claim 6 wherein said durometer reading is approximately 40 Shore A.

8. The device of claim 1 or 2 or 3 wherein said porous cuff is made from hydroxyapatite or titanium.

9. The device of any one of claims 1 to 8 wherein said cuff is positioned subcutaneously.

10. The device of any one of claims 1 to 9 wherein said cuff is positioned percutaneously.

11. The device of any one of claims 1 to 10 wherein the interior of the pores in said porous cuff is impregnated with a substance which further promotes cellular growth and/or inhibits bacterial growth.

12. The device of any one of claims 1 to 11 wherein said pores have an average diameter in the range of 30 to 500 micrometres.

13. The device of any one of claims 1 to 12 wherein said cuff has a porosity of greater than 20%.

14. The device of any one of claims 1 to 13 wherein said cuff has a porosity of between 25% and 85%.

15. The device of any one of claims 1 to 14 wherein said biocompatible material is formed by use of the "replamineform process" wherein skeletal structures of marine invertebrates are used as template molds whereby a homogeneous,

interconnected porous structure is obtained.

16. The device of any one of claims 1 to 15 wherein the size of the pores in said porous structure are selected to allow ingrowth and nuturing of fibroblasts which lay down collagen forming fibrous tissue to ankylose said conduit.

17. The device of any one of claims 1 to 16 wherein

downgrowth of dermal and epidermal tissue is supported by said porous structure so as to form a seal which acts to prevent ingress of micro-organisms which would elicit a pathological state.

18. A method of forming a cuff from biocompatible material for enclosing a conduit for the purpose of anchoring said conduit within skin layers and promoting a biological seal; said method comprising forming said biocompatible material in such a manner that its structure comprises a homogeneous, interconnected porous structure.

19. The method of claim 18 wherein said biocompatible material has a porosity of greater than 20%.

20. The method of claim 19 wherein said material has a porosity in the range 25% to 85%.

21. The method of claim 18, 19 or 20 wherein said pores have an average diameter in the range of 30 to 500

micrometers.

22. The method of any one of claims 18 to 21 wherein said method includes use of the "replamineform" process to produce said biocompatible material.

23. A tissue interface material supportive of a surface wherein a tissue seal is formed between said surface and said tissue interface material so as to seal said surface within the body, said tissue interface material comprising

biocompatible material having a homogeneous, interconnected structure whereby said tissue interface material has a structure having controlled porosity and a compliance in a preselected range.

24. The interface material of claim 23 wherein said surface extends percutaneously.

25. The interface material of claim 24 wherein said tissue seal acts to prevent ingress of micro-organisms which would elicit a pathological state.

26. The interface material of claim 23, 24 or 25 wherein said surface is the external surface of a conduit adapted to pass into the human body through a surgical incision.

27. The interface material of claim 23 or 24 or 25 or 26 wherein said porosity of said structure is greater than 20%.

28. The interface material of claim 23 or 27 wherein said compliance is in the range 21 to 60 Shore A points.

29. The tissue interface material of claim 28 wherein said compliance is in the range 35 to 45 Shore A points.

30. The tissue interface material of claim 29 wherein said compliance is approximately 40 Shore A points.

31. The tissue interface material of any one of claims 23 to 30 wherein said structure includes pores all selected to lie in the size range of 30 to 500 micrometers.

32. The tissue interface material of any one of claims 23 to 30, wherein said structure includes pores all selected to lie in the size range of 75 to 300 um.

33. The tissue interface material of any one of claims 23 to 30, wherein said structure includes pores all selected to lie in the size range of 100 to 220 um.

34. The tissue interface material of any one of claims 23 to 30, wherein said structure includes pores which are all approximately 200 um in size.

35. The tissue interface material of any one of claims 23 to 34 wherein said homogeneous, interconnected structure of said biocompatible material is produced by use of the replamineform process.