WO2008126061A2

WO2008126061A2 - Medical device

Info

Publication number: WO2008126061A2
Application number: PCT/IB2008/051457
Authority: WO
Inventors: Aik Huang Terence Tan
Original assignee: Individual
Current assignee: Individual
Priority date: 2007-04-16
Filing date: 2008-04-16
Publication date: 2008-10-23
Anticipated expiration: 2009-10-16
Also published as: WO2008126061A3

Abstract

There is provided a medical device (34) for implanting into a body of an animal or a human being. The medical device comprises a block container (26) comprising at least one receiving portion (24), a cover (20) that is configured to be attached to the block container (24) for enclosing the at least one receiving portion (24) and a first duct (14) connecting between a first opening (25) on an external surface (27) of the block container (26) and the at least one receiving portion (24)

Description

Description MEDICAL DEVICE

[ 1 ] FIELD OF TECHNLOGY

[2] The present application relates to a medical device for implanting into a body of an animal or a human being. The present application also relates to methods of using and making the medical device for implanting into a body of an animal or a human being. The present application further relates a vascularized medical device and methods of using and making the vascularized medical device.

[3] BACKGROUND

[4] Many cancer patients suffer from their cancers and resistance of their cancers to standard treatments. These cases pose significant challenges to oncologists and doctors to prescribe and adapt correct, effective, and efficient treatment with accurate dosage and duration of treatments. Often, the oncologists and the doctors have to resort to trial and error strategies for prescribing the treatments. The trial and error strategies frequently cause delay or even fail to provide the correct treatment in time because health condition of a cancer patient deteriorates when an erroneous treatment is practiced on the patient over a period of time. On the other hand, even a correct treatment can require a long period of observation to prove its effectiveness at correct dosages. Sometimes, it is too late to introduce a correct treatment due to the deterioration of a patient's health condition over a long period of treatment.

[5] Therefore, there is a need exist for providing a medical device and a method for shortening the time required for the trial and error strategies.

[6] EMBODIMENTS

[7] According to present application, there is provided a first method comprising the following steps:

[8] - extracting a predetermined part of the body,

[9] - implanting the extracted part of the body at/in another location in the body,

[lϋ] - subjecting the implanted part of the body to a predetermined treatment, and

[11] - observing the treated part of the body.

[12] There is provided a second method according to the first method, comprising a further step of determining the outcome of the treatment.

[13] There is provided a third method according to one of the aforementioned methods, wherein the step of observing the treated part of the body includes a step of purging liquid from the treated part of the body and a step of measuring predetermined characteristics of the purged liquid.

[14] There is provided a fourth method according to one of the aforementioned methods, wherein the step of observing the treated part of the body includes an optical ver- ification or a verification with electro-magnetic radiation. [15] There is provided a fifth method according to one of the aforementioned methods, wherein before the step of implanting the extracted part of the body at/in another location in the body, there is provided a step of implanting a receptacle device at the location of the body, the receptacle device being formed to receive the extracted part of the body. [16] There is provided a sixth method according to the fifth method, wherein the receptacle device is left such a time within the body that at least one contact area for receiving the extracted part of the body is vascularized at the time of implanting the extracted part of the body into the receptacle device. [17] There is provided a seventh method according to the fifth method or the sixth method, wherein at least one part of the receptacle device is replaced by a covering means at the time at the time of implanting the extracted part of the body into the receptacle device. [18] There is provided an eighth method according to one of the fifth method to the seventh method, wherein the step of implanting the receptacle device at the location of the body is done such that the receptacle is covered fully under a skin portion of the body. [19] There is provided a ninth method, wherein the step of implanting the receptacle device at the location of the body is done such that the receptacle is partially underneath a skin portion of the body, partially protruding from the body. [20] According to present application, there is also provided a tenth method comprising the following steps: [21] - performing the steps of testing the effectiveness of two or more treatments on two or more parts of a body of an animal or of a human being at the same time with the steps according to one or more of the aforementioned methods, [22] - selecting the most effective treatment, and

[23] - treating the body of the animal or human being according to the selected treatment.

[24] There is provided a eleventh method for treating an animal or a human being according to the tenth method, wherein during the step of treating the body of the animal or human being according to the selected treatment, the steps according to one or more of first to ninth methods is/are continued. [25] According to the present application, there is also provided a twelfth device for receiving a part of a body of an animal or of a human being, the device comprising the following features:

[26] - a block device of biocompatible material,

[27] - a detachable covering means of biocompatible material,

[28] - at least one receiving area provided by the block device and the covering means. [29] wherein at least the block device comprises duct means extending between at least one outer surface area of the block device and the at least one receiving area. [30] There is provided a thirteenth device according to the twelfth device, wherein the biocompatible material comprises bone mineral material. [31] There is provided a fourteenth device according to the thirteenth device, wherein at least part of the block device comprises bone morphogenetic protein-7 (BMP7). [32] There is provided a fifteen device according to the twelfth device, wherein the biocompatible material comprises titanium or polydimethylsiloxane (PDMS) material. [33] There is provided a sixteenth device according to one of the twelfth device to the fifteenth device, wherein at least part of the block device comprises angiogenesis growth factors. [34] There is provided a seventeenth device according to the sixteenth device, wherein the angiogenesis growth factors are mixed in a biocompatible solvent. [35] There is provided an eighteenth device according to the sixteenth device wherein the angiogenesis growth factors are solid. [36] There is provided a nineteenth device according to one of the twelfth method to the eighteenth method, wherein at least part of the block device comprises stem cells. [37] There is provided a twentieth device according to one of the twelfth method to the nineteenth method, wherein two or more of the at least one receiving areas are provided. [38] There is provided a twenty-first device according to one of the twelfth method to the nineteenth method, wherein the at least one receiving area comprises a detachable filling means. [39] There is provided a twenty-second device according to the twenty-first method, wherein the filling means is a part of the covering means. [40] There is provided a twenty-third device according to the twelfth device, wherein the covering means is mechanically compatible with the block device. [41] There is provided a twenty-fourth device according to the twenty-third device, wherein the covering means comprises biocompatible material. [42] There is provided a twenty-fifth device according to the twenty-fourth device, wherein the biocompatible material comprises bone mineral material. [43] There is provided a twenty-sixth device according to the twenty-fifth device, wherein at least part of the covering means comprises bone morphogenetic protein-7 (BMP7). [44] There is provided a twenty-seventh device according to the twenty-fourth device, wherein the biocompatible material comprises titanium or polydimethylsiloxane

(PDMS) material. [45] There is provided a twenty-eighth device according to one of the twenty-third device to the twenty-seventh device, wherein at least part of the covering device comprises angiogenesis growth factors. [46] There is provided a twenty-ninth device according to the twenty-eighth device, wherein the angiogenesis growth factors are mixed in a biocompatible solvent. [47] There is provided a thirtieth device according to the twenty-eighth device, wherein the angiogenesis growth factors are solid. [48] There is provided a thirty-first device according to one of the twenty-third device to the thirtieth device, wherein at least part of the covering means comprises stem cells. [49] There is provided a thirty-second device according to one of the twenty-third device to the thirty-first device, wherein two or more receiving areas are provided. [50] There is provided a thirty-third device according to one of the twenty-third device to the thirty-first device, wherein at least one internal reservoir is provided in the vicinity of at least one receiving area. [51] There is provided a thirty-fourth device according to the thirty-third device, wherein at least one internal reservoir comprises at least one a duct extending between the reservoir and the receiving area. [52] There is provided a thirty-fifth device according to the thirty-third device or the thirty-fourth device, wherein the duct comprises an operable valve for at least partly opening or at least partly closing the duct. [53] There is provided a thirty-sixth device according to the thirty-fifth device, wherein the valve is operable by external means. [54] There is provided a thirty-seventh device according to one of the thirty-third device to the thirty-sixth device, wherein the duct comprises an operable pump. [55] There is provided a thirty-eighth device according to the thirty-seventh device, wherein the pump is operable by external means. [56] There is provided a thirty-ninth device according to one of the thirty-third device to the thirty-eighth device, wherein the reservoir is pre-filled with agents. [57] According to the present application, there is provided a fortieth block device for use with a covering means, the covering means being mechanically compatible with the block device. [58] There is provided a forty-first block device according to the fortieth block device, wherein the block device comprises biocompatible material. [59] There is provided a forty-second block device according to the forty-first block device, wherein the biocompatible material comprises bone mineral material. [60] There is provided a forty-third block device according to the forty-second block device, wherein at least part of the block device comprises bone morphogenetic protein-7 (BMP7). [61] There is provided a forty-fourth block device according to the forty-first block device, wherein the biocompatible material comprises titanium or poly- dimethylsiloxane (PDMS) material. [62] There is provided a forty-fifth block device according to one of the fortieth block device to the forty-fourth block device, wherein at least part of the block device comprises angiogenesis growth factors. [63] There is provided a forty-sixth block device according to the forty-fifth block device, wherein the angiogenesis growth factors are mixed in a biocompatible solvent. [64] There is provided a forty-seventh block device according to the forty-fifth block device, wherein the angiogenesis growth factors are solid. [65] There is provided a forty-eighth block device according to one of the fortieth block device to the forty-seventh block device, wherein at least part of the block device comprises stem cells. [66] There is provided a forty-ninth block device according to one of the fortieth block device to the forty-eighth block device, wherein two or more receiving areas are provided. [67] There is provided a fiftieth block device according to one of the fortieth block device to the forty-ninth block device, wherein at least one internal reservoir is provided in the vicinity of at least one receiving area. [68] There is provided a fifty-first block device according to the fiftieth block device, wherein at least one internal reservoir comprises at least one a duct extending between the reservoir and the receiving area. [69] There is provided a fifty-second block device according to the fiftieth block device or the fifty-first block device, wherein the duct comprises an operable valve for at least partly opening or at least partly closing the duct. [70] There is provided a fifty-third block device according to the fifty-second block device, wherein the valve is operable by external means. [71] There is provided a fifty-fourth block device according to one of the fifty-first block device to the fifty-third block device, wherein the duct comprises an operable pump. [72] There is provided a fifty-fifth block device according to the fifty-fourth block device, wherein the pump is operable by external means. [73] There is provided a fifty-sixth block device according to one of the fiftieth block device to the fifty-fifth block device, wherein the reservoir is pre-filled with agents. [74] According to present application, there is provided a fifty-seventh method comprising the following steps: [75] - implanting a receptacle device at a predetermined location of the body, the receptacle device being formed to receive at least one predetermined part of the body, [76] - waiting a predetermined time for the predetermined

