Technology Overview

INTRODUCTION Research Focus: development of bioresorbable bone implants using 3D printing technology. Medical Applications: bone defects of various genesis or caused by traumatic bone damage, such as comminuted fractures, surgical removal of bone tissue as a result of severe medical conditions; osteomyelitis and osteosarcoma, etc. Working Principle: an implant serves as a scaffold to support the body’s regenerative processes for restoration of bone tissue. Primary Products: ceramic-based implants produced using the Binder Jet Printing technology and polymer-based implants produced using the Fused Filament Fabrication printing technology. •

December 2020 Advanced Development of Additive Manufacturing, Inc. ©

A.D.A.M. TECHNOLOGY

Implants

Ceramic bone implants - biomaterial based on glass-ceramic and bioactive calcium-based materials. Polymer bone implants - medical grade polymer and calcium-based bioactive material.

Printers

Binder Jetting Printer with powder thickening modification Fused Filament Fabrication Printer with inbuilt sterilization system

Digital Platform

Cloud-based service for storage of CT and MRI scans, implant 3D-modelling and user-customer interaction

Quality Management System

Ensures 3D-printed implants will be safe and effective and otherwise in compliance with applicable regulations

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OVERVIEW OF PROGRAMS

Properties:

• provide osteoinductive and osteoconductive activity at the site of transplantation with the

• subsequent replacement of the implant with native bone tissue providing sufficient strength indicators to withstand implant loads for use in orthopedic surgery;

• can be used to produce implants of any size and shape using 3D modelling technology.

Advantages:

• no requirement of reoperation which improves the quality of treatment and facilitates the patient’s healing process.

• expected to degrade progressively over a period of time to assist as scaffolds and, due to the nature of its composition, to improve the bone healing process.

• eliminate otherwise required bone marrow autoplasty which can be traumatizing for patients.

Ceramic Bone Implants

A.D.A.M.’s ceramic bioresorbable bone implants are made from a biomaterial based on glass-ceramic and bioactive calcium-based materials. These implants are suitable for reconstruction of non-weight-bearing bones (e.g. cranium). Bioceramic materials are highly bioactive. Implants made from bioceramics have an open porous structure that allows for tissue ingrowth into the deep layers of the implant, which greatly improves bone resorption process. A.D.A.M. uses Binder Jet Printing technology for ceramic implant production.

Expected parameters: - Composition: borosilicate

glass-hydroxyapatite, borosilicate glass-bioglass

- Porosity: 40 - 75% (open porous structure)

- Apparent density: 1.2 - 1.8 g/cm3

- Ultimate strength at central-axial compression: > 40 MPa

- Maximum application temperature (sintering): 1150°C

- Abrasion resistance: Medium

Biopolymer Bone Implants

A.D.A.M.’s polymer bioresorbable bone implants are based on medical grade polymer and calcium-based bioactive material. Polymer implants are suitable for weight-bearing bone replacement (e.g. radius, humerus). The implant composition is not porous due to polymer properties, so it is 3D-modeled in such a way that it has an inner lattice structure to allow for vascularization and the ingrowth of soft tissues into the implant. This structure improves process of implant engraftment and its subsequent resorption. A.D.A.M. uses extrusion-based 3D printing through Fused Filament Fabrication for polymer implant production.

Expected parameters: - Composition: polycaprolactone

hydroxyapatite, polycaprolactone-bioglass

- Controlled macroporosity: up to 85%

- Apparent density: 1.5 - 2.5 g/cm3

- Ultimate strength at central-axial compression: more than 90 MPa

- Maximum application temperature (extrusion heating): 200°C

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OVERVIEW OF PROGRAMS

Experimental animals: wistar rats Testing period: 1, 4, 12 weeks Findings: - Macroscopic examination of the site of

implantation of both implant types showed no hematoma, edema, scarring, degenerative changes, tumors, tissue necrosis and other severe abnormalities.

- Analysis of histologic specimens - implantation caused development of cellular reactions typical for aseptic inflammation, indicating biocompatibility of the implants.

- Ceramic bone implant. Porous structure

allows for cell migration and germination of connective tissue strands into the implants. The slight destruction of the implant was also observed. The cellular reactions increased as the study progressed.

- Polymer bone implant. Intensity of cellular

reactions was low in 1-4 weeks but increased substantially 12 weeks after the implantation. But 12 weeks after their implantation, there was an increase in the intensity of cellular reactions, which had increased reactivity and were pronounced in intensity. Typical cellular elements of the capsules were polymorphonuclear cells and macrophages.

F

Fig. 1. (x200) Connective tissue capsule (CTC) around the implanted specimens (Imp - ceramic 3-D bone implant) 1 week after implantation. H&E Staining.