[77] part of the body being received in the receptacle device,

[78] - evaluating the predetermined part of the body being received in the receptacle device.

[79] There is provided a fifty-eighth method according to the fifty-sixth method, wherein the receptacle device is left such a time within the body that at least one contact area for receiving the extracted part of the body is vascularized at the time of implanting the extracted part of the body into the receptacle device.

[80] There is provided a fifty-ninth method according to the fifty-seventh method or the fifty-eighth method, wherein at least one part of the receptacle device is replaced by a covering means before the step of waiting a predetermined time for the predetermined part of the body being received in the receptacle device.

[81] There is provided a sixtieth method according to one of the fifty-seventh method to the fifty-ninth method, wherein at least one part of the receptacle device is replaced by a covering means after the step of waiting a predetermined time for the predetermined part of the body being received in the receptacle device and before the step of evaluating the predetermined part of the body being received in the receptacle device.

[82] There is provided a sixty-first method according to the fifty-seventh method to the sixtieth method, wherein the step of implanting the receptacle device at the location of the body is done such that the receptacle is covered fully under a skin portion of the body.

[83] There is provided a sixty-second method according to one of the fifty-seventh method to the sixty-first method, wherein the step of implanting the receptacle device at the location of the body is done such that the receptacle is partially underneath a skin portion of the body, partially protruding from the body.

[84] There is provided a sixty-third method according to one of the fifty-seventh method to the sixty-second method, wherein the step of evaluating the predetermined part of the body being received in the receptacle device includes a step of purging liquid from the treated part of the body and a step of measuring predetermined characteristics of the purged liquid.

[85] There is provided a sixty-fourth method according to one of the fifty-seventh method to the sixty-third method, wherein the step of evaluating the predetermined part of the body being received in the receptacle device includes an optical analysis and verification or an analysis and verification with electro-magnetic radiation.

[86] According to the present application, there is provided a sixty-fifth method for treating an animal or a human being, the method comprising the following steps:

[87] - performing the steps of testing the effectiveness of two or more treatments on two or more parts of a body of an animal or of a human being at the same time with the steps according to one or more of the aforementioned methods,

[88] - selecting the most effective treatment, and

[89] - treating the body of the animal or human being according to the selected treatment. [90] According to the present application, there is provided a sixty-sixth device for receiving a part of a body of an animal or of a human being, the device comprising the following features:

[91] - a block device of biocompatible material,

[92] - at least one receiving area provided by the block device,

[93] wherein the block device comprises duct means extending between at least one outer surface area of the block device and the at least one receiving area. [94] There is provided a sixty-seventh device according to the sixty-sixth device, wherein a detachable covering means of biocompatible material is provided on the block device. [95] There is provided a sixty-eighth device according to the sixty-seventh device, wherein at least one receiving area provided by the covering means. [96] There is provided a sixty-ninth device according to one of the sixty-sixth device to the sixty-eighth device, wherein the biocompatible material comprises bone mineral material. [97] There is provided a seventieth device according to the sixty-ninth device, wherein at least part of the block device comprises bone morphogenetic protein-7 (BMP7). [98] There is provided a seventy-first device according to one of the sixty-sixth device to the sixty-eighth device, wherein the biocompatible material comprises titanium or polydimethylsiloxane (PDMS) material. [99] There is provided a seventy-second device according to one of the sixty-sixth device to the seventy-first device, wherein at least part of the block device comprises an- giogenesis growth factors, [lϋϋ] There is provided a seventy-third device according to the seventy-second device, wherein the angiogenesis growth factors are mixed in a biocompatible solvent. [ 101] There is provided a seventy-fourth device according to the seventy-third device, wherein the angiogenesis growth factors are solid. [102] There is provided a seventy-fifth device according to one of the sixty-sixth device to the seventy-fourth device, wherein at least part of the block device comprises stem cells. [103] There is provided a seventy-sixth device according to one of the sixty-sixth device to the seventy-fifth device, wherein two or more of the at least one receiving areas are provided. [104] There is provided a seventy-seventh device according to one of the sixty-sixth device to the seventy-sixth device, wherein the covering means is mechanically compatible with the block device. [105] There is provided a seventy-eighth device according to the seventy-seventh device, wherein the covering means comprises biocompatible material. [106] There is provided a seventy-ninth device according to the seventy-eighth device, wherein the biocompatible material comprises bone mineral material. [107] There is provided an eighth device according to the seventy-ninth device, wherein at least part of the covering means comprises bone morphogenetic protein-7 (BMP7). [108] There is provided an eighty-first device according to the seventy-eighth device, wherein the biocompatible material comprises titanium or polydimethylsiloxane

(PDMS) material. [109] There is provided an eighty-second device according to one of the sixty-seventh device to the eighty-first device, wherein at least part of the covering means comprises angiogenesis growth factors. [110] There is provided an eighty-third device according to the eighty-second device, wherein the angiogenesis growth factors are mixed in a biocompatible solvent. [I l l] There is provided an eighty-fourth device according to the eighty-second device, wherein the angiogenesis growth factors are solid. [112] There is provided an eighty-fifth device according to one of the seventy-seventh device to the eighty-fourth device, wherein at least part of the covering means comprises stem cells. [113] There is provided an eighty-sixth device according to one of the seventy-sixth device to the eighty-fifth device, wherein two or more receiving areas are provided. [114] There is provided an eighty-seventh device according to one of the seventy-seventh device to the eighty-sixth device, wherein at least one internal reservoir is provided in the vicinity of at least one receiving area. [115] There is provided an eighty-eighth device according to the eighty-seventh device, wherein at least one internal reservoir comprises at least one a duct extending between the reservoir and the receiving area. [116] There is provided an eighty-ninth device according to the eighty-eighth device, wherein the duct comprises an operable valve for at least partly opening or at least partly closing the duct. [117] There is provided a ninetieth device according to the eighty-ninth device, wherein the valve is operable by external means. [118] There is provided a ninety-first device according to one of the eighty-eighth device to the ninetieth device, wherein the duct comprises an operable pump. [119] There is provided a ninety-second device according to the ninety-first device, wherein the pump is operable by external means. [120] There is provided a ninety-third device according to one of the eighty-seventh device to the ninety-second device, wherein the reservoir is pre-filled with agents. [121] There is provided a ninety-fourth device according to one of the seventy-seventh device to the ninety-third device, wherein the block device is mechanically compatible with the covering means. [122] There is provided a ninety-fifth device according to the ninety-fourth device, wherein the block device comprises biocompatible material. [123] There is provided a ninety-sixth device according to the ninety-fifth device, wherein the biocompatible material comprises bone mineral material. [124] There is provided a ninety-seventh device according to the ninety-sixth device, wherein at least part of the block device comprises bone morphogenetic protein-7

(BMP7). [125] There is provided a ninety-eighth device according to the ninety-fifth device, wherein the biocompatible material comprises titanium or polydimethylsiloxane (PDMS) material. [126] There is provided a ninety-ninth device according to one of the ninety-fourth device to the ninety-eighth device, wherein at least part of the block device comprises an- giogenesis growth factors. [127] There is provided a one hundredth device according to the ninety-ninth device, wherein the angiogenesis growth factors are mixed in a biocompatible solvent. [128] There is provided a one hundred-first device according to the one hundredth device, wherein the angiogenesis growth factors are solid. [129] There is provided a one hundred-second device according to one of the ninety-fourth device to the one hundred-first device, wherein at least part of the block device comprises

[130] stem cells. [131] There is provided a one hundred-third device according to one of the ninety-fourth device to the one hundred-second device, wherein two or more receiving areas are provided. [132] There is provided a one hundred-fourth device according to one of the ninety-fourth device to the one hundred-third device, wherein at least one internal reservoir is provided in the vicinity of at least one receiving area. [133] There is provided a one hundred-fifth device according to the one hundred-fourth device, wherein at least one internal reservoir comprises at least one a duct extending between the reservoir and the receiving area. [134] There is provided a one hundred-sixth device according to the one hundred-fifth device, wherein the duct comprises an operable valve for at least partly opening or at least partly closing the duct. [135] There is provided a one hundred-seventh device according to the one hundred-sixth device, wherein the valve is operable by remote external means.

[136] There is provided a one hundred-eighth device according to one of the one hundred- sixth device to the one hundred seventh device, wherein the duct comprises an operable pump.

[137] There is provided a one hundred-ninth device according to the one hundred-eighth, wherein the pump is operable by external means.

[138] There is provided a one hundred-tenth device according to one of the one hundred- fifth device to the one hundred-ninth device, wherein the reservoir is pre-filled with agents.

[139] According to present application, there is provided a one hundred-eleventh method comprising the following steps:

[140] - implanting a receptacle device at a predetermined

[141] location of a body,

[142] - waiting a predetermined time for the receptacle device to be vascularized, and

[143] - analyzing the blood stream through the vascularized receptacle device with optical means and / or with electromagnetical radiation.

[144] There is provided a one hundred-twelfth method according to the one hundred- eleventh method, wherein the analysis is done from outside of the body.

[145] There is provided a one hundred-thirteenth vascularized medical device that is implanted into a living body of an animal or a human being, the medical device comprising:

[146] - a block container comprising at least one receiving portion,

[147] - a cover that is attached to the block container for enclosing the at least one receiving portion,

[148] - a duct connecting between an opening of the block container and the at least one receiving portion, and

[149] - a blood vessel being connected to the at least one receiving portion through the opening.

[150] The duct (e.g. a first duct, a second duct) can be configured to be vascularized with blood vessels.

[151] The device and parts of it may comprise 'biological material¹ and 'biocompatible material¹. Throughout the application, 'biological material¹ may comprise bone mineral material and substances such as bone morphogenetic protein-7 (BMP7) or cells such as stem cells which may be added to stimulate development of the bone mineral block into solid bone when implanted in the body. Throughout the application, 'biocompatible material¹ may comprise biocompatible polymers e.g. polydimethylsiloxane (PDMS) as well as titanium or other biocompatible substances. 'Biocompatible material¹ is materials that when implanted into the body of a human or of an animal, will not elicit a host immune response that results in the rejection of the implant or internal injuries to the host at the implant site through unwanted inflammatory processes. [152] The device may comprise angiogenesis growth factors which are mixed in a biocompatible solvent, in a solution, in a gel or which are provided in solid form. The device may further comprise stem cells, endothelium activating factors like in- terleukin- 1 β or TNFα, selectins, integrins, chemokines, antibodies, extracellular matrix.

[153] In the present application, the step of 'waiting¹ does not mean that nothing is done but it expresses that there may be some time between implanting the device and the step of evaluating the content of the device. In the case of evaluating simple liquids like blood or body liquid the delay between implanting and evaluation may be rather short. In the case of catching certain cells, the delay may be longer. The receptacle device is left such a time within the body that at least one contact area for receiving the moved part of the body is vascularized, which means that it has built up blood vessels for supplying the device with blood of the body, at the time of implanting the moved (portion) part of the body into the receptacle device or after the predetermined part of the body has moved in. At least one part of the receptacle device may be replaced by a covering means before the step of waiting a predetermined time for the predetermined part of the body being received in the receptacle device.

[154] At least one part of the receptacle device is replaced by a covering means after the step of waiting a predetermined time for the predetermined part of the body being received in the receptacle device and before the step of evaluating the predetermined part of the body being 5 received in the receptacle device. Other features of the device used for the latter method may be chosen similar to the device used for the methods which were described initially. This applies to all aspects of the respective devices, such as materials, appliances, parts, components, etc. Information on reservoirs and valves exemplified, inter alia, by US2007/0016163 and US 2007/0036835, which are incorporated here by reference. Proprietary reservoir arrays, drugs or biosensors can be stored within the reservoirs, thereby protecting these reservoir contents from the environment (e.g., a patient's body) until they are needed. Preprogrammed microprocessors, wireless telemetry, or sensor feedback loops can provide active control of the opening of the reservoirs to initiate drug release or expose enclosed biosensors, thus giving the physician or patient greater control over therapy. Alternatively, layers or other combinations of controlled release, polymeric matrices can provide passive control of the release or exposure of the reservoir contents in applications that do not require microprocessors or power sources. When one provides a receiving area, which is connected with blood vessels, pressure is likely to build up in the reservoir, the pressure being caused by interstitial fluid collection build-up. This is due to fluid that leaves the blood vessel and enters the receiving area. A connecting drainage reservoir may be provided for that, the drainage reservoir being connected with the receiving area by a special duct. Further, a drainage duct leading from the drainage reservoir to the outside of the device may be provided.

[155] Some advantages of the subject matter are provided below. This generic method and design to create in vivo vascularized laboratory devices is the result of the search for innovative solutions to treat cancer patients resistant to standard treatments. Although the subject matter can also be used in other non-cancer domains, its nature and functions are well understood from its origin in solving problems associated with treatment-resistant cancer.

[156] Right from the moment of pathological diagnosis from biopsy samples, the application provides for a better characterization within the existing classification system for naming diseases. The nosology of this application is based on a historical nomenclature of anatomical and histological terms. This application thus enables the experimenter to uncover different underlying molecular mechanisms that may result in the same histological or anatomical appearance. More importantly, it allows a real-time observation and matching of our fixed nomenclature of diseases does with the reality of ongoing changes in diseases over time. Hence disease ¹X¹ over time may evolve into 1Xa¹ or ¹Xb¹ in different individuals and these important transformations can now be reflected in the standard name ¹X¹. This makes it possible to avoid blind lumping of apparently similar 5 but actually different diseases in clinical trials. Hence the strategy of clinical trials solves the problem of treatment-resistant cancer cases at the individual level. The application provides a technology that will allow us to detect very early response of cancer to treatment. Current imaging techniques like Magnetic Resonance Imaging (MRI), CT Scans and standard X-rays use changes in tumor size as the criteria for anatomical response to therapy. But major changes in tumor volume tend to occur late after the start of treatment and this can be observed. Hence, treatment is considered effective when there is a large decrease in tumor size indicated by consecutive images measured 3 to 4 months later. The application provides a reduction in time of diagnosis in the face of fast-growing cancers that are repeatedly resistant to standard treatments based on clinical trial data. More cutting-edge technologies like FDG-PET scan and Diffusion-weighted MRI may be able to cut down the waiting period to a week or more depending on tumor type, but no technology exists to date to reliably detect whether the tumor is responding to therapy or not within a day or two. This time factor for early detection of tumor responsiveness is clearly important since the earlier we know that a tumor is not responding to certain drugs, the earlier we can switch treatment strategies to find the right therapeutic drug/s for the patient. Instead of waiting weeks later when the patient's functional status has already deteriorated from disease progression and he or she may no longer be able to tolerate further treatment. Moreover FDG-PET scan and Diffusion-weighted MRI can be used to indirectly predict tumor responsiveness by measuring changes in metabolic activity and intracellular water movement respectively. The application provides a method or technology to provide us a direct assessment of tumor apoptosis or programmed cell death in the human body, which is the gold standard of treatment efficacy. This is true also for blood malignancies like leukemia, which is more 'fluid¹ in nature and does not exist as a solid tumor.

[157] The application provides a method which, once the cancer in the body is being treated via intravascular administration of therapeutic agents, there is more than only one chance of getting it right. If the cancerous tissues in one receiving area do not respond, then one is left knowing whether the biological profile of the tumor has changed significantly from the failed treatment or not by simply referring to another receiving area. One is also not left without knowledge of whether the failure is due to inadequate concentrations of therapeutic agent/s reaching the cancer cells in the tumor, i.e. pharmacokinetics, or whether the failure is due to problems associated with drug- target interactions i.e. pharmacodynamics. Several receiving areas that are run under different conditions provide different information at the same time. Hence in the standard of care according to the application, once treatment is administered and the cancer does not respond, we are not left with unknowns. The default assumption then almost always leans towards pharmacodynamic inefficacy and the tumor is then rightly or wrongly considered to be resistant to that particular therapeutic agent/s without convincing proof.

[158] Also, the application enables the use of cancer cell cultures or animal cancer models to predict cancer response to treatment suffers from difficulty in exactly matching the actual tumor and its environment in the human body. These techniques may be useful clinically to treat patients at the bedside.