F

Fig. 4. (x400) Connective tissue capsule (CTC) around the implanted specimens (Imp - polymer 3-D bone implant) 1 week after implantation. H&E Staining

Completed Testing for Bioceramic Bone Implants: - ISO 10993-10: 2010 “Biological

evaluation of medical devices. Part 10. Test for irritation and skin sensitization.”

- EN ISO 10993-11: 2015 “Biological evaluation of medical devices. Part 11. Test for systemic toxicity.”

- ISO 10993-5: 2015 (EN ISO 10993-5: 2009, IT; ISO 10993-5: 2009, IDT) “Biological evaluation of medical devices. Part 5. In vitro cytotoxicity test.”

- (EN ISO 11137-1:2018) Sterilization of health care products — Radiation

Completed Testing for Biopolymer Bone Implants: - ISO 10993-10:2010 “Biological

evaluation of medical devices – Part 10: Tests for irritation and skin sensitization.

- ISO 10993-11: 2015 (EN ISO 10993-11: 2009, IDT; ISO 10993-11: 2006, IDT) “Biological evaluation of medical devices. Part 11. Systemic toxicity test.”

- ISO 10993-5: 2015 (EN ISO 10993-5: 2009, IT; ISO 10993-5: 2009, IDT) "Biological evaluation of medical devices. Part 5. In vitro cytotoxicity test. "

- (EN ISO 11137-1:2018) Sterilization of health care products — Radiation

Fig.Fig. 2. (x200) Connective tissue capsule (CTC) around implanted specimens (Imp - ceramic 3-D bone implant) and germination of connective tissue (T) strands deep into the material 4 weeks after implantation. H&E Staining

Fig. 5. (x400) Connective

Fig. 5. (x400) Connective tissue capsule (CTC) around implanted specimens (Imp - polymer 3-D bone implants) 4 weeks after implantation. H&E Staining

Fig. 3. (x200) The connective tissue capsule (CTC) around the implanted specimens (Imp - ceramic 3-D bone implant) and the germination of connective tissue strands (T) deep into the material 12 weeks after implantation. H&E Staining

Fig. 6. (x400) Connective tissue capsule (CTC) around implanted specimens (Imp - polymer 3-D bone implant) 12 weeks after implantation. H&E Staining

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OVERVIEW OF PROGRAMS

A.D.A.M. currently develops FFF (Fused Filament Fabrication) and BJP (Binder Jet Printing) 3D printers. The printers are being modified by A.D.A.M. to ensure the best results for production of bone implants using company-specific material compositions.

Binder Jetting Printer

A 3D ceramic printer produces implants using ceramic powders. A.D.A.M. 's BJP printer will include a printer modification to thicken the powder during printing, thus significantly increasing the density of the implants. This characteristic is crucial for bone tissue substitutes. Binder Jet Printing technology allows us to use calcium-based powder materials in 3D-printing. This technology enables A.D.A.M. to produce implants that are of complex shapes and have sufficient strength parameters. BJP printing allows the use of ceramic materials to provide the implant with the open porosity structure.

Specifications: - Expected printing speed is up to

150 cm­³/h - Printing process takes up to 36

hours - Temperature of sintering is up to

1150°C - Maximum implant size is

12x12x15 cm

Medical Fused Filament Fabrication Printer

Fused Filament Fabrication (FFF) is a three-dimensional printer with an in-built sterilization module, comprised of the gas (formaldehyde) sterilization and ultraviolet emitters within the hermetically sealed chamber of a printer with subsequent neutralization of sterilizing gas. Thereby, a printing chamber is efficiently sterilized. Ultraviolet emitters are added to the printing chamber to maintain sterility during the printing process and after printing is finished. Production of initially sterile individual implants will ease the treatment of patients making it safer and faster.

Specifications: - Working temperature of polymer

printing is 250°C max - Pre-printing gas sterilization is

180 min + 20 min neutralization = 200 min of sterilizing process before the printing process starts

- Expected printing speed is up to 40 cm­³/h

- Maximum implant size is 25x25x30 cm

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OVERVIEW OF PROGRAMS

A.D.A.M. has developed a digital platform for keeping personal medical information in a specialized secured cloud storage so that competent medical service providers can access it in case of emergency and use it for providing medical support for the patient. In early stages of the Platform development its main functionality is concentrated around storage of the patients’ MRI and CT scans. Final version of the platform will have expanded functions, including implant 3D-modelling capability using the patients’ medical data. Eventually, all interaction between medical providers and A.D.A.M. (including trainings, technical support, etc.) will be done through the digital platform.