[159] This method and subject matter of creating novel vascularized laboratory devices in vivo seeks to resolve all the aforementioned inadequacies present in the state-of-the-art treatment of cancer. Other novel in vivo vascularized laboratory devices for analytical purposes besides cancer can also be created using the same method to generate vascularization of the device in vivo. Tissue engineering work has been done in humans and pigs on growing a vascularized bone graft in vivo and transplanting it thereafter to repair bone defects. However, this is not a method for creating vascularized laboratory devices in vivo as described by this application.

[160] This application documents a generic method and design for creating vascularized laboratory devices in vivo. These devices may be constructed in different scales of science, that is macro- and micro-sciences, using the same method and design. Materials used to fabricate the scaffold of a device can be biological materials e.g. bone or biocompatible materials e.g. polydimethylsiloxane (PDMS) or titanium. The device is initially filled with angiogenesis growth factors that may be mixed in a biocompatible solvent or solid, with or without stem cells. It is then implanted in the body to generate new blood vessels in it. The in vivo vascularized device may be used for different analytical purposes. Per se, it may be used as a base for analysis of blood vessels and blood contents. A unique detachable cover and reciprocal plug-cavity design creates spaces in the device to receive and house transplanted living tissues, e.g. cancerous tissue, or cells. These living tissues or cells are kept viable in the vascularized chambers of the implanted device hence making them amenable to experimental analysis in vivo.

[161] There are further advantages of the subject matter provided below. This generic method and design to create in vivo vascularized laboratory devices can also be utilized for other biological purposes as described below. The subject matter provides a tool and a technique to allow transplanted living materials e.g. cells, tissues or organs to grow viably in the body in separate implanted compartments. The expression 'separate implanted compartments' includes implanted compartments made to locate in or at any part of the body but are not at the beginning of implantation, a natural continuous integral part of that location. This application provides an example method and an example design for doing so by means of vascularizing such compartments in the body and bringing living materials of interest into close proximity with the blood vessels of the implanted device. This approximation maintains the viability of the living material. The advantages of keeping living materials alive in separate implanted compartments in vivo are manifold.

[162] 1. Living Histology and Physiology

[163] The subject matter confers new abilities to creating and maintaining a standard row of living materials in the body for observation and study of their dynamic characteristics, which is an in vivo living and dynamic histology. This would help to better define and refine existing classification systems and nosologies. The subject matter applies to creating a new method to directly examine dynamic events of living bone marrow histology and physiology. At the present moment, bone marrow histology and physiology is poorly understood due to lack of methods for direct assessment since normal bone marrow is surrounded by thick cortical bone that impedes direct observation and experimental manipulation. Observation may be performed by:

[164] a) Instruments for optical analysis e.g. direct microscopic imaging or confocal microscopic imaging or fluorescence imaging or bioluminescence imaging, or intravital videomicroscopy, etc;

[165] b) Instruments that use electro-magnetic radiation like X-Ray, CT Scan, MRI, NMR, Positron Emission Tomography (PET) imaging, thermo imaging, infrared imaging etc, or [166] c) mass spectrophotometer.

[167] 2. Tissue engineering and transplantation

[168] The subject matter confers new abilities to separation and house living materials in individual vascularized chambers without contact influences, chemical and molecular influences from the surrounding tissue cells in which they are embedded. The same is true if growth and development of the living materials in their own unique vascularized space or chambers is desired. This confers the ability to grow and develop a wide variety of cellular or tissue grafts in vivo at any location in preparation for future transplantation in the same body. Graft rejection from the immune system is not expected to occur unless there is auto-immunity and if present can be detected at the very early stages of viability and growth. Possible methods of observation are as described in 1 ) above.

[169] 3. Normal tissue and Disease Models

[170] The subject matter confers new abilities to maintaining viability, growth or development of living tissues that by nature of being in vivo and having their own individual separate microeiivironments, better replicating the molecular and morphogenic behaviors and microenvironmental interactions of their cellular or tissue counterparts elsewhere in the same body. In essence, more accurate model systems for the study of normal cellular/tissue/organ development and pathogenesis of diseases are created. Possible methods of observation are as described in 1 ) above.

[171] 4. In vivo Experimentation:

[172] The subject matter confers new abilities to performing in vivo experimentation and analysis of living materials in similar microeiivironments without involving their normal or diseased counterpart elsewhere in the same body. In vivo experimentation and analysis can be done with different treatment or analytical agents. The behavioral responses of the treated living materials simulate and predict for the same responses to occur in their normal or diseased counterpart elsewhere in the same body should the latter be treated similarly. Perform in vivo experimentation and analysis of living materials in different pre-determined microeiivironments or extracellular matrices for living materials with migratory capabilities like leukoctyes, circulating tumor cells etc. These cells normally migrate from one microenvironment to another. Their behaviors in different microeiivironments can be recreated and tested by this method. Possible methods of observation are as described in 1 ) above.

[173] 5. Diagnostic and Prognostic studies

[174] The subject matter confers new abilities to better diagnosing and prognosticating the normal or diseased state of health of a human body or of an animal body, through a combination of the aforementioned observation, study, characterization, modeling and in vivo experimentation steps. For example, circulating tumor cells in the blood of cancer patients can be attracted to attach to activated endothelium of the vascularized chamber, and then be attracted to migrate and extravasate pass the endothelial wall of the capillary by chemokines in the chamber contained within different tissue-specific extracellular matrices or tissue specific extracts or living tissues. Detection of this phenomenon prognosticates for different organ-specific metastases in patients with circulating tumor cells in the blood only. A further step would include performing in vivo experimentation using different treatment or analytical agents to better characterize and diagnose the metastatic cells for treatment of the whole body. Possible methods of observation are as described in 1 ) above.

[175] 6. Early detection of treatment response

[176] The subject matter confers new abilities to detecting early molecular-cellular changes or response of the implanted living tissues when treatment is given to the whole body of a human or animal, via direct or intravital microscopy techniques or other fluorescent bio-imaging techniques. For example, in the treatment of cancer, this application provides a technology that will allow us to detect very early response of different organ-specific metastatic tissues to treatment by directly imaging for apoptosis of the living tissues in the chambers while the patient is being infused with chemotherapy. If apoptosis is not observed in the implanted chambers, the application allows for further in vivo experimentation, as afore-described, to search for the next best drug combination to be given to the patient as a whole. This method is also possible for blood malignancies like leukemia which is more 'fluid¹ in nature since the application may be in the form of a bone housing the diseased element. To date, no technology exists to directly image for in vivo molecular-cellular treatment efficacy when chemotherapy is being administered to the leukemic patient. And no technology exists to allow in vivo experimentation and direct observation of responses, as afore- described, on diseased bone marrow.

[177] This time factor for early detection of cancer responsiveness is clearly important since the earlier we know that the cancer is not responding to certain drugs, the earlier we can switch treatment strategies to find the right therapeutic drug/s for the patient. Instead of waiting weeks or months later when the patient's functional status has already deteriorated from disease progression and he or she may no longer be able to tolerate further treatment. Possible methods of observation are as described in 1 ) above.

[178] 7. Direct Pharmacodynamic assessment of treatment efficacy

[179] The subject matter confers new abilities to assessing directly for drug-target interactions or pharmacodynamic efficacy of different treatment agents on their targeted molecules in living cells or tissue. If pharmacodynamic efficacy of a treatment agent is proven by the application and upon treating the patient as a whole with the same agent. there is no response, then problems with inadequate concentrations of therapeutic agent/s reaching the cancer cells in the tumor, i. e. pharmacokinetics should be investigated. Possible methods of observation are as described in 1 ) above.

[180] 8. Angiogenesis and hematological studies

[181] The subject matter confers new abilities to better understanding the mechanisms of angiogenesis, thrombus formation and other hematological studies through a combination of the aforementioned observation, study, characterization, modeling and in vivo experimentation steps on blood vessels. Possible methods of observation are as described in 1 ) above. 5

[182] Although tissue engineering work has been done in humans and pigs on growing a vascularized bone graft in vivo and transplanting it thereafter to repair bone defects, this is however not a method for creating vascularized laboratory devices in vivo as described by this application.

[183] BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

[184] Fig. 1 illustrates a bone device with a first cover according to the application,

[185] Fig. 2 illustrates a vascularized bone device,

[186] Fig. 3 illustrates a further vascularized bone device with a second cover according to the application,

[187] Fig. 4 illustrates an example of observation and monitoring in vivo by a minimally invasive microscopic probe,

[188] Fig. 5 illustrates a further bone device with a third cover integrated with internal reservoirs interconnected by valves and ducts,

[189] Fig. 6 illustrates a polydimethylsiloxane (PDMS) MEMS (Micro-Electro-Mechanical Systems ) device of the application,

[190] Fig. 7 illustrates vascularization of the micro-device in vivo of Fig. 6,

[191] Fig. 8 illustrates a further bone device with another cover with biocompatible membranes,

[192] Fig. 9 illustrates an example of observation and monitoring of response to treatment in vivo by a minimally invasive microscopic probe,

[193] Fig. 10 illustrates a further bone device with another cover containing internal reservoirs with interconnecting valves and ducts,

[194] Fig. 11 illustrates a bone device with integrated optoelectronic components,

[195] Fig. 12 illustrates a bone device with external optoelectronic components,

[196] Fig. 13 illustrates a bone device with both integrated optoelectronic components and external optoelectronic components,

[197] Fig. 14 illustrates extravasations of circulating tumors cells into the device,

[198] Fig. 15 illustrates an introduction of the chemokine SDF-I (CXCL12) into the device. [199] Fig. 16 illustrates micro-metastatic tissue growth in the device.

[200] Fig. 17 illustrates a method of making a medical device for implanting into a living body of an animal or a human being,

[201] Fig. 18 illustrates a further method of using a medical device for implanting into a living body of an animal or a human being, and

[202] Fig. 19 illustrates a method of using a vascularized medical device.

[203] DETAILED DESCRIPTION

[204] In the following description, details are provided to describe the embodiments of the applications. It shall be apparent to one skilled in the art, however, that the embodiments may be practiced without such details.

[205] Figs. 1 and 2 illustrate a first embodiment.

[206] Fig. 1 illustrates a bone device 28 with a first cover 20 according to the application. The bone device 28 comprises a first cover 20 and a block container 26. The first cover 20 comprises a rectangular block 22 protruding from a broad surface 21 of the first cover 20 in a centre position. The block container 26 comprises a receiving portion 24 in the form of a cavity. The receiving portion 24 is provided in on a broad surface 23 of the block container 26 in a centre position, which is corresponding to the broad surface 21 of the first cover 20. The receiving portion 24 is configured to receive and secure the rectangular block 22 inside the receiving portion 24. In other words, the receiving portion 24 comprises a comparable shape of the rectangular block 22, which resembles a plug-socket matching mechanism. A depth of the receiving portion 24 is greater than a height of the rectangular block 22 such that there is empty space left in the receiving portion 24 when the rectangular block 22 is fully inserted into the receiving portion 24. The block container 26 further comprises a first duct 19 that connects a first opening 25 on an outer surface 27 of the block container 26 to the receiving portion 24. There is a second opening 31 provided on an opposite surface 29 of the block container 26 such that the receiving portion 24 is also connected to exterior of the bone device 28 by a second duct 18. In other words, there is a channel provided from the first openings 25, the first duct 19, the receiving portion 24, the second duct 18 to the second opening 31 between two opposite sides 27, 29.

[207] Fig. 1 further illustrates a closed bone device 30. The closed bone device 30 comprises the first cover 20 and the block container 26 that are attached to each other. In other words, the broad surface 21 of the first cover 20 is in contact with the broad surface 23 of the block container 26, while the rectangular block 22 is inserted into the receiving portion 24 with tight fitting. Consequently, the receiving portion 24 is sealed by the first cover 20 at the broad surface 23 and also is connected to the exterior via the duct 25.

[208] Fig. 1 also illustrates an implanted bone device 34 under a skin 32 of a living body of a human being. The implanted bone device 34 comprises the closed bone device 30 and the receiving portion 24 is connected to the living body of a human being via the duct 25. The implanted bone device 34 is provided between an artery and a vein. The first opening 25 and the second opening 31 are positioned neighboring to the artery and the vein under the skin 32 respectively.

[209] The bone device 28 is made of bone mineral material (i. e. bone mineral block). The closed bone device 30 is firstly impregnated with angiogenesis growth factors with stem cells and is subsequently implanted in vivo. Bone morphogenetic protein-7 (BMP7) is also added to stimulate development of the bone device 28. The closed bone device 30 develops into solid bone structure after being implanted under the skin of a living body of a human being after a predetermined period of time.

[210] Fig. 2 illustrates a vascularized bone device 34, which is developed from the implanted bone device 34. The vascularized bone device 34 is provided below the skin 32 and the first cover 20 is closely attached to the block container 26 such that the receiving portion 24 is sealed. There are further developed blood vessels connecting the receiving portion 24 to the exterior of the vascularized bone device 34. In other words, an artery 38 is provided connecting the first opening 25 to the receiving portion 24 and a vein 36 is also provided connecting the second opening 31 to the receiving portion 24.

[211] Fig. 2 further illustrates that the vascularized bone device 34 is opened by exposing the receiving portion 24. Some diseased cells 40 which are extracted from an infected part of a human being is put inside the receiving portion 24. The first cover 20 is later attached back to the block container 26 such that the receiving portion 24 is sealed off. The diseased cells 40 are provided with blood supply from the artery 38 to the vein 36 on the opposite surfaces 27, 29 respectively.

[212] The bone device 28 is made from bone mineral material extracted from a part of the body the human being so that the living body of the human being does not reject the bone device 28 as being foreign after that the bone device 28 is implanted into the living body. The bone device 28 is filled with arteriogenesis and/or arteriogenesis growth factors mixed with a biocompatible solvent with stem cells. Bone morphogenetic protein-7 (BMP7) is added to stimulate the development of the bone device 28 into solid bone after the bone device 28 is implanted under the skin 32 of the body of the human being. The first cover 20 is made polydimethylsiloxane (PDMS), which is a type of biocompatible material.

[213] The first cover is detachable so that the cells (e.g. diseased cells 40) can be deposited or removed from the receiving portion 24. Inspection and application of treatment material can also be through an opened receiving portion 24 conveniently.

[214] The bone device 28 is provided and used according to the following steps as an in vivo vascularized laboratory device.

[215] Firstly, both the bone device is fabricated by using polydimethylsiloxane (PDMS), including the first cover 20 and the block container 26 . The first cover 20 is made with similar dimensions as the receiving portion 24 of the block container 26 such that the first cover is both detachable from the first cover 20 and also provide good sealing enclosure to the receiving portion 24.

[216] Secondly, the receiving portion 24 is filled with arteriogenesis and angiogenesis growth factors that are mixed in a biocompatible solvent with stem cells.

[217] Thirdly, the first cover 20 is attached to the block container 26 such that the first cover 20 encloses the receiving portion 24.

[218] Fourthly, The device is surgically implanted in the body by a surgery.

[219] Fifthly, a period of waiting time is provided such that the bone device 28 is vascularized with the blood vessels 38, 36 connecting the receiving portion 24 to the exterior of the bond device 28.

[220] Sixthly, the first cover 20 is detached from the vascularized bone device 34 by a surgery. The diseased cells 40 (e.g. infected tissues, cancerous tissues, diseased bone, etc ) are transplanted into the receiving portion 24.

[221] Seventhly, the vascularized bone device 34 with the diseased cells 40 are put back to the human being. At the same time, therapeutic and analytical agents are also injected into the receiving portion 24. The first cover 20 is put back and encloses the receiving portion 24.

[222] Eighthly, a clinical researcher performs inspection on the effect of the therapeutic agent on the diseased cells 40 by using a variety of in vivo bio-imaging techniques, such as intravital videomicroscopy, fluorescence microscopic imaging, optical coherence topography, etc.

[223] The diseased cells 40 can not only be put into the receiving portion 24 by transplantation, but also can be extravasated and migrated into the receiving portion 24.

[224] The bond device 28 can alternatively be made in a single integral form. In other words, the block container 26 with the receiving portion 24 pre-filled with the diseased cells 40 and sealed off with a cover. The cells are provided with nutrition so that they 40 are alive after being implanted inside the body of the human being. The artery 38 and the vein 36 are later developed and connected to ducts of the bond device in single integral form, being vascularized. When needed, the bond device 28 in single integral form can be cut open for inspection.

[225] The bone device 28 including the first cover 20 can be made in macro-scale or micro-scale. Macro-scale refers to dimensions (e.g. overall length) of the bone device 2 8 to be larger than 1000 micrometers. Micro-scale refers to dimensions (e.g. overall length) of the bone device 28 to be less than 1000 micrometers. [226] The bone device 28 can be made in the form of PDMS microchip device. Fabrication or making the bone device 28 may broadly include steps of designing and fabricating a silicon wafer, pouring PDMS prepolymer on the silicon wafer and curing, peeling the PDMS replica from the silicon master, exposing the PDMS replica to oxygen plasma and attaching the cured the PDMS replica to a mating surface.

[227] The first opening 25 and the second opening 31 can be made as small orifices such that circulating cells (e.g. tumor cells) can be kept inside the receiving portion 24 for medical treatment, rather than escaping from the bone device 28.

[228] The bone device 28 can comprise multiple receiving portions that are can be individually sealed. A same cover or multiple covers can also seal the multiple receiving portions. The receiving portion 24 can also be in the form of porous structure or ducts. The receiving portion/s can be sealed by plug/s that are either integral with or separate from the first cover broad surface 21 of the first cover 20 for the attaching.

[229] The first cover 20 can be attached to the block container 26 by fasten means structure, adhesive, or in combination of any of these. For example, the first cover 20 can be tightened to the block container 26 by screws. The first cover 20 can also be tightened to the block container 26 by slot/catch mechanism. A biocompatible adhesive is also useful to be spread over the broad surface 23 of the block container 26 and the broad surface of the first cover 21 for binding.