Technical Specifications

The Platform supports the latest version of Google Chrome, Mozilla Firefox, and Apple Safari web browsers and has an adaptive web interface for 18x9, 16x9, 18,5x9, 4x3 aspect ratios Android and Apple smartphones and tablets. The MVP version of the digital platform supports up to 1 000 registered users with the average 5 GB storage size per user.

For A.D.A.M. For Users For Clinics

Uploadable Medical Content Specs

– to test users' engagement in a service provided;

– to gather DICOM data sets, and to subsequently process and analyze it in a depersonalized manner for bone implants 3d printing technology testing and development.

– to have a cloud

storage designed for personal medical testing results in order to be able to effectively access them.

– to access

patients’ medical data subject to their approval;

– to 3D-model personalized implants for every particular clinical case;

– to access trainings and technical support;

– to interact with A.D.A.M. team.

Digital platform recognizes files of medical data created utilizing DICOM standard. Digital Imaging and Communications in Medicine (DICOM) is the standard for the communication and management of medical imaging information and related data. There are a number of medical study types supported by DICOM standard. The Platform properly reads and analyzes Computer Tomography (CT) and Magnetic Resonance Tomography (MR) types. The Platform recognizes and reads uploaded DICOM files, then finds and collects metadata.

QUALITY AND REGULATORY COMPLIANCE If you think a document that looks this good has to be difficult to format, think again! We've created styles that let you match the formatting in this brochure with a click. On the Home tab of the ribbon, check out the Styles gallery.

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OVERVIEW OF PROGRAMS

Quality Management System

Regulatory Essentials

3D-printed bone implants are classified as Class II Implanted Medical Devices (CFR, Title 21, Part 860). A.D.A.M.’s R&D and trials activities comply with Current good manufacturing practice (CGMP) requirements for medical devices (CFR, Title 21, Part 820). The developed and functioning Quality Management System (QMS) provides the methods used in, and the facilities and controls used for, the design, manufacture, packaging, labeling, storage, installation, and servicing of all finished devices intended for human use. The QMS ensures 3D-printed implants will be safe and effective and otherwise in compliance with the Federal Food, Drug, and Cosmetic Act (FD&C Act). QMS complies with CFR, Title 21, 820 and is developed in accordance with ISO 13485 (Medical devices -- Quality management systems -- Requirements for regulatory purposes). It also complies with requirement of the legislation in other jurisdictions, such as EU Medical Devices Directive (93/42/EEC) QMS has been maintained since the start of R&D operations and will be certified by respective regulatory authorities in jurisdictions of operation The organizational structure ensures that products are designed and produced in accordance with applicable regulatory requirements. A.D.A.M. has appointed a management representative who has the authority over and responsibility for maintenance of the QMS requirements and reporting on the performance. The suitability and effectiveness of the QMS is reviewed on a regular basis. A Quality Plan is established. QMS procedures are established and quality audits are performed. The sufficient personnel are hired. Personnel training is constantly performed.

Due to the risk classification of the 3D-printed bone implants (class II), the product is eligible for 510(K) pathway. 510(K) is a premarket submission made to FDA to demonstrate that the device to be marketed is as safe and effective, that is, substantially equivalent, to a legally marketed device (section 513(i)(1)(A) FD&C Act) that is not subject to premarket approval. The product does not require human studies for the product to be approved within 510(K) procedure. FDA requires that additional animal studies are conducted using larger experimental mammals than wistar rats. A.D.A.M. has received an official confirmation of the 510(K) eligibility for its 3D-printed bone implants on August 3, 2020 in an FDA response to a Q-Submission. As of December 2020, the company is undergoing the Animal Study Protocol design process. It is planned that the study will be performed at the University of Connecticut (UConn), which maintains a functioning Institutional Animal Care and Use Committee (IACUC). The overall time necessary for FDA clearance of 3D-printed bone implants is 1.5 years (1 year for completion of the animal studies, 6 months for the completion of the regulatory procedure).

Product Quality Principles

The 3D-printed implants are designed and manufactured in such a way that they do not compromise the clinical condition or the safety of patients. The solutions adopted by A.D.A.M. for the design and manufacturing conform with safety principles, taking account of the generally acknowledged state of the art. The 3D-printed implants achieve characteristics and performances appropriate for their functions and are not adversely affected to such a degree that the clinical conditions and safety of the patients and, where applicable, of other persons are compromised during the lifetime of the device as indicated by the manufacturer when the device is subjected to the stresses which can occur during normal conditions of use. The 3D-printed implants are designed, manufactured and packed in a way that their characteristics and performances during their intended use will not be adversely affected during transportation and storage. Conformity with the essential quality requirements is demonstrated through clinical evaluation.