[230] The first cover can alternatively be made directly by a piece of bone of the body of the human being or by titanium.

[231] The receiving portion 24 can alternatively be filled with pieces of bones that are affected by diseases like metastatic solid cancers to the bone, leukemia, lymphoma, multiple myeloma, etc.

[232] The arteriogenesis and angiogenesis growth factors can alternatively be mixed in a biocompatible solution, gel or solid.

[233] The stem cells can also be left out with being filled inside the receiving portion 24 is filled with arteriogenesis and angiogenesis growth factors mixed in a biocompatible solvent.

[234] The first duct 19 and the second duct 18 can be provided various positions of the bone device 28, instead of being aligned in an cylindrical axis as shown in Fig. 1. When arranged in the various profiles (e.g. in a V-profile), the artery 38 and the vein 36 can be developed to connect the receiving portion 24.

[235] The bone device 28 can not only be provided in a rectangular block form, but also can take various 3-D forms, such as a sphere, a cube, an egg form, a cylinder, etc.

[236] The first cover 20 can alternatively be made to cover the receiving portion 24 partially. The partially covered receiving portion 24 provides drainage of excessive fluids when the bone device 28 is inside the living body. [237] Figs. 3 and 4 illustrate a second embodiment. The second embodiment comprises parts that are similar to the first embodiment in Figs. 1 and 2. The similar parts are labeled with same reference numerals or the same reference numerals with prime symbols respectively. Descriptions of the similar parts on structures, functions, advantages, and methods of the similar parts are hereby incorporated by reference.

[238] Fig. 3 illustrates a further bone device 48 with a second cover 42 according to the application. The further bone device 48 is vascularized with an artery 38 and a vein 36. T he second cover 42 comprises biocompatible membrane 44 in a central position of the second cover 42 on the broad surface 21. The membrane 44 allows injection of the therapeutic and/or biocompatible agents by a needle 46 into the receiving portion 24 of a vascularized bone device 48 with the membrane 44. Alternatively, an external tubing mechanism attached to the second cover 42 can provide the injection of the therapeutic and/or bio-compatible agents for in vivo experimental analysis on the translated diseased cells 40.

[239] Fig. 4 illustrates an example of observation and monitoring in vivo by a minimally invasive microscopic probe 50. The microscopic probe 50 pierce through the membrane 44 so that an external apparatus can capture the images of the diseased cell 40, which is being treated by the therapeutic agent/s.

[240] The membrane 44 can alternatively be provided on the block container 26 if the second cover 42 comprises a reservoir or other structures.

[241] Figs. 5 illustrates a third embodiment. The third embodiment comprises parts that are similar to the previous embodiments in Figs. 1-4. The similar parts are labeled with same reference numerals or the same reference numerals with prime symbols respectively. Descriptions of the similar parts on structures, functions, advantages, and methods of the similar parts are hereby incorporated by reference.

[242] Fig. 5 illustrates a further bone device 58 with a third cover 52 integrated with internal reservoirs 54 interconnected by valves 56 and ducts 58. The first internal reservoir 54 and the second internal reservoir 54' are pre-filled with therapeutic and/or analytical agents while the valves 56 and ducts 58 are provided to channel these agents into the receiving portion 24 for in vivo experimental analysis.

[243] Figs. 6 and 7 illustrates a fourth embodiment. The fourth embodiment comprises parts that are similar to the previous embodiments in Figs. 1-5. The similar parts are labeled with same reference numerals or the same reference numerals with prime symbols respectively. Descriptions of the similar parts on structures, functions, advantages, and methods of the similar parts are hereby incorporated by reference.

[244] Fig. 6 illustrates a polydimethylsiloxane (PDMS) MEMS (Micro-Electro-Mechanical Systems ) device 75 of the application. The micro device 75 comprises a cover 60 and a block container 71, the cover 60 being receivable by the block container 71. There is a square-profiled protruding block 64 and a circular protruding block 66 provided on a board surface 21 of the cover 60. The block container 71 comprises a square-profiled receiving portion 70 and a circular receiving portion 77 on a broad surface 23. The square-profiled protruding block 64 and the circular protruding block 66 are receivable by the square-profiled receiving portion 70 and the circular receiving portion 77 in the block container 71 for enclosing. The square-profiled receiving portion 70 comprises a front opening 68 and a back opening 72 that are connected to the square-profiled receiving portion 70. A duct 63 is thus formed by the front opening 68, the square- profiled receiving portion 70, and the back opening 72. Similarly, another duct 65 is formed by a second front opening 74, the circular receiving portion 77, and a second back opening 76.

[245] When the cover 60 encloses the block container 71, there are spaces available in each of the receiving portions70, 77 below the cover 60. The enclosed micro device 75 is subsequently implanted under the skin 32 of the living body of the human being. The front opening 68 and the other front opening 74 is positioned near veins, while the back opening 72 and the other back opening 76 are located near arteries.

[246] Fig. 7 illustrates vascularization of the micro-device in vivo of Fig. 6. An artery 38 is grown linking to the back opening 72, while a vein 36 is also grown linking to the front opening 68 of the square-profiled receiving portion 70. Similarly, another artery 38' is grown linking to the other back opening 76, while another vein 36' is also grown linking to the other front opening 74 of the circular profiled receiving portion 70. In other words, a vascularized micro-device 80 is implanted under the skin 32 of a human being.

[247] Fig. 7 further illustrates that the cover 60 is removed after the blood vessels 36, 36', 38, 38' are connected inside the receiving portions 70, 77. In other words, the cover 60 is detached after a predetermined period of time which shows that the artery 38 is linked to the vein 36 inside the square-profiled receiving portion 70. The other artery 38' is linked to the other vein 36' inside the circular receiving portion 77. Once the micro device 75 is opened, two parts of the diseased tissue 40 is put inside the receiving portions 70, 77 respectively. The cover 60 is subsequently attached to the block container 78 enclosing the receiving portions 70, 77. The micro device 75 is then become a vascularized micro device 80.

[248] Figs. 8 and 9 illustrates a fifth embodiment. The fifth embodiment comprises parts that are similar to the previous embodiments. The similar parts are labeled with same reference numerals or the same reference numerals with prime symbols respectively. Descriptions of the similar parts on structures, functions, advantages, and methods of the similar parts are hereby incorporated by reference.

[249] Fig. 8 illustrates a further bone device 83 with another cover with biocompatible membranes 82, 84. Instead of the square-profiled protruding block 64 and the circular protruding block 66, there are a square-profiled membrane 82 and a circular membrane 84 in place. The square-profiled membrane 82 and the circular membrane 84 are used to enclose the receiving portions 70, 77 in the vascularized bone device 83. The membranes 82, 84 are biocompatible and are used for injecting therapeutic and/or bio- imaging agents. The circular profiled receiving portion 77 and the square-profiled receiving portion 70 are sealed and separated from each other once a cover 81 is attached to the block container 78.

[250] Fig. 9 illustrates an example of observation and monitoring of response to treatment in vivo by a minimally invasive microscopic probe 48. The membranes 82, 84 can further be used for in vivo experimental analysis on any transplanted tissue inside the receiving portions 70, 77.

[251] Figs. 10 illustrates a sixth embodiment. The sixth embodiment comprises parts that are similar to the previous embodiments. The similar parts are labeled with same reference numerals or the same reference numerals with prime symbols respectively. Descriptions of the similar parts on structures, functions, advantages, and methods of the similar parts are hereby incorporated by reference.

[252] Fig. 10 illustrates a further bone device 86 with the cover 52 containing internal reservoirs 54, 54' with interconnecting valves 56 and ducts 58. The further bone device 86 is vascularized. The reservoirs 54, 54' are pre-filled with therapeutic and/or analytical agents. The valves 56 and the ducts 58 are to release the therapeutic and/or analytical agents to the diseased tissues 40, 40' in the two different receiving portions 70, 77 respectively in a controlled manner. For example, the therapeutic and/or analytical agents are injected to the receiving portion 70, 77 at a constant rate. The valves 56 are used to release or cut off the supply of the therapeutic and/or analytical agents by an external control means.

[253] Figs. 11 illustrates a seventh embodiment. The seventh embodiment comprises parts that are similar to the previous embodiments. The similar parts are labeled with same reference numerals or the same reference numerals with prime symbols respectively. Descriptions of the similar parts on structures, functions, advantages, and methods of the similar parts are hereby incorporated by reference.

[254] Fig. 11 illustrates a bone device with integrated optoelectronic components 88, 90.

Only a container block 89 of the bone device of Fig. 11 is shown. A first optoelectronic component 88 is provided inside the square-profiled receiving portion 70, while a second optoelectronic component 90 is provided inside the circular receiving portion 77. The optoelectronic components are used to analyze blood contents of a vascularized bone device with the optoelectronic components 88, 90 . In the present case, a laser examination technique with reflection at inner part of the block container device 89 is adopted. A laser beam is brought into the block container device 89 by an external laser source.

[255] Alternatively, no reflection is required from the inner part of the block container device 89 during the analysis. With regards to the type of blood contents that can be analyzed optically, these include white blood cells and all their sub-types, red blood cells and all their sub-types, platelets and all their sub-types, stem cells and all their sub-types, circulating tumor cells and all their sub-types, circulating endothelial cells and all their sub-types, bacteria, fungus, viruses, parasites, thrombus, blood clot formation, circulating proteins (e.g. albumin, globulin, biomarkers etc), circulating hormones (e.g. Cortisol, thyroid hormone, growth hormone etc), circulating fats and lipids, circulating carbohydrates (e.g. glucose), circulating free nucleic acids, circulating antibodies, circulating radio-labeled antibodies, circulating fluorescent- labeled antibodies, circulating chemical/drugtagged antibodies, circulating radiocontrast agents, circulating drugs and small molecules targeted agents, chemicals, alcohol, bio-chemicals, oxygen, carbon dioxide, carbon monoxide, ions (e.g. sodium, potassium, chloride, bicarbonate, urea, creatinine, calcium, phosphorus, magnesium etc ), circulating cancer bio-markers (e.g. PSA, 40c CEA, CA 125 etc) etc. Essentially all the components of blood that make up blood whether it is treated blood or untreated blood. Types of blood vessels that can be analyzed include all types of blood vessels, veins, capillaries, arteries etc.

[256] Fig. 12 illustrates a bone device with external optoelectronic components 88', 90'. Only a container block 92 of the bone device of Fig. 12 is shown.

[257] Fig. 13 illustrates a bone device 94 with both integrated optoelectronic components 88, 90 and external optoelectronic components 88', 90'. Only a container block 94 of the bone device of Fig. 13 is shown.

[258] Figs. 14-16 give some examples on how a medical device for implanting into a living body of an animal or a human being can be used on circulating tumor cells. The medical device is similar to the bone devices mentioned earlier, which can be termed as a laboratory device. The medical device is used for characterizing, studying, quantifying, diagnosing, prognosticating, testing, simulating, modeling, transplanting or growing a normal or disease state of an animal or of a human being, and for being used as a method for treating an animal or a human being.

[259] The medical device comprises membranes 82, 84 for injection and inspection on its block container. The medical device of Figs. 14-16 incorporate suitable features of any one of the previously mentioned bone devices 34, 48, 58, 80, 83, 86. Each embodiment of Figs. 14-16 comprises parts or steps that are similar to the previous embodiments in Figs. 1-13. The similar parts or steps are labeled with same reference numerals or the same reference numerals with prime symbols respectively. Descriptions of the similar parts or steps on structures, functions, advantages, and methods of the similar parts are hereby incorporated by reference.

[260] Fig. 14 illustrates extravasations of circulating tumors cells into a medical device 99, 99'. The medical device 99 is a polydimethylsiloxane (PDMS) MEMS (Micro-Electro-Mechanical Systems) device having internal reservoirs 54, 54' in its cover 52. The first reservoir 54 contains interleukin- lβ 96, while the second reservoir 54' contains TNFα 97. The receiving portions 70, 77 are filled with extracellular matrix (ECM) and angiogenesis growth factors and stem cells. The micro device 99 is implanted into the human body.

[261] The interleukin- lβ 96 and TNFα 97 are injected to the respective receiving portions 70, 77. Endothelial cells 98, which are deposited into the receiving portions 70, 77 beforehand, are activated by expressing E-Selectin into the receiving portions 70, 77 for tumor cell adhesion. Fig. 14 further shows an alternative of reservoirs released interleukin- lβ 96' and TNFα 97' in another medical device 99'.

[262] Fig. 15 illustrates an introduction of the chemokine SDF-I (CXCL12) 106, 106¹ into the device 103. The device 103 of Fig. 15 is a micro-device 103 in vivo that is stimulated by angiogenesis growth factors. Interleukin- lβ 96 and TNFα 97 are released into the receiving portions 70, 77 to activate endothelial cells to express E- Selectin. The introduction of the chemokine SDF-I (CXCL12) 106 is achieved by needle 46 injections through membranes of the device 103. Circulating tumor cells 104 are introduced into ECM. Some of the circulating tumor cells 104 are later attached to the endothelial cells 98 as adhered tumor cells 105. Fig. 15 further illustrates an alternative of reservoirs 54, 54' released chemokine SDF-I (CXCL12) 106¹ in another device 103¹.

[263] Fig. 16 illustrates micro-metastatic tissue growth in the device 108. Fig. 16 shows needle 46 injected SDF-I (CXCL12) 106 into the receiving portions 70, 77. Circulating tumor cells 104 firstly adhere to the activated endothelial cells 98 and then extravasate into the receiving portions 70, 77. The circulating tumor cells 104 also grow in ECM into organ-specific m icro-metastatic tissue 112. Multi-targeted therapy agents 114 and apoptotic bio-imaging agents 116 (e.g. fluorescent-labeled annexin-V) are needle 46, 46' injected into the receiving portions 70, 77. In vivo observation of apoptosis to treatment is carried out by various in vivo microscopic methods. Fig. 16 also illustrates an alternative of reservoirs 54, 54' released multi-targeted therapy agents 114' and bio-imaging agent (e.g. fluorescent-labeled annexin-V) 116' in a device 108¹.

[264] For all the three devices described in Figs. 14-16, 'decompressing¹ micro-channels are be designed and fabricated as part of the devices 99. 99', 103, 103', 108, 108', to lead accumulating interstitial fluid (but not cells) away from the main tissue chamber into an external collection point that is accessible ex vivo for drainage and biochemical analysis of the microenvironment. Alternatively, the interstitial fluid can be re-directed back into the surrounding tissues of the body for lymphatic drainage to reduce pressure build-up in the chambers and to direct metabolic wastes products back into the devices of Figs. 14-16 respectively.

[265] Another example of creating an in vivo vascularized laboratory is given below. A device at the micro-level is a vascularized device designed to capture circulating tumor cells from the bloodstream of metastatic cancer patients. The receiving portions 70, 77 of the micro device may be filled with different kinds of extracellular matrix which may be made from tissue specific extracts and impregnated with angiogenesis growth factors with or without stem cells. Reservoirs in the cover of the micro device are pre- filled with endothelium activating factors like interleukin- lβ and/or TNFα. A second reservoir is pre-filled with Stromal cell Derived Factor- 1 (CXCL12) which is a chemokine. The micro device is initially implanted in a human body and vascularization of the device takes place after the implantation. The first reservoir containing interleukin- lβ and/or TNFα is released to activate the endothelial cells to express E- Selectin. Circulating tumor cells with corresponding ligands will adhere to the endothelial wall. A second reservoir containing SDF-I (CXCL 12) is then release to attract the circulating tumor cells to extravasate and migrate into the receiving portions 70, 77. Such a device would be useful for prognosticating future events in the metastatic cancer patient and also useful for studying a poorly understood area of organ-specific metastasis.

[266] Once the circulating tumor cells have extravasated in the receiving portions 70, 77 of the device, they can then be amenable to further in vivo experimentation in the micro device to find the best drug combination for apoptosis.

[267] There can be mirror or reflecting layer provided at the bottom of the receiving portions 70, 77 with transparent cover for observation with microscope from outside. Many types of sensors can be provided inside the medical device. The sensor types include pH sensor, 02 sensor, electrical sensors, electro-magnetic sensors, and radioactivity sensors, etc. The radioactive sensor can be used in conjunction with the application of radioactive substance inside the receiving portions 70, 77. The receiving portions can be supplied or purged with tubes connected to external.

[268] Fig. 17 illustrates a method 120 of making a medical device for implanting into a living body of an animal or a human being, the method comprising the steps of:

[269] - providing a block container comprising at least one receiving portion 122,

[270] - providing a cover for enclosing the at least one receiving portion 124, and

[271] - providing a first duct connecting between a first opening of the block container and the at least one receiving portion 126. [272] Fig. 18 illustrates a method 130 of using a medical device for implanting into a living body of an animal or a human being, the method comprising the steps of:

[273] - implanting the medical device in the living body 128,

[274] - extracting a predetermined part of the living body 134,

[275] - putting the predetermined part of the living body into a receiving portion of the medical device 136,

[276] - subjecting the predetermined part of the living body to medical treatment or inspection 138, and

[277] - observing the predetermined part of the living body 142.

[278] Fig. 19 illustrates a method 140 of using the vascularized medical device of claim 24 comprising the steps of:

[279] - opening the cover of the medical device 144,

[280] - putting the predetermined part of the living body into a receiving portion of the medical device 146,

[281] - subjecting the predetermined part of the living body to medical treatment or inspection 148, and

[282] - observing the predetermined part of the living body 152.

[283] The following documents are herewith incorporated by reference. These documents describe in detail how a mineral bone block can successfully be implanted into an animal. This knowledge is adopted to the embodiments for implanting the vascularized medical device of the application.

[284] 1. P.H. Warlike, I.N.G. Springer, J. Wiltfang, Y. Acil, H. Eufinger, M. Wehmoller, P.A.J. Russo, H. Bolte, E. Sherry, E. Behrens, H. Terheyden. 'Growth and transplantation of a custom vascularized bone graft in a man¹. Lancet 2004; 364: 766-770 25

[285] 2. H. Terheyden, C Knak, S. Jepsen, S. Palmie, D.R. Rueger. 'Mandibular reconstruction with a prefabricated vascularized bone graft using recombinant human osteogenic protein- 1: an experimental study in miniature pigs'. Part I: 30 Pre- fabrication. Int. J. Oral Maxillofac. Surg. 2001:30: 373-379 31

[286] 3. H. Terheyden, P. Wamke, A. Dunsche, S. Jepsen, W. Brenner, S. Palmie, C. Toth, D.R. Rueger. 'Mandibular reconstruction with prefabricated vascularized bone grafts using recombinant human osteogenic protein- 1 : an experi- 5

[287] mental study in miniature pigs'. Part II: Transplantation. Int. J. Oral Maxillofac. Surg 2001:30: 469-478

[288] Further helpful remarks are provided below.

[289] The subject matter described herein documents a generic method and design that can be used for creating the vascularized foundation of vascularized laboratory devices in vivo at different scales of science using biological and/or biocompatible materials. In parallel, a novel method for early detection of cancer response to various treatment agents is also described.

[290] This generic method and design consists of filling a prefabricated or fabricated structure with angiogenesis growth factors which may be mixed in a biocompatible solvent or solid, with or without stem cells. Subsequently the device is surgically implanted in the body. The angiogenesis growth factors stimulate generation of new blood vessels in the device in vivo. The vascularized in vivo device can then be used as a base for different experimental purposes. If the device is meant for analysis of blood vessels and/or blood contents in vivo, opto-electronic structures for this purpose may be in-built into the device before implantation.

[291] However, a broader use of the device for a variety of purposes is made possible

(achieved) with a unique structural feature that comprises of a detachable cover and reciprocal plug-cavity design that creates spaces in the device to receive transplanted living tissues, e.g. cancerous tissue, or cells. A third cover converts these open spaces into enclosed vascularized chambers. The transplanted tissue or cells in each chamber will re-establish connection with the microvascular circulation of the device to remain viable.

[292] The third cover can be designed to allow delivery of therapeutic agents into the chambers. These transplanted living tissues or cells are then amenable to experimental analysis in vivo in the chambers and their responses predict closely or exactly that of the original tissue from which they came from.

[293] If the vascularized chambers contain cancerous tissues, different theories of the type of cancer the patient has e.g. ¹Xa¹, ¹Xb¹, ¹Xc¹ etc can be used to design specific targeted strategies of treatment. These different treatment strategies can then be tested separately on the cancer tissues in the chambers of the vascularized device which act as controlled environments for experimental analysis. In vivo simulation testing on tissues and cells is thus made possible and the response of the main bulk of cancer can be expected to be very similar when the patient is treated systemically with the chosen therapeutic agent of choice after simulation testing. Because relatively small amounts of therapeutic agents are used in the chambers at any moment in time, these agents are expected to be mainly used up by their mode of action on the transplanted tissues or cells and undergo local metabolism. Even if some of these agents escape into their immediate venous circulation, their relatively small amounts will be diluted further to insignificant levels. However, vascular micro-dialysis techniques or continuous veno- venous hemofiltration techniques can be used to remove any escaped drugs at the venous end of the device if necessary.

[294] Because the device may be surgically implanted just beneath the skin surface, it may be supported by a variety of noninvasive or minimally invasive microscopic or bio- imaging techniques, and fluorescent molecular labeling techniques to quickly detect experimental end-points e.g. cell apoptosis (programmed cell death) in the different vascularized chambers. This method affords for very early detection and prediction of the cancer's response to different treatment strategies before the main bulk of the patient's cancer is treated systemically. Hence, a novel method for early detection of the response of cancerous tissue to various therapeutic agents is made possible.

[295] Another benefit of this method is its ability to test directly for the efficacy of targeted drug therapy i.e. pharmacodynamics without involving bloodstream drug delivery. Hence when the patient begins actual systemic treatment for the main bulk of disease and there is no response, the problem should then lie likely in drug delivery or pharmacokinetics. Even if preliminary testing of therapeutic agents on the cancerous tissues in the vascularized in vivo device is not done and the patient is treated systemically right from the start, this unique method and device can still give us very early detection of cancer response to treatment in conjunction with bio-imaging techniques.

[296] Although the above description contains much specificity, these should not be construed as limiting the scope of the embodiments but merely providing illustration of the foreseeable embodiments. Especially the above stated advantages of the embodiments should not be construed as limiting the scope of the embodiments but merely to explain possible achievements if the described embodiments are put into practice. Thus, the scope of the embodiments should be determined by the claims and their equivalents, rather than by the examples given per se.

Claims

[1] A medical device comprising:

- a block container comprising at least one receiving portion,

- a detachable cover that is configured to be attached to the block container for enclosing the at least one receiving portion,

- a first duct connecting between a first opening of on an external surface of the block container and the at least one receiving portion, and

- a second duct connecting between a second opening on an external surface of the block container and the at least one receiving portion, wherein the at least a part of the medical device is made of a biocompatible material. [2] The medical device of claim 1, wherein at least one part of the medical device comprises at least one angiogenic growth factor. [3] The medical device of claim 1 or claim 2 further comprising a membrane for injection of experimental agents into the receiving portion. [4] The medical device of any of the preceding claims further comprising a valve, a pump, a reservoir, or in combination of any of these for releasing the experimental agents into the at least one receiving portion. [5] A medical device comprising:

- a block container comprising at least one receiving portion,

- a cover that is configured to be attached to the block container for enclosing the at least one receiving portion, and

- a duct connecting between a first opening on an external surface of the block container and the at least one receiving portion.

[6] The medical device of claim 5, wherein the cover is detachable for exposing or enclosing the receiving portion. [7] The medical device of claim 5 or claim 6 further comprising: a second opening and a second duct that are connected to the first opening through the at least one receiving portion. [8] The medical device of any of the claim 5 to claim 7, wherein at least one part of the medical device comprises at least one angiogenic growth factor. [9] The medical device of claim 8, wherein the at least one angiogenic growth factor is mixed with a biocompatible solvent, [lϋ] The medical device of claim 8, wherein the at least one angiogenic growth factor is solid. [11] The medical device of any of the claim 5 to claim lϋ, wherein at least one part of the medical device is made of biocompatible material. [12] The medical device of claim 11, wherein the biocompatible material comprises a bone mineral block, titanium, or poly- dimethylsiloxane (PDMS) material. [13] The medical device of any of the claim 5 to claim 12, wherein at least one part of the medical device comprises bond morphogenetic protein-7

(BMP7). [14] The medical device of claim 5, wherein the medical device comprises a membrane for injecting experimental agents. [15] The medical device of claim 5 further comprising a pump, a valve, a reservoir, or in combination of any of these for releasing the experimental agents into the at least one receiving portion. [16] The medical device of any of the claim 5 to claim 16 except claim 6, wherein the cover and the block container are integrally formed. [17] 17. A method of making a medical device, the method comprising:

- providing a block container comprising at least one receiving portion and a cover for enclosing the at least one receiving portion, the block container and/or the cover comprising biocompatible material, and

- providing a first duct connecting between a first opening of the block container and the at least one receiving portion.

[18] The method of claim 17 further comprising the step of providing a second opening and a second duct that are connected to the first opening through the at least one receiving portion.

[19] The method of claim 17 or claim 18, wherein the step of providing the block container comprising the step of extracting a predetermined part of a body of an animal or a human being for making at least part of the medical device.

[20] A method of using a medical device, the method comprising the steps of:

- implanting the medical device in the body,

- extracting a predetermined part of the body,

- putting the predetermined part of the body into a receiving portion of the medical device,

- subjecting the predetermined part of the body to medical treatment or inspection, and

- observing the predetermined part of the body.

[21] The method of claim 20 wherein the step of subjecting the predetermined part of the body to medical treatment or inspection comprising the step of

- subjecting multiple pieces of the predetermined part of the body to multiple treatment or inspection simultaneously. [22] The method of claim 20 or claim 21 further comprising

- performing the steps of testing effectiveness of two or more treatments on two or more parts of the body for selecting the most effective treatment.

[23] The method of any of the claim 20 to claim 22, wherein the implanting the medical device in the body further comprises the step of providing the medical device between blood vessels of the body such that a first opening of the medical device is adjacent to an artery and a second opening is adjacent to a vein for vascularizing the medical device.

[24] A method of using a vascularized medical device of claim 24 comprising:

- opening the cover of the medical device,

- observing the predetermined part of the body. [25] The method of claim 24, wherein the putting the predetermined part of the body into a receiving portion of the medical device comprises circulating tumor cells in a receiving portion of the vascularized medical device